Direct carbocyclization of aldehydes with alkynes: Combining gold catalysis with aminocatalysis

Article abstract of DOI:10.1021/ol800092p

A combination of gold(l) complexes and amine bases catalyzes the 5-exo-dig cyclization of formyl alkynes. This direct α-functionalization of aldehydes with unactivated alkynes does not involve the use of preformed enol equivalents.

Full text of DOI:10.1021/ol800092p

ORGANIC
LETTERS
2008
Vol. 10, No. 5
1025-1028
Direct Carbocyclization of Aldehydes
with Alkynes: Combining Gold
Catalysis with Aminocatalysis
Jo1rg T. Binder, Benedikt Crone, Timm T. Haug, Helge Menz, and
Stefan F. Kirsch*
Department Chemie, Technische UniVersita¨t Mu¨nchen, Lichtenbergstrasse 4,
85747 Garching, Germany
stefan.kirsch@ch.tum.de
Received January 15, 2008
ABSTRACT
A combination of gold(I) complexes and amine bases catalyzes the 5-exo-dig cyclization of formyl alkynes. This direct
aldehydes with unactivated alkynes does not involve the use of preformed enol equivalents.
r-functionalization of
Cyclization reactions involving homogeneous gold catalysts
as carbophilic Lewis acids have emerged as a powerful
strategy to construct complex carbocyles.1 Among the many
different C-C bond formations that proceed through a gold-
(I)-catalyzed activation of alkynes toward nucleophilic attack,
the addition of activated methylene compounds such as
malonates and â-ketoesters to an unactivated alkyne (Scheme
1) has been particularly well-studied.2 However, less eno-
lizable carbonyls lack the required nucleophilicity to react
directly with gold(I)-complexed alkynes under C-C bond-
forming R-functionalization, instead suffering an initial C-O
bond formation.3,4 As an alternative strategy, a variety of
enol equivalents derived from ketones and aldehydes were
employed in gold(I)-catalyzed cyclization reactions. For
instance, electron-rich alkyl enol ethers,5 silyl enol ethers,6
silyl ketene amides,7 and enamines8 efficiently attack gold-
(I)-alkyne complexes, although their synthetic utility is
Scheme 1. Combining Gold Catalysis with Enamine Catalysis
(1) (a) Hashmi, A. S. K. Chem. ReV. 2007, 107, 2180. (b) Jime´nez-Nunez,
E.; Echavarren, A. M. Chem. Commun. 2007, 333. (c) Fu¨rstner, A.; Davies,
P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (d) Gorin, D. J.; Toste, F. D.
Nature 2007, 446, 395. (e) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
(f) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45,
7896. (g) Hoffmann-Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3,
387.
(2) (a) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2004, 43, 5350. (b) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F.
D. J. Am. Chem. Soc. 2004, 126, 4526.
10.1021/ol800092p CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/31/2008

