Free radical-mediated aryl amination: Convergent two- and three-component couplings to chiral 2,3-disubstituted indolines

Article abstract of DOI:10.1021/jo702523u

(Chemical Equation Presented) 5-exo-trig Cyclization of an aryl radical to the nitrogen of an azomethine is used as the key annulating step in a modular preparation of 2,3-cis- and trans-disubstituted indolines. The precursors are readily prepared by phas

Full text of DOI:10.1021/jo702523u

Free Radical-Mediated Aryl Amination: Convergent Two- and
Three-Component Couplings to Chiral 2,3-Disubstituted Indolines
Rajesh Viswanathan,1 Colin R. Smith,2 Erode N. Prabhakaran,3 and Jeffrey N. Johnston*
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt UniVersity,
NashVille, Tennessee 37235-1822
jeffrey.n.johnston@Vanderbilt.edu
ReceiVed December 9, 2007
5-exo-trig Cyclization of an aryl radical to the nitrogen of an azomethine is used as the key annulating
step in a modular preparation of 2,3-cis- and trans-disubstituted indolines. The precursors are readily
prepared by phase-transfer-catalyzed Michael addition of a glycine Schiff base to a variety of acceptors.
When the more reactive alkylidene malonate Michael acceptors are implemented, a one-pot three-
component coupling is possible. The net result is a convergent [3 + 2] coupling strategy for the construction
of highly functionalized indolines, a substructure occurring in numerous biologically active natural products.
CHART 1. Representative Biologically Active Indoline
Small Molecules
Introduction
The indoline substructure is a recurring structural feature
within heterocyclic alkaloid natural products (Chart 1), perhaps
second only to the pyrrolidine and piperidine nitrogen hetero-
cycles. Indoline natural products are often both structurally
appealing and biologically active4 and can range in complexity
from relatively simplified fused tricycles such as physostigmine5
to the very complex polycycles vinblastine,6 aspidospermidine,7
(1) Current address: Department of Chemistry, University of Utah, Salt
Lake City, UT 84112.
(2) Current address: Seradyn, Indianapolis, IN 46268.
(3) Current address: The Department of Organic Chemistry, Indian
Institute of Science, Bangalore, India.
(4) Dewick, P. M. Medicinal Natural ProductssA Biosynthetic Approach,
2nd ed.; John Wiley and Sons, Ltd.: New York, 2002.
(5) Yu, Q. S.; Lu, B. Y.; Pei, X. F. Heterocycles 1994, 39, 519. Wijnberg,
J.; Speckamp, W. N. Tetrahedron 1978, 34, 2399. Overman, L. E. Pure
Appl. Chem. 1994, 66, 1423. Node, M.; Itoh, A.; Masaki, Y.; Fuji, K.
Heterocycles 1991, 32, 1705. Lee, T. B. K.; Wong, G. S. K. J. Org. Chem.
1991, 56, 872.
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Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc. 2002, 124, 2137.
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Tokuyama, H.; Fukuyama, T. Pure Appl. Chem. 2003, 75, 29.
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Rubio, M. B.; Cao, G. F.; de Dios, A. J. Am. Chem. Soc. 2002, 124, 13398.
ajmaline,8 and strychnine.9 Indoline heterocycles are also
structural components of pharmaceutical small molecules; the
angiotensin converting enzyme (ACE) inhibitor Pentopril is
largely built upon (S)-indoline-2-carboxylic acid.10 This template
has also spawned the development of “natural product like”
libraries based on an aminoindoline framework.11 Accordingly,
(8) Li, J.; Wang, T.; Yu, P.; Peterson, A.; Weber, R.; Soerens, D.;
Grubisha, D.; Bennett, D.; Cook, J. M. J. Am. Chem. Soc. 1999, 121, 6998.
