Direct, enantioselective synthesis of pyrroloindolines and indolines from simple indole derivatives

Article abstract of DOI:10.1016/j.tet.2013.04.003

The (R)-BINOL·SnCl₄-catalyzed formal (3+2) cycloaddition between 3-substituted indoles and benzyl 2-trifluoroacetamidoacrylate is a direct, enantioselective method to prepare pyrroloindolines from simple starting materials. However, under the originally disclosed conditions, the pyrroloindolines are formed as mixtures of diastereomers, typically in the range of 3:1 to 5:1 favoring the exo-product. The poor diastereoselectivity detracts from the synthetic utility of the reaction. We report here that use of methyl 2-trifluoroacetamidoacrylate in conjunction with (R)-3,3′-dichloro- BINOL·SnCl₄ provides the corresponding pyrroloindolines with improved diastereoselectivity (typically ≥10:1). Guided by mechanistic studies, a one-flask synthesis of enantioenriched indolines by in situ reduction of a persistent iminium ion is also described.

Full text of DOI:10.1016/j.tet.2013.04.003

Tetrahedron 69 (2013) 5622e5633
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Direct, enantioselective synthesis of pyrroloindolines and indolines
from simple indole derivatives
*
Jane Ni, Haoxuan Wang, Sarah E. Reisman
The Warren and Katharine Schlinger Laboratory of Chemistry and Chemical Engineering, Division of Chemistry and Chemical Engineering,
California Institute of Technology, Pasadena, CA 91125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The (R)-BINOL$SnCl4-catalyzed formal (3þ2) cycloaddition between 3-substituted indoles and benzyl
2-trifluoroacetamidoacrylate is a direct, enantioselective method to prepare pyrroloindolines from
simple starting materials. However, under the originally disclosed conditions, the pyrroloindolines are
formed as mixtures of diastereomers, typically in the range of 3:1 to 5:1 favoring the exo-product. The
poor diastereoselectivity detracts from the synthetic utility of the reaction. We report here that use of
methyl 2-trifluoroacetamidoacrylate in conjunction with (R)-3,30-dichloro-BINOL$SnCl4 provides the
corresponding pyrroloindolines with improved diastereoselectivity (typically ꢀ10:1). Guided by mech-
anistic studies, a one-flask synthesis of enantioenriched indolines by in situ reduction of a persistent
iminium ion is also described.
Received 18 January 2013
Received in revised form 28 March 2013
Accepted 1 April 2013
Available online 6 April 2013
Keywords:
Pyrroloindoline
(3þ2) cycloaddition
Enantioselective catalysis
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
pyrroloindoline, and the synthetic challenge presented by this
structural feature has driven innovative research aimed at the
Nitrogen-containing heterocycles, such as indolines1 and pyr-
roloindolines,2 are prevalent in a variety of natural products that
exhibit an array of promising biological activities (see Fig. 1 for
representative examples).3 Many of these compounds possess
all-carbon quaternary stereocenters at C3 of the indoline or
discovery of new methods to stereoselectively prepare such het-
erocycles. These methods include several stereoselective trans-
formations starting from tryptophan,4 as well as catalytic
asymmetric reactions using both organo-5 and transition metal
catalysts.6
Fig. 1. Indoline and pyrroloindoline containing natural products.
In 2010, our group reported an enantioselective synthesis of
pyrroloindolines (8) via an (R)-BINOL$SnCl4-catalyzed formal (3þ2)
cycloaddition between 3-substituted indoles (5) and benzyl 2-
trifluoroacetamidoacrylate (6) (Scheme 1).7 Good yields, moderate
* Corresponding author. E-mail address: reisman@caltech.edu (S.E. Reisman).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.04.003

J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
5623
exo/endo diastereoselectivity, and high enantioselectivities were
obtained for a variety of indole substrates. Unexpectedly, studies
aimed at epimerizing C2 revealed that exo-8 and endo-8 possess the
opposite absolute configurations at the bridgehead carbons.
The proposed mechanism is consistent with Yamamoto’s prior
reports that (R)-BINOL$SnCl4 (11) behaves as a Lewis acid-
assisted Brønsted acid (LBA), which is capable of catalyzing the
enantioselective protonation of silyl enolates.9 However, the
Scheme 1. (R)-BINOL$SnCl4-catalyzed pyrroloindoline formation.
Although further mechanistic studies are required, this obser-
vation led us to propose a cooperative Lewis acid/Lewis acid-
assisted Brønsted acid (LBA) mechanism, shown in Scheme 2. Ac-
tivation of acrylate 6 by coordination to SnCl4 would result in re-
versible conjugate addition by the indole to generate a racemic
mixture of Sn-enolates 9 and ent-9. Highly face-selective pro-
tonation of 9/ent-9 by an (R)-BINOL$SnCl4 complex (11) would
serve to resolve the two enantiomers into diastereomers in a rate-
and stereoselectivity-determining step. In this scenario, the ee of
the two pyrroloindoline products would reflect the facial selectivity
of the protonation step, while the dr would reflect the difference in
protonation rates for the two chiral enolates 9 and ent-9, due to
matching and mismatching effects with chiral complex 11.8 The
stoichiometric proton source required to turn over complex 12
could potentially be the NeH of trifluoroacetamide exo-13/ent-
endo-13, which upon coordination to SnCl4 would be rendered
sufficiently acidic.
pyrroloindoline formation described above constitutes the first
example of a tandem conjugate addition/asymmetric protonation
process catalyzed by 11. Based on our mechanistic proposal for
pyrroloindoline formation, we recently identified similar condi-
tions for the synthesis of unnatural tryptophan derivatives (18)
from 2-substituted indoles (15) and methyl 2-acetamidoacrylate
(16), in which the sole stereogenic center is set during an
asymmetric protonation step (Scheme 3).10 This tandem Frie-
deleCrafts conjugate addition/asymmetric protonation reaction
provides direct access to a variety of tryptophan derivatives
(18) without the need for pre-functionalization of the indole
substrate.
Returning to the enantioselective pyrroloindoline synthesis
shown in Scheme 1, the fact that exo-8 and ent-endo-8 are of op-
posite enantiomeric series presents a practical challenge for syn-
thetic applications. Specifically, in order to preclude erosion of ee
during subsequent synthetic steps, it is imperative to separate the
Scheme 2. Proposed mechanism for pyrroloindoline formation.

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J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
Table 1
Catalyst screen
Entry
BINOL derivative
Yield (%)a
drb
ee (%)c
1
2
3
4
5
6
H (7)
88
63
65
63
63
73
10:1
6:1
8:1
8:1
16:1
14:1
90
82
86
90
90
91
6,60-(OMe)2 (22)
6,60-Br2 (23)
3,30-Me2 (24)
3,30-Br2 (17)
3,30-Cl2 (25)
Scheme 3. 17$SnCl4-catalyzed conjugate addition/asymmetric protonation.
a
Isolated yield of exo:endo mixture.
b
c
Determined by 1H NMR analysis of crude reaction mixture.
Determined by HPLC using chiral stationary phase.
two diastereomers. Unfortunately, depending on the indole sub-
stitution pattern, separation of the diastereomers can be tedious
using standard silica gel chromatography. In addition, the modest
diastereoselectivity results in lower isolated yields of the pure exo-
diastereomer. In an effort to identify conditions more amenable to
application in total synthesis endeavors, we sought to re-optimize
the reaction parameters for the formal (3þ2) cycloaddition with
the objective of improving the diastereoselectivity while maintain-
ing synthetically useful enantioselectivity. Herein, we report the
successful realization of this objective, as well as mechanism-
guided studies that resulted in the development of a one-flask re-
duction process for the direct synthesis of related indoline
derivatives.
With these newly optimized conditions in hand, a survey of
indole substrates was conducted (Table 2). As previously observed,
indoles bearing electron-donating substituents on the aryl back-
bone provide the highest yields; however, both electron-rich and
electron-poor substrates provide high ee’s. More sterically-
hindered indoles are less reactive and require 1.6 equiv of SnCl4,
but nevertheless furnish the desired pyrroloindolines in good yield
with high selectivity.
Having identified conditions that provide the pyrroloindoline
products with improved diastereoselectivity, we sought to obtain
further mechanistic insight by monitoring the reaction using in situ
1H NMR spectroscopy. For this purpose, we returned to the reaction
between 1,3-dimethylindole (5a) and benzyl 2-trifluoroacetami-
doacrylate (6) because it is homogeneous over the course of the
reaction. Fig. 2 shows a sample of 1H NMR spectra taken over the
first 9 h of the reaction, and reveals several interesting aspects of
this transformation. Notably, upon addition of SnCl4 and (R)-BINOL
(7) to a mixture of 5a and 6, the indole proton resonances broaden
significantly (Fig. 2, t¼0). This broadening is also observed in the
absence of acrylate 6; however, SnCl4 alone does not alter the 1H
NMR spectrum of 5a. It is possible that this broadening is due to
a rapid, dynamic proton exchange process promoted by 7$SnCl4,
2. Results and discussion
The optimization studies disclosed in our original report de-
termined that the enantio- and diastereoselectivity of pyrro-
loindoline formation was highly dependent on the substitution of
the 2-amidoacrylate: the highest enantioselectivity was obtained
using benzyl 2-trifluoroacetamidoacrylate (6), while the highest
diastereoselectivity was attained using methyl 2-trifluoroacetamido-
acrylate (20) (Scheme 4). In the latter case, the ee’s of the two di-
astereomers were only modestly reduced. Thus, we returned to the
use of acrylate 20 in the cycloaddition, and sought to improve the ee
and dr by optimizing the catalyst structure.
Scheme 4. Dependence of diastereoselectivity on acrylate substitution.
A screen of (R)-BINOL derivatives revealed that several catalysts
containing substitution at the 3- and 30-positions provided an
improvement in both dr and ee. Hypothesizing that catalyst se-
lectivity might correlate to the pKa of the BINOL OeH protons,
several 6,60-derivatives were also prepared in order to isolate the
electronic and steric effects; however, no linear correlation was
observed. Ultimately, (R)-3,30-Cl2-BINOL (25) was identified as the
catalyst that provided the optimal combination of ee, dr, and
overall yield (Table 1).
which is consistent with the finding that deuterated 5a undergoes
rapid DeH exchange under the reaction conditions. Interestingly,
the chemical shifts of the acrylate remain unchanged, indicating
that there is no significant accumulation of an acrylateeSnCl4
complex. Over the course of the reaction, resonances correspond-
ing to an indoleeacrylate adduct grow in; however, these peaks do
not correspond to the pyrroloindoline product.
We hypothesized that in the presence of a strong Lewis acid,
such as SnCl4, coordination of the amide might favor the ring-

