Au-containing all-carbon 1,4-dipoles: Generation and [4 + 2] annulation in the formation of carbo-/heterocycles

Article abstract of DOI:10.1021/ja077948e

A novel concept of Au-containing all-carbon 1,n-dipoles is advanced. From 1-(1-alkynyl)cyclopropyl ketones, Au-containing all-carbon 1,4-dipoles are presumably generated in situ and can efficiently participate in [4 + 2] annulation with dipolarophiles inc

Full text of DOI:10.1021/ja077948e

Published on Web 01/19/2008
Au-Containing All-Carbon 1,4-Dipoles: Generation and [4 + 2] Annulation in
the Formation of Carbo-/Heterocycles
Guozhu Zhang, Xiaogen Huang, Guotao Li, and Liming Zhang*
Department of Chemistry/216, UniVersity of NeVada, Reno, 1664 North Virginia Street, Reno, NeVada 89557
Received October 16, 2007; E-mail: lzhang@ unr.edu
Scheme 1. Au-Containing All-Carbon 1,n-Dipole: Concept and
Reactivity
Au catalysis is a recent phenomenon that has attracted much
attention and resulted in a variety of versatile synthetic methods.1
Au-catalyzed cyclizations or cycloisomerizations have thus far been
the major focus of this rapidly evolving research area, rendering a
diverse range of functionalized cyclic structures. Intermolecular
cycloaddition/annulation reactions are powerful methods for rapidly
increasing molecular complexities and constructing polycyclic
structures; however, Au complexes have been of limited use in
catalyzing this versatile class of reactions except in a few studies.2
Our continued effort in exploring new Au chemistry and
conceiving of novel Au catalysis has led to a new concept: Au-
containing all-carbon 1,n-dipoles. Charge-separated carbon chains,
i.e., all-carbon 1,n-dipoles, are usually transient species and often
difficult to harness toward cycloaddition/annulation reactions.3,4
However, we envision that the negatively charged end of such a
dipole can be masked by a Au complex, thus substantially tempering
its nucleophilicity (i.e., intermediate A, Scheme 1). Consequently,
the dipole becomes more stable and could participate in [n + m]
annulation processes if the dipole chain is not long enough for self-
cyclization.5 We anticipate that the cationic end of such a dipole
can initiate a bimolecular process by reacting with a dipolarophile,
relaying the positive charge close to the Au-capped anionic end
(i.e., the Au-C bond). The Au-C bond, preferably a Au-C(sp2)
bond, could then react with the cationic center,6 forming a second
bond and thus the cycloadduct (Scheme 1).
Scheme 2. Formation of Au-Containing All-Carbon 1,4-Dipoles
from 1-(1-Alkynylcyclopropyl) Ketones
Table 1. [4 + 2] Annulation of Ketone 1 and Indole 2: Condition
Optimization
yield
(%)b
conv.
entry
catalyst
conditionsa
2/1
(%)
1
2
3
5 mol % IPrAuNTf2
5 mol % PtCl2
5 mol % AuCl
DCE, rt, 8 h
toluene, 80 °C, 8 h
DCE, rt, 8 h
1.5 56
72
74
85
74
c
1.5
1.5
3
6
4
5
6
5 mol % Ph3PAuNTf2 DCE, rt, 8 h
1.5 19
5 mol % TsOH
DCE, rt, 8 h
DCE, rt, 8 h
1.5
1.5
c
2
d
5 mol % LAuCl2
11
To put this concept into practice, we sought to generate Au-
containing all-carbon 1,4-dipoles, which would undergo favorable
stepwise [4 + 2] annulation and at the same time minimize self-
cyclization. One system that attracted our attention is the 1-(1-
alkynyl)cyclopropyl ketones used previously by Zhang and Schmalz7
for gold(I)-catalyzed formation of trisubstituted furans. While the
mechanism was not completely defined in their study, we envisioned
that furan intermediate C could be formed via oxocarbenium B
from monocyclic substrates (Scheme 2). Importantly, intermediate
C has charge separation and can serve as an example of the Au-
containing all-carbon 1,4-dipoles. Herein, we report our study in
employing this type of novel dipoles in [4 + 2] annulations, which
lead to the formation of not only 6-membered carbocycles but also
oxygen-/nitrogen-containing heterocycles in good efficiencies and
excellent regioselectivities.
We began by treating a mixture of cyclopropyl ketone 1 and
1-(2-ben-zenesulfonylethyl)-1H-indole (2)8 with IPrAuNTf29 [1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidenegold(I) bis(trifluoro-
methanesulfonyl)imide, 5 mol %] at room temperature. Gratifyingly,
the [4 + 2] annulation indeed happened, and tetracyclic furan 310
was formed in 56% yield with 28% of ketone 1 left after 8 h (entry
1, Table 1). Optimization of the reaction conditions, as shown in
Table 1, led to 87% yield of adduct 3 when 3 equiv of indole 2
was used and the reaction was run at 70 °C with 0.1 M of substrate
concentration (entry 10). It is notable that TsOH did not catalyze
the reaction (entry 5) and elevated reaction temperatures facilitated
the conversion.
