N-heterocyclic carbene-catalyzed cascade reaction involving the hydroacylation of unactivated alkynes

Article abstract of DOI:10.1021/ja102130s

The N-heterocyclic carbene (NHC)-catalyzed hydroacylation of unactivated alkynes to provide α,β-unsaturated ketones is reported. In addition, a rare case of an efficient and selective dually NHC-catalyzed cascade reaction involving the hydroacylation of a

Full text of DOI:10.1021/ja102130s

Published on Web 04/12/2010
N-Heterocyclic Carbene-Catalyzed Cascade Reaction Involving the
Hydroacylation of Unactivated Alkynes
Akkattu T. Biju, Nathalie E. Wurz, and Frank Glorius*
Organisch-Chemisches Institut der Westfa¨lischen Wilhelms-UniVersita¨t Mu¨nster, Corrensstrasse 40, 48149 Mu¨nster, Germany
Received March 12, 2010; E-mail: glorius@uni-muenster.de
Table 1. Hydroacylation of Unactivated Alkynesa
The transition-metal-catalyzed hydroacylation of alkenes is an
attractive, inherently atom-economical transformation that has found
many applications in organic synthesis.1 Intriguingly, the same
transformation of actiVated olefins, the Stetter reaction,2 can also be
organocatalyzed by cyanide or N-heterocyclic carbenes (NHCs).3 Very
recently, and related to the work of She et al.,4 we reported the NHC-
organocatalyzed hydroacylation of unactivated double bonds.5 Re-
markably, the corresponding transition-metal-catalyzed hydroacylation
entry
X
R1
R2
product
yield (%)
reaction of alkynes,6 which results in the formation of valuable R,ꢀ-
unsaturated ketones, is much less common, and to the best of our
knowledge, the NHC-organocatalyzed hydroacylation of alkynes has
not been reported. The latter would be attractive, since it avoids the
use of transition-metal catalysts and prevents undesired decarbonylation
pathways. Herein, we report the NHC-organocatalyzed hydroacylation
of unactivated alkynes, which leads to the formation of R,ꢀ-unsaturated
chromanones (eq 1), and the application of this reaction in a unique
cascade process involving hydroacylation of an unactivated triple bond
followed by an intermolecular Stetter reaction (eq 2).
1
2
3
4
5
6
7
8
9b
O
O
O
O
O
O
O
O
H
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
86
95
78
84
72
74
78
80
63
3-OMe
5-Cl
5-F
H
4-MeOC6H4
4-MeC6H4
4-EtOC(O)C6H4
2-FC6H4
H
H
H
H
NTs
Ph
a General conditions: 1 (1.0 mmol), 3 (5 mol %), K2CO3 (10 mol %),
THF (2.0 mL), 70 °C, 2 h; isolated yields are reported. b Run on a 0.35
mmol scale using 10 mol % 3 and 20 mol % K2CO3 for 4 h.
Table 2. NHC-Catalyzed Hydroacylation-Stetter Cascade: Scope
of Propargylic Aldehydesa
We commenced our study with the organocatalyzed hydroacylation
of unactivated internal alkynes 1 (Table 1). Treatment of 1a with the
sterically hindered carbene generated from thiazolium salt 37 (5 mol
%) by deprotonation with K2CO3 resulted in smooth formation of
chromanone 2a, which bears a synthetically valuable exocyclic olefin,
as a single isomer in 86% yield (Table 1, entry 1). Variations on both
aromatic rings were well-tolerated, providing good yields for electron-
donating and -withdrawing substituents. Moreover, the reaction could
also be successfully run with a nitrogen tether, furnishing quinolin-
4-one 2i (entry 9). Competition experiments of differently substituted
alkynes revealed that the rate increases in the order 1e (4-OMe) < 1a
(4-H) < 1g (4-CO2Et), with 1g reacting ∼55 times faster than 1e.8,9
Thus, it is reasonable to assume that formation of the Breslow
intermediate10 is reversible under the reaction conditions and that the
alkyne plays an active role in the rate-determining step, with electron-
poor alkynes reacting faster than electron-rich ones.
a General conditions: 4 (1.0 mmol), 5a (1.0 mmol), 3 (5 mol %), K2CO3
(10 mol %), THF (2.0 mL), 70 °C, 2 h; Ar ) 4-ClC6H4. Isolated yields are
b
1
given. dr based on H NMR analysis of the crude reaction mixture.
