Asymmetric esterification of ketenes catalyzed by an N-heterocyclic carbene

Article abstract of DOI:10.1039/b815139c

The chiral N-heterocyclic carbene precursor 2, derived from L-pyroglutamic acid, was found to be an efficient precatalyst for the enantioselective esterification of alkylarylketenes with benzhydrol to give the corresponding esters in good yields with good to high enantioselectivities (up to 95% ee).

Full text of DOI:10.1039/b815139c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Asymmetric esterification of ketenes catalyzed by an N-heterocyclic carbene†
Xiao-Na Wang, Hui Lv, Xue-Liang Huang and Song Ye*
Received 1st September 2008, Accepted 17th October 2008
First published as an Advance Article on the web 18th November 2008
DOI: 10.1039/b815139c
The chiral N-heterocyclic carbene precursor 2, derived from L-pyroglutamic acid, was found to be an
efficient precatalyst for the enantioselective esterification of alkylarylketenes with benzhydrol to give the
corresponding esters in good yields with good to high enantioselectivities (up to 95% ee).
give the corresponding b-lactams,15 b-lactones16 and d-lactones,17
Introduction
respectively, in good yields with high enantioselectivities. The
The asymmetric esterification of unsymmetrical disubstituted
ready availability of chiral NHCs and the successful activation
ketenes with alcohols is a useful approach to synthesize op-
tically active esters bearing an a chiral center.1 Two general
methodologies, namely auxiliary-controlled reactions using chiral
alcohols and catalyst-controlled reactions, have been developed.
The auxiliary-controlled methodology was firstly attempted by
Weiss in 1919,2 and met great success with chemists at the
Merck laboratories, with 99.5% diastereoselectivity achieved.3,4
In 1960s, Pracejus reported the brucine- and benzoylquinine-
catalyzed enantioselective esterification of phenyl(methyl) ketene
with methanol to afford the phenyl propionic ester with up to
76% ee.5 Recently, Fu and co-workers introduced the designed
planar-chiral catalysts of DMAP derivatives, and reported highly
enantioselective esterifications of alkylarylketenes with methanol,
phenol and enolizable diphenylacetaldehyde (Scheme 1).6 It is
interesting that two mechanisms, namely nucleophilic catalysis and
Brønsted acid catalysis, have been proposed for those reactions.
of disubstituted ketenes by NHCs encouraged us to explore the
asymmetric esterification of ketenes with alcohols catalyzed by
chiral NHCs.
Results and discussion
It was found that the NHC 2¢, generated in situ from the
NHC precursor 215a (10 mol%) and Cs2CO3 (10 mol%), could
catalyze the addition of methanol to ethylphenylketene 3a to give
the corresponding ester in good yield, albeit with only 13% ee
(Method A, Table 1, entry 1). Control experiments showed that the
Table 1 Optimization of conditions for the asymmetric esterification of
ketene 3a
Entry 4: ROH
3a:4 Methoda T (◦C) Yield (%)b,c ee (%)d
1
2
3
4
5
6
7
8
9
MeOH
Ph(CH2)2OH 1.5:1
PhCH2OH
t-BuOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
Ph2CHOH
1.5:1
A
A
A
A
A
A
A
A
B
-78
-78
-78
-78
-78
-40
-30
rt
-40
-40
-40
-40
84 (36)
99 (63)
65 (17)
Trace
16 (0)
37 (0)
52
39 (trace)
78
73
13
11
36
—
46
66
53
11
76
89
91
95
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
1:1.5
1:1.5
1:2
Scheme 1 Fu’s asymmetric esterification of ketenes.
Recently, N-heterocyclic carbenes (NHCs) were found to be
efficient organocatalysts for the umpolung reaction of aldehydes
in the benzoin and Stetter reactions,7 the extended umpolung
reaction of functional aldehydes,8 the intramolecular b-alkylation
of Michael acceptors,9 the aza-Mortia–Baylis–Hillman reaction,10
transesterification,11 activation of silylated nucleophiles12 and
other reactions.13,14 In the line with our research on NHC-
catalyzed reactions, we found that chiral NHCs could catalyze the
reactions of alkylarylketenes with imines, aldehydes and enones to
10
11
12e
B
C
C
74
75
a General Conditions: Method A: To the mixture of NHC precursor 2
(10 mol%), Cs2CO3 (10 mol%), alcohol (1.0 mmol) in toluene (9 mL) was
added the solution of ketene (1.5 mmol) in toluene (10 mL). Method B:
The same as Method A, except that the solution of ketene was added
via a syringe pump over 30 min. Method C: To the mixture of ketene
(0.5 mmol), alcohol (0.75 or 1.0 mmol) in toluene (2 mL) at -40 oC,
was added the solution of NHC, which was freshly prepared from NHC
precursor 2 (10 mol% or 12 mol%) and Cs2CO3 (10 mol%) in toluene/ether
(1/1, 2 mL) at rt for 1 h. b Isolated yield. c The yield of controlled reaction
without catalyst is shown in parentheses. d Determined by chiral HPLC.
e NHC precursor 2 (12 mol%) and Cs2CO3 (10 mol%) were employed.