7
8
9
10
5 mol % IPrAuNTf2
5 mol % IPrAuNTf2
5 mol % IPrAuNTf2
DCE, 50 °C, 12 h
DCE, 50 °C, 2 h
DCE, 70 °C, 15 min
1.5 59
100
100
100
3
3
3
69
78
5 mol % IPrAuNTf2 DCE, 70 °C, 15 min
87e 100
a The concentration of 1 is 0.05 M except in entries 9 and 10, where 0.1
M was used. b Reaction run in vial; yield estimated by 1H NMR using diethyl
phthalate as internal standard. c No reaction. d L ) pyridine-2-carboxylato.
e Flask reaction; isolated yield.
The scope of this cycloaddition was then promptly studied, and
the results are shown in Table 2. Various 1-(1-alkynyl)cyclopropyl
ketones (i.e., 4) were allowed, and [4 + 2] annulations proceeded
in mostly good to excellent efficiencies. Reaction of ketone 4
containing an additional substitution11 at the cyclopropane ring (i.e.,
R3 ) Me or Ph) led to highly regioselective formation of the adduct
with the substituent R to the indoline ring (e.g., 5b-5g) although
the diastereoselectivities12 were low. Tetracyclic indoles 5d and 5f
were isolated in fairly good overall yield upon subsequent dehy-
drogenation with MnO2 in order to simplify their characterization.
Various substituents including cyclopropyl, cyclohexyl, phenyl, and
oxygenated alkyl groups, were allowed at the alkyne terminus and
at the carbonyl group, but a sterically demanding cyclohexyl group
at the alkyne terminus led to only 47% yield of 5g along with a
substantial amount of uncyclized indole 7. In addition to sulfonyl-
ethyl indole 2, PMB-protected indole 6 was also suitable (e.g., 5d).
Expanding the scope of this chemistry using ketones/aldehydes
as the dipolarophile was surprisingly uneventful. As shown in Table
3, this [4 + 2] annulation worked well with carbonyl compounds
9
1814
J. AM. CHEM. SOC. 2008, 130, 1814-1815
10.1021/ja077948e CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. [4 + 2] Annulation of Ketone 1 and Indole 2: Scope
(Scheme 2) is most likely the reactive intermediate instead of
oxocarbenium B for the subsequent [4 + 2] annulation as
nucleophilic attack of the methine group of the cyclopropane ring
in B is expected to be sterically disfavored. The cation-initiated
nature of the [4 + 2] annulation is further supported by the
observation that isomeric trisubstituted furan 11 was formed
exclusively when cyclopropyl aldehyde 10 was used (eq 2). In this
reaction, the oxocarbenium intermediate formed upon the nucleo-
philic attack by acetaldehyde selectively cyclized to the furan
2-position, favored sterically and likely electronically, suggesting
the weak nucleophilic nature of the alkenylgold moiety.
Studya
In summary, a novel concept of Au-containing all-carbon 1,n-
dipoles is advanced, and its application in [4 + 2] annulation led
to efficient formation of 6-membered carbo-/heterocycles. Polycy-
clic, fully substituted furans were easily accessible. Further ap-
plications of this novel concept are to be pursued.
Acknowledgment. We thank the generous financial support by
ACS PRF (43905-G1), ORAU, and Merck. The acquisition of an
NMR spectrometer and upgrade of an existing NMR spectrometer
are funded by NSF CHE-0521191.
a The concentration of 4 was 0.1 M, and 3 equiv of 2 or 6 was used.
b After reaction, the reaction mixture was treated with excess MnO2 at
70 °C for 3 h.
Supporting Information Available: Experimental procedures,
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
Table 3. [4 + 2] Cycloaddition with Aldehyde/Ketones
References
(1) For recent reviews on gold catalysis, see: (a) Zhang, L.; Sun, J.; Kozmin,
S. A. AdV. Synth. Catal. 2006, 348, 2271-2296. (b) Jimenez-Nunez, E.;
Echavarren, A. M. Chem. Commun. 2007, 333-346. (c) Gorin, D. J.;
Toste, F. D. Nature 2007, 446, 395-403. (d) Fu¨rstner, A.; Davis, P. W.
Angew. Chem., Int. Ed. 2007, 46, 3410-3449. (e) Hashmi, A. S. K. Chem.
ReV. 2007, 107, 3180-3211.
(2) (a) Asao, N.; Takahashi, K.; Lee, S.; Kasahara, T.; Yamamoto, Y. J. Am.