Table 1. Effect of Catalysts on the Cyclization of 1a
yield [%]a
entry
catalyst A (mol %)
catalyst B (mol %)
conditions
1a:2a:3a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
120 °C, toluene, 24 h
70 °C, CDCl3, 6 h
70 °C, CDCl3, 6 h
70 °C, CDCl3, 6 h
70 °C, CDCl3, 6 h
70 °C, CDCl3, 10 h
70 °C, CH3NO2, 6 h
70 °C, CDCl3, 3 h
70 °C, CDCl3, 3 h
70 °C, CDCl3, 3 h
70 °C, CDCl3, 6 h
70 °C, CDCl3, 2 h
70 °C, CDCl3, 24 h
70 °C, CDCl3, 2 h
120 °C, toluene, 24 h
100:0:0b
0:0:0b
(Ph3P)AuSbF6 (10)
[(Ph3PAu)3O]BF4 (10)
82:0:0
100:0:0b
0:0:82
0:0:75
0:0:80
0:0:86
0:0:83
0:0:74
0:0:74
0:0:13
0:0:16
0:0:59
0:0:50
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
HN(i-Pr)(c-Hex) (20)
H2N(i-Pr) (20)
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
HN(i-Pr)2 (20)
(Ph3P)AuSbF6 (10)
(Ph3P)AuSbF6 (2)
(Ph3P)AuSbF6 (10)
[(Ph3PAu)3O]BF4 (10)
[(Ph3PAu)3O]BF4 (10)
[(Ph3PAu)3O]BF4 (10)
LAuSbF6 (10)c
(Ph3P)AuNTf2 (10)
AgSbF6 (10)
AgOTf (10)
PtCl2 (10)
a Yield of pure product after column chromatography unless otherwise indicated. b The ratios were determined by 1H NMR spectroscopy. c L ) 2-(biphenyl)di-
tert-butylphosphine. d Traces of 3a (<5%) were detected by capillary gas chromatography in the absence of HN(i-Pr)2.
somewhat diminished due to the fact that the synthesis of
these preformed enol equivalents involves an additional
synthetic step.
for the first time catalytically generated enol equivalents in
a gold(I)-catalyzed cyclization reaction and thereby to access
a mode of reaction that leads to the direct R-functionalization
of aldehydes with unactivated alkynes. More specifically,
we hypothesized that the combined use of an amine as a
Lewis base catalyst and a gold(I) complex as a Lewis acid
catalyst should activate formyl alkynes toward a C-C bond
formation not currently possible without employing pre-
formed enol equivalents.11 Herein, we describe the direct
cyclization of formyl alkynes catalyzed by the combined
action of an amine and a cationic gold(I) complex.
On the other hand, simple aldehydes react in an intramo-
lecular Michael reaction with enones by using amines as
organocatalysts.9,10 In this reaction, the catalytically generated
enamine is the actual nucleophilic carbanion equivalent,
which promotes R-carbonyl functionalization with the ap-
propriate electrophile. Given the established capacity of
preformed enamines to cyclize onto gold(I)-alkyne com-
plexes,8 we questioned whether it might be possible to utilize
Since previous studies demonstrated that soft noble-metal
cations catalyze cascade reactions, of which one step is an
intermolecular amine condensation,8d,12 gold(I) π-acids were
likely to maintain their chemoselectivity toward the alkyne
moiety even in the presence of amines and water. To test
this activation concept, the catalyzed cyclization was first
evaluated with use of formyl alkyne 1a (Table 1). In fact,
treatment of formyl alkyne 1a with both (Ph3P)AuSbF6 (10
mol %) and i-Pr2NH (20 mol %) in CDCl3 at 70 °C resulted
in the formation of the cyclization product 3a in 82% isolated
yield, but the reaction did not produce the double bond
isomer 2a that was expected to be initially formed through
(3) For selected examples, see: (a) Hashmi, A. S. K.; Schwarz, L.; Choi,
J.-H.; Frost, T. M. Angew. Chem., Int. Ed. 2000, 39, 2285. (b) Asao, N.
Synlett 2006, 1645. (c) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc.
2006, 128, 12050. (d) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259. (e)
Schwier, T.; Sromek, A. W.; Yap, D. M. L.; Chernyak, D.; Gevorgyan, V.
J. Am. Chem. Soc. 2007, 129, 9868.
(4) For a related Hg(II)-induced carbocyclization, see: Boaventura, M.
A.; Drouin, J. Synth. Commun. 1987, 17, 975.
(5) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem. Eur. J. 2003,
2627.
(6) (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.;
LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991. (b)
Dankwardt, J. W. Tetrahedron Lett. 2001, 42, 5809. (c) Lee, K.; Lee, P. H.
AdV. Synth. Catal. 2007, 349, 2092.
(7) Minnihan, E. C.; Colletti, S. L.; Toste, F. D.; Shen, H. C. J. Org.
Chem. 2007, 72, 6287.
(8) (a) Harrison, T. J.; Patrick, B. O.; Dake, G. R. Org. Lett. 2007, 9,
367. (b) Belmont, P.; Belhadj, T. Org. Lett. 2005, 7, 1793. (c) Harrison, T.
J.; Dake, G. R. Org. Lett. 2004, 6, 5023. (d) Abbiati, G.; Arcadi, A.; Bianchi,
G.; Di Giuseppe, S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68, 6959.
(9) For reviews, see: (a) List, B. Chem. Commun. 2006, 819. (b) Seayad,
J.; List, B. Org. Biomol. Chem. 2005, 3, 719. (c) List, B. Acc. Chem. Res.
2004, 37, 548.
(10) For selected organocatalytic intramolecular Michael reactions, see:
(a) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji,
M. J. Am. Chem. Soc. 2005, 127, 16028. (b) Hechavarria, M. T.; List, B.
Angew. Chem., Int. Ed. 2004, 43, 3958.
(11) For the use of catalytically generated enamines in transition metal-
catalyzed reactions, see: (a) Ibrahem, I.; Co´rdova, A. Angew. Chem., Int.
Ed. 2006, 45, 1952. (b) Ding, Q.; Wu, J. Org. Lett. 2007, 9, 4959.
(12) (a) Binder, J. T.; Kirsch, S. F. Org. Lett. 2006, 8, 2151. (b) Binder,
J. T.; Crone, B.; Kirsch, S. F.; Lie´bert, C.; Menz, H. Eur. J. Org. Chem.
2007, 1636. (c) Harrison, T. J.; Kozak, J. A.; Corbella-Pane´, M.; Dake, G.
R. J. Org. Chem. 2006, 71, 4525. (d) Arcadi, A.; Di Giuseppe, S.; Marinelli,
F.; Rossi, E. AdV. Synth. Catal. 2001, 343, 443.
1026
Org. Lett., Vol. 10, No. 5, 2008

