Asymmetric reactions of axially chiral amides: Use of removable ortho-substituents in radical cyclizations of o-iodoacrylanilides and N-allyl-N-o-iodoacrylamides

Article abstract of DOI:10.1016/j.tet.2004.05.116

Radical cyclizations of enantiomerically enriched o-iodoacrylanilides and N-allyl-o-iodoanilides bearing a removable ortho-substituent such as trimethylsilyl or bromine provide oxindoles and indoles in good yields and with good to excellent levels of chirality transfer from the N-Ar axis to the new stereocenter. Transition state models for the chirality transfer are suggested. Chemoselectivity of the radical cyclization in favor of the iodine in the case of 2-iodo-6-bromo-N-allylacrylamides has been exploited for the synthesis of chiral pyrroloquinolinones by a one-pot sequence of 5-exo and 6-endo cyclizations.

Full text of DOI:10.1016/j.tet.2004.05.116

Tetrahedron 60 (2004) 7543–7552
Asymmetric reactions of axially chiral amides: use of removable
ortho-substituents in radical cyclizations of o-iodoacrylanilides
and N-allyl-N-o-iodoacrylamidesq
†
Marc Petit, Steven J. Geib and Dennis P. Curran
*
Department of Chemistry, University of Pittsburgh, 219 Parkman Ave, Pittsburgh, PA 15260, USA
Received 21 April 2004; revised 19 May 2004; accepted 21 May 2004
Available online 6 July 2004
Dedicated to Professor Dieter Seebach in honor of his receipt of the Tetrahedron Prize
Abstract—Radical cyclizations of enantiomerically enriched o-iodoacrylanilides and N-allyl-o-iodoanilides bearing a removable ortho-
substituent such as trimethylsilyl or bromine provide oxindoles and indoles in good yields and with good to excellent levels of chirality
transfer from the N–Ar axis to the new stereocenter. Transition state models for the chirality transfer are suggested. Chemoselectivity of the
radical cyclization in favor of the iodine in the case of 2-iodo-6-bromo-N-allylacrylamides has been exploited for the synthesis of chiral
pyrroloquinolinones by a one-pot sequence of 5-exo and 6-endo cyclizations.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
droindol-2-ones R-2 with high levels of chirality transfer
from the vanishing N–Ar axis to the forming stereocenter
(Scheme 1).6,7 Similarly high levels of transfer were
observed during the cyclization of N-allyl-o-iodoanilides
M-3 with the radical acceptor on the N-substituent; these
precursors produce chiral N-acyl dihydroindoles R-4.7
However, in both cases a second ortho-substituent such as
the methyl group is needed to increase the rotation barrier to
obtain separable, stable atropisomers at room temperature.
Related o-iodoanilides lacking the o-methyl substituent
have rotation barriers of ,20 kcal/mol.1
Like biaryls, appropriately substituted amides, imides and
related heterocycles exhibit axial chirality and have high
rotation barriers due to hindered rotation around sp2–sp2
C–C or C–N bonds. Early studies on axially chiral amides
and imides focused on structure, resolution and rotation
barrier measurements,1 but over the last decade a diverse
assortment of asymmetric reactions of these classes of
molecules have been identified.2,3a We and others have
focused on asymmetric reactions of amides and imides
where axial chirality emanates from a N–Ar bond.3,4
Because of their high rates, radical reactions5 can often
occur much faster than N–Ar bond rotations, and asym-
metric induction or transfer of chirality from the axis to a
new stereocenter often results.
Oxindole alkaloids have generated a great deal of synthetic
interest, and many syntheses in both racemic and enan-
tioenriched forms have been achieved.8,9 Like the repre-
sentative natural products (2)-horsfiline10 and
spirotryprostatin B8 shown below, most members of this
family lack ortho-substituents and none have ortho-methyl
groups. To extend this methodology to the synthesis of
natural oxindole alkaloids, we sought to identify temporary
ortho-substituents that met three requirements: (1) they
should be large enough to ensure that the N–Ar rotation
barrier is sufficiently high for resolution and radical
cyclization at room temperature, (2) they should promote
high levels of chirality transfer, and (3) they should be
readily removed or replaced. Here we report that both a
trimethylsilyl group and a bromine atom meet the needs of a
temporary ortho-substituent and allow syntheses of unsub-
stituted oxindoles. We also report a new synthesis of chiral
pyrroloindolone analogs by a cascade 5-exo-trig/6-endo-trig
We have shown previously6,7 that o-haloanilides such as M-
1 and M-3 exist as stable atropisomers with rotation barriers
for the N–Ar bond of 28–31 kcal/mol. Anilides M-1 with a
radical acceptor on the acyl group of the amide smoothly
undergo 5-exo cyclizations to give substituted 1,3-dihy-
q Supplementary data associated with this article can be found in the online
version, at doi: 10.1016/j.tet.2004.05.116
Keywords: Axially chiral amides; Asymmetric radical reactions.
