Annulation of alkenyl-substituted heterocycles via rhodium-catalyzed intramolecular C-H activated coupling reactions

Full text of DOI:10.1021/ja0058738

J. Am. Chem. Soc. 2001, 123, 2685-2686
2685
with 10 mol % (Ph3P)3RhCl (Wilkinson’s catalyst) at 160 °C.
Monitoring the reaction by 1H NMR spectroscopy demonstrated
that 1 undergoes double bond positional isomerization rapidly
under the reaction conditions, leading to an initial mixture of
alkenes with the disubstituted isomer 2 predominating (eq 1). Over
time the mixture was converted to tricyclic product 4 and
decomposition products, contaminated only with trace amounts
of 1, 2, and 3.
Annulation of Alkenyl-Substituted Heterocycles via
Rhodium-Catalyzed Intramolecular C-H Activated
Coupling Reactions
K. L. Tan, R. G. Bergman,* and J. A. Ellman*
Center for New Directions in Organic Synthesis
Department of Chemistry, UniVersity of California†
Berkeley, California 94720
ReceiVed December 12, 2000
Transition metal catalyzed C-H bond activation has been
developing rapidly as a method for the formation of carbon-
carbon bonds.1 One of the most useful transformations of this
type is directed C-H bond activation exemplified by the
regioselective ortho alkylation of aromatic carbonyl compounds
with ruthenium catalysts by Murai.2 Subsequently, several groups
have expanded the scope of intermolecular alkylation of arenes
by incorporating a variety of directing groups such as imines,
pyridines, and esters.3 Although broadly applicable, this inter-
molecular coupling occurs predominantly at the terminus of the
alkenyl chain, and thus gives only linear products. We report here
an intramolecular4 variant of this methodology that couples a vinyl
carbon in a tethered alkene to imidazole rings via a novel and a
selective C-H bond activation at the position R to the
heteroatom.5-8 This reaction is successful with a wide range of
substrates, allowing for the synthesis of a variety of annulated
heterocycles in good yield. In a significant departure from earlier
work, disubstituted and even trisubstituted alkenes have been
cyclized in a regioselective manner, yielding complex fused
heterocyclic/carbocyclic skeletons with stereogenic centers.
In an effort to expand the scope of catalytic C-H activation
and direct coupling to alkenes, we began by investigating the
cyclization of N-homoallyl benzimidazole 1. Although attempts
to cyclize 1 with RuH2CO(PPh3)3, Cp*Rh(C2H2SiMe3)2, [Rh-
(Diphos)]22ClO4, and [RhCl(coe)2]2 proved unsuccessful, benz-
imidazole 1 was converted to carbocycle 4 in 60% 1H NMR yield
To optimize the reaction conditions, a range of phosphine
additives with varying steric and electronic properties were
surveyed (Table 1). With [RhCl(coe)2]2 as the catalyst precursor,
1
the use of P(p-tolyl)3 resulted in 56% H NMR yield at 160 °C
after 40 h. Although the addition of P(t-Bu)3 did not improve the
yield, the addition of the electron-rich but less sterically encum-
bering PCy3 effected the cyclization of alkene 1 to carbocycle 4
1
in 86% yield in 3.5 h at 160 °C as determined by H NMR
spectroscopy. Isomerization to an intermediate mixture of alkenes
1 and 2 was observed, with 2 predominating, and again both
isomers were cleanly converted to product with further heating
(eq 1). Upon optimization of the conditions, it was found that 1
cyclized to 4 in 79% isolated yield, with a reduction of catalyst
loading to 5 mol % [RhCl(coe)2]2 and 7.5 mol % PCy3 (Table 2,
entry 1).
Table 1. Survey of Phosphine Effects on Cyclizationa
† The Center for New Directions in Organic Synthesis is supported by
Bristol-Myers Squibb as Sponsoring Member.
phosphine
time, h
1H NMR yield, %
(1) For reviews, see: (a) Kakiuchi, F.; Murai, S. Activation of Unreactive
C-H Bonds. In Top. Organomet. Chem. 1999, 3, 47-79. (b) Guari, Y.; Sabo-
Etienne, S.; Chaudret, B. Eur. J. Inorg. Chem. 1999, 1047-1055. (c) Dyker,
G. Angew. Chem., Int. Ed. 1999, 38, 1699-1712. (d) Shilov, A. E.; Shul’pin,
G. B. Chem. ReV. 1997, 97, 2879-2932.
(2) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.;
Sonoda, M.; Chatani, N. Pure Appl. Chem. 1994, 66, 1527-1534. (b) Kakiuchi,
F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N.; Murai, S.
