Stereoselective synthesis of 2,3-disubstituted indoline diastereoisomers by chemoenzymatic processes

Article abstract of DOI:10.1021/jo301307q

Racemic indolines including a variety of structural motifs such as C-2 and C-3 substitutions (alkyl or aryl), cis/trans relative stereochemistry and functionalization of the aromatic ring (fluoro, methyl or methoxy groups) have been efficiently prepared through Fischer indolization and subsequent diastereoselective reduction of the unprotected indoles. Combination of Candida antarctica lipase type A and allyl 3-methoxyphenyl carbonate has been identified as the best tandem for their kinetic resolutions, observing excellent stereodiscriminations for most of the tested indolines.

Full text of DOI:10.1021/jo301307q

Article
pubs.acs.org/joc
Stereoselective Synthesis of 2,3-Disubstituted Indoline
Diastereoisomers by Chemoenzymatic Processes
María Lopez-Iglesias, Eduardo Busto, Vicente Gotor, and Vicente Gotor-Fernandez*
́
́
Departamento de Química Organ
Oviedo, Spain
́ ́
ica e Inorganica, Instituto Universitario de Biotecnología de Asturias, Universidad de Oviedo, 33006
S
* Supporting Information
ABSTRACT: Racemic indolines including a variety of
structural motifs such as C-2 and C-3 substitutions (alkyl or
aryl), cis/trans relative stereochemistry and functionalization of
the aromatic ring (fluoro, methyl or methoxy groups) have
been efficiently prepared through Fischer indolization and
subsequent diastereoselective reduction of the unprotected
indoles. Combination of Candida antarctica lipase type A and
allyl 3-methoxyphenyl carbonate has been identified as the best
tandem for their kinetic resolutions, observing excellent stereodiscriminations for most of the tested indolines.
family of cis-2,3-substituted indolines, studying later in depth
INTRODUCTION
■
their lipase-catalyzed kinetic resolution processes through
alkoxycarbonylation reactions. In this manner, the level of
structural complexity has been increased dealing with the
production of indoline diasteroisomers by controlling the
chirality of both stereogenic centers for the production of the
carbamates and amines with cis-configuration in enantiopure
form.
Optically active 2,3-disubstituted indolines are targeted
compounds in medicinal and natural products chemistry since
their structures are present in many natural occurring alkaloids
(i.e., Vindoline, (−)-Strychnine, (−)-Physostigmine, etc.)1 but
also in synthetic drugs such as the antipsychotic agent WAY-
163909.2 The presence of two chiral centers in the indoline
moiety leads to four possible diastereoisomers, each of them
having the possibility to display very different chemical, physical
and biological activities. Therefore, the development of
stereoselective routes for the preparation of indoline single
diastereoisomers continues to be a highly demanded goal in
synthetic organic chemistry. Until now, asymmetric trans-
formations leading to optically active 2,3-indolines have been
based on different synthetic approaches such as catalytic
hydrogenation3 or hydrosilylation of the corresponding
indoles,4 nonenzymatic kinetic resolution of indolines5 and a
broad range of convergent methodologies as free radical
promoted aryl aminations,6 intramolecular shifting of sulfonyl
groups,7 asymmetric electrophilic cyclization processes8 or
palladium catalyzed coupling reactions.9
RESULTS AND DISCUSSION
■
To explore the possibilities of lipases in the kinetic resolution of
this class of heterocyclic amines, 2,3-dimethylindoline (2a) was
selected as the model substrate because of its easy accessibility
through simple chemical reduction of 2,3-dimethyl-1H-indole
(1a). Depending on the reducing agent, it is possible to drive
the reaction toward the formation of the cis- or the trans-isomer
(Scheme 1), so when using sodium cyanoborohydride
(NaBH3CN) predominately occurs the formation of the
trans-isomer (ratio trans/cis 3:1),5a,12 while the formation of
Although enzymes are ideal catalysts for the preparation of
optically active cyclic secondary amines under very mild
reaction conditions,10 the chemoenzymatic production of 2,3-
disubstituted indolines remains nowadays unexplored. In
particular our research group has demonstrated the usefulness
of lipases for the kinetic resolution of mono 2- and 3-
substituted indolines by means of alkoxycarbonylation
processes,11 identifying lipases from Candida antarctica type A
(CAL-A) and Candida antarctica type B (CAL-B) as the best
catalysts. Thus, while the combination of CAL-A and allyl 3-
methoxyphenyl carbonate has efficiently led to the resolution of
2-substituted derivatives, less hindered 3-methylindoline was
efficiently resolved using CAL-B and diallyl carbonate. Herein,
we report a general and robust approach for the synthesis of a
Scheme 1. Reduction of 2,3-Dimethyl-1H-indole (1a) for the
Synthesis of ( )-trans- and ( )-cis-2,3-Dimethyl-indoline
(2a)
Received: June 22, 2012
Published: August 22, 2012
© 2012 American Chemical Society
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Article
the cis-isomer is favored with platinum catalyzed hydrogenation
(ratio trans/cis 1:6).13
ments were conducted with diallyl carbonate (3a), and we
observed a low reaction rate but a complete enantioselectivity
toward the formation of the carbamate (2R,3R)-4a (entry 1).
This promising result in terms of stereoselectivity made us
move forward to the use of a more reactive carbonate such as
allyl 3-methoxyphenyl carbonate (3b). Satisfyingly, conversion
reached 50% after 24 h, isolating both substrate (2S,3S)-2a and
product (2R,3R)-4a nearly in enantiopure form (entry 2). The
use of higher temperatures (45 °C) did not improve the
reaction rate, and we observed a slight decrease of the optical
purity for both substrate and product (entry 3). Similar results
in terms of excellent enantioselectivity were achieved with other
solvents such as Et2O, THF, n-hexane or toluene (entries 4−7),
although lower conversion values were attained. For the
Trying to optimize the production of a single diaster-
eoisomer, the hydrogenation of 1a was performed over Adams’
catalyst (PtO2), and although the analysis of the reaction crude
revealed complete conversion, large amounts of the undesired
trans-isomer were detected leading to the cis-indoline in 50% de.
At this point, similar conditions to the ones reported by Wee
and co-workers for 2-ethyl-3-methylindole were attempted for
the production of the corresponding cis-indoline.14 Then, Pd−
C was used as catalyst, and a combination of a perchloric acid
solution in acetic acid (5% v/v) was chosen as reaction
medium. Data are summarized in Table 1. Satisfyingly, racemic
Table 1. Optimization of the Diastereoselective Reduction of
2,3-Dimethyl-1H-indole (1a) for the Production of cis-2a
Using 10% Pd−C in a Solution of HClO4 in AcOH
assignment of the absolute configuration, the optical rotation
20
of the so-obtained enantioenriched amine cis-2a ([α]D
=
−29.0 (c 0.83, CHCl3) in 99% ee) was compared with the one
reported in the literature ([α]D20= +26.6 (c 0.83, CHCl3) for
(2R,3R)-2a in 92% ee).3b According to this, the product
configurations in the lipase-catalyzed resolution of the indoline
were assigned as (2S,3S) for the amine 2a and (2R,3R) for the
carbamate 4a.
Encouraged by the excellent results achieved for cis-2a, the
influence of the relative disposition (cis/trans) of the methyl
groups was explored in its enzymatic resolution. So, the kinetic
resolution of the racemic amine trans-2a was attempted using a
representative set of catalysts such as CAL-A, CAL-B, Candida
rugosa lipase (CRL), pig pancreas lipase (PPL), Thermomyces
lanuginose lipase (TLL), Rhizomucor miehei lipase (RM-IM) and
lipase AK from Pseudomonas fluorescens in the presence of
diallyl carbonate (3a) or the more reactive allyl 3-methox-
yphenyl carbonate (3b) in dry TBME, but unfortunately, the
starting materials were recovered unaltered.
a
b
b
entry
HClO4 (%)
c (%)
de (%)
1
2
3
5
10
30
50
56
>97
>97
>97
>97 (85)
a
b
Ratio in v/v. Conversion and diasteromeric excess determined by
1H NMR of the crude. Isolated yields in parentheses.
cis-indoline 2a was exclusively obtained as reaction product,
although in moderate conversion (50%, entry 1). In our search
for higher conversion values, the amount of HClO4 was
increased to 10% (v/v), and we observed a slight improvement
of the conversion value (56%, entry 2), finding the best results
with a higher loading of HClO4 (30% v/v), which exclusively
led to the racemic indoline cis-2a in very good isolated yield
(entry 3).