*
Corresponding author. Tel.: þ1-4126248240; fax: þ1-4126249861;
e-mail address: curran@pitt.edu
Direct inquiries regarding the crystal structures to this author at
geib@pitt.edu
†
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.05.116

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M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
Scheme 1.
Scheme 2.
radical cyclization of o-iodo-o-bromoanilides.
chloride provided an inseparable mixture of two diaster-
eomeric acetates (not shown) that was used directly in the
next step. Hydrolysis of the acetate with sodium hydroxide
provided a mixture of M-7-I and P-7-I (1.7/1) that was
readily separated into its two pure components by flash
chromatography. The individual isomers were then sub-
jected to a classic sequence described by Taguchi13
involving substitution of the in situ-generated mesylate by
lithium phenylselenide, oxidation and elimination to give
M-8a-I and P-8a-I with enantiomeric ratios (er) of 94/6 and
98/2. A similar sequence of reactions starting from 2-
bromo-6-iodo-4-methyl aniline provided the bromides M-7-
Br and P-7-Br (1.2/1), which were separated and then
converted to M-8a-Br and P-8a-Br (See Supporting
information).
2. Results and discussion
We initially focused on using the trimethylsilyl (TMS)
group as removable ortho-substituent. We prepared acryla-
nilide enantiomers M-8a and P-8a, measured their rotation
barriers, and studied the cyclizations of the derived radicals.
The synthesis of M-8a/P-8a is summarized in Scheme 2.
Two successive protections of 2,6-diiodo-4-methylaniline11
with trimethylsilyl chloride afforded bis-trimethylsilylani-
line 5 in 95% yield. Metal–halogen exchange with sec-
butyllithium induced the migration of one of the TMS
groups to the ortho position,12 and the resulting nitrogen
anion was quenched with methyl iodide to give 6 in 85%
yield. Acylation of 6 with (S)-(2)-2-acetoxypropionyl
The absolute configurations of P-8a-I and P-8a-Br were
assigned by solving the crystal structures of the intermediate
alcohols P-7-I and P-7-Br (see Supporting information).
Enantioenriched samples of M-8a-I and M-8a-Br (92/8 and
94/6 er) were racemized by heating at 95–100 8C in
hexanes, and the decrease in er was measured as a function
of time by chiral HPLC analysis. The rotation (enantiomer-
ization) barrier was measured to be 30.8 kcal/mol for the 2-
iodoanilide M-8a-I and 28.2 kcal/mol for the 2-bromoani-
lide M-8a-Br. The decreased rotation barrier of M-8a-Br
relative to M-8a-I (about 2.6 kcal/mol) presumably reflects

M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
7545
the decreased size of bromine relative to iodine; however,
Table 1. Chirality transfer in radical cyclizations of M/P8a–c
both compounds are stable enantiomers at room temperature
(25 8C). Interestingly, the measurements indicate that the
TMS group has about the same effective size as a methyl
group in this rotation since M-8a-I and compounds M-16
(RE, RZ¼H) have about the same rotation barriers.
The rotational features of the amide N–CO bond (standard
amide rotation) are also of interest in these molecules (Fig.
1
1). M/P-8a-Br/I exist as single rotamers according to H
c
d
erP
Entry Precursor-Xa RE RZ Product %Yieldb erSM
%cte
NMR analysis, and crystal structures (see below) prove that
this is the expected E-rotamer (CvO and Ar trans).
Likewise P-7-Br/I exist as predominately the E-rotamer.
In contrast, M-7-Br/I exists as approximately 1.7/1 mixtures
of amide rotamers. The barriers to amide N–CO bond
rotation have not been measured, but they must be
significantly lower than the barriers to N–Ar bond rotation.
