Unexpected regiochemistry in the benzannulation reaction of Fischer carbene complexes in the synthesis of cyclophanes [14]

Full text of DOI:10.1021/ja0020106

9862
J. Am. Chem. Soc. 2000, 122, 9862-9863
Unexpected Regiochemistry in the Benzannulation
Reaction of Fischer Carbene Complexes in the
Synthesis of Cyclophanes
Scheme 1
Huan Wang and William D. Wulff*,†
Department of Chemistry, Searle Chemistry Laboratory
The UniVersity of Chicago, Chicago, Illinois 60637
Arnold L. Rheingold
Department of Chemistry, The UniVersity of Delaware
Newark, Delaware, 19716
ReceiVed June 6, 2000
Scheme 2
The benzannulation reaction of Fischer carbene complexes with
alkynes is one of the most versatile methods for the construction
1
of substituted phenols. The two possible regiochemical outcomes
that have previously been observed are illustrated in 4-methoxy-
phenols 2a and 2b which differ in the direction of alkyne
incorporation. The regiochemistry of alkyne incorporation is
normally controlled by the steric differential between the two
substituents of the alkyne2 and the largest substituent is
preferentially introduced adjacent to the phenol function, as
illustrated in 2a. The disconnection for the overall process is
indicated in the assembly of the three subunits in 3. We report
here the observation of phenol 4, a new regioisomer for this
reaction which was unanticipated since its formation would
formally require the breaking of the carbon-carbon bond between
,3
1
the carbene-carbon and the carbon-bearing substituent R in
complex 1. The overall assembly of the pieces in the formation
of phenol 4 is indicated in 5 where the vinyl group of the starting
carbene complex is incorporated in a fashion that is reversed from
normal phenols 2a and 2b.We recently reported that â-tethered
vinyl chromium carbene complex 6 would undergo an intramo-
lecular benzannulation with incorporation of the tethered terminal
alkyne to give m-cyclophane 8b in 58% yield.4 This method
gives synthetically useful yields of m-cyclophanes and has been
examined for tether lengths up to 17 methylenes with no drop-
off in yield (60% yield for n ) 17). The m-cyclophane 8b was
expected from this reaction on the basis of the regiochemistry
observed for intermolecular reactions, which give phenol 2a as
the major isomer with the larger substituent of the alkyne
incorporated adjacent to the phenol function. The same analysis
leads to the expectation that R-tethered complexes of the type 13
would lead to the formation of p-cyclophanes 14.
,5
6
readily separated. Attempts to generate the dianion of 12 by
reaction with 2 equiv of butyllithium or 3 equiv of tert-
butyllithium failed to give any significant yield of the desired
Complexes 13 were prepared in two steps from the R,ω-diynes
1 as outlined in Scheme 2. Bromoboration with 1 equiv of
1
7-9
carbene complex. This problem was solved by deprotonation
9-bromo-9-BBN and subsequent hydrolysis gave a statistical
of 12 with phenyllithium and then subsequent metal halogen
exchange with tert-butyllithium to give the dianion of 12, which
underwent selective reaction with chromium hexacarbonyl by the
vinyl anion.
As anticipated, p-cyclophane 14b was isolated from the
intramolecular benzannulation of complex 13b accompanied by
a nearly equal amount of [10,10]-p,p-cyclophane 16b. However,
the major products of the reaction were [10]-m-cyclophane 8b
and bicyclo[3.1.0]hexenone 15b. The formation of m-cyclophane
8b from this reaction was particularly surprising since this is the
mixture of products from which the bromoenyne 12 could be
†
Current address: Department of Chemistry, Michigan State University,
East Lansing, MI 48824.
(
1) For recent reviews on carbene complexes in organic chemistry, see:
(
a) Wulff, W. D. In ComprehensiVe Organometallic Chemistry II; Abel, E.
W., Stone, R. G. A., Wilkinson, G., Eds.; Pergemon Press: New York, 1995;
Vol. 12, p 469. (b) Bernasconi, C. F. Chem. Soc. ReV. 1997, 26, 299. (c)
Hegedus, L. S. Tetrahedron 1997, 53, 4105. (d) Wulff, W. D. Organometallics
1
1
998, 17, 3116. (e) D o¨ tz, K. H.; Tomuschatt, P. Chem. Soc. ReV. 1999, 28
87. (f) Herndon, J. W. Coord. Chem. ReV. 1999, 181, 177. (g) D o¨ rwald, F.
