Cobalt-Mediated [2+2+2] Cycloadditions of Alkynes to Benzo-[ b ]furans and Benzo[ b ]thiophenes: A Potential Route toward Morphanoids

Article abstract of DOI:10.1055/s-0036-1589147

Exploratory studies of the CpCo-mediated [2+2+2] cycloaddition of alkynes to the 2,3-double bond of benzo[ b ]furans (and some benzo[ b ]thiophenes) are presented, with the general aim to access morphinan substructures. The basic feasibility of constructing Co-complexed tetrahydrophenanthro[4,5- bcd ]furans (and -thiophenes) in moderate to good yields is demonstrated, with complete to extensive diastereoselectivity. Limitations are the apparent necessity for bulky (silylated) monoalkynes, the lack of regioselectivity in the cocyclization with unsymmetrical alkynes, and the sensitivity of the ligands, both complexed and uncomplexed, with respect to ring opening and rearrangement.

Full text of DOI:10.1055/s-0036-1589147

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–AK
paper
A
en
T. Aechtner et al.
Paper
Synthesis
Cobalt-Mediated [2+2+2] Cycloadditions of Alkynes to Benzo-
[b]furans and Benzo[b]thiophenes: A Potential Route toward
Morphanoids
Tobias Aechtner
OTIPS
OTIPS
HO
HO
David A. Barry
SiMe3
Co
CoCp
SiMe3
Ellen David
+
54%
Cédric Ghellamallah
Daniel F. Harvey
Alix de la Houpliere
Monika Knopp
O
SiMe3
O
MeO
SiMe3
H
OMe
(excess)
Diastereoselective
Michael J. Malaska
Dolores Pérez
Kaspar A. Schärer
Brian A. Siesel
K. Peter C. Vollhardt*
Robert Zitterbart
0
0
0
0
0-
0
0
2
5-
8
9
1
1-
3
2
0
Department of Chemistry, University of California at Berkeley,
Berkeley, California 94720-1460, USA
kpcv@berkeley.edu
Received: 12.10.2017
Accepted after revision: 14.11.2017
Published online: 21.12.2017
We chose the morphine alkaloids [e.g., morphine (1) and
codeine (2); Figure 1] as a guiding motif of our efforts, be-
cause of their continuing attraction to synthetic and medic-
inal chemists.5 Moreover, key members of this class of com-
pounds, such as the multiton industrial intermediates
thebaine (3) and its metabolite oripavine (4), contain ring C
in the form of a cyclohexadiene that appeared directly ac-
cessible by our methodology.6 The retrosynthetic essence of
the latter, 5 ⇒ 6, is outlined in Scheme 1, exhibiting the
variables that will be addressed in the following narrative.
DOI: 10.1055/s-0036-1589147; Art ID: ss-2017-m0659-op
Abstract Exploratory studies of the CpCo-mediated [2+2+2] cycload-
dition of alkynes to the 2,3-double bond of benzo[b]furans (and some
benzo[b]thiophenes) are presented, with the general aim to access
morphinan substructures. The basic feasibility of constructing Co-com-
plexed tetrahydrophenanthro[4,5-bcd]furans (and -thiophenes) in
moderate to good yields is demonstrated, with complete to extensive
diastereoselectivity. Limitations are the apparent necessity for bulky (si-
lylated) monoalkynes, the lack of regioselectivity in the cocyclization
with unsymmetrical alkynes, and the sensitivity of the ligands, both
complexed and uncomplexed, with respect to ring opening and rear-
rangement.
NMe
NMe
10
9
H
D
8
B
14
13
7
A
C
Key words alkynes, benzofurans, cobalt, cycloaddition, morphine
E
O
6
5
O
RO
OMe
RO
OH
Morphine 1, R = H
Codeine 2, R = Me
Thebaine 3, R = Me
Oripavine 4, R = H
In a series of papers, we have reported on the cobalt-
mediated [2+2+2] cycloaddition1 of alkynes to heteroaro-
matic double bonds2 and the elaboration of the resulting
CpCo(diene) complexes. Herein we present an extension of
this work to benzo[b]furans and -thiophenes.3 These choic-
es were predicated on the finding that the related cycload-
ditions to the parent furan and thiophene systems resulted
in skeletal rearrangements (dubbed ‘enol ether walk’) and
were complicated by competing alkyne C–H insertions.2j
Thus, it was hoped that benzofusion would enable cleaner
desired product formation, providing unique methodology
for synthetic chemists interested in annulated benzo[b]-
furan frames. The latter and their thia analogues are import-
ant substructures in natural and pharmaceutical products.4
Figure 1
Before embarking on what was envisaged to be a rela-
tively involved preparation of starting materials 6, valida-
tion of the proposed plan was sought on the simpler model
7 (Scheme 2). This compound could be made readily by
lithiation of benzo[b]furan,7 alkylation with 1-(triiso-
propylsilyl)-5-iodo-1-pentyne,8 and desilylation with fluo-
ride. Cocyclization of 7 with bis(trimethylsilyl)acetylene
(8), a standard reaction partner because of its resilience to
autotrimerization,2 resulted in sensitive 9 in modest (unop-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

B
T. Aechtner et al.
Paper
Synthesis
(4-methoxyphenyl)acetic acid (13) (Scheme 3). Standard
esterification and DIBAL-H reduction at –78 °C led to the
known 14,11 from which ethynylation12 produced 15 and its
subsequent elaboration 16 and 17, respectively. Notably,
the latter is a new analogue of the designer drug 4-methoxy-
amphetamine.13
X
Z
Y
X
Y
CpCoL2
CoCp
R'
Z
R'
+
O
O
MeO
R
MeO
R
5
6
O
O
Scheme 1 Retrosynthetic analysis of thebaine substructure 5 featuring
an AE → ABCE ring construction strategy with CpCo as the mediator of
the cyclization of 6 with alkynes
LiC≡CSiMe3 (1.2 equiv),
THF, –78 °C,
1. H2SO4, MeOH, Δ, 5 h
2. DIBAL-H (1.05 equiv),
PhMe, –78 °C, 1.5 h
H
OH
then r.t., 7 h
80%
71%
timized) yield as one diastereomer. Unlike the analogous
furan series,2j the benzofuran moiety emerges anti to CpCo,
through an endo-mode of coordination to the incipient co-
baltacyclopentadiene intermediate. This assignment rested
on the diagnostic low-field position [δ = 3.54 ppm (s)] of
the tertiary hydrogen at C6a of the tetrahydrobenzindeno-
furan system. Importantly, and in contrast to the furan
counterparts,2j the benzofusion obviates rearrangement via
the corresponding zwitterionic isomer 10.
OMe
OMe
14
13
1. MsCl (1.1 equiv), Et3N (1.5 equiv),
CH2Cl2, –10 °C, 1 h, then r.t. 30 min
2. NaN3 (5.0 equiv), DMF, r.t., 20 h
3. SnCl2·2H2O (1.5 equiv), MeOH,
r.t., 22 h
4. TBAF (1.2 equiv), EtOH (3 equiv),
THF, r.t., 1 h
NH2
OH
SiMe3
57%
EtOH (3 equiv),
TBAF (1.2 equiv),
THF, r.t., 1 h
OMe
17
OMe
OH
Me3Si-≡-SiMe3
SiMe3
Me3Si
15
(8, cosolvent), THF,
CoCp
H
CpCo(CO)2 (2.0
equiv), hν, r.t., 12 h
87%
6a
33%
O
O
7
9
OMe
CuCl2·2H2O
(14 equiv),
MeCN, Et3N,
0 °C, 10 min,
then r.t., 1 h
?
16
SiMe3
Me3Si
H
SiMe3
CoCp
Scheme 3
Me3Si
H
31%
O
+
Armed with this experimental expertise, 12 was con-
verted efficiently into 20 and the corresponding silyl ether
21, through the intermediacy of 18 and 19 (Scheme 4). An
alternative construction of 18 via Et3SiH reduction of the
S-methyl ester14 of 12 was equally effective [87%; see ex-
perimental section and Supporting Information (SI)]. Alco-
hol 19 was transformed into amine 22, a relay point for the
assembly of 24 via 23 and of 26 via 25.
The stage was now set to run cocyclizations of several of
these alkynes with 8, the results of which are summarized
in Scheme 5. Gratifyingly, complexes 27–31 were obtained
as air-, heat-, and protic-solvent-sensitive compounds in
modest to good yields and with complete diastereoselectiv-
ity, the benzofuran moiety now emerging syn to CpCo, sug-
gesting preferential exo-incorporation of the heterocycle.
The selective positioning of the substituent at C8 anti to
CpCo appears to be the result of its inclination toward a
pseudo-equatorial disposition in the cobaltacyclopenta-
diene precursor, as indicated by molecular models (i.e., A in
Figure 2). One notes that this hypothesis predicts that a
benzylic substituent Y should exhibit the opposite stereo-
chemistry in analogous cyclization products, via B, a pre-
diction that was verified by results to be described later.
11
O–
10
Scheme 2
Interestingly, the chromatographic behavior of 9 re-
vealed substantial polarity, as it requires up to 80% EtOAc in
hexane to elute from silica gel, perhaps indicative of the
equilibrium presence of 10 or at least a highly polarized
O–Ctert bond. However, attempts to trap the former with
NaBH4, Ac2O, or 2-propen-1-amine left 9 untouched. On the
other hand, oxidative demetalation furnished the free li-
gand 11. Finally, an attempt to extend the substrate scope
to the homologue of 7, 2-(5-hexynyl)benzo[b]furan,9 failed.
The preceding results gave rise to cautious optimism re-
garding the analogous potential chemistry of substrates of
the type 6 (Scheme 1), for which the products would be de-
void of the strained spirofusion present in 9 and 11. As a
first target, we chose derivatives of 6 with Y = Z = H, X = OR,
NRR′, in turn thought to be readily accessible from the
known (7-methoxybenzo[b]furan-4-yl)acetic acid (12,
Scheme 4).10 Since the assembly of 12 required seven
steps, a model study toward the topologically equivalent
alkynes 16 and 17 was executed starting with commercial
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

C
T. Aechtner et al.
Paper
Synthesis
O
O
LiC≡CSiMe3
H
(3.0 equiv),
THF, –78 °C,
then r.t., 5 h
1. H2SO4, MeOH, Δ, 9 h
OH 2. DIBAL-H (1.05 equiv),
PhMe, –78 °C, 5 h
MeO
MeO
Y
H
O
X
O
O
H
CpCo
Me3Si
CpCo
Me3Si
79%
86%
O
SiMe3
SiMe3
OMe
OMe
18
12
A
B
1. MsCl (3.6 equiv),
py, CH2Cl2, 1 h
2. NaN3 (5.0 equiv),
DMF, r.t., 24 h
3. SnCl2·2H2O (2.0 equiv),
MeOH, r.t., 20 h
Figure 2 Models that explain the conformational preference of X in
27–31 (A) and presage that of Y in the corresponding benzylic ana-
logues (B)
NH2
OH
SiMe3
SiMe3
93%
O
OMe
22
O
thebaine (32) (Scheme 6), which was anticipated to adopt
the opposite stereochemistry with respect to CpCo to those
in 27–31 by analogy with the similarly prepared Fe(CO)3
complex, the structure of which had been ascertained by
X-ray analysis.16 Indeed, relative to, for example, 30, com-
plex 33 has a relatively deshielded H7a (δ = 4.86 vs 4.00
ppm) and shielded H4 (δ = 2.17 vs 2.92 ppm), corroborating
the syn-disposition of CpCo to the former, its anti-arrange-
ment to the latter. In addition, H1eq, which exhibits only
one large coupling17 and is located anti to the metal in the
Fe(CO)3 complex, appears uniquely shielded at δ = 1.57
ppm, consistent with a close proximity of the CpCo moiety
to the aza bridge (for NMR spectral assignments, see SI).
Convex metalation of the phenanthrofuran segment of the-
baine appears to be the consequence of easier steric ac-
cess.18 Finally, the stereochemistry of the series was con-
firmed rigorously by an X-ray structural determination of
31.2h One notes that the relative disposition of stereocenters
C4a, C9c, and C8 coincides with that observed for morphine
and its analogues (Figure 1).
OMe
19
BnMe3N+F–
(1.3 equiv),
THF, r.t., 1 h
Ac2O (2 equiv),
py (2 equiv),
CH2Cl2, r.t.,
45 min
BnMe3N+F–
(1.3 equiv),
THF, r.t., 1 h
90%
95%
98%
O
R1
NR2
OR
N
R2
O
O
O
OMe
OMe
20, R = H
OMe
23, R = H
25, R1 = H, R2 = SiMe3
CH2=O (4.6 equiv),
KOH (4
TMSCl (3.3 equiv),
HMDS (3.3 equiv),
PhMe, r.t., 20 h
NaCNBH3 (1.6 equiv),
AcOH, H2O, MeCN,
r.t., 20 h
equiv), MeI (2
equiv), DMSO,
0 °C, 45 min
53%
97%
82%
21, R = SiMe3
24, R = Me
26, R1 = Me, R2 = H
Scheme 4
Table 1 Selection of Comparative NMR Data for 27–31
CpCo(CH2=CH2)2
(1.04–1.1 equiv),
Et2O, 0 °C or r.t.,
~1 h
X
X
8
9
H8 (δ)a
H4a (δ)
H9c (δ)
J
4a–9c (Hz)b
SiMe3
Complex
7a
7
9a
1
CoCp
SiMe3
H
9b
+
27
28
29
30
31
3.77
3.92
3.75
2.92
5.27
3.92
3.80
3.98
4.00
4.11
2.56
2.19
3.05
2.07
2.04
7.1
7.1
7.1
7.0
7.0
2
9c
4a
6
3
5
SiMe3
8 (excess)
3a
O
O
MeO
MeO
SiMe3
H
20, X = OH
27, X = OH, 63%
21, X = OSiMe3
23, X = NH2
24, X = NMe2
26, X = NAcMe
28, X = OSiMe3, 53%
29, X = NH2, 66%
30, X = NMe2, 72%
31, X = NAcMe, 70%
a For numbering scheme, see Scheme 5.
b Average of the two J values, ranging from 7.0–7.2 Hz.
Scheme 5 Synthesis of 27–31. The numbering in the product is strictly
applicable only to 27 and 29–31 (see also SI).
A brief foray was made into extending this methodology
to the corresponding benzo[b]thiophene analogues, specifi-
cally those of 9 and 27. With respect to the former,
benzo[b]thiophene was converted into 34, in a sequence
corresponding to the synthesis of 7 (vide supra, Scheme 2,
and experimental section and SI), followed by cocyclization
with 8 to give 35 in good yield, accompanied by cyclo-
butadiene complex 36 (Scheme 7). The stereochemical
The structural assignments of 27–31 were based on
careful NMR analysis of 27, including two-dimensional, ful-
ly coupled,15 and DEPT NMR techniques, and their selective
application to the other systems (see also SI). The entire se-
ries exhibited very similar chemical shifts, multiplicities,
and coupling constants, with the exception of local varia-
tions induced by the nature of X (Table 1). Further support
was obtained by the synthesis of the CpCo complex 33 of
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

D
T. Aechtner et al.
Paper
Synthesis
1. NaOH (30 equiv),
3NMe
4
NMe
CpCo(CH2=CH2)2
(5.5 equiv),
Et2O, r.t., 50 h
AcCl (3 equiv),
AlCl3 (4 equiv),
CH2Cl2, 0 °C or
r.t., 1 h
H2O, reflux, 4.5 h
2. Cu (4 equiv),
quinoline,
O
2
1
13
12
4a
5
11
CoCp
6
200 °C, 1 h
10
12a
8a
98%
12b
CN
CN
7a
7
84%
Quantitative
9
S
S
O
O
OMe
OMe
MeO
MeO
H
H
OMe
OMe
32
33
37
38
Scheme 6 Synthesis of the CpCo complex 33 of thebaine
1. EtSH, DCC (1.05 equiv),
DMAP (0.1 equiv), CH2Cl2,
0 °C, 1 h, then r.t., 30 min
2. Et3SiH (3.3 equiv),
1. S (2.5 equiv),
morpholine (7.2 equiv),
129 °C, 12 h
2. NaOH, H2O,
100 °C, 11 h
O
O
OH
S
5% Pd/C, CH2Cl2, 45 min
identity of 35, the same as that of 9, rests on the observa-
1
tion of a relatively deshielded H6a nucleus in the H NMR
S
64%
77%
spectrum at δ = 5.35 ppm, syn with respect to CpCo.
OMe
OMe
39
40
SiMe3
Me3Si
CoCp
H
O
OH
LiC≡CSiMe3
(2.3 equiv),
THF,
–78 °C,
then r.t., 5 h
BnMe3N+F–
(1.3 equiv),
THF, 80 °C,
6a
Me3Si−≡−SiMe3
H
S
(8, 5.3 equiv),
S
SiMe3
5 min
CpCo(CH2=CH2)2
(1.1 equiv),
Et2O, r.t., 1.3 h
35 (61%)
81%
83%
S
+
OMe
OMe
S
SiMe3
SiMe3
41
42
34
OH
CoCp
8 (5.2 equiv),
S
CpCo(CH2=CH2)2
9
8
36 (9%)
(1.1 equiv),
7
CoCp
SiMe3
H
Et2O, r.t.
Scheme 7
9c
20%
4a
S
S
MeO
SiMe3
H
OMe
Similarly, the sulfur analogue of 27 was approached via
43 (Scheme 8), constructed starting with the known 3719
through a sequence that paralleled that of the assembly of
the benzofuran relative 20 (Scheme 4) and featured the
new intermediates 38–42.
43
44
Scheme 8
tential intramolecular cyclization. Such was deemed feasi-
ble via attack of the amide function, masked as an enolate
equivalent, on the CpCo(cyclohexadienylium) cation unit
generated by hydride abstraction from C9c, as depicted by
C in Scheme 9. The anticipation of regioselectivity in the
latter was justified by the observed preference for the for-
mation of the less stable cationic ligands (i.e., those with
smaller HOMO–LUMO gaps and hence better ligating abili-
ty) in the chemistry of the isolobal (cyclohexadiene)Fe(CO)3
complexes,20,21 in addition to encouraging observations by
us in related CpCo systems,22 in particular a closely related
indole derivative.22a
Surprisingly, subjecting 43 to Co-mediated cocyclization
with bis(trimethylsilyl)acetylene (8) did not engender the
expected alcohol complex, but rather dehydration product
44, as evidenced by the mass and 1H NMR spectra. The lat-
ter revealed the absence of the signals expected for the
hydroxyethylene bridge and the presence of two doublets
corresponding to H8 and H9. The relative shielding of H4a
and H9c corroborates their exo-positioning with respect to
CpCo. The spectral data of 44 are in consonance with simi-
lar dihydrophenanthrene complexes (see 99 and 102,
Schemes 19 and 21) accessed from related C9-hydroxy de-
rivatives by deliberate dehydration (vide infra). Assuming
that this unexpected elimination of water proceeds through
the acid-catalyzed formation of a Co-stabilized C8-cation, it
is possible that the relatively lesser electronegativity of S
versus O is responsible for the generation of 44 in contrast
to the stability of 27.
In the event, all attempts to turn 31 into its silyl ketene
aminal23 resulted in decomposition. Hypothesizing that the
aminal might be too sensitive to be isolable, in situ trapping
by hydride abstraction with Tr+PF6 was tried, leading to a
–
complex mixture containing 45 as the only identifiable
product. This compound was the endpoint of a number of
other treatments of 31, such as Fe(NO3)3 (Scheme 9), CuCl2,
Me3NO, or simply air, further attesting to the sensitivity of
the starting complex with respect to aromatizing decom-
plexation. The structure of 45 was assigned readily on the
Having demonstrated the viability of this AE → ABCE
approach to part of the morphine skeleton, the task of forg-
ing the remaining D ring was tackled. Since this required
the installation of a two-carbon bridge between C8 and
C9c, efforts concentrated on the acetamide 31 and its po-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

E
T. Aechtner et al.
Paper
Synthesis
A first strategy was patterned after those depicted in
Schemes 4 and 8 to aldehydes 18 and 41, respectively, and
began with the readily available N,N-dimethylamine 47
(Scheme 10).27
O
N
1. BuLi or LDA,
THF, –78 °C
SiMe3
O
N
2. TMSCl
3. Tr+PF6
H2C
–
Me
4. BnMe3N+F–
CoCp
SiMe3
H
O
H
+
SiMe3
CoCp
SiMe3
9c
O
O
MeO
MeO
SiMe3
H
NMe2
N
O
31
C
CCl3
–
Tr+PF6
(1.2 equiv),
CH2Cl2,
Fe(NO3)3·9H2O (2 equiv),
THF, MeCN, H2O, –78 °C,
5 min, then r.t., 30 min
TrocCl (1.2. equiv),
CH2Cl2, r.t., 24 h
73%
O
O
92%
83%
–78 °C, 1 h
OMe
47
Br2
(1 equiv),
CHCl3,
OMe
O
48
O
AcCl (3 equiv),
AlCl3 (3 equiv),
CH2Cl2, 0 °C, 1 h
Br2 (1 equiv),
AcOH,
r.t., 2 h
K2CO3 (2.8 equiv),
CH2Cl2,
–78 °C, 2 min
Hα
N
Hα
Hβ
N
Hβ
82%
89% 72%
H
H
+
−
0 °C, 4 h
10
9
PF6
CoCp
SiMe3
8
1
9
10
8
1
O
O
Quantitative
4a
2
SiMe3
7
7
NMe2
2
3
4
N
N
O
H
5
6
O
4
3
O
6
5
MeO
OH
SiMe3
Br
Br
MeO
OH
SiMe3
46
45
CCl3
CCl3
Scheme 9 The numbering in 45 and 46 adheres to the IUPAC phenan-
O
O
O
threne scheme
OMe
OMe
51
OMe
50
49
basis of spectral data, including the diagnostic low-field 1H
NMR absorption signal for H5 (for a complete assignment,
see experimental section).24
Scheme 10
In the hope that H9c might be removed as a hydride to
form the corresponding cation, 31 was exposed to solely
Tr+PF6– (Scheme 9). Instead of the desired process, protona-
tion of the dihydrobenzofuran oxygen and subsequent ring
opening occurred to furnish 46 cleanly. Switching the re-
The nitrogen was deactivated and the superfluous sec-
ond methyl group removed simultaneously with TrocCl to
supply 48. The regioselective acylation of 48 at C4 was not
assured,4f,28 but gratifyingly proceeded to 49 cleanly. Simi-
larly, bromination of 48 furnished only 50, as indicated by
–25
1
agent to NO+BF4 did not change this outcome. The NMR
the characteristic H NMR signals in the aromatic region.
spectra are in agreement with those for related CpCo2k or
These assignments were corroborated by the 1H NMR spec-
tra for the product 51 of bromination of 47, and of the
deprotection of 49 and 50 (Zn, AcOH, 5 h; see experimental
26
1
Fe(CO)3 cationic complexes, notably the characteristic H
NMR singlets at δ = 5.75, 4.50, and 2.55 ppm arising from
H4, H1, and H4a. Further corroboration of the structure de-
rived from the ready and quantitative deprotonation–de-
complexation to 45 (Scheme 9).
section),
to
1-{7-methoxy-3-[2-(methylamino)ethyl]-
benzo[b]furan-4-yl}ethanone (52) and 2-(4-bromo-7-
methoxybenzo[b]furan-3-yl)-N-methylethanamine
(53),
While the preceding narrative validates the retrosyn-
thetic disconnection in Scheme 1, the degradation de-
scribed in Scheme 9 severely limits the application of the
strategy to the synthesis of more complex derivatives along
the guiding principle outlined in the introductory para-
graph. The focus therefore shifted to systems 5/6 (Scheme
1) in which Z ≠ H (as in Z = CH2CH2OR or CH2CH2NRR′), ob-
viating aromatization and hopefully providing an alterna-
tive handle for morphanoid D ring construction. The fol-
lowing text describes chemistry designed to functionalize
the benzo[b]furan nucleus to bear suitable substituents at
C3 and C4. Some of the initial efforts were not successful for
the purpose intended. Nevertheless, they yielded new de-
rivatives that might be useful to others engaged in related
work, and they are therefore reported here.
respectively.
The next tasks were to elaborate the C4 substituents in
49–51 to a suitable 3-butynyl group. Unfortunately, at-
tempted Willgerodt–Kindler reaction (S, morpholine) of 49
led only to decomposition. Similarly, various transition-
metal-catalyzed coupling reactions to 50, featuring syn-
thons such as (Z)-1-(tributylstannyl)-4-(trimethylsilyl)-1-
buten-3-yne29 or (trimethylsilyl)butadiyne,30 failed to pro-
vide reasonable amounts of tractable materials.
In view of the above failures, attention turned to the ex-
ploration of analogous 2-oxyethyl (instead of 2-aminoethyl)
systems. A suitable starting point was ester 55,31 for which
an alternative preparation more amenable for scale-up was
developed, via the Pd-catalyzed cyclization32 of 54, in turn
derived by etherification of 2-bromo-6-methoxyphenol33
with methyl trans-4-bromo-2-butenoate (91%, see experi-
mental section). Reduction of 55 resulted in 56,34 which
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

