On the validity of au-vinylidenes in the gold-catalyzed 1,2-migratory cycloisomerization of skipped propargylpyridines

Article abstract of DOI:10.1021/ol1024794

A mechanism of the Au-catalyzed cycloisomerization of propargylpyridines has been investigated. Both DFT computational and experimental results strongly support generation of a Au-carbene via a cyclization/proton transfer sequence over the previously proposed path involving a Au-vinylidene intermediate. For the β-Si-substituted Au-carbene (G = SiR₃), a 1,2-Si migration was shown to be kinetically favored over a 1,2-H shift. This study highlights the importance of alternative pathways that could explain reactivities commonly attributed to an alkyne-vinylidene isomerization in Au catalysis.

Full text of DOI:10.1021/ol1024794

ORGANIC
LETTERS
2
010
Vol. 12, No. 23
538-5541
On the Validity of Au-vinylidenes in the
Gold-Catalyzed 1,2-Migratory
Cycloisomerization of Skipped
Propargylpyridines
5
†
,‡
§
Yuanzhi Xia, Alexander S. Dudnik, Yahong Li,* and Vladimir Gevorgyan*
,†
,§
Key Laboratory of Organic Synthesis of Jiangsu ProVince, Department of Chemistry
and Chemical Engineering, Soochow UniVersity, Suzhou 215006, China, College of
Chemistry and Material Engineering, Wenzhou UniVersity, Wenzhou 325035, China,
and Department of Chemistry, UniVersity of Illinois at Chicago, Chicago,
Illinois 60607, United States
liyahong@suda.edu.cn; Vlad@uic.edu
Received October 13, 2010
ABSTRACT
A mechanism of the Au-catalyzed cycloisomerization of propargylpyridines has been investigated. Both DFT computational and experimental
results strongly support generation of a Au-carbene via a cyclization/proton transfer sequence over the previously proposed path involving
3
a Au-vinylidene intermediate. For the ꢀ-Si-substituted Au-carbene (G ) SiR ), a 1,2-Si migration was shown to be kinetically favored over a
1,2-H shift. This study highlights the importance of alternative pathways that could explain reactivities commonly attributed to an
alkyne-vinylidene isomerization in Au catalysis.
Catalytic transformations featuring metal-vinylidene inter-
terminal alkynes upon the alkyne-vinylidene isomerization,
mediates are powerful C-C and C-heteroatom bond form-
ing strategies in organic synthesis. In one of the commonly
accepted scenarios, metal-vinylidenes can be generated from
involving an initial coordination of the metal to a triple bond
1
1
of the alkyne followed by a direct [1,2]-H shift. Besides
2
3
4
5
3 3
hydrogen, other groups, such as SiR , SnR , SR, SeR,
†
Soochow University.
Wenzhou University.
University of Illinois at Chicago.
‡
(2) (a) Movassaghi, M.; Hill, M. D. J. Am. Chem. Soc. 2006, 128, 4592.
(b) Katayama, H.; Wada, C.; Taniguchi, K.; Ozawa, F. Organometallics
2002, 21, 3285. (c) Naka, A.; Okada, T.; Kunai, A.; Ishikawa, M. J.
Organomet. Chem. 1997, 547, 149. (d) Dankwardt, J. W. Tetrahedron Lett.
2001, 42, 5809.
§
(
1) For reviews, see: (a) Metal Vinylidenes and Allenylidenes in
Catalysis: From ReactiVity to Applications in Synthesis; Bruneau, C.,
Dixneuf, P. H., Eds.; Wiley-VCH: Weinheim, 2008. (b) Bruce, M. I. Chem.
ReV. 1991, 91, 197. (c) Bruneau, C.; Dixneuf, P. H. Angew. Chem., Int.
Ed. 2006, 45, 2176. (d) McDonald, F. E. Chem.sEur. J. 1999, 5, 3103. (e)
Varela, J. A.; Sa a´ , C. Chem.sEur. J. 2006, 12, 6450. (f) Bruneau, C.;
Dixneuf, P. H. Acc. Chem. Res. 1999, 32, 311. (g) Trost, B. M.; McClory,
A. Chem. Asian J. 2008, 3, 164. (h) Lynam, J. M. Chem.sEur. J. 2010,
(3) Shirakawa, E.; Morita, R.; Tsuchimoto, T.; Kawakami, Y. J. Am.
Chem. Soc. 2004, 126, 13614.
(4) Miller, D. C.; Angelici, R. J. Organometallics 1991, 10, 79.
