N-heterocyclic carbene catalyzed transformations of 3-halopropenals to the equivalents of β-acylvinyl anions

Article abstract of DOI:10.1021/ol902961y

[Chemical equation presented] 3-Halopropenals 1 can behave as an alternative equivalent of β-acylvinyl anions (I) In the presence of N-heterocyclic carbene precursor (IPr-HCI) and DBU to afford cyclic αβ-unsaturated carbonyl derivatives, butenolides 4 and

Full text of DOI:10.1021/ol902961y

ORGANIC
LETTERS
2010
Vol. 12, No. 3
640-643
N-Heterocyclic Carbene Catalyzed
Transformations of 3-Halopropenals to
the Equivalents of ꢀ-Acylvinyl Anions
Yihua Wu, Weijun Yao, Lianjie Pan, Yiping Zhang, and Cheng Ma*
Department of Chemistry, Zhejiang UniVersity, 20 Yugu Road, Hangzhou 310027,
People’s Republic of China
mcorg@zju.edu.cn
Received December 26, 2009
ABSTRACT
3-Halopropenals 1 can behave as an alternative equivalent of ꢀ-acylvinyl anions (I) in the presence of N-heterocyclic carbene precursor
(IPr·HCl) and DBU to afford cyclic r,ꢀ-unsaturated carbonyl derivatives, butenolides 4 and pyrazolone 6, after cyclization with 2 and 5, respectively.
Umpolung reactivity of functional groups allows chemists
the opportunity to view bond disconnections in nontraditional
ways.1 In this context, ꢀ-acylvinyl anions (I) can be
considered as sp2-hybridized umpoled d3 synthons and are
appropriate intermediates to provide a ꢀ-bonded R,ꢀ-unsatur-
ated functionality.2 Traditional methodology toward I or their
equivalents relies on the stoichiometric generation of stabi-
lized carbanions and is hence hampered by some limitations
such as harsh reaction conditions and tedious manipulations.
Therefore, vinylboronate and vinylstannane compounds have
been employed as altenative precursors of I upon treatment
with transition-metal catalysts.3 Whereas significant progress
has been made by these protocols, few organocatalyzed
routes to ꢀ-acylvinyl anions or equivalents for subsequent
ꢀ-functionaliztion exist to date.4
N-Heterocyclic carbene (NHC)-catalyzed redox transfor-
mations of aldehydes constitute an important class of
organocatalysis and have found a broad range of applications
in synthetic organic chemistry.5 Remarkably, the proposed
NHC-bound homoenolate intermediates, generated from R,ꢀ-
unsaturated aldehydes by NHCs, can react with various
electrophiles resulting in a variety of cyclic compounds.6,7
Intriguingly, these annulations only made use of ꢀ-mono-
substituted substrates, presumably due to the instability of
(4) For organocatalyzed ꢀ-protonation of propargylic aldehydes, pro-
posed via allenol or ꢀ-acylvinyl anion intermediates, leading to the synthesis
of R,ꢀ-unsaturated esters, see: (a) Zeitler, K. Org. Lett. 2006, 8, 637. (b)
Maki, B. E.; Chan, A.; Scheidt, K. A. Synthesis 2008, 1306.
(5) For reviews on NHCs as organocatalysts, see: (a) Enders, D.;
Niemeier, O.; Henseler, A. Chem. ReV. 2007, 107, 5606. (b) Enders, D.;
Balensiefer, T. Acc. Chem. Res. 2004, 37, 534. Minireviews: (c) Rovis, T.
Chem. Lett. 2008, 2. (d) Marion, N.; D´ıez-Gonza´lez, S.; Nolan, S. P. Angew.
Chem., Int. Ed. 2007, 46, 2988. Highlights: (e) Christmann, M. Angew.
Chem., Int. Ed. 2005, 44, 2632. (f) Zeitler, K. Angew. Chem., Int. Ed. 2005,
44, 7506. Perspective: (g) Enders, D.; Narine, A. A. J. Org. Chem. 2008,
73, 7857.
(1) Seebach, D. Angew. Chem., Int. Ed. 1979, 18, 239.
(2) For a review, see: Chinchilla, R.; Na´jera, C. Chem. ReV. 2000, 100,
1891.
(3) For a transition-metal-catalyzed coupling reaction, see: (a) Metal-
Catalyzed Cross-Coupling Reactions; Diedrich, F., Stang, P. J., Eds.; Wiley-
VCH: Weinheim, 1998. (b) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95,
2457.
10.1021/ol902961y  2010 American Chemical Society
Published on Web 01/12/2010