Beijing National Laboratory for Molecular Sciences, Laboratory of Chem-
ical Biology, Institute of Chemistry, Chinese Academy of Sciences, Beijing,
100190, China. E-mail: songye@iccas.ac.cn
† Electronic supplementary information (ESI) available: Further
experimental details and compound characterization. See DOI:
10.1039/b815139c
346 | Org. Biomol. Chem., 2009, 7, 346–350
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Table 2 Asymmetric esterification of ketenes catalyzed by NHCa,b
Entry
3 (Ar, R)
Time (h)
5
Yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
9
Ph, Et
20
24
24
21
24
20
20
44
24
22
26
5a
5b
5c
5d
5e
5f
5g
5h
5i
75
62
59
74
77
69
49
60
67
24
34
95
89
93
80
83
56
36
61
87
33
11
4-MeC6H4, Et
4-MeOC6H4, Et
4-ClC6H4, Et
4-BrC6H4, Et
3-ClC6H4, Et
2-ClC6H4, Et
Ph, n-Pr
4-ClC6H4, n-Bu
4-ClC6H4, i-Pr
PhCH2, Et
Scheme 2 Chemical transformation of chiral esters.
The absolute configuration of compound 6 was determined by
comparison of its chiral HPLC with the literature.6d
10
11
5j
5k
Taking into account the better result of Method C over
A (Table 1) and the strong nucleophilic addition of NHC to
ketenes,15–17 the nucleophilic catalysis mechanism may be more
favored than the Brønsted acid catalysis mechanism for this
NHC-catalyzed reaction (Fig. 1). The addition of NHC to ketene
gives triazolium enolate 8, which is stereoselectively protonated
with alcohol to give acyl triazolium 9. The substitution reaction
of triazolium 9 with alkoxide furnishes the desired ester and
regenerates the NHC.
a We followed the general condition of Method C in Table 1. b Ketene
(0.5 mmol), benzhydrol (1.0 mmol) and NHC precursor 2 (0.06 mol)/
Cs2CO3 (0.05 mmol) were employed. c Isolated yield. d Determined by
chiral HPLC.
esterification of ketenes could also occur without catalysis. After
screening of a variety of alcohols and optimizing the reaction tem-
perature (entries 2–8), it was found that the uncatalyzed reaction
was negligible for the reaction of ketene 3a with benzhydrol at or
below room temperature and an enantiomeric excess of 66% was
realized for the reaction at -40 ◦C (entry 6).
Slow addition of ketene (Method B) benefited the reactions
(entries 9 and 10) and the enantioselectivity was further improved
to 89% ee by employing excess alcohol (entry 10). Careful
investigation revealed that Cs2CO3 alone could also promote
the esterification reaction and other side reactions. Thus the
addition sequence was changed to Method C, which features
the prior stirring of the mixture of NHC precursor and Cs2CO3
for 1 h at room temperature before the addition of ketene (slow
addition is not required) and alcohol (entry 11). To ensure the
full consumption of the base (10 mol%), a slight excess of NHC
precursor (12 mol%) was employed, and then 75% yield and 95% ee
were reached for the asymmetric esterification reaction (entry 12).
A variety of alkylarylketenes were then tested for the NHC-
catalyzed asymmetric esterification reaction (Table 2). It was
found that both electron-donating groups (4-Me, 4-MeO) and
electron-withdrawing groups (4-Cl, 4-Br) gave good results.
Ketenes with electron-donating groups resulted in slightly better
enantioselectivities (entries 2 and 3), while those with electron-
withdrawing groups offered somewhat better yields (entries 4
and 5). The reaction of 3-chlorophenylethylketene went well but
only with moderate enantioselectivity (entry 6), and the reaction
of 2-chlorophenylethylketene showed a further decrease in yield
and enantioselectivity (entry 7). Alkyl groups other than ethyl
were then tested. It was found that linear alkyl groups (n-Pr,
n-Bu) are tolerated (entries 8 and 9), and that the reaction of
4-chlorophenylisopropylketene resulted in very low yield and
enantioselectivity (entry 10). Benzylethylketene did not work well
for this reaction (entry 11).
Fig. 1 Possible catalytic cycle.
In conclusion, the readily available chiral N-heterocyclic car-
bene precursor 2, derived from cheap L-pyroglutamic aicd, is
found to be an efficient precatalyst for the esterification of
alkylarylketenes with benzhydrol to give the corresponding esters
in good yields with good to highly enantioselectivities. Studies
into the NHC-catalyzed asymmetric esterification of ketenes with
enolizable aldehydes and ketones is underway in our laboratory.