At this point, and considering that CAL-A displays good
catalytic activities for indolines in relative cis-disposition, we
have considered two substitution patterns in the cis-indoline
core to correctly expand the potential of our synthetic
approach, those bearing different functionalities in the aromatic
ring (methyl, methoxy or fluoro in C-5 or C-7), and
alternatively varying the substituents in the C-2 and C-3
positions of the unsaturated ring (alkyl or aryl rests). Because of
the lack of commercial availability for substituted indoles 1b−i,
Once the synthesis of cis-( )-2a was optimized, its lipase-
catalyzed alkoxycarbonylation was analyzed on the basis of the
excellent results previously achieved in the resolution of mono
2- or 3-substituted indolines,11 and also indoline-2-carboxylic
acid derivatives,15 selecting CAL-A, a very active catalyst for
sterically hindered indolines,16 diallyl carbonate or allyl 3-
methoxyphenyl carbonate as alkoxycarbonylating agents, and a
variety of organic solvents for an exhaustive study of the
enzymatic resolution of cis-( )-2a (Table 2). Initial experi-
Table 2. Enzymatic Kinetic Resolution of Indoline cis-2a Using 2.5 equiv of Carbonates 3a,b in Different Organic Solvents
a
a
b
c
entry
carbonate
T (°C)
t (h)
solvent
eep (%)
ees (%)
c (%)
E
1
2
3
4
5
6
7
3a
3b
3b
3b
3b
3b
3b
30
30
45
30
30
30
30
167
24
24
24
24
24
24
TBME
TBME
TBME
Et2O
>99
98 (35)
96
19
16
50
50
49
6
>200
>200
>200
>200
>200
>200
>200
99 (30)
98
94
6
99
THF
99
n-hexane
toluene
99
63
70
39
41
99
a
b
c
Determined by HPLC. Isolated yields in parentheses calculated from the conversion value. c = ees/(ees + eep). E = ln[(1 − c)(1 − eep)]/ln[(1 −
c)(1 + eep)].17
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Scheme 2. Synthesis of Racemic Indolines cis-2b−i through Fischer Indolization and Diasteroselective Palladium Catalyzed
Hydrogenation
they were prepared following a general route by means of
Fischer indolization reaction of the corresponding phenyl
hydrazines (5a−e) and a variety of ketones (6a−e) in refluxing
acetic acid,18 yielding indoles 1b−i in good to high yields after
2 h (65−92%, Scheme 2).
Next, the diasteroselective catalytic hydrogenation of 1b−i
was studied using the optimized reaction conditions for 1a.
Remarkably, in all cases the racemic cis-indolines were isolated
as the unique products without observing the formation of the
trans-isomers after 24 h. Higher conversions were achieved for
the indoles 1b,c with electron-donating groups at the 5-
position, isolating the cis-indolines in good yields (65%, Table
3, entries 1−2). On the other hand, moderate conversions were
4). Excellent enantiopreferences were observed for indolines
with different groups linked to the C-5 position (entries 2−4),
especially in very short span for the activating methyl and
methoxy groups (entries 2−3). An opposite behavior was
observed for cis-2e, with a methyl group at the 7-position, so
close to the reactive point, not detecting any reaction after 111
h (entry 5).
The introduction of conformationally flexible ethyl groups at
C-2 or C-3 positions led to excellent stereopreferences,
although moderate conversions at 30 °C obtaining 31%
conversion for 2f after 67 h (entry 6) and 20% for 2g after
71 h (entry 8), longer reaction times without increasing these
conversion values. When the use of higher temperatures
(entries 7 and 9) or alternative alkoxycarbonylating agents
(data not shown) were examined, neither substantially improve
the conversions. On the other hand, efficient kinetic resolutions
take place with indolines bearing bulky rests such as cyclohexyl
(2h) or 2-phenyl (2i). Biotranformations reached 50%
conversion after 34 h for the cyclohexyl derivative (2h)
isolating substrate and product in near enantiopure form (entry
10). Similar results were obtained for the 2-phenyl derivative
cis-2i isolating both (2R,3S)-amine and (2S,3R)-carbamate in
excellent enantiomeric excess after 72 h (entry 11), where the
C-2 carbon configuration has changed due to the higher
priority of the phenyl group in the CIP rules.
Table 3. Synthesis of Racemic Indolines 2b−i through
Fischer Indolization and Subsequent Palladium Catalyzed
Hydrogenation
indole 1b−i
H2
(atm)
indoline 2b−i
a
b
entry
R1
R2
R3
(%)
(%)
1
2
3
4
5
6
7
8
5-Me
Me
Me
Me
Me
Me
Et
85 (b)
85 (c)
91 (d)
76 (e)
92 (f)
75 (g)
65 (h)
82 (i)
1
1
1
1
1
1
1
8
65 (80)
65 (76)
41 (69)
27 (57)
47 (>97)
46 (>97)
63 (>97)
35 (>97)
5-OMe Me
5-F
7-Me
H
Me
Me
Me
Et
H
Me
H
−(CH2)4−
Ph Me
CONCLUSIONS
H
■
a
b
The chemical syntheses of a panel of nine 2,3-disubstituted
indolines have been possible by means of a sequence consisting
of a Fischer indolization reaction followed by the catalytic
diastereoselective hydrogenation of the resulting unprotected
indoles. Lipase-catalyzed kinetic resolutions of the so-obtained
indolines were later studied using different biocatalysts and
alkoxycarbonylating agents searching for the generation of two
chiral centers in the indoline core. This synthetic approach has
allowed us to study the influence of different structural vectors
such as cis/trans relative stereochemistry, functionalization in
the aromatic ring (fluoro, methyl and methoxy) and different
groups at the C-2 and C-3 positions (alkyl or aryl) in the
enzymatic catalysis. The combination of Candida antarctica
lipase type A and allyl 3-methoxyphenyl carbonate has been
found as the best tandem, the enzymatic alkoxycarbonylations
being found highly dependent on the indoline structure.
Remarkably, a complete absence of reactivity was detected for
trans-isomers or with cis-2,3,7-trimethylindoline, containing the
substitution closer to the reactive point. However, efficient
Isolated yields. Isolated yields. Conversion in brackets determined
1
by H NMR of the crude.
attained for the 5-F and 7-Me derivatives isolating the amines
cis-1d,e in low to moderate yields (27−41%, entries 3−4). Full
conversions were attained for the hydrogenation of indoles
bearing aliphatic rests such as ethyl groups in C-2 or C-3 (1f,g)
and also the carbazole derivative (1h), achieving the
diastereomercally pure cis-indolines 2f−h in moderate isolated
yields (47−63%, entries 5−7). However, a very low conversion
(less than 5%) was noticed for the hydrogenation of indole 1i,
with a phenyl group linked to the C-2 position (data not
shown). To overcome this limitation, the catalytic hydro-
genation was carried out at a higher hydrogen pressure (8 atm),
allowing the complete disappearance of the starting material
and the isolation of indoline cis-2i in 35% yield without
observing the formation of the trans isomer (entry 8).
