Mitsunobu cyclodehydration of N-pivaloyl-2-aminophenethyl alcohol for asymmetric synthesis of trans-2,3-disubstituted indolines

Article abstract of DOI:10.1016/j.tet.2013.01.063

Highly enantioenriched trans-2,3-disubstituted indolines have been prepared by Mitsunobu cyclodehydration of the amino alcohols obtained from (-)- or (+)-sparteine-mediated lithiation-substitution of ortho-alkyl substituted N-pivaloylanilines. Optimized c

Full text of DOI:10.1016/j.tet.2013.01.063

Tetrahedron 69 (2013) 2542e2549
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Mitsunobu cyclodehydration of N-pivaloyl-2-aminophenethyl
alcohol for asymmetric synthesis of trans-2,3-disubstituted
indolines
*
Kyoung Hee Kang, Yelim Kim, Chan Im, Yong Sun Park
Department of Chemistry and KFnSC, Konkuk University, Seoul 143-701, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Highly enantioenriched trans-2,3-disubstituted indolines have been prepared by Mitsunobu cyclo-
dehydration of the amino alcohols obtained from (ꢀ)- or (þ)-sparteine-mediated lithiationesubstitution
of ortho-alkyl substituted N-pivaloylanilines. Optimized cyclodehydration conditions are described, from
which the combination of DEAD and PBu3 in CH3CN provides the best results.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 21 December 2012
Received in revised form 18 January 2013
Accepted 22 January 2013
Available online 31 January 2013
1. Introduction
2. Results and discussion
Cyclodehydration of amino alcohol is an attractive method to
make saturated nitrogen containing heterocycles.1 We recently
reported an acid-catalyzed cyclodehydration of N-pivaloyl-2-
aminophenethyl alcohol for the asymmetric synthesis of 2,3-
disubstituted indoline rings as shown in Fig. 1.2 The amino alco-
hols with an aryl or styryl substituent (R1) produced indoline de-
rivatives in good yields via a carbocation. However, the scope of the
reaction was narrow and aliphatic alkyl or electron-withdrawing
aryl substituted amino alcohols gave none of product desired for
a route to alkaloids.3 In continuation of our work in the asymmetric
synthesis of selected indoline derivatives, we report herein a novel
asymmetric synthetic method for a wide range of trans-2,3-
disubstituted indolines by Mitsunobu intramolecular cyclization.
A few reports have shown that the Mitsunobu reaction, tradi-
tionally a proven stereospecific cyclodehydration methodology, can
be applied to the intramolecular displacement of secondary alco-
hols by amide nucleophiles.4 These earlier findings stimulated our
interest in exploring Mitsunobu cyclodehydration of an aliphatic
alkyl (R1) substituted alcohol with N-pivaloylamino group as
shown in Scheme 1. Highly enantioenriched amino alcohol 2 was
prepared from the asymmetric lateral lithiation of ortho-benzyl
substituted N-pivaloylaniline 1 and subsequent electrophilic sub-
stitution.5 When the lithiation was carried out in the presence of
(ꢀ)-sparteine at ꢀ20 ꢁC and followed by the addition of hydro-
cinnamaldehyde at ꢀ78 ꢁC, amino alcohol (R,R)-2 was obtained in
81% yield as a 98:2 mixture of two inseparable diastereomers with
enantiomeric ratios (ers) of 99:1 and 91:9, respectively.6
When the 98:2 diastereomeric mixture of 2 was treated with
PPh3 and diisopropyl azodicarboxylate (DIAD) in THF at room
temperature, the nucleophilic attack by N-pivaloyl amide nucleo-
phile provided trans-indoline 3a with 99:1 er and no cis-indoline
was detected.6 Compound trans-3a might be produced from the
major diastereomer of 2 (99:1 er) via SN2 mechanism with in-
version of configuration as depicted in Scheme 1. We reasoned that
the repulsion between phenyl and phenethyl group in the transi-
tion state structure of minor diastereomer prevents formation of
the cis-product. However, the Mitsunobu condition afforded a large
amount of elimination product 4 (3a/4¼62:38). Alkene 4 results
from the elimination of triphenylphosphine oxide as shown in
Scheme 1 and the driving force of the elimination is perhaps the
extended conjugation in the product. The bulky amide nitrogen
may be involved in a competing act as a nucleophile and as an
acceptor of the benzylic proton in the elimination.7
R2
R2
OH
R1
-H2O
R1
N
Piv
NHPiv
when R1=Ph, Styryl, 62-78% yields
HCl catalyzed :
Present Study:
when R1 = Alkyl, p-CF3-Ph, No Reactions
Broad substrate scope
Mild condition
Better enantioselectivity
Fig. 1. Cyclodehydrations for indoline synthesis.
* Corresponding author. E-mail address: parkyong@konkuk.ac.kr (Y.S. Park).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.01.063

K.H. Kang et al. / Tetrahedron 69 (2013) 2542e2549
2543
demanding PEt2Ph (
thermore, as steric hindrance around the electrophilic center was
decreased using PBu3 (
significantly increased to a ratio of 98:2 (entry 9). On the other
q
¼136ꢁ) with DEAD in CH3CN (entry 8). Fur-
Ph
Ph
OH
n-BuLi/(-)-sparteine;
¼132ꢁ), the proportion of substitution was
PhCH2CH2CHO
q
Ph
81% yield
NHPiv
NHPiv
hand, the reactions with more bulky phosphines such as PCy3
¼170ꢁ) and P(o-Tol)3
(q
¼194ꢁ) gave neither substitution product
1
2
(q
98:2 dr, 99:1 er
nor elimination product and N-pivaloylamino alcohol 2 was re-
covered (entries 10 and 11). These results indicate that the sub-
stitution seems dependent on the steric bulk of phosphine, with
the greater extent of steric congestion resulting in competing
elimination.10
PPh3, DIAD
Thus, the optimized combination of DEAD/PBu3 in CH3CN was
selected for the subsequent studies to expand the scope of this
methodology to a series of 2-alkyl substituted 3-phenylindolines as
shown in Table 2. Lithiation of 1 in the presence of (ꢀ)-sparteine
at ꢀ20 ꢁC in methyl tert-butyl ether (MTBE) and following addition
of acetaldehyde at ꢀ78 ꢁC provided corresponding amino alcohol as
a 98:2 mixture of two inseparable diastereomers. Since the minor
diastereomer did not provide the cyclized product, separation of the
major diastereomer was not required. Therefore, the crude mixture
of diastereomers was directly subjected to our optimized Mitsunobu
+
H
Ph
OPPh3
H
N
Piv
Ph
Ph
Ph
+
3a:4 = 62:38
Ph
N
Piv
NH
Piv
4
Table 2
Ph
Asymmetric synthesis of 3-phenylindolines with various R1 substituents
3a (trans) 99:1 er
Ph
Ph
1) n-BuLi/(-)-sparteine;
Scheme 1. Mitsunobu cyclodehydration of amino alcohol 2.
R1
R1CHO
N
Piv
3b-l
NHPiv
2) DEAD, PBu3
The undesired formation of elimination product led us to seek
1
a
more efficient condition for the preparation of trans-2,3-
Entry
1
R1
Yielda (%)
erb
disubstituted indolines. As shown in Table 1, various Mitsunobu
conditions were examined with N-pivaloylamino alcohol 2 of 98:2
diastereomeric ratio (dr). When diethyl azodicarboxylate (DEAD)
was used as azo reagent, a slightly improved ratio (69:31) was
observed (entry 2). With the choice of DEAD as azo reagent and
varying solvents, the best result was obtained in CH3CN, in which
3a and 4 were obtained in a ratio of 78:22 in 92% combined yield
(entries 3e7).