Experimental
Unless otherwise indicated, all starting materials were obtained
from commercial supplies and used as received. Anhydrous
toluene and Et2O were distilled from sodium and benzophenone,
Chiral triazolium salt 2 was synthesized according to previous
report.15a 2-Phenylethanol was purified by shaking with a solution
Optically active esters could be reduced by LiAlH4 and Grignard
reagents to give primary and tertiary alcohols, respectively, in
good yields and without erosion of enantiopurities (Scheme 2).
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of ferrous sulfate, and the alcohol layer was washed with distilled
water and fractionally distilled. Ketenes were prepared according
to literature.18 All reactions were carried out under an argon at-
mosphere in oven-dried glassware with magnetic stirring. Column
chromatography was performed with silica gel 200–300 mesh.
140.3, 140.2, 131.0, 129.1, 128.4, 128.3, 127.61, 127.59, 127.2,
126.8, 114.0, 76.99, 55.2, 52.8, 26.3, 12.0; IR (KBr) n 2964,
2933, 1734, 1512, 1252, 1154, 699 cm-1; MS (EI): m/z 360 (M+,
10.7), 167 (Ph2CH+, 73.2), 149 (CH3OC6H4CH+C2H5, 100), 121
(CH3OC6H4CH2 , 16.5); HRMS (EI) calcd for C24H24O3 [M]+
+
20
360.1725, found 360.1728; [a]D -5.4 (c 0.5, CHCl3); HPLC
analysis: 93% ee [Daicel CHIRALPAK AD-H column; 20 ◦C;
1.0 mL/min; solvent system: 2-propanol/hexane = 1:99; retention
times: 51.6 min (minor), 55.1 min (major)].
Asymmetric Esterification of Ketenes Catalyzed by NHC
General procedure. To the mixture of ketene (0.5 mmol) and
benzhydrol (184.3 mg, 1.0 mmol) in toluene (2 mL) at -40 ◦C was
added the solution of NHC 2¢, which was freshly prepared from
NHC precursor 2 (34.2 mg, 0.06 mmol) and Cs2CO3 (16.3 mg,
0.05 mol) in toluene/ether (1/1, 2 mL) at rt for 1 h. The reaction
mixture was stirred at -40 ◦C for specified time (See Table 2). After
quenched with silica gel and further stirred for 10 min, the reaction
mixture was diluted with diethyl ether, and passed through a short
silica pad. The solvent was removed under reduced pressure and
the residue was purified by chromatography on silica gel to give
the desired product.
(R)-Benzhydryl 2-(4-chlorophenyl)butanoate (5d). Yield:
135.6 mg, 74%; Rf = 0.34 (Et2O/petroleum ether = 1:80);
1
colorless oil. H NMR (300 MHz, CDCl3) d 7.27–7.13 (m, 7H),
7.11–7.07 (m, 5H), 7.01–6.99 (m, 2H), 6.73 (s, 1H), 3.45 (t, J =
7.7 Hz, 1H), 2.07–1.93 (m, 1H), 1.75–1.61 (m, 1H), 0.74 (t, J =
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 172.3, 140.0, 139.8,
137.2, 133.0, 129.4, 128.6, 128.4, 128.3, 127.9, 127.7, 127.1, 126.6,
77.2, 52.9, 26.2, 11.9; IR (KBr) n 2966, 2933, 1738, 1493, 1263,
1155, 1092, 822, 756, 699 cm-1; MS (EI): m/z 364 (M+, 1.9), 167
(Ph2CH+, 100); HRMS (EI) calcd for C23H21O2Cl [M]+ 364.1230,
Racemic samples of esters for the standard of chiral HPLC spec-
tra were prepared using 10 mol% Cs2CO3 as catalyst for esters 5a-h,
5j, 5k and the achiral NHC precursor, 2-phenyl-6,7-dihydro-5H-
pyrrolo[2,1-c][1,2,4]triazol-2-ium tetrafluoroborate,13d for ester 5i.
20
found 364.1233; [a]D -7.0 (c 0.5, CHCl3); HPLC analysis: 80%
ee [Daicel CHIRALPAK AD-H column; 20 ◦C; 1.0 mL/min;
solvent system: 2-propanol/hexane = 5:95; retention times:
13.4 min (minor), 14.6 min (major)].