J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
5625
Table 2
Given that iminium ions exo-14/ent-endo-14 are observed under
the reaction conditions, we wondered if it would be possible to trap
these intermediates with an external hydride source. The resulting
product would be an indoline-containing amino acid derivative
bearing an all-carbon quaternary stereocenter at the C3-position
(Scheme 5). Commonly employed strategies for the enantiose-
lective generation of indolines include asymmetric hydrogenation
of prochiral indoles,12 reduction of oxindoles,13 CeH activation of
substituted anilines,14 and kinetic resolution of racemic mixtures of
indolines.15 However, these methods are often limited in scope or
require multiple steps.
Substrate scope of pyrroloindoline formation
To assess the feasibility of our proposed transformation, the
formal (3þ2) cycloaddition was performed under the previously
optimized conditions, but in the presence of a reductant (Table 3).
Whereas weaker reductants such as triethylsilane and sodium
triacetoxyborohydride proved ineffective, we were pleased to
find that use of Hantzsch ester 29 did provide the indoline
product, albeit in low yield (entry 3). Alternatively, use of sodium
borohydride furnishes 28a in good yield, 15:1 dr, and 92% ee
(entry 5). The more soluble reducing agent lithium borohydride
provided
a lower yield of the desired product along with
a greater amount of byproducts. The limited solubility of NaBH4
and LiBH4 in methylene chloride likely contributes to the com-
patibility of all the reagents, allowing the reaction to be carried
out in one pot.
Having identified an optimal reducing agent, a survey of indole
substrates was conducted (Table 4). Indoles with either electron-
donating or -withdrawing substituents are good substrates for
the reaction. At the 3-position, n-butyl and phenylethyl groups are
tolerated, but reactivity decreases with increasing steric bulk, and
1.6 equiv of SnCl4 are required to achieve good reactivity. Whereas
cleavage of the protecting group was observed when TBS-protected
tryptophol was employed, use of the TIPS-protected trpytophol
furnished 28k in good yield. The indole nitrogen can also be pro-
tected with an allyl group, making this method more useful when
an N-Me functionality is not desired in the product.
a Determined by 1H NMR analysis of crude reaction mixture. Values in parentheses
are dr obtained using acrylate 6 and catalyst 7. b Determined by SFC using chiral
stationary phase. Values in parentheses are ee obtained using acrylate 6 and catalyst 7.
c Isolated yield of exo-diastereomer. d 1.6 equiv SnCl4 was employed.
The reduced products 28 are formed with the same di-
astereomeric and enantiomeric ratios as the corresponding pyrro-
loindolines, suggesting that the reduction does not affect the
selectivities of the other steps. If a methylene chloride solution of
pyrroloindoline exo-8a and SnCl4 is re-exposed to sodium boro-
hydride, the pyrroloindoline is reduced to indoline 28a in quanti-
tative yield (Scheme 6).
opened iminium ions exo-14/ent-endo-14. To test this hypothesis,
we resubjected diastereomerically pure exo-8a to SnCl4 (1.2 equiv)
and varying equivalents of (R)-BINOL (7) (Fig. 3). The NMR spectra
of the mixtures were dependent on the concentration of 7. In the
presence of 20 mol % 7, the 1H NMR spectrum closely resembles
that of the indoleeacrylate adduct observed in the 1H NMR ex-
periment. Notably, this species exhibits a resonance between 9 and
10 ppm (depending on concentration of 7, Fig. 3a and b), which we
assign to the indolinium proton (Hb). In addition, the N-methyl
group (Ha) in this species is shifted downfield relative to the pyr-
roloindoline (4.0 ppm vs 3.1 and 2.9 ppm for the two rotamers of
the exo-diastereomer), and is consistent with literature data for
other iminium ions.11 This structural assignment is further sup-
ported by 2D 1He13C NMR correlation data. In the presence of SnCl4
alone, the pyrroloindoline peaks broaden, likely due to dynamic
interconversion between the ring-opened and -closed forms
(Fig. 3c). The fact that addition of 1.2 equiv of 7 resolves this mixture
into one species suggests that 7$SnCl4, an LBA,9a might preferen-
tially stabilize the open structure. Importantly, following aqueous
work-up, pyrroloindoline exo-8a is cleanly reisolated with no in-
dication of epimerization or racemization.
3. Conclusion
Building on our initial report of a formal (3þ2) cycloaddition
between 3-substituted indoles and 2-amidoacrylates to yield
enantioenriched pyrroloindolines, we have further optimized the
catalyst structure to significantly improve the diastereoselectivity
of this reaction while maintaining comparable yields and ee’s.
Subsequent NMR studies have provided a more thorough un-
derstanding of this reaction, revealing that the initial product of the
reaction is an indolinium ion. Based on these findings, a method has
been developed to trap this intermediate with sodium borohydride
to yield enantioenriched indoline products with a quaternary
stereocenter at C3. The study and development of additional
transformations that proceed by cooperative Lewis acideLBA
mechanisms are the subject of ongoing research in our laboratory.
The progress of the reaction can be quantified by integrating the
vinyl protons of the acrylate relative to 1,4-diethylbenzene as an
internal standard. However, further kinetic analysis of the (R)-
BINOL-catalyzed reaction has been complicated by several factors,
including the racemic background reaction (particularly at higher
SnCl4: (R)-BINOL ratios) and product inhibition.
4. Experimental section
4.1. General
Unless otherwise stated, reactions were performed under a ni-
trogen atmosphere using freshly dried solvents. Tetrahydrofuran

5626
J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
Fig. 2. In situ monitoring of the formal (3þ2) cycloaddition using 1H NMR.
Fig. 3. NMR spectra of (a) pyrroloindoline exo-8a, SnCl4 (1.2 equiv), (R)-BINOL (7) (1.2 equiv) (b) pyrroloindoline exo-8a, SnCl4 (1.2 equiv), (R)-BINOL (7) (0.2 equiv) (c) pyrro-
loindoine exo-8a, SnCl4 (1.2 equiv) (d) pyrroloindoline exo-8a.

J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
5627
t¼triplet, q¼quartet, m¼multiplet, br¼broad, app¼apparent. IR
spectra were recorded on a Perkin Elmer Paragon 1000 spec-
trometer and are reported in frequency of absorption (cmꢁ1).
Preparatory HPLC was performed with either an Agilent 1100 or
1200 Series HPLC utilizing an Agilent Zorbax RX-SIL 5 mm column
(9.4ꢂ250 mm). Analytical SFC was performed with a Mettler SFC
supercritical CO2 analytical chromatography system with Chiralcel
AD-H, OJ-H columns (4.6 mmꢂ25 cm). Melting points were de-
€
termined using a Buchi B-545 capillary melting point apparatus
and the values reported are uncorrected. HRMS were acquired
using either an Agilent 6200 Series TOF with an Agilent G1978A
Multimode source in electrospray ionization (ESI), atmospheric
pressure chemical ionization (APCI) or mixed (MM) ionization
mode, or obtained from the Caltech Mass Spectral Facility.
Abbreviations used: BINOL: 1,10-Bi(2-naphthol); IPA: iso-
propanol; dba: dibenzylidineacetone.
Scheme 5. Intercepting an iminium ion intermediate to yield indolines.
4.2. Preparation of indole substrates
4.2.1. 1,3,4-Trimethyl-1H-indole. Procedure for VilsmeiereHaack
reaction followed by LiAlH4 reduction was adapted from Petit
et al.16 In a flame-dried flask under nitrogen, POCl3 (0.42 mL,
4.6 mmol) was added at 0 ꢃC to 4-methyl-1H-indole (0.5 g,
3.8 mmol) in DMF (7.6 mL). The reaction was stirred at room
temperature overnight. 2 N NaOH(aq) was then added, the solution
was stirred for 2 h, then poured into EtOAc. The organic layer was
washed with brine, dried (Na2SO4), filtered, and concentrated. The
crude aldehyde was carried forward without further purification.
In a flame-dried flask under nitrogen, a solution of the Vils-
meiereHaack product (0.39 g, 2.5 mmol) in THF (5 mL) was added
dropwise to a suspension of LiAlH4 (0.19 g, 5 mmol) in THF (1.6 mL).
The reaction was heated to reflux for 4 h, then cooled to room
temperature and stirred overnight. The reaction was diluted with
Et2O and cooled to 0 ꢃC. Water (0.19 mL) was added slowly, then
15% NaOH(aq) (0.19 mL), then water (0.6 mL) were added. The
mixture was warmed to room temperature and stirred for 15 min.
Some MgSO4 was added, the mixture was stirred for 15 min, fil-
tered, and concentrated. The crude indole was carried forward
without further purification.
Table 3
Screen of reducing agents
Entry
Reductant
Yield (%)
1
2
3
4
5
Et3SiH
0
0
3
NaBH(OAc)3
Hantzsch ester 29
LiBH4
85
NaBH4
93a
a
Product isolated in 15:1 dr and 92% ee.
In a flame-dried flask, the indole (0.3 g, 2.1 mmol) was dissolved
in THF (13 mL). Sodium hydride (60% w/w, 124 mg, 3.1 mmol) was
added in one portion, then methyl iodide (0.26 mL, 4.1 mmol) was
added dropwise. The reaction was stirred at room temperature
until consumption of starting material was observed by TLC. The
reaction was diluted with ethyl acetate and the excess NaH was
quenched with water. The organic layer was separated, and the
aqueous layer was extracted 3ꢂ with ethyl acetate. The combined
organic layers were washed with brine, dried (MgSO4), filtered, and
concentrated under reduced pressure. The crude residue was pu-
rified by flash chromatography. 44% yield over three steps.
(THF), methylene chloride (CH2Cl2), and toluene were dried by
passing through activated alumina columns. Deuterated methylene
chloride (CD2Cl2) was dried by passing through a plug of activated
alumina in a glovebox. Dimethylformamide (DMF) was dried over
activated molecular sieves, dichloroethane (DCE) was distilled over
calcium hydride. All other commercially obtained reagents were
used as received unless specifically indicated. All reactions were
monitored by thin-layer chromatography using EMD/Merck silica
gel 60 F254 pre-coated plates (0.25 mm). Flash column chroma-
tography was performed either as described by Still et al. (Still, W.
C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923e2925.) using
silica gel (particle size 0.032e0.063) purchased from Silicycle or
using pre-packaged RediSepÒRf columns on a CombiFlash Rf sys-
tem (Teledyne ISCO Inc.). Diastereomeric ratios were determined
by integration of crude NMR spectra. Optical rotations were mea-
sured on a Jasco P-2000 polarimeter using a 100 mm path-length
cell at 589 nm. 1H and 13C NMR spectra were recorded on a Varian
Mercury 300 (at 300 MHz and 75 MHz, respectively), a Varian 400
(at 400 MHz and 100 MHz, respectively) or a Varian Inova 500 (at
500 MHz and 125 MHz, respectively), and are reported relative to
1H NMR (500 MHz, CDCl3)
1.4, 0.8 Hz, 1H), 6.76 (d, J¼0.9 Hz, 1H), 3.69 (s, 3H), 2.72 (s, 3H), 2.51
(s, 3H); 13C NMR (100 MHz, CDCl3)
137.5, 131.4, 126.9, 126.7, 121.5,
d
7.12e7.05 (m, 2H), 6.81 (ddd, J¼6.6,
d
120.0, 110.9, 107.0, 32.5, 20.0, 12.8; IR (NaCl/thin film): 2918, 1608,
1573, 1551, 1497, 1453, 1417, 1313, 1250, 1205, 1157, 1057, 767,
739 cmꢁ1
.
4.2.2. 1,3,7-Trimethyl-1H-indole. Prepared according to the pro-
cedure for 1,3,4-trimethyl-1H-indole. Spectral data matches that
reported in the literature.17
4.2.3. 1,3-Dimethyl-5-reverse prenyl-1H-indole. In
a
glovebox,
internal chloroform (1H,
d
¼7.26, 13C,
d
¼77.0). Data for 1H NMR
Pd2(dba)3 (51 mg, 6 mmol) and SPhos (91 mg, 22 mmol) in THF
(3 mL) were stirred at room temperature for 1 h until a dark
yellow homogeneous solution was formed. The solution was then
transferred to a Schlenk tube, and 5-iodo-1,3-dimethyl-1H-indole
spectra are reported as follows: chemical shift (d parts per million)
(multiplicity, coupling constant (Hertz), integration). Multiplicity
and qualifier abbreviations are as follows: s¼singlet, d¼doublet,

