Phase-transfer-catalyzed asymmetric Darzens reaction using a new chiral ammonium salt

Article abstract of DOI:10.1016/j.tetlet.2004.01.009

Catalytic asymmetric Darzens reaction of haloamides is described. A new and easily-prepared bis-ammonium salt derived from BINOL acts as an effective phase-transfer catalyst and efficiently promotes the reaction to give the desired epoxides under quite mild conditions with up to 70% ee.

Full text of DOI:10.1016/j.tetlet.2004.01.009

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1845–1848
Phase-transfer-catalyzed asymmetric Darzens reaction using a new
chiral ammonium salt
Shigeru Arai,* Kazuyuki Tokumaru and Toyohiko Aoyama
Graduate School of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya 467-8603, Japan
Received 12 December 2003; revised 6 January 2004; accepted 6 January 2004
Abstract—Catalytic asymmetric Darzens reaction of haloamides is described. A new and easily-prepared bis-ammonium salt derived
from BINOL acts as an effective phase-transfer catalyst and efficiently promotes the reaction to give the desired epoxides under quite
mild conditions with up to 70% ee.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Phase-transfer catalysts (PTCs) are some of the most
powerful reagents in chemical transformation because
they are easy to use, economical and environmentally
benign.1 In particular, chiral onium salts, as PTCs, have
attracted considerable attraction as potential tools for
asymmetric synthesis because they are easy to prepare
and structurally diverse. Many potential applications of
chiral PTCs derived from natural and synthetic com-
pounds have been investigated over the past few dec-
ades2 since the first independent reports of successful
asymmetric alkylations by Dolling3 and OꢀDonnell.4 We
have also developed a variety of PTC-promoted asym-
metric reactions and recently reported a new and effi-
side product (MX) during C–C and C–O bond forma-
tion. Ammonium halides, however, react with an eno-
late to provide active species and give the desired
epoxides catalytically. Thus, regeneration of chiral QX
could provide a catalytic asymmetric protocol, as shown
in Figure 1. Based on this strategy, we have developed
catalytic asymmetric Darzens reactions of a-chloro
acyclic8a;b and cyclic8c ketones and a sulfone9 using
cinchona alkaloid derivatives as PTCs. To the best of
our knowledge, there have been no reports of a suc-
cessful phase-transfer-catalyzed asymmetric Darzens
reaction to give glycidic acid derivatives. The products
of this asymmetric transformation are expected to have
rich and useful functionality, and therefore its further
development is an important goal in organic synthesis.
In this communication, we report the results of the first
successful asymmetric synthesis of glycidic amides via a
catalytic Darzens strategy.10
cient PTC derived from L
-tartrate.5 While the Darzens
reaction,6 which gives very important synthetic inter-
mediates, is one of the most powerful and challenging
chemical transformations, there have been few reports
on its successful application to asymmetric synthesis
(not catalytic).7 In general, a stoichiometric amount of
strong base is required to effectively promote the reac-
tion. To achieve a catalytic asymmetric Darzens
sequence, onium salts as PTCs would be expected to be
useful agents because they can be regenerated by react-
ing with an inorganic base to establish a catalytic cycle.
Initially, a new chiral PTC was designed by modifying
quaternary ammonium salts derived from cinchona
alkaloids. Their rigid structures prevent the synthesis of
derivatives, which reduces the generality of possible
substrates in each asymmetric transformation. More-
over, it has been reported that the substituents on the
quinuclidine nitrogen greatly affect the enantioselectivity
due to steric and electronic effects. Therefore, simplifi-
cation and modification of the catalyst would be
expected to overcome these problems, and an easily
prepared new PTC in which a chiral source is directly
introduced to the quinuclidine nitrogen was examined
(Fig. 2). Furthermore, a large twist angle between two
naphthyl moieties would be expected due to both steric
and dipole repulsion between bulky bis-ammonium
For example, metal reagents act as a base and can easily
abstract an a-proton to be converted into the unreusable
Keywords: Darzens reaction; Phase-transfer; Asymmetric synthesis.
* Corresponding author at present address: Graduate School of Phar-
maceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku,
Chiba 263-8522, Japan. Tel.: +81-43-290-2908; fax: +81-43-290-2909;
e-mail: arai@p.chiba-u.ac.jp
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.01.009