(R)-Benzhydryl 2-phenylbutanoate (5a). Yield: 123.9 mg, 75%;
Rf = 0.24 (Et2O/petroleum ether = 1:90); colorless oil. 1H NMR
(300 MHz, CDCl3) d 7.18–7.07 (m, 13H), 7.01–6.97 (m, 2H), 6.74
(s, 1H), 3.49 (t, J = 7.7 Hz, 1H), 2.09–1.97 (m, 1H), 1.81–1.69
(m, 1H), 0.77 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 172.7, 140.2, 140.1, 138.8, 128.5, 128.4, 128.2, 128.1, 127.8,
127.6, 127.2, 127.1, 126.7, 77.0, 53.7, 26.2, 12.0; IR (KBr) n 3063,
3031, 2965, 2933, 1736, 1496, 1454, 1151, 980, 741, 697 cm-1; MS
(R)-Benzhydryl 2-(4-bromophenyl)butanoate (5e). Yield:
157.7 mg, 77%; Rf = 0.34 (Et2O/petroleum ether = 1:80);
1
colorless oil. H NMR (300 MHz, CDCl3) d 7.32–7.29 (m, 2H),
7.29–7.10 (m, 8H), 7.05–6.99 (m, 4H), 6.73 (s, 1H), 4.39 (t, J =
7.7 Hz, 1H), 2.05–1.93 (m, 1H), 1.73–1.64 (m, 1H), 0.75 (t, J =
7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 172.3, 140.0, 139.8,
137.7, 131.6, 129.8, 128.4, 128.3, 127.9, 127.7, 127.1, 126.6,
121.1, 77.2, 53.0, 26.2, 11.9; IR (KBr) n 2965, 2933, 1736, 1489,
1455, 1153, 741, 698 cm-1; MS (EI): m/z 408 (C23H21O279Br+,
1.8), 410 (C23H21O281Br+, 1.8), 197 (79BrC6H4CH+C2H5, 12.2),
199 (81BrC6H4CH+C2H5, 12.2), 167 (Ph2CH+, 100); HRMS (EI)
calcd for C23H21O279Br [M]+ 408.0725, found 408.0728, calcd for
+
(EI): m/z 330 (M+, 4.3), 167 (Ph2CH+, 100), 91 (PhCH2 , 18.3);
HRMS (EI) calcd for C23H22O2 [M]+ 330.1620, found 330.1622;
20
[a]D -18.0 (c 0.5, CHCl3); HPLC analysis: 95% ee [Daicel
CHIRALPAK AD-H column; 20 ◦C; 0.5 mL/min; solvent system:
2-propanol/hexane = 10:90; retention times: 13.7 min (major),
15.3 min (minor)].
C23H21O281Br [M]+ 410.0704, found 410.0709; [a]D -11.0 (c 0.5,
20
CHCl3); HPLC analysis: 83% ee [Daicel CHIRALPAK AD-H
column; 20 ◦C; 1.0 mL/min; solvent system: 2-propanol/hexane =
5:95; retention times: 8.8 min (minor), 9.7 min (major)].
(R)-Benzhydryl 2-p-tolylbutanoate (5b). Yield: 106.2 mg, 62%:
Rf = 0.28 (Et2O/petroleum ether = 1:80); colorless oil. 1H NMR
(300 MHz, CDCl3) d 7.36–7.14 (m, 5H), 7.12–7.07 (m, 5H), 7.02–
6.99 (m, 4H), 6.73 (s, 1H), 3.45 (t, J = 7.7 Hz, 1H), 2.23 (s, 3H),
2.07–1.95 (m, 1H), 1.76–1.67 (m, 1H), 0.76 (t, J = 7.4 Hz, 3H);
13C NMR (75 MHz, CDCl3) d 173.0, 140.2, 140.1, 136.7, 135.7,
129.2, 128.4, 128.2, 127.9, 127.8, 127.5, 127.2, 126.6, 76.9, 53.2,
26.3, 21.0, 12.0; IR (KBr) n 3031, 2965, 2931, 1737, 1513, 1496,
1455, 1154, 699 cm-1; MS (EI): m/z 344 (M+, 3.7), 167 (Ph2CH+,
(R)-Benzhydryl
2-(3-chlorophenyl)butanoate
(5f). Yield:
125.8 mg, 69%; Rf = 0.28 (Et2O/petroleum ether = 1:80);
colorless oil. 1H NMR (300 MHz, CDCl3) d 7.79–7.12 (m, 14H),
6.83 (s, 1H), 3.55 (t, J = 7.7 Hz, 1H), 2.16–2.06 (m, 1H), 1.87–1.75
(m, 1H), 0.86 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 172.2, 140.8, 140.1, 139.9, 134.4, 129.7, 128.5, 128.4, 128.3,
127.9, 127.8, 127.4, 127.2, 126.8, 126.4, 77.4, 53.4, 26.3, 12.0;
IR (KBr) n 2966, 2933, 1737, 1595, 1573, 1495, 1455, 1155,
979, 697 cm-1; HRMS (EI) calcd for C23H21O2Cl [M]+ 364.1230,
100), 133 (CH3C6H4CH+C2H5, 56.1), 105 (CH3C6H4CH2 , 42.1);
+
HRMS (EI) calcd for C24H24O2 [M]+ 344.1776, found 344.1779;
20
[a]D -19.4 (c 0.5, CHCl3); HPLC analysis: 89% ee [Daicel
CHIRALPAK AD-H column; 20 ◦C; 1.0 mL/min; solvent system:
2-propanol/hexane = 0.5:99.5; retention times: 30.4 min (minor),
32.4 min (major)].
