Catalytic asymmetric cyano-ethoxycarbonylation reaction of aldehydes using a novel C2-symmetric chiral N,N′-dioxide titanium complex

Article abstract of DOI:10.1055/s-2006-947322

The asymmetric addition of ethyl cyanoformate to a range of aldehydes was efficiently catalyzed by a easily prepared C₂-symmetric chiral N,N′-dioxide-Ti(IV) complex in high yields with up to 90% ee under mild conditions. A linear effect between

Full text of DOI:10.1055/s-2006-947322

LETTER
1675
Catalytic Asymmetric Cyano-Ethoxycarbonylation Reaction of Aldehydes
Using a Novel C2-Symmetric Chiral N,N¢-Dioxide Titanium Complex
Catalytic
A
symme
i
tric Cy
n
a
no-Ethoxyc
g
arbonylation
h
R
eaction of
a
A
ldehyde
s
n Li,a Lu Chang,a Xiaohua Liu,a Xiaoming Feng*a,b
a
Key Laboratory of Green Chemistry & Technology (Sichuan University), Ministry of Education, College of Chemistry,
Sichuan University, Chengdu 610064, P. R. of China
b
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, P. R. of China
Fax +86(28)85418249; E-mail: xmfeng@scu.edu.cn
Received 1 April 2006
Then the N-terminal effect of the catalyst was investigat-
ed, a variety of proline-based N,N¢-dioxides, bearing the
optimal 2-tert-butylphenylamine terminus, were prepared
and examined (Table 1, entries 7, 8). Lower enantioselec-
Abstract: The asymmetric addition of ethyl cyanoformate to a
range of aldehydes was efficiently catalyzed by a easily prepared
C2-symmetric chiral N,N¢-dioxide–Ti(IV) complex in high yields
with up to 90% ee under mild conditions. A linear effect between
the enantiopurity of the ligand and the enantiopurity of the product tivity than 1c was observed when the size of the N-termi-
was observed.
nal substituents was increased (Table 1, entry 7). Ligands
bearing electron-poor substituents (1h) also led to low
reactivity and enantioselectivity (Table 1, entry 8). In
addition, in order to compare with catalyst 1c–Ti(Oi-Pr)4,
complex 3–Ti(Oi-Pr)4 was also examined in this reaction
under the same conditions, but it was less efficient than
1c–Ti(Oi-Pr)4 (Table 1, entry 10). While the alternative
diastereomer 2–Ti(Oi-Pr)4 promoted the same selective
transformation to afford the alternative product antipode
(Table 1, entry 9). Thus 1c was identified as the most
effective catalyst (Table 1, entry 3).
Key words: C2-symmetric chiral N,N¢-dioxide ligand, ethyl cyano-
formate, aldehydes, enantioselectivity, organotitanium
Cyanoformate esters (ROCOCN) are known to react with
aldehydes and ketones, leading directly to cyanohydrin
carbonates.1 Recently, asymmetric catalysts for this reac-
tion have been reported. While, the majority of chiral cat-
alysts used for this goal are cinchona alkaloid derivatives,
oxynitrilase enzyme and chiral metal complexes.2 In re-
cent years, chiral N-oxides have been used in several
asymmetric procedures, such as the allylation of alde-
hydes,3 the addition of Et2Zn to aldehydes,4 the reduction
of ketones,5 the epoxide openings,6 the aldol reaction7 and
the cyanosilylation of carbonyl compounds.8 Herein, we
wish to repot the results on the asymmetric cyano-ethoxy-
carbonylation reaction of aldehydes using a novel, easily
prepared C2-symmetric chiral N,N¢-dioxide (Figure 1)
titanium complexes.