Mashimo, K.; Sato, Y. Chem. Pharm. Bull. 1970, 18, 353. van Tamelen,
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10.1021/jo702523u CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/20/2008
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J. Org. Chem. 2008, 73, 3040-3046

Free Radical-Mediated Aryl Amination
this structural diversity has stimulated a wide range of methods
aimed at the stereoselective construction12-14 or functionaliza-
tion15 of indoline rings. Few of these methods comprise
enantioselective annulation methodssperhaps an indication that
even modern methods remain inadequate for building certain
common chiral heterocycles.16
We have considered the indoline annulation problem our-
selves and recently reported an enantioselective indoline annu-
lation in two steps, leading to enantioenriched 2-substituted
indolines.13 The first step of the sequence is an enantioselective
phase-transfer-catalyzed glycine Schiff base alkylation.17 Free
radical-mediated aryl amination immediately follows as an
enabling technology in this context, as it delivers the 2-substi-
tuted indoline under mild conditions and in protected form for
further manipulation. We have since pursued a variation on this
(9) Selected total syntheses: Woodward, R. B.; Cava, M. P.; Ollis, W.
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Kucera, D. J.; Overman, L. E. J. Org. Chem. 1989, 54, 5846. (c) Donde,
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(13) (a) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran,
E. N. Org. Lett. 2001, 3, 1009. (b) Viswanathan, R.; Prabhakaran, E. N.;
Plotkin, M. A.; Johnston, J. N. J. Am. Chem. Soc. 2003, 125, 163. (c)
Srinivasan, J. M.; Burks, H. E.; Smith, C. R.; Viswanathan, R.; Johnston,
J. N. Synthesis 2005, 330.
FIGURE 1. Indoline annulation via two- and three-component
couplings and free radical-mediated aryl amination.
theme that targets the 2,3-disubstituted indoline ring system but
retains the convergency offered by the basic modular assembly
beginning from a glycine Schiff base. We report a convergent
synthesis of 2,3-disubstituted indolines (Figure 1, type I, eq 1)
resulting from a straightforward sequence involving conjugate
addition and free radical-mediated aryl amination. Additional
modularity can be obtained by slight operational change to
incorporate a third component (Figure 1, type II, eq 2) by
judicious choice of Michael acceptor. Both incarnations utilize
the phase-transfer-catalyzed Michael addition of a protected
glycine Schiff base to activated styrene derivatives.17-19 The
key annulation step is effected by a free radical reaction in which
an aryl radical adds (nonconventionally) to the nitrogen of the
azomethine.13,20-23
Results and Discussion
Type I: [3 + 2] Indoline Annulation via Sequential
Michael Addition/Free Radical-Mediated Aryl Amination.
A variety of Michael acceptors were synthesized from o-
bromobenzaldehyde by olefination with the appropriate Wittig
reagent.24 A 6:1 E:Z ratio of (inseparable) geometric isomers
of ethyl cinnamate 1a25 was exposed to glycine Schiff base 226
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1997, 119, 8451. (b) Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito,
Y. J. Am. Chem. Soc. 2000, 122, 7614.
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Jackson, R. F. W. J. Chem. Soc., Perkin Trans. 1 2002, 733. Ganton, M.
D.; Kerr, M. A. Org. Lett. 2005, 7, 4777. Smith, A. B.; Kurti, L.; Davulcu,
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Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130. Zhang, L. M. J. Am.
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(17) Reviews: O’Donnell, M. J. Aldrichimica Acta 2001, 34, 3. Albanese,
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M. J.; Delgado, F.; Dominguez, E.; de Blas, J.; Scott, W. L. Tetrahedron:
Asymmetry 2001, 12, 821. O’Donnell, M. J.; Boniece, J. M.; Earp, S. E.
Tetrahedron Lett. 1978, 19, 2641. O’Donnell, M. J.; Eckrich, T. M.
Tetrahedron Lett. 1978, 19, 4625. Patterson, D. E.; Xie, S. P.; Jones, L.
A.; Osterhout, M. H.; Henry, C. G.; Roper, T. D. Org. Process Res. DeV.
2007, 11, 624. Park, H. G.; Jeong, B. S.; Yoo, M. S.; Lee, J. H.; Park, M.
K.; Lee, Y. J.; Kim, M. J.; Jew, S. S. Angew. Chem., Int. Ed. 2002, 41,
3036. Ooi, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526. Ooi, T.; Kameda,
M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121, 6519. O’Donnell, M. J.;
Delgado, F.; Hostettler, C.; Schwesinger, R. Tetrahedron Lett. 1998, 39,
8775. Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595. Lygo,
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Jeong, B. S.; Park, I. Y.; Park, H. G. Org. Lett. 2002, 4, 4245. Corey, E. J.;
Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414. Andrus, M. B.;
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2005, 70, 9470. Andrus, M. B.; Christiansen, M. A.; Hicken, E. J.; Gainer,
M. J.; Bedke, D. K.; Harper, K. C.; Mikkelson, S. R.; Dodson, D. S.; Harris,
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(19) Additional selected references: Ma, B.; Parkinson, J. L.; Castle, S.