20
found 364.1233; [a]D -6.2 (c 0.5, CHCl3); HPLC analysis: 56%
ee [Daicel CHIRALPAK AD-H column; 20 ◦C; 0.5 mL/min;
solvent system: 2-propanol/hexane = 10:90; retention times:
11.5 min (major), 12.6 min (minor)].
(R)-Benzhydryl 2-(4-methoxyphenyl)butanoate (5c). Yield:
105.6 mg, 59%; Rf = 0.14 (Et2O/petroleum ether = 1:60); colorless
(R)-Benzhydryl 2-(2-chlorophenyl)butanoate (5g). Yield:
90.2 mg, 49%; Rf = 0.31 (Et2O/petroleum ether = 1:80); colorless
oil. 1H NMR (300 MHz, CDCl3) d 7.49–7.29 (m, 1H), 7.23–7.02
(m, 13H), 6.76 (s, 1H), 4.15 (t, J = 7.5 Hz, 1H), 2.09–1.97 (m, 1H),
1.82–1.67 (m, 1H), 0.81 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz,
1
oil. H NMR (300 MHz, CDCl3) d 7.23–7.10 (m, 10H), 7.04–
7.01 (m, 2H), 6.76–6.73 (m, 3H), 3.69 (s, 3H), 3.44 (t, J =
7.7 Hz, 1H), 2.06–1.97 (m, 1H), 1.78–1.66 (m, 1H), 0.76 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 173.0, 158.9,
348 | Org. Biomol. Chem., 2009, 7, 346–350
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CDCl3) d 172.2, 140.3, 140.1, 136.7, 134.4, 129.6, 128.8, 128.4,
128.3, 128.2, 127.9, 127.6, 127.2, 127.0, 126.7, 77.3, 49.1, 25.7,
11.9; IR (KBr) n 3064, 3032, 2967, 2934, 1738, 1496, 1474, 1455,
1164, 748, 698 cm-1; MS (EI): m/z 364 (M+, 6.5), 167 (Ph2CH+,
0.76 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 174.5,
140.1, 140.0, 139.2, 128.9, 128.4, 128.4, 128.3, 127.8, 127.6, 127.3,
127.0, 126.2, 76.6, 49.4, 38.1, 25.4, 11.7; IR (KBr) n 3030, 2963,
2930, 1735, 1495, 1454, 1193, 1149, 742, 697 cm-1; MS (EI): m/z
344 (M+, 6.0), 167 (Ph2CH+, 100), 91 (PhCH2 , 29.5); HRMS (EI)
+
+
100), 125 (ClC6H4CH2 , 17.9); HRMS (EI) calcd for C23H21O2Cl
[M]+ 364.1230, found 364.1234; [a]D -14.8 (c 0.5, CHCl3);
calcd for C24H24O2 [M]+ 344.1776, found 344.1778; [a]D -1.6 (c
20
20
HP◦LC analysis: 36% ee [Daicel CHIRALPAK AD-H column;
20 C; 1.0 mL/min; solvent system: 2-propanol/hexane = 5:95;
retention times: 7.7 min (major), 8.7 min (minor)].
0.3, CHCl3); HPLC analysis: 11% ee [Daicel CHIRALPAK AD-H
column; 20 ◦C; 0.5 mL/min; solvent system: 2-propanol/hexane =
10:90; retention times: 11.5 min (major), 12.3 min (minor)].
(R)-Benzhydryl 2-phenylpentanoate (5h). Yield: 102.4 mg,
60%; Rf = 0.36 (Et2O/petroleum ether = 1:80); colorless oil.
1H NMR (300 MHz, CDCl3) d 7.90–7.11 (m, 13H), 7.02–6.99
(m, 2H), 6.74 (s, 1H), 3.61 (t, J = 7.7 Hz, 1H), 2.06–1.97 (m,
1H), 1.75–1.68 (m, 1H), 1.21–1.14 (m, 2H), 0.80 (t, J = 7.4 Hz,
3H); 13C NMR (75 MHz, CDCl3) d 172.8, 140.3, 140.1, 139.0,
128.5, 128.4, 128.3, 128.1, 127.8, 127.6, 127.2, 127.1, 126.7, 77.1,
51.7, 35.1, 20.6, 13.7; IR (KBr) n 3031, 2958, 2932, 1737, 1495,
1454, 1260, 1151, 743, 697 cm-1; MS (EI): m/z 344 (M+, 4.8), 167
Preparation of (R)-2-(4-methoxyphenyl)butan-1-ol(6)6d. LiAlH4
(19.1 mg, 0.50 mmol) was added to a solution of ester 5c
(0.25 mmol, 90.5 mg) in Et2O (2.8 mL) at room temperature
and the solution was stirred under N2 at room temperature for
2h until TLC indicated complete consumption of the ester. The
reaction was quenched by the addition of saturated K2CO3(aq)
(0.1 mL), and then diluted with diethyl ether, passed through a
short silica pad. The solvent was removed under reduced pressure
and the residue was purified by chromatography on silica gel (ethyl
acetate/petroleum ether = 1:10) to give the desired alcohol 6 as
a colorless oil. Yield: 93%; 1H NMR (300 MHz, CDCl3) d 7.06–
7.02 (m, 2H), 6.82–6.77 (m, 2H), 3.72 (s, 3H), 3.65–3.59 (m, 2H),
2.58–2.55 (m, 1H), 1.68–1.61 (m, 1H), 1.50–1.44 (m, 1H), 1.34
(br, 1H), 0.75 (t, J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d
(Ph2CH+, 100), 91 (PhCH2 , 25.6); HRMS (EI) calcd for C24H24O2
+
[M]+ 344.1776, found 344.1778; [a]D -13.6 (c 0.5, CHCl3); HPLC
20
analysis: 61% ee [Daicel CHIRALPAK AD-H column; 20 ◦C;
1.0 mL/min; solvent system: 2-propanol/hexane = 5:95; retention
times: 8.7 min (major), 10.4 min (minor)].
