Asymmetric radical cyclization reactions of axially chiral N-allyl-o-iodoanilides to form enantioenriched N-acyl dihydroindoles

Article abstract of DOI:10.1016/j.tet.2004.02.064

Radical cyclizations of enantiomerically enriched N-allyl-o-iodoanilides provide N-acyl-3-alkyl-2,3-dihydroindoles in good yields and with good to excellent levels of chirality transfer from the N-Ar axis to the new stereocenter. In competitive cyclizations of N-acryloyl-N-allyl-o-iodoanilides, the addition of an o-methyl group reverses the regioselectivity of the radical cyclization from the acryloyl group to the allyl group. Approximate rate constants for representative radical cyclizations have been measured to provide insight into the origin of these observations.

Full text of DOI:10.1016/j.tet.2004.02.064

Tetrahedron 60 (2004) 4413–4424
Asymmetric radical cyclization reactions of axially chiral
N-allyl-o-iodoanilides to form enantioenriched
N-acyl dihydroindolesq;qq
†
Dennis P. Curran, Christine H.-T. Chen, Steven J. Geib and Andre J. B. Lapierre
*
Department of Chemistry, University of Pittsburgh, Parkman Avenue, University Drive, Pittsburgh, PA 15260, USA
Received 13 January 2004; revised 9 February 2004; accepted 23 February 2004
We dedicate this paper to Professor Leo Paquette on the occasion of his 70th birthday
Abstract—Radical cyclizations of enantiomerically enriched N-allyl-o-iodoanilides provide N-acyl-3-alkyl-2,3-dihydroindoles in good
yields and with good to excellent levels of chirality transfer from the N–Ar axis to the new stereocenter. In competitive cyclizations of
N-acryloyl-N-allyl-o-iodoanilides, the addition of an o-methyl group reverses the regioselectivity of the radical cyclization from the acryloyl
group to the allyl group. Approximate rate constants for representative radical cyclizations have been measured to provide insight into the
origin of these observations.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Axially chiral benzamides, anilides and related imides have
been known for several decades,1 and work over the last 10
years has focused on asymmetric reactions of these
species.2–6 A recurring theme is the occurrence of an
inter- or intramolecular reaction more rapidly than rotation
of a C–N or C–C bond of an amide. Intermolecular
reactions usually result in formation of a new stereocenter
with retention of the chiral axis (asymmetric induction),
while intramolecular reactions often result in formation of a
new stereocenter with loss of the chiral axis (chirality
transfer). Representative examples of intermolecular
reactions are shown in Figure 1 and include the nitrile
oxide cycloaddition reaction to o-tert-butylacrylanilide 1
(asymmetric induction by a C–N axis) to give 22 and the
addition of PhMgBr to o-formylnaphthamide 3 (asymmetric
induction by a C–C axis) to give alcohol 4.7
The radical cyclization of N-acryloyl anilide 5 to provide 6
(Fig. 2) is an example of an intramolecular reaction that
occurs with faithful chirality transfer (enantiomer ratios
Figure 1. Examples of asymmetric induction with axially chiral anilides
(top) and naphthamides (bottom).
.90/10).2c In this reaction, the intermediate aryl radical 7
must have a much lower barrier of rotation than its precursor
5, but its barrier to cyclization to give 8 is even lower yet, so
racemization of the intermediate radical is not a significant
reaction.
q CDRI Communication No. 6414.
qq Supplementary data associated with this article can be found, in the
online version at doi: 10.1016/j.tet.2004.02.064
Keywords: Axially chiral N-allyl-o-iodoanilides; Intramolecular reaction;
Radical cyclization.
Radical cyclizations of o-haloanilides lacking another ortho
substituent to provide racemic products predate the above
asymmetric cyclizations,8–11 and these cyclizations occur
whether the radical acceptor is present in the N-acyl group
*
Corresponding author. Tel.: þ1-412-624-8240; fax: þ1-412-624-9861;
e-mail address: curran@pitt.edu
Direct questions regarding the X-ray crystal structures to this author
†
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.064

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D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
observed that cyclization of N-allyl derivative 11 provided
12. When the two types of cyclizations were pitted against
each other by Jones and Storey in substrate 13, then closure
to the crotonoyl group dominated and 14 was the only
observed product.9a,12 Jones and McCarthy also reported
attempted asymmetric cyclizations of chiral anilides like 15,
but the diastereomeric ratios of 16 were very poor.13 These
poor selectivities were interpreted in terms of a traditional
chiral auxiliary model where a single radical passes through
two diastereomeric transition states that are close in energy.
However, our results2c,d suggest that an equally plausible
model is that there are two diastereomeric iodides 15, which
in turn are precursors of two diastereomeric radicals, each of
which cyclizes predominantly to a different isomer of 16.
Following up on our previous studies on asymmetric
cyclization reactions of enantioenriched N-acryloyl-o-
iodoanilides,2c we now describe a complementary study of
cyclization reactions of axially chiral N-allyl-o-iodoanilides
17 (Eq. 1). These reactions are general and good levels of
chirality transfer to 18 are observed. The absolute
configurations of the precursors and products are assigned,
and a model is put forth to explain the observed chirality
transfer. Finally, we have discovered that the presence of the
Figure 2. Chirality transfer in radical cyclizations of o-iodoacryanilides.
or the N-alkyl group (Fig. 3). For example, Bowman and
coworkers11a have reported that cyclization of N-crotonoyl
derivative 9 provided 10, while Dittami8a and Toga8b
Figure 3. Radical cyclizations of iodo/bromoanilides lacking ortho substituents.

D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
4415
o-methyl group in these substrates reverses the regio-
selectivity in competitive cyclizations like that described by
Jones (13!14), and we have measured approximate rate
constants for representative cyclizations to help provide
insight into the origin of this surprising observation.
ð1Þ
Figure 4. Rotation barriers for four axially chiral anilides.
Racemic precursors 17a-g were resolved on a semi-
preparative column ((S,S)-Whelk-O1, 25 cm£10.0 mm
I.D., 10–40% iPrOH in hexanes, 8–10 mL/min).15
Preparative injections ranged from 40 to 80 mg, depending
on the effectiveness of the separation, and several hundred
milligrams of most of the precursors were obtained in ees
ranging from 96 to 99%. All the racemic products 18a-g
were injected into an analytical (S,S)-Whelk-O1 column and
each pair of enantiomers was well resolved, thereby paving
the way for a convenient quantitative analysis of chirality
transfer experiments by chiral hplc.
2. Results and discussion
2.1. Precursor and product preparation, resolution and
rotation barriers
All of the cyclization precursors 17a-i used in this study
were prepared as racemates from 2-iodo-4,6-dimethyl-
aniline 1914 by a straightforward sequence of N-acylation
followed by N-allylation, as shown in Eq. 2. Racemic
standards of all the cyclization products 18 (see Eq. 1) were
readily prepared from all these precursors by standard tin
hydride mediated cyclizations. Section 4 contains
representative procedures along with complete characteriz-
ation data for the racemates.
Rotation barriers for four of the precursors were also
measured (Fig. 4). In a typical experiment, phenmethyl-
substituted anilide 17c (.99% ee) was heated at 140 8C in
9:1 hexane:iPrOH, and the decrease in ee was measured as a
function of time by chiral hplc analysis. A standard plot of
this data (see Supplementary information) showed the
expected first order racemization, and provided a rotation
barrier of 32.6 kcal/mol. Phenethyl-substituted amide 17g
exhibited a similar rotation barrier of 32.7 kcal/mol, while
benzamides 17a and 17b exhibited slightly lower rotation
barriers of 30.7 and 29.7 kcal/mol, respectively. All of these
barriers are well within the range to permit convenient
handling of these compounds at room temperature. The
lower barriers of benzamides have been observed
previously,14b and presumably result because the phenyl
ring of the benzamide group can twist out of plane with
respect to the amide carbonyl group and thereby present a
smaller substituent for the iodine or methyl group of the
anilide to rotate past in the transition state.
ð2Þ
2.2. Chirality transfer in radical cyclizations
With the enantioenriched radical precursors in hand, tin
hydride cyclizations were conducted to measure the level of
chirality transfer. The radical cyclization of substrate 17a is
typical of all the cyclizations and is summarized in Eq. 3.
Triethylborane16 (1.0 equiv.) was added to an aerated
benzene solution of 17c and Bu3SnH (1.5 equiv., 0.01 M)
to initiate the reaction, and progress was monitored by tlc.
After about 30 min, the reaction was worked up and the

