Studies on the synthesis of Richardianidin-1 via the tautomer-arrested annulation of Fischer carbene complexes

Article abstract of DOI:10.1055/s-2006-950313

A strategy for the synthesis of richardianidin-1 is evaluated which has as its key step the tautomer-arrested annulation of chromium-carbene complexes. Both inter- and intramolecular variations of the strategy are examined. The intramolecular reaction involves the tethering of the alkyne to the oxygen stabilizing substituent of the carbene carbon. The outcome of the intramolecular tautomer-arrested annulation was found to be highly dependent on the nature of the tether and the on the type of substituent on the alkyne. The product distribution from these reactions included the desired hydrindenone resulting from tautomer-arrested annulation, a naphthalenedione, and a spirocyclohexadienone. The latter two products result from CO insertion prior to cyclization. The optimal tether length for the tautomer-arrested product is four atoms between the alkyne and the carbene carbon. The yields for the intramolecular reaction dropped significantly for a substituent on the alkyne terminus that was larger than a methyl group and this was not suitable for a synthesis of richardianidin-1. Initial studies on the intermolecular tautomer-arrested annulation focused on the regioselectivity of alkyne incorporation. The reaction with isopropyl(methyl)acetylene gives a single regioisomer and reveals that the tautomer-arrested annulation is more regioselective than the normal benzannulation. Furthermore, the intermolecular reaction is more tolerant of larger substituents on the terminus of the alkyne. As a result of the studies on the intermolecular tautomer-arrested annulation a suitable alkyne was found that introduces all of the carbons present in the six-membered lactone of richardianidin-1. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950313

PAPER
3679
Studies on the Synthesis of Richardianidin-1 via the Tautomer-Arrested
Annulation of Fischer Carbene Complexes
S
tudies on the Synthes
a
is of Richar
r
dianidin
y
-1 Ellen Bos, Catherine Loncaric, Chunrui Wu, William D. Wulff*
Department of Chemistry, Michigan State University, East Lansing, MI 48824, USA
E-mail: wulffw@msu.edu
Received 6 July 2006; revised 13 July 2006
O
O
Me
Me
Me
Abstract: A strategy for the synthesis of richardianidin-1 is evalu-
Me
ated which has as its key step the tautomer-arrested annulation of
chromium–carbene complexes. Both inter- and intramolecular vari-
ations of the strategy are examined. The intramolecular reaction in-
volves the tethering of the alkyne to the oxygen stabilizing
substituent of the carbene carbon. The outcome of the intramolecu-
lar tautomer-arrested annulation was found to be highly dependent
on the nature of the tether and the on the type of substituent on the
alkyne. The product distribution from these reactions included the
desired hydrindenone resulting from tautomer-arrested annulation,
a naphthalenedione, and a spirocyclohexadienone. The latter two
products result from CO insertion prior to cyclization. The optimal
tether length for the tautomer-arrested product is four atoms be-
tween the alkyne and the carbene carbon. The yields for the in-
tramolecular reaction dropped significantly for a substituent on the
alkyne terminus that was larger than a methyl group and this was not
suitable for a synthesis of richardianidin-1. Initial studies on the in-
termolecular tautomer-arrested annulation focused on the regiose-
lectivity of alkyne incorporation. The reaction with
isopropyl(methyl)acetylene gives a single regioisomer and reveals
that the tautomer-arrested annulation is more regioselective than the
normal benzannulation. Furthermore, the intermolecular reaction is
more tolerant of larger substituents on the terminus of the alkyne.
As a result of the studies on the intermolecular tautomer-arrested
annulation a suitable alkyne was found that introduces all of the car-
bons present in the six-membered lactone of richardianidin-1.
H
O
O
O
O
O
O
H
OAc
H
H
OAc
H
O
H
H
Me
Me
O
Richardianidin-1 (1)
Me
Richardianidin-2 (2)
O
O
O
H
H
OAc
3
BCD ring system
Figure 1
which focuses on a unique organometallic approach to the
AB ring system.
The retrosynthetic analysis of richardianidin-1 (1) is
shown in Scheme 1. The butyrolactone ring is unmasked
as the homoallylic alcohol 4 which in turn is envisioned to
arise from a 2,3-Wittig rearrangement from the stannyl-
methyl ether 5.4 The stannyl ether 5 in turn should be acces-
sible from the stereoselective reduction and alkylation of
the hydrindenone 6, the key intermediate in our strategy.
The assembly of hydrindenone 6 is envisioned to proceed
from the extension of an untested synthetic methodology,
the tautomer-arrested annulation that has previously been
developed in our laboratories.5 This reaction involves the
formation of hydrindenones from the reaction of alkynes
with 2,6-disubstituted 4-hydroxyphenylcarbene complex-
es of the type 9. The implementation of this method could
potentially be realized in either an intermolecular or in-
tramolecular venue. A first-order analysis of the retrosyn-
thesis would lead to the conclusion that the intramolecular
version is the more attractive since only a single regioiso-
mer of the hydrindenone would be possible. The intermo-
lecular approach has the potential of producing either the
desired regioisomer 6 or the undesired regioisomer 10.
We present here an evaluation of both intermolecular and
intramolecular approaches of the tautomer-arrested annu-
lation to the synthesis of richardianidin-1 (1) within the
context of the strategy presented in Scheme 1.
Key words: richardianidin-1, chromium–carbene complexes, an-
nulation, carbon monoxide insertion, cyclization
The rather rare 6,7-seco-6,11-cyclolabdane skeleton is
present in richardianidin-1 (1) and richardianidin-2 (2),
which were isolated from the leaves of a toxic plant that
grows in the mountainous regions of western and southern
Saudi Arabia.1 This plant, Cluytia richardiana L., is one
of several species of Cluytia which are widely used in folk
medicine. Several other related labdane-type diterpenes
have been isolated from this plant and, of these, richard-
ianidin-1 (1) and richardianidin-2 (2), along with saudin,
have the highest hypoglycemic activity both in vitro and
in vivo and support the historical use of this plant.2 A syn-
thetic study on route to the richardianidins has been pub-
lished in which the strategy was demonstrated in the
construction of the BCD ring system in 3 as shown in
Figure 1.3 We report here our strategy for the synthesis of
richardianidins and the initial evaluation of the strategy,
The reaction of Fischer carbene complexes with alkynes
is one of the most useful methods for the synthesis of sub-
stituted phenols.6 This is illustrated in the reaction of the
2-methoxyphenylcarbene complex 11 with alkyl-substi-
SYNTHESIS 2006, No. 21, pp 3679–3705
Advanced online publication: 12.10.2006
DOI: 10.1055/s-2006-950313; Art ID: Z14006SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
0
6

3680
M. E. Bos et al.
PAPER
OR3
O
OR3
OR3
Me
SnBu3
Me
lactone
ring
Me
Me
O
O
Me
O
2,3-Wittig
H
O
O
H
O
O
O
rearrangement
formation
OR2
OR2
H
OAc
OR2
H
OR1
OR1
OR1
Me
Me
Me
Me
HO
O
Richardianidin-(1)
4
5
6
path b
path a
intermolecular
intramolecular
tautomer-arrested
annulation
R3O
OR3
O
HO
Me
OR2
Me
OR1
O
+
O
HO
Me
O
Me Cr(CO)5
OR3
R2
R2O
O
R1
OR1
Me
O
Me Cr(CO)5
10
9
8
7
Scheme 1
tuted acetylenes (Scheme 2, Table 1).7 The primary prod- on a variety of factors including concentration, tempera-
ucts of this benzannulation are 4-methoxynaphthols and ture, and the nature of the solvent as illustrated by the data
in the case of unsymmetrical acetylenes the two possible in Equation 1 and Table 2. In general, the six-membered
regioisomeric products are the naphthols 12a and 12b. For ring product is favored by high concentration, nonpolar
ease of determining the regioselectivity, the naphthols 12a solvents, and lower reaction temperatures.
and 12b were converted into the corresponding quinones
Table 1 Reaction of 11 with Alkyl-Substituted Acetylenes
13a and 13b. The regioselectivity is largely controlled by
the steric bulk of the two different acetylene substituents
R1
Me
H
R2
Pr
Yield (%)
Ratio 13a/13b
2.9:1.0
with the larger substituent becoming incorporated into the
position adjacent to the phenol function.7,8 Internal
alkynes generally give mixtures of the two regioisomers,
whereas, terminal alkynes generally give greater than
100:1 selectivity. The reaction of Fischer carbene com-
plexes of chromium with alkynes generally gives the ben-
zannulated products, but one of the more common of the
many side products are indenes, which are mechanistical-
ly related to the phenol products but differ in that the final
CO insertion does not occur. This is illustrated in the re-
action of complex 11 with hex-3-yne, which gives, after
oxidative workup, mixtures of the quinone 14 and the
five-membered annulated products 15 and 16.9 The ratio
of six- to five-membered annulated products is dependent
64
74
61
Pr
>111:1
Me
i-Pr
4.8:1.0
The five-membered ring annulated product is the general-
ly the only product of the reaction of alkynes with 2,6-di-
substituted phenylcarbene complexes.10 As an example,
the reaction of the 2,6-dimethylphenyl complex 17 with
hex-3-yne gives the indenes 18a and 18b as a mixture of
metal-coordinated and metal-free forms (Equation 2).
Note that the tautomer-arrested annulation requires a
OH
OH
R2
R1
R1
R2
R2
R1
1)
+
OMe
THF
45 °C, 24 h
MeO
Cr(CO)5
MeO
OMe
MeO
2) CAN
OMe
12a
12b
11
O
O
R2
R1
R1
R2
+
MeO
O
MeO
O
13a
13b
Scheme 2
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3681
O
Et
Et
O
Et
Et
1)
Et
Et
+
Et
Et
OMe
solvent, temp
2) CAN
+
MeO
Cr(CO)5
OMe
MeO
O
MeO
MeO
11
14
15
16
Equation 1
sible to intercept the 1,5-shift of the methyl group by a
tautomerization of intermediate 21 to give the hydrinden-
5-one 22 rather than the inden-6-ol 23. This, in fact,
proved to be possible and the degree to which this was
successful was dependent on the nature of the alkyne sub-
stituents. The reaction of complex 19 with diphenylacety-
lene gave a 1:1 mixture of 22 and 23 and hex-3-yne gave
exclusively the hydrindenone product 22 in 75% yield
(Table 3).5 The corresponding tert-butyldimethylsilyl-
protected complex 24 has no recourse but to give the in-
dene product 25 and this was isolated in 64% yield. It was
thus the success of this tautomer-arrested annulation that
led to the consideration of the retrosynthetic analysis for
richardianidin-1 presented in Scheme 1.
Table 2 Effect of Various Conditions on the Ratio of 15 to 16
Solvent
Temp
(°C)
Concn
(M)
Yield
(%)
Ratio
15/16
14
15 + 16
THF
110
110
110
45
0.005
0.005
0.5
trace
<1
29
75
71
43
7
87:13
4:96
benzene
benzene
benzene
THF
14:86
29:71
78:22
0.5
77
45
0.5
61
23
Table 3 Reaction of Complex 19 with Acetylenes
much higher temperature than the normal benzannulation
(Equation 1, Table 2) and possible reasons for this will be
presented in the conclusion to this work. The formation of
the aromatic ring in the indene product results from a 1,5-
sigmatropic rearrangement of a methyl group from an in-
termediate of the type 21 which in turn results from the cy-
clization of the carbene-complexed intermediate 20 that
results from insertion of the alkyne into the metal–carbene
double bond in carbene complex 19 (Scheme 3). We rea-
soned that if the carbene complex had a hydroxy group in
the para-position as in complex 19, then it might be pos-
R
Yield (%) 22 + 23
Ratio 22/23
49:51
Ph
Et
88
75
100:0
For the reasons discussed above and summarized in
Scheme 1, the strategy involving the intramolecular tau-
tomer-arrested annulation was experimental broached
first since it would not be complicated by the possibility
Me
Me
Me
Et
Et
Et
Et
+
Et
Et
OMe
benzene
110 °C, 13 h
(OC)3Cr
Me Cr(CO)5
OMe
18a
OMe
Me
Me
65 : 35
17
18b
100% yield
Equation 2
R
Me
Me
HO
HO
Me
HO
Cr(CO)4
R
R
R
R
OMe
benzene
R
(OC)3Cr
OMe
110 °C, 13 h
Me
Me Cr(CO)5
Me MeO
21
19
20
R
Me
Me
R
R
O
HO
+
R
OMe
22
OMe
Me
Me
23
Scheme 3
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3682
M. E. Bos et al.
PAPER
Me
and then without purification, using it to alkylate the tet-
ramethylammonium acylate 31. This produced a red solu-
tion of the carbene complex 40 which was not purified but
rather directly desilylated with sodium methoxide in
methanol to give the 4-hydroxy-2,6-dimethylphenylcar-
bene complex 29 in 44% yield in three steps from 37. The
thermolysis of carbene complex 29 did not produce the
expected hydrindenone 28, but rather, the spirocyclic
diketone 41. This type of product has been seen before in
the intermolecular tautomer-arrested annulation.5 The
normal tautomer-arrested product 22 (Scheme 3) is re-
placed by a diketone of the type 41 if the reaction solvent
is acetonitrile instead of benzene. The formation of 41 in
the present work represents the first time that this product
has been seen in a reaction carried out in benzene. The for-
mation of this product is thought to result from a spirocy-
clization of the vinylketene intermediate 39 onto the para-
position of a phenol. The vinylketene complex 39 presum-
ably results from a CO insertion in a vinylcarbene-com-
plexed intermediate similar to 20 in Scheme 3.
Et
TBSO
Me
TBSO
Et
Et
Et
OMe
benzene
110 °C, 13 h
OMe
25 64%
Me Cr(CO)5
Me
24
Equation 3
of the formation of regioisomers. In addition, rather than
initially undertaking the likely time-consuming develop-
ment of a synthesis of the highly functionalized carbene
complex 7 (Scheme 1), the synthesis of the much simpler
analogue 29 was targeted (Scheme 4). This particular
complex with a 2-alkoxyethyl tether was chosen since
Semmelhack had previously demonstrated that an ethyl-
enedioxy tether can be successfully employed as a remov-
able tether in the intramolecular benzannulation of
Fischer carbene complexes with alkynes in the total syn-
thesis of deoxyfrenolicin.11 The tether will be introduced
via alkylation of the ammonium acylate 31 with the trif-
late 30. The alkyne portion of this triflate will contain all
five carbons of the lactone ring in richardianidin-1 but not
the furyl substituent. The intramolecular tautomer-arrest-
ed annulation of complex 29 would be expected to pro-
duce the hydrindenone 28 from which the tether can be
liberated by hydrolysis of the enol ether to give 27 and
then subsequent cleavage of the 2-hydroxyethyl ether to
give 26.
The failure of the intramolecular cyclization of the car-
bene complex 29 to give a hydrindenone product prompt-
ed a more fundamental examination of the intramolecular
tautomer-arrested annulation. The series of carbene com-
plexes 42a–c have identically functionalized alkyne teth-
ers and differ only by the number of methylene units
separating the alkyne and the carbene complex. Thus, they
were designed to probe the effect of the size of the newly
formed oxacyclic ring on the yield of the tautomer-arrest-
ed product as well as on the entire product distribution.
These complexes were prepared in 56–86% yields utiliz-
ing a procedure similar to that developed for the complex
29 (Scheme 5) and involves the alkylation of the metal
acylate 31 with an alkynyl triflate derived from the appro-
priate alkynol. The results of the thermolysis of complex-
es 42a–c are presented in Scheme 6 and clearly show that
the hydrindenone product is favored when a six-mem-
bered oxacyclic product is formed giving a 64% yield of
43b upon thermolysis at 60 °C in benzene at 0.005 M.
With the exception of a tentatively identified trace product
from the thermolysis of complex 42b, none of the reac-
tions in Scheme 6 gave a spirocyclic diketone product
The preparation and intramolecular annulation of com-
plex 29 is outlined in Scheme 5. The key step in the syn-
thesis of the alkyne tether involves the iodine-induced
coupling of a secondary alkyl group and an alkyne medi-
ated by an in situ generated borate to generate the alkyne
36.12 This coupling is set up by the hydroboration of the
enol ether 32, subsequent addition of the lithium acetylide
35 and then addition of iodine. The lithium acetylide 35 in
turn is generated from the 2-hydroxyethyl propargyl ether
33, which was prepared according to the procedure of
Semmelhack for closely related compounds.11c The cou-
pling of the alkyne fragment to the carbene complex was
affected by conversion of the alcohol 37 into the triflate 30
OBn
OBn
OBn
Me
Me
Me
O
O
O
O
OH
O
O
O
O
Me
Me
Me
OH
26
27
28
TBSO
Me
HO
Me
Me
+
O
O
OBn
O–NMe4
O
OBn
+
OTf
Me Cr(CO)5
Me Cr(CO)5
31
30
29
Scheme 4
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3683
1) BnBr, NaH
DMSO, r.t.
1) BH3-THF
0 °C
O
Bn
O
OBn
OH
TBSO
2) 35, 0 °C
2) DMSO, t-BuOK
100 °C, 6 h
Me
36 57%
32 71%
3) I2, –78 °C
E/Z = 7.9:1
TBAF
O
O
TBSCl
O
OBn
TBSO
M
HO
RO
HO
DMAP, py
33
34 M = H 78%
35 M = Li
n-BuLi
37 98%
Tf2O, py
CH2Cl2
Me
Br
TBSO
Me
1) t-BuLi (2 equiv), THF
O
OBn
O– NMe4
+
2) Cr(CO)6, THF
3) Me4NBr, H2O
TfO
Me
38a R = H
Me Cr(CO)5
30
CH2Cl2
r.t., 1 h
31 63%
99%
38b R = TBS
TBSO
Me
O
O
O
C
Me
OBn
HO
OBn
C
Me Cr(CO)5
40
Cr(CO)3
O
Me
O
NaOMe, MeOH
39
O
H
O
HO
Me
O
benzene
BnO
O
OBn
60 °C, 4 h
41 48%
(8:5 dr)
O
Me Cr(CO)5
29 44%
O
Br
Me
Me
Me
Me
Me
Me
n-BuLi
+
THF
50 °C
OTBS
38b
OTBS
OTBS
A
B
Scheme 5
similar to that seen in the thermolysis of complex 29 action produced the three products 49–51 in proportions
(Scheme 5). In contrast, these reactions produced the cy- that were somewhat dependent on the temperature, con-
clohexadienone-annulated products 44 either as a side centration, and the mode of addition. The results show
product or, in some cases, as the major product of the re- that the total mass balance and the proportion of the hy-
action. These products presumably arose from the cycliza- drindenone product 49 increase with lower concentration.
tion of a vinylketene-complexed intermediate of the type In addition, the proportion of the hydrindenone product
39 (Scheme 5) where closure occurs ipso to the methyl increases at higher temperature. However, the addition of
group. There is not a great temperature effect on the prod- the carbene complex 48 slowly via syringe pump does not
uct distribution for 42a but for 42c, an increase in mass result in a significant change compared to the addition of
balance was observed at higher temperature along with a the carbene complex all at once to a 0.005 M solution. As
slight shift towards the CO inserted product 44c. Finally, a point of comparison, all of the reactions in Scheme 6
as a control, the cyclization of the complex 45 gives a sim- were performed at 0.005 M and thus the cyclization of 48
ilar product distribution as that of the complex 42a indi- gives roughly the same yields of the hydrindenone and cy-
cating that the presence of the para-hydroxy group on the clohexadienone products as its methylene analogue 42c in
phenyl ring of the carbene complex does not greatly affect Scheme 6. Thus, the presence of the ‘extra’ oxygen in the
the outcome.
tether of complex 48 does not seem to have a detrimental
effect on the yield of the tautomer-arrested product. Small
amounts of the spirocyclic product 51 are observed in the
cyclizations of 48, but no spirocyclic product could be de-
tected in the crude 1H NMR spectrum of the thermolysis
In an effort to properly calibrate the effect of a 2-(propar-
gyloxy)ethoxy tether in the carbene complex, the complex
48 was prepared and its thermolysis investigated. This re-
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3684
M. E. Bos et al.
PAPER
Me
O
Me
O
Me
Me
O
O
Me
HO
Me
benzene
+
O
Me
O
Me
Me Cr(CO)5
Temp (°C)
60
43a
44a
42a
20%
14%
51%
46%
110
O
O
O
Me
Me
Me
Me
O
O
Me
HO
Me
O
benzene
60 °C
+
O
Me
Me
Me Cr(CO)5
42b
43b
44b
Me
64%
<5%
Me
Me
Me
O
O
Me
HO
Me
O
benzene
+
O
Me
Me
O
Me Cr(CO)5
42c
Temp (°C)
60
43c
44c
26%
36%
14%
30%
110
Me
O
Me
Me
Me
Me
Me
O
benzene
110 °C
+
HO
O
Me
O
Me
Me Cr(CO)5
46 17%
47 37%
45
Scheme 6
of complex 42c (Scheme 6). The results of these studies vanced intermediate in the synthesis of richardianidin-1.