In view of these interesting results and since R,ꢀ-unsaturated ketones
can act as substrates in the Stetter reaction, we envisioned a dually
NHC-catalyzed hydroacylation cascade comprising an initial hydroa-
cylation of an unactivated triple bond and a subsequent intermolecular
Stetter reaction. Cascade catalysis, with its multiple bond-forming
events, represents an efficient method for the rapid construction of
organic molecules,11 often reducing labor and waste and allowing the
use of more readily available starting materials for a given transforma-
tion.12 Moreover, reactions that result in reactive or labile intermediates
can often only be utilized by means of cascade catalysis. Although
organocatalysts play a prominent role in cascade catalysis13 and NHC-
catalyzed reactions have found widespread applications,3,14 the use
of NHCs in this realm of catalysis has received only scant attention.15
To test our hypothesis, we employed a second aldehyde as the
coupling partner for enone 2 to yield a chromanone with a 1,4-diketone
motif (eq 2). Intriguingly, in this process, many selectivity issues arose,
and the formation of undesired benzoin and Stetter products could be
largely suppressed by using the NHC catalyst derived from 3 (in
contrast to other NHCs).8
A series of substrates with different substituents on the aromatic
ring of 4 was examined (Table 2). The unsubstituted parent system
bearing a terminal alkyne worked well (6a),16 and various electron-
9
5970 J. AM. CHEM. SOC. 2010, 132, 5970–5971
10.1021/ja102130s  2010 American Chemical Society

C O M M U N I C A T I O N S
donating groups at the 2-position were tolerated very well (6b-d),
with isolated yields above 90% in each case. Also, aldehydes containing
different halogen substituents or a trifluoromethyl group afforded the
corresponding chromanones (6e-h) in good yields. Finally, a sub-
stituent on the progargylic moiety was also well-tolerated, giving the
product in 70% yield with a 3:1 trans/cis ratio.
In addition, we also examined the variation of substituents on
aldehyde 5 (Table 3). Benzaldehyde and other aromatic aldehydes
bearing substituents in the 2- or 3-position afforded the chromanones
in good yields (6l-q). In what can be seen as an intramolecular
competition experiment, the 2-allyloxy-substituted substrate (entry 4)
was transformed into 6o in 65% yield, demonstrating the preferential
attack of the acyl anion equivalent on the triple bond over the one on
the double bond in the hydroacylation step. Moreover, various electron-
donating and -withdrawing groups in the 4-position of the ring were
well-tolerated (6r-u). Gratifyingly, heterocyclic and aliphatic alde-
hydes also provided good yields of the desired products (6w-x),
significantly expanding the scope of this novel cascade reaction.
Supporting Information Available: Experimental and characteriza-
tion details. This material is available free of charge via the Internet at
http://pubs.acs.org.
References
(1) For an excellent review, see: Willis, M. C. Chem. ReV. 2010, 110, 725.
(2) (a) Stetter, H.; Schreckenberg, M. Angew. Chem., Int. Ed. Engl. 1973, 12,
81. (b) Stetter, H.; Kuhlmann, H. Angew. Chem., Int. Ed. Engl. 1974, 13,
539.
(3) For reviews of NHC organocatalysis, see: (a) Nair, V.; Vellalath, S.; Babu,
B. P. Chem. Soc. ReV. 2008, 37, 2691. (b) Enders, D.; Niemeier, O.;
Henseler, A. Chem. ReV. 2007, 107, 5606. (c) Marion, N.; D´ıez-Gonza´lez,
S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (d) Phillips, E. M.;
Chan, A.; Scheidt, K. A. Aldrichimica Acta 2009, 42, 55.