This means that amide bond rotation occurs without
racemization. The similarities of the chemical shift of the
resonances of major rotamer of M-7-I/Br with the
resonances of P-7-I/Br suggest that the major rotamer of
M-7-I/Br is E, as shown in Figure 1.
1
2
3
4
5
6
7
8
M-8a-I
P-8a-I
M-8a-Br
P-8a-Br
M-8b-I
P-8b-I
H
H
H
H
Me
Me
H
H
H
H
H
H
R-9a
S-9a
R-9a
S-9a
R-9b
S-9b
76
78
10
10
76
77
90
92
94/6
98/2
95/5
95/5
96/4
99/1
88/12 94
94/6
91/9
nd
96
96
nd
87/13 91
91/9 92
M-8c-I
P-8c-I
Me Me R-9c
Me Me S-9a
.99/1 73/27 73
.99/1 73/27 73
a
Under the standard HPLC conditions, the first eluting enantiomer (M) of
the precursor gives the second eluting enantiomer (R) of the product.
Isolated yield after chromatography.
Enantiomeric ratio of precursor 8.
Enantiomeric ratio of product 9.
% Chirality transfer ¼ yield (not excess) of the major enantiomer
expected from an enantiopure precursor; (% major enantiomer
SM)/(%major enantiomer product).
b
c
d
e
Radical cyclizations were conducted by a standard pro-
cedure.14 Benzene solutions (0.005 M) of M-8a-I (94/6 er)
and P-8a-I (98/2 er), Bu3SnH (1.1 equiv.) and Et3B
(1.0 equiv.) were stirred at room temperature for 30–
60 min, during which time oxindole 9a formed. The
enantiomer ratios of 9a were measured by HPLC with an
analytical (S,S)-Whelk-O115 column and found to be 88/12
and 96/4 (see Table 1, entries 1 and 2). Taking into account
the enantiopurity of the precursors, this corresponds to a
94–96% transfer of chirality from the axis in 8a to the
stereocenter in 9a. Isolated yields of R-9a and S-9a were 76
and 78% after flash chromatographic purification. Bromide
M-8a-Br cyclized to give R-9a with about the same level of
chirality transfer as the iodide (95%), but the conversion
was very low (10% isolated yield), and most of the
precursor was recovered unreacted (entry 3). Due to the
poor conversion, the er measurement of P-8a-Br was not
conducted, and subsequent work was focused on the more
reactive iodides.
The generality of this chirality transfer was probed by
synthesizing and cyclizing two more pairs of enantiomers.
Racemic crotonoyl anilide 8b and 3,3-dimethylacryloyl
anilide 8c (Table 1) were obtained in 79 and 82% yield by
mixing 6 with the appropriate acyl chloride. The racemates
were resolved on semi-preparative column ((S,S)-Whelk-
O1, 25 cm£21.1 mm I.D., 2–10% iPrOH in hexanes, 10 ml/
min, 25–50 mg per injection) to give the individual
enantiomeric components.
Highly enantioenriched compounds M-8b,c and P-8b,c
were cyclized by using the standard conditions, and the
results of these experiments are shown in Table 1, entries 5–
8. Isolated yields of cyclized products ranged from 76–
92%.16 Crotonoyl precursors M/P-8b gave levels of
chirality transfer (91–92%) similar to the acryloyl analogs
(compare entries 1–4 with 5 and 6), while the 3,3-
dimethylacryloyl precursors 8c gave a lower but still
significant level of chirality transfer (73%, entries 7/8).
This is the same trend that was observed with the o-methyl
substituted acrylanilides: precursors with RZ¼H give higher
levels of chirality transfer (.90%), while those with
RZ¼Me are less selective (70–75%).6
To date, the absolute configurations of all products from N-
acryloyl radical cyclizations6 have been assigned by
analogy to a single optical rotation calculation17 and by
using the trend that the first eluting enantiomer precursor in
HPLC always gave the second eluting enantiomer of
cyclized compound. This HPLC trend held for all the
examples in Table 1, and we were able to confirm the
computational assignment of absolute configuration by
solving two key crystal structures by the anomalous
Figure 1. Amide Rotamer Preferences of 7 and 8a.

7546
M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
dispersion method. The structures and associated chemistry
for this assignment are shown in Scheme 3.
mers of the precursors 8 give the second eluting R-
enantiomers of the products 9.