63 (3b)
99:1
99:1
99:1
CH3
CH3
2
3
70 (3c)
72 (3d)
CH3
CH3
4
67 (3e)
99:1
Table 1
CH3
Optimization of Mitsunobu cyclodehydration of 2
Entrya
Condition
Ratiob (3a/4)
Yieldc (%)
5
6
68 (3f)
66 (3g)
99:1
99:1
OCH2Ph
1
2
3
4
5
6
7
8
DIAD, PPh3, THF
DEAD, PPh3, THF
62:38
69:31
66:34
31:69
54:46
76:24
78:22
85:15
98:2
80
82
64
21
93
73
92
91
92
d
NHBoc
DEAD, PPh3, toluene
DEAD, PPh3, n-hexane
DEAD, PPh3, DMF
DEAD, PPh3, CHCl3
DEAD, PPh3, CH3CN
DEAD, PEt2Ph, CH3CN
DEAD, PBu3, CH3CN
DEAD, PCy3, CH3CN
DEAD, P(o-Tol)3, CH3CN
O
CH3
7
8
9
68 (3h)
70 (3i)
75 (3j)
97:3
99:1
99:1
O
9
10
11
CH3
d
d
d
a
All reactions were performed with a 98:2 diastereomeric mixture of 2 for 6 h at
rt.
b
The ratio was determined by 1H NMR of the reaction mixture.
Combined isolated yield of 3a and 4.
c
10
70 (3k)
72 (3l)
99:1
98:2
The steric bulk of tertiary phosphine has been known as
a major factor governing the stereochemistry of various organic
reactions.8 We envisioned that the proportion of substitution
would increase with the decreased crowding at the electrophilic
carbon, and thus examined small cone angle phosphines for the
activation of the amino alcohol.9 Pleasingly, the proportion of
substitution relative to the elimination was slightly improved to
11
CF3
a
Overall yields after two steps.
a ratio of 85:15 when PPh3 (
q
¼145ꢁ) was replaced by sterically less
Determined by CSP-HPLC using Chiralpak AD-H column.
b

2544
K.H. Kang et al. / Tetrahedron 69 (2013) 2542e2549
Table 3
cyclodehydration condition, which afforded trans-2-methyl-3-
phenylindoline 3b of 99:1 er in 63% overall yield (entry 1). As
shown in entries 2e4, the same procedure with propionaldehyde,
hexanal, and isobutyraldehyde provided 2,3-disubstituted indolines
3cee with an excellent level of asymmetric induction in 72e67%
overall yields. To demonstrate the compatibility with other func-
tional groups, we carried out the cyclodehydration of amino alco-
hols obtained from the reactions with selected aldehydes including
benzyloxyacetaldehyde, N-Boc aminoacetaldehyde, ethyl oxoace-
tate, and 2-butenal. It is noteworthy that the mild cyclodehydration
condition with DEAD and PBu3 gave highly enantioenriched 2-
hydroxymethyl, 2-aminomethyl, 2-carboxylate, and 2-alkenyl
substituted 3-phenylindolines 3fei with good yields (entries 5e8).
We have previously reported that the HCl-catalyzed cyclo-
dehydration of amino alcohols from benzaldehyde and 1-naphthal-
dehyde produced indolines 3j and 3k with 98:2 er and 96:4 er, re-
spectively.2 A better enantioselectivity was observed under the Mit-
sunobu cyclodehydration condition to afford both indolines 3j and 3k
with 99:1 er (entries 9 and 10). Also, it was reported that an electron-
withdrawing p-trifluoromethylphenyl-substituted amino alcohol did
not undergo cyclodehydration to give indoline product under the acid-
catalyzed condition.2 In the case of the amino alcohol, which is not
capable of ionization to form a reasonable carbocation, cyclo-
dehydration with DEAD and PBu3 is an efficient way to make indoline
ring. For example, p-trifluoromethylphenyl-substituted indoline 3l
was obtained under the Mitsunobu condition with 98:2 er in 68%
overall yield (entry 11). The reactions with the aldehydes shown in
Table 2 show that the substitutionecyclodehydration sequence pro-
vides highly enantioenriched indolines 3bel regardless of steric and
electronic character of aldehydes.
Asymmetric synthesis of indolines with various R1 and R2 substituents
R2
R2
1) n-BuLi/(-)-sparteine;
R1
R1CHO
N
Piv
NHPiv
2) DEAD, PBu3
5 (R2 = methyl)
3m-v
6 (R2 = 5-methyl-2-thienyl)
7 (R2 = 2-benzothienyl)
Entrya
R2
R1
Yieldb (%)
erc
1
2
CH3
50 (3m)
55 (3n)
92:8
Ph
CH3
90:10
3
64 (3o)
92:8
Cl
4
5
58 (3p)
75 (3q)
91:9
97:3
OCH3
Ph
6
7
70 (3r)
73 (3s)
96:4
99:1
CH3
Ph
S
These results encouraged us to apply this synthetic methodology
to other ortho-alkyl substituted N-pivaloylanilines in order to syn-
thesize selected R2 substitutedindolines asshowninTable 3. Previous
report showed that (ꢀ)-sparteine-mediated lithiationesubstitution
of ortho-ethyl substituted N-pivaloylaniline 5 with various electro-
philes gave substituted products with enantioselectivities ranging
from95:5erto 83:17 er.11a The analogous reactionof 5 inthepresence
of (ꢀ)-sparteine at ꢀ20 ꢁC and following addition of hydro-
cinnamaldehyde at ꢀ78 ꢁC in MTBE provided the corresponding
amino alcohol as an 86:14 mixture of two diastereomers. Subsequent
Mitsunobu cyclodehydration of the amino alcohol afforded trans-
indoline 3m with 92:8 er in 50% overall yield6 (entry 1). Similarly, as
shown in entries 2e4, 3-methyl substituted indolines 3nep were
obtained by the substitutionecyclodehydration sequence with
somewhat lower enantioselectivities and yields when compared to
the reactions of ortho-benzyl N-pivaloylaniline 1 in Table 2.
Cl
8
9
74 (3t)
69 (3u)
97:3
97:3
CH3
Ph
S
10
70 (3v)
97:3
a
The lithiationesubstitution was performed in t-BuOMe for entries 1e4 and in
diethyl ether for entries 5e10.
b
Overall yields after two steps.
c
Determined by CSP-HPLC using Chiralpak AD-H and Chiralcel OD columns.
To further probe the scope of the reaction, we have prepared two
different ortho-thienylmethyl substituted N-pivaloylanilines 6 and 7.
There are no examples reported in the literature of the lateral lith-
iationesubstitution of the ortho-thienylmethyl substituted anilines,
so we first applied the original lithiationesubstitution condition in
MTBE. We were pleased to find that the reaction of ortho-(5-methyl-
2-thienylmethyl) N-pivaloylaniline 6 with hydrocinnamaldehyde
gave corresponding amino alcohols with 89:11 dr and 95:5 er. To
improve the stereoselectivity of the substitution, we tested several
solvents and found that the use of diethyl ether resulted in the best
stereoselectivities of 95:5 dr and 97:3 er. Subsequent Mitsunobu
cyclodehydration afforded highly enantioenriched 3-thiophenyl
substituted indoline 3q with 97:3 er in 75% overall yields6 (entry
5). Moreover, the analogous reactions of 6 with cinnamaldehyde and
4-chlorobenzaldehyde successfully afforded indolines 3r and 3s with
96:4 and 99:1 ers, respectively (entries 6 and 7). The results dem-
onstrate that the thiophene group of N-pivaloylaniline is tolerant to
the reaction conditions employed and gives high stereoselectivity.
In addition, the substitution of ortho-(2-benzothienylmethyl)
cyclodehydration proceeded generally in good yields to provide
highly enantioenriched indolines 3tev as shown in entries 8e10.
Many mild and chemoselective desulfurization procedures of thio-
phene are well established, hence the thiophenyl substituted indo-
lines can be readily transformed into highly functionalized indolines
that are otherwise difficult to access.12
The opposite enantiomers of trans-2,3-disubstituted indolines 3
can be readily obtained by the use of commercially available
(þ)-sparteine. As shown in Scheme 2, (þ)-sparteine-mediated
substitution with selected aldehydes and subsequent cyclo-
dehydration provided highly enantioenriched trans-2,3-
disubstituted indolines ent-3j, ent-3o, ent-3s, and ent-3v from or-
tho-alkyl substituted N-pivaloylanilines 1, 5, 6, and 7, respectively.13
3. Conclusion
We have described the successful use of the Mitsunobu reaction
for the synthesis of highly enantioenriched trans-2,3-disubstituted
indolines from ortho-alkyl substituted N-pivaloylanilines. The facile
N-pivaloylaniline
7 with selected aldehydes and subsequent

K.H. Kang et al. / Tetrahedron 69 (2013) 2542e2549
2545
R2
R2
(2 mL) was added PBu3 (2.5 equiv) and DEAD (2.5 equiv) and the
mixture was stirred at room temperature for 6 h. After the solvent
was removed in vacuo, chromatographic separation of the crude
mixture on silica gel (EtOAc/hexanes solvents) afforded indolines
3aev in 75e50% overall yields shown in Tables 2 and 3.