20
(R)-Benzhydryl
2-(4-chlorophenyl)hexanoate
(5i). Yield:
158.3, 134.1, 128.9, 113.1, 67.4, 55.2, 49.6, 25.1, 11.9; [a]D -12.8 (c
131.7 mg, 67%; Rf = 0.34 (Et2O/petroleum ether = 1:80);
colorless oil. 1H NMR (300 MHz, CDCl3) d 7.20–7.11 (m,
12H), 7.02–6.99 (m, 2H), 6.73 (s, 1H), 3.54 (t, J = 7.7 Hz, 1H),
2.04–1.92 (m, 1H), 1.72–1.60 (m, 1H), 1.20–1.06 (m, 4H), 0.73
(t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 172.5, 140.0,
139.8, 137.4, 133.0, 129.4, 128.6, 128.4, 128.3, 127.9, 127.7,
127.1, 126.7, 77.2, 51.2, 32.8, 29.58, 22.3, 13.8; IR (KBr) n 2956,
2930, 1738, 1493, 1153, 1092, 757, 699 cm-1; MS (EI): m/z 392
0.5, CHCl3); HPLC analysis: 92% ee [Daicel CHIRALPAK OD-H
column; 20 ◦C; 1.0 mL/min; solvent system: 2-propanol/hexane =
1:99; retention times: 17.7 min (minor), 19.1 min (major)].
Preparation of (R)-2-methyl-3-phenylpentan-2-ol (7). MeMg-
Br (3M in ether, 0.55 mL, 1.65 mmol) was added to a solution of
ester 5a (0.33 mmol, 109 mg) in Et2O (2.0 mL) at room temperature
and the solution was stirred under N2 at room temperature for
3.5 h until TLC indicated complete consumption of the ester. The
reaction was quenched by several drops of 0.5 mol/L HCl(aq),
and extracted with ethyl acetate. The collected organic layer
was washed with brine, dried over Na2SO4. The solution was
concentrated under reduced pressure and the residue was purified
by chromatography on silica gel (ethyl acetate/petroleum ether =
(M+, 3.4), 167 (Ph2CH+, 100), 125 (ClC6H4CH2 , 22.6); HRMS
+
(EI) calcd for C25H25O2Cl [M] + 392.1543, found 392.1546;
20
[a]D -12.2 (c 0.5, CHCl3); HPLC analysis: 87% ee [Daicel
CHIRALPAK AD-H column; 20 ◦C; 1.0 mL/min; solvent
system: 2-propanol/hexane = 5:95; retention times: 9.0 min
(minor), 13.3 min (major)].
1
1:20) to give the desired product 7. Yield: 95%; colorless oil; H
(R)-Benzhydryl 2-(4-chlorophenyl)-3-methylbutanoate (5j).