We then further optimized the reaction conditions by
exploring the use of other Lewis acids. The results were
summarized in Table 1. Ti(Oi-Pr)4 gave more promising
enantioselectivity (63% ee) than other Lewis acids
R2
NH
C
R2
HN
1a R1 = Me, R2 = cyclohexyl
1b R1 = Me, R2 = o-tolyl
1c R1 = Me, R2 = 2-tert-butylphenyl
O
C O
1d R1 = Me, R2 = 2,6-diisopropylphenyl
O
O
For the initial studies, the addition of ethyl cyanoformate
to benzaldehyde catalyzed by chiral N,N¢-dioxide ligands
1a–h (Figure 1) with titanium complexes were investigat-
ed at –20 °C. As illustrated in Table 1, ligand 1a afforded
cyanohydrin ethyl carbonates with 90% yield and 38% ee
(Table 1, entry 1). Based on the successful ligand 1a skel-
eton, we then modified the prolinamide parts and prepared
N
OH
N
1e R1 = Me, R2 = 1-adamantyl
1f R1 = Me, R2 = diphenylmethyl
1g R1 = t-Bu, R2 = 2-tert-butylphenyl
1h R1 = Cl, R2 = 2-tert-butylphenyl
R1 1a-h
a
series of chiral N,N¢-dioxide derivatives 1b–h
(Figure 1).9 It was found that the amide substituent played
an important role on the enantioselectivity. Ligand 1c,10
which contained a 2-tert-butylphenyl group, gave good
enantioselectivity (Table 1, entry 3 vs. entries 1, 2, 4–8).
Increasing the size of the prolinamide parts resulted in ef-
ficiency with lower enantioselectivities than 1c (Table 1,
entries 5, 6).
t-Bu
t-Bu
t-Bu
t-Bu
NH
C
HN
NH
C
HN
C
O
O
C O
O
O
O
N
OH
N
N
OH
N
2
3
SYNLETT 2006, No. 11, pp 1675–1678
Advanced online publication: 04.07.2006
DOI: 10.1055/s-2006-947322; Art ID: W06906ST
© Georg Thieme Verlag Stuttgart · New York
1
2
.0
7
.2
0
0
6
Figure 1 Ligands evaluated for asymmetric addition of ethyl cyano-
formate to benzaldehyde.

1676
Q. Li et al.
LETTER
Table 2 Optimization of the Addition of Ethyl Cyanoformate to
Benzaldehyde in the Presence of 1c–Ti(IV) Complexa
Table 1 Asymmetric Addition of Ethyl Cyanoformate to
Benzaldehyde by Different C2-Symmetric Chiral N,N¢-Dioxide
Ligand–Titanium Complexesa
Entry 1c
(mol%)
Solvent
Temp
(°C)
Time (h) Yield
(%)b
ee (%)c
OCO2Et
O
5 mol% L*–Metal
*
CN
H
1d
2d
3d
4
5
CH2Cl2
Toluene
Et2O
–20
–20
–20
–20
–20
–20
–20
–20
–20
–20
0
36
36
36
36
36
36
36
30
30
30
8
86
34
30
92
54
94
97
98
98
93
85
85
53
63
33
27
65
57
54
72
69
65
78
66
86
86
2.0 equiv EtOCOCN
CH2Cl2, –20 °C, 36 h
5
5
Entry
1
Ligandf
Metal
Yield (%)b ee (%)c
1a
1b
1c
1d
1e
1f
1g
1h
2
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
AlEt3
90
91
86
64
80
84
86
76
83
75
40
–
38
39
63
37
36
36
44
38
63g
27
23
–
5
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
2
5e
5
3
6f
5
4
7
10
15
30
10
10
10
10
5
8
6
9
7
10g
11g
12g
13g
8
9
–45
–78
48
48
10
11
12
13d
14e
3
1c
1c
1c
1c
a Unless otherwise specified, reactions were carried out on a 0.25
mmol scale of benzaldehyde in 0.5 mL of solvent; EtOCOCN (2.0
equiv); 1c: Ti(Oi-Pr)4 (10 mol%) = 1:1.
b Isolated yield of cyanohydrin carbonates.
c Determined by HPLC on a Chiralcel OD-H column.
d [Benzaldehyde] = 0.25 M.
Ti(Oi-Pr)4
Ti(Oi-Pr)4
Ti(Oi-Pr)4
10
17
36
43
e [Benzaldehyde] = 0.125 M.
a Reactions were carried out on a 0.25 mmol scale of benzaldehyde in
1.0 mL of CH2Cl2; ligand:metal (5 mol%) = 1:1; EtOCOCN (2.0
equiv).
f [Benzaldehyde] = 1.0 M.
g In the presence of 4 Å MS (20 mg).
b Isolated yield of the cyanohydrin carbonates.
c Determined by HPLC on a Chiralcel OD-H column.
d Ratio 1c:Ti(Oi-Pr)4 (5 mol%) = 1:2.