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L.; Srikanth, G. S. C. Org. Lett. 2003, 5, 3611.
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Johnston, J. N. Org. Lett. 2002, 4, 4197. Nugent, B. M.; Williams, A. L.;
Prabhakaran, E. N.; Johnston, J. N. Tetrahedron 2003, 59, 8877.
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37, 149. (c) Tomaszewski, M. J.; Warkentin, J. Tetrahedron Lett. 1992,
33, 2123. (d) Tomaszewski, M. J.; Warkentin, J.; Werstiuk, N. H. Aust. J.
Chem. 1995, 48, 291.
(22) (a) Bowman, W. R.; Stephenson, P. T.; Terrett, N. K.; Young, A.
R. Tetrahedron Lett. 1994, 35, 6369. (b) Bowman, W. R.; Stephenson, P.
T.; Terrett, N. K.; Young, A. R. Tetrahedron 1995, 51, 7959. (c) McClure,
C. K.; Kiessling, A. J.; Link, J. S. Tetrahedron 1998, 54, 7121. (d) Orito,
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(23) Reviews of carbon radical additions to azomethine derivatives:
Friestad, G. K. Tetrahedron 2001, 57, 5461. Friestad, G. K.; Mathies, A.
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(24) Deschamp, B.; Lefebvre, G.; Redjal, A.; Seydenpenne, J. Tetrahe-
dron 1973, 29, 2437.
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Viswanathan et al.
SCHEME 1. Two-Component (Type I) Indoline Synthesis
from Cinnamate Precursors (Eq 1)a
SCHEME 2. Two-Component (Type I) Indoline Synthesis
from â-Arylacrylonitrile (Eq 1)a
a Reagents and conditions: (a) 20 mol % BnEt3N+Cl-, 50% aq NaOH,
CH2Cl2, 25 °C (94% from 6:1 (E)-1a:(Z)-1a); (b) Bu3SnH, AIBN, C6H6,
80 °C (cis-3a, 65%; trans-3a, 84%).
a Reagents and conditions: (a) 20 mol % BnEt3N+Cl-, 50% aq NaOH,
CH2Cl2, 25 °C (70% from (E)-1b, 89% from (Z)-1b (58:42 dr)); (b)
nBu3SnH, AIBN, C6H6, 80 °C (cis-3b, 61%; trans-3b, 80%).
n
using liquid-liquid-phase transfer conditions (BnEt3N+Cl-,
50% aq NaOH, CH2Cl2) (Scheme 1). The resulting adducts were
obtained as an 86:14 cis-6a:trans-6a mixture (as depicted) in a
combined 94% yield. The adducts were separated by flash
chromatography and individually subjected to stannane and
initiator (AIBN) to effect the annulation event. Indoline cis-3a
was obtained in 65% isolated yield, and the trans-stereoisomer
was retrieved in 84% yield. The assigned stereochemistry could
be confirmed at this point by NOE measurements on both
diastereomers individually. Although no single example was
exhaustively optimized, the different concentrations (10 vs 5
µM) for the cyclization reflect empirically determined, subtle
differences in maintaining an efficient propagating radical
reaction. Isolated yields may potentially be further improved
by finely tuning the stannane addition rate in concert with the
reaction concentration. Generally, no product of direct reduction
is observed in these or subsequent examples.
Acrylonitrile derivative 1b provided convenient access to the
cis-adduct as well (Scheme 2). In contrast to cinnamates 1a,
the geometric isomers of nitrile 1b were readily separated by
flash chromatography, thereby allowing measurement of the
impact of the olefin geometry on addition diastereoselectivity.
Michael addition to â-arylacrylonitrile (E)-1b using liquid-
liquid-phase transfer conditions readily occurred to provide the
adduct 6b as a separable 87:13 mixture of cis- and trans-
diastereomers. Use of (Z)-1b was equally efficient (89% yield)
but substantially less selective (1.4:1 cis:trans). Following
chromatographic separation, the adducts 6b were individually
cyclized to indolines 3b. Not unexpectedly, cyclization to the
fully protected indoline R-amino acids cis-3b and trans-3b
transpired as before in 61% and 80% yields, resepectively.