Yield: 44.7 mg, 24%; Rf = 0.24 (Et2O/petroleum ether = 1:80);
colorless oil. 1H NMR (300 MHz, CDCl3) d 7.23–7.12 (m,
12H), 7.05–7.03 (m, 2H), 6.73 (s, 1H), 3.18 (d, J = 10.5 Hz,
1H), 2.29–2.24 (m, 1H), 0.87 (d, J = 6.5 Hz, 3H), 0.62 (d,
J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 172.3, 140.1,
139.8, 136.6, 133.2, 130.0, 128.6, 128.4, 128.3, 127.9, 127.8,
127.3, 126.8, 77.3, 59.6, 31.6, 21.3, 20.1; IR (KBr) n 2962, 2931,
1736, 1492, 1152, 1115, 1092, 819, 743, 698 cm-1; MS (EI): m/z
NMR (300 MHz, CDCl3) d 7.21–7.17 (m, 2H), 7.16–7.08 (m,
3H), 2.38 (dd, J = 11.9, 3.2 Hz, 1H), 1.83–1.79 (m, 1H), 1.72
(br, 1H), 1.72–1.63 (m, 1H), 1.07 (s, 3H), 1.05 (s, 3H), 0.62 (t,
J = 7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) d 141.1, 129.5,
127.9, 126.3, 72.6, 59.29, 27.8, 27.7, 22.1, 12.8; IR (KBr) n 3440,
2967, 2875, 1493, 1453, 1377, 1138, 728, 702 cm-1; MS (EI):
m/z 178 (M+, 2.4), 120 (M+ - CH3COCH3, 52.4), 91 (PhCH2 ,
+
+
=
100), 59 ((CH3)2C OH , 23.2); HRMS (EI) calcd for C12H18O
20
+
378 (M+, 3.0), 167 (Ph2CH+, 100), 125 (ClC6H4CH2 , 10.7);
178.1358, found 178.1361; [a]D +8 (c 0.05, CHCl3); HPLC
analysis: 94% ee [Daicel CHIRALPAK AD-H column; 20 ◦C;
1.0 mL/min; solvent system: 2-propanol/hexane = 1:99; retention
times: 9.4 min (minor), 10.3 min (major)].
HRMS (EI) calcd for C24H23O2Cl [M]+ 378.1387, found 378.1385;
20
[a]D -3.0 (c 0.5, CHCl3); HPLC analysis: 33% ee [Daicel
CHIRALPAK AD-H column; 20 ◦C; 1.0 mL/min; solvent
system: 2-propanol/hexane = 5:95; retention times: 7.1 min
(minor), 7.7 min (major)].
Acknowledgements
(R)-Benzhydryl 2-benzylbutanoate (5k). Yield: 59.2 mg, 34%;
Rf = 0.30 (Et2O/petroleum ether = 1:80); colorless oil. 1H NMR
(300 MHz, CDCl3) d 7.25–7.10 (m, 11H), 7.03–6.98 (m, 4H), 6.75
(s, 1H), 2.88–2.84 (m, 1H), 2.73–2.64 (m, 2H), 1.62–1.52 (m, 2H),
We are grateful to the Chinese Academy of Sciences and Nat-
ural Sciences Foundation of China (No 20602036) for financial
support.
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The Royal Society of Chemistry 2009
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10 (a) L. He, T.-Y. Jian and S. Ye, J. Org. Chem, 2007, 72, 7466; (b) L. He,
Y.-R. Zhang, X.-L. Huang and S. Ye, Synthesis, 2008, 2825.
11 (a) C. Bakhtiar and E. H. Smith, J. Chem. Soc. Perkin Trans., 1994, 1,
239; (b) G. A. Grasa, R. M. Kissling and S. P. Nolan, Org. Lett., 2002,
4, 3583; (c) G. W. Nyce, J. A. Lamboy, E. F. Connor, R. M. Waymouth
and J. L. Hedrick, Org. Lett., 2002, 4, 3587.
12 (a) A. Blanrue and R. Wilhelm, Synlett, 2004, 2621; (b) J. Wu, X. Sun,
S. Ye and W. Sun, Tetrahedron Lett., 2006, 47, 4813; (c) J. J. Song, F.
Gallou, J. T. Reeves, Z. L. Tan, N. K. Yee and C. H. Senanayake, J.
Org. Chem., 2006, 71, 1273; (d) J. J. Song, Z. Tan, J. T. Reeves, N. K.
Yee and C. H. Senanayake, Org. Lett., 2007, 9, 1013.
13 (a) E. F. Connor, G. W. Nyce, M. Myers, A. Mo¨ck and J. L. Hedrick, J.
Am. Chem. Soc., 2002, 124, 914; (b) H. Zhou, E. J. Campbell and S. T.
Nguyen, Org. Lett., 2001, 3, 2229; (c) W. Ye, G. Cai, Z. Zhuang, X. Jia
and H. Zhai, Org. Lett., 2005, 7, 3769; (d) J. E. Thomson;, K. Rix and
A. D. Smith, Org. Lett., 2006, 8, 3785; (e) Y. K. Liu, R. Li, L. Yue, B. J.
Li, Y. C. Chen, Y. Wu and L. S. Ding, Org. Lett., 2006, 8, 1521; (f) X.
Sun, S. Ye and J. Wu, Eur. J. Org. Chem., 2006, 4787; (g) Y. Suzuki, S.
Ota, Y. Fukuta, Y. Ueda and M. Sato, J. Org. Chem., 2008, 73, 2420;
(h) D.-D. Chen, X.-L. Hou and L.-X. Dai, J. Org. Chem., 2008, 73,
5578.
14 For reviews, see: (a) D. Enders and T. Balensiefer, Acc. Chem. Res., 2004,
37, 534; (b) N. Marion, S. D´ıez-Gonza´lez and S. P. Nolan, Angew. Chem.