affected the yield and the enantioselectivity. The satisfy-
ing temperature was –45 °C (Table 2, entry 12). Increas-
ing the temperature caused a drop in enantioselectivity
(Table 2, entry 11). Further decreasing the temperature
led to a dramatic decrease in reactivity without any im-
provement in enantioselectivity (Table 2, entry 13).
e Ratio 1c:Ti(Oi-Pr)4 (5 mol%) = 1.25:1.
f Structural identity of all ligands were determined by 1H NMR,
13C NMR and HRMS.
g The configurations was S, determined by comparison of optical
rotation with reported in the literature, and the others were R.2b
Extensive screening showed that the optimized catalytic
system was 10 mol% 1c–Ti(Oi-Pr)4 (1:1), 0.5 M benz-
aldehyde, 2.0 equivalents EtOCOCN in 0.5 mL of CH2Cl2
in the presence of 4 Å MS (20 mg) at –45 °C (Table 2,
entry 13).
(Table 1, entries 11, 12). Changing the molar ratio be-
tween Ti(Oi-Pr)4:1c led to low yields and enantioselectiv-
ities (Table 1, entries 13, 14 vs. entry 3). Therefore, the
complex 1c–Ti(Oi-Pr)4 (1:1) was employed in screening
other conditions.
Encouraged by the result obtained for the benzaldehyde,
the addition of ethyl cyanoformate to other aldehydes was
then investigated under the optimized conditions,11 and
the results were shown in Table 3. The asymmetric cy-
anosilylation of aromatic, a,b-unsaturated and aliphatic
aldehydes proceeded smoothly to provide the corre-
sponding cyanohydrin carbonates in high yields with
moderate to good enantioselectivities (Table 3). Electron-
rich or electron-withdrawing aromatic aldehydes were
found to be good substrates for this reaction, giving
enantioselectivities of cyanohydrin carbonates similar to
those obtained with benzaldehyde (Table 3, entries 2–8).
b-Naphthaldehyde was found to be excellent substrate
Firstly, a series of solvents including toluene, Et2O,
CH2Cl2 were screened (Table 2, entries 1–3). The best sol-
vent was found to be CH2Cl2 (Table 2, entry 1). Further
studies indicated that the concentration of benzaldehyde
had a slight influence upon the enantioselectivity
(Table 2, entries 4–6). The optimum concentration of
benzaldehyde was 0.5 M (Table 2, entry 4). Both the yield
and enantioselectivity were dramatically influenced by
catalyst loading. The most favorable catalyst loading was
found to be 10 mol% (Table 2, entry 7). The effect of ad-
ditives showed that 4 Å MS was most promising in this
catalytic system (Table 2, entry 10). Temperature clearly
Synlett 2006, No. 11, 1675–1678 © Thieme Stuttgart · New York

LETTER
Catalytic Asymmetric Cyano-Ethoxycarbonylation Reaction of Aldehydes
1677
Table 3 Asymmetric Addition of Ethyl Cyanoformate to Aldehydes
Catalyzed by 1c–Ti(IV) Complexa
(Figure 2). The result simply indicated that homochiral
polymeric 1c– Ti(Oi-Pr)4 (1:1) complexes are more stable
than heterochiral polymers in the stereodiscriminating
step of the reaction.12
O
10 mol% 1c–Ti(Oi-Pr)4
OCO2Et
R
H
2.0 equiv EtOCOCN
CH2Cl2, –45 °C, 4 Å MS
R
*
CN
In conclusion, asymmetric cyanation of aldehydes has
been achieved using 10 mol% of the C2-symmetric chiral
N,N¢-dioxide–Ti(IV) complex and good yields of the cor-
responding cyanohydrin carbonates are obtained with
high enantioselectivities (up to 90% ee) under mild reac-
tion conditions. Further investigations are planned to
search for more effective chiral N-oxide ligands and pro-
vide additional information with regard to the scope and
precise mechanism.
