Asymmetric synthesis of trans-2,3-disubstituted indoline derivatives

Article abstract of DOI:10.1021/jo2023526

A novel method for asymmetric synthesis of trans-2,3-disubstituted indolines has been developed. The strategy involves the (-)-sparteine-mediated electrophilic substitution of 2-benzyl N-pivaloylaniline with aromatic or α,β-unsaturated aldehydes and subse

Full text of DOI:10.1021/jo2023526

Note
pubs.acs.org/joc
Asymmetric Synthesis of trans-2,3-Disubstituted Indoline Derivatives
Kyoung Hee Kang, Junghwan Do, and Yong Sun Park*
Department of Chemistry, Konkuk University, Seoul 143-701, Korea
S
* Supporting Information
ABSTRACT: A novel method for asymmetric synthesis of trans-2,3-
disubstituted indolines has been developed. The strategy involves the
(−)-sparteine-mediated electrophilic substitution of 2-benzyl N-pivaloylaniline
with aromatic or α,β-unsaturated aldehydes and subsequent intramolecular
nucleophilic substitution. The simple protocol for two-step process can produce
highly enantioenriched indolines 3a−o up to 98:2 er.
Scheme 1. Asymmetric Electrophilic Substitution and
Cyclization
ndolines bearing substituents at both 2- and 3-positions are
frequently found as a substructure in a number of alkaloids
I
and natural products.1 Since individual stereoisomers display
different biological acitivities, it is desirable to develop a highly
stereoselective route to 2,3-disubstituted indolines. Although
some progress has recently been made toward the development
of asymmetric synthetic methods for 2,3-disubstituted indo-
lines, it still remains a great challenge in organic synthesis.2 In
the course of our studies on asymmetric substitution of 2-
substituted aniline derivatives, we envisaged a simple synthetic
method for indolines bearing two substituents at both 2- and 3-
positions. Our strategy involves an asymmetric electrophilic
substitution of 2-alkyl aniline with aldehydes (step A) and
subsequent intramolecular nucleophilic substitution (step B) as
illustrated retrosynthetically in Figure 1. Herein, we report a
Figure 1. Restrosynthesis of trans-2,3-disubstituted indolines.
novel asymmetric synthetic method for trans-2,3-disubstituted
indolines via (−)-sparteine-mediated electrophilic substitution
of 2-(α-lithiobenzyl)-N-pivaloylaniline with various aldehydes
and subsequent acid-catalyzed intramolecular substitution.
We have recently reported that (−)-sparteine-mediated
asymmetric lateral substitutions of 2-benzyl-N-pivaloylaniline
1a take place with almost complete control of the configuration
at benzylic position.3 For example, the substitution of 1a with
benzaldehyde can provide highly enantioenriched 2-(1′,2′-
diphenyl-2′-hydroxyethyl)-N-pivaloylaniline 2a by allowing the
diastereomeric organolithium intermediates to reach thermody-
namic equilibrium prior to electrophilic substitution (Scheme
1). When the lithiation was carried out in the presence of
(−)-sparteine at −25 °C and followed by the addition of
benzaldehyde at −78 °C, (1′R)-2a was obtained in 81% yield as
a 92:8 mixture of two inseparable diastereomers with
enantiomeric ratios (er) of 99:1 and 90:10.3a Since the
hydroxyl group can be converted to a leaving group, we
envisioned that the enantioenriched 2-aminophenethyl alcohol
2a could serve as a substrate for the synthesis of 2,3-
disubstituted indolines by intramolecular nucleophilic sub-
stitution.
For the intramolecular nucleophilic substitution of 2a, the
key is how to effect the cyclization in an efficient and
stereocontrolled manner. Several reports have shown that a
Mitsunobu type displacement of secondary alcohols by amide
nucleophile is a useful and practical method for stereospecific
intramolecular C−N bond formation.4 Thus, we examined
whether the N-pivaloyl amine of 2a could be used as the
Received: November 18, 2011
Published: December 9, 2011
© 2011 American Chemical Society
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nucleophilic component for the intramolecular cyclization in
Mitsunobu conditions without affecting the integrity of the
stereogenic centers of 2a. When a 92:8 diastereomeric mixture
of 2a was treated with PPh3 and DIAD in THF at rt, the
reaction provided the desired 2,3-disubstituted indoline 3a in
34% yield. Only trans-indoline was produced with 99:1 er, and
no cis-indoline was detected.5 The trans-3a might be produced
from the major diastereomer of 2a (99:1 er) via SN2
mechanism with inversion of configuration as depicted in
Scheme 1 (method a). We reasoned that the repulsion between
two phenyl substituents in the transition state structure of 2a-
minor prevents formation of the cis-product. However, the
standard Mitsunobu conditions afforded a large amount (45%)
of the elimination products. The mixture of isomeric alkenes
results from dehydration of secondary alcohol 2a by conversion
of a hydroxyl group to an oxyphosphonium ion intermediate
and elimination of triphenylphosphine oxide in succession.6
The undesired formation of elimination products led us to seek
a more efficient cyclization method of 2a for the preparation of
2,3-disubstituted indolines.
