Vinylogous Nicholas reactions in the synthesis of bi- and tricyclic cycloheptynedicobalt complexes

Article abstract of DOI:10.1039/c5ob01684c

The Lewis acid mediated intramolecular Nicholas reactions of allylic acetate enyne-Co₂(CO)₆ complexes afford cycloheptenyne-Co₂(CO)₆ complexes in three manifestations. Electron rich aryl substituted alkyne complexes give tricyclic 6,7,x-benzocycloheptenyne complexes, with x = 5, 6, or 7. Allylsilane substituted complexes afford exo methylene bicyclic x,7-cycloheptenyne complexes (x = 6,7). The allyl acetate function may also be replaced by a benzylic acetate, to afford dibenzocycloheptyne-Co₂(CO)₆ complexes. Following reductive complexation, the methodology may be applied to the synthesis of the icetexane diterpene carbon framework.

Full text of DOI:10.1039/c5ob01684c

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Vinylogous Nicholas Reactions in the Synthesis of Bi- and Tricyclic Cycloheptynedicobalt
Complexes
Izabela Kolodziej, James R. Green*a
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, N9B 3P4,
Canada
Abstract
The Lewis acid mediated intramolecular Nicholas reactions of allylic acetate enyne-Co2(CO)6
complexes afford cycloheptenyne-Co2(CO)6 complexes in three manifestations. Electron rich
aryl substituted alkyne complexes give tricyclic 6,7,x- benzocycloheptenyne complexes, with x =
5, 6, or 7. Allylsilane substituted complexes afford exo methylene bicyclic x,7- cycloheptenyne
complexes (x = 6,7). The allyl acetate function may also be replaced by a benzylic acetate, to
afford dibenzocycloheptyne-Co2(CO)6 complexes. Following reductive complexation, the
methodology may be applied to the synthesis of the icetexane diterpene carbon framework.
Introduction
The chemistry of cycloheptyne-Co2(CO)6 complexes is of interest from several aspects.1 The ca.
140 o bond angle of the alkynedicobalt complex2 renders stable complexes of otherwise unstable
alkyne functions. The intermediacy of these complexes has proved central in the synthesis of
several groups of seven- membered ring containing compounds.3 In addition, its presence in
compounds with adjacent π- systems have raised important questions in bonding.4
Synthesis of this class of compounds has been accomplished in a limited number of cases
via ring closing methathesis,5 a carbonylative Heck reaction,6 Diels-Alder reactions,7 Hososmi-
Sakurai reactions,8 ene- reaction chemistry,3e Mukaiyama aldol reactions,9 and Michael
chemistry,10 but most often by intramolecular nucleophilic attack on propargyldicobalt cations
(Nicholas reaction chemistry).11,12 In some cases they have provided an excellent way of
favouring cyclization to the seven- membered ring system over the five membered ring isomer.
The potential use of vinylogous Nicholas reaction chemistry for access to cycloheptynedicobalt
complexes, however, has not been investigated previously. The use of vinylogous propargyl
a Corresponding author. E‐mail address: jgreen@uwindsor.ca
†Electronic supplementary information (ESI) available: Experimental details and spectroscopic data, 1H and 13
NMR spectra for new compounds.
C
1

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cation complexes in reactions with nucleophiles not only favour remote attack with most
nucleophiles,13 but competitive proximal attack in substrates such as 1 would result in a
prohibitively angle strained cyclopentynedicobalt complex. As a result, there is a good likelihood
of success for the vinylogous Nicholas reactions (1 → 2) of allyl propargyl cation complexes to
result in the preparation of cycloheptyne complexes (Scheme 1).
OAc
(OR)m
(OR)m
()n
( )n
Co2(CO)6
1
Co2(CO)6
Co2(CO)6
R2
2
OAc
( )n
( )n
(OC)6Co2
4
Me3Si
3
(OR)m
(OR)m
OAc
R1
(OC)6Co 2
OMe
Co2(CO)6
5
6
R
Scheme 1. Intramolecular vinylogous Nicholas reactions.
Of the tricyclic systems reflected in 2, the 6,7,6- system that would result from
cyclization reactions with arene nucleophiles, the n = 1 systems are heavily encountered in the
icetexane and faveline diterpenes.14 These classes of compounds have been the subject of a
number of different synthetic tactics,15,16,17,18,19,20,21,22 but have not been approached by Nicholas
reaction chemistry; consequently we were interested in the application of these vinylogous
Nicholas reactions in the construction of the icetexane ring system. In addition, we have interest
in the viability of nucleophiles other than arenes, particular allylsilane nucleophiles (3), in
accomplishing analogous chemistry, to afford bicyclic complexes 4. Finally, it is in principle
possible for the use of arenes as opposed to cyclic alkenes as the spacers between the
alkynedicobalt complex and leaving group (5) to give dibenzocycloheptyne complexes 6; we
wished to determine the viability of this transformation, particularly given the occurrence of
2

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dibenzo[a,d]cycloheptenes in tricyclic antidepressants.23 We have reported on some aspects of
the chemistry in preliminary fashion24 and now describe a complete report.
Results and discussion
The initial attempts at vinylogous Nicholas reaction chemistry involved the choice of electron
rich arene nucleophiles (1), with the intent of generation 6,7,x- systems upon cyclization (2). The
starting materials for the cyclization precursors were alkynylarenes 7, which were subjected to
Sonogashira coupling reactions with 2-bromocyclopentenecarbaldehyde (8a), 2-
bromocyclohexenecarbaldehyde (8b), or 2-bromocycloheptenecarbaldehyde (8c), to give aryl
substituted cyclic enynecarbaldehydes 9 (Scheme 2, Table 1). In three cases, the
corresponding(trimethylsilyl)alkynylarene (7’d, 7’i) was employed instead, with a desilylative
Sonogashira coupling25 giving 9e, 9f and 9p in straightforward fashion. Reduction of the
aldehyde function and acetylation of resultant alcohol gave acetates 10, which underwent ready
complexation reactions with Co2(CO)8 to form the enyne/allylic acetate complexes 1 in good to
excellent yields.
R2
R1
R2
R1
R2
R1
R2
R1
Pd(PPh3)4, CuI,
Et3N-DMF
CHO
1) DIBAL-H, THF,
-78 oC
R3
Co2(CO)8
R3
R3
R3
+
Et2O, 0 oC
OAc
( )n Br
2) Ac2O, pyridine,
DMAP, -78 oC - rt
R4
R5
R4
R5
R4
R4
CHO
OAc
(OC)6Co2
E
7, E = H
7', E = SiMe3
8a, n = 1
8b, n = 2
8c, n = 3
9
10
( )n
( )n
( )n
1
Scheme 2. Preparation of aryl substituted allylic acetate alkyne-Co2(CO)6 complexes.
Table 1. Preparation of aryl substituted allylic acetate alkyne-Co2(CO)6 complexes.
7
R1
R2
R3
R4
R5
n
9, 10, 1
Yield of Yield of Yield of
9 (%)
72
82
74
10 (%)
89
86
89
89
88
91
90
1 (%)
90
89
92
93
86
92
91
83
85
87
94
91
89
a
a
H
H
H
H
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
OMe
H
H
H
H
H
H
OMe
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
Me
H
0
1
1
1
0
1
0
1
2
0
1
1
0
a
b
c
d
e
b
c
7’d
7’d
e
e
e
f
f
OMe OMe
80
H
H
H
H
H
OMe
OMe
H
H
H
91b
90b
79
f
g
h
i
85
74
86
82
–
83
90
85
92
OMe OMe OMe
OMe OMe OMe
OMe OMe OMe
j
H
H
k
kk
l
89
f
g
89b
89
OMe OMe OMe
H
3

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g
g
g
h
OMe OMe OMe
OMe OMe OMe
OMe OMe OMe
H
H
H
H
H
H
H
Ph
H
H
1
2
1
1
1
m
n
mm
o
85
86
–
86
80
88
90
80c
90
94
86
92
87
89
91
i-Pr
OMe OMe
3-thienyl
7’i
p
a n-Bu4NF (TBAF) added in reaction mixture. b Use of MeLi in pace of DIBAL-H. c Use of
PhMgBr in place of DIBAL-H.
Experiments on the Lewis acid mediated cyclization reactions were conducted in CH2Cl2
o
(0.007 M) at 0 C, with BF3-OEt2 (3 equiv). The substrates with simple phenyl substituents
(1a,b) on the alkynedicobalt unit failed to give any cyclization products (2); 1a underwent
complete decomposition, and the use of TiCl4 or SnCl4 did not give any improvement. In the
case of 1b, TiCl4 and SnCl4 did give the elimination product 11b, with SnCl4 giving 11b in 52%
yield (Equation 1, Figure 1, Table 2). These results were not entirely surprising, as the Mayr
electrophilicity (propargyldicobalt cation) and nucleophilicity (benzene) values suggest a too
slow reaction of unactivated arenes with propargyldicobalt cations.26 In the presence of more
electron rich aryls, the cyclizations were much more successful. 3-Methoxy- substituted 1c gave
2c in 82% yield as 4.9:1 separable mixture of isomers (2c, 2c’) stemming from reaction at C-6
and C-2 respectively; this isomer ratio improved noticeably with minimal loss in yield when
cooling the reaction successively to -40 oC and -78 oC. Similarly, 3,4-dimethoxy- substituted 1d
gave 2d and 2d’ as a separable regioisomeric mixture (90% yield, 2d:2d’ = 8.8:1). Amongst the
other dimethoxyaryl- substituted substrates, the 3,5-dimethoxyphenyl- substituted cases afforded
excellent yields of cyclization products for both cyclopentene- and cyclohexene- containing
cases (2e, 85%; 2f, 85%), while the less electron rich 2,5-dimethoxyphenyl- substituted cases
worked poorly with BF3-OEt2, SnCl4, or TiCl4 in the cyclopentene- containing case (2g, 6% with
BF3-OEt2) but very well in the cyclohexene- and cycloheptene- substituted cases (2h 82%; 2i,
85%). The trimethoxyphenyl- substituted substrates showed an analogous trend. The less
electron rich 2,3,4-trimethylphenyl- cases gave very poor yields in the cyclopentene- cases (2j,
8%), and better but still modest yields for the cyclohexene- spacer (2k, 39%; 2kk, 39%); these
substrates required SnCl4 rather than BF3-OEt2 as Lewis acid to give any products whatsoever.