Finally the enzymatic resolution of racemic indolines cis-2b−
i was attempted under the optimized conditions for 2a (Table
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Article
Table 4. CAL-A Catalyzed Kinetic Resolution of ( )-cis-2a−i Using 2.5 equiv of Carbonate 3b in TBME at 250 rpm
a
a
b
c
entry
indoline
T (°C)
t (h)
eep (%)
ees (%)
c (%)
E
1
2a
2b
2c
2d
2e
2f
30
30
30
30
30
30
45
30
45
30
30
24
6.5
4
98 (35)
97 (36)
97 (38)
99 (35)
−
99 (30)
>99 (29)
>99 (30)
99 (29)
−
50
50
50
50
−
31
34
20
26
50
49
>200
>200
>200
>200
−
>200
>200
>200
>200
>200
>200
2
3
4
24
111
67
67
71
71
34
72
5
6
>99
45
7
2f
>99
51
8
2g
2g
2h
2i
>99
25
9
>99
34
10
98 (39)
97 (25)
96 (20)
11
>99 (25)
a
b
c
Determined by HPLC. Isolated yields in parentheses. c = ees/(ees + eep). E = ln[(1 − c)(1 − eep)]/ln[(1 − c)(1 + eep)].17
(lit. 64−65 °C);19 IR (KBr) ν 3393, 2919, 2855, 2362, 1595, 1478,
1449, 1417, 1303, 1265, 791, 740 cm−1; 1H NMR (300.13 MHz,
CDCl3) δ 2.31 (s, 3H), 2.44 (s, 3H), 2.52 (s, 3H), 6.98−7.05 (m, 1H),
kinetic resolutions were attained for cis-indolines bearing
different groups at C-2, C-3 or C-5 positions observing in all
cases excellent enantioselectivity values.
3
3
7.10 (t, JHH= 7.5 Hz, 1H), 7.42 (d, JHH= 7.8 Hz, 1H), 7.64 (br s,
1H); 13C NMR (75.5 MHz, CDCl3) δ 8.7 (CH3), 11.7 (CH3), 16.7
(CH3), 107.7 (C), 115.8 (CH), 119.2 (C), 119.3 (CH), 121.7 (CH),
129.1 (C), 130.4 (C), 134.7 (C); HRMS (ESI+, m/z) calcd for
(C22H27N2)+ (2M + H)+ 319.2169, found 319.2181. 1f (419 mg, 92%
yield): Rf (10% Et2O/n-hexane) 0.24; IR (NaCl) ν 3406, 3055, 2964,
2930, 2869, 1612, 1461, 1338, 1299, 1265, 1235, 1011, 741, 704, 665
EXPERIMENTAL SECTION
■
General Procedure for the Synthesis of Indoles 1b−i.
Phenylhydrazine hydrochloride 5a−e (2.86 mmol) was added to a
solution of the corresponding ketone 6a−e (8.90 mmol) in AcOH
(14.3 mL), and the solution was stirred at 120 °C for 2 h. After this
time, EtOAc (60 mL) was added, the organic phase was washed with
brine (2 × 150 mL) and with a saturated solution of NaHCO3 (150
mL) and dried over Na2SO4, and the solvent was removed by
distillation under reduced pressure affording the indoles 1b−i (65−
92%). 1b (387 mg, 85% yield): Rf (10% EtOAc/n-hexane) 0.38; mp
104−106 °C (lit 98−99 °C);19 IR (KBr) ν 3393, 2919, 2855, 2362,
1595, 1478, 1449, 1417, 1303, 1265, 791, 740 cm−1; 1H NMR (300.13
MHz, CDCl3) δ 2.35 (s, 3H), 2.37 (s, 3H), 2.63 (s, 3H), 7.10 (dd,
1
3
cm−1; H NMR (400.13 MHz, CDCl3) δ 1.52 (t, JHH= 7.3 Hz, 3H),
3
2.39 (s, 3H), 3.00 (q, JHH= 7.3 Hz, 2H), 7.20 (br s, 1H), 7.24−7.33
(m, 1H), 7.39−7.49 (m, 2H), 7.81−7.91 (m, 1H); 13C NMR (100.6
MHz, CDCl3) δ 11.4 (CH3), 15.5 (CH3), 17.5 (CH2), 110.3 (CH),
113.9 (C), 118.1 (CH), 119.0 (CH), 120.8 (CH), 128.5 (C), 130.3
(C), 135.3 (C); HRMS (ESI−, m/z) calcd for (C11H12N)− (M − H)−
158.0975, found 158.0957. 1g (341 mg, 75% yield): Rf (10% EtOAc/n-
hexane) 0.28; mp 57−59 °C (lit. 61−62 °C);20 IR (KBr) ν 3464,
3410, 3054, 2971, 2922, 2873, 2305, 1618, 1589, 1464, 1383, 1318,
1265, 1153, 1010, 896, 740, 705 cm−1; 1H NMR (300.13 MHz,
CDCl3) δ 1.33 (t, 3JHH= 7.6 Hz, 3H), 2.33 (s, 3H), 2.80 (q, 3JHH= 7.6
Hz, 2H), 7.05−7.35 (m, 3H), 7.47−7.63 (m, 1H), 7.66 (br s, 1H); 13C
NMR (75.5 MHz, CDCl3) δ 8.4 (CH3), 14.1 (CH3), 19.5 (CH2),
106.2 (C), 110.3 (CH), 118.1 (CH), 119.1 (CH), 121.0 (CH), 129.6
(C), 135.2 (C), 136.7 (C); HRMS (ESI+, m/z) calcd for (C11H13N)+
(M)+ 159.1043, found 159.1043. 1h (318 mg, 65% yield): Rf (10%
EtOAc/n-hexane) 0.38; mp 103−107 °C (lit. 110−115 °C);21 IR
(KBr) 3406, 3055, 2964, 2930, 2869, 1261, 1461, 1299, 1265, 1234,
4
3
3JHH= 8.1, JHH= 1.4 Hz, 1H), 7.17 (d, JHH= 8.1 Hz, 1H), 7.35 (br s,
1H), 7.43 (d, 4JHH= 0.6 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 8.5
(CH3), 11.4 (CH3), 21.6 (CH3), 106.5 (C), 109.9 (CH), 117.8 (CH),
122.4 (CH), 128.1 (C), 129.7 (C), 131.0 (C), 133.6 (C); HRMS
(ESI−, m/z) calcd for (C22H25N2)− (2M − H)− 317.2023, found
317.2008. 1c (426 mg, 85% yield): Rf (10% EtOAc/n-hexane) 0.21;
mp 106−109 °C (lit. 108−109 °C);19 IR (KBr) ν 3463, 3406, 3049,
2919, 2359, 1595, 1484, 1268, 1217, 1137, 1029, 736 cm−1; H NMR
1
(400.13 MHz, CDCl3) δ 2.22 (s, 3H), 2.35 (s, 3H), 3.89 (s, 3H), 6.79
3
(d, 3JHH= 8.6 Hz, 1H), 6.95 (s, 1H), 7.14 (d, JHH= 8.6 Hz, 1H), 7.57
1
1011, 741 cm−1; H NMR (300.13 MHz, CDCl3) δ 1.95−2.12 (m,
(br s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 8.6 (CH3), 11.7 (CH3),
56.1 (CH3), 100.6 (CH), 107.1 (C), 110.6 (CH), 110.8 (CH), 130.0
(C), 130.4 (C), 131.8 (C), 153.9 (C); HRMS (ESI+, m/z) calcd for
(C11H14NO)+ (M + H)+ 176.1070, found 176.1064. 1d (425 mg, 91%
yield): Rf (5% EtOAc/n-hexane) 0.14; mp 98−99 °C (lit. 98−99
°C);19 IR (KBr) ν 3465, 3365, 2913, 2869, 1594, 1487, 1437, 1270
1229, 1176, 794, 734 cm−1; 1H NMR (300.13 MHz, CDCl3) δ 2.22 (s,
3H), 2.36 (s, 3H), 6.85−6.92 (m, 1H), 7.13−7.17 (m, 2H), 7.64 (br s,
1H); 13C NMR (75.5 MHz, CDCl3) δ 8.6 (CH3), 11.7 (CH3), 103.1
4H), 2.68−2.81 (m, 2H), 2.82−2.93 (m, 2H), 7.21−7.34 (m, 3H),
7.39 (br s, 1H), 7.60−7.69 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ
21.0 (CH2), 23.2 (CH2), 23.3 (CH2), 23.4 (CH2), 110.0 (C), 110.5
(CH), 117.8 (CH), 119.1 (CH), 120.9 (CH), 127.8 (C), 134.2 (C),
135.7 (C); HRMS (ESI−, m/z) calcd for (C12H12N)− (M − H)−
170.0975, found 170.0966. 1i (486 mg, 82% yield): Rf (10% Et2O/n-
hexane) 0.28; mp 89−92 °C (lit. 87−90 °C);19 IR (KBr) ν 3457,
3054, 2984, 2921, 2305, 1686, 1604, 1459, 1333, 1305, 1265, 740, 702
cm−1; 1H NMR (300.13 MHz, CDCl3) δ 2.64 (s, 3H), 7.32−7.47 (m,
3H), 7.47−4.55 (m, 1H), 7.57−7.65 (m, 2H), 7.65−7.72 (m, 2H),
7.77−7.85 (m, 1H), 7.68 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ
9.7 (CH3), 108.6 (C), 110.8 (CH), 119.0 (CH), 119.6 (CH), 122.3
(CH), 127.3 (CH), 127.8 (2CH), 128.8 (2CH), 130.1 (C), 133.3 (C),
2
4
2
(d, JCF= 23.3 Hz, CH), 107.5 (d, JCF= 4.5 Hz, C), 108.9 (d, JCF
=
3
3
26.1 Hz, CH), 110.6 (d, JCF= 9.7 Hz, CH), 130.0 (d, JCF= 9.5 Hz,
C), 131.7 (C), 132.9 (C), 157.9 (d, 1JCF= 233.3 Hz, C); HRMS (ESI−,
m/z) calcd for (C10H9FN)− (M − H)− 162.0725, found 162.0720. 1e
(346 mg, 76% yield): Rf (10% EtOAc/n-hexane) 0.38; mp 58−64 °C
8052
dx.doi.org/10.1021/jo301307q | J. Org. Chem. 2012, 77, 8049−8055

The Journal of Organic Chemistry
Article
2
3
134.1 (C), 135.9 (C); HRMS (ESI+, m/z) calcd for (C15H13N)+ (M)+
207.1043, found 207.1048.