1) n-BuLi/(+)-sparteine;
R1CHO
R1
N
Piv
NHPiv
2) DEAD, PBu3
ent-3j 99:1 er, 69% yield
ent-3o 93:7 er, 62% yield
ent-3s 98:2 er, 73% yield
ent-3v 97:3 er, 65% yield
1, 5, 6 and 7
4.2.1. N-Pivaloyl-(S)-2-phenethyl-(R)-3-phenylindoline (3a). A col-
orless oil (142 mg, 74% overall yield). 1H NMR (CDCl3, 400 MHz) 8.14
(d, J¼8.4 Hz, 1H), 7.31e6.94 (m, 14H), 4.44 (dd, J¼8.8 and 4.0 Hz,
1H), 4.21 (s, 1H), 2.97e2.76 (m, 2H), 2.07e1.94 (m, 2H), 1.06 (s, 9H);
13C NMR (CDCl3, 100 MHz) 176.5 (quat.), 144.4 (quat.), 142.3 (quat.),
140.6 (quat.), 133.3 (quat.), 128.7 (CH), 128.6 (CH), 128.4 (CH), 128.1
(CH), 127.3 (CH), 127.1 (CH), 126.3 (CH), 125.7 (CH), 124.5 (CH), 119.8
(CH), 68.9 (CH), 51.9 (CH), 40.5 (quat.), 37.2 (CH2), 32.1 (CH2), 28.1
(CH3); IR (neat, cmꢀ1) 3206, 2923, 2853, 1644, 1494, 1370, 1357,
1190, 699; HRMS (FAB) calcd for C27H30NO (Mþþ1): 384.2327.
Scheme 2. Asymmetric synthesis of ent-3j, ent-3o, ent-3s, and ent-3v using
(þ)-sparteine.
access to both enantiomers of
a broad range of trans-2,3-
disubstituted indolines makes this an attractive route to this im-
portant class of molecules. Further application of this methodology
to the asymmetric synthesis of various indoline alkaloids is in
progress.
Found 384.2328; [
a
]
20 ꢀ37.5 (c 0.013, CHCl3); CSP-HPLC (Chiralpak
D
AD-H column; 2% 2-propanol in hexane; 0.5 mL/min) 99:1 er,
31.2 min (major enantiomer), 49.0 min (minor enantiomer).
4. Experimental
4.1. General
4.2.2. N-Pivaloyl-2-(10,40-diphenyl-10-butenyl)aniline (4). 1H NMR
(CDCl3, 400 MHz) 8.38 (d, J¼8.0 Hz, 1H), 7.38e6.96 (m, 13H), 6.45 (t,
J¼7.2 Hz, 1H), 2.73 (t, J¼7.6 Hz, 2H), 2.34 (q, J¼7.2 Hz, 2H), 0.98 (s,
9H); 13C NMR (CDCl3, 100 MHz) 176.3 (quat.), 141.1 (quat.), 139.5
(quat.), 138.1 (quat.), 135.8 (quat.), 131.5 (CH), 130.3 (CH), 128.7
(quat.), 128.6 (CH), 128.5 (CH), 128.43 (CH), 128.42 (CH), 127.8 (CH),
126.1 (CH),126.0 (CH),123.7 (CH),120.6 (CH), 39.7 (quat.), 35.7 (CH2),
31.5 (CH2), 27.2 (CH3); IR (neat, cmꢀ1) 3427, 3024, 2958, 2863, 1686,
1581, 1518, 1443, 1303, 1159, 762, 697. Anal. Calcd for C27H29NO: C,
84.55; H, 7.62; N, 3.65. Found: C, 84.43; H, 7.55; N, 3.75.
All reactions were performed in oven-dried glassware under
nitrogen atmosphere with freshly distilled solvents. tert-Butyl
methyl ether (MTBE) and tetrahydrofuran (THF) were distilled from
sodium/benzophenone under nitrogen. Toluene was distilled from
CaH2 under nitrogen. All other commercial reagents were used
without further purification, unless otherwise indicated. Analytical
thin layer chromatography (TLC) was performed on silica gel plates
with QF-254 indicator and TLC visualization was carried out with
UV-light. Flash column chromatography was performed with
230e400 mesh silica gel. Analytical chiral stationary phase HPLC
was performed on pump system coupled to absorbance detector
(217 nm). Chiralpak AD-H column (25 cmꢂ4.6 mm i.d.) and Chir-
alcel OD column (25 cmꢂ4.6 mm i.d.) with isopropanol/hexane
mobile phase were used to determine enantiomeric ratios. 1H and
13C NMR spectra were acquired on Bruker (400 MHz 1H, 100.6 MHz
13C) spectrometer using chloroform-d (CDCl3) as the internal
4.2.3. N-Pivaloyl-(S)-2-methyl-(R)-3-phenylindoline (3b). A color-
less oil (92 mg, 63% overall yield). 1H NMR (CDCl3, 400 MHz) 8.17 (d,
J¼8.4 Hz, 1H), 7.33e6.91 (m, 8H), 4.60 (q, J¼6.0 Hz, 1H), 3.95 (s, 1H),
1.43 (d, J¼6.0 Hz, 3H), 1.14 (s, 9H); 13C NMR (CDCl3, 100 MHz) 176.5
(quat.), 143.7 (quat.), 142.4 (quat.), 133.3 (quat.), 128.7 (CH), 128.0
(CH), 127.2 (CH), 127.1 (CH), 125.7 (CH), 124.4 (CH), 120.1 (CH), 64.8
(CH), 54.9 (CH), 40.6 (quat.), 28.3 (CH3), 22.6 (CH3); IR (neat, cmꢀ1
)
3446, 2975, 2925, 2854, 1633, 1472, 1400, 1359, 1242, 1196, 755,
standard. Chemical shifts (d) are reported in parts per million (ppm)
668. Anal. Calcd for C20H23NO: C, 81.87; H, 7.90; N, 4.77. Found: C,
relative to chloroform-d (7.26 ppm 1H, 77.07 ppm 13C). Multiplici-
ties are indicated by: s (singlet), d (doublet), t (triplet), q (quartet),
and br (broad). Coupling constants (J) are reported in hertz (Hz).
Purity of the compounds was established to be >95% based on 1H
and 13C NMR spectra. Infrared (IR) spectra were recorded on
a Nicolet 6700 FT-IR spectrometer. Optical rotations were measured
at 20 ꢁC on a JASCO P-2000 polarimeter using a quartz cell with a Na
high-pressure lamp. Elemental analyses were performed by the
Organic Chemistry Research Center (OCRC) operated by Sogang
University. Mass spectrometric data were acquired at Korea Basic
Science Institute (KBSI), mass spectrometry laboratory.
20
81.75; H, 7.92; N, 4.71; [
a
]
ꢀ27.7 (c 0.016, CHCl3); CSP-HPLC
D
(Chiralpak AD-H column; 5% 2-propanol in hexane; 0.5 mL/min)
99:1 er, 11.8 min (major enantiomer), 28.9 min (minor enantiomer).
Removal of N-pivaloyl group of 3b: To a solution of 3b (50 mg,
0.17 mmol) in 1,4-dioxane (1 mL) was added water (1 mL) and
concd HCl (1 mL). The solution was heated at reflux for 36 h. Upon
cooling of the solution to room temperature, the solvent was re-
moved in vacuo. Chromatographic separation on silica gel afforded
trans-2-methyl-3-phenylindoline (21 mg, 0.10 mmol) in 61% yield.