Z. Metal Carbenes in Organic Synthesis; Wiley-VCH: New York, 1999.
(
2) (a) Wulff, W. D.; Tang, P. C.; McCallum, J. J. Am. Chem. Soc. 1981,
1
03, 7677. (b) D o¨ tz, K. H.; M u¨ hlemeier, J.; Schubert, U.; Orama, O. J.
(6) Hara, S.; Dojo, H.; Takinami, S.; Suzuki, A. Tetrahedron Lett. 1983,
24, 731.
(7) Reaction of 12a with 1 equiv of NaH or EtMgBr and then 2 equiv of
tert-butyllithium failed to give more than 2% of 13a.
(8) For successful related transformations, see: (a) Barluenga, J.; Sanz,
R.; Fananas, F. J. Chem. Eur. J. 1997, 3, 1324. (b) Henniges, H.; Meyer, F.
E.; Schick, U.; Funke, F.; Parson, P. J.; de Meijere, A. Tetrahedron 1996, 52,
11545. (c) Furber, M.; Taylor, R. J. K. J. Organomet. Chem. 1986, 311, C35.
(9) This failure may be related to observations made with haloaryl acids:
Beak, P.; Musick, T.; Chen, C.-W. J. Am. Chem. Soc. 1988, 110, 3538.
Organomet. Chem. 1983, 247, 187. (c) Yamashita, A.; Toy, A. Tetrahedron
Lett. 1986, 27, 3471.
(
3) (a) Chamberlin, S.; Waters, M. L.; Wulff, W. D. J. Am. Chem. Soc.
1
994, 116, 3113. (b) Brandvold, T. A.; Wulff, W. D.; Rheingold, A. L. J.
Am. Chem. Soc. 1991, 113, 5459. (c) Brandvold, T. A.; Wulff, W. D.;
Rheingold, A. L. J. Am. Chem. Soc. 1990, 112, 1645.
(
4) Wang, H.; Wulff, W. D. J. Am. Chem. Soc. 1998, 120, 10573.
(
5) For an additional example, see: D o¨ tz, K. H.; Gerhardt, A. J. Organomet.
Chem. 1999, 578, 223.
1
0.1021/ja0020106 CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/21/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 40, 2000 9863
Table 1. Macrocyclizations of Complexes 13a
Scheme 3
temp time yield yield yield yield
entry series
n
(°C)
(h)
8
14
15
16
1
2
3
4
5
6
7
a
b
b
b
c
c
d
6
100
2
10
1
19
20
22
12
36b
9
11
10
10
6
10 100
10 100
10
13 100
13
30
13
30
16
20
1
7
6
8
3
1
26
42
31
38
40
2
70
c
65
16 100
56
10
a
b
Reaction performed at 0.002 M. A 13% yield of trimer was also
c
3
isolated. Reaction performed with 3 equiv of Et N.
same product produced from the thermolysis of â-tethered carbene
complex 6. The isolation of 8b from the thermolysis of 13b
corresponds to the regiochemistry indicated in phenol 4 (Scheme
1) and is unprecedented from the reaction of a carbene complex
and an alkyne. The formation of bicyclo[3.1.0]hexenone 15b from
the thermolysis of 13b was equally a surprise and is a product
type that has never before been reported from the reaction of a
carbene complex and an alkyne. The structure of 15b was assigned
by a series of NMR experiments and confirmed by an X-ray
analysis of a single crystal.10 The carbon-carbon bond connectiv-
ity in 15b is related to that of the unexpected m-cyclophane 8b
by the cleavage of a cyclopropane bond. It was thus anticipated
that 15b might be a precursor to 8b and it was found that this
interconversion occurs both thermally and under acid catalysis.
The thermolysis of a 44:56 mixture of 8b:15b for 45 h in THF at
insertion of the alkyne and then carbon monoxide insertion to
give the η -vinyl ketene complex 17. In this intermediate the
4
100 °C resulted in conversion to an 86:14 mixture in 96% yield.
substituted alkyne carbon is incorporated into the C-1 position
of the ketene function. Electrocyclic ring-closure to the cyclo-
hexadienone 20 and subsequent tautomerization would give the
phenol 14 which is the expected product from the reaction of
carbene complexes with alkynes. However, in the case of tethers
less than 16 methylenes, the p-cyclophane 14 is a minor product
of the reaction. One possible explanation for this may result from
Treatment of this mixture with trifluoroacetic acid in chloroform
at room temperature led to complete conversion to 8b in 98%
yield within 2 h.
