Organocatalytic enantioselective Mannich-type reactions of fluorinated keto esters with N-Boc-aldimines

Article abstract of DOI:10.1055/s-0030-1259319

The catalytic enantioselective Mannich reaction promoted by chiral bifunctional organocatalysts is described. The treatment of α-fluoro β- keto esters with N-Boc aldimines under mild reaction conditions afforded the corresponding β-aminated α-fluoro-β-keto esters with excellent enantioselectivities (up to 98% ee). Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0030-1259319

420
LETTER
Organocatalytic Enantioselective Mannich-Type Reactions of Fluorinated
Keto Esters with N-Boc-Aldimines
M
annich-Type
u
R
eactions
o
n
f
Fluorinated
g
Ketoesters
with
N
J
-Boc-Ald
e
imines Yoon, Young Ku Kang, Dae Young Kim*
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Korea
Fax +82(41)5301247; E-mail: dyoung@sch.ac.kr
Received 4 November 2010
using tryptophan-derived organocatalyst and chiral bicy-
Abstract: The catalytic enantioselective Mannich reaction promot-
ed by chiral bifunctional organocatalysts is described. The treat-
ment of a-fluoro-b-keto esters with N-Boc aldimines under mild
reaction conditions afforded the corresponding b-aminated a-fluo-
ro-b-keto esters with excellent enantioselectivities (up to 98% ee).
clic guanidine catalyst.12
As part of a research program related to the development
of synthetic methods for the enantioselective construction
of stereogenic carbon centers,13 we recently reported
chiral amine–thiourea bifunctional organocatalyst I
(Figure 1) to be a highly selective catalyst for the enantio-
selective addition of active methines.7f,11f–h,14 We envi-
sioned that the assembly of a structurally well-defined
chiral 1,2-diamine and binaphthyl scaffold with a thiourea
motif could constitute a new class of bifunctional organo-
catalyst. The rigid binaphthyl structure can serve as an ef-
Key words: Mannich reaction, asymmetric catalysis, bifunctional
organocatalyst, a-fluoro-b-keto esters, aldimines
The chemistry of bioactive organofluorine compounds is
a rapidly developing area of research because of their im-
portance in biochemical and medicinal application.1 Intro-
duction of fluorine atom into biologically active
compounds often leads to improvement of their biological
characteristics due to unique properties of the fluorine at-
om.2 Chiral organofluorine compounds have been utilized
in studies of enzyme mechanisms and as intermediates in
asymmetric syntheses.3
N
N
HN
HN
HN
HN
S
Among various strategies, electrophilic fluorination of ac-
tive methines and C–C bond-formation reaction of fluoro-
carbon nucleophiles are two typical approaches for the
construction of fluorine-containing molecules, and their
asymmetric versions are particularly attractive. Enanti-
oselective electrophilic fluorination has been achieved
with the aid of electrophilic fluorinating agents using
chiral transition metal catalysts and organocatalysts with
excellent enantioselectivities.4,5 On the other hand, the use
of fluorinated active methine nucleophiles such as fluoro-
malonate,6 a-fluoro-b-keto esters,7 and fluorobis(phenyl-
sulfonyl)methane8 for a catalytic asymmetric reaction has
become increasingly popular. Several groups have devel-
oped organocatalytic conjugate addition to nitroal-
kenes,7d–f Michael reaction to a,b-unsaturated ketone,7h
phase-transfer catalytic amination to azodicarboxylate7b
using nucleophilic a-fluoro-b-keto esters. Enantioselec-
tive Mannich reactions are efficient and powerful meth-
ods to prepare chiral b-amino carbonyl derivatives.9
Tremendous efforts have been made in the development
of efficient chiral catalysts for enantioselective Mannich
reactions with preformed enolates10 and enolizable b-di-
carbonyl and related compounds.11 Recently, Lu and Tan
groups reported the catalytic enantioselective Mannich
reactions of a-fluoro-b-keto esters with N-Boc aldimines
O
CF3
CF3
F3C
F3C
II
I
N
N
HN
HN
HN
HN
O
O
S
N
F3C
CF3
IV
III
MeO
N
S
CF3
CF3
N
H
HN
N
V
SYNLETT 2011, No. 3, pp 0420–0424
Advanced online publication: 13.01.2011
DOI: 10.1055/s-0030-1259319; Art ID: U09810ST
x
x.
x
x.