1H NMR (CDCl3, 400 MHz) 7.33e6.68 (m, 9H), 3.93 (d, J¼9.6 Hz, 1H),
3.85 (q, J¼5.9 Hz, 1H), 1.33 (d, J¼6.0 Hz, 3H). The spectral data were
identical to those of the authentic material reported previously.6
4.2. General procedure for the asymmetric preparation of
indolines 3
4.2.4. N-Pivaloyl-(S)-2-ethyl-(R)-3-phenylindoline (3c). A colorless
oil (108 mg, 70% overall yield). 1H NMR (CDCl3, 400 MHz) 8.17 (d,
J¼8.0 Hz, 1H), 7.32e6.92 (m, 8H), 4.27 (dd, J¼10.4 and 2.0 Hz, 1H),
4.12 (s, 1H), 1.83e1.65 (m, 2H), 1.12 (m, 12H); 13C NMR (CDCl3,
100 MHz) 176.5 (quat.), 144.5 (quat.), 142.6 (quat.), 133.2 (quat.),
128.7 (CH), 128.0 (CH), 127.3 (CH), 126.9 (CH), 125.7 (CH), 124.3
(CH), 119.6 (CH), 70.8 (CH), 51.3 (CH), 40.6 (quat.), 28.5 (CH2), 28.2
(CH3), 10.1 (CH3); IR (neat, cmꢀ1) 2961, 2929, 1645, 1475, 1399, 1357,
1190, 1077, 699. Anal. Calcd for C21H25NO: C, 82.04; H, 8.20; N, 4.56.
To a solution of N-pivaloylanilines 1, 5, 6, and 7 (0.5 mmol) and
(ꢀ)-sparteine (258 mg, 2.2 equiv) in 3 mL of MTBE (or diethyl ether)
at ꢀ20 ꢁC was added n-BuLi (0.7 mL, 1.6 M in hexane, 2.2 equiv).
After the mixture was stirred at ꢀ20 ꢁC for 1 h, an aldehyde
(2.5 equiv) was added at ꢀ78 ꢁC. The mixture was stirred for 20 min
at ꢀ78 ꢁC and then quenched with excess methanol. The resulting
mixture was dissolved in EtOAc, washed with satd NH4Cl, dried
with MgSO4, and concentrated in vacuo. The resulting residue was
purified by passing through a short silica gel column (EtOAc/hex-
anes solvents) to afford the amino alcohol as an inseparable mix-
ture of two diastereomers. To a solution of the products in CH3CN
Found: C, 82.12; H, 8.30; N, 4.43; [
a]
20 ꢀ40.8 (c 0.011, CHCl3); CSP-
D
HPLC (Chiralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/
min) 99:1 er, 12.3 min (major enantiomer), 17.9 min (minor
enantiomer).

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K.H. Kang et al. / Tetrahedron 69 (2013) 2542e2549
4.2.5. N-Pivaloyl-(S)-2-pentyl-(R)-3-phenylindoline (3d). A color-
less oil (126 mg, 72% overall yield). 1H NMR (CDCl3, 400 MHz) 8.16
(d, J¼8.4 Hz, 1H), 7.32e6.91 (m, 8H), 4.23 (dd, J¼10.4 and 2.4 Hz,
1H), 4.11 (s, 1H), 1.74e1.33 (m, 8H), 1.12 (s, 9H), 0.91 (t, J¼8.0 Hz,
3H); 13C NMR (CDCl3, 100 MHz) 176.4 (quat.), 144.4 (quat.), 142.6
(quat.), 133.2 (quat.), 128.7 (CH), 128.0 (CH), 127.3 (CH), 126.9 (CH),
125.7 (CH), 124.3 (CH), 119.7 (CH), 69.7 (CH), 51.8 (CH), 40.6 (quat.),
35.6 (CH2), 31.7 (CH2), 28.2 (CH3), 25.6 (CH2), 22.6 (CH2), 14.0 (CH3);
IR (neat, cmꢀ1) 2923, 2853, 1649, 1596, 1473, 1357, 1245, 1185, 1096;
HRMS (FAB) calcd for C24H32NO (Mþþ1): 350.2484. Found
701. Anal. Calcd for C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C,
20
75.11; H, 7.20; N, 3.95; [
(Chiralpak AD-H column; 2% 2-propanol in hexane; 0.5 mL/min)
97:3 er, 55.4 min (major enantiomer), 83.1 min (minor enantiomer).
a
]
ꢀ33.2 (c 0.016, CHCl3); CSP-HPLC
D
4.2.10. N-Pivaloyl-(R)-3-phenyl-(S)-2-(1-propenyl)indoline (3i). A
colorless oil (112 mg, 70% overall yield). 1H NMR (CDCl3, 400 MHz)
8.22 (d, J¼8.0 Hz, 1H), 7.33e6.96 (m, 8H), 5.59 (m, 2H), 4.95 (m, 1H),
4.09 (s, 1H), 1.64 (m, 3H), 1.11 (s, 9H); 13C NMR (CDCl3, 100 MHz)
177.2 (quat.), 144.7 (quat.), 142.5 (quat.), 132.8 (quat.), 131.4 (CH),
128.7 (CH), 128.0 (CH), 127.2 (CH), 127.1 (CH), 126.2 (CH), 125.5 (CH),
124.4 (CH), 119.5 (CH), 69.8 (CH), 55.0 (CH), 40.5 (quat.), 28.4 (CH3),
17.7 (CH3); IR (neat, cmꢀ1) 2923, 2850, 1646, 1479, 1397, 963, 701;
HRMS (FAB) calcd for C22H26NO (Mþþ1): 320.2014. Found
350.2486; [
a]
20 ꢀ29.7 (c 0.012, CHCl3); CSP-HPLC (Chiralpak AD-H
D
column; 1% 2-propanol in hexane; 0.5 mL/min) 99:1 er, 42.5 min
(major enantiomer), 50.1 min (minor enantiomer).
4.2.6. N-Pivaloyl-(S)-2-isopropyl-(R)-3-phenylindoline (3e). A yel-
low oil (108 mg, 67% overall yield). 1H NMR (CDCl3, 400 MHz) 8.11
(d, J¼8.0 Hz, 1H), 7.30e6.93 (m, 8H), 4.38 (d, J¼3.2 Hz, 1H), 4.16 (s,
1H), 2.24e2.20 (m, 1H), 1.15 (m, 12H), 0.64 (d, J¼6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) 177.3 (quat.), 145.5 (quat.), 143.5 (quat.),
134.3 (quat.), 128.7 (CH), 127.9 (CH), 127.4 (CH), 126.8 (CH), 124.6
(CH), 124.3 (CH), 118.7 (CH), 73.3 (CH), 47.1 (CH), 41.2 (quat.), 33.9
(CH), 28.7 (CH3), 18.8 (CH3), 16.2 (CH3); IR (neat, cmꢀ1) 2951, 2923,
320.2014; [
a
]
20 ꢀ34.4 (c 0.020, CHCl3); CSP-HPLC (Chiralpak AD-H
D
column; 10% 2-propanol in hexane; 0.5 mL/min) 99:1 er, 8.8 min
(major enantiomer), 17.7 min (minor enantiomer).
4.2.11. N-Pivaloyl-(R)-2-phenyl-(R)-3-phenylindoline (3j). A color-
less oil (133 mg, 75% overall yield). 1H NMR (CDCl3, 400 MHz) 8.35 (d,
J¼8.0 Hz, 1H), 7.38e7.03 (m, 13H), 5.61 (s, 1H), 4.26 (s, 1H), 1.02 (s,
9H). The spectral data of 3j were identical to those of the authentic
2847, 1645, 1477, 1357, 1189, 699; HRMS (FAB) calcd for C22H28NO
material reported previously.2 [
(Chiralpak AD-H column; 10% 2-propanol in hexane; 0.5 mL/min)
99:1 er, 10.0 min (major enantiomer), 13.0 min (minor enantiomer).
a]
D
20 ꢀ27.9 (c 0.034, CHCl3); CSP-HPLC
20
(Mþþ1): 322.2171. Found 322.2173; [
a]
ꢀ22.7 (c 0.016, CHCl3);
D
CSP-HPLC (Chiralpak AD-H column; 1% 2-propanol in hexane;
0.5 mL/min) 99:1 er, 16.3 min (major enantiomer), 25.8 min (minor
enantiomer).