Conversely, the more electron rich 3,4,5-trimethoxyphenyl- substituted cases cyclized readily
and in good yields regardless of the ring size in which the alkene spacer was present (2l 85%;
2m, 86%; 2n, 84%). Substitution of the reactive site was somewhat detrimental here, however,
as allylic benzylic acetate 1mm gave only 34% of, along with elimination product 11mm (40%).
4

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However, switching the Lewis acid to SnCl4, under otherwise identical conditions gave 2mm as
the sole tractable product in 79% yield. Isopropyldimethoxy- substituted 1o underwent
cyclization quite smoothly to give a 79% yield of a mixture of isomers, with the site p- to the
methoxy function reacting preferentially to that p- to the isopropyl (2o:2o’ = 14:1). Finally, 3-
thienyl substituted 1p gave excellent yields of 2p (90%), with cyclization occurring solely
through C-2 of the thiophene unit.
R1
R3
R5
R5
R2
R2
BF3-OEt2,
CH2Cl2
(1)
1
R1
R3
0
oC
( )n
( )n
R4
Co2(CO)6
Co2(CO)6
2'
2
Table 2. Intramolecular vinylogous Nicholas reactions of 1
Starting Time Product Yield
material (h)
(%)
52a
68
14
69
10
72
9
1b
1c
2
1.5
11b
2c
2c’
2c
2c’
2c
2c’
1c
1c
1d
2b
3c
2
2d’
81
9
1e
1f
1g
1h
1i
0.75 2e
0.75 2f
85
85
6
82
85
8a
2
1
1
1
1
2g
2h
2i
2j
1j
1k
1kk
1l
1m
1mm
1n
1o
2k
39a
39a
85
86
79a
84
74
5
2kk
2l
2m
2mm
2n
0.5
0.5
1
0.5
2o
2o’
1p
0.67 2p
90
a SnCl4 as Lewis acid. b at -40 oC. c at -78 oC, 2.15 h; warmed to 0 oC
Figure 1. Tricyclic 6,7,x- benzocycloheptenyne complexes prepared via Equation 1
5

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MeO
MeO
R5
MeO
R2
R2
OMe
OMe
OMe
OMe
( )n
( )n
( )n
OMe
Co2(CO)6
2g, n = 0
, n = 1
2i, n = 2
OMe
Co2(CO)6
Co2(CO)6
Co2(CO)6
Co2(CO)6
2
2c, R2 = H
2c'
2j, n = 0, R5 = H
2k
2e, n = 0
2f, n = 1
, R = H
2d R2 = OMe
2d' R2 = OMe
, n = 1, R5 = H
2h
, n = 1, R5 = Me
2kk
MeO
OMe
R5
i-Pr
OMe
R1
OMe
OMe
S
R2
R3
Pr-i
R5
OMe
OMe
( )n
Co 2(CO)6
Co 2(CO)6
Co2(CO)6
Co2(CO)6
2p
(OC)6Co2
2l, n = 0, R5 = H
2m, n = 1, R5 = H
2n, n = 2, R5 = H
2o'
2o
11b, R1 = R2
=
R5 = H, R3 = OMe
11mm, R1 = R2 = R3 = OMe, R5 = Ph
2mm, n = 1, R5 = Ph
Some trends become apparent among the above results. The intramolecular Nicholas
reactions can succeed with each of 5-, 6- and 7- membered cycloalkene spacers separating the
allylic acetate and alkynedicobalt function, but the yields of cyclopentene- containing products
become compromised more readily as the arene nucleophiles become less electron rich. This is
likely due to greater angle strain caused by the five membered ring on the incipient cycloheptyne
complexes relative to the six- and seven- membered homologues.
Secondly, the results with the allylic phenyl- substituted 1mm were of additional interest.
Reactions conducted with BF3-OEt2 at lower temperature (-50 - -60 oC) revealed greater amounts
of elimination product 11mm relative to 2mm. This suggests that 11mm is actually the dominant
initial product of reaction of 1mm in all cases, but in the presence of liberated acid during the
reaction it may be in equilibrium with the allyl propargyl cation complex, which can in turn
ultimately funnel towards 2mm. The stronger acid generated in the SnCl4 mediated cases then
allows this latter process to go to completion. The use of enyne-Co2(CO)6 complexes as
propargyldicobalt cation precursors is well established, particularly by Smit and Caple.27
We wished to demonstrate the ability of allylsilanes to participate in this type of
intramolecular vinylogous Nicholas reactions chemistry (3 → 4, Scheme 1), and as a result
targeted complexes 3a and 3b as potential substrates (Scheme 3). These cyclization precursors
could be prepared from bromocycloalkene carbaldehydes 8a,b. The Sonogashira reactions of 8
with trimethylsilylacetylene afforded 2-alkynylcyclohexenecarbaldehyde 12a (85% yield) and 2-
alkynylcycloheptenecarbaldehyde 12b (90% yield) readily. Attempts to desilylate 12a,b at this
point gave materials which decomposed rapidly after isolation, and consequently the aldehyde
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functions of 12 were reduced with DIBAL-H and the products immediately acetylated, to give
allylic alcohols 13a (91% yield) and 13b (94%). Desilylation of these intermediates with KF-
2H2O then gave terminal alkynes 14a (88% yield) and 14b (82% yield), which were subjected to
Sonogashira coupling with 2-bromoallyltrimethylsilane, affording 15a (86% yield) and 15b
(90% yield) in excellent yields. Complexation of alkyne functions of 15 then gave 3a (92%
yield) and 3b (93% yield).
1) DIBAL-H, THF,
-78 oC
CHO
CHO
SiMe3
OAc
( )n
Pd(PPh3)4, CuI,
Et3N-THF
( )n
( )n
Br
2) Ac2O, pyridine, DMAP,
-78 oC - rt
SiMe3
SiMe3
8a, n = 1
8b, n = 2
13a, n = 1, 91%
13b, n = 2, 94%
12a, n = 1, 85%
12b, n = 2, 90%
Br
OAc
OAc
Co2(CO)8
Et2O, 0 oC
SiMe3
KF-2H2O, DMF
0 oC - rt
OAc
( )n
( )n
( )n
Pd(PPh3)4, CuI,
Et3N-THF
(OC)6Co2
H
Me 3Si
Me 3Si
14a, n = 1, 88%
14b, n = 2, 82%
3a, n = 1, 92%
3b, n = 2, 93%
15a, n = 1, 86%
15b, n = 2, 90%
Scheme 3. Preparation of allylsilane substituted allylic acetate alkyne-Co2(CO)6 complexes.
The attempts at Lewis acid mediated cyclizations were less straightforward than the best
cases of the 1 → 2 transformation. The use of BF3-OEt2 in cyclization of 3a gave 4a
contaminated with double bond isomer 16a (Equation 2). The use of TiCl4 and SnCl4 gave
successively smaller amounts of impurity 16a, and the use of SnCl4 (3 equiv) in the presence of
i-Pr2NEt (1.5 equiv) afforded 4a (79% yield) devoid of any 16a impurity. Employing analogous
reaction conditions on 3b resulted in the formation of 4b (83%) as the sole isolable product.
SnCl4 (3 equiv),
i-Pr2NEt (1.5 equiv)
(2)
3a,b
( )n
CH2Cl2, 0 oC, 20 min
0.007 M
Co2(CO)6
4a, n = 1, 79%
4b, n = 2, 83%
Co2(CO)6
16a
As an extension to the ability of vinylogous propargyldicobalt cations to undergo
intramolecular Nicholas reaction chemistry, a more stringent test would be to determine whether
7

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the analogous benzylic cations, i.e., 17, could lead to dibenzocycloheptynedicobalt complexes (5
→ 6, Scheme 1). While it is highly unlikely that such cations would have the same stability as
simple propargyldicobalt cations, alkynedicobalt complexes are known as activating groups in
electrophilic aromatic substitution,28 and benzylic cation generation under reasonably mild
conditions has become a subject of recent interest.29
+
EDG
Co2(CO)6
17
For investigation of this possibility, a number of ortho- arylalkynylbenzyl acetates 5a-d
were targeted. Beginning with 2-ethynylbenzaldehyde (Scheme 4), Sonogashira reaction with 3-
iodoanisole then afforded 18a (84% yield), while the use of 1-bromo-3,5-dimethoxybenzene
gave 18b (79% yield). Reduction with DIBAL-H followed by acetylation produced 19a (85%
yield) and 19b (85% yield) from 18a and 18b, respectively. Finally, complexation of 19a and
19b with Co2(CO)8 resulted the production of 5a (94% yield) and 5b (94% yield), respectively.