4a–k
Entry Aldehydes
Yield
(%)b
ee (%)c
(Config)d
1
2
Benzaldehyde (4a)
88
86
92
83
93
91
92
88
82
83
81
86 (R)
84 (R)
86
4-Methylbenzaldehyde (4b)
2-Methylbenzaldehyde (4c)
4-Methoxybenzaldehyde (4d)
3-Methoxybenzaldehyde (4e)
2-Methoxybenzaldehyde (4f)
3-Phenoxybenzaldehyde (4g)
4-Fluorobenzaldehyde (4h)
b-Naphthaldehyde (4i)
3
4
82 (R)
80 (R)
86 (R)
88
Acknowledgment
5
The authors thank the National Natural Science Foundation of
China (No. 20225206, 20390055, 20502019 and 20472056) and the
Ministry of Education, China (Nos. 104209, 20030610021 and
others) for financial support.
6
7
8
83
9
90 (R)
62 (R)
68 (R)
References and Notes
(1) For reviews on synthesis of cyanohydrin carbonates, see:
(a) Okimoto, M.; Chiba, T. Synthesis 1996, 1188.
10
11
(E)-Cinnamaldehyde (4j)
Cyclohexanecarbaldehyde (4k)
(b) Poirier, D.; Berthiaume, D.; Boivin, R. P. Synlett 1999,
1423. (c) Berthiaume, D.; Poirier, D. Tetrahedron 2000, 56,
5995. (d) Deardorff, D. R.; Taniguchi, C. M.; Tafti, S. A.;
Kim, H. Y.; Choi, S. Y.; Downey, K. J.; Nguyen, T. V. J.
Org. Chem. 2001, 66, 7191. (e) Iwanami, K.; Hinakubo, Y.;
Oriyama, T. Tetrahedron Lett. 2005, 46, 5881. (f) Scholl,
M.; Lim, C.-K.; Fu, G.-C. J. Org. Chem. 1995, 60, 6229.
(2) (a) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123,
6195. (b) Tian, J.; Yamagiwa, N.; Matsunaga, S.; Shibasaki,
M. Angew. Chem. Int. Ed. 2002, 41, 3636. (c) Tian, J.;
Yamagiwa, N.; Matsunaga, S.; Shibasaki, M. Org. Lett.
2003, 5, 3021. (d) Casas, J.; Baeza, A.; Sansano, J. M.;
Nájera, C.; Saá, J. M. Tetrahedron: Asymmetry 2003, 14,
197. (e) Belokon, Y. N.; Blacker, A. J.; Clutterbuck, L. A.;
North, M. Org. Lett. 2003, 5, 4505. (f) Belokon, Y. N.;
Blacker, A. J.; Carta, P.; Clutterbuck, L. A.; North, M.
Tetrahedron 2004, 60, 10433. (g) Lundgren, S.;
a See ref. 11 for a general procedure of the reaction; EtOCOCN (2.0
equiv), ratio 1c:Ti(Oi-Pr)4 (10 mol%) = 1:1, 4 Å MS, –45 °C.
b Isolated yield of the cyanohydrin carbonates.
c Determined by chiral HPLC analysis (Chiralcel OD-H column) or
GC on a Chirasil DEX CB.
d Absolute configurations were determined by comparison of optical
rotations with those reported in the literature.2b,f
giving cyanohydrin carbonate with 90% enantiomeric
excess, while (E)-cinnamaldehyde and cyclohexane-
carbaldehyde only gave moderate enantioselectivities
(Table 3, entries 13, 14).
Finally, in order to obtain the information on possible
structure of the C2-symmetric chiral N,N¢-dioxide–Ti(IV)
complex in solution, a series of experiments about the
relationship between the enantiopurity of the ligand 1c
(Figure 1) and the enantioselectivity of the product were
studied. A clear linear effect was observed in this reaction
Wingstrand, E.; Penhoat, M.; Moberg, C. J. Am. Chem. Soc.
2005, 127, 11592. (h) Yamagiwa, N.; Tian, J.; Matsunaga,
S.; Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413.
(i) Suzuki, M.; Kato, N.; Kanai, M.; Shibasaki, M. Org. Lett.
2005, 7, 2527. (j) Purkarthofer, T.; Stranc, W.; Weber, H.;
Griengl, H.; Wubbolts, M.; Scholz, G.; Pochlauer, P.
Tetrahedron 2004, 60, 735. (k) Baeza, A.; Casas, J.; Nájera,
C.; Sansano, J. M.; Saá, J. M. Angew. Chem. Int. Ed. 2003,
14, 3143. (l) Achard, T. R. J.; Clutterbuck, L. A.; North, M.