First, we solved the crystal structure of the first eluting
enantiomer of the precursor with the 3,3-dimethylacryloyl
group and showed that this was M-8c-I. Next, we cyclized
this as above (Table 1, entry 7) to provide 9c in a 73/27 ratio
with the second eluting enantiomer predominating. The
enriched mixture 9c was then treated with ICl to provide a
73/27 mixture of aryl iodide 16c with the second eluting
enantiomer again predominating. The minor (first eluting)
enantiomer of this mixture was isolated by semi-preparative
chiral HPLC, was crystallized, and its structure was shown
by X-ray to be S-16c. In turn, this means that the major
enantiomeric product from the radical cyclization of M-8c-I
must be R-9c. This is the first example where crystal
structures of both a precursor and a product have been
solved to secure configuration assignment, and this assign-
ment agrees with our existing model derived from rotation
calculations and retention trends.6,7 Thus, we can now with
good confidence conclude that the first eluting M-enantio-
Based on the low reactivity of the bromides 9-Br, we
hypothesized that radical cyclization of an o-iodo o0-
bromoanilide would occur selectivity at the iodide-bearing
carbon, leaving the bromine atom intact for a subsequent
reaction.18 To test this hypothesis, we prepared 2-bromo-6-
iodo-4-methylaniline 10 from 2,6-dibromo-4-methylaniline
by iodination with BTMA·ICl2 in presence of calcium
carbonate (see Supporting information). A one-pot sequence
of deprotonation of 10, N-methylation with iodomethane,
deprotonation again, and subsequent N-acylation with
acryloyl chloride gave 11 in racemic form. Resolution by
semi-prep HPLC (Chiralcel OD 25 cm£2 cm, 4% iPrOH in
hexanes, 10 ml/min, 30 mg per injection) gave 2-bromo-6-
iodo-4-methylaniline anilides M-11 and P-11 with good er
(96/4 and 99/1). The absolute configuration of the first
eluting enantiomer of 11 was determined to be P by X-ray
crystallography (see Supporting information). M-11 was
racemized by heating at 78–82 8C in hexanes, and the
Scheme 3.

M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
7547
decrease in er was measured as a function of time by chiral
HPLC analysis. The rotation barrier was measured to be
30.4 kcal/mol, indicating that these are stable enantiomers
at room temperature.
The two enantiomers of 11 were then submitted to the usual
cyclization conditions to give oxindolones R-12 and S-12 in
47 and 45% yield after flash chromatography (Scheme 4).
We also isolated lesser amounts (20–22%) of the
phenylated compound 13 from both reactions. This
compound must arise because radical addition to the solvent
benzene competes with the cyclization. Such additions are
well known for aryl radicals.19 The reaction progress was
followed by gas chromatography and no formation of the
oxindole 16 was observed, confirming that the abstraction
reaction is totally chemoselective for iodine. Compounds R-
12 and S-12 were obtained with good transfer of chirality of
96% from M-11 and 95% for P-11. In this case, the first
eluting enantiomer P-11 on HPLC (Chiralcel-OD) gave the
first eluting enantiomer S-12. The absolute configuration of
R-12 was confirmed by exposure of silane R-9a to bromine
in dichloromethane to provide bromide R-12 (not shown).
This sample matched the retention time of the product from
the cyclization of M-11 on chiral HPLC analysis.
With a good understanding of how to make and cyclize the
o-silyl and o-bromoacrylanilides, we next investigated ways
to remove and replace the substituents. In the case of the
silicon, we initially tried the standard methods of desilyla-
tion by using fluoride reagents. We first submitted oxindole
R-9a to TBAF, but the only isolated compound (76% yield)
was racemic 3-hydroxy-1,3-dihydroindol-2-one 14a. This
must arise from base-promoted air oxidation during
desilylation.20 When R-9a was reacted with an excess of
HF/pyridine, the expected desilylated compound 15a was
obtained but in low conversion (50%). Finally, exposure of
S-9a,c to trifluoroacetic acid gave the oxindoles S-15a,c in
97 and 95% yield, respectively, without racemization of the
stereocenter (Scheme 5). The silicon group can also serve as
a precursor for new functionality. For example, exposure of
R-9a and R-9c to ICl induced clean exchange between the
silicon and the iodine, and 6-iodo-oxindoles R-16a and R-
16c were formed in 95 and 98% yields. This exchange opens
Scheme 5.
the possibility of introducing different substituents by using
standard organometallic coupling reactions. On the other
hand, the bromine in S-12 was removed by reduction with
an excess of tributyltin hydride in refluxing dichloro-
methane to give S-15a in 75% yield. These representative
transformations open the door to a diverse assortment of
enantioenriched oxindoles.