(Schemes 6 and 7, Table 4) clearly show optimal hydrin- Fischer carbene complexes that have the oxygen hetero-
denone formation is to be expected when a six-membered atom stabilizing substituent incorporated into a methoxy-
oxacycle is formed in the tautomer-arrested reaction.
methyl ether (MOM) group are known13 and do not differ
significantly in stability from simple alkoxy-stabilized
complexes and can be handled without special precau-
tions and can be chromatographically purified on silica
gel. However, alkynes that are tethered through the oxy-
gen-stabilizing substituent via an acetal linkage have not
been previously reported.
In considering a redesign of the removal tether, the acetal
carbene complex 55f provides a very attractive second
generation target. The complex should be preparable via
the direct alkylation with the chloromethyl ether 56f, its
cyclization produces the six-membered oxygen heterocy-
cle in 53f, and subsequent to hydrindenone formation, the
linker for the tethered alkyne could be liberated in a single The preparation of the acetal tethered carbene complexes
step (Scheme 8). Hydrolysis of the enol ether in 53f would 54 required access to the chloromethyl propargyl ethers
leave a hemiacetal that would further hydrolyze to the oxo 56. As indicated in Scheme 9 and Table 5, these were syn-
alcohol 52f, which in turn could serve as an attractive ad- thesized from the analogous propargyl alcohol and chlo-
Me
O
O
Me
O
Me
Me
O
O
O
Me
O
Me
HO
Me
+
+
benzene
O
O
O
O
Me
49
Me
50
O
O
Me Cr(CO)5
51
48
Scheme 7
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3685
Table 4 Hydrindenone Formation
Concn (M)
Temp (°C)
Yield (%)
Ratio 49/(50 + 51) Total Yield (%)
49
50
5
51
21
13
16
6
0.05
0.05
0.005
0.005
spaa
60
110
60
15
20
27
38
35
39
0.58
0.95
0.87
1.58
1.30
1.70
41
41
58
62
61
62
8
15
18
15
19
110
80
12
4
spab
110
a Syringe pump addition of 48 (0.27 mmol) in benzene (20 mL) to refluxing benzene (25 mL) over 4 h.
b Syringe pump addition of 48 (0.38 mmol) in toluene (10 mL) to refluxing toluene (50 mL) over 1.25 h.
OBn
OBn
O
OBn
Me
Me
HO
Me
O
O
O
O
OH
Me Cr(CO)5
54f
O
O
Me
Me
52f
53f
OBn
OBn
TBSO
Me
TBSO
Me
+
O– NMe4
+
O
O
Cl
O
Me Cr(CO)5
55f
Me Cr(CO)5
56f
31
Scheme 8
rotrimethylsilane and paraformaldehyde according to the
procedure reported by Shipov, Savostyanova, and
Baukov.14 The chloromethyl ethers 56 were not purified,
but directly reacted with a slight deficiency of the ammo-
nium acylate salt 31 to give 68–98% yields of the carbene
complex 55 which is the tert-butyldimethylsilyl-protected
form of 54. The deprotection of complex 55 to give 54
was accomplished with sodium methoxide in methanol in
37–54% yield. No attempt was made to optimize this
deprotection by screening other nucleophiles. It was
pleasing to find that the thermolysis of complex 54a
(R1 = Me, R2 = H) gave the hydrindenone 53 in 51%
yield, consistent with the finding that the carbene complex
42b (Scheme 6), which gives a six-membered oxygen het-
erocycle in the intramolecular tautomer-arrested annula-
tion, gave the highest yield of hydrindenone product of all
the complexes in Scheme 6. However, it was quickly
found that the outcome of the reaction was very sensitive
to the nature of the substituent on the alkyne in complex
54. When the substituent R1 is changed from methyl to
ethyl, the yield of 53 drops to 9% and when it is isopropyl,
the only product that could be identified from the crude re-
action mixture was the cyclohexadienone 58 in 16% yield.
Table 5 Yield of Compounds 53, 57, and 58
53, 57, 58
R1
Yield (%)
53
57
58
a
b
c
Me
Et
51
9
trace
25
16
i-Pr
uct distribution for thermolysis of this complex is similar
to that seen for the complex 54b in Scheme 9, indicating
that the a-propargyl substituent does not have a large im-
pact on the reaction. The reaction manifold for the ther-
molysis of complex 54e is diverted from any of the
products seen to this point, and instead, this reaction pro-
duced a 58% yield of the cyclobutenone 61a. This out-
come can most rationally be ascribed to an electrocyclic
ring closure of the vinylketene complexed intermediate
61b. The failure to be able to incorporate a vinyl group on
the acetylene will necessitate a slight revamping to the ret-
rosynthesis outlined in Scheme 1. To this end, the com-
plex 54f was prepared and its thermolysis was carried out,
however, a complicate mixture of compounds was pro-
duced which resisted attempts at their separation and fur-
ther analysis was discontinued.
The reaction of the a-substituted propargyl ether tethered
complex 54d also resulted in a disappointingly low yield
of the hydrindenone product 53d (Scheme 10). The prod-
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3686
M. E. Bos et al.
PAPER
R1
R1
R
R
R2
Me3SiCl
(CH2O)n
Me3SiCl
(CH2O)n
R2
Ar
Ar
Cl
O
OH
59
Cl
O
OH
56
60
R1
R1
Me
O
O
Me
R1
Me
R1
O
O
HO
+
O
HO
Me
Cr
benzene
+
O
O
60 °C
R2 = H
O
O
O
O
Me
54
R2
Me
Me
Me
58
(CO)5
53
57
1) 56
2) NaOMe, MeOH
Me
TBSO
O– NMe4
+
Me
Cr
(CO)5
31
Scheme 9
O
O
Pr-n
Et
Me
Me
HO
Me
O
O
Pr-n
Pr-n
benzene
60 °C
O
O
+
Et
O
O
Me Cr(CO)5
Et
Me
Me
O
54d
53d 18%
53d 21%
HO
O
O
Me
HO
Me
O
C
Me
HO
benzene
Me
O
C
60 °C
CH3
Me
Me Cr(CO)5
O
Cr(CO)3
O
Me
O
O
54e
61b
61a 51%
OBn
HO
Me
O
benzene
60 °C
Inseparable
mixture
O
Me Cr(CO)5
54f
Scheme 10
Given the less than encouraging results from the above lectivity of alkyne incorporation (Scheme 11). The
studies aimed at probing the efficacy of an approach to the products were assigned as hydrindenone 62 and the in-
synthesis of richardianidin-1 featuring an intramolecular dene 63 which have both incorporated the alkyne with the
tautomer-arrested annulation as the key step, the alterna- same regiochemistry. In some runs, there was a trace of a
tive intermolecular variation outlined in Scheme 1 was third compound, which was also found to be isomeric with
next considered. The regioselectivity of the tautomer-ar- 62 and 63. This compound was isolated with 62 and was
rested annulation has not been extensively investigated,5 obtained in a 14:1 ratio. The 1H and 13C NMR spectrum of
and thus, we initially set out to determine the degree of the an enriched sample of this minor component allowed the
regioselectivity for an alkyne where the determinant is the structures 64a to 64d to be ruled out as possibilities. The
simple steric difference between and isopropyl group and spectral data was consistent with a product that did not re-
a methyl group.7,8 Note that for the benzannulation reac- sult from cyclization onto the aryl ring. It is not clear why
tion outlined in Scheme 2, the regioselectivity with iso- the tautomer-arrested reaction of complex 19 occurs with
propyl(methyl)acetylene was found to be 4.8:1 in favor of much higher regioselectivity than the reaction of complex
the phenol 12a over 12b. The reaction of complex 19 with 11 with the same acetylene (Scheme 2), but the result is
the same alkyne gave a 3:1 mixture of isomers, however, clearly important in terms of providing a regioselective
after careful analysis, it was determined that these two iso- route to richardianidin-1 via an intermolecular tautomer-
meric products were not the result of a different regiose- arrested annulation as outlined in Scheme 1. Based on this
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3687
Me
HO
Me
HO
O
benzene
110 °C
+
+
OMe
Me Cr(CO)5
OMe
63 15%
OMe
Me
Me
19
62 44%
Me
O
HO
HO
HO
OMe
OMe
OMe
OMe
Me
Me
Me
64b
Me
Me
64a
64c
Me
64d
HO
HO
O
benzene
110 °C
+
+
OMe
OMe
66 41%
Me Cr(CO)5
OMe
65 18%
Me
Me
19
Scheme 11
result, it would thus be expected that the reaction of com- form a chelated vinyllithium that upon reaction with
plex 19 with tert-butyl(methyl)acetylene would also be methyl iodide gives the enyne 70 as a single diastereomer
highly regioselective and this in fact found to be the case in 49% yield after distillation. The enynes 71 and 72 were
although the reaction gave a smaller proportion of the tau- made in a two-step process that is outlined in Scheme 12.
tomer-arrested product 65 relative to the methyl-migrated The terminal acetylenes 73 were converted into the pen-
product 66.
tynones 74 by reaction of the corresponding lithium
acetylide with the Weinreb amide of acetic acid. Subse-
quent Wittig reaction with (methoxymethylene)phospho-
rane gave the enynes 71 and 72 in good yields and as a
nearly equal mixture of isomers in each case.
The finding that isopropyl(methyl)acetylene gave a single
regioisomer of the tautomer-arrested product with car-
bene complex 19, then prompted an examination of the set
of enynes in Scheme 12 each of which has all five of the
carbons present in the lactone ring of richardianidin-1. The reaction of the commercially available enyne 68 with
The enyne 68 is commercially available and enyne 69 is carbene complex 19 produced a very complicated reaction
prepared by the silylation of the commercially available mixture of a number of products and it was suspected that
(Z)-1-methoxybut-1-en-3-yne.15 The enyne 70 is made by among them were oligomers or polymers of the enyne.
the methylation of 69 in a procedure that is a slight modi- Based on the outcome of the intramolecular reaction of
fication of that originally reported by Zweifel.15 In a quite complex 54e (Scheme 10), a cyclobutenone product of the
unexpected process, the treatment of 69 with n-butyllithi- type 61a may also be among the many products produced
um in the presence of N,N,N¢,N¢-tetramethylethylenedi- in the reaction of enyne 68 with complex 19. The reaction
amine results in metalation on the propargylic carbon of the enyne (Z)-69 is a much cleaner reaction with the
which is b to the oxygen and then the resulting vinyllithi- major silica gel mobile component identified as the de-
um undergoes isomerization about the double bond to sired tautomer-arrested product 75 which was isolated in
OMe
OMe
OMe
Me
Me
Me
Me
OMe
Me
Me
TMS
TMS
70
OTIPS
68
69
71
72
O
Me
Cl–
N
OMe
R
OMe
2)
R
O
1) t-BuLi,
THF, –40 °C
R
Ph3P CH2OMe
t-BuLi
73a R = H
73b R = OTIPS
74a R = H
60%
71 R = H
72 R = OTIPS
89%
67%
74bR = OTIPS 67%
Scheme 12
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3688
M. E. Bos et al.
PAPER
37% yield as a 1:1 mixture of E- and Z-isomers reaction of the pure E-isomer of 71 in benzene gives the
(Scheme 13). The hydrindenone 75 was isolated as a sin- product 80 with a 96:4 mixture of E- to Z-isomers. In-
gle regioisomer, which is a little surprising given the steric creased amounts of the Z-isomer was found in other sol-
differential between the two substituents of the alkyne. vents. The reaction of (Z)-71 gives predominantly (Z)-80
However, it is likely in this case that the enol ether is elec- in similar yields. The optimal conditions for this reaction
tronically affecting the regioselectivity. Although sterics are those in Table 6, entry 3 which involves reaction in
are usually the predominant factor in controlling the re- benzene at 0.05 M in 19 at 110–120 °C. The yield of 80
giochemistry of alkyne incorporation, it has been ob- was similar in toluene, but dropped significantly in hep-
served that electron-withdrawing groups will prefer to be tane and in polar solvents such as tetrahydrofuran and
incorporated a to the methoxy group and electron-donat- acetonitrile. Syringe pump addition of 71 over two hours
ing groups will prefer to incorporated b to the methoxy did not improve the yield of the reaction (entries 9 and 10)
group.16 The reaction of enyne (E)-70 also gave a single neither did raising the temperature to 145 °C (entries 3
regioisomer 76a in 40% yield along with a small amount and 8). The maximum yield of hydrindenone 80 under the
of the aromatized product 77. An assignment of the regio- optimum conditions for the reaction of carbene complex
chemistry of these reactions was made possible when 76a 19 and enyne 71 was 60% (entry 3).
was reduced with diisobutylaluminum hydride to give a
In an effort to further optimize the tautomer arrested an-
4:1 mixture of isomers of 78 in 72–80% yield. This alco-
nulation with the enyne 71 the (dimethylamino)carbene
hol was not stable to silica gel or magnesium sulfate and
complex 83 was synthesized. It is well known that ami-
nocarbene complex have a much higher tendency to give
non-CO inserted products in the normal benzannulation,
underwent ready hydrolysis to give the bright yellow al-
dehyde 79. The regioisomeric hydrindenone 76b cannot
undergo hydrolysis to give this unsaturated aldehyde. This
but this has yet to be tested in the tautomer-arrested annu-
regiochemical assignment of 76a was confirmed by an X-
lation.17 It was curious to find that there was no reaction
between the carbene complex 24 and dimethylamine;
ray diffraction analysis.
The fact that the enynes (Z)-69 and (E)-70 did not give any most aryl complexes will react within minutes at room
of the cyclobutenone product of the type 61a (Scheme 10) temperature. The lack of reactivity of 24 is presumably
and that they both give a single regioisomer of the tau- due to the steric hindrance presented by the 2,6-dimethyl-
tomer-arrested products 75 and 76a was quite encourag- substituted arene ring. The only way complex 82 could be
ing for a continued investigation of the intermolecular prepared was to first react complex 24 with ammonia to
strategy for the synthesis of richardianidin-1 outlined in give the primary amino complex 81 in 88% yield and then
Scheme 1. The next phase of the study involved the opti- to exhaustively methylate with methyl iodide under phase
mization of the tautomer-arrested reaction of carbene transfer catalysis to give the desired dimethylamino com-
complex 19 with the enyne 71 was utilized as a 1:1 mix- plex 82 in 75% yield (Scheme 14). Finally, the para-hy-
ture of isomers (Table 6). The isomers of 71 could be sep- droxy group is liberated by treatment of 82 with hydrogen
arated with some care and were reacted individually. The fluoride–pyridine to give 83 in 50% yield.
Me
HO
Me
OMe
TMS
O
TMS
heptane
+
OMe
110 °C, 10 h
MeO
(Z)-69
Me Cr(CO)5
OMe
Me
75 37% (E/Z 1:1)
19
OMe
OMe
Me
Me
Me
HO
Me
Me
HO
Me
O
benzene
+
TMS
+
TMS
TMS
OMe
110 °C, 8 h
OMe
(E)-70
Me Cr(CO)5
OMe
77 4%
OMe
76a 40%
Me
Me
19
DIBAL-H
OMe
TMS
O
Me
Me
Me
Me
silica
gel
TMS
Me
H
O
HO
TMS
OMe
OMe
Me
OMe
OMe
79
Me
Me
76b
78
Scheme 13
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3689
Table 6 Optimization of the Reaction of Carbene Complex 19 with Alkyne 71a
OMe
Me
Me
HO
Me
Me
O
solvent
+
Me
Me
OMe
OMe
OMe
110–120 °C
Me Cr(CO)5
Me
80
71
19
Entry
1
Solvent
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
toluene
toluene
heptane
Cl(CH2)2Cl
DME
Concn (M)
Time (h)
Yield (%) of 80
Recovery (%) of 19
0.5
8
8
8
8
8
2
4
4
8
8
8
8
8
8
8
47
52
60
30
30
41
43
55b
51
50c
28
30
22
<20
–
–
2
0.1
–
3
0.05
0.01
0.005
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
–
4
28
43
20
12
7
5
6
7
8
9
<5
–
10
11
12
13
14
15
15
17
10
–
THF
MeCN
–
a Reactions with 71 (2 equiv).
b Reaction at 145 °C.
c Syringe addition of 71 over 2 h.
TBSO
Me
complexes are usually less reactive than their methoxy an-
alogues and thus the reaction of amino complex 83 with
diphenylacetylene was investigated in diglyme (not
shown). Reaction with diphenylacetylene at 140 °C for 10
hours gave no detectable products and the recovery of the
carbene complex and raising the temperature to 180 °C
for a few hours resulted in >90% conversion of the car-
bene complex, however, no silica gel mobile products
were formed. The benzannulations of aryl tungsten and
aryl molybdenum carbene complexes are also known to
give fewer CO insertion products than their chromium
counterparts.18 The tautomer-arrested annulation has not
been previously examined with tungsten or molybdenum
complexes. Complex 85 and 86 were prepared in a man-
ner similar to its chromium analogue 19. When the reac-
tions of the complexes 85 and 86 with hex-3-yne was
carried out in benzene at 110 °C no evidence for the for-
mation of 22b could be obtained. The carbene complexes
were largely consumed in each case but, as was the case
with the amino complex 83, there were no products pro-
duced that were mobile on silica gel. Finally, isopropoxy-
TBSO
Me
NH3
NH2
OMe
THF, –40 °C
2–3 d
Me Cr(CO)5
Me Cr(CO)5
81 88%
24
HNMe2
MeI, NaOH
TBAB
CH2Cl2, H2O
HO
Me
TBSO
Me
HF-py
NMe2
NMe2
CH2Cl2
r.t., 4–6 h
Me Cr(CO)5
Me Cr(CO)5
83 50%
82 75%
Scheme 14
The reaction of the amino complex 83 with hex-3-yne
failed to give any of the hydrindenone product 84
Scheme 15). Most of the carbene complex was recovered
after reaction in tetrahydrofuran at 110 °C. Aminocarbene
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3690
M. E. Bos et al.
PAPER
Et
Me
HO
Me
O
Et
Et
Et
NMe2
benzene
110 °C, 13 h
NMe2
Me Cr(CO)5
Me
83
84
Et
Me
HO
Me
OMe
O
Et
Et
Et
OMe
benzene
110 °C, 13 h
Me M(CO)5
Me
M = Mo
M = W
85
86
22b
OMe
CH3
Me
Me
HO
Me
O
Me
O
benzene
Me
+
OMe
110–120 °C
8 h
Me Cr(CO)5
O
Me
88 62%
71
87
Scheme 15
carbene complexes have been shown in some instances to cohol and the carbene complex 19 is prepared in four steps
give higher yields than methoxy complexes in the benzan- from 4-bromo-3,5-dimethylphenol.
nulation reaction.19 Therefore, the isopropoxy complex 87
was prepared and its reaction with enyne 71 was carried
out under the optimized conditions developed for the
methoxy analogue 19 (Table 6). The hydrindenone 88
A summary of the important pieces of information gained
during the course of this study on the inter- and intramo-
lecular tautomer-arrested annulation will be presented in
the context of a mechanistic accounting of the various
was isolated in 62% yield, which is not significantly great-
products and competing pathways (Scheme 17). The for-
er than the methoxy complex 19.
mation of the tautomer-arrested product 94 begins with
Finally, the reaction of the enyne 72 was investigated. the loss of a carbon monoxide ligand on the starting car-
This enyne has a triisopropylsilyl-protected oxygenated bene complex 90 to form the unsaturated 16-electron
carbon substituent on the acetylene, which will allow for complex 91. In the normal benzannulation reaction this is
eventual introduction of the 2-furyl substituent at the na- the rate-limiting step of the reaction, although it is consid-
scent C6 carbon of the lactone ring of richardianidin-1. ered unlikely to be the case for the tautomer-arrested an-
The reaction of carbene complex 19 with enyne (E)-72 nulation since the thermal requirement is ~50 °C higher
under the optimized conditions for enyne 71 (Table 6) than that for the benzannulation reaction and since it
gave the hydrindenone 89 in 40% yield (Scheme 16). would not be expected that the energy barrier for the CO
While optimization studies may increase the yield of this dissociation from 90 would significantly depend on the
reaction, the preparation of 89 via the tautomer-arrested presence of the two methyl groups on the arene ring. In
annulation allows for the rapidly assembly of an advanced fact, if anything, the energy barrier for CO dissociation
intermediate in the synthesis of richardianidin-1. Aside, from 90 would be expected to be lowered to relieve steric
from the final introduction of the furan unit, the interme- interactions. At the present time, no kinetic studies have
diate 89 has all the carbons but one present in the core been carried out for the tautomer-arrested annulation reac-
structure of richardianidin-1 and with an oxygen present tion to confirm these expectations. The next step would be
on all the carbons that are oxygenated in the natural prod- the coupling of 91 with the alkyne to give the h1,h3-vinyl-
uct. Access to 89 is very straightforward since the starting carbene-complexed intermediate 92 where a carbon–car-
enyne (E)-72 is prepared in three steps from propargyl al- bon bond is formed between the original carbene carbon
OMe
Me
HO
Me
Me
TIPSO
Me
O
OTIPS
benzene
+
OMe
OMe
110–120 °C
8 h
Me Cr(CO)5
OMe
89 40% (E/Z 87:13)
Me
19
(E)-72
Scheme 16
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3691
and the carbon of the alkyne bearing the smallest substit- complexes in Schemes 9 and 10 do not give the spirocy-
uent. An electrocyclic ring closure then generates the in- clic product. Could it be that the oxygens in the tether of
denyl derivative 93 from which there is a competition complex 29 serve to affect a ligand displacement in the vi-
between a tautomerization to give hydrindenone 94 and a nylketene complex 96 rendering a vinylketene in which
1,5-sigmatropic shift of methyl restoring the aromaticity there is no metal coordinated to the four carbons of the vi-
of the arene and giving the hydroxyindene 95.
nyl ketene?