Table 1. Electrophilic Substitution of 1a with Various
Aldehydes and Cyclization
Recent reports on the preparation of indoline derivatives by
the acid-catalyzed intramolecular nucleophilic substitution of 2-
aminophenethyl alcohol derivatives led us to explore acid-
catalyzed substitution of 2a via carbocationic intermediate.7 In
our preliminary investigation of the acid-catalyzed reaction, we
found that treatment of 2a with a refluxing 6 M HCl solution
for 0.5 h produced 2,3-disubstituted indoline 3a with 98:2 er in
53% yield. Hydrolysis of the pivalamide moiety was not
observed in the reaction, and isomeric alkenes resulting from
dehydration were produced as side products (14% yield).
Analogous to the Mitsunobu reaction of 2a, only trans-indoline
was detected, and no cis-indoline was tracked in the reaction of
a 92:8 diastereomeric mixture of 2a.7c This result can be taken
to suggest a cationic transition state as shown in Scheme 1
(method b), which avoids repulsion between two phenyl
substituents. Following nucleophilic attack of amino group on
the carbocation can give trans-indoline 3a with 98:2 er from the
reaction of a 92:8 diastereomeric mixture of 2a-major (99:1 er)
and 2a-minor (90:10 er). After trying different acids (HBr, HI,
CF3CO2H) and various reaction conditions such as temper-
ature, concentration, solvent, and reaction time, we found that
the best conditions for the cyclization involved the use of 4.5 M
HCl solution in water and p-dioxane (3:1) for 1 h at 80 °C to
give trans-3a in 72% isolated yield with 98:2 er and the
elimination products with less than 10% yield.
a
b
Combined isolated yield of two diastereomers. The ratio was
c
determined by 1H NMR of the reaction mixture. Determined by CSP-
HPLC using racemic material as a standard. Er-values of major and
minor products.
d
Next, we initiated investigations into the reaction’s scope
with various aldehydes for the preparation of 2-substituted 3-
phenylindolines as shown in Table 1.8,9 Lithiation of 1a in the
presence of (−)-sparteine at −25 °C in MTBE and following
addition of 4-chlorobenzaldehyde at −78 °C provided 2-
aminophenethyl alcohol 2b in 82% yield as an 94:6 mixture of
two inseperable diastereomers with ers of 99:1 and 92:8.
Subjecting this material to our optimized cyclization condition
afforded trans-2-(p-chlorophenyl)-3-phenylindoline 3b of 98:2
er in 65% yield. As shown in entries 2 and 3 (Table 1), the
same procedure with 4-methoxybenzaldehyde and 1-naphthal-
dehyde provided 2,3-disubstituted indolines 3c and 3d with
excellent levels of asymmetric induction. However, intra-
molecular cyclization of 2-aminonophenethyl alcohol 2e from
the reaction with 4-trifluoromethylbenzaldehyde did not occur
under the same reaction condition, and 2e was quantitatively
recovered. (Table 1, entry 4) Also, the reactions of 2-
aminophenethyl alcohols from aliphatic aldehydes (R1 = CH3
or CH2CH2Ph) gave no cyclized products. These results imply
that the formation of stable carbocation intermediate is
required prior to cyclization. In addition, 2-styryl-substituted
3-phenylindolines 3f−i were successfully prepared by the
electrophilic substitution with corresponding cinnamaldehydes
and following cyclization (Table 1, entries 5−8).
We next investigated the feasibility of a procedure that avoids
purification of 2-aminophenethyl alcohol and uses the crude
material in the subsequent cyclization step as shown in Table 2.
After extractive workup of the reaction mixture of the first step,
subjecting the crude reaction mixture to the optimized
cyclization condition afforded 2,3-disubstituted indolines in
comparable yields and enantioselectivities over the two steps.
For the synthesis of 3-phenyl-2-styrylindoline 3f, the procedure
leads to the product with 97:3 er in 74% yield over the two
steps (Table 2, entry 1), which compares well with the result
using purified alcohol shown in Table 1, entry 5. With a
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catalyzed intramolecular substitution of secondary alcohol by
N-pivaloyl amine as the key reaction. The simple protocol can
provide highly functionalized indoline rings and would allow
further functionalization and growing to access more complex
target molecules.
