Diastereoselective Darzens reactions of α-chloroesters, amides and nitriles with aromatic aldehydes under phase-transfer catalyzed conditions

Article abstract of DOI:10.1016/S0040-4039(01)02248-1

The development of the highly diastereoselective catalytic synthesis of glycidic acid derivatives via Darzens reaction is described. The reaction of α-chloroesters and amides with aromatic aldehydes smoothly proceeds in the presence of a quaternary ammonium salt as a phase-transfer catalyst to give the corresponding cis and trans desired products in satisfactory yields, respectively.

Full text of DOI:10.1016/S0040-4039(01)02248-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 833–836
Diastereoselective Darzens reactions of a-chloroesters,
amides and nitriles with aromatic aldehydes under
phase-transfer catalyzed conditions
Shigeru Arai,* Yukari Suzuki, Kazuyuki Tokumaru and Takayuki Shioiri*
Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 15 October 2001; revised 19 November 2001; accepted 22 November 2001
Abstract—The development of the highly diastereoselective catalytic synthesis of glycidic acid derivatives via Darzens reaction is
described. The reaction of a-chloroesters and amides with aromatic aldehydes smoothly proceeds in the presence of a quaternary
ammonium salt as a phase-transfer catalyst to give the corresponding cis and trans desired products in satisfactory yields,
respectively. © 2002 Elsevier Science Ltd. All rights reserved.
The use of phase-transfer catalysts (PTC) have many
advantages with respect to economics, operational sim-
plicity and environmental consciousness in modern
organic synthesis so that PTC chemistry has been uti-
lized in green chemistry.1 In particular, Darzens reac-
tion, which is promoted by using bases, has been widely
recognized as one of the most potential methodologies
to obtain a,b-epoxy carbonyl compounds (Scheme 1).2
Their diastereo and enantio controls are still a challeng-
ing goal. We have already reported some examples of
the asymmetric Darzens reaction utilizing chiral PTCs
by use of a-chloroketones3 and a sulfone4 as the carbon
nucleophiles with complete diastereo control. The
observed diastereoselectivities in the products are
strongly dependent on the kinetics of the corresponding
aldol intermediates during the cyclization step and trans
isomers are generally formed. On the other hand, few
examples of the catalytic diastereoselective synthesis of
trolled highly diastereoselective synthesis of glycidic
acid derivatives (EWG=CO2R, CN and CONPh2).
Initially, the solvent effect was examined using 4-tert-
butylbenzaldehyde (1a) and tert-butyl chloroacetate
(2a) in the presence of KOH and 10 mol% of tetra-
hexylammonium bromide (THAB) as the PTC,7,8 as
shown in Table 1. First of all, toluene was used under
PTC conditions. Initial survey of reaction conditions in
toluene using 1.2 equiv. of KOH revealed that the
reaction became slow after 5 h and addition of more 1.2
equiv. of KOH after 5 h not only accelerated the
reaction but also increased the chemical yields.9 Thus,
the reaction was conducted through the twice addition
of KOH. As expected, the desired product 3a was
formed in good yield and fortunately, 3a was obtained
in a much lower yield in the absence of the PTC (entry
1 versus 2). The diastereoselectivity of entry 1 was
found to be 3.9:1. When the chloroester 2a was used in
large excess from the initial stage of the reaction, the
diastereoselectivity of 3a greatly decreased because the
a,b-epoxyesters
via
carbonꢀcarbon5
and
car-
bonꢀoxygen6 bond forming reactions are reported. In
this communication, we wish to report the PTC-con-
Scheme 1.
Keywords: Darzens reactions; diastereoselection; epoxides; phase-transfer.
* Corresponding authors. Tel./fax: +82-52-834-4172; e-mail: shioiri@phar.nagoya-cu.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02248-1