CHO
OMe
CHO
1) DIBAL-H, THF,
-78 oC
H
R
X
Pd(PPh3)4, CuI,
Et3N-DMF
2) Ac2O, pyridine,
DMAP , -78 oC - rt
R = H, X = I
R = OMe, X = Br
OMe
R
18a, R = H, X = I, 84%
18b, R = OMe, X = Br, 79%
OAc
OAc
Co2(CO)8
CH2Cl2
(OC)6Co2
OMe
OMe
R
R
19a, R = H, 85%
19b, R = OMe, 85%
5a, R = H, 94%
5b, R = OMe, 94%
Scheme 4. Preparation of benzylic acetates complexes.
Substrates with thiophene and furan spacers between the potential acetate leaving group
and the alkynedicobalt complex were prepared in a similar manner, starting with 3-
bromothiophene-2-carbaldehyde or 3-bromofurancarbaldehyde. Desilylative Sonogashira
reactions with 7’d gave 18c (77% yield) and 18d (82% yield) (Scheme 5). DIBAL-H reduction
and acetylation afforded benzylic acetates 19c (93% yield) and 19d (88% yield), and
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complexation of these alkynes with Co2(CO)8 gave 5c (84% yield) and 5d (96% yield),
respectively.
MeO
TBAF, Pd(PPh3)4,
X
CHO
CuI, Et3N-THF
SiMe3
+
Br
MeO
7'c
X
X
CHO
1) DIBAL-H, THF,
-78 oC
OAc
2) Ac2O, pyridine,
DMAP, -78 oC - rt
OMe
OMe
MeO
MeO
18c, X = S, 77%
18d, X = O, 82%
19c, X = S, 93%
19d, X = O, 88%
X
OAc
Co2(CO)8
CH2Cl2
5c, X = S, 84%
5d, X = O, 96%
(OC)6Co 2
OMe
MeO
Scheme 5. Preparation of heterocyclic benzylic acetate complexes.
Initial attempts at the Lewis acid mediated cyclization of 5a were unsuccessful. The use
of BF3-OEt2 (3 equiv, CH2Cl2) gave complete decomposition of the substrate, and the additional
presence of i-Pr2NEt, the use of a Bronsted acid (H2SO4) in place of BF3-OEt2, or the
employment of 1,1,1,3,3,3-hexafluoroisopropanol as solvent did not improve the results.
o
Conversely, the use of SnCl4 as Lewis acid (3 equiv, CH2Cl2, 0 C – rt) induced the conversion
of 5a into 6a (66% yield), as a mixture of regioisomers resulting from reactions para- (6a) and
ortho- (6a’) to the methoxy group (6a:6a’ = 3.7:1) (Scheme 6). Under these conditions, 5b also
transformed into 6b, in moderate yield (51%).
The thienyl- and furyl- analogues 5c,d were also subjected to these reaction conditions,
and underwent starting material consumption somewhat more rapidly. Thienyl substrate 5c gave
tricyclic complex 6c in good yield (73%), but even under these condition the furyl substrate 5d
gave significant amounts of decomposition; nevertheless, a small amount of tricycle 6d (17%
yield) could be isolated.
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R2
6a, R1 = OMe, R2 = H
6a', R1 = H, R2 = OMe
66%, 6a:6a' = 3.7:1
SnCl4 (3 equiv)
CH2Cl2, 0 oC - rt
R1
5a,b
6b, R1 = R2 = OMe,
51%
Co2(CO)6
Me O
SnCl4 (3 equiv)
CH2Cl2, 0 oC
X
OMe
6c, X = S, 73%
6d, X = O, 17%
5c,d
Co2(CO)6
Scheme 6. Intramolecular vinylogous Nicholas reactions of benzylic acetate complexes (5).
Studies on reductive removal of the Co2(CO)6 unit focused on 2d (Scheme 7). The use of
our hydrosilylation-protodesilylation modification3c,d of the Isobe hydrosilylation protocol30 was
o
investigated first. Addition of Et3SiH/bis(trimethylsilylacetylene) (BTMSA) at 65 C, followed
by CF3CO2H at room temperature gave successful removal of the hexacarbonyldicobalt group,
but resulted in overreduction of any initial alkene products and isolation of 20 (81% yield) as a
ca. 1:1 diastereomeric mixture. Separation of the process in the two discrete steps was more
successful, as the Et3SiH/BTMSA/1,2-dichloroethane protocol gave vinylsilane 21 in 86% yield,
as a (94:6) mixture of vinylsilane regioisomers (major shown); subjecting this compound mixture
to CF3CO2H then afforded diene 22 in 97% yield. Alternatively, the use of NaH2PO2-H2O/2-
methoxyethanol31 also gave 22 from 2d in a one pot procedure (76% yield).
Me O
MeO
Et3SiH, BTMSA
21
MeO
ClCH2CH2Cl, 65 o
86%
C
MeO
H
MeO
Et3Si
Co2(CO)6
CF3CO2H,
ClCH2CH2Cl
MeO
2d
97%
H
20
NaH2PO2-H2O
MeO
2d
22
MeOCH2CH2OH, 65 o
76%
C
MeO
Scheme 7. Reductive decomplexation of 2d.
Application of this vinylogous Nicholas reaction chemistry to the synthesis of the
icetexane framework of pisferin essentially originated with gem-
dimethyltetrahydrobenzodioxinone 23, itself prepared by dimethylation of 24.32 Addition of
(trimethylsilyl)ethynyllithium to 23, followed by acidic workup, afforded enynone 25 in 84%
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yield (Scheme 8). Straightforward desilylation (26, 88% yield), followed by Sonogashira
reaction with iodoisopropylanisole 27, gave 28 (70% yield). Alcohol acetylation of 28 gave 29
(94% yield).
SiMe3
O
1) Li
SiMe3
R
O
THF, -78 oC - rt
KF-2H2O
R
OH
2) 3M HCl(aq), THF
DMF, 0 oC
O
24, R = H
23, R = Me
O
25, 84%
MeO
H
27
MeO
I
OH
OH
O
Pd(PPh3)4, CuI,
Et3N-DMF
O
26, 88%
28, 70%
MeO
MeO
Ac2O, pyridine,
DMAP, -78 oC - rt
Co2(CO)6
OAc
OAc
29, 94%
30
O
O
Scheme 8. Preparation of icetexane ring systems precursors.
Attempted Co2(CO)8 based complexation of 29 presumably resulted in the formation of
30, but this material possessed very limited stability and decomposed by the concentration phase
of a typical workup. Attempts at cyclization reactions with either BF3-OEt2, SnCl4 or Bu2BOTf
without isolation and purification of 30 gave in turn material with a limited lifetime. As a result,
we chose to adapt the one pot complexation-Nicholas reaction-decomplexation tactic employed
by the Tyrrell group33 to our needs. Reaction of a slight excess of Co2(CO)8 in CH2Cl2 with 29
o
for 3h was followed by addition of i-Pr2NEt (1.5 equiv) and SnCl4 (3 equiv) at 0 C - rt. When
monitoring by TLC indicated that the presumed 30 had been consumed (15 h), workup and
filtration through a short plug of silica gel, with subsequent reductive decomplexation using
NaH2PO2-H2O in 2-methoxyethanol, gave icetexane framework structure 31 in a modest yield
(28%) (Equation 3).
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O
1) Co2(CO)8, CH2Cl2
OMe
2) i-Pr2NEt (1.5 equiv), SnCl4
(3.0 equiv), CH2Cl2, 0 oC - rt
(3)
30
3) NaH2PO2-H2O (5 equiv),
2-methoxyethanol, 65 oC
31, 28%
Conclusion
In conclusion, we have demonstrated the utility of vinylogous Nicholas reaction chemistry in the
preparation of cycloheptynedicobalt complexes. Arene nucleophiles work well given sufficient
electron richness, affording tricyclic 6,7,x- systems (x = 5,6,7), and allylsilanes also serve as
acceptable nucleophiles to give bicyclic cycloheptynes. In some cases, aromatic spacers may be
used in place of alkene spacers, although the yields are variable. Finally, the icetexane ring
system may be constructed by the chemistry by way of a one pot complexation-Nicholas
reaction-reductive decomplexation protocol, although the steric hindrance imposed by the gem-
dimethyl groups appears to limit the yields in this construction.
Experimental Section
General Methods: All reaction solvents were used after passage through a solvent purification
system. Commercial BF3-OEt2 was distilled and stored under nitrogen. All reactions were
conducted under a nitrogen atmosphere unless otherwise noted. Flash chromatography was
performed as described by Still using silica gel 60 (230-400 mesh).34 All new compounds are
>95% purity as determined by 1H and 13C NMR spectroscopy. NMR spectra were run on Bruker
Avance 500 or 300 spectrometers at 500 MHz or 300 MHz for 1H and 125 MHz or 75 MHz for
13C in CDCl3 unless otherwise stated; chemical shifts are given in ppm and coupling constants
(J) are given in Hz. High resolution mass spectra were run on a Waters/Micromass GCT (time of
flight) mass spectrometer, in EI mode, at 70 eV.