4.2.12. N-Pivaloyl-(R)-2-(1-naphthyl)-(R)-3-phenylindoline (3k). A
pale yellow oil (142 mg, 70% overall yield). 1H NMR (CDCl3,
400 MHz) 8.48 (d, J¼8.4 Hz, 1H), 8.03e6.91 (m, 15H), 6.31 (s, 1H),
4.21 (s, 1H), 1.06 (s, 9H). The spectral data of 3k were identical to
4.2.7. N-Pivaloyl-(R)-2-benzyloxymethyl-(R)-3-phenylindoline
(3f). A yellow oil (136 mg, 68% overall yield). 1H NMR (CDCl3,
400 MHz) 8.11 (d, J¼8.0 Hz, 1H), 7.38e6.96 (m, 13H), 4.64e4.59 (m,
2H), 4.50 (d, J¼12.0 Hz, 1H), 4.45 (s, 1H), 3.68 (dd, J¼9.2 and 3.6 Hz,
1H), 3.36 (dd, J¼9.6 and 9.6 Hz, 1H), 1.07 (s, 9H); 13C NMR (CDCl3,
100 MHz) 176.7 (quat.), 144.7 (quat.), 142.1 (quat.), 137.7 (quat.),
132.8 (quat.), 128.6 (CH), 128.5 (CH), 127.9 (CH), 127.8 (CH), 127.7
(CH), 127.5 (CH), 126.9 (CH), 125.9 (CH), 124.6 (CH), 119.5 (CH), 73.4
(CH2), 71.3 (CH2), 68.0 (CH), 50.5(CH), 40.6 (quat.), 28.0 (CH3); IR
(neat, cmꢀ1) 3028, 2972, 2863, 1649, 1474, 1400, 1353, 1245, 1188,
1088, 699; HRMS (FAB) calcd for C27H30NO2 (Mþþ1): 400.2277.
those of the authentic material reported previously.2 [
0.018, CHCl3); CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol
in hexane; 0.5 mL/min) 99:1 er, 13.1 min (major enantiomer),
15.4 min (minor enantiomer).
a
]
20 ꢀ44.0 (c
D
4.2.13. N-Pivaloyl-(R)-3-phenyl-(R)-2-(4-trifluoromethylphenyl) in-
doline (3l). A colorless oil (152 mg, 72% overall yield). 1H NMR
(CDCl3, 400 MHz) 8.35 (d, J¼8.0 Hz, 1H), 7.58e7.03 (m, 12H), 5.65 (s,
1H), 4.22 (s, 1H), 1.02 (s, 9H); 13C NMR (CDCl3, 100 MHz) 177.3
(quat.), 147.4 (quat.), 145.0 (quat.), 142.4 (quat.), 131.4 (quat.), 129.1
(CH), 128.6 (CH), 127.6 (CH), 127.1 (CH), 126.0 (CH), 125.9 (quat.),
125.7 (CH), 125.6 (CH), 125.1 (CH), 119.2 (CH), 71.7 (CH), 57.9 (CH),
40.5 (quat.), 28.3 (CH3); IR (neat, cmꢀ1) 3423, 2978, 2926, 1650,
1476, 1359, 1324, 1184, 1126, 1066, 1017, 830, 759, 702. Anal. Calcd
Found 400.2278; [
AD-H column; 10% 2-propanol in hexane; 0.5 mL/min) 99:1 er,
11.8 min (major enantiomer), 21.4 min (minor enantiomer).
a
]
20 ꢀ34.2 (c 0.022, CHCl3); CSP-HPLC (Chiralpak
D
4.2.8. N-Pivaloyl-(R)-2-(N-Boc-aminomethyl)-(R)-3-phenylindoline
(3g). A colorless oil (135 mg, 66% overall yield). 1H NMR (CDCl3,
400 MHz) 8.08 (d, J¼8.4 Hz, 1H), 7.33e6.89 (m, 8H), 4.90 (br, 1H),
4.72 (br, 1H), 4.29 (s, 1H), 3.51 (m, 1H), 3.05 (m, 1H), 1.49 (s, 9H), 1.14
(s, 9H); 13C NMR (CDCl3, 100 MHz) 177.3 (quat.), 155.9 (quat.), 144.2
(quat.), 141.9 (quat.), 132.5 (quat.), 128.7 (CH), 128.1 (CH), 127.5 (CH),
127.0 (CH), 125.9 (CH), 124.7 (CH), 120.0 (CH), 79.8 (quat.), 68.0
(CH), 49.8 (CH), 44.0 (CH2), 40.6 (quat.), 28.4 (CH3), 28.2 (CH3); IR
(neat, cmꢀ1) 3343, 2976, 2929, 1708, 1633, 1475, 1401, 1363, 1276,
1168, 700; HRMS (FAB) calcd for C25H33N2O3 (Mþþ1): 409.2491.
for C26H24F3NO: C, 73.74; H, 5.71; N, 3.31. Found: C, 73.77; H, 5.68;
20
N, 3.21; [
a
]
D
ꢀ16.9 (c 0.013, CHCl3); CSP-HPLC (Chiralpak AD-H
column; 5% 2-propanol in hexane; 0.5 mL/min) 98:2 er, 8.68 min
(major enantiomer), 10.55 min (minor enantiomer).
4.2.14. N-Pivaloyl-(S)-3-methyl-(S)-2-phenethylindoline (3m). A col-
orless oil (80 mg, 50% overall yield). 1H NMR (CDCl3, 400 MHz) 8.05
(d, J¼8.4 Hz,1H), 7.29e7.02 (m, 8H), 4.25 (dd, J¼10.4 and 2.4 Hz, 1H),
3.08 (q, J¼7.2 Hz, 1H), 2.75e2.61 (m, 2H), 1.94e1.81 (m, 2H), 1.27 (m,
12H); 13C NMR (CDCl3, 100 MHz) 176.6 (quat.), 143.0 (quat.), 140.7
(quat.), 136.3 (quat.), 128.5 (CH), 128.4 (CH), 127.4 (CH), 126.2 (CH),
124.2 (CH), 124.0 (CH), 119.5 (CH), 66.8 (CH), 41.0 (CH), 40.6 (quat.),
36.5 (CH2), 32.0 (CH2), 28.3 (CH3), 20.9 (CH3); IR (neat, cmꢀ1) 2922,
Found 409.2491; [
AD-H column; 10% 2-propanol in hexane; 0.5 mL/min) 99:1 er,
14.0 min (major enantiomer), 15.5 min (minor enantiomer).
a
]
20 ꢀ16.4 (c 0.016, CHCl3); CSP-HPLC (Chiralpak
D
4.2.9. N-Pivaloyl-(R)-2-ethoxycarbonyl-(R)-3-phenylindoline (3h). A
colorless oil (119 mg, 68% overall yield). 1H NMR (CDCl3, 400 MHz)
8.26 (d, J¼8.4 Hz, 1H), 7.32e7.04 (m, 8H), 5.06 (s, 1H), 4.50 (s, 1H),
4.23 (q, J¼7.2 Hz, 2H), 1.27 (t, J¼7.2 Hz, 3H), 1.15 (s, 9H); 13C NMR
(CDCl3, 100 MHz) 176.4 (quat.), 171.4 (quat.), 144.8 (quat.), 141.9
(quat.), 131.5 (quat.), 128.9 (CH), 128.5 (CH), 127.6 (CH), 127.1 (CH),
124.9 (CH), 124.5 (CH), 119.1 (CH), 70.2 (CH), 61.9 (CH2), 52.4 (CH),
40.3 (quat.), 27.8 (CH3),14.1 (CH3); IR (neat, cmꢀ1) 3422, 2973, 2924,
2360, 2341, 1745, 1650, 1480, 1399, 1358, 1245, 1187, 1115, 1019, 775,
2853, 1642, 1474, 1460, 1357, 1287; HRMS (FAB) calcd for C22H28NO
20
(Mþþ1): 322.2171. Found 322.2172; [
a]
D
ꢀ21.3 (c 0.028, CHCl3);
CSP-HPLC (Chiralpak AD-H column; 5% 2-propanol in hexane;
0.5 mL/min) 92:8 er, 27.7 min (major enantiomer), 17.1 min (minor
enantiomer).