F
T. Aechtner et al.
Paper
Synthesis
was brominated to 57, protected as in 58 (or its TIPS coun-
terpart, see experimental section), and then subjected to
Ni-catalyzed coupling with the Grignard reagent derived
from 2-bromo-1,1-dimethoxyethane35 to supply 59
(Scheme 11).
trans-4-bromo-2-butenyl acetate),42 or CH2NHMe (from 60
and trans-1,4-dibromo-2-butene, followed by MeNH2) (see
experimental section and SI). These tries failed, possibly
due to allylic activation by Pd, including eliminations,43 as
confirmed for the methylamino variant by the isolation of
60% of 60.
Formyl ester 62 proved to be a difficult substrate in at-
tempted olefination reactions, perhaps ascribable to the
presence of relatively acidic furanylic protons. Thus,
[(trimethylsilyl)propargyl]triphenylphosphonium bromide
(BuLi, THF, –78 °C),44 the corresponding phosphonates (var-
ious bases, THF or MeCN, –78 °C),45 (iodomethyl)triphenyl-
phosphonium iodide [NaN(TMS)2, THF, HMPA, –78 °C],46
and 1,3-bis(triisopropylsilyl)propyne (BuLi, THF, –78 °C)47
failed to generate any useful products. In contrast, Wittig
homologation with (methoxymethyl)triphenylphosphoni-
um chloride48 proved successful to furnish 63 as a mixture
of cis- and trans-isomers (1:2) (Scheme 12). A reduction–
Pd(PPh3)4
(0.1 equiv),
K2CO3
(4 equiv),
O
O
OMe
LAH (5 equiv),
THF, r.t., 4 h
Br
O
OMe
PhMe, Δ, 5 h
45%
88%
O
OMe
OMe
54
55
TBDMSCl
(2 equiv),
imidazole
(3 equiv), DMF,
r.t., 2 h
OH
OH
Br
Br2 (1 equiv),
CHCl3, 0 °C, 4 h
89%
98%
O
O
OMe
OMe
56
O
57
Br
Pd(OAc)2 (0.05 equiv),
NaI (0.15 equiv),
Et3N (2.7 equiv),
MeCN–H2O (30:1),
r.t., 24 h
OMe
(1.2 equiv),
K2CO3 (1.2 equiv),
DMF, r.t., 12 h
O
OMe
CHO
CHO
OMe
OMe
1. Mg, Et2O, Δ, 2 h,
2. (MeO)2CHCH2Br,
Et2O, Ni(dppe)Cl2,
Δ, 20 h
OTBDMS
OTBDMS
I
I
Br
MeO
85%
86%
OH
O
OMe
81%
O
O
60
61
OMe
OMe
OMe
OMe
OMe
58
59
MOMPPh3Cl (1.5 equiv),
KOt-Bu (1.5 equiv),
THF, 0 °C, 2 h
CHO
OMe
O
Scheme 11
O
70%
O
O
Unfortunately, this reaction turned out to be capricious
and poorly reproducible, possibly due to the instability of
the organometal with respect to elimination.35d These diffi-
culties were manifest also in other strategies, such as those
based on Negishi couplings36 or Pd-catalyzed α-aryla-
tions.37 Hence, we abandoned the use of bromide 58 as a
precursor to the desired 4-arylethanal of the type 18 or 41.
Instead, we switched to a Wittig extension tactic, featuring
aldehyde 62, made by reaction of 6038 with methyl trans-4-
bromo-2-butenoate to give 61, and subsequent Heck cy-
clization (Scheme 12). The latter benefitted from added
NaI,39 which served to obviate deleterious deiodination of
starting material. An alternative route to 62 proceeded
through the bromo analogues of 60 and 61, 2-bromo-3-
hydroxy-4-methoxybenzaldehyde40 and methyl trans-4-(2-
bromo-3-formyl-6-methoxyphenoxy)-2-butenoate, respec-
tively (see experimental section and SI).
While the ester function in 62 might, in principle, be
appropriately altered in subsequent transformations, for
the purposes of added convergence, the Heck cyclization
was attempted on modified versions of 61 in which the me-
thoxycarbonyl substituent had been replaced by
CH2OTBDMS [from 60 and trans-1-bromo-4-(tert-butyl-
dimethylsilyloxy)-2-butene],41 CH2OAc (in situ from 60 and
OMe
62
63
HO
1. LAH (1 equiv),
THF, r.t., 12 h
2. 1 N HCl, THF,
Δ, 4 h
O
CHO
OH
40%
O
O
OMe
64
OMe
1.
Si
Si
SiMe3
HC CMgBr
(4 equiv),
THF, 0 °C, 6 h
73%
67, BuLi, THF,
–78 °C, 1 h
2. 64 (0.3 equiv),
THF, –78 °C to r.t.,
OH
OR
25%
3 h
OH
O
OH
OMe
PvCl, py,
CH2Cl2,
0 °C, 6 h
Si
O
Me3Si
MeO
Si
65, R = H
66, R = Pv
42%
68
Scheme 12
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G
T. Aechtner et al.
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Synthesis
hydrolysis sequence then presented 64 as a mixture of
aldehyde and hemiacetal (0.6:1), which could be ethynylated
to 65,49 thus finally delivering a 3-alkylated analogue of 20
(Scheme 4). For comparison with the results of subsequent
Co-mediated cyclizations (vide infra), the primary hydroxy
function was protected selectively with PvCl50 to provide
66. In addition, the all-intramolecular substrate for cyclo-
addition 68 could be assembled from synthon 67 (Scheme 12),
in turn constructed by monosilylation of 1,2-bis(ethynyl-
dimethylsilyl)ethane.51
peared to be aldehyde 62, which had to be altered by reduc-
tion of the potentially deleterious benzylic ester function
(vide supra). Accordingly (Scheme 14), 62 was acetalized
with 1,2-ethanediol to 70, the latter in turn also derivable
from the analogous acetals of 60 and 61, both sequences
emerging as equally effective (see experimental section).
HOCH2CH2OH
OMe
(cosolvent),
PPTS (0.05 equiv),
PhMe, Δ, 12 h
O
O
LAH (4.6 equiv),
THF, 0 °C, 30 min
O
62
88%
97%
Encouragingly, cocyclization of 66 with 8 provided 69
(Scheme 13), albeit in low yield, although with good stereo-
selectivity (admixed with another isomer in the ratio = 6:1).
Its stereochemical assignment rests on the similarity of the
NMR data with those of 27; for example, the chemical shifts
of H4a (δ = 4.06 vs 3.92 ppm), H7 (δ = 5.45 vs 5.11 ppm),
and H8 (δ = 3.78 vs 3.77 ppm), in addition to the carbon sig-
nals (for assignments, see SI). The identity of the minor iso-
mer could not be verified with certainty, but it is likely the
one bearing the C8 hydroxy group cis to CpCo, judging from
the relatively unaltered positions of the singlets for the
(tentatively assigned) Cp, H4a, and H7 nuclei at δ = 4.17,
5.53, and 5.40 ppm, respectively.
O
OMe
70
RCl
PPTS
OH (1.6 or 2.5 equiv),
imidazole
OR
(0.2 or 0.04 equiv),
H2O, acetone, Δ,
1 h or r.t., 16 h
O
O
O
O
(2 or 3.7 equiv),
DMF, r.t., 17 h
O
O
OMe
OMe
71
72, R = TIPS 96%
73, R = TBDMS 99%
HC≡CCH2MgBr
(3.1 or 7.1 equiv),
HgCl2 (0.3 or 1%), HO
Et2O,
OR
OR
O
H
0 °C to r.t., 30 min
O
CpCo(CH2=CH2)2
SiMe3
SiMe3
(1.1 equiv), THF,
r.t., 21 h
O
9
OH
O
O
8
66
+
1
7a
7
OMe
OMe
16%
9a
CoCp
SiMe3
9b
2
74, R = TIPS 90%
75, R = TBDMS 54%
76, R = TIPS 85%
77, R = TBDMS 83%
9c
6
4a
3
5
8 (cosolvent)
3a
O
MeO
SiMe3
H
69
I (1.4 equiv),
Ph3P
THF, –78 °C to 0 °C, 30 min
(for 75)
51%
Scheme 13 For comparative purposes, the numbering in the reference
complex 27 was retained
1. Cl2Pd(PPh3)2 (0.04 equiv),
CuI (0.08 equiv),
OTBDMS
OTBDMS
Et3N, Me3SiC≡CH (2.0 equiv),
I
Unfortunately, the analogous reaction of 65 gave an in-
separable mixture of Co complexes in miniscule amounts,
whereas that of 68 returned only starting material, even
when conducted in boiling PhMe. Thus, it appears that the
increased steric burden introduced by the substitution of
the benzofuran nucleus at C3 in 65 and 66 is disadvanta-
geous to the outcome of the Co-mediated cycloaddition, a
facet observed in related cyclizations,2i,n and prohibitive in
the presence of the additional hindrance in 68.
Our strategy was therefore revised to exploring cycliza-
tion substrates 6 (Scheme 1), in which X = H, Y = OH, and Z ≠ H,
i.e. derivatives regioisomeric to type 65 with the OH group
transposed from the sterically compromising propargylic to
the benzylic position. While this change nullified the origi-
nally planned intramolecular displacement scheme for the
eventual construction of the D ring in morphine, it left open
the option of accomplishing such by dehydration and ring
closure involving the C9,C10-double bond (morphine num-
bering).5 A ready entry point to the required alcohols ap-
THF, r.t., 16 h
2. K2CO3 (1.8 equiv),
MeOH, Et2O, 2 h, r.t.
O
O
88%
OMe
OMe
79
78
Scheme 14
LAH reduction of 70 gave alcohol 71, which was silyl
protected (as 72 or 73) and then deacetalized to aldehydes
74 or 75; propargylation to 76 or 77 was then achieved
readily. Devoid of the ester function of 62, these aldehydes
seemed suitable substrates for a Wittig cis-olefination,
which would install the requisite double bond in the even-
tual cyclization product early. Indeed, such was demon-
strated with 75, which furnished 78 using (iodometh-
yl)triphenylphosphonium iodide,46 its cis-stereochemistry
established by NMR comparison with the also generated
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H
T. Aechtner et al.
Paper
Synthesis
trans-isomer (ratio = 4:1; Jcis = 8.3 Hz, Jtrans = 14.6 Hz). Iodo-
alkene 78 was then further elaborated by (trimethyl-
silyl)ethynylation and protodesilylation to provide 79.
The stage was now set to attempt Co-mediated cycliza-
tions with these substrates. Gratifyingly, the transforma-
tions of 76 and 77 proceeded much more cleanly than that
of 66, and with essentially complete diastereoselectivity to
give 80 and 81, respectively (Scheme 15). A determined
search for another isomer, executed by preparative HPLC in
the assembly of 81, yielded another complex in 1.6% yield,
with very similar NMR data except for the signals around
C9, especially the relatively shielded signal for H1, suggest-
ing the C9 epimeric alcohol (see experimental section and
SI). While the yields reported in Scheme 15 appear modest,
NMR analyses of the crude products of various runs indi-
cate that substantially better values (70–80%) may be at-
tainable.
deshielded H8 (δ = 2.33 and 2.36 ppm, respectively) as that
positioned syn to the metal (relative to H8anti, δ = 1.48 and
1.50 ppm, respectively), and its characteristic Jtrans coupling
to H9 (9.6 and 8.5 Hz, respectively). These assignments
were confirmed by an X-ray structural analysis of 81 (Fig-
ure 3).52
CpCo(CH2=CH2)2
OR
HO
(1.3 or 1.0 equiv),
Et2O or THF, r.t.,
~13 h or 30 min
9
8
SiMe3
76
R = TIPS
77
1
9a
7a
7
CoCp
SiMe3
+
9b
9c
4a
2
6
R = TBDMS
3
5
SiMe3
3a
O
MeO
SiMe3
H
8 (excess)
80, R = TIPS 54%
81, R = TBDMS 38%
Figure 3 Structure of 81 in the crystal
SiMe3
Me3Si
CpCo
SiMe3
OTBDMS
As presaged in Figure 2 (vide supra), the selective posi-
tioning of the OH at C9 as syn to CpCo is in consonance with
its pseudo-equatorial location in the cobaltacyclopenta-
diene(benzofuran) precursor, as shown in B (Figure 2). In
contrast to these successes, 79 formed only trans-cyclobuta-
diene complex 82 (Jtrans = 15.6 Hz), the added rigidity of the
alkyne side chain evidently precluding effective heterocycle
participation in the cyclization (Scheme 15). The observed
double-bond isomerization was unexpected2e–g and likely
occurred during workup. This impediment to the desired
process remained even when using the sterically less en-
cumbered (trimethylsilyl)acetylene as a cooligomerization
partner. In this case, produced as the major product, was
the cis-[2,5-bis(trimethylsilyl)styrenyl] derivative of 79 (the
2,5-loci of substitution tentatively assigned based on litera-
ture precedent),53 emerging from the cycloaddition of two
silylacetylene units to the alkyne terminus (15%; see exper-
imental section and SI). Yet another mode of reactivity sur-
faced when 3-hexyne was employed, C–H activation occur-
ring to furnish 83 as the only identifiable product, albeit in
low yield. Its gross structural assignment rested on a com-
CpCo(CH2=CH2)2,
Et2O, r.t., 30 min
79
+
70%
SiMe3
8 (excess)
O
OMe
82
OTBDMS
CpCo(CH2=CH2)2,
THF, r.t., 30 min
79
+
7%
O
(5 equiv)
OMe
83
Scheme 15 For comparative purposes, the numbering in the reference
complex 27 was retained for 80 and 81
The anti-disposition of the CpCo moiety was again es-
tablished by the comparatively shielded H4a nuclei (δ = 4.08
and 4.06 ppm, respectively). H7 was found to be slightly
shielded (δ = 4.91 and 4.92 ppm, respectively) relative to its
counterpart in 69 (δ = 5.45 ppm), the result of the removal
of the allylic OH function (for NMR spectral assignments,
see SI). The stereochemistry of the C9-OH was indicated as
syn to CpCo, based on a tentative assignment of the more
1
parison of its H NMR spectrum with those of similar ben-
zofulvenes54 and its tentative stereochemical definition on
mechanistic considerations.2c,d,j,55 All of the preceding pro-
cesses are known competing reactions in the [2+2+2] cyclo-
addition enabled by CpCo.2
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T. Aechtner et al.
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As a consequence of the difficulties encountered in the
cocyclizations of 79, further investigations of the scope of
the reaction concentrated on 76. The necessity of bulky
substituents in the cocyclization partner (as in 8) was
quickly ascertained in a test run with acetylene, which
again provided only the acetylene cocyclotrimerization
product with the triple bond of 76 (47%; see experimental
section and SI). In choosing a substituted alkyne, attention
turned to alkoxyalkynes, as their successful application
would introduce an oxygen into what was envisaged to be-
come the C ring of the morphine skeleton (Figure 1). Not
surprisingly, ethoxyacetylene led only to a complex mix-
ture containing 1,2,4-triethoxybenzene, leaving 76 largely
intact. Ethoxy(trimethylsilyl)acetylene56 gave crude materi-
al, which, by mass and NMR spectral inspection, appeared
to be composed of only the CpCo(cyclobutadiene) complex
derived from the alkoxyacetylene57 and cooligomerization
products of 76 not involving the benzofuran nucleus. This
outcome was disappointing, in as much as me-
thoxy(trimethylsilyl)acetylene had been moderately suc-
cessful in attacking double bonds of indole and pyrrole de-
rivatives in the desired manner.2n,o Tinkering further with
steric variations, phenoxy(trimethylsilyl)- and 2,6-dimethyl-
phenoxy(trimethylsilyl)acetylene were prepared following
the general strategy of Greene,58 but their fate in the pres-
ence of 76 and CpCo(C2H4)2 was the same as that observed
for ethoxy(trimethylsilyl)acetylene (see experimental sec-
tion and SI).
R1,2 = SiMe2Oi-Pr, SiMe3), 84h (25% of 87, R1,2 = SiMe2Ph,
SiMe3), and 84c [9% of the cobalt complex, R1,2 = SiMe(OEt)2,
SiMe3 by H NMR analysis], the other substrates failing to
engender any of the desired product (see experimental sec-
tion and SI).
1
OTIPS
HO
9
8
CpCo(CH2=CH2)2
(1.04 equiv),
THF, r.t., 15 min
1
9a
7a
7
CoCp
9b
9c
4a
76
+
84b
R2
2
6
(21 equiv)
42%
3
5
3a
O
MeO
R1
H
85a, R1 = SiMe2OMe, R2 = SiMe3
85b, R1 = SiMe3, R2 = SiMe2OMe
1:1
Scheme 16 Cocyclization of 76 with 84b to give 85a and 85b (re-
giochemistry assigned arbitrarily) in a 1:1 ratio. For comparative pur-
poses, the numbering in the reference complex 27 was retained.
While the yields might have been improved by appro-
priate tinkering with the reaction conditions, the (near)
complete lack of regioselectivity discouraged any further
attempts to implement this strategy.
In a separate line of enquiry, complementary to that
employing the ethers 76 and 77, appropriate synthons were
sought that incorporated the nitrogen of ring D of mor-
phine and its analogues in precursors of the type 6 (Scheme
1; Z = 2-aminoethyl). In a first approach, the readily avail-
able acetalized ester 70 (Scheme 14) was converted into
amides 88 and 89, respectively (Scheme 17). However, at-
tempted reduction of the amide function with LAH,
LiEt3BH, or DIBAL-H failed, and silane-based reagents65 fur-
nished the lactams 90 and 91, respectively. Similar ring clo-
sures have precedence, for example in approaches toward
the galanthamine framework.66
The preceding letdown encouraged a return to bissilyl-
alkynes as cocyclization partners, in particular unsymmet-
rical systems, in which one silyl group might function as a
masked hydroxy function in the morphanoid product.59 For
this purpose, a collection of variously alkoxy- and phenyl-
substituted (trimethylsilyl)alkynes 84 was assembled (Fig-
ure 4). Alkynes 84a,60 84b,61 84c,62 84f,63 and 84h64 were
known, whereas 84d, 84e, and 84g were synthesized by
standard procedures (see experimental section and SI).
R
O
TMSCl, NaBH4,
THF, Δ, 15 h
or Et3SiH, TFA,
MeNH2 or
NH4OH
H2O, MeOH,
r.t., 24 or 10 h
O
N
O
O
NHR
MeCN, Δ, 12 h
70
Si(OMe)3
SiMe2OMe
SiMe(OEt)2
SiMe2Oi-Pr
O
O
OMe
OMe
Me3Si
Me3Si
Me3Si
Me3Si
90, R = Me, 73%
91, R = H, 54%
88, R = Me, 73%
89, R = H, 66%
84a
84b
84c
84d
Scheme 17
SiEt2Oi-Pr
SiPh3
SiPh2OMe
SiMe2Ph
Stymied by the presence of the insufficiently protected
formyl group at C4, a modified strategy involved its removal
by reduction. Accordingly, 62 was treated with LAH to fur-
nish diol 92, in turn to be selectively oxidized with DDQ to
the hydroxy aldehyde 93, which, unlike 64, adopted the
open-chain non-hemiacetal configuration (Scheme 18). The
choice of the oxidizing agent was the result of extensive ex-
perimentation, as many reagents led to mixtures of aldehy-
dic (and other) products, and the results of a reagent screen
are presented in the SI. The desired amino function in pro-
Me3Si
Me3Si
84f
Me3Si
Me3Si
84e
84h
84g
Figure 4 Alkoxy- and phenyl-substituted potential cocyclization part-
ners of 76
The results of the cocyclizations of these substrates with
76 were, regrettably, poor. With respect to yield, the
conversion of 84b into 85 had the best outcome (42%;
Scheme 16), but steadily diminished with 84d (36% of 86,
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J
T. Aechtner et al.
Paper
Synthesis
tected form was then introduced by exposure of 93 to tert-
butyl [(2-nitrophenyl)sulfonyl]carbamate, DEAD, and
Ph3P67 to render 94. Propargylation to 95 proved to be ca-
pricious, generating small amounts of desired product in
mixtures that included starting material and the partly
deprotected 97. The identity of the latter was confirmed by
selective hydrolysis of 94 with 2-mercaptoacetic acid67 to
give 96, followed by propargylation to 97, the second step
also marred by low yields.
reminiscent of the transformation of 31 to 46 (Scheme 9).
Its structure rests on analytical data and the diagnostic
complexed cyclohexadienyl cation NMR chemical shifts,68
particularly in comparison with the corresponding signals
in 46. The problem was solved by treatment of 80 with
MsCl and Et3N (or TsCl, py), which created 99 in reasonable
yields (Scheme 19; for NMR spectral assignments, see SI).
HO
OTIPS
CoCp
SiMe3
OH
OH
LAH
(2.2 equiv),
THF,
HO
CHO
DDQ (1.2 equiv),
CH2Cl2, r.t., 1 h
O
MeO
SiMe3
0 °C, 1 h
62
80
99%
79%
O
O
CF3COOH (2 equiv),
CHCl3, r.t., 1 min
MsCl (5 equiv), Et3N (10 equiv),
CH2Cl2, 0 °C, 5 min
75%
Quan-
titative
(1H NMR)
OMe
OMe
92
NO2
93
OTIPS
CoCp
OTIPS
O2
O
CoCp
SiMe3
O
S
S
HSCH2COOH
(4.4 equiv),
LiOH·H2O
(7.6 equiv),
DMF, r.t., 12 h
NH
Boc
SiMe3
,
Boc
N
NH
Boc
NO2
CHO
OMe
CHO
O
MeO
SiMe3
OH
MeO
SiMe3
CF3COO
DEAD, Ph3P,
C6H6, r.t., 3 h
98
99
98%
60%
O
O
Scheme 19
OMe
94
96
Br
(5 equiv)
Mg, Et2O, –78 °C
Br
The need for the presence of the protecting CpCo in this
chemistry became apparent when the free ligands 100 and
101 were made by quite effective oxidative demetalation
,
8%
27%
Mg, Et2O,
–70 to 0 °C
NO2
2
with CuCl2 (Scheme 20; for NMR spectral assignments of
O
Boc
O
NH
S
100, see SI). Perhaps not unexpectedly, these compounds
turned out to be even more (particularly acid) sensitive
than their metal-protected relatives, decomposing on
standing at room temperature over the course of 2 days,
more rapidly in the presence of acid, base, and a number of
oxidizing agents (e.g., MCPBA, DMDO, I2), the engagement
of the latter aimed at tinkering with their frame.
OH
N
Boc
OH
O
O
OMe
97
OMe
95
Scheme 18
HO
CuCl2·(H2O)2
(2.6 equiv),
THF, MeCN,
r.t., 5 min
HO
OTIPS
OTIPS
In view of the limited available amounts of 95 and 97,
only qualitative cocyclization experiments were carried
out, lamentably not showing any improvement over those
involving 76 and 77.
CoCp
SiMe3
SiMe3
SiMe3
84%
O
O
100
MeO
SiMe3
MeO
80
Attention therefore returned to 80 and 81 and their yet
to be realized free ligands, in order to explore their basic
chemical behavior and potential manipulation toward mor-
phine. With respect to the latter, what needed to be ad-
dressed was the metamorphosis of the C-ring diene into a
conjugated enone, conversion of the TIPS-protected alcohol
moiety into a protected amine, and elimination of the ben-
zylic hydroxy function to provide functionality to C9 (mor-
phine numbering) for the final D-ring closure.
HO
OTBDMS
CoCp
HO
OTBDMS
CuCl2·H2O,
DME, H2O, Et3N,
0 °C to r.t., 1 h
SiMe3
SiMe3
SiMe3
89%
O
O
101
MeO
SiMe3
MeO
81
Scheme 20
Our studies commenced with the last task and an at-
tempt to effect acid-catalyzed dehydration of 80. Such was
successful, but only with concomitant furan ring opening to
provide the cation 98 quantitatively (Scheme 19), behavior
Hence, exploratory work continued with the complexed
versions, deemed to be more predictable in their behavior,
an assumption attenuated by some surprises. Indeed, treat-
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K
T. Aechtner et al.
Paper
Synthesis
ment of 99 with TBAF not only removed the TIPS protecting
group but also one of the TMS substituents, completely se-
lectively at C6, to construct 102 (Scheme 21). Such, presum-
ably steric, preference in protomonodesilylations have pre-
cedence in other [bis(trimethylsilyl)cyclohexadiene]CpCo
complexes,2m,69 and might be exploited in regioselective
oxidation schemes of ring C.70 Interestingly, alcohol 81 be-
haved normally under the same conditions, giving 103
(Scheme 21).
signments, see SI). Noteworthy is the downfield shift of the
hydroxy proton when comparing the 1H NMR spectra of
104 (δ = 5.71 ppm) and 105 (δ = 9.45 ppm), likely the result
of intramolecular hydrogen bonding to the tetrahydrofuran
oxygen in the latter (calculated distance 2.05 Å).71 The 13C
NMR spectrum of the mixture revealed the expected 38
lines, appearing in the five spectral windows expected on
comparison with the 13C NMR spectrum of 102: 140–150 (4
peaks), 108–133 (12 peaks), 77–90 (8 peaks), 45–67 (12
peaks) ppm, and the silyl region (2 peaks).
These assignments were greatly aided by the selective
crystallization of 104 from the mixture to give crystals suit-
able for an X-ray structural determination (Figure 5)52 and
by the NMR spectral monitoring of its equilibration with
105 (ratio 104/105 = 2:3).
OH
OTIPS
TBAF (3 equiv), THF,
0 °C to r.t., 1.5 h
CoCp
SiMe3
CoCp
SiMe3
58%
O
O
MeO
SiMe3
MeO
102
99
HO
HO
OTBDMS
CoCp
OH
TBAF (2.7 equiv),
THF, 0 °C to r.t., 1.5 h
CoCp
SiMe3
SiMe3
67%
O
O
MeO
SiMe3
MeO
SiMe3
81
103
Scheme 21
Another unexpected finding was that 102 was unstable
in solution, completely disappearing over a period of days
to be replaced by a mixture of two equilibrating com-
pounds, eventually identified as its isomers 104 and 105
1
(Scheme 22). Unlike that of 102, the H NMR spectrum of
Figure 5 Structure of 104 in the crystal
104 exhibits two diagnostic shielded, complexed terminal
diene hydrogen signals2 at δ = 3.73 and 2.88 ppm, and only
one internal neighbor at δ = 4.98 ppm. In contrast, its spiro
counterpart 105 features only internal complexed diene ab-
sorptions at δ = 5.18 and 4.98 ppm (for 1H NMR spectral as-
A plausible mechanism (see also Schemes 2, 9, and 19)
for the reorganization of 102 is depicted in Scheme 22 and
surmises intramolecular dissociation to the zwitterion D,
probably relatively facilitated (in comparison to 9, 31, and
80) by the additional C8,C9-double bond. This intermediate
can then function as a relay point for the equilibration with
(and between) 104 and 105. A similar mechanism was pos-
tulated for the analogous propella to spiro fusion exchange
in a topologically related indole system, also assembled by
CpCo-catalyzed cycloaddition.72
OH
OH
8
9
7a
7
CoCp
7a
CoCp
6
9c
4a
5
4a
O
MeO
MeO
SiMe3
O
SiMe3
Notwithstanding the thermal lability of 102, it was pos-
sible to replace its hydroxy function with an N-methyl-
benzenesulfonamide moiety by a variant of the Mitsunobu
reaction73 to present 106, albeit in only modest yield
(Scheme 23). The ligand is very similar to a number of late-
stage intermediates on route to the morphinan nucleus.5,6,74
Unfortunately, attempts at oxidative demetalation gave
mixtures of compounds, and a (long) shot at closing ring D
by dissolving metal reductive coupling led to decomposi-
tion. Building on the cumulative knowledge assembled by
the chemistry described, we are directing future research at
the cocyclization of 97 (or its N-methyl derivative) with
102
D
Ring
closure to
C7a
Ring
closure to
C4a
O
7
7
CoCp
6
6
4a
CoCp
5
5
4a
MeO
OH
SiMe3
O
SiMe3
MeO
OH
104
105
Scheme 22 For comparative purposes, the numbering in the reference
complex 27 was retained
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

L
T. Aechtner et al.
Paper
Synthesis
or AV600 (600 MHz) spectrometers. Data are reported as: chemical
shifts (δ) in parts per million (ppm) and referenced to residual solvent
peaks (δ = 7.25 ppm for CDCl3, 7.16 ppm for C6D6); multiplicity; cou-
pling constants (J) in hertz (Hz); and number of integrated protons.
Mass spectra were obtained on a Hewlett-Packard 5970A mass selec-
tive detector or provided by the Mass Spectral Service at the Universi-
ty of California at Berkeley, utilizing AEI-MS12, Finnigan 4000, or
Kratos MS 50 instruments. Elemental analyses were performed by the
Microanalytical Laboratory.
Me
PhSO2NHMe,
1,1'-(azodicarbonyl)dipiperidine
(5 equiv),
NSO2Ph
CoCp
Bu3P (5 equiv), C6H6, r.t., 27 h
102
35%
O
MeO
SiMe3
106
Scheme 23
2-(4-Pentynyl)benzo[b]furan (7)
alkynyl boronates,2b which, after suitable oxidation, should
provide ring C oxygenated derivatives better amenable to
locking the final ring.
Benzo[b]furan (661 μL, 709 mg, 6.00 mmol) in THF (15 mL) was treat-
ed with BuLi in hexane (1.5 M; 4.0 mL, 6.00 mmol) at –78 °C and then
at 0 °C for 10 min each.7 Renewed cooling to –78 °C was followed by
addition of 1-(triisopropylsilyl)-5-iodo-1-pentyne (600 mg, 1.71
mmol),8 warming to 0 °C for 3 h, and then to r.t. The reaction mixture
was subjected to sat. aq NH4Cl (5 mL), then extracted with Et2O
(4 × 10 mL), and the combined extracts were dried over MgSO4. Col-
umn chromatography on silica gel, eluting with hexanes, gave 2-[5-
(triisopropylsilyl)-4-pentynyl]benzo[b]furan (410 mg, 70%) as a col-
orless oil.
In summary, this paper describes the feasibility of the
CpCo-mediated [2+2+2] cycloaddition of alkynes to the 2,3-
double bond of benzo[b]furans (and some benzo[b]thio-
phenes). The cyclizations proceed generally in moderate to
good yields, with complete to extensive diastereoselectivi-
ty, but lacking regioselectivity in the case of unsymmetrical
alkynes. The complexes can be chemically manipulated
leading to the uncovering of unusual transformations, such
as CpCo-facilitated ring openings and rearrangements. Syn-
thetic efforts directed at constructing morphinan substruc-
tures have provided access to a plethora of new functional-
ized benzo[b]furans and benzo[b]thiophenes.
IR (film): 2940, 2860, 2170, 1460, 1005, 880, 730, 675, 660 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.44 (m, 1 H), 7.40 (m, 1 H), 7.18 (m, 2
H), 6.40 (s, 1 H), 2.91 (t, J = 7.4 Hz, 2 H), 2.33 (t, J = 7.4 Hz, 2 H), 1.96
(quin, J = 7.4 Hz, 2 H), 1.09 (s, 21 H).
HRMS (EI, 70 eV): m/z [M+] calcd for C22H32OSi: 340.2222; found:
340.2215.
The above 2-[5-(triisopropylsilyl)-4-pentynyl]benzo[b]furan (41.6
mg, 0.122 mmol) in THF (1 mL) was treated with TBAF in THF (1 M;
0.3 mL, 0.3 mmol) at r.t. for 1.5 h. The reaction mixture was subjected
to sat. aq NaHCO3 (5 mL), then extracted with Et2O (4 × 10 mL), and
the combined extracts were dried over MgSO4. Column chromatogra-
phy on silica gel, eluting with hexanes, gave 7 (21.6 mg, 96%) as a col-
orless oil.
All reactions were performed under N2 or Ar, using anhydrous sol-
vents and solutions deoxygenated with N2 or Ar. Procedures involving
oxygen- and/or moisture-sensitive materials were handled in a Vacu-
um Atmospheres Inc. glovebox, via syringe, or employing standard
Schlenk techniques, respectively. THF, Et2O, DME, C6H6, and PhMe
were distilled under N2 from sodium, while CH2Cl2, MeCN, DMSO, and
pentane were distilled similarly from CaH2. DMF was purified by fil-
tration through alumina, followed by distillation at reduced pressure.
Quinoline was distilled from zinc at reduced pressure after drying
over Na2SO4. BuLi solutions were titrated with diphenylacetic acid. In
experiments requiring slow addition of reagents, Hamilton Gastight
syringes were employed, mounted on Sage Instruments single or dou-
ble syringe pumps. Irradiation of solutions containing CpCo(CO)2 uti-
lized a Sylvania ELH 300 W tungsten halogen slide projector lamp
with an applied potential of 60–70 V, positioned at a distance of 3–5
cm from the reaction vessel. TLC was executed on Analtech Uniplate
silica gel GHLF or Merck (0.25 mm silica gel 60, F254) plates. Column
chromatography relied on EM Science silica gel (230–400 mesh) or
Alfa Aesar alumina (–60 mesh). Reverse-phase HPLC relied on an IBM
LC-9533 instrument equipped with an LC-9522 fixed wavelength
(254 nm) detector. GLC was performed with a Hewlett-Packard 5880
instrument on a 6 ft × 2 mm i.d. glass column containing 3% OV-101
on Chromosorb W-HP (80–100 mesh), or a 30 m × 0.20 mm capillary
column loaded with cross-linked 5% phenyl methyl silicone. Melting
points were determined with a Thomas Hoover Uni-melt apparatus
and are uncorrected. IR spectra were recorded on Perkin Elmer Mod-
els 681, 1320, or 2000 FT-IR spectrophotometers. Electronic spectra
were acquired on a Hewlett-Packard 8450A UV-Visible diode array
spectrophotometer, a Hewlett-Packard 8453 UV-Vis ChemStation, or
a Perkin Elmer Lambda 35 machine. NMR spectra were collected on
Bruker AMX300 (300 MHz), AMX400 (400 MHz), DRX500 (500 MHz),
IR (film): 3300, 2940, 2860, 2120, 1600, 1510, 1450, 1150, 1080,
1000, 800, 730, 675, 640 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.53 (m, 1 H), 7.46 (m, 1 H), 7.24 (m, 2
H), 6.47 (s, 1 H), 2.95 (t, J = 7.4 Hz, 2 H), 2.34 (td, J = 7.4, 2.6 Hz, 2 H),
2.05 (t, J = 2.6 Hz, 1 H), 2.02 (quin, J = 7.4 Hz, 2 H).
endo-(η5-Cyclopentadienyl)[(3a,4,5,6-η4)(6aR*,11aS*)-1,2,3,6a-tet-
rahydro-5,6-bis(trimethylsilyl)benz[b]indeno[4,3a-d]furan]co-
balt (9)
Alkynylbenzofuran 7 (17.2 mg, 0.094 mmol) and CpCo(CO)2 (25 μL, 34
mg, 0.19 mmol) in a mixture of THF (2 mL) and bis(trimethylsi-
lyl)acetylene (8; 2 mL) were added via syringe pump over 12 h to irra-
diated and stirred 8 (0.5 mL) at r.t. The volatiles were removed under
reduced pressure and the residue was chromatographed on silica gel,
eluting first with hexanes to remove side products and then hexanes–
EtOAc (gradient, 1:1 to 1:4), to sequester 9 (15.0 mg, 33%) as an air-
and heat-sensitive red oil.
IR (film): 2948, 2900, 2850, 1425, 1240, 1090, 830, 805 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 6.98 (d, J = 7.6 Hz, 1 H), 6.90 (t, J = 7.6
Hz, 1 H), 6.61 (t, J = 7.3 Hz, 1 H), 6.41 (d, J = 7.9 Hz, 1 H), 4.75 (s, 1 H),
4.68 (s, 5 H), 3.54 (s, 1 H), 2.71 (m, 1 H), 2.16 (m, 3 H), 1.97 (m, 1 H),
1.58 (m, 1 H), 0.32 (s, 9 H), 0.12 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 478 ([M+], 42), 405 (17), 339 (13), 280 (12),
265 (23), 251 (53), 73 (100).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