The spirocyclic cyclohexadienone 97 represents a rare For most of the intramolecular annulations described in
outcome of the tautomer-arrested and previously had only this work the two most common products are the hydrin-
been observed in intermolecular reactions in acetonitrile denone 94 and the naphthalenedione 99. For the normal
solvent. This product results from a CO insertion in the benzannulation (Scheme 2), the CO insertion to give a vi-
h1,h3-vinylcarbene-complexed intermediate 92 to give the nylketene complex and cyclization to a phenol occur at
h4-vinylketene complex 96, which is presumably on the temperatures of 45–60 °C. The tautomer-arrested annula-
pathway to 97 but also the branch point between 97 and tion of complexes of the type 90 require temperatures in
the tetralone derivatives 99 and 100. The fact that it had excess of 110 °C to achieve similar rates. Three possible
only been observed before in acetonitrile suggests that the explanations for this are: (1) the CO insertion in the vinyl
solvent will affected a ligand displacement on complex 96 carbene complexed intermediate 92 is reversible and that
to give the metal-free vinylketene which then cyclizes via the electrocyclic ring closure of the vinylketene complex
an electrophilic addition to the ipso aromatic carbon rather 96 is slowed by the presence of the methyl groups on the
than an electrocyclic ring closure to give a tetralone deriv- arene ring, or (2) the rate of CO insertion in the vinylcar-
ative. This selectivity for closure could be the result of bene-complexed intermediate 92 is depressed as a result
combined electronic and steric effects. It is not clear why of the presence of the methyl groups which may be possi-
the intramolecular annulation of complex 29 produces the ble if coordination of the chromium to one of the double
spirocyclic product 41 (Schemes 5 and 7). This is likely bonds of the chromium occurs concurrent with CO inser-
related to the oxygen atom in the tether since none of the tion, or (3) the rate of addition of the alkyne to the unsat-
complexes in Scheme 6 give this product. It must also be urated intermediate 91 is slowed by the presence of the
related to the position of the oxygen in the tether since the methyl groups. A differentiation between these possibili-
HO
Me
C
OR
HO
Me
HO
Me
Me
RL
– CO
RL
RS
C
RS
OR
OR
C
OC
Cr CO
Me Cr(CO)5
Me Cr(CO)4
C
O
90
91
92
C
O
HO
Me
OR
C
RL
O
Me
Cr(CO)3
RS
HO
O
Me
RL
O
C
RS
C
C
Cr
O
OR
RS
OR
RL
Me
93
CO
C
C
O
97
96
O
O
Me
RL
Me
RL
RS
Me
Me
HO
RL
HO
O
HO
RL
Cr(CO)3
RS
RS
RS
OR
OR
Me OR
Me OR
Me
Me
95
98
100
94
HO
HO
Me
C
O
Me
OR
O
Me
Me
O
RL
O
C
RS
Me
C
C
Me
RO
RS
RS
Cr
R2
CO
Me OR
99
R1
C
C
O
101
102
O
Scheme 17
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3692
M. E. Bos et al.
PAPER
Benzyl Prop-1-enyl Ether (32)
ties will have to await further mechanistic studies. In any
event, the branch point between the hydrindenone product
94 and the naphthalenedione product 99 is the vinylcar-
bene complexed intermediate 92. Clearly, for the intramo-
lecular reactions examined in this work (Schemes 6
and 9) the partition between these two products is a func-
tion of size of the newly formed heterocyclic ring with the
greatest proportion of the hydrindenone product when a
six-membered ring is formed. Increased amounts of the
naphthalenedione product were observed when five- or
seven-membered heterocyclic rings are formed
(Scheme 6). This correlation of the product distribution
with the size of the heterocyclic ring that is formed may
be a function of the strain that this newly formed ring in-
troduces into the product. The idea that ring strain is a
controlling factor is this product distribution is consistent
with the observation that naphthalenedione products have
not yet been observed from an inter-molecular tautomer-
arrested annulation. The observation that the distribution
between products 53 and 58 is a function of the size of the
substituent R1 on the end of the tethered alkyne in com-
Allyl benzyl ether was prepared by adding allyl alcohol (13.6 mL,
200 mmol) in DMSO (20 mL) to a slurry of NaH (60 wt%, 8.4 g,
210 mmol), which had been washed with hexanes (2 ×) under N2,
and DMSO (60 mL) at 0 °C over 30 min. After H2 evolution ceased,
benzyl bromide (24.4 mL, 205 mmol) was added quickly and the
mixture was stirred overnight. The solids were filtered off and upon
heating allyl benzyl ether co-distilled with DMSO into a clean flask
at ambient pressure. To this was added t-BuOK (2 g) and the mix-
ture was heated at 100 °C for 6 h. The mixture was cooled and
poured into hexanes and the DMSO was extracted with several por-
tions of H2O (1 L total). Drying (MgSO4), concentration, and
Kugelrohr distillation gave enol ether 32 as a colorless oil; yield:
21.09 g (71%); ratio E/Z 7.9:1; Rf = 0.33 (hexanes).
IR (neat): 1669 s, 1454 m, 1357 m, 1126 s, 1094 s, 1075 s, 733 m,
697 s cm–1.
1H NMR (CDCl3): d = (isomer A) 1.64 (dd, J = 6.8, 1.3 Hz, 3 H),
4.42–4.47 (m, 1 H), 4.80 (s, 2 H), 6.02 (dq, J = 1.4, 7.8 Hz, 1 H),
7.28–7.36 (m, 5 H, mixture with B).
1H NMR (CDCl3): d = (isomer B) 1.58 (dd, J = 6.7, 1.3 Hz, 3 H),
4.70 (s, 2 H), 4.83–4.91 (m, 1 H), 6.30 (br d, J = 12.4 Hz, 1 H),
7.28–7.36 (m, 5 H, mixture with A).
plex 54 could be accounted for by the effect that this 3-[2-(tert-Butyldimethylsiloxy)ethoxy]prop-1-yne (34)
2-(Prop-2-ynyloxy)ethanol (33) was prepared by a procedure devel-
oped by Semmelhack for closely related compounds.11c In CH2Cl2
(100 mL) were combined 33 (7.7 g, 76.9 mmol), TBSCl (13.91 g,
92.3 mmol), pyridine (8.7 mL, 107 mmol), and DMAP (940 mg,
0.77 mmol). After stirring overnight, the solvent was removed and
the residue mixed with pentane (100 mL). The solids were filtered
off on a Celite pad and washed with additional pentane. The pentane
was washed sat. NH4Cl (2 × 50 mL), dried (MgSO4), and concen-
trated. Kugelrohr distillation at 65 °C/0.7 mbar gave 34 as a color-
less oil; yield: 12.842 g (78%); Rf = 0.58 (Et2O–CH2Cl2–hexanes,
1:1:20).
change in substitution would be expected to have on the
relative rates of cyclization of vinylcarbene-complexed
intermediate 92 versus vinylketene complex 96. In the cy-
clization of the vinylcarbene complex 92, the substituent
RL comes a lot closer to one of the methyl groups on the
arene ring than in the cyclization of the vinylketene com-
plex 96. Finally, the reaction of an enyne with an alkyl
substituent on the double bond leads to the formation of
the cyclobutanone 61a (Scheme 10), whereas, enynes that
have an oxygen substituent on the double bond do not
(Schemes 13 and 15 and Table 6). A reasonable explana-
tion of these results is that when substituent R2 in 101
(Scheme 17) is an ether oxygen, then the vinylketene
complex would be expected to be stabilized as a vinylo-
gous ester relative to the cyclobutanone in which the oxy-
gen is no longer conjugated to the carbon–oxygen double
bond.
IR (neat): 2117 w, 1256 m, 1106 s, 837 s cm–1.
1H NMR (CDCl3): d = 0.09 (s, 6 H, Si-t-BuMe2), 0.91 (s, 9 H, Si-t-
BuMe2), 2.42 (t, J = 2.1 Hz, 1 H, C≡C-H), 3.61 (t, J = 5.2 Hz, 2 H,
OCH2CH2O), 3.79 (t, J = 5.2 Hz, 2 H, OCH2CH2O), 4.20 (d, J = 2.3
Hz, 2 H, C≡CCH2O).
5-Benzyloxy-1-[2-(tert-butyldimethylsiloxy)ethoxy]-4-methyl-
pent-2-yne (36)
To THF (25 mL) at 0 °C under N2 was added 32 (4.41 g, 29.8 mmol)
followed by 1.0 M BH3 in THF (9.9 mL, 9.92 mmol). The mixture
was stirred at 0 °C for 20 min and at r.t. for 10 min, the clear color-
less soln was then cooled to 0 °C and a soln of 35 [formed by treat-
ment of alkyne 34 (2.13 g, 9.92 mmol) with 1.6 M n-BuLi (6.2 mL,
9.92 mmol) in THF (20 mL) at 0 °C under argon for 30 min] was
transferred via cannula with additional THF (5 mL). After 5 min,
the colorless soln was cooled to –78 °C, and I2 (2.52 g, 9.92 mmol)
in Et2O (50 mL) was added dropwise to give a dark red soln in
which a precipitate eventually formed. After stirring for 1 h, the or-
ange slurry was brought to r.t. and the mixture was washed with 3
M KOH [2 × 20 mL, spiked with sat. Na2S2O3 soln (1 mL)]. The
aqueous layers were back-extracted with Et2O (20 mL). The com-
bined pale yellow organic layers were treated with 3 M NaOH (3.3
mL) and 30 wt% H2O2 (1.3 mL) for 20 min (slightly exothermic re-
action). The reaction was washed with NaHCO3 and brine, dried,
and concentrated. Chromatography (silica gel, Et2O–CH2Cl2–hex-
anes, 1:1:30) gave 36 as a clear colorless oil; yield: 1.98 g (57%).
All experiments were performed under an argon atmosphere. Ben-
zene, THF, and Et2O were distilled from sodium benzophenone
ketyl under nitrogen. Methylene chloride was distilled from calci-
um hydride under nitrogen. Isopropanol was distilled from NaBH4
onto 4 Å MS. Other reagents were purified by simple distillation or
by passing through a pad of activated silica gel. 1H and 13C NMR
spectra were recorded on a General Electric QE-300 (300 MHz 1H,
1
75.5 MHz 13C) or Bruker Avance (400 MHz H, 100 MHz 13C)
1
spectrometer in CDCl3 using residual CHCl3 (7.25 ppm H, 77.25
ppm 13C) as an internal reference unless otherwise stated. Analytical
thin-layer chromatography (TLC) was performed on Merck silica
gel plates with F-254 indicator. Components were visualized by il-
lumination with long-wave ultraviolet light, exposure to iodine va-
por, or by staining with one of the following reagents (followed by
heating): p-anisaldehyde (or vanillin) in ethanol/sulfuric acid; 7%
phosphomolybdic acid in ethanol; 0.04 M ammonium molybdate in
10% sulfuric acid. Solvents for extraction and chromatography
were reagent grade and used as received. Flash column chromatog-
raphy was performed with E. Merck silica gel 60 (230–400 mesh).
IR (neat): 2954 s, 2930 s, 2885 m, 2857 s, 2244 w, 1254 m, 1099 vs,
827 s, 778 m cm–1.
1H NMR (CDCl3): d = 0.08 (s, 6 H), 0.91 (s, 9 H), 1.22 (d, J = 7.0
Hz, 3 H), 2.79 (m, 1 H), 3.36 (dd, J = 8.8, 7.8 Hz, 1 H), 3.53 (dd,
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3693
J = 9.0, 6.1 Hz, 1 H), 3.57 (t, J = 5.3 Hz, 2 H), 3.77 (t, J = 5.2 Hz, 2
H), 4.18 (d, J = 1.8 Hz, 2 H), 4.54 (d, J = 2.8 Hz, 2 H), 7.25–7.33
(m, 5 H).
13C NMR (CDCl3): d = –5.31, 17.68, 18.31, 25.88, 26.70, 58.84,
62.57, 70.94, 72.91, 73.86, 76.87, 88.34, 127.50, 128.27, 138.13 (1
aryl carbon not located).
-CH2CH2CH2CH3), 2.25 (s, 6 H, aryl H), 2.51 (br t, 2 H,
-CH2CH2CH2CH3), 6.49 (s, 2 H, aryl H).
MS: m/z (%) = 292 [M+] (26), 277 (17), 249 (49), 235 [M – n-Bu]
(100), 193 (24), 179 (37).
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl](oxido)meth-
ylene}pentacarbonylchromium(0) Tetramethylammonium Salt
(31)
5-Benzyloxy-1-[2-hydroxyethoxy]-4-methylpent-2-yne (37)
A soln of 36 (1.98 g, 5.47 mmol) dissolved in THF (30 mL) under
N2 at r.t. was treated with 1.0 M TBAF THF (7.4 mL, 7.4 mmol) for
5 h. The mixture was poured into brine overlaid with Et2O, dried
(MgSO4), and concentrated. Chromatography (silica gel, 40%
EtOAc–hexanes) gave 37 as a clear oil; yield: 1.32 g (98%);
Rf = 0.38 (40% EtOAc–hexanes).
To bromide 38b (3.70 g, 11.7 mmol) in THF (20 mL) at –40 °C un-
der argon was added dropwise over 7 min 1.7 M t-BuLi in pentane
(14.5 mL, 24.7 mmol). The temperature rose to –30 °C and a yellow
color developed. After 20 min, precipitation occurred and the mix-
ture was stirred at 0 °C for 30 min. The soln was transferred via can-
nula into Cr(CO)6 (2.99 g, 13.6 mmol) in THF (10 mL) at 0 °C.
After warming to r.t., the dark brown soln was stirred 2–3 h, and the
THF was removed. Note: the concentrated lithium acylate can de-
compose exothermically in air, so caution is required in handling.
To the residue was added N2-purged H2O (bubbled through for 30
min) and the material was filtered through Celite under an N2 blan-
ket. The filtrate was transferred to a separatory funnel, and shaken
quickly with N2-purged hexanes, discarding the hexanes. The aque-
ous layer was treated with Me4NBr or Me4NCl portionwise until no
precipitation was observed. The yellow slurry was filtered onto a
Celite pad under an inverted N2 umbrella and washed with H2O and
hexanes. The receiver flask was changed and the yellow solid
washed through with purged CH2Cl2. Drying (MgSO4), trituration
with hexanes or benzene, and solvent removal gave a yellow to
gold-green solid; yield: 3.90 g (63%).
IR (neat): 3425 br m, 2933 s, 2861 s, 2237 w, 1454 m, 1356 m, 1099
s, 1076 s, 739 s, 699 s cm–1.
1H NMR (CDCl3): d = 1.21 (d, J = 6.8 Hz, 3 H), 1.97 (br s, 1 H),
2.78 (br q, J = 6.8 Hz, 1 H), 3.36 (dd, J = 7.3, 1.7 Hz, 1 H), 3.50 (dd,
J = 6.4, 2.6 Hz, 1 H), 3.60 (t, J = 4.5 Hz, 2 H), 3.73 (br s, 2 H), 4.17
(d, J = 1.8 Hz, 2 H), 4.53 (d, J = 1.2 Hz, 2 H), 7.25–7.30 (m, 5 H).
2-Bromo-5-(tert-butyldimethylsiloxy)-1,3-dimethylbenzene
(38b)
To TBSCl (8.55 g, 56.7 mmol) was added 4-bromo-3,5-dimeth-
ylphenol (38a; 10.87 g, 54 mmol) followed by CH2Cl2 (60 mL). To
this slurry was added Et3N (9.9 mL, 70 mmol) with dissolution of
the phenol occurring within 5 min. After stirring at r.t. for 12 h, the
solvent was removed and the residue mixed with hexanes. Filtration
through Celite to remove solids, evaporative removal of volatiles,
and Kugelrohr distillation (120–130 °C/5.3 mbar) gave 38b as a
colorless oil at r.t., white solid at 0 °C; yield: 16.93 g (99%);
Rf = 0.62 (hexanes).
IR (neat): 1466 m, 1323 m, 1169 m, 841 s cm–1.
1H NMR (CDCl3): d = 0.17 (s, 6 H, Si-t-BuMe2), 0.95 (s, 9 H, Si-t-
BuMe2), 2.33 (s, 6 H, aryl CH3), 6.56 (s, 2 H, aryl H).
13C NMR (CDCl3): d = –4.4, 18.2, 23.9, 25.7, 119.0, 119.9, 139.0,
154.1.
MS: m/z (%) = 316 [M+, 81Br] (21), 314 [M+, 79Br] (21), 260 (81Br,
32), 258 (79Br, 32), 259 (81Br, 100), 257 (79Br, 100), 178 (82), 177
(52), 163 (31), 139 (81Br, 18), 137 (79Br, 18), 73 (17).
1H NMR (acetone-d6, broadened): d = 0.15 (s, 6 H), 0.96 (s, 9 H),
2.13 (s, 6 H), 3.39 (s, 12 H), 6.32 (s, 2 H).
{[2-(5-Benzyloxy-4-methylpent-2-yloxy)ethoxy][4-hydroxy-2,6-
dimethylphenyl]methylene}pentacarbonylchromium(0) (29)
A soln of alkynol 37 (299.1 mg, 1.20 mmol) in CH2Cl2 (10 mL) at
0 °C under N2 was treated sequentially with pyridine (125 mL, 1.6
mmol) and Tf2O (243 mL, 1.44 mmol). The mixture was stirred for
1.5 h and then poured into brine. The layers were separated and the
organic layer added directly to a soln of ammonium salt 31 (700 mg,
1.32 mmol) in CH2Cl2 (5 mL) under N2 at r.t. After 45 min, the
orange soln of complex 40 was washed with brine and the CH2Cl2
removed in vacuo. Et2O (20 mL) was added followed by 25 wt%
NaOMe in MeOH (4 mL). The mixture was stirred under argon until
TLC showed complete desilylation. Chromatography (20%
EtOAc–hexanes) gave complex 29; yield: 300 mg (44%).
Anal. Calcd for C14H23BrOSi: C, 53.33; H, 7.35. Found: C, 53.61;
H, 7.28.
5-Benzyloxy-4-methyl-1-[2-(triflyloxy)ethoxy]pent-2-yne (30)
Rf = 0.55 (Et2O–CH2Cl2–hexanes, 1:1:4).
1-(tert-Butyldimethylsiloxy)-3,5-dimethylbenzene (A) and 2-
Butyl-5-(tert-butyldimethylsiloxy)-1,3-dimethylbenzene (B)
To a soln of bromide 38b (496 mg, 1.6 mmol) in THF (2 mL) at
–50 °C was added 1.6 M n-BuLi in hexanes (1.2 mL, 1.9 mmol). An
aliquot removed after 30 min was quenched with sat. NH4Cl soln
and examined by GC. Three peaks were observed, corresponding to
reduced product A (64%), starting material 38b (5%) and butyl-sub-
stituted product B (31%). After an additional hour, the ratio be-
tween A and B had changed: A (30%), starting material (5%), and
B (64%). Through workup and chromatography with hexanes, it
was possible to isolate by shaving fractions a small amount of B for
MS analysis.
IR (neat): 2244 w, 1413 s, 1245 s, 1207 s, 1147 s, 1126 s, 1105 s,
931 s cm–1.
1H NMR (CDCl3): d = 1.22 (d, J = 6.8 Hz, 3 H), 2.80 (br q, J = 6.7
Hz, 1 H), 3.38 (dd, J = 8.8, 7.3 Hz, 1 H), 3.50 (dd, J = 8.9, 6.5 Hz,
1 H), 3.81 (t, J = 4.4 Hz, 2 H), 4.21 (d, J = 1.7 Hz, 2 H), 4.54 (s, 2
H), 4.60 (t, J = 4.4 Hz, 2 H), 7.26–7.34 (m, 5 H).
{[2-(5-Benzyloxy-4-methylpent-2-yloxy)ethoxy][4-hydroxy-2,6-
dimethylphenyl]methylene}pentacarbonylchromium(0) (29)
Red oil; Rf = 0.24 (20% EtOAc–hexanes).
IR (neat): 3301 br w, 2977 m, 2062 s, 1988 s, 1935 vs, 1314 m, 1255
m, 1173 m, 1136 s, 1116 s, 661 s cm–1.
1H NMR (CDCl3): d = 1.21 (d, J = 7.0 Hz, 3 H), 2.11 (s, 6 H), 2.76–
2.80 (m, 1 H), 3.36 (m, 2 H), 3.94 (br s, 2 H), 4.17 (br s, 2 H), 4.23
(d, J = 1.4 Hz, 2 H), 4.54 (s, 2 H), 4.8–5.0 (br s, 1 H), 6.47 (s, 2 H),
7.25–7.33 (m, 5 H).