Hz, CH), 113.1 (d, JCF= 23.2 Hz, CH), 136.2 (d, JCF= 7.5 Hz, C),
146.1 (C), 157.3 (d, 1JCF= 234.8 Hz, C); HRMS (ESI+, m/z) calcd for
(C10H13FN)+ (M + H)+ 166.1027, found 166.1046. [α]D20= −24.6 (c
0.5, CH2Cl2) [for (2S,3S)-2d in 99% ee]. cis-2e (41 mg, 27% yield): Rf
(40% CH2Cl2/n-hexane) 0.24; IR (NaCl) ν 3365, 3050, 3022, 2965,
2928, 2870, 1888, 1836, 1602, 1465, 1378, 1351, 1318, 1257, 1228,
1203, 1093, 1058, 924, 771, 747 cm−1; 1H NMR (300.13 MHz,
CDCl3) δ 1.20 (d, 3JHH= 6.5 Hz, 3H), 1.22 (d, 3JHH= 7.1 Hz, 3H), 2.17
(s, 3H), 3.15−3.43 (m, 1H), 3.30 (br s, 1H), 3.92−4.06 (m, 1H), 6.73
Synthesis of Racemic trans-2,3-Dimethylindoline (trans-2a).
NaBH3CN (1.30 g, 20.64 mmol) was slowly added to a solution of
2,3-dimethylindole (1a, 1 g, 6.88 mmol) in AcOH (60 mL), and the
solution was stirred for 5 h. After this time, the reaction was stopped
with a saturated solution of Na2CO3 (150 mL) and extracted with
CH2Cl2 (3 × 100 mL), the organic phases were combined and dried,
and the solvent was removed by distillation under reduced pressure.
The crude was purified by flash chromatography (100% CH2Cl2)
affording 385 mg of ( )-trans-2a as a colorless oil (38%): Rf (100%
CH2Cl2) 0.37; IR (NaCl) ν 3367, 3050, 3032, 2967, 2865, 1615, 1487,
3
3
3
(t, JHH= 7.2 Hz, 1H), 6.91 (d, JHH= 7.2 Hz, 1H), 6.98 (d, JHH= 7.2
Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 13.9 (CH3), 16.6 (CH3),
16.8 (CH3), 39.8 (CH), 58.3 (CH), 118.7 (C), 119.0 (CH), 121.4
(CH), 128.3 (CH), 133.8 (C), 148.7 (C); HRMS (ESI+, m/z) calcd
for (C11H16N)+ (M + H)+ 162.1277, found 162.1281. cis-2f (71 mg,
47% yield): Rf (10% Et2O/n-hexane) 0.15; IR (NaCl) ν 3353, 3056,
2942, 2488, 1682, 1570, 1539, 1455, 1429, 1325, 1251, 996, 789, 670
1
1468, 1254, 1095, cm−1; H NMR (300.13 MHz, CDCl3) δ 1.36 (d,
3
3JHH= 6.6 Hz, 3H), 1.37 (d, JHH= 6.3 Hz, 3H), 2.77−3.02 (m, 1H),
3.47−3.56 (m, 1H), 3.83 (br s, 1H), 6.66 (d, 3JHH= 7.6 Hz, 1H), 6.75−
6.87 (m, 1H), 7.03−7.18 (m, 2H); 13C NMR (75.5 MHz, CDCl3) δ
17.3 (CH3), 20.6 (CH3), 44.4 (CH), 64.0 (CH), 109.2 (CH), 118.6
(CH), 123.3 (CH), 127.4 (CH), 134.3 (C), 150.6 (C); HRMS (ESI+,
m/z) calcd for (C10H14N)+ (M + H)+ 148.1121, found 148.1122.