(5) (a) Kim, H.; Lee, C. J. Am. Chem. Soc. 2005, 127, 10180. (b) Hill,
A. F.; Hulkes, A. G.; White, A. J. P.; Williams, D. J. Organometallics 2000,
19, 371.
1
6, 8238. (i) Wakatsuki, Y. J. Organomet. Chem. 2004, 689, 4092.
10.1021/ol1024794  2010 American Chemical Society
Published on Web 11/11/2010

6
and I, have been shown to undergo the 1,2-migration during
simulate such a base with a simple three-water molecule
14
this process. Traditionally, generation of metal-vinylidenes
from alkynes is well-precedented for W, Mo, Ru, Rh, Ir,
Co, Mn, and Re complexes; however, it has recently been
cluster. Employment of pyridine or the substrate molecules
as proton shuttles in place of the water cluster in DFT
calculations did not affect the overall energetic profile of
1
7
8
15
evidenced to play a key role in Pt- and Au-catalyzed
the reaction. The computed energy surface for the AuBr-
16
transformations. Along this line, we recently reported the
Au-catalyzed cycloisomerization of propargylpyridines 1 into
indolizines, featuring the 1,2-shifts of H- and Si-, Sn-, and
Ge-containing groups via a putative Au-vinylidene interme-
catalyzed cycloisomerization of propargylpyridine 1′ pos-
sessing a terminal alkyne moiety is provided in Figure 1.
8
a,b
diate i (eq 1).
Besides, based on the DFT-computational
and labeling experiments, formation of Pt-vinylidene species
was established by Yamamoto in the synthesis of indenes
7
a
(
eq 2). Furthermore, F u¨ rstner observed a 1,2-halogen shift
in the phenanthrene synthesis, proceeding through the Au-
8c
vinylidene (eq 3), intermediacy of which was later validated
8
d
by the DFT calculations. Nonetheless, evidence was
8
e,9
12
accumulated in support of alternative pathways in Au-,
Pt-,
2
d,10
11
and even “classical” W- and Ru-catalyzed
processes that could account for the reactivities commonly
attributed to the alkyne-metal-vinylidene isomerization. This
prompted us to investigate the validity of the proposed Au-
vinylidene species i in the Au-catalyzed cycloisomerization
of 1 (eq 1). Herein, we report our theoretical and experi-
mental results on the mechanism of this transformation. Our
studies indicate that the observed 1,2-H and 1,2-Si shifts are,
indeed, outcomes of a sequence of elementary steps alterna-
tive to the formation of the Au-vinylidene.
Figure 1. Potential energy surfaces for the AuBr-catalyzed cycloi-
somerization of terminal pyridylalkynes 1′.
According to it, coordination of AuBr to the alkyne moiety
of 1′ gives the π-complex 2′ with the free energy decreased
by 15.7 kcal/mol in toluene solution. A subsequent alkyne-
vinylidene isomerization of 2′ should occur via the transition
To shed light on a mechanism of the above-mentioned
13
cycloisomerization, DFT calculations have been performed
first. Considering the fact that a basic pyridine moiety of a
substrate may play a significant role in possible H-migration
steps during the cycloisomerization of 1, we decided to
(
9) Dias Jurberg, I.; Odabachian, Y.; Gagosz, F. J. Am. Chem. Soc. 2010,
1
32, 3543.
(10) Vadola, P. A.; Sames, D. J. Am. Chem. Soc. 2009, 131, 16525.
(11) (a) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120, 1928.
(
b) Iwasawa, N.; Maeyama, K.; Kusama, H. Org. Lett. 2001, 3, 3871. (c)
Kusama, H.; Yamabe, H.; Iwasawa, N. Org. Lett. 2002, 4, 2569. (d)
Iwasawa, N.; Miura, T.; Kiyota, K.; Kusama, H.; Lee, K.; Lee, P. H. Org.
Lett. 2002, 4, 4463. See also: (e) Onizawa, Y.; Kusama, H.; Iwasawa, N.
J. Am. Chem. Soc. 2008, 130, 802.
(
(
6) (a) Miura, T.; Iwasawa, N. J. Am. Chem. Soc. 2002, 124, 518.