Table 2. Asymmetric Synthesis of Indolines by Practical
Two-Step Process
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Indolines 3a−o.
To a solution of N-pivaloylaniline 1a−d (0.5 mmol) and (−)-sparteine
(258 mg, 2.2 equiv) in MTBE (3 mL) at −25 °C was added n-BuLi
(0.7 mL, 1.6 M in hexane, 2.2 equiv). After the mixture was stirred at
−25 °C for 1 h, an aldehyde (2.5 equiv) was added at −78 °C. The
mixture was stirred for 10 min at −78 °C and then quenched with
excess methanol. The resulting mixture was dissolved in EtOAc,
washed with saturated NH4Cl, dried with MgSO4, and concentrated in
vacuo. Chromatographic separation on silica gel (EtOAc/hexanes
solvents) afforded 2a−i as an inseparable mixture of two diastereomers
(87−64% yields shown in Table 1). To a solution of 2-amino-
phenethyl ethanol 2a−i (or crude product from 1b−d) in 1,4-dioxane
(2 mL) were added water (3 mL) and concentrated HCl (3 mL). The
solution was heated at 80 °C for 1 h. Upon cooling of the solution to
room temperature, the solvent was removed in vacuo. Chromato-
graphic separation on silica gel (EtOAc/hexanes solvents) afforded
indolines 3a−i in 78−62% yields shown in Table 1 and indolines 3j−o
in 74−65% overall yields shown in Table 2.
N-Pivaloyl-(R)-2-phenyl-(R)-3-phenylindoline (3a). A colorless
1
oil (103 mg, 58% overall yield): H NMR (CDCl3, 400 MHz) δ 8.36
(d, J = 8.0 Hz, 1H), 7.35−7.04 (m, 13H), 5.61 (s, 1H), 4.26 (s, 1H),
1.02 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.8 (quat.), 145.4
(quat.), 143.4 (quat.), 142.9 (quat.), 131.9 (quat.), 129.0 (CH), 128.3
(CH), 127.33 (CH), 127.31 (CH), 127.2 (CH), 125.8 (CH), 125.1
(CH), 124.8 (CH), 119.1 (CH), 72.2 (CH), 58.2 (CH), 40.6 (quat.),
28.5 (CH3); HRMS calcd for C25H26NO (M+ + 1) 356.2014, found
356.2015; CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol in
hexane; 0.5 mL/min) 95:5 er, 10.3 min (major enantiomer), 13.6 min
(minor enantiomer).
N-Pivaloyl-(R)-2-(p-chlorophenyl)-(R)-3-phenylindoline
1
(3b). A colorless oil (103 mg, 53% overall yield): H NMR (CDCl3,
400 MHz) δ 8.37 (d, J = 8.0 Hz, 1H), 7.68−7.01 (m, 12H), 5.60 (s,
1H), 4.30 (s, 1H), 1.02 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.3
(quat.), 145.1 (quat.), 142.5 (quat.), 141.9 (quat.), 133.2 (quat.),
131.6 (quat.), 129.1 (CH), 129.0 (CH), 128.5 (CH), 127.5 (CH),
127.1 (CH), 126.6 (CH), 125.8 (CH), 125.0 (CH), 119.2 (CH), 71.5
(CH), 58.1 (CH), 40.6 (quat.), 28.4 (CH3); HRMS calcd for
C25H25ClNO (M+ + 1) 390.1625, found 390.1624; CSP-HPLC
(Chiralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/min)
98:2 er, 9.3 min (major enantiomer), 12.9 min (minor enantiomer).
N-Pivaloyl-(R)-2-(p-methoxyphenyl)-(R)-3-phenylindoline
(3c). A pale yellow oil (114 mg, 58% overall yield): 1H NMR (CDCl3,
400 MHz) δ 8.36 (d, J = 8.2 Hz, 1H), 7.36−6.81 (m, 12H), 5.56 (s,
1H), 4.22 (s, 1H), 3.75 (s, 3H), 1.02 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 177.5 (quat.), 158.8 (quat.), 145.4 (quat.), 142.9 (quat.),
135.5 (quat.), 132.1 (quat.), 128.9 (CH), 128.3 (CH), 127.3 (CH),
127.2 (CH), 126.3 (CH), 125.8 (CH), 124.8 (CH), 119.1 (CH),
114.3 (CH), 71.6 (CH), 58.2 (CH), 55.2 (CH3), 40.6 (quat.), 28.4
(CH3); HRMS calcd for C26H28NO2 (M+ + 1) 386.2120, found
386.2121; CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol in
hexane; 0.5 mL/min) 95:5 er, 12.3 min (major enantiomer), 31.7 min
(minor enantiomer).