General Procedure for the Synthesis of Racemic cis-
Indolines 2a−h. To a suspension containing the corresponding
indole 1a−g (0.94 mmol) and Pd−C 10% (34 mg) in a 100 mL
round-bottom flask was connected a H2 balloon. Then, AcOH (3.0
mL) and HClO4 (1 mL) were carefully added. The resulting
suspension was stirred at room temperature during 24 h, and after
this time, the reaction was stopped, filtering the mixture through
diatomaceous earth. The crude was basified with NaOH 4 N (100
mL), extracted with CH2Cl2 (3 × 30 mL), and dried, and the solvent
was removed under reduced pressure, affording a reaction crude that
was purified by flash chromatography (Et2O/n-hexane mixtures)
affording the cis indolines 2a−h as colorless oils (27−85%). cis-2a (118
mg, 85% yield): Rf (10% EtOAc/n-hexane) 0.27; IR (NaCl) ν 3367,
3049, 3032, 2966, 2919, 2870, 1610, 1484, 1463, 1250, 1092, 1011,
cm−1; H NMR (300.13 MHz, CDCl3) δ 1.13 (t, JHH= 7.4 Hz, 3H),
1
3
1.23 (d, 3JHH= 6.5 Hz, 3H), 1.61−1.89 (m, 2H), 3.11 (q, 3JHH= 7.5 Hz,
1H), 3.64 (br s, 1H), 4.05 (dq, 3JHH= 13.2, 6.5 Hz, 1H), 6.71 (d, 3JHH
=
=
7.7 Hz, 1H), 6.82 (dt, 3JHH= 7.4 Hz; 4JHH= 0.9 Hz, 1H), 7.13 (t, 3JHH
7.6 Hz, 1H), 7.20 (d, JHH= 7.3 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3) δ 12.5 (CH3), 15.9 (CH3), 20.8 (CH2), 46.7 (CH), 58.4
(CH), 109.5 (CH), 118.4 (CH), 124.4 (CH), 127.3 (CH), 132.7 (C),
150.6 (C); HRMS (ESI+, m/z) calcd for (C11H16N)+ (M + H)+
162.1277, found 162.1269. [α]D20= −2.4 (c 1.35, CHCl3) [for (2S,3S)-
2f in 54% ee] and [α]D20= +6.8 (c 1, CHCl3) [for (2R,3R)-2f in >99%
ee obtained from (2R,3R)-4f]22 [lit. [α]D20= +4.3 (c 1.34, CHCl3) for
(2R,3R)-2f in 93% ee].4 cis-2g (70 mg, 46% yield): Rf (20% EtOAc/n-
hexane) 0.44; IR (NaCl) ν 3365, 3050, 3030, 2962, 2932, 2874, 1609,
3
1483, 1462, 1380, 1242, 1097, 1020, 741 cm−1; H NMR (300.13
MHz, CDCl3) δ 1.08 (t, JHH= 7.4 Hz, 3H), 1.22 (d, JHH= 7.2 Hz,
1
3
3
3
3
3H), 1.53−1.79 (m, 2H), 3.33 (q, JHH= 7.3 Hz, 1H), 3.74 (td, JHH
=
8.1, 5.9 Hz, 1H), 3.96 (br s, 1H), 6.70 (d, 3JHH= 7.7 Hz, 1H), 6.82 (dt,
1
3
922, 742 cm−1; H NMR (300.13 MHz, CDCl3) δ 1.17 (d, JHH= 6.5
3JHH= 7.4 Hz; JHH= 0.9 Hz, 1H), 7.08−7.14 (m, 1H), 7.17 (d, JHH
=
4
3
Hz, 3H), 1.22 (d, 3JHH= 7.2 Hz, 3H), 3.30 (q, 3JHH= 7.3 Hz, 1H), 3.47
7.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 11.5 (CH3), 14.3
3
(br s, 1H), 3.91−4.03 (m, 1H), 6.65 (d, JHH= 7.7 Hz, 1H), 6.77 (dt,
(CH3), 23.2 (CH2), 38.9 (CH), 64.9 (CH), 109.3 (CH), 118.7 (CH),
3JHH= 7.7 Hz; 4JHH= 0.9 Hz, 1H), 6.97−7.18 (m, 2H); 13C NMR (75.5
MHz, CDCl3) δ 13.7 (CH3), 16.4 (CH3), 39.5 (CH), 58.4 (CH),
109.4 (CH), 118.8 (CH), 123.9 (CH), 127.3 (CH), 134.4 (C), 150.2
(C); HRMS (ESI+, m/z) calcd for (C10H14N)+ (M + H)+ 148.1121,
found 148.1118. [α]D20= −29.0 (c 0.83, CHCl3) [for (2S,3S)-2a in
99% ee] [lit. [α]D20= +26.6 (c 0.83, CHCl3) for (2R,3R)-2a in 92%
ee].3b cis-2b (99 mg, 65% yield): Rf (10% Et2O/n-hexane) 0.16; IR
(NaCl) ν 3362, 3010, 2965, 2918, 2866, 1618, 1494, 1448, 1378, 1249,
1115, 1095, 925, 807 cm−1; 1H NMR (300.13 MHz, CDCl3) δ 1.15 (d,
123.8 (CH), 127.3 (CH), 135.3 (C), 150.1 (C); HRMS (ESI+, m/z)
20
calcd for (C11H16N)+ (M + H)+ 162.1277, found 162.1282. [α]D
=
+0.55 (c 0.91, CHCl3) [for (2S,3S)-2g in 34% ee] and [α]D20= −4.0 (c
0.25, CHCl3) [for (2R,3R)-2g in >99% ee obtained from (2R,3R)-
4g]22 [lit. [α]D20= +2.5 (c 0.90, CHCl3) for (2S,3S)-2g in 90% ee].4 cis-
2h (102 mg, 63% yield): Rf (20% Et2O/n-hexane) 0.29; IR (NaCl) ν
3362, 3048, 3030, 2928, 2854, 1763, 1610, 1477, 1460, 1249, 1151,
1017, 974, 749 cm−1; H NMR (300.13 MHz, CDCl3) δ 1.31−1.46
1
3
(m, 3H), 1.69−1.52 (m, 3H), 1.73−1.82 (m, 2H), 3.11 (q, JHH= 6.6
3JHH= 6.6 Hz, 3H), 1.18 (d, JHH= 7.2 Hz, 3H), 2.28 (s, 3H), 3.00−
3
3
Hz, 1H), 3.65 (br s, 1H), 3.70−3.79 (m, 1H), 6.69 (d, JHH= 7.7 Hz,
3
3
3.47 (m, 1H), 3.87−4.03 (m, 1H), 6.55 (d, 3JHH= 7.8 Hz, 1H), 6.84 (d,
3JHH= 7.8 Hz, 1H), 6.91 (s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 13.8
(CH3), 16.4 (CH3), 21.0 (CH3), 39.7 (CH), 58.7 (CH), 109.5 (CH),
124.7 (CH), 127.7 (CH), 128.2 (C), 134.8 (C), 147.9 (C); HRMS
(ESI+, m/z) calcd for (C11H16N)+ (M + H)+ 162.1277, found
162.1268. [α]D20= −28.4 (c 1, CH2Cl2) [for (2S,3S)-2b in >99% ee].
cis-2c (108 mg, 65% yield): Rf (20% EtOAc/n-hexane) 0.16; IR
(NaCl) ν 3358, 2964, 2933, 2831, 1598, 1491, 1434, 1379, 1286, 1232,
1H), 6.75 (t, JHH= 7.3 Hz, 1H), 7.04 (t, JHH= 7.7 Hz, 1H), 7.10 (d,
3JHH= 7.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3) δ 21.8 (CH2), 22.7
(CH2), 27.1 (CH2), 29.3 (CH2), 41.1 (CH), 59.8 (CH), 110.3 (CH),
118.9 (CH), 123.3 (CH), 127.1 (CH), 133.7 (C), 150.9 (C); HRMS
(ESI+, m/z) calcd for (C12H16N)+ (M + H)+ 174.1277, found
174.1290. [α]D20= −32.4 (c 0.33, CHCl3) [for (2S,3S)-2h in 97% ee].
