Nucleophilic acylation of α-haloketones with aldehydes: An umpolung strategy for the synthesis of 1,3-diketones

Article abstract of DOI:10.1016/j.tetlet.2010.10.175

The first example of N-heterocyclic carbene (NHC)-promoted intermolecular acylation of α-haloketones with aldehydes and α,β-unsaturated aldehydes (enals) is reported. The protocol involves carbonyl umpolung reactivity of aldehydes and enals in which the carbonyl carbon attacks nucleophilically on electrophilic terminal of α-haloketones to afford 1,3-diketones and α,β-unsaturated 1,3-diketones, respectively. Short reaction time, ambient temperature, operational simplicity, and high yields are the salient features of the present procedure.

Full text of DOI:10.1016/j.tetlet.2010.10.175

Tetrahedron Letters 52 (2011) 125–128
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nucleophilic acylation of a-haloketones with aldehydes: an umpolung
strategy for the synthesis of 1,3-diketones
Santosh Singh a, Pankaj Singh a, Vijai K. Rai a,b, Ritu Kapoor a, Lal Dhar S. Yadav a,
⇑
a Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
b School of Biotechnology, Shri Mata Vaishno Devi University, Katra, Jammu & Kashmir182 320, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The first example of N-heterocyclic carbene (NHC)-promoted intermolecular acylation of
with aldehydes and ,b-unsaturated aldehydes (enals) is reported. The protocol involves carbonyl umpo-
lung reactivity of aldehydes and enals in which the carbonyl carbon attacks nucleophilically on electro-
philic terminal of -haloketones to afford 1,3-diketones and ,b-unsaturated 1,3-diketones, respectively.
a-haloketones
Received 20 September 2010
Revised 28 October 2010
Accepted 31 October 2010
Available online 5 November 2010
a
a
a
Short reaction time, ambient temperature, operational simplicity, and high yields are the salient features
of the present procedure.
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
N-Heterocyclic carbenes
Acylation
1,3-Diketones
a
,b-Unsaturated 1,3-diketones
Nucleophilic substitution
-Haloketones
a
1,3-Diketones are important building blocks,1 and their useful-
O
ness in preparations of heterocycles such as pyrazoles, isoxazoles,
triazoles, and benzopyran-4-ones has been well documented.2
They are widely represented in natural products, pharmaceuticals,
and other biologically active compounds.1 Many naturally occur-
ring 1,3-diketones exhibit some biological activities such as antiox-
idant, antitumor, antibacterial, antimicrobial, antiviral, and
O
O
Ar1
H
1
Ar1
Ar2
3, DBU
4
O
O
X
Ar2
antifungal.1 The preparation of 1,3-diketones and
a,b-unsaturated
O
O
Ar
H
2
1,3-diketones is a challenging goal, and the majority of their recent
syntheses are generally carried out by Claisen condensation using
reagents such as SmI3, LiHMDS, NaH/dibenzo 18-crown-6, sodium
hydride, lithium amide, sodamide, and the use of LDA to perform
an enolate from a ketone followed by C-acylation through reaction
with an acyl chloride.3 To date, only a few procedures for the direct
synthesis of 1,3-diketones from aldehydes have been reported.4
However, in most of these methods the regio- and chemoselectiv-
ity of enolate formation are not easy to control and the formation
of a mixture of O- and C-acylated products takes place which is dif-
ficult to separate. Herein, we report a simple and expeditious
1'
Ar
Ar2
4'
3, DBU
Ph
Cl
Ph
Mes
Ph
N
N
N
N
Cl
N
Ph
N
Cl
N
Mes
N
S
ClO4
Ph
3b
3c
3a
3d
Ph
Mes = 2, 4, 6-trimethylphenyl
Scheme 1. Synthesis of 1,3-diketones 4 and 40.
method for direct access to 1,3-diketones and
a,b-unsaturated
1,3-diketones framework via NHC-promoted intermolecular ali-
phatic nucleophilic substitution reaction (Scheme 1).
The attractive feature of NHCs is their ability to catalyze the
polarity reversal, or umpolung, of various carbonyl compounds.
Umpolung reactivity can be a valuable synthetic strategy because
it offers unconventional bond-forming tactic for the synthesis of
biologically active target molecules.5 N-Heterocyclic carbenes have
been used to catalyze organic transformations such as benzoin-
and Stetter-type reactions,6 homoenolate formation,7 and transe-
sterification reactions.8 Although the development of carbonyl
⇑
Corresponding author. Tel.: +91 532 2500652; fax: +91 532 2460533.