a
b
Overall yields after two steps. Determined by CSP-HPLC using
racemic material as a standard.
practical procedure in hand, we examined the scope of the
methodology with three different 2-benzyl-N-pivaloylanilines
1b−d. Under the same reaction conditions, this methodology is
also efficient for the asymmetric preparation of 5-chloro-
substituted indolines 3j and 3k with 96:4 and 95:5 er. (Table 2,
entries 2 and 3) The simple two-step reactions of 2-(p-
bromobenzyl)-N-pivaloylaniline 1c and 5-chloro-2-(o-fluoro-
benzyl)-N-pivaloylaniline 1d afforded 3-styryl-substituted indo-
lines 3l, 3n and 3-p-chlorophenyl substituted indolines 3m, 3o
with er-values ranging from 97:3 to 95:5 in 74−65% overall
yields. (Table 2, entries 4−7)
N-Pivaloyl-(R)-2-(1-naphtyl)-(R)-3-phenylindoline (3d). A
1
pale yellow oil (87 mg, 43% overall yield): H NMR (CDCl3, 400
MHz) δ 8.48 (d, J = 8.4 Hz, 1H), 8.03−6.91 (m, 15H), 6.31 (s, 1H),
4.21 (s, 1H), 1.06 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.5
(quat.), 145.4 (quat.), 142.9 (quat.), 138.3 (quat.), 134.3 (quat.),
133.6 (quat.), 129.6 (CH), 129.3 (quat.), 129.1 (CH), 128.3 (CH),
128.0 (CH), 127.5 (CH), 127.4 (CH), 126.7 (CH), 125.9 (CH),
125.6 (CH), 125.5 (CH), 124.8 (CH), 122.7 (CH), 119.2 (CH), 68.8
(CH), 56.8 (CH), 40.8 (quat.), 28.4 (CH3); HRMS calcd for
C29H28NO (M+ + 1) 406.2171, found 406.2170; CSP-HPLC
In summary, we have developed a novel method for the
asymmetric synthesis of trans-2,3-disubstituted indolines. The
highly enantioselective process includes the stereoselective acid-
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(Chiralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/min)
95:5 er, 12.8 min (major enantiomer), 14.7 min (minor enantiomer).
N-Pivaloyl-(R)-3-phenyl-(S)-2-styrylindoline (3f). A colorless
(CH), 127.8 (CH), 127.0 (CH), 126.5 (CH), 125.9 (CH), 120.1
(CH), 71.6 (CH), 57.9 (CH), 40.6 (quat.), 28.3 (CH3); HRMS calcd
for C25H24Cl2NO (M+ + 1) 424.1235, found 424.1236; CSP-HPLC
(Chiralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/min)
95:5 er, 10.7 min (major enantiomer), 12.3 min (minor enantiomer).
N-Pivaloyl-(R)-3-(p-bromophenyl)-(S)-2-styrylindoline (3l). A
1
oil (130 mg, 68% overall yield): H NMR (CDCl3, 400 MHz) δ 8.28
(d, J = 8.0 Hz, 1H), 7.28−7.01 (m, 14H), 6.47 (d, J = 16.0 Hz, 1H),
6.34 (dd, J = 5.2 and 16.0 Hz, 1H), 5.19 (d, J = 5.2 Hz, 1H), 4.21 (s,
1H), 1.14 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.2 (quat.),
144.6 (quat.), 142.3 (quat.), 136.2 (quat.), 132.6 (quat.), 130.3 (CH),
129.8 (CH), 128.8 (CH), 128.6 (CH), 128.2 (CH), 127.9 (CH),
127.3 (CH), 127.2 (CH), 126.5 (CH), 125.6 (CH), 124.6 (CH),
119.7 (CH), 70.1 (CH), 55.1 (CH), 40.6 (quat.), 28.6 (CH3); HRMS
calcd for C27H28NO (M+ + 1) 382.2171, found 382.2171; CSP-HPLC
(Chiralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/min)
97:3 er, 11.1 min (major enantiomer), 12.9 min (minor enantiomer).
N-Pivaloyl-(R)-3-phenyl-(S)-2-(β-phenylstyryl)indoline (3g).