7) (a) Bajracharya, G. B.; Pahadi, N. K.; Gridnev, I. D.; Yamamoto,
Y. J. Org. Chem. 2006, 71, 6204. (b) Tobisu, M.; Nakai, H.; Chatani, N.
J. Org. Chem. 2009, 74, 5471. (c) Bigeault, J.; Giordano, L.; de Riggi, I.;
Gimbert, Y.; Buono, G. Org. Lett. 2007, 9, 3567. (d) Mart ´ı n-Matute, B.;
Nevado, C.; C a´ rdenas, D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2003,
(12) Lin, M.-Y.; Maddirala, S. J.; Liu, R.-S. Org. Lett. 2005, 7, 1745.
(13) The B3LYP/6-31G*(LANL2DZ for Au and Br) method was used
for all the calculations, and solvation effect was calculated by the CPCM
model. See Supporting Information for details.
1
25, 5757.
(
8) (a) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128,
(14) For examples of DFT calculations demonstrating the importance
of the water molecule or water clusters in various catalytic reactions, see:
(a) Shi, F.-Q.; Li, X.; Xia, Y.; Zhang, L.; Yu, Z.-X. J. Am. Chem. Soc.
2007, 129, 15503. (b) Rossin, A.; Gonsalvi, L.; Phillips, A. D.; Maresca,
O.; Lled o´ s, A.; Peruzzini, M. Organometallics 2007, 26, 3289. (c) Xia, Y.;
Liang, Y.; Chen, Y.; Wang, M.; Jiao, L.; Huang, F.; Liu, S.; Li, Y.; Yu,
Z.-X. J. Am. Chem. Soc. 2007, 129, 3470.
1
2
2
2
2050. (b) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Tetrahedron
008, 64, 6876. (c) Mamane, V.; Hannen, P.; F u¨ rstner, A. Chem.sEur. J.
004, 10, 4556. (d) Soriano, E.; Marco-Contelles, J. Organometallics 2006,
5, 4542. (e) Raba aˆ , H.; Engels, B.; Hupp, T.; Hashmi, A. S. K. Int. J.
Quantum Chem. 2007, 107, 359. (f) Lavallo, V.; Frey, G. D.; Kousar, S.;
Donnadieu, B.; Bertrand, G. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 13569.
Org. Lett., Vol. 12, No. 23, 2010
5539

state TS′. However, the corresponding vinylidene structure
i could not be located, probably due to its instability. Instead,
the 1,2-H migration via TS′ leads to a cyclic intermediate ii
directly, and this process has a high 16.4 kcal/mol activation
free energy barrier. In contrast, according to an alternative
mechanism, a highly exergonic direct 5-endo-dig cyclization
of 2′ into 3′ via TS1′ needs only a 5.1 kcal/mol activation
barrier. Next, coordination of the water cluster to the H-atom
in 3′ endergonic by 11.4 kcal/mol (4′) is followed by a proton
abstraction via TS2′ with 6.2 kcal/mol activation free energy
to give the Au-indolizine species 5′. A facile ꢀ-protonation
of the vinyl-Au moiety in 5′ via 6′ and TS3′ leads to 7′ and
requires 4.2 kcal/mol free energy. An exergonic decoordi-
nation of the water cluster from 7′ furnishes the Au-carbene
Scheme 1. Deuterium-Labeling Studies
8
′. The formal 1,3-H shift from 3′ through 5′ to give 8′ via
a stepwise H-abstraction-donation is a reversible process. An
alternative R-protonation of the vinyl-Au moiety in 5′ via
TS4′ (6.5 kcal/mol activation energy) gives indolizine 9′.
Overall, formation of the product 9′ from 3′ and 8′ via a
water-assisted formal 1,2-H shift needs 17.6 and 27.7 kcal/
mol free energy, respectively. Barriers for the direct 1,2-H
shift to the Au center in 3′ or 8′ are as high as 23.9 and 34.6
1
7
kcal/mol, respectively.
To validate the above computational results, D-labeling
studies have been performed. The results are outlined in
Scheme 1. We find them in complete agreement with the
results of the DFT calculations. Accordingly, a reversible
formation of the Au-carbene 8′ explains the distribution of
a D-label between the C2 and C3 positions in indolizine 2a-d
upon the cycloisomerization of a terminally labeled 1a
(
Scheme 1, A). The scrambling of the D-label was observed
1
8
for both AuBr
3
and AuCl catalysts. A partial loss of the
D-label at both the C2 and C3 in 2a-d (18-22% out of 70)
was observed when reaction was performed in anhydrous
toluene. The loss of the D-label becomes even more severe
2
with the employment of H O-saturated toluene solvent
(Scheme 1, A). These observations fully support the involve-
DFT calculations. On the basis of these results, the originally
ment of a stepwise water- or base-assisted H-abstraction-do-
nation process established by the DFT calculations. Further-
more, the DFT-predicted reversible formation of the Au-carbene
proposed reaction pathway featuring the alkyne-vinylidene
isomerization is considered to be less likely.