E-mail address: ldsyadav@hotmail.com (L.D.S. Yadav).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.175

126
S. Singh et al. / Tetrahedron Letters 52 (2011) 125–128
anion addition reactions has received significant attention,6–8 the
nucleophilic substitution reactions catalyzed by NHC have received
considerably less attention. There have been only a few reports on
the application of NHCs to these types of organocatalytic transfor-
mations such as aroylation of p-nitrofluorobenzene9a and hetero-
aryl chlorides9b via acyl anion equivalent of aldehydes. Recently,
He et al. reported a facile route via NHC-catalyzed intramolecular
nucleophilic substitution reaction for the construction of benzopy-
rones and benzofuranones.10 Most recently, Lin et al. reported the
NHCs-mediated intermolecular nucleophilic acylation of benzyl
halides with aromatic aldehydes.11 However, there has been no re-
Table 1
Optimization of reaction conditions for the formation of representative compound 4a
and 40aa
O
O
O
O
(30 mol %)
3
Br
2a
Ar1
Ph
Ar1
H
Ph
base (30 mol %)
solvent, 15 min., r.t
1
4
Entry Precatalyst
(mol %)
Base
Solvent
Yield (%)b
4a
Ar0 = Ph
40a
Ar0 = PhCH@CH
1
2
3
4
3a (30)
3a (30)
3a (30)
3a (30)
TEA
K2CO3
THF
THF
DABCO THF
52
42
53
ND
62
port on NHC-catalyzed acylation of
equivalent of aldehydes and enals.
a-haloketones via acyl anion
58
ND
68
The synthetic utility of NHC-catalyzed acyl anion equivalent
DBU
THF/
ButOHc
CH2Cl2
CH3CN
DMF
THF
THF
THF
THF
THF
reactivity of aldehydes,12 including
a,b-unsaturated aldehydes (en-
5
6
7
8
9
10
11
12
13
14
3a (30)
3a (30)
3a (30)
3a (30)
3b (30)
3c (30)
3d (30)
3a (25)
3a (35)
—
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
61
51
48
89
29
28
35
78
89
—
57
41
39
86
22
ND
31
81
86
—
als),7 has attracted considerable interest. Enals are rendered d3
nucleophiles in addition to an appropriate, highly hindered NHC
and the reaction proceeds through Breslow or homoenolate inter-
mediate.7 Similarly, NHC-catalyzed reactions of enals rendering
them d1 nucleophiles would also be of significant synthetic utility.
However, following a few examples available in the seminal paper
of Stetter et al.,13 there have been only two reports on such reac-
tions.14a,b Prompted by this remarkable gap in the literature and
our efforts to develop synthetically useful processes,14 we report
herein a novel methodology developed for an efficient construction
of chemically and pharmaceutically potent 1,3-diketones 4 and
THF
THF
a
b
c
For the experimental procedure, see Ref. 15.
Yield of isolated and purified product.
THF/ButOH; 10:01 were used.
a
,b-unsaturated 1,3-diketones 40. The protocol involves the first
example of the NHC-promoted intermolecular acylation of
haloketones 2 with aromatic aldehydes 1 and enals 10 (Scheme
1), and it is the best example in which 1,3-diketones and ,b-
a
-
erocyclic carbene precursors 3a–d were tested and 3a was found
to be the most effective for the preparation of 4a and 40a under
the present reaction conditions (Table 1, entry 8). Then, we opti-
mized the base and found that DBU was the best among TEA, DAB-
CO, DBU, and K2CO3 (Table 1, entries 1–3 and 8). In the case of
DABCO desired products 4a and 40a were not obtained probably
because DABCO readily forms salt with phenacyl halides (Table 1,
a
unsaturated 1,3-diketones can be synthesized by the same method
and mechanism (Scheme 2).
In a pilot experiment, we investigated the optimization of reac-
tion conditions in regard with NHC-promoter, base, and solvent.