Hence, 2,3-cis- and 2,3-trans-disubstituted indoline R-amino
acids are readily prepared in diastereomerically pure form (>95:
5) from the corresponding activated styrenes. Diastereoselection
is considerably higher in additions to the (E)-olefins relative to
their (Z)-isomers. These examples establish a baseline efficiency
for the two-step annulation using an aryl radical cyclization to
a benzophenone imine. We anticipate that this step will broadly
tolerate substitution of the aryl radical on the basis of our
previous studies.13
Type II: [3 + 2] Indoline Annulation via Sequential
Michael Addition/Alkylation/Free Radical-Mediated Aryl
Amination. At room temperature, the rate of phase-transfer-
catalyzed alkylation is comparable to that of Michael addition
with electrophiles 1a and 1b. We hypothesized that, by
increasing the electrophilicity of the Michael acceptor, a
sequential Michael addition/alkylation could be effected with
phase-transfer catalysis in one pot. Use of alkylidene malonates
4a allowed reduction of this strategy to practice (Figure 1, eq
2, and Table 1, eq 3).
In the absence of an alkylating agent, alkylidene malonate
4a provided an equal amount of cis- and trans-Michael adducts
7a (Table 1, entry 1). Addition of methyl iodide to the basic
reaction mixture resulted in the desired sequence of Michael
addition/malonate alkylation (Table 1, entry 2). Although the
differential rates of Michael addition/alkylation enable addition
of the alkylating agent at the beginning of the reaction, the
process is fully optimized by adding the alkylating agent to the
reaction mixture after the mixture is stirred for 3-4 h. In this
way, the Michael adduct (7b) is obtained in 94% isolated yield.
The stereoisomers were then separated and subjected to free
radical conditions to complete the annulation. This step is again
highly efficient, producing cis-5b and trans-5b in 80% and 93%
isolated yields, respectively.
(25) Spencer, A. J. Organomet. Chem. 1984, 265, 323.
(26) O’Donnell, M. J.; Polt, R. L. J. Org. Chem. 1982, 47, 2663.
3042 J. Org. Chem., Vol. 73, No. 8, 2008

Free Radical-Mediated Aryl Amination
TABLE 1. Three-Component (Type II) Indoline Synthesis (Eq 3)a
SCHEME 3. ACCRI Mechanism for r-Amino Ester
Epimerization during Cyclization of cis-Michael Adducts
vinyl group (a potential radical acceptor via addition) bears
additional steric hindrance allowed isolation of cis-5e in a
modest 30% yield. This behavior continued with the activated
allyl derivative cis-7f (Table 1, entry 7) in which trans-indoline
5f was obtained in 82% yield, but the cis-isomer was not formed
selectively to any measurable extent. Alkylation of the Michael
adduct with tert-butyl R-chloroacetate provided malonate de-
rivative 7g in 76% yield. The cis-isomer cyclized to cis-5g in
45% isolated yield, whereas trans-7g produced trans-5g in 85%
yield (Table 1, entry 8). Although propargyl electrophiles can
be sequenced in the same manner, the cyclization was ac-
companied by hydrostannation of the terminal alkyne. The
examples in Table 1 were not individually optimized for
selectivity or yield, so the results provide an indication of the
generality of a standard protocol.
Selective Epimerization of the r-Amino Ester Stereo-
center: Azacyclopentenyl Carbinyl Radical Isomerization
(ACCRI). Several of the Michael adducts 7 exhibited a drop
in diastereopurity during the indoline annulation step. While
this stereochemical erosion was absent or minimal in most cases,
cis-7a, cis-7e, and cis-7g were more susceptible to the isomer-
ization, and the observation was most pronounced in the latter
two. This epimerization is highly unusual since free radical
conditions are exceptionally mild (pH-neutral) and tolerant of
a wide range of functionality.27
a See the Supporting Information for complete details. Relative stereo-
chemistry measured by NOE difference measurements. Ratios of diaster-
eomers measured by 1H NMR (400 MHz). b Isolated yield of both
diastereomers. c Isolated yield. d Diastereomeric ratio: >20:1 cis-7a f 5:1
cis-5a; >20:1 cis-7e f 10:1 cis-5e; 10:1 cis-7g f 2:1 cis-5g. e A
cinchonidine-derived ammonium salt was used. f Solid-liquid-phase-transfer
conditions used: solid NaOH (20 equiv), CH2Cl2. g The indoline intermedi-
ate reacts further to unidentified products. h Stereo-nonselective hydrostan-
nation is competitive with cyclization.