4.2.15. N-Pivaloyl-(S)-3-methyl-(S)-2-pentylindoline (3n). A color-
less oil (79 mg, 55% overall yield). 1H NMR (CDCl3, 400 MHz) 8.08 (d,
J¼8.4 Hz, 1H), 7.27e7.01 (m, 3H), 4.16 (dd, J¼10.8 and 2.4 Hz, 1H),

K.H. Kang et al. / Tetrahedron 69 (2013) 2542e2549
2547
2.96 (q, J¼7.2 Hz, 1H), 1.61e1.25 (m, 8H), 1.38 (s, 9H), 1.22 (d,
J¼7.2 Hz, 3H), 0.87 (t, J¼6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
176.5 (quat.), 143.0 (quat.), 136.4 (quat.), 127.4 (CH), 124.2 (CH),
123.9 (CH), 119.3 (CH), 67.9 (CH), 41.0 (CH), 40.8 (quat.), 36.2 (CH2),
31.7 (CH2), 28.4 (CH3), 25.4 (CH2), 22.5 (CH2), 21.1 (CH3), 13.9 (CH3);
IR (neat, cmꢀ1) 2958, 2923, 2853, 1652, 1562, 1473, 1391, 668, 647;
CSP-HPLC (Chiralpak AD-H column; 5% 2-propanol in hexane;
0.5 mL/min) 96:4 er, 15.0 min (major enantiomer), 20.3 min (mi-
nor enantiomer).
4.2.20. N-Pivaloyl-(R)-2-(4-chlorophenyl)-(R)-3-(5-methyl-2-
thienyl) indoline (3s). A yellow oil (149 mg, 73% overall yield). 1H
NMR (CDCl3, 400 MHz) 8.31 (d, J¼8.4 Hz, 1H), 7.37e7.05 (m, 7H),
6.53 (m, 1H), 6.49 (d, J¼3.2 Hz, 1H), 5.68 (s, 1H), 4.34 (s, 1H), 2.41 (s,
3H), 1.08 (s, 9H); 13C NMR (CDCl3, 100 MHz) 177.4 (quat.), 144.6
(quat.), 143.3 (quat.), 141.3 (quat.), 139.3 (quat.), 133.3 (quat.), 131.2
(quat.), 129.2 (CH), 128.8 (CH), 126.7 (CH), 125.6 (CH), 124.9 (CH),
124.8 (CH), 124.4 (CH), 119.3 (CH), 71.9 (CH), 53.0 (CH), 40.6 (quat.),
28.4 (CH3), 15.4 (CH3); IR (neat, cmꢀ1) 2970, 2928, 1652, 1475, 1355,
HRMS (FAB) calcd for C19H30NO (Mþþ1): 288.2327. Found
20
288.2328; [
a]
ꢀ20.8 (c 0.018, CHCl3); CSP-HPLC (Chiralpak AD-H
D
column; 2% 2-propanol in hexane; 0.5 mL/min) 90:10 er, 61.6 min
(major enantiomer), 13.0 min (minor enantiomer).
4.2.16. N-Pivaloyl-(R)-2-(4-chlorophenyl)-(S)-3-methylindoline
(3o). A colorless oil (105 mg, 64% overall yield). 1H NMR (CDCl3,
400 MHz) 8.25 (d, J¼8.4 Hz, 1H), 7.29e7.04 (m, 7H), 5.39 (s, 1H),
3.08 (q, J¼7.2 Hz, 1H), 1.42 (d, J¼7.2 Hz, 3H), 1.22 (s, 9H); 13C NMR
(CDCl3, 100 MHz) 177.4 (quat.), 143.7 (quat.), 142.0 (quat.), 134.4
(quat.), 132.9 (quat.), 128.9 (CH), 127.9 (CH), 126.4 (CH), 124.5 (CH),
124.3 (CH), 118.8 (CH), 69.9 (CH), 47.3 (CH), 40.7 (quat.), 28.5 (CH3),
22.1 (CH3); IR (neat, cmꢀ1) 3423, 2964, 2924, 2854, 1643, 1475,
1400, 1355, 1322, 1190, 1088, 1013, 811, 758, 669. Anal. Calcd for
1188, 1092, 1013, 754, 737. Anal. Calcd for C24H24ClNOS: C, 70.31; H,
20
5.90; N, 3.42; S, 7.82. Found: C, 70.38; H, 5.81; N, 3.32; S, 7.67; [a]
D
ꢀ38.4 (c 0.055, CHCl3); CSP-HPLC (Chiralpak AD-H column; 5% 2-
propanol in hexane; 0.5 mL/min) 99:1 er, 11.0 min (major enan-
tiomer), 19.2 min (minor enantiomer).
4.2.21. N-Pivaloyl-(R)-3-(2-benzothienyl)-(S)-2-ethylindoline (3t). A
colorless oil (134 mg, 74% overall yield). 1H NMR (CDCl3, 400 MHz)
8.18 (d, J¼8.4 Hz, 1H), 7.73e7.10 (m, 7H), 6.68 (s, 1H), 4.52 (dd,
J¼10.8 and 2.4 Hz, 1H), 4.37 (s, 1H), 1.84e1.63 (m, 2H), 1.17 (s, 9H),
1.13 (t, J¼7.6 Hz, 3H); 13C NMR (CDCl3, 100 MHz) 176.6 (quat.),
146.7 (quat.), 144.0 (quat.), 140.0 (quat.), 139.4 (quat.), 132.1
(quat.), 128.6 (CH), 125.7 (CH), 124.4 (CH), 124.3 (CH), 124.0 (CH),
123.4 (CH), 122.3 (CH), 121.3 (CH), 119.8 (CH), 70.4 (CH), 47.1 (CH),
C20H22ClNO: C, 73.27; H, 6.76; N, 4.27. Found: C, 73.28; H, 6.74; N,
20
4.25; [
a
]
þ49.4 (c 0.038, CHCl3); CSP-HPLC (Chiralpak AD-H col-
D
umn; 2% 2-propanol in hexane; 0.5 mL/min) 92:8 er, 15.0 min
(major enantiomer), 13.3 min (minor enantiomer).
4.2.17. N-Pivaloyl-(R)-2-(4-methoxyphenyl)-(S)-3-methylindoline
(3p). A colorless oil (94 mg, 58% overall yield). 1H NMR (CDCl3,
400 MHz) 8.27 (d, J¼8.4 Hz, 1H), 7.28e6.75 (m, 7H), 5.38 (s, 1H),
3.73 (s, 3H), 3.09 (q, J¼7.2 Hz,1H), 1.40 (d, J¼7.2 Hz, 3H),1.23 (s, 9H);
13C NMR (CDCl3, 100 MHz) 177.6 (quat.), 158.6 (quat.), 144.0 (quat.),
135.6 (quat.), 134.9 (quat.), 127.7 (CH), 126.1 (CH), 124.3 (CH), 118.8
(CH), 114.0 (CH), 70.0 (CH), 55.2 (CH3), 47.4 (CH), 40.7 (quat.), 28.5
(CH3), 22.1 (CH3); IR (neat, cmꢀ1) 3447, 2963, 2924, 2863, 1639,
1511, 1475, 1357, 1247, 1177, 1030, 820, 765, 669. Anal. Calcd for
40.7 (quat.), 28.3 (CH3), 28.2 (CH2), 10.0 (CH3); IR (neat, cmꢀ1
)
2961, 2923, 2869, 1644, 1473, 1457, 1356, 1185, 1077, 723. Anal.
Calcd for C23H25NOS: C, 75.99; H, 6.93; N, 3.85; S, 8.82. Found: C,
20
75.81; H, 6.99; N, 3.91; S, 8.82; [
a
]
þ10.1 (c 0.011, CHCl3); CSP-
D
HPLC (Chiralpak AD-H column; 1% 2-propanol in hexane;
0.5 mL/min) 97:3 er, 38.4 min (major enantiomer), 49.4 min (mi-
nor enantiomer).