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D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
ð3Þ
product was purified by flash chromatography and then
analyzed by chiral hplc. Oxindole S-18c was produced in
54% yield and 93% ee starting from P-17c of 99% ee while
R-18c was produced in 53% yield and 87% ee starting from
M-17c of 97% ee. The levels of chirality transfer are 97 and
95%, and these levels are within experimental error, as
expected for enantiomers. These results prove that the
cyclization of intermediate radicals 20 and ent-20 is much
more rapid than their interconversion by N-aryl bond
rotation.
Cyclizations of the other resolved precursors were con-
ducted by similar procedures, and the data for this set of
reactions are summarized in Table 1. These data reveal a
number of trends. In all cases, the dextrorotatory (þ)
enantiomer of the precursor gave the dextrorotatory
enantiomer of the product, and vice versa. In six of the
Table 1. Summary of radical cyclizations of 17a-g
c
d
Entry
Precursora
Ar
n
RZ
RE
Product
Yieldb
%eeSM
%eeP
Chirality transfere (%)
1
2
3
4
5
6
7
8
P-17a
M-17a
P-17b
M-17b
P-17c
M-17c
P-17d
M-17d
P-17e
M-17e
P-17f
Ph
Ph
4-BrC6H4
4-BrC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
0
0
0
0
1
1
1
1
1
1
1
1
2
2
H
H
Me
Me
H
H
H
H
H
H
H
Me
Me
H
S-18a
R-18a
S-18b
R-18b
S-18c
R-18c
S-18d
R-18d
S-18e
R-18e
S-18f
95
92
72
95
54
53
40
50
77
71
79
81
67
74
99
.99
99
98
.99
97
86
87
48
47
93
87
74
76
79
83
63
57
85
90
93
93
72
72
97
95
87
88
89
91
81
78
94
95
H
Ph
Ph
Me
Me
Me
Me
H
.99
98
9
.99
.99
.99
.99
96
10
11
12
13
14
H
Me
Me
H
M-17f
P-17g
M-17g
R-18f
S-18g
R-18g
H
H
.99
a
The P configuration is assigned to the dextrorotatory enantiomers and M to levorotatory.
b
c
d
e
Isolated yield after chromatography.
ee of precursor.
ee of product 18.
Yield (not excess) of the major enantiomer of 18 expected from an enantiopure sample of 17.

D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
4417
Figure 5. ORTEP representations of crystal structures of precursor M-17b (top) and product R-18b (bottom, the iso-propyl methyl groups are disordered and
removed for clarity).
seven enantiomeric pairs, the first eluting enantiomer of
the precursor gave the second eluting enantiomer of the
product, and vice versa. The exception to this trend was
17a/18a.
transfer and rotation sign, we assigned the absolute
configurations of all of the other compounds by analogy,
and these assignments are shown in Table 1.
A model for chirality transfer that follows from these results
is shown in Figure 6. To obtain a favorable geometry for
cyclization, the aryl ring of perpendicular radical 21/22
must twist towards the allyl group. The alkene can twist its
terminal CH2 group either away from the radical to expose
the back side of the alkene (as in 21!23) or towards the
radical to expose the front side (as in 22!24). The
formation of the product is consistent with twisting away
from the radical (21!23!25). In striking contrast, the
current model for cyclization of radicals derived from
N-acryloyl anilides like 26 involves twisting of the acryloyl
group towards the aryl radical as in 27 to give 28.2c The only
difference between the two classes of substrates is the
location of the amide carbonyl group, which is either outside
of (N-allyl) or within (N-acryloyl) the forming ring.
The last column of Table 1 records the level of chirality
transfer, which corresponds to the yield of the major
enantiomer of 18 expected from an enantiopure sample of
17. This is an enantiomer ratio, not an enantiomeric excess.
Levels of chirality transfer exhibited by enantiomeric
pairs were comparable. All substrates with terminal or
E-disubstituted acceptors cyclized with good to excellent
levels of chirality transfer (87–97%, see entries 1/2, 5/6,
7/8, 9/10, 13/14), while acceptors with terminal Z-sub-
stituents exhibited somewhat lower selectivities (72–81%,
entries 3/4, 11/12). These trends with the N-allyl acceptors
are remarkably similar to those exhibited by the previously
studied N-acryloyl class.2c
The absolute configurations of precursor 17b (second
eluting enantiomer) and its derived product 18b (first
eluting enantiomer) were determined by X-ray crystal-
lography using the anomalous dispersion method, and the
crystal structures of these compounds are shown in
Figure 5.17 The amide plane of precursor 17b is nearly
perpendicular to the N-Ar plane (1178), and the benzamide
aryl plane is also significantly twisted (368). The amide
group is planar and the N-aryl group and the amide oxygen
are trans, as expected. Product 18b is strikingly different—
the amide nitrogen is pyramidalized towards the viewer
(sum of angles is 3498), with larger (OvC)NC1 and
(OvC)NC2 angles (123 and 1228) not compensating for
the small C1NC2 angle (1048). The N–Ar group is now more
nearly cis to the carbonyl oxygen (angle 108) while the
N–CH2 group is more nearly trans (angle 1508). This
unusual geometry is a reflection of the severe strain that is
imposed by the o-methyl group in standard planar
geometries. Based on the trends observed in chirality
2.3. Regioselectivity, competitive cyclizations and rate
constants
As a comparison to the Jones internal competition
experiment in Figure 3, we also studied the cyclization of
rac-17h (Eq. 4). This substrate has the same N-crotonoyl
and N-allyl groups as Jones’s compound 13,9a but the aryl
ring now has an o-methyl group in place of hydrogen.
(There is also a p-methyl group in place of H, but this is
presumably inconsequential) To our surprise, cyclization of
rac-17h occurred to produce not the expected 30h resulting
from cyclization to the crotonoyl group, but instead
produced exclusively 18h resulting from cyclization to the
N-allyl group. Dihydroindole 18h was isolated in 65% yield
1
by flash chromatography, and a careful analysis of the H
NMR spectrum of the crude product did not reveal any
resonances attributable to the expected product 30h. To
ensure that the Jones structure assignment was correct, we

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D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
Figure 6. Transition state models for chiralitry transfer.
remade precursor 13 and, as billed,9a this provided
exclusively 14, and 29 was not detected. Accordingly, the
regioselectivity in the cyclization of these anilide radicals is
completely controlled by the presence or absence of an
ortho methyl group.
constant for cyclization of radical 37 derived from Jones
substrate 13 at 80 8C; however, the cyclization of this
radical was so fast that only traces of reduced product
(,5%) were detected at the highest tin hydride concen-
trations (1–2 M). From this result, we can estimate a lower
ð4Þ
To help understand the reversal in regioselectivity, we
prepared racemic substrates rac-17i and 32 and measured
their cyclization rate constants by standard competition
kinetics with Bu3SnH at 80 8C. Data for these experiments
are summarized in Figure 7, and the calculated rate
constants are summarized in Figure 8.18 Consistent with
the observed regioselectivity of 17h (Eq. 4), the rate
constant for cyclization of 35 (3.0£109 s21) was found to be
about 40 times larger than the rate constant for cyclization
of 39 (7.8£107 s21). We also attempted to measure the rate
limit for cyclization of radical 37 at about 1010 s21
.
These results show that cyclization to the N-acryloyl group
(37!38) is inherently extremely fast, but is retarded by at
least two orders of magnitude by introduction of an
o-methyl group (37!38). This dramatic retardation allows
the inherently less favorable cyclization to the N-allyl group
(35!36) to intervene in the cyclization of 17h. Figure 9
speculates on why cyclization to the acryloyl group
is dramatically retarded by an o-methyl group while