related homoenolate intermediates or inherent steric hin-
drance.8 We therefore envisioned that if 3-halo-2-propenals
1 (bearing a electronegative and small halogen atom at the
ꢀ-position) can be attacked by NHCs, we may access to
zwitterions II, which should produce cyclic R,ꢀ-unsaturated
carbonyl derivatives 4 via a tandem cyclization/elimination
process (Scheme 1).9 In conjunction with our efforts on
Table 1. Optimization of the Reaction of 1a and 2aa
entry
3
base
solvent
time (h) yielde (%)
Scheme 1
.
NHC-Catalyzed Reactions to the Equivents of
1
2
3
4
3a DBU
3b DBU
3c DBU
3d DBU
3b DBU
THF
THF
THF
THF
THF
5
2
35
75
18
trace
46
31
23
56
17
7
ꢀ-Acylvinyl Anions I
12
12
12
12
12
2
6
12
3
5b
6c
7
3b Cs2CO3 THF
3b DIPEA THF
8d
9
3b DBU
3b DBU
3b DBU
3b DBU
3b DBU
THF
toluene
CH2Cl2
EtOAc
10
11
12
25
62
THF-tBuOH (10:1)
2
a Reaction conditions: a mixture of 1a (0.75 mmol), 2a (0.5 mmol), 3
(10 mol %), solvent (8 mL), and base (0.75 mmol) in 2 mL of solvent was
added slowly at -20 °C with stirring over 2 h and the mixture reacted for
indicated time. b 0.5 mmol of DBU. c Cs2CO3 was added in one pot. d At
25 °C. e Yield of isolated product. DBU ) 1,8-diazabicyclo[5.4.0]undec-7-ene.
extending the reactivity of NHCs,10 herein we report a novel
reaction that converts substituted 3-halo-2-propenals (1) into
an alternative equivalent of ꢀ-acylvinyl anionic synthons by
NHCs under mild conditions.
triazolium 3c and 3d gave only low yield or trace of product,
respectively (Figure 1 and Table 1, entries 1-4). Among
We initiated our investigation by reacting 3-chloro-3-
phenyl-2-propenal 1a with benzaldehyde in the presence of
carbene precursor 3a (10 mol %) and DBU (12 mol %) in
THF. Disappointingly, no expected cross-coupling products
were observed, even with an excess amount of DBU (150
mol %). In contrast, while switching the electrophile to ꢀ,γ-
unsaturated R-keto ester 2a instead, to our delight, butenolide
4a was obtained in 35% yield (Table 1, entry 1).11,12 An
initial experiment revealed that at least 150 mol % of base
was required to complete the conversion (Table 1, entries 2
vs 5). Of the two common classes of azolium salts,
imidazolium 3a and 3b proved to be effective, whereas
Figure 1. Structures of azolium salts 3.
those tested azolium precursors, sterically more demanding
imidazolium salt 3b was found to be the most efficient
catalyst. A brief solvent screen revealed THF to be optimal,
providing the desired product in 75% yield at -20 °C after
2 h (Table 1, entry 2).
(6) For seminal studies, see: (a) Sohn, S. S.; Rosen, E. L.; Bode, J. W.
J. Am. Chem. Soc. 2004, 126, 14370. (b) Burstein, C.; Glorius, F. Angew.
Chem., Int. Ed. 2004, 43, 6205.
Under the optimized conditions, the scope of the NHC-
catalyzed cyclization/elimination reaction was examined, and
the results are presented in Table 2. This process tolerated a
variety of enones 2, including both electron-rich and electron-
deficient aryl derivatives (Table 2, entries 2, 3, and 7), as
well as heterocyclic and aliphatic examples (Table 2, entries
8 and 9). Additionally, other unsaturated R-keto esters
bearing an extended dienylic system and an alkyne also
underwent the annulation to provide 4d and 4l, respectively
(Table 2, entry 4, and Scheme 2). Moreover, variation in
the aromatic moiety of ꢀ-haloenals was possible, and the
necessary substrates 1 were easily accessible from the
corresponding ketones with Vilsmeier-Haack reagent.13 As
expected, ꢀ-bromo-substituted enal 1b could perform the
(7) For recent reviews on NHC-bound homoenolate, see: (a) Nair, V.;
Vellalath, S.; Babu, B. P. Chem. Soc. ReV. 2008, 37, 2691. (b) Johnson,
J. S. Curr. Opin. Drug DiscoVery DeV. 2007, 10, 691.
(8) For recent examples, see: (a) Rommel, M.; Fukuzumi, T.; Bode,
J. W. J. Am. Chem. Soc. 2008, 130, 17266. (b) Chiang, P.-C.; Rommel,
M.; Bode, J. W. J. Am. Chem. Soc. 2009, 131, 8714. (c) Maki, B. E.;
Patterson, E. V.; Cramer, C. J.; Scheidt, K. A. Org. Lett. 2009, 11, 3942.
(9) For conversion of R-haloaldehyde into acylating agent, see: (a)
Reynolds, N. T.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2004, 126,
9518. (b) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127, 16406.
(10) (a) Ding, H.; Ma, C.; Yang, Y.; Wang, Y. Org. Lett. 2005, 7, 2125.
(b) Ma, C.; Ding, H.; Zhang, Y.; Bian, M. Angew. Chem., Int. Ed. 2006,
45, 7793. (c) Ma, C.; Ding, H.; Wu, G.; Yang, Y. J. Org. Chem. 2005, 70,
8919. (d) Ding, H.; Zhang, Y.; Bian, M.; Yao, W.; Ma, C. J. Org. Chem.
2008, 73, 578.
(11) For reviews of butenolides, see: (a) Carter, N. B.; Nadany, A. E.;
Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1 2002, 2324. (b) Rao, Y. S.
Chem. ReV. 1976, 76, 625. (c) Bellina, F.; Rossi, R. Curr. Org. Chem. 2004,
8, 1089
.
Org. Lett., Vol. 12, No. 3, 2010
641