2-(Phenylethynyl)cyclopent-1-enecarbaldehyde (9a)
General Procedure A: To a mixture of Pd(PPh3)4 (0.1699 g, 0.147 mmol, 3 mol%) and CuI
(0.0467 g, 0.245 mmol, 5 mol%) was added a solution of 2-bromocyclopent-1-ene-1-
carbaldehyde (8a)35 (1.2860 g, 7.3496 mmol) in DMF (5 mL), followed by a solution of
phenylacetylene (7a) (0.5000 g, 4.900 mmol) in DMF (5 mL). Triethylamine (32 mL) was
o
added, and the reaction mixture stirred at 75 C for 20 h. The mixture was filtered through
Celite® and subjected to a conventional extractive workup (Et2O). Compound 9a was isolated by
1
preparative TLC (25:1 hexanes:Et2O) as a yellow oil (0.6907 g, 3.522 mmol, 72%). H-NMR
(500 MHz, CDCl3): 10.16 (s, 1H), 7.49 (apparent dd, 2H, J = 7.6, J = 1.8), 7.33-7.38 (m, 3H),
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13
2.79 (t, 2H, J = 7.9), 2.64 (t, 2H, J = 7.9), 1.98 (apparent pentet, 2H, J = 7.9); C-NMR (75
MHz, CDCl3): 188.9, 148.1, 143.2, 132.0, 129.5, 128.7, 122.2, 100.8, 83.4, 39.1, 29.8, 22.3; IR
(KBr): 3312, 3081, 2969, 2850, 2811, 2722, 2199, 1676, 1353; HRMS: m/e for C14H12O
calculated 196.0888 (M+), found 196.0883.
2-[(3-Methoxyphenyl)ethynyl]cyclohex-1-enecarbaldehyde (9c)
Compound 9c was synthesized according to General Procedure A from 7b36 (0.4596 g, 3.480
mmol) and 2-bromocyclohex-1-ene-1-carbaldehyde 8b (0.9918 g, 5.220 mmol). The product
was isolated as a yellow oil (0.6204 g, 2.584 mmol, 74%) via preparative TLC (20:1
1
hexanes:Et2O). H-NMR (500 MHz, CDCl3): 10.32 (s, 1H), 7.26 (apparent t, 1H, J = 8.0), 7.07
(d of t, 1H, J = 7.6, J = 1.2), 6.99 (dd, 1H, J = 2.5, J = 1.4), 6.93 (ddd, 1H, J = 8.3, J = 2.6, J =
0.9), 3.82 (s, 3H), 2.50-2.53 (m, 2H), 2.30-2.33 (m, 2H), 1.66-1.75 (m, 4H); 13C-NMR (75 MHz,
CDCl3): 193.0, 159.5, 142.8, 140.0, 129.7, 124.3, 123.4, 116.4, 115.9, 98.6, 86.2, 55.4, 32.4,
22.2, 22.0, 21.2; IR (KBr): 2937, 2835, 2194, 1673, 1212; HRMS: m/e for C16H16O2 calculated
240.1150 (M+), found 240.1158.
2-[(3,5-Dimethoxyphenyl)ethynyl]cyclopent-1-enecarbaldehyde (9e)
General Procedure B. To a mixture of Pd(PPh3)4 (0.1552 g, 0.1344 mmol, 3 mol%) and CuI
(0.0427 g, 0.224 mmol, 5 mol%) was added 2-bromocyclopent-1-ene-1-carbaldehyde (8a)
(1.1764 g, 6.7213 mmol) in THF (7.5 mL), followed by compound 7’d37 (1.0490 g, 4.4808
mmol) in THF (7.5 mL). After triethylamine (30 mL) was added, the mixture was cooled to 0 oC
and tetra-n-butylammonium fluoride (TBAF) (1.0 M in THF, 9.0 mL, 9.0 mmol) was added.
o
After stirring for 10 min, the mixture was warmed to 75 C for 20 h. The reaction was filtered
through Celite® and subjected to a conventional extractive workup (Et2O). The product 9e was
isolated as a pale yellow solid (1.0474 g, 4.0896 mmol, 91%) following flash chromatography
1
(10:1 hexanes:Et2O). mp. 120-122 oC; H-NMR (300 MHz, CDCl3): 10.16 (s, 1H), 6.64 (d, 2H,
J = 2.3), 6.50 (apparent t, 1H, J = 2.3), 3.79 (s, 6H), 2.80 (t, 2H, J = 7.6), 2.65 (t, 2H, J = 7.6),
2.00 (apparent pentet, 2H, J = 7.6); 13C-NMR (75 MHz, CDCl3): 188.9, 160.7, 148.2, 143.0,
123.3, 109.6, 102.9, 100.9, 82.8, 55.5, 38.9, 29.7, 22.2; IR (KBr): 3080, 2995, 2936, 2838, 2190,
1669, 1587, 1156; HRMS: m/e for C16H16O3 calculated 256.1099 (M+), found 256.1096.
[2-(Phenylethynyl)cyclopent-1-enyl]methyl acetate (10a)
o
General Procedure C. To a -78 C solution of compound 9a (0.5077 g, 2.589 mmol) in THF
(30 mL) was added DIBAL-H (1.0 M in THF, 5.2 mL, 5.2 mmol) in a dropwise fashion. After 1
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h at -78 oC, pyridine (6.2 mL, 78 mmol) was added, followed by acetic anhydride (12.2 mL, 130
mmol) and DMAP (1.577 g, 12.9 mmol). The reaction was allowed to warm to room temperature
for 20 h. NH4Cl (aq, sat) was added and the mixture subjected to a conventional extractive
workup (Et2O). Product 10a was isolated by preparative TLC (15:1 hexanes:Et2O) as a yellow
1
oil (0.5531 g, 2.303 mmol, 89%). H-NMR (500 MHz, CDCl3): 7.45 (apparent dd, 2H, J = 6.5, J
= 3.1), 7.31-7.33 (m, 3H), 4.89 (s, 2H), 2.63 (t, 2H, J = 7.7), 2.52 (t, 2H, J = 7.9), 2.10 (s, 3H),
1.97 (apparent pentet, 2H, J = 7.7); 13C-NMR (75 MHz, CDCl3): 171.2, 144.8, 131.6, 128.4,
128.3, 123.4, 123.1, 95.0, 84.7, 62.1, 37.1, 34.2, 22.5, 21.0; IR (KBr): 2960, 2852, 1743, 1225;
HRMS: m/e for C16H16O2 calculated 240.1150 (M+), found 240.1145.
[2-((3-Methoxyphenyl)ethynyl)cyclohex-1-enyl]methyl acetate (10c)
Compound 9c (0.6204 g, 2.584 mmol) was subjected to General Procedure C. The product 10c
was isolated as a pale yellow oil (0.6542 g, 2.302 mmol, 89%) via preparative TLC (10:1
1
hexanes:Et2O). H-NMR (500 MHz, CDCl3): 7.22 (apparent t, 1H, J = 8.0), 7.03 (d of t, 1H, J =
7.6, J = 1.0), 6.96 (dd, 1H, J = 2.4, J = 1.4), 6.86 (ddd, 1H, J = 8.4, J = 2.6, J = 0.7), 4.90 (s, 2H),
13
3.81 (s, 3H), 2.31 (m, 2H), 2.17 (m, 2H), 2.10 (s, 3H), 1.65-1.71 (m, 4H); C-NMR (75 MHz,
CDCl3): 171.3, 159.4, 139.3, 129.4, 124.5, 124.1, 120.0, 116.2, 114.9, 93.1, 88.0, 66.6, 55.4,
30.3, 27.2, 22.2, 22.1, 21.1; IR (KBr): 3002, 2935, 2861, 2198, 1738, 1596, 1230; HRMS: m/e
for C18H20O3 calculated 284.1412 (M+), found 284.1415.
Hexacarbonyl[μ-η4(2-(Phenylethynyl)cyclopent-1-enyl]methyl acetate)]dicobalt (1a)
General Procedure D. Compound 10a (0.5067 g, 2.110 mmol) and dicobalt octacarbonyl
(excess) were dissolved in dry CH2Cl2 (25 mL). The mixture was allowed to stir at room
temperature, for 2 h. The solvent was then removed under reduced pressure, and the solid loaded
onto a column of silica. The column was washed with 100% hexanes to remove excess,
uncomplexed dicobalt octacarbonyl. Subsequently, elution with 15:1 hexanes:Et2O afforded
1
product 1a, which was isolated as a dark brown solid (1.002 g, 1.9051 mmol, 90%). H-NMR
(500 MHz, CDCl3): 7.44-7.47 (m, 2H), 7.30-7.37 (m, 3H), 4.63 (s, 2H), 2.79 (t, 2H, J = 7.8),
2.56 (t, 2H, J = 7.9), 2.03 (apparent pentet, 2H, J = 7.9), 2.00 (s, 3H); 13C-NMR (75 MHz,
CDCl3): 199.4, 170.8, 138.5, 137.6, 137.2, 129.3, 128.9, 127.9, 93.1, 84.7, 61.2, 39.9, 36.3, 21.9,
20.9; IR (KBr): 3077, 2957, 2848, 2089, 2050, 2021, 1745, 1231; HRMS: m/e for C22H16Co2O8
calculated 497.9560 (M-CO+), found 497.9552.