C21H25NO2: C, 77.98; H, 7.79; N, 4.33. Found: C, 77.89; H, 7.65; N,
20
4.17; [
a]
þ52.0 (c 0.015, CHCl3); CSP-HPLC (Chiralpak AD-H col-
4.2.22. N-Pivaloyl-(R)-3-(2-benzothienyl)-(S)-2-styrylindoline
(3u). A colorless oil (151 mg, 69% overall yield). 1H NMR (CDCl3,
400 MHz) 8.30 (d, J¼8.0 Hz, 1H), 7.75e7.10 (m, 13H), 6.78 (s, 1H),
6.51 (d, J¼16.0 Hz, 1H), 6.34 (dd, J¼16.0 and 5.2 Hz, 1H), 5.43 (d,
J¼5.2 Hz, 1H), 4.48 (s, 1H), 1.19 (s, 9H); 13C NMR (CDCl3, 100 MHz)
177.3 (quat.), 145.8 (quat.), 144.2 (quat.), 139.5 (quat.), 139.4
(quat.), 136.0 (quat.), 131.6 (quat.), 131.0 (CH), 129.0 (CH), 128.8
(CH), 128.6 (CH), 128.0 (CH), 126.5 (CH), 125.6 (CH), 124.6 (CH),
124.5 (CH), 124.2 (CH), 123.5 (CH), 122.3 (CH), 121.6 (CH), 119.9
D
umn; 2% 2-propanol in hexane; 0.5 mL/min) 91:9 er, 27.4 min
(major enantiomer), 32.2 min (minor enantiomer).
4.2.18. N-Pivaloyl-(R)-3-(5-methyl-2-thienyl)-(S)-2-phenethylindoline
(3q). A colorless oil (151 mg, 75% overall yield). 1H NMR (CDCl3,
400 MHz) 8.09 (d, J¼8.0 Hz, 1H), 7.30e7.06 (m, 8H), 6.47 (dd, J¼2.8
and 0.8 Hz, 1H), 6.28 (d, J¼3.2 Hz, 1H), 4.53 (dd, J¼10.4 and 2.8 Hz,
1H), 4.32 (s, 1H), 2.88e2.72 (m, 2H), 2.38 (s, 3H), 2.03e1.94 (m, 2H),
1.11 (s, 9H); 13C NMR (CDCl3, 100 MHz) 176.6 (quat.), 143.8 (quat.),
143.3 (quat.), 140.5 (quat.), 138.8 (quat.), 132.9 (quat.), 128.6 (CH),
128.5 (CH), 128.3 (CH), 126.3 (CH), 125.5 (CH), 124.8 (CH), 124.4 (CH),
124.2 (CH), 119.5 (CH), 68.9 (CH), 47.0 (CH), 40.5 (quat.), 36.6 (CH2),
32.1 (CH2), 28.1 (CH3), 15.3 (CH3); IR (neat, cmꢀ1) 3059, 2920, 2853,
1645, 1475, 1403, 1357, 1189, 1083, 795, 700; HRMS (FAB) calcd for
(CH), 69.7 (CH), 50.8 (CH), 40.7 (quat.), 28.5 (CH3); IR (neat, cmꢀ1
)
3442, 3026, 2973, 2930, 2360, 2341, 1641, 1476, 1401, 1356, 1186,
739, 691. Anal. Calcd for C29H27NOS: C, 79.60; H, 6.22; N, 3.20; S,
7.33. Found: C, 79.72; H, 6.28; N, 3.31; S, 7.42; [
a
]
20 ꢀ39.2 (c 0.013,
D
CHCl3); CSP-HPLC (Chiralpak AD-H column; 2% 2-propanol in
hexane; 0.5 mL/min) 97:3 er, 41.0 min (major enantiomer),
34.2 min (minor enantiomer).
C26H30NOS (Mþþ1): 404.2048. Found 404.2047; [
a]
D
20 þ18.0 (c 0.012,
CHCl3); CSP-HPLC (Chiralpak AD-H column; 5% 2-propanol in hex-
ane; 0.5 mL/min) 97:3 er, 18.4 min (major enantiomer), 36.9 min
(minor enantiomer).
4.2.23. N-Pivaloyl-(R)-3-(2-benzothienyl)-(R)-2-phenylindoline
(3v). A colorless oil (144 mg, 70% overall yield). 1H NMR (CDCl3,
400 MHz) 8.39 (d, J¼8.0 Hz, 1H), 7.78e7.09 (m, 13H), 6.83(s, 1H),
5.86(s, 1H), 4.53 (s, 1H), 1.06 (s, 9H); 13C NMR (CDCl3, 100 MHz)
177.6 (quat.), 146.6 (quat.), 145.0 (quat.), 142.7 (quat.), 139.6 (quat.),
139.5 (quat.), 130.7 (quat.), 129.0 (CH), 128.9 (CH), 127.6 (CH), 125.8
(CH), 125.2 (CH), 124.7 (CH), 124.5 (CH), 124.2 (CH), 123.5 (CH),
122.4 (CH), 121.4 (CH), 119.3 (CH), 71.6 (CH), 53.6 (CH), 40.7 (quat.),
28.4 (CH3); IR (neat, cmꢀ1) 3056, 2971, 2920, 1641, 1473, 1356, 1185,
748, 694. Anal. Calcd for C27H25NOS: C, 78.80; H, 6.12; N, 3.40; S,
4.2.19. N-Pivaloyl-(R)-3-(5-methyl-2-thienyl)-(S)-2-styrylindoline
(3r). A colorless oil (140 mg, 70% overall yield). 1H NMR (CDCl3,
400 MHz) 8.25 (d, J¼8.0 Hz, 1H), 7.34e7.06 (m, 8H), 6.51e6.26 (m,
4H), 5.29 (d, J¼5.2 Hz, 1H), 4.35 (s, 1H),2.39 (s, 3H), 1.21 (s, 9H); 13C
NMR (CDCl3, 100 MHz) 177.3 (quat.), 144.0 (quat.), 143.0 (quat.),
139.1 (quat.), 136.1(quat.), 132.4 (quat.), 130.7 (CH), 129.2 (CH),
128.6 (CH), 128.5 (CH), 127.9 (CH), 126.5 (CH), 125.4 (CH), 124.8
(CH), 124.5 (CH), 119.7 (CH), 70.3 (CH), 50.2 (CH), 40.6 (quat.), 28.5
(CH3), 15.4 (CH3); IR (neat, cmꢀ1) 2961, 2922, 1646, 1474, 1401,
7.79. Found: C, 78.97; H, 6.20; N, 3.41; S, 7.81; [
a
]
20 ꢀ20.4 (c 0.010,
D
CHCl3); CSP-HPLC (Chiralcel OD column; 1% 2-propanol in hexane;
0.5 mL/min) 97:3 er, 15.9 min (major enantiomer), 23.8 min (minor
enantiomer).
1356, 1186, 967, 799, 737, 693; HRMS (FAB) calcd for C26H28NOS
20
(Mþþ1): 402.1892. Found 402.1891; [
a
]
ꢀ49.7 (c 0.018, CHCl3);
D

2548
K.H. Kang et al. / Tetrahedron 69 (2013) 2542e2549
4.3. Asymmetric preparation of indolines ent-3j, ent-3o, ent-
3s, and ent-3v
2.41 (s, 3H), 1.17 (s, 9H); 13C NMR (CDCl3, 100 MHz) 176.7 (quat.),
139.6 (quat.), 139.3 (quat.), 136.2 (quat.), 130.5 (quat.), 130.3 (CH),
128.0 (CH), 125.0 (CH), 124.9 (CH), 123.7 (CH), 39.6 (quat.), 33.4
(CH2), 27.4 (CH3), 15.3 (CH3); IR (neat, cmꢀ1) 3421, 3269, 2956,
2870, 1644, 1485, 1186, 804, 757, 669. Anal. Calcd for C17H21NOS: C,
71.04; H, 7.36; N, 4.87; S, 11.16. Found: C, 71.06; H, 7.44; N, 4.74; S,
11.28.
The same procedure with (ꢀ)-sparteine described above was
used for the preparation of indolines ent-3j, ent-3o, ent-3s, and ent-
3v using commercially available (þ)-sparteine (CAS No: 492-08-0).
From the reactions of 1, 5, 6, and 7 (0.5 mmol), enantioenriched
indolines ent-3j, ent-3o, ent-3s, and ent-3v were obtained in
73e62% yields as shown in Scheme 2.