5628
J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
Table 4
In situ reduction for the synthesis of indolines
a Determined by 1H NMR analysis of crude reaction mixture.
b Determined by SFC using chiral stationary phase.
c Isolated yield of exo-diastereomer. d 1.6 equiv SnCl4 was employed.
(300 mg, 1.11 mmol), trifluorosilane18 (256 mg in 2.1 mL THF,
1.66 mmol), TBAF (1 M solution in THF, 1.66 mL), and THF (7 mL)
were added. The reaction mixture was heated to 60 ꢃC for 36 h.
Additional portions of TBAF (1 M solution in THF, 0.55 mL) were
added at 12-h intervals. 5% EtOAc in hexanes was then added to
the reaction, and the mixture was filtered through a silica gel
plug. The solution was concentrated, and the crude orange oil
was purified by flash chromatography (5%e9% EtOAc in hexanes)
to give the reverse prenylated indole as a light yellow oil (177 mg,
0.84 mmol, 76% yield). 1H NMR (500 MHz, CDCl3) 7.51 (t,
J¼0.9 Hz, 1H), 7.24 (dd, J¼8.7, 1.83 Hz, 1H), 7.21 (d, J¼8.5 Hz, 1H),
6.80 (d, J¼1.0 Hz, 1H), 6.13 (dd, J¼17.5, 10.6 Hz, 1H), 5.09 (dd,
J¼17.6, 1.5 Hz, 1H), 5.04 (dd, J¼10.5, 1.5 Hz, 1H), 3.71 (s, 3H), 2.32
(d, J¼1.0 Hz, 3H), 1.49 (s, 6H); 13C NMR (126 MHz, CDCl3) 149.1,
138.8, 135.4, 128.3, 126.7, 120.6, 115.5, 110.1, 109.9, 108.5, 41.1, 32.5,
28.8, 9.5; IR (NaCl/thin film): 3080, 2964, 2920, 1634, 1489, 1455,
1425, 1387, 1376, 1365, 1292, 1256, 1201, 1152, 1053, 1004, 909,
874, 788; HRMS (MM) calcd for C15H19N [MþH]þ 214.1590, found
214.1592.
4.3. General procedure for the formal (3D2) cycloaddition of
indoles and acrylates
To a flame-dried flask was added indole (0.20 mmol, 1.00 equiv),
acrylate (0.20 mmol, 1.00 equiv), and (R)-3,30-dichloro-BINOL
(0.04 mmol, 0.20 equiv). The flask was charged with CH2Cl2
(1.5 mL), followed by addition of SnCl4 (0.24 mmol, 1.20 equiv un-
less specifically indicated, 1 M in CH2Cl2), then stirred at room
temperature. The reaction was quenched by diluting with 1 mL
MeCN and 1 mL 1 M HCl, followed by addition of 5 mL H2O. The
aqueous layer was extracted with diethyl ether (3ꢂ15 mL) and the
combined organic layers were washed with 3 N NaOH(aq) (10 mL).
The combined organic layers were dried (MgSO4), filtered,
and concentrated. The crude residue was purified by flash
chromatography.
4.3.1. Pyrroloindoline 21a. The dr was determined to be 14:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (5/10% ethyl acetate/hexanes)
to yield 49.4 mg (73% yield) of 21a. The enantiomeric excess was
determined to be 91% by chiral SFC analysis (AD-H, 2.5 mL/min, 7%
IPA in CO2,
l
¼254 nm): tR (major)¼2.9 min tR (minor)¼2.4 min.
Spectral data matches that reported in the literature.7
4.3.2. Pyrroloindoline 21b. The dr was determined to be 7:1 by 1
H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (0/10% ethyl acetate/hexanes)
to yield 49.1 mg (69% yield) of 21b. The enantiomeric excess was
Scheme 6. Re-exposure of pyrroloindoline exo-8a to SnCl4 and NaBH4.

