A facile one-pot synthesis of a?-halo-a?-allyl-aldehydes from a?,a?-Dihaloketoncs Using Allylsamarium Bromide and DMF

Article abstract of DOI:10.1055/s-2008-1078418

A convenient, one-pot synthesis of a range of a?-halo-a?-allyl aldehydes is described. The protocol involves the reaction of allylsamarium bromide with various a?,a?-dihalo ketones. A possible mechanism of the transformation is proposed.

Full text of DOI:10.1055/s-2008-1078418

LETTER
1491
A Facile One-Pot Synthesis of a-Halo-a-allyl-aldehydes from
a,a-Dihaloketones Using Allylsamarium Bromide and DMF
One-Pot
S
u
ynthesisof
a
c
-Halo-
a
-
all
a
yl-aldehyde
i
s
Di, Songlin Zhang*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, Dushu
Lake Campus, Suzhou, 215123, P. R. of China
Fax +86(512)65880089; E-mail: zhangsl@suda.edu.cn
Received 13 December 2007
Table 1 Comparison of the Effect of Bases in the Reaction of a,a-
Abstract: A convenient, one-pot synthesis of a range of a-halo-a-
Dibromo-1-phenylethanone with Allylsamarium Bromidea
allyl aldehydes is described. The protocol involves the reaction of
allylsamarium bromide with various a,a-dihalo ketones. A possible
Entry
1
Base
Time (h)
Yield (%)b
mechanism of the transformation is proposed.
None
12
24
1
0
0
Key words: samarium, rearrangements, halides, aldehydes, synthe-
sis
2
K2CO3 (10 mmol)
K2CO3 (10 mmol)c
K2CO3 (10 mmol)c
K2CO3 (10 mmol)d
HNEt2 (10 mL)e
Et3N (10 mL)e
Pyridine (10 mL)e
NaOH (10 mL)
HMPA (10 mL)e
DMF (10 mL)e
DMSO (10 mL)e
CaH2 (10 mmol)f
3
39
0
The reactions of allylmetals with carbonyl compounds are
of interest to synthetic chemists. Homoallyl alcohols are
the usual products from those reactions.1 In a few instanc-
es, carbonyl compounds treated with allylmetals provide
final products that contain an active halide functionality.2
Organic compounds containing three or four different la-
bile functional groups are categorized as multifunctional
carbon compounds.3 Therefore, a-halo-a-allyl aldehydes
may be called trifunctional carbon compounds. These al-
dehydes have three active functional groups that can be
potentially manipulated for further chemical synthesis.
These compounds should be of considerable significance
in theoretical and synthetic organic chemistry. To the best
of our knowledge, the synthesis of a-halo-a-allyl-carbon-
yl compounds has never been reported before. In this pa-
per, we first report a facile protocol for the synthesis of a
range of a-halo-a-allyl carbonyl compounds.
4
10
12
2
5
12
34
32
7
6
7
1
8
1
9
10
0.25
0.25
0.25
12
16
52
54
52
53
10
11
12
13
a All reactions were carried out in THF at r.t.
b Isolated yields based on a,a-dibromo-ketones.
c Methanol (10 mL) was added to the reaction mixture.
O
R1
X
d tert-Butyl alcohol (10 mL) was added to the reaction mixture.
e Distilled from sodium or CaH2 under nitrogen.
SmBr
, THF, 10 min
R2
R2
1)
R1
f DMSO (10 mL) was added to the reaction mixture.
2) base
Br
X
O
1
2
aldehyde could be detected in the reaction (entry 1). In-
stead of the desired compound 1,1-dibromo-2-phenyl-
pent-4-en-2-ol4 (3a) was obtained after the reaction was
quenched by water (Scheme 2).