Herein, benzaldehyde 1a, cinnamaldehyde 10a, and phenacyl bro-
mide 2a were chosen as model substrates for the synthesis of rep-
resentative 1,3-diketones 4a and 40a, and the reaction was
performed at room temperature (Table 1). Different types of N-het-
entry 3). In the case of cinnamaldehyde 10a only
a,b-unsaturated
1,3-diketone 40a was obtained via the nucleophilic attack of acyl
anion equivalent (d1 nucleophile) of the enal on the electrophilic
Ph
Ph
O
O
Ph
Ar
O
O
Ar1
H
H
N
N
N
N
N
N
1'
1
Ar1
Ar
H
H
7
6
8
Ph
Ph
Ph
Ph
Ph
Ph
OH
OH
OH
N
N
N
Ar1
Ar
Ar
N
N
N
9
7''
7'
Ph
Ph
Ph
Ar2
Ar2
X
Br
2
O
O
2
O
O
Ph
Ph
Ph
Ar2
Ar1
Ar2
N
N
N
N
N
Ar
OH
OH
N
6
O
O
Ph
Ar
Ph
O
O
Ph
Ar2
Ar1
Ar2
4'
4
Scheme 2. A plausible mechanism for the formation of 1,3-diketones 4 and a
,b-unsaturated 1,3-diketones 40.

S. Singh et al. / Tetrahedron Letters 52 (2011) 125–128
127
Table 2
Reaction of aldehydes 1 with phenacyl halide 2 yielding 1,3-diketones 4 and 40
O
O
O
O
(30 mol %)
3a
X
Ar1
Ar2
Ar2
H
Ar1
DBU (30 mol %)
THF, r.t
4 and 4'
1
2
Entry
Ar1
Ar2, X
Product 4 and 40
Timea (min)
Yieldb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph (1a)
Ph, Br (2a)
Ph, Br (2a)
Ph, Br (2a)
Ph, Br (2a)
Ph, Cl (2b)
Ph, Cl (2b)
4-ClC6H4, Br (2c)
4-ClC6H4, Br (2c)
4-ClC6H4, Br (2c)
4-MeOC6H4, Br (2d)
4-MeOC6H4, Br (2d)
Ph, Br (2a)
4-ClC6H4, Br (2c)
4-MeOC6H4, Br (2d)
Ph, Br (2a)
4a
4b
4c
4d
4e
4f
4g
4h
4i
15
15
18
20
19
17
15
17
19
16
22
15
15
18
20
19
21
89
90
84
78
79
82
91
85
81
84
71
86
87
76
63
66
61
4-NO2C6H4 (1b)
4-ClC6H4 (1c)
4-MeOC6H4 (1d)
Ph (1a)
4-NO2C6H4 (1b)
4-NO2C6H4 (1b)
4-ClC6H4, (1c)
4-MeOC6H4 (1d)
4-NO2C6H4 (1b)
4-MeOC6H4 (1d)
PhCH@CH (10a)
PhCH@CH (10a)
PhCH@CH (10a)
CH3CH@CH (10b)
CH3CH@CH (10b)
CH3CH@CH (10b)
4j
4k
40a
40b
40c
40d
40e
40f
4-ClC6H4, Br (2c)
4-MeOC6H4, Br (2d)
a
b
c
Stirring time at room temperature.
Yield of isolated and purified product 4a and 40a.
All compounds gave C, H and N analyses within 0.38% and satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
Present disconnection
approach
center of phenacyl bromide to substitute bromine atom. The opti-
mum loading for the carbene precursor 3a was found to be
30 mol % along with 30 mol % of DBU. When the amount of 3a
was decreased from 30 mol % to 25 mol % relative to substrate 1a
and 10a, the yield of the 1,3-diketone 4a and 40a reduced (Table
1, entry 12), but the use of 35 mol % of 3a did not affect the yield
(Table 1, entries 5 and 13). The reaction did not occur without
using the carbene precursor 3 (Table 1, entry 14). It was also noted
that a higher reaction temperature, for example, in a refluxing sol-
vent instead of room temperature did not increase the yield. Opti-
mization of solvents for the synthesis of 4a and 40a employing the
precatalyst 3a was also undertaken and it was found that among
CH3CN, DMF, CH2Cl2, THF/ButOH, and THF (Table 1, entries 4–8),
the best solvent in terms of yield was THF (Table 1, entry 8) and
we used this solvent (THF) throughout the present study.
keto-enol moiety
O
O
electrophilic carbonyl group
Michael acceptor
Ar2
acidic α′-Hs
electrophilic
substitution
electrophilic
substitution
4'
Ar
nucleophilic
addition
Figure 1. Diversely functionalized products 40.
