The highly trans-selective Darzens reaction via ammonium ylides

Article abstract of DOI:10.1055/s-2005-864799

The Darzens reaction using electron deficient p-substituted benzyltriethylammonium chlorides with aromatic aldehydes afforded 2,3-diaryl epoxides with trans selectivity (>99%) while the corresponding reaction with electron releasing p-substituted benzyltriethylammonium salts gave the epoxides as diastereomeric mixtures. Epoxide formation of p-trifluoromethylbenzylammonium salt, prepared from p-trifluoromethylbenzyl chloride and DABCO, afforded the corresponding 2,3-diaryl epoxide in high yield (>98%).

Full text of DOI:10.1055/s-2005-864799

842
LETTER
The Highly trans-Selective Darzens Reaction via Ammonium Ylides
H
ighly trans-Se
e
lective
D
ar
t
zens
R
s
eactionvi
u
a
A
mmonium
t
Y
lide
a
s
ro Kimachi,* Hiroyo Kinoshita, Kumiko Kusaka, Yukiko Takeuchi, Mai Aoe, Motoharu Ju-ichi
Faculty of Pharmaceutical Sciences, Mukogawa Women’s University, 9-11-68, Koshien, Nishinomiya 663-8179, Hyogo, Japan
Fax +81(798)412792; E-mail: tkimachi@mwu.mukogawa-u.ac.jp
Received 16 November 2004
of the anti-betaine intermediates and cis-epoxides are de-
Abstract: The Darzens reaction using electron deficient p-substi-
rived from formation of the syn-betaine intermediates.
Our results suggest that aromatic bearing electron-with-
drawing groups stabilizes an anti-betaine or promotes for-
tuted benzyltriethylammonium chlorides with aromatic aldehydes
afforded 2,3-diaryl epoxides with trans selectivity (>99%) while
the corresponding reaction with electron releasing p-substituted
benzyltriethylammonium salts gave the epoxides as diastereomeric mation of an anti-betaine which then leads to a trans-
mixtures. Epoxide formation of p-trifluoromethylbenzylammonium
salt, prepared from p-trifluoromethylbenzyl chloride and DABCO,
epoxide.
afforded the corresponding 2,3-diaryl epoxide in high yield (>98%).
Table 1 Diastereoselective Synthesis of 2,3-Diaryl Epoxides from
p-Substituted Benzyltriethylammonium Chlorides and Benzaldehyde
Key words: Darzens reaction, ammonium ylides, 2,3-diaryl ep-
oxides
ꢀ
Cl
2 t-BuOK
R
+
THF
N
PhCHO
r.t., 1 h
Recent progress on asymmetric Darzens glycidic ester
formation catalyzed by phase-transfer catalysts1 or chiral
sulfur ylides2 includes the development of environmental-
ly benign and mild conditions. A novel Darzens reaction
via ammonium ylides was reported by Jonczyk et al.,3
which, however, is unsatisfactory in chemical yield and
stereoselectivity compared with that using phase-transfer
catalysts or sulfur ylides. Encouraged by Jonczyk’s re-
port, we undertook to study the scope and limitations of
Darzens reaction via ammonium ylides. Here we report
the high trans-selective Darzens reaction of various sub-
stituted benzyl ammonium chlorides with aromatic alde-
hydes. Furthermore, we demonstrate successive
formation of trans-2,3-diaryl epoxides without isolation
of derived ammonium salts. The substituted benzylic qua-
ternary ammonium salts (1a–i) were prepared from the
corresponding benzylic chlorides by treatment with trieth-
ylamine under reflux conditions.4,5 After a screening of
suitable conditions, we found that epoxides were formed
when p-substituted benzyltriethylammonium chlorides
and benzaldehyde were treated with 2 equivalents of t-
BuOK in THF under anhydrous conditions.6 The results
are summarized in Table 1. Remarkably, starting ammo-
nium chlorides having electron-withdrawing group exclu-
sively afforded trans-2,3-diaryl epoxides in moderate to
good yields at room temperature (Table 1, entries 4–9).
