Stereoselective dimerization of benzylic amines derived from indoline

Article abstract of DOI:10.1002/jhet.5570390507

Treatment of benzylic amines derived from 2-(acyloxymethyl)-5-nitroindolines with sodium hexamethyldisilazide leads to dimeric products resulting from deprotonation in the benzylic position, oxidation of the resulting carbanion to radical by the nitroaren

Full text of DOI:10.1002/jhet.5570390507

Sep-Oct 2002
Stereoselective Dimerization of Benzylic Amines
Derived from Indoline
895
a,b
c
Ireneusz Nowak*
and Clifford George
a
Drug Discovery Program, Institute for Neurology, Georgetown University Medical Center, 3900 Reservoir
Road NW, Washington, DC 20007-2197, USA.
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA.
b
E-mail: inowak@mailchem.byu.edu
Naval Research Laboratory, 4555 Overlook Ave. SW, Washington, DC 20375-5341, USA.
c
Received November 8, 2001
Treatment of benzylic amines derived from 2-(acyloxymethyl)-5-nitroindolines with sodium hexamethyl-
disilazide leads to dimeric products resulting from deprotonation in the benzylic position, oxidation of the
resulting carbanion to radical by the nitroarene moiety of another molecule, and stereoselective radical
recombination. Only those two of six possible diastereoisomers are formed in which the recombination takes
place from the less hindered face in the more stable conformation of the presumably near-planar radical.
J. Heterocyclic Chem., 39, 895 (2002).
Radical recombination reactions are the subject of con-
observed when the reaction mixture was quenched with
tinuing interest and provide one possible way to form C-C
bonds. More specifically, radicals generated by Kolbe
electrolysis of carboxylates as well as those derived from
C-H acids by deprotonation and oxidation can undergo
coupling reactions [1-4]. During attempts at deprotonation
of benzylic amines derived from indoline, we noticed the
formation of interesting dimerization products. Exposure
of compounds 1-7 at -78 to 0 °C to an excess of the steri-
cally hindered base, sodium hexamethyldisilazide
(NaHMDS, 5.0 eq), in the presence of an excess of N-
methylmorpholine (7.0 eq) in THF resulted in low to mod-
erate yields of the products 8-13 (Scheme 1), the structure
of which was not immediately apparent. Modification of
the reaction conditions was carried out in order to gain
more insight into the reaction. Replacement of sodium
with lithium or a change of solvent from THF to toluene
suppressed the reaction as did the omission of the tertiary
amine base from the reaction medium. No reaction was
saturated NH Cl at -25 °C or below, but the reaction took
4
place upon temperature increase to above -25 °C as evi-
denced by the appearance of a brown precipitate which
redissolved upon acidic quench.
Table 1
Results of the Dehydrogenative Dimerization Reaction
Amine
[a]
R
Ar
Product
Yield
(%) [b]
A/B
[c]
1
2
3
4
5
6
7
N-Boc-L-valyl
MeCO
Phenyl
Phenyl
Phenyl
8
-
9
10
11
12
13
51
-
[d]
-
PhCO
22
67
67
60
60
20/80
26/74
27/73
62/38
74/26
Me CCO
Phenyl
3
Me CCO
4-Bromophenyl
2-Bromophenyl
2-Iodophenyl
3
Me CCO
3
Me CCO
3
[a] - starting material racemic except in the case of compound 1, which
has S-configuration in its indoline moiety; [b] - isolated yield; [c] - ratio
1
was established by H nmr of crude reaction mixture; [d] - essentially one
isomer, its stereochemical structure was not established with certainty.
The results for the enantiomerically pure starting mater-
ial 1 and the racemic starting materials 2-7 are summarized
in Table 1. Amine 1 gave a single dimer 8 in 51% yield. In
the case of amines 3-7, mixtures of two isomers (9-13A
and B) were formed, the ratio of which depends on the
position of the aromatic substituent. Satisfactory yields
(60-67%) were obtained only for the pivalic acid esters,
while the benzoate 3 gave a low (22%) yield of product,
and the acetate 2 failed to provide any product at all, prob-
ably because its acetyl group is far more acidic than its
benzylic methylene group. Analytical data are consistent
with a dehydrodimer structure of the products; however,
the highest masses observed in their mass spectra are
(M/2)+ ions. The only significant and consistent difference
in the 1H NMR spectra of the A and B type isomers is the
relative chemical shift of their geminal benzylic protons.