5-exo-dig cyclization.13,14 The reaction can be run at low
catalyst loadings for (Ph3P)AuSbF6 (2 mol %), while
lowering the amine percentage led to a significant loss in
reaction efficiency. In the presence of i-Pr2NH (20 mol %),
[(Ph3PAu)3O]BF4 is slightly superior in terms of practicability
due to the fact that competing decomposition was not
observed. This cyclization reaction is accomplished by using
a wide variety of transition metal catalysts other than (Ph3P)-
AuSbF6 and [(Ph3PAu)3O]BF4 including several gold(I)
complexes as well as silver(I) and platinum(II) salts, albeit
in significantly reduced yields. The identity of the base
catalyst proved to be less relevant as other bases such as
i-PrNH2, pyrrolidine, and (c-C6H11)(i-Pr)NH gave the desired
cyclization product with similar yields.
cyclization followed by double bond migration gave 2-me-
thylcyclopent-1-enecarbaldehyde products 3 (Table 2, entries
1-6). To create all-carbon quaternary stereocenters, we then
employed substrates that bear an additional substituent in
the R-position. In general, R-branched aldehydes were found
to be less reactive in these direct R-functionalizations with
unactivated alkynes. Consequently, a longer reaction time
was required to achieve complete consumption of 1 (Table
2, entries 7-10). As exemplified for the reaction of 1h,
reactions of R-branched aldehydes should be conducted
utilizing [(Ph3PAu)3O]BF4 as π-acid catalyst; in the case of
(Ph3P)AuSbF6, a significant decrease in yield was observed
due to decomposition.
Treatment of cyclic ketones such as 4 with (Ph3P)AuSbF6
(10 mol %) and H2N(i-Pr) (20 mol %) in CDCl3 at 90 °C in
a sealed tube gave the desired cyclization products as well
(eq 1), but the reaction was slowed markedly. In the case of
the five-membered cyclic ketone 6 (n ) 0), cyclization gave
the double bond isomer 8 as the major product.6c Unexpect-
edly, slightly different reaction conditions [10 mol % (Ph3P)-
AuOTf, 20 mol % (c-C6H11)(i-Pr)NH, 150 °C, xylenes]
resulted in a formal [3+2]-cycloaddition16 to produce 9 as a
single diastereoisomer in 67% isolated yield (eq 2). The
structure of compound 9 was established by analysis of 1H-
1H COSY, HMBC, and NOESY data.17
Table 2. Catalyzed Cyclization of Formyl Alkynes
Since the presence of the amine base was required for
cyclization in all cases, this outcome is in accord with the
hypothesis that a combination of a Lewis acidic gold(I)
complex and a Lewis basic amine can act as a viable catalyst
system for the dual activation of formyl alkynes. At least
two conceivable mechanisms can be proposed for this gold-
catalyzed cyclization. In one, product formation may be
rationalized by nucleophilic attack of an enamine intermedi-
a Yield of pure product after column chromatography. Reaction mixture
1
was stirred in a sealed vial until TLC analysis (or H NMR of the crude
reaction mixture) indicated full conversion. b Conditions: substrate, 10 mol
% (Ph3P)AuSbF6, 20 mol % HN(i-Pr)2, 70 °C, CDCl3. c Conditions:
substrate, 7.5 mol % [(Ph3PAu)3O]BF4, 20 mol % HN(i-Pr)(c-Hex), 70 °C,
CDCl3. d Conditions: substrate, 7.5 mol % [(Ph3PAu)3O]BF4, 20 mol %
H2N(i-Pr), 70 °C, CDCl3. e Conditions: substrate, 10 mol % AgOTf, 20
mol % HN(i-Pr)2, 70 °C, CDCl3.
(15) General Procedure. Synthesis of 2h (Table 2, entry 7): A solution
of 1h (100 mg, 0.42 mmol) and (c-C6H11)(i-Pr)NH (20 mol %, 12 mg) in
CDCl3 (0.4 mL) was added to [(Ph3PAu)3O]BF4 (7.5 mol %, 45 mg), and
the reaction vial was sealed, protected from light, and stirred at 70 °C for
18 h (until 1H NMR analysis of the reaction mixture indicated complete
conversion). The mixture was concentrated under reduced pressure.
Purification of the residue by flash chromatography on silica gel (pentanes/
EtOAc ) 95/5) gave 2h as a colorless oil (71 mg, 0.30 mmol, 71%). Rf
0.48 (pentanes/EtOAc ) 90/10); 1H NMR (360 MHz, CDCl3) δ 1.26 (s, 3
H), 2.23 (d, J ) 14.0 Hz, 1 H), 2.92-3.07 (m, 3 H), 3.73 (s, 3 H), 3.74 (s,
3 H), 4.95 (app. t, J ) 2.2 Hz, 1 H), 5.22 (app. t, J ) 1.9 Hz, 1 H), 9.29
(s, 1 H); 13C NMR (90.6 MHz, CDCl3) δ 21.8, 40.5, 41.2, 53.1, 53.1, 56.9,
As revealed in Table 2, a range of formyl alkynes
underwent cycloisomerization catalyzed by a gold(I) complex
and an amine.15 Reaction of R-unbranched aldehydes through
(13) We assume that initially formed 2a isomerizes directly into the more
stable conjugated compound 3a in the presence of HN(i-Pr)2 at 70 °C.
(14) All reactions reported herein can be conducted with 1,2-DCE or
CHCl3 as solvent to provide the cyclization products in mostly identical
yields as accomplished in CDCl3. The use of CDCl3 facilitates the realization
of complete conversion by 1H NMR analysis of the crude reaction mixtures.
58.1, 110.9, 149.5, 171.7, 171.9, 199.8; LRMS (EI) 209 (19%) [M+
-
CH3O], 180 (18%), 152 (95%), 93 (100%); HRMS 209.0815 [209.0814
calcd for C11H13O4 (M+ - CH3O)].
(16) Huang, X.; Zhang, L. J. Am. Chem. Soc. 2007, 129, 6398.
(17) This ring system has not been previously described in the literature.
Org. Lett., Vol. 10, No. 5, 2008
1027