[lit. [α]D20= +23.4 (c 1.2, CHCl3) for (2R,3R)-2h in 91% ee].3b
Synthesis of cis-3-Methyl-2-phenylindoline (cis-2i). 3-Methyl-
2-phenyl-1H-indole (1i, 750 mg, 3.62 mmol), Pd−C (133 mg), AcOH
(13.4 mL) and HClO4 (4 mL) were put together in the reaction vessel
of a Parr hydrogenator. Then, the air was evacuated, and H2 (8 atm of
pressure) was introduced into the system. The suspension was stirred
for 24 h at room temperature, and after this time, the reaction was
stopped, filtering the mixture through diatomaceous earth. The crude
was basified with a saturated solution of NaHCO3 (150 mL), extracted
with CH2Cl2 (3 × 30 mL), and dried, and the solvent was removed
under reduced pressure, affording a reaction crude that was purified by
flash chromatography (5−10% Et2O/n-hexane) affording cis-1i as a
colorless oil (265 mg, 35%). Rf (20% Et2O/n-hexane) 0.48; IR (NaCl)
ν 3370, 3030, 2966, 2925, 2869, 1609, 1484, 1454, 1398, 1358, 1324,
1203, 1150, 1041, 908, 866, 806, 717 cm−1; H NMR (400.13 MHz,
CD3CN) δ 1.05 (d, JHH= 6.5 Hz, 3H), 1.08 (d, JHH= 7.2 Hz, 3H),
2.28 (br s, 1H), 3.12 (q, JHH= 7.3 Hz, 1H), 3.67 (s, 3H), 3.77−3.84
(m, 1H), 6.44 (d, JHH= 8.3 Hz, 1H), 6.52 (dd, JHH= 8.3 Hz; JHH
1
3
3
3
3
3
4
=
2.4 Hz, 2H), 6.68 (d, JHH= 2.4 Hz, 1H); 13C NMR (100.6 MHz,
CD3CN) δ 13.9 (CH3), 16.2 (CH3), 40.8 (CH), 56.3 (CH), 59.5
(CH3), 110.1 (CH), 111.7 (CH), 112.7 (CH), 137.0 (C), 145.7 (C),
154.1 (C); HRMS (ESI+, m/z) calcd for (C11H16NO)+ (M + H)+
178.1226, found 178.1217. [α]20D −29.0 (c 0.5, CH2Cl2) [for (2S,3S)-
2c in >99% ee]. cis-2d (64 mg, 41% yield): Rf (40% CH2Cl2/n-hexane)
0.21; IR (NaCl) ν 3372, 2969, 2924, 2873, 1606, 1484, 1436, 1201,
3
1
3
798; H NMR (300.13 MHz, CDCl3) δ 1.14 (d, JHH= 6.5 Hz, 3H),
1.17 (d, 3JHH= 7.2 Hz, 3H), 3.19−3.32 (m, 1H), 3.33 (br s, 1H), 3.86−
4.07 (m, 1H), 6.48−6.54 (m, 1H), 6.65−6.76 (m, 1H), 6.76−6.84 (m,
1H); 13C NMR (75.5 MHz, CDCl3) δ 13.6 (CH3), 16.3 (CH3), 39.9
1089, 1027, 806, 740, 702 cm−1; H NMR (300.13 MHz, CDCl3) δ
1
0.86 (d, 3JHH= 7.2 Hz, 3H), 3.53−3.68 (m, 1H), 4.09 (br s, 1H), 5.03
(d, 3JHH= 8.7 Hz, 1H), 6.57−6.87 (m, 2H), 6.98−7.17 (m, 2H), 7.21−
7.42 (m, 5H).13C NMR (75.5 MHz, CDCl3) δ 15.9 (CH3), 41.3
3
2
(CH), 59.1 (CH), 109.6 (d, JCF= 8.2 Hz, CH), 111.3 (d, JCF= 23.6
8053
dx.doi.org/10.1021/jo301307q | J. Org. Chem. 2012, 77, 8049−8055

The Journal of Organic Chemistry
Article
(CH), 67.4 (CH), 108.9 (CH), 119.0 (CH), 124.2 (CH), 127.3
(2CH), 127.4 (CH), 127.6 (CH), 128.3 (2CH), 133.9 (C), 140.9 (C),
150.6 (C); HRMS (ESI+, m/z) calcd for (C15H16N)+ (M + H)+
210.1277, found 210.1265. [α]D20= +176.4 (c 0.5, CH2Cl2) [for
(2R,3S)-2i in 96% ee].
(100.6 MHz, (CD3)2SO, 75 °C) δ 12.1 (CH3), 14.2 (CH3), 38.0
2
(CH), 60.4 (CH), 66.0 (CH2), 111.5 (d, JCF= 24.2 Hz, CH), 113.8
2
3
(d, JCF= 23.1 Hz, CH), 115.9 (d, JCF= 8.3 Hz CH), 118.2 (CH2),
3
133.6 (CH), 137.4 (C), 138.5 (d, JCF= 7.9 Hz, C), 152.4 (C), 159.2
2
(d, JCF
=
238.7 Hz, C); HRMS (ESI+, m/z) calcd for
20
(C14H16FNNaO2)+ (M + Na)+ 272.1057, found 272.1051. [α]D
=
General Procedure for the Synthesis of Racemic Carba-
mates trans-4a and cis-4a−i. To a solution of racemic trans-2a or
cis-2a-i (0.25 mmol) in dry CH2Cl2 (0.9 mL) were successively added
pyridine (19 μL, 0.27 mmol) and allyl chloroformate (29 μL, 0.27
mmol). The reaction was stirred at room temperature for 3 h, and after
this time, the solvent was removed by distillation under reduced
pressure. The crude was purified by flash chromatography (EtOAc/n-
hexane mixtures) affording the corresponding carbamates trans-4a and
cis-4a-h as colorless oils and cis-4i as a white solid (72−95%). trans-4a
(55 mg, 95% yield): Rf (5% EtOAc/n-hexane) 0.16; IR (NaCl) ν 3047,
2979, 2877, 1705, 1607, 1483, 1280, 1149, 1068, 1021 cm−1; 1H NMR
−38.8 (c 1, CH2Cl2) [for (2R,3R)-4d in 99% ee]. cis-4e (48 mg, 78%
yield): Rf (10% EtOAc/n-hexane) 0.33; IR (NaCl) ν 3047, 3017, 2970,
2934, 2874, 1713, 1597, 1464, 1390, 1338, 1296, 1261, 1064, 1028,
996, 931, 763 cm−1; 1H NMR (300.13 MHz, CDCl3) δ 1.09 (d, 3JHH
=
6.5 Hz, 3H), 1.24 (d, 3JHH= 7.1 Hz, 3H), 2.29 (s, 3H), 3.55−3.65 (m,
1H), 4.70−4.82 (m, 3H), 5.24−5.44 (m, 2H), 5.95−6.08 (m, 1H),
6.95−7.02 (m, 2H), 7.03−7.10 (m, 2H); 13C NMR (75.5 MHz,
CDCl3) δ 12.1 (CH3), 14.6 (CH3), 20.1 (CH3), 39.1 (CH), 63.0
(CH), 66.3 (CH2), 117.9 (CH2), 120.5 (CH), 124.8 (CH), 128.1 (C),
130.0 (CH), 132.9 (CH), 138.2 (C), 139.9 (C), 153.8 (C); HRMS
(ESI+, m/z) calcd for (C15H20NO2)+ (M + H)+ 246.1489, found
246.1485. cis-4f (54 mg, 88% yield): Rf (10% Et2O/n-hexane) 0.15; IR
(NaCl) ν 3081, 3048, 2963, 2936, 2877, 1707, 1649, 1603, 1484, 1462,
1401, 1325, 1279, 1149, 1074, 1454, 933, 752 cm−1; 1H NMR (400.13
MHz, (CD3)2SO, 75 °C) δ 1.04−1.17 (m, 6H), 1.51−1.67 (m, 1H),
1.92−2.13 (m, 1H), 3.30−3.41 (m, 1H), 4.55−4.68 (m, 1H), 4.70−
3
(400.13 MHz, (CD3)2SO, 50 °C) δ 1.14 (d, JHH= 7.0 Hz, 3H), 1.20
3
(d, JHH= 6.3 Hz, 3H), 2.81−2.92 (m, 1H), 4.86−4.52 (m, 2H), 5.25
3
3
2
(d, JHH= 10.5 Hz, 1H), 5.33 (dd, JHH= 17.2 Hz, JHH= 1.0 Hz, 1H),
5.92−6.07 (m, 1H), 6.99 (t, 3JHH= 7.4 Hz, 1H), 7.18 (t, 3JHH= 7.7 Hz,
1H), 7.23 (d, JHH= 7.3 Hz, 3H), 7.60 (br s, 1H); 13C NMR (100.6
3
MHz, (CD3)2SO, 50 °C) δ 21.5 (CH3), 22.8 (CH3), 43.7 (CH), 64.5
(CH), 66.9 (CH2), 116.0 (CH), 119.1 (CH2), 124.4 (CH), 126.0
(CH), 128.9 (CH), 134.2 (CH), 137.2 (C), 141.3 (C), 153.9 (C);
HRMS (ESI+, m/z) calcd for (C14H17NNaO2)+ (M + Na)+ 254.1151,
found 254.1149. cis-4a (45 mg, 78% yield): Rf (10% EtOAc/n-hexane)
0.40; IR (NaCl) ν 3047, 2979, 2940, 2875, 1707, 1603, 1483, 1402,
1277, 1149, 1068, 1024, 932, 752 cm−1; 1H NMR (400.13 MHz,
3
3
4.81 (m, 2H), 5.30 (d, JHH= 10.4 Hz, 1H), 5.42 (d, JHH= 17.2 Hz,
3
1H), 5.99−6.15 (m, 1H), 7.02 (t, JHH= 7.4 Hz, 1H), 7.30−7.14 (m,
2H), 7.65 (d, JHH= 7.8 Hz, 1H); 13C NMR (100.6 MHz, (CD3)2SO,
3
75 °C) δ 13.1 (CH3), 13.6 (CH3), 20.0 (CH2), 45.5 (CH), 59.3 (CH),
65.9 (CH2), 115.2 (CH), 118.1 (CH2), 123.2 (CH), 124.0 (CH),
127.8 (CH), 133.7 (CH), 134.8 (C), 141.3 (C), 152.4 (C); HRMS
(ESI+, m/z) calcd for (C15H19NNaO2)+ (M + Na)+ 268.1308, found
268.1301. [α]D20= −37.0 (c 0.1, CH2Cl2) [for (2R,3R)-4f in >99% ee].