2
0
1
1
Figure 1 Structures of various chiral thiourea–tertiary amine cata-
lysts
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mannich-Type Reactions of Fluorinated Keto Esters with N-Boc-Aldimines
421
ficient stereocontrolling axial chiral element. Herein, we the solvents probed, the best results (97% yield, 85:15 dr,
wish to describe the direct enantioselective Mannich reac- and 85% ee) were achieved when the reaction was con-
tion of a-fluoro-b-keto esters with simple N-Boc imines ducted in Et2O (entry 8). We then explored the possibility
catalyzed by bifunctional organocatalysts bearing both of using a wide range of N-Boc-protected substituted aro-
central and axial chiral elements.
matic and heteroaromatic aldimines 2 with a-fluoro-b-
keto ester 1a under the optimized reaction condition. As
shown in Table 2, the products 3a–g were formed in high
yields (80–98%), excellent diastereoselectivities (73:27–
99:1), and excellent enantioselectivities (81–98%).
In an attempt to validate the feasibility of the organocata-
lytic enantioselective Mannich reaction of a-fluoro-b-
keto esters, we initially investigated the reaction system
with a-fluoro-b-keto ester 1a and N-Boc aldimine 2a in
the presence of 10 mol% of catalyst in toluene at room To examine the generality of the catalytic enantioselective
temperature. We first examined the impact of the structure Mannich reaction of a-fluoro-b-keto esters 1 by using new
of catalysts I–V on enantioselectivities (Tables 1, 24– bifunctional organocatalyst I, we studied the addition of
76% ee, entries 1–5).
various a-fluoro-b-keto esters 1 to N-Boc aldimine 2f. As
Table 2 Variation of N-Boc Aldimines
Table 1 Optimization of the Reaction Conditions
O
O
O
O
O
O
F
F
NBoc
NBoc
cat. I (10 mol%)
Et2O, r.t., 24 h
+
OEt
Ph
OEt
Ph
OEt
NHBoc
Ph
O
O
Ar
cat. (10 mol%)
F
+
Ar
NHBoc
3a–g
Ph
OEt
solvent, r.t., 24 h
1a
2
F
1a
2a
3a
Entry
2, Ar
Yield (%)a
3a, 98
3b, 80
3c, 98
dr (%)b
83:17
85:15
88:12
91:9
ee (%)c
88
Entry Catalyst Solvent
Yield (%)a dr (%)b ee (%)c
1
2
3
4
5
6
7
2a, 4-MeC6H4
2b, 4-BrC6H4
2c, 4-ClC6H4
2d, Ph
1
2
I
toluene
toluene
toluene
toluene
toluene
CH2Cl2
THF
97
98
60
69
97
64
27
97
98
98
98
77:23
88:22
50:50
77:23
80:20
82:18
79:21
85:15
79:21
81:19
79:21
76
37
24
63
45
63
30
88
62
68
85
89
II
III
IV
V
I
81
3
3d, 84
3e, 98
88
4
2e, 2-ClC6H4
2f, 2-furyl
>99:1
73:27
95:5
86
5
3f, 98
98
6
2g, 2-thienyl
3g, 78
95
7
I
a Yield of isolated product.
b The diastereomeric ratio was determined by 1H NMR spectroscopic
analysis of the crude product.
8
I
Et2O
c Enantiopurity of the major diastereomer of 3 was determined by
HPLC analysis with Chiralpak AD-H (for 3a) and IA (for 3b–g) col-
umns.
9
I
TBME
Ph2O
10
11
I
I
EtOCH=CH2
Table 3 Variation of a-Fluoro-b-Keto Esters
a Isolated yield.
O
O
O
b The diastereomeric ratio was determined by 1H NMR spectroscopic
analysis of the crude product.
F
O
O
NBoc
Ar
OEt
NHBoc
3h–k
+
cat. I (10 mol%)
c Enantiomeric excess of the major diastereomer was determined by
HPLC analysis using Chiralpak AD-H column.