1-(tert-Butyldimethylsiloxy)-3,5-dimethylbenzene (A)
1H NMR (CDCl3): d = 0.18 (s, 6 H, Si-t-BuMe2), 0.97 (s, 9 H, Si-t-
BuMe2), 2.24 (s, 6 H, aryl CH3), 6.45 (s, 2 H, aryl m-H), 6.58 (s, 1
H, aryl H).
2-Butyl-5-(tert-butyldimethylsiloxy)-1,3-dimethylbenzene (B)
1H NMR (CDCl3): d = 0.18 (s, 6 H, Si-t-BuMe2), 0.95–0.98
(m, 12 H, Si-t-BuMe2 and -CH2CH2CH2CH3), 1.38–1.43 (m, 4 H,
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3694
M. E. Bos et al.
PAPER
13C NMR (CDCl3): d = 17.51, 19.40, 26.64, 59.03, 66.98, 72.97,
73.79, 76.12, 77.16, 89.31, 114.89, 127.68, 127.81, 128.33, 128.65,
137.79, 143.66, 155.34, 216.12, 224.57, 364.54.
1H NMR (C6D6): d = 0.81 (d, J = 7.1 Hz, 3 H, major), 0.96 (d,
J = 7.1 Hz, 3 H, minor), 1.520 (s, 3 H, major), 1.522 (s, 3 H, minor),
1.53 (s, 3 H, minor), 1.64 (s, 3 H, major), 1.98–2.01 (m, 1 H, major),
2.40–2.44 (m, 1 H, minor), 3.16–3.19 (m), 3.27–3.37 (m), 3.45 (s),
3.48 (dd, J = 8.9, 6.4 Hz), 3.57–3.67 (m), 3.79 (t, J = 8.6 Hz), 3.86
(d, J = 15.6 Hz), 3.95–3.98 (m), 4.02 (d, J = 15.5 Hz), 4.20–4.23
(m), 4.28 (d, J = 12.3 Hz), 4.39 (d, J = 12 Hz), 4.43 (d, J = 12 Hz).
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl](meth-
oxy)methylene}pentacarbonylchromium(0) (24)
The lithium acylate can be prepared as described above in the prep-
aration of the ammonium acylate 31. The lithium acylate was dis-
solved in CH2Cl2 and treated with methyl fluorosulfonate (1.3
equiv) for 30 min to 1 h. The soln was poured into Et2O and brine
and separated. Back extraction of the aqueous layer with Et2O and
washing of the combined organic layers with brine was performed,
followed by drying (MgSO4), and solvent removal. Chromatogra-
phy on silica gel (5% Et2O–hexanes) gave 24; yield: 57%; orange
needles from hexane, discolors at 66 °C; mp 86–87 °C; Rf = 0.30
(hexanes).
IR (CHCl3): 2064 w, 1948 vs cm–1.
1H NMR (CDCl3): d = 0.21 (s, 6 H), 0.99 (s, 9 H), 2.09 (s, 6 H), 3.98
(br s, 3 H), 6.50 (s, 2 H).
13C NMR (CDCl3): d = –3.95, 18.64, 19.83, 26.08, 65.08, 120.12,
128.61, 144.49, 155.69, 216.84, 224.99, 366.19.
MS: m/z (%) = 470 [M+] (1), 442 (3), 414 (13), 386 (5), 358 (13),
330 (100), 300 (32), 247 (13), 126 (22).
MS: m/z (%) = 408 M+ (12), 317 (19), 149 (9), 91 (100), 83 (27), 73
(17).
Pentacarbonyl[(4-hydroxy-2,6-dimethylphenyl)(pent-3-ynyl-
oxy)methylene]chromium(0) (42a); Typical Procedure
To a slurry of the adduct of Tf2O (1.85 mL, 11 mmol) and pyridine
(1.05 mL, 13 mmol) in CH2Cl2 (20 mL) at 0 °C under N2 was added
commercially available pent-3-yn-1-ol to give a pink suspension.
This was stirred for 1 h, then washed with brine. After drying
(MgSO4) and solvent removal, the residue was dissolved in CH2Cl2
(~20 mL) and ammonium salt 31 (1.5 g, 2.83 mmol) was added. Af-
ter stirring for 1 h, the red soln was washed with brine, dried
(MgSO4), and the solvent removed. To the resultant red oil was add-
ed sequentially anhyd Et2O (20 mL) and 25 wt% NaOMe in MeOH
(4 mL) under argon. The reaction was stirred for 1 h at r.t. when
TLC indicated completion and then was poured into brine and addi-
tional Et2O (20 mL). The layers were separated without shaking,
and the aqueous layer treated with 10% HCl (20 mL). This was re-
extracted with Et2O (40 mL), then washed with brine. The com-
bined organic extracts were dried (MgSO4), concentrated, and chro-
matographed (silica gel, 20% EtOAc–hexanes). In this manner,
complex 42a was obtained as a dark red oil; yield: 990.3 mg (86%).
No crystallization could be induced upon cooling in hexanes to
–78 °C. This complex failed to give satisfactory MS. Additionally,
because it was impossible to thoroughly remove all traces of solvent
by high vacuum without observing product decomposition, no at-
tempts at obtaining combustion analysis data were made; Rf = 0.48
(tails) (20% EtOAc–hexanes).
Anal. Calcd for C21H26CrO7Si: C, 53.61; H, 5.57. Found: C, 53.74,
H, 5.63.
Pentacarbonyl[(4-hydroxy-2,6-dimethylphenyl)(methoxy)meth-
ylene]chromium(0) (19)
Desilylation of the purified 4-siloxy complex 24 was performed
(vide infra) to give the 4-hydroxy complex 19 in 91% yield. How-
ever, the 4-hydroxy complex may be obtained most conveniently
without chromatographic isolation of the silylated complex 24. In
this case, the crude 4-siloxy complex (preceding preparation) was
dissolved in Et2O (ca. 30 mL) under argon (for 10 mmol scale) and
treated with 25% wt% NaOMe in MeOH (5 mL) until TLC (20%
EtOAc–hexanes) showed no further starting material, ca. 30 min to
1 h. The slurry was poured into Et2O and brine and the layers sepa-
rated. The Et2O was washed with additional brine and set aside. The
colored aqueous layer (dark brown to green) was neutralized with
10% HCl and extracted with Et2O (1 ×). After washing this layer
with brine, the combined extracts were dried, the solvents were re-
moved, and the residue was chromatographed (silica gel, 20%
EtOAc–hexanes) to give 19 in 72–83% yield.
IR (neat): 3374 br w, 2063 vs, 1928 vs, 1255 m, 1168 m, 1131 s, 682
m, 653 m, 617 m cm–1.
1H NMR (CDCl3): d = 1.74 (s, 3 H), 2.10 (s, 6 H), 2.76 (s, 2 H), 4.02
(s, 2 H), 6.51 (s, 2 H) (line broadened, hydroxy not observed).
13C NMR (CDCl3): d = 3.23, 19.36, 19.79, 73.66, 76.15, 78.66,
114.94, 128.68, 144.08, 154.89, 216.27, 224.56, 363.87.
Pentacarbonyl[(hex-4-ynyloxy)(4-hydroxy-2,6-dimethylphe-
nyl)methylene]chromium(0) (42b)
The triflic ester of hex-4-yn-1-ol was prepared from hex-4-yn-1-ol
(1.01 g, 11.3 mmol) by the general procedure and purified by bulb-
to-bulb distillation at 60 °C. The alkynyl triflate (652 mg, 2.83
mmol) was then reacted with ammonium salt 31 (1.00 g, 1.88
mmol) according to the general procedure. Purification of the prod-
uct as for 42a gave two fractions of complex 42b; one containing
pure material as a red oil (493.0 mg, 62%) and another consisting of
slightly impure material (149 mg, ~18%); Rf = 0.32 (20% EtOAc–
hexanes).
Cyclization of Complex 29 in Benzene
A soln of complex 29 (118 mg, 0.21 mmol) in benzene (0.01 M,
20.6 mL) was added to a single-necked flask that had the 14/20 joint
replaced with a threaded high-vacuum Teflon stopcock. The soln
was deoxygenated (freeze–pump–thaw, 2 cycles) and then back-
filled with 1 atm argon at r.t. and the flask sealed. The flask was
placed in an oil bath at 60 °C for 4 h. Benzene was removed in vac-
uo and the residue chromatographed (silica gel, 40% EtOAc–hex-
anes). Several fast eluting bands were not collected/characterized;
these were minor products by TLC and crude NMR. Two bands
were yellow and possibly contained small amounts of the diaste-
reomeric hydrindenone products. The major uncolored band was
collected and found to contain the two diastereomeric spiroketones
41 as a colorless oil; yield: 38.1 mg (48%); 8:5 ratio. The spectra
were collected on the mixture of isomers; Rf = 0.30 (40% EtOAc–
hexanes).
IR (neat): 3386 br m, 2062 vs, 1927 vs, 1253 s, 1168 s, 1132 s, 663
s cm–1.
1H NMR (CDCl3): d = 1.75 (br s, 3 H), 2.13 (br s, 8 H), 2.46 (br s,
2 H), 4.10 (br s, 2 H), 5.0–5.5 (br s, 1 H), 6.50 (s, 2 H) (line broad-
ened).
13C NMR (CDCl3): d = 3.31, 14.69, 15.20, 19.35, 28.29, 66.00,
76.74, 114.85, 128.47, 144.20, 155.13, 214.44, 224.49, 364.22.
MS: m/z (%) = 366 [M+ – 2 CO] (1), 338 [M+ – 3 CO] (0.5), 310 [M+
– 4 CO] (1), 282 [M+ –5 CO] (5), 230 [M+ –Cr(CO)5] (6), 83 (100)
(molecular ion not observed).
IR (neat): 1754 m, 1670 m, 1658 s, 1629 m, 1617 m, 1384 m, 1291
m, 1092 m, 750 m cm–1.
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

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Studies on the Synthesis of Richardianidin-1
3695
Pentacarbonyl[(hept-5-ynyloxy)(4-hydroxy-2,6-dimethylphe-
nyl)methylene]chromium(0) (42c)
This complex was prepared from hept-5-yn-1-ol (407 mg, 3.63
mmol) and ammonium salt 31 (1.5 g, 2.83 mmol) according to the
general procedure. Purification in the same manner gave complex
42c as an orange-red oil; yield: 694 mg (56%); Rf = 0.45 (20%
EtOAc–hexanes).
cyclohexadienone products in the same fractions off the column,
typically in less than 5% combined yield. The assignments for the
spiroketone and cyclohexadienone 44b are made only on the bases
of the following discernible chemical shifts in the mixtures:
spiroketone: quartet at 3.15 (1 H), singlets at 6.22 and 6.28 (1 H
each), and at 1.82 and 1.89 (3 H each); cyclohexadienone 44b: dou-
blet at 2.87 (1 H, large J), singlets at 5.80 (1 H), 2.29 (3 H), and 1.90
(3 H).
IR (neat): 3398 br w, 2062 s, 1988 s, 1958 s, 1309 m, 1254 m, 1166
m, 1133 s cm–1.
1H NMR (CDCl3): d = 1.73 (br m, 2 H), 1.77 (s, 3 H), 2.04 (br s, 2
H), 2.11 (br s, 6 H), 2.24 (br s, 2 H), 4.05 (br s, 2 H), 5.27 (s, 1 H),
6.52 (br s, 2 H).
13C NMR (CDCl3): d = 3.24, 18.17, 19.30, 25.11, 28.20, 53.37,
78.19, 114.90, 128.40, 144.15, 154.80, 216.36, 224.42, 363.39 (1
alkynyl carbon not located).
Indeno[1,2-b]pyran-7(2H)-one 43b
Bright yellow solid; mp 150 °C; Rf = 0.25 (20% EtOAc–hexanes).
IR (CHCl3): 1630 m, 1561 s, 1343 m, 1145 m, 1094 m cm–1.
1H NMR (CDCl3): d = 1.08 (s, 3 H), 1.84 (s, 3 H), 1.89 (d, J = 14.9
Hz, 1 H), 1.91–1.94 (m, 2 H), 2.21 (d, J = 1 Hz, 3 H), 2.44 (d,
J = 14.9 Hz, 1 H), 2.47–2.50 (m, 2 H), 4.18 (t, J = 5.2 Hz, 2 H), 5.57
(s, 1 H).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 42a; Typical Procedure
13C NMR (CDCl3): d = 10.08, 20.61, 20.77, 22.29, 22.70, 46.58,
51.00, 67.97, 118.95, 119.47, 128.20, 150.83, 154.25, 155.21,
199.24.
MS: m/z (%) = 230 [M+] (100), 215 (56), 187 (56), 159 (40), 131
(12).
A soln of complex 42a (112.6 mg, 0.28 mmol) in benzene (0.005 M,
55.2 mL) was added to a single-necked flask that had the 14/20 joint
replaced with a threaded high-vacuum Teflon stopcock. The soln
was deoxygenated by the freeze–thaw method (–196 °C/25 °C, 2
cycles), backfilled with 1 atm argon at r.t.. The flask was sealed
placed in an oil bath at 60 °C for 1.5 h. After opening to air and fil-
tration through Celite, the mixture was stripped of volatiles. Chro-
matographic purification (silica gel, 40% EtOAc–hexanes) gave
two compounds: hydrindenone 43a (12.2 mg, 20%), and cyclohexa-
dienone 44a (34.6 mg, 51%). When the reaction was carried out at
110 °C and 0.005 M the products were 43a (14%) and 44a (46%).
HRMS: m/z [M+] calcd for C15H18O2: 230.1308; found: 230.1311.
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 42c
Thermolysis of complex 42c (149 mg, 0.34 mmol) was carried out
according to the typical procedure at 60 °C for 12 h. Purification by
chromatography (silica gel, 20% EtOAc–hexanes) gave 43c (21.8
mg) contaminated with benzene(tricarbonyl)chromium (26% after
repurification) and 44c (13.1 mg, 14%). When the reaction was car-
ried out at 110 °C and 0.005 M the reaction gave 43c (35.7 mg,
36%) and 44c (33.4 mg, 30%) and no spiro compound was observed
in the crude 1H NMR.
Indeno[1,2-b]furan-6-one 43a
Yellow solid; Rf = 0.16 (20% EtOAc–hexanes).
IR (CHCl3): 2975 w, 2855 w, 1666 m, 1639 s, 1596 s, 1335 w, 1119
w, 1085w cm–1.
1H NMR (CDCl3): d = 1.16 (s, 3 H), 1.88 (s, 3 H), 2.08 (d, J = 14.8
Hz, 1 H), 2.16 (s, 3 H), 2.45 (d, J = 14.8 Hz, 1 H), 2.72–2.75 (m, 2
H), 4.87–4.93 (m, 2 H), 5.59 (s, 1 H).
Indeno[1,2-b]oxepin-8-one 43c
Yellow solid; Rf = 0.33 (20% EtOAc–hexanes).
IR (CHCl3): 2929 m, 2855 m, 1629 vs, 1572 s, 1462 m, 1379 m,
1369 m, 1348 s, 1305 m, 1142 m, 1100 m, 902 m cm–1.
MS: m/z (%) = 216 [M+] (100), 201 (62), 173 (84), 145 (12), 115
(11), 91 (10).
1H NMR (CDCl3): d = 1.07 (s, 3 H), 1.69–1.78 (m, 2 H), 1.84 (s, 3
H), 1.91 (d, J = 15 Hz, 1 H), 1.94–1.99 (m, 2 H), 2.23 (d, J = 0.8 Hz,
3 H), 2.42–2.48 (m, 3 H), 3.97–4.01 (m, 1 H), 4.08–4.13 (m, 1 H),
5.63 (s, 1 H).
13C NMR (CDCl3): d = 12.45, 22.55, 24.45, 26.99, 27.46, 33.03,
47.71, 52.53, 72.64, 120.16, 123.92, 135.02, 148.28, 150.73,
157.91, 195.58.
HRMS: m/z [M+] calcd for C14H16O2: 216.1150; found: 216.1144.
Naphtho[1,2-b]furan-5,7-dione 44a
Yellow solid, discolors at 140 °C; mp 159–165 °C; Rf = 0.22 (40%
EtOAc–hexanes).
IR (CHCl3): 1653 vs, 1594 m, 1569 w, 1337 m cm–1.
1H NMR (CDCl3): d = 1.23 (s, 3 H), 1.98 (s, 3 H), 2.28 (d, J = 16.9
Hz, 1 H), 2.30 (s, 3 H), 2.86 (d, J = 16.9 Hz, 1 H), 3.00–3.05 (m, 2
H), 4.47 (apparent quartet, J = 8.2 Hz, 1 H), 4.56 (dt, J = 8.7, 6.1
Hz, 1 H), 5.78 (s, 1 H).
MS: m/z (%) = 244 [M+] (100), 229 (17), 201 (21), 187 (33), 173
(12), 159 (30), 145 (11), 131 (13), 115 (17).
HRMS: m/z [M+] calcd for C16H20O2: 244.1463; found: 244.1463.
13C NMR (CDCl3): d = 12.42, 23.32, 27.81, 28.50, 44.53, 47.58,
70.57, 115.02, 125.15, 129.21, 148.35, 152.07, 152.18, 197.26,
202.52.
Naphtho[1,2-b]oxepin-7,9-dione 44c
Yellow solid; mp 112–3 °C; Rf = 0.22 (20% EtOAc–hexanes).
IR (CHCl3): 2931 w, 1657 vs, 1621 m, 1570 w, 1363 w, 1339 w,
1105 w cm–1.
MS: m/z (%) = 244 [M+] (100), 229 (65), 201 (97), 188 (17), 185
(18), 173 (29), 115 (15), 91 (22), 83 (71).
HRMS: m/z [M+] calcd for C15H16O3: 244.1099; found: 244.1092.
1H NMR (CDCl3): d = 1.23 (s, 3 H), 1.84–1.99 (m, 4 H), 2.01 (s, 3
H), 2.32 (d, J = 16.9 Hz, 1 H), 2.35 (d, J = 1 Hz, 3 H), 2.59–2.63 (m,
1 H), 2.77–2.82 (m, 1 H), 2.91 (d, J = 17 Hz, 1 H), 3.64–3.69 (m, 1
H), 4.23–4.26 (m, 1 H), 5.89 (s, 1 H).
13C NMR (CDCl3): d = 11.60, 24.35, 25.99, 27.36, 29.74, 29.90,
44.51, 48.49, 75.27, 128.61, 128.91, 131.32, 151.66, 152.30,
154.10, 197.20, 202.81.
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 42b
The thermolysis of complex 42b (297.8 mg, 0.71 mmol) was carried
out according to the typical procedure at 60 °C for 6.5 h and 0.05 M
in 42b. Purification of the mixture gave 43b (104.4 mg, 64%) and a
compound tentatively identified as a spiroketone (7.0 mg, 4%, relat-
ed in structure to 41). Subsequent reactions gave spiroketone and
MS: m/z (%) = 272 [M+] (100), 257 (42), 244 (11), 229 (49), 201
(21), 187 (32), 159 (22), 149 (44), 123 (33), 115 (23), 105 (15).
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M. E. Bos et al.
PAPER
HRMS: m/z [M+] calcd for C17H20O3: 272.1412; found: 272.1413.
umn. The purple band was somewhat air-sensitive and decomposed
to the orange band before solvent could be removed. Upon dissolu-
tion in benzene and heating at 110 °C, this material proceeded
mainly to naphthalenone 47. The orange band could be separated
into two components. The orange band also proceeded to product
upon resubmission to reaction conditions.
Pentacarbonyl[(2,6-dimethylphenyl)(pent-3-ynyloxy)methyl-
ene]chromium(0) (45)
Pentacarbonyl[(2,6-dimethylphenyl)(oxido)methylene]chromi-
um(0) Tetramethylammonium Salt
A soln of 2-bromo-m-xylene (1.33 mL, 10 mmol) in Et2O (10 mL)
was treated with 1.7 M t-BuLi in pentane (12.4 mL, 21 mmol) at
–78 °C for 30 min, then warmed to r.t. for 30 min. The yellow soln
was transferred via cannula into a slurry of Cr(CO)6 (2.42 g, 11
mmol) in Et2O (20 mL) at 0 °C, then warmed to r.t. for 1 h. The sol-
vent was then removed in vacuo to leave a brown oil residue, which
was taken up in H2O and filtered through Celite to remove undis-
solved solids. The aqueous layer was then shaken with hexanes (2
×, discarded), and treated with solid Me4NBr until precipitation of
the yellow salt was no longer observed. After standing for 5 min, the
salt was filtered onto a pad of Celite and washed with H2O and hex-
anes. The collection flask was changed and the solids washed
through with CH2Cl2. After drying (MgSO4), the solvent was re-
moved to leave pentacarbonyl[(2,6-dimethylphenyl)(oxido)methyl-
Naphtho[1,2-b]furan-5(4H)-one 47
Yellow solid; Rf = 0.40 (10% EtOAc–hexanes).