1
pale yellow oil (170 mg, 74% overall yield): H NMR (CDCl3, 400
MHz) δ 8.28 (d, J = 8.0 Hz, 1H), 7.32−6.88 (m, 13H), 6.46 (d, J =
16.0 Hz, 1H), 6.31 (dd, J = 5.2 and 16.0 Hz, 1H), 5.15 (d, J = 5.2 Hz,
1H), 4.16 (s, 1H), 1.16 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.3
(quat.), 144.6 (quat.), 141.3 (quat.), 136.1 (quat.), 132.2 (quat.),
131.9 (CH), 130.6 (CH), 129.5 (CH), 129.0 (CH), 128.6 (CH),
128.5 (CH), 128.0 (CH), 126.5 (CH), 125.5 (CH), 124.8 (CH),
121.2 (quat.), 119.8 (CH), 69.8 (CH), 54.6 (CH), 40.6 (quat.), 28.5
(CH3); CSP-HPLC (Chiralcel OD column; 10% 2-propanol in
hexane; 0.5 mL/min) 97:3 er, 10.7 min (major enantiomer), 9.5 min
(minor enantiomer). Anal. Calcd for C27H26BrNO: C, 70.44; H, 5.69;
N, 3.04. Found: C, 70.34; H, 5.71; N, 3.13.
1
A pale yellow oil (110 mg, 48% overall yield): H NMR (CDCl3, 400
MHz) δ 8.28 (d, J = 8.0 Hz, 1H), 7.34−7.13 (m, 16H), 6.68 (m, 2H),
6.16 (d, J = 8.0 Hz, 1H), 5.11 (d, J = 8.0 Hz, 1H), 4.25 (s, 1H), 0.99
(s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.2 (quat.), 143.9 (quat.),
142.7 (quat.), 141.3 (quat.), 138.9 (quat.), 134.2 (quat.), 131.0 (CH),
129.7 (CH), 128.7 (CH), 128.5 (CH), 128.3 (CH), 128.1 (CH),
128.0 (CH), 127.8 (CH), 127.5 (CH), 127.2 (CH), 127.0 (CH),
125.2 (CH), 124.6 (CH), 120.6 (CH), 70.1 (CH), 55.1 (CH), 40.6
(quat.), 28.5 (CH3); HRMS calcd for C33H32NO (M+ + 1) 458.2484,
found 458.2484; CSP-HPLC (Chiralpak AD-H column; 1% 2-
propanol in hexane; 0.5 mL/min) 95:5 er, 48.9 min (major
enantiomer), 42.9 min (minor enantiomer).
N-Pivaloyl-(R)-3-(p-bromophenyl)-(S)-2-(p-chlorophenyl)-
1
indoline (3m). A pale yellow oil (162 mg, 69% overall yield): H
NMR (CDCl3, 400 MHz) δ 8.32 (d, J = 8.0 Hz, 1H), 7.44−6.93 (m,
11H), 5.53 (s, 1H), 4.15 (s, 1H), 1.03 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 177.4 (quat.), 145.0 (quat.), 141.6 (quat.), 141.5 (quat.),
133.4 (quat.), 132.1 (CH), 131.1 (quat.), 129.2 (CH), 128.9 (CH),
128.8 (CH), 126.5 (CH), 125.7 (CH), 125.1 (CH), 121.4 (quat.),
119.3 (CH), 71.2 (CH), 57.5 (CH), 40.6 (quat.), 28.4 (CH3); HRMS
calcd for C25H24BrClNO (M+ + 1) 470.0709, found 470.0707; CSP-
HPLC (Chiralcel OD column; 1% 2-propanol in hexane; 0.5 mL/min)
96:4 er, 22.9 min (major enantiomer), 20.7 min (minor enantiomer).
N-Pivaloyl-5-chloro-(R)-3-(o-fluorophenyl)-(S)-2-styrylindo-
N-Pivaloyl-(R)-2-(α-methylstyryl)-(R)-3-phenylindoline (3h).
1
A yellow oil (107 mg, 54% overall yield): H NMR (CDCl3, 400
MHz) δ 8.30 (d, J = 8.0 Hz, 1H), 7.30−7.04 (m, 13H), 6.31 (s, 1H),
4.93 (s, 1H), 4.25 (s, 1H), 2.05 (s, 3H), 1.16 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 177.4 (quat.), 145.4 (quat.), 143.3 (quat.), 137.1
(quat.), 136.5 (quat.), 132.6 (quat.), 128.9 (CH), 128.2 (CH), 128.1
(CH), 127.2 (CH), 127.1 (CH), 126.6 (CH), 125.6 (CH), 125.1
(CH), 124.5 (CH), 119.0 (CH), 74.5 (CH), 53.8 (CH), 40.8 (quat.),
28.3 (CH3), 15.8 (CH3); HRMS calcd for C28H30NO (M+ + 1)
396.2327, found 396.2326; CSP-HPLC (Chiralpak AD-H column; 1%
2-propanol in hexane; 0.5 mL/min) 95:5 er, 29.1 min (major
enantiomer), 32.1 min (minor enantiomer).