D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
4419
Figure 7. Data from competition experiments with 17i and 32.
cyclization to the allyl group is not. Cyclization to the
acryloyl group probably requires considerable twisting of
the aryl radical and the alkene towards each other. When
R8¼Me, this results in a considerable steric interaction
between this Me group and the CH2 of the N-allyl group. In
contrast, the N-allyl group is not constrained by amide
resonance. The alkene can reach out to meet the aryl radical
better (by rotation of the N–CH2 bond) and less twisting of
the aryl ring is required. This cyclization of the aryl radical
to the N-allyl group does not result in a comparable steric
interaction between the o-methyl group and the CvO on the
other side. From the preparative standpoint, this analysis
suggests that the regioselectivity of these reactions can be
reversed by any medium or large ortho-substituent.
3. Conclusions
In summary, radical cyclizations of axially chiral N-allyl-o-
iodoanilides mirror their predecessor N-acryloyl-o-iodo-
anilides in both selectivity and trends, but give opposite
enantiomeric products. Useful levels of chirality transfer are
observed in many cases, and a straightforward model can be
applied to predict the configuration of the major stereoisomer.
Figure 9. Twisting and effects of the o-methyl group on N-acryloyl (left)
and N-allyl (right) cyclizations.
Figure 8. Competition experiments and rate constants.

4420
D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
In all these reactions, the removal of the large iodine atom to
generate a tiny radical is expected to dramatically reduce the
barrier to rotation with attendant racemization, but the speed
of the radical cyclization is so high that rotation cannot
compete. Speed alone is not sufficient to ensure chirality
transfer, yet one of two possible transition states is lower in
energy, thereby ensuring selectivity. The presence of the
o-substituent dictates not only stereoselectivity but also
regioselectivity, in a surprising reversal from N-acryloyl
cyclization to N-allyl cyclization. The detailed under-
standing of rotation barriers, regio- and stereoselectivity in
this class of molecules sets the stage for future synthetic
applications in asymmetric synthesis of oxindoles, dihydro-
indoles and related molecules.
gel eluting with hexanes/diethyl ether (9:1) provided the
respective dihydroindole.
4.4. General procedure for Et3B initiated radical
cyclization of anilides (IV)
To a benzene solution of the respective o-iodoanilide
(1.0 equiv. and Bu3SnH (1.5 equiv., 0.01 M) was added a
hexane solution (1.0 M) of Et3B (1.0 equiv.). The reaction
mixture was sealed and stirred at room temperature until the
starting material was deemed consumed by TLC. The
solvents were removed in vacuo and the crude was
submitted the DBU workup.18 Purification of the crude
product by flash column chromatography on silica gel
eluting with hexanes/diethyl ether (typically 100%
hexanes!8:2) provided the respective dihydroindole.
4. Experimental
4.4.1. N-(2-Iodo-4,6-dimethylphenyl)benzamide. This
compound was prepared according to general procedure I.
A white, crystalline solid (mp 175–176 8C) was obtained in
quantitative yield. IR (thin film, CH2Cl2, NaCl, cm21) 1679,
1500, 1480, 1265, 1257; 1H NMR (300 MHz, CDCl3) d 2.25
(s, 6H), 7.06 (s, 1H), 7.45–7.60 (m, 3H), 7.55 (s, 1H), 7.65
(s, 1H), 7.97 (d, J¼7.1 Hz, 2H; 13C NMR (75 MHz, CDCl3)
d 19.6, 20.5, 99.3, 127.4, 128.7, 131.8, 131.9, 134.2, 134.4,
137.2, 137.3, 139.1, 165.6; HRMS (EI) calcd for C15H14INO
351.0120, found 351.0107; LRMS (EI) m/z 351 (Mþ, 50), 259
(29), 246 (51), 224 (49), 105 (100), 77 (50).
4.1. General procedure for acylation of 2-iodo-4,6-
dimethylaniline (I)
To a CH2Cl2 (0.3 M) solution of 2-iodo-4,6-dimethylaniline
(1.0 equiv.) was added triethylamine (1.1 equiv.). The
reaction mixture was cooled to 0 8C and the respective
acid chloride (1.1 equiv.) was added dropwise. The solution
was warmed to room temperature. The reaction mixture was
monitored by TLC and quenched accordingly with water
upon completion. After separation of the layers, the aqueous
layer was extracted with CH2Cl2 (3£). The combined organic
layers were washed with brine (1£) and dried with MgSO4.
Filtration and solvent evaporation in vacuo followed by
purification by using flash chromatography on silica gel
eluting with hexanes/ethyl acetate or recrystallization from
hexanes provided the corresponding o-iodoanilide.
4.4.2. N-(2-Iodo-4,6-dimethylphenyl)-2-phenylaceta-
mide. This compound was prepared according to general
procedure I. A white, crystalline solid (mp 161–162 8C)
was obtained in 47% yield. IR (thin film, CHCl3, NaCl,
cm21) 3388, 3015, 2923, 1680, 1601, 1558, 1490, 1283,
1236, 852; 1H NMR (300 MHz, CDCl3) d 2.18 (s, 3H), 2.24
(s, 3H), 3.80 (s, 2H), 6.70 (s, 1H), 6.99 (s, 1H), 7.45 (m, 5H),
7.47 (s, 1H); 13C NMR (75 MHz, CDCl3) d 19.4, 20.4, 44.1,
99.0, 127.6, 129.2, 129.9, 131.7, 134.2, 134.6, 136.9, 137.0,
139.1, 169.1; HRMS (EI) calcd for C16H16INO 365.0277,
found 365.0289; LRMS (EI) m/z 365 (Mþ, 3), 274 (3), 27 3
(4), 247 (66), 238 (100), 91 (71).
4.2. General procedure for N-allylation of anilides (II)
To a THF slurry of NaH (1.1 equiv.) at 0 8C was added the
respective o-iodoanilide (1.0 equiv.) dissolved in THF
(2 mL/mmol iodoanilide). The reaction mixture was stirred
until the solution became clear and then the appropriate allyl
bromide/iodide (1.3 equiv.) was added dropwise. The
solution was warmed to room temperature. The reaction
mixture was monitored by TLC and quenched with water
upon completion. The resulting mixture was extracted with
diethyl ether (3£, 25 mL/mmol of anilide). The combined
organic layers were washed with brine (1£) and dried with
MgSO4. Filtration and solvent evaporation in vacuo
followed by purification by flash chromatography on silica
gel eluting with hexanes/diethyl ether (typically 9:1!7:3)
provided the respective anilide.
4.4.3. N-(2-Iodo-4,6-dimethylphenyl)-3-phenylpropiona-
mide. This compound was prepared according to general
procedure I. A white, crystalline solid (mp 156–157 8C)
was obtained in 76% yield. IR (thin film, CH2Cl2, NaCl,
cm21) 1689, 1482, 1421, 1265; 1H NMR (300 MHz, CDCl3) d
2.13 (s, 3H), 2.25 (s, 3H), 2.74 (t, J¼8.1 Hz, 2H), 3.10 (t,
J¼8.1 Hz, 2H), 6.93 (s, 1H), 6.98 (s, 1H), 7.15–7.45 (m, 5H),
7.49 (s, 1H); 13C NMR (75 MHz, CDCl3) d 19.5, 20.4, 31.5,
38.3, 99.4, 126.3, 128.5, 128.6, 131.7, 134.4, 137.0, 137.1,
139.0, 140.7, 170.5; HRMS (EI) calcd for C17H18INO
379.0433, found 379.0439; LRMS (EI) m/z 379 (Mþ, 37),
351 (88), 252 (68), 247 (53), 224 (99), 111 (80), 105 (100).
4.3. General procedure for thermally initiated radical
cyclization of anilides to make racemic cyclization
products (III)
4.4.4. N-(2-Iodo-4,6-dimethylphenyl)-4-bromobenza-
mide. This compound was prepared according to general
procedure I. A white, crystalline solid (mp 242–244 8C)
was obtained in 82% yield. IR (thin film, CH–2Cl2, NaCl,
To a benzene solution of the respective o-iodoanilide
(1.0 equiv.) was added Bu3SnH (1.5 equiv., 0.01 M) and
AIBN (0.2 equiv.). The reaction mixture was refluxed until
the starting material was consumed by TLC (typically less
than 1 h). The solvents were removed in vacuo and the crude
was submitted to the DBU workup.19 Purification of the
remaining crude by flash column chromatography on silica
1
cm21) 1681, 1477, 1421, 1271, 896; H NMR (300 MHz,
CDCl3) d 2.30 (s, 6H), 7.09 (s, 1H), 7.45 (bs, 1H), 7.57 (s,
1H), 7.65 (d, J¼6.8 Hz, 2H), 7.68 (d, J¼6.8 Hz, 2H); 13C
NMR (75 MHz, CDCl3) d 19.6, 20.5, 99.1, 126.8, 129.0,