Int. Ed., 2007, 46, 2988; (c) D. Enders, O. Niemeier and A. Henseler,
Chem. Rev., 2007, 107, 5606; (d) V. Nair, S. Bindu and V. Sreekumar,
Angew. Chem. Int. Ed., 2004, 43, 5130.
References
1 (a) T. T. Tidwell, Angew. Chem. Int. Ed., 2005, 44, 6812; (b) R. K. Orr
and M. A. Calter, Tetrahedron, 2003, 59, 3545; (c) T. T. Tidwell, Ketenes
2nd ed., John Wiley & Sons, Hoboken, New Jersey, 2006.
2 (a) R. Weiss, Monatsh. Chem., 1919, 40, 391; (b) A. McKenzie and E.
W. Christie, J. Chem. Soc., 1934, 1070; (c) E. Anders, E. Ruch and I.
Ugi, Angew. Chem. Int. Ed., 1973, 12, 25.
3 R. D. Larsen, E. G. Corley, P. Davis, P. J. Reider and E. J. J. Grabowski,
J. Am. Chem. Soc., 1989, 111, 7650.
4 For the theoretical study of the additions of chiral alcohols to ketenes,
see:(a) C. E. Cannizzaro, T. Strassner and K. N. Houk, J. Am. Chem.
Soc., 2001, 123, 2668; (b) C. E. Cannizzaro and K. N. Houk, J. Am.
Chem. Soc., 2004, 126, 10992.
5 (a) H. Pracejus, Justus Liebigs Ann. Chem., 1960, 634, 9; (b) H. Pracejus
and G. Kohl, Justus Liebigs Ann. Chem., 1969, 722, 1.
6 (a) J. C. Ruble and G. C. Fu, J. Org. Chem., 1996, 61, 7230; (b) B. L.
Hodous, J. C. Ruble and G. C. Fu, J. Am. Chem. Soc., 1999, 121, 2637;
(c) S. L. Wiskur and G. C. Fu, J. Am. Chem. Soc., 2005, 127, 6176;
(d) C. Schaefer and G. C. Fu, Angew. Chem. Int. Ed., 2005, 44, 4606.
7 (a) T. Ugai, S. Tanaka and S. Dokawa, J. Pharm. Soc. Jpn., 1943, 63,
296; (b) R. Breslow, J. Am. Chem. Soc, 1958, 80, 3719; (c) H. Stetter,
Angew. Chem. Int. Ed., 1976, 15, 639; (d) D. Enders and U. Kallfass,
Angew. Chem. Int. Ed., 2002, 41, 1743; (e) G. Q. Li, L.-X. Dai and S.-L.
You, Chem. Comm., 2007, 852.
8 (a) K. Zeitler, Angew. Chem. Int. Ed., 2005, 44, 7506; (b) C. Burstein
and F. Glorius, Angew. Chem. Int. Ed., 2004, 43, 6205; (c) S. S. Sohn,
E. L. Rosen and J. W. Bode, J. Am. Chem. Soc., 2004, 126, 14370;
(d) G.-Q. Li, Y. Li;, L.-X. Dai and S.-L. You, Org. Lett., 2007, 9, 3519;
(e) A. Chan and K. A. Scheidt, J. Am. Chem. Soc., 2008, 130, 2740;
(f) M. He and J. W. Bode, J. Am. Chem. Soc., 2008, 130, 418; (g) H. U.
Vora and T. Rovis, J. Am. Chem. Soc., 2007, 129, 13796; (h) V. Nair,
S. Vellalath, M. Poonoth and E. Suresh, J. Am. Chem. Soc., 2006, 128,
8736.
15 (a) Y. R. Zhang, L. He, X. Wu, P. L. Shao and S. Ye, Org. Lett., 2008,
10, 277; (b) Smith et al. have simultaneously reported their results of
the NHC-catalyzed formal cycloaddition of disubstituted ketenes with
imines: N. Duguet, C. D. Campbell, A. M. Z. Slawin and A. D. Smith,
Org. Biomol. Chem., 2008, 6, 1108.
16 L. He, H. Lv, Y.-R. Zhang and S. Ye, J. Org. Chem., 2008, 73, 8101.
17 Y.-R. Zhang, H. Lv, D. Zhou and S. Ye, Chem. Eur. J, 2008, 14, 8473.
18 (a) L. M. Baigrie, H. R. Seiklay and T. T. Tidwelll, J. Am. Chem. Soc.,
1985, 107, 5391; (b) A. D. Allen, L. M. Baigrie, L. Gong and T. T.
Tidwelll, Can. J. Chem., 1991, 69, 138.
9 C. Fisher, S. W. Smith, D. A. Powell and G. C. Fu, J. Am. Chem. Soc.,
2006, 128, 1472.
350 | Org. Biomol. Chem., 2009, 7, 346–350
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The Royal Society of Chemistry 2009
©