1
line (3n). A pale yellow oil (152 mg, 70% overall yield): H NMR
(CDCl3, 400 MHz) δ 8.22 (d, J = 8.8 Hz, 1H), 7.34−7.11 (m, 9H),
6.97 (t, J = 7.6 Hz, 1H), 6.53−6.46 (m, 2H), 6.34 (dd, J = 4.8 and 16.0
Hz, 1H), 5.21 (d, J = 4.4 Hz, 1H), 4.52 (s, 1H), 1.10 (s, 9H); 13C
NMR (CDCl3, 100 MHz) δ 177.2 (quat.), 160.0 (d, quat.), 143.7
(quat.), 135.9 (quat.), 132.7 (quat.), 130.9 (CH), 129.5 (quat.), 129.2
(d, CH), 128.8 (quat.), 128.74 (CH), 128.72 (d, CH), 128.6 (CH),
128.5 (CH), 128.1 (CH), 126.6 (CH), 125.9 (CH), 124.5 (d, CH),
120.7 (CH), 115.3 (d, CH), 69.4 (CH), 47.2 (CH), 40.4 (quat.), 28.3
(CH3); HRMS calcd for C27H26ClFNO (M+ + 1) 434.1687, found
434.1688; CSP-HPLC (Chiralcel AD-H column; 10% 2-propanol in
hexane; 0.5 mL/min) 95:5 er, 13.7 min (major enantiomer), 25.7 min
(minor enantiomer).
N-Pivaloyl-5-chloro-(R)-2-(p-chlorophenyl)-(R)-3-(o-
fluorophenyl)indoline (3o). A pale yellow oil (144 mg, 65% overall
yield): 1H NMR (CDCl3, 400 MHz) δ 8.27 (d, J = 8.8 Hz, 1H), 7.38−
7.16 (m, 7H), 7.06 (s, 1H), 7.00 (t, J = 7.6 Hz, 1H), 6.52 (t, J = 7.6
Hz, 1H), 5.60 (s, 1H), 4.53 (s, 1H), 0.96 (s, 9H); 13C NMR (CDCl3,
100 MHz) δ 177.3 (quat.), 160.1 (d, quat.), 144.1 (quat.), 140.7
(quat.), 133.5 (quat.), 131.7 (quat.), 129.9 (quat.), 129.4 (d, CH),
129.2 (CH), 128.9 (CH), 128.8 (d, CH), 127.7 (quat.), 126.8 (CH),
126.1 (CH), 124.6 (d, CH), 120.3 (CH), 115.5 (d, CH), 70.8 (CH),
50.0 (CH), 40.4 (quat.), 28.0 (CH3); HRMS calcd for C25H23Cl2FNO
(M+ + 1) 442.1141, found 442.1140; CSP-HPLC (Chiralcel AD-H
column; 10% 2-propanol in hexane; 0.5 mL/min) 96:4 er, 10.2 min
(major enantiomer), 28.3 min (minor enantiomer).
N-Pivaloyl-(R)-2-(α-bromostyryl)-(R)-3-phenylindoline (3i).
1
A pale yellow oil (147 mg, 64% overall yield): H NMR (CDCl3,
400 MHz) δ 8.30 (d, J = 8.0 Hz, 1H), 7.43−7.10 (m, 13H), 6.78 (s,
1H), 5.20 (s, 1H), 4.63 (s, 1H), 1.15 (s, 9H); 13C NMR (CDCl3, 100
MHz) δ 177.2 (quat.), 144.9 (quat.), 142.1 (quat.), 134.7 (quat.),
131.5 (quat.), 129.0 (CH), 128.8 (CH), 128.4 (CH), 128.3 (CH),
128.1 (CH), 127.4 (CH), 127.3 (CH), 127.2 (CH), 126.1 (quat.),
126.0 (CH), 125.0 (CH), 118.9 (CH), 75.8 (CH), 53.5 (CH), 40.8
(quat.), 28.1 (CH3); HRMS calcd for C27H27BrNO (M+ + 1)
460.1276, found 460.1277; CSP-HPLC (Chiralpak AD-H column; 1%
2-propanol in hexane; 0.5 mL/min) 97:3 er, 19.1 min (major
enantiomer), 21.3 min (minor enantiomer).