Bull. Chem. Soc. Jpn. 1995, 68, 62-83.
PPh3
3.5
3.5
3.5
3.5
3.5
22 (61)b
<5 (<5)b
20 (57)b
20 (56)b
86
P(o-tolyl)3
P(t-Bu)3
P(p-tolyl)3
PCy3
a Reactions were preformed with 10 mol % [RhCl(coe)2]2 and 30
mol % PR3 at 160 °C in d8-toluene. b 1H NMR yield at complete
conversion.
(3) (a) Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616-
6623. (b) Lim, Y. G.; Kang, J. B.; Kim, Y. H. J. Chem. Soc., Perkin Trans.
1 1996, 2201-2206. (c) Lim, Y. G.; Kim, Y. H.; Kang, J. B. J. Chem. Soc.,
Chem. Commun. 1994, 2267-2268. (d) Jun, C. H.; Hong, J. B.; Kim, Y. H.;
Chung, K. Y. Angew. Chem., Int. Ed. 2000, 39, 3440-3441. (e) Trost showed
that alkenes could also be functionalized in similar fashion. Trost, B. M.;
Imi, K.; Davies, I. W. J. Am. Chem. Soc. 1995, 117, 5371-5372.
(4) Murai has demonstrated directed intramolecular cyclization of 1,5 and
1,6 dienes. Fujii, N.; Kakiuchi, F.; Yamada, A.; Chatani, N.; Murai, S. Bull.
Chem. Soc. Jpn. 1998, 71, 285-298.
The reaction scope was quite general with respect to substitu-
tion at the alkenyl group (Table 2). In an unprecedented direct
coupling of a C-H bond with a trisubstituted double bond,
tetracycle 12 was formed from 5 in good yield and high
diastereoselectivity for the cis-ring fusion (15:1 by 1H NMR) as
established by X-ray crystallographic analysis (Table 2, entry 2).9
Cyclization of 1,2-disubstituted alkene 6 yielded the five-
membered ring 13 in good yield with no other cyclic products
observed (Table 2, entry 3). Six-membered rings were accessible
with the appropriate substitution as demonstrated for products
14 and 15 (Table 2, entries 4 and 5). Apparently, internal geminal
alkene substitution or allylic R,R-dibranching leads to the
(5) Jordan and Taylor showed the coupling of pyridine to propene. Jordan,
R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778-779.
(6) Fujiwara has successfully cyclized electron-deficient alkenes and alkynes
to aromatic rings with palladium. Jia, C. G.; Piao, D. G.; Oyamada, J. Z.; Lu,
W. J.; Kitamura, T.; Fujiwara, Y. Science 2000, 287, 1992-1995.
(7) Murai and Moore have shown the selective acylation of heteroaromatics
with Ru3(CO)12. (a) Moore, E. J.; Pretzer, W. R.; O’Connell, T. J.; Harris, J.;
Labounty, L.; Chou, L.; Grimmer, S. S. J. Am. Chem. Soc. 1992, 114, 5888-
5890. (b) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem.
Soc. 1996, 118, 493-494. (c) Chatani, N.; Ie, Y.; Kakiuchi, F.; Murai, S. J.
Org. Chem. 1997, 62, 2604-2610. (d) Fukuyama, T.; Chatani, N.; Tatsumi,
J.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1998, 120, 11522-11523.
(8) Intermolecular addition of C-H bonds in imines to alkenes has been
reported by Suggs et al. and Jun et al. (a) Suggs, J. W. J. Am. Chem. Soc.
1979, 101, 489-489. (b) Jun, C. H.; Lee, H.; Hong, J. B. J. Org. Chem.
1997, 62, 1200-1201.
(9) This result was unexpected, since insertion into the trisubstituted alkene
is believed to initially form the trans-ring juncture. However, the rapid
isomerization seen in previous cases suggests that the cis- or trans-ring juncture
would be accessible, and our observations indicate that the cis adduct
reductively eliminates more rapidly than the trans adduct (refer to Figure S-2
in the Supporting Information for the mechanism).