(4) (a) He, J.; Tang, S.; Liu, J.; Su, Y.; Pan, X.; She, X. Tetrahedron 2008,
64, 8797. For hydroacylation of nitriles, see: (b) Vedachalam, S.; Zeng, J.;
Gorityala, B. K.; Antonio, M.; Liu, X.-W. Org. Lett. 2010, 12, 352.
(5) Hirano, K.; Biju, A. T.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131,
14190.
(6) For selected papers, see: (a) Jun, C.-H.; Lee, H.; Hong, J.-B.; Kwon, B.-I.
Angew. Chem., Int. Ed. 2002, 41, 2146. (b) Tanaka, K.; Fu, G. C. J. Am.
Chem. Soc. 2001, 123, 11492. (c) Tsuda, T.; Kiyoi, T.; Saegusa, T. J. Org.
Chem. 1990, 55, 2554. For a related gold-catalyzed hydroacylation, see:
(d) Skouta, R.; Li, C.-J. Angew. Chem., Int. Ed. 2007, 46, 1117.
(7) (a) Lebeuf, R.; Hirano, K.; Glorius, F. Org. Lett. 2008, 10, 4243. (b) Hirano,
K.; Piel, I.; Glorius, F. AdV. Synth. Catal. 2008, 350, 984.
Table 3. Variation of the Coupling Aldehyde 5a
(8) See the Supporting Information for details.
(9) For a mechanistic discussion of related processes, see: (a) Roveda, J.-G.;
Clavette, C.; Hunt, A. D.; Gorelsky, S. I.; Whipp, C. J.; Beauchemin, A. M.
J. Am. Chem. Soc. 2009, 131, 8740. (b) Moran, J.; Gorelsky, S. I.;
Dimitrijevic, E.; Lebrun, M.-E.; Be´dard, A.-C.; Se´guin, C.; Beauchemin,
A. M. J. Am. Chem. Soc. 2008, 130, 17893.
(10) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
entry
R
product
yield (%)
(11) For reviews, see: (a) MacMillan, D. W. C.; Walji, A. M. Synlett 2007,
1477. (b) Chapman, C. J.; Frost, C. G. Synthesis 2007, 1. (c) Wasilke,
J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. ReV. 2005, 105, 1001.
(d) Ajamian, A.; Gleason, J. L. Angew. Chem., Int. Ed. 2004, 43, 3754. (e)
Bruggink, A.; Schoevaart, R.; Kieboom, T. Org. Process Res. DeV. 2003,
7, 622.
1
2
3
4
5
6
7
8
9
10
11
12
13
phenyl
6l
90
66
67
65
82
85
93
90
88
77
86
85
68
2-chlorophenyl
2-methylphenyl
2-allyloxyphenyl
3-bromophenyl
3-methoxyphenyl
4-bromophenyl
4-methylphenyl
4-methoxyphenyl
4-carbomethoxyphenyl
1-naphthyl
6m
6n
6o
6p
6q
6r
6s
(12) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew. Chem., Int. Ed.
2006, 45, 7134.
(13) For reviews, see: (a) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037.
(b) Enders, D.; Grondal, C.; Hu¨ttl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570. For selected examples, see: (c) Jiang, H.; Elsner, P.; Jensen, K. L.;
Falcicchio, A.; Marcos, V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2009,
48, 6844. (d) Simmons, B.; Walji, A. M.; MacMillan, D. W. C. Angew.
Chem., Int. Ed. 2009, 48, 4349. (e) Ishikawa, H.; Suzuki, T.; Hayashi, Y.