Table 2. NHC-Catalyzed Reactions of 1 and 2a
Table 3. NHC-Catalyzed Directly Amination of 1 and 5a
time yieldc
b
1, R1
1a, Ph
1a, Ph
1a, Ph
1c, 4-BrC6H4
1i, 4-MeC6H4
1d, 4-MeOC6H4 i-PrO i-PrO 5b
1a, Ph
1a, Ph
R3
R4
5
time (h) yield (%)
entry
1, R1, X
1a, Ph, Cl
1a, Ph, Cl
1a, Ph, Cl
1a, Ph, Cl
1b, Ph, Br
1c, 4-BrC6H4, Cl
1c, 4-BrC6H4, Cl
1c, 4-BrC6H4, Cl
1c, 4-BrC6H4, Cl
1d,4-MeOC6H4,Cl 2e, 2-MeC6H4, Et
1e, 4-NO2C6H4, Cl 2a, Ph, Et
2, R2, R
2a, Ph, Et
2b, 4-FC6H4, Me
2c, 4-ClC6H4, Et
2d, styryl, Et
2a, Ph, Et
2e, 2-MeC6H4, Et
2f, 4-MeOC6H4, Et
2g, 2-fury, Et
2h, nPr, Et
(h)
(%)
entry
1
2
3
4
5
6
7
8
EtO
EtO
5a
12
12
12
12
18
24
12
12
6a, 54
6b, 73
6c, 68
6d, 61
6e, 42
6f, 22
trace
1
2
2
2
2
12
2
3
8
5
4
8
4a, 75
4b, 63
4c, 58
4d, 53
4a, 61
4e, 81
4f, 42
4g, 45
4h, 32
4i, 83
4j, 21
4k, 36
N.R.
i-PrO i-PrO 5b
BnO BnO 5c
i-PrO i-PrO 5b
i-PrO i-PrO 5b
3
4b
5
6
7
8
9
10
11
12
13
Ph
Ph
Ph
MeO 5e
5d
N.R.
a Reaction conditions: 1 (0.5 mmol), 5 (1.5 mmol), and 3b (10 mol %)
in 8 mL of THF and DBU (1.25 mmol) in 2 mL of THF were added slowly
over 2 h at -20 °C and the mixture reacted for the indicated time. b Yield
of isolated product.
3
8
12
1f, styryl, Cl
1g, 1-naphthyl, Cl 2a, Ph, Et
2i, Ph, Me
a Reaction conditions: 1 (0.75 mmol), 2 (0.5 mmol), and 3b (10 mol
%) in 8 mL of THF and DBU (0.75 mmol) in 2 mL of THF were added
slowly over 2 h at -20 °C and the mixture eacted for indicated time. b 20
mol % of 3b. c Yield of isolated product.
electron-rich enal 1d conducted this reaction sluggishly and
rendered the corresponding product 6f in reduced yield,
accompanying by the formation of hydrazine 7 (Table 3,
entry 6).16 Moreover, the electronic property of diazenes
played a critical role in the cyclization reaction; currently,
N,N′-dibenzoyldiazene 5d and azocarboxylate 5e yielded no
desired products.
Scheme 2. Cross-Coupling of 1a and 2j
A postulated catalytic cycle for the NHCs-catalyzed
tandem cross-cyclization/elimination reaction is depicted in
Scheme 3. Thus, 3-chloroenal 1 is first attacked by the in
situ formed imidazolium carbene I to afford ꢀ-chloro-
conjugated Breslow intermediate II,17 which could be
stabilized by resonance to homoenolate III. This in turn
attacks activated diazene 5, followed by tautomerization to
produce zwitterion IV. The latter intermediate undergoes
intramolecular acylation to furnish lactam V with the
similar conversion, albeit in a reduced yield (Table 2, entry
5). Interestingly, it occurs smoothly with a dienal 1f also,
rendering 4k selectively in 36% yield (Table 2, entry 12).
However, the placement of 1-naphthyl in the ꢀ-position, 1g,
provided none of the desired butenolide (Table 2, entry 13).
This result indicated that the steric nature in the aromatic
tether of 1 conducted dramatic effects on this conversion.
The incongruity between the substrate scope of the current
butenolide-forming cyclizations and that of the usual cin-
namaldehyde lactonization6,14 invited further exploration on
their unique reactivity of ꢀ-chloroenals in the prescence of
NHCs. Thus, 1a and different activated diazenes 5 were
reacted to explore the possibility of a direct elctrophilic
amination in the presence of 3b.15 Not surprisingly, while