D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
4421
132.0, 132.1, 133.0, 134.1, 137.1, 137.3, 139.4; HRMS (EI)
calcd for C15H13NOBrI 428.9225, found 428.9225; LRMS
(EI) m/z 429 (Mþ,23), 302 (87), 183 (100).
7.21 (d, J¼7.6 Hz, 1H), 7.39 (d, J¼7.0 Hz, 2H); 13C NMR
(75 MHz, CDCl3) d 19.8, 20.3, 53.1, 101.4, 119.0, 127.3,
127.9, 129.8, 132.0, 132.5, 135.8, 137.6, 138.3, 139.3,
140.7; HRMS (EI) calcd for C18H18INO 391.0433, found
391.0432; LRMS (EI) m/z 391 (Mþ, 27), 264 (70), 223 (31),
144 (32), 105 (100), 77 (58). The racemate was submitted to
preparative chiral HPLC separation (Regis Technologies
(S,S)-Whelk-O1; 25 cm£10.0 mm I.D.; 10 mL/min hexanes:
iPrOH; first eluting enantiomer (P) a2D3 þ140, 87% ee (c
5.4 mg/mL, CHCl3); second eluting enantiomer (M) aD23
2191, 97% ee (c 2.4 mg/mL, CHCl3).
4.4.5. N-(2-Iodo-4,6-dimethylphenyl)acetamide. This
compound was prepared according to general procedure I.
A tan, crystalline solid (169–170 8C) was obtained in 82%
yield. IR (thin film, CHCl3, NaCl, cm21) 3416, 3377, 2924,
1687, 1486, 1369, 1245; 1H NMR (300 MHz, CDCl3) d 2.21
(s, 3H), 2.29 (s, 3H), 2.31 (s, 3H), 6.95 (s, 1H), 7.01 (s, 1H),
7.60 (s, 1H); 13C NMR (75 MHz, CDCl3) d 19.5, 20.4, 23.4,
99.5, 131.8, 134.5, 137.0, 137.8, 139.2, 168.6; HRMS (EI)
calcd for C10H12INO 288.9964, found 288.9974; LRMS
(EI) m/z 289 (MþþH, 7), 247 (61), 224 (16), 162 (100), 120
(48), 91 (30).
4.4.10. rac-N-(2-Iodo-4,6-dimethylphenyl)-N-(3-methyl-
but-2-enyl)-4-bromobenzamide (17b). This compound
was prepared according to general procedure II. A white,
crystalline solid was obtained in 66% yield. IR (thin film,
CH2Cl2, NaCl, cm21) 2927, 1642, 1442, 1399, 1264, 1012;
1H NMR (300 MHz, CDCl3) d 1.44 (s, 3H), 1.66 (s, 3H),
2.08 (s, 3H), 2.23 (s, 3H), 4.11 (dd, J¼14.5, 8.6 Hz, 1H),
4.71 (dd, J¼14.5, 6.8 Hz, 1H), 5.42 (app t, J¼7.0 Hz, 1H),
6.85 (s, 1H), 7.28 (m, 4H), 7.52 (s, 1H); 13C NMR (75 MHz,
CDCl3) d 17.6, 19.6, 20.3, 25.7, 47.5, 101.2, 118.4, 124.3,
129.7, 130.6, 132.1, 134.9, 136.9, 137.7, 138.5, 139.5,
140.6, 168.8; HRMS (EI) calcd for C20H23IBrNO 496.9851,
found 496.9859; LRMS (EI) m/z 497 (Mþ, 37), 454 (13),
429 (28), 302 (32), 191 (100). The racemate was submitted
to preparative chiral HPLC separation (Regis Technologies
(S,S)-Whelk-O1; 25 cm£10.0 mm I.D.; 10 mL/min hexanes:
iPrOH; first eluting enantiomer (M) a2D3 þ156, 99% ee (c
1.4 mg/mL, CHCl3); second eluting enantiomer (P) aD23
2146, 98% ee (c 1.5 mg/mL, CHCl3).
4.4.6. N-(2-Iodo-4,6-dimethylphenyl)-trans-crotonamide.
This compound was prepared according to general pro-
cedure I. A white, crystalline solid was obtained in 31%
yield. IR 3396, 2913, 1620, 1478, 1286; 1H NMR
(300 MHz, CDCl3) 1.95 (d, J¼5.6 Hz, 3H), 2.17 (s, 3H),
2.22 (s, 3H), 6.06 (d, J¼13.9 Hz, 1H), 6.89 (dq, J¼13.9,
5.6 Hz, 1H), 6.94 (s,1H), 7.46 (s, 1H). 13C NMR (75 MHz,
CDCl3) 19.4, 20.4, 41.6, 99.3, 120.3, 131.2, 131.6, 134.2,
138.7, 138.9, 141.4, 169.2; HRMS (EI) calcd for
C12H14INO 315.0120, found 315.0127; LRMS (EI) m/z
315 (Mþ, 33), 247 (62), 188 (100), 69 (73).
4.4.7. 3,5,7-Trimethyl-2,3-dihydroindole. This compound
was prepared according to general procedure III. A clear,
orange oil was obtained in 72% yield. IR (thin film, CHCl3,
NaCl, cm21) 2964, 2927, 2872, 2857, 1660, 1605, 1486,
1