Alkylation of the intermediate malonate with benzyl bromide
resulted in an outcome similar to that of alkylation with methyl
iodide, providing the stereoisomeric Michael adducts in 95%
combined yield (Table 1, entry 3). Despite the possibility of
1,5-hydrogen atom transfer from the benzylic carbon to the
intermediate aryl radical, cyclization of this inseparable mixture
of diastereomers furnished the cyclized products in 82%
combined yield with no evidence of aryl radical direct reduction.
Moreover, the adduct diastereomeric ratio could be manipulated
to favor (10:1) cis-7c through the use of a solid-liquid-phase-
transfer protocol (NaOH-CH2Cl2) (Table 1, entry 4). The high
selectivity notwithstanding, a more complete picture of the
reaction sequence (vide infra) was obtained by generation of
both diastereomers using the nonselective liquid-liquid-phase-
transfer conditions.
A variety of different malonate alkylating agents can be used
(Table 1, entries 5-9). Allylation with either allyl bromide or
methallyl bromide (Table 1, entries 5 and 6, respectively)
proceeded to adducts 7d and 7e in 87% and 95% yield. In both
cases, the cis- and trans-diastereomers were separable. Whereas
trans-7d and trans-7e cyclized uneventfully in 84% and 78%
yield, respectively, cyclization of their cis-counterparts was
complicated by the generation of several products. Although
the exact nature of these products was not ultimately determined,
that aryl-nitrogen bond formation occurred was evident from
the signature upfield shifts of the aromatic ring protons in the
crude reaction mixture. Accordingly, adduct cis-7e in which the
We have previously described ACCRI in an enantioenriched
indoline R-amino acid system analogous to the indolines
described here.28
By extension of those examples in which loss of enantiomeric
excess was correlated to the isomerization, loss of diastereo-
purity from 7 can be explained by the course of events detailed
in Scheme 3. This isomerization proceeds from the radical 8
formed by aryl radical addition to the azomethine nitrogen. A
key feature of the isomerization is the nucleophilic nature of 8
and the electrophilic character of 9, which, in concert, lower
the activation barrier via a polarization effect.29 Using conditions
that allow isomerization to compete with direct hydrogen atom
transfer to 8 (low effective stannane concentration), the cis-
(27) For leading references to epimerization of unactivated C-H bonds,
see: Tanner, M. E.; Kenyon, G. L. In ComprehensiVe Biological Catalysis;
Sinnott, M., Ed.; Academic Press: San Diego, 1988; Vol. 2. Frey, P. A.
Chem. ReV. 1990, 90, 1343.
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(29) Polar effects in radical reactions: Della, E. W.; Kostakis, C.; Smith,
P. A. Org. Lett. 1999, 1, 363. Tedder, J. M. Tetrahedron 1982, 38, 313.
J. Org. Chem, Vol. 73, No. 8, 2008 3043

Viswanathan et al.
FIGURE 2. Proposed competing transition states for (E)-olefin acceptors to rationalize syn-selectivity.
FIGURE 3. Proposed competing transition states for (Z)-olefin acceptors to rationalize low diastereoselection.
indoline ring can homolytically fragment at the carbon-nitrogen
σ-bond. Following a thermodynamically driven σ-bond rotation,
the carbon-nitrogen bond re-forms to give the trans-isomer.