Ar
OEt
Et2O, r.t., 36 h
F
O
1
2f
While chiral bifunctional organocatalysts I–V bearing
both central and axial chiral elements or cinchona alkaloid
backbone effectively promoted the addition in high yield
but with moderate enantioselectivity (entries 1–5), cata-
lyst I gave the desired product 3a with high enantioselec-
tivity (entry 1). Based on the exploratory studies, we
decided to select catalyst I for further optimization of re-
action conditions. A survey of the reaction media indicat-
ed that many common solvents, such as toluene, CH2Cl2,
THF, Et2O, TBME, diphenyl ether, and ethyl vinyl ether
(entries 6–11), were well tolerated in this Mannich reac-
tion with moderate to high enantioselectivities. Among
Entry
1, Ar
Yield (%)a dr (%)b
ee (%)c
1
2
3
4
1b, 4-O2NC6H4
1c, 4-F3CC6H4
1d, 4-MeOC6H4
1e, 4-BrC6H4
3h, 88
3i, 88
3j, 84
3k, 80
78:22
62:38
75:25
74:26
98
96
96
98
a Yield of isolated product.
b The diastereomeric ratio was determined by 1H NMR spectroscopic
analysis of the crude product.
c Enantiopurity of the major diastereomer of 3h–k was determined by
HPLC analysis with Chiralpak IA column.
Synlett 2011, No. 3, 420–424 © Thieme Stuttgart · New York

422
S. J. Yoon et al.
LETTER
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Horikawa, T.; Yasuda, N.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem. Int. Ed. 2008, 47, 4157. (j) Lee, N. R.; Kim,
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2783.
it can be seen by the results summarized in Table 3, the
corresponding products 3h–k were obtained in high to ex-
cellent yields (80–88%), high diastereoselectivities
(62:38–78:22), and excellent enantioselectivities (96–
98%).15 Absolute configuration of the major diastereomer
of 3a was determined to be (2S,3S) by comparison of the
optical rotation and chiral HPLC data with the published
values of ref. 12.
(6) For asymmetric Michael-type reactions of a-
In conclusion, we have developed a highly efficient cata-
lytic enantioselective Mannich reaction of a-fluoro-b-
keto esters using chiral bifunctional organocatalyst. The
desired b-aminated products were obtained in good to
high yields, and high enantioselectivities (81–98% ee)
were observed for all the substrates examined in this
work. We believe that this method provides a practical en-
try for the preparation of chiral b-aminated a-fluoro-b-
keto ester derivatives. Further study of these bifunctional
organocatalysts in other asymmetric reactions is currently
being investigated.
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Synlett 2011, No. 3, 420–424 © Thieme Stuttgart · New York

LETTER
Mannich-Type Reactions of Fluorinated Keto Esters with N-Boc-Aldimines
423
2005, 44, 1525. (e) Kim, E. J.; Kang, Y. K.; Kim, D. Y. Bull.
diastereomer: [a]28D 55.5 (c = 1.0, CHCl3). 1H NMR (200
MHz, CDCl3): d = 1.28 (t, J = 12.1 Hz, 3 H), 1.39 (s, 9 H),
4.23–4.35 (m, 2 H), 5.55 (d, J = 10.1 Hz, 1 H), 6.47 (dd, J =
26.1, 10.1 Hz, 1 H), 7.10–7.18 (m, 2 H), 7.33–7.55 (m, 5 H),
7.87–7.91 (m, 2 H). 13C NMR (50 MHz, CDCl3): d = 13.53,
27.88, 53.62 (d, J = 18.7 Hz), 63.02, 79.84, 101.30 (d, J =
205.4 Hz), 126.76, 128.30, 128.85, 129.09, 129.22, 129.85
(2), 133.71, 134.57, 134.97, 153.89, 165.15 (d, J = 26.7 Hz),
190.22 (d, J = 24.9 Hz). HPLC (Chiralpak IA column; n-
hexane–i-PrOH, 85:15; l = 254 nm, flow rate: 0.5 mL/min);
tR = 30.4 min (minor), tR = 51.2 min (major); 86% ee.