J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
5629
x
determined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 7%
IPA in CO2,
major diastereomer was separated by flash chromatography
(0/10% ethyl acetate/hexanes). 1H NMR (500 MHz, CDCl3; com-
pound exists as a 3.7:1 mixture of rotamers, the major rotamer is
by *, minor rotamer denoted by
)
d
172.6*, 170.6x, 159.1x (q,
l¼254 nm): tR (major)¼3.1 min tR (minor)¼2.3 min. The
JCeF¼37.9 Hz), 149.6*, 149.4x, 139.0x, 138.9*, 131.5*, 131.4x, 121.2*x,
120.6x, 119.3*, 116.1* (q, JCeF¼288.4 Hz), 110.4x, 108.9*, 93.5*, 91.9x,
61.3x, 60.3*, 53.0*, 52.9x, 52.5x, 49.0*, 44.0*, 40.5x, 36.7*, 34.6x, 23.6*,
23.0x, 21.7*; IR (NaCl/thin film): 2958, 2929, 2875, 2813, 1750, 1697,
denoted by *, minor rotamer denoted by x)
d
7.08 (t, J¼7.8 Hz, 1H*,
1617,1594,1499,1435,1382,1356,1341,1294,1257,1203,1190,1148,
25
1Hx), 6.65e6.57 (m,1Hx), 6.55 (d, J¼7.6 Hz,1H*), 6.45e6.40 (m,1Hx),
6.38 (d, J¼7.8 Hz, 1H*), 5.49 (s, 1H*), 5.29 (s, 1Hx), 4.74 (d, J¼9.3 Hz,
1H*), 4.45 (m, 1Hx), 3.83 (s, 3H*), 3.78 (s, 3Hx), 3.12 (s, 3H*), 2.85 (s,
3Hx), 2.68 (dd, J¼13.3, 9.7 Hz, 1H*), 2.64e2.59 (m, 1Hx), 2.53 (dd,
J¼13.3, 1.6 Hz, 1H*), 2.33 (s, 3Hx), 2.31 (s, 3H*), 2.20e2.10 (m, 1Hx),
1.60 (s, 3Hx), 1.47 (s, 3H*); 13C NMR (125 MHz, CDCl3; compound
exists as a 3.7:1 mixture of rotamersx, the major rotamer is denoted
1111,1094,1059,1034,1006, 985, 877, 852, 803, 763, 729 cmꢁ1; [
a]
D
ꢁ115.4 (c 1.54, CHCl3). HRMS (MM) calcd for C17H19F3N2O3 [MþH]þ
357.1421, found 357.1434.
4.3.5. Pyrroloindoline 21e. The dr was determined to be 15:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (5/25% ethyl acetate/hexanes)
to yield 48.1 mg (68% yield) of 21e (major diastereomer only). The
enantiomeric excess was determined to be 93% by chiral SFC
by *, minor rotamer denoted by
) d
172.7*, 170.5x, 159.0x (q,
JCeF¼37.2 Hz), 150.6*, 149.7x, 133.1x, 132.7*, 131.6*, 130.9x, 128.8*x,
122.6x, 121.5*, 116.1* (q, JCeF¼288.3 Hz), 107.3x, 106.2*, 94.0*, 92.0x,
61.3x, 60.0*, 53.1*, 52.6x, 50.0*, 42.7*, 39.4x, 37.4*, 34.6x, 24.1*, 23.3x,
18.5*x; IR (NaCl/thin film): 3047, 2957, 2930, 2880, 2825, 1752, 1701,
1596, 1477, 1434, 1385, 1356, 1338, 1293, 1263, 1254, 1216, 1204,
analysis (AD-H, 2.5 mL/min, 7% IPA in CO2,
l¼254 nm): tR (major)¼
3.6 min tR (minor)¼2.5 min. 1H NMR (500 MHz, CDCl3; compound
exists as a 6.1:1 mixture of rotamers, the major rotamer is denoted
by *, minor rotamer denoted by x)
d 7.05e7.00 (m, 1H*), 7.00e6.93
1155, 1097, 1064, 1020, 989, 854, 772, 744, 727 cmꢁ1; [
a]
25 ꢁ158.8 (c
(m, 2H*, 1Hx), 6.91 (d, J¼7.2 Hz, 1Hx), 6.82 (t, J¼7.4 Hz, 1Hx), 5.27 (s,
1Hx), 5.14 (d, J¼1.6 Hz, 1H*), 4.59 (dd, J¼9.1, 2.3 Hz, 1Hx), 4.06 (dd,
J¼11.2, 6.6 Hz, 1H*), 3.80 (s, 3Hx), 3.72 (s, 3H*), 3.26 (s, 3Hx), 2.99
(s, 3H*), 2.67 (dd, J¼12.6, 6.6 Hz, 1H*), 2.57 (dd, J¼13.4, 9.2 Hz, 1Hx),
2.30 (s, 3Hx), 2.22 (s, 3H*), 2.13e2.03 (m, 1H*, 1Hx), 1.47 (s, 3H*), 1.42
(s, 3Hx); 13C NMR (125 MHz, CDCl3; compound exists as a 6.1:1
mixture of rotamers, the major rotamer is denoted by *, minor
D
1.01, CHCl3). HRMS (APCI) calcd for C17H19F3N2O3 [MþH]þ 357.1421,
found 357.1426.
4.3.3. Pyrroloindoline 21c. The dr was determined to be 13:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (0/10% ethyl acetate/hexanes)
to yield 51.3 mg (72% yield) of 21c. The enantiomeric excess was
determined to be 89% by chiral SFC analysis (AD-H, 2.5 mL/min, 5%
rotamer denoted by x) 172.6x, 171.1*, 158.7*, 149.9*, 148.8x, 136.6*x,
d
131.4x, 131.0*, 126.6*, 124.01*, 122.6x, 121.2x, 119.6*, 119.4x, 116.0* (q,
JCeF¼285.8 Hz), 95.6x, 92.5*, 60.3*, 59.2x, 55.1*, 52.9x, 52.4*, 49.7x,
44.0x, 41.9x, 41.0*, 38.6*, 26.3*, 26.0x, 18.9x, 17.5*; IR (NaCl/thin film):
IPA in CO2,
l
¼254 nm): tR (major)¼4.4 min tR (minor)¼2.7 min. The
major diastereomer was separated by flash chromatography
(0/10% ethyl acetate/hexanes). 1H NMR (500 MHz, CDCl3; com-
pound exists as a 1.9:1 mixture of rotamers, the major rotamer is
2963, 1753, 1684, 1437, 1359, 1269, 1162, 1120, 1103, 1086, 1067,
25
977 cmꢁ1; [
a]
ꢁ27.0 (c 0.91, CH2Cl2). HRMS (MM) calcd for
D
denoted by *, minor rotamer denoted by x)
d
6.98 (d, J¼7.4 Hz, 1H*,
C17H19F3N2O3 [MþH]þ 357.1421, found 357.1434.
1Hx), 6.87 (s, 1Hx), 6.84 (s, 1H*), 6.50 (d, J¼7.8 Hz, 1Hx), 6.43
(d, J¼8.0 Hz, 1H*), 5.57 (s, 1H*), 5.27 (s, 1Hx), 4.73 (d, J¼9.3 Hz, 1H*),
4.41 (t, J¼7.6 Hz, 1Hx), 3.82 (s, 3H*), 3.76 (s, 3Hx), 3.05 (s, 3H*), 2.86
(s, 3Hx), 2.59 (dd, J¼13.3, 9.7 Hz, 1H*), 2.55e2.48 (m, 1Hx), 2.35 (dd,
J¼13.5, 2.2 Hz,1H*), 2.28 (br s, 3Hx), 2.20e2.10 (m,1Hx),1.49 (s, 3Hx),
1.38 (s, 3H*); 13C NMR (125 MHz, CDCl3; compound exists as a 1.9:1
mixture of rotamers, xthe major rotamer is denoted by *, minor
4.3.6. Pyrroloindoline 21f. The dr was determined to be 10:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (5/25% ethyl acetate/hexanes) to
yield 41.4 mg (58% yield) of 21f. The enantiomeric excess was de-
termined to be 92% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA
in CO2,
l
¼254 nm): tR (major)¼3.7 min tR (minor)¼2.3 min. The
rotamer denoted by
)
d
172.6*, 170.7x, 159.1x (q, JCeF¼37.0 Hz),
major diastereomer was separated by flash chromatography
(0/10% ethyl acetate/hexanes). 1H NMR (500 MHz, CDCl3; com-
pound exists as a 2.0:1 mixture of rotamers, the major rotamer is
147.3*, 147.2x, 134.4*x, 129.7x, 129.2x, 129.1*, 128.2*, 122.3*x, 116.1* (q,
JCeF¼288.2 Hz), 109.9x, 108.2*, 93.8*, 92.1x, 61.2x, 60.3*, 53.2x, 53.0*,
52.5x, 49.2*, 44.0*, 40.3x, 37.4*, 35.5x, 23.5*, 23.2x, 20.8*x; IR (NaCl/
thin film): 2958, 2924, 2873, 2822, 1750, 1699, 1618, 1500, 1435,
denoted by *, minor rotamer denoted by x) 6.92e6.82 (m,1H*,1Hx),
d
6.81e6.76 (m, 1Hx), 6.74 (dd, J¼8.0, 2.7 Hz, 1H*), 6.50 (dd, J¼8.6,
4.1 Hz, 1Hx), 6.40 (dd, J¼8.6, 4.1 Hz, 1H*), 5.60 (s, 1H*), 5.31 (s, 1Hx),
4.74 (d, J¼9.3 Hz, 1H*), 4.43 (t, J¼7.8 Hz, 1Hx), 3.82 (s, 3H*), 3.77 (s,
3Hx), 3.04 (s, 3H*), 2.85 (s, 3Hx), 2.58 (dd, J¼13.5, 9.6 Hz, 1H*),
2.53e2.45(m,1Hx), 2.40e2.32(m,1H*), 2.06 (dd, J¼13.3, 6.6 Hz,1Hx),
1.49 (s, 3Hx), 1.38 (s, 3H*); 13C NMR (125 MHz, CDCl3; compound
exists as a 2.0:1 mixture of rotamersx, the major rotamer is denoted
1384, 1356, 1339, 1288, 1257, 1201, 1152, 1117, 1094, 1057, 1035, 986,
25
874, 844, 807, 761, 728 cmꢁ1; [
a
]
ꢁ128.4 (c 1.08, CHCl3). HRMS
D
(APCI) calcd for C17H19F3N2O3 [MþH]þ 357.1421, found 357.1407.
4.3.4. Pyrroloindoline 21d. The dr was determined to be 14:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (0/10% ethyl acetate/hexanes)
to yield 56.3 mg (79% yield) of 21d. The enantiomeric excess was
determined to be 89% by chiral SFC analysis (AD-H, 2.5 mL/min, 5%
by *, minor rotamer denoted by
) d
172.4*, 170.5x, 159.0x (q,
JCeF¼35.8 Hz), 157.9*, 156.7x, 156.0*, 145.6*, 145.4x, 135.8x (d,
JCeF¼8.7 Hz),135.6* (d, JCeF¼7.5 Hz),116.0* (q, JCeF¼289.2 Hz),115.1x,
114.8* (d, JCeF¼23.2 Hz), 110.5x (d, JCeF¼7.3 Hz), 110.2x (d,
JCeF¼24.3 Hz), 109.4x (d, JCeF¼24.1 Hz), 109.3* (d, JCeF¼24.4 Hz),
108.6* (d, JCeF¼8.1 Hz), 105.9x (d, JCeFCeF¼8.0 Hz), 93.8*, 92.1x, 61.1x,
60.2*, 53.2x, 53.1*, 52.6x, 49.2x, 43.8*, 40.1x, 37.6*, 35.5x, 23.4*, 22.9x;
IR (NaCl/thin film): 2959, 2880, 2825, 1750, 1699, 1611, 1495, 1436,
1386,1356,1339,1270,1229,1202,1178,1152,1118,1091,1052,1034,
IPA in CO2,
l
¼254 nm): tR (major)¼3.4 min tR (minor)¼2.8 min. The
major diastereomer was separated by flash chromatography
(0/10% ethyl acetate/hexanes). 1H NMR (500 MHz, CDCl3; com-
pound exists as a 2.4:1 mixture of rotamexrs, the major rotamer is
denoted by *, minor rotamer denoted by )
d
6.99e6.93 (m, 1Hx),
6.91 (d, J¼7.4 Hz, 1H*), 6.65 (d, J¼6.7 Hz, 1Hx), 6.58 (d, J¼7.3 Hz,
1H*), 6.41 (s, 1Hx), 6.34 (s, 1H*), 5.60 (s, 1H*), 5.31 (s, 1Hx), 4.72 (d,
J¼9.0 Hz, 1H*), 4.48e4.39 (m, 1Hx), 3.82 (s, 3H*), 3.77 (s, 3Hx), 3.06
(s, 3H*), 2.86 (s, 3Hx), 2.58 (dd, J¼13.2, 9.2 Hz, 1H*), 2.52e2.45 (m,
1Hx), 2.39e2.33 (m, 1H*), 2.32 (br s, 3H*, 3Hx), 2.10e2.00 (m, 1Hx),
1.49 (s, 3Hx), 1.38 (s, 3H*); 13C NMR (125 MHz, CDCl3; compound
exists as a 2.4:1 mixture of rotamers, the major rotamer is denoted
986, 872, 845, 808, 756, 728 cmꢁ1; [
a
]
25 ꢁ108.5 (c 1.08, CHCl3). HRMS
D
(APCI) calcd for C16H16F4N2O3 [MþH]þ 361.1170, found 361.1187.
4.3.7. Pyrroloindoline 21g. The dr was determined to be 10:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (0/10% ethyl acetate/hexanes)