On the other hand, using electron-rich substrates (entries
1–3) resulted low to moderate epoxide formation with
poor diastereoselectivity (Table 1, entries 1–3). The
trans-selectivity in the reaction of ammonium ylides and
aldehydes appears to proceed via formation of the anti- or
syn-betaine intermediates same as that of sulfonium ylides
and aldehydes.2 In the addition of benzylsulfonium ylides
to aldehydes, trans-epoxides are derived from formation
R
O
2a–i
1a–i
Entry Substrate (R)
Product
2a
Yield (%) dr (cis:trans) b
1
2
3
4
5
6
7
8
9a
1a (-CH3)
67
18
26
89
70
68
54
96
30
57:43
1b (-OCH3)
1c (-H)
2b
67:33
2c
23:73
1d (-CONEt2)
1e (-CO2t-Bu)
1f (-CO2Et)
1g (-CN)
2d
<1:>99
<1:>99
<1:>99
<1:>99
<1:>99
<1:>99
2e
2f
2g
1h (-CF3)
2h
1i (-NO2)
2i
a 50% aq NaOH was used as a base. The reaction mixture was
continuously stirred for 18 h.
b trans-Configuration was confirmed by X-ray analysis.
The reaction between a p-substituted benzylchloride and
benzaldehyde under the same conditions resulted in re-
covery of starting materials (Table 3, entry 1). Advantag-
es in using ammonium salts are easy formation of the
reactive ammonium ylides and recovery of the reusable
tertiary amines after completion of the reaction. However,
it is not practical to use triethylammoium salts as a leaving
group because of the ready volatility of triethylamine,
causing poor recovery in the work up procedure. We
found DABCO (diazabicyclo[2,2,2]-octane) to be a suit-
able amine candidate to improve the recovery of tertiary
amine. DABCO, which is more nucleophilic than triethyl-
amine, led to the rapid formation of the corresponding am-
monium salt in reaction with p-trifluoromethylbenzyl
chloride (3) in acetone. Using isolable ammonium salts 4,
SYNLETT 2005, No. 5, pp 0842–0844
2
1.
0
3.
2
0
0
5
Advanced online publication: 09.03.2005
DOI: 10.1055/s-2005-864799; Art ID: U30904ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Highly trans-Selective Darzens Reaction via Ammonium Ylides
843
reaction with benzaldehyde afforded epoxide with 91% these events, 2,3-diaryl epoxide (2h) was obtained in
trans-selectivity. DABCO was recovered in >90% as de- 43%, 67%, respectively, as cis and trans mixture
scribed in the typical experimental section. Furthermore, (cis:trans = 43:57). These results suggest that one-pot cat-
the ammonium salt prepared from DABCO and p-trifluo- alytic epoxide formation shown in Table 3 proceeds not
romethylbenzyl chloride (3) in THF, upon in situ treat- only via ammonium salt which can form anti-betaine in-
ment with t-BuOK (2 equiv) and benzaldehyde, afforded termediate to preferentially afford trans-epoxide, but also
the corresponding epoxide (2h) quantitatively. Hence, no via another pathway to afford cis- and trans-epoxide mix-
isolation and purification of prepared ammonium salt is ture as a result. One of the probable pathways other than
required.7 Formation of epoxides using other aryl alde- that via ammonium salt consists of a route via chlorohy-
hydes was carried out and the results are summarized in drin intermediate directly formed from benzylic chloride
Table 2.8 In order to investigate the nature of the counter and benzaldehyde, catalyzed by DABCO itself or ammo-
anion, chloride was replaced by Br–, I–, and NO3 . Thus, nium salt (4).9
–
using the corresponding benzylic ammonium bromide,
benzylic ammonium iodide, and benzylic ammonium ni-
Table 3 Catalytic Potency of DABCO in One-Pot Preparation of 2h
trate afforded the 2,3-diaryl epoxides (in 77%, 31%, 81%,
respectively) with trans-selectivity.
N
F3C
N
Table 2 One-Pot and Successive Preparation of trans-2,3-Diaryl
Epoxides
(0–1 equiv)
Cl
t-BuOK
PhCHO
r.t., THF
O
not isolated
F3C
3
N
2h
N
N
+
Entry
DABCO
(equiv)
Yield (%)
dr (cis:trans) Time (h)
N
(1.5 equiv)
Cl
ꢀ
Cl
THF
reflux, 2 h
F3C
F3C
4
1
2
3
4
0
0
35
45
48
–
16
16
4
3
0.01
0.1
1
43:57
50:50
40:60
ArCHO
2 t-BuOK
1 h, r.t.