R1 = Ph, 4-FC6H4, 4-ClC6H4, 4-MeC6H4, C6H13
R2 = H, Me
X = Br, Cl
Scheme 1
The same result appeared when K2CO3 was used as the
base in the reaction. But when K2CO3 together with
MeOH or t-BuOH were used, aldehyde 2a was obtained
(entries 3 and 5). The yield of the aldehyde was also de-
pendent on the reaction time (Scheme 3). When the reac-
As shown in Scheme 1, a,a-dihaloketones (1) were treat-
ed with allylsamarium bromide in THF at room tempera-
ture, followed by the addition of a base to give a-halo-a-
allyl aldehydes 2.
First, a systematic study was carried out to evaluate the ef-
fect of the base on the product yield of 2a. The results are
summarized in Table 1. Initially, without base, no desired
O
OH
SmBr
, THF, 10 min
Br
1)
2)
Br
Ph
Ph
H2O
Br
Br
SYNLETT 2008, No. 10, pp 1491–1494
Advanced online publication: 16.05.2008
x
x
.x
x
.2
0
0
8
1a
3a
DOI: 10.1055/s-2008-1078418; Art ID: W21707ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2

1492
J. Di, S. Zhang
LETTER
O
SmBr
, THF, 10 min
HO CH(OMe)2
Br
CHO
Br
1)
2)
Ph
+
Ph
Ph
K2CO3, MeOH, THF
Br
4a
2a
Time (h)
39%
0
5%
84%
1
10
Scheme 3
O
tion time was short (1 h), the yield of the aldehyde 2a was
39%, and 1,1-dimethoxy-2-phenylpent-4-en-2-ol5 (4a)
was also obtained in 5% yield. If the reaction mixture was
stirred for ten hours, 2a was not detected and 4a was ob-
tained in a yield of 84%.
O
SmBr
1)
2) DMF
, THF, 10 min
Ph
Br
Ph
Ph
Ph
X
X
1k,l
5k,l
1k, X = Br, 67%
1l, X = Cl, 65%
Additionally, some bases, such as HNEt2, Et3N, pyridine,
or NaOH, had an effect on the reaction, but yields were
generally lower (entries 6–9). When DMF, DMSO, CaH2,
or HMPA was used as base, the yields of product were
very similar (entries 10–13). After screening different
bases, DMF appeared to be a good choice and used in this
method
Scheme 4
more reactive than Cl. When R1 = 4-O2NC6H4, 3-
O2NC6H4, or 2-ClC6H4 (entries 8–10), no reaction oc-
curred.
To evaluate the scope and generality of this method, a
number of a,a-dihaloketones were further subjected to the
reaction under the optimized reaction conditions. The re-
sults are shown in Table 2.
When R2 = Me (entry 7), the reaction gave a lower prod-
uct yield (36%), and when R2 was even larger (R2 = Ph,
entries 11, 12), no desired products were obtained. In-
stead, a-haloketones 5k,l were obtained (Scheme 4).
When X = Cl (entry 5), the reaction also gave a lower
product yield (34%). The reason probably was that Br is
In addition, some other organometallic reagents were tried
in the experiment in the hope of resulting in a similar re-
action type. We found that when 2,2-dibromo-1-phenyle-
thanone (1a) was treated with allylic zinc bromide
reagent6 or allylic indium bromide reagent7 (Allyl3In2Br3)
under the same conditions, no aldehyde was detected and
the products were not characterized. We also found that
Reformatsky reagent8 (BrZnCH2CO2Et) and Grignard re-
agent [C6H13MgBr, 4-MeC6H4MgBr) did not react with
2,2-dibromo-1-phenylethanone (1a)10 in THF at room
temperature.
A possible mechanism was proposed according to the
literature9 in Scheme 5. First, a,a-dihaloketone A under-
went allylation leading to the intermediate B. If the reac-
tion was quenched by water, product C could be obtained.
If dry DMF was added to the solution of B, the oxygen
atom of DMF would coordinate to the Sm atom of B. This
coordination resulted in the enhanced nucleophilicity of
the oxygen atom. Therefore, intermediate B underwent in-
tramolecular nucleophilic substitution to provide an a-ha-
loepoxide D, which was converted into the desired
product E. Interestingly, when DMF was added to the so-
lution of compound C (using 3a, R1 = Ph, R2 = H, X = Br)
in THF, and the reaction mixture was stirred for ten hours,
no reaction occurred. However, initial deprotonation of
compound C using 1.5 equivalents of allylsamarium bro-
mide in THF, followed by the addition of anhydrous
DMF, the desired aldehyde E (compound 2a11) could also
be formed.