Rotation of one of the carbon-carbon bonds of the chain must
occur, in addition to radical inversion, to reach the epimeric
indoline radical intermediate.28 This process is consistent with
the observation that cis-indolines are more prone to isomeriza-
tion than their trans-counterparts. It is significant to note that
the isomerization can be prevented by several means, including
the use of an electron-deficient benzophenone imine.28 We were
unable to locate the reduction product corresponding to 9,
consistent with our determination that ACCRI favors the ring
isomer at equilibrium and that subsequent chain-terminating
hydrogen atom transfer is reasonably fast relative to reduction
of the equilibrium concentration of 9.
their (Z)-isomers.30 We rationalize this using purely steric
considerations and the two transition states outlined in Figure
2. The first assumption is the intermediacy of an (E)-enolate
derived from the glycine Schiff base due to the steric bias of
the large ammonium counterion. In the case of the (E)-isomer
of the Michael adduct, the transition state 10 arising from attack
of the enolate on the Re face leads to the trans-isomer in the
product (trans-6b). This conformational arrangement suffers
from nonbonded interactions involving both aryl and nitrile
groups. Attack of the enolate on the Si face of the Michael
acceptor leads to transition state 11, eventually forming cis-6b.
In this transition state, these nonbonded interactions are
minimized and therefore would be lower in energy. This is
reflected in the observed 87:13 ratio favoring the cis-isomer.
The lower selectivity (58:42 dr) observed for addition to (Z)-
1b might be rationalized by the competition depicted in Figure
3. Addition of the enolate to the olefin Re face leads to
transition-state assembly 12. This transition state suffers from
nonbonded interactions between the aryl group and the imine.
Stereochemical Models for Diastereoselective Michael
Additions. The diastereoselection observed in additions of
glycine Schiff base 2 to unsaturated esters and nitriles was
considerably higher (4:1) when using (E)-olefins 1b relative to
(30) Oare, D. A.; Heathcock, C. H. J. Org. Chem. 1990, 55, 157. Oare,
D. A.; Heathcock, C. H. Top. Stereochem. 1989, 20, 87.
3044 J. Org. Chem., Vol. 73, No. 8, 2008

Free Radical-Mediated Aryl Amination
SCHEME 4
(cis/trans-7e). A dichloromethane solution of alkylidene malonate
4a (250 mg, 764 µmol), Schiff base 2 (225 mg, 764 µmol, 0.34
M), methallyl bromide (204 mg, 1.52 mmol), benzyltriethylam-
monium chloride (20 mol %), and 50% aq NaOH (20 equiv) was
stirred rapidly at room temperature for 8 h. The mixture was diluted
with ether, and the organic layer was washed with water and dried
(MgSO4). The residue obtained by filtration and concentration was
then purified by flash chromatography (neutral alumina, 5% diethyl
ether in hexanes) to afford the desired adducts as a separable 1:1
cis/trans mixture and colorless oil (486 mg, 95%): (cis-7e) Rf )
0.28 (20% EtOAc/hexanes); IR (film) 3062, 2978, 1732, 1625, 1190
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.66 (d, J ) 8.3 Hz, 2H),
7.52 (dd, J ) 8.0, 1.2 Hz, 1H), 7.42-7.39 (m, 3H), 7.35 (d, J )
7.6 Hz, 1H), 7.32-7.28 (m, 2H), 7.23-7.20 (m, 3H), 7.13 (td, J
) 7.2, 1.0 Hz, 1H), 7.03 (td, J ) 8.0, 1.6 Hz, 1H), 5.20 (d, J )
10.0 Hz, 1H), 4.74 (d, J ) 10.0 Hz, 1H), 4.71 (s, 1H), 4.62 (s,
1H), 4.12-4.01 (m, 2H), 3.97-3.92 (m, 2H), 2.92 (d, J ) 14.4
Hz, 1H), 2.45 (d, J ) 14.4 Hz, 1H), 1.61 (s, 3H), 1.14 (t, J ) 7.1
Hz, 3H), 1.09 (t, J ) 7.1 Hz, 3H), 0.97 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 170.8, 170.0, 169.8, 169.2, 142.2, 140.1, 137.8,
136.8, 133.0, 131.0, 130.3, 129.2, 128.7, 128.4, 128.2, 127.8, 126.8,
114.3, 80.7, 68.8, 61.1, 60.9, 60.5, 53.8, 43.4, 27.4, 24.0, 13.9, 13.8;
Similarly, Si face addition of the enolate would lead to transition
state 13 in which nonbonded interactions exist among the cyano
group, enolate oxygen, and quaternary ammonium counterion.
Therefore, neither transition state would be preferred as they
each suffer from torsional strain in the transition state, and this
is reflected in the nearly 1:1 ratio of diastereomeric addition
products formed.