Synlett 2005, 1828. (m) Li, Y.; He, B.; Qin, B.; Feng, X.-M.;
Zhang, G.-L. J. Org. Chem. 2004, 69, 7910.
(3) (a) Nakajima, M.; Saito, M.; Shiro, M.; Hashimoto, S. I. J.
Am. Chem. Soc. 1998, 120, 6419. (b) Shimada, T.; Kina, A.;
Hayashi, T. J. Org. Chem. 2003, 68, 6329. (c) Malkov, A.
V.; Bell, M.; Orsini, M.; Parnazza, D.; Massa, A.; Herrmann,
P.; Meghani, P.; Kocovasky, P. J. Org. Chem. 2003, 68,
9659. (d) Traverse, J. F.; Zhao, Y.; Hoveyda, A. H.;
Snapper, M. L. Org. Lett. 2005, 7, 3151. (e) Malkov, A. V.;
Bell, M.; Castelluzzo, F.; Kocovsky, P. Org. Lett. 2005, 7,
3219.
Figure 2 NLE in asymmetric addition of ethyl cyanoformate to
benzaldehyde catalyzed by 1c– Ti(Oi-Pr)4 (Figure 1).
(4) Derdau, V.; Laschat, S.; Hupe, E.; Koning, W. A.; Dix, I.;
Jones, P. G. Eur. J. Inorg. Chem. 1999, 1001.
Synlett 2006, No. 11, 1675–1678 © Thieme Stuttgart · New York

1678
Q. Li et al.
LETTER
(5) O’Neil, I. A.; Turner, C. D.; Kalindjian, S. B. Synlett 1997,
777.
(6) Tao, B.; Lo, M. M.-C.; Fu, G. C. J. Am. Chem. Soc. 2001,
123, 353.
r.t. for 12 h before it was diluted with H2O (50 mL) and Et2O
(50 mL). The two phases were separated and the aqueous
phase was extracted with Et2O three times and the combined
organic phases were washed with H2O (20 mL), brine (20
mL), dried over Na2SO4, and evaporated. The residue was
purified by silic gel column chromatography to give the
foam product. Next, MCPBA (13 mmol) was added at –78
°C to a solution of the above product and anhyd K2CO3 in
CH2Cl2. The resulting mixture was stirred at the same
temperature and the reaction was monitored by TLC. After
completion, the mixture was allowed to warm slowly to r.t.
and filtered. The solvents were evaporated under reduced
pressure. Purification of the residue by silica gel column
chromatography (Et2O–MeOH, 10:1 and Et2O–MeOH, 6:1)
to afford the corresponding (2S,2¢S)-1,1¢-[(2-hydroxy-5-
methyl-1,3-phenylene)di(methylene)]bis[N-(2-tert-
(7) Denmark, S. E.; Fan, Y. J. Am. Chem. Soc. 2002, 124, 4233.
(8) (a) Liu, B.; Feng, X.-M.; Chen, F.-X.; Zhang, G.-L.; Jiang,
Y.-Z. Synlett 2001, 1551. (b) Shen, Y.-C.; Feng, X.-M.;
Zhang, G.-L.; Jiang, Y.-Z. Synlett 2002, 1353. (c) Jiao, Z.-
G.; Feng, X.-M.; Liu, B.; Chen, F.-X.; Zhang, G.-L.; Jiang,
Y.-Z. Eur. J. Org. Chem. 2003, 3818. (d) Shen, Y.-C.;
Feng, X.-M.; Li, Y.; Zhang, G.-L.; Jiang, Y.-Z. Eur. J. Org.
Chem. 2004, 129. (e) Wen, Y.-H.; Huang, X.; Hang, J.-L.;
Xiong, Y.; Qin, B.; Feng, X.-M. Synlett 2005, 2445.
(f) Chen, F.-X.; Zhou, H.; Liu, X.-H.; Qin, B.; Feng, X.-M.