Previous work in our laboratory7 has also shown that radical
cyclizations of enantiomerically enriched N-allyl-o-iodo-
anilides (Scheme 1, 3!4) occur in good yields with good to
Scheme 4.

7548
M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
Scheme 7.
combined with the above conversion of the trimethylsilyl
to iodine followed by a second radical cyclization to give
direct access to tetrahydropyrroloquinolones 27a from 20a.
Because of ring strain in the forming tricyclic system, we
expected the second radical cyclization to occur in a 6-endo
fashion.21 As it turned out, the first cyclization also provided
minor amounts of 6-endo product, depending on the
substitution pattern of the double bond.
Scheme 6.
excellent levels of chirality transfer. Furthermore, competi-
tive cyclization of compound rac-17 bearing both N-
crotonoyl and N-allyl groups produced exclusively rac-
18a resulting from the cyclization to the N-allyl group
(Scheme 6).7 The regioisomer rac-18b was not observed.
We hypothesized that this regioselectivity could be
Precursors 20a-c were prepared starting from 2,6-diiodo-4-
methylaniline 5 by the silyl migration route shown in
Scheme 2. Treatment of 5 with sec-BuLi followed by the
appropriate allyl halide provided intermediates 19a–c
(Scheme 7). These were not purified but were directly
Table 2.
a
b
erP
d
erP
Entry
Precursor
R1
R2
R3
R4
erSM
5-exo
Yield
ctc
6-endo
Yield
ctc
1
2
3
4
5
6
M-20a
P-20a
M-20b
P-20b
M-20c
P-20c
H
H
Me
Me
H
H
H
H
H
Me
Me
H
H
H
H
Me
Me
H
H
Me
Me
Me
Me
.99/1
95/5
.99/1
.99/1
.99/1
.99/1
R-21a
S-21a
21b
21b
R-21c
S-21c
47
48
21
21
88
90
97/3
90/10
—
—
86/14
82/18
97
95
—
—
86
82
22a
22a
R-22b
S-22b
22c
22
21
57
55
0
—
—
73/27
70/30
—
—
—
73
70
—
—
H
22c
0
—
a
Enantiomeric ratio of precursor 20.
Enantiomeric ratio of product 21.
b
c
d
Chirality transfer ¼ yield (not excess) of the major enantiomer calculated for a 100% conversion from a starting material with an er .99/1.
Enantiomeric ratio of product 22.

M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
7549
acylated to provide 20a–c, which were isolated in pure form
by flash chromatography in 56–68% overall yield.
determined by X-ray crystallography using the anomalous
dispersion method (see Supporting information), and the
configurations of 21a,b were assigned by assuming that
their enantiomers elute in the same order. In these
cyclizations, the first eluting enantiomers of 20 ((S,S)-
Whelk-O1 column) again gave the second eluting enantio-
mer by using the (S,S)-Whelk-O1 column (poor resolution)
and gave the first eluting enantiomer 21 by using the
Chiralcel OD column (good resolution). That both pairs of
enantiomers switch elution order on the two columns
increases the level of confidence in the use of elution order
to assign configuration. We currently have no firm assign-
ment of the configuration of any of the precursors 20, so
these were tentatively assigned as shown in Table 2 by using
the transition state model described in scheme (see below).
Racemic precursors 20a–c were resolved on a semi-
preparative HPLC column ((S,S)-Whelk-O1, 25 cm£
21.1 mm I.D., 2–10% iPrOH in hexanes, 10 ml/min). The
enantioenriched compounds were then subjected to the
usual conditions for radical cyclization, and the results of
this series of experiments are shown in Table 2. Cyclization
of unsubstituted M-20a (R1–R4¼H) followed by flash
chromatography provided the 5-exo product R-21a in 47%
yield alongside the 6-endo product 22a in 22% yield (entry
1). The level of chirality transfer to the 5-exo product was
excellent (97%), while the 6-endo product is achiral. Similar
results were obtained with enantiomer P-20a (entry 2).