5630
J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
to yield 44.8 mg (61% yield) of 21g. The enantiomeric excess was
determined to be 90% by chiral SFC analysis (AD-H, 2.5 mL/min, 5%
NMR (125 MHz, CDCl3; compound exists as a 4.9:1 mixture of
rotamers, thxe major rotamer is denoted by *, minor rotamer
IPA in CO2,
l
¼254 nm): tR (major)¼3.8 min tR (minor)¼2.5 min. The
denoted by
)
d
172.6*, 170.6x, 158.9x (q, JCeF¼36.9 Hz), 148.4*,
major diastereomer was separated by flash chromatography
134.7*, 133.8*, 133.3x, 128.7*, 121.7x, 121.5*, 120.3x, 118.8*, 117.8x,
116.8*, 116.0* (q, JCeF¼288.4 Hz), 110.8x, 108.5*, 91.3*, 89.6x, 60.9x,
59.9*, 53.0*, 52.5x, 51.8*, 50.4x, 49.4*, 44.3*, 40.8x, 23.7*, 23.4x; IR
(NaCl/thin film): 3053, 2958, 2877, 1751, 1700, 1691, 1685, 1642,
1608,1487,1437,1384,1356,1340,1309,1257,1205,1151,1106,1093,
(0/10% ethyl acetate/hexanes). 1H NMR (500 MHz, CDCl3; com-
pound exists as a 1.8:1 mixture of rotamers, the major rotamer is
x
denoted by *, minor rotamer denoted by )
d 6.75e6.70 (m, 1H*,
1Hx), 6.67e6.65 (m, 1Hx), 6.64 (d, J¼2.4 Hz, 1H*), 6.55 (d, J¼8.5 Hz,
1Hx), 6.45 (d, J¼8.5 Hz, 1H*), 5.55 (s, 1H*), 5.24 (s, 1Hx), 4.74 (d,
J¼9.4 Hz,1H*), 4.38 (t, J¼8.0 Hz,1Hx), 3.81 (s, 3H*), 3.77 (s, 3Hx), 3.76
(s, 3H*, 3Hx), 3.04 (s, 3H*), 2.86 (s, 3Hx), 2.59 (dd, J¼13.5, 9.6 Hz,
1H*), 2.52 (dd, J¼13.0, 8.7 Hz, 1Hx), 2.35 (dd, J¼13.5, 2.5 Hz, 1H*),
2.09e2.00 (m, 1Hx), 1.48 (s, 3Hx), 1.38 (s, 3H*); 13C NMR (125 MHz,
CDCl3; compound exists as a 1.8:1 mixture of rotamersx, the major
1027, 991, 925, 841, 817, 792, 744 cmꢁ1; [
a
]
25 ꢁ146.2 (c 1.60, CHCl3).
D
HRMS (APCI) calcd for C18H19F3N2O3 [MþH]þ 369.1421, found
369.1416.
4.3.10. Pyrroloindoline ent-endo-21i. 1H NMR (500 MHz, CDCl3;
compound exists as a 15.0:1 mixture of rotamers, the major
x
rotamer is denoted by *, minor rotamer denoted by
) d 172.5*,
rotamer is denoted by *, minor rotamer denoted by )
d 7.11e7.07
170.7x, 159.0x (q, JCeF¼37.1, 36.6 Hz), 154.6x, 153.6*, 143.7*, 143.6x,
135.9x, 135.7*, 116.1* (q, JCeF¼288.3 Hz), 113.3x, 113.0*, 111.4x,
109.02*, 108.98*, 108.8x, 94.1*, 92.3x, 61.0x, 60.3*, 56.0*, 55.9x, 53.6x,
53.1*, 52.6x, 49.3*, 43.9*, 39.9x, 38.1*, 36.8x, 23.5*x; IR (NaCl/thin
film): 2958, 2833, 1750, 1691, 1598, 1497, 1434, 1384, 1356, 1341,
1281, 1259, 1231, 1203, 1154, 1093, 1062, 1031, 986, 870, 844, 808,
(m, 1Hx), 7.06 (td, J¼7.6, 1.3 Hz, 1H*), 7.06e7.03 (m, 1Hx), 6.98 (dd,
J¼7.3, 0.7 Hz,1H*), 6.73 (td, J¼7.4, 1.0 Hz,1Hx), 6.66 (td, J¼7.4, 1.0 Hz,
1H*), 6.46e6.44 (m, 1Hx), 6.44 (d, J¼7.9 Hz, 1H*), 5.87 (dddd, J¼17.1,
10.3, 5.9, 5.1 Hz, 1H*), 5.82e5.75 (m, 1Hx), 5.57 (s, 1H*), 5.53 (d,
J¼1.4 Hz, 1Hx), 5.30 (dq, J¼17.2, 1.7 Hz, 1H*), 5.22e5.19 (m, 1Hx), 5.16
(dq, J¼10.2, 1.5 Hz, 1H*), 5.10 (dd, J¼9.5, 4.5 Hz, 1Hx), 4.75 (dt, J¼8.4,
1.3 Hz,1H*), 4.24e4.13 (m, 2H*), 3.85 (ddd, J¼49.3,17.2, 5.1 Hz, 2Hx),
3.53 (s, 3Hx), 3.17 (s, 3H*), 2.85 (d, J¼13.0 Hz, 1H*), 2.50 (dd, J¼13.2,
4.5 Hz, 1Hx), 2.39 (dd, J¼13.0, 8.4 Hz, 1H*), 2.25 (dd, J¼13.3, 9.6 Hz,
1Hx), 1.44 (s, 3Hx), 1.42 (s, 3H*); 13C NMR (125 MHz, CDCl3; com-
756, 728 cmꢁ1; [
a]
25 ꢁ103.2 (c 0.82, CHCl3). HRMS (APCI) calcd for
D
C17H19F3N2O4 [MþH]þ 373.1370, found 373.1383.
4.3.8. Pyrroloindoline 21h. The dr was determined to be 13:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (5/20% ethyl acetate/hexanes)
to yield 74.1 mg (86% yield) of 21h. The enantiomeric excess was
determined to be 87% by chiral SFC analysis (AD-H, 2.5 mL/min, 8%
pound exists as a 15.0:1 mixture of rotamers, the major rotamer is
x
denoted by *, minor rotamer denoted by
) d
170.0*, 156.8x (q,
JCeF¼36.8 Hz), 149.3*, 147.8x, 134.2*, 133.2x, 132.6x, 132.0*, 128.9*,
128.6x, 122.5*, 121.7x, 118.7x, 118.0*, 117.1x, 116.3*, 116.1* (q,
JCeF¼288.6 Hz), 108.0x, 106.8*, 88.7x, 88.1*, 60.3x, 60.1* (q,
JCeF¼3.1 Hz), 52.6x, 52.5x, 52.4*, 50.6*, 49.0*, 46.6x, 42.5*, 41.4x,
25.7*, 22.9x; IR (NaCl/thin film): 3055, 2954, 2869, 1760, 1742, 1699,
1607, 1490, 1447, 1436, 1338,1317, 1274, 1254, 1208, 1183, 1144, 1105,
IPA in CO2,
l
¼254 nm): tR (major)¼5.3 min tR (minor)¼8.1 min. The
major diastereomer was separated by flash chromatography (5%
ethyl acetate/hexanes). 1H NMR (500 MHz, CDCl3; compound exists
as a 2.6:1 mixture of rotamers, the major rotamer is denoted by *,
x
d
7.32e7.15 (m, 4H*, 4Hx), 7.08 (br t,
1093, 1032, 999, 942, 922, 887, 842, 859, 742 cmꢁ1; [
a]
25 þ188.1 (c
minor rotamer denoted by )
D
J¼7.7 Hz, 3H*, 3Hx), 6.95e6.75 (m, 1H*, 1Hx), 6.65e6.50 (m, 1H*,
1Hx), 5.72 (br s, 1H*), 5.46 (br s, 1Hx), 4.65 (br d, J¼6.3 Hz, 1H*), 4.33
(br s, 1Hx), 3.78 (br s, 3H*, 3Hx), 3.13 (br s, 3H*), 2.90 (br s, 3Hx),
2.76e1.87 (m, 6H*, 6Hx); 13C NMR (125 MHz, CDCl3; compound
exists as a 2.6:1 mixture of rotamersx, the major rotamer is denoted
0.275, CHCl3). HRMS (APCI) calcd for C18H19F3N2O3 [MþH]þ
369.1421, found 369.1429.
4.3.11. Pyrroloindoline 21j. The dr was determined to be 18:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (0/10% ethyl acetate/hexanes)
to yield 68.6 mg (84% yield) of 21j. The enantiomeric excess was
determined to be 92% by chiral SFC analysis (OD, 2.5 mL/min, 3% IPA
by *, minor rotamer denoted by
) d
172.6*, 170.6x, 159.0* (q,
JCeF¼37.5 Hz), 150.3*x, 141.1*x, 131.9*, 131.7x, 129.0*x, 128.5*x, 128.2*x,
126.1*x,122.0*,121.2* (q, JCeF¼278.2 Hz),119.0*,117.2x,114.9x,109.8x,
108.3*, 90.5*, 89.2x; IR (NaCl/thin film): 3026, 2952, 1751, 1701, 1607,
in CO2,
l
¼254 nm): tR (major)¼6.5 min tR (minor)¼5.6 min. The
25
1491, 1437, 1355, 1204, 1151, 985, 749 cmꢁ1; [
a
]
ꢁ128.3 (c 1.22,
D
major diastereomer was separated by flash chromatography
(0/10% ethyl acetate/hexanes). 1H NMR (500 MHz, CDCl3; com-
pound exists as a 2.1:1 mixture of rotamers the major rotamer is
CH2Cl2). HRMS (MM) calcd for C23H23F3N2O3 [MþH]þ 433.1734,
found 433.1750.
denoted by *, minor rotamer denoted by x)
d
7.16 (d, J¼8.1 Hz, 1H*,
4.3.9. Pyrroloindoline 21i. The dr was determined to be 5:1 by 1H
NMR analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (5/15% ethyl acetate/hexanes)
to yield 61.1 mg of white needles 21i (84% yield). The enantiomeric
excess was determined to be 92% by chiral SFC analysis (AD-H,
1Hx), 7.02 (s, 1Hx), 6.99 (s, 1H*), 6.52 (d, J¼7.7 Hz, 1Hx), 6.45 (d,
J¼8.2 Hz, 1H*), 6.00 (dd, J¼17.3, 10.5 Hz, 1H*, 1Hx), 5.60 (s, 1H*), 5.31
(s, 1Hx), 5.07e4.96 (m, 2H*, 2Hx), 4.73 (d, J¼9.3 Hz, 1H*), 4.47e4.41
(m, 1Hx), 3.82 (s, 1H*), 3.77 (s, 1Hx), 3.06 (s, 1H*), 2.86 (s, 1Hx), 2.60
(dd, J¼13.1, 9.9 Hz, 1H*), 2.52 (t, J¼10.7 Hz, 1Hx), 2.38 (d, J¼12.5 Hz,
1H*), 2.14e1.98 (m, 1Hx), 1.57e1.31 (m, 9H*, 9Hx); 13C NMR
(126 MHz, CDCl3); IR (NaCl/thin film): 3081, 2965, 2874, 2822, 1753,
2.5 mL/min, 5% IPA in CO2,
l
¼254 nm): tR (major)¼7.8 min tR
(minor)¼3.5 min. The major and minor diastereomers were sepa-
rated by reverse phase preparatory HPLC (50/95% acetonitrile/
water, 0.05% trifluoroacetic acid). 1H NMR (500 MHz, CDCl3; com-
pound exists as a 4.9:1 mixture of rotamers, the major rotamer is
1698, 1618, 1496, 1434, 1359, 1283, 1257, 1204, 1156, 1117, 1054, 995,
25
912, 844, 813; [
a
]
D
ꢁ115 (c 0.450, CHCl3). HRMS (ESI) calcd for
C21H25F3N2O3 [MþH]þ 411.1890, found 411.1901.
denoted by *, minor rotamer denoted by x)
d
7.14 (td, J¼7.7, 1.3 Hz,
1H*, 1Hx), 7.03 (br d, J¼7.3 Hz, 1H*, 1Hx), 6.90e6.80 (br s, 1Hx), 6.76
(t, J¼7.4 Hz, 1H*), 6.67e6.58 (br s, 1Hx), 6.54 (d, J¼7.9 Hz, 1H*), 5.81
(dtd, J¼16.5, 11.6, 11.1, 6.2 Hz, 1H*, 1Hx), 5.74 (s, 1H*), 5.51 (br s, 1Hx),
5.27 (br d, J¼17.1 Hz, 1H*, 1Hx), 5.14 (br d, J¼10.2 Hz, 1H*, 1Hx), 4.72
(d, J¼9.1 Hz, 1H*), 4.34 (br s, 1Hx), 4.25 (dd, J¼16.5, 3.6 Hz, 1H*), 4.04
(dd, J¼16.5, 6.2 Hz, 1H*), 4.00e3.94 (m, 1Hx), 3.82 (s, 3H*), 3.76 (s,
3Hx), 2.62 (dd, J¼13.3, 9.7 Hz, 1H*), 2.58e2.49 (m, 1Hx), 2.40 (dd,
J¼13.5, 2.6 Hz, 1H*), 2.11 (br s, 1Hx), 1.48 (s, 3Hx), 1.39 (s, 3H*); 13C
4.4. General procedure for the formal (3D2) cycloaddition/in
situ reduction
To a flame-dried flask was added indole (0.20 mmol, 1.00 equiv),
acrylate (0.20 mmol, 1.00 equiv), and (R)-3,30-dichloro-BINOL
(0.04 mmol, 0.20 equiv). The flask was charged with CH2Cl2
(1.5 mL), followed by addition of SnCl4 (0.24 mmol, 1.20 equiv