(2S,3S)-Ethyl 2-Benzoyl-3-(tert-butoxycarbonylamino)-
2-fluoro-3-(furan)propanoate (3f): major diastereomer:
[a]28D 35.3 (c = 1.0, CHCl3). 1H NMR (200 MHz, CDCl3):
d = 1.28 (t, J = 14.0 Hz, 3 H), 1.43 (s, 9 H), 4.18–4.38 (m, 2
H), 5.35 (d, J = 10.7 Hz, 1 H), 6.17 (dd, J = 28.2, 10.7 Hz, 1
H), 6.24–6.26 (m, 2 H), 7.27–7.29 (m, 1 H), 7.38–7.46 (m, 2
H), 7.53–7.60 (m, 1 H), 7.90–7.94 (m, 2 H). 13C NMR (50
MHz, CDCl3): d = 13.79, 28.15, 52.07 (d, J = 19.7 Hz),
63.24, 80.33, 101.45 (d, J = 204.5 Hz), 108.84, 110.30,
128.51, 129.49, 129.61, 133.90, 142.37, 149.35, 154.32,
164.90 (d, J = 26.6 Hz), 190.39 (d, J = 25.2 Hz). HPLC
(Chiralpak IA column; n-hexane–i-PrOH, 85:15; l = 254
nm, flow rate: 0.5 mL/min); tR = 20.9 min (minor), tR = 34.5
min (major); 98% ee.
Korean Chem. Soc. 2009, 30, 1437. (f) Kang, Y. K.; Kim,
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(12) (a) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y.
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2001, 42, 6299. (b) Kim, D. Y.; Huh, S. C. Tetrahedron
2001, 57, 8933. (c) Park, E. J.; Kim, M. H.; Kim, D. Y.
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(15) Typical General Procedure for the Mannich-Type
Reaction of a-Fluoro-b-keto Ester 1 with N-Boc Aldimine
2: To a solution of a-fluoro-b-keto ester 1 (0.3 mmol) and
catalyst I (0.03 mmol, 20 mg) in Et2O (6 mL) was added N-
Boc aldimine 2 (0.45 mmol). The reaction mixture was
stirred for 24–36 h. The catalyst I was removed by short
column chromatography (EtOAc–hexane, 1:5). The crude
oil was purified by flash column chromatography (EtOAc–
hexane, 1:7) to afford the Mannich adduct 3.
(2S,3S)-Ethyl 2-Benzoyl-3-(tert-butoxycarbonylamino)-
2-fluoro-3-(thiophene)propanoate (3g): major
diastereomer: [a]26D 54.7 (c = 1.0, CHCl3). 1H NMR (200
MHz, CDCl3): d = 1.27 (t, J = 13.9 Hz, 3 H), 1.41 (s, 9 H),
4.17–4.40 (m, 2 H), 5.36 (d, J = 10.4 Hz, 1 H), 6.31 (dd, J =
28.3, 10.4 Hz, 1 H), 6.86–6.90 (m, 1 H), 7.06–7.08 (m, 1 H),
7.16–7.18 (m, 1 H), 7.36–7.44 (m, 2 H), 7.51–7.59 (m, 1 H),
7.89–7.93 (m, 2 H). 13C NMR (50 MHz, CDCl3): d = 13.74,
28.10, 53.53 (d, J = 19.35 Hz), 63.12, 80.27, 101.92 (d, J =
204.2 Hz), 125.53, 126.56, 127.18, 128.46, 129.45, 129.56,
133.91, 138.75, 154.11, 164.96 (d, J = 26.9 Hz), 190.34 (d,
J = 25.3 Hz). HPLC (Chiralpak IA column; n-hexane–i-
PrOH, 90:10; l = 254 nm, flow rate: 0.5 mL/min); tR = 30.9
min (minor), tR = 44.4 min (major); 95% ee.