Increasing the terminal substitution on the N-allyl group
suppressed the 6-endo cyclization. Cyclization of N-(3,3-
dimethylallyl)-N-crotonoyl precursor M-20c provided
exclusively the 5-exo product R-21c (R1¼H, R2-R4¼Me)
in 88% yield with 86% chirality transfer. Again, enantiomer
P-20c behaved similarly (entries 5 and 6).
As in the previous study,7 the three cyclizations are totally
regioselective and occurred only on the allyl group. The
levels of chirality transfer in the 5-exo cyclizations are good
to excellent (entries 1/2 and 5/6) and always a little lower for
precursors with a Z substituent on the allyl group. This trend
with N-allyl acceptors is similar to that exhibited by the
Cyclization of N-crotyl, N-crotonoyl derivatives M/P-20b
gave achiral 5-exo product 21b in 21% yield alongside the
6-endo product 22b in 55–57% yield (entries 3 and 4).
Interestingly, the 6-endo products are significantly enan-
tioenriched, and the level of chirality transfer of the methyl
bearing stereocenter is 70–73% (entries 3 and 4). There is
no opportunity for chirality transfer from the N–Ar axis in
the 6-endo cyclization process, but instead the transfer
occurs during the bimolecular hydrogen abstraction reaction
with Bu3SnH (see Eq. 1). This is the first example of this
type of transfer from a chiral axis to a stereocenter in a
radical hydrogen transfer reaction. The configuration of the
6-endo compound 22b is not known.
ð1Þ
We were not able to fully resolve the cyclized enantiomers
of 21a and 21c by using an analytical (S,S)-Whelk-O1
column but the enantiomer ratio was accurately measured
by using an analytical Chiralcel OD column. The ratio of
enantiomers 22b was determined after desilylation (TFA)
by using a (S,S)-Whelk-O1 column. The absolute configur-
ation of compound R-21c (first eluting enantiomer) was
Scheme 8.

7550
M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
Scheme 9.
previously studied methyl ortho-substituted class of com-
pounds.7
To obtain precursors for the tricyclic compounds, we
submitted compounds 21a, 21c, 22a and 22b to silicon/
iodine exchange reaction with ICl. Results varied depending
upon the ring size, as shown in Scheme 8. The dihydroin-
doles gave the expected iodides as the exclusive or major
products. Iodide 23a was formed from 21a in 95% yield,
while 21c provided a mixture 67/33 of the iodinated
compound 23c and the desilylated compound 24c. These
were separated on a semi-preparative column ((S,S)-Whelk-
O1, 25 cm£21.1 mm I.D, 10% iPrOH in hexanes, 10 ml/
min, 50 mg per injection). In contrast, the tetrahydroquino-
lines 22a and 22b provided the desilylated compounds as
the major (26a) or exclusive (26b) products.
Scheme 10.
that iodine abstraction is highly favored over bromine
abstraction. This is crucial for chirality transfer, since iodine
and bromine abstraction give quasienantiomeric radicals
that will ultimately result in enantiomeric tricyclic products.
Resolution of rac-28 by semi prep HPLC (Chiralcel OD
25 cm£2 cm, 4% iPrOH in hexanes, 10 ml/min, 30 mg per
injection) gave 6-bromo-2-iodo-4-methyl-anilides M-28
and P-28 with 97/3 and 95/5 er. These compounds were
then subjected to the usual conditions of radical cyclization,
and the results are shown in Scheme 11. Bromodihydrole
indoles R/S-29 were the only isolated products from these
reactions in good yields (67 and 65%) and enantiomer ratios
(94/6 and 89/11, corresponding to chirality transfer levels of
We then submitted iodides rac-23a and rac-23c to the
standard cyclization conditions to provide the pyrroloqui-
nolones rac-27a and rac-27c in 52 and 54% yields after
flash chromatographic purification (Scheme 9). Tricycle 27c
was characterized as an inseparable 1/1 mixture of
diastereomers. These tricyclic quinolinones result from
regioselective 6-endo cyclization, and products of 5-exo
cyclization were not observed. Related observations have
been made by Dankwardt and co-workers who studied the
regioselectivity of an intramolecular Heck reaction. In this
work, a preformed five membered ring directed the formation
of a six membered ring for the second cyclization.22
Finally, to eliminate the need for silicon/iodine exchange,
we studied both the sequential and one-pot cyclizations of
two o-iodo o0-bromo anilides. Precursor rac-28 was
synthesized from 6 by a one-pot sequence of deprotonation,
N-alkylation with trans-cinnamyl bromide, deprotonation,
and subsequent N-acylation with trans-crotonoyl chloride
(Scheme 10). When rac-28 was exposed to 1 equiv. of
tributyltin hydride, a single new product was formed whose
mass spectrum was consistent with rac-29. Upon addition of
two more equivalents of tin hydride, 29 was consumed and a
single new product was formed. This was isolated in 57%
yield and identified as pyrroloquinolone rac-30. These
results confirm the earlier observations (Scheme 4) showing
Scheme 11.