M
T. Aechtner et al.
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(6aR*,11aS*)-1,2,3,6a-Tetrahydro-5,6-bis(trimethylsilyl)benz[b]in-
deno[4,3a-d]furan (11)
1H NMR (300 MHz, CDCl3): δ = 7.18 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.7
Hz, 2 H), 4.48 (dd, J = 12.0, 6.1 Hz, 1 H), 3.77 (s, 3 H), 2.92 (ABXm, 2 H),
2.21 (d, J = 5.6 Hz, 1 H), 0.16 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 158.3, 130.7, 128.4, 113.5, 106.2, 90.0,
63.5, 55.0, 42.9, –0.29.
To a solution of 9 (33.5 mg, 0.070 mmol) in Et3N (1 mL) and MeCN (1
mL) at 0 °C was added CuCl2·2H2O (170 mg, 1.0 mmol). After 10 min,
the cooling bath was removed and the mixture stirred at r.t. for 1 h.
The solution was poured onto aq NH4Cl, extracted with Et2O (4 × 10
mL), and the combined organic layers were dried (MgSO4). Removal of
the volatiles under reduced pressure left a residue that was chroma-
tographed on silica gel, eluting with hexanes–EtOAc (3:2), to afford 11
(7.6 mg, 31%) as a clear oil.
MS (EI, 70 eV): m/z (%) = 248 ([M+], 15), 233 (11), 230 (5), 215 (7), 122
(67), 121 (100), 83 (46), 75 (63), 73 (22).
UV/VIS (MeCN): λmax (log ε) = 226 (4.04), 267 (sh, 3.10), 276 (3.26),
283 nm (3.19).
Anal. Calcd for C14H20O2Si: C, 67.69; H, 8.12. Found: C, 67.78; H, 8.09.
1H NMR (300 MHz, CDCl3): δ = 7.43 (d, J = 7.6 Hz, 1 H), 7.10 (t, J = 7.6
Hz, 1 H), 6.81 (t, J = 7.3 Hz, 1 H), 6.68 (d, J = 7.8 Hz, 1 H), 6.10 (t, J = 1.8
Hz, 1 H), 4.20 (s, 1 H), 2.73 (m, 1 H), 2.45 (m, 1 H), 2.12 (m, 1 H), 1.97
(m, 1 H), 1.70 (m, 1 H), 1.55 (m, 1 H), 0.32 (s, 9 H), 0.15 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 354 ([M+], 51), 339 (65), 281 (33), 280 (34),
270 (32), 265 (41), 251 (57), 73 (100).
1-(4-Methoxyphenyl)-3-butyn-2-ol (16)
To alcohol 15 (290 mg, 1.17 mmol) and EtOH (206 μL, 163 mg, 3.53
mmol) in THF (5 mL) was added TBAF in THF (1.0 M; 1.40 mL, 1.40
mmol) and the mixture stirred at r.t. for 1 h. The clear orange solution
was diluted with H2O (60 mL) and extracted with Et2O (5 × 40 mL).
The combined organic phases were dried over Na2SO4, and the solvent
was removed to leave a yellow-orange oil. Distillation provided alky-
nol 16 (179 mg, 87%) as a clear liquid; bp (Kugelrohr, 0.4 torr) 190 °C.
HRMS (EI, 70 eV): m/z [M+] calcd for C21H30OSi2: 354.1835; found:
354.1828.
(4-Methoxyphenyl)acetaldehyde (14)11
IR (film): 3400 (br), 2959, 2936, 2835, 2110, 1615, 1510, 1302, 1244,
(4-Methoxyphenyl)acetic acid (13) (30.30 g, 182.3 mmol) in concd
H2SO4 (15.2 mL, 273.5 mmol) and MeOH (100 mL) was heated at re-
flux for 5 h. The light yellow solution was cooled to r.t., diluted with
H2O (400 mL), and extracted with C6H6 (4 × 150 mL). The combined
organic phases were washed with H2O (200 mL), 5% aq NaHCO3 (200
mL), and H2O (200 mL). The solvents were removed by rotary evapo-
ration, and the residue was distilled to give methyl (4-methoxyphe-
nyl)acetate (29.35 g, 89%) as a colorless liquid; bp 98–102 °C/1 torr
(Lit.11b 116–117 °C/2.5 torr).
1178, 1033, 805, 647 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.19 (d, J = 8.6 Hz, 2 H), 6.85 (d, J = 8.6
Hz, 2 H), 4.52 (td, J = 6.4, 2.1 Hz, 1 H), 3.78 (s, 3 H), 2.94 (ABXm, 2 H),
2.47 (d, J = 2.1 Hz, 1 H), 1.91 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 158.4, 130.7, 128.2, 113.7, 84.2, 73.7,
63.0, 55.1, 42.8.
MS (EI, 70 eV): m/z (%) = 176 ([M+], 52), 122 (63), 121 (100), 115 (25),
91 (60), 78 (69), 77 (72), 51 (57).
DIBAL-H in CH2Cl2 (1.0 M; 5.96 mL, 5.96 mmol) was transferred by sy-
ringe to a solution of methyl (4-methoxyphenyl)acetate (1.024 g, 5.68
mmol) in PhMe (20 mL) at –78 °C. After stirring for 1.5 h, the reaction
mixture was quenched by the addition of aq HCl (1 N; 4 mL). The
cloudy white mixture was stirred at –78 °C for 15 min, allowed to
warm to r.t. over 15 min, diluted with aq HCl (1 N; 20 mL), and ex-
tracted with Et2O (4 × 40 mL). The combined organic phases were
washed with sat. aq NaHCO3 (40 mL) and dried over MgSO4. Removal
of the solvents by rotary evaporation, followed by distillation of the
residue, furnished 14 (686.4 mg, 80%) as a clear liquid; bp (Kugelrohr,
1.8 torr) 150 °C (Lit.11c 110–115 °C/1 torr).
HRMS (EI, 70 eV): m/z [M+] calcd for C11H12O2: 176.0837; found:
176.0837.
UV/VIS (MeCN): λmax (log ε) = 225 (4.02), 268 (sh, 3.10), 276 (3.19),
283 nm (3.12).
Anal. Calcd for C11H12O2: C, 74.98; H, 6.86. Found: C, 74.85; H, 6.95.
1-(4-Methoxyphenyl)-3-butyn-2-amine (17)
To a solution of 15 (1.11 g, 4.47 mmol) and Et3N (940 μL, 682 mg, 6.74
mmol) in CH2Cl2 (20 mL) at –10 °C was added by syringe MsCl (380
μL, 562 mg, 4.91 mmol) and the cloudy, light yellow mixture allowed
to stir for 1 h at –10 °C, then 30 min at r.t. It was then washed with
H2O (20 mL), aq HCl (2 N; 20 mL), sat. aq NaHCO3 (20 mL), and sat. aq
NaCl (20 mL), before it was dried over MgSO4. Removal of the solvents
by rotary evaporation provided 1-(4-methoxyphenyl)-4-(trimethylsi-
lyl)-3-butyn-2-yl methanesulfonate (1.179 g, 81%), as a yellow-orange
liquid, which was used as such in the next step. As attempted distilla-
tion resulted in decomposition, an analytical sample was prepared by
silica gel chromatography, eluting with EtOAc–hexane (1:1), to fur-
nish a clear oil.
1-(4-Methoxyphenyl)-4-(trimethylsilyl)-3-butyn-2-ol (15)
Using a modification of Zweifel’s12 procedure, (trimethylsilyl)ethynyl-
lithium was generated by injecting MeLi–LiBr in Et2O (1.5 M; 2.83 mL,
4.25 mmol) into a stirred solution of 8 (915 μL, 724 mg, 4.25 mmol) in
THF (5 mL) at 0 °C. The mixture was stirred for 30 min at 0 °C, then 30
min at r.t., then cooled to –78 °C, whereupon a solution of 14 (532
mg, 3.54 mmol) in THF (5 mL) was added slowly by syringe. Warming
to r.t. over 7 h was followed by quenching with H2O (0.5 mL). After
stirring for 10 min, the volatiles were removed by rotary evaporation,
and the residue was partitioned between Et2O (20 mL) and aq HCl (2
N; 40 mL). The layers were separated, and the aqueous phase was ex-
tracted with Et2O (3 × 20 mL). The combined organic phases were
washed with sat. aq NaHCO3 (40 mL) and dried over Na2SO4. The sol-
vent was removed by rotary evaporation and the remaining light yel-
low oil distilled to provide 15 (701.4 mg, 80%) as a clear viscous liq-
uid; bp (Kugelrohr, 0.2 torr) 230 °C.
IR (film): 2966, 2942, 2840, 2182, 1616, 1516, 1367, 1304, 1251,
1178, 1036, 928, 849 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.17 (d, J = 8.6 Hz, 2 H), 6.83 (d, J = 8.7
Hz, 2 H), 5.21 (t, J = 6.6 Hz, 1 H), 3.78 (s, 3 H), 3.09 (ABXm, 2 H), 2.97
(s, 3 H), 0.15 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 158.7, 130.8, 126.5, 113.6, 99.9, 95.1,
72.5, 55.0, 40.9, 38.8, –0.62.
MS (EI, 70 eV): m/z (%) = 326 ([M+], 26), 230 (71), 215 (75), 185 (63),
153 (60), 141 (50), 121 (100), 107 (45), 91 (51), 78 (57), 73 (89), 59
(58).
IR (film): 3450 (br), 2955, 2925, 2834, 2172, 1613, 1514, 1301, 1243,
1040, 844, 759 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

N
T. Aechtner et al.
Paper
Synthesis
HRMS (EI, 70 eV): m/z [M+] calcd for C15H22O4SSi: 326.1008; found:
MS (EI, 70 eV): m/z (%) = 175 ([M+], 14), 160 (10), 144 (21), 121 (89),
326.1003.
91 (26), 78 (35), 77 (37), 54 (100).
UV/VIS (MeCN): λmax (log ε) = 227 (4.04), 275 (3.18), 282 nm (3.12).
HRMS (EI, 70 eV): m/z [M+] calcd for C11H13NO: 175.0997; found:
175.0995.
Anal. Calcd for C15H22O4SSi: C, 55.18; H, 6.79. Found: C, 55.63; H, 6.81.
UV/VIS (MeCN): λmax (log ε) = 226 (3.99), 276 (3.20), 283 nm (3.14).
A suspension of the preceding 1-(4-methoxyphenyl)-4-(trimethylsi-
lyl)-3-butyn-2-yl methanesulfonate (1.282 g, 3.93 mmol) and NaN3
(1.28 g, 19.6 mmol) in DMF (20 mL) was stirred at r.t. for 20 h. The
cloudy yellow mixture was partitioned between Et2O (150 mL) and
H2O (50 mL). The organic layer was washed with H2O (3 × 50 mL) and
the combined aqueous phases were extracted with Et2O (50 mL). The
organic phases were combined, dried over Na2SO4, and the solvents
removed by rotary evaporation to provide 3-azido-4-(4-methoxyphe-
nyl)-1-(trimethylsilyl)-1-butyne (965.8 mg, 90%), as a light yellow oil,
which was converted as such in the next step. An analytical sample
was prepared by silica gel chromatography, eluting with EtOAc–hex-
ane (1:1), to render the product as a clear liquid.
(7-Methoxybenzo[b]furan-4-yl)acetaldehyde (18) from 12 via
DIBAL-H Reduction of Its Methyl Ester
Concd H2SO4 (3.0 mL) in MeOH (120 mL) was added to a stirred boil-
ing solution of acid 12 (7.39 g, 35.8 mmol). After stirring at reflux for
9 h, the dark red-brown mixture was cooled and poured into a sepa-
ratory funnel containing H2O (250 mL). The layers were separated, the
aqueous phase extracted with CH2Cl2 (5 × 100 mL), the combined or-
ganic phases dried over MgSO4, and the solvents removed under re-
duced pressure to give methyl (7-methoxybenzo[b]furan-4-yl)acetate
(7.51 g, 95%) as a cranberry red oil, the bulk of which was carried on
to the next step without further purification. An analytical sample
was obtained by silica gel chromatography, eluting with EtOAc–hex-
anes (3:1), followed by distillation to afford a clear yellow liquid; bp
(Kugelrohr, 0.3 torr) 125 °C.
IR (film): 2964, 2176, 2111, 1613, 1514, 1247, 1176, 1036, 842 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.15 (d, J = 8.7 Hz, 2 H), 6.83 (d, J = 8.7
Hz, 2 H), 4.18 (t, J = 6.8 Hz, 1 H), 3.78 (s, 3 H), 2.89 (ABXm, 2 H), 0.17
(s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 158.6, 130.6, 128.1, 113.6, 100.1, 93.1,
55.2, 54.8, 40.7, –0.19.
MS (EI, 70 eV): m/z (%) = 273 ([M+], 1), 245 (14), 173 (21), 146 (30),
121 (100), 73 (81).
HRMS (EI, 70 eV): m/z [M+] calcd for C14H19N3OSi: 273.1297; found:
273.1300.
IR (film): 2956, 2843, 1725, 1627, 1499, 1344, 1281, 1191, 1159,
1133, 1090, 961, 875, 786, 732 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 2.1 Hz, 1 H), 7.04 (dt, J = 8.0,
0.6 Hz, 1 H), 6.81 (d, J = 2.1 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 3.99 (s, 3
H), 3.77 (br s, 2 H), 3.67 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.4, 144.6, 144.5, 143.7, 128.5,
123.8, 118.7, 106.0, 105.3, 55.5, 51.5, 37.9.
UV/VIS (MeCN): λmax (log ε) = 227 (4.07), 276 (3.23), 282 nm (3.17).
MS (EI, 70 eV): m/z (%) = 220 ([M+], 71), 162 (27), 161 (100), 146 (14),
118 (19), 90 (9), 89 (11).
Anal. Calcd for C14H19N3OSi: C, 61.50; H, 7.00; N, 15.37. Found: C,
62.01; H, 7.13; N, 15.75.
UV/VIS (MeCN): λmax (log ε) = 240 (sh, 3.90), 247 (4.03), 254 (4.01),
Following the method of Micetich,75 to the above 3-azido-4-(4-me-
thoxyphenyl)-1-(trimethylsilyl)-1-butyne (150 mg, 0.55 mmol) in
MeOH (5 mL) was added solid SnCl2·2H2O (187 mg, 0.83 mmol) and
the resulting light yellow solution allowed to stir at r.t. for 22 h. The
solvent was removed by rotary evaporation and the yellow sludge di-
luted with aq NaOH (1 N; 50 mL) and extracted with Et2O (4 × 20 mL).
The combined organic phases were concentrated under reduced pres-
sure to supply crude 1-(4-methoxyphenyl)-4-(trimethylsilyl)-3-bu-
tyn-2-amine (136 mg, 100%) as an orange-yellow liquid.
279 (3.30), 288 nm (3.21).
Anal. Calcd for C12H12O4: C, 65.45; H, 5.49. Found: C, 65.15; H, 5.34.
Into methyl (7-methoxybenzo[b]furan-4-yl)acetate (7.26 g, 33.0
mmol) (from above) in PhMe (150 mL) at –78 °C was injected DIBAL-
H in CH2Cl2 (1.0 M; 34.6 mL, 34.6 mmol). After stirring at –78 °C for 5
h, the reaction mixture was quenched with aq HCl (1 N; 23.4 mL),
stirred at –78 °C for 10 min, and warmed to r.t. The muddy-brown
mixture was poured into a separatory funnel containing Et2O (200
mL) and aq H3PO4 (1 N; 500 mL). The layers were separated and the
aqueous part extracted with Et2O (3 × 150 mL). The combined organic
phases were washed with sat. aq NaHCO3 (200 mL) and dried over
Na2SO4. The solvents were removed under reduced pressure, followed
by silica gel chromatography, eluting with EtOAc–cyclohexane (3:1),
to sequester 18 (5.70 g, 91%), as a colorless liquid; bp (Kugelrohr, 0.15
torr) 120 °C.
1H NMR (300 MHz, CDCl3): δ = 7.17 (d, J = 8.6 Hz, 2 H), 6.82 (d, J = 8.6
Hz, 2 H), 3.77 (s, 3 H), 3.73 (t, J = 6.6 Hz, 1 H), 2.86 (dd, J = 13.5, 6.4 Hz,
1 H), 2.78 (dd, J = 13.5, 6.4 Hz, 1 H), 1.63 (br s, 2 H), 0.13 (s, 9 H).
Crude
1-(4-methoxyphenyl)-4-(trimethylsilyl)-3-butyn-2-amine
(136 mg, 0.55 mmol) from above was dissolved in EtOH (96.8 μL, 76.3
mg, 1.66 mmol) and THF (5 mL) and subjected to TBAF in THF (1.0 M;
660 μL, 0.660 mmol). The mixture was stirred at r.t. for 1 h and the
clear orange solution diluted with aq NaOH (1 N; 50 mL) and extract-
ed with Et2O (5 × 20 mL). The combined organic phases were dried
over Na2SO4 and the volatiles removed by rotary evaporation to leave
an orange oil. Distillation delivered 17 (75 mg, 78%) as a clear liquid;
bp (Kugelrohr, 0.3 torr) 210 °C.
IR (film): 2952, 2841, 2724, 1728, 1629, 1503, 1410, 1345, 1281,
1204, 1191, 1159, 1133, 1092, 961, 877, 792, 737 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 9.74 (t, J = 2.5 Hz, 1 H), 7.66 (d, J = 2.2
Hz, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.80 (d, J = 8.0 Hz, 1 H), 6.73 (d, J = 2.2
Hz, 1 H), 4.02 (s, 3 H), 3.83 (d, J = 2.5 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 198.7, 145.1, 144.9, 144.0, 128.9,
124.5, 116.4, 106.4, 105.0, 55.8, 47.4.
IR (film): 3371, 3286, 2954, 2914, 2836, 2182, 1610, 1582, 1511,
1298, 1251, 1176, 1031, 819, 642 cm–1
.
MS (EI, 70 eV): m/z (%) = 190 ([M+], 58), 162 (28), 161 (100), 146 (20),
118 (18), 90 (11), 89 (14).
1H NMR (300 MHz, CDCl3): δ = 7.17 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.7
Hz, 2 H), 3.78 (s, 3 H), 3.75 (td, J = 6.6, 2.2 Hz, 1 H), 2.89 (dd, J = 13.5,
6.4 Hz, 1 H), 2.80 (dd, J = 13.5, 6.4 Hz, 1 H), 2.29 (d, J = 2.2 Hz, 1 H),
1.58 (br s, 2 H).
UV/VIS (MeCN): λmax (log ε) = 240 (sh, 3.94), 248 (4.05), 255 (4.04),
280 (3.32), 289 (3.27), 303 nm (sh, 2.78).
13C NMR (75 MHz, CDCl3): δ = 158.3, 130.5, 129.2, 113.7, 86.8, 71.2,
Anal. Calcd for C11H10O3: C, 69.46; H, 5.30. Found: C, 69.20; H, 5.50.
55.1, 44.7, 43.0.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

O
T. Aechtner et al.
Paper
Synthesis
(7-Methoxybenzo[b]furan-4-yl)acetaldehyde (18) from 12 via
Et3SiH Reduction of Its S-Ethyl Ester14
1-(7-Methoxybenzo[b]furan-4-yl)-3-butyn-2-ol (20)
Benzyltrimethylammonium fluoride (155 mg, 0.92 mmol) in THF (5
mL) was added to a stirred solution of 19 (211 mg, 0.73 mmol) in THF
(5 mL) at r.t. After 1 h, the clear yellow reaction mixture was poured
into a separatory funnel containing H2O (25 mL) and Et2O (25 mL).
The layers were separated, and the aqueous layer was extracted with
Et2O (2 × 15 mL). The combined organic phases were washed with aq
NaHCO3 (10%; 20 mL) and dried over Na2SO4. Removal of the solvent
under reduced pressure and silica gel chromatography, eluting with
CH2Cl2–Et2O (7:1), afforded 20 (150 mg, 95%) as a clear viscous oil; bp
(Kugelrohr, 0.1 torr) 175 °C.
(7-Methoxybenzo[b]furan-4-yl)acetic acid (12) (3.96 g, 19.2 mmol)
and DMAP (235 mg, 1.92 mmol) in anhydrous CH2Cl2 (200 mL) were
admixed with EtSH (4.3 mL, 3.71 g, 59.6 mmol), the mixture was
cooled to 0 °C, and DCC (4.16 g, 20.2 mmol) was added. After stirring
at 0 °C for 1 h and r.t. for 2 h, the resulting suspension was filtered,
the solvent removed by rotary evaporation, and the residue chroma-
tographed on silica gel, eluting with CH2Cl2–PE (1:1), to isolate S-ethyl
(7-methoxybenzo[b]furan-4-yl)ethanethioate (4.78 g, 99%) as a clear
oil.
IR (film): 3000, 2960, 2930, 2840, 1675, 1625, 1550, 1500, 1450,
IR (film): 3400 (br), 2951, 2840, 2116, 1628, 1503, 1409, 1281, 1167,
1420, 1343, 1280, 1165, 1140, 1090, 1050, 965, 870 cm–1
.
1092, 1051, 877, 679 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.63 (d, J = 2.2 Hz, 1 H), 7.05 (d, J = 8.1
Hz, 1 H), 6.82 (d, J = 2.2 Hz, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 4.00 (s, 3 H),
3.95 (s, 2 H), 2.83 (q, J = 7.4 Hz, 2 H), 1.97 (t, J = 7.4 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 197.9, 145.44, 145.37, 144.3, 129.3,
125.1, 119.0, 106.6, 106.0, 56.4, 48.1, 24.0, 14.9.
1H NMR (300 MHz, CDCl3): δ = 7.61 (d, J = 2.2 Hz, 1 H), 7.06 (d, J = 8.1
Hz, 1 H), 6.84 (d, J = 2.2 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 4.63 (td, J =
6.4, 2.1 Hz, 1 H), 3.99 (s, 3 H), 3.18 (ABXm, 2 H), 2.45 (d, J = 2.1 Hz, 1
H), 1.76 (br s, 1 H).
13C NMR (75 MHz, CDCl3): δ = 144.7, 144.5, 143.9, 129.1, 124.4, 121.3,
106.1, 105.7, 84.3, 73.6, 62.6, 53.7, 40.7.
MS (EI, 70 eV): m/z (%) = 216 ([M+], 15), 162 (29), 161 (100), 146 (19),
118 (31), 89 (19).
MS (EI, 70 eV): m/z (%) = 250 ([M+], 22), 161 (100).
Anal. Calcd for C13H14O3S: C, 62.38; H, 5.64. Found: C, 62.37; H, 5.69.
S-Ethyl (7-methoxybenzo[b]furan-4-yl)ethanethioate (1.69 g, 6.75
mmol) (from above) in anhydrous deoxygenated CH2Cl2 was charged
with 5% Pd/C (460 mg). N2 was passed through the suspension for 5
min, Et3SiH (3.5 mL, 2.55 g, 21.9 mmol) added by syringe, and the
solution stirred at r.t. until the starting material was consumed (TLC,
30 min). The mixture was filtered through Celite, the volatiles were
removed under reduced pressure, and the residue was chromato-
graphed on silica gel, eluting with CH2Cl2, to afford 18 (1.125 g, 88%)
as a colorless liquid.
UV/VIS (MeCN): λmax (log ε) = 238 (sh, 3.92), 247 (4.10), 255 (4.07),
273 (sh, 3.22), 280 (3.30), 2.89 nm (3.22).
Anal. Calcd for C13H12O3: C, 72.21; H, 5.59. Found: C, 71.90; H, 5.91.
1-(7-Methoxybenzo[b]furan-4-yl)-2-(trimethylsilyloxy)-3-butyne
(21)
TMSCl (290 μL, 248 mg, 2.28 mmol) and HMDS (485 μL, 363 mg, 2.25
mmol) were added to a stirred solution of alcohol 20 (150 mg, 0.69
mmol) in PhMe (10 mL) at r.t. After stirring at reflux for 20 h, the reac-
tion mixture was cooled to r.t. and poured into a separatory funnel
containing Et2O (20 mL) and aq HCl (2 N; 20 mL). The layers were sep-
arated, and the aqueous layer was neutralized with solid NaHCO3 and
extracted with Et2O (2 × 10 mL). The combined organic phases were
dried (MgSO4), the volatiles evaporated, and the residue subjected to
silica gel chromatography, eluting with CH2Cl2, resulting in 21 (165
mg, 82%) as a clear liquid; bp (Kugelrohr, 0.2 torr) 190 °C.
1-(7-Methoxybenzo[b]furan-4-yl)-4-(trimethylsilyl)-3-butyn-2-ol
(19)
(Trimethylsilyl)ethynyllithium was generated by slow addition of
BuLi in hexanes (2.3 M; 7.72 mL, 17.8 mmol) to stirred (trimethylsi-
lyl)acetylene (2.75 mL, 1.90 g, 19.3 mmol) in anhydrous THF (40 mL)
at –78 °C. The cooling bath was removed, stirring continued at r.t. for
1 h, the mixture cooled back to –78 °C, and a solution of 18 (1.125 g,
5.91 mmol) in THF (50 mL) added dropwise via cannula over the
course of 5 h. After warming to r.t., the solution was treated with sat.
aq NH4Cl–H2O (100 mL, 1:1), stirred for 3 min, the layers separated,
the aqueous phase extracted with Et2O (3 × 50 mL), and the combined
organic phases were washed with sat. aq NaCl, dried over Na2SO4, and
concentrated under reduced pressure. Silica gel chromatography,
eluting with CH2Cl2, supplied 19 (1.35 g, 79%) as a clear oil.
IR (film): 3296, 2954, 2840, 2112, 1627, 1594, 1547, 1502, 1409,
1347, 1281, 1252, 1078, 843, 735, 638 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.59 (d, J = 2.0 Hz, 1 H), 7.00 (d, J = 8.1
Hz, 1 H), 6.81 (d, J = 2.1 Hz, 1 H), 6.72 (d, J = 8.1 Hz, 1 H), 4.49 (td, J =
6.7, 2.1 Hz, 1 H), 3.98 (s, 3 H), 3.13 (apparent d, J = 6.7 Hz, 2 H), 2.39
(d, J = 2.1 Hz, 1 H), –0.03 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 144.4, 144.2, 143.7, 129.2, 124.2, 122.4,
105.94, 105.93, 84.9, 72.8, 63.3, 55.8, 41.8, –0.35.
IR (film): 3450 (br), 2980, 2860, 2190, 1640, 1605, 1555, 1510, 1415,
1290, 1260, 1060, 850, 760, 740 cm–1
.
MS (EI, 70 eV): m/z (%) = 288 ([M+], 20), 273 (9), 257 (11), 199 (11),
162 (35), 161 (100).
1H NMR (500 MHz, CDCl3): δ = 7.61 (d, J = 2.1 Hz, 1 H), 7.05 (d, J = 8.1
Hz, 1 H), 6.86 (d, J = 2.2 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 4.61 (dd, J =
12.2, 6.1 Hz, 1 H), 4.00 (s, 3 H), 3.20 (dd, J = 13.8, 5.8 Hz, 1 H), 3.15 (dd,
J = 13.7, 6.8 Hz, 1 H), 1.87 (d, J = 5.0 Hz, 1 H), 0.12 (s, 9 H).
UV/VIS (MeCN): λmax (log ε) = 238 (sh, 3.93), 247 (4.12), 255 (4.09),
272 (sh, 3.25), 2.80 (3.32), 2.89 nm (3.25).
13C NMR (75 MHz, CDCl3): δ = 144.5, 144.4, 143.9, 129.2, 124.5, 121.5,
Anal. Calcd for C16H20O3Si: C, 66.63; H, 6.99. Found: C, 67.02; H, 7.21.
106.10, 106.06, 105.95, 90.1, 63.2, 56.0, 40.7, –0.33.
MS (EI, 70 eV): m/z (%) = 288 ([M+], 12), 273 (3), 258 (4), 162 (42), 161
(100), 146 (12), 118, (16), 90 (7), 89 (7), 73 (9).
1-(7-Methoxybenzo[b]furan-4-yl)-4-(trimethylsilyl)-3-butyn-2-
amine (22)
MsCl (1.23 mL, 1.82 g, 15.9 mmol) was added to a stirred solution of
alcohol 19 (1.28 g, 4.44 mmol) in py (25 mL) at –15 °C. After stirring at
r.t. for 1 h, the mixture was diluted with CH2Cl2 (50 mL), washed se-
quentially with aq HCl (10%; 3 × 50 mL), sat. aq NaHCO3 (2 × 50 mL),
and sat. aq NaCl (50 mL), and then dried over Na2SO4. Removal of the
UV/VIS (MeCN): λmax (log ε) = 239 (sh, 3.92), 248 (4.09), 255 (4.06),
272 (sh, 3.20), 280 (3.20), 289 nm (3.20).
Anal. Calcd for C16H20O3Si: C, 66.63; H, 6.99. Found: C, 66.49; H, 6.99.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