1463; H NMR (300 MHz, CDCl3) d 1.42 (d, J¼6.8 Hz,
4.4.11. rac-N-Allyl-N-(2-iodo-4,6-dimethylphenyl)-2-
phenylacetamide (17c). This compound was prepared
according to general procedure II. A clear, colorless oil
was obtained in 93% yield. IR (thin film, CHCl3, NaCl,
cm21) 3066, 3024, 3013, 2961, 2926, 2858, 1652, 1466,
1456, 1389, 1261, 990; 1H NMR (300 MHz, CDCl3) d 2.05
(s, 3H), 2.33 (s, 3H), 3.22 (d, J¼15.0 Hz, 1H), 3.40 (d, J¼
15.0 Hz, 1H), 4.00 (dd, J¼14.3, 7.5 Hz, 1H), 4.45 (dd, J¼
14.3, 6.3 Hz, 1H), 5.05 (dd, J¼10.0, 1.4 Hz, 1H), 5.09 (dd,
J¼17.3, 1.4 Hz, 1H), 5.96 (dddd, J¼17.3, 10.0, 7.5, 6.3 Hz,
1H), 7.04 (s, 1H), 7.09 (d, J¼6.2 Hz, 2H), 7.26 (m, 3H),
7.64 (s, 1H); 13C NMR (75 MHz, CDCl3) d 19.8, 20.8, 41.8,
52.3, 102.3, 119.1, 119.2, 127.0, 128.5, 130.0, 132.5, 133.2,
134.9, 138.7, 140.4, 140.7, 171.0; HRMS (EI) calcd for
C19H20INO 405.0590, found 405.0601; LRMS (EI) m/z 405
(Mþ, 43), 314 (19), 287 (26), 278 (100), 187 (58), 158 (52),
91 (97). The racemate was submitted to preparative chiral
HPLC separation (Regis Technologies (S,S)-Whelk-O1;
25 cm£10.0 mm I.D.; 10 mL/min hexanes:iPrOH; first
eluting enantiomer (P) a2D3 255, 97% ee (c 3.5 mg/mL,
CHCl3); second eluting enantiomer (M) a2D3 þ59, .99% ee
(c 1.4 mg/mL, CHCl3).
3H), 2.22 (s, 3H), 2.37 (s, 3H), 3.19 (t, J¼8.6 Hz, 1H),
3.38–3.50 (m, 1H), 3.78 (t, J¼8.6 Hz, 1H), 6.82 (s, 1H),
6.89 (s, 1H); 13C NMR (75 MHz, CDCl3) d 16.5, 18.6, 20.7,
36.9, 55.4, 118.8, 121.4, 128.1, 128.7, 133.9, 147.2; HRMS
(EI) calcd for C11H15N– 161.1204, found 161.1211; LRMS
(EI) m/z 161 (Mþ, 67), 146 (100), 131 (67).
4.4.8. rac-N-Allyl-N-(2-iodophenyl)-trans-crotonamide
(13).9a This compound was prepared according to general
procedure I. A clear, yellow oil was obtained in 59% yield.
IR (thin film, CH2Cl2, NaCl, cm21) 1666, 1630, 1470, 1422,
1
1386, 1271; H NMR (300 MHz, CDCl3) d 1.67 (d, J¼
7.0 Hz, 3H), 3.62 (dd, J¼14.6, 7.6 Hz, 1H), 4.83 (dd, J¼
14.6, 5.2 Hz, 1H), 4.98–5.11 (m, 2H), 5.44 (d, J¼15.0 Hz,
1H), 5.80–5.98 (m, 1H), 6.94 (dq, J¼14.6, 7.0 Hz, 1H),
7.06 (t, J¼7.6 Hz, 1H), 7.13 (d, J¼7.6 Hz, 1H), 7.36 (t,
J¼7.6 Hz, 1H), 7.91 (d, J¼7.6 Hz, 1H); 13C NMR (75 MHz,
CDCl3) d 17.9, 51.1, 100.7, 118.4, 122.3, 129.1, 129.6,
130.9, 132.6, 139.6, 142.1, 143.8, 165.2; HRMS (EI) calcd
for C13H14INO 327.0120, found 327.0123; LRMS (EI) m/z
327 (Mþ, 3), 259 (21), 200 (99), 130 (33), 69 (100).
4.4.9. rac-N-Allyl-N-(2-iodo-4,6-dimethylphenyl)benza-
mide (17a). This compound was prepared according to
general procedure II. A clear, colorless oil was obtained in
35% yield. IR (thin film, CH2Cl2, NaCl, cm21) 2927, 1641,
4.4.12. rac-N-(2-Iodo-4,6-dimethylphenyl)-N-(3-phenyl-
allyl)-2-phenylacetamide (17d). This compound was
prepared according to general procedure II. A clear, yellow
oil was obtained in 100% yield. IR (thin film, CHCl3, NaCl,
cm21) 3008, 2925, 1652, 1495, 1465, 1455, 1393, 1351,
1
1380, 1258; H NMR (300 MHz, CDCl3) d 2.10 (s, 3H),
1
2.18 (s, 3H), 4.04 (dd, J¼14.2, 7.9 Hz, 1H), 4.80 (dd, J¼
14.2, 6.1 Hz, 1H), 5.05–5.20 (m, 2H), 6.08 (dddd, J¼14.0,
9.9, 7.8, 6.2 Hz, 1H), 6.82 (s, 1H), 7.13 (t, J¼7.6 Hz, 2H),
1310, 1247, 968; H NMR (300 MHz, CDCl3) d 2.05 (s,
3H), 2.32 (s, 3H), 3.23 (d, J¼15.0 Hz, 1H), 3.43 (d,
J¼15.0 Hz, 1H), 4.19 (m, 1H), 4.57 (m, 1H), 6.37–6.40 (m,

