Highly selective catalytic cross-aldol reactions of chloral with aliphatic aldehydes

Article abstract of DOI:10.1055/s-2006-948164

An efficient synthetic method for β-trichloromethyl-β-hydroxy aldehydes is described. Using piperidine or L-prolinamide as the catalyst, direct cross-aldol reactions of chloral with aliphatic aldehydes occur smoothly at room temperature. The cross-aldol condensation products are isolated in high yields (up to 95%), and a moderate to high enantioselectivity (up to 88% ee) is observed in the case of L-prolinamide. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-948164

LETTER
1703
Highly Selective Catalytic Cross-Aldol Reactions of Chloral with Aliphatic
Aldehydes
C
F
ross-Aldol
R
a
eactions of
n
Chloral with
g
A
liphatic
A
l
ldehyd
i
es n Zhang, Ning Su, Yuefa Gong*
Department of Chemistry, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. of China
Fax +86(27)87543632; E-mail: gongyf@mail.hust.edu.cn
Received 15 February 2006
In this paper, the catalytic cross-aldol reactions between
chloral and some simple aliphatic aldehydes were studied.
We found that the yield of the desired b-trichloromethyl-
Abstract: An efficient synthetic method for b-trichloromethyl-b-
hydroxy aldehydes is described. Using piperidine or L-prolinamide
as the catalyst, direct cross-aldol reactions of chloral with aliphatic
aldehydes occur smoothly at room temperature. The cross-aldol b-hydroxy aldehydes was not satisfactory when L-proline
condensation products are isolated in high yields (up to 95%), and was used as the catalyst, but could be markedly improved
a moderate to high enantioselectivity (up to 88% ee) is observed in
the case of L-prolinamide.
using other catalysts like piperidine or L-prolinamide
(
Scheme 1).
Key words: b-trichloromethyl-b-hydroxy aldehydes, cross-aldol
reaction, chloral, piperidine, L-prolinamide
O
OH
O
OH
O
catalyst (30 mol%)
solvent, r.t.
+
CCl3CHO
+
3
Cl C
Preparation of a-trichloromethyl alcohols is of great im-
portance because this skeleton is one of the most versatile
precursors for the synthesis of various useful products
R
R
R
R
1
R = Et
2 R = Et
R = Me
3
1
2
3
such as a-hydroxy acids, a-amino acids, a-fluoro acids,
4 R = i-Pr
5 R = Pent
4
5
terminal alkynes, and vinyl dichlorides. Nowadays, syn-
thetic routes to the a-trichloromethyl alcohols from chlo-
ral mainly involve the individual aldol reactions with
Scheme 1 Cross-aldol reactions of chloral with aliphatic aldehydes
6
7
8
9
ketones, enamines, or enol ethers, the ene reactions,
First catalytic aldol reaction was carried out by mixing
chloral (148 mg, 1.0 mmol) and butanal (72 mg, 1.0
mmol) in the presence of L-proline (35 mg, 30 mol%) in
DMSO at room temperature. Product analysis by GC
clearly indicated that the main product was the self-aldol
product 1 rather than the cross-adduct 2 under these con-
ditions (Table 1, entry 1). Considering the marked influ-
ence of reaction media used,16 we next examined the
reactions in different solvents. The results observed were
1
0
and nucleophilic addition with terminal alkynes. Among
the known a-trichloromethyl alcohols, b-trichloromethyl-
b-hydroxy aldehydes are not only important intermediates
in the synthesis of biologically important compounds and
natural products; they can also be easily transformed to
a variety of functional arrays.11a,12 To the best of our
knowledge, however, no report was referred to their syn-
thesis via direct cross-aldol reaction between chloral and
aliphatic aldehydes hitherto, though they could be pre-
pared via the ring-opening reaction of 4-trichloromethyl-
1
1
1
5
Table 1 Effect of Solvents on the Reactions of Chloral with
1
1a
2
-oxetanone.
Butanala
Recently, we noticed that the aldol reactions of aldehydes
can be efficiently promoted by some organocatalysts, es-
Entry Solvents
Yield of 2 Molar ratio dr for 2
ee (%)c
anti:syn
b
(
%)
(2:1)
1:3
1:2
2:3
3:2
5:3
3:1
–
anti:syn
73:27
61:29
83:17
85:15
64:36
70:30
–
1
3
pecially by L-proline. However, few work was focused
on the direct cross-aldol reactions between different ali-
1
2
3
4
5
6
DMSO
DMF
21
27
35
52
56
64
<5
53:3
47:1
75:57
78:42
68:53
83:54
–
1
4
phatic aldehydes. First proline-catalyzed aldol reaction
between different aldehydes was reported by MacMillan
and co-workers, in which the cross-aldol products were
afforded in synthetically useful yields and selectivity. In
this case, controlling the rate of addition of aliphatic alde-
hyde was necessarily required. This pioneering work
aroused our interest in preparing b-trichloromethyl-b-hy-
droxy aldehydes by direct catalytic cross-aldol reactions
of reactive chloral with other aliphatic aldehydes.
Dioxane
THF
MeCN
CH Cl
2
2
7
Hexane
a
Butanal (1 mmol) was added to chloral (1 mmol) and L-proline
(
0.3 mmol) in a solvent (8 mL), and the mixture was stirred at r.t.
Determined by GC.
Determined by chiral GC analysis.
SYNLETT 2006, No. 11, pp 1703–1706
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-948164; Art ID: W03206ST
1
2
.0
7
.2
0
0
6
b
c
©
Georg Thieme Verlag Stuttgart · New York

1
704
F. Zhang et al.
LETTER
given in Table 1. Apparently, the yield of 2 was somewhat As we know, some amino acids and secondary amines can
related to the property of the solvents (entry 2–6). Among act as efficient catalysts for the aldol reactions of alde-
17
the solvents used, dichloromethane was the most suitable hydes in organic solvents. Thus we utilized three other
to promote cross-aldol condensation reaction (entry 6).
natural amino acids, piperidine and L-prolinamide to cat-
alyze the aldol condensation between chloral and butanal.
All the reactions were performed in the presence of 30
mol% of the catalyst in dichloromethane at room temper-
ature, and the yield and anti:syn ratio of 2 was determined
In addition, it was noticed that the structure identities of
1
anti and syn isomers of 2 could not be determined by H
NMR spectroscopy as there was no coupling between the
H-2 and H-3 signals, thus the isomeric ratio of 2 was
1
1
8
by GC and H NMR.
determined by GC analysis as described. Under the GC
conditions, the anti isomer of 2 possessed an earlier re- With glycine or L-tyrosine as the catalyst, the conversion
tention time than its syn isomer. This result was further was extremely low and only trace amounts of 2 and the
confirmed by comparing with the corresponding retention self-aldol product 1 were detected by GC (Table 2, entries
times and the coupling constants of other cross-adducts 3, 4). In the cases of L-alanine or L-phenylalanine, the de-
3
–5. The ee value of 2 was determined by chiral GC, and sired cross-aldol product 2 was generated in low yield
a moderate to high diastereoselectivity and enantioselec- with moderate enantioselectivity (Table 2, entries 5, 6). In
tivity was observed.
contrast, 2 was generated in high yield (89%) when pipe-
ridine was used as the catalyst, and only about 5% of 1
was detected by GC (Table 2, entry 2). Among the cata-
lysts used, L-prolinamide was identified to be the best as
it provided the desired product 2 in 96% yield and a trace
amount of self-aldol product 1 (Table 2, entry 8). More-
The main problem remained for the above catalytic pro-
cesses is the competitive self-aldol reaction of butanal,
though its proportion can be decreased to some extent by
choosing an appropriate solvent. Our further effort was
therefore directed to improve the yield of the cross-aldol
product 2 by choosing a more efficient catalyst than L-pro-
line. The catalytic role of several well-known catalysts
has been assessed below for this purpose.
1
over, the anti:syn ratio of 2 determined by H NMR was
further conformed by GC, and the formation of anti iso-
mer was favored in all the cases. These results clearly in-
dicated that cyclic secondary amines were much more
efficient catalysts for the above cross-aldol reaction.
Sodium hydroxide, a common catalyst for aldol reaction,
was first examined to catalyze the cross-aldol reaction in
aqueous solution (Table 2, entry 1). However, the pre-
dominant products were the self-aldol product 1 and its
corresponding a,b-unsaturated aldehyde generated by
subsequent dehydration. Only a very little amount of the
cross-aldol product 2 was detected. The low yield of 2
might be attributed to the low reactivity of hydrated chlo-
ral. For this reason, we turned our attention to the catalytic
reactions in organic solvents.
Encouraged by these results, we further explored the
scope of this cross-aldol reactions with other aliphatic al-
dehydes containing a-hydrogen using piperidine or L-pro-
linamide as the catalyst. All the reactions were carried out
according to the typical procedures described below.18
Product analysis showed that the expected cross-aldol
1
9
products 3–5 were afforded in high yields in the respec-
tive reactions with propanal, 3-methylbutanal and hepta-
nal in the presence of piperidine as the catalyst (Table 3).
In the case of L-prolinamide, the reactions afforded good
Table 2 Effect of Catalysts on the Reactions of Chloral with Bu-
a
tanal
Table 3 Direct Cross-Aldol Reactions between Chloral and Ali-
phatic Aldehydes
Entry
Catalyst
Yield (%)
of 2
dr for 2
anti:syn
ee (%)c
anti:syn
b
Entry
R
Catalysta Products
(yield, %)
dr
anti:syn
ee (%)c
anti:syn
b
1
2
3
4
5
6
7
NaOH
<5
–
–
Piperidine
Glycine
89
69:31
–
–
1
2
3
4
5
6
7
Me
A
A
A
A
B
B
B
B
3 (81)
2 (87)
4 (83)
5 (76)
3 (92)
2 (95)
4 (35)
5 (81)
58:42
60:40
83:17
71:29
45:55
85:15
80:20
69:31
–
Trace
Trace
15
–
Et
–
L-Tyrosine
L-Alanine
L-Phenylalanine
L-Proline
–
–
i-Pro
n-Pent
Me
–
77:23
64:36
70:30
85:15
65:29
45:66
83:54
75:65
–
18
88:78
75:65
70:65
68:40
64
Et
8
L-Prolinamide
96
i-Pro
n-Pent
a
The reaction was done by mixing butanal (1 mmol), chloral (1
mmol) and catalyst (0.3 mmol) in CH Cl (8 mL), and stirred for 24 h
8
2
2
a
at r.t.
A: piperidine; B: L-prolinamide.
Determined by H NMR.
Determined by chiral GC.
b
1
b
c
1
Determined by GC and H NMR.
Determined by chiral GC.
c
Synlett 2006, No. 11, 1703–1706 © Thieme Stuttgart · New York

LETTER
Cross-Aldol Reactions of Chloral with Aliphatic Aldehydes
1705
to excellent yields of the desired cross-aldol products ex-
(12) (a) Pirrung, M. C.; Han, H.; Nunn, D. S. J. Org. Chem. 1994,
9, 2423. (b) Tan, Z.; Negishi, E. I. Angew. Chem. Int. Ed.
5
cept for 3-methylbutanal. Moreover, the anti:syn ratios of
1
2005, 44, 1.
3
–5 could be easily determined by H NMR because the
(
13) (a) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem.
Soc. 2000, 122, 2395. (b) Sakthivel, K.; Notz, W.; Bui, T.;
Barbas, C. F. III. J. Am. Chem. Soc. 2001, 123, 5260.
anti isomers of 3–5 showed larger coupling constants J2–3
than those of the syn isomers. These ratios were well con-
sistent with those determined by GC analysis according to
their different retention times, and the formation of anti
isomer was favored in most cases except for propanal
(
2
c) Cordova, A.; Notz, W.; Barbas, C. F. III. J. Org. Chem.
002, 67, 301.
(14) (a) Northrup, A. B.; MacMillan, D. W. C. J. Am. Chem. Soc.
2002, 124, 6798. (b) Chowdari, N. S.; Ramachary, D. B.;
Cordova, A.; Barbas, C. F. III. Tetrahedron Lett. 2002, 43,
(
Table 3, entry 5).
This cross-aldol reaction was also applicable to produce
–5 on a large scale. For example, the reaction of chloral
9591. (c) Storer, R. I.; MacMillan, D. W. C. Tetrahedron
3
2004, 60, 7705. (d) Pihko, P. M.; Erkkila, A. Tetrahedron
with propanal on a 50 mmol scale affording 8.65 g (81%
yield) of 4,4,4-trichloro-3-hydroxy-2-methylbutanal
Lett. 2003, 44, 7607. (e) Thayumanavan, R.; Tanaka, F. J.;
Barbas, C. F. III. Org. Lett. 2004, 6, 3541. (f) Northrup, A.
B.; Mangion, I. K.; MacMillan, D. W. C. Angew. Chem. Int.
Ed. 2004, 43, 2152. (g) Casas, J.; Engqvist, M.; Ibrahem, I.;
Kaynak, B.; Córdova, A. Angew. Chem. Int. Ed. 2005, 44,
(
Table 3, entry 1), a useful intermediate for preparing vi-
1
2b
nyl dichloride and trisubstituted olefins.
In conclusion, we reported that piperidine and L-prolina-
mide were efficient catalysts for the cross-aldol reaction
between chloral and aliphatic aldehydes. This catalytic
process was suitable for preparing b-trichloromethyl-b-
hydroxy aldehydes in high yields under mild conditions,
in which aliphatic aldehyde could be added in one portion
without the necessity of slow addition. Further studies on
improving the reaction enantioselectivity are currently
under investigation.
1
343. (h) Córdova, A. Tetrahedron Lett. 2004, 45, 3949.
1
(
15) Compound 2: H NMR (400 MHz, CDCl ): d = 1.08 (t,
3
J = 7.2 Hz, 3 H, CH CH ), 1.82 (dq, J = 7.2 Hz, 2 H,
2
3
CH CH ), 1.93 (dq, J = 7.2 Hz, 2 H, CH CH ), 3.03 (t,
2
3
2
3
J = 7.2 Hz, 1 H, CHCH
.16 (s, 1 H, CHOH), 4.29 (s, 1 H, CHOH), 4.30 (s, 1 H,
CHOH), 9.75 (d, J = 2.4 Hz, 1 H, CHO), 9.94 (d, J = 2.8 Hz,
), 3.17 (t, J = 7.2 Hz, 1 H, CHCH ),
2
2
4
1
1
H, CHO). IR (film): n = 3435, 2968, 2936, 2843, 2769,
–1
713, 1124, 808 cm . MS (EI, 70 eV): m/z (%) = 55.22
(100), 73.05 (90), 136.69 (95), 191.82 (30), 218.90 (15)
+
[
M] .
(
(
16) List, B.; Pojarliev, P.; Castello, C. Org. Lett. 2001, 3, 573.
17) (a) Cordova, A.; Ibrahem, I.; Casas, J.; Henrik, S.; Engqvist,
M.; Reyes, E. Chem. Eur. J. 2005, 11, 4772. (b) Mase, N.;
Tanaka, F. J.; Barbas, C. F. III. Org. Lett. 2003, 5, 4369.
Acknowledgment
This work was supported by National Natural Science Foundation
of China (B20572028).
(
c) Mase, N.; Tanaka, F. J.; Barbas, C. F. III. Angew. Chem.
Int. Ed. 2004, 43, 2420.
18) A Typical Procedure.
References and Notes
(
To a suspension of chloral (148 mg, 1.0 mmol) and a
catalytic amount of L-prolinamide (34 mg, 0.3 mmol) in
(
1) Wynberg, H.; Emiel, G. J. S. J. Am. Chem. Soc. 1982, 104,
66.
1
CH Cl (8 mL) was added freshly distilled butanal (72 mg,
(
(
2) Corey, E. J.; John, O. L. J. Am. Chem. Soc. 1992, 114, 1906.
3) Achot, P. K.; James, E. O.; Rolland, M. W.; Panicker, S.;
Nicholson, J. M.; Klun, J. A. Tetrahedron: Asymmetry 1996,
2
2
1.0 mmol) in one portion at 0 °C. The reaction mixture was
first stirred at 0 °C for 1 h, then for additional 24 h at r.t. The
reaction mixture was treated with H O (10 mL). Then the
7, 37.
2
(4) Wang, Z.; Campagna, S.; Yang, K. H.; Xu, G. Y.; Piece, M.
solution was extracted with EtOAc (3 ´ 10 mL). The
E.; Fortunak, J. M.; Confalone, P. N. J. Org. Chem. 2000, 65,
combined organic layer was dried over anhyd MgSO ,
4
1
889.
5) Li, J.; Xu, X. L.; Zhang, Y. M. Tetrahedron Lett. 2003, 44,
349.
filtered, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel using 6:1 (v/v)
hexane–EtOAc as eluent, collecting 209 mg of product 2 in
95% yield (R = 0.43 for 1; R = 0.31 for 2). The ee was
(
(
9
6) (a) Torii, H.; Nakadai, M.; Ishihara, K.; Saito, S.;
f
f
Yamamoto, H. Angew. Chem. Int. Ed. 2004, 43, 1983.
determined by chiral GC analysis with a DIKMA Chirasil-
DEX CB (25 m ´ 0.25 mm) column. Temperature program:
from 70 °C to 170 °C at a rate of 10 °C/min, then isotherm
for 20 min at 170 °C; t (major) = 16.6 min; t (minor) = 17.2
(
2
b) Guirado, A.; Martiz, B.; Andreu, R. Tetrahedron Lett.
004, 45, 8523.
(
(
(
7) Funabiki, K.; Honma, N.; Hashimoto, W.; Matsui, M. Org.
Lett. 2003, 5, 2059.
8) Lerm, M.; Joachim, H. G.; Cheng, K. J.; Vermeeren, C. J.
Am. Chem. Soc. 2003, 125, 9653.
R
R
min for anti isomer; t = 17.5 min, 18.3 min for syn isomer.
R
2
0
[a]D –2.9 (c 1.0, CHCl3).
19) Compound 3: R = 0.21, 6:1 (v/v) hexane–EtOAc. H NMR
1
(
f
9) Faller, J. W.; Liu, X. Tetrahedron Lett. 1996, 37, 3449.
(
1
400 MHz, CDCl ): d = 1.39 (d, J = 7.6 Hz, 3 H, CHCH ),
3
3
(
(
10) (a) Si, Y. G.; Guo, S. P.; Wang, W. J.; Jiang, B. J. Org.
Chem. 2005, 70, 1494. (b) Jiang, B.; Si, Y. G. Adv. Synth.
Catal. 2004, 346, 669.
11) (a) Tennyson, R. L.; Cortez, G. S.; Galicia, H. J.; Kreiman,
C. R.; Thompson, C. M.; Romo, D. Org. Lett. 2002, 4, 533.
.41 (d, J = 7.6 Hz, 3 H, CHCH ), 3.12–3.18 (m, 1 H,
3
CHCH ), 3.19–3.23 (m, 1 H, CHCH ), 4.15 (br s, 1 H,
3
3
CHOH), 4.23 (s, 1 H, CHOH), 4.75 (d, J = 3.2 Hz, 1 H,
CHOH), 9.67 (s, 1 H, CHO), 9.95 (d, J = 2.8 Hz, 1 H, CHO).
IR (film): n = 3438, 2982, 2941, 2844, 2734, 1722, 1124, 808
(b) Michellys, P. Y.; Ardecky, R. J.; Chen, J. H.; Crombie,
–1
cm . MS (EI, 70 eV): m/z (%) = 121.92 (100), 140.79 (43),
D. L.; Etgen, G. J. J. Med. Chem. 2003, 46, 2683.
+
20
2
04.47 (15) [M] . [a]D +4.9 (c 1.0, CHCl3).
1
Compound 4: R = 0.36, 6:1 (v/v) hexane–EtOAc. H NMR
f
(
400 MHz, CDCl ): d = 1.08, 1.18 [d, J = 7.2 Hz, 6 H,
3
CH(CH ) ], 1.11, 1.12 [d, J = 7.2 Hz, 6H, CH(CH ) ], 2.35–
3
2
3 2
2
.40 [m, J = 7.2 Hz, 1 H,CH(CH ) ], 2.52–2.56 [m, J = 7.2
3 2
Synlett 2006, No. 11, 1703–1706 © Thieme Stuttgart · New York

1
706
F. Zhang et al.
LETTER
Hz, 1 H, CH(CH ) ], 2.87 (dd, J = 6.8, 3.2 Hz, 1 H,
1.32–1.45 (m, 6 H, CH CH CH CH ), 1.73–1.87 (m, 2 H,
3
2
2
2
2
3
CHCHO), 2.98 (dd, J = 6.0, 2.4 Hz, 1 H, CHCHO), 3.04 (br
s, 1 H, CHOH), 4.37 (d, J = 6.8 Hz, 1 H, CHOH), 4.82 (d,
J = 7.2 Hz, 1 H, CHOH), 9.87 (d, 1 H, J = 2.8 Hz, CHO),
CHCH ), 4.16 (s, 1 H, CHOH), 4.56 (d, J = 2.8 Hz, 1 H,
2
CHOH), 4.28 (s, 1 H, CHOH), 9.74 (d, J = 2.4 Hz, 1 H,
CHO), 9.94 (d, J = 2.8 Hz, 1 H, CHO). IR (film): n = 3436,
–
1
9
.96 (q, 1 H, J = 1.2 Hz, CHO). IR (film): n = 3437, 2953,
2958, 2930, 2862, 2734, 1713, 1128, 816 cm . MS (EI, 70
–1
2935, 2852, 2734, 1713, 1126, 813 cm .
eV): m/z (%) = 73.08 (100), 121.94 (35), 142.99 (43),
1
+
20
Compound 5: R = 0.49, 6:1 (v/v) hexane–EtOAc. H NMR
189.79 (25), 260.96 (5) [M] . [a]D –4.0 (c 1.0, CHCl3).
f
(
400 MHz, CDCl ): d = 0.90 (t, J = 6.4 Hz, 3 H, CH CH ),
3
2
3
Synlett 2006, No. 11, 1703–1706 © Thieme Stuttgart · New York