P
T. Aechtner et al.
Paper
Synthesis
solvents under reduced pressure left 1-(7-methoxybenzo[b]furan-4-
yl)-4-(trimethylsilyl)-3-butyn-2-yl methanesulfonate (1.61 g, 99%) as
a clear yellow oil that was carried on to the next step without further
purification.
MS (EI, 70 eV): m/z (%) = 287 ([M+], 10), 161 (62), 126 (100).
HRMS (EI, 70 eV): m/z [M+] calcd for C16H21NO2Si: 287.1342; found:
287.1343.
UV/VIS (MeCN): λmax (log ε) = 238 (sh, 3.89), 248 (3.97), 256 (3.94),
272 (sh, 3.25), 280 (3.27), 2.90 nm (3.16).
IR (film): 2960, 2860, 2180, 1350, 1280, 1250, 1170, 1105, 970, 900,
850, 840 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.62 (d, J = 2.1 Hz, 1 H), 7.06 (d, J = 8.1
Hz, 1 H), 6.85 (d, J = 2.2 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 5.32 (t, J =
6.71 Hz, 1 H), 3.99 (s, 3 H), 3.36 (dd, J = 14.0, 6.6 Hz, 1 H), 3.31 (dd, J =
14.0, 6.9 Hz, 1 H), 2.93 (s, 3 H), 0.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 144.92, 144.87, 143.9, 129.2, 124.9,
119.5, 106.1, 105.7, 99.9, 95.2, 72.1, 56.0, 38.93, 38.86, –0.57.
1-(7-Methoxybenzo[b]furan-4-yl)-3-butyn-2-amine (23)
Benzyltrimethylammonium fluoride (359 mg, 2.12 mmol) was added
to a stirred solution of 22 (488 mg, 1.70 mmol) in THF (15 mL) at r.t.
After 1 h, the reaction mixture was diluted with Et2O (15 mL), washed
with sat. aq NaHCO3, and dried over MgSO4. Removal of the solvent
under reduced pressure, followed by chromatography on neutral alu-
mina, grade III, eluting with CH2Cl2, gave amine 23 (360 mg, 98%) as a
clear oil.
MS (EI, 70 eV): m/z (%) = 366 ([M+], 3), 270 (12), 255 (9), 174 (13), 161
(100).
HRMS (EI, 70 eV): m/z [M+] calcd for C17H22O5SSi: 366.0957; found:
366.0966.
IR (film): 3380, 2970, 2860, 2120, 1500, 1380, 1280, 1100, 960, 870
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.61 (d, J = 2.1 Hz, 1 H), 7.05 (d, J = 8.0
Hz, 1 H), 6.84 (d, J = 2.0 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 3.99 (s, 3 H),
3.88 (td, J = 6.6, 2.0 Hz, 1 H), 3.14 (dd, J = 13.5, 6.5 Hz, 1 H), 3.03 (dd,
J = 13.5, 7.2 Hz, 1 H), 2.27 (d, J = 2.1 Hz, 1 H), 1.45 (br s, 2 H).
13C NMR (75 MHz, CDCl3): δ = 144.7, 144.4, 144.0, 128.9, 124.2, 122.4,
106.1, 105.7, 87.0, 71.1, 56.0, 44.3, 41.0.
MS (EI, 70 eV): m/z (%) = 215 ([M+], 36), 200 (17), 184 (20), 161 (100),
146 (27), 118 (33).
HRMS (EI, 70 eV): m/z [M+] calcd for C13H13NO2: 215.0946; found:
215.0941.
NaN3 (941 mg, 14.5 mmol) was added to a yellow, stirred suspension
of the preceding 1-(7-methoxybenzo[b]furan-4-yl)-4-(trimethylsi-
lyl)-3-butyn-2-yl methanesulfonate (1.06 g, 2.89 mmol) in DMF (15
mL) at r.t. After 24 h, the reaction mixture was poured into a separato-
ry funnel containing Et2O (30 mL) and H2O (25 mL). The layers were
separated and the organic phase was washed with H2O (3 × 25 mL);
the combined aqueous layers were extracted with Et2O (2 × 25 mL)
and the combined organic phases dried over Na2SO4. Removal of the
volatiles followed by silica gel chromatography, eluting with pen-
tane–Et2O (9:1), supplied 3-azido-4-(7-methoxybenzo[b]furan-4-yl)-
1-(trimethylsilyl)-1-butyne (855 mg, 94%) as a clear yellow oil.
The hydrochloride of 23 was prepared as follows: AcCl (1 mL, 1.1 g, 14
mmol) in EtOAc (5 mL) was treated with MeOH (0.6 mL, 0.5 g, 15
mmol) at 0 °C and the mixture warmed to r.t., followed by stirring for
15 min. A portion of this solution (1.5 mL, ~3 mmol) was then added
to 23 (40 mg, 0.19 mmol), resulting in a colorless precipitate, which
was collected by filtration, washed with EtOAc (1 mL), then Et2O (1
mL), and recrystallized from EtOAc to generate a colorless crystalline
solid; mp 292–295 °C.
IR (film): 2960, 2100, 1500, 1280, 1190, 900, 840 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.62 (d, J = 2.0 Hz, 1 H), 7.03 (d, J = 8.0
Hz, 1 H), 6.83 (dd, J = 2.0, 0.5 Hz, 1 H), 6.75 (d, J = 8.0 Hz, 1 H), 4.30 (t,
J = 6.9 Hz, 1 H), 3.99 (s, 3 H), 3.16 (dd, J = 13.8, 6.8 Hz, 1 H), 3.11 (dd,
J = 13.8, 6.8 Hz, 1 H), 0.14 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 144.8, 144.7, 143.9, 129.1, 124.5, 121.2,
106.2, 105.7, 100.1, 93.2, 56.1, 54.4, 38.6, –0.22.
MS (EI, 70 eV): m/z (%) = 313 ([M+], 0.4), 285 (2), 270 (5), 161 (66), 97
(16), 85 (65), 73 (100).
Anal. Calcd for C13H14ClNO2: C, 62.03; H, 5.61; N, 5.56. Found: C,
61.78; H, 5.74; N, 5.74.
UV/VIS (MeCN): λmax (log ε) = 238 (sh, 3.41), 249 (3.54), 257 (3.53),
273 (sh, 2.65), 2.80 (2.66), 2.89 nm (2.58).
1-(7-Methoxybenzo[b]furan-4-yl)-N,N-dimethyl-3-butyn-2-amine
(24)76
Anal. Calcd for C16H19N3O2Si: C, 61.31; H, 6.11; N, 13.41. Found: C,
61.12; H, 6.13; N, 13.31.
Aq formaldehyde (345 μL of a 37% w/w solution, 128 mg, 4.25 mmol)
and NaCNBH3 (93 mg, 1.48 mmol) were added to stirred amine 23
(198 mg, 0.92 mmol) in MeCN (3 mL) at r.t. After 5 min, AcOH was
dripped in until the solution tested neutral on wet pH paper. Stirring
was continued for 55 min and AcOH added periodically to maintain a
pH of 7. The volatiles were removed under reduced pressure and aq
KOH (2 N; 4 mL) was added. The aqueous phase was extracted with
Et2O (3 × 15 mL), and the combined organic phases were washed with
KOH (0.5 N) and extracted with aq HCl (10%; 3 × 5 mL). The aqueous
layers were turned alkaline by treatment with solid KOH and extract-
ed with CH2Cl2 (4 × 15 mL). Evaporation of the solvent and drying un-
der high vacuum gave dimethylamine 24 (118 mg, 53%) as a colorless
crystalline solid; mp 94–95 °C.
SnCl2·2H2O (1.81 g, 8.0 mmol)75 was added to a stirred suspension of
the above 3-azido-4-(7-methoxybenzo[b]furan-4-yl)-1-(trimethylsi-
lyl)-1-butyne (1.25 g, 4.0 mmol) in MeOH (75 mL) at r.t. After 20 h,
the solvent was removed under reduced pressure and the residue dis-
solved in CH2Cl2 (30 mL). The solution was washed with aq NaOH
(10%; 2 × 25 mL) and the aqueous layer extracted with CH2Cl2 (3 × 35
mL). The combined organic phases were washed with sat. aq NaCl,
dried over Na2SO4, concentrated, and subjected to silica gel chroma-
tography, eluting with Et2O–acetone (1:1), to provide 22 (1.15 g,
100%) as a clear yellow oil.
IR (film): 3480, 3400, 3000, 2960, 2180, 1630, 1495, 1460, 1400,
1280, 1163, 1072, 903, 873, 835 cm–1
.
IR (KBr): 3105, 2940, 2860, 2780, 1440, 1405, 1337, 1283, 1160, 1130,
1H NMR (500 MHz, CDCl3): δ = 7.60 (d, J = 2.1 Hz, 1 H), 7.04 (d, J = 8.1
Hz, 1 H), 6.86 (d, J = 2.1 Hz, 1 H), 6.74 (d, J = 8.1 Hz, 1 H), 3.99 (s, 3 H),
3.87 (t, J = 6.6 Hz, 1 H), 3.13 (dd, J = 13.5, 6.4 Hz, 1 H), 3.03 (dd, J =
13.5, 7.0 Hz, 1 H), 1.43 (br s, 2 H), 0.11 (s, 9 H).
1085, 1038, 955, 733 cm–1
.
1H NMR (300 MHz, CD2Cl2): δ = 7.64 (d, J = 2.2 Hz, 1 H), 7.06 (d, J = 8.1
Hz, 1 H), 6.86 (d, J = 2.2 Hz, 1 H), 6.76 (d, J = 8.1 Hz, 1 H), 3.97 (s, 3 H),
3.67 (m, 1 H), 3.08 (m, 2 H), 2.31 (d, J = 2.2 Hz, 1 H), 2.30 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 144.5, 144.4, 143.9, 129.0, 124.2,
122.7, 109.2, 106.2, 105.9, 87.0, 55.9, 45.1, 40.9, –0.23.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

Q
T. Aechtner et al.
Paper
Synthesis
13C NMR (75 MHz, CD2Cl2): δ = 145.0, 144.6, 144.3, 129.0, 124.1,
123.9, 106.4, 105.8, 80.7, 74.3, 59.0, 56.2, 41.3, 37.5.
Anal. Calcd for C16H17NO3: C, 70.83; H, 6.32; N, 5.16. Found: C, 70.93;
H, 6.11; N, 5.03.
MS (FAB, 70 eV): m/z (%) = 244 ([M+ + H], 100).
HRMS (EI, 70 eV): m/z [M+] calcd for C15H17NO2: 243.1259; found:
Cobalt-Mediated Cyclizations; General Procedures
Method A: Under Ar, the butynylbenzofuran in 8–Et2O (1:1) and Cp-
243.1259.
77
Co(C2H4)2 in Et2O (5 mL) were simultaneously added over a period
of 30 min (dual syringe pump) to stirred Et2O (10 mL) in a Schlenk
flask at 0 °C. Subsequently, the cooling bath was removed and stirring
maintained until the benzofuran starting material had been con-
sumed (~1 h), as determined by TLC. The solvent was evaporated by
vacuum transfer, which was followed by rapid silica gel chromatogra-
phy under N2 pressure, eluting with Ar-deoxygenated solvents.
N-[1-(7-Methoxybenzo[b]furan-4-yl)-4-(trimethylsilyl)-3-butyn-
2-yl]acetamide (25)
Py (600 μL, 590 mg, 7.45 mmol) and Ac2O (700 μL, 756 mg, 7.40
mmol) were added to a stirred solution of 22 (1.06 g, 3.69 mmol) in
CH2Cl2 (100 mL) at 0 °C. After stirring at r.t. for 45 min, the mixture
was washed sequentially with aq HCl (10%; 25 mL), aq NaOH (10%; 25
mL), and sat. aq NaCl (25 mL). The organic phase was dried over Na2-
SO4 and the solvent removed under reduced pressure, followed by sil-
ica gel chromatography, eluting with EtOAc–PE (1:2.5), to render
monoacetylamine 25 (1.09 g, 90%) as a clear oil.
Method B: Under Ar, CpCo(C2H4)2 in 8 (5 mL) was added over a period
of 5 min to stirred butynylbenzofuran in 8–Et2O (1:1) at r.t. Stirring
was continued until the benzofuran starting material had been con-
sumed. Isolation of the complex was accomplished as described in
Method A.
IR (film): 3445, 3000, 2960, 2180, 1665, 1630, 1495, 1410, 1370,
1340, 1280, 1250, 1167, 1140, 1095, 1050, 970, 880, 845 cm–1
.
exo-(η5-Cyclopentadienyl)[(5,6,7,7a-η4)(4aR*,8R*,9cS*)-4a,8,9,9c-
tetrahydro-3-methoxy-5,6-bis(trimethylsilyl)phenanthro[4,5-
bcd]furan-8-ol]cobalt (27)
1H NMR (400 MHz, CDCl3): δ = 7.60 (d, J = 2.1 Hz, 1 H), 7.03 (d, J = 8.1
Hz, 1 H), 6.92 (d, J = 2.1 Hz, 1 H), 6.73 (d, J = 8.1 Hz, 1 H), 5.65 (br d, J =
7.9 Hz, 1 H), 5.02 (ddd, J = 8.2, 7.9, 4.2 Hz, 1 H), 3.99 (s, 3 H), 3.13
(ABXm, 2 H), 1.93 (s, 3 H), 0.08 (s, 9 H).
13C NMR (75 MHz, CD2Cl2): δ = 168.9, 144.5, 144.4, 143.8, 129.4,
124.7, 121.5, 106.0, 105.9, 89.0, 72.5, 56.0, 43.4, 38.1, 23.1, –0.32.
Benzofuran 20 (569 mg, 2.63 mmol), 8 (2.98 mL, 2.36 g, 13.8 mmol),
and CpCo(C2H4)2 (521 mg, 2.89 mmol) were subjected to Method A.
Silica gel chromatography, eluting with EtOAc–hexane (1:1), provided
complex 27 (843 mg, 63%) as a red-orange, thermally sensitive solid;
mp (sealed tube, Ar) 60 °C (dec).
MS (EI, 70 eV): m/z (%) = 329 ([M+], 5), 314 (3), 270 (52), 161 (100),
126 (33).
IR (KBr): 3400 (br), 2957, 2896, 2837, 1641, 1600, 1502, 1451, 1248,
1151, 1007, 996, 942, 845, 805, 754, 681, 624 cm–1
.
HRMS (EI, 70 eV): m/z [M+ + H] calcd for C18H24NO3Si: 330.1525;
1H NMR (500 MHz, C6D6): δ = 6.74 (d, J = 8.0 Hz, 1 H), 6.59 (d, J = 8.0
Hz, 1 H), 5.11 (s, 1 H), 4.26 (s, 5 H), 3.92 (d, J = 7.2 Hz, 1 H), 3.77 (ddd,
J = 8.1, 4.4, 2.7 Hz, 1 H), 3.64 (s, 3 H), 3.13 (dd, J = 17.1, 7.9 Hz, 1 H),
2.75 (dd, J = 17.1, 2.8 Hz, 1 H), 2.56 (d, J = 7.0 Hz, 1 H), 1.28 (d, J = 4.4
Hz, 1 H, exchanges with D2O), 0.46 (s, 9 H), 0.32 (s, 9 H).
13C NMR (100 MHz, CD2Cl2): δ = 146.3, 143.6, 135.7, 128.2, 119.4,
113.7, 91.4, 83.3, 82.7, 81.2, 76.9, 73.3, 63.0, 57.1, 40.6, 37.4, 3.07,
2.94.
MS (EI, 70 eV): m/z (%) = 510 ([M+], 0.4), 382 (52), 368 (31), 353 (28),
352 (39), 351 (32), 338 (30), 337 (30), 321 (23), 189 (35), 124 (11), 73
(100).
HRMS (EI, 70 eV): m/z [M+] calcd for C26H35CoO3Si2: 510.1457; found:
510.1466.
found: 330.1526.
N-[1-(7-Methoxybenzo[b]furan-4-yl)-3-butyn-2-yl]-N-methylac-
etamide (26)
Freshly powdered KOH (490 mg, 8.70 mmol), suspended in DMSO
(1.5 mL) at 0 °C, was stirred for 5 min and then treated with 25 (715
mg, 2.17 mmol) in DMSO (2 mL), followed by MeI (270 μL, 616 mg,
4.34 mmol), to generate a dark brown mixture. After stirring for 45
min at 0 °C, the color cleared, and the solution was poured into a sep-
aratory funnel containing H2O (100 mL) and CH2Cl2 (50 mL). The lay-
ers were separated, and the aqueous phase was extracted with CH2Cl2
(2 × 25 mL). The combined organic phases were washed with sat. aq
NaCl (50 mL) and dried over Na2SO4. Removal of the solvent under re-
duced pressure, followed by silica gel chromatography, eluting with
EtOAc–hexane (1:1), resulted in 26 (573 mg, 97%) as a colorless solid;
mp 78–79 °C.
UV/VIS (MeCN): λmax (log ε) = 283 (4.02), 316 (sh, 3.49), 356 nm (sh,
2.96).
IR (KBr): 3310, 3000, 2935, 1630, 1500, 1410, 1283, 1165, 1140, 1090,
exo-(η5-Cyclopentadienyl)[(1,2,3,9a-η4)(3aR*,9R*,9bS*)-3a,8,9,9b-
tetrahydro-5-methoxy-2,3-bis(trimethylsilyl)-9-(trimethylsily-
loxy)phenanthro[4,5-bcd]furan]cobalt (28)
1050, 965, 880 cm–1
.
1H NMR (500 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (4:1); δ
values for resolved signals of the minor rotamer in square brackets] =
7.60 [7.65] (d, J = 2.12 Hz, 1 H), 7.02 [6.90] (d, J = 8.1 Hz, 1 H), 6.99
[6.77] (d, J = 2.1 Hz, 1 H), 6.71 (d, J = 8.1 Hz, 1 H), 5.74 [4.67] (ddd, J =
8.2, 6.4, 2.4 Hz, 1 H), 3.95 (s, 3 H), 3.06 (m, 2 H), 2.96 [2.99] (s, 3 H),
2.26 [2.43] (d, J = 2.3 Hz, 1 H), 2.05 [1.60] (s, 3 H).
13C NMR (125 MHz, CDCl3, 20 °C): δ [mixture of two rotamers (4:1); δ
values for resolved signals (tentative) of the minor rotamer in square
brackets] = 170.0 [169.9], 144.8 [145.28], 144.5 [145.27], 143.9
[145.9], 128.9 [128.1], 124.0 [124.1], 121.6 [120.9], 105.9 [106.3],
105.6 [104.6], 81.2 [80.6], 73.8 [73.9], 55.9 [53.4], 46.9 [51.6], 36.7
[37.6], 31.8 [28.3], 22.0 [21.0].
Benzofuran 21 (800 mg, 2.78 mmol), 8 (5.0 mL, 3.95 g, 23.2 mmol),
and CpCo(C2H4)2 (549 mg, 3.05 mmol) were transformed according to
Method A. Silica gel chromatography, eluting with CH2Cl2–pentane
(1:3), led to complex 28 (860 mg, 53%) as a red-orange solid, crystal-
lized from pentane; mp (sealed tube, Ar) 133–135 °C (dec).
IR (KBr): 2950, 2900, 2830, 1595, 1490, 1440, 1245, 1180, 1148, 1087,
1060, 862, 805, 747 cm–1
.
1H NMR (300 MHz, C6D6): δ = 6.78 (d, J = 8.0 Hz, 1 H), 6.62 (d, J = 8.0
Hz, 1 H), 4.95 (br s, 1 H), 4.66 (s, 5 H), 3.92 (dd, J = 9.7, 5.6 Hz, 1 H),
3.80 (d, J = 7.2 Hz, 1 H), 3.66 (s, 3 H), 3.26 (dd, J = 17.3, 9.3 Hz, 1 H),
2.65 (dd, J = 17.1, 5.7 Hz, 1 H), 2.19 (d, J = 7.0 Hz, 1 H), 0.50 (s, 9 H),
0.36 (s, 9 H), 0.11 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 271 ([M+], 11), 198 (50), 161 (100), 118 (14),
68 (43).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