1846
S. Arai et al. / Tetrahedron Letters 45 (2004) 1845–1848
inorganic
base
OM
O
O
X
X
COY
Y
Y
QX
R
MX
OQ
: quaternary ammonium cation
: Metal
: halide
Q
M
X
QO
COY
X
R
Y
: OR or NR
Y
2
X
RCHO
Figure 1. Proposed catalytic cycle in the Darzens reaction.
Next, we investigated the asymmetric Darzens reaction
using PTC A. a-Protons of benzylamide 2a were acidic
enough to be abstracted by an inorganic base (KOH)
and the reaction proceeded smoothly to give the desired
epoxide 3a in good yield in both the presence and
absence of an achiral PTC (THAB, 10 mol %), as shown
in Table 1 (entries 1 and 2). Moreover, PTC A (2 mol %)
was found to be effective in the reaction of THF to give
an ee value of up to 20% (entry 3). Solvent screening
using 2a showed that dichloromethane gave the best
results, with up to 37% ee (entry 4). Unfortunately,
other attempts using N,N-dialkylamides as nucleophiles
gave unsuccessful results. N,N-Diphenylamides were
found to be the best substrates, and the enantioselec-
tivity of both cis and trans 3b improved to 51% and 52%
ee, respectively, with reasonable yields (entry 5). More-
over, rubidium hydroxide monohydrate gave a better
result with regard to diastereoselectivity (43% de) and a-
bromo amide 2c underwent rapid transformation to the
corresponding epoxide 3b within 6.5 h with 58% ee (cis)
and 63% ee (trans), respectively (entries 6 and 7). These
results are summarized in Table 1.
X
X
HO
N
N
Ar
Ar
*
N
cinchoninium salt
modified PTC
Figure 2. Simplification of chiral quaternary salt.
units and it would affect enantioselectivity. PTC A was
prepared in quantitative yield by bromination of (R)-
2,20-dimethyl-1,10-binaphthyl, which is readily available
from (S)-BINOL,11 and subsequent condensation with
quinuclidine (2 equiv) under reflux conditions, as out-
lined in Scheme 1.12
N
a, b
Me
Me
2Br
N
Encouraged by these results, we next investigated the
scope and limitations of PTC A in this asymmetric
process. PTC A effectively promoted the reaction with
various aldehydes, as summarized in Table 2.13 For
example, aromatic aldehydes such as 1b–e were
PTC A
Scheme 1. Synthesis of PTC. Reagents and conditions: (a) NBS,
(BzO)2, cyclohexane, 64%; (b) quinuclidine, THF, reflux, quant.
Table 1. Phase-transfer-catalyzed asymmetric Darzens reaction of a-haloamides 2
O
O
PTC (2 mol%)
O
PhCHO
+
X
NPhR
Ph
NPhR
base (2.4 eq), rt
2a : X = Cl, R = Bn
2b : X = Cl, R = Ph
2c : X = Br, R = Ph
1a
3
Entry
Amide PTC
Base
Conditions
Product
Yield (%)
cis/trans
Ee of cis (%)
Ee of trans (%)
1
2
3
4
5
6
7
2a
2a
2a
2a
2b
2b
2c
None
KOH
KOH
KOH
KOH
KOH
THF, 12 h
THF, 12 h
THF, 6 h
3a: R ¼ Bn
3a: R ¼ Bn
3a: R ¼ Bn
3a: R ¼ Bn
3b: R ¼ Ph
3b: R ¼ Ph
3b: R ¼ Ph
61
69
66
82
87
81
81
0.71
1.2
1.2
1.0
2.5
3.5
2.3
––
––
12
27
51
52
58
––
––
20
37
52
51
63
THABa
PTC A
PTC A
PTC A
PTC A
PTC A
CH2Cl2, 12 h
CH2Cl2, 4 h
RbOHÆH2O
RbOHÆH2O
CH2Cl2, 31 h
CH2Cl2, 6.5 h
THAB: tetrahexylammonium bromide.
a THAB (10 mol %) was used.