834
S. Arai et al. / Tetrahedron Letters 43 (2002) 833–836
Table 1. Solvent effect
Entry
Solvent
THAB (mol %)
Time (h)
3a (%)
cis:trans
1
2
3
4
5
6
7
8
Toluene
Toluene
CH2Cl2
Et2O
THF
THF
10
None
10
10
10
None
10
10
19
19
19
19
25
21
18
19
77
4
3.9:1
1.3:1
3.1:1
9.7:1
cis only
1.2:1
3.4:1
3.5:1
70
77
61
46
82a
86
THF
BTFb
a Excess amount of 2 (2.4 equiv.) was used.
b Benzotrifluroide.
potassium enolate, probably a mixture of cis- and
trans-isomers, may be produced in large amount and
the reaction may proceed without PTC. Each isomer
was easily separated by flash column chromatography
As shown in Table 2, the combination of a catalytic
amount of THAB and KOH in THF at room tempera-
ture was investigated in other aromatic aldehydes. As
expected, these conditions were quite sufficient to give
the desired Darzens adduct 3 as the sole product with
complete cis-diastereoselectivity. For example, 2-substi-
tuted aldehydes such as 1b and 1c gave the correspond-
ing Darzens adducts in 54 and 43% yield, respectively
(entries 1 and 2). Aldehydes 1d and 1e also gave similar
results to 1a (entries 3 and 4). Electron withdrawing
groups such as CF3 and NO2 were also found to be
applied to this system, though the chemical yields were
reduced (entries 5 and 6). Although other aliphatic
aldehydes were examined, the reaction did not
smoothly proceed due to decomposition of the alde-
hydes under strong basic conditions.
1
and their stereochemistry was determined by H NMR
analysis to be cis as the major product.
Dichloromethane was found not to be effective because
of the lower de (entry 3). Fortunately, diethyl ether
gave a better diastereoselectivity in good yield (entry 4).
We were pleased to find that THF was quite effective
for exclusively producing the cis isomer in satisfactory
chemical yield. Surprisingly, the trans isomer was also
formed in an almost equal ratio in the absence of PTC
(entry 5 versus 6) in THF.10 This result is the obvious
evidence that PTC plays a very important role in
determing the diastereomeric ratio of the product in the
PTC-catalyzed Darzens reaction. Using an excess of 2
resulted in a lower diastereomeric ratio, as shown in
entry 7. Weaker bases such as LiOH or K2CO3 were
not strong enough to abstract the a proton of 2 and
little or no reaction proceeded. Encouraged by these
results, other substrates were examined under similar
reaction conditions for further investigation.11
Finally, we attempted to use a various carbon nucleo-
philes for the investigation of the broad generality. In
the case of the aryl ester 2b, weaker base should be used
to avoid its decomposition and the reaction smoothly
proceeded to give 3b in 87% yield using benzotrifluoride
as a solvent and Rb2CO3 as a base in which no product
Table 2.
Entry
Aldehyde
Time (h)
3 (%)a
1
2
3
4
5
6
1b: a-Naphthyl
1c: 2-Cl-C6H4
1d: Ph
1e: 4-Me-C6H4
1f: 4-CF3-C6H4
1g: 4-NO2-C6H4
25
23
22
24
23
27
3b: 54
3c: 43
3d: 52
3e: 59
3f: 36
3g: 31
a Only cis-isomer was formed.