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T. Aechtner et al.
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Synthesis
13C NMR (75 MHz, C6D6): δ = 146.6, 143.8, 135.1, 128.4, 119.5, 115.0,
89.5, 80.9, 79.5, 78.4, 77.7, 72.4, 60.3, 56.9, 44.8, 38.9, 3.01, 2.98, 0.13.
MS (EI, 70 eV): m/z (%) = 582 ([M+], 48), 492 (44), 458 (100).
exo-(η5-Cyclopentadienyl){N-methyl-N-[(5,6,7,7a-η4)(4aR*,8R*,9cS*)-
4a,8,9,9c-tetrahydro-3-methoxy-5,6-bis(trimethylsilyl)phenan-
thro[4,5-bcd]furan-8-yl]acetamido}cobalt (31)
Benzofuran 26 (90.1 mg, 0.33 mmol), 8 (0.52 mL, 410 mg, 2.42 mmol),
and CpCo(C2H4)2 (66.2 mg, 0.37 mmol) were converted following
Method B. Silica gel chromatography, eluting with CH2Cl2–Et2O (4:1),
provided complex 31 (131 mg, 70%) as a red solid, crystallized from
pentane–THF (9:1); mp (sealed tube, Ar) 141 °C (dec).
HRMS (EI, 70 eV): m/z [M+] calcd for C29H43CoO3Si3: 582.1852; found:
582.1835.
exo-(η5-Cyclopentadienyl)[(5,6,7,7a-η4)(4aR*,8R*,9cS*)-4a,8,9,9c-
tetrahydro-3-methoxy-5,6-bis(trimethylsilyl)phenanthro[4,5-
bcd]furan-8-amine]cobalt (29)
IR (KBr): 2942, 2895, 2835, 1630, 1493, 1440, 1395, 1320, 1243, 1073,
990, 940, 830, 805 cm–1
.
Benzofuran 23 (468 mg, 2.17 mmol), 8 (3.60 mL, 2.85 g, 16.7 mmol),
and CpCo(C2H4)2 (414 mg, 2.30 mmol) were subjected to Method A.
Silica gel chromatography, eluting with Et2O–acetone (1:1), seques-
tered complex 29 (731 mg, 66%) as an orange-red solid, crystallized
from C6H6; mp (sealed tube, Ar) 145–147 °C.
1H NMR (400 MHz, C6D6): δ = 6.71 (d, J = 7.8 Hz, 1 H), 6.63 (d, J = 7.9
Hz, 1 H), 5.27 (t, J = 11 Hz, 1 H), 5.15 (s, 1 H), 4.52 (s, 5 H), 4.11 (d, J =
7.1 Hz, 1 H), 3.64 (s, 3 H), 2.89 (dd, J = 14, 8.2 Hz, 1 H), 2.41 (dd, J = 14,
9.2 Hz, 1 H), 2.29 (s, 3 H), 2.04 (br d, J = 7.0 Hz, 1 H), 1.78 (s, 3 H), 0.48
(s, 9 H), 0.33 (s, 9 H).
13C NMR [100 MHz (DEPT), C6D6]: δ = 170.0 (C), 146.8 (C), 144.5 (C),
135.5 (C), 127.6 (C), 119.2 (CH), 114.0 (CH), 91.5 (CH), 83.8 (CH), 82.5
(CH), 82.1 (C), 82.0 (CH), 74.2 (C), 61.0 (C), 56.7 (Me), 55.6 (Me), 44.6
(CH), 30.2 (CH2), 21.6 (Me), 3.25 (Me), 3.22 (Me).
MS (FAB, 70 eV): m/z (%) = 566 ([M+ + H], 79), 565 ([M+], 97), 368
(100).
HRMS (FAB, 70 eV): m/z [M+] calcd for C29H40CoNO3Si2: 565.1879;
found: 565.1886.
IR (KBr): 3480, 3400, 2940, 2890, 2830, 1490, 1275, 1235, 1145, 1085,
930, 825, 800 cm–1
.
1H NMR (400 MHz, C6D6): δ = 6.84 (d, J = 7.9 Hz, 1 H), 6.71 (d, J = 7.9
Hz, 1 H), 5.00 (s, 1 H), 4.43 (s, 5 H), 3.98 (d, J = 7.2 Hz, 1 H), 3.75 (dd, J =
8.4, 4.4 Hz, 1 H), 3.70 (s, 3 H), 3.05 (d, J = 7.0 Hz, 1 H), 3.01 (dd, J = 16.2,
8.4 Hz, 1 H), 2.73 (dd, J = 16.2, 4.1 Hz, 1 H), 1.82 (s, 2 H), 0.44 (s, 9 H),
0.27 (s, 9 H).
13C NMR (100 MHz, C6D6): δ = 147.1, 144.1, 136.5, 128.5, 118.9, 114.8,
90.9, 82.7, 81.3, 81.1, 79.3, 62.7, 61.4, 57.1, 42.8, 29.0, 3.24, 3.04.
MS (EI, 70 eV): m/z (%) = 509 ([M+], 6), 492 (4), 462 (3), 368 (45), 189
(65), 66 (100).
Anal. Calcd for C29H40CoNO3Si2: C, 61.57; H, 7.13; N, 2.48. Found: C,
61.27; H, 6.84; N, 2.87.
HRMS (EI, 70 eV): m/z [M+] calcd for C26H36CoNO2Si2: 509.1617;
found: 509.1619.
Thebaine Complex 33
To a suspension of thebaine (32) (75 mg, 0.24 mmol) in anhydrous
Et2O (10 mL) was added a solution of CpCo(C2H4)2 (237 mg, 1.32
mmol) in Et2O (5 mL) over a period of 2 h. After stirring under Ar for
48 h, the solvent was removed by vacuum transfer and the residue
chromatographed through basic alumina (activity II), eluting with
Et2O–DMF (99:1), to supply 33 (102 mg, 98%) as a red solid, crystal-
lized from C6H6 by slow evaporation of solvent; mp 163–165 °C.
UV/VIS (MeCN): λmax (log ε) = 254 (sh, 4.34), 284 (4.26), 312 nm (sh,
3.78).
exo-(η5-Cyclopentadienyl)[(5,6,7,7a-η4)(4aR*,8R*,9cS*)-4a,8,9,9c-
tetrahydro-3-methoxy-N,N-dimethyl-5,6-bis(trimethylsi-
lyl)phenanthro[4,5-bcd]furan-8-amine]cobalt (30)
Benzofuran 24 (58 mg, 0.24 mmol), 8 (5.0 mL, 3.95 g, 23.2 mmol), and
CpCo(C2H4)2 (45 mg, 0.25 mmol) were reacted according to Method B.
Silica gel chromatography, eluting with Et2O–acetone (1:1), gave com-
plex 30 (93 mg, 72%) as a bright red crystalline solid, crystallized
from hexane; mp (sealed tube, Ar) 93–95 °C.
IR (KBr): 2900, 2875, 1585, 1490, 1430, 1270, 1245, 1200, 1140 cm–1
.
1H NMR (400 MHz, C6D6): δ = 6.64 (d, J = 8 Hz, 1 H), 6.51 (d, J = 8 Hz, 1
H), 4.86 (d, J = 1.6 Hz, 1 H), 4.78 (s, 5 H), 4.67 (dd, J = 4.8, 1.6 Hz, 1 H),
3.93 (d, J = 4.8 Hz, 1 H), 3.52 (s, 3 H), 3.03 (s, 3 H), 2.49–2.21 (m, 5 H),
2.17 (d, J = 6.8 Hz, 1 H), 2.13 (s, 3 H), 1.57 (br d, J = 10.4 Hz, 1 H).
13C NMR [100 MHz (DEPT), C6D6]: δ = 145.2 (C), 143.2 (C), 138.0 (C),
119.8 (CH), 114.9 (CH), 109.7 (C), 108.3 (C), 91.3 (CH), 80.1 (CH), 68.0
(CH), 63.4 (CH), 62.9 (CH), 56.8 (Me), 54.5 (Me), 48.4 (C), 46.5 (CH2),
43.3 (Me), 38.5 (CH2), 26.3 (CH2) (one C obscured by solvent peaks).
IR (KBr): 2940, 2890, 2830, 2775, 1600, 1490, 1440, 1305, 1240, 1177,
1145, 1070, 1054, 1013, 987, 940, 825, 805, 750 cm–1
.
1H NMR (400 MHz, C6D6): δ = 6.79 (d, J = 7.8 Hz, 1 H), 6.70 (d, J = 7.8
Hz, 1 H), 5.63 (s, 1 H), 4.32 (s, 5 H), 4.00 (d, J = 7.1 Hz, 1 H), 3.69 (s, 3
H), 2.92 (t, J = 7.4 Hz, 1 H), 2.62 (app br d, J = 7.6 Hz, 2 H), 2.13 (s, 6 H),
2.07 (d, J = 7.0 Hz, 1 H), 0.49 (s, 9 H), 0.37 (s, 9 H).
13C NMR [100 MHz (DEPT), C6D6]: δ = 146.9 (C), 144.1 (C), 136.0 (C),
128.8 (C), 119.0 (CH), 114.3 (CH), 91.2 (CH), 85.0 (CH), 81.9 (CH), 81.8
(C), 76.6 (C), 67.3 (CH), 60.7 (C), 56.9 (Me), 44.4 (CH), 40.4 (Me), 25.5
(CH2), 3.27 (Me), 3.23 (Me).
MS (EI, 70 eV): m/z (%) = 435 ([M+], 100), 365 (16), 310 (34), 280 (20).
HRMS (EI, 70 eV): m/z [M+] calcd for C24H26CoNO3: 435.1245; found:
435.1239.
2-(4-Pentynyl)benzo[b]thiophene (34)
MS (EI, 70 eV): m/z (%) = 537 ([M+], 3), 494 (3), 413 (13), 368 (59), 338
(45), 266 (30), 189 (70), 57 (100).
HRMS (EI, 70 eV): m/z [M+] calcd for C28H40CoNO2Si2: 537.1930;
found: 537.1936.
Benzo[b]thiophene (117 μL, 135 mg, 1.00 mmol) in THF (10 mL) was
treated with BuLi in hexane (1.41 M; 1.55 mL, 2.18 mmol) at –78 °C
for 10 min and then at 0 °C for 45 min.7 Renewed cooling to –78 °C
was followed by dropwise injection of 1-(triisopropylsilyl)-5-iodo-1-
pentyne (525 mg, 1.5 mmol)8 in THF (5 mL) and warming to r.t.
during 1 h. The reaction mixture was subjected to aq NH4Cl (5%; 15
mL), then extracted with Et2O (2 × 15 mL), and the combined extracts
were dried over MgSO4. Column chromatography on silica gel, eluting
with hexanes, gave 2-[5-(triisopropylsilyl)-4-pentynyl]benzo[b]thio-
phene (230 mg, 64%) as a colorless oil.
Anal. Calcd for C28H40CoNO2Si2: C, 62.54; H, 7.50; N, 2.61. Found: C,
62.47; H, 7.56; N, 2.56.
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T. Aechtner et al.
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Synthesis
1H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 7.7 Hz, 1 H), 7.66 (d, J = 7.7.
Hz, 1 H), 7.29 (td, J = 7.2, 1.0 Hz, 1 H), 7.24 (td, J = 7.2, 1.0 Hz, 1 H), 7.03
(s, 1 H), 3.07 (t, J = 7.4 Hz, 2 H), 2.35 (br t, J = 6.8 Hz, 2 H), 1.95 (quin, 2
H), 1.04 (m, 21 H).
13C NMR [75 MHz (DEPT), CDCl3]: δ = 152.4 (C), 149.9 (C), 144.9 (C),
144.7 (C), 132.9 (CH), 126.0 (CH), 125.2 (CH), 124.5 (CH), 86.7 (CH),
79.3 (C), 79.0 (CH), 38.2 (CH), 37.3 (CH), 32.9 (CH2), 32.1 (CH2), 29.3
(CH2), 4.11 (CH3), 3.17 (CH3).
13C NMR (75 MHz, CDCl3): δ = 145.3, 140.1, 139.3, 124.0, 123.4, 122.7,
MS (EI, 70 eV): m/z (%) = 494 ([M+], 7), 421 (53), 281 (48), 73 (100).
122.1, 121.0, 108.0, 81.2, 30.2, 29.4, 19.1, 18.7, 11.3.
HRMS (EI, 70 eV): m/z [M+] calcd for C26H35CoSSi2: 494.1330; found:
494.1319.
MS (EI, 70 eV): m/z (%) = 356 ([M+], 10), 313 (100), 285 (20), 271 (30),
257 (12), 243 (25), 195 (12), 167 (13), 165 (16), 147 (21), 128 (20), 91
(28), 71 (24).
4-Acetyl-7-methoxybenzo[b]thiophene-2-carbonitrile (38)
A stirred solution of 37 (950 mg, 5.02 mmol)19 in anhydrous CH2Cl2
(30 mL) at 0 °C was treated with freshly distilled AcCl (1.10 mL, 1.21 g,
15.4 mmol). AlCl3 (2.69 g, 20.2 mmol) was then introduced in por-
tions over a period of 30 min, the cooling bath removed, and stirring
continued for 30 min. The mixture was poured onto ice–H2O (25 mL)
containing concd aq HCl (2 mL) in a separatory funnel. The two
phases were separated, the aqueous layer was extracted with CH2Cl2
(3 × 25 mL), and the combined organic phases were washed with sat.
aq NaCl and dried over MgSO4. Removal of solvent left keto nitrile 38
(1.17 g, 100%) as a colorless solid; mp 182–183 °C (from CH2Cl2–Et2O).
The above 2-[5-(triisopropylsilyl)-4-pentynyl]benzo[b]thiophene
(178 mg, 0.50 mmol) in THF (5 mL) was treated with benzyltrimeth-
ylammonium fluoride (106 mg, 0.63 mmol) under Ar and the mixture
heated to reflux for 4 h. The solution was subjected to sat. aq NaHCO3
(5 mL), then extracted with Et2O (2 × 20 mL), and the combined ex-
tracts were dried over MgSO4. Column chromatography on silica gel,
eluting with PE–EtOAc (98:2), gave 34 (80 mg, 80%) as a pale yellow
oil.
1H NMR (300 MHz, CDCl3): δ = 7.78 (d, J = 7.8 Hz, 1 H), 7.69 (d, J = 7.4.
Hz, 1 H), 7.36–7.25 (m, 2 H), 7.05 (s, 1 H), 3.05 (t, J = 7.4 Hz, 2 H), 2.30
(td, J = 6.9, 2.6 Hz, 2 H), 2.05 (t, J = 2.6 Hz, 1 H), 1.98 (quin, J = 7.2 Hz, 2
H).
1H NMR (300 MHz, CDCl3): δ = 8.94 (s, 1 H), 8.04 (d, J = 8.3 Hz, 1 H),
6.92 (d, J = 8.3 Hz, 1 H), 4.08 (s, 3 H), 2.66 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 145.0, 140.0, 139.3, 124.0, 123.4, 122.7,
13C NMR (75 MHz, CDCl3): δ = 196.8, 157.5, 137.4, 136.9, 132.7, 132.0,
122.0, 121.0, 83.6, 69.1, 29.6, 29.4, 17.7.
126.3, 114.4, 112.5, 105.5, 56.3, 27.4.
MS (EI, 70 eV): m/z (%) = 200 ([M+], 55), 185 (12), 167 (46), 160 (32),
MS (EI, 70 eV): m/z (%) = 231 ([M+], 79), 216 (100), 188 (44), 173 (14),
147 (100), 115 (19).
158 (23), 145 (30), 94 (10).
HRMS (EI, 70 eV): m/z [M+] calcd for C13H12S: 200.0660; found:
200.0661.
1-(7-Methoxybenzo[b]thiophen-4-yl)ethanone (39)
Keto nitrile 38 (5.00 g, 21.6 mmol) was suspended in aq NaOH (10%;
150 mL, 0.65 mol) and the mixture heated to reflux for 4.5 h, when all
material had dissolved. The pale brown reaction mixture was allowed
to reach r.t., poured onto ice–H2O (200 mL), and acidified with concd
aq HCl (70 mL). A dense white suspension was obtained that was
cooled in a refrigerator overnight. The solid was collected by filtration
and dried under reduced pressure in a desiccator containing P2O5 to
give 4-acetyl-7-methoxybenzo[b]thiophene-2-carboxylic acid (5.40
g, 100%) as a colorless solid.
1H NMR (300 MHz, DMSO-d6): δ = 8.78 (s, 1 H), 8.20 (d, J = 8.3 Hz, 1
H), 7.16 (d, J = 8.3 Hz, 1 H), 4.06 (s, 3 H), 3.35 (br s, 1 H), 2.63 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 197.2, 163.3, 157.3, 137.8, 137.5,
132.4, 131.7, 130.7, 126.0, 106.1, 56.5, 27.6.
MS (EI, 70 eV): m/z (%) = 250 ([M+], 75), 235 (100), 207 (36), 57 (21).
endo-(η5-Cyclopentadienyl)[(3a,4,5,6-η4)(6aR*,11aS*)-1,2,3,6a-tet-
rahydro-5,6-bis(trimethylsilyl)benz[b]indeno[4,3a-d]thiophene]-
cobalt (35)
To stirred Et2O (5 mL) under Ar was added by syringe pump a solution
of 34 (80 mg, 0.40 mmol) and 8 (455 μL, 360 mg, 2.11 mmol) in Et2O
(5 mL), while a separate solution of CpCo(C2H4)2 (81 mg, 0.45 mmol)
in Et2O (5 mL) was injected simultaneously by a second syringe pump
over 1 h at r.t. After stirring for another 15 min, the volatiles were re-
moved by vacuum transfer, and the residue was chromatographed
rapidly on silica gel under N2 pressure, eluting with C6H6–PE (1:2), to
separate first {(1,2,3,4-η4)-1-[3-(benzo[b]thiophen-2-yl)propyl]-2,3-
bis(trimethylsilyl)-1,3-cyclobutadiene}(η5-cyclopentadienyl)cobalt (36)
(18 mg, 9%) as a yellow solid.
1H NMR (300 MHz, CDCl3): δ = 7.76 (d, J = 7.5 Hz, 1 H), 7.66 (d, J = 7.5
Hz, 1 H), 7.30–7.25 (m, 2 H), 6.99 (br s, 1 H), 4.82 (s, 5 H), 4.19 (s, 1 H),
2.90 (t, J = 7.2 Hz, 2 H), 1.98 (m, 2 H), 1.83 (m, 2 H), 0.11 (s, 9 H), 0.06
(s, 9 H).
MS (EI, 70 eV): m/z (%) = 494 ([M+], 100), 421 (9), 396 (16), 330 (39),
294 (75), 281 (57), 73 (97).
HRMS (EI, 70 eV): m/z [M+] calcd for C26H35CoSSi2: 494.1330; found:
494.1333.
A second fraction contained endo-(η5-cyclopentadienyl)[(3a,4,5,6-
η4)(6aR*,11aS*)-1,2,3,6a-tetrahydro-5,6-bis(trimethylsilyl)benz[b]in-
deno[4,3a-d]thiophene]cobalt (35) (121 mg, 61%), as a bright orange-
red solid.
1H NMR (300 MHz, CDCl3): δ = 7.42–7.29 (m, 2 H), 6.99 (m, 2 H), 5.35
(br s, 1 H), 5.23 (br s, 1 H), 4.63 (s, 5 H), 2.72 (m, 1 H), 2.29 (m, 2 H),
2.23–2.10 (m, 1 H), 1.90 (m, 1 H), 1.50 (m, 1 H), 0.32 (s, 18 H).
4-Acetyl-7-methoxybenzo[b]thiophene-2-carboxylic acid (5.27 g,
21.1 mmol) from above and Cu powder (5.36 g, 84.3 mmol) were sus-
pended in freshly distilled quinoline (20 mL) and heated at 200 °C
(external sand bath temperature) for 1 h, while venting under an N2
stream. The resulting mixture was filtered through Celite, the filter
washed with CH2Cl2, and the combined filtrates were extracted with
aq HCl (2 N; 3 × 150 mL), dried over Na2SO4, and concentrated. Silica
gel chromatography, eluting with EtOAc–PE (1:3), afforded ben-
zothiophene 39 (3.66 g, 84%), further purified by sublimation (70–
75 °C, 0.5 torr), as colorless crystals; mp 83–84 °C.
1H NMR (300 MHz, CDCl3): δ = 8.39 (d, J = 5.5 Hz, 1 H), 7.93 (d, J = 8.3
Hz, 1 H), 7.59 (d, J = 5.5 Hz, 1 H), 6.74 (d, J = 8.3 Hz, 1 H), 4.04 (s, 3 H),
2.65 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 197.5, 158.0, 139.8, 130.8, 130.4, 129.4,
125.60, 125.57, 102.7, 55.9, 27.6.
MS (EI, 70 eV): m/z (%) = 206 ([M+], 46), 191 (100), 163 (32), 133 (16),
120 (23), 69 (17), 57 (25), 55 (25).
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Anal. Calcd for C11H10O2S: C, 64.05; H, 4.89. Found: C, 64.00; H, 4.99.
1-(7-Methoxybenzo[b]thiophen-4-yl)-4-(trimethylsilyl)-3-butyn-
2-ol (42)
(7-Methoxybenzo[b]thiophen-4-yl)acetic Acid (40)
(Trimethylsilyl)ethynyllithium was generated by slow addition of
BuLi in hexanes (1.1 M; 1.65 mL, 1.81 mmol) to stirred (trimethylsi-
lyl)acetylene (280 μL, 193 mg, 1.96 mmol) in anhydrous THF (5 mL) at
–78 °C. The cooling bath was removed, stirring continued at r.t. for 1.5
h, the mixture cooled back to –78 °C, and a solution of 41 (150 mg,
0.79 mmol) in THF (5 mL) added via syringe. Stirring was continued
for 5 h, while allowing the mixture to warm to r.t., before the reaction
was quenched with HCl (1 N; 0.5 mL). Addition of Et2O (10 mL) and
H2O (10 mL) was followed by extraction of the aqueous phase with
Et2O (2 × 5 mL). The combined organic phases were dried over MgSO4,
the volatiles removed, and the remains chromatographed on silica
gel, eluting with CH2Cl2, delivering silylated alcohol 42 (195 mg, 81%)
as a colorless oil.
A mixture of 39 (3.0 g, 14.5 mmol), sulfur (1.17 g, 36.5 mmol), and
morpholine (9.0 mL, 9.1 g, 104 mmol) was boiled under N2 overnight.
After cooling to r.t., the volume was reduced to half, the mixture fil-
tered through Celite, the Celite pad washed with CH2Cl2, and the re-
sulting solution washed with aq HCl (2 N; 3 × 25 mL) and H2O (25
mL). The organic layer was dried over MgSO4, the volatiles were re-
moved, and the residue was chromatographed on silica gel, eluting
with CH2Cl2–Et2O (95:5), to yield 2-(7-methoxybenzo[b]thiophen-4-
yl)-1-morpholinoethanone (3.01 g, 70%) as a pale yellow solid.
1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 5.4 Hz, 1 H), 7.40 (d, J = 5.4
Hz, 1 H), 7.19 (d, J = 8.0 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 4.56 (s, 2 H),
4.37 (t, J = 4.8 Hz, 2 H), 3.96 (s, 3 H), 3.74 (t, J = 4.8 Hz, 2 H), 3.52 (br s,
2 H), 3.34 (t, J = 4.6 Hz, 2 H).
1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 5.5 Hz, 1 H), 7.43 (d, J = 5.5
Hz, 1 H), 7.21 (d, J = 8.0 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 4.63 (t, J = 6.6
Hz, 1 H), 3.99 (s, 3 H), 3.29 (m, 2 H), 1.86 (br s, 1 H), 0.13 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 199.9, 153.5, 139.3, 129.0, 127.4, 123.9,
122.6, 121.3, 104.0, 66.3, 66.1, 55.6, 50.7, 50.1 (br), 47.8 (br).
2-(7-Methoxybenzo[b]thiophen-4-yl)-1-morpholinoethanone (3.0 g,
10.3 mmol) from above was heated at reflux in aq NaOH (5%; 75 mL)
for 11 h. The reaction mixture was cooled, filtered, and acidified to
pH 1 by addition of concd HCl. After cooling to 5 °C, the precipitate
was collected by filtration and dried in a desiccator to give a major
portion of product (1.79 g). The filtrates were extracted with CH2Cl2
(3 × 50 mL), the organic layers dried over Na2SO4, and the volatiles re-
moved to give an additional batch (315 mg). Acid 40 (2.10 g, 92%) was
obtained as a colorless solid, crystallized from CH2Cl2; mp 161–
162 °C.
1-(7-Methoxybenzo[b]thiophen-4-yl)-3-butyn-2-ol (43)
To a solution of 42 (190 mg, 0.62 mmol) in THF (10 mL) was added
benzyltrimethylammonium fluoride (132 mg, 0.78 mmol) and the
mixture stirred at 80 °C for 5 min. The THF was removed under re-
duced pressure, the residue dissolved in CH2Cl2 (30 mL), and the solu-
tion washed with sat. aq NaHCO3 (2 × 25 mL). The combined aqueous
layers were extracted with CH2Cl2 (25 mL) and the combined organic
phases dried over Na2SO4, concentrated, and chromatographed on sil-
ica gel, eluting with Et2O–CH2Cl2 (2:98), to provide alcohol 43 (120
mg, 83%) as a pale yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.44 (s, 2 H), 7.22 (d, J = 8.0 Hz, 1 H),
6.73 (d, J = 7.9 Hz, 1 H), 4.65 (ddd, J = 7.75, 7.32, 2.06 Hz, 1 H), 3.99 (s,
3 H), 3.30 (m, 2 H), 2.46 (d, J = 2.06 Hz, 1 H), 2.19 (br s, 1 H).
13C NMR [75 MHz (DEPT), CDCl3]: δ = 153.7 (C), 140.8 (C), 128.8 (C),
127.0 (CH), 126.7 (CH), 123.5 (C), 122.3 (CH), 103.9 (CH), 84.3 (CH),
73.7 (CH), 62.7, 55.5, 41.2 (CH2).
1H NMR (300 MHz, CDCl3): δ = 7.46 (d, J = 5.4 Hz, 1 H), 7.38 (d, J = 5.3
Hz, 1 H), 7.20 (d, J = 8 Hz, 1 H), 6.73 (d, J = 8 Hz, 1 H), 5.30 (br s, 1 H),
3.98 (s, 3 H), 3.89 (s, 2 H).
MS (EI, 70 eV): m/z (%) = 222 ([M+], 38), 177 (100), 134 (29), 57 (14).
Anal. Calcd for C11H10O3S: C, 59.44; H, 4.53; S, 14.43. Found: C, 59.11;
H, 4.57; S, 14.66.
(7-Methoxybenzo[b]thiophen-4-yl)acetaldehyde (41)
exo-(η5-Cyclopentadienyl)[(5,6,7,7a-η4)(4aR*,9cS*)-4a,9c-dihydro-
3-methoxy-5,6-bis(trimethylsilyl)phenanthro[4,5-bcd]thio-
phene]cobalt (44)
Acid 40 (222 mg, 1.00 mmol) and DMAP (12.2 mg, 0.10 mmol) in
CH2Cl2 (10 mL) were cooled to 0 °C, EtSH (225 μL, 194 mg, 3.12 mmol)
and DCC (217 mg, 1.05 mmol) added, and the mixture was stirred at
0 °C for 1 h and at r.t. for 30 min. The suspension was filtered, the vol-
atiles were removed, and the residue was chromatographed on silica
gel, eluting with CH2Cl2, to afford S-ethyl (7-methoxybenzo[b]-
thiophen-4-yl)ethanethioate (229 mg, 86%) as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.47 (d, J = 5.5 Hz, 1 H), 7.40 (d, J = 5.5
Hz, 1 H), 7.21 (d, J = 7.9 Hz, 1 H), 6.74 (d, J = 7.8 Hz, 1 H), 4.06 (s, 2 H),
3.99 (s, 3 H), 2.80 (q, J = 6.9 Hz, 2 H), 1.19 (t, J = 6.9 Hz, 3 H).
A solution of alcohol 43 (76 mg, 0.33 mmol) and 8 (370 μL, 293 mg,
1.72 mmol) in Et2O (8 mL) and a separate solution of CpCo(C2H4)2 (66
mg, 0.37 mmol) in Et2O (5 mL) were simultaneously syringed into
Et2O (10 mL) at r.t. over a period of 1 h. The solvent was evaporated
under reduced pressure and the residue chromatographed under N2
pressure on silica gel, eluting with anhydrous deoxygenated CH2Cl2–
pentane (1:1), to separate 44 (35 mg, 20%) as a red crystalline mass.
1H NMR (300 MHz, CDCl3): δ = 6.79 (d, J = 8.1 Hz, 1 H), 6.62 (d, J = 9.1
Hz, 1 H), 6.45 (d, J = 8.1 Hz, 1 H), 5.61 (d, J = 9.1 Hz, 1 H), 5.19 (d, J =
0.97 Hz, 1 H), 4.33 (s, 5 H), 3.36 (s, 3 H), 2.81 (d, J = 7.7 Hz, 1 H), 2.45
(d, J = 7.7 Hz, 1 H), 0.46 (s, 9 H), 0.33 (s, 9 H).
The preceding thioester (229 mg, 0.86 mmol) in CH2Cl2 (7 mL) con-
taining Pd/C (5%; 100 mg) was treated with Et3SiH (450 μL, 328 mg,
2.82 mmol). The mixture was stirred at r.t. until no more starting ma-
terial was visible by TLC (45 min), then filtered through Celite, fol-
lowed by washing the Celite pad with CH2Cl2, evaporation of the vola-
tiles, and chromatography on silica gel, eluting with EtOAc–PE (1:3),
to furnish 41 (158 mg, 89%) as colorless crystals.
1H NMR (300 MHz, CDCl3): δ = 9.71 (t, J = 2.5 Hz, 1 H), 7.47 (d, J = 5.5
Hz, 1 H), 7.29 (d, J = 5.5 Hz, 1 H), 7.15 (d, J = 7.9 Hz, 1 H), 6.75 (d, J = 7.9
Hz, 1 H), 3.98 (s, 3 H), 3.90 (d, J = 2.4 Hz, 2 H).
HRMS (FAB, 70 eV): m/z [M+] calcd for C26H33CoOSSi2: 508.1123;
found: 508.1126.
N-[9,10-Dihydro-4-hydroxy-3-methoxy-6,7-bis(trimethylsilyl)-9-
phenanthrenyl]-N-methylacetamide (45)
Complex 31 (67 mg, 0.12 mmol) in THF (3 mL) at –78 °C was treated
dropwise with Fe(NO3)3·9H2O (96 mg, 0.24 mmol) in MeCN–H2O (3:1,
2 mL). After 5 min, the dark mixture was warmed to r.t. for 30 min,
then poured onto H2O–CH2Cl2 (1:1, 10 mL) and the aqueous phase ex-
tracted with CH2Cl2 (2 × 20 mL). The combined organic phases were
13C NMR (75 MHz, CDCl3): δ = 199.1, 154.0, 140.6, 129.1, 127.4, 127.0,
121.7, 118.7, 104.0, 55.6, 48.2.
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T. Aechtner et al.
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Synthesis
washed with sat. aq NaCl, dried over Na2SO4, and concentrated under
reduced pressure. Silica gel chromatography, eluting with CH2Cl2,
supplied 45 (49 mg, 92%), as a light colorless oil.
Acetamide 45 from 46
Solid anhydrous K2CO3 (20 mg, 0.14 mmol) was added to a clear red,
stirred solution of 46 (36 mg, 0.05 mmol) in CH2Cl2 (5 mL) at –78 °C.
After 2 min, the green reaction mixture showed complete conversion
of the starting material by TLC, eluting with CH2Cl2–Et2O (4:1), to a
polar compound. Removal of the solvent followed by silica gel chro-
matography, eluting with CH2Cl2–Et2O (4:1), provided 45 (22 mg,
100%) as a colorless oil.
IR (KBr): 3505, 2995, 2950, 1630, 1460, 1440, 1400, 1250, 1120, 920,
835 cm–1
.
1H NMR (400 MHz, C6D6, 25 °C): δ [mixture of two rotamers (1:1)] =
9.32 (s, 1 H, H5), 9.27 (s, 1 H, H5), 7.70 (s, 1 H, H8), 7.57 (s, 1 H, H8),
6.55 (d, J = 8.0 Hz, 1 H, H1), 6.52 (d, J = 8.0 Hz, 1 H, H1), 6.37 (d, J = 7.9
Hz, 1 H, H2), 6.34 (m obscured by H2, 1 H, H9), 6.31 (d, J = 8.0 Hz, 1 H,
H2), 6.20 (s, 1 H, disappears with D2O, OH), 6.18 (s, 1 H, disappears
with D2O, OH), 4.74 (dd, J = 13.6, 4.5 Hz, 1 H, H10α), 3.15 (s, 3 H, OMe),
3.14 (s, 3 H, OMe), 2.98 (dd, J = 14.7, 8.7 Hz, 1 H, H10β), 2.83 (s, 3 H,
NMe), 2.72 (dd, J = 14.6, 5.4 Hz, 1 H, H10β), 2.34 (dd, J = 13.8, 4.6 Hz, 1
H, H10α), 2.20 (s, 3 H, NMe), 1.78 (s, 3 H, COMe), 1.75 (s, 3 H, COMe),
0.53 (s, 9 H, SiMe3), 0.50 (s, 9 H, SiMe3), 0.43 (s, 9 H, SiMe3), 0.40 (s, 9
H, SiMe3).
13C NMR (75 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (1:1)] =
145.9, 145.4, 145.2, 144.8, 144.7, 143.6, 143.5, 135.7, 135.6, 133.7,
132.9, 132.8, 130.5, 129.0, 119.8 (br), 118.9, 118.6, 109.5, 56.29,
56.28, 51.8, 34.6, 33.7, 28.6, 23.0 (br), 22.1, 1.90, 1.84.
MS (EI, 70 eV): m/z (%) = 441 ([M+], 4), 440 (10), 368 (100), 338 (49),
296 (41), 130 (24), 73 (88).
2,2,2-Trichloroethyl [2-(7-Methoxybenzo[b]furan-3-yl)eth-
yl](methyl)carbamate (48)
To a solution of 4727 (3.50 g, 16.0 mmol) in CH2Cl2 (40 mL) was added
trichloroethyl chloroformate (2.65 mL, 4.08 g, 19.3 mmol) and the
mixture stirred at r.t. for 24 h. It was then washed with 10% aq HCl,
sat. aq NaHCO3, and sat. aq NaCl, dried over Na2SO4, and concentrated.
Flash chromatography on silica gel, eluting with CH2Cl2, afforded pure
carbamate 48 (5.03 g, 83%) as a colorless oil.
1H NMR (300 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (1.3:1);
δ values for resolved signals of the minor rotamer in square brackets]
= 7.42 [7.43] (s, 1 H), 7.16–7.12 (m, 2 H), 6.78 (dd, J = 6.8, 1.8 Hz, 1 H),
4.69 [4.72] (s, 2 H), 3.95 (s, 3 H), 3.59 (t, J = 7.5 Hz, 2 H), 2.92 (t, J = 7.5
Hz, 2 H), 2.92 (s, 3 H).
1H NMR (300 MHz, C6D6, 25 °C): δ [mixture of two rotamers (1:1)] =
7.20–7.04 (m, 3 H), 6.48 (dd, J = 6.8, 1.8 Hz, 1 H), 4.61 (s, 1 H), 4.57 (s,
1 H), 3.48 (s, 1.5 H), 3.47 (s, 1.5 H), 3.30 (t, J = 7.5 Hz, 1 H), 3.20 (t, J =
7.5 Hz, 1 H), 2.60 (t, J = 7.5 Hz, 2 H), 2.56 (s, 1.5 H), 2.47 (s, 1.5 H).
13C NMR (75 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (1:1)] =
154.2, 154.0, 145.4, 145.3, 144.0, 141.72, 141.65, 129.4, 129.3, 123.2,
117.15, 117.12, 111.6, 106.3, 95.48, 95.45, 74.9, 55.87, 55.85, 49.1,
48.8, 35.3, 34.6, 22.5, 21.8.
MS (FAB, 70 eV): m/z (%) = 442 ([M+ + H], 64), 368 (100).
HRMS (FAB, 70 eV): m/z [M+ + Li] calcd for C24H35LiNO3Si2: 448.2315;
found: 448.2313.
Anal. Calcd for C24H35NO3Si2: C, 65.23; H, 7.99; N, 3.17. Found: C,
64.73; H, 7.83; N, 3.30.
exo-(η5-Cyclopentadienyl)[(1,2,3,10a-η4)-(4aR*,10R*)-10-(N-ace-
tyl-N-methylamino)-4,4a,9,10-tetrahydro-5-hydroxy-6-methoxy-
2,3-bis(trimethylsilyl)-4-phenanthrenylium]cobalt Hexafluoro-
phosphate (46)
MS (FAB, 70 eV): m/z (%) = 384 (19), 383 (33), 382 (62), 381 (81), 380
([M+ + H], 80), 379 (77), 378 (25), 232 (57), 220 (90), 218 (94), 175
(100).
TrPF6 (41 mg, 0.11 mmol) was added to a stirred solution of 31 (50
mg, 0.09 mmol) in CH2Cl2 (5 mL) at –78 °C over the course of 3 min.
After stirring for 1 h, the reaction mixture was warmed to r.t., the vol-
atiles removed, and the residue filtered through a short column of
Celite, eluting first with Et2O, then CH2Cl2, to deliver 46 (47 mg, 73%)
as orange crystals.
2,2,2-Trichloroethyl [2-(4-Acetyl-7-methoxybenzo[b]furan-3-
yl)ethyl](methyl)carbamate (49)
A solution of 48 (358 mg, 0.94 mmol) in CH2Cl2 (5 mL) was slowly
added to AcCl (200 μL, 220 mg, 2.80 mmol) and AlCl3 (377 mg, 2.83
mmol) in CH2Cl2 (5 mL) at 0 °C. After stirring for 1 h, the reaction mix-
ture was poured onto ice–H2O and acidified with concd HCl (2 mL).
The organic phase was washed with sat. aq NaCl, dried over Na2SO4,
concentrated, and chromatographed on silica gel, eluting with CH2-
Cl2–Et2O (97:3), to give 49 (288 mg, 72%) as a yellow oil.
1H NMR (400 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (1.3:1);
δ values for resolved signals of the minor rotamer in square brackets]
= 7.70 [7.72] (d, J = 8.5 Hz, 1 H), 7.50 [7.54] (s, 1 H), 6.76 [6.75] (d, J =
8.5 Hz, 1 H), 4.60 [4.67] (s, 2 H), 4.02 [4.01] (s, 3 H), 3.51 (m, 2 H), 3.15
(m, 2 H), 2.96 [2.97] (s, 3 H), 2.62 [2.64] (s, 3 H).
IR (CHCl3): 3505, 3005, 1630, 1515, 1470, 1440, 1400, 935, 915, 835
cm–1
.
1H NMR (400 MHz, CD2Cl2): δ = 7.00 (d, J = 7.8 Hz, 1 H, H7 or H8), 6.94
(d, J = 7.8 Hz, 1 H, H7 or H8), 6.03 (s, 1 H, disappears with D2O, OH),
5.75 (br s, 1 H, H4), 5.43 (s, 5 H, Cp), 5.15 (dd, J = 8.4, 5.7 Hz, 1 H, H10),
4.50 (s, 1 H, H1), 3.95 (s, 3 H, OMe), 3.64 (dd, J = 14.7, 5.6 Hz, 1 H, H9α),
3.05 (dd, J = 14.6, 8.5 Hz, 1 H, H9β), 2.64 (s, 3 H, NMe), 2.55 (s, 1 H,
H4a), 2.03 (s, 3 H, COMe), 0.62 (s, 9 H, SiMe3), 0.39 (s, 9 H, SiMe3).
13C NMR (100 MHz, C6D6): δ = 167.4, 146.3, 141.3, 132.2, 125.0, 123.6,
115.2, 95.2, 89.9, 89.4, 85.3, 72.8, 72.4, 63.2, 60.7, 55.1, 46.2, 31.3,
23.2, 1.53, 1.47.
13C NMR (100 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (1.3:1)]
= 197.7, 197.4, 154.1, 148.9, 148.8, 145.7, 144.9, 127.7, 127.4, 127.3,
126.1, 125.9, 119.0, 118.9, 112.6, 104.7, 95.7, 95.6, 74.8, 56.0, 53.2,
49.9, 49.8, 35.1, 34.1, 27.7, 24.7, 24.0.
MS (FAB, 70 eV): m/z (%) = 566 ([M+ cation], 100).
HRMS (FAB, 70 eV): m/z [M+ cation] calcd for C29H41CoNO3Si2:
566.1957; found: 566.1947.
2,2,2-Trichloroethyl [2-(4-Bromo-7-methoxybenzo[b]furan-3-
yl)ethyl](methyl)carbamate (50)
Anal. Calcd for C29H41CoF6NO3PSi2: C, 48.94; H, 5.81; N, 1.97. Found: C,
48.73; H, 5.66; N, 1.92.
To 48 (2.10 g, 5.52 mmol) in AcOH (40 mL) was added Br2 in AcOH
(0.97 M; 5.70 mL, 5.53 mmol) at r.t., the mixture stirred for 2 h, dilut-
ed with PE–Et2O (4:1, 500 mL), and washed with sat. aq Na2S2O3 (100
mL), H2O (2 × 100 mL), and sat. aq NaHCO3 (100 mL). The organic layer
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Synthesis
was dried over MgSO4, the volatiles removed, and the residue chro-
matographed on silica gel, eluting with CH2Cl2, to render 50 (2.27 g,
89%) as a colorless solid.
1H NMR (400 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (1.3:1);
δ values for resolved signals of the minor rotamer in square brackets]
= 7.42 [7.47] (s, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 6.63 (d, J = 8.4 Hz, 1 H),
4.64 [4.72] (s, 2 H), 3.94 (s, 3 H), 3.66 (m, 2 H), 3.14 (m, 2 H), 2.95 (s, 3
H).
1H NMR (300 MHz, CDCl3): δ = 7.09 (dt, J = 15.6, 4.5 Hz, 1 H), 7.08 (dd,
J = 7.8, 1.5 Hz, 1 H), 6.90 (t, J = 8.1 Hz, 1 H), 6.81 (dd, J = 8.4, 1.5 Hz, 1
H), 6.27 (dt, J = 15.6, 2.1 Hz, 1 H), 4.63 (dd, J = 4.5, 2.1 Hz, 2 H), 3.81 (s,
3 H), 3.73 (s, 3 H).
MS (EI, 70 eV): m/z (%) = 302, 300 (1:1, [M+], 25), 203, 201 (1:1, 100),
94 (80).
Methyl (7-Methoxybenzo[b]furan-3-yl)acetate (55)
13C NMR (100 MHz, CDCl3, 25 °C): δ [mixture of two rotamers (1.3:1)]
= 154.3, 145.6, 145.3, 143.5, 127.7, 126.1, 118.1, 109.4, 107.9, 104.3,
95.8, 95.7, 75.1, 56.3, 50.1, 49.9, 35.4, 34.7, 22.5, 22.2, 22.0.
A Schlenk tube containing 54 (9.03 g, 30.0 mmol) in PhMe (150 mL)
was charged with anhydrous K2CO3 (16.6 g, 120 mmol) and the mix-
ture degassed by three freeze–pump–thaw cycles. Subsequently,
Pd(PPh3)4 (3.47 g, 3.00 mmol) was added, and the mixture heated to
108 °C for 5 h, cooled, filtered through Celite, and washed with EtOAc.
The solvents were removed, and the residue was dissolved in EtOAc,
washed with aq NaOH (2 M) and sat. aq Na2SO4, and dried over
Na2SO4. Filtration was followed by evaporation of the solvent and
chromatography on silica gel, eluting with hexanes–EtOAc (4:1), to
deliver 5531 (2.99 g, 45%) as a slight yellow oil.
MS (EI, 70 eV): m/z (%) = 463 (10), 462 (6), 461 (34), 460 (9), 459
([M+], 54), 458 (5), 457 ([M+], 27), 254 (23), 252 (23), 239 (16), 237
(16), 220 (100), 218 (100).
Anal. Calcd for C15H15BrCl3NO4: C, 39.20; H, 3.29; N, 3.05. Found: C,
39.12; H, 3.36; N, 2.95.
2-(4-Bromo-7-methoxybenzo[b]furan-3-yl)-N,N-dimethylethana-
mine (51)
2-(7-Methoxybenzo[b]furan-3-yl)ethanol (56)
Br2 (0.26 g, 1.63 mmol) in CHCl3 (1 mL) was added to a solution of
4727 (0.36 g, 1.64 mmol) in CHCl3 (3 mL) at 0 °C and the solution
stirred for 4 h. The mixture was washed with H2O, aq NaHSO3 (10%),
and sat. aq NaHCO3. The volatiles were removed and the residue chro-
matographed on silica gel, eluting with hexanes–Et2O (10:1), to allow
the isolation of 51 (0.40 g, 82%) as a pale yellow liquid.
1H NMR (300 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.23 (d, J = 8.4 Hz, 1 H),
6.61 (d, J = 8.4 Hz, 1 H), 3.94 (s, 3 H), 3.04 (t, J = 8.4 Hz, 2 H), 2.63 (t, J =
8.4 Hz, 2 H), 2.33 (s, 6 H).
Methyl ester 55 (0.96 g, 4.36 mmol)31 in THF (20 mL) was dripped into
a suspension of LAH (0.82 g, 21.6 mmol) in THF (5 mL) at r.t. The mix-
ture was stirred for 4 h and then treated with aq NaOH (10%; 3 mL).
The resulting precipitate was removed by filtration, washed thor-
oughly with CH2Cl2, and the combined organic fractions were dried
over MgSO4. The solvent was removed and the residue purified by
column chromatography on silica gel, eluting with hexanes–Et2O
(1:3), to furnish 56 (0.74 g, 88%) as a yellow liquid.
IR (film): 3365 (br), 2942, 2841, 1625, 1589, 1494, 1436, 1360, 1266,
1203, 1179, 1094, 1057, 925, 914, 842, 783, 733, 682 cm–1
.
1-{7-Methoxy-3-[2-(methylamino)ethyl]benzo[b]furan-4-yl}etha-
none (52) and 2-(4-Bromo-7-methoxybenzo[b]furan-3-yl)-N-meth-
ylethanamine (53) by Deprotection of 49 and 50
1H NMR (300 MHz, CDCl3): δ = 7.47 (s, 1 H), 7.13 (m, 2 H), 6.78 (m, 1
H), 3.97 (s, 3 H), 3.86 (t, J = 5.6 Hz, 2 H), 2.88 (t, J = 5.6 Hz, 2 H), 2.08
(br s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 145.6, 142.2, 129.7, 123.2, 117.2,
111.9, 106.5, 61.7, 56.1, 27.1.
Compound 49 (300 mg, 0.71 mmol) in AcOH (2 mL) was stirred with
Zn dust (325 mg, 5.00 mmol) for 5 h. Addition of CH2Cl2 (10 mL) was
followed by filtration and extraction with aq HCl (3 × 25 mL). The
aqueous extracts were washed with CH2Cl2 (10 mL), turned alkaline
with aq NaOH (15%), and extracted with CH2Cl2 (2 × 25 mL and 2 × 15
mL) to give 52 (160 mg, 91%) as a light yellow oil.
MS (EI, 70 eV): m/z (%) = 192 ([M+], 47), 161 (100), 146 (9), 118 (10),
103 (8), 89 (10), 77 (10), 63 (8).
1H NMR (300 MHz, CDCl3): δ = 7.69 (d, J = 8.4 Hz, 1 H), 7.60 (s, 1 H),
6.77 (d, J = 8.4 Hz, 1 H), 4.04 (s, 3 H), 3.12 (t, J = 6.9 Hz, 2 H), 2.82 (t, J =
7.0 Hz, 2 H), 2.63 (s, 3 H), 2.48 (s, 3 H).
2-(4-Bromo-7-methoxybenzo[b]furan-3-yl)ethanol (57)
Br2 (0.50 g, 3.12 mmol) in CHCl3 (2 mL) was dripped into a solution of
56 (0.60 g, 3.12 mmol) in CHCl3 (6 mL) at 0 °C and the mixture stirred
for 4 h. Then, it was washed with H2O, sat. aq Na2S2O3, and sat. aq
NaHCO3. After drying over MgSO4, the solvent was removed and the
residue chromatographed on silica gel, eluting with hexanes–Et2O
(1:2), to lead to 57 (0.75 g, 89%) as a colorless powder, crystallized
from hexanes–Et2O (2:1); mp 76–77 °C.
Compound 50 (300 mg, 0.65 mmol) was treated as described for 49
with Zn (215 mg, 3.29 mmol) to generate 53 (161 mg, 87%) as a light
yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.25 (d, J = 8.5 Hz, 1 H),
6.64 (d, J = 8.5 Hz, 1 H), 3.95 (s, 3 H), 3.08 (t, J = 6.8 Hz, 2 H), 2.96 (t, J =
6.8 Hz, 2 H), 2.49 (s, 3 H), 2.21 [br s, 2 H (NH and H2O)].
IR (KBr): 3357 (br), 2936, 1618, 1579, 1487, 1442, 1394, 1339, 1271,
1183, 1102, 1059, 1014, 898, 811, 793, 741 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.21 (d, J = 8.5 Hz, 1 H),
6.60 (d, J = 8.5 Hz, 1 H), 3.93 (s, 3 H), 3.90 (t, J = 6.0 Hz, 2 H), 3.09 (t, J =
6.0 Hz, 2 H), 2.03 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 145.4, 145.2, 143.6, 127.7, 126.9,
117.8, 107.5, 104.4, 62.3, 56.2, 27.3.
Methyl trans-4-(2-Bromo-6-methoxyphenoxy)-2-butenoate (54)
2-Bromo-6-methoxyphenol (8.46 g, 41.7 mmol) in DMF (50 mL) was
treated with anhydrous K2CO3 (6.91 g, 50.0 mmol) and methyl trans-
4-bromo-2-butenoate (5.88 mL, 8.95 g, 50.0 mmol) and the suspen-
sion stirred at r.t. for 8 h. The mixture was poured into H2O and ex-
tracted with CH2Cl2. The organic layer was washed with sat. aq
Na2SO4 and dried over Na2SO4. After filtration and evaporation of the
solvent, the residue was chromatographed on silica gel, eluting with
hexanes–EtOAc (4:1), to give 54 (11.4 g, 91%) as a yellow oil, used
without further purification.
MS (EI, 70 eV): m/z (%) = 272, 270 (1:1, [M+], 68), 241, 239 (1:1, 100),
227, 225 (1:1, 14), 161 (9), 102 (7), 89 (8), 63 (9).
Anal. Calcd for C11H11BrO3: C, 48.73; H, 4.09. Found: C, 48.85; H, 4.02.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