Chem. Soc. 2002, 124, 12650-12651. (b) Johansson, M. J.; Gorin, D. J.;
Staben, S. T.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 18002-18003.
(c) Kusama, H.; Miyashita, Y.; Takaya, J.; Iwasawa, N. Org. Lett. 2006,
8, 289-292. (d) Gorin, D. J.; Dube, P.; Toste, F. D. J. Am. Chem. Soc.
2006, 128, 14480-14481. (e) Schelweis, M.; Dempwolff, A. L.; Rominger,
F.; Helmchen, G. Angew. Chem., Int. Ed. 2007, 46, 5598-5601. (f) Hsu,
Y.-C.; Datta, S.; Ting, C.-M.; Liu, R.-S. Org. Lett. 2008. 10, 521-524.
For a review on [4 + 2] benzannulation, see: (g) Patil, N. T.; Yamamoto,
Y. ArkiVoc 2007, (V), 6-19.
(3) For reviews on all-carbon 1,3-dipoles and their surrogates, see: (a)
Yamago, S.; Nakamura, E. Org. React. 2002, 61, 1-217. (b) Little, R.
D. ComprehensiVe Organic Synthesis, 1st ed.; Trost, B. M., Fleming, I.,
Eds.; Pergamon: Oxford; New York, 1991; Vol. 3, pp 239-270. (c) Chan,
D. M. T. ComprehensiVe Organic Synthesis, 1st ed.; Trost, B. M., Fleming,
I., Eds.; Pergamon: Oxford; New York, 1991; Vol. 3, pp 271-314. For
our recent studies evoking all-carbon 1,3-dipoles, see: (d) Huang, X.;
Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398-6399.
(4) For examples of surrogates of all carbon 1,4-dipoles, see: (a) Zhu, X.-F.;
Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716-4717. (b) Wurz,
R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234-12235. (c) Hauser,
F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178.
of various natures, including benzaldehyde, pivalaldehyde, anisal-
dehyde, cyclohexenone, acetophenone, and 3-(4-methoxyphenyl)-
propenal, and dihydropyran-fused, fully substituted furans 8 were
isolated in fairly good to excellent yields. The tolerance of steric
hindrance and the allowance of conjugated enal/enone substrates
are noteworthy, and products containing quaternary carbon centers
and functionalized substituents can be easily accessed. Similar to
the indole cases, the [4 + 2] annulation of anisaldehyde with 4c
containing a methyl group at the cyclopropane ring also proceeded
with excellent regioselectivity (eq 1).
To our delight, both imines and silyl enol ethers are suitable
dipolarophiles as well, and two examples are shown in eqs 3 and
4. Further examination of other potential dipolarophiles revealed
that furan, N-methylpyrrole, benzofuran, thiophene, and styrene did
not participate in the [4 + 2] annulation reactions under the current
reaction conditions.
(5) We have previously reported a study involving the generation and
cyclization of Au-containing all-carbon 1,6-dipoles, see: Wang, S.; Zhang,
L. J. Am. Chem. Soc. 2006, 128, 14274-14275.
(6) The reaction between an electrophile and an alkenylgold is most likely
involving the attack of the electrophile by the alkene π-electrons
accompanied by simultaneous Au-C bond cleavage. For selected
examples, see: (a) Shi, Z.; He, C. J. Am. Chem. Soc. 2004, 126, 5964-
5965. (b) Zhang, L. J. Am. Chem. Soc. 2005, 127, 16804-16805. (c)
Reference 5. (d) Jimenez-Nunez, E.; Claverie, C. K.; Nieto-Oberhuber,
C.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5452-5455.
(7) Zhang, J. L.; Schmalz, H. G. Angew. Chem., Int. Ed. 2006, 45, 6704-
6707. For the first study of Au-catalyzed cyclization of propargylic
ketones, see: Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M.
Angew. Chem., Int. Ed. 2000, 39, 2285-2288.
(8) The use of the polar 2-benzenesulfonylethyl group to protect indole is to
facilitate product purification.
(9) (a) Li, G.; Zhang, L. Angew. Chem., Int. Ed. 2007, 46, 5156-5159. (b)
Ricard, L.; Gagosz, F. Organometallics 2007, 26, 4704-4707.
(10) The expected cis ring fusion of 3 was supported by 1D NOESY.
(11) These substituted ketones 4 were prepared diastereomerically pure; see
the Supporting Information for details.
(12) The diastereomers were not separable. In the case of 5c, 1D NOESY
studies indicated that the isomer with the Me group residing on the concave
side of the tetracycle was the major one.
The high regioselectivities observed with substituted cyclopropyl
ketones suggest that the Au-containing all-carbon 1,4-dipole C
JA077948E
9
J. AM. CHEM. SOC. VOL. 130, NO. 6, 2008 1815