Having established a mechanism for terminal alkynes (eq
1
9,20
8′ suggests that an analogous distribution and loss of the D-label
1
, G ) H), DFT calculations have been performed for the
should be observed in the Au-catalyzed cycloisomerization of
the isotopomer 1b. Indeed, these predictions have been con-
firmed experimentally (Scheme 1, B).
AuBr-catalyzed cycloisomerization of the silyl-substituted
propargylpyridine 1′′ (Figure 2). The computed potential
energy surfaces are analogous to that for 1′ (Figure 1). Thus,
a coordination of AuBr to the alkyne moiety of 1′′ leads to
the π-complex 2′′. Formation of the Au-vinylidene iii upon
the alkyne-vinylidene isomerization of 2′′ with a 1,2-Si shift
is possible; however, it requires 12.9 kcal/mol activation free
Furthermore, almost equal incorporation of the D-label at
C2 and C3 positions was achieved upon the cycloisomer-
ization of the H-isotopomer 1c in D
2
O-saturated toluene
media (Scheme 1, C), which is expected according to the
(
(
15) See Supporting Information for details.
16) For selected reviews on Au chemistry, see: (a) F u¨ rstner, A.; Davies,
(19) In addition, DFT calculations showed that another alternative
prototropic isomerization of the alkyne 1 into an allene is a reversible process
requiring 18.5 kcal/mol activation free energy. No loss of the D-label was
observed in 1b recovered from the Au-catalyzed cycloisomerization reaction
at 50% conversion. On the basis of this, the allenization route can be ruled
out. See Supporting Information for details.
P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (b) Hashmi, A. S. K. Chem.
ReV. 2007, 107, 3180. (c) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010,
4
2
9, 5232. (d) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed.
006, 45, 7896. (e) Kirsch, S. F. Synthesis 2008, 3183. (f) Li, Z.; Brouwer,
C.; He, C. Chem. ReV. 2008, 108, 3239. (g) Gorin, D. J.; Sherry, B. D.;
(20) The initially proposed mechanism (eq 1), involving two [1,2]-H
shifts, could account for the equal distribution of the D-label between the
C-2 and C-3 positions in 2a-d upon the Au-catalyzed cycloisomerization
of 1a-d under anhydrous conditions (see ref 8a). However, the observed
significant loss of the D-label during the cycloisomerization of 1a-d in the
Toste, F. D. Chem. ReV. 2008, 108, 3351.
(17) For a 1,2-H shift in Au-carbenes, see: (a) Gorin, D. J.; Davis, N. R.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 11260. (b) Luzung, M. R.;
Markham, J. P.; Toste, F. D. J. Am. Chem. Soc. 2004, 126, 10858. (c) Lee,
J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46, 912.
2
presence of H O contradicts the concerted nature of the 1,2-H migrations
(
18) Computational results for AuBr
3
are similar to those for AuBr.
suggested in the previous mechanistic rationale.
5540
Org. Lett., Vol. 12, No. 23, 2010

Figure 2. Potential energy surfaces for the AuBr-catalyzed cycloisomerization of silyl-substituted pyridylalkynes 1′′.
energy (TS′′). Instead, following the alternative mechanism,
′′ undergoes a more facile irreversible 5-endo-dig cyclization
Au species upon irreversible 5-endo-dig cyclization, (b)
ꢀ-protonation of the vinyl-Au, and (c) the [1,2]-Si- or a base-
assisted stepwise 1,2-H migration to the generated Au-
carbene center. This route constitutes a feasible, yet hard to
envision, alternative to the originally proposed alkyne-vinyli-
dene isomerization path. In the case of the Si-substituted
alkynes, the cycloisomerization proceeds via a formation of
the ꢀ-Si-Au-carbene intermediate, wherein the 1,2-Si migra-
tion is kinetically favored over the 1,2-H shift. Finally, the
present study highlights the importance of the alternative
mechanistic pathways that could mimic reactivities typically
explained by the intermediacy of metal-vinylidenes. In
addition, this work provides a better understanding of the
existing reactions of alkynes activated by Au complexes and
may guide design of new transformations in the future.
2
via TS1′′ that has only a 5.6 kcal/mol activation barrier.