cis-4g (48 mg, 79% yield): Rf (20% EtOAc/n-hexane) 0.48; IR (NaCl)
ν 3082, 3049, 2963, 2877, 1707, 1649, 1603, 1484, 1401, 1279, 1149,
3
3
(CD3)2SO, 100 °C) δ 1.13 (d, JHH= 6.5 Hz, 3H), 1.32 (d, JHH= 7.1
3
Hz, 3H), 3.59 (q, JHH= 7.4 Hz, 1H), 4.57−4.64 (m, 1H), 4.76 (d,
3JHH= 5.4 Hz, 2H), 5.30 (d, JHH= 10.5 Hz, 1H), 5.42 (d, JHH= 17.3
3
3
3
3
Hz, 1H), 6.08 (ddt, JHH= 16.2, 10.5, 5.4 Hz, 1H), 7.03 (t, JHH= 7.4
Hz, 1H), 7.18−7.22 (m, 2H), 7.64 (d, JHH= 7.9 Hz, 1H); 13C NMR
3
1
1074, 1054, 933, 752, 709 cm−1; H NMR (300.13 MHz, CDCl3) δ
(100.6 MHz, (CD3)2SO, 100 °C) δ 12.2 (CH3), 14.0 (CH3), 37.7
(CH), 59.9 (CH), 65.7 (CH2), 115.0 (CH), 117.9 (CH2), 123.1
(CH), 123.7 (CH), 127.6 (CH), 133.5 (CH), 135.8 (C), 141.0 (C),
152.4 (C); HRMS (ESI+, m/z) calcd for (C14H17NNaO2)+ (M + Na)+
254.1151, found 254.1146. [α]D20= −42.6 (c 1, CH2Cl2) [for (2R,3R)-
4a in 98% ee]. cis-4b (47 mg, 77% yield): Rf (20% Et2O/n-hexane)
0.48; IR (NaCl) ν 2977, 2940, 2872, 1707, 1490, 1397, 1275, 1141,
1071, 818, 760 cm−1; 1H NMR (400.13 MHz, CD3CN, 70 °C) δ 1.13
(d, 3JHH= 6.5 Hz, 3H), 1.32 (d, 3JHH= 7.1 Hz, 3H), 2.33 (s, 3H), 3.47−
3.60 (m, 1H), 4.53−4.65 (m, 1H), 4.74 (d, 3JHH= 4.8 Hz, 2H), 5.28 (d,
3JHH= 10.5 Hz, 1H), 5.41 (d, 3JHH= 17.3 Hz, 1H), 6.01−6.14 (m, 1H),
0.87 (t, 3JHH= 7.5 Hz, 3H), 1.38 (d, 3JHH= 7.2 Hz, 3H), 1.44−1.59 (m,
1H), 1.70−1.84 (m, 1H), 3.56−3.66 (m, 1H), 4.51−4.58 (m, 1H),
3
3
4
4.77 (d, JHH= 5.6 Hz, 2H), 5.28 (dd, JHH= 10.4 Hz; JHH= 1.2 Hz,
1H), 5.40 (dd, 3JHH= 17.2 Hz; 4JHH= 1.4 Hz, 1H), 5.98−6.11 (m, 1H),
7.00−7.29 (m, 3H), 7.69 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ
10.5 (CH3), 11.8 (CH3), 22.4 (CH2), 38.3 (CH), 64.9 (CH), 66.1
(CH2), 115.7 (CH), 117.9 (CH2), 122.6 (CH), 123.1 (CH), 127.4
(CH), 132.8 (CH), 136.5 (C), 141.7 (C), 153.3 (C); HRMS (ESI+,
m/z) calcd for (C15H19NNaO2)+ (M + Na)+ 268.1308, found
268.1318. [α]D20= −38.4 (c 0.5, CH2Cl2) [for (2R,3R)-4g in >99%
ee]. cis-4h (60 mg, 94% yield): Rf (10% EtOAc/n-hexane) 0.35; IR
(NaCl) ν 3356, 3049, 2932, 2859, 1707, 1604, 1480, 1402, 1323, 1276,
3
6.96−7.04 (m, 2H), 7.55 (d, JHH= 7.8 Hz, 1H); 13C NMR (100.6
MHz, CD3CN, 70 °C) δ 12.7 (CH3), 14.6 (CH3), 21.4 (CH3), 39.1
(CH), 61.5 (CH), 66.9 (CH2), 116.1 (CH), 118.2 (CH2), 125.5
(CH), 129.0 (CH), 133.8 (C), 134.8 (CH), 137.3 (C), 140.2 (C),
153.9 (C); HRMS (ESI+, m/z) calcd for (C15H19NNaO2)+ (M + Na)+
268.1308, found 268.1314. [α]D20= −39.2 (c 1, CH2Cl2) [for (2R,3R)-
4b in 97% ee]. cis-4c (48 mg, 73% yield): Rf (10% EtOAc/n-hexane)
0.26; IR (NaCl) ν 3052, 2985, 1692, 1490, 1401, 1260, 1068, 735
1
1254, 1141, 1089, 933, 754 cm−1; H NMR (300.13 MHz, CDCl3) δ
1.09−1.41 (m, 3H), 1.52−1.70 (m, 2H), 1.74−1.97 (m, 1H), 2.28 (ad,
3JHH= 14.2 Hz, 1H), 3.42−3.58 (m, 1H), 4.36−4.63 (m, 1H), 4.76 (d,
3
3
3JHH= 5.2 Hz, 2H), 5.28 (d, JHH= 10.4 Hz, 1H), 5.39 (d, JHH= 17.2
3
Hz, 1H), 5.95−6.13 (m, 1H), 7.03 (t, JHH= 7.4 Hz, 1H), 7.10−7.40
(m, 2H), 7.76 (br s, 1H); 13C NMR (75.5 MHz, CDCl3) δ 21.0
(CH2), 22.4 (CH2), 24.1 (CH2), 27.3 (CH2), 39.5 (CH), 60.6 (CH),
66.0 (CH2), 115.7 (CH), 117.9 (CH2), 122.8 (CH), 122.9 (CH),
127.5 (CH), 132.9 (CH), 133.8 (C), 141.9 (C), 152.8 (C); HRMS
(ESI+, m/z) calcd for (C16H19NNaO2)+ (M + Na)+ 280.1308, found
280.1299. [α]D20= −43.2 (c 1, CH2Cl2) [for (2R,3R)-4h in 98% ee].