If the interaction between the aromatic ring of the acceptor
and azomethine (and its substituents) of the donor in 10 is a
destabilizing influence as we postulate, then an increase in the
effective size of the aromatic ring might lead to enhanced
diastereoselection. We examined this possibility through the use
of acceptor 14 (Scheme 4), as the ortho,ortho-disubstitution
leads to a nonplanar styrene, and a corresponding increase in
the steric destabilization in the transition state leads to the trans-
adduct. Addition to 14 was indeed more diastereoselective,
leading solely (>20:1) to cis-15 in 75% yield. The putative
transition state 17 describes how the ortho-substituents lead to
a nonplanar acceptor and how its bromine substituents would
be best accommodated away from the diphenylmethylene of
the azomethine (cf. 10 and 11). Cyclization of this intermediate
to indoline cis-16 proceeded well, but in moderate yield due to
competitive product debromination.
1
(trans-7e) Rf ) 0.23 (20% EtOAc/hexanes); H NMR (400 MHz,
CDCl3) δ 8.27 (dd, J ) 8.0, 1.6 Hz, 1H), 7.59 (d, J ) 7.1 Hz, 1H),
7.53 (d, J ) 8.0 Hz, 1H), 7.41-7.39 (m, 3H), 7.36 (d, J ) 8.0 Hz,
1H), 7.34-7.29 (m, 3H), 7.15-7.12 (m, 2H), 7.09 (td, J ) 8.0,
1.6 Hz, 1H), 4.99 (d, J ) 4.6 Hz, 1H), 4.70 (s, 1H), 4.62 (d, J )
4.6 Hz, 1H), 4.52 (s, 1H), 4.07-4.04 (m, 3H), 3.89-3.80 (m, 1H),
2.70 (d, J ) 1.2 Hz, 2H), 1.59 (s, 3H), 1.22 (s, 9H), 1.15 (t, J )
7.1 Hz, 3H), 1.05 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 171.0, 170.12, 170.08, 169.2, 142.1, 139.8, 137.2, 136.6, 133.5,
132.4, 130.4, 129.0, 128.9, 128.7, 128.6, 128.3, 128.03, 128.00,
126.6, 114.7, 81.5, 67.2, 61.3, 61.2, 60.6, 49.5, 42.4, 27.8, 23.6,
13.8; HRMS (EI) exact mass calcd for C33H3379BrNO6 [M -
C4H9]+, 618.1491, found 618.1464.
trans-2-(1-Benzhydryl-2-(tert-butoxycarbonyl)-2,3-dihydro-
1H-indol-3-yl)-2-(2-methylallyl)malonic Acid Diethyl Ester (trans-
5e). A benzene solution of Michael adduct trans-7e (80 mg, 118
µmol), and nBu3SnH (144 µL, 534 µmol) in benzene (50 µM) was
warmed to 85 °C. AIBN (23 mg, 142 µmol) was then added as a
benzene solution by syringe pump over a 4-5 h period. The solution
was refluxed for an additional hour, cooled, and concentrated. The
residue was treated with a 1:1 (v/v) ether-satd aq KF solution and
the resulting mixture stirred vigorously until a white precipitate
formed. The organic layer was washed with water, dried (MgSO4),
filtered, and concentrated. The residue was then purified by flash
chromatography (10% diethyl ether in hexanes) to furnish the
indoline as a white solid (55 mg, 78%): mp 131.5-133.5 °C; Rf
) 0.34 (20% EtOAc/hexanes); IR (film) 3062, 2978, 1732, 1602
Conclusion
In summary, two- and three-component couplings are de-
scribed here that constitute strategically innovative approaches
to the synthesis of 2,3-disubstituted indolines. Diastereoselection
is maximized when ortho,ortho-disubstituted activated styrenes
are employed in the Michael addition step. The multifunctional
nature of the products is enhanced by their orthogonal protection
(nitrile or ethyl ester vs tert-butyl ester, diphenylmethylamine).
Incidentally, we have recently applied this annulation method
to the preparation of the indole framework of ambiguine G.31
Whereas the free radical-mediated aryl amination step is both
efficient and easily manipulated, there remains a need for highly
enantioselective direct additions of glycine Schiff base 2 to
styrene-derived Michael acceptors.17,32-34 Ultimately, the de-
velopment of this type of enantioselective reaction in combina-
tion with the strategies disclosed here may directly advance the
enantioselective construction of complex indoline alkaloids.