4.5.2. N-Pivaloyl-2-(20-benzothienylmethyl)aniline (7). A colorless
oil (60% overall yield). 1H NMR (CDCl3, 400 MHz) 7.89 (d, J¼8.0 Hz,
1H), 7.76e7.16 (m, 7H), 6.93 (s, 1H), 4.21 (s, 2H), 1.13 (s, 9H); 13C
NMR (CDCl3, 100 MHz) 176.8 (quat.), 143.2 (quat.), 139.8 (quat.),
139.6 (quat.), 136.1 (quat.), 130.5 (CH), 130.4 (quat.), 128.2 (CH),
125.4 (CH),124.5 (CH),124.4 (CH),124.1 (CH),123.1 (CH),122.2 (CH),
121.8 (CH), 39.5 (quat.), 33.9 (CH2), 27.5 (CH3); IR (neat, cmꢀ1) 3421,
2956, 2927, 1661, 1516, 1448, 1434, 1301, 1168, 761, 561. Anal. Calcd
for C20H21NOS: C, 74.27; H, 6.54; N, 4.33; S, 9.91. Found: C, 74.34; H,
6.63; N, 4.41; S, 9.86.
4.4. Asymmetric preparation of amino alcohol 2
To a solution of N-pivaloylaniline 1 (0.5 mmol) and (ꢀ)-sparteine
(258 mg, 2.2 equiv) in 3 mL of MTBE (or diethyl ether) at ꢀ20 ꢁC was
added n-BuLi (0.7 mL, 1.6 M in hexane, 2.2 equiv). After the mixture
was stirred at ꢀ20 ꢁC for 1 h, hydrocinnamaldehyde (2.5 equiv) was
added at ꢀ78 ꢁC. The mixture was stirred for 20 min at ꢀ78 ꢁC and
then quenched with excess methanol. The resulting mixture was
dissolved in EtOAc, washed with satd NH4Cl, dried with MgSO4, and
concentrated in vacuo. The resulting residue was purified by a silica
gel column chromatography (EtOAc/hexanes solvents) to afford
amino alcohol 2 as an inseparable mixture of two diastereomers
(98:2 dr) in 81% yield (163 mg) as a pale yellow oil. 1H NMR (CDCl3,
400 MHz, major diastereomer) 7.70 (d, J¼8.0 Hz, 1H), 7.35e7.11 (m,
14H), 4.34 (m,1H), 4.03 (d, J¼6.0 Hz, 1H), 2.86e2.72 (m, 2H), 1.99 (m,
1H), 1.70 (m, 1H), 1.55 (d, J¼5.6 Hz, 1H), 1.19 (s, 9H); 13C NMR (CDCl3,
100 MHz, major diastereomer) 176.8 (quat.), 141.6 (quat.), 139.5
(quat.), 135.7 (quat.), 134.2 (quat.), 129.5 (CH), 129.0 (CH), 128.6 (CH),
128.5 (CH), 128.3 (CH), 127.5 (CH), 127.2 (CH), 126.0 (CH), 125.3 (CH),
125.2 (CH), 72.7 (CH), 51.8 (CH), 39.5 (quat.), 37.3 (CH2), 32.3 (CH2),
27.6 (CH3); IR (neat, cmꢀ1) 3398, 3297, 2957, 2923, 2843, 1654, 1516,
1449, 1302, 1170, 699. Anal. Calcd for C27H312N0 O2: C, 80.76; H, 7.78; N,
Acknowledgements
We thank Prof. Peter Beak for helpful discussion and comments.
This work was supported by Seoul R&BD Program (WR090671) and
Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education,
Science and Technology (2012R1A1A2004794).
Supplementary data
The NMR and/or HPLC data of compounds 3aev, 2, 4, 6, and 7.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2013.01.063.
3.49. Found: C, 80.61; H, 7.59; N, 3.60; [
a
]
ꢀ17.6 (c 0.019, CHCl3);
D
CSP-HPLC (Chiralpak AD-H column; 10% 2-propanol in hexane;
0.5 mL/min) major diastereomer, 99:1 er, 17.7 min (major enantio-
mer), 19.4 min (minor enantiomer); minor diastereomer, 91:9 er,
37.9 min (major enantiomer), 35.2 min (minor enantiomer).
References and notes
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4.5. General procedure for the preparation of 6 and 7
2. Kang, K. H.; Do, J.; Park, Y. S. J. Org. Chem. 2012, 77, 808.
3. (a) Liu, D.; Zhao, G.; Xiang, L. Eur. J. Org. Chem. 2010, 3975; (b) Schammel, A. W.;
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Lampard, C.; Kennedy, A. R.; Murphy, J. A. Tetrahedron Lett. 1999, 40, 161; (c)
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Shin, E.-k.; Beak, P.; Park, Y. S. Synthesis 2006, 3805.
6. The absolute and relative configurations of the amino alcohols and trans-in-
dolines from 1 and 5 have been assigned in previous studies.2,5,11 We assume
the same stereochemical assignments for all new indolines 3. The trans con-
figuration of 3b is confirmed after the removal of N-pivaloyl group by com-
parison of NMR spectral data with those of trans-2-methyl-3-phenylindoline
reported previously Katayev, D.; Nakanishi, M.; Burgi, T.; Kundig, E. P. Chem. Sci.
2012, 3, 1422.
7. The (Z)-configuration of the major elimination product obtained in the prepa-
ration of 3b has been assigned by comparison of 1H NMR spectrum with that of
authentic product derived from (Z)-2-(1-phenyl-1-propenyl)aniline Yunai, H.;
Mimura, H.; Kawada, K.; Taguchi, T. Tetrahedron 2007, 63, 2153 The configura-
tion of 4 is assigned by analogy to the predominant formation of the (Z)-
product.
8. (a) Schilz, M.; Plenio, H. J. Org. Chem. 2012, 77, 2798; (b) Goto, A.; Otake, K.;
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9, 635.
To
a solution of 2-methylthiophene (or thionaphthene)
(4.5 mmol) in 25 mL of anhydrous THF at ꢀ78 ꢁC was added n-BuLi
(1.6 M in hexane, 1.0 equiv). After the solution was allowed to warm
to room temperature and stirred for 12 h, the solution of 2-
cyanoaniline (1.0 equiv) in 5 mL of anhydrous THF was slowly
added at ꢀ78 ꢁC. The mixture was stirred for additional 10 h at
room temperature and then quenched with 4 N HCl solution
(100 mL) at 0 ꢁC. The resulting mixture was dissolved in diethyl
ether, washed with brine, dried with MgSO4, and concentrated in
vacuo. The resulting residue was purified by passing through
a short silica gel column (EtOAc/hexanes solvents) to afford corre-
sponding ketone. The solution of the product in ether (20 mL) was
added dropwise to a suspension of lithium aluminum hydride
(1.0 equiv) in ether (10 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. The filtrate
was concentrated and the residue was treated with pivaloyl chlo-
ride (1.0 equiv) and Et3N (2.0 equiv) for 3 h in methylene chloride.
The resulting mixture was dissolved in EtOAc, washed with satd
NH4Cl, dried with MgSO4, and concentrated in vacuo. Chromato-
graphic separation on silica gel (EtOAc/hexanes solvents) afforded
the product.
9. Tolman, C. A. Chem. Rev. 1977, 77, 313.
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6876.
4.5.1. N-Pivaloyl-2-(50-methyl-20-thienylmethyl)aniline (6). A color-
less oil (54% overall yield). 1H NMR (CDCl3, 400 MHz) 7.93 (d,
J¼8.0 Hz, 1H), 7.32e7.10 (m, 3H), 6.57e6.49 (m, 2H), 4.05 (s, 2H),

K.H. Kang et al. / Tetrahedron 69 (2013) 2542e2549
2549
11. (a) Basu, A.; Beak, P. J. Am. Chem. Soc. 1996, 118, 3757; (b) Basu, A.; Gallagher, D.
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13. We have prepared indolines ent-3aev for the convenience of chiral stationary
phase HPLC analysis (see Supplementary data for details).
ꢀ
ꢀ
ꢀ
ꢁꢀ
ꢁꢀ
ꢁ
ꢀ
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
12. (a) Safar, P.; Zuziova, J.; Bobosíkova, M.; Marchalín, S.; Tothova, E.; Pronayova,
ꢀ
ꢀ
ꢁ
N.; Svorc, L.; Vrabel, V.; Daïch, A. Tetrahedron: Asymmetry 2009, 20, 2137; (b)