S. Arai et al. / Tetrahedron Letters 45 (2004) 1845–1848
Table 2. Catalytic asymmetric Darzens reaction using various aldehydes
1847
O
O
O
PTC A (2 mol%)
base (2.4 eq), CH Cl
RCHO
+
X
NPh
R
2
NPh
2
2
2
1
2b or 2c
4
Entry
Aldehyde
Amide
2c
Base
Conditions
Yield (%)
cis/trans
Ee of cis (%)
Ee of trans (%)
1
2
3
4
5
6
7
1b: R ¼ 3-Br-Ph
RbOHÆH2O
RbOHÆH2O
RbOHÆH2O
RbOHÆH2O
RbOHÆH2O
Cs2CO3
rt, 14 h
rt, 24 h
4b: 93
4c: 82
4d: quant
4e: 77
4f: 70
2.4
8.1
2.2
2.0
2.8
4.4
5.0
51
62
57
64
63
57
60
60
60
67
70
64
40
48
1c: R ¼ 4-MeO-Ph 2c
1d: R ¼ 2-MeO-Ph 2c
)10 ꢁC, 132 h
)30 ꢁC, 137 h
rt, 34 h
1e: R ¼ 2-Me-Ph
1f: R ¼ 4-t-Bu-Ph
1g: R ¼ i-Pr
2c
2c
2b
2b
rt, 70 h
rt, 70 h
4g: 77
4h: 61
1h: R ¼ c-Hex
Cs2CO3
O
References and notes
O
MeLi, TMEDA
COMe
CONPh
2
Ph
Ph
THF, -30 °C, 62%
1. For books on PTC, see: (a) Phase-Transfer Catalysis.
Mechanism and Synthesis; Halpern, M. E., Ed.; American
Chemical Society: Washington, DC, 1997; (b) Handbook
of Phase-Transfer Catalysis; Sasson, Y., Neumann, R.,
Eds.; Blackie A. & M.: London, 1997.
(3R, 4S)-5
trans-3b
(63% ee)
63% ee from trans-3b
25
[α]
-65.0 (c 1.0, CHCl )
3
D
Pd/C, H
AcOEt, 80%
2
2. For a review, see: (a) Nelson, A. Angew Chem. Int. Ed.
1999, 38, 1583–1585; (b) Maruoka, K.; Ooi, T. Chem. Rev
2003, 103, 3013–3028.
3. Dolling, U.-H.; Davis, P.; Grabowski, E. J. J. J. Am.
Chem. Soc 1984, 106, 446–447.
4. OꢀDonnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem.
Soc 1989, 111, 2353–2355.
5. (a) Arai, S.; Tsuji, R.; Nishida, A. Tetrahedron Lett. 2002,
43, 9535–9537; (b) Ohshima, T.; Shibasaki, M. Tetra-
hedron Lett. 2002, 43, 9539–9543.
Pd/C, H
AcOEt, 82%
2
O
CONPh
Ph
2
CONPh
2
Ph
OH
cis-3b
(58% ee)
(R)-6
63% ee from trans-3b
25
[α]
-164.2 (c 0.2, CHCl )
3
D
58% ee from cis-3b
25
[α]
-155.2 (c 0.2, CHCl )
3
D
6. For a review, see: Rosen, T. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Heathcock, C. H.,
Eds.; Pergamon: Oxford, 1991; 2, p 409.
Scheme 2. Determination of the absolute stereochemistry of 3b.
7. For some examples of the asymmetric Darzens reaction
using chiral auxiliary or external ligands, see: (a) Ohkata,
K.; Shinohara, Y.; Takagi, R.; Hiraga, Y. Chem. Commun.
1996, 2411–2412; (b) Takahashi, T.; Muraoka, M.; Capo,
M.; Koga, K. Chem. Pharm. Bull. 1995, 43, 1821–1823;
For an excellent result using a chiral sulfone amide, see:
Aggarwal, V. K.; Hynd, G.; Picoul, W.; Vasse, J.-L. J.
Am. Chem. Soc. 2002, 124, 9964–9965.
8. (a) Arai, S.; Shioiri, T. Tetrahedron Lett. 1998, 39, 2145–
2148; (b) Arai, S.; Shirai, Y.; Ishida, T.; Shioiri, T.
Tetrahedron 1999, 55, 6375–6386; (c) Arai, S.; Shirai, Y.;
Ishida, T.; Shioiri, T. Chem. Commun 1999, 49–50; For
smoothly converted into the corresponding epoxides 4b–e
with good enantioselectivity in excellent yield (entries
1–4). Especially, trans-4e was obtained with 70% ee
(entry 4). In the case of aliphatic aldehydes 1g and h, a
weaker base such as Cs2CO3 with 2b was found to be the
most effective and products 4g were obtained with 57%
ee for cis and 40% ee for trans, while 4h was obtained
with 60% ee for cis and 48% ee for trans, respectively
(entries 6 and 7).14
The absolute configurations of 3b were determined by
comparison to the literature to be 2R,3S after trans-3b
was converted to the corresponding methyl ketone 5.15
Cis and trans-3b were converted to (2R)-a-hydroxya-
mide 6 by hydrogenation without racemization, and the
absolute stereochemistry of the cis-isomer was assigned
by optical rotation to be 2R,3R, as outlined in Scheme 2.
ꢀ
chiral crown ethers as PTCs, see: Bako, P.; Szollosy, A.;
Bombicz, P.; Toke, L. Synlett 1997, 291–292.
€ ~
~
9. (a) Arai, S.; Ishida, T.; Shioiri, T. Tetrahedron Lett. 1998,
39, 8299–8302; (b) Arai, S.; Shioiri, T. Tetrahedron 2002,
58, 1407–1413.
10. For successful examples via catalytic asymmetric epoxi-
dation, see: (a) Nemoto, T.; Ohshima, T.; Shibasaki, M. J.
Am. Chem. Soc. 2001, 123, 9474–9475; (b) Nemoto, T.;
Kakei, H.; Gnanadesikan, V.; Tosaki, S.; Shibasaki, M. J.
Am. Chem. Soc. 2002, 124, 14544–14545; Via carbenoid,
see: Imashiro, R.; Yamanaka, T.; Seki, M. Tetrahedron:
Asymmetry 1999, 10, 2845–2851.
In conclusion, we have developed a catalytic asymmetric
Darzens reaction using a-haloamides promoted by a
new chiral PTC. As described above, both aromatic and
aliphatic aldehydes can be used with quite low catalyst
loading (2 mol %) to give the desired epoxides with up to
70% ee. However, the diastereo- and enantiocontrol are
still unsatisfactory, and further modification and opti-
mization of the catalyst are now under investigation.
11. Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc.
1999, 121, 6519–6520.
12. (S)-2,20-Bis(quinuclidiniomethyl)-1,10-binaphthyl dibro-
1
mide (PTC A): white solid; mp 218 ꢁC (decomposed); H
NMR (CDCl3, 270 MHz) d 1.69 (br, 6H), 1.95 (br, 1H),