1
cm-1; H NMR (400 MHz, CDCl3) δ 7.45 (d, J ) 7.7 Hz, 2H),
7.41 (d, J ) 7.8 Hz, 2H), 7.29-7.27 (m, 3H), 7.23-7.19 (m, 3H),
7.13 (d, J ) 7.3 Hz, 1H), 6.82 (t, J ) 7.6 Hz, 1H), 6.57 (t, J ) 7.5
(32) Preliminary screening of cinchonidine-derived phase-transfer cata-
lysts (only) failed to produce products with significant enantioenrichment.
See the following leading references for enantioselective Schiff base
conjugate additions: Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron:
Asymmetry 2007, 18, 299. Arai, S.; Tokumaru, K.; Aoyama, T. Chem.
Pharm. Bull. 2004, 52, 646. Chinchilla, R.; Mazon, P.; Najera, C.; Ortega,
F. J.; Yus, M. ArkiVoc 2005, 222. Lygo, B.; Allbutt, B.; Kirton, E. H. M.
Tetrahedron Lett. 2005, 46, 4461. Ramachandran, P. V.; Madhi, S.; Bland-
Berry, L.; Reddy, M. V. R.; O’Donnell, M. J. J. Am. Chem. Soc. 2005,
127, 13450. Shibuguchi, T.; Mihara, H.; Kuramochi, A.; Ohshima, T.;
Shibasaki, M. Chem.sAsian J. 2007, 2, 794.
(33) Reviews: (a) Christoffers, J.; Baro, A. Angew. Chem., Int. Ed. 2003,
42, 1688. (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001, 171.
(34) (a) Dominguez, E.; O’Donnell, M. J.; Scott, W. L. Tetrahedron Lett.
1998, 39, 2167. (b) Perrard, T.; Plaquevent, J. C.; Desmurs, J. R.; Hebrault,
D. Org. Lett. 2000, 2, 2959.
Experimental Section
cis/trans-2-(Benzhydrylideneamino)-3-(2-bromophenyl)-4,4-
bis(ethoxycarbonyl)-6-methylhept-6-enoic Acid tert-Butyl Ester
(31) Chandra, A.; Viswanathan, R.; Johnston, J. N. Org. Lett. 2007, 9,
5027.
J. Org. Chem, Vol. 73, No. 8, 2008 3045

Viswanathan et al.
Hz, 1H), 5.90 (d, J ) 8.0 Hz, 1H), 5.58 (s, 1H), 4.78 (s, 1H), 4.69
(s, 1H), 4.28 (d, J ) 2.2 Hz, 1H), 4.19-4.07 (m, 3H), 4.00 (d, J
) 2.2 Hz, 1H), 3.98-3.94 (m, 1H), 2.96 (d, J ) 14.4 Hz, 1H),
2.70 (d, J ) 14.4 Hz, 1H), 1.72 (s, 3H), 1.26 (s, 9H), 1.16 (t, J )
7.2 Hz, 3H), 0.93 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 171.5, 170.4, 170.3, 151.1, 143.1, 141.8, 140.6, 129.7, 128.7,
128.6, 128.4, 127.9, 127.6, 127.3, 127.1, 126.3, 118.0, 115.2, 109.6,
81.2, 67.5, 67.3, 61.2, 61.1, 42.0, 27.9, 23.8, 14.0, 13.7; HRMS
(EI) exact mass calculated for C37H4379BrNO6 [M]+, 597.3090,
found 597.3093. Anal. Calcd for C37H43NO6: C, 74.35; H, 7.25;
N, 2.34. Found: C, 74.39; H, 7.38; N, 2.25.
Acknowledgment. This work was supported by the National
Institutes of Health (Grant GM 063577). R.V. was supported
in part as a Lubrizol fellow (2002-3), and much of this work
was performed at Indiana University. We are grateful to Dr.
Jeremy Wilt for assistance in preparing NMR spectral reproduc-
tions for the Supporting Information.
Supporting Information Available: Experimental procedures
and analytical data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO702523U
3046 J. Org. Chem., Vol. 73, No. 8, 2008