IR (neat): 1672 vs, 1589 s, 1082 s cm–1.
1H NMR (CDCl3): d = 1.25 (s, 6 H), 2.56 (s, 3 H), 2.75 (t, J = 9.4
Hz, 2 H), 4.46 (t, J = 9.4 Hz, 2 H), 7.16 (t, J = 7.6 Hz, 1 H), 7.29 (d,
J = 6.9 Hz, 1 H), 7.86 (d, J = 7.7 Hz, 1 H).
13C NMR (CDCl3): d = 21.65, 24.82, 29.37, 44.56, 69.32, 118.49,
126.14, 127.27, 129.68, 130.13, 133.61, 137.35, 147.00, 204.14.
MS: m/z (%) = 228 [M+] (19), 213 (100), 185 (15), 170 (5).
HRMS: m/z [M+] calcd for C15H16O2: 228.1150; found: 228.1145.
Indan-1-one 46
ene]chromium (0) tetramethylammonium salt as
a yellow
IR (CHCl3): 3400 br s, 2963 m, 1702 vs, 1594 s cm–1.
crystalline solid; yield: 3.36 g (84%); pure by NMR assay.
1H NMR (CDCl3): d = 1.11 (s, 3 H), 1.44 (s, 3 H), 1.79–1.91 (m, 2
H), 2.50 (dd, J = 9.4, 4.2 Hz, 1 H), 2.59 (s, 3 H), 3.75–3.83 (m, 1 H),
3.93–3.98 (m, 1 H), 7.10 (d, J = 7.4 Hz, 1 H), 7.29 (d, J = 7.6 Hz, 1
H), 7.46 (t, J = 7.5 Hz, 1 H).
1H NMR (acetone-d6): d = 2.17 (s, 6 H), 3.36 (s, 12 H), 6.79 (s, 3 H).
Pentacarbonyl[(2,6-dimethylphenyl)(pent-3-ynyloxy)methyl-
ene]chromium(0) (45)
In CH2Cl2 (20 mL) at 0 °C under N2 were combined Tf2O (1.0 mL,
6.0 mmol) and pyridine (526 mL, 6.5 mmol). After 5 min, pent-3-yn-
1-ol (553 mL) was added and the slurry stirred at 0 °C for 20 min.
To this was added the above ammonium salt (2.0 g, 5.0 mmol) and
stirring was continued for 30 min. The red soln was poured into
Et2O and washed with brine and NaHCO3. After drying, the organic
layer was stripped and the residue taken up in hexanes. Again it was
filtered through Celite and concentrated. Chromatography (Et2O–
CH2Cl2–hexanes, 1:1:20) gave complex 45 as a red oil; yield: 1.467
g (75%); contains a small amount of alkynol impurity by NMR.
This material could be crystallized (CHCl3–hexanes) at –78 °C to
give an orange solid; mp 75–76 °C; Rf = 0.41 (Et2O–CH2Cl2–hex-
anes, 1:1:20).
IR (CHCl3): 2064 vs, 1991 s, 1932 vs, 1142 m cm–1.
1H NMR (CDCl3): d = 1.74 (t, J = 2.5 Hz, 3 H), 2.15 (s, 6 H), 2.72–
2.84 (br s, 2 H), 3.94–4.08 (br s, 2 H), 7.0–7.13 ( m, 3 H).
13C NMR (CDCl3): d = 3.32, 19.33, 19.87, 73.54, 77.71, 102.57,
126.42, 128.10, 128.33, 150.24, 216.27, 224.47, 362.50.
MS: m/z (%) = 364 [M+ – CO] (2), 336 [M+ – 2 CO] (7), 308 [M+ –
3 CO] (2), 280 [M+ – 4 CO] (16), 252 [M+ – 5 CO] (43), 213 (11),
185 (28), 84 (100), 52 (64) (molecular ion not observed).
13C NMR (CDCl3): d = 18.46, 26.79, 27.90, 28.52, 41.64, 60.29,
62.71, 120.55, 129.37, 131.48, 134.50, 138.82, 163.62, 209.85.
{[2-(But-2-ynyloxy)ethoxy](4-hydroxy-2,6-dimethylphen-
yl)methylene}pentacarbonylchromium(0) (48)
2-(But-2-ynyloxy)ethanol was prepared by a procedure developed
by Semmelhack for closely related compounds.11c A mixture of 2-
(but-2-ynyloxy)ethanol (1.01 g, 8.89 mmol) and pyridine (935 mL,
11.6 mmol) in CH2Cl2 (20 mL) at 0 °C was treated with Tf2O (1.65
mL, 9.8 mmol) to give an exothermic reaction with precipitation oc-
curring. After several hours stirring at 0 °C, the reaction was
washed with H2O and brine, and concentrated to give a dark brown
oil, 1.65 g crude weight. From this was removed alkynyl triflate
(1.34 g, 5.5 mmol), which was dissolved in CH2Cl2 (10 mL) at r.t..
To this was added ammonium salt 31 (1.5 g, 2.83 mmol) neat; an
immediate red coloration developed. The alkylation reaction was
stirred for 40 min, then washed with brine, dried, and solvent re-
moved. Et2O (20 mL) was added to the residue followed by 25 wt%
NaOMe in MeOH (4 mL), and the whole was stirred at r.t. for 1 h.
Extractive workup as usual followed by chromatography (20%
EtOAc–hexanes) gave complex 48 as a red oil; yield: 982 mg
(79%). No crystallization could be induced upon cooling in hexanes
to –78 °C. This complex failed to give satisfactory MS. Additional-
ly, because it was impossible to thoroughly remove all traces of sol-
vent by high vacuum without observing product decomposition, no
attempts at obtaining combustion analysis were made; Rf = 0.25
(20% EtOAc–hexanes).
HRMS: m/z [M – CO]+ calcd for C18H16CrO5: 364.0403; found:
364.0395.
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 45
IR (neat): 3383 br w, 2063 m, 1932 vs cm–1.
A deoxygenated soln of 45 (180.0 mg, 0.46 mmol) in benzene
(0.005 M, 90 mL) was heated under argon at 110 °C for 16 h. A met-
alloid species (perhaps a tricarbonyl complex of 47) co-elutes with
the product and persists after stirring in air overnight. Thus, the sol-
vent was removed, the residue dissolved in THF (30 mL) and treat-
ed with FeCl3–DMF (1.75 g, 3.2 mmol) at r.t. for 30 min. The soln
was washed with H2O and brine and then dried (MgSO4). Chroma-
tography (5% to 20% EtOAc–hexanes) gave naphthalenone 47
(39.0 mg, 37%) and indanone 46 (18.8 mg). The latter compound
was repurified by preparative TLC (20% EtOAc–hexanes) to give
46 (16.6 mg, 17%). If the reaction was stopped before complete
conversion and chromatographed under the same solvent condi-
tions, an orange band and a purple band could be eluted off the col-
1H NMR (CDCl3): d = 1.85 (t, J = 2.1 Hz, 3 H), 2.12 (s, 6 H), 3.90–
4.02 (br s, 2 H), 4.1–4.25 (br m, 4 H), 4.68–4.85 (br s, 1 H), 6.48 (s,
2 H).
13C NMR (CDCl3): d = 3.53, 19.45, 59.20, 67.08, 74.40, 77.21,
83.24, 114.92, 128.87, 143.81, 155.11, 216.35, 224.59, 364.46.
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 48 at 60 °C and 0.05 M; Typical Procedure
A soln of complex 48 (125.9 mg, 0.29 mmol) in benzene (0.05 M,
5.7 mL) was added to a 25-mL single-necked flask that had the 14/
20 joint replaced with a threaded high-vacuum Teflon stopcock.
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3697
The mixture was deoxygenated by the freeze–thaw method (–196
°C/25 °C, 3 cycles) and back-flushed with 1 atm of argon at r.t.. The
flask was sealed and placed in an oil bath and heated at 60 °C for 13
h to give a dark brown mixture. Solvent was removed and the resi-
due dissolved in Et2O. Filtration through Celite gave a clear yellow
filtrate. After chromatography (40% EtOAc–hexanes), 49 (10.8 mg,
15%), 50 (4.0 mg, 5%), and 51 (16.2 mg, 21%) were recovered. Re-
actions performed under different conditions were chromato-
graphed differently.
tained by combining material from several reactions followed by
careful chromatography (20% EtOAc–hexanes).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 48 in Benzene at Reflux
A 100-mL 2-necked round-bottomed flask was fitted with a con-
denser and septum inlet and flushed with N2. A N2 bubbler protected
the condenser top. To this was added anhyd, degassed benzene (25
mL) (distilled directly from benzophenone ketyl) and the solvent
brought to reflux in a 100 °C oil bath. The carbene complex 48
(119.3 mg, 0.27 mmol) was weighed into a separate flask which was
evacuated and flushed with argon. Benzene (20 mL) was added and
the orange soln drawn back up into the syringe. The carbene com-
plex was added through the septum dropwise via syringe pump (6.5
mL/hour) to the refluxing soln. When the addition was complete,
the reaction was heated an additional hour, then cooled and filtered.
Concentration and chromatography gave combined 49 and 50 (34.1
mg; ratio 49/50 2.4:1, 35% and 15% respectively) followed by 51
(8.7 mg, 12%).
Indeno[1,2-e][1,4]dioxepin-8(5H)-one 49
Yellow solid; Rf = 0.49 (40% EtOAc–hexanes).
IR (neat): 2958 w, 1652 m, 1633 vs, 1569 vs, 1407 w, 1154 s cm–1.
1H NMR (CDCl3): d = 1.10 (s, 3 H), 1.88 (s, 3 H), 1.96 (d, J = 15
Hz, 1 H), 2.24 (s, 3 H), 2.49 (d, J = 15 Hz, 1 H), 3.97–4.14 (m, 4 H),
4.35 (d, J = 14.2 Hz, 1 H), 4.46 (d, J = 14.2 Hz, 1 H), 5.68 (s, 1 H).
13C NMR (CDCl3): d = 10.31, 20.74, 22.54, 46.31, 52.57, 65.88,
73.60, 73.66, 122.40, 125.85, 135.47, 150.30, 154.33, 158.30,
199.11.
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 48 at 110 °C and 0.05 M
This reaction, in which complex 48 (117.9 mg, 0.27 mmol) was
thermolyzed according to the typical procedure at 110 °C in ben-
zene (0.05 M, 5.3 mL) for 30 min, gave 49 (20%), 50 (8%), and 51
(13%).
MS: m/z (%) = 246 [M+] (100), 231 (12), 203 (8), 187 (35), 174 (12),
159 (35), 131 (14), 115 (13), 91 (20), 83 (63).
HRMS: m/z [M+] calcd for C15H18O3: 246.1256; found: 246.1256.
Naphtho[1,2-e][1,4]dioxepin-7,9-dione 50
Yellow solid; Rf = 0.30 (40% EtOAc–hexanes).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 48 at 110 °C and 0.005 M
A soln of complex 48 (100.1 mg, 0.23 mmol) was thermolyzed ac-
cording to the typical procedure in benzene (0.005 M, 46 mL) for
20 h. The usual workup and purification resulted in isolation of 49
(21.1 mg, 38%), 50 (11.1 mg, 18%), and 51 (4.0 mg, 6%).
IR (CHCl3): 2859 m, 1720 m, 1667 vs, 1625 s, 1573 m, 1363 m,
1342 m, 1127 m cm–1.
1H NMR (CDCl3): d = 1.25 (s, 3 H), 2.07 (s, 3 H), 2.32 (d, J = 17
Hz, 1 H), 2.35 (d, J = 1 Hz, 3 H), 2.91 (d, J = 17 Hz, 1 H), 3.92–3.98
(m, 3 H), 4.10–4.33 (m, 1 H), 4.53 (d, J = 13 Hz, 1 H), 4.66 (d,
J = 13 Hz, 1 H), 5.91 (s, 1 H).
MS: m/z (%) = 274 [M+] (12), 259 (6), 231 (4), 187 (10), 159 (6),
149 (6), 91 (8), 83 (100).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 48 in Toluene at Reflux
In a 100-mL sidearm flask with N2-protected condenser was placed
toluene (50 mL) and N2 was bubbled through a submerged needle
inserted through the sidearm for 30 min. The flask was immersed in
a hot oil bath and brought to reflux. The carbene complex 48 (166.1
mg, 0.38 mmol) was taken up in purged toluene (10 mL) under ar-
gon and added dropwise (1 drop/3–4 s) over 75 min. TLC indicated
complete reaction. After cooling, the mixture was filtered through
Celite to give a bright yellow soln. Chromatography (40% EtOAc–
hexanes) gave 49 (36.0 mg, 39%), 50 (19.8 mg, 19%), and 51 (3.7
mg, 4%).
HRMS: m/z [M+] calcd for C16H18O4: 274.1205; found: 274.1206.
Spiro[cyclohexa-2,5-diene-1,8¢-cyclopenta[e][1,4]dioxepin]-
4,7¢(6¢H)-dione 51
White solid; mp 124 °C (dec.); Rf = 0.15 (40% EtOAc–hexanes).
IR (neat): 1756 m, 1660 s, 1629 m, 1287 m cm–1.
1H NMR (CDCl3): d = 1.31 (d, J = 7.3 Hz, 3 H), 1.86 (d, J = 1 Hz,
3 H), 1.90 (s, 3 H), 3.24 (q, J = 7.2 Hz, 1 H), 3.87–3.90 (m, 2 H),
4.17 (t, J = 3.6 Hz, 2 H), 4.37 (d, J = 4.6 Hz, 2 H), 6.23 (d, J = 1.2
Hz, 1 H), 6.27 (d, J = 1.3 Hz, 1 H).
13C NMR (CDCl3): d = 14.73, 20.05, 20.86, 50.49, 67.96, 71.39,
71.99, 74.86, 116.95, 129.51, 130.18, 150.21, 152.49, 152.93,
186.14, 209.78.
{[(But-2-ynyloxy)methoxy](4-hydroxy-2,6-dimethylphen-
yl)methylene}pentacarbonylchromium(0) (54a); Typical
Procedures: But-2-ynyl Chloromethyl Ether (56a)
But-2-yn-1-ol (175 mg, 2.50 mmol) was added dropwise to a sus-
pension of paraformaldehyde (75.0 mg, 2.50 mmol) in TMSCl (1.25
mL, 10.0 mmol) at r.t.. The mixture was stirred at r.t. until the
paraformaldehyde had been consumed. The clear soln was evapo-
rated under reduced pressure to remove the excess TMSCl to afford
but-2-ynyl chloromethyl ether (56a). The purity of the chloromethyl
ether was checked by 1H NMR, and then used without further puri-
fication.
1H NMR (CDCl3): d = 1.82 (t, J = 2.2 Hz, 3 H), 4.29 (q, J = 2.2 Hz,
2 H), 5.54 (s, 2 H).
13C NMR (CDCl3): d = 54.98, 56.60, 72.48, 80.05, 84.30.
MS: m/z (%) = 274 [M+[ (33), 259 (16), 247 (96), 231 (29), 187 (31),
149 (100).
HRMS: m/z [M+] calcd for C16H18O4: 274.1205; found: 274.1205.
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 48 at 60 °C and 0.005 M
A deoxygenated soln of complex 48 (131.8 mg, 0.30 mmol) in ben-
zene (0.005 M, 57 mL) was thermolyzed according to the general
procedure at 60 °C for 13 h. Chromatography (40% EtOAc–hex-
anes) gave two bands. (Note: The CO- and non-CO inserted prod-
ucts elute so similarly that they were collected in one fraction and
yields were determined by NMR integration of the vinylic proton a
to the enone carbonyl.) In this manner, enones 49 and 50 (31.9 mg)
were obtained, comprised of 49 (27%) and 50 (15%), as well as 51
(13.4 mg, 16%). Analytical samples of enones 49 and 50 were ob-
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl](but-2-yn-
yloxy)methoxy]methylene}pentacarbonylchromium(0) (55a)
The freshly prepared chloromethyl ether 56a (2.50 mmol) in
CH2Cl2 (5 mL) was added drop wise to a soln of ammonium salt 31
(recrystallized from CH2Cl2) (1.08 g, 2.00 mmol) in CH2Cl2 (20
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3698
M. E. Bos et al.
PAPER
mL) at r.t.. The resulting red soln was stirred at r.t. for 15 min under
argon, and then passed through a short silica gel column (3 × 10 cm)
to give the TBS-protected carbene complex 55a as a red oil; yield:
980 mg (91%); Rf = 0.60 (hexane–Et2O, 9:1).
MS: m/z (%) = 552 [M+] (0.02), 412 (25), 410 (16), 383 (26), 382
(79), 380 (23), 301 (20), 263 (22), 179 (30), 126 (17), 107 (16), 80
(31), 75 (33), 73 (68), 67 (16), 52 (100).
Pentacarbonyl{(4-hydroxy-2,6-dimethylphenyl)[(pent-2-ynyl-
oxy)methoxy]methylene}chromium(0) (54b)
The carbene complex 55b (1.05 g, 1.90 mmol) was desilylated ac-
cording to the above procedure to give phenol carbene complex 54b
as a red oil; yield: 384 mg (46%); Rf = 0.24 (hexane–Et2O, 4:1).
IR (neat): 2957 m, 2932 m, 2860 m, 2230 vw, 2064 s, 1991 s, 1941
vs, 1601 m, 1471 w, 1315 m, 1157 s, 1060 m, 841 s, 656 s cm–1.
1H NMR (CDCl3): d = 0.18 (s, 6 H), 0.95 (s, 9 H), 1.84 (s, 3 H), 2.09
(s, 6 H), 4.52 (s, 2 H), 5.25 (s, 2 H), 6.47 (s, 2 H).
13C NMR (CDCl3): d = –4.46, 12.36, 13.50, 19.52, 25.58, 57.69,
72.70, 90.73, 97.14, 119.54, 128.15, 144.85, 155.24, 216.26,
224.65, 365.35.
MS: m/z (%) = 510 [M+ – CO] (0.09), 398 [M+ – 5 CO] (18), 369
(23), 368 (63), 275 (57), 263 (24), 163 (16), 125 (25), 105 (16), 75
(35), 73 (73), 53 (55), 52 (100).
IR (neat): 3407 br w, 2982 w, 2938 w, 2232 vw, 2064 s, 1937 vs,
1607 m, 1308 m, 1238 m, 1152 m, 1069 m, 891 m, 654 m cm–1.
1H NMR (CDCl3): d = 1.12 (t, J = 7.4 Hz, 3 H), 2.11 (s, 6 H), 2.20
(qt, J = 7.4, 2.2 Hz, 2 H), 4.55 (t, J = 2.2 Hz, 2 H), 5.28 (br s, 2 H),
6.48 (s, 2 H).
13C NMR (CDCl3): d = 12.37, 13.49, 19.50, 57.73, 72.67, 90.81,
97.01, 114.96, 128.69, 144.22, 155.22, 216.24, 224.56, 365.31.
MS: m/z (%) = 438 [M+] (0.03), 410 (0.05), 216 (15), 188 (16), 187
(55), 149 (100), 137 (17), 121 (27), 115 (16), 108 (33), 91 (37), 80
(42), 79 (18), 77 (35), 74 920), 67 (22), 65 (17), 59 (24), 55 (19), 54
(22), 52 (69), 51 (23).
{[(But-2-ynyloxy)methoxy](4-hydroxy-2,6-dimethylphen-
yl)methylene}pentacarbonylchromium(0) (54a)
The TBS-protected carbene complex 55a (2.14 g, 3.97 mmol) was
dissolved in anhyd Et2O (20 mL), and then treated with NaOMe in
MeOH (2 equiv). The mixture was stirred under argon at r.t. until
TLC showed complete desilylation. The mixture was then quenched
with H2O, and extracted with Et2O (2 × 10 mL). The combined or-
ganic layer was washed with brine (1 × 10 mL), dried (MgSO4),
concentrated, and chromatographed to afford the carbene complex
with free hydroxy group 54a as a red oil; yield: 995 mg, (59%). In
most cases the carbene complex was characterized as the TBS de-
rivative 55. The p-phenol complex 54 was typically generated and
utilized in the next step directly although it could be stored for peri-
ods of a day or so without decomposition; Rf = 0.20 (hexane–
EtOAc, 2:1).
Pentacarbonyl{(4-hydroxy-2,6-dimethylphenyl)[(4-methyl-
pent-2-ynyloxy)methoxy]methylene}chromium(0) (54c)
Chloromethyl 4-Methylpent-2-ynyl Ether (56c)
The chloromethyl ether 56c was prepared from 4-methylpent-2-yn-
1-ol (392 mg, 4.00 mmol) according to the typical procedure.
1H NMR (CDCl3): d = 1.17 (d, J = 7.1 Hz, 6 H), 2.56–2.59 (m, 1 H),
4.35 (d, J = 2.2 Hz, 2 H), 5.57 (s, 2 H).
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl][(4-methyl-
pent-2-ynyloxy)methoxy]methylene}pentacarbonylchromi-
um(0) (55c)
IR (neat): 3397 br w, 2965 w, 2933 w, 2231 w, 2068 s, 1917 vs,
1609 s, 1456 m, 1309 m, 1236 m, 1152 m, 897 m, 791 m cm–1.