(2S,3S)-Ethyl 2-Benzoyl-3-(tert-butoxycarbonylamino)-
2-fluoro-3-(4-chlorophenyl)propanoate (3c): major
diastereomer: [a]26D 7.0 (c = 1.0, CHCl3). 1H NMR (200
MHz, CDCl3): d = 1.28 (t, J = 13.9 Hz, 3 H), 1.39 (s, 9 H),
4.18–4.41 (m, 2 H), 5.45 (d, J = 10.4 Hz, 1 H), 5.87 (dd, J =
28.8, 10.4 Hz, 1 H), 7.35–7.44 (m, 5 H), 7.54–7.58 (m, 2 H),
7.80–7.84 (m, 2 H). 13C NMR (50 MHz, CDCl3): d = 13.82,
28.15, 56.78 (d, J = 17.7 Hz), 63.32, 80.35, 102.01 (d, J =
204.4 Hz), 128.54, 129.56, 129.81, 130.24 (2), 134.01,
135.12, 154.30, 165.32 (d, J = 26.5 Hz), 190.33 (d, J = 25.7
Hz). HPLC (Chiralpak IA column; n-hexane–i-PrOH, 85:15;
l = 254 nm, flow rate: 0.5 mL/min); tR = 23.8 min (minor),
tR = 28.1 min (major); 81% ee.
(2S,3S)-Ethyl 2-(4-Nitrobenzoyl)-3-(tert-butoxy-
carbonylamino)-2-fluoro-3-(furan)propanoate (3h):
major diastereomer: [a]31D 19.7 (c = 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): d = 1.31 (t, J = 14.4 Hz, 3 H), 1.44 (s, 9
H), 4.20–4.41 (m, 2 H), 5.36 (d, J = 10.2 Hz, 1 H), 6.15 (dd,
J = 28.2, 10.2 Hz, 1 H), 6.27–6.31 (m, 2 H), 7.30 (m, 1 H),
8.01–8.06 (m, 2 H), 8.24–8.28 (m, 2 H). 13C NMR (50 MHz,
CDCl3): d = 13.83, 28.16, 52.21 (d, J = 19.3 Hz), 63.69,
80.67, 101.58 (d, J = 204.4 Hz), 109.13, 110.48, 123.62,
130.64, 138.59, 142.66, 148.90, 150.51, 154.30, 164.15 (d,
J = 26.7 Hz), 189.96 (d, J = 25.7 Hz). HPLC (Chiralpak IA
column; n-hexane–i-PrOH, 85:15; l = 254 nm, flow rate: 0.5
mL/min); tR = 26.8 min (minor), tR = 45.6 min (major); 98%
ee.
(2S,3S)-Ethyl 2-[4-(Trifluoromethyl)phenyl]-3-(tert-
butoxycarbonylamino)-2-fluoro-3-(furan)propanoate
(3i): major diastereomer: [a]30D 26.0 (c = 1.0, CHCl3). 1H
NMR (200 MHz, CDCl3): d = 1.30 (t, J = 14.5 Hz, 3 H), 1.44
(s, 9 H), 4.20–4.40 (m, 2 H), 5.35 (d, J = 10.5 Hz, 1 H), 6.17
(dd, J = 28.4, 10.5 Hz, 1 H), 6.25–6.27 (m, 2 H), 7.27–7.29
(m, 1 H), 7.67–7.71 (m, 2 H), 7.99–8.03 (m, 2 H). 13C NMR
(50 MHz, CDCl3): d = 13.79, 28.14, 52.14 (d, J = 19.2 Hz),
63.51, 80.53, 101.54 (d, J = 204.5 Hz), 109.01, 110.39,
123.35 (q, J = 271.5 Hz), 125.55, 129.80, 134.94 (q, J = 32.5
Hz), 136.66, 142.55, 149.07, 154.31, 164.42 (d, J = 26.6 Hz),
189.56 (d, J = 29.0 Hz). HPLC (Chiralpak IA column; n-
hexane–i-PrOH, 85:15; l = 254 nm, flow rate: 0.5 mL/min);
tR = 15.7 min (minor), tR = 28.5 min (major); 96% ee.