4422
D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
2H), 7.02 (s, 1H), 7.07–7.12 (m, 2H), 7.18–7.30 (m, 8H),
7.64 (s, 1H); 13C NMR (75 MHz, CDCl3) d 19.3, 20.4, 41.3,
51.3, 101.3, 124.1, 126.3, 126.6, 127.5, 128.1, 128.4, 129.5,
132.2, 133.4, 134.4, 136.5, 138.1, 138.3, 140.0, 140.1,
170.6; HRMS (EI) calcd for C25H24INO 481.0903, found
481.0927; LRMS (EI) m/z 481 (Mþ, 58), 390 (44), 363 (8),
236 (27), 158 (21), 117 (100), 91 (84). The racemate was
submitted to preparative chiral HPLC separation (Regis
Technologies (S,S)-Whelk-O1; 25 cm£10.0 mm I.D.;
10 mL/min hexanes:iPrOH; first eluting enantiomer (P)
a2D3 217, 94% ee (c 6.3 mg/mL, CHCl3); second eluting
enantiomer (M) a2D3 þ11, 98% ee (c 9.9 mg/mL, CHCl3).
7.6 Hz, 1H), 4.54 (dd, J¼14.3, 6.5 Hz, 1H), 5.04–5.15 (m,
2H), 5.97 (dddd, J¼6.5, 7.5, 9.8, 13.7 Hz, 1H), 7.02 (s, 1H),
7.10–7.20 (m, 3H), 7.23 (d, J¼6.7 Hz, 2H), 7.58 (s, 1H);
13C NMR (75 MHz, CDCl3) d 19.4, 20.4, 31.2, 36.3, 51.6,
101.4, 118.7, 125.9, 128.3, 128.5, 132.1, 132.9, 137.7,
138.3, 139.9, 140.1, 141.4, 171.8; HRMS (EI) calcd for
C20H22INO 419.0746, found 419.0743; LRMS (EI) m/z 419
(Mþ, 32), 292 (100), 160 (37), 158 (32), 155 (25), 131 (34),
105 (59). The racemate was submitted to preparative chiral
HPLC separation (Regis Technologies (S,S)-Whelk-O1;
25 cm£10.0 mm I.D.; 10 mL/min hexanes:iPrOH; first
eluting enantiomer (P) a2D3 260, 99% ee (c 3.8 mg/mL,
CHCl3); second eluting enantiomer (M) a2D3 þ58, 99% ee (c
4.3 mg/mL, CHCl3).
4.4.13. rac-N-But-2E-enyl-N-(2-iodo-4,6-dimethyl-
phenyl)-2-phenylacetamide (17e). This compound was
prepared according to general procedure II. A clear, yellow
oil was obtained in 41% yield. IR (thin film, CHCl3, NaCl,
cm21) 3012, 2921, 2856, 1650, 1496, 1465, 1455, 1393,
1313, 1262, 1247, 1165, 970; 1H NMR (300 MHz, CDCl3) d
1.59 (d, J¼5.9 Hz, 3H), 2.04 (s, 3H), 2.33 (s, 3H), 3.20 (d,
J¼15.0 Hz, 1H), 3.39 (d, J¼15.0 Hz, 1H), 3.94 (dd, J¼14.0,
7.1 Hz, 1H), 4.38 (dd, J¼14.0, 6.3 Hz, 1H), 5.53 (m, 2H),
7.03 (s, 1H), 7.08 (m, 2H), 7.22 (m, 3H), 7.63 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 17.5, 19.2, 20.3, 41.4, 50.9,
101.9, 125.5, 126.5, 128.0, 129.1, 129.5, 129.9, 132.0,
134.6, 138.2, 139.8, 140.3, 170.4; HRMS (EI) calcd for
C20H22INO 419.0746, found 419.0737; LRMS (EI) m/z 419
(Mþ, 55), 292 (44), 238 (37), 174 (30), 158 (33), 91 (98),
55(100). The racemate was submitted to preparative chiral
HPLC separation (Regis Technologies (S,S)-Whelk-O1;
25 cm£10.0 mm I.D.; 10 mL/min hexanes:iPrOH; first
eluting enantiomer (P) a2D3 246, 99% ee (c 4.7 mg/mL,
CHCl3); second eluting enantiomer (M) a2D3 þ41, 99% ee (c
11.4 mg/mL, CHCl3).
4.4.16. rac-N-Allyl-N-(2-iodo-4,6-dimethylphenyl)-trans-
crotonamide (17h). This compound was prepared accord-
ing to general procedure I. A white, crystalline solid was
obtained in 64% yield. IR (thin film, CH2Cl2, NaCl, cm21
)
2984, 2854, 1666, 1629, 1445, 1384, 1273; 1H NMR
(300 MHz, CDCl3) d 1.73 (dd, J¼6.9, 1.5 Hz, 3H), 2.18 (s,
3H), 2.31 (s, 3H), 3.94 (ddd, J¼14.3, 7.1, 0.6 Hz, 1H), 4.58
(dd, J¼14.3, 6.4 Hz, 1H), 5.02–5.11 (m, 2H), 5.48 (dd, J¼
15.0, 1.7 Hz, 1H), 5.97 (dddd, J¼17.0, 10.0, 7.7, 6.5 Hz,
1H), 7.00 (dq, J¼15.0, 6.9 Hz, 1H), 7.04 (s, 1H), 7.60 (s,
1H); 13C NMR (75 MHz, CDCl3) d 18.0, 19.7, 20.5 51.6,
101.6, 118.7, 121.9, 125.4, 132.0, 133.1, 138.2, 138.8,
139.9, 140.0, 142.4, 165.8; HRMS (EI) calcd for
C15H18INO 355.0433, found 355.0445; LRMS (EI) m/z
355 (Mþ, 25), 340 (20), 313 (13), 287 (16), 228 (100), 18
(39), 158 (32), 69 (68).
4.4.17. rac-N-(2-Iodo-4,6-dimethylphenyl)-N-(3-methyl-
but-2E-enyl)acetamide (17i). This compound was pre-
pared according to general procedure I. An orange-yellow
oil was obtained in 84% yield. IR (thin film, CHCl3, NaCl,
cm21) 3005, 2926, 2858, 1643, 1553, 1467, 1440, 1396,
4.4.14. rac-N-(2-Iodo-4,6-dimethylphenyl)-N-(3-methyl-
but-2-enyl)-2-phenylacetamide (17f). This compound was
prepared according to general procedure II. A clear, yellow
oil was obtained in 79% yield. IR (thin film, CHCl3, NaCl,
cm21) 3026, 3014, 2925, 2861, 1650, 1495, 1455, 1383,
1236, 1186, 1162, 1032; 1H NMR (300 MHz, CDCl3) d 1.43
(s, 3H), 1.62 (s, 3H), 2.03 (s, 3H), 2.43 (s, 3H), 3.21 (d,
J¼15.0 Hz, 1H), 3.39 (d, J¼15.0 Hz, 1H), 4.04 (dd, J¼14.3,
8.0 Hz, 1H), 4.45 (dd, J¼14.3, 7.1 Hz, 1H), 5.03 (dd, J¼7.0,
7.0 Hz, 1H), 7.03 (s, 1H), 7.18 (m, 5H), 7.62 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 17.4, 19.0, 20.3, 25.5, 41.1, 45.9,
53.8, 101.7, 118.7, 126.4, 127.9, 129.4, 131.9, 134.5, 136.2,
138.1, 139.7, 140.0, 170.4; HRMS (EI) calcd for
C21H24INO 433.0903, found 433.0901; LRMS (EI) m/z
433 (Mþ, 100), 390 (9), 365 (27), 300 (21), 273 (14), 247
(17), 238 (41), 91 (93), 69 (66). The racemate was
submitted to preparative chiral HPLC separation (Regis
Technologies (S,S)-Whelk-O1; 25 cm£10.0 mm I.D.;
10 mL/min hexanes:iPrOH; first eluting enantiomer (P)
a2D3 249, 99% ee (c 2.2 mg/mL, CHCl3); second eluting
enantiomer (M) a2D3 þ43, 99% ee (c 4.5 mg/mL, CHCl3).
1
1289, 1034, 908; H NMR (300 MHz, CDCl3) d 1.42 (s,
3H), 1.62 (s, 3H), 1.74 (s, 3H), 2.20 (s, 3H), 2.28 (s, 3H),
3.94 (dd, J¼14.5, 8.2 Hz, 1H), 4.50 (dd, J¼14.5, 7.1 Hz,
1H), 5.26 (m, 1H), 7.03 (s, 1H), 7.57 (s, 1H); 13C NMR
(75 MHz, CDCl3) d 17.6, 19.4, 20.5, 22.4, 25.7, 45.6, 101.2,
118.9, 132.0, 136.4, 137.9, 138.3, 139.8, 140.9, 170.3;
HRMS (EI) calcd for C15H20INO 357.0590, found
357.0603; LRMS (EI) m/z 357 (Mþ, 95), 314 (37), 300 (46),
289 (83), 247 (56), 232 (46), 162 (87), 69 (100).
4.4.18. Phenyl-(3,5,7-trimethyl-2,3-dihydroindol-1-
yl)methanone (18a). This compound was prepared accord-
ing to general procedure IV. The atropisomer M-17a
(.99% ee, second eluting enantiomer) yielded a white,
crystalline solid in 92% yield (87% ee, 23, second eluting
enantiomer). The atropisomer P-17a (99% ee, first eluting
enantioimer) yielded a white, crystalline solid in 95% yield
(86% ee, þ3, first eluting enantiomer). A racemic standard
of the title compound was prepared in 98% yield by radical
cyclization of rac-17a according to general procedure III.
IR (thin film, CH2Cl2, NaCl, cm21) 2966, 1649, 1371, 1264;
1H NMR (300 MHz, CDCl3) d 1.24 (d, J¼7.0 Hz, 3H), 2.20
(s, 3H), 2.34 (s, 3H), 3.33 (sex, J¼7.3 Hz, 1H), 3.65 (dd,
J¼10.4, 7.6 Hz, 1H), 4.22 (dd, J¼10.4, 7.7 Hz, 1H), 6.88 (s,
1H), 6.91 (s, 1H), 7.40–7.55 (m, 3H), 7.74 (d, J¼6.7 Hz,
2H); 13C NMR (75 MHz, CDCl3) d 17.8, 19.9, 21.1, 36.9,
4.4.15. rac-N-Allyl-N-(2-iodo-4,6-dimethylphenyl)-3-
phenylpropionamide (17g). This compound was prepared
according to general procedure II. A clear, yellow oil was
obtained in 97% yield. IR (thin film, CHCl3, NaCl, cm21
2926, 1649, 1395; H NMR (300 MHz, CDCl3) d 2.12 (s,
3H), 2.28 (s, 3H), 2.95–3.05 (m, 2H), 3.96 (dd, J¼14.3,
)
1