M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
7551
Scheme 12.
97 and 95%). We have no crystal structures in this series,
and the absolute configurations of the precursors were
assigned by the elution order trend in HPLC.
To complete this study, we needed only to conduct this
sequence starting from a resolved precursor to form an
enriched product quinolinone. For that, we choose, 2-
bromo-6-iodo-4-methyl-anilide 31. This has an acryloyl
group in place of the crotonoyl group in 28, and accordingly
can only give a single enantiomer in the second cyclization.
Anilide rac-31 was prepared by using the method described
for 28 (see Supporting information). After resolution by
preparative HPLC (Chiralcel OD), we obtained the M-31
and P-31 with 99/1 and 94/6 er. These two enantiomers were
submitted to the double cyclization conditions to give the
two quinolines R-32 and S-32 in 50 and 52% isolated yields
(Scheme 12, only the M/R enantiomer series is shown).
Again, the double cyclization was regioselective and the
only compound isolated was the quinoline arising from the
sequence 5-exo then 6-endo radical cyclizations. The
chirality transfer levels were 95 and 94% as ascertained
by the usual chiral HPLC analysis on the (S,S)-Whelk-O1
column, and absolute configurations were assigned by
HPLC elution orders.
Scheme 13.
would be sacrificed, and the transition state geometry is
reached mainly by twisting of the two key bonds only (see
arrows).
Models for chirality transfer for both N-acryloyl and N-allyl
cyclizations of o-iodo anilides bearing o0-methyl groups
have been previously proposed,6,7 and the straightforward
applications of these models to the o0-silyl and o0-bromo
substrates 33 and 36 are shown in Scheme 13. Both models
34 and 37 involve twisting of the aryl ring bearing the
radical and the alkene acceptor towards each other, but the
alkene acceptor twists in opposite directions. This is
surprising because the two cyclizations only differ by the
presence of a CH2 (N-allyl) or CvO (N-acryloyl) group
along the connecting chain between the radical and the
acceptor. We have suggested that the increased flexibility of
the N-allyl group allows it to reach out to the aryl radical and
this alters significantly the geometry of cyclization tran-
sition state 37.7 In contrast, the N-acryloyl group of 34
resists reaching out to the radical because amide resonance
In this work, the structures of several precursors and
products in the N-acryloyl series have been rigorously
determined by a combination of X-ray analysis and inter-
conversion. Since the original model was based on tentative
assignments,6 this greatly increases the confidence that the
original structure assignments were correct and that the
model can now be used to assign absolute configuration of
products from precursors. In contrast, in the N-allyl series,
the stereochemical model was already based on prior crystal
structure work,7 and the configuration of the products in
Table 2 were primarily assigned based on the model. These
assignments are fully consistent with the assignments made
based on the trends in order of elution of the precursors and
products on chiral HPLC, thereby further increasing the
confidence that the assignments are correct.

7552
M. Petit et al. / Tetrahedron 60 (2004) 7543–7552
Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron: Asymmetry
3. Conclusions
1997, 8, 3955–3975. (c) Curran, D. P.; Geib, S. J.; DeMello,
N. Tetrahedron 1999, 55, 5681–5704.
In summary, we have shown that a removable ortho-
substituent can be used for radical cyclizations of axially
chiral N-acryloyl-o-iodoanilides and N-allyl-o-iodoanilides.