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Hexacarbonyl[μ-η4(2-((3-methoxyphenyl)ethynyl)cyclohex-1-enyl]methyl acetate)]dicobalt
(1c)
Compound 10c (0.6542 g, 2.302 mmol) was subjected to complexation as outlined in General
Procedure D. The complexed product 1c was isolated as a dark brown solid (1.2123 g, 2.1269
mmol, 92%) by flash chromatography (10:1 hexanes:Et2O), after washing through excess,
1
uncomplexed Co2(CO)8 with 100% hexanes. H-NMR (500 MHz, CDCl3): 7.26 (t, 1H, J = 7.9),
7.01 (apparent ddd, 1H, J = 7.6, J = 1.6, J = 0.9), 6.95 (dd, 1H, J = 2.4, J = 1.7), 6.85 (ddd, 1H, J
= 8.3, J = 2.6, J = 0.9), 4.55 (s, 2H), 3.83 (s, 3H), 2.38 (t, 2H, J = 6.0), 2.13 (t, 2H, J = 6.1), 1.97
(s, 3H), 1.72-1.79 (m, 4H); 13C-NMR (75 MHz, CDCl3): 199.6, 170.9, 159.6, 140.2, 133.5,
132.0, 129.8, 122.0, 115.2, 113.0, 93.5, 91.7, 65.3, 55.3, 33.3, 28.5, 23.4, 22.2, 20.8; IR (KBr):
2088, 2049, 2019, 1742, 1230; HRMS: m/e for C24H20Co2O9 calculated 430.0026 (M-5CO+),
found 430.0021.
Hexacarbonyl[μ-η4([2-((3,5-dimethoxyphenyl)ethynyl)cyclopent-1-enylmethyl
acetate)]dicobalt (1e)
Compound 10e (1.0852 g, 3.6157 mmol) was subjected to complexation according to General
Procedure D. The complexed compound 1e was isolated via flash chromatography (5:1
hexanes:Et2O) following removal of excess, uncomplexed Co2(CO)8 with 100% hexanes. The
1
product was isolated as a dark brown solid (1.8212 g, 3.1080 mmol, 86%). H-NMR (500 MHz,
CDCl3): 6.62 (d, 2H, J = 2.2), 6.42 (t, 1H, J = 2.1), 4.67 (s, 2H), 3.81 (s, 6H), 2.79 (t, 2H, J =
13
7.8), 2.55 (t, 2H, J = 7.9), 2.02 (apparent pentet, 2H, J = 7.9), 2.02 (s, 3H); C-NMR (75 MHz,
CDCl3): 199.9, 170.8, 160.8, 140.5, 137.7, 137.1, 107.6, 99.9, 93.1, 84.6, 61.1, 55.4, 39.8, 36.3,
21.9, 20.7; IR (Pt/diamond ATR): 3020, 2977, 2838, 2087, 2046, 2005, 1989, 1734, 1586, 1205;
HRMS: m/e for C24H20Co2O10 calculated 473.9925 (M-4CO+), found 473.9930.
Hexacarbonyl[μ-η4-((10,11-η:10,11-η)-2,3,4,5-tetrahydro-8-methoxy-1H-
dibenzo[a,d]cycloheptene)]dicobalt (2c) and Hexacarbonyl[μ-η4-((10,11-η:10,11-η)-2,3,4,5-
tetrahydro-6-methoxy-1H-dibenzo[a,d]cycloheptene)]dicobalt (2c')
General Procedure E. To a solution of complexed compound 1c (0.0322 g, 0.0565 mmol) in
CH2Cl2 (8 mL, 7 x 10-3 M) at 0 oC was added BF3-OEt2 (21 μL, 0.17 mmol). After 1.5 h, starting
material consumption was complete and the reaction was subjected to a conventional extractive
workup (CH2Cl2). The product regioisomers were separable by flash chromatography using
100% hexanes. The major product 2c (0.0195 g, 0.0382 mmol, 68%) eluted as the second band,
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1
and as a dark maroon solid. H-NMR (500 MHz, CDCl3): 7.20 (d, 1H, J = 2.7), 7.04 (d, 1H, J =
8.3), 6.84 (dd, 1H, J = 8.4, J = 2.7), 3.58 (s, 3H), 3.20 (s, 2H), 2.36 (t, 2H, J = 5.8), 2.28 (t, 2H, J
= 6.0), 1.67-1.78 (m, 4H); 13C-NMR (75 MHz, CDCl3): 200.0, 159.0, 139.0, 137.2, 130.1, 129.9,
129.3, 117.4, 113.6, 94.9, 89.5, 55.3, 42.1, 33.7, 30.5, 23.0, 22.7; IR (KBr): 2930, 2086, 2046,
2017, 1270; HRMS: m/e for C22H16Co2O7 calculated 481.9625 (M-CO+), found 481.9634.
Compound 2c' eluted as the first band, as a dark maroon solid, and as the minor product (0.0040
g, 0.0078 mmol, 14%). The product ratio of major:minor 2c:2c’ (i.e., para attack:ortho attack)
1
was 4.9:1, with a combined yield of 82%. H-NMR (500 MHz, CDCl3): 7.28 (dd, 1H, J = 7.9, J
= 1.2), 7.23 (apparent t, 1H, J = 7.8), 6.90 (dd, 1H, J = 8.0, J = 1.1), 3.87 (s, 3H), 3.33 (s, 2H),
13
2.31-2.35 (m, 4H), 1.67-1.77 (m, 4H); C-NMR (75 MHz, CDCl3): 200.2, 155.9, 139.6, 137.7,
130.9, 127.6, 125.4, 124.8, 110.7, 95.2, 90.0, 56.0, 33.8, 32.3, 30.5, 23.1, 22.8; IR (KBr): 2933,
2086, 2046, 2017, 1570, 1262; HRMS: m/e for C22H16Co2O7 calculated 481.9611 (M-CO+),
found 481.9624.
Hexacarbonyl[μ-η4-(9,10-didehydro-5,7-dimethoxy-1,2,3,4-
tetrahydrobenzo[f]azulene)]dicobalt (2e)
Compound 1e (0.1874 g, 0.3198 mmol) was reacted according to General Procedure E using
BF3-OEt2 (121 μL, 0.959 mmol). The reaction was complete within 45 minutes, as assessed by
TLC analysis. The cyclized product (2e) was isolated by flash chromatography (15:1
1
hexanes:Et2O) as a maroon solid (0.1433 g, 0.2724 mmol, 85%). H-NMR (500 MHz, CDCl3):
6.82 (d, 1H, J = 2.2), 6.48 (d, 1H, J = 2.4), 3.85 (s, 3H), 3.83 (s, 3H), 3.50 (s, 2H), 2.71 (t, 2H, J
13
= 7.6), 2.54 (t, 2H, J = 7.7), 2.05 (apparent pentet, 2H, J = 7.6); C-NMR (75 MHz, CDCl3):
199.8, 159.3, 157.3, 142.4, 139.6, 134.6, 116.3, 109.3, 99.0, 91.0, 87.8, 55.9, 55.4, 39.4, 35.4,
27.1, 22.6; IR (KBr): 3004, 2956, 2838, 2087, 2047, 2016, 1600, 1458, 1141; HRMS: m/e for
C22H16Co2O8 calculated 525.9509 (M+), found 525.9510.
Hexacarbonyl[μ–η4-(10,11-didehydro-2,3,4,5-tetrahydro-7-methoxy-1H-
dibenzo[a,d]cycloheptene)]dicobalt (2f)
Compound 1f (see Supporting Information) (0.0783 g, 0.130 mmol) was reacted according to
General Procedure E using BF3-OEt2 (50 μL, 0.39 mmol). The reaction was complete within 45
minutes, as assessed by TLC analysis. The cyclized product (2f) was isolated by flash
1
chromatography (15:1 hexanes:Et2O) as a maroon solid (0.0601 g, 0.111 mmol, 85%). H-NMR
(500 MHz, CDCl3): 6.80 (d, 1H, J = 2.2), 6.49 (d, 1H, J = 2.1), 3.84 (s, 3H), 3.83 (s, 3H), 3.25 (s,
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13
2H), 2.30-2.34 (m, 4H), 1.66-1.78 (m, 4H); C-NMR (125 MHz, CDCl3): 200.0, 159.2, 156.7,
140.1, 138.2, 130.5, 118.2, 108.0, 98.8, 95.2, 90.4, 55.9, 55.4, 33.7, 31.8, 30.4, 23.0, 22.8; IR
(KBr): 3020, 2086, 2046, 2015, 1600, 1279; HRMS: m/e for C23H18Co2O8 calculated 539.9666
(M+), found 539.9669.
Hexacarbonyl[μ-η4-((10,11-η:10,11-η)-10,11-didehydro-2,3,4,5-tetrahydro-6,9-dimethoxy-
1H-dibenzo[a,d]cycloheptene)] dicobalt (2h)
Compound 1h (see Supporting Information) (0.3248 g, 0.5413 mmol) was reacted according to
General Procedure E using BF3-OEt2 (206 μL, 1.62 mmol). The reaction was complete after 1 h,
as assessed by TLC analysis. The cyclized product (2h) was isolated by flash chromatography
(15:1 hexanes:Et2O) as a maroon solid (0.2405 g, 0.4454 mmol, 82%). 1H-NMR (500 MHz,
CDCl3): 6.92 (d, 1H, J = 9.0), 6.74 (d, 1H, J = 9.0), 3.87 (s, 3H), 3.82 (s, 3H), 3.34 (s, 2H), 2.30-
2.36 (m, 4H), 1.73-1.78 (m, 2H), 1.66-1.71 (m, 2H); 13C-NMR (125 MHz, CDCl3): 200.4, 154.0,
150.3, 136.3, 131.5, 127.4, 126.6, 112.2, 108.7, 96.0, 84.8, 56.7, 54.7, 33.6, 32.8, 30.5, 23.1,
22.9; IR (KBr): 2924, 2850, 2085, 2046, 2026, 1739, 1463, 1261; HRMS: m/e for C23H18Co2O8
calculated 539.9666 (M+), found 539.9669.