1,3-diketones 40. No product formation via nucleophilic attack by
the homoenolate anion 700 (d3 nucleophile) was observed. In previ-
ous reports, the equilibrium was shifted mostly toward homoeno-
late700 employing an appropriate, highly hindered catalyst (Scheme
2).7a,b,16 On the basis of these reports7a,b,16 as well as the work of
Stetter et al. on enals,13 we reasoned that an appropriately substi-
tuted NHC could shepherd the umpolung reactivity of enals to the
carbonyl group presumably by sterically blocking the b-position.
To our delight, the NHC 3a mediated reaction of enals 10 with
We next explored the generality of the methodology and sub-
strate scope, another three analogous aldehyde and two analogous
a-haloketone substrates were scrutinized under the present opti-
mized reaction conditions and the yields were found to be good
to excellent 61–91% (Table 2). Besides these aromatic aldehydes,
enals and
phatic aldehydes and
a
-haloketones we also attempted the reaction using ali-
-haloketones like, acetaldehyde, and -bro-
a
a
phenacyl halide 2 proceeded well via acyl anion to afford
a,b-
unsaturated 1,3-diketones 40 in good to excellent yields (Table 2).
moacetone, but yields were poor (15–25%) in these cases. This
might be due to the side reaction like aldol reaction under the pres-
ent basic conditions. Furthermore, the present reaction products
In summary, we have developed a convenient, efficient, and
one-pot route for synthesis of 1,3-diketones and
1,3-diketones via direct NHC-promoted nucleophilic acylation of
-haloketones with aromatic aldehydes and enals in good to excel-
lent yields. Therefore, we believe that this reaction would offer an
important methodology for the synthesis of chemically and phar-
a,b-unsaturated
a
,b-unsaturated 1,3-diketones 40 incorporate densely populated
chemo-specific functional groups including carbonyl,
a,b-unsatu-
a
rated carbonyl (Michael acceptor), and active methylene groups,
thereby provide handles for further manipulation in a multitude
of synthetic organic transformations (Fig. 1).
maceutically relevant 1,3-diketones and
tones via the same procedure.
a,b-unsaturated 1,3-dike-
The formation of 1,3-diketone 4 may be tentatively rationalized
by initial generation of nucleophilic carbene 6 by deprotonation of
benzimidazolium salt 3a. Carbene 6 adds to aldehyde 1 to form
intermediate 8 followed by H-migration to produce an acyl anion
equivalent (Breslow intermediate) 9 which reacts with phenacyl
halide 2 to form the desired product 1,3-diketone 4 (Scheme 2).
Similarly, enals 10 also react with phenacyl halide 2 through the
Acknowledgments
We sincerely thank SAIF, Punjab University, Chandigarh, for
providing microanalyses and spectra. S.S. is grateful to the CSIR,
New Delhi, and P.S. is grateful to the UGC, New Delhi, for the award
of a SRF and JRF, respectively.
Breslow intermediate 70 (d1 nucleophile) to afford
a,b-unsaturated

128
S. Singh et al. / Tetrahedron Letters 52 (2011) 125–128
12. (a) Johnson, J. S. Angew. Chem., Int. Ed. 2004, 43, 1326–1328; (b) Enders, D.;
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R.; Srivastava, V. P.; Yadav, L. D. S. Adv. Synth. Catal. 2010, 352, 1610–1614; (d)
Yadav, L. D. S.; Singh, S.; Rai, V. K. Green Chem. 2009, 11, 878–882.
1. (a) Kel’in, A. V. Curr. Org. Chem. 2003, 7, 1691–1711; (b) Kel’in, A. V.; Maioli, A.
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P., Jr.; Van Engen, D.; Pascal, R. A., Jr. J. Org. Chem. 1992, 57, 784–786; (e) Felix, C.
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15. General procedure for the synthesis of 1,3-diketones 4 and 40: A flame-dried round
bottomed flask was charged with benzimidazolium salt 3a (0.3 mmol),
aldehyde 1 or 10 (1.0 mmol), and 5 mL of THF under positive pressure of
nitrogen followed by addition of DBU (0.3 mmol) with a syringe after 5 min,
added the solution of phenacyl halide 2 (1.0 mmol) in 1 mL THF. The resulting
yellow-orange solution was stirred for 15–22 min. at room temperature (Table
2). After completion of the reaction (monitored by TLC), the reaction mixture
was concentrated under reduced pressure. The residue was purified by silica
gel column chromatography hexane/EtOAc; (20:1) to afford analytically pure 4
and 40. Characterization Data of Representative Compounds. Compound 4b
(enol tautomer): The product was purified with a hexane/ethyl acetate mixture
(20:1) as eluent. The 1H NMR spectroscopic data are in agreement with those
reported in the literature.17a IR (KBr): max = 3104, 3031, 1612 cmꢀ1 1H NMR
m .