High levels of chirality transfer are observed in many cases
and an ortho-substituent such as bromine or silicon can be
easily removed or replaced with retention of the enantio-
purity. In the case of 6-bromo-2-iodoanilide, we observed
total chemoselectivity in favor of the iodine in the tin
hydride reduction. The regioselectivity of the competitive
cyclization to the N-allyl group over the N-acryloyl group
discovered in previous work was extended. For axially
chiral N-acryloyl-o-iodoanilides, we proved the sense of
chirality transfer by obtaining several X-ray structures of
precursors and cyclized compounds. Finally, we demon-
strated that the cyclization of axially chiral N-acryloyl-o-
iodoanilides and N-allyl-o-iodoanilides can be applied
toward the synthesis of chiral dihydrooxindoles and
dihydroindoles, and can also be extended to the synthesis
of chiral pyrroloquinolinones by using a chemo-, regio- and
stereoselective double radical cyclization.
4. (a) Kitagawa, O.; Momose, S.; Fushimi, Y.; Taguchi, T.
Tetrahedron Lett. 1999, 40, 8827–8831. (b) Kitagawa, O.;
Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.; Shiro, M. J. Org.
Chem. 1998, 63, 2634–2640. (c) Kitagawa, O.; Izawa, H.;
Taguchi, T.; Shiro, M. Tetrahedron Lett. 1997, 38,
4447–4450. (d) Hata, T.; Koide, H.; Taniguchi, N.; Uemura,
M. Org. Lett. 2000, 2, 1907–1910. (e) Hata, T.; Koide, H.;
Uemura, M. Synlett 2000, 1145–1147. (f) Clayden, J.;
Westlund, N.; Wilson, F. X. Tetrahedron Lett. 1996, 37,
5577–5580.
5. For review on enantioselective radical reactions: Sibi, M. P.;
Manyem, S.; Zimmerman, J. Chem. Rev. 2003, 103,
3263–3296.
6. Curran, D. P.; Liu, W. D.; Chen, C. H.-T. J. Am. Chem. Soc.
1999, 121, 11012–11013.
7. Curran, D. P.; Chen, C. H.-T.; Geib, S. J.; Lapierre, A. J. B.
Tetrahedron 2004, 60, 4413–4424.
8. For review on oxindole alkaloids see: Marti, C.; Carreira, E.
Eur. J. Org. Chem. 2003, 2209–2219.
9. Llabres, J. M.; Viladomat, F.; Bastida, J.; Codina, C.;
Rubriralta, M. Phytochemistry 1986, 25, 2637–2640.
10. Jones, K.; Wilkinson, J. J. Chem. Soc., Chem. Commun. 1992,
24, 1767–1769.
Supporting information available
Full experimental details of the synthesis, separation,
cyclization, and characterization of all compounds
described in this paper are available (part 1, pages 1–42)
along with complete details of all the crystal structures (part
2, pages 43–111) and copies of representative spectra (part
3, pages 112–155).
11. Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.;
Okamoto, T. Bull. Chem. Soc. Jpn 1988, 61, 600–602.
¨
12. Hellwinkel, D.; Lammerzahl, F.; Hofmann, G. Chem. Ber.
1983, 116, 3375–3405.
13. Kitagawa, O.; Izawa, H.; Sato, K.; Dobashi, A.; Taguchi, T.;
Shiro, M. J. Org. Chem. 1998, 63, 2634–2640.
14. Miura, K.; Ichinose, Y.; Nozaki, K.; Fugami, K.; Oshima, K.;
Utimoto, K. Bull. Chem. Soc. Jpn 1989, 62, 143–147.
15. Cass, Q. B.; Degani, A. L. G.; Tiritan, M. E.; Matlin, S. A.;
Curran, D. P.; Balog, A. Chirality 1997, 9, 109–112.
16. Traces of uncyclized, reduced compounds (between 1–5%)
were also isolated by chromatography on silica gel.
17. Kondru, R. K.; Chen, C. H. T.; Curran, D. P.; Beratan, D. N.;
Wipf, P. Tetrahedron: Asymmetry 1999, 10, 4143–4150.
18. Rate constant measurements show that aryl iodides are about
400 times more reactive than aryl bromides towards tributyltin
radical. Curran, D. P.; Jasperse, C. P.; Totleben, M. J. J. Org.
Chem. 1991, 56, 7169–7172.
Acknowledgements
We thank the National Science Foundation for funding this
work.
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