The carbene complex 55c was prepared from the salt 31 (1.61 g,
3.00 mmol) and chloromethyl ether 56c as red oil; yield: 1.16 g
(68%); Rf = 0.40 (hexane–Et2O, 4:1).
1H NMR (CDCl3): d = 1.84 (s, 3 H), 2.11 (s, 6 H), 4.52 (s, 2 H), 4.84
(s, 1 H), 5.26 (s, 2 H), 6.48 (s, 2 H).
13C NMR (CDCl3): d = 3.56, 19.47, 57.80, 72.60, 85.07, 97.08,
114.96, 128.74, 144.32, 155.17, 216.24, 224.56, 365.39.
MS: m/z (%) = 424 [M+] (0.07), 159 (31), 149 (63), 122 (35), 119
(33), 115 (22), 108 (15), 107 (47), 104 (17), 91 (47), 82 (16), 80
(34), 79 (25), 77 (47), 69 (24), 65 (17), 54 (18), 53 (55), 52 (100),
50 (16).
IR (neat): 2936 m, 2250 w, 2086 s, 1935 vs, 1601 m, 1474 w, 1315
m, 1156 s, 910 s, 841 s, 656 s cm–1.
1H NMR (CDCl3): d = 0.18 (s, 6 H), 0.96 (s, 9 H), 1.14 (d, J = 6.9
Hz, 6 H), 2.10 (s, 6 H), 2.55 (m, 1 H), 4.55 (d, J = 2.2 Hz, 2 H), 5.25
(br s, 2 H), 6.48 (s, 2 H).
13C NMR (CDCl3): d = –4.47, 18.14, 19.51, 19.56, 20.39, 22.39,
22.73, 25.57, 65.56, 93.45, 97.36, 119.43, 119.63, 127.87, 128.30,
144.88, 155.20, 216.32, 224.63, 364.69.
Pentacarbonyl{(4-hydroxy-2,6-dimethylphenyl)[(pent-2-ynyl-
oxy)methoxy]methylene}chromium(0) (54b)
Chloromethyl Pent-2-ynyl Ether (56b)
The chloromethyl ether 56b was prepared from pent-2-yn-1-ol (210
mg, 2.50 mmol) according to the typical procedure.
1H NMR (CDCl3): d = 1.09–1.16 (m, 3 H), 2.19–2.24 (m, 2 H), 4.35
(t, J = 2.2 Hz, 2 H), 5.58 (s, 2 H).
MS m/z (%) = 538 [M+ – CO] (0.03), 426 [M+ – 5 CO] (32), 397
(31), 396 (100), 358 (19), 357 (79), 351 (21), 329 (25), 303 (36),
301 (39), 263 (57), 229 (18), 219 (18), 215 (17), 191 (15), 179 (40),
163 (22), 126 (21), 125 (20), 108 (19), 103 (18), 102 (21), 91 (19),
82 (34), 81 (38), 79 (52), 75 (40), 74 (30), 73 (91), 72 (77), 57 (19),
52 (68).
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl][(pent-2-
ynyloxy)methoxy]methylene}pentacarbonylchromium(0) (55b)
The carbene complex 55b was prepared from the salt 31 (1.08 g,
2.00 mmol) and chloromethyl ether 56b (2.50 mmol) as red oil;
yield: 1.07 g (97%); Rf = 0.25 (hexane–CH2Cl2, 9:1).
Pentacarbonyl{(4-hydroxy-2,6-dimethylphenyl)[(4-methyl-
pent-2-ynyloxy)methoxy]methylene}chromium(0) (54c)
The carbene complex 55c (467 mg, 0.825 mmol) was desilylated
according to the typical procedure to give of phenol carbene com-
plex 54c as a red oil; yield: 206 mg (55%); Rf = 0.15 (hexane–
CH2Cl2, 1:1).
IR (neat): 2959 m, 2934 m, 2861 w, 2064 s, 1991 s, 1937 s, 1601
m, 1473 w, 1315 m, 1157 s, 1069 m, 841 s, 655 s cm–1.
IR (neat): 3402 br m, 2976 m, 2936 w, 2257 vw, 2068 s, 1927 vs,
1608 m, 1590 m, 1454 m, 1308 m, 1237 m, 1150 s, 1070 s, 898 s,
709 s cm–1.
1H NMR (CDCl3): d = 1.13 (d, J = 6.9 Hz, 6 H), 2.11 (s, 6 H), 2.56
(sept, J = 6.9 Hz, 1 H), 3.76 (br s, 1 H), 4.55 (d, J = 1.9 Hz, 2 H),
5.25 (s, 2 H), 6.48 (s, 2 H).
1H NMR (CDCl3): d = 0.18 (s, 6 H), 0.96 (s, 9 H), 1.12 (t, J = 7.7
Hz, 3 H), 2.10 (s, 6 H), 2.17 (qt, J = 7.7, 2.2 Hz, 2 H), 4.55 (t, J = 2.2
Hz, 2 H), 5.26 (br s, 2 H), 6.48 (s, 2 H).
13C NMR (CDCl3): d = –4.44, 12.39, 13.52, 18.16, 19.53, 25.60,
57.71, 72.74, 90.76, 97.19, 119.56, 128.17, 144.91, 155.26, 216.28,
224.66, 365.40.
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

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Studies on the Synthesis of Richardianidin-1
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13C NMR (CDCl3): d = 19.52, 20.48, 22.62, 57.64, 72.49, 94.85,
Pentacarbonyl{(4-hydroxy-2,6-dimethylphenyl)[(4-methyl-
pent-4-en-2-ynyloxy)methoxy]methylene}chromium(0) (54e)
Chloromethyl 4-Methylpent-4-en-2-ynyl Ether (56e)
The chloromethyl ether 56e was prepared from 4-methylpent-4-en-
2-yn-1-ol (384 mg, 4.00 mmol) according to the typical procedure.
1H NMR (CDCl3): d = 1.87 (s, 3 H), 4.48 (s, 2 H), 5.26 (s, 1 H), 5.32
(s, 1 H), 5.57 (s, 2 H).
96.95, 114.93, 128.69, 144.30, 155.18, 216.24, 224.56, 365.33.
MS m/z (%) = 452 [M+] (0.03), 312 [M+ – 5 CO] (2), 187 (30), 180
(15), 149 (100), 121 (30), 91 (15), 90 (18), 80 (27), 79 (19), 77 (31),
53 (16), 52 (42).
Pentacarbonyl{[(1-ethylhex-2-ynyloxy)methoxy](4-hydroxy-
2,6-dimethylphenyl)methylene}chromium(0) (54d)
Chloromethyl 1-Ethylhex-2-ynyl Ether (56d)
The chloromethyl ether 56d was prepared from oct-4-yn-3-ol (315
mg, 2.50 mmol) according to the typical procedure.
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl][(4-methyl-
pent-4-en-2-ynyloxy)methoxy]methylene}pentacarbonylchro-
mium(0) (55e)
The carbene complex 55e was prepared from the salt 31 (1.34 g,
2.50 mmol) and chloromethyl ether 56e as a red oil; yield: 919 mg
(65%); Rf = 0.24 (hexane–CH2Cl2, 9:1).
1H NMR (CDCl3): d = 0.97 (t, J = 7.4 Hz, 3 H), 0.98 (t, J = 7.1 Hz,
3 H), 1.52 (m, 2 H), 1.72 (m, 2 H), 2.19 (td, J = 7.2, 1.9, 2 H Hz),
4.46 (t, J = 6.3 Hz, 1 H), 5.56 (d, J = 5.4 Hz, 1 H), 5.72 (d, J = 5.4
Hz, 1 H).
IR (neat): 2957 w, 2932 w, 2220 vw, 2064 s, 1940 s, 1601 w, 1315
w, 1155 w, 841 m, 653 m cm–1.
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl][(2-ethyl-
hex-2-ynyloxy)methoxy]methylene}pentacarbonylchromi-
um(0) (55d)
The carbene complex 55d was prepared from the salt 31 (1.05 g,
1.95 mmol) and chloromethyl ether 56d as a red oil; yield: 1.16 g
(100%); Rf = 0.13 (hexane).
1H NMR (CDCl3): d = 0.18 (s, 6 H), 0.96 (s, 9 H), 1.86 (s, 3 H), 2.10
(s, 6 H), 4.69 (s, 2 H), 5.27–5.30 (4 H), 6.48 (s, 2 H).
13C NMR (CDCl3): d = –4.44, 18.15, 19.54, 23.07, 25.59, 57.63,
81.24, 89.47, 97.03, 119.58, 123.29, 125.72, 128.19, 155.30,
216.25, 224.64, 365.59.
MS m/z (%) = 564 [M+] (0.08), 263 (17), 262 (25), 221 (23), 220
(40), 207 (46), 191 (16), 179 (94), 177 (12), 163 (16), 149 (14), 107
(62), 105 (27), 86 (64), 84 (98), 80 (100), 77 (16), 75 (100), 73 (47),
59 (55), 57 (16), 51 (100), 49 (94), 45 (27).
IR (neat): 2963 m, 2936 m, 2886 w, 2237 vw, 2084 s, 1940 vs, 1601
m, 1471 m, 1315 m, 1253 m, 1155 s, 1064 m, 912 m, 841 s, 655 s
cm–1.
1H NMR (CDCl3): d = 0.18 (s, 6 H), 0.94 (t, J = 7.4 Hz, 3 H), 0.96
(s, 9 H), 1.03 (t, J = 7.5 Hz, 3 H), 1.49 (q, J = 7.5 Hz, 2 H), 1.80 (m,
2 H), 2.10 (s, 6 H), 2.16 (td, J = 6.8, 1.9 Hz, 2 H), 4.67 (t, J = 6.4
Hz, 1 H), 5.20 (br s, 1 H), 5.43 (br s, 1 H), 6.47 (s, 2 H).
13C NMR (CDCl3): d = –4.48, 9.43, 13.36, 18.14, 19.44, 19.54,
20.58, 21.92, 25.58, 29.08, 71.06, 88.59, 97.67, 119.46, 119.62,
127.90, 128.24, 145.00, 155.21, 216.33, 224.63, 364.34.
Pentacarbonyl& lcub;(4-hydroxy-2,6-dimethylphenyl)[(4-
methylpent-4-en-2-ynyloxy)methoxy]methylene}chromium(0)
(54e)
The carbene complex 55e (722 mg, 1.28 mmol) was desilylated ac-
cording to the typical procedure to give phenol carbene complex
54e as a red oil; yield: 287 mg (50%); Rf = 0.21 (hexane–Et2O, 2:1).
MS m/z (%) = 594 [M+] (0.03), 454 [M+ – 5 CO] (19), 425 (18), 424
(47), 423 (37), 422 (91), 420 (25), 385 (15), 373 (15), 372 (24), 371
(22), 358 (20), 357 (33), 356 (39), 343 (16), 330 (20), 329 (53), 327
(25), 315 (23), 271 (17), 263 (63), 257 (33), 243 (17), 191 (23), 165
(16), 163 (18), 128 (19), 125 (18), 115 (19), 75 (36), 74 (24), 73
(100), 72 (64), 59 (18), 57 (36), 56 (28), 55 (24), 52 (47), 51 (25).
IR (neat): 3384 br w, 2959 w, 2928 w, 2228 vw, 2064 sm 1940 vs,
1609 m, 1456 m, 1307 m, 1236 m, 1150 m, 1064 m, 897 m, 653 s
cm–1.
1H NMR (CDCl3): d = 1.86 (s, 3 H), 2.12 (s, 6 H), 4.69 (s, 2 H), 5.05
(br s, 4 H), 6.47 (s, 2 H).
13C NMR (CDCl3) d = 19.53, 23.09, 57.66, 81.19, 89.48, 96.84,
114.97, 123.37, 125.69, 128.75, 144.27, 155.18, 216.23, 224.56,
365.52.
Pentacarbonyl{[(1-ethylhex-2-ynyloxy)methoxy](4-hydroxy-
2,6-dimethylphenyl)methylene}chromium(0) (54d)
MS m/z (%) = 394 [M+ – 2 CO] (0.2), 228 (12), 213 (15), 187 (10),
185 (16), 149 (100), 121 (16), 115 (12), 108 (11), 91 (29), 80 (16),
79 (30), 78 (14), 77 (52), 53 (15), 52 (23), 51 (15).
The carbene complex 55d (951 mg, 1.60 mmol) was desilylated ac-
cording to the typical procedure to give phenol carbene complex
54d as a red oil; yield: 309 mg (40%); Rf = 0.25 (hexane–Et2O, 4:1).
IR (neat): 3400 br w, 2970 w, 2933 w, 2881 w, 2237 vw, 2064 s,
1943 vs, 1149 m, 904 m, 654 m cm–1.
1H NMR (CDCl3): d = 0.93 (t, J = 7.4 Hz, 3 H), 1.03 (t, J = 7.4 Hz,
3 H), 1.49 (q, J = 7.1 Hz, 2 H), 1.80 (m, 2 H), 2.12 (s, 6 H), 2.17 (t,
J = 7.1 Hz, 2 H), 4.67 (br s, 1 H), 5.28 (br s, 1 H), 5.44 (br, 1 H),
6.48 (s, 2 H).
13C NMR (CDCl3): d = 9.43, 13.37, 19.44, 19.55, 20.58, 21.90,
29.07, 71.15, 88.72, 97.54, 114.88, 115.02, 128.46, 128.82, 144.40,
155.12, 216.31, 224.56, 364.30.
MS m/z (%) = 480 [M+] (0.03), 318 (32), 290 (15), 289 (77), 275
(16), 261 (22), 25), 247 (43), 245 (47), 231 (25), 220 (17), 219 (17),
218 (19), 217 (100), 203 (40), 189 (39) 187 (20), 175 (42), 161 (27),
159 (15), 149 (65), 147 (22), 145 (16), 13 (20), 128 (18), 122 (31),
121 (31), 119 (19), 115 (24), 109 (18), 108 (49), 107 939), 105 (30),
97 (24), 95 (15), 94 (18), 93 (26), 91 (58), 81 (37), 80 (76), 79 (69),
78 (19), 77 (69), 69 (23), 67 (54), 65 (25), 57 (35), 55 (46), 53 (38),
52 (98).
{[(5-Benzyloxy-4-methylpent-2-ynyloxy)methoxy](4-hydroxy-
2,6-dimethylphenyl)methylene}pentacarbonylchromium(0)
(54f)
5-Benzyloxy-4-methylpent-2-ynyl Chloromethyl Ether (56f)
The chloromethyl ether 56f was prepared from 4-(benzyloxy)meth-
yl)pent-2-yn-1-ol (334 mg, 1.64 mmol) according to the typical pro-
cedure.
1H NMR (CDCl3): d = 1.19 (d, J = 6.9 Hz, 3 H), 2.77 (m, 1 H), 3.37
(dd, 1 H), 3.49 (dd, 1 H), 4.36 (d, J = 2.2 Hz, 2 H), 4.54 (s, 2 H),
5.56 (s, 2 H), 7.32 (m, 5 H).
{[(5-Benzyloxy-4-methylpent-2-ynyloxy)methoxy][4-(tert-
butyldimethylsiloxy)-2,6-dimethylphenyl]methylene}penta-
carbonylchromium(0) (55f)
The carbene complex 55f was prepared from the salt 31 (700 mg,
1.30 mmol) and chloromethyl ether 56f as red oil; yield: 748 mg
(86%); Rf = 0.45 (hexane–EtOAc, 9:1).
1H NMR (CDCl3): d = 0.18 (s, 6 H), 0.96 (s, 9 H), 1.18 (d, J = 7.1
Hz, 3 H), 2.08 (s, 6 H), 2.77 (m, 1 H), 3.36 (dd, 1 H), 3.47 (dd, 1 H),
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3700
M. E. Bos et al.
PAPER
4.51 (s, 2 H), 4.56 (d, J = 2.2 Hz, 2 H), 5.24 (br s, 2 H), 6.47 (s, 2
H), 7.27–7.35 (m, 5 H).
(m, 1 H), 2.85 (d, J = 16.8 Hz, 1 H), 4.81 (q, J = 16.5 Hz, 2 H), 5.09
(d, J = 5.7 Hz, 1 H), 5.24 (d, J = 5.7 Hz, 1 H), 5.84 (s, 1 H).
13C NMR (CDCl3): d = –4.44, 17.45, 18.15, 19.54, 25.59, 26.83,
57.56, 73.02, 73.60, 74.30, 91.03, 97.00, 119.55, 127.57, 127.65,
128.17, 128.35, 138.05, 144.91, 155.27, 216.26, 224.64, 365.58.
13C NMR (CDCl3): d = 12.12, 17.83, 24.79, 26.96, 44.07, 48.57,
65.18, 90.63, 122.56, 127.60, 135.37, 136.66, 145.81, 151.81,
196.97, 200.84.
IR (neat): 2959 w, 2933 w, 2862 w, 2243 w, 2064 s, 1943 vs, 1601
m, 1471 w, 1316 m, 1156 m, 841 m, 655s cm–1.
MS m/z (%) = 274 [M+] (38), 259 (15), 231 (26), 230 (21), 229
(100), 216 (38), 215 (27), 202 (17), 201 (56), 188 (27), 159 (23), 93
(19), 91 (17), 77 (20), 65 (15).
{[(5-Benzyloxy-4-methylpent-2-ynyloxy)methoxy](4-hydroxy-
2,6-dimethylphenyl)methylene}pentacarbonylchromium(0)
(54f)
The carbene complex 55f (560 mg, 0.832 mmol) was desilylated ac-
cording to the typical procedure to give phenol carbene complex 54f
as a red oil; yield: 175 mg (36%).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 54c
A soln of carbene complex 54c (206 mg, 0.456 mmol) in benzene
(45.6 mL) was heated according to the typical procedure to give 58c
(20.3 mg, 16%) as a yellow solid after purification; Rf = 0.22 (hex-
anes–Et2O, 1:1).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 54a; Typical Procedure
IR (neat): 2926 m, 1661 s, 1615 m, 1383 m, 1251 m, 1186 m, 1074
s cm–1.
A 100-mL single-necked flask which had its 14/20 joint replaced
with a threaded Teflon high-vacuum stop-cock was flushed with N2
for 10 min before it was charged with the carbene complex 54a (155
mg, 0.365 mmol) and benzene (0.1 M, 36.5 mL). The mixture was
deoxygenated by the freeze–thaw method (–196 °C/25 °C, 3 cy-
cles), back-filled with 1 atm of argon at r.t., sealed and heated at
60 °C for 4 h. The mixture was cooled to r.t., and then diluted with
Et2O. After stirring at r.t. for 2 h in air, the soln was passed through
Celite, concentrated, and then purified by chromatography (silica
gel, hexane–EtOAc, 2:1) to afford the cyclized product 53a as a yel-
low solid ; yield: 44.5 mg (51%); Rf = 0.20 (hexane–EtOAc, 2:1).
1H NMR (CDCl3): d = 1.15 (s, 3 H), 1.16 (d, J = 6.8 Hz, 3 H), 1.27
(d, J = 6.8 Hz, 3 H), 2.27 (d, J = 17.0 Hz, 1 H), 2.31 (s, 3 H), 2.58
(m, 1 H), 2.81 (d, J = 17.0 Hz, 1 H), 4.72 (d, J = 16.8 Hz, 1 H), 4.95
(d, J = 16.8 Hz, 1 H), 5.07 (d, J = 5.5 Hz, 1 H), 5.23 (d, J = 5.5 Hz,
1 H), 5.86 (s, 1 H).
13C NMR (CDCl3): d = 18.68, 21.22, 24.91, 25.90, 27.36, 29.70,
43.46, 65.47, 90.41, 121.93, 127.72, 135.65, 138.60, 146.16,
151.40, 197.20, 201.32.
MS m/z (%) = 289 (16), 288 [M+] (57), 273 (18), 259 (20), 258 (86),
245 (52), 244 (100), 243 (26), 231 (26), 216 (33), 215 (40), 203
(17), 201 (24), 189 (18), 188 (24), 187 (43), 176 (19), 173 (24), 159
(26), 145 (20), 131 (15), 115 (20), 91 (23), 77 (30), 51 (16).
IR (neat): 2958 w, 2920 w, 1642 s, 1575s, 1443 w, 1424 w, 1180 m,
1072 m cm–1.
1H NMR (CDCl3): d = 1.06 (s, 3 H), 1.79 (s, 3 H), 1.88 (d, J = 14.8
Hz, 1 H), 2.17 (s, 3 H), 2.43 (d, J = 14.8 Hz, 1 H), 4.69 (s, 2 H), 5.16
(s, 2 H), 5.61 (s, 1 H).
13C NMR (CDCl3): d = 10.16, 20.50, 22.55, 46.28, 51.47, 65.28,
92.16, 120.14, 120.80, 125.38, 150.03, 150.30, 152.07, 198.81.
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 54d
A soln of carbene complex 54d (120 mg, 0.250 mmol) in benzene
(25.0 mL) was heated according to the typical procedure to give 53d
(13.1 mg, 18%) and 58d (16.8 mg, 21%) after purification.