N-Pivaloyl-5-chloro-(R)-3-phenyl-(S)-2-styrylindoline (3j). A
1
pale yellow oil (143 mg, 69% overall yield): H NMR (CDCl3, 400
MHz) δ 8.23 (d, J = 8.8 Hz, 1H), 7.29−7.00 (m, 13H), 6.44 (d, J =
16.0 Hz, 1H), 6.33 (dd, J = 5.2 and 16.0 Hz, 1H), 5.19 (d, J = 5.2 Hz,
1H), 4.17 (s, 1H), 1.14 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 177.2
(quat.), 143.3 (quat.), 141.5 (quat.), 135.9 (quat.), 134.6 (quat.),
130.5 (CH), 129.4 (quat.), 129.3 (CH), 128.9 (CH), 128.6 (CH),
128.2 (CH), 128.0 (CH), 127.6 (CH), 127.1 (CH), 126.5 (CH),
125.7 (CH), 120.6 (CH), 70.2 (CH), 54.9 (CH), 40.6 (quat.), 28.4
(CH3); HRMS calcd for C27H27ClNO (M+ + 1) 416.1781, found
416.1779; CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol in
hexane; 0.5 mL/min) 96:4 er, 13.6 min (major enantiomer), 20.5 min
(minor enantiomer).
N-Pivaloyl-5-chloro-(R)-2-(p-chlorophenyl)-(R)-3-phenylin-
doline (3k). A pale yellow oil (150 mg, 71% overall yield): 1H NMR
(CDCl3, 400 MHz) δ 8.37 (d, J = 8.0 Hz, 1H), 7.34−7.01 (m, 11H),
5.58 (s, 1H), 4.16 (s, 1H), 1.01 (s, 9H); 13C NMR (CDCl3, 100 MHz)
δ 177.4 (quat.), 143.8 (quat.), 141.8 (quat.), 141.5 (quat.), 133.6
(quat.), 133.5 (quat.), 129.8 (quat.), 129.3 (CH), 129.1 (CH), 128.6
General Procedure for the Preparation of 1b−d. A solution
of the corresponding 2-aminobenzophenone (1.0 mmol) in ether (5
mL) was added dropwise to a suspension of lithium aluminum hydride
(152 mg, 4.0 equiv) in ether (5 mL), and the mixture was refluxed for
6 h. The solution was cooled, the excess of lithium aluminum hydride
was destroyed with water, and the solids were removed.10 The filtrate
was concentrated, and the residue was treated with pivaloyl chloride
(1.2 equiv) and Et3N (2.5 equiv) for 3 h in methylene chloride. The
resulting mixture was dissolved in EtOAc, washed with saturated
NH4Cl, dried with MgSO4, and concentrated in vacuo. Chromato-
graphic separation on silica gel (EtOAc/hexanes solvents) afforded
1b−d in 67−81% yields.
N-Pivaloyl-2-benzyl-4-chloroaniline (1b). The general proce-
dure was followed with 2-amino-5-chlorobenzophenone to afford 1b
811
dx.doi.org/10.1021/jo2023526 | J. Org. Chem. 2012, 77, 808−812

The Journal of Organic Chemistry
Note
(245 mg) in 81% yield: 1H NMR (CDCl3, 400 MHz) δ 7.95 (d, J = 8.4
Hz, 1H), 7.35−7.12 (m, 7H), 6.98 (br, 1H), 3.97 (s, 2H), 1.05 (s,
9H); 13C NMR (CDCl3, 100 MHz) δ 176.6 (quat.), 137.8 (quat.),
134.9 (quat.), 132.0 (quat.), 130.8 (CH), 129.7 (quat.), 129.2 (CH),
128.2 (CH), 127.6 (CH), 127.2 (CH), 124.6 (CH), 39.5 (quat.), 38.4
(CH2), 27.3 (CH3). Anal. Calcd for C18H20ClNO: C, 71.63; H, 6.68;
N, 4.64. Found: C, 71.65; H, 6.77; N, 4.77.
products. Also, the trans-relationship of two substituents of 3a−o is
assigned by NMR spectroscopy, which shows no coupling between
C2−C3 hydrogens.7c,8
(6) (a) Cherney, R. J.; Wang, L. J. Org. Chem. 1996, 61, 2544.
(b) Aoyagu, Y.; Gui, M.-Y.; Jin, Y.-R.; Li, X.-W.; Noguchi, T.; Fukaya,
H.; Hasuda, T.; Takeya, K. Tetrahedron Lett. 2004, 45, 1421.