The m-cyclophane that would have been possible from the
thermolysis of 13b is 10, which corresponds to an intramolecular
cyclization with inverted regiochemical incorporation of the
alkyne as indicated by the substitution pattern in phenol 2b. It
was shown that 10 is not the product of this reaction by an
independent synthesis from carbene complex 7. Thermolysis of
4
the strain in the conformation of the η -vinyl ketene complex 17
that is necessary for the electrocyclic ring-closure to give the
normal product 14. As a result it is possible that the vinyl ketene
7
gave m-cyclophane 9b and then 10 upon methylation and
3c
complex may isomerize to the s-cis,s-trans conformation 18 and
deprotection. m-Cyclophane 10 was found to have spectral data
nonidentical with 8b. The structure of 10 prepared in this manner
was confirmed by X-ray diffraction analysis of a single crystal.11
The effect of the tether link on the macrocyclization of complex
then undergo a cyclization to the metallabicyclo[4.1.0]heptenone
19. This cyclization could be driven by the release in strain
accompanied by the change in hybridization of the cyclopropyl
carbon attached to the chromium in 19. Reductive elimination
from 19 would give the bicyclo[3.1.0]hexenone 15 that is isolated
from the thermolysis of 13. Another explanation for the shift in
product distribution from 14 for shorter tethers is that a 1,2-
hydride shift in 21 (perhaps via a chromium hydride species) to
give 22 followed by a 1,2-alkyl shift to give the meta-bridged
species 23 would upon tautomerization give the observed phenol
13 was examined for tethers ranging from n ) 6 to 16 and the
results are presented in Table 1. The results show that the
chemoselectivity of these reactions falls into three distinct regions.
The thermolysis of complex 13a (n ) 6) produces predominantly
dimeric cyclophane 16a (36% yield) and also a 13% yield of the
trimeric cyclophane. Complexes 13b and 13c, with n ) 10 and
12
1
[
3, respectively, give predominantly m-cyclophane 8 and bicyclo-
3.1.0]hexenone 15. The ratio of these two products varies, but
the combined yield is constant (55-63%). The reaction in entry
in the table was performed in the presence of 3 equiv of
8. Further rearrangement of 23 to 24 and then electrocyclic ring
closure could then account for the formation of 15. At this point
we do not have any experimental evidence to distinguish between
these two mechanisms.
6
The initial results from the present and other recent studies4,5
on the intramolecular benzannulation of alkyne tethered carbene
complexes have revealed that while this reaction is useful for the
synthesis of a number of different types of macrocyclic cyclo-
phanes, it produces a few surprises as well. Further studies on
the scope of macrocyclic synthesis with carbene complexes are
planned as well as applications to molecules of biological and
structural interest.
triethylamine but did not have any clear effect on the product.
The thermolysis of complex 13d (n ) 16) is the only intramo-
lecular benzannulation that is chemoselective for the formation
of p-cyclophanes, giving 14d in 56% isolated yield.
A mechanism is presented in Scheme 3 to account for the
formation of p-cyclophane 8 as well as for bicyclo[3.1.0]hexenone
1
5. In the normal course of events, the R-tethered vinyl carbene
complex 13 would be expected to undergo an intramolecular
Acknowledgment. This work was supported by the National Science
Foundation. We thank Professor Jeff Stryker for helpful discussions.
(
10) Crystal data for 15b: C17
H
26
O
2
, fw ) 262.38, monoclinic, P2 /c, a )
1
o
9
1
2
.785(2) Å, b ) 14.622(2) Å, c ) 11.357(2) Å, â ) 109.897(3) , V )
3
-3
527.8(7) Å , Z ) 4, D
c
) 1.141 g cm , T ) 173 K, R ) 7.76, wR2 )
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
4.74%.
(11) Crystal data for 10: C17
H
26
2
O , fw ) 262.38, monoclinic, P2 /c, a )
1
o
1
3
2
2.3276(9) Å, b ) 28.236(2) Å, c ) 11.9241(7) Å, â ) 99.169(3) , V )
3
-
3
066.6(4) Å , Z ) 8, D
c
) 1.137 g cm , T ) 173 K, R ) 9.18, wR2 )
JA0020106
6.49%. The asymmetric unit contains two crystallographically independent,
chemically similar, molecules.
(12) We would like to thank a reviewer for suggesting this mechanism.