Coordination of the water cluster (4′′) followed by the water-
assisted proton abstraction (TS2′′) furnishes the Au-indolizine
species 5′′. The ꢀ-protonation of the vinyl-Au moiety in 5′′
through the intermediate 6′′ and the corresponding TS3′′
affords the Au-carbene 7′′ reversibly, requiring a total of
6
.2 kcal/mol free energy for two steps. An alternative
R-protonation of 5′′ leading to indolizine 9′′ has a 2.0 kcal/
mol higher in energy transition state TS4′′ (-14.6 vs -16.6
kcal/mol for TS3′′) and, thus, is less favorable. Decoordi-
nation of the water cluster from 7′′ gives the Au-carbene 8′′
21
exergonically. A subsequent direct 1,2-Si shift (TS5′′, 16.4
kcal/mol activation free energy) produces indolizine 10′′,
which is in complete agreement with the experimentally
observed formation of the C2-silyl-substituted products. A
direct 1,2-H shift in 8′′ via TS6′′ is kinetically not feasible
owing to its very high, over 30 kcal/mol, barrier.
Acknowledgment. This work was supported by the
Natural Science Foundation of China (20872105 and
21002073) and the National Institutes of Health of the U.S.
(GM-64444).
Supporting the above DFT predictions, a notable loss
(
Scheme 1, D) and incorporation (Scheme 1, E) of the
Supporting Information Available: Computational and
experimental details as well as full citation of computational
methods. This material is available free of charge via the
Internet at http://pubs.acs.org.
D-label were observed in the Au(I)- and Au(III)-catalyzed
cycloisomerizations of the silyl-substituted alkynes 1d and
1
e, analogously to that for the terminal alkynes 1a-c.
In summary, the mechanism of the Au-catalyzed cycloi-
OL1024794
somerization of propargylpyridines into indolizines was
investigated using DFT computational and experimental
studies. It was found that this transformation occurs via a
sequence of steps consisting of (a) formation of the vinyl-
(
22) For selected examples of a transition-metal-catalyzed synthesis of
2
2
indolizines, see: (a) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org.
Lett. 2007, 9, 3433. See also: (b) Chernyak, D.; Skontos, C.; Gevorgyan,
V. Org. Lett. 2010, 12, 3242. (c) Chernyak, D.; Gadamsetty, S. B.;
Gevorgyan, V. Org. Lett. 2008, 10, 2307. (d) Schwier, T.; Sromek, A. W.;
Yap, D. M. L.; Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007,
129, 9868. (e) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem.
Soc. 2001, 123, 2074. (f) Hardin, A. R.; Sarpong, R. Org. Lett. 2007, 9,
4547. (g) Liu, Y.; Song, Z.; Yan, B. Org. Lett. 2007, 9, 409. (h) Chuprakov,
S.; Gevorgyan, V. Org. Lett. 2007, 9, 4463. (i) Yan, B.; Zhou, Y.; Zhang,
H.; Chen, J.; Liu, Y. J. Org. Chem. 2007, 72, 7783. (j) Yan, B.; Liu, Y.
Org. Lett. 2007, 9, 4323. (k) Smith, C. R.; Bunnelle, E. M.; Rhodes, A. J.;
Sarpong, R. Org. Lett. 2007, 9, 1169. (l) Chuprakov, S.; Hwang, F. W.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2007, 46, 4757. (m) Su, S.; Porco,
J. A., Jr. J. Am. Chem. Soc. 2007, 129, 7744. (n) Chernyak, N.; Gevorgyan,
V. Angew. Chem., Int. Ed. 2010, 49, 2743.
(
21) For selected examples of a 1,2-Si migration over a 1,2-H shift to
Au-carbene centers, see: (a) Dudnik, A. S.; Xia, Y.; Li, Y.; Gevorgyan, V.
J. Am. Chem. Soc. 2010, 132, 7645. For 1,2-Hal shift, see: (b) Xia, Y.;
Dudnik, A. S.; Gevorgyan, V.; Li, Y. J. Am. Chem. Soc. 2008, 130, 6940.
(
c) Dudnik, A. S.; Sromek, A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.;
Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 1440. (d) Sromek, A. W.;
Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500. For 1,2-
alkyl shifts to cationic centers, see: (e) Davies, P. W.; Martin, N. Org. Lett.
2
009, 11, 2293. Also see: (f) Dudnik, A. S.; Gevorgyan, V. Angew. Chem.,
Int. Ed. 2007, 46, 5195. (g) Crone, B.; Kirsch, S. F. Chem.sEur. J. 2008,
4, 3514.
1
Org. Lett., Vol. 12, No. 23, 2010
5541