W
T. Aechtner et al.
Paper
Synthesis
4-Bromo-3-[2-(tert-butyldimethylsilyloxy)ethyl]-7-methoxyben-
zo[b]furan (58)
der Ar and poured into H2O. A light brown precipitate was collected
by filtration, washed with cold EtOAc, and dried under high vacuum
to give 61 (22.4 g, 85%) as a colorless powder; mp 127–128 °C.
Imidazole (0.61 g, 9.0 mmol) and TBDMSCl (0.90 g, 6.0 mmol) were
added to alcohol 57 (0.81 g, 3.0 mmol) in DMF (6 mL) at r.t. After stir-
ring for 2 h, the mixture was poured into Et2O, washed twice with
H2O, dried over MgSO4, and the solvent removed. The residue was
chromatographed on silica gel, eluting with hexanes–Et2O (10:1), to
supply 58 (1.13 g, 98%) as a colorless oil.
IR (KBr): 3020, 2944, 1724, 1681, 1578, 1438, 1363, , 1278, 1254,
1216, 1141, 994, 940, 899, 851, 809, 780 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.00 (s, 1 H), 7.74 (d, J = 8.6 Hz, 1 H),
7.14 (dt, J = 15.7, 4.4 Hz, 1 H), 6.99 (d, J = 8.6 Hz, 1 H), 6.39 (dt, J = 15.7,
2.0 Hz, 1 H), 4.68 (dd, J = 4.4, 2.0 Hz, 2 H), 3.95 (s, 3 H), 3.79 (s, 3 H).
IR (film): 2955, 2857, 1619, 1579, 1487, 1392, 1247, 1214, 1172,
13C NMR (100 MHz, CDCl3): δ = 194.9, 157.1, 142.6, 131.2, 129.0,
127.8, 127.1, 122.0, 111.9, 100.5, 71.0, 56.3, 51.7.
MS (EI, 70 eV): m/z (%) = 376 ([M+], 1), 278 (100), 250 (29), 218 (40),
175 (30), 161 (16), 127 (21), 103 (6), 91 (17), 77 (15), 65 (17).
1097, 1030, 898, 836, 777 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50 (s, 1 H), 7.25 (d, J = 8.8 Hz, 1 H),
6.63 (d, J = 8.8 Hz, 1 H), 3.96 (s, 3 H), 3.92 (t, J = 6.6 Hz, 2 H), 3.09 (t, J =
6.6 Hz, 2 H), 0.87 (s, 9 H), 0.00 (s, 6 H).
Anal. Calcd for C13H13IO5: C, 41.51; H, 3.48. Found: C, 41.47; H, 3.59.
13C NMR (100 MHz, CDCl3): δ = 145.2, 143.7 (2 C), 126.8 (2 C), 118.3,
107.3, 104.5, 63.0, 56.2, 27.5, 25.9, 18.3, –5.31.
Methyl (4-Formyl-7-methoxybenzo[b]furan-3-yl)acetate (62)
MS (EI, 70 eV): m/z (%) = 386, 384 (1:1, [M+], 1), 330, 328 (1:1, 100),
297 (56), 283, 281 (1:1, 10), 233 (16), 217 (7), 203 (7), 174 (8), 102
(6), 73 (17), 59 (8).
To a degassed mixture of Et3N (5 mL, 3.63 g, 35.8 mmol), H2O (10 mL),
and MeCN (300 mL) were added, in sequence, iodoarene 61 (5.00 g,
13.3 mmol), Pd(OAc)2 (148 mg, 0.66 mmol), and NaI (300 mg, 2.00
mmol). The dark reddish brown mixture was stirred at r.t. for 24 h,
diluted with CH2Cl2 (100 mL), and washed with aq Na2S2O3 (1 M; 50
mL) and H2O (200 mL). The aqueous layer was extracted with CH2Cl2
(2 × 100 mL) and the combined organic phases were dried over
MgSO4. The solvent was evaporated and the residue subjected to silica
gel chromatography, eluting with Et2O–CH2Cl2 (5:95), to furnish 62
(2.84 g, 86%) as light yellow crystals; mp 135–136 °C.
Anal. Calcd for C17H25BrO3Si: C, 52.98; H, 6.54. Found: C, 53.36; H,
6.73.
A procedure identical to the above, but featuring TIPSCl, led to 4-bro-
mo-7-methoxy-3-[2-(triisopropylsilyloxy)ethyl]benzo[b]furan (98%)
as a colorless oil.
1H NMR (300 MHz, CDCl3): δ = 7.52 (s, 1 H), 7.26 (d, J = 8.5 Hz, 1 H),
6.64 (d, J = 8.5 Hz, 1 H), 4.01 (t, J = 6.7 Hz, 2 H), 3.97 (s, 3 H), 3.13 (t, J =
6.7 Hz, 2 H), 1.04 (m, 21 H).
13C NMR (100 MHz): δ = 145.1, 143.8, 128.1, 126.7, 123.4, 118.4,
107.2, 104.5, 63.2, 56.2, 27.6, 18.0, 11.9.
MS (EI, 70 eV): m/z (%) = 428, 426 (1:1, [M+], 1), 385, 383 (1:1, 100),
313, 311 (1:1, 30).
IR (KBr): 3110, 3012, 2984, 2967, 2943, 2897, 2839, 1737, 1686, 1620,
1563, 1400, 1362, 1297, 1268, 1236, 1171, 1127, 1068, 1034, 998,
810, 772, 750, 680 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 9.88 (s, 1 H), 7.67 (d, J = 8.4 Hz, 1 H),
7.65 (s, 1 H), 6.89 (d, J = 8.4 Hz, 1 H), 4.06 (s, 3 H), 4.04 (s, 2 H), 3.70 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 190.8, 172.0, 150.3, 146.1, 145.7,
133.7, 127.7, 124.7, 115.4, 105.6, 56.4, 52.0, 31.9.
MS (EI, 70 eV): m/z (%) = 248 ([M+], 46), 216 (67), 188 (100), 161 (60),
146 (15), 130 (13), 118 (18), 103 (25), 89 (35), 77 (23), 63 (29), 51
(14).
3-[2-(tert-Butyldimethylsilyloxy)ethyl]-4-(2,2-dimethoxyethyl)-7-
methoxybenzo[b]furan (59)
2-Bromo-1,1-dimethoxyethane (0.22 g, 1.30 mmol) in Et2O (5 mL)
was added to Mg powder (32 mg, 1.31 mmol) and the mixture heated
to reflux for 2 h. The Grignard reagent was then transferred into a
solution of 58 (0.42 g, 1.09 mmol) and Ni(dppe)Cl2 (4.3 mg, 0.008
mmol) in Et2O (5 mL) at r.t. After stirring for 20 min, the reaction mix-
ture was heated to reflux for 20 h, washed with aq HCl (1 M), and the
layers were separated. The aqueous layer was extracted with Et2O
(3 × 5 mL), and the combined organic layers were washed with H2O
and then sat. aq NaHCO3. After drying over MgSO4, the solvent was re-
moved and the crude product subjected to column chromatography
on silica gel, eluting with hexanes–Et2O (5:1), to produce 59 (0.35 g,
81%) as a colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.24 (d, J = 8.3 Hz, 1 H),
6.62 (d, J = 8.3 Hz, 1 H), 4.53 (t, J = 5.4 Hz, 1 H), 3.95 (s, 3 H), 3.91 (t, J =
5.8 Hz, 2 H), 3.38 (s, 6 H), 3.35 (d, J = 5.4 Hz, 2 H), 3.08 (t, J = 6.1 Hz, 2
H), 0.86 (s, 9 H), 0.01 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 145.2, 143.7, 128.1, 126.8, 118.3,
107.3, 104.5, 103.0, 81.0, 63.0, 56.2, 53.9, 30.7, 27.5, 25.9, 18.3, –5.3.
Anal. Calcd for C13H12O5: C, 62.90; H, 4.87. Found: C, 62.93; H, 4.84.
Methyl (4-Formyl-7-methoxybenzo[b]furan-3-yl)acetate (62) from
2-Bromo-3-hydroxy-4-methoxybenzaldehyde
3-Hydroxy-4-methoxybenzaldehyde (10.0 g, 65.7 mmol) in CH2Cl2
(150 mL) was treated with NBS (11.7 g, 65.7 mmol) for 30 min at r.t. to
give 2-bromo-3-hydroxy-4-methoxybenzaldehyde (14.1 g, 93%).40
The preceding 2-bromo-3-hydroxy-4-methoxybenzaldehyde (20.4 g,
88.3 mmol) in DMF (200 mL) was treated with anhydrous K2CO3 (14.7
g, 106 mmol) and methyl trans-4-bromo-2-butenoate (11.5 mL, 17.5
g, 97.8 mmol), the suspension stirred under Ar for 12 h, poured into
H2O, and the light brown precipitate collected by filtration, washed
with cold EtOAc, and dried under high vacuum to give methyl trans-
4-(2-bromo-3-formyl-6-methoxyphenoxy)-2-butenoate (28.4 g, 98%)
as a colorless powder; mp 125–126 °C.
IR (film): 2951, 1730, 1719, 1670, 1583, 1489, 1366, 1280, 1254,
Methyl trans-4-(3-Formyl-2-iodo-6-methoxyphenoxy)-2-bute-
noate (61)
1231, 1176, 994, 971, 945, 900, 782 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.24 (d, J = 0.8 Hz, 1 H), 7.75 (d, J = 8.8
Hz, 1 H), 7.11 (dt, J = 15.6, 4.4 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.33
(dt, J = 15.7, 2.0 Hz, 1 H), 4.69 (dd, J = 4.4, 2.0 Hz, 2 H), 3.94 (s, 3 H),
3.77 (s, 3 H).
To 60 (19.5 g, 70.1 mmol) in DMF (50 mL) were added anhydrous
K2CO3 (11.6 g, 83.9 mmol) and methyl trans-4-bromo-2-butenoate
(10.0 mL, 15.2 g, 84.9 mmol). The suspension was stirred for 12 h un-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