Angew. Chem., Int. Ed. 2009, 48, 1304. (f) Wang, J.; Li, H.; Xie, H.-X.;
Zu, L.-S.; Shen, X.; Wang, W. Angew. Chem., Int. Ed. 2007, 46, 9050. (g)
Enders, D.; Hu¨ttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006, 441,
861.
(14) For selected examples of benzoin reactions, see: (a) Enders, D.; Kallfass,
U. Angew. Chem., Int. Ed. 2002, 41, 1743. (b) Enders, D.; Niemeier, O.;
Balensiefer, T. Angew. Chem., Int. Ed. 2006, 45, 1463. (c) Takikawa, H.;
Hachisu, Y.; Bode, J. W.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45,
3492. (d) White, M. J.; Leeper, F. J. J. Org. Chem. 2001, 66, 5124. For
reviews of the Stetter reaction, see: (e) Read de Alaniz, J.; Rovis, T. Synlett
2009, 1189. (f) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632.
Also see: (g) Read de Alaniz, J.; Kerr, M. S.; Moore, J. L.; Rovis, T. J.
Org. Chem. 2008, 73, 2033. (h) Enders, D.; Breuer, K.; Runsink, J. HelV.
Chim. Acta 1996, 79, 1899. For selected work in homoenolate chemistry,
see: (i) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
(j) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370. (k) He, M.; Bode, J. W. Org. Lett. 2005, 7, 3131. (l) Nair, V.;
Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736.
(m) Burstein, C.; Tschan, S.; Xie, X.; Glorius, F. Synthesis 2006, 2418.
(n) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 5334. (o) Phillips,
E. M.; Reynolds, T. E.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2416.
(15) For the application of NHCs in cascade catalysis, see: (a) Lathrop, S. P.;
Rovis, T. J. Am. Chem. Soc. 2009, 131, 13628. (b) Ye, W.; Cai, G.; Zhuang,
Z.; Jia, X.; Zhai, H. Org. Lett. 2005, 7, 3769. (c) Stetter, H.; Kuhlmann,
H. Org. React. 1991, 40, 407.
6t
6u
6v
6w
6x
2-furyl
isopropyl
a General conditions: 4b (1.0 mmol), 5 (1.0 mmol), 3 (5 mol %), K2CO3
(10 mol %), THF (2.0 mL), 70 °C, 2 h. Isolated yields are given.
This novel methodology was applied to the one-pot synthesis of
benzopyranopyrrole derivative 7 by generation of the chromanone
derivative through a hydroacylation-Stetter reaction cascade followed
by condensation with p-toluidine (eq 3):
In conclusion, we have developed an NHC-organocatalyzed hy-
droacylation of unactivated alkynes to provide R,ꢀ-unsaturated ketone
products.17 In addition, we have also reported a rare case of an efficient
and selective dually NHC-catalyzed cascade reaction involving the
hydroacylation of alkynes and a subsequent intermolecular Stetter
reaction.
(16) Treatment of 4a with the carbene generated from 3 resulted in the formation
of chromanone 4a′ in 86% yield, presumably by the addition of second
molecule of 4a to the intermediate enone. For a related report, see: Stetter,
H.; Bender, H.-J. Angew. Chem., Int. Ed. Engl. 1978, 17, 131.
Acknowledgment. Financial support by the Deutsche Fors-
chungsgemeinschaft (SPP 1179), the Alexander von Humboldt Foun-
dation (A.T.B.), and the Deutsche Telekom Stiftung (N.E.W.) is
gratefully acknowledged. The research of F.G. was supported by the
Alfried Krupp Prize for Young University Teachers of the Alfried
Krupp von Bohlen und Halbach Foundation. We also thank Marwin
Segler for assistance.
(17) For the addition of aldehydes to activated alkynes using stoichiometric
amounts of NHC, see: (a) Ma, C.; Yang, Y. Org. Lett. 2005, 7, 1343. (b)
Ma, C.; Ding, H.; Wu, G.; Yang, Y. J. Org. Chem. 2005, 70, 8919.
JA102130S
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