́
(7) (a) Metro, T.-X.; Fayet, C.; Arnaud, F.; Rameix, N.; Fraisse, P.;
N-Pivaloyl-2-(p-bromobenzyl)aniline (1c). The general proce-
dure was followed with 2-amino-4′-bromobenzophenone to afford 1c
(266 mg) in 77% yield: 1H NMR (CDCl3, 400 MHz) δ 7.89 (d, J = 8.4
Hz, 1H), 7.32−6.99 (m, 8H), 3.94 (s, 2H), 1.12 (s, 9H); 13C NMR
(CDCl3, 100 MHz) δ 176.5 (quat.), 137.9 (quat.), 136.0 (quat.), 132.0
(CH), 131.0 (CH), 130.4 (quat.), 130.0 (CH), 127.9 (CH), 125.2
(CH), 124.0 (CH), 120.6 (quat.), 39.5 (quat.), 37.8 (CH2), 27.4
(CH3). Anal. Calcd for C18H20BrNO: C, 62.44; H, 5.82; N, 4.05.
Found: C, 62.50; H, 5.97; N, 4.20.
Janody, S.; Sevrin, M.; George, P.; Vogel, R. Synlett 2011, 684.
(b) Parcerisa, J.; Romero, M.; Pujol, M. D. Tetrahedron 2008, 64, 500.
(c) Wang, Z.; Wan, W.; Jiang, H.; Hao, J. J. Org. Chem. 2007, 72, 9364.
(8) The reaction of 2-ethyl-N-pivaloylaniline under the same
procedure shown below afforded trans-N-pivaloyl-3-methyl-2-phenyl-
indoline with 81:19 er. The stereochemistry of N-pivaloyl indoline is
assigned after conversion to N-acetyl indoline by the comparison of 1H
NMR of authentic material in the following literature. McComas, C.
C.; Gilbert, E. J.; Vranken, D. L. V. J. Org. Chem. 1997, 62, 8600 .
N-Pivaloyl-4-chloro-2-(o-fluorobenzyl)aniline (1d). The gen-
eral procedure was followed with 2-amino-5-chloro-2′-fluorobenzo-
1
phenone to afford 1d (214 mg) in 67% yield: H NMR (CDCl3, 400
MHz) δ 7.85 (d, J = 8.4 Hz, 1H), 7.27−6.97 (m, 7H), 3.94 (s, 2H),
1.15 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 176.7 (quat.), 160.6 (d,
quat.), 134.4 (quat.), 131.9 (quat.), 130.5 (CH), 130.2 (quat.), 130.0
(d, CH), 128.9 (d, CH), 127.7 (CH), 125.3 (CH), 125.0 (d, quat.),
124.8 (d, CH), 115.5 (d, CH), 39.6 (quat.), 30.4 (CH2), 27.3 (CH3).
Anal. Calcd for C18H19ClFNO: C, 67.60; H, 5.99; N, 4.38. Found: C,
67.60; H, 5.94; N, 4.53.
(9) In our investigation with ketone electrophiles, the reaction of 1a
with benzophenone produced 2-(1′,2′,2′-triphenyl-2′-hydroxyethyl)-N-
pivaloylaniline with 96:4 er. The subsequent acid-catalyzed cyclization,
however, gave only elimination product. Also, the electrophilic
substitution of 1a with chalcone under the same reaction condition
gave mainly 1,4-addition products with 70:30 dr and 98:2 er for both
isomers.
ASSOCIATED CONTENT
* Supporting Information
■
S
The NMR and/or HPLC data of compounds 1b−d and 3a−o
and the X-ray crystal structure and CIF file of 3l. This material
is available free of charge via the Internet at http://pubs.acs.org.
(10) Wardrop, A. W. H.; Sainsbury, G. L.; Harrison, J. M.; Inch, T. D.
J. Chem. Soc., Perkin Trans. 1 1976, 1279.
AUTHOR INFORMATION
Corresponding Author
*E-mail: parkyong@konkuk.ac.kr.
■
ACKNOWLEDGMENTS
■
We thank Prof. Peter Beak for helpful discussion and
comments. This paper was supported by Konkuk University
in 2010.
REFERENCES
■
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(5) The absolute and relative configurations of 3-(4-bromophenyl)-
substituted 3l were confirmed by X-ray crystallographic analysis. Since
indoline 3l exhibits S-configuration at the 2-position and R-
configuration at the 3-position, we assume the same stereochemical
outcome for all indolines 3a−o that were obtained as exclusive
812
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