1848
S. Arai et al. / Tetrahedron Letters 45 (2004) 1845–1848
3.04 (br, 3H), 3.53 (br, 3H), 4.08 (d, J ¼ 13:2 Hz, 1H), 5.51
extracted with AcOEt (2.0 mL · 3), washed with brine and
dried over Na2SO4. After the solvents were removed in
vacuo, the crude product was purified by flash column
chromatography (hexane/AcOEt ¼ 3:1) to give the desired
products as a white amorphous (for trans: 15 mg, 24% and
(d, J ¼ 13:2 Hz,1H), 7.30–7.36 (m, 2H), 7.53–7.60 (m, 1H),
8.03 (d, J ¼ 8:1 Hz, 1H), 8.17–8.21 (m, 1H), 8.39 (d,
J ¼ 8:6 Hz, 1H); 13C NMR (CD3OD, 67.8 MHz) d 19.3,
23.9, 55.1, 65.5, 125.4, 127.2, 127.6, 129.2, 130.0, 132.3,
132.4, 133.8, 137.3; IR (KBr) m 2942, 2886, 1464 cmꢀ1; MS
(FAB) m=z 581 (Mþ)Br), 470, 391, 307, 154; HRMS
cis: 36 mg, 56%). Both enantiomeric excesses were deter-
25
mined by chiral HPLC analysis. For trans-3b (63% ee, ½aꢁ
D
(FAB) calcd for C36H42 79BrN2: 581.2531. Found
+44.2ꢁ (c 1.0, CHCl3): Daicel Chiralpak AD, 254 nm, flow
25
D
581.2535; ½aꢁ +132.6ꢁ (c 0.5, CHCl3). PTC A is a quite
rate: 1.0 mL/min, hexane/i-PrOH ¼ 4:1, tR: 17.6 min
25
D
air-stable compound and can be stored at rt over
6 months. And it shows enough solubility in CH2Cl2,
CHCl3 and MeOH however toluene and THF are not easy
to be dissolved.
(major) and 25.0 min (minor). For cis-3b (58% ee, ½aꢁ
+142.0ꢁ (c 1.0, CHCl3)): Daicel Chiralpak AD, 254 nm,
flow rate: 1.0 mL/min, hexane/i-PrOH ¼ 4:1, tR: 10.3 min
(major) and 12.5 min (minor), respectively.
13. Representative experimental procedure for a catalytic
asymmetric Darzens reaction; synthesis of 3b (Table 1,
entry 7): To a solution of benzaldehyde 1a (20 lL,
0.20 mmol), bromoamide 2c (69 mg, 0.24 mmol) and cat-
alyst (2.6 mg, 0.004 mmol, 2 mol %) in dichloromethane
(1.0 mL) was added RbOHÆH2O (58 mg, 0.48 mmol) at rt.
After being stirred for 6.5 h, the reaction was quenched
with 1 N HCl (1.0 mL) and the resulting organic layer was
14. However derivatives of PTC A were investigated, any
attempts to introduce substituents on aromatic rings and
quaternary ammonium moieties gave unsatisfactory
results in enantiomeric excess.
15. (a) Nemoto, T.; Ohshima, T.; Yamaguchi, K.; Shibasaki,
M. J. Am. Chem. Soc. 2001, 123, 2725–2732; (b) Meth-
Cohn, O.; Chen, Y. Tetrahedron Lett. 1999, 40, 6069–
6072.