ate onto a Au(I)-alkyne complex as envisaged at the outset
of the project (Scheme 2, A). This hypothesis is supported
this mechanism appears less likely since the use of tertiary
amines such as EtN(i-Pr)2 fails to give significant amounts
of the corresponding cyclization products after 7 d at 70 °C
in CDCl3 utilizing [(Ph3PAu)3O]BF4 as π-acid catalyst. On
the other hand, it merits note that treatment of formyl alkyne
1h with EtN(i-Pr)2 (20 mol %) in CDCl3 at 70 °C gave the
cyclization product 2h in 73% isolated yield when AgOTf
(10 mol %) is used as the Lewis acid catalyst. This
observation may indicate that the silver-catalyzed cyclization
occurs through an in situ enolate generation.
Scheme 2. Possible Mechanism
In conclusion, we have shown that formyl alkynes undergo
previously unknown cyclizations on activation with catalytic
amounts of a Au(I) complex and an amine, thus opening a
new entry into the direct R-functionalization of aldehydes
with unactivated alkynes. Therefore, this protocol constitutes
a valuable supplement to existing methodology for the Au-
(I)-catalyzed cyclization of enol equivalents onto alkynes.
Acknowledgment. This project was supported by the
DFG and the FCI.
Supporting Information Available: Representative
experimental procedures for catalytic formation of 2 and
3, and copies of H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
1
by the fact that aldehydes such as i-PrCHO were found to
undergo condensation with amines under the reaction condi-
tions. An alternative mechanism involves the initial formation
of an aldehyde-derived Au(I)-enolate18 in the presence of
the amine base (Scheme 2, B). In the gold-catalyzed case,
OL800092P
(18) Ito, Y.; Inouye, M.; Suginome, M.; Muratami, M. J. Organomet.
Chem. 1988, 342, C41.
1028
Org. Lett., Vol. 10, No. 5, 2008