X
T. Aechtner et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 190.7, 166.5, 158.4, 144.7, 142.6,
MS (EI, 70 eV): m/z (%) = 330 ([M+ – Br], 80), 278 (71), 277 (77), 175
127.3, 126.8, 123.1, 121.8, 110.9, 71.2, 56.3, 51.7.
(75), 161 (69), 53 (100).
MS (EI, 70 eV): m/z (%) = 330, 328 (1:1, [M+], 75), 299, 297 (1:1, 26),
Anal. Calcd for C12H12BrIO3: C, 35.07; H, 2.94. Found: C, 34.96; H, 3.04.
231, 229 (1:1, 96), 175, 173 (1:1, 49), 99 (100), 94 (89), 68 (57).
HRMS (EI, 70 eV): m/z [M+] calcd for C13H13BrO5: 327.9946; found:
327.9948.
To trans-3-(4-bromo-2-butenyloxy)-2-iodo-4-methoxybenzaldehyde
(56 mg, 0.136 mmol) was added MeNH2 in THF (2 M; 5 mL, 10 mmol).
After stirring for 1 h at r.t., the volatiles were removed under reduced
pressure, MeOH (5 mL) and H2O (1 mL) added, and the mixture was
stirred for 5 h. The solvent was removed, and the residue dried under
reduced pressure, followed by chromatography on silica gel, eluting
with EtOAc–Et3N (9:1), to yield trans-2-iodo-4-methoxy-3-[4-(me-
thylamino)-2-butenyloxy]benzaldehyde (22 mg, 45%) as a colorless
oil.
1H NMR (400 MHz, C6D6): δ = 10.25 (s, 1 H), 7.72 (d, J = 8.7 Hz, 1 H),
6.22 (d, J = 8.7 Hz, 1 H), 6.03 (dt, J = 15.5, 5.9 Hz, 1 H), 5.90 (dt, J = 15.2,
6.4 Hz, 1 H), 4.50 (d, J = 6.4 Hz, 2 H), 3.03 (s, 3 H), 2.83 (d, J = 6.0 Hz, 2
H), 2.09 (s, 3 H); NH not detected.
The conditions used for the intramolecular Heck coupling of iodide
61 failed for the corresponding bromide. The following recipe is the
result of a screen of catalyst, base, solvent, and amount of NaI (see SI),
scaled up. Methyl trans-4-(2-bromo-3-formyl-6-methoxyphenoxy)-
2-butenoate (914 mg, 2.78 mmol) and Pd2(dba)3 (145 mg, 0.158
mmol) were added to K2CO3 (782 mg, 5.66 mmol) in MeCN (30 mL) at
r.t. under N2. The mixture was stirred at 80–90 °C for 24 h, after
which TLC revealed the absence of starting material. Filtration
through a pad of Celite was followed by removal of the volatiles, dis-
solution of the residue in warm Et2O, and addition of pentane until
cloudiness appeared. After cooling to 4 °C for 12 h, 62 (587 mg, 85%)
precipitated as light brown crystals.
13C NMR (125 MHz, CDCl3): δ = 195.1, 157.7, 147.5, 129.0, 127.9,
127.3, 126.0, 111.7, 101.1, 73.0, 61.5, 56.2, 45.0.
trans-3-[4-(tert-Butyldimethylsilyloxy)-2-butenyloxy]-2-iodo-4-
methoxybenzaldehyde
Methyl cis- and trans-[7-Methoxy-4-(2-methoxyvinyl)benzo[b]fu-
ran-3-yl]acetate (63)
trans-1-Bromo-4-(tert-butyldimethylsilyloxy)-2-butene41 (640 mg,
2.41 mmol) was added to 60 (670 mg, 2.41 mmol) and anhydrous
K2CO3 (333 mg, 2.41 mmol) in DMF (4 mL) at r.t. After stirring for 12 h,
the mixture was poured into Et2O, washed twice with H2O, and dried
over MgSO4. Removal of the volatiles and chromatography on silica
gel, eluting with hexanes–Et2O (1:1), gave trans-3-[4-(tert-butyldi-
methylsilyloxy)-2-butenyloxy]-2-iodo-4-methoxybenzaldehyde (892
mg, 80%) as a colorless oil.
A stirred suspension of MOMPPh3Cl (10.3 g, 30.0 mmol) in THF
(60 mL) at 0 °C was treated with increments of KOt-Bu (3.37 g,
30 mmol) over a period of 15 min, and stirring continued for another
45 min, followed by the addition of 62 (4.96 g, 20 mmol) over a peri-
od of 15 min. After further stirring for 2 h at 0 °C, the mixture was
treated with H2O (100 mL), the volatiles were removed under reduced
pressure, and the residue was extracted with EtOAc (3 × 150 mL). The
combined organic layers were washed with sat. aq NH4Cl, then sat. aq
Na2SO4, dried over Na2SO4, filtered, and the solvent was removed un-
der reduced pressure. Column chromatography on silica gel, eluting
with PE–EtOAc (gradient, 7:3 to 6:4), yielded compound 63 (3.89 g,
70%) as a yellow solid consisting of a mixture of cis- and trans-iso-
mers (1:2).
1H NMR (300 MHz, CDCl3): δ (cis-isomer) = 7.64 (d, J = 8.4 Hz, 1 H),
7.57 (s, 1 H), 6.77 (d, J = 8.4 Hz, 1 H), 6.17 (d, J = 7.2 Hz, 1 H), 5.55 (d,
J = 7.2 Hz, 1 H), 3.975 (s, 3 H), 3.83 (br s, 2 H), 3.74 (s, 3 H), 3.70 (s, 3
H).
1H NMR (300 MHz, CDCl3): δ (trans-isomer) = 7.57 (s, 1 H), 6.99 (d, J =
8.4 Hz, 1 H), 6.75 (d, J = 12.6 Hz, 1 H), 6.71 (d, J = 8.4 Hz, 1 H), 6.16 (d,
J = 12.6 Hz, 1 H), 3.969 (s, 3 H), 3.82 (br s, 2 H), 3.687 (s, 3 H), 3.685 (s,
3 H).
IR (film): 2954, 2885, 2856, 1683, 1575, 1480, 1439, 1361, 1300,
1276, 1255, 1136, 1102, 1025, 836, 777, 734 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 9.99 (s, 1 H), 7.68 (d, J = 8.6 Hz, 1 H),
6.93 (d, J = 8.6 Hz, 1 H), 6.03 (dt, J = 15.4, 6.0 Hz, 1 H), 5.91 (dt, J = 15.4,
4.2 Hz, 1 H), 4.54 (d, J = 6.0 Hz, 2 H), 4.19 (d, J = 4.2 Hz, 2 H), 3.73 (s, 3
H), 0.88 (s, 9 H), 0.07 (s, 3 H), 0.04 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 195.2, 157.8, 147.6, 134.3, 130.5,
129.0, 127.3, 124.7, 111.7, 73.1, 62.9, 56.2, 25.9, 18.4, –5.22.
MS (EI, 70 eV): m/z (%) = 335 ([M+ – I], 2), 309 (21), 294 (7), 278 (100),
254 (27), 218 (6), 206 (6), 189 (6), 161 (6), 127 (16), 101 (10), 75 (52),
57 (13).
trans-2-Iodo-4-methoxy-3-[4-(methylamino)-2-butenyloxy]benz-
aldehyde
13C NMR (75 MHz, CDCl3): δ = 171.5, 149.1, 147.4, 144.9, 144.1, 143.8,
143.4, 126.4, 124.2, 122.9, 121.7, 120.5, 113.9, 106.8, 106.5, 101.2,
56.1, 56.0, 52.1, 30.8.
A mixture of 60 (2.00 g, 7.19 mmol) and anhydrous K2CO3 (1.00 g,
7.24 mmol) in DMF (20 mL) was stirred for 10 min under N2 at r.t.,
followed by the addition of trans-1,4-dibromo-2-butene (3.00 g,
14.03 mmol). After stirring for 3 h, the solution was diluted with H2O
(20 mL), extracted with CH2Cl2 (3 × 50 mL), the organic extracts dried
over Na2SO4, and the volatiles removed. The residue was chromato-
graphed on silica gel, eluting with Et2O–hexanes (4:1), to afford trans-
3-(4-bromo-2-butenyloxy)-2-iodo-4-methoxybenzaldehyde (1.60 g,
54%) as a colorless solid.
MS (EI, 70 eV): m/z (%) = 276 ([M+], 100), 261 (11), 201 (84), 185 (17).
3,4,6,7-Tetrahydro-10-methoxyoxocino[4,5,6-cd]benzo[b]furan-6-
ol and [3-(2-Hydroxyethyl)-7-methoxybenzo[b]furan-4-yl]acetal-
dehyde (64)
Ester 63 (1.93 g, 6.99 mmol) in THF (25 mL) was added dropwise to
LAH (265 mg, 6.99 mmol) in THF (10 mL) at r.t. After stirring for 12 h,
the mixture was treated with aq HCl (1 N; 1 mL) and the solution fil-
tered through a pad of silica gel, eluting thoroughly with THF, provid-
ing cis- and trans-2-[7-methoxy-4-(2-methoxyvinyl)benzo[b]furan-
3-yl]ethanol in THF, to be used directly in the next step.
IR (KBr): 1673, 1576, 1480, 1277, 1254, 1022 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 10.02 (s, 1 H), 7.72 (d, J = 8.6 Hz, 1 H),
6.98 (d, J = 8.6 Hz, 1 H), 6.11 (m, 2 H), 4.55 (d, J = 3.8 Hz, 2 H), 4.00 (d,
J = 3.8 Hz, 2 H), 3.95 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 195.0, 157.7, 147.4, 130.2, 130.1,
129.0, 127.6, 111.8, 101.0, 72.2, 56.3, 31.6.
MS (EI, 70 eV): m/z (%) = 248 ([M+], 100), 215 (29), 185 (18), 174 (15),
115 (19).
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To the above solution was added aq HCl (1 N; 5 mL), and the mixture
heated at reflux for 4 h, cooled, H2O (30 mL) added, and most of the
THF removed under reduced pressure. The remainder was extracted
with EtOAc, the combined organic layers were washed with sat. aq
NaHCO3 and sat. aq Na2SO4, dried over Na2SO4, filtered, and the sol-
vent was removed under reduced pressure. Column chromatography
on silica gel, eluting with PE–EtOAc (gradient, 7:3 to 2:3), sequestered
64 (663 mg, 40%) as a colorless solid consisting of an equilibrating
mixture of aldehyde and hemiacetal (0.6:1).
duced pressure and the residue purified by silica gel chromatography,
eluting with PE–EtOAc (gradient, 7:3 to1:1), to supply 66 (44.0 mg,
28%; 42% based on recovered 65) as a colorless oil, followed by 65
(39.0 mg, 33%).
1H NMR (500 MHz, CDCl3): δ = 7.44 (s, 1 H), 7.04 (d, J = 8.1 Hz, 1 H),
6.45 (d, J = 8.1 Hz, 1 H), 4.59 (td, J = 6.6, 2.1 Hz, 1 H), 4.35 (m, 2 H),
3.96 (s, 3 H), 3.29 (d, J = 6.6 Hz, 2 H), 3.15 (t, J = 6.8 Hz, 2 H), 2.43 (d, J =
2.1 Hz, 1 H), 1.16 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 178.7, 145.0, 144.7, 142.6, 127.9,
125.3, 121.8, 116.9, 106.1, 84.0, 73.9, 63.49, 63.42, 56.0, 39.8, 38.7,
27.1, 24.7.
IR (KBr): 3593, 3013, 2939, 2841, 1724, 1630, 1585, 1516, 1464, 1411,
1362, 1285, 1252, 1226, 1212, 1171, 1101, 1065, 1043, 909, 802, 784,
679, 630, 556 cm–1
.
MS (EI, 70 eV): m/z (%) = 344 ([M+], 13), 289 (89), 205 (31), 57 (100).
1H NMR (500 MHz, acetone-d6): δ (aldehyde isomer) = 9.72 (t, J = 1.5
Hz, 1 H), 7.65 (s, 1 H), 6.99 (d, J = 8.0 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H),
4.03 (d, J = 1.5 Hz, 2 H), 3.94 (s, 3 H), 3.83 (t, J = 7.0 Hz, 2 H), 2.93 (t, J =
7.0 Hz, 2 H); OH not detected.
{2-[Dimethyl(trimethylsilylethynyl)silyl]ethyl}(ethynyl)dimethyl-
silane (67)
To 1,2-bis(ethynyldimethylsilyl)ethane (972 mg, 5.00 mmol)51 in THF
(10 mL) at –78 °C was added dropwise BuLi in hexanes (2.5 M;
400 μL, 1.00 mmol), the mixture stirred for 1 h, and TMSCl (152 μL,
130 mg, 1.2 mmol) added slowly. The solution was stirred for another
h at –78 °C and then allowed to warm to r.t. during 2 h. The volatiles
were removed under reduced pressure, the residue was dissolved in
Et2O, and the solution washed with H2O and sat. aq Na2SO4, dried over
Na2SO4, filtered, and concentrated to an oil. Vacuum transfer (10–3
torr) at 110 °C (oil bath temperature) sequestered recovered starting
material (363 mg), leaving behind 67 (103 mg, 39%) as a light yellow
oil.
1H NMR (500 MHz, acetone-d6): δ (acetal isomer) = 7.54 (s, 1 H), 6.88
(d, J = 8.0 Hz, 1 H), 6.73 (d, J = 8.0 Hz, 1 H), 5.36 (d, J = 4.5 Hz, 1 H), 5.07
(dt, J = 13.0, 4.5 Hz, 1 H), 4.39 (ddd, J = 13.0, 7.3, 2.7 Hz, 1 H), 3.92 (s, 3
H), 3.52 (dddd, J = 11.7, 6.5, 4.7, 1.0 Hz, 1 H), 3.28 (dd, J = 14.3, 8.6 Hz,
1 H), 3.21 (dddd, J = 14.2, 6.5, 4.7, 1.0 Hz, 1 H), 2.99 (ddd, J = 14.3, 3.0,
1.2 Hz, 1 H), 2.89 (m, 1 H).
13C NMR (125 MHz, acetone-d6): δ = 200.2, 145.6, 145.5, 145.5, 143.6,
141.4, 132.2, 129.2, 126.3, 124.5, 124.0, 119.6, 119.0, 118.8, 107.2,
106.9, 96.1, 62.4, 62.3, 60.3, 56.2, 56.2, 47.7, 41.0, 28.9, 26.1.
MS (EI, 70 eV): m/z (%) = 234 ([M+], 60), 205 (51), 175 (100), 163 (32).
1H NMR (500 MHz, CDCl3): δ = 2.38 (s, 1 H), 0.60 (s, 4 H), 0.18 (s, 6 H),
0.16 (s, 9 H), 0.14 (s, 6 H).
1-[3-(2-Hydroxyethyl)-7-methoxybenzo[b]furan-4-yl]-3-butyn-2-
13C NMR (125 MHz, CDCl3): δ = 114.5, 112.8, 93.5, 89.3, 8.24, 8.10,
ol (65)
A solution of 64 (117 mg, 0.50 mmol) in THF (1 mL) at 0 °C was treat-
ed with ethynylmagnesium bromide in THF (0.5 M; 4.00 mL,
2.00 mmol) and the mixture allowed to reach r.t. during 6 h. Sat. aq
NH4Cl was added, the solvent removed under reduced pressure, and
the residue diluted with EtOAc and washed with H2O and sat. aq Na2-
SO4. The organic layer was dried over Na2SO4, filtered, and the solvent
evaporated to give a crude oil, which was subjected to silica gel chro-
matography, eluting with PE–EtOAc (1:1), to result in 65 (95.0 mg,
73%) as a colorless solid.
1H NMR (500 MHz, CDCl3): δ = 7.50 (s, 1 H), 7.04 (d, J = 8.1 Hz, 1 H),
6.75 (d, J = 8.1 Hz, 1 H), 4.61 (br t, J = 5.4 Hz, 1 H), 3.96 (s, 3 H), 3.95
(td, J = 6.5, 1.8 Hz, 2 H), 3.30 (ABXm, 2 H), 3.11 (tt, J = 6.5, 1.3 Hz, 2 H),
2.46 (d, J = 2.1 Hz, 1 H), 2.22 (br s, 1 H), 1.63 (br s, 1 H).
–0.05, –2.37, –2.50.
MS (EI, 70 eV): m/z (%) = 266 ([M+], 1), 251 (50), 223 (22), 155 (100),
140 (21), 83 (20), 73 (31).
Benzo[b]furanyldiynediol 68
To compound 67 (103 mg, 0.386 mmol) in THF (1 mL) at –78 °C was
added dropwise BuLi in hexanes (2.5 M; 154 μL, 0.385 mmol) and the
mixture stirred for
1 h at –78 °C. Subsequently, 64 (30.0 mg,
0.128 mmol) in THF (1 mL) was added slowly and the solution al-
lowed to reach r.t. over a period of 3 h. After treatment with sat. aq
NH4Cl, the solvent was removed under reduced pressure, the residue
taken up in EtOAc, washed with H2O, then sat. aq Na2SO4, and the or-
ganic layer dried over Na2SO4. Filtration, followed by removal of sol-
vent, gave a crude oil, which was purified by silica gel chromatogra-
phy, eluting with PE–EtOAc (gradient, 7:3 to 1:1), to yield 68 (16.0 mg,
25%) as a pale yellow oil.
13C NMR (125 MHz, CDCl3): δ = 145.1, 144.8, 142.6, 128.0, 125.1,
121.9, 117.4, 106.1, 84.0, 74.0, 63.4, 62.2, 56.0, 39.8, 28.4.
MS (EI, 70 eV): m/z (%) = 260 ([M+], 14), 205 (100), 163 (41).
1H NMR (500 MHz, CDCl3): δ = 7.48 (s, 1 H), 7.04 (d, J = 8.1 Hz, 1 H),
6.74 (d, J = 8.1 Hz, 1 H), 4.58 (t, J = 6.5 Hz, 1 H), 3.96 (s, 3 H), 3.95 (td,
J = 6.5, 1.5 Hz, 2 H), 3.25 (d, J = 6.5 Hz, 2 H), 3.11–3.08 (m, 2 H), 1.86
(br s, 2 H), 0.51 (s, 4 H), 0.15 (s, 9 H), 0.12 (s, 6 H), 0.08 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 145.1, 144.7, 142.5, 128.1, 125.4,
122.0, 117.5, 114.6, 113.0, 106.1, 89.9, 64.0, 62.1, 56.0, 55.2, 39.8,
28.5, 8.2, 8.1, –0.1, –2.4, –2.5.
2-[4-(2-Hydroxy-3-butynyl)-7-methoxybenzo[b]furan-3-yl]ethyl
2,2-Dimethylpropanoate (66)
To a solution of 65 (119 mg, 0.46 mmol) in py–CH2Cl2 (1:1, 4 mL) at
0 °C was added PvCl (56.0 μL, 55.0 mg, 0.46 mmol) in one portion. Af-
ter stirring for 4 h at 0 °C, additional PvCl (20.0 μL, 19.6 mg,
0.16 mmol) was introduced and stirring continued for 2 h. Although
some 65 remained [TLC; Rf = 0.60 (PE–EtOAc, 1:1)], the mixture was
treated with H2O (50 mL) and EtOAc (10 mL), and the organic layer
washed with aq HCl (1 M), sat. aq CuSO4, and sat. aq Na2SO4. After
drying over Na2SO4 and filtration, the solvent was removed under re-
HRMS (EI, 70 eV): m/z [M+] calcd for C26H40O4Si3: 500.2234; found:
500.2231.
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exo-(η5-Cyclopentadienyl){(5,6,7,7a-η4)-2-[(4aR*,8R*,9cS*)-
4a,8,9,9c-tetrahydro-8-hydroxy-3-methoxy-5,6-bis(trimethylsi-
lyl)phenanthro[4,5-bcd]furan-9c-yl]ethyl 2,2-Dimethylpropa-
noate}cobalt (69)
Anal. Calcd for C10H11IO4: C, 37.29; H, 3.44. Found: C, 37.06; H, 3.01.
To the preceding 3-(1,3-dioxolan-2-yl)-2-iodo-6-methoxyphenol
(640 mg, 1.99 mmol) and K2CO3 (275 mg, 2.0 mmol) in DMF (4 mL)
was added methyl trans-4-bromo-2-butenoate (430 mg, 2.40 mmol),
the mixture stirred at r.t. for 12 h, and then poured into Et2O and
washed twice with H2O. After drying over MgSO4, silica gel chroma-
tography, eluting with hexanes–Et2O (1:1), gave methyl trans-4-[3-
(1,3-dioxolan-2-yl)-2-iodo-6-methoxyphenoxy]-2-butenoate (0.67 g,
80%). Alternatively, to 61 (2.25 g, 5.98 mmol) in C6H6 (100 mL) were
added 1,2-ethanediol (1.12 g, 18.0 mmol) and PPTS (251 mg, 1.00
mmol), and the mixture was heated to reflux for 3 h, while the evolv-
ing H2O was collected in a Dean–Stark trap. The volatiles were re-
moved, the residue was taken up in CH2Cl2, the solution washed with
sat. aq NaHCO3 (1 M; 100 mL), dried over MgSO4, and the solvent
evaporated. Silica gel chromatography, eluting with hexanes–Et2O
(1:1), supplied the same butenoate (2.40 g, 96%) as a colorless pow-
der; mp 82–84 °C.
CpCo(C2H4)2 (25.0 mg, 0.139 mmol) in 8 (2.5 mL) was added over a
period of 10 min at r.t. to 66 (44.0 mg, 0.128 mmol) in THF–8 (1:1,
5 mL) and the mixture stirred for 21 h. The volatiles were removed
under high vacuum, and the residue was subjected to silica gel chro-
matography, eluting with PE–EtOAc (9:1), to yield 69 admixed with a
minor isomer (6:1; 11.0 mg, 13%; 16% based on recovered 66) as a red
oil, followed by 66 (6.00 mg, 14%).
1H NMR (500 MHz, C6D6): δ = 6.74 (d, J = 7.9 Hz, 1 H), 6.61 (dt, J = 7.9,
0.9 Hz, 1 H), 5.45 (s, 1 H), 4.39 (ddd, J = 11.0, 8.5, 6.0 Hz, 1 H), 4.23 (s,
5 H), 4.06 (s, 1 H), 3.81–3.76 (m, 2 H), 3.65 (s, 3 H), 3.17 (dd, J = 16.8,
8.6 Hz, 1 H), 2.85 (ddd, J = 16.8, 8.6, 0.9 Hz, 1 H), 2.14 (d, J = 5.8 Hz, 1
H), 2.10–2.00 (m, 2 H), 1.06 (s, 9 H), 0.46 (s, 9 H), 0.38 (s, 9 H).
13C NMR (125 MHz, C6D6): δ = 177.8, 146.4, 144.0, 138.6, 128.3, 119.1,
113.8, 96.8, 84.4, 82.6, 81.4, 77.9, 73.2, 58.5, 56.4, 50.7, 38.3 (2 C),
26.9, 2.73, 2.67; one Cquat not detected.
IR (KBr): 2952, 2894, 2838, 1719, 1664, 1588, 1483, 1440, 1379, 1304,
1280, 1254, 1170, 1143, 1106, 1072, 1027, 960, 904, 835, 811, 737,
682, 664, 627 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.29 (d, J = 8.6 Hz, 1 H), 7.10 (dt, J =
17.7, 4.3 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 6.34 (dt, J = 17.7, 2.0 Hz, 1
H), 5.89 (s, 1 H), 4.62 (dd, J = 4.3, 2.0 Hz, 2 H), 4.12 (AA′m, 2 H), 4.03
(BB′m, 2 H), 3.82 (s, 3 H), 3.74 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.8, 153.2, 147.0, 143.2, 132.3,
123.8, 121.6, 112.1, 106.3, 96.5, 70.8, 65.3, 56.1, 51.7.
MS (EI, 70 eV): m/z (%) = 420 ([M+], 1), 362 (8), 322 (100), 277 (49),
250 (49), 234 (25), 219 (31), 207 (12), 195 (23), 175 (35), 151 (15),
127 (41), 91 (17), 73 (64), 51 (28).
Methyl [4-(1,3-Dioxolan-2-yl)-7-methoxybenzo[b]furan-3-yl]ace-
tate (70)
A solution of 62 (4.81 g, 19.4 mmol) and PPTS (251 mg, 1.00 mmol) in
1,2-ethanediol (10 mL) and PhMe (110 mL) was boiled for 12 h, while
the evolving H2O was collected in a Dean–Stark trap. The mixture was
washed with aq NaHCO3 (1 M; 100 mL), dried over MgSO4, and con-
centrated to yield 70 (5.50 g, 97%) as a clear oil. The material was
>95% pure by GC/MS and 1H NMR analysis, but can be purified further
by silica gel chromatography, eluting with PE–EtOAc (2:1), to produce
a colorless solid; mp 94–95 °C.
Anal. Calcd for C15H17IO6: C, 42.88; H, 4.08. Found: C, 43.10; H, 4.01.
IR (KBr): 2953, 2893, 2843, 1736, 1629, 1583, 1437, 1395, 1289, 1235,
The preceding methyl trans-4-[3-(1,3-dioxolan-2-yl)-2-iodo-6-me-
thoxyphenoxy]-2-butenoate (840 mg, 2.00 mmol) in stirred MeCN (6
mL) and H2O (0.4 mL) at r.t. was treated with Et3N (0.51 g, 5 mmol),
then Pd(OAc)2 (11 mg, 0.05 mmol) and TPPTS (50 mg, 0.09 mmol),
and stirring continued for 10 h. The reaction mixture was diluted
with CH2Cl2, washed with aq NH4Cl, dried over MgSO4, and the prod-
uct purified by silica gel chromatography, eluting with hexanes–Et2O
(1:4), to give 70 (580 mg, 99%).
1198, 1175, 1119, 1086, 1050, 1022, 964, 938, 914, 802, 736 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.64 (s, 1 H), 7.35 (d, J = 8.3 Hz, 1 H),
6.75 (d, J = 8.3 Hz, 1 H), 6.05 (s, 1 H), 4.15 (AA′m, 2 H), 4.05 (BB′m, 2
H), 3.98 (s, 3 H), 3.87 (s, 2 H), 3.69 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 171.8, 146.3, 145.3, 144.2, 126.7,
122.6, 121.7, 113.6, 105.5, 102.1, 64.8, 56.1, 52.1, 30.9.
MS (EI, 70 eV): m/z (%) = 292 ([M+], 100), 232 (40), 220 (43), 219 (43),
189 (55), 161 (53).
2-[4-(1,3-Dioxolan-2-yl)-7-methoxybenzo[b]furan-3-yl]ethanol
(71)
Acetal 70 from 3-Hydroxy-2-iodo-4-methoxybenzaldehyde (60)
A solution of 70 (1.26 g, 4.31 mmol) in THF (40 mL) was cooled to 0 °C
and added via cannula to a stirred suspension of LAH pellets (760 mg,
20.0 mmol) in THF (20 mL) at 0 °C under N2. After stirring for 30 min
at 0 °C, aq NaOH (1 M; 20 mL) was introduced cautiously. The result-
ing gray precipitate was removed by filtration, the residual liquid di-
luted with EtOAc (50 mL) and washed with H2O (50 mL), the organic
layer dried over Na2SO4, and finally the volatiles removed to give 71
(1.00 g, 88%) as a clear oil, >95% pure by GC/MS and 1H NMR analysis.
To 60 (2.78 g, 10 mmol) in C6H6 (100 mL) were added 1,2-ethanediol
(1.86 g, 29 mmol) and PPTS (251 mg, 1 mmol), and the mixture was
heated to reflux for 3 h, while the evolving H2O was collected in a
Dean–Stark trap. The volatiles were removed, the residue was taken
up in CH2Cl2, the solution washed with sat. aq NaHCO3 (1 M; 100 mL),
dried over MgSO4, and the solvent evaporated. Silica gel chromatogra-
phy, eluting with hexanes–Et2O (1:2), delivered 3-(1,3-dioxolan-2-yl)-
2-iodo-6-methoxyphenol (2.13 g, 66%) as a pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 7.56 (s, 1 H), 7.42 (d, J = 8.1 Hz, 1 H),
6.80 (d, J = 8.1 Hz, 1 H), 6.22 (s, 1 H), 4.21 (AA′m, 2 H), 4.10 (BB′m, 2
H), 4.01 (s, 3 H), 3.96 (t, J = 6.2 Hz, 2 H), 3.11 (t, J = 6.2 Hz, 2 H); OH not
detected.
IR (film): 3425, 2943, 2877, 1671, 1585, 1560, 1490, 1283, 1203,
1087, 1013, 808, 654, 514 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.10 (d, J = 8.4 Hz, 1 H), 6.80 (d, J = 8.4
Hz, 1 H), 6.31 (br s, 1 H), 5.92 (s, 1 H), 4.12 (AA′m, 2 H), 4.03 (BB′m, 2
H), 3.85 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 146.7, 145.5, 132.0, 119.1, 110.1,
106.2, 85.1, 65.2, 56.4.
4-(1,3-Dioxolan-2-yl)-7-methoxy-3-[2-(triisopropylsilyloxy)eth-
yl]benzo[b]furan (72)
To 71 (3.00 g, 11.4 mmol) and imidazole (1.55 g, 22.8 mmol) in DMF
(10 mL) was added dropwise TIPSCl (3.90 mL, 3.51 g, 18.2 mmol) and
the mixture stirred at r.t. for 17 h. The solution was poured into aq
MS (EI, 70 eV): m/z (%) = 322 ([M+], 100), 277 (31), 250 (17), 235 (8),
195 (9), 151 (19), 122 (12), 73 (86), 63 (11), 51 (17).
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NaHCO3 (1 M; 50 mL), extracted with Et2O (2 × 50 mL), and the com-
bined organic layers were washed with H2O and sat. aq Na2SO4. After
drying over Na2SO4 and filtration, the solvent was removed and the
residue subjected to silica gel chromatography, eluting with PE–EtOAc
(gradient, 9:1 to 7:3), to yield 72 (4.60 g, 96%) as a colorless oil.
IR (film): 3011, 2937, 1694, 1620, 1563, 1463, 1395, 1291, 1098,
1040, 915, 806, 784 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.1 (s, 1 H), 7.71 (d, J = 8.4 Hz, 1 H),
7.59 (s, 1 H), 6.83 (d, J = 8.4 Hz, 1 H), 4.02 (s, 3 H), 3.86 (t, J = 6.0 Hz, 2
H), 3.14 (t, J = 6.0 Hz, 2 H), 0.81 (s, 9 H), –0.08 (s, 6 H).
1H NMR (300 MHz, CDCl3): δ = 7.52 (s, 1 H), 7.38 (d, J = 8.4 Hz, 1 H),
6.74 (d, J = 8.4 Hz, 1 H), 6.21 (s, 1 H), 4.15 (AA′m, 2 H), 4.05 (BB′m, 2
H), 3.98 (s, 3 H), 3.97 (t, J = 7.1 Hz, 2 H), 3.03 (t, J = 7.1 Hz, 2 H), 1.05
(m, 21 H).
13C NMR (125 MHz, CDCl3): δ = 146.1, 144.9, 143.0, 130.8, 122.9,
121.0, 117.9, 105.2, 101.7, 65.0, 63.1, 56.0, 28.8, 18.0, 11.9.
MS (EI, 70 eV): m/z (%) = 277 ([M+ – 57], 100), 175 (40), 75 (42).
Anal. Calcd for C18H26O4Si: C, 64.64; H, 7.83. Found: C, 64.69; H, 8.12.
1-{7-Methoxy-3-[2-(triisopropylsilyloxy)ethyl]benzo[b]furan-4-
yl}-3-butyn-1-ol (76)
A solution of 2-propynylmagnesium bromide was prepared by stir-
ring Mg turnings (598 mg, 24.6 mmol) in Et2O (20 mL) and dripping in
3-bromo-1-propyne in PhMe (8.36 M; 2.5 mL, 20.9 mmol) at a rate
slow enough to avoid excessive boiling. A small amount of HgCl2 (5
mg, 0.018 mmol) was added to speed the initiation of the Grignard
formation. After stirring for 30 min, the cloudy mixture was cooled in
an ice bath, 74 (2.53 g, 6.72 mmol) in Et2O (40 mL) added via cannula,
and stirring continued for another 30 min. Quenching with sat. aq
NH4Cl (10 mL) was followed by separation of the organic layer, which
was washed with aq NaHCO3 (1 M; 50 mL), dried over MgSO4, and
concentrated. The residue was chromatographed on silica gel, eluting
with hexanes–EtOAc (5:1), to yield 76 (2.38 g, 85%) as a clear oil.
MS (EI, 70 eV): m/z (%) = 420 ([M+], 74), 333 (35), 261 (21), 203 (100),
175 (90), 131 (23), 103 (18), 73 (27).
3-[2-(tert-Butyldimethylsilyloxy)ethyl]-4-(1,3-dioxolan-2-yl)-7-
methoxybenzo[b]furan (73)
To 71 (2.10 g, 7.95 mmol) in DMF (10 mL) was added imidazole (2.00
g, 29.4 mmol) and TBDMSCl (3.00 g, 19.9 mmol). The resulting yellow
solution was stirred for 2 h at r.t., poured into aq NaHCO3 (1 M; 50
mL), extracted with Et2O (2 × 50 mL), and the combined organic layers
were dried over Na2SO4. Evaporation of the volatiles delivered 73
(2.97 g, 99%) as a yellow oil.
IR (CH2Cl2): 2954, 2930, 2892, 2857, 1691, 1627, 1579, 1549, 1513,
1483, 1463, 1393, 1289, 1255, 1225, 1174, 1099, 1058, 1024, 835,
IR (film): 3312, 2941, 2865, 2121, 1628, 1579, 1509, 1464, 1390,
1367, 1287, 1213, 1172, 1104, 1059, 919, 883, 851, 803, 741, 682,
798, 776 cm–1
.
640, 509 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.52 (s, 1 H), 7.41 (d, J = 8.4 Hz, 1 H),
6.77 (d, J = 8.4 Hz, 1 H), 6.24 (s, 1 H), 4.17 (AA′m, 2 H), 4.08 (BB′m, 2
H), 4.00 (s, 3 H), 3.92 (t, J = 7.1 Hz, 2 H), 3.04 (t, J = 7.1 Hz, 2 H), 0.89 (s,
9 H), 0.03 (s, 6 H).
1H NMR (500 MHz, CDCl3): δ = 7.55 (s, 1 H), 7.31 (d, J = 8.4 Hz, 1 H),
6.78 (d, J = 8.4 Hz, 1 H), 5.40 (td, J = 6.3, 2.0 Hz, 1 H), 4.02 (t, J = 6.6 Hz,
2 H), 3.99 (s, 3 H), 3.07 (ABXm, 2 H), 2.76 (m, 2 H), 2.55 (br d, J =
3.0 Hz, 1 H), 2.07 (t, J = 2.4 Hz, 1 H), 1.04 (m, 21 H).
13C NMR (100 MHz, CDCl3): δ = 146.1, 144.9, 142.9, 127.3, 122.9,
13C NMR (125 MHz, CDCl3): δ = 145.2, 144.7, 143.0, 128.1, 126.9,
120.9, 117.7, 105.2, 101.6, 64.9, 62.8, 55.9, 25.8, 18.2, –5.46.
119.8, 117.6, 105.7, 80.8, 70.9, 68.4, 63.3, 56.0, 29.0, 28.7, 17.9, 11.9.
MS (EI, 70 eV): m/z (%) = 378 ([M+], 25), 277 (30), 203 (52), 175 (45),
MS (EI, 70 eV): m/z (%) = 416 ([M+], 1), 398 (12), 377 (13), 333 (60),
73 (100).
225 (100), 203 (80), 175 (27).
Anal. Calcd for C20H30O5Si: C, 63.46; H, 7.99. Found: C, 63.49; H, 7.91.
Anal. Calcd for C24H36O4Si: C, 69.19; H, 8.71. Found: C, 69.06; H, 8.95.
7-Methoxy-3-[2-(triisopropylsilyloxy)ethyl]benzo[b]furan-4-car-
1-{3-[2-(tert-Butyldimethylsilyloxy)ethyl]-7-methoxybenzo[b]fu-
baldehyde (74)
ran-4-yl}-3-butyn-1-ol (77)
A solution of 72 (3.15 g, 7.49 mmol) and PPTS (374 mg, 1.49 mmol) in
acetone (100 mL) and H2O (10 mL) was heated to reflux for 1 h. Aq
NaHCO3 (1 M; 50 mL) was added, the solution extracted with Et2O
(3 × 50 mL), and the combined organic extracts were dried over
MgSO4 and concentrated to yield 74 (2.53 g, 90%) as a yellow liquid.
1H NMR (500 MHz, CDCl3): δ = 10.2 (s, 1 H), 7.75 (d, J = 8.4 Hz, 1 H),
7.65 (s, 1 H), 6.87 (d, J = 8.4 Hz, 1 H), 4.06 (s, 3 H), 3.98 (t, J = 6.0 Hz, 2
H), 3.19 (td, J = 6.0, 0.9 Hz, 2 H), 1.00 (m, 3 H), 0.99 (s, 18 H).
13C NMR (125 MHz, CDCl3): δ = 189.9, 150.1, 145.5, 145.2, 130.7,
129.0, 124.7, 119.1, 105.4, 62.9, 56.3, 30.0, 17.9, 11.9.
MS (EI, 70 eV): m/z (%) = 333 ([M+ – 43], 100), 261 (17), 203 (20), 175
(35).
A solution of 2-propynylmagnesium bromide was prepared by stir-
ring Mg turnings (292 mg, 12.0 mmol) in Et2O (2 mL) and dripping in
3-bromo-1-propyne in PhMe (8.36 M; 71 μL, 0.59 mmol). A small
amount of HgCl2 (5 mg, 0.018 mmol) was added as initiator. After vis-
ible cloudiness signaled initiation of the Grignard reagent formation,
more 3-bromo-1-propyne in PhMe (1.26 mL, 10.5 mmol) and Et2O (6
mL) was added in portions via syringe. The mixture was stirred for 30
min, using a cold H2O bath to regulate the temperature when reflux
became too vigorous. The solution was cooled in an ice bath, 75 (526
mg, 1.57 mmol) in Et2O (10 mL) added, and the mixture stirred for 30
min and warmed to r.t. Dilution with Et2O (10 mL) was followed by
quenching with sat. aq NH4Cl (3 mL), while cooling in an ice bath. The
organic layer was washed with H2O (2 × 20 mL), dried over MgSO4,
concentrated, and the residue chromatographed on silica gel, eluting
with hexanes–Et2O (2:1), to deliver 77 (488 mg, 83%) as a light yellow
oil.
3-[2-(tert-Butyldimethylsilyloxy)ethyl]-7-methoxybenzo[b]furan-
4-carbaldehyde (75)
A solution of 73 (3.75 g, 9.91 mmol) and PPTS (100 mg, 0.40 mmol) in
acetone (50 mL) and H2O (5 mL) was stirred at r.t. for 16 h. The mix-
ture was treated with aq NaHCO3 (1 M; 50 mL) and extracted with
Et2O (3 × 50 mL). The organic extracts were dried over MgSO4 and
concentrated to obtain 75 (1.79 g, 54%) as a light yellow oil.
IR (film): 3408, 3310, 2954, 2930, 2857, 2121, 1628, 1579, 1510,
1471, 1464, 1403, 1287, 1256, 1215, 1172, 1097, 1057, 1031, 908,
837, 810, 778, 639 cm–1
.
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T. Aechtner et al.
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Synthesis
1H NMR (500 MHz, CDCl3): δ = 7.52 (s, 1 H), 7.31 (d, J = 8.2 Hz, 1 H),
6.80 (d, J = 8.2 Hz, 1 H), 5.40 (ddd, J = 6.5, 6.4, 4.5 Hz, 1 H), 4.00 (s, 3 H),
3.94 (t, J = 6.4 Hz, 2 H), 3.06 (m, 2 H), 2.77 (dd, J = 6.4, 2.6 Hz, 2 H),
2.70 (d, J = 4.5 Hz, 1 H), 2.08 (t, J = 2.6 Hz, 1 H), 0.86 (s, 9 H), 0.01 (s, 6
H).
To the preceding cis-3-[2-(tert-butyldimethylsilyloxy)ethyl]-7-me-
thoxy-4-[4-(trimethylsilyl)-1-buten-3-ynyl]benzo[b]furan (240 mg,
0.56 mmol) in MeOH (20 mL) and Et2O (10 mL) was added K2CO3 (138
mg, 1.00 mmol). The mixture was stirred for 2 h at r.t., washed with
H2O (2 × 10 mL), the organic layer dried over MgSO4, and the solvent
removed to present 79 (197 mg, 99%) as a yellow oil.
13C NMR (100 MHz, CDCl3): δ = 145.2, 144.7, 142.8, 126.9, 119.8,
117.6, 105.7, 80.8, 70.8, 68.4, 63.2, 55.9, 28.6, 28.5, 25.8, 18.2, –5.52 (2
C).
MS (EI, 70 eV): m/z (%) = 374 ([M+], 1), 356 (19), 277 (51), 225 (92),
1H NMR (500 MHz, CDCl3): δ = 8.09 (d, J = 8.4 Hz, 1 H), 7.49 (s, 1 H),
7.25 (d, J = 11.9 Hz, 1 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.70 (dd, J = 11.9, 2.6
Hz, 1 H), 4.02 (s, 3 H), 3.89 (t, J = 7.0 Hz, 2 H), 3.22 (d, J = 2.6 Hz, 1 H),
2.99 (t, J = 7.0 Hz, 2 H), 0.88 (s, 9 H), 0.01 (s, 6 H).
13C NMR (125 MHz, CDCl3): δ = 145.7, 144.6, 143.0, 137.4, 127.8,
123.5, 122.7, 120.1, 118.0, 105.7, 82.6, 82.1, 62.8, 56.0, 28.9, 25.9,
18.3, –5.42.
203 (100), 186 (20), 175 (25), 75 (37).
cis-3-[2-(tert-Butyldimethylsilyloxy)ethyl]-4-(2-iodovinyl)-7-me-
thoxybenzo[b]furan (78)
MS (EI, 70 eV): m/z (%) = 356 ([M+], 58), 299 (41), 284 (52), 281 (47),
253 (35), 225 (100), 207 (64), 75 (42), 73 (32).
A suspension of (iodomethyl)triphenylphosphonium iodide (1.77 g,
3.34 mmol) in THF (15 mL) at –78 °C was treated with NaN(TMS)2 in
THF (1.0 M; 3.25 mL, 3.25 mmol). After stirring for 1 min, 75 (761 mg,
2.28 mmol) in THF (15 mL) was added via cannula and the mixture
allowed to warm to r.t. over 30 min. It was then poured into hexanes
(50 mL), washed with H2O (2 × 50 mL), and the organic layer dried
over MgSO4 and concentrated. The residue was chromatographed on
silica gel, eluting with hexanes–CH2Cl2 (1:1), to deliver a mixture of
the cis- and trans-isomers (4:1) of the product. Further chromatogra-
phy on silica gel, eluting with hexanes–EtOAc (9:1), gave first 78 (418
mg, 51%), followed by the trans-isomer (105 mg, 13%).
exo-(η5-Cyclopentadienyl){(5,6,7,7a-η4)(4aR*,9R*,9cS*)-4a,8,9,9c-
tetrahydro-3-methoxy-9c-[2-(triisopropylsilyloxy)ethyl]-5,6-
bis(trimethylsilyl)phenanthro[4,5-bcd]furan-9-ol}cobalt (80)
Compound 76 (1.04 g, 2.50 mmol) in 8–Et2O (3:1, 20 mL) was sy-
ringed by pump into CpCo(C2H4)2 (495 mg, 2.75 mmol) in 8 (5 mL)
over a period of 1 h. The mixture was stirred for 1 h at r.t., followed by
further addition of CpCo(C2H4)2 (75.0 mg, 0.42 mmol) in 8–Et2O (1:1,
4 mL) and stirring for 11 h. Filtration through a pad of silica gel and
evaporation of the volatiles by high-vacuum transfer resulted in a
black residue, which was purified by column chromatography on sili-
ca gel, eluting with PE–EtOAc (7:1), to yield the complex 80 (764 mg,
43%; 54% based on recovered 76) as a red solid, followed by 76
(289 mg, 28%).
1H NMR (400 MHz, CDCl3): δ = 7.64 (d, J = 8.3 Hz, 1 H), 7.50 (s, 1 H),
7.37 (d, J = 8.3 Hz, 1 H), 6.82 (d, J = 8.3 Hz, 1 H), 6.66 (d, J = 8.3 Hz, 1 H),
4.03 (s, 3 H), 3.84 (t, J = 6.9 Hz, 2 H), 2.92 (t, J = 6.9 Hz, 2 H), 0.88 (s, 9
H), 0.00 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 146.0, 144.8, 142.8, 137.2, 127.3,
124.1, 123.7, 118.0, 105.4, 82.2, 63.0, 56.0, 28.2, 25.9, 18.3, –5.39.
MS (EI, 70 eV): m/z (%) = 458 ([M+], 21), 401 (100), 274 (31), 244 (29),
IR (KBr): 3450, 2944, 2896, 2866, 1504, 1465, 1247, 1161, 1112, 1064,
1013, 998, 932, 882, 854, 758, 682 cm–1
.
229 (24), 199 (32), 185 (36), 73 (42).
1H NMR (500 MHz, C6D6): δ = 7.07 (d, J = 8.1 Hz, 1 H), 6.90 (d, J =
8.1 Hz, 1 H), 4.95 (dd, J = 9.6, 3.3 Hz, 1 H), 4.91 (s, 1 H), 4.47 (s, 5 H),
4.08 (s, 1 H), 3.65 (ddd, J = 11.5, 8.5, 6.0 Hz, 1 H), 3.64 (s, 3 H), 3.41
(ddd, J = 10.5, 9.0, 5.5 Hz, 1 H), 2.33 (dd, J = 16.5, 9.6 Hz, 1 H), 1.98 (m,
1 H), 1.64 (m, 1 H), 1.48 (dd, J = 16.5, 3.4 Hz, 1 H), 1.23 (br s, 1 H), 1.03
(m, 21 H), 0.47 (s, 9 H), 0.39 (s, 9 H).
13C NMR (125 MHz, C6D6): δ = 146.8, 145.2, 137.9, 132.0, 117.3, 114.6,
96.8, 82.9, 82.6, 81.6, 74.4, 66.7, 61.9, 58.5, 57.2, 52.9, 42.5, 37.6, 18.9,
12.9, 3.69 (2 C).
trans-Isomer
1H NMR (300 MHz, CDCl3): δ = 7.92 (d, J = 14.6 Hz, 1 H), 7.50 (s, 1 H),
7.15 (dd, J = 8.3, 0.9 Hz, 1 H), 6.75 (d, J = 8.1 Hz, 1 H), 6.65 (d, J = 14.6
Hz, 1 H), 4.00 (s, 3 H), 3.91 (t, J = 6.6 Hz, 2 H), 2.98 (td, J = 6.9, 0.9 Hz, 2
H), 0.88 (s, 9 H), 0.02 (s, 6 H).
cis-4-(1-Buten-3-ynyl)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-7-
methoxybenzo[b]furan (79)
MS (FAB, 70 eV): m/z (%) = 710 ([M+], 100), 692 (23).
Iodoalkene 78 (288 mg, 0.628 mmol) in Et3N (12 mL) and THF (6 mL)
was treated with Cl2Pd(PPh3)2 (18 mg, 0.026 mmol), followed by CuI
(10 mg, 0.053 mmol) and (trimethylsilyl)acetylene (180 μL, 124 mg,
1.26 mmol). After stirring for 16 h at r.t., the mixture was poured into
Et2O, and the organic fraction washed with sat. aq NH4Cl (20 mL),
dried over MgSO4, and concentrated. Chromatography on silica gel,
eluting with hexanes–CH2Cl2 (3:1), produced cis-3-[2-(tert-butyldi-
methylsilyloxy)ethyl]-7-methoxy-4-[4-(trimethylsilyl)-1-buten-3-
ynyl]benzo[b]furan (240 mg, 89%) as a yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.26 (d, J = 8.5 Hz, 1 H), 7.49 (s, 1 H),
7.19 (d, J = 12.0 Hz, 1 H), 6.77 (d, J = 8.5 Hz, 1 H), 5.72 (d, J = 12.0 Hz, 1
H), 4.04 (s, 3 H), 3.90 (t, J = 7 Hz, 2 H), 3.00 (t, J = 7 Hz, 2 H), 0.88 (s, 9
H), 0.24 (s, 9 H), 0.02 (s, 6 H).
Anal. Calcd for C37H59CoO4Si3: C, 62.50; H, 8.36. Found: C, 62.54; H,
8.39.
exo-(η5-Cyclopentadienyl){(5,6,7,7a-η4)(4aR*,9R*,9cS*)-9c-[2-
(tert-butyldimethylsilyloxy)ethyl]-4a,8,9,9c-tetrahydro-3-me-
thoxy-5,6-bis(trimethylsilyl)phenanthro[4,5-bcd]furan-9-ol}co-
balt (81)
To 77 (138 mg, 0.368 mmol) in 8–THF (1:1, 10 mL) was added Cp-
Co(C2H4)2 (66 mg, 0.366 mmol) in 8 (5 mL) via syringe pump over 10
min at r.t. After stirring for an additional 20 min, evaporation of the
volatiles by high-vacuum transfer was followed by chromatography
on silica gel, eluting with hexanes–Et2O (3:2), to separate 81 (93 mg,
38%) as a red oil, crystallized from PE as red plates; mp 120 °C (dec).
13C NMR (100 MHz, CDCl3): δ = 145.6, 144.6, 142.9, 136.2, 127.8,
123.5, 123.0, 118.0, 106.2, 105.5, 104.0, 100.8, 62.7, 56.0, 29.0, 25.8,
18.2, 0.28, –5.47.
IR (KBr): 3450, 2954, 2931, 2887, 2858, 1631, 1505, 1463, 1450, 1438,
1247, 1159, 1111, 1078, 932, 855, 836, 758 cm–1
.
MS (EI, 70 eV): m/z (%) = 428 ([M+], 18), 371 (14), 356 (13), 147 (53),
73 (100).
1H NMR (400 MHz, C6D6): δ = 7.14 (d, J = 8.4 Hz, 1 H), 6.86 (d, J = 8.4
Hz, 1 H), 5.02 (dd, J = 9.6, 3.3 Hz, 1 H), 4.92 (s, 1 H), 4.48 (s, 5 H), 4.06
(s, 1 H), 3.65 (s, 3 H), 3.54 (ddd, J = 11.5, 8.5, 6.0 Hz, 1 H), 3.35 (ddd, J =
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