azodicarboxylate 5a proved to be unsuitable nitrogen-
containing electrophile for cinnamaldehyde amination,15a it
readily cyclized with 1a to afford pyrazolone 6a in the
presence of imidazolium salt 3b and DBU (Table 3, entry
1). By using 3 equiv of diazenes, the reaction scope
accommodated various ꢀ-aryl chloroenals 1 as well as a set
of azodicarboxylates 5a-c (Table 3, entries 1-6). However,
(12) For previous condensation of enals and enones via homoenolate,
see: (a) Nair, V.; Vellalath, S.; Poonoth, M.; Suresh, E. J. Am. Chem. Soc.
2006, 128, 8736. (b) Wadamoto, M.; Phillips, E. M.; Reynolds, T. E.;
Scheidt, K. A. J. Am. Chem. Soc. 2007, 129, 10098. (c) Chiang, P.-C.;
Kaeobamrung, J.; Bode, J. W. J. Am. Chem. Soc. 2007, 129, 3520. (d)
Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 3107. (e) Nair, V.; Babu, B. P.; Vellalath, S.; Varghese,
V.; Raveendran, A. E.; Suresh, E. Org. Lett. 2009, 11, 2507. (f) Kaeobam-
rung, J.; Bode, J. W. Org. Lett. 2009, 11, 677.
(13) Arnold, Z.; Holy´, A. Collect. Czech. Chem. Commun. 1961, 26,
3059. (b) Robertson, I. R.; Sharp, J. T. Tetrahedron 1984, 40, 3095. (c)
Lilienkampf, A.; Johansson, M. P.; Wahala, K. Org. Lett. 2003, 5, 3387,
and references cited therein.
(14) (a) Hirano, K.; Piel, I.; Glorius, F. AdV. Synth. Catal. 2008, 350,
984. (b) Li, Y.; Zhao, Z.-A.; He, H.; You, S.-L. AdV. Synth. Catal. 2008,
350, 1885.
(15) For previous NHCs catalyzed elctrophilic C-N bond formation,
see: (a) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2008, 130, 2740. (b)
Huang, X.-L.; He, L.; Shao, P.-L.; Ye, S. Angew. Chem., Int. Ed. 2009, 48,
192. (c) Seayad, J.; Patra, P. K.; Zhang, Y.; Ying, J. Y. Org. Lett. 2008,
10, 953. (d) Yang, L.; Tan, B.; Wang, F.; Zhong, G. F. J. Org. Chem.
2009, 74, 1744.
(16) Similar results were observed in the reaction of acylaryldiazene
with cinnamaldehyde, which presumably due to the related concomitant
hydride transfer, which consumed the homoenolate and thus decreased the
yield of 6f; see ref 15a.
(17) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
642
Org. Lett., Vol. 12, No. 3, 2010

In summary, we have presented a novel N-heterocyclic
carbene-catalyzed umpolung reaction which converts 3-ha-
lopropenals into the equivalent of ꢀ-acylvinyl anionic syn-
thons for the direct synthesis of cyclic R,ꢀ-unsaturated
carbonyl derivatives, butenolides 4 and pyrazolone 6, in the
presence of DBU. Efforts to utilize this reactivity in other
transformation as well as asymmetric variants are currently
underway.
Scheme 3
.
Plausible Mechanism of the Reaction of 1 and 5
(NR3 ) DBU; Ar ) 2,6-di-iPrC6H3)
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Grant Nos. 20672096 and
20772106) and Chinese Universities Scientific Fund for
financial support.
Supporting Information Available: Experimental pro-
1
cedures and 13C and H NMR and HRMS data for experi-
mental procedures and characterization of the products 4, 6,
7 and X-ray crystallographic data (CIF) for 4b and 6d. This
material is available free of charge via the Internet at
http://pubs.acs.org.
regeneration of the carbene catalyst. Finally, ꢀ-elimination
ensues, assisted by DBU, yielding pyrazolone 6.
OL902961Y
Org. Lett., Vol. 12, No. 3, 2010
643