(2S,3S)-Ethyl 2-Benzoyl-3-(tert-butoxycarbonylamino)-
2-fluoro-3-propanoate (3d): major diastereomer: [a]29
D
39.3 (c = 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): d = 1.26
(t, J = 13.6 Hz, 3 H), 1.38 (s, 9 H), 4.16–4.39 (m, 2 H), 5.57
(d, J = 10.5 Hz, 1 H), 6.02 (dd, J = 28.8, 10.5 Hz, 1 H), 7.19–
7.33 (m, 4 H), 7.36–7.51 (m, 4 H), 7.80–7.83 (m, 2 H). 13
C
NMR (50 MHz, CDCl3): d = 13.75, 28.08, 57.38 (d, J = 18.5
Hz), 63.11, 79.97, 102.19 (d, J = 204.0 Hz), 128.01, 128.26,
128.34, 128.74, 129.28, 129.39, 133.69, 136.50, 154.31,
165.38 (d, J = 27.1 Hz), 190.80 (d, J = 25.6 Hz). HPLC
(Chiralpak IA column; n-hexane–i-PrOH, 85:15; l = 254
nm, flow rate: 0.5 mL/min); tR = 23.5 min (minor), tR = 31.0
min (major); 88% ee.
(2S,3S)-Ethyl 2-Benzoyl-3-(tert-butoxycarbonylamino)-
2-fluoro-3-(2-chlorophenyl)propanoate (3e): major
Synlett 2011, No. 3, 420–424 © Thieme Stuttgart · New York

424
S. J. Yoon et al.
LETTER
(2S,3S)-Ethyl 2-(4-Bromobenzoyl)-3-(tert-butoxy-
(2S,3S)-Ethyl 2-(4-Methoxybenzoyl)-3-(tert-butoxy-
carbonylamino)-2-fluoro-3-(furan)propanoate (3j):
major diastereomer: [a]30D 19.1 (c = 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): d = 1.26 (t, J = 13.9 Hz, 3 H), 1.43 (s, 9
H), 3.84 (s, 3 H), 4.16–4.36 (m, 2 H), 5.36 (d, J = 10.5 Hz, 1
H), 6.16 (dd, J = 28.3, 10.5 Hz, 1 H), 6.23–6.25 (m, 2 H),
6.86–6.93 (m, 2 H), 7.79 (m, 1 H), 7.95–8.00 (m, 2 H).
13C NMR (50 MHz, CDCl3): d = 13.74, 28.10, 51.96 (d, J =
19.5 Hz), 55.42, 63.06, 80.19, 101.50 (d, J = 204.4 Hz),
108.70, 110.24, 113.79, 126.60, 132.25, 142.22, 149.57,
154.31, 164.18, 165.20 (d, J = 26.9 Hz), 188.24 (d, J = 24.3
Hz). HPLC (Chiralpak IA column; n-hexane–i-PrOH, 85:15;
l = 254 nm, flow rate: 0.5 mL/min); tR = 26.6 min (minor),
tR = 49.6 min (major); 96% ee.
carbonylamino)-2-fluoro-3-(furan)propanoate (3k):
major diastereomer: [a]31D 21.1 (c = 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): d = 1.28 (t, J = 14.0 Hz, 3 H), 1.43 (s, 9
H), 4.19–4.37 (m, 2 H), 5.32 (d, J = 10.1 Hz, 1 H), 6.14 (dd,
J = 28.4, 10.1 Hz, 1 H), 6.23–6.31 (m, 2 H), 7.27–7.29 (m, 1
H), 7.54–7.59 (m, 2 H), 7.78–7.81 (m, 2 H). 13C NMR (50
MHz, CDCl3): d = 13.81, 28.16, 52.08 (d, J = 19.3 Hz),
63.40, 80.45, 101.51 (d, J = 204.1 Hz), 108.93, 110.36,
129.47, 131.00, 131.92, 132.48, 142.46, 149.22, 154.31,
164.68 (d, J = 27.9 Hz), 189.64 (d, J = 25.5 Hz). HPLC
(Chiralpak IA column; n-hexane–i-PrOH, 90:10; l = 254
nm, flow rate: 0.5 mL/min); tR = 24.7 min (minor), tR = 55.2
min (major); 98% ee.
Synlett 2011, No. 3, 420–424 © Thieme Stuttgart · New York

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