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T. Aechtner et al.
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Synthesis
10.5, 9.0, 5.5 Hz, 1 H), 2.36 (dd, J = 16.5, 8.5 Hz, 1 H), 1.91 (ddd, J =
14.0, 8.5, 5.5 Hz, 1 H), 1.53 (m, 1 H), 1.50 (dd, J = 16.5, 3.4 Hz, 1 H),
1.23 (br s, 1 H), 0.91 (s, 9 H), 0.46 (s, 9 H), 0.36 (s, 9 H), 0.01 (s, 3 H), –
0.02 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.52 (m, 3 H), 7.14 (s, 1 H), 7.05 (d, J =
12.0 Hz, 1 H), 6.96 (d, J = 8.4 Hz, 1 H), 6.72 (d, J = 8.4 Hz, 1 H), 6.50 (d,
J = 8.4 Hz, 1 H), 3.94 (t, J = 6.9 Hz, 2 H), 3.93 (s, 3 H), 3.09 (t, J = 6.9 Hz,
2 H), 0.89 (s, 9 H), 0.40 (s, 9 H), 0.03 (s, 9 H), –0.06 (s, 6 H).
13C NMR (100 MHz, C6D6): δ = 146.0, 144.3, 136.8, 131.1, 116.3, 113.6,
95.9, 81.9, 81.7, 80.6, 73.5, 66.8, 60.6, 57.6, 56.2, 52.1, 41.5, 36.5, 25.7,
18.0, 2.76, 2.75, –5.58, –5.64.
MS (EI, 70 eV): m/z (%) = 552 ([M+], 45), 407 (13), 405 (12), 333 (11),
317 (25), 281 (11), 253 (12), 207 (67), 73 (100).
MS (EI, 70 eV): m/z (%) = 668 ([M+], 10), 667 (22), 666 (42), 507 (100),
277 (25), 203 (33), 73 (60).
(Z)-1-[2-(tert-Butyldimethylsilyloxy)ethyl]-6-[(E)-2-ethyl-2-pent-
en-1-ylidene]-4-methoxy-6H-indeno[5,4-b]furan (83)
MS (FAB, 70 eV): m/z (%) = 668 ([M+], 100), 650 (13).
To 79 (58 mg, 0.16 mmol) and 3-hexyne (36 μL, 26 mg, 0.32 mmol)
was added simultaneously by two separate syringe pumps Cp-
Co(C2H4)2 (29 mg, 0.16 mmol) in THF (5 mL) and 3-hexyne (54 μL, 39
mg, 0.48 mmol) in THF (5 mL) over 30 min. The solvent was removed
under reduced pressure and the residue chromatographed on silica
gel, eluting with hexanes–CH2Cl2 (3:2), to yield 83 (4.8 mg, 7%).
1H NMR (300 MHz, CDCl3): δ = 7.46 (s, 1 H), 7.14 (d, J = 5.7 Hz, 1 H),
7.12 (s, 1 H), 7.02 (s, 1 H), 6.87 (d, J = 5.7 Hz, 1 H), 5.94 (t, J = 7.5 Hz, 1
H), 4.05 (s, 3 H), 3.92 (t, J = 6.9 Hz, 2 H), 3.02 (t, J = 6.9 Hz, 2 H), 2.53 (q,
J = 7.5 Hz, 2 H), 2.29 (quin, J = 7.5 Hz, 2 H), 1.15 (t, J = 8 Hz, 3 H), 1.10
(t, J = 7.4 Hz, 3 H), 0.87 (s, 9 H), 0.01 (s, 6 H).
Anal. Calcd for C34H53CoO4Si3: C, 61.04; H, 7.99. Found: C, 61.13; H,
7.99.
A second red fraction was subjected to HPLC to give what appears to
be a C9-diastereomer of 81 (3.9 mg, 1.6%).
1H NMR (500 MHz, C6D6): δ = 6.80 (d, J = 8.0 Hz, 1 H), 6.77 (d, J = 8.0
Hz, 1 H), 5.00 (br d, J = 7.5 Hz, 1 H), 4.92 (s, 1 H), 4.30 (s, 5 H), 4.10 (s,
1 H), 3.71 (s, 3 H), 3.62 (dt, J = 10.0, 6.5 Hz, 1 H), 3.35 (dt, J = 10.5, 6.5
Hz, 1 H), 2.37 (dt, J = 14.5, 6.5 Hz, 1 H), 2.18 (ddd, J = 11.5, 2.5, 1.0 Hz,
1 H), 2.02 (dd, J = 11.5, 8.5 Hz, 1 H), 2.01 (br s, 1 H), 1.95 (ddd, J = 14.5,
6.5, 6.0 Hz, 1 H), 1.01 (s, 9 H), 0.51 (s, 9 H), 0.44 (s, 9 H), 0.06 (s, 3 H),
0.04 (s, 3 H).
13C NMR (125 MHz, C6D6): δ = 147.0, 145.1, 139.8, 130.4, 120.1, 114.5,
96.7, 82.0, 81.3, 78.9, 78.2, 67.8, 60.9, 56.2, 56.2, 51.9, 41.2, 38.6, 25.8,
18.1, 2.73, 2.67, –5.70 (2 C).
MS (EI, 70 eV): m/z (%) = 438 ([M+], 100), 423 (21), 281 (13), 207 (82),
73 (12).
2-{7-Methoxy-3-[2-(triisopropylsilyloxy)ethyl]benzo[b]furan-4-
yl}-1-phenylethanol
To 76 (182 mg, 0.44 mmol) in hexane (20 mL) saturated with acety-
lene was added CpCo(C2H4)2 (98 mg, 0.54 mmol) in Et2O (20 mL) via
syringe pump over 20 min. After stirring for another 20 min, the sol-
vent was removed under reduced pressure and the residue chromato-
graphed on silica gel, eluting with hexanes–EtOAc (gradient, 4:1 to
1:1), to yield relatively pure product (96 mg, 47%) as a light yellow oil.
1H NMR (300 MHz, CDCl3): δ = 7.52 (s, 1 H), 7.36 (d, J = 8.4 Hz, 1 H),
7.23 (m, 5 H), 6.81 (d, J = 8.4 Hz, 1 H), 5.40 (m, 1 H), 4.03 (s, 3 H), 4.00
(m, 2 H), 3.07 (m, 2 H), 2.07 (m, 2 H), 1.58 (s, 1 H), 1.04 (m, 21 H).
[(1,2,3,4-η4)-1-(trans-2-{3-[2-(tert-Butyldimethylsilyloxy)ethyl]-
7-methoxybenzo[b]furan-4-yl}ethenyl)-2,3-bis(trimethylsilyl)-
1,3-cyclobutadiene](η5-cyclopentadienyl)cobalt (82)
To 79 (99 mg, 0.28 mmol) in 8–Et2O (1:1, 5 mL) was added Cp-
Co(C2H4)2 (50 mg, 0.28 mmol) in 8 (5 mL) by syringe pump over 10
min at r.t. After stirring for 20 min, the volatiles were removed by vac-
uum transfer, and the resulting orange-brown residue was chromato-
graphed on silica gel, eluting with hexanes–CH2Cl2 (1:1), to present
82 (126 mg, 70%) as an orange solid.
1H NMR (400 MHz, CDCl3): δ = 7.47 (s, 1 H), 7.25 (d, J = 8.4 Hz, 1 H),
6.99 (d, J = 15.6 Hz, 1 H), 6.76 (d, J = 8.4 Hz, 1 H), 6.33 (d, J = 15.6 Hz, 1
H), 4.86 (s, 5 H), 4.75 (s, 1 H), 3.99 (s, 3 H), 3.90 (m, 2 H), 3.04 (t, J = 8.0
Hz, 2 H), 0.91 (s, 9 H), 0.23 (s, 9 H), 0.12 (s, 9 H), 0.05 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 144.4, 142.5, 126.6, 126.3, 125.9,
121.7, 119.0, 118.0, 106.8, 85.5, 79.3, 68.6, 65.5, 62.8, 56.1, 52.9, 29.1,
25.9, 18.2, 8.18, 0.86, –0.09, –5.33, –5.39.
MS (EI, 70 eV): m/z (%) = 650 ([M+], 100), 526 (25), 454 (49), 294 (29),
277 (28), 73 (68).
MS (EI, 70 eV): m/z (%) = 468 ([M+], 1), 450 (95), 407 (100), 362 (49),
335 (29).
2,6-Dimethylphenoxy(trimethylsilyl)acetylene and Its Cocycliza-
tion with 76
To 2,6-dimethylphenol (1.53 g, 12.5 mmol) in THF (25 mL) was added
trichloroethene (1.20 mL, 1.75 g, 13.3 mmol) followed by KOH (1.47 g,
26.2 mmol). The mixture was heated to reflux and stirred for 3 h, be-
fore being poured into aq NaHCO3 (1 M; 75 mL) and extracted with
Et2O (50 mL). The organic layer was dried (MgSO4), concentrated to an
oil, and filtered through a pad of silica gel with hexanes. The solvent
was removed to yield (E)-2-[(1,2-dichlorovinyl)oxy]-1,3-dimethyl-
benzene (2.17 g, 80%).58b
HRMS (EI, 70 eV): m/z [M+] calcd for C34H51CoO3Si3: 650.2478; found:
650.2485.
1H NMR (400 MHz, C6D6): δ = 7.06 (s, 3 H), 5.58 (s, 1 H), 2.29 (s, 6 H).
MS (EI, 70 eV): m/z (%) = 218 ([M+], 31), 216 ([M+], 48), 181 (17), 145
cis-3-[2-(tert-Butyldimethylsilyloxy)ethyl]-7-methoxy-4-{2-[2,5-
bis(trimethylsilyl)phenyl]ethenyl}benzo[b]furan
To 79 (58 mg, 0.16 mmol) and (trimethylsilyl)acetylene (23 μL, 15.9
mg, 0.16 mmol) was added simultaneously by two separate syringe
pumps CpCo(C2H4)2 (29 mg, 0.16 mmol) in Et2O (5 mL) and (trimeth-
ylsilyl)acetylene (23 μL, 15.9 mg, 0.16 mmol) in Et2O (5 mL) over 30
min. The solvent was removed under reduced pressure and the resi-
due chromatographed on silica gel, eluting with hexanes–CH2Cl2
(3:1), to yield relatively pure product (13.3 mg, 15%) as a light yellow
oil.
(18), 140 (17), 105 (100), 103 (27), 79 (33), 77 (37).
Under N2, the preceding dichloroenol ether (2.17 g, 10 mmol) in Et2O
(20 mL) at –30 °C was treated with BuLi in hexanes (2.1 M; 10 mL, 21
mmol) in five portions over 10 min. After stirring for 20 min, TMSCl
(3.20 mL, 2.74 g, 25 mmol) was added, the mixture warmed to r.t.,
stirred for an additional 1 h, and poured into aq NaHCO3 (1 M; 50 mL).
The organic layer was dried (MgSO4), concentrated to an oil, and fil-
tered through a pad of silica gel with hexanes. The solvent was re-
moved to furnish 2,6-dimethylphenoxy(trimethylsilyl)acetylene
(1.35 g, 62%) as a clear oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK

AD
T. Aechtner et al.
Paper
Synthesis
1H NMR (400 MHz, C6D6): δ = 7.04 (s, 3 H), 2.39 (s, 6 H), 0.14 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 218 ([M+], 12), 203 (100), 129 (27), 77 (12).
13C NMR (125 MHz, CDCl3): δ = 159.0, 129.2, 122.3, 116.6, 114.2, 87.8,
81.0, –0.57.
MS (EI, 70 eV): m/z (%) = 504 ([M+], 100), 314 (7), 217 (10), 124 (7), 73
(16).
HRMS (EI, 70 eV): m/z [M+] calcd for C27H33CoO2Si2: 504.1351; found:
504.1354.
Into an Ar-degassed solution of 2,6-dimethylphenoxy(trimethylsi-
lyl)acetylene (437 mg, 2.0 mmol) and benzofuran 76 (120 mg, 0.29
mmol) in THF (10 mL) was syringed via pump CpCo(C2H4)2 (63 mg,
0.35 mmol) in degassed THF (20 mL) over 10 min. The mixture was
stirred for 1 h at r.t., the solvent removed under reduced pressure, and
the residue chromatographed over silica gel, eluting with hexanes–
EtOAc (5:1), to separate two major products. The first was [1,2-
bis(2,6-dimethylphenoxy)-3,4-bis(trimethylsilyl)cyclobutadiene](η5-
cyclopentadienyl)cobalt (regiochemistry tentative)78 (96 mg, 59%) as
a dark red oil.
Other fractions contained, among other unidentifiable compounds,
the (unisolated) product of the cocyclization of 2 equivalents of the
alkoxyalkyne with the triple bond in 76, assigned tentatively on the
basis of the similarity of its 1H NMR spectrum with that of the 2,6-
dimethylphenoxy analogue above.
1H NMR (400 MHz, C6D6): δ = 6.84 (s, 6 H), 5.08 (s, 5 H), 2.31 (br s, 12
H), 0.11 (s, 18 H).
1-[Isopropoxy(dimethyl)silyl]-2-(trimethylsilyl)acetylene (84d)
A solution of isopropoxy(dimethyl)silyl chloride was prepared by
treating dichloro(dimethyl)silane (6.10 mL, 6.47 g, 50.1 mmol) in
hexanes (50 mL) with 2-propanol (3.83 mL, 3.01 g, 50.1 mmol), while
the flask was purged with N2 passing through an aq NaOH trap. After
stirring at r.t. for 2 h, a solution of (trimethylsilyl)ethynyllithium (52
mmol; prepared according to the procedure for 42) was added by
cannula, the mixture stirred for 30 min, then filtered. The solvent was
removed under reduced pressure and the remaining liquid vacuum-
transferred to afford 84d (9.33 g, 87%) as a clear liquid.
The second component of the mixture was the result of the cocycliza-
tion of 2 equivalents of the alkoxyalkyne with the triple bond in 76,
1-[3,4-bis(2,6-dimethylphenoxy)-2,5-bis(trimethylsilyl)phenyl]-2-
{7-methoxy-3-[2-(triisopropylsilyloxy)ethyl]benzo[b]furan-4-yl}eth-
anol (regiochemistry tentative)78 (44 mg, 18%).
1H NMR (400 MHz): δ = 7.45 (s, 1 H), 6.82 (s, 7 H), 6.79 (d, J = 8.4 Hz, 1
H), 6.59 (d, J = 8.4 Hz, 1 H), 5.45 (m, 1 H), 3.99 (m, 2 H), 3.69 (m, 1 H),
3.58 (s, 3 H), 3.45 (m, 1 H), 3.20 (m, 2 H), 2.10 (br s, 1 H), 1.75 (s, 9 H),
1.70 (s, 3 H), 1.11 (br s, 21 H), 0.60 (s, 9 H), 0.23 (s, 9 H).
1H NMR (400 MHz, CDCl3): δ = 4.15 (sept, J = 6 Hz, 1 H), 1.20 (d, J = 6
MS (FAB, 70 eV): m/z (%) = 852 ([M+], 2), 836 (20), 794 (7), 661 (27),
Hz, 6 H), 0.25 (s, 6 H), 0.19 (s, 9 H).
MS (EI, 70 eV): m/z (%) = 214 ([M+], 1), 199 (100), 157 (70), 155 (47),
523 (43), 476 (53), 203 (100).
141 (19), 73 (18).
Phenoxy(trimethylsilyl)acetylene58c and Its Cocyclization with 76
HRMS (EI, 70 eV): m/z [M+] calcd for C10H22OSi2: 214.1209; found:
A
procedure similar to that used above for 2,6-dimethylphe-
214.1207.
noxy(trimethylsilyl)acetylene was followed, except that phenol (862
mg, 9.16 mmol) was used in place of 2,6-dimethylphenol. The identi-
ty of the intermediate (E)-2-[(1,2-dichlorovinyl)oxy]benzene was
confirmed as follows:
1H NMR (400 MHz, CDCl3): δ = 7.40 (t, J = 7.5 Hz, 2 H), 7.19 (t, J = 7.2
Hz, 1 H), 7.08 (d, J = 7.5 Hz, 2 H), 5.98 (s, 1 H).
1-[Diethyl(isopropoxy)silyl]-2-(trimethylsilyl)acetylene (84e)
To a solution of dichloro(diethyl)silane (10 mL, 10.6 g, 67.5 mmol) in
hexanes (50 mL) was added 2-propanol (5.1 mL, 4.01 g, 66.7 mmol) in
a dropwise fashion, while the flask was purged with N2 passing
through an aq NaOH trap. After stirring at r.t. for 2 h, a solution of
(trimethylsilyl)ethynyllithium (67 mmol; prepared according to the
procedure for 42) was added by cannula, the mixture stirred for 10
min, then filtered. The solvent was removed under reduced pressure
and the remaining liquid vacuum-transferred to afford 84e (11.0 g,
68%) as a clear oil.
MS (EI, 70 eV): m/z (%) = 190 ([M+], 34), 188 ([M+], 54), 125 (71), 112
(43), 77 (100), 51 (30).
The crude final product mixture was chromatographed on silica gel,
eluting with Et2O–hexanes (gradient, 0:1 to 0.1:1) to sequester phe-
noxy(trimethylsilyl)acetylene (330 mg, 19%) as a light yellow oil.
1H NMR (300 MHz, C6D6): δ = 7.19 (d, J = 7.5 Hz, 2 H), 6.92 (t, J = 7.5
Hz, 2 H), 6.74 (t, J = 7.5 Hz, 1 H), 0.23 (s, 9 H).
13C NMR (125 MHz, C6D6): δ = 156.4, 130.2, 125.1, 115.5, 103.6, 45.2,
0.96.
IR (film): 3003, 2964, 2937, 2915, 2878, 1460, 1383, 1370, 1251,
1174, 1120, 1008, 858, 846 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 4.16 (sept, J = 8 Hz, 1 H), 1.20 (d, J = 8
Hz, 6 H), 1.01 (t, J = 10 Hz, 6 H), 0.66 (q, J = 10 Hz, 4 H), 0.19 (s, 9 H).
13C NMR (125 MHz, CDCl3): δ = 114.9, 109.8, 66.0, 25.5, 6.44, 6.39, –
MS (EI, 70 eV): m/z (%) = 190 ([M+], 16), 175 (100), 145 (8), 77 (8).
0.38.
An Ar-degassed solution of phenoxy(trimethylsilyl)acetylene (104
mg, 0.55 mmol) and benzofuran 76 (76 mg, 0.18 mmol) in THF (10
mL) was syringed via pump into CpCo(C2H4)2 (45 mg, 0.25 mmol) in
degassed THF (10 mL) over 10 min. The mixture was stirred for 0.5 h
at r.t., the solvent removed under reduced pressure, and the residue
chromatographed over silica gel, eluting with hexanes–EtOAc (5:1), to
yield [1,2-bis(trimethylsilyl)-3,4-diphenoxycyclobutadiene](η5-cy-
clopentadienyl)cobalt (regiochemistry tentative)78 (51 mg, 56%) as a
red oil.
MS (EI, 70 eV): m/z (%) = 241 ([M+ – H], 1), 213 (100), 171 (37), 143
(23).
1-[Methoxy(diphenyl)silyl]-2-(trimethylsilyl)acetylene (84g)
A solution of (trimethylsilyl)ethynyllithium (50 mmol; prepared ac-
cording to the procedure for 42) was added by cannula to dime-
thoxy(diphenyl)silane (8.80 mL, 9.50 g, 38.9 mmol) in THF (10 mL) at
r.t. After stirring for 30 min, the mixture was poured into hexanes (20
mL) and aq NH4Cl (1 M; 20 mL). The organic layer was dried and con-
centrated, and the residue chromatographed over silica gel, eluting
with hexanes, to yield 84g (10.3 g, 85%) as a colorless liquid.
IR (film): 2958, 1711, 1592, 1490, 1439, 1335, 1315, 1248, 1219, 1162
cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.30 (t, J = 8 Hz, 4 H), 7.03 (t, J = 8 Hz, 2
H), 6.99 (d, J = 8 Hz, 4 H), 5.03 (s, 5 H), –0.02 (s, 18 H).
1H NMR (400 MHz, CDCl3): δ = 7.88 (m, 4 H), 7.53 (m, 6 H), 3.77 (s, 3
H), 0.41 (s, 9 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–AK