896
I. Nowak and C. George
Vol. 39
In type A isomers, the lower field resonance of one of
these protons appears as a doublet of doublets, and the
higher field signal of the second one as a doublet. This pat-
tern is reversed for B type isomers.
As the information gathered from the spectroscopic
properties of the products was insufficient to firmly estab-
lish their structure, we sought to obtain crystals for X-ray
structure analysis. Compound 8 failed to crystallize, possi-
bly as a consequence of the conformational flexibility of
its protected valyl substituent. Three of the pivalic acid
esters, however, could be crystallized, and one example
each for both types of isomers (compounds 11B and 12A,
respectively) was selected for X-ray crystallography. Both
compounds have "dimeric" structures but they differ in the
relative stereochemistry at their four stereocenters (Figures
1, 2). In the A series, both the pair of stereocenters residing
in the indoline moieties and that residing on the bibenzyl
moieties are each of opposite configuration, and so are
pairs of adjacent stereocenters belonging to non-identical
moieties. In the B series, stereocenters within pairs of
identical moieties are of the same configuration, and those
within the indoline moieties are of the opposite configura-
tion compared to those within the bibenzyl moieties. In
both structures, both of the indoline moieties adopt orien-
tations in which the bulky pivaloyloxymethyl substituents
point away from the crowded central C-C bond of the
bibenzyl partial structure. Additional diastereoisomers that
could theoretically be formed were not observed.
Figure 2. ORTEP plot and labeling for dimer 12A.
then takes place exclusively in ortho position, [5-7] with
the amine nitrogen providing stabilization of the resulting
aryllithium species through chelation. In the present case,
acidification of the benzylic position is achieved by a com-
bination of resonance (phenyl ring), a weak dipole contri-
bution [8] of the p-nitro substituent, and chelation by one
of the ester oxygen atoms. Usually, nitrogen-substituted
benzylic carbanions require stronger organolithium bases
for their formation; [9-14] in the present case, the electron-
withdrawing effect of the nitro group and chelation of the
sodium cation acidify the benzylic methylene group suffi-
ciently that a weaker amide base can be used. The role of
the tertiary amine may include additional stabilization of
the organosodium intermediate as a consequence of its bet-
ter donor properties compared to THF.
Single-electron transfer from carbanions to aromatic
nitro compounds is well established and gives as a side
product the radical anion of the nitro compound [3]. The
fate of the carbanion-derived radical depends on its redox
potential and structure: it can, for example, be further oxi-
dized or deprotonated, react with the radical anion of the
nitro compound, disproportionate, or dimerize. No defined
products derived from reduction of the nitro group were
isolated in the present investigation. Alternatively, nitro
compounds may participate in non-electron-transfer
processes when treated with bases and nucleophiles. In the
present case, this type of reaction does not intervene
because of the low nucleophilicity of NaHMDS and the
aprotic reaction medium.
Figure 1. ORTEP plot and labeling for dimer 11B.
The stereochemical outcome is readily understood by
inspecting a list of all possible six diastereoisomers (Figure
3) generated from conformational formulas derived from
the ORTEP plots (Figures 1, 2) by keeping the indolinyl
substituents in place while permutating the configurations
at the two central carbon atoms. No attempt was made to
The formation of "dimeric" products can be accounted
for by assuming deprotonation at the benzylic site and sub-
sequent oxidative coupling. The deprotonation of simple
tertiary benzylic amines, for example N,N-dimethyl-
benzylamine, is known to require organolithium bases and

Sep-Oct 2002
Stereoselective Dimerization of Benzylic Amines Derived from Indoline
897
Figure 3. The six theoretically possible diastereoisomers A-F of compounds 9-13, and the two near-planar conformations a and b of their precursor
radical. Nitro groups on the indoline moieties have been omitted for clarity. X = CH OCOCMe or CH OCOC H .
2
3
2
6 5
adjust