J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
5631
unless specifically indicated, 1 M in CH2Cl2). NaBH4 (0.30 mmol,
1.50 equiv) was then added, and the reaction was stirred at room
temperature for 24 h (unless specifically indicated). The reaction
was quenched by diluting with 1 mL MeCN and 1 mL 1 M HCl,
followed by addition of 5 mL H2O. The aqueous layer was extracted
with ethyl acetate (3ꢂ15 mL) and the combined organic layers were
washed with saturated NaHCO3(aq) (10 mL). The aqueous layer was
extracted with ethyl acetate (10 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated. The crude residue
was purified by flash chromatography.
J¼6.5 Hz, 2H), 1.39 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
171.0, 156.7
(q, JCeF¼37.5 Hz), 150.0, 135.5, 128.9, 128.8, 123.3, 115.6 (q,
JCeF¼287.9 Hz), 108.7, 69.0, 52.7, 51.5, 42.7, 42.1, 36.4, 26.07, 20.7; IR
(NaCl/thin film): 3326, 2955, 2922, 2863, 2806, 1752, 1719, 1555,
25
1499, 1452, 1209, 1163, 806 cmꢁ1; [
a
]
þ42.3 (c 0.87, CH2Cl2).
D
HRMS (MM) calcd for C17H21F3N2O3 [MþH]þ 359.1577, found
359.1565.
4.4.4. Indoline 28d. Prepared from 1,3,6-trimethyl-1H-indole and
methyl 2-trifluoroacetamidoacrylate using the general procedure.
The dr was determined to be 17:1 by 1H NMR analysis of the crude
reaction mixture. The crude residue was purified by flash chro-
matography (5/30% ethyl acetate/hexanes) to yield 65.0 mg (91%
yield) of 28d, a yellow oil. The enantiomeric excess of the major
diastereomer was determined to be 92% by chiral SFC analysis (AD-
4.4.1. Indoline 28a. Prepared from 1,3-dimethyl-1H-indole19 and
methyl 2-trifluoroacetamidoacrylate using the general procedure.
The dr was determined to be 15:1 by 1H NMR analysis of the crude
reaction mixture. The crude residue was purified by flash chro-
matography (5/25% ethyl acetate/hexanes) to yield 64.1 mg (93%
yield) of 28a, a pale yellow oil. The enantiomeric excess of the
major diastereomer was determined to be 92% by chiral SFC
H, 2.5 mL/min, 5% IPA in CO2,
l
¼254 nm): tR (major)¼11.1 min tR
(minor)¼5.0 min. The major diastereomer was separated by flash
chromatography (5% ethyl acetate/hexanes). 1H NMR (500 MHz,
analysis (AD-H, 2.5 mL/min, 5% IPA in CO2,
l
¼254 nm): tR (major)¼
CDCl3)
d
7.29 (d, J¼5.7 Hz, 1H), 6.88 (d, J¼7.5 Hz, 1H), 6.58 (d,
9.9 min tR (minor)¼5.9 min. The major diastereomer was sepa-
J¼7.5 Hz, 1H), 6.37 (s, 1H), 4.22 (td, J¼7.5, 4.9 Hz), 3.66 (s, 3H), 3.29
rated by flash chromatography (5% ethyl acetate/hexanes). 1H
(d, J¼9.1 Hz, 1H), 2.96 (d, J¼9.1 Hz, 1H), 2.72 (s, 3H), 2.30 (s, 3H),
NMR (500 MHz, CDCl3)
d
7.23 (br d, J¼5.9 Hz, 1H), 7.14 (td, J¼7.7,
2.20e2.11 (m, 2H), 1.38 (s, 3H); 13C NMR (125 MHz, CDCl3)
d 171.1,
1.2 Hz, 1H), 6.99 (dd, J¼7.3, 0.8 Hz, 1H), 6.76 (td, J¼7.4, 0.8 Hz, 1H),
6.54 (d, J¼7.9 Hz, 1H), 4.27 (br td, J¼7.7, 4.7 Hz, 1H), 3.65 (s, 3H),
3.31 (d, J¼9.1 Hz, 1H), 2.98 (d, J¼9.1 Hz, 1H), 2.74 (s, 3H), 2.21 (dd,
J¼14.7, 4.7 Hz, 1H), 2.15 (dd, J¼14.7, 8.2 Hz, 1H), 1.40 (s, 3H); 13C
156.6 (q, JCeF¼37.5 Hz), 152.3, 138.6, 132.5, 122.2, 119.8, 115.6 (q,
JCeF¼287.8 Hz), 109.3, 68.6, 52.7, 51.4, 42.5, 42.2, 35.8, 26.2, 21.6; IR
(NaCl/thin film): 3321, 2956, 2923, 2870, 2804, 1750, 1716, 1615,
1557, 1497, 1455, 1208, 1179, 802 cmꢁ1; [
a
]
D
25 þ76.0 (c 1.56, CH2Cl2).
NMR (125 MHz, CDCl3)
d
171.1, 156.6 (q, JCeF¼37.5 Hz), 152.1, 153.3,
HRMS (MM) calcd for C17H21F3N2O3 [MþH]þ 359.1577, found
128.5, 122.4, 119.0, 115.6 (q, JCeF¼287.9 Hz), 108.4, 68.3, 52.7, 51.2,
359.1577.
42.8, 42.1, 35.8, 26.1; IR (NaCl/thin film): 3319, 2956, 2858, 2811,
25
1751, 1718, 1607, 1559, 1491, 1452, 1209, 1179, 744 cmꢁ1; [
a
]
4.4.5. Indoline 28e. Prepared from 1,3,7-trimethyl-1H-indole and
methyl 2-trifluoroacetamidoacrylate using the general procedure.
The dr was determined to be 17:1 by 1H NMR analysis of the crude
reaction mixture. The crude residue was purified by flash chro-
matography (5/30% ethyl acetate/hexanes) to yield 58 mg (81%
yield) of 28e, a pale yellow oil. The enantiomeric excess of the
major diastereomer was determined to be 94% by chiral SFC
D
þ79.6 (c 1.32, CH2Cl2). HRMS (MM) calcd for [MþH]þ
C16H19F3N2O3 345.1421, found 345.1423.
4.4.2. Indoline 28b. Prepared from 1,3,4-trimethyl-1H-indole and
methyl 2-trifluoroacetamidoacrylate using the general procedure.
The dr was determined to be 11:1 by 1H NMR analysis of the crude
reaction mixture. The crude residue was purified by flash chro-
matography (5/25% ethyl acetate/hexanes) to yield 56.8 mg (79%
yield, yellow oil) of 28b as a single diastereomer. The enantiomeric
excess of the major diastereomer was determined to be 93% by
analysis (AD-H, 2.5 mL/min, 6% IPA in CO2,
l
¼254 nm): tR (major)¼
4.3 min tR (minor)¼3.3 min. The major diastereomer was sepa-
rated by flash chromatography (5% ethyl acetate/hexanes). 1H
NMR (500 MHz, CDCl3)
d
7.44 (d, J¼4.7 Hz, 1H), 6.90 (d, J¼7.5 Hz,
chiral SFC analysis (AD-H, 2.5 mL/min, 6% IPA in CO2,
l¼254 nm): tR
1H), 6.86 (d, J¼7.4 Hz, 1H), 6.73 (t, J¼7.4 Hz, 1H), 4.14e4.08 (m, 1H),
3.66 (s, 3H), 3.29 (d, J¼9.6 Hz, 1H), 2.97 (d, J¼9.6 Hz, 1H), 2.93 (s,
3H), 2.37 (s, 3H), 2.17e2.06 (m, 2H), 1.40 (s, 3H); 13C NMR
(major)¼3.9 min tR (minor)¼3.5 min. 1H NMR (500 MHz, CDCl3)
d
7.64 (br d, J¼4.9 Hz, 1H), 7.06 (t, J¼7.7 Hz, 1H), 6.54 (d, J¼7.6 Hz,
1H), 6.42 (d, J¼7.9 Hz), 4.10 (ddd, J¼9.0, 6.5, 4.2 Hz, 1H), 3.65 (s, 3H),
3.32 (d, J¼9.3 Hz, 1H), 2.95 (d, J¼9.2 Hz, 1H), 2.71 (s, 3H), 2.45 (dd,
J¼15.0, 4.0 Hz, 1H), 2.30 (s, 3H), 2.13 (dd, J¼14.8, 8.9 Hz, 1H), 1.50 (s,
(125 MHz, CDCl3)
d
171.1, 156.7 (q, JCeF¼37.5 Hz), 149.9, 136.1, 131.8,
121.2, 120.4, 120.3, 115.6 (q, JCeF¼287.8 Hz), 69.7, 52.7, 51.3, 42.8,
42.3, 39.5, 26.6, 19.5; IR (NaCl/thin film): 3322, 2959, 2924, 1750,
25
3H); 13C NMR (125 MHz, CDCl3)
d
171.0, 156.7 (q, JCeF¼37.5 Hz),
1713, 1557, 1480, 1456, 1412, 1208, 1180, 1071, 750 cmꢁ1; [
a]
D
152.8, 134.5, 131.5, 128.8, 122.4, 115.6 (q, JCeF¼287.9 Hz), 106.7, 68.6,
þ84.9 (c 1.20, CH2Cl2). HRMS (APCI) calcd for C17H21F3N2O3
[MþH]þ 359.1577, found 359.1595.
52.7, 51.7, 43.7, 40.9, 35.9, 26.6, 18.7; IR (NaCl/thin film): 3315, 2956,
25
2812, 1750, 1710, 1593, 1559, 1484, 1457, 1209, 1179, 774 cmꢁ1; [
a]
D
þ66.0 (c 1.04, CH2Cl2). HRMS (MM) calcd for C17H21F3N2O3 [MþH]þ
4.4.6. Indoline 28f. Prepared from 5-fluoro-1,3-dimethyl-1H-in-
dole and methyl 2-trifluoroacetamidoacrylate using the general
procedure. The dr was determined to be 13:1 by 1H NMR analysis of
the crude reaction mixture. The crude residue was purified by flash
chromatography (10/30% ethyl acetate/hexanes) to yield 57.0 mg
(79% yield) of 28f, a pale yellow oil. The enantiomeric excess of the
major diastereomer was determined to be 90% by chiral SFC anal-
359.1577, found 359.1591.
4.4.3. Indoline 28c. Prepared from 1,3,5-trimethyl-1H-indole and
methyl 2-trifluoroacetamidoacrylate using the general procedure.
The dr was determined to be 17:1 by 1H NMR analysis of the crude
reaction mixture. The crude residue was purified by flash chro-
matography (10/25% ethyl acetate/hexanes) to yield 52.6 mg (73%
yield) of 28c, a yellow oil. The enantiomeric excess of the major
diastereomer was determined to be 89% by chiral SFC analysis (AD-
ysis (AD-H, 2.5 mL/min, 6% IPA in CO2,
l¼254 nm): tR (major)¼
3.9 min tR (minor)¼2.9 min. The major diastereomer was separated
by preparatory TLC (40% CH2Cl2/hexanes then 50% CH2Cl2/hex-
H, 2.5 mL/min, 6% IPA in CO2,
l
¼254 nm): tR (major)¼4.8 min tR
anes). 1H NMR (300 MHz, CDCl3)
d
7.31 (br d, JCeH¼5.8 Hz, 1H), 6.83
(minor)¼3.4 min. The major diastereomer was separated by flash
(td, JCeH¼8.8, 2.6 Hz, 1H), 6.72 (dd, JCeH¼8.2, 2.6 Hz, 1H), 6.44 (dd,
JCeH¼8.5, 4.1 Hz, 1H), 4.25 (td, JCeH¼7.7, 4.8 Hz, 1H), 3.68 (s, 3H),
3.31 (d, JCeH¼9.2 Hz, 1H), 2.97 (d, JCeH¼9.2 Hz,1H), 2.70 (s, 3H), 2.21
(dd, JCeH¼14.7, 4.8 Hz, 1H), 2.12 (dd, JCeH¼14.7, 8.1 Hz, 1H), 1.38 (s,
chromatography (7% ethyl acetate/hexanes). 1H NMR (500 MHz,
CDCl3)
d
7.43 (br d, J¼4.8 Hz, 1H), 6.95 (d, J¼7.9 Hz, 1H), 6.81 (s, 1H),
6.47 (d, J¼7.9 Hz, 1H), 4.16 (q, J¼6.5 Hz, 1H), 3.67 (s, 3H), 3.27 (d,
J¼9.1 Hz, 1H), 2.91 (d, J¼9.1 Hz, 1H), 2.70 (s, 3H), 2.25 (s, 3H), 2.17 (d,
3H); 13C NMR (125 MHz, CDCl3)
d
171.0, 157.2 (d, JCeF¼237.2 Hz),