F3C
1
Ar
O
In conclusion, we have achieved a highly trans-selective
Darzens reaction of electron deficient p-substituted ben-
zylammonium chlorides with aromatic aldehydes to give
2,3-diaryl epoxides. p-Trifluoromethylbenzylammonium
salt of DABCO not only provide the corresponding trans-
2,3-diaryl epoxide in high yield but also allowed recovery
of DABCO in 90% by extraction. Studies on the enanti-
oselective version of this trans-selective Darzens reaction
using optically active tertiary amines (e.g. chiral diazabi-
cyclo[2,2,2]octane derivatives or chiral quinuclidine de-
rivatives) and the development of the environmentally
benign synthesis using resin-supported tertiary amines are
in progress.
2h, 5, 6, 7
Ar
Product
Yield (%)
quant.
83
dr (cis:trans)
<1:>99
<1:>99
<1:>99
5:95
C6H5-
2h
5
4-CH3OC6H4-
4-ClC6H4-
6
81
4-NCC6H4-
7
55
p-Trifluoromethylbenzyl chloride (3) undergoes reaction
with DABCO to slowly form the corresponding ammoni-
um salt even at room temperature. This encouraged us to
study catalytic potency of DABCO in one-pot procedure.
Various amounts of DABCO [0, 0.01, 0.1, 1 equivalent to
p-trifluoromethylbenzyl chloride (3)] and 3, benzalde-
hyde and t-BuOK were mixed at once and the mixture was
stirred for the appropriate times described in Table 3. As
illustrated in Table 3, the presence of DABCO was neces-
sary for the formation of epoxides, but observed dia-
stereoselectivity was quite low (entries 1–4). In order to
investigate the role of catalytic amount of DABCO, we at-
tempted the reactions of p-trifluoromethylbenzyl chloride
(3) and benzaldehyde with or without catalytic amount of
DABCO, and together with catalytic amount of quaterna-
ry ammonium salt (4) prepared from 3 and DABCO. In
Acknowledgment
We thank Professor Yoshiji Takemoto (Graduate School of Phar-
maceutical Sciences, Kyoto University, Japan) for informative dis-
cussion and advice. We also thank Professor Toshihiro Hashimoto
(Faculty of Pharmaceutical Sciences, Tokushima Bunri University,
Tokushima, Japan) for the X-ray crystal structure analysis of
epoxide 2d.
References
(1) (a) Arai, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2145.
(b) Arai, S.; Shioiri, T. Tetrahedron 2002, 58, 1407; and
references cited therein.
Synlett 2005, No. 5, 842–844 © Thieme Stuttgart · New York

844
T. Kimachi et al.
LETTER
(2) (a) Li, A.-H.; Dai, L.-X.; Aggarwal, V. K. Chem. Rev. 1997,
97, 2341. (b) Aggarwal, V. K.; Calamai, S.; Ford, J. G. J.
Chem. Soc., Perkin Trans. 1 1997, 593. (c) Aggarwal, V.
K.; Ford, J. G.; Fonquerna, S.; Adams, H.; Jones, R. V. H.;
Fieldhouse, R. J. Am. Chem. Soc. 1998, 120, 8328.
(d) Julienne, K.; Metzner, P.; Henryon, V. J. Chem. Soc.,
Perkin Trans. 1 1999, 731. (e) Aggarwal, V. K.; Winn, C. L.
Acc. Chem. Res. 2004, 37, 611.
with CHCl3 and sat. aq NH4Cl. The mixture was separated
and the aqueous layer was washed with H2O, brine, and then
dried over MgSO4. Removal of the solvent and purification
by flash chromatography (hexane–EtOAc = 1:1) afforded
N,N-diethyl-4-(3-phenyloxiranyl)benzamide (2d, 264 mg,
89%) as a colorless solid; mp 83–85 °C. 1H NMR (400 MHz,
CDCl3): d = 1.20 (m, 6 H), 3.30 (m, 2 H), 3.54 (m, 2 H), 3.86
(d, 1 H, J = 1.83 Hz), 3.88 (d, 1 H, J = 1.83 Hz), 7.32–7.41
(m, 9 H). 13C NMR (126 MHz, CDCl3): d = 13.0, 14.2, 39.3,
43.3, 62.4, 62.9, 125.6, 126.7, 128.5, 128.6, 136.9, 137.4,
138.2, 170.9. IR (CHCl3): nmax = 3000, 1612, 1565, 1510
cm–1. HRMS (EI+): m/z calcd for C19H21NO2: 295.1572;
found: 295.1572. Anal. Calcd for C19H21NO2: C, 77.25; H,
7.17; N, 4.74. Found: C, 77.13; H, 7.28; N, 4.71. DABCO
dissolved in the aqueous layer as an ammonium ion was
recovered when the aqueous layer was basified by KOH and
extracted with CH2Cl2.
