Highly stereoselective formal [3 + 3] cycloaddition of enals and azomethine imines catalyzed by N-heterocyclic carbenes

Article abstract of DOI:10.1021/ja0709167

N-Heterocyclic carbenes derived from N-mesityl benzimidazolium salts are effective catalysts for generating homoenolate species from α,β-unsaturated aldehydes. The nucleophilic intermediate adds to azomethine imines, and the resulting activated carbonyl u

Full text of DOI:10.1021/ja0709167

Published on Web 04/04/2007
Highly Stereoselective Formal [3 + 3] Cycloaddition of Enals and Azomethine
Imines Catalyzed by N-Heterocyclic Carbenes
Audrey Chan and Karl A. Scheidt*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road, EVanston, Illinois 60208
Received February 8, 2007; E-mail: scheidt@northwestern.edu
Scheme 1. Proposed Catalytic Pathway
Intermolecular cycloadditions are powerful methods for the
convergent synthesis of cyclic compounds from simple precursors.1
While major advances have been made in the area of metal-cata-
lyzed cycloadditions over the past decade,2 there is great potential
for these reactions using organic molecules as catalysts.3 In 1968,
Dorn and co-workers demonstrated that 3-oxopyrazolidin-1-ium-
2-ides such as 2 are stable and easily handled compounds.4,5 Fu,
Hayashi, and Suga have separately shown that these compounds
are efficient substrates in metal-catalyzed cycloadditions to furnish
five- and six-membered heterocycles.6 We have been interested in
developing new reactions catalyzed by N-heterocyclic carbenes
(NHCs) derived from azolium salts.7 Our recent studies, along with
those of Glorius, Bode, and Nair, have shown that the combination
of NHCs and R,â-unsaturated aldehydes generates unique homo-
enolate species.8,9 The use of an organic molecule to catalyze a
formal [3 + 3] cycloaddition of azomethine imines has yet to be
realized.10 Herein, we report the direct synthesis of pyridazinones
(3) by the NHC-catalyzed reaction of aldehyde (1) and azomethine
imines (2, eq 1).
Table 1. Optimization of Conditionsa
Our proposed pathway for this formal [3 + 3] cycloaddition
involves the addition of an NHC to an R,â-unsaturated aldehyde
(1) to afford the extended Breslow intermediate (I) after addition
and rearrangement (Scheme 1). The homoenolate intermediate
undergoes addition to the azomethine imine (2) and subsequently
generates enol II. After tautomerization of II, the resulting activated
heteroazolium species III releases the NHC catalyst and affords
the pyridazinone (3) by an intramolecular acylation.
A challenge with NHC catalysis is the presence of two separate
electrophiles during a reaction. A successful process must allow
for selective interaction between the carbene and the R,â-unsaturated
aldehyde. Irreversible addition of the carbene to the secondary
electrophile (e.g., azomethine imine) would result in no reaction.
Our studies began with cinnamaldehyde (1a), azomethine imine
2a, and heteroazolium salts A-C (Table 1, entries 1-3). To our
gratification, all three catalysts derived from heteroazolium salts
A-C produced the desired product 4 as a single diastereomer.11
While benzimidazolium salt C afforded the highest yield (39%,
entry 3), the process clearly required improvement. Reactions in
THF required heating to induce homogeneity (entries 4 and 5) but
did not improve yields compared to CH2Cl2. Carefully monitoring
the reaction revealed that shorter times (3 vs 24 h) significantly
improve the yield of 4 (entries 6 and 7). Additionally, increasing
the temperature of the reaction to 40 °C favors the [3 + 3]
cycloaddition manifold with a further increase in yield (79%, entry
8). With these temperature parameters identified, an extensive re-
entry
catalyst
conditions
yield (%)b
drc
1
2
3
4
5
6
7
8
9d
A
B
C
C
C
C
C
C
C
CH2Cl2, 23 °C, 24 h
CH2Cl2, 23 °C, 24 h
CH2Cl2, 23 °C, 24 h
THF, 50 °C, 24 h
35
29
39
15
23
45
59
79
46
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10:1 THF/tBuOH, 50 °C, 24 h
CH2Cl2, 23 °C, 3 h
10:1 THF/tBuOH, 50 °C, 3 h
CH2Cl2, 40 °C, 2 h
CH2Cl2, 40 °C, 2 h
a With 2 equiv of 1a and 1 equiv of 2a. b Isolated yield after purification.
c As determined by H NMR spectroscopy. d With 10 mol % of C and 10
1
mol % of DBU.
examination of different azolium salts confirmed that the placement
of a single N-mesityl substituent on the benzimidazole core is
necessary for good yields. Decreasing the catalyst loading of C
decreases the yield of 4 to 46% (entry 9).
With the optimal parameters established for this formal [3 + 3]
cycloaddition process, we turned out attention to investigate the
scope of this reaction (Table 2, eq 3). A survey of the R,â-
unsaturated aldehyde reveals that the process accommodates
electron-donating groups on the aryl ring (entries 1-5), but electron-
withdrawing groups (entry 8) do not yield products. The reaction
also tolerates â-alkyl substituents and extended dienylic systems
to afford 9 and 10 in moderate yields (entries 6 and 7). An
9
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J. AM. CHEM. SOC. 2007, 129, 5334-5335
10.1021/ja0709167 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Substrate Scopea
esters or amides in excellent yields upon addition of alcohols or
amines. Further studies generating nucleophiles with unique proper-
ties using N-heterocyclic carbene catalysis are ongoing.
Acknowledgment. Research support was generously provided
by NIGMS (RO1 GM73072), Abbott Laboratories, Amgen, 3M,
and Boehringer Ingelheim. A.C. is the recipient of a Dow Chemical
Company Fellowship. We thank FMCLithium, Sigma-Aldrich, and
BASF for providing reagents used in this research, Troy Reynolds
(NU) for assistance with X-ray crystallography, and Prof. Regan
Thomson (NU) for helpful discussions. Funding for the NU
Analytical Services Laboratory has been furnished in part by the
NSF (CHE-9871268).
entry
R
R1
product
yield (%)b
drc
1
2
Ph (1a)
Ph (2a)
4
5
79
76
79
94
77
67
51
0
87
82
93
78
76
67
0
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4-OMePh (1b)
3-OMePh (1c)
2-OMePh (1d)
2-naphthyl (1e)
CH2CH2CH3 (1f)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
3
6
4
7
5
8
6
9
7
HCdCHCH3 (1g) Ph (2a)
10
11
12
13
14
15
16
17
18
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
8
4-ClPh (1h)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (2a)
4-BrPh (2b)
4-FPh (2c)
3-CF3Ph (2d)
3-BrPh (2e)
3-CH3Ph (2f)
3-OMePh (2g)
cyclohexyl (2h)
9
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
10
11
12
13
14
15
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In summary, we have developed the first formal [3 + 3]
cycloaddition reaction catalyzed by N-heterocyclic carbenes. The
addition of an N-mesityl benzimidazolyl carbene to an R,â-
unsaturated aldehyde generates a homoenolate intermediate that
undergoes an addition/acylation sequence with an azomethine imine
to afford new bicyclic heterocycles with excellent diastereoselec-
tivity. The pyridazinone products can be manipulated to provide
(11) Azomethine imines lacking the phenyl substituent on the ring afford
products, but in reduced yields.
(12) The Z(O) enol isomer of I in IV minimizes interactions between the
N-mesityl group and the imine phenyl ring.
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heterocycles are ongoing.
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