D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
4423
61.6, 121.2, 128.4, 128.5, 128.6, 130.3, 131.1, 135.2, 136.2,
139.2, 139.5, 169.6; HRMS (EI) calcd for C18H19NO
265.1467, found 265.1462; LRMS (EI) m/z 265 (Mþ, 39),
105 (100), 77 (35).
130.9, 135.0, 135.1, 127.7, 137.7, 139.2; HRMS (EI) calcd
for C25H25NO 355.1936, found 355.1938; LRMS (EI) m/z
355 (Mþ, 37), 146 (100), 131 (20), 105 (18), 91 (62).
4.4.22. 1-(3-Ethyl-5,7-dimethyl-2,3-dihydroindol-1-yl)-2-
phenylethanone (18e). This compound was prepared
according to general procedure IV. The atropisomer
M-17e (.99% ee, first eluting enantiomer) yielded a clear
oil in 71% yield (83% ee, 238, second eluting enantiomer).
The atropisomer P-17e (.99% ee, second eluting enantio-
mer) yielded a clear oil in 77% yield (79% ee, þ34, first
eluting enantiomer). A racemic standard of the title
compound was prepared in 97% yield by radical cyclization
of rac-17e according to general procedure III. IR (thin film,
CH2Cl2, NaCl, cm21) 2927, 2876, 1656, 1598, 1379, 1268;
1H NMR (300 MHz, CDCl3) d 0.84 (t, J¼7.4 Hz, 3H),
1.25–1.35 (m, 1H), 1.61–1.70 (m, 1H), 2.26 (s, 3H), 2.30
(s, 3H), 2.95 (m, 1H), 3.69 (dd, J¼10.3, 5.4 Hz, 1H), 3.88 (s,
2H), 4.09 (app t, J¼8.8 Hz, 1H), 6.82 (s, 1H), 6.87 (s, 1H),
7.20–7.34 (m, 5H); 13C NMR (75 MHz, CDCl3) d 11.5,
20.5, 20.9, 26.2, 56.2, 64.7, 121.7, 126.8, 128.7, 128.8,
130.0, 130.6, 134.9, 135.2, 138.4, 139.1; HRMS (EI) calcd
for C20H23NO 293.1780, found 293.1779; LRMS (EI) m/z
293 (Mþ, 64), 175 (86), 146 (100), 91 (56).
4.4.19. (4-Bromophenyl)-(3-isopropyl-5,7-dimethyl-2,3-
dihydroinol-1-yl)methanone (18b). This compound was
prepared according to general procedure IV. The atrop-
isomer P-17b (99% ee, first eluting enantiomer) yielded a
white, crystalline solid in 72% yield (48% ee, þ16, second
eluting enantiomer). The atropisomer M-17b (98% ee,
second eluting enantiomer) yielded a white, crystalline solid
in 95% yield (47% ee, 215, first eluting enantiomer). IR
(thin film, CH2Cl2, NaCl, cm21) 1649, 1421, 1267, 896; 1H
NMR (300 MHz, CDCl3) d 0.79 (d, J¼6.8 Hz, 3H), 0.88 (d,
J¼7.2 Hz, 3), 1.92 (sex, J¼6.7 Hz, 1H), 2.16 (s, 3H), 2.33
(s, 3H), 2.99 (m, 1H), 3.86 (dd, J¼10.8, 3.3 Hz, 1H), 4.08
(dd, J¼10.8, 8.1 Hz, 1H), 6.89 (s, 1H), 6.91 (s, 1H), 7.60 (s,
4H); 13C NMR (75 MHz, CDCl3) d 18.3, 20.0, 20.3, 21.1,
30.8, 48.2, 56.2, 122.8, 125.7, 128.4, 130.2, 130.6, 131.7,
135.1, 134.2, 136.8, 139.6, 168.6; HRMS (EI) calcd for
C20H22N–OBr 371.0885, found 371.0870; LRMS (EI) m/z
371 (Mþ, 33), 183 (87), 91 (100).
4.4.20. 1-(3-Methyl-5,7-dimethyl-2,3-dihydroindol-1-yl)-
2-phenylethanone (18c). This compound was prepared
according to general procedure IV. The atropisomer M-17c
(97% ee, first eluting enantiomer) yielded a clear oil in 53%
yield (87% ee, 232, second eluting enantiomer). The
atropisomer P-17c (.99% ee, second eluting enantiomer)
yielded a clear oil in 54% yield (93% ee, þ27, first eluting
enantiomer). A racemic standard of the title compound was
prepared in 74% yield by radical cyclization of rac-17c
according to general procedure III. IR (thin film, CHCl3,
NaCl, cm21) 2965, 2928, 1649, 1388; 1H NMR (300 MHz,
CDCl3) d 1.15 (d, J¼6.8 Hz, 3H), 2.26 (s, 3H), 2.30 (s, 3H),
3.21 (sex, J¼6.9 Hz, 1H), 3.52 (dd, J¼10.3, 7.3 Hz, 1H),
3.88 (s, 2H), 4.17 (app t, J¼8.5 Hz, 1H), 6.81 (s, 1H), 6.87
(s, 1H), 7.23–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) d
19.4, 20.5, 20.9, 36.5, 43.4, 58.4, 121.0, 126.8, 127.1, 128.6,
128.7, 129.6, 130.4, 135.0, 135.1, 136.0, no carbonyl signal
observed; IR (thin film, CH2Cl2, NaCl, cm21) 1679, 1500,
1480, 1265, 1257; HRMS (EI) calcd for C19H21NO
279.1623, found 279.1627; LRMS (EI) m/z 279 (Mþ, 64),
188 (7), 161 (100), 146 (69), 91 (52).
4.4.23. 1-(3-Isopropyl-5,7-dimethyl-2,3-dihydroindol-1-
yl)-2-phenylethanone (18f). This compound was prepared
according to general procedure IV. The atropisomer P-17f
(.99% ee, first eluting enantiomer) yielded a white, waxy
solid in 79% yield (60% ee, þ12, second eluting
enantiomer). The atropisomer M-17f (.99% ee, second
eluting enantiomer) yielded a white, waxy solid in 81%
yield (58% ee, 211, first eluting enantiomer). A racemic
standard of the title compound was prepared in 63% yield by
radical cyclization of rac-17f according to general pro-
cedure III. IR (thin film, CH2Cl2, NaCl, cm21) 1656, 1602,
1
1378; H NMR (300 MHz, CDCl3) d 0.68 (d, J¼6.7 Hz,
3H), 0.88 (d, J¼6.8 Hz, 3H), 1.77 (o, J¼6.7 Hz, 1H), 2.24
(s, 3H), 2.29 (s, 3H), 2.83 (q, J¼5.9 Hz, 1H), 3.86 (m, 2H),
3.92 (m, 2H), 6.81 (s, 1H), 6.87 (s, 1H), 7.33 (m, 5H); 13C
NMR (75 MHz, CDCl3) d 18.5, 20.3, 20.7, 21.0, 30.5, 43.7,
48.1, 54.5, 122.8, 126.9, 128.7, 128.9, 130.7, 134.6, 135.0,
136.9, 136.9, 139.4, 168.9; LRMS (EI) m/z 307 (Mþ, 22),
189 (19), 146 (100), 91 (47), 69 (16); HRMS (EI) calcd for
C19H20INO 307.1936, found 307.1931; LRMS (EI) m/z 307
(Mþ, 27), 189 (22), 146 (100), 91 (37).
4.4.21. 1-(3-Benzyl-5,7-dimethyl-2,3-dihydroindol-1-yl)-
2-phenylethanone (18d). This compound was prepared
according to general procedure IV. The atropisomer M-17d
(94% ee, first eluting eluting enantiomer) yielded a clear oil
in 72% yield (75% ee, 229, second eluting enantiomer).
The atropisomer P-17d (.99% ee, second eluting enantio-
mer) yielded a clear oil in 95% yield (75% ee, þ24, first
eluting enantiomer). A racemic standard of the title
compound was prepared in 79% yield by radical cyclization
of rac-17d according to general procedure III. IR (thin film,
4.4.24. 1-(3-Methyl-5,7-dimethyl-2,3-dihydroindol-1-yl)-
3-phenylpropanone (18g). This compound was prepared
according to general procedure IV. The atropisomer M-17g
(.99% ee, first eluting enantiomer) yielded a clear oil in
74% yield (90% ee, 225, second eluting enantiomer). The
atropisomer P-17g (96% ee, second eluting enantiomer)
yielded a clear oil in 67% yield (85% ee, þ24, first eluting
enantiomer). A racemic standard of the title compound was
prepared in 68% yield by radical cyclization of rac-17g
according to general procedure III. IR (thin film, CH2Cl2,
NaCl, cm21) 1641, 1421, 1264; 1H NMR (300 MHz,
CDCl3) d 1.18 (d, J¼6.8 Hz, 3H), 2.20 (s, 3H), 2.30 (s,
3H), 2.8 (t, J¼7.5 Hz, 2H), 3.09 (t, J¼7.5 Hz, 2H), 3.08–
3.20 (m, 1H), 3.46 (dd, J¼10.1, 7.7 Hz, 1H), 4.10 (m, 1H),
6.81 (s, 1H), 6.86 (s, 1H), 7.15–7.35 (m, 5H); 13C NMR
(75 MHz, CDCl3) d 17.8, 21.0, 29.7, 31.8, 35.9, 41.4, 58.4,
1
CH2Cl2, NaCl, cm21) 2927, 1660, 1377, 1268; H NMR
(300 MHz, CDCl3) d 2.27 (s, 3H), 2.29 (s, 3H), 2.53 (dd,
J¼13.9. 9.9 Hz, 1H), 2.96 (dd, J¼13.9, 5.3 Hz, 1H), 3.35
(m, 1H), 3.76 (m, 1H), 3.82 (d, J¼3.2 Hz, 2H), 3.94 (dd,
J¼10.6, 7.4 Hz, 1H), 6.75 (s, 1H), 6.91 (s, 1H), 7.30 (m,
10H); 13C NMR (75 MHz, CDCl3) d 20.6, 21.0, 29.7, 39.6,
43.6, 55.9, 121.8, 126.4, 126.9, 128.6 (2C), 128.8 (6C),