Table 2 Reactions of a,a-Dihalo-ketones with Allylsamarium Bro-
mide followed by Addition of DMF
Entry
1
R1
R2
H
X
Yield (%)a
54
Ph
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Br
Cl
2
4-MeC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
C6H13
H
41
3
H
45
4
H
52
5
H
34
6
H
49
7
Ph
Me
H
36
8
4-O2NC6H4
3-O2NC6H4
2-ClC6H4
Ph
n.r.
9
H
n.r.
10
11
12
H
n.r.
In summary, we have described a method for the synthesis
of trifunctional carbon compounds: a-halo-a-allyl-alde-
hydes from various a,a-dihaloketones and allylsamarium
bromide. The advantages such as low reaction tempera-
ture, fast reaction rate, and one-pot operation make this
method an attractive and practical synthesis for a-halo-a-
allyl-aldehydes.
Ph
Ph
0 (67b)
0 (65c)
Ph
a Isolated yield based on a,a-dihaloketones.
b The yield of 5k.
c The yield of 5l.
Synlett 2008, No. 10, 1491–1494 © Thieme Stuttgart · New York

LETTER
One-Pot Synthesis of a-Halo-a-allyl-aldehydes
1493
R2 Br
O
R2 Br
R2
SmBr
X
DMF
R1
R1 OSmBr
X
R1 OSmBr
Br
X
NMe2
H
A
O
B
H2O
SmBr2
R2 Br
X
DMF
X
O
R2
R1 OH
R1 = Ph, R2 = H, X = Br
R1
X
C
D
SmBr
DMF
R2 Br
R1
X
R2
X
R1 OSmBr
O
B
E
Scheme 5
(10) General Procedure for the Preparation of a,a-Dihalo-
ketones
Acknowledgment
We thank the Key Laboratory of Organic Synthesis of Jiangsu Pro-
vince (KJS0616), Suzhou University, Suzhou LAC Co., LTD
(www.suzhoulac.com) for financial support. The Project sponsored
by SRF for ROCS, SEM No. K5109611.
Ketone (10 mmol) in glacial AcOH (10 mL) was heated to
50 °C with stirring, and bromine (22 mmol) in glacial AcOH
(5 mL) was added dropwise. When the bromine ceased
decoloration, NaOAc (7 g) was added portionwise. The
reaction mixture was stirred for 15 min after the addition of
bromine, and cooled in refrigerator for 2 h, and then poured
into cold H2O. Finally, the crystals were filtered off, and
recrystallized from 95% MeOH if necessary.
References and Notes
(1) Yamamoto, Y.; Asao, N. Chem. Rev. 1993, 93, 2207.
(2) Yadav, J. S.; Subba Reddy, B. V.; Vishnumurthy, P.;
Swapan, B. K. Tetrahedron Lett. 2007, 48, 6641.
(3) Fujiwara, T.; Takeuchi, Y. J. Fluorine Chem. 2005, 126,
941.
(4) 1,1-Dibromo-2-phenylpent-4-en-2-ol (3a)
1H NMR (400 MHz, CDCl3): d = 7.46–7.30 (m, 5 H), 5.98
(s, 1 H), 5.56–5.46 (m, 1 H), 5.15–5.05 (m, 2 H), 2.92 (d, 2
H, J = 6.8 Hz), 2.83 (s, 1 H). 13C NMR (100 MHz, CDCl3):
d = 140.55, 132.39, 128.59, 128.34, 126.58, 120.55, 78.99,
57.68, 43.89. HRMS (EI+): m/z calcd for C8H7Br79Br81O
[M+ – C3H5]: 278.8843; found: 278.8813.