5632
J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
156.6 (q, JCeF¼37.8 Hz), 148.4, 137.1 (d, JCeF¼7.1 Hz), 116.7, 114.5 (d,
JCeF¼23.3 Hz), 110.1 (d, JCeF¼24.0 Hz), 108.8 (d, JCeF¼8.1 Hz), 68.6,
52.8, 51.1, 42.8, 42.0, 36.4, 26.1; IR (NaCl/thin film): 3319, 2958,
major diastereomer was determined to be 92% by chiral SFC anal-
ysis (AD-H, 2.5 mL/min, 5% IPA in CO2,
l¼254 nm): tR (major)¼
7.2 min tR (minor)¼5.3 min. The major diastereomer was separated
2866, 2811, 1745, 1711, 1552, 1494, 1468, 1267, 1210, 1179, 808 cmꢁ1
;
by flash chromatography (5% ethyl acetate/hexanes). 1H NMR
25
[
a]
þ63.7 (c 0.62, CH2Cl2). HRMS (ESI) calcd for C16H18F4N2O3
(500 MHz, CDCl3)
d
7.30 (br d, JCeH¼5.5 Hz, 1H), 7.13 (td, JCeH¼7.7,
D
[MþH]þ 363.1326, found 363.1334.
1.2 Hz, 1H), 6.96 (dd, JCeH¼7.3, 0.7 Hz, 1H), 6.75 (t, JCeH¼7.3 Hz, 1H),
6.53 (d, JCeH¼7.8 Hz, 1H), 4.22e4.15 (m, 1H), 3.64 (s, 3H), 3.24 (d,
JCeH¼9.3 Hz, 1H), 3.08 (d, JCeH¼9.3 Hz, 1H), 2.74 (s, 3H), 2.23 (dd,
JCeH¼14.7, 8.4 Hz,1H), 2.17 (dd, JCeH¼14.7, 4.7 Hz,1H),1.86e1.77 (m,
1H), 1.69e1.57 (m, 1H), 1.40e1.24 (m, 3H), 1.19e1.08 (m, 1H), 0.89 (t,
4.4.7. Indoline 28g. Prepared from 5-methoxy-1,3-dimethyl-1H-
indole and methyl 2-trifluoroacetamidoacrylate using the general
procedure. The reaction was allowed to run for 18.5 h. The dr was
determined to be 14:1 by 1H NMR analysis of the crude reaction
mixture. The crude residue was purified by flash chromatography
(10/30% ethyl acetate/hexanes) to yield 68.5 mg (91% yield) of
28g, a yellow oil. The enantiomeric excess of the major di-
astereomer was determined to be 88% by chiral SFC analysis (AD-H,
JCeH¼7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d 171.2, 156.6 (q,
JCeF¼37.5 Hz), 152.3, 134.3, 128.6, 123.0, 119.0, 115.5 (q,
JCeF¼287.8 Hz), 108.4, 66.4, 52.7, 51.2, 46.2, 40.6, 39.3, 35.9, 26.5,
23.2, 14.0; IR (NaCl/thin film): 3319, 2956, 2932, 2860, 2809, 1751,
25
1718, 1606, 1559, 1491, 1465, 1207, 1178, 743 cmꢁ1; [
a]
þ62.0 (c
D
2.5 mL/min, 7% IPA in CO2,
l
¼254 nm): tR (major)¼7.1 min tR
1.15, CH2Cl2). HRMS (ESI) calcd for C19H25F3N2O3 [MþH]þ 387.1890,
(minor)¼3.6 min. 1H NMR (500 MHz, CDCl3)
d
7.81 (br d,
found 387.1902.
JCeH¼5.0 Hz, 1H), 6.70 (dd, JCeH¼8.4, 1.9 Hz, 1H), 6.62 (d,
JCeH¼1.8 Hz, 1H), 6.50 (d, JCeH¼8.3 Hz, 1H), 4.01 (dd, JCeH¼13.1,
6.3 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.28 (d, JCeH¼8.6 Hz, 1H), 2.89
4.4.10. Indoline 28j. Prepared from 1-methyl-3-phenethyl-1H-in-
dole and methyl 2-trifluoroacetamidoacrylate using the general
procedure, except the formal (3þ2) cycloaddition was allowed to
run for 24 h before adding NaBH4. After adding NaBH4, the reaction
was allowed to run for another 24 h. The dr was determined to be
12:1 by 1H NMR analysis of the crude reaction mixture. The crude
residue was purified by flash chromatography (5/20% ethyl ace-
tate/hexanes) to yield 77.6 mg (89% yield) of 28j. The enantiomeric
excess of the major diastereomer was determined to be 89% by
(d, JCeH¼9.1 Hz,1H), 2.68 (s, 3H), 2.23e2.08 (m, 2H), 1.30 (s, 3H); 13
C
NMR (125 MHz, CDCl3)
d
171.0, 156.8 (q, JCeF¼37.5 Hz), 154.1, 146.1,
137.0, 115.6 (q, JCeF¼287.8 Hz), 113.1, 110.8, 109.6, 69.0, 55.8, 52.7,
51.5, 43.0, 42.0, 36.9, 26.2; IR (NaCl/thin film): 3319, 2955, 2804,
1751, 1718, 1555, 1496, 1468, 1214, 1179, 1031 cmꢁ1; [
a]
þ26.3 (c
25
D
1.24, CH2Cl2). HRMS (APCI) calcd for C17H21F3N2O4 [MþH]þ
375.1526, found 375.1542.
chiral SFC analysis (AD-H, 2.5 mL/min, 7% IPA in CO2,
l
¼254 nm): tR
4.4.8. Indoline 28h. Prepared from 1-allyl-3-methyl-1H-indole and
methyl 2-trifluoroacetamidoacrylate using the general procedure,
except the formal (3þ2) cycloaddition was allowed to run for 24 h
before adding NaBH4. After adding NaBH4, the reaction was
allowed to run for another 24 h. The dr was determined to be 5:1
by 1H NMR analysis of the crude reaction mixture. The crude
residue was purified by flash chromatography (5/20% ethyl ace-
tate/hexanes) to yield 60.0 mg (81% yield) of 28h, a yellow oil. The
enantiomeric excess of the major diastereomer was determined to
be 90% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO2,
(major)¼9.5 min tR (minor)¼8.1 min. The major diastereomer was
separated by flash chromatography (10% ethyl acetate/hexanes). 1H
NMR (400 MHz, CDCl3) d 7.30e7.22 (m, 3H), 7.21e7.11 (m, 4H), 6.99
(dd, JCeH¼7.4, 1.0 Hz, 1H), 6.75 (td, JCeH¼7.4, 0.7 Hz, 1H), 6.55 (d,
JCeH¼7.9 Hz, 1H), 4.27 (dt, JCeH¼12.6, 6.4 Hz, 1H), 3.63 (s, 3H), 3.30
(d, JCeH¼9.3 Hz, 1H), 3.17 (d, JCeH¼9.3 Hz, 1H), 2.76 (s, 3H), 2.68 (td,
JCeH¼13.0, 5.0 Hz,1H), 2.47 (td, JCeH¼12.9, 4.7 Hz,1H), 2.34e2.22 (m,
2H), 2.13 (ddd, JCeH¼13.7,12.3, 5.1 Hz,1H),1.97 (ddd, JCeH¼13.8,12.6,
4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3)
d 171.1, 156.6 (q,
JCeF¼37.5 Hz), 152.4, 141.7, 133.5, 128.7, 128.5, 128.2, 126.0, 122.9,
l
¼254 nm): tR (major)¼7.2 min tR (minor)¼6.2 min. Isolated as
119.0, 115.5 (q, JCeF¼287.8 Hz), 108.4, 66.0, 52.7, 51.1, 46.3, 41.5, 40.7,
a 5:1 mixture of diastereomers; the major diastereomer is denoted
35.8, 30.8; IR (NaCl/thin film): 3317, 2951, 2858, 2812, 1749, 1716,
x
26
by *, minor diastereomer denoted by . 1H NMR (500 MHz, CDCl3)
1606, 1555, 1494, 1453, 1208, 1178, 745 cmꢁ1; [
a]
D
þ23.1 (c 0.87,
d
8.26 (br d, J¼8.5 Hz, 1Hx), 7.16e7.05 (m, 2H*, 1Hx), 6.98 (ddd,
CH2Cl2). HRMS (MM) calcd for C23H25F3N2O3 [MþH]þ 435.1890,
J¼7.4, 1.2, 0.5 Hz, 1H*, 1Hx), 6.78 (td, J¼7.4, 1.0 Hz, 1Hx), 6.72 (td,
J¼7.4, 1.0 Hz, 1H*), 6.64 (d, J¼7.9 Hz, 1Hx), 6.56 (d, J¼7.9 Hz, 1H*),
5.93e5.83 (m, 1H*, 1Hx), 5.32e5.20 (m, 1H*, 1Hx), 4.81e4.75 (m,
1Hx), 4.40 (td, J¼7.6, 5.0, 1H*), 3.79 (ddt, J¼15.0, 5.9, 1.4 Hz, 1H*,
1Hx), 3.73e3.70 (m, 1Hx), 3.65e3.59 (m, 1H*), 3.63 (s, 3H*), 3.42 (s,
3Hx), 3.31 (d, J¼9.3 Hz, 1H*), 3.28 (d, J¼9.6 Hz, 1Hx), 3.07 (d,
J¼9.6 Hz, 1Hx), 3.05 (d, J¼9.3 Hz, 1H*), 2.35 (ddd, J¼14.8, 5.9, 0.6 Hz,
1Hx), 2.23 (dd, J¼14.6, 4.9 Hz, 1H*), 2.18 (dd, J¼14.9, 4.6 Hz, 1Hx),
2.13 (dd, J¼14.7, 7.8 Hz, 1H*), 1.41 (s, 3Hx), 1.38 (s, 3H*); 13C NMR
found 435.1882.
4.4.11. Indoline 28k. Prepared from 1-methyl-3-(2-((triisopro-
pylsilyl)oxy)ethyl)-1H-indole and methyl 2-trifluoroacetamidoa-
crylate using the general procedure, except the formal (3þ2)
cycloaddition was allowed to run for 20.5 h before adding
NaBH4. After adding NaBH4, the reaction was allowed to run for
another 24 h. The dr was determined to be >20:1 by 1H NMR
analysis of the crude reaction mixture. The crude residue was
purified by flash chromatography (5/30% ethyl acetate/hex-
anes) to yield 68.3 mg (64% yield) of 28k, a yellow oil. The en-
antiomeric excess of the major diastereomer was determined to
be 85% by chiral SFC analysis (AD-H, 2.5 mL/min, 5% IPA in CO2,
(100 MHz, CDCl3)
d
171.2*, 170.1x, 156.6* (q, JCeF¼37.6 Hz), 150.8*,
135.4*, 133.3*, 132.4x, 128.6x, 128.4*, 123.3x, 122.5*, 119.4x, 118.9x,
118.7*, 118.1*, 115.5* (q, JCeF¼287.9 Hz), 109.9x, 108.4*, 65.2x, 65.1*,
52.7*, 52.5x, 52.1x, 51.8*, 50.9*, 50.5x, 42.7x, 42.6*, 42.5x, 42.1*, 27.8x,
26.1*; IR (NaCl/thin film): 3316, 2957, 2923, 1750, 1718, 1605, 1554,
l
¼254 nm): tR (major)¼8.7 min tR (minor)¼7.5 min. 1H NMR
25
1487, 1460, 1437, 1209, 1165, 744 cmꢁ1; [
a
]
D
þ33.412 (c 1.62,
(500 MHz, CDCl3)
d
7.51 (br s, 1H), 7.15 (t, JCeH¼7.6 Hz, 1H), 7.00
CH2Cl2). HRMS (MM) calcd for C18H21F3N2O3 [MþH]þ 371.1577,
(d, JCeH¼7.2 Hz, 1H), 6.75 (t, JCeH¼7.1 Hz, 1H), 6.54 (d,
JCeH¼7.3 Hz, 1H), 4.22e4.15 (m, 1H), 3.81 (dd, JCeH¼6.96, 5.35 Hz,
2H), 3.64 (s, 3H), 3.34e3.26 (m, 1H), 3.26e3.18 (m, 1H), 2.74 (s,
3H), 2.46e2.36 (m, 1H), 2.24 (dd, JCeH¼14.7, 3.7 Hz, 1H),
2.11e1.94 (m, 2H), 1.08e1.03 (m, 21H); 13C NMR (125 MHz,
found 371.1582.
4.4.9. Indoline 28i. Prepared from 3-butyl-1-methyl-1H-indole
and methyl 2-trifluoroacetamidoacrylate using the general pro-
cedure. The dr was determined to be >20:1 by 1H NMR analysis of
the crude reaction mixture. The crude residue was purified by flash
chromatography (5/20% ethyl acetate/hexanes) to yield 63.4 mg
(82% yield) of 28i, a pale yellow oil. The enantiomeric excess of the
CDCl3)
d
171.1, 156.7 (q, JCeF¼37.6 Hz), 152.1, 134.3, 128.7, 123.0,
118.9, 115.6 (q, JCeF¼287.8 Hz), 108.5, 67.6, 60.0, 52.6, 51.2, 45.3,
41.2, 39.5, 18.0, 18.0, 11.9; IR (NaCl/thin film): 3323, 2943,
2866, 1719, 1606, 1552, 1491, 1463, 1207, 1175, 1104, 882,