10.1021/ja0058738 CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/21/2001

2686 J. Am. Chem. Soc., Vol. 123, No. 11, 2001
Table 2. Rhodium-Catalyzed Cyclizationa
Communications to the Editor
compound 7-d1 with 5 mol % catalyst and 7.5 mol % PCy3 at
135 °C afforded 14-d with deuterium incorporated at the two
positions indicated in eq 2. This result is consistent with rapid
alkene insertion and â-hydride elimination before the formation
of the final product.10 Analysis of 14-d by electrospray mass
spectrometry revealed that deuterium was exchanged between
molecules during the course of its formation, since in the mass
spectrum of the product, mass ions for 14-d0, -d1, -d2, and -d3
were observed. Notably, reaction of alkene 7 under catalytic
conditions in d8-toluene showed no deuterium incorporation into
7 or 14, ruling out exchange of deuterium with the solvent. The
proposed intermolecular deuterium exchange was confirmed by
the following crossover experiment (Figure 1). Carrying out the
catalytic reaction with a 50:50 mixture of 9 and 1-d1 gave products
16-d and 4-d, which were both shown to have deuterium
incorporated by 1H NMR and mass spectrometry. The crossover
could be occurring through an intermolecular alkene insertion
followed by rapid â-elimination, allowing for scrambling of
deuterium between molecules. In light of the rapid intermolecular
deuterium exchange observed here, it is interesting that no
intermolecular coupling was observed. Furthermore, attempts to
couple N-methylbenzimidazole to neo-hexene proved unsuccess-
ful.
a Reactions were run with 5% [RhCl(coe)2]2 and 7.5% PCy3 at 160
°C for 20 h in THF unless otherwise noted. b Reactions were run with
10% [RhCl(coe)2]2 and 15% PCy3 at 180 °C for 20 h in toluene.
c Reaction was run with 10% [RhCl(coe)2]2 and 15% PCy3 at 180 °C
for 3 days. d 75% yield of cis; diastereoselectivity of 15:1 based on 1H
NMR.
Figure 1. Deutrium crossover experiment.
In summary, we have developed a general method for carbon-
carbon bond formation without necessitating pre-functionalization
of the reaction partners. The new carbocyclization can be used
to form both five- and six-membered rings via catalytic C-H
bond activation. A range of substrates including mono-, di-, and
trisubstituted alkenes has allowed the formation of complex
structures with stereogenic centers. Mechanistic studies and
application to other heterocyclic classes are under way.
exclusive formation of the larger rings. Geminal substitution may
favor the six-membered ring due to the difficulty of cyclizing to
form a quaternary center.
In addition to modulating the regioselectivity, the level of
substitution at the alkenyl position also has a dramatic impact on
the rate of the reaction. Both 1,2-disubstituted alkene 6 and
trisubstituted alkene 5 require more vigorous conditions than
alkenes 1 and 9 to effect complete cyclization. Interestingly,
terminal alkene 10 cyclizes more slowly than geminally substi-
tuted alkene 9 and monosubstituted alkene 1, even though all three
yield five-membered carbocycles (Table 1, entries 7, 6, and 1).
Acknowledgment. This work was supported by the NIH GM50353
(to J.A.E), the Director and Office of Energy Research, Office of Basic
Energy Sciences, Chemical Sciences Division, U.S. Department of Energy,
under Contract No. DE-AC03-76SF00098 (to R.G.B). We thank Dr. Fred
Hollander and Dr. Alan Oliver of the UC Berkeley CHEXRAY facility
for carrying out the X-ray diffraction studies.
1
Monitoring the cyclization of 9 to 16 by H NMR spectroscopy
shows that 9 does not undergo much double bond isomerization
during the reaction, which may account for at least part of the
difference in reactivity of 9 versus 10. In addition, geminal
substitution may provide an enhancement in the overall rate. The
successful cyclization of imidazole 11 raises the possibility of
extending the scope of this chemistry to other heterocycles.
In an effort to obtain preliminary information about the
mechanism of these cyclizations, deuterium tracer (eq 2) and
crossover experiments (Figure 1) were undertaken. Treatment of
Supporting Information Available: Experimental details, including
analytical data for all compounds described in the article, a possible
mechanism for formation of 12, and X-ray diffraction data for 12 (PDF).
This material is available free of charge via the Internet at http://pubs.acs.org.
JA0058738
(10) Similar results were observed by Murai in ref 4.