(5) 1,1-Dimethoxy-2-phenylpent-4-en-2-ol (4a)
1H NMR (400 MHz, CDCl3): d = 7.53–7.23 (m, 5 H), 5.69–
5.55 (m, 1 H), 5.11–5.00 (m, 2 H), 4.26 (s, 1 H), 3.41 (d, 6
H, J = 14.4 Hz), 2.83–2.63 (m, 2 H), 2.66 (s, 1 H). 13C NMR
(100 MHz, CDCl3): d = 142.51, 133.82 128.31, 127.39,
126.83, 118.99, 110.86, 78.06, 58.48 (d, J = 9.7 Hz), 41.26.
HRMS (EI+): m/z calcd for C13H16O2 [M+ – H2O]: 204.1150;
found: 204.1192.
(6) Xu, X.-H.; Huang, R.-X.; Lu, R.-L.; Zhang, Q.-L. Chin. J.
Org. Chem. 2003, 23, 865.
(7) Araki, S.; Shimizu, T.; Johar, P. S.; Jin, S.-J.; Butsugan, Y.
J. Org. Chem. 1991, 56, 2538.
(8) Vaughan, W. R.; Bernstein, S. C.; Lorber, M. E. J. Org.
Chem. 1965, 30, 1790.
(9) (a) Arasaki, H.; Iwata, M.; Nishimura, D.; Itoh, A.; Masaki,
Y. Synlett 2004, 546. (b) Masaki, Y.; Arasaki, H.; Iwata, M.
Chem. Lett. 2003, 32, 4.
(11) General Procedure for the Synthesis of a-Halo,a-allyl-
aldehyde
Allyl bromide (1.2 mmol) and Sm (1.1 mmol) in dry THF
(10 mL) were mixed under a nitrogen atmosphere at r.t. The
mixture was stirred for about 5 min, and a color changed to
purple. The stirring was continued until the Sm powder
disappeared (1 h). Then, the solution of substrates a,a-
dihaloketones(1 mmol) was added dropwise to the reaction
mixture (the reaction was monitored by TLC). The reaction
mixture was stirred for 10 min and then dry DMF (10 mL)
was added. The reaction mixture was stirred for another 15
min (when X = Cl, the reaction mixture was stirred for 10 h)
and then was poured into cold H2O and 5% HCl (10 mL) was
added. The resulting mixture was extracted with Et2O (4 ×
15 mL), the Et2O solution was dried over anhyd MgSO4. The
solvent was removed by evaporation under reduced
pressure. Purification by column chromatography on silica
gel afforded the product (300–400 mesh, PE as eluent).
Analytical Data
2-Bromo-2-phenylpent-4-enal (2a)
1H NMR (400 MHz, CDCl3): d = 9.47 (s, 1 H), 7.44–7.34 (m,
5 H), 5.74–5.60 (m, 1 H), 5.11–5.05 (m, 2 H), 3.11 (d, 2 H,
J = 9.2 Hz). 13C NMR (100 MHz, CDCl3): d = 190.37,
135.63, 132.61, 129.23, 129.29, 128.58, 120.23, 74.06,
43.39. HRMS (EI+): m/z calcd for C11H11Br81O [M+]:
239.9973; found: 240.0038; m/z calcd for C11H11Br79O [M+]:
237.9993; found: 238.0006.
2-Bromo-2-p-tolylpent-4-enal
1H NMR (400 MHz, CDCl3): d = 9.44 (s, 1 H), 7.32–7.17 (m,
Synlett 2008, No. 10, 1491–1494 © Thieme Stuttgart · New York

1494
J. Di, S. Zhang
LETTER
4 H), 5.73–5.63 (m, 1 H), 5.10–5.05 (m, 2 H), 3.10 (d, 2 H,
J = 6.8 Hz), 2.35 (s, 3 H). 13C NMR (100 MHz, CDCl3): d =
190.41, 139.27, 132.77, 132.70, 129.92, 128.43, 120.00,
74.06, 43.22, 21.44. HRMS (EI+): m/z calcd for C12H13Br81O
[M+]: 254.0129; found: 254.0130; m/z calcd for C12H13Br79O
[M+]: 252.0150; found: 252.0162.