J. Ni et al. / Tetrahedron 69 (2013) 5622e5633
5633
25
742 cmꢁ1; [
a
]
þ27.4 (c 0.85, CH2Cl2). HRMS (APCI) calcd for
2. (a) Tuntiwachwuttikul, P.; Taechowisan, T.; Wanbanjob, A.; Thadaniti, S.; Taylor,
W. C. Tetrahedron 2008, 64, 7583; (b) Hauser, D.; Weber, H. P.; Sigg, H. P. Helv.
Chim. Acta 1970, 53, 1061; (c) Ding, G.; Jiang, L. H.; Guo, L. D.; Chen, X. L.; Zhang,
H.; Che, Y. S. J. Nat. Prod. 2008, 71, 1861; (d) Zheng, C.-J.; Kim, C.-J.; Bae, K. S.;
Kim, Y.-H.; Kim, W.-G. J. Nat. Prod. 2006, 69, 1816; (e) Mansour, M.; Lemenoli, L.;
Levy, J.; Lemen, J. Phytochemistry 1974, 13, 2861; (f) Massiot, G.; Thepenier, P.;
Jacquier, M. J.; Lemenolivier, L.; Delaude, C. Heterocycles 1989, 29, 1435; (g)
Goodson, J. A.; Henry, T. A. J. Chem. Soc., Trans. 1925, 127, 1640; (h) Polonovski,
M. Bull. Soc. Chim. Fr. 1916, 19, 46.
3. Selected indoline syntheses: (a) Boger, D. L.; Coleman, R. S. J. Org. Chem. 1984,
49, 2240; (b) Uchiyama, M.; Kameda, M.; Mishima, O.; Yokoyama, N.; Koike, M.;
Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc. 1998, 120, 4934; (c) Nicolaou, K. C.;
Roecker, A. J.; Pfefferkorn, J. A.; Cao, G.-Q. J. Am. Chem. Soc. 2000, 122, 2966; (d)
Bailey, W. F.; Mealy, M. J. J. Am. Chem. Soc. 2000, 122, 6787; (e) Viswanathan, R.;
Prabhakaran, E. N.; Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125,
163; (f) Yamada, K.; Kurokawa, T.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc.
2003, 125, 6630; (g) Danheiser, R. L.; Dunetz, J. R. J. Am. Chem. Soc. 2005, 127,
5776; (h) Correa, A.; Tellitu, I.; Domínguez, E.; SanMartin, R. J. Org. Chem. 2006,
71, 8316; (i) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130,
1558; (j) Boal, B. W.; Schammel, A. W.; Garg, N. K. Org. Lett. 2009, 11, 3458.
4. (a) Taniguchi, M.; Hino, T. Tetrahedron 1981, 37, 1487; (b) Bruncko, M.; Crich, D.;
Samy, R. J. Org. Chem. 1994, 59, 5543; (c) Marsden, S. P.; Depew, K. M.; Dani-
shefsky, S. J. J. Am. Chem. Soc. 1994, 116, 11143.
D
C26H41F3N2O4Si [MþH]þ 531.2860, found 531.2883.
4.5. General procedure for in situ monitoring of the formal
(3D2) cycloaddition by 1H NMR
In the glovebox, a 1 M solution of 1,3-dimethylindole, a 1 M
solution of benzyl trifluoroacetamidoacrylate (with 0.3 equiv 1,4-
diethylbenzene as an internal standard), a 0.72 M solution of SnCl4,
and a 0.0675 M solution of (R)-BINOL in CD2Cl2 were made. To an
oven-dried NMR tube equipped with a Teflon-lined cap were added
90
m
L of the indole solution, 90
m
L of the acrylateþinternal standard
solution, 267
mL of the (R)-BINOL solution, and 186
m
L of CD2Cl2. A
1H NMR spectrum was taken (1 scan) to determine the initial ratio
of substrates, (R)-BINOL, and internal standard. Immediately before
beginning the collection of kinetics data, SnCl4 was added via
a microsyringe through the Teflon cap of the NMR tube. The tube
was inverted once, then quickly inserted into the instrument.
The concentration of acrylate over the course of the reaction was
determined by integrating its resonance at 6.3 ppm, then normal-
izing by the internal standard’s resonance at 2.74 ppm.
5. (a) Bui, T.; Syed, S.; Barbas, C. F. J. Am. Chem. Soc. 2009, 131, 8758; (b) Austin, J. F.;
Kim, S. G.; Sinz, C. J.; Xiao, W. J.; MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5482.
6. (a) Ashimori, A.; Matsuura, T.; Overman, L. E.; Poon, D. J. J. Org. Chem. 1993, 58,
6949; (b) Huang, A.; Kodanko, J. J.; Overman, L. E. J. Am. Chem. Soc. 2004, 126,
14043; (c) Trost, B. M.; Zhang, Y. J. Am. Chem. Soc. 2006, 128, 4590; (d) Ma, S.;
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7. Repka, L. M.; Ni, J.; Reisman, S. E. J. Am. Chem. Soc. 2010, 132, 14418.
8. An alternative scenario would involve a moderately enantioselective, irre-
versible conjugate addition, followed by a highly selective, catalyst-controlled
irreversible protonation.
9. (a) Ishihara, K.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 11179;
(b) Ishihara, K.; Nakamura, S.; Kaneeda, M.; Yamamoto, H. J. Am. Chem. Soc.
1996, 118, 12854; (c) Ishihara, K.; Kurihara, H.; Yamamoto, H. J. Am. Chem. Soc.
1996, 118, 3049; (d) Ishihara, K.; Nakashima, D.; Hiraiwa, Y.; Yamamoto, H. J. Am.
Chem. Soc. 2003, 125, 24; (e) Rauniyar, V.; Zhai, H. M.; Hall, D. G. J. Am. Chem.
Soc. 2008, 130, 8481.
10. Kieffer, M. E.; Repka, L. M.; Reisman, S. E. J. Am. Chem. Soc. 2012, 134, 5131.
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Chem. 1987, 52, 1857.
12. (a) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000,
122, 7615; (b) Baeza, A.; Pfaltz, A. Chem.dEur. J. 2010, 16, 2036; (c) Rueping, M.;
Brinkmann, C.; Antonchick, A. P.; Atodiresei, I. Org. Lett. 2010, 12, 4604; (d)
Wang, D.-S.; Chen, Q.-A.; Li, W.; Yu, C.-B.; Zhou, Y.-G.; Zhang, X. J. Am. Chem. Soc.
2010, 132, 8909; (e) Xiao, Y.-C.; Wang, C.; Yao, Y.; Sun, J.; Chen, Y.-C. Angew.
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Acknowledgements
We thank Dr. David VanderVelde for assistance with NMR
structure determination, as well as Prof. Brian Stoltz, Dr. Scott
Virgil, and the Caltech Center for Catalysis and Chemical Syn-
thesis for access to analytical equipment. We also thank Sigma-
eAldrich for a kind donation of chemicals. NMR spectra were
obtained on a spectrometer funded by the NIH (RR027690). Fel-
lowship support was provided by Natural Sciences and Engi-
neering Research Council (NSERC) of Canada (J.N., PGS
D
scholarship). S.E.R. is a fellow of the Alfred P. Sloan Foundation
and a Camille Dreyfus Teacher-Scholar. Financial support from
the California Institute of Technology, the NIH (NIGMS
RGM097582A), and the donors of the ACS Petroleum Research
Fund is gratefully acknowledged.
13. Zhu, Q.; Lu, Y. Angew. Chem., Int. Ed. 2010, 49, 7753.
14. Nakanishi, M.; Katayev, D.; Besnard, C.; Kundig, E. P. Angew. Chem., Int. Ed. 2011,
References and notes
€
50, 7438.
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