Chem. Eur. J. 2004, 10, 4790. (g) He, B.; Chen, F.-X.; Li,
Y.; Feng, X.-M.; Zhang, G.-L. Eur. J. Org. Chem. 2004,
4657. (h) Chen, F.-X.; Feng, X.-M.; Qin, B.; Zhang, G.-L.;
Jiang, Y.-Z. Org. Lett. 2003, 5, 949. (i) Chen, F.-X.; Qin,
B.; Feng, X.-M.; Zhang, G.-L.; Jiang, Y.-Z. Tetrahedron
2004, 60, 10449. (j) Li, Y.; He, B.; Feng, X.-M.; Zhang, G.-
L. Synlett 2004, 1598. (k) Chen, F.-X.; Feng, X.-M. Synlett
2005, 892.
butylphenyl)pyrrolidine-2-carboxamide]-N,N¢-dioxide (1c).
(10) The following are the physical, NMR and HRMS data of 1c:
mp 127–129 °C; [a]D25 –7.3 (c 2.12, CH2Cl2). 1H NMR (400
MHz, CDCl3): d = 8.54 (s, 2 H), 7.25–7.33 (m, 4 H,), 7.07–
7.15 (m, 4 H), 6.82 (s, 2 H), 3.82–3.85 (d, J = 12 Hz, 2 H),
3.59–3.62 (d, J = 12 Hz, 2 H), 3.30–3.34 (m, 2 H), 2.95–3.00
(m, 2 H), 2.39–2.46 (m, 2 H), 2.19 (s, 3H), 1.99–2.05 (m, 4
H), 1.76–1.79 (m, 4 H), 1.44 (s, 18 H,). 13C NMR (400 MHz,
CDCl3): d = 20.39, 24.01, 30.16, 30.56, 34.54, 53.83, 55.78,
67.42, 123.07, 125.89, 126.34, 126.58, 127.8, 129.74,
135.08, 142.76, 153.32, 172.28. HRMS: m/z calcd for
C38H52N4O5: 657.4016 [M + H]+; found: 657.4005 [M + H]+.
(11) General Procedure for Asymmetric Addition of Ethyl
Cyanoformate to Aldehydes.
To a solution of 1c (16.4 mg, 0.025 mmol) and 4 Å MS (20
mg) in CH2Cl2 (0.5 mL) was added Ti(Oi-Pr)4 (1 M in
toluene, 25 mL, 0.025 mmol) at r.t., then the mixture was
stirred at 35 °C for 1 h under N2 atmosphere. To this solution
aldehyde (0.25 mmol) and EtOCOCN (50 mL, 0.5 mmol)
were added at –45 °C under N2 atmosphere. After the
complete conversion of the aldehyde (monitored by TLC,
48–100 h), the crude product was purified by column
chromatography on silica gel (PE–Et2O, 10:1) to give the
corresponding cyanohydrin carbonates for further analysis.
(12) (a) Girard, C.; Kagan, H. B. Angew. Chem. Int. Ed. 1998, 37,
2922. (b) Avalos, M.; Babiano, R.; Cintas, P.; Jiménez, J. L.;
Palacios, J. C. Tetrahedron: Asymmetry 1997, 8, 2997.
(9) General Procedure for the Preparation of C2-Symmetric
N,N¢-Dioxide Ligands.
(a) To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-
2-carboxylic acid (2.3 g, 10.0 mmol) in CH2Cl2 was added
Et3N (4 mL), isobutyl carbonochloride (1.44 mL, 10.0
mmol) at 0 °C under stirring After 25 min, the amine (10.2
mmol) was added. It was allowed to warm to r.t. and stirred
for 8 h. The mixture was washed with 1 M KHSO4 (20 mL),
sat. NaHCO3 (20 mL), brine (20 mL), dried over Na2SO4 and
concentrated. The residue in CH2Cl2 (25 mL) was added
TFA (10 mL) and stirred for 2 h. Then, the solvent was
evaporated, and H2O (20 mL) was added. The pH of the
mixture was brought into the range of 8–10 by the addition
of 2 M NaOH. The aqueous phase was extracted with
CH2Cl2 (50 mL). The CH2Cl2 extracts were pooled, washed
with brine, dried over Na2SO4 and evaporated in vacuo. The
residue was used for next step directly.
(b) 2,6-Di(bromomethyl)-4-methylphenol (5.1 mmol) was
added in one portion to a stirred and cooled solution of (S)-
pyrrolidine-2-carboxamide (10.2 mmol) and K2CO3 (21
mmol) in dry DMF (8 mL). The ice bath was removed after
the addition and the resulting solution was allowed to stir at
Synlett 2006, No. 11, 1675–1678 © Thieme Stuttgart · New York