(400 MHz, CDCl3): d = 6.72 (s, 1H), 7.88–7.71 (m, 7H, Ar-H), 8.11–8.03 (m, 2H,
Ar-H), OH unfound. 13C NMR (100 MHz, CDCl3): d = 93.5, 123.4, 128.1, 128.9,
130.8, 135.4, 136.5, 137.7, 139.4, 183.8, 188.9. MS (EI): m/z = 269 (M+). Anal.
Calcd for C15H11NO4: C, 66.91; H, 4.12; N, 5.20. Found: 67.19; H, 4.28; N, 5.01.
Compound 4i (enol tautomer): The product was purified with a hexane/ethyl
acetate mixture (20:1) as eluent. IR (KBr): m .
max = 3107, 3034, 1607 cmꢀ1 1H
NMR (400 MHz, CDCl3): d = 7.68–7.57 (m, 4H, Ar), 7.35–7.29 (m, 2H, Ar), 6.96–
6.91 (m, 2H, Ar), 6.85 (s, 1H), 3.92 (s, 1H, OCH3), OH unfound. 13C NMR
(100 MHz, CDCl3): d = 188.4, 183.1, 159.4, 132.7, 130.5, 129.4, 128.3, 127.1,
126.8, 116.6, 93.1, 54.8. MS (EI): m/z = 288, 290 (M+; M+2). Anal. Calcd for
4. (a) Fargeas, V.; Baalouch, M.; Metay, E.; Baffreau, J.; Menard, D.; Gosselin, P.;
C
16H13ClO3: C, 66.56; H, 4.54. Found: 66.18; H, 4.68. Compound 40a (enol
´
Berge, J.-P.; Barthomeufd, C.; Lebretona, J. Tetrahedron 2004, 60, 10359–10364;
tautomer): The product was purified with a hexane/ethyl acetate mixture
(b) Fukuyama, T.; Doi, T.; Minamino, S.; Omura, S.; Ryu, I. Angew. Chem., Int. Ed.
2007, 46, 5559–5561; (c) Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. J. Org.
Chem. 1990, 55, 5297–5299.
(20:1) as eluent. The 1H NMR spectroscopic data are in agreement with those
reported in the literature.17b IR (KBr):
m
max = 3112, 3041, 1641, 1581,
1552 cmꢀ1
.
1H NMR (400 MHz, CDCl3): d = 8.03 (m, 2H, Ar), 7.68 (1H, d,
5. (a) Grobel, B. T.; Seebach, D. Synthesis 1977, 357–402; (b) Seebach, D. Angew.
Chem., Int. Ed. 1979, 18, 239–258.
J = 15.4 Hz), 7.68–7.55 (m, 3H, Ar), 7.50 (m, 2H), 7.39–7.28 (m, 3H), 6.71 (d, 1H,
J = 15.4 Hz), 6.41 (s, 1H), OH unfound. 13C NMR (100 MHz, CDCl3): d = 190.3,
178.2, 139.4, 136.1, 134.8, 132.1, 130.5, 128.1, 128.9, 127.5, 126.8, 123.6, 98.7.
MS (EI): m/z = 250 (M+). Anal. Calcd for C17H14O2: C, 81.58; H, 5.64. Found:
81.82; H, 5.26. Compound 40e (enol tautomer): The product was purified with a
6. (a) Enders, D.; Kallfass, U. Angew. Chem., Int. Ed. 2002, 41, 1743–1745; (b) Kerr,
M. S.; de Alaniz, J. R.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298–10299; (c)
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hexane/ethyl acetate mixture (20:1) as eluent. IR (KBr):
mmax = 3083, 3011,
1657, 1598, 1549 cmꢀ1 1H NMR (400 MHz, CDCl3): d = 7.89 (2H, m), 7.21 (2H,
.
m), 6.96 (dq, 1H, J = 15.4, 7 Hz), 6.19 (1H, s), 6.02 (br dq, 1H, J = 15.4, 1.6 Hz),
1.89 (3H, dd, J = 7.0, 1.6 Hz), OH unfound. 13C NMR (100 MHz, CDCl3): d = 190.4,
182.1, 141.2, 137.8, 134.7, 132.8, 129.6, 128.1, 95.6, 18.7. MS (EI): m/z = 222,
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