cis-4i (60 mg, 82% yield): Rf (20% EtOAc/n-hexane) 0.51; mp 50−52
°C; IR (KBr) ν 3033, 2969, 2934, 2876, 1707, 1652, 1602, 1484, 1456,
1
3
cm−1; H NMR (400.13 MHz, CD3CN, 70 °C) δ 1.08 (d, JHH= 6.5
Hz, 3H), 1.26 (d, 3JHH= 7.1 Hz, 3H), 3.43−3.56 (m, 1H), 3.74 (s, 3H),
3
3
4.48−4.57 (m, 1H), 4.68 (d, JHH= 5.2 Hz, 2H), 5.22 (d, JHH= 10.4
3
Hz, 1H), 5.34 (d, JHH= 17.2 Hz, 1H), 5.94−6.08 (m, 1H), 6.70 (d,
3JHH= 8.4 Hz, 1H), 6.74 (s, 1H), 7.51 (d, JHH= 8.4 Hz, 1H); 13C
3
NMR (100.6 MHz, CD3CN, 70 °C) δ 12.6 (CH3), 14.6 (CH3), 39.3
(CH), 56.8 (CH), 61.5 (CH3), 66.8 (CH2), 111.6 (CH), 113.4 (CH),
116.9 (CH), 118.2 (CH2), 134.8 (CH), 136.1 (C), 138.8 (C), 153.8
(C), 157.8 (C); HRMS (ESI+, m/z) calcd for (C15H19NNaO3)+ (M +
Na)+ 284.1257, found 284.1251. [α]D20= −19.1 (c 1, CH2Cl2) [for
(2R,3R)-4c in 97% ee]. cis-4d (45 mg, 72% yield): Rf (10% EtOAc/n-
hexane) 0.4; IR (NaCl) ν 3374, 3036, 2968, 2929, 2871, 1611, 1487,
1321, 1268, 1143, 1076, 1041, 933, 822, 739, 701 cm−1; H NMR
1
(400.13 MHz, (CD3)2SO, 75 °C) δ 0.90 (d, 3JHH= 7.1 Hz, 3H), 3.86−
3.99 (m, 1H), 4.43−4.66 (m, 2H), 4.98−5.22 (m, 2H), 5.58 (d, 3JHH
=
=
3
9.8 Hz, 1H), 5.70−5.90 (m, 1H), 7.02−7.12 (m, 3H), 7.21 (d, JHH
7.3 Hz, 1H), 7.25−7.34 (m, 4H), 7.82 (d, JHH= 7.9 Hz, 1H); 13C
NMR (100.6 MHz, (CD3)2SO, 75 °C) δ 14.4 (CH3), 39.1 (CH), 65.7
(CH2), 67.6 (CH), 114.2 (CH), 117.3 (CH2), 123.6 (CH), 124.2
(CH), 126.9 (CH), 127.8 (CH), 128.1 (CH), 128.6 (CH), 133.3
(CH), 135.5 (C), 139.6 (C), 143.0 (C), 152.6 (C); HRMS (ESI+, m/
z) calcd for (C19H19NNaO2)+ (M + Na)+ 316.1308, found 316.1323.
[α]D20= −115.0 (c 1, CH2Cl2) [for (2S,3R)-4i in >99% ee].
3
1
1440, 1381, 1276, 1245, 1224, 1186, 1131, 918, 865, 808 cm−1; H
NMR (400.13 MHz, (CD3)2SO, 75 °C) δ 1.12 (d, 3JHH= 6.5 Hz, 3H),
3
1.30 (d, JHH= 7.1 Hz, 3H), 3.50−3.68 (m, 1H), 4.57−4.67 (m, 1H),
3
3
4.74 (d, JHH= 4.1 Hz, 2H), 5.30 (d, JHH= 10.4 Hz, 1H), 5.41 (d,
3JHH= 17.3 Hz, 1H), 6.06 (ddt, JHH= 16.0, 10.5, 5.4 Hz, 1H), 6.95−
3
7.03 (m, 1H), 7.04−7.10 (m, 1H), 7.54−7.66 (m, 1H); 13C NMR
8054
dx.doi.org/10.1021/jo301307q | J. Org. Chem. 2012, 77, 8049−8055

The Journal of Organic Chemistry
Article
General Procedure for the Enzymatic Kinetic Resolution of
Racemic Indolines cis-2a−i. A suspension containing the
corresponding indoline 2a−i (0.48 mmol), allyl 3-methoxyphenyl
carbonate (3b, 252 mg, 1.21 mmol) and CAL-A (ratio 1:2 in weight
amine/enzyme) in dry TBME (3.2 mL) was shaken at 30 °C and 250
rpm for the necessary time to achieve a good kinetic resolution (see
Tables 2 and 4 in the article). The reaction was followed by HPLC
analysis, and after this time, the enzyme was filtered off and the solvent
was evaporated under reduced pressure, obtaining a reaction crude
that was purified by flash chromatography.
(10) Busto, E.; Gotor-Fernan
3998−4035.
(11) Gotor-Fernan
Tetrahedron: Asymmetry 2006, 17, 2558−2564.
(12) (a) Gribble, A. W.; Hoffman, J. H. Synthesis 1977, 859−860.
(b) Yamada, F.; Kawanishi, A.; Tomita, A.; Somei, M. ARKIVOC
2003, viii, 102−111.
(13) Kulkarni, A.; Zhou, W.; Torok, B. Org. Lett. 2011, 13, 5124−
5127.
́
dez, V.; Gotor, V. Chem. Rev. 2011, 111,
́
́
dez, V.; Fernandez-Torres, P.; Gotor, V.
̈
̈
(14) Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chem. 1992, 57, 4404−
4414.
ASSOCIATED CONTENT
(15) Alatorre-Santamaría, S.; Rodríguez-Mata, M.; Gotor-Fernan
V.; de Mattos, M. C.; Sayago, F.; Jimenez, A. I.; Cativiela, C.; Gotor, V.
Tetrahedron: Asymmetry 2008, 19, 1714−1719.
́
dez,
■
́
S
* Supporting Information
General methods, experimental procedures, characterization
(16) Domínguez de María, P.; Carboni-Oerlemans, C.; Tuin, B.;
Bargeman, G.; van de Meer, A.; Van Gemert, R. J. Mol. Catal. B:
Enzym. 2005, 37, 36−46.
data for new compounds and copies of H, 13C and DEPT
1
NMR experiments. This material is available free of charge via
the Internet at http://pubs.acs.org.
(17) Chen, C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem.
Soc. 1982, 102, 7294−7299.
AUTHOR INFORMATION
Corresponding Author
*E-mail: vicgotfer@uniovi.es. Phone: +34 98 5103454. Fax:
+34 98 5103448.
(18) Takemoto, M.; Iwakiri, Y.; Tanaka, K. Heterocycles 2007, 72,
373.
■
(19) Tursky, M.; Lorentz-Petersen, L .L.; Olsen, L. B.; Madesen, R.
Org. Biomol. Chem. 2010, 8, 5576−5583.
(20) Jin, Z.; Guo, S.-X.; Qiu, L.-L.; Wu, G.-P.; Fang, J. X. Appl.
Organomet. Chem. 2011, 25, 502−507.
Notes
The authors declare no competing financial interest.
(21) Banwell, G. M.; Kelly, D. B.; Okanya, J.; Lupton, D. W. Org.
Lett. 2003, 5, 2497−2500.
(22) General procedure for the deprotection of enantiopure
carbamates (R,R)-4f,g. To a solution of Pd(OAc)2 (2.3 mg, 0.01
mmol), PPh3 (8 mg, 0.03 mmol) and 1,3-dimethylbarbituric acid (43
mg, 0.27 mmol) in dry CH2Cl2 (1.3 mL) was added the corresponding
enantiopure carbamate (R,R)-4f,g (25 mg, 0.10 mmol) under a
nitrogen atmosphere. The mixture was stirred for 4 h at 35 °C; after
this time the reaction was diluted with CH2Cl2 (10 mL), and the
organic layer was washed with H2O (10 mL). The organic layer was
dried with Na2SO4 and filtered, and the solvent was removed by
distillation under reduced pressure affording a reaction crude that was
purified by flash chromatography (10% Et2O/n-hexane), yielding
(R,R)-2f (15 mg, 92%) and (R,R)-2g (5 mg, 31%), respectively.
ACKNOWLEDGMENTS
We thank Novo Nordisk Co. for the generous gift of the CAL-
B (Novozyme 435). Financial support of this work by the
Spanish Ministerio de Ciencia e Innovacion (MICINN)
́
through the CTQ-2007-61126 and CTQ-2011-24237 projects
is gratefully acknowledged. V.G.-F. thanks MICINN for a
■
́
postdoctoral grant (Ramon y Cajal Program). M.L.-I. thanks
FICYT for a predoctoral fellowship.
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