[2-((Trimethylsilyl)ethynyl)cyclohex-1-enyl]methyl acetate (13a)
Compound 12a38 (1.4485 g, 7.0277 mmol) was subjected to General Procedure C. The product
was isolated as a pale yellow oil (1.6033 g, 6.4096 mmol, 91%) via flash chromatography (10:1
1
hexanes:Et2O). H-NMR (500 MHz, C6D6): 4.94 (s, 2H), 2.08 (t, 2H, J = 6.1), 1.91 (t, 2H, J =
13
6.1), 1.66 (s, 3H), 1.26-1.33 (m, 4H), -0.15 (s, 9H); C-NMR (75 MHz, C6D6): 169.6, 140.5,
119.7, 104.5, 97.7, 66.0, 29.9, 26.7, 21.9, 21.8, 20.1, -0.2; IR (ATR): 2933, 2861, 2140, 1741,
1366, 1227; HRMS: m/e for C14H22O2Si calculated 250.1389 (M+), found 250.1386.
(2-Ethynylcyclohex-1-enyl)methyl acetate (14a)
General Procedure F. To a 0 oC solution of compound 13a (1.6033 g, 6.4096 mmol) in DMF (5
mL) was added KF-2H2O (0.7843 g, 8.332 mmol, 1.3 equiv). The mixture was allowed to warm
to room temperature over 2 h at which point, TLC analysis showed the desilylation to be
complete. The mixture was filtered and the filtrate was subjected to a conventional extractive
workup (Et2O). Compound 14a was isolated as a yellow oil (1.0047 g, 5.6412 mmol, 88%)
1
following flash chromatography (10:1 hexanes:Et2O). H-NMR (500 MHz, C6D6): 4.84 (s, 2H),
13
2.98 (s, 1H), 2.03 (t, 2H, J = 6.0), 1.89 (t, 2H, J = 6.0), 1.70 (s, 3H), 1.26-1.33 (m, 4H); C-
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NMR (75 MHz, C6D6): 169.8, 140.7, 118.7, 82.4, 81.4, 65.9, 29.9, 26.6, 21.8, 21.7, 20.1; IR
(ATR): 3286, 2932, 2861, 1736, 1366, 1227; HRMS: m/e for C11H14O2 calculated 178.0994
(M+), found 178.0998.
[2-(3-((Trimethylsilyl)methyl)but-3-en-1-ynyl)cyclohex-1-enyl]methyl acetate (15a)
Compound 14a (1.0047 g, 5.6412 mmol) was subjected to Sonogashira conditions according to
General Procedure A with 2-bromo-3-(trimethylsilyl)-1-propene39 (1.8413 g, 9.5901 mmol). The
coupled compound 15a was isolated as a yellow oil (1.4095 g, 4.8575 mmol, 86%) using flash
1
chromatography (10:1 hexanes:Et2O). H-NMR (500 MHz, CDCl3): 5.15 (d, 1H, J = 2.0), 4.98
(m, 1H), 4.77 (s, 2H), 2.18 (m, 2H), 2.10 (m, 2H), 2.05 (s, 3H), 1.66 (s, 2H), 1.58-1.65 (m, 4H),
13
0.04 (s, 9H); C-NMR (125 MHz, CDCl3): 171.0, 138.3, 128.8, 120.1, 118.6, 95.3, 87.0, 66.5,
30.1, 28.3, 26.9, 22.1, 22.0, 20.9, -1.6; IR (KBr): 2934, 2894, 2862, 2195, 1743, 1594, 1376,
1232; HRMS: m/e for C17H26O2Si calculated 290.1702 (M+), found 290.1708.
Hexacarbonyl[μ-η4-(2-(3-((trimethylsilyl)methyl)but-3-en-1-ynyl)cyclohex-1-enyl)methyl
acetate)]dicobalt (3a)
General Procedure G. Compound 15a (1.4095 g, 4.8575 mmol) was dissolved in Et2O (dry)
(56.2 mL) along with excess Co2(CO)8. The solution was cooled to 0 oC, and allowed to stir for
1 h at that temperature under a nitrogen atmosphere. Following the hour, the solvent was
removed under reduced pressure, and the residue was loaded onto a flash chromatographic
column containing neutralized silica. The complexed compound (3a) was isolated by first
washing the column with 100% hexanes to remove any excess, uncomplexed Co2(CO)8,
followed by 10:1 hexanes:Et2O to elute the product as a maroon solid (2.5800 g, 4.4791 mmol,
1
92%). H-NMR (500 MHz, C6D6): 5.41 (s, 1H), 5.17 (s, 1H), 4.92 (s, 2H), 2.35 (t, 2H, J = 5.9),
1.98 (t, 2H, J = 6.1), 1.85 (s, 2H), 1.70 (s, 3H), 1.44-1.49 (m, 2H), 1.34-1.39 (m, 2H), 0.07 (s,
9H); 13C-NMR (75 MHz, C6D6): 200.0, 169.8, 144.1, 133.8, 131.4, 116.0, 100.0, 93.9, 65.0,
33.4, 28.1, 26.8, 23.2, 22.0, 20.1, -1.1; IR (KBr): 2938, 2863, 2087, 2048, 2020, 1744, 1607,
1377, 1231; HRMS: m/e for C23H26Co2O8Si calculated 408.0366 (M+-6CO), found 408.0363.
Hexacarbonyl[μ-η4-(8,9-dehydro-2,3,4,5,6,7-hexahydro-7-methylene-1H-
benzo[7]annulene)]dicobalt (4a)
General Procedure H. Complexed compound 3a (0.1836 g, 0.3187 mmol) was placed in a
round bottom flask, and placed under vacuum for 5 minutes. The flask was then purged with
nitrogen. This was repeated two times more. Dry CH2Cl2 (45.5 mL) was added to the reaction
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flask, and the solution was cooled to 0 oC. N,N-Diisopropylethylamine (83 μL, 0.48 mmol) was
added to the solution, followed by the dropwise addition of SnCl4 (112 μL, 0.956 mmol). The
reaction was allowed to stir for 20 minutes under nitrogen, at which point TLC analysis showed
complete starting material consumption. NH4Cl (aq, sat) was added, and the mixture was
subjected to a conventional extractive workup (CH2Cl2). Flash chromatography on neutralized
silica using 100% hexanes eluted compound 4a (0.1115 g, 0.2512 mmol, 79%) as a maroon
1
solid. H-NMR (300 MHz, C6D6): 5.63-5.64 (m, 1H), 5.24 (apparent q, 1H, J = 1.3), 2.34-2.38
(m, 2H), 2.27-2.30 (m, 2H), 1.99-2.02 (m, 2H), 1.68-1.72 (m, 2H), 1.42-1.50 (m, 2H), 1.30-1.39
13
(m, 2H); C-NMR (75 MHz, C6D6): 200.3, 147.7, 140.5, 128.4, 118.9, 94.2, 89.1, 35.9, 33.7,
33.2, 30.2, 22.9, 22.6; IR (KBr): 2933, 2863, 2087, 2053, 1612, 1432, 1237; HRMS: m/e for
C18H14Co2O6 calculated 415.9505 (M-CO+), found 415.9513.
2-[(Methoxyphenyl)ethynyl]benzyl acetate (19a)
Compound 18a (0.8583 g, 3.646 mmol) was subjected to General Procedure C. Flash
chromatography (15:1 hexanes:Et2O) afforded compound 19a as a pale yellow oil (0.8677 g,
1
3.098 mmol, 85%). H-NMR (500 MHz, CDCl3): 7.59 (dd, 1H, J = 7.4, J = 1.6), 7.44 (dd, 1H, J
= 7.3, J = 1.2), 7.31-7.37 (m, 2H), 7.72 (apparent t, 1H, J = 8.0), 7.18 (d of apparent t, 1H, J =
7.6, J = 1.2), 7.11-7.12 (m, 1H), 6.92 (ddd, 1H, J = 8.3, J = 2.6, J = 1.0), 5.40 (s, 2H), 3.81 (s,
13
3H), 2.13 (s, 3H); C-NMR (75 MHz, CDCl3): 170.8, 159.5, 137.6, 132.3, 129.6, 128.6, 128.5,
128.2, 124.2, 124.1, 122.7, 116.4, 115.2, 94.4, 86.5, 64.8, 55.3, 21.0; IR (ATR): 3002, 2938,
1737, 1573, 1492; HRMS: m/e for C18H16O3 calculated 280.1099 (M+), found 280.1100.