4424
D. P. Curran et al. / Tetrahedron 60 (2004) 4413–4424
6. (a) Hata, T.; Koide, H.; Taniguchi, N.; Uemura, M. Org. Lett.
2000, 2, 1907–1910. (b) Hata, T.; Koide, H.; Uemura, M.
Synlett 2000, 1145–1147.
118.1, 121.1, 126.0, 126.2, 127.6, 128.5, 129.0, 130.4, 132.0,
133.0, 134.9, 138.2, 138.9, 141.1, 172.1; HRMS (EI) calcd
for C20H23NO 293.1780, found 279.1792; LRMS (EI) m/z
293 (Mþ, 34), 205 (9), 161 (100), 146 (38), 105 (25), 91 (44).
7. Clayden, J.; Westlund, N.; Wilson, F. X. Tetrahedron Lett.
1996, 37, 5577–5580.
8. (a) Dittami, J. P.; Ramanathan, H. Tetrahedron Lett. 1988, 29,
4133–4137. (b) Togo, H.; Kikuchi, O. Heterocycles 1989, 28,
373–381.
4.4.25. 1-(3-Methyl-5,7-dimethyl-2,3-dihydroindol-1-yl)-
but-2-enone (18h). IR (thin film, CH2Cl2, NaCl, cm21
)
1666, 1630, 1470, 1423; 1H NMR (300 MHz, CDCl3) d 1.26
(d, J¼6.7 Hz, 3H), 1.92 (dd, J¼6.9, 1.5 Hz, 3H), 2.22 (s, 3H),
2.31 (s, 3H), 3.32 (sex, J¼7.1 Hz, 1H), 3.61 (dd, J¼10.2,
7.6 Hz, 1H), 4.33 (app t, J¼8.2 Hz, 1H), 6.17 (d, J¼15.0 Hz,
1H), 6.85 (s, 1H), 6.87 (s, 1H), 7.00 (dt, J¼15.0, 6.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) d 18.1, 18.2, 20.2, 21.0, 21.1,
36.5, 58.9, 121.3, 124.6, 130.4, 134.9, 138.9, 140.2, 141.7,
165.4; HRMS (EI) calcd for C11H15N– 161.1204, found
161.1211; LRMS (EI) m/z 161 (Mþ, 67), 146 (100), 131 (67).
9. (a) Jones, K.; Storey, J. M. D. J. Chem. Soc., Chem. Commun.
1992, 1766–1767. (b) Jones, K.; Storey, J. M. D. Tetrahedron
Lett. 1993, 34, 7797–7798. (c) Jones, K.; Wilkinson, J.; Ewin,
R. Tetrahedron Lett. 1994, 35, 7673–7676. (d) Brunton, S. A.;
Jones, K. J. Chem. Soc., Perkin Trans. 1 2000, 763–768.
10. Curran, D. P.; Demello, N. C. J. Chem. Soc., Chem. Commun.
1993, 1314–1317.
11. (a) Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron
Lett. 1988, 29, 6657–6660. (b) Ozaki, S.; Matsushita, H.;
Ohmori, H. J. Chem. Soc., Perkin Trans. 1 1993, 2339–2344.
(c) Ishibashi, H.; Kobayashi, T.; Machida, N.; Tamura, O.
Tetrahedron 2000, 56, 1469–1473. (d) Munusamy, R.;
Dhathathreyan, K. S.; Balasubramanian, K. K.; Venkatachalam,
C. S. J. Chem. Soc., Perkin Trans. 2 2001, 1154–1166.
(e) Ganguly, A.; Wang, C. H.; David, M.; Bartner, P.; Chan,
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4.4.26. 1-(3-Isopropyl-5,7-dimethyl-2,3-dihydroindol-1-
yl)-methanone (18i). This compound was prepared
according to general procedure III in 80% yield. IR
(thin film, CH2Cl2, NaCl, cm21) 2957, 2925, 2872, 1667,
1477, 1386; 1H NMR (300 MHz, CDCl3) d 0.85 (d,
J¼6.8 Hz, 3H), 0.98 (d, J¼6.9 Hz, 3H), 1.89–2.03 (m,
1H), 2.22 (s, 6H), 2.30 (s, 3H), 2.85–3.00 (m, 1H), 3.80–
4.05 (m, 2H), 6.85 (s, 1H0, 6.86 (s, 1H); HRMS (EI)
calcd mass for C15H15NO 231.1623, found 231.1619; LRMS
(EI) m/z 231 (Mþ, 19), 189 (8), 146 (100), 130 (22), 115 (6).
12. Similar preferences are seen for reactions on the N-acyl side of
many anilide radicals. See: (a) Curran, D. P.; Abraham, A. C.
Tetrahedron 1993, 49, 4821–4840. (b) Beckwith, A. L. J.;
Storey, J. M. D. J. Chem. Soc., Chem. Commun. 1995,
977–978. (c) Ganguly, A. K.; Wang, C. H.; Chan, T. M.; Ing,
Y. H.; Buevich, A. V. Tetrahedron Lett. 1989, 30, 2657–2660.
13. Jones, K.; McCarthy, C. Tetrahedron Lett. 2004, 45, 883–886.
14. Kajigaeshi, S.; Kakinami, T.; Yamasaki, H.; Fujisaki, S.;
Okamoto, T. Bull. Chem. Soc. Jpn 1988, 61, 600–606.
15. (a) Cass, Q. B.; Degani, A. L. G.; Tiritan, M. E.; Matlin, S. A.;
Curran, D. P.; Balog, A. Chirality 1997, 9, 109. (b) Curran,
D. P.; Hale, G. R.; Geib, S. J.; Balog, A.; Cass, Q. B.; Degani,
A. L. G.; Hernandes, M. Z.; Freitas, L. C. G. Tetrahedron:
Asymmetry 1997, 8, 3955–3975.
Acknowledgements
We thank the National Science Foundation for funding this
work. We also thank Dr. Ali Ates for preparing sample
R-18b for X-ray analysis.
References and notes
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