MS m/z (%) = 233 (48), 232 [M+] (94), 203 (17), 202 (96), 187 (75),
174 (85), 159 (100), 131 (51), 115 (21), 91 (27), 51 (15).
Indeno[1,2-d][1,3]dioxin-7(4H)-one 53d
Yellow solid; Rf = 0.30 (hexanes–Et2O, 1:1).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 54b
A soln of carbene complex 54b (134 mg, 0.307 mmol) in benzene
(30.7 mL) was heated according to the typical procedure to give 53b
(7.0 mg, 9%) and 58b (21.0 mg, 25%) after purification.
IR (neat): 2963 m, 1657 m, 1632 s, 1568 s, 1557 m, 1425 w, 1182
w, 1065 m, 922 m cm–1.
1H NMR (CDCl3): d = 0.95 (t, J = 7.4 Hz, 3 H), 1.01 (t, J = 7.4 Hz,
3 H), 1.09 (s, 3 H), 1.12–1.40 (m, 2 H), 1.50–1.62 (m, 1 H), 1.81–
1.88 (m, 2 H), 1.93 (d, J = 14.7 Hz, 1 H), 2.10–2.26 (m, 1 H), 2.19
(s, 3 H), 2.53 (d, J = 14.7 Hz, 1 H), 4.70 (t, J = 6.1 Hz, 1 H), 5.09
(d, J = 5.8 Hz, 1 H), 5.25 (d, J = 5.8 Hz, 1 H), 5.63 (s, 1 H).
Indeno[1,2-d][1,3]dioxin-7(4H)-one 53b
Rf = 0.25 (hexanes–EtOAc, 2:1).
13C NMR (CDCl3): d = 9.33, 14.69, 20.68, 22.51, 22.76, 25.69,
28.83, 46.77, 51.77, 76.13, 88.87, 119.58, 120.72, 129.67, 150.42,
150.90, 157.34, 198.89.
MS m/z (%) = 288 [M+] (34), 258 (46), 243 (21), 229 (25), 217 (16),
216 (96), 215 (100), 201 (39), 188 (39), 187 (67), 173 (23), 171
(15), 159 (31), 145 (20), 143 (17), 141 (20), 129 (26), 128 (51), 115
(32), 105 (21), 93 (18), 91 (39), 77 (26), 65 (19), 57 (15), 55 (18),
53 (17).
IR (neat): 2924 m, 1635 s, 1578 s, 1456 m, 1180 m, 1074 m, 918 m
cm–1.
1H NMR (CDCl3): d = 1.07 (t, J = 7.7 Hz, 3 H), 1.10 (s, 3 H), 1.95
(d, J = 14.8 Hz, 1 H), 2.19 (s, 3 H), 2.22–2.32 (m, 2 H), 2.42 (d,
J = 14.8 Hz, 1 H), 4.76 (s, 2 H), 5.18 (s, 2 H), 5.65 (s, 1 H).
13C NMR (CDCl3): d = 13.09, 19.30, 20.65, 22.57, 46.54, 51.76,
65.50, 91.98, 119.72, 120.84, 125.53, 150.15, 150.36, 157.90.
198.86.
MS m/z (%) = 246 [M+] (55), 216 (30), 188 (100), 187 (73), 160
(28), 159 (38), 131 (27), 91 (15).
Naphtho[1,2-d][1,3]dioxin-6,8-dione 58d
Yellow solid; Rf = 0.27 (hexanes–Et2O, 2:1).
IR (neat): 2967 m, 2930 w, 2874 w, 1771 w, 1663 s, 1620 w, 1361
w, 1076, 1012 w cm–1.
1H NMR (CDCl3): d = 0.97 (t, J = 7.5 Hz, 3 H), 1.04 (t, J = 7.4 Hz,
3 H), 1.16 (s, 3 H), 1.33–1.40 (m, 1 H), 1.45–1.49 (m, 1 H), 1.82–
1.88 (m, 2 H), 2.10–2.16 (m, 1 H), 2.28 (dd, J = 16.7, 1.1 Hz, 1 H),
2.31 (s, 3 H), 2.37–2.39 (m, 1 H), 2.82 (dd, J = 16.7, 1.1 Hz, 1 H),
Naphtho[1,2-d][1,3]dioxin-6,8-dione 58b
Rf = 0.11 (hexanes–EtOAc, 2:1).
IR (neat): 2971 w, 1659 s, 1626 m, 1363 w, 1251 m, 1184 m, 1076
m cm–1.
1H NMR (CDCl3): d = 0.98 (t, J = 7.4 Hz, 3 H), 1.19 (s, 3 H), 2.10–
2.20 (m, 1 H), 2.26 (d, J = 16.8 Hz, 1 H), 2.30 (s, 3 H), 2.35–2.44
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3701
4.94 (dd, J = 7.1, 4.0 Hz, 1 H), 4.97 (d, J = 5.8 Hz, 1 H), 5.21 (d,
J = 5.8 Hz, 1 H), 5.86 (t, J = 1.1 Hz, 1 H).
IR (neat): 3386 br, 2983 s, 2932 m, 2874 w, 1644 w, 1609 m, 1468
m, 1360 m, 1306 m, 1145 m cm–1.
13C NMR (CDCl3): d = 9.12, 14.54, 21.90, 24.81, 26.49, 28.14,
28.61, 43.79, 48.42, 74.79, 88.10, 121.12, 127.34, 135.42, 141.05,
148.85, 151.33, 197.06, 202.44.
1H NMR (CDCl3): d = 0.54 (d, J = 6.6 Hz, 3 H), 0.94 (d, J = 6.6 Hz,
3 H), 1.16 (s, 3 H), 1.79 (s, 3 H), 1.89 (m, 1 H), 2.44 (s, 3 H), 3.72
(s, 3 H), 4.81 (s, 1 H), 6.43 (s, 1 H), 6.64 (s, 1 H).
MS m/z (%) = 316 [M+] (17), 286 (39), 271 (100), 257 (22), 243
(63), 173 (43), 215 (55), 201 (25), 187 (39), 159 (24), 149 (29), 129
(16), 128 (37), 115 (24), 107 (23), 93 (20), 92 (38), 91 (45), 79 (27),
77 (19), 76 (35), 67 (27), 64 (15), 57 (19), 55 (26), 53 (20).
13C NMR (CDCl3): d = 8.72, 17.32, 17.91, 21.86, 33.83, 51.92,
60.14, 60.20, 108.46, 115.24, 129.86, 130.04, 130.66, 151.65,
152.96, 153.37.
MS m/z (%) = 247 (31), 246 [M+] (95), 231 (61), 204 (29), 203
(100), 189 (26), 175 (38), 171 (17), 161 (25), 149 (32), 91 (18).
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 54e
A soln of carbene complex 54e (184 mg, 0.408 mmol) in benzene
(40.8 mL) was heated according to the typical procedure to give 61
(59.1 mg, 51%) as a light yellow solid after purification; Rf = 0.31
(hexanes–Et2O, 1:1).
In one instance the reaction of complex 19 (reaction temperature
varied between 90 and 110 °C) with isopropyl(methyl)acetylene
gave inden-5-one 62 that was pure. In other reactions at 110 °C the
inden-5-one 62 co-eluted with another compound which has re-
mained unidentified. The ratio of 62 to unknown is typically about
14:1. GC-MS of the mixture reveals that the unknown is an isomer
of 62.
IR (neat): 3400 br, 2924 m, 2857 w, 1754 s, 1611 m, 1318 m, 1194
s, 1157 m, 1017 m, 904 w, 736 w cm–1.
1H NMR (CDCl3): d = 1.56 (s, 3 H), 2.20 (s, 6 H), 2.96 (s, 2 H), 4.61
(s, 2 H), 5.15 (s, 2 H), 5.40 (s, 1 H), 6.50 (s, 2 H).
13C NMR (CDCl3): d = 16.49, 19.75, 51.67, 64.53, 90.38, 105.44,
114.53, 126.31, 139.23, 140.96, 150.59, 156.03, 168.65, 188.81.
MS m/z (%) = 286 [M+] (20), 241 (59), 213 (58), 185 (23), 149
(100), 121 (28), 91 (33), 77 (27).
MS: m/z (%) = 247 (57), 246 [M+] (100), 231 (49), 204 (20), 203
(19), 189 (17), 175 (30), 161 (17).
In an effort to obtain 13C NMR data for the unknown compound the
reaction was repeated on carbene complex 19 (1.174 g, 3.30 mmol)
to give phenol 63 (414 mg, 51%) and of a mixture of 62 and the un-
known (14:1, 233 mg, 29%). The 13C NMR spectrum of this mixture
revealed a peak at d = 170.2 and 232.6 for the unknown but no other
peaks in between. This rules out the regioisomeric 64a as a structure
for the unknown (Scheme 11). Indenes of the type 64b and 64c
(Scheme 11) with a methoxy group at a sp3-carbon adjacent to the
benzene ring would be expected to have the methoxy group show
Intramolecular Tautomer-Arrested Annulation of Carbene
Complex 54f
A soln of carbene complex 54f (87.0 mg, 0.156 mmol) in benzene
(15.6 mL) was heated according to the typical procedure to give un-
stable cyclized product, which was decomposed during isolation.
1
an absorption between d = 3.0 and 3.5 ppm in the H NMR.9 The
lack of any absorption in the 1H NMR in this region would allow us
to eliminate structures 64b and 64c as possibilities. While there is a
methoxy at d = 3.84 that would be in the range expected for the
methoxy in structure 64d (Scheme 11), the lack of two different ar-
omatic protons in the region of d = 6–7 ppm can be used to rule out
structure 64d. There is a singlet 2 H absorption (relative to the meth-
oxy at d = 3.84 ppm) at d = 6.52 ppm that suggests that cyclization
to the aryl group has not occurred and that the aryl ring is still sym-
metrical. The two aryl protons in 63 are at d = 6.43 and 6.64 ppm
and it would not be expected that the two aryl protons in the closely
related compound 64d would have identical shifts. This conclusion
is also supported by the pattern of the aryl carbons in the 13C NMR
spectrum. Compound 63 has three carbons between d = 129–131
ppm and three carbons between d = 151–153 ppm. In the 13C NMR
spectrum of the mixture of 62 and the unknown, there could be at
most three carbons in these two ranges. There does appear to be car-
bons from the unknown at d = 170.2, 157.6, 152.6, 137.5, 124.5
ppm. Although the structure of the unknown could not be deter-
mined, the spectral data that was obtained on the mixture are not
consistent with structures 64a–d in Scheme 11 and thus with any
cyclized structure resulting from the incorporation of the alkyne
with the opposite regiochemistry observed for 62.
Intermolecular Reaction of Carbene Complex 19 with Isopro-
pyl(methyl)acetylene; Typical Procedure
A 25-mL single-necked flask which had its 14/20 joint replaced
with a threaded Teflon high-vacuum stop-cock was flushed with N2
for 10 min before it was charged with the carbene complex 19 (173
mg, 0.486), isopropyl(methyl)acetylene (79.5 mg, 0.97 mmol), and
benzene (9.72 mL). The mixture was deoxygenated by the freeze–
thaw method (–196 °C/25 °C, 3 cycles), back-filled with 1 atm of
argon at r.t., sealed and heated at 110 °C for 8 h. The mixture was
cooled to r.t., and then diluted with Et2O. After stirring at r.t. for 2
h in air, the soln was passed through Celite, concentrated, and then
purified by chromatography (silica gel, hexanes–Et2O, 2:1) to give
compound 62 (52.1 mg, 44%) and compound 63 (17.9 mg, 15%).
Inden-5-one 62
Rf = 0.24 (hexane–Et2O, 2:1).
IR (neat): 2963 m, 2932 w, 1655 s, 1626 m, 1570 s, 1445 w, 1318
m, 1119 w cm–1.
1H NMR (CDCl3): d = 1.06 (s, 3 H), 1.12 (d, J = 7.1 Hz, 3 H), 1.20
(d, J = 7.2 Hz, 3 H), 1.88 (d, J = 15.1 Hz, 1 H), 1.93 (s, 3 H), 2.21
(s, 3 H), 2.55 (d, J = 15.0 Hz, 1 H), 2.62 (sept, J = 7.1 Hz, 1 H), 3.72
(s, 3 H), 5.67 (s, 1 H).
Intermolecular Reaction of Carbene Complex 19 with tert-
Butyl(methyl)acetylene
13C NMR (CDCl3): d = 10.76, 20.29, 21.31, 21.70, 21.79, 27.04,
46.34, 52.35, 60.73, 122.69, 128.07, 131.82, 149.44, 159.89,
163.19, 199.55.
MS m/z (%) = 247 (54), 246 [M+] (100), 245 (22), 244 (44), 231
(57), 204 (37), 203 (89), 201 (35), 189 (38), 188 (15), 187 (17), 176
(15), 175 (63), 173 (22), 171 (17), 161 (26), 160 (18), 159 (17), 145
(22), 115 (15), 91 (21), 77 (16).
A soln containing carbene complex 19 (142 mg, 0.40 mmol) and
tert-butyl(methyl)acetylene (77.0 mg, 0.8 mmol) in benzene (8 mL)
was reacted at 110 °C for 8 h according to the typical procedure.
The mixture was cooled to r.t., and then diluted with Et2O. After
stirring at r.t. for 2 h in air, the soln was passed through Celite, con-
centrated, and then purified by chromatography (silica gel, hexane–
Et2O, 2:1) to give compound 65 (18.6 mg, 18%) and compound 66
(42.8 mg, 41%).
Inden-6-ol 63
Rf = 0.37 (hexane–Et2O, 2:1).
Inden-5-one 65
Rf = 0.21 (hexane–Et2O, 2:1).
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3702
M. E. Bos et al.
PAPER
IR (neat): 2961 m, 1655 s, 1622 s, 1570 m, 1547 m, 1447 m, 1395
m, 1329 m, 1124 m cm–1.
13C NMR (300 MHz, CDCl3): d = 4.15, 14.03, 59.85, 79.55, 82.30,
97.44, 151.70.
1H NMR (CDCl3): d = 1.24 (s, 3 H), 1.28 (s, 9 H), 1.99 (s, 3 H), 2.07
(d, J = 15.3 Hz, 1 H), 2.22 (s, 3 H), 2.98 (d, J = 15.3 Hz, 1 H), 3.69
(s, 3 H), 5.72 (s, 1 H).
13C NMR (CDCl3): d = 12.40, 20.48, 22.70, 30.83, 35.96, 47.26,
53.88, 60.83, 122.84, 129.05, 133.40, 149.13, 159.45, 164.43,
199.83.
(Z)-1-Methoxy-2-methylpent-1-en-3-yne [(Z)-71]
Light yellow liquid; Rf = 0.52 (hexanes–Et2O, 95:5).
1H NMR (300 MHz, CDCl3): d = 1.64 (s, 3 H), 1.98 (s, 3 H), 3.64
(s, 3 H), 6.10 (br s, 1 H).
13C NMR (300 MHz, CDCl3): d = 4.46, 13.93, 59.93, 76.53, 89.73,
95.24, 150.79.
MS m/z (%) = 261 (47), 260 [M+] (100), 245 (18), 204 (53), 203
(20), 189 (69), 175 (17), 161 (22).
1-Methoxy-2-methyl-5-(triisopropylsiloxy)pent-1-en-3-yne (72)
This compound was prepared from the ketone 74b according to the
typical procedure. Purification gave 72; yield: 67%; ratio E/Z 50:50.
A gradient of hexanes–Et2O from 100:0 to 95:5 was used to separate
the Z- and E-isomers.
Inden-6-ol 66
White solid; Rf = 0.38 (hexane–Et2O, 2:1).
IR (neat): 3387 br m, 2961 s, 1635 m, 1597 m, 1359 s, 1302 m, 1251
m, 1155 m, 1136 m, 1708 m, 1007 m, 860 w cm–1.
1H NMR (CDCl3): d = 0.90 (s, 9 H), 1.18 (s, 3 H), 1.90 (s, 3 H), 2.44
(E)-1-Methoxy-2-methyl-5-(triisopropylsiloxy)pent-1-en-3-yne
[(E)-72]
Light yellow liquid; Rf = 0.60 (hexanes–Et2O, 95:5).
1H NMR (300 MHz, CDCl3): d = 1.10 (m, 21 H), 1.71 (d, J = 1.5
Hz, 3 H), 3.68 (s, 3 H), 4.50 (s, 2 H), 6.37 (d, J = 1.5 Hz, 1 H).
(s, 3 H), 3.72 (s, 3 H), 4.69 (br s, 1 H), 6.42 (s, 1 H), 6.71 (s, 1 H).
13C NMR (CDCl3): d = 11.72, 17.72, 17.86, 27.22, 35.81, 54.76,
59.87, 110.13, 115.13, 129.43, 130.54, 130.79, 152.37, 152.78,
154.85.
13C NMR (300 MHz, CDCl3): d = 12.53, 17.86, 22.64, 31.58, 52.46,
60.06, 85.20, 96.65, 152.90.
MS m/z (%) = 260 [M+] (5), 204 (17), 203 (100), 188 (9), 145 (5).
5-(Triisopropylsiloxy)pent-3-yn-2-one (74b); Typical Proce-
dure
(Z)-1-Methoxy-2-methyl-5-(triisopropylsiloxy)pent-1-en-3-yne
[(Z)-72]
Light yellow liquid; Rf = 0.50 (hexanes–Et2O, 95:5).
1H NMR (300 MHz, CDCl3): d = 1.09 (m, 21 H), 1.70 (s, 3 H), 3.69
(s, 3 H), 4.58 (s, 2 H), 6.17 (s broad, 1 H).
13C NMR (300 MHz, CDCl3): d = 12.04, 17.95, 22.65, 31.59, 52.65,
60.11, 81.81, 92.19, 151.84.
A soln of 3-(triisopropylsiloxy)prop-1-yne (73b; 5.4 g, 25.5 mmol)
in THF (120 mL) was cooled at –40 °C. A soln of 1.7 M n-BuLi in
pentane (16.5 mL, 28 mmol) was added slowly. After 1 h at –40 °C,
N-methoxy-N-methylacetamide (2.88 g, 28 mmol) was added. The
mixture was warmed up to r.t. slowly and stirred for a further 1 h.
After addition of H2O (50 mL), the organic layer was extracted with
Et2O (3 × 25 mL). The combined organic layers were dried
(MgSO4). The product was purified by column chromatography
(silica gel, hexanes–Et2O, 9:1) to give 74b as a light yellow liquid;
yield: 67%; Rf = 0.55 (hexanes–Et2O, 9:1).
Intermolecular Reaction of Carbene Complex 19 with 1-Meth-
oxy-4-(trimethylsilyl)but-1-en-3-yne (69)
A 25-mL single-necked flask which had its 14/20 joint replaced
with a threaded Teflon high-vacuum stop-cock was flushed with N2
for 10 min before it was charged with the carbene complex 19 (247
mg, 0.69 mmol), (Z)-enyne (Z)-6915 (321 mg, 2.1 mmol) and hep-
tane (0.5 M, 1.4 mL). The mixture was deoxygenated by the freeze–
thaw method (–196 °C/25 °C, 3 cycles), back-filled with 1 atm of
argon at r.t., sealed and heated at 110 °C for 10 h. The reaction was
diluted with Et2O and stirred in air overnight. After filtration and
concentration, the residue was column chromatographed (silica gel,
20% EtOAc–hexanes). The first band collected was rechromato-
graphed (Et2O–CH2Cl2–hexanes, 1:1:10 and then with 1:1:4) to
give (E)-75 (40.0 mg, 18%). The second band contained (Z)-75
(41.5 mg, 19%), which isomerized slowly upon standing to the E
compound.
1H NMR (300 MHz, CDCl3): d = 1.09 (m, 21 H), 2.36 (s, 3 H), 4.56
(s, 2 H).
13C NMR (300 MHz, CDCl3): d = 11.85, 17.80, 32.50, 51.73, 84.04,
90.25, 184.19.
MS (EI): m/z (%) = 211 (84), 169 (71), 141 (100), 125 (51), 111
(37), 99 (14), 87 (12), 75 (23), 61 (29), 43 (26).
1-Methoxy-2-methylpent-1-en-3-yne (71); Typical Procedure
Into a round–bottomed flask containing Et2O (250 mL) was intro-
duced Ph3PCH2OMeCl (36.7 g, 107 mmol). The soln was cooled to
–78 °C under a blanket of argon and 1.7 M t-BuLi in pentane (63
mL, 107 mmol) was added slowly. The red mixture was stirred at
–78 °C for 0.5 h. Then ketone 74a (7.95 g, 97 mmol) was added and
the mixture was stirred for a further 2 h. Before warming to r.t., H2O
(60 mL) was added. The organic layer was separated and the aque-
ous layer was extracted with Et2O (3 × 10 mL). The combined or-
ganic layers were dried (MgSO4), filtered, and the amount of Et2O
was reduced to ~10 mL. Hexanes (50 mL) was added to the soln to
remove much of the phosphine oxide. After filtration and evapora-
tion, the mixture was purified by column chromatography (silica
gel, gradient of pentane–Et2O from 100:0 to 95:5) to separate the Z-
and E-isomers. The isomeric ratio varies from 60:40 to 50:50 and
the combined yield is typically 65%.