Hexacarbonyl[μ-η4-(2-((methoxyphenyl)ethynyl)benzyl acetate)]dicobalt (5a)
Compound 19a (0.8677 g, 3.098 mmol) was subjected to General Procedure D. Following flash
chromatography (15:1 hexanes:Et2O) compound 5a was isolated as a dark brown solid (1.6404 g,
1
2.8985 mmol, 94%). H-NMR (500 MHz, CDCl3): 7.67 (dd, 1H, J = 7.8, J = 1.4), 7.43 (dd, 1H,
J = 7.4, J = 1.4), 7.34-7.40 (m, 2H), 7.30 (apparent t, 1H, J = 8.0), 7.07 (ddd, 1H, J = 7.6, J = 1.6,
J = 0.9), 7.01-7.02 (m, 1H), 6.91 (ddd, 1H, J = 8.2, J = 2.5, J = 0.9), 5.13 (s, 2H), 3.83 (s, 3H),
2.04 (s, 3H); 13C-NMR (125 MHz, CDCl3): 199.1, 170.5, 159.8, 140.0, 136.1, 134.5, 132.4,
129.9, 129.6, 128.8, 128.4, 121.8, 115.0, 113.4, 95.0, 88.9, 63.6, 55.2, 20.8; IR (ATR): 3019,
2905, 2087, 2048, 2010, 1993, 1748, 1584, 1231; HRMS: m/e for C24H16Co2O9 calculated
509.9560 (M-2CO+), found 509.9543.
3-[(3,5-Dimethoxyphenyl)ethynyl]thiophene-2-carbaldehyde (18c)
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[(3,5-Dimethoxyphenyl)ethynyl]trimethylsilane 7’d (0.7501 g, 3.204 mmol) was subjected to
tandem desilylation/Sonogashira chemistry according to General Procedure B with 3-
bromothiophene-2-carbaldehyde (1.0648 g, 5.6071 mmol), with the exception that the reaction
was warmed to rt. The product 18c was isolated via flash chromatography (7:1 hexanes:Et2O) as
o
1
a colourless solid (0.6715 g, 2.468 mmol, 77%). mp. 94.5-95 C; H-NMR (300 MHz, CDCl3):
10.21 (d, 1H, J = 0.7), 7.67 (dd, 1H, J = 0.7, J = 5.0), 7.23 (d, 1H, J = 5.0), 6.68 (d, 2H, J = 2.3),
6.50 (t, 1H, J = 2.2), 3.79 (s, 6H); 13C-NMR (75 MHz, CDCl3): 183.0, 160.7, 143.7, 134.0,
131.6, 130.8, 123.2, 109.6, 102.7, 96.2, 81.1, 55.5; IR (ATR): 3008, 2964, 2835, 2209, 1659,
1585, 1203; HRMS: m/e for C15H12O3S calculated 272.0507 (M+), found 272.0512.
[3-((3,5-Dimethoxyphenyl)ethynyl)thiophen-2-yl]methyl acetate (19c)
Compound 18c (0.6715 g, 2.468 mmol) was reduced and acetylated according to General
Procedure C. The product 19c was isolated as a yellow oil (0.7250 g, 2.294 mmol, 93%) using
1
flash chromatography (5:1 hexanes:Et2O). H-NMR (500 MHz, CDCl3): 7.29 (d, 1H, J = 5.0),
13
7.12 (d, 1H, J = 5.0), 6.69 (m, 2H), 6.48 (m, 1H), 5.42 (s, 2H), 3.81 (s, 6H), 2.12 (s, 3H); C-
NMR (125 MHz, CDCl3): 170.7, 160.6, 140.5, 129.7, 125.8, 124.2, 122.4, 109.3, 101.9, 92.9,
82.3, 59.4, 55.4, 20.9; IR (ATR): 3000, 2838, 1736, 1586, 1419, 1155; HRMS: m/e for
C17H16O4S calculated 316.0769 (M+), found 316.0756.
Hexacarbonyl[μ-η4-(3-((3,5-dimethoxyphenyl)ethynyl)thiophen-2-ylmethyl
acetate)]dicobalt (5c)
Compound 19c (0.7250 g, 2.294 mmol) was subjected to complexation according to General
Procedure D. The product 5c was isolated as a dark brown solid (1.1616 g, 1.9298 mmol, 84%)
using flash chromatography (5:1 hexanes:Et2O), after removing excess, uncomplexed Co2(CO)8
1
with 100% hexanes. H-NMR (500 MHz, CDCl3): 7.31 (d, 1H, J = 5.2), 7.15 (d, 1H, J = 5.2),
6.67 (d, 2H, J = 2.3), 6.46 (t, 1H, J = 2.2), 5.23 (s, 2H), 3.80 (s, 6H), 2.03 (s, 3H); 13C-NMR (125
MHz, CDCl3): 199.0, 170.5, 160.9, 140.3, 136.5, 134.9, 130.5, 126.1, 107.5, 99.9, 93.3, 82.4,
58.6, 55.3, 20.6; IR (ATR): 2966, 2840, 2086, 2044, 1990, 1741, 1579, 1227; HRMS: m/e for
C23H16Co2O10S calculated 517.9281 (M-3CO+), found 517.9290.
Hexacarbonyl[μ-η4-(10,11-dehydro-2-methoxy-5H-dibenzo[a,d]cycloheptene)]dicobalt (6a)
and
Hexacarbonyl[μ-(10,11-dehydro4-methoxy-5H-dibenzo[a,d]cycloheptene)]dicobalt
(6a')
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Compound 5a (0.2279 g, 0.4027 mmol) was reacted according to General Procedure E, using
SnCl4 (141 μL, 1.21 mmol). The reaction mixture was allowed to warm to room temperature
over the course of 15 h, at which point the reaction was complete (as determined by TLC). Flash
chromatography (15:1 hexanes:Et2O) on neutralized silica afforded compound 6a as the major
product (and the second band on the column) as a dark maroon solid (0.1060 g, 0.2095 mmol,
1
52%). H-NMR (500 MHz, CDCl3): 7.69-7.71 (m, 1H), 7.32-7.36 (m, 2H), 7.27-7.31 (m, 1H),
7.26 (d, 1H, J = 2.8), 7.22 (d, 1H, J = 8.6), 6.89 (dd, 1H, J = 8.5, J = 2.8), 3.87 (s, 2H), 3.86 (s,
3H); 13C-NMR (75 MHz, CDCl3): 199.4, 159.2, 138.4, 137.7, 137.1, 132.1, 130.4, 130.0, 129.3,
128.6, 127.7, 117.4, 113.8, 90.8, 55.3, 42.1; IR (ATR): 2942, 2843, 2087, 2048, 2034, 2019,
1995, 1270; HRMS: m/e for C22H12Co2O7 calculated 449.9349 (M-2CO+), found 449.9361.
Compound 6a' was isolated as the minor product (and the first band off the column) as a dark
maroon solid (0.0286 g, 0.0565 mmol, 14%). The combined yield was 66%, with a 3.7:1
1
para:ortho attack (i.e., major:minor products). H-NMR (500 MHz, CDCl3): 7.68-7.70 (m, 1H),
7.36-7.38 (m, 1H), 7.32-7.34 (m, 3H), 7.29 (apparent t, 1H, J = 8.0), 6.94 (d, 1H, J = 8.3), 4.01
(s, 2H), 3.92 (s, 3H); 13C-NMR (75 MHz, CDCl3): 199.6, 156.3, 138.8, 137.7, 137.6, 131.9,
129.9, 128.6, 127.9, 127.6, 125.7, 124.6, 111.1, 91.2, 90.8, 56.1, 32.2; IR (ATR): 2920, 2839,
2091, 2047, 2018, 2002, 1568, 1254; HRMS: m/e for C22H12Co2O7 calculated 477.9298 (M-
CO+), found 477.9301.
Hexacarbonyl[μ-η4-(4,5-dehydro-7,9-dimethoxy-10H-benzo[5,6]cyclohepta[1,2-b]
thiophene)]dicobalt (6c)
Compound 5c (0.1291 g, 0.2145 mmol) was subjected to Nicholas reaction chemistry according
to General Procedure E, using SnCl4 (75 μL, 0.64 mmol). The reaction was complete after 10
minutes, as determined by TLC, and the product (6c) was isolated as a dark maroon solid
1
(0.0851 g, 0.157 mmol, 73%) using flash chromatography (15:1 hexanes:Et2O). H-NMR (500
MHz, CDCl3): 7.24 (½ ABq, 1H, J = 13.7), 7.18 (½ ABq, 1H, J = 5.4), 6.86 (d, 1H, J = 2.6), 6.53
13
(d, 1H, J = 2.6), 4.11 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H); C-NMR (75 MHz, CDCl3): 199.5,
159.7, 157.1, 134.0, 137.4, 135.8, 129.4, 123.8, 116.0, 109.4, 99.1, 91.2, 84.6, 56.1, 55.4, 25.0;
IR (ATR): 2963, 2832, 2086, 2035, 2004, 1567, 1210; HRMS: m/e for C21H12Co2O8S calculated
513.8968 (M-CO+), found 513.8949.
2,3,4,5-Tetrahydro-7,8-dimethoxy-10-triethylsilyl-1H-dibenzo[a,d]cycloheptene (21)
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To a stirred solution of compound 2d (0.1437 g, 0.2661 mmol) dissolved in degassed 1,2-
dichloroethane (4.1 mL) was added bis(trimethylsilyl)acetylene (121 μL, 0.532 mmol) and
o
triethylsilane (213μL, 1.33 mmol). The reaction was placed in an oil bath set at 65 C, and
allowed to stir for 6 h under a nitrogen atmosphere. Following the 6 h, the reaction was cooled,
dissolved in Et2O (75 mL) and subjected to a conventional extractive workup (Et2O).