2-Chloro-2-(4-chlorophenyl)pent-4-enal
1H NMR (400 MHz, CDCl3): d = 9.39 (s, 1 H), 7.38 (m, 4 H),
5.70–5.61 (m, 1 H), 5.13–5.08 (m, 2 H), 3.01 (d, 2 H, J = 6.8
Hz). 13C NMR (100 MHz, CDCl3): d = 191.92, 135.47,
134.09, 131.26, 129.48, 129.08, 120.83, 77.18, 42.91.
HRMS (EI+): m/z calcd for C11H10Cl352O [M+]: 228.0109;
found: 228.0112; m/z calcd for C11H10Cl35Cl37O [M+]:
230.0079; found: 230.0141.
2-Bromo-2-(4-fluorophenyl)pent-4-enal
1H NMR (400 MHz, CDCl3): d = 9.46 (s, 1 H), 7.44–7.06 (m,
4 H), 5.72–5.63 (m, 1 H), 5.13–5.06 (m, 2 H), 3.10 (d, 2 H,
J = 3.2 Hz). 13C NMR (100 MHz, CDCl3): d = 190.23,
163.14 (1JCF = 248.2 Hz), 132.36, 131.66, 130.58 (3JCF = 8.4
Hz), 120.53, 116.26 (2JCF = 21.7 Hz), 73.11, 43.47. HRMS
(EI+): m/z calcd for C11H10OFBr81 [M+]: 257.9879; found:
257.9884; m/z calcd for C11H10OFBr79 [M+]: 255.9899;
found: 255.9874.
2-Allyl-2-bromooctanal
1H NMR (400 MHz, CDCl3): d = 9.39 (s, 1 H), 5.84–5.74 (m,
1 H), 5.21–5.17 (m, 2 H), 2.77 (t, 2 H, J = 6.8 Hz), 2.01–1.91
(m, 2 H), 1.29–1.45 (m, 8 H), 0.88 (t, 3 H). 13C NMR (100
MHz, CDCl3): d = 193.98, 132.50, 120.29, 73.39, 40.77,
36.72, 31.92, 29.68, 25.61, 22.96, 14.48. HRMS (EI+): m/z
calcd for C11H19Br81O [M+]: 248.0599; found: 248.0952; m/z
calcd for C11H19Br79O [M+]: 246.0619; found: 246.0674.
3-Bromo-3-phenylhex-5-en-2-one
2-Bromo-2-(4-chlorophenyl)pent-4-enal
1H NMR (400 MHz, CDCl3): d = 9.45 (s, 1 H), 7.37 (m, 4 H),
5.71–5.61 (m, 1 H), 5.13–5.06 (m, 2 H), 3.09 (d, 2 H, J = 3.2
Hz). 13C NMR (100 MHz, CDCl3): d = 190.06, 135.48,
134.33, 132.21, 130.06, 129.44, 120.66, 73.06, 43.36.
HRMS (EI+): m/z calcd for C11H10OCl35Br79 [M+]: 271.9604;
found: 271.9599; m/z calcd for C11H10OCl35Br81 [M+]:
273.9583; found: 273.9567.
1H NMR (400 MHz, CDCl3): d = 7.42–7.29 (m, 5 H), 5.64–
5.54 (m, 1 H), 5.03–4.97 (m, 2 H), 3.15–3.01 (m, 2 H), 2.21
(s, 3 H). 13C NMR (100 MHz, CDCl3): d = 201.48, 137.83,
133.26, 129.08, 128.72, 127.77, 119.61, 75.79, 46.10, 26.32.
HRMS (EI+): m/z calcd for C12H13Br79O [M+]: 252.0150;
found: 252.0138; m/z calcd for C12H13Br81O [M+]: 254.0129;
found: 254.0159.
Synlett 2008, No. 10, 1491–1494 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.