(Z)-75
Yellow oil.
1H NMR (CDCl3): d = 0.29 (s, 9 H), 1.19 (s, 3 H), 1.97 (d, J = 15.6
Hz, 1 H), 2.26 (d, J = 0.9 Hz, 3 H), 3.09 (d, J = 15.7 Hz, 1 H), 3.69
(s, 3 H), 3.71 (s, 3 H), 5.18 (d, J = 7.5 Hz, 1 H), 5.73 (br s, 1 H), 5.95
(d, J = 7.3 Hz, 1 H).
MS m/z (%) = 318 [M+] (69), 303 (23), 288 (8), 260 (6), 245 (9), 89
(18), 73 (100).
(E)-75
(E)-1-Methoxy-2-methylpent-1-en-3-yne [(E)-71]
Colorless liquid; Rf = 0.65 (hexanes–Et2O, 95:5).
1H NMR (300 MHz, CDCl3): d = 1.70 (s, 3 H), 1.93 (s, 3 H), 3.64
(s, 3 H), 6.31 (br s, 1 H).
Yellow oil; Rf = 0.31 (20% EtOAc–hexanes).
1H NMR (CDCl3): d = 0.33 (s, 9 H), 1.22 (s, 3 H), 2.19 (d, J = 15.4
Hz, 1 H), 2.27 (s, 3 H), 2.60 (d, J = 15.4 Hz, 1 H), 3.67 (s, 3 H), 3.69
(s, 3 H), 5.66 (s, 1 H), 5.94 (d, J = 13 Hz, 1 H), 6.84 (d, J = 13 Hz,
1 H).
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

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Studies on the Synthesis of Richardianidin-1
3703
13C NMR (CDCl3): d = 0.53, 20.36, 25.90, 48.73, 53.81, 57.24,
62.06, 102.82, 122.42, 130.91, 135.58, 149.78, 150.79, 164.58,
167.65, 199.11.
13C NMR (CDCl3): d = 0.85, 14.29, 20.59, 23.55, 47.17, 55.47,
59.74, 61.57, 111.29, 123.02, 129.93, 137.48, 145.97, 149.98,
163.27, 173.84, 199.42.
MS m/z (%) = 318 [M+] (62), 303 (23), 288 (7), 275 (11), 260 (8),
MS m/z (%) = 332 [M+] (49), 317 (10), 302 (8), 259 (6), 213 (10),
245 (9), 115 (9), 83 (32), 73 (100).
89 (16), 73 (100).
HRMS: m/z [M+] calcd for C19H28O3Si: 332.1808; found: 332.1850.
(E)-1-Methoxy-2-methyl-4-(trimethylsilyl)but-1-en-3-yne [(E)-
70]
The regiochemistry of the inden-5-one 76a from the reaction of car-
bene complex 19 and enyne (E)-70 was assigned based on the fact
that reduction of 76a with DIBAL-H at 0 °C gave a 4:1 mixture of
the alcohols 78 which when treated with silica gel underwent hy-
drolysis and dehydration to give an a bright yellow oil that was as-
signed the structure of aldehyde 79. The other possible regioisomer
76b could not undergo hydrolysis and dehydration to give 79. Spec-
tra data for major isomer of 79 is given; Rf = 0.64 (20% EtOAc–hex-
anes).
This was prepared by a modification of a procedure original pub-
lished by Zweifel.15 To a soln of (Z)-1-methoxy-4-(trimethylsi-
lyl)but-1-en-3-yne (69; 8.21 g, 53.2 mmol) and TMEDA (8.0 mL,
53.2 mmol) in THF (120 mL) at –78 °C was added 2.5 M n-BuLi in
hexanes (21.3 mL, 53.2 mmol) over 15 min. The pale yellow soln
was stirred at –78 °C for 2 h. MeI (6.6 mL, 106.4 mmol) was added
all at once and the mixture was stirred at –78 °C for a further 2 h and
then overnight at 0 °C. After quenching with H2O at 0 °C, the mix-
ture was poured into pentane, washed with H2O and brine, dried
(MgSO4), and concentrated via distillation at ambient pressure un-
der N2. Distillation at 2.4–2.7 mbar into an ice-cooled receiver gave
two fractions: (1) bp 45–54 °C, pure (E)-70 (4.42 g, 49%) and (2)
bp 52–74 °C, slightly impure (E)-70 (1.20 g, contains about 10%
(Z)-69). (E)-70 was obtained as a colorless, musty-smelling liquid,
slowly oxidized with molybdate; Rf = 0.20 (pentane).
IR (CHCl3): 2957 m, 1652 vs, 1495 s, 1336 m, 1249 m, 845 s cm–1.
1H NMR (CDCl3): d = 0.28 (s, 9 H), 0.99 (s, 3 H), 1.91 (s, 3 H), 2.10
(s, 3 H), 2.18 (d, J = 17 Hz, 1 H), 2.80 (dd, J = 17, 5.7 Hz, 1 H), 3.88
(s, 3 H), 5.96–6.01 (m, 2 H), 9.71 (s, 1 H).
Finally the structure of 76a was confirmed by X-ray diffraction
analysis.
IR (neat): 2959 s, 2935 m, 2229 m, 2144 s, 2113 m, 1641 s, 1250 s,
1227 s, 1139 s, 871 s, 841 s, 760 s cm–1.
1H NMR (CDCl3): d = 0.14 (s, 9 H), 1.68 (d, J = 1.4 Hz, 3 H), 3.65
(s, 3 H), 6.45 (q, J = 1.4 Hz, 1 H).
Intermolecular Reaction of Carbene Complex 19 with 1-Meth-
oxy-2-methylpent-1-en-3-yne [(E)-71]; Typical Procedure
The chromium carbene complex 19 (142 mg, 0.4 mmol), (E)-1-
methoxy-2-methylpent-1-en-3-yne [(E)-71; 88 mg, 0.8 mmol), and
benzene (0.05 M, 8 mL) were placed in a flame-dried, single-
necked flask that had been modified by replacement of the 14/20
joint with a 10-mm threaded high-vacuum stopcock. The mixture
was deoxygenated by the freeze–thaw method (–196 °C/25 °C, 3
cycles). Then the flask was backfilled with 1 atm of argon at r.t.,
sealed with the stopcock and heated at 110 °C for 8 h. After removal
of solvent, the crude mixture was purified (silica gel, hexanes–
CH2Cl2–Et2O, 4:1:1) to give 80; yield: 60%; ratio E/Z 96:4. In-
creased amounts of the Z-isomer can be found in reactions in differ-
ent solvents. The reaction of (Z)-71 gives predominately (Z)-80 in
similar yields.
13C NMR (CDCl3): d = 0.14, 13.62, 60.06, 90.58, 106.23, 154.03.
Alkyne (E)-70 was photolyzed in benzene in a Rayonet reactor to
give a sample of (Z)-70.
1H NMR (CDCl3): d = 0.17 (s, 9 H), 1.93 (s, 3 H), 3.69 (s, 3 H), 6.17
(s, 1 H).
Intermolecular Reaction of Carbene Complex 19 with Zweifel’s
Enyne (E)-70
An 8-mL heavy-walled tube that was topped with a threaded Teflon
high-vacuum stop-cock was flushed with N2 for 10 min before it
was charged with the carbene complex 19 (106 mg, 0.30 mmol),
(E)-70 (100 mg, 0.59 mmol), and benzene (0.5 M, 0.60 mL). The
mixture was deoxygenated by the freeze–thaw method (–196 °C/
25 °C, 3 cycles), back-filled with 1 atm of argon at r.t., sealed and
heated at 110 °C for 8 h. Purification by chromatography (silica gel,
Et2O–CH2Cl2–hexanes, 1:1:4) gave a mixture of 76a and isomeric
aromatized indanol 77; combined yield: 44.1 mg (44%); ratio 9:1.
(E)-Inden-5-one (E)-80
Rf = 0.36 (hexanes–CH2Cl2–Et2O, 4:1:1).
1H NMR (300 MHz, CDCl3): d = 1.04 (s, 3 H), 1.75 (d, J = 1.5 Hz,
3 H), 1.93 (s, 3 H), 2.04 (d, J = 15.3 Hz, 1 H), 2.23 (d, J = 1.2 Hz, 3
H), 2.70 (d, J = 15.3 Hz, 1 H), 3.64 (s, 3 H), 3.76 (s, 3 H), 5.69 (s, 1
H), 5.95 (br s, 1 H).
13C NMR (300 MHz, CDCl3): d = 11.67, 14.11, 20.57, 23.48, 47.26,
52.81, 59.86, 60.68, 108.89, 122.65, 128.92, 133.72, 147.02,
149.54, 156.74, 158.76, 198.35.
Inden-6-ol 77
Pale yellow oil; Rf = 0.46 (20% EtOAc–hexanes).
IR (neat): 3396 br w, 2954 m, 2933 m, 1603 m, 1554 m, 1285 m,
1247 m, 1221 m, 1125 s, 862 m, 836 s cm–1.
1H NMR (CDCl3): d = 0.23 (s, 9 H), 1.06 (s, 3 H), 1.34 (s, 3 H), 2.48
(s, 3 H), 3.64 (s, 3 H), 3.72 (s, 3 H), 4.63 (br s, 1 H), 6.09 (s, 1 H),
6.46 (m, 2 H).
MS (EI): m/z (%) = 274 (50), 259 (13), 243 (6), 227 (9), 211 (3), 199
(10), 171 (11), 129 (14), 115 (14), 91 (14), 84 (100), 47 (18).
HRMS: m/z [M+] calcd for C17H22O3: 274.1575; found: 274.1569.
Anal. Calcd for C17H22O3: C, 74.42; H, 8.08. Found: C, 74.23; H,
8.22.
Inden-5-one 76a
Yellow oil at r.t., can be crystallized (CHCl3–hexanes, 0 °C); Rf =
0.42 (20% EtOAc–hexanes).
(Z)-Inden-5-one (Z)-80
Rf = 0.35 (hexanes–CH2Cl2–Et2O, 4:1:1).
1H NMR (300 MHz, CDCl3): d = 1.10 (s, 3 H), 1.71 (s, 3 H), 1.86
(s, 3 H), 2.14 (d, J = 15 Hz, 1 H), 2.64 (d, J = 15 Hz, 1 H), 2.27 (s,
3 H), 3.55 (s, 3 H), 3.83 (s, 3 H), 5.74 (s, 1 H), 6.02 (br s, 1 H).
IR (CHCl3): 2957 m, 1657 s, 1586 vs, 1443 m, 1268 m, 1248 s, 1227
s, 1160 m, 1131 s, 1103 m cm–1.
1H NMR (CDCl3): d = 0.25 (s, 9 H), 1.09 (s, 3 H), 1.74 (d, J = 1 Hz,
3 H), 2.08 (d, J = 15.3 Hz, 1 H), 2.26 (s, 3 H), 2.63 (d, J = 15 Hz, 1
H), 3.65 (s, 3 H), 3.71 (s, 3 H), 5.70 (s, 1 H), 5.81 (br s, 1 H).
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

3704
M. E. Bos et al.
PAPER
Intermolecular Reaction of Carbene Complex 87 with (E)-1-
Methoxy-2-methylpent-1-en-3-yne [(E)-71]
13C NMR (300 MHz, CDCl3): d = –4.28, 14.26, 19.71, 25.71,
119.36, 128.75, 145.48, 154.34, 216.76, 216.59 (Ccarb not located).
The chromium carbene complex 87 (142 mg, 0.37 mmol), (E)-71
(88 mg, 0.8 mmol) were reacted according to the typical procedure
to give (E)-88; yield: 62% ratio E/Z >98%:
1H NMR (300 MHz, CDCl3): d = 1.04 (s, 3 H), 1.28 (d, J = 8 Hz, 6
H), 1.74 (s, 3 H), 1.91 (s, 3 H), 2.00 (d, J = 15.3 Hz, 1 H), 2.23 (d,
J = 1.2 Hz, 3 H), 2.66 (d, J = 15.3 Hz, 1 H), 3.63 (s, 3 H), 4.37 (sept,
J = 6.3 Hz, 1 H), 5.68 (s, 1 H), 5.88 (br s, 1 H).
13C NMR (300 MHz, CDCl3): d = 12.13, 14.01, 20.92, 22.44, 23.21,
42.28, 52.88, 59.72, 74.69, 108.65, 122.65, 129.77, 133.71, 147.02,
146.95, 150.65, 156.95, 157.31, 199.44.
MS (EI): m/z (%) = 399 [M+ – 2 CO] (1), 343 [M+ – 4 CO] (1), 315
[M+ – 5 CO] (21), 263 (17), 204 (100), 188 (14), 179 (27), 130 (64),
121 (14), 115 (12), 105 (23), 75 (64), 41 (43).
HRMS: m/z [M + H]+ calcd for C20H26CrNO6Si: 456.0935; found:
456.0942.
Anal. Calcd for C20H25CrNO6Si: C, 52.74; H, 5.53; N, 3.08. Found:
C, 52.72; H, 5.54; N, 3.15.
{[4-(tert-Butyldimethylsiloxy)-2,6-dimethylphenyl](dimethyl-
amino)methylene}pentacarbonylchromium(0) (82)
In a 10-mL round-bottomed flask was placed TBAB (0.1 g, 0.32
mmol), NaOH (1.05 g, 25.6 mmol) and amino carbene complex 81
(1.46 g, 3.2 mmol). CH2Cl2 (2 mL), H2O (1 mL), and MeI (0.6 mL,
9.6 mmol) were then added. The mixture was followed by TLC and
stirred for 5–6 h at r.t.. The organic layer was separated and the
aqueous layer was extracted with CH2Cl2 (3 × 1 mL). The combined
organic phases were dried (MgSO4) and the solvent evaporated. The
product was purified by column chromatography (silica gel, hex-
anes–Et2O, 50:50) to give 82 as a yellow solid; yield: 1.16 g (75%);
mp 120 °C (dec.); Rf = 0.52 (hexanes–Et2O, 50:50).
1H NMR (300 MHz, CDCl3): d = 0.16 (s, 6 H), 0.95 (s, 9 H), 1.99
(s, 6 H), 3.04 (s, 3 H), 4.00 (s, 3 H), 6.49 (s, 2 H).
13C NMR (300 MHz, CDCl3): d = –4.32, 18.31, 19.48, 25.76, 44.47,
48.37, 119.67, 127.08, 145.28, 153.71, 216.69, 222.97 (Ccarb not lo-
cated).
Intermolecular Reaction of Carbene Complex 19 with (E)-1-
Methoxy-2-methyl-5-(triisopropylsiloxy)pent-1-en-3-yne [(E)-
72]
The chromium carbene complex 19 (82 mg, 0.23 mmol), (E)-1-
methoxy-2-methyl-5-(triisopropylsiloxy)pent-1-en-3-yne [(E)-72;
130 mg, 0.46 mmol] were reacted according to the typical proce-
dure to give (E)-89 and (Z)-89; yield: 40%; ratio E/Z 87:13.
(E)-Inden-5-one (E)-89
Rf = 0.34 (hexanes–CH2Cl2–Et2O, 4:1:1).
IR (neat): 2944 m, 2867 m, 1657 m, 1612 m, 1462 w, 1229 m, 1136
s, 1059 w, 881 w, 681 m cm–1.
1H NMR (300 MHz, CDCl3): d = 1.06 (s, 24 H), 1.75 (s, 3 H), 2.09
(d, J = 15.1 Hz, 1 H), 2.25 (s, 3 H), 2.68 (d, J = 15.1 Hz, 1 H), 3.64
(s, 3 H), 3.87 (s, 3 H), 4.37 (d, J = 11.2 Hz, 1 H), 4.52 (d, J = 11.2
Hz, 1 H), 5.70 (s, 1 H), 6.04 (s, 1 H).
13C NMR (CDCl3): d = 12.11, 13.86, 18.08, 20.57 23.20, 47.22,
52.71, 59.64, 59.81, 61.12, 108.45, 122.79, 128.98, 135.76, 147.67,
150.36, 159.31, 160.10, 199.33.
MS (EI): m/z (%) = 455 (2), 427 (4), 399 (9), 371 (8), 343 (99), 300
(36), 276 (17), 204 (23), 244 (11), 204 (10), 162 (10), 143 (10), 126
(56), 95 (35), 73 (47), 52 (100).
HRMS: m/z [M+] calcd for C22H29CrNO6Si: 483.1169; found:
483.1191.
MS m/z (%) = 447 (28), 446 [M+] (74), 388 (55), 345 (28), 273 (24),
241 (57), 226 (43), 75 (100), 59 (87).
Anal. Calcd for C22H29CrNO6Si: C, 54.64; H, 6.04; N, 2.90. Found:
C, 54.83; H, 5.98; N, 2.96.
(Z)-Inden-5-one (Z)-89
Rf = 0.32 (hexanes–CH2Cl2–Et2O, 4:1:1).
Pentacarbonyl[(dimethylamino)(4-hydroxy-2,6-dimethylphe-
nyl)methylene]chromium(0) (83)
IR (neat): 2944 m, 2867 m, 1657 m, 1613 m, 1462 m, 1140 s, 1062
m, 884 m, 681 m cm–1.
1H NMR (300 MHz, CDCl3): d = 1.03 (m, 21 H), 1.07 (s, 3 H), 1.70
(s, 3 H), 2.13 (d, J = 15.0 Hz, 1 H), 2.24 (s, 3 H), 2.58 (d, J = 15.0
Hz, 1 H), 3.47 (s, 3 H), 3.94 (s, 3 H), 4.36 (d, J = 3.2 Hz, 2 H), 5.69
(s, 1 H), 5.97 (s, 1 H).
13C NMR (CDCl3): d = 11.99, 18.00, 18.56, 20.68, 22.68, 47.78,
52.23, 57.74, 59.40, 60.14, 107.01, 122.46, 128.61, 136.90, 145.37,
150.90, 156.28, 159.16, 199.96.
The dimethylamino carbene complex 82 (0.92 g, 1.9 mmol) was
dissolved in THF (25 mL). HF–pyridine complex (3.2 mL) was
added at r.t. over 4–6 h until no starting material was observed by
TLC. Sat. Na2CO3 (10 mL) was added slowly. The layers were sep-
arated and the aqueous phase was extracted with CH2Cl2 (3 × 5 mL).
The organic layers were combined and dried (MgSO4). After evap-
oration, purification of the product by column chromatography (sil-
ica gel, hexanes–Et2O, 50:50) gave 83 as a yellow solid; yield: 0.35
g (50%); mp 150 °C (dec.); Rf = 0.26 (hexanes–Et2O 50:50).
1H NMR (300 MHz, acetone-d6): d = 0.86 (s, 6 H), 1.98 (s, 3 H),
2.90 (s, 3 H), 5.34 (s, 2 H), 7.40 (br s, 1 H).
13C NMR (300 MHz, acetone-d6): d = 19.55, 44.89, 51.14, 115.38,
128.16, 144.62, 156.40, 206.55, 217.69 (Ccarb not located).
MS m/z (%) = 447 (18), 446 [M+] (52), 388 (37), 241 (47), 199 (38),
145 (46), 115 (63), 75 (100), 59 (87);
{Amino[4-(tert-butyldimethylsiloxy)-2,6-dimethylphenyl]meth-
ylene}pentacarbonylchromium(0) (81)
MS (EI): m/z (%) = 271 (4), 257 (1), 243 (22), 229 (12), 200 (19),
175 (17), 162 (31), 147 (80), 135 (58), 121 (100), 115 (27), 103
(25), 95 (45), 91 (76), 77 (27), 52 (78), 44 (89).
To a 100-mL round–bottomed flask equipped with a dry ice con-
denser was added chromium carbene complex 24 (1.88 g, 4 mmol)
and THF (40 mL). The mixture was cooled at –40 °C and ammonia
gas was introduced via a cannula. The reaction was followed by
TLC and stirred at –40 °C for 2–3 d. After warming up at r.t. and
evaporation of the solvent, the product was purified by column
chromatography (silica gel, hexanes–Et2O, 80:20) to give 81 as a
yellow solid; yield: 1.60 g (88%); mp 120 °C (dec.); Rf = 0.20 (hex-
anes–Et2O, 80:20).
Anal. Calcd for C16H15CrNO6: C, 52.04; H, 4.09; N, 3.79. Found: C,
52.31; H, 4.22; N, 3.75.
Acknowledgment
This work was supported by the NIH (GM 33589). One of the au-
thors (WDW) would like to extend a large measure of gratitude to
Professor Martin Semmelhack who introduced him to organochro-
mium chemistry and showed him how to do organic synthesis.
1H NMR (300 MHz, CDCl3): d = 0.17 (s, 6 H), 0.96 (s, 9 H), 2.14
(s, 6 H), 6.48 (s, 2 H), 8.45 (br s, 1 H), 9.24 (br s, 1 H).
Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York

PAPER
Studies on the Synthesis of Richardianidin-1
3705
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Synthesis 2006, No. 21, 3679–3705 © Thieme Stuttgart · New York