(3) Jonczyk, A.; Konarska, A. Synlett 1999, 1085.
(4) Typical Procedure for the Preparation of p-Substituted
Benzyltriethylammonium Chlorides (1d).
A mixture of 4-chloromethyl-N,N-diethylbenzamide (2.25 g,
10 mmol) and Et3N (5.5 mL, 40 mmol) in acetone (5 mL)
was heated under reflux for 16 h. Acetone was removed in
vacuo and EtOAc was added. The formed colorless solid
was filtered off to afford 4-diethylcarbamyl-benzyltriethyl-
ammonium chloride (1d, 2.27 g, 6.95 mmol) in 70% yield as
white solid; mp 125–127 °C. 1H NMR (400 MHz, CDCl3):
d = 1.11 (m, 3 H), 1.26 (m, 3 H), 1.48 (t, 9 H, J = 7.3 Hz),
3.44 (m, 2 H), 3.47 (q, 8 H, J = 7.3 Hz), 5.03 (s, 2 H), 7.45
(d, 2 H, J = 8.4 Hz), 7.7 (d, 2 H, J = 8.1 Hz). 13C NMR (126
MHz, CDCl3): d = 8.5, 12.9, 14.3, 39.4, 43.4, 53.2, 61.1,
127.3, 128.4, 133.0, 139.6, 170.0. IR (CHCl3): nmax = 2900,
1615, 1565, 1510 cm–1. HRMS (FAB+): m/z calcd for
[C18H31N2O]+: 291.2436; found: 291.2434. Anal. Calcd for
C18H31N2OCl·H2O: C, 62.7; H, 9.65; N, 8.12. Found: C,
62.55; H, 9.99; N, 8.12.
(7) Quinuclidine (the second N of DABCO is replaced by CH)
was also tried as an amine candidate. The ammonium salt
was formed but it was too moisture sensitive to be isolated.
When one-pot and successive preparation of trans-2,3-diaryl
epoxide was carried out using quinuclidine, 2h was obtained
in 89%. Thus, the role of the second N of DABCO is not
clear to date.
(8) When carbonyl compounds such as aliphatic aldehydes and
ketones, other than aryl aldehydes were used under the
reaction condition, no epoxides were formed and carbonyl
compounds were recovered.
(5) Quaternary ammonium salts containing methyl groups are
known to promote 2,3-Stevens-type rearrangement reaction
under strong basic condition. See: Marko, I. E. In
Comprehensive Organic Synthesis, Vol. 3; Trost, B., Ed.;
Pergamon Press: Oxford England, 1991, 913.
(6) Typical Procedure.
(9) According to the literature method,10 we have tried the
reaction using benzylic chloride [e.g. (p-chloromethyl)benzo-
nitrile, p-nitrobenzyl chloride] and benzaldehyde in the
presence of phase-transfer catalyst. Corresponding epoxides
were obtained in 88% and 70%, respectively, as
To an ice cooled stirred solution of 4-diethylcarbamyl
benzyltriethylammonium chloride (1d, 326.8 mg, 1 mmol)
and benzaldehyde (0.1 mL, 1 mmol) in THF (4 mL) was
slowly added t-BuOK (224.4 mg, 2 mmol). Yellow colored
suspension was stirred for 1 h at r.t. The mixture was diluted
diastereomeric mixtures.
(10) (a) Dilling, W. L.; Hickner, R. A.; Farber, H. A. J. Org.
Chem. 1967, 32, 3489. (b) Taranko, L. B.; Perry, R. H. Jr. J.
Org. Chem. 1969, 34, 226.
Synlett 2005, No. 5, 842–844 © Thieme Stuttgart · New York