Preparative TLC (15:1 hexanes:Et2O) afforded compound 21 as the major isomer, and as a
o
colourless solid (0.0862 g, 0.233 mmol, 86% combined yield). mp. 95-97 C; 1H-NMR (500
MHz, CDCl3): 6.88 (s, 1H), 6.62 (s, 1H), 6.52 (s, 1H), 3.90 (s, 3H), 3.87 (s, 3H), 2.76 (s, 2H),
2.33 (m, 2H), 2.08 (m, 2H), 1.60 (m, 4H), 0.96 (t, 9H, J = 7.8), 0.78 (q, 6H, J = 7.8); NOE (500
MHz, CDCl3): Irradiation of the 0.96 ppm (SiEt3) resonance gave enhancement of the 6.88 ppm
(1.0%) and 6.51 ppm (1.0%) resonances; 13C-NMR (125 MHz, CDCl3): 148.2, 146.1, 142.4,
138.4, 135.5, 131.8, 131.6, 128.4, 110.5, 110.4, 55.9, 55.8, 40.4, 30.9, 28.8, 22.9, 22.8, 7.6, 4.5;
IR (KBr): 2950, 2932, 2873, 1604, 1508, 1463, 1262; HRMS: m/e for C23H24O2Si calculated
370.2328 (M+), found 370.2325.
2,3,4,5-Tetrahydro-7,8-dimethoxy-1H-dibenzo[a,d]cycloheptene (22)
METHOD 1: To a stirred solution of 21 (0.0849 g, 0.229 mmol) in degassed 1,2-dichoroethane
(3.5 mL) was added trifluoroacetic acid (88 μL, 1.2 mmol), and the solution was allowed to stir
for 3 h at room temperature under a nitrogen atmosphere. The mixture was dissolved in Et2O (75
mL) and subjected to a conventional extractive workup (Et2O).
Preparative TLC (15:1
hexanes:Et2O) afforded compound 22 as a colourless solid (0.0570 g, 0.222 mmol, 97%). mp.
88-90 oC.
METHOD 2: To a stirred solution of 2d (0.3209 g, 0.5943 mmol) in degassed 2-
methoxyethanol (9.1 mL) was added sodium hypophosphite monohydrate (0.3149 g, 2.972
mmol). The solution was placed in an oil bath set at 65 oC, and allowed to stir overnight (18 h)
under a nitrogen atmosphere. The reaction mixture was filtered through Celite® and subjected to
a conventional extractive workup (EtOAc). Preparative TLC afforded compound 22 as
1
colourless crystals (0.1164 g, 0.4544 mmol, 76%). H-NMR (300 MHz, CDCl3): 6.84 (d, 1H, J
= 11.6), 6.81 (s, 1H), 6.65 (s, 1H), 6.24 (d, 1H, J = 11.5), 3.91 (s, 3H), 3.88 (s, 3H), 2.89 (s, 2H),
2.35 (m, 2H), 2.12 (m, 2H), 1.56-1.66 (m, 4H); 13C-NMR (75 MHz, CDCl3): 149.7, 146.9, 132.2,
129.8, 129.5, 128.8, 128.1, 110.4, 110.1, 56.1, 40.5, 31.6, 29.4, 23.1, 23.0; IR (KBr): 2998, 2930,
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2833, 1605, 1510, 1353, 1263; HRMS: m/e for C17H20O2 calculated 256.1463 (M+), found
256.1457.
1,2,3,5,-Tetrahydro-8-isopropyl-7-methoxy-1,1,8-trimethyl-4H-Dibenzo[a,d]cyclohepten-4-
one
(31)
Compound 29 (0.2507 g, 0.6809 mmol) was dissolved in dry CH2Cl2 (97.2 mL) along with a
slight excess of Co2(CO)8. The solution was allowed to stir at room temperature under a
o
nitrogen atmosphere for 2 h. The reaction flask was cooled 0 C. SnCl4 (238 μL, 2.04 mmol)
was added dropwise into the reaction, followed by N,N-diisoproplyethylamine (178 μL, 1.02
mmol). The reaction was then allowed to stir under a nitrogen atmosphere for another 15 h,
while warming to room temperature. Following the 15 h, TLC analysis showed complete
+
starting material consumption, and NH4 Cl- (aq., sat., 75 mL) was added. The organic portion
+
was rinsed once more with NH4 Cl- (aq., sat., 75 mL) in a separatory funnel, and then with brine
(75 mL). The organic fraction was then dried over MgSO4, filtered, removed under reduced
pressure, and the remaining residue quickly passed through a short column of silica to remove
any excess impurities (100% hexanes, then 3:1 hexanes:Et2O). The collected fraction (~0.16 g,
~0.27 mmol) was dissolved in degassed 2-methoxyethanol (4.1 mL) along with 5 equivalents of
NaH2PO2-H2O (0.1185 g, 1.347 mmol). The solution was allowed to stir at 65 oC for 20 h under
a nitrogen atmosphere. The reaction mixture was filtered through Celite®, and the collected
fraction subjected to a conventional extractive workup (EtOAc). Preparative TLC
chromatography (2:1 hexanes:Et2O) isolated the product as a yellow oil (0.0592 g, 0.191 mmol,
1
28%). H-NMR (500 MHz, CD2Cl2): 7.30 (d, 1H, J = 12.0), 7.15 (s, 1H), 6.77 (s, 1H), 6.67 (d,
1H, J = 11.9), 3.85 (s, 3H), 3.22-3.30 (m, 3H), 2.42 (t, 2H, J = 6.8), 1.82 (t, 2H, J = 6.8), 1.20 (s,
9H), 1.18 (s, 3H); NOE (500 MHz, CDCl3): Irradiation at δ 7.14 resonance gave enhancement of
doublet further downfield and isopropyl protons at δ 1.21. Irradiation at δ 6.79 resonance gave
13
enhancement of methoxy protons at δ 3.87; C-NMR (75 MHz, CD2Cl2): 196.3, 158.8, 155.9,
138.4, 137.1, 134.6, 128.3, 126.0, 125.8, 109.3, 55.5, 37.2, 34.8, 34.4, 30.5, 27.6, 26.6, 22.4; IR
(ATR): 2957, 2923, 2866, 1657, 1496, 1255; HRMS: m/e for C21H26O2 calculated 310.1933
(M+), found 310.1932.
Acknowledgements. The authors are grateful to NSERC (Canada), the Canada Foundation for
Innovation (CFI), and the Ontario Innovation Trust (OIT) for support of this research.
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Notes and references
1 For reviews, see: (a) J. R. Green, Eur. J. Org. Chem. 2008, 6053; (b) J. R. Green, Synlett
2012, 23, 1271.
2 M. J. Went, Adv. Organomet. Chem. 1997, 41, 69.
3 (a) T. Nakamura, T. Matsui, K. Tanino, and I. Kuwajima, J. Org. Chem. 2007, 62, 3032; (b)
K. Tanino, K. Onuki, K. Asano, M. Miyashita, T. Nakamura, Y. Takahashi, and I. Kuwajima,
J. Am. Chem. Soc. 2003, 125, 1498; (c) S. Djurdjevic and J. R. Green, Org. Lett. 2007, 9,
5505; (d) S. Djurdjevic, F. Yang, and J. R. Green, J. Org. Chem. 2010, 75, 8241; (e) Y.-T
Lin, F.-Y. Lin, and M. Isobe, Org. Lett. 2014, 16, 5948; (f) S. Djurdjevic and J. R. Green,
Synlett 2014, 25, 2467.
4 (a) S. Amiralaei, J. Gauld, and J. R. Green, Chem. - Eur. J. 2011, 17, 4157; (b) S. Amiralaei
and J. R. Green, Chem. Commun. 2008, 4971.
5 (a) J. R. Green, Synlett 2001, 353; (b) D. G. J. Young, J. A. Burlison, and U. Peters, J. Org.
Chem. 2003, 68, 3494.
6 N. Iwasawa and H. Satoh, J. Am. Chem. Soc. 1999, 121, 7951.
7 (a) N. Iwasawa, F. Sakurada, and M. Iwamoto, Org. Lett. 2000, 2, 871; (b) N. Iwasawa, K.
Inaba, S. Nakayama, and M. Aoki, Angew. Chem. Int. Ed. 2005, 44, 7447.
8 K. Tanino, T. Simizu, M. Miyama, and I. Kuwajima, J. Am. Chem. Soc. 2000, 122, 6116.
9 K. Tanino, F. Kondo, T. Shimizu, and M. Miyashita, Org. Lett. 2002, 4, 2217.
10 K. Inaba, J. Tanaka, and N. Iwasawa, Chem. Lett. 2007, 36, 474.
11 See reference 3 and: (a) S. L. Schreiber, T. Sammakia, and W. E. Crowe, J. Am. Chem. Soc.
1986, 108, 3128; (b) J. R. Green, Chem. Commun. 1998, 1751; (c) M. M. Patel and J. R.
Green, Chem. Commun. 1999, 509; (d) Y. Lu and J. R. Green, Synlett 2001, 243; (e) L. J.
Golovko, M. J. Hope-Weeks, M. J. Mays, M. McPartlin, A. M. Sloan and A. D. Woods,
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