S. Arai et al. / Tetrahedron Letters 43 (2002) 833–836
835
Table 3.
Entry
1
2
Conditionsa
3 (%)
cis:trans
2b: EWG=
Rb2CO3, BTF, 34 h
3b: 54
1:3
2
3
4
5
2c: EWG=CN
2c: EWG=CN
2d: EWG=CONPh2
2d: EWG=CONPh2
KOH, THF, 27 h
KOH, Et2O, 29 h
KOH, THF, 31 h
LiOH, THF, 25 h
3c: 86
3c: 21
3d: 40
3d: 91
0.8:1
40:1
30:1
trans only
a Excess amount of base (2.4 equiv.) was used in all entries.
was produced in the absence of PTC, though its
diastereoselectivity was found to be lower than 2a. On
the other hand, nitrile 2c gave the satisfactory
diastereoselectivity to produce 3c in a ratio of 40:1
when the reaction was carried out in diethyl ether
instead of THF though the yield decreased (entry 2
versus 3). The Darzens reaction of the N,N-diarylamide
2d using KOH gave the epoxy-amide 3d with good cis
selectivity though in low yield (entry 4). Surprisingly,
however, the use of milder base (LiOH) afforded 3d in
good yield with complete stereocontrol, as shown in
Table 3.
4. Arai, S.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1998, 39,
8229–8302.
5. Successful results for the formation of trans or cis-epox-
ides via the aldol reaction using a-haloesters or amides
were reported, see: for trans-epoxide; (a) Corey, E. J.;
Choi, S. Tetrahedron Lett. 1991, 32, 2857–2860. For
cis-epoxide; (b) Pridgen, L. N.; Abdel-Magid, A. F.;
Lantos, I.; Shilcrat, S.; Eggleston, D. S. J. Org. Chem.
1993, 58, 5107–5117 and references cited therein; (c)
Abdel-Magid, A.; Lantos, I.; Pridgen, L. N. Tetrahedron
Lett. 1984, 25, 3273–3276.
6. Enantioselective synthesis of cis glycidic esters is
reported, see: (a) Jacobsen, E. N.; Furukawa, Y.; Mar-
tinez, L. E. Tetrahedron, 1994, 50, 4323–4334. Quite
recently Shibasaki and co-workers reported the catalytic
asymmetric epoxidation of a,b-unsaturated imidazolides,
see: (b) Nemoto, T.; Ohshima, T.; Shibasaki, M. J. Am.
Chem. Soc. 2001, 123, 2725–2726.
In summary, we have realized that commercially avail-
able THAB acts as quite an effective PTC under mild
reaction conditions to achieve high diastereoselectivities
in the Darzens reaction using tert-butyl chloroacetate,
chloroacetonitrile and N,N-diphenylacetamide with
aromatic aldehydes. Further investigations will lead
more satisfactory results, and the application of new
chiral PTCs is under development.
7. For a recent example of the utility of THAB as a PTC,
see: Arai, S.; Nakayama, K.; Hatano, K.; Shioiri, T. J.
Org. Chem. 1998, 63, 9572–9575.
8. Trials to use other commercially available quaternary
ammonium salts such as (n-Bu)4NBr, BnNEt3Br and
CetNMe3Br gave no better results than THAB.
9. In the case of the initial addition of 2.4 equiv. of KOH,
the reaction was slow to afford 3a in 61% (cis:trans=3:1)
even after 32 h.
10. A successful result for the synthesis of chiral trans-gly-
cidic esters with a stoichiometric amount of base via
Darzens reaction was reported, see: (a) Takahashi, T.;
Muraoka, M.; Capo, M.; Koga, K. Chem. Pharm. Bull.
1995, 43, 1821–1823. Moderate de in the stoichiometric
asymmetric Darzens reaction was achieved, see: (b) Tak-
agi, R.; Kimura, J.; Shinohara, Y.; Ohba, Y.; Takezono,
K.; Hiraga, Y.; Kojima, S.; Ohkata, K. J. Chem. Soc.,
Perkin Trans. 1, 1998, 689–698 and references cited
therein. See also Ref. 6b.
References
1. For recent books on PTC, see: (a) Phase-Transfer Cataly-
sis. Mechanism and Synthesis; Halpern, M. E., Ed.;
American Chemical Society: Washington, DC, 1997; (b)
Handbook of Phase Transfer Catalysis; Sasson, Y.; Neu-
mann, R., Eds.; Blackie A. & M.: London, 1997; (c)
Shioiri, T.; Arai, S. In Stimulating Concepts in Chemistry;
Vogtle, F.; Stoddart, J. F.; Shibasaki, M., Eds.; Wiley-
VCH: Germany, 2000; pp. 123–143
2. Newman, M. S.; Magerlein, B. J. Organic Reactions,
1949; Chapter 10, pp. 413–441.
3. For an acyclic ketone system, see: (a) Arai, S.; Shioiri, T.
Tetrahedron Lett. 1998, 39, 2145–2148; (b) Arai, S.; Shi-
rai, Y.; Ishida, T.; Shioiri, T. Tetrahedron 1999, 55,
6375–6386. For a cyclic ketone system, see: (c) Arai, S.;
Shirai, Y.; Ishida, T.; Shioiri, T. Chem. Commun. 1999,
49–50.
11. Typical procedure of PTC-catalyzed Darzens reaction,
synthesis of 3a: To a solution of 1a (0.5 mL, 3.0 mmol),
2a (0.52 mL, 3.6 mmol), and THAB (130 mg, 0.3 mmol)
in THF (9.0 mL) was added KOH (200 mg, 3.6 mmol) in
one portion at room temperature. After the mixture was

836
S. Arai et al. / Tetrahedron Letters 43 (2002) 833–836
stirred for 5.5 h, additional KOH (200 mg, 3.6 mmol) was
added to the reaction mixture. After stirring for 19.5 h, the
reaction was quenched with water and the mixture was
extracted with ethyl acetate (15 mL×3). The combined
organic layer was washed with brine and solvent, and con-
centrated under reduced pressure. Purification by flash
column chromatography (hexane:AcOEt=50:1) exclusively
gave 3a as a pale yellow oil (508 mg, 61%). 1H NMR
(CDCl3, 270 MHz) l: 1.16 (s, 9H), 1.29 (s, 9H), 3.69 (d,
J=4.6 Hz, 1H), 4.21 (d, J=4.6 Hz, 1H), 7.34 (s, 4H); 13C
NMR (CDCl3, 67.8 MHz) l: 27.5 (CH3×3), 31.3 (CH3×3),
34.5 (4°), 55.9 (CH), 56.9 (CH), 82.2 (4°, 124.7 (CH×2),
126.4 (CH×2), 130.2 (4°), 151.3 (4°), 166.0 (4°); IR (neat)
wmax: 2967, 1752, 1368, 1159 cm−1; MS m/z: 220 (M+−
Me3CH), 163 (base peak), 57. Anal. calcd for C17H24O3: C,
73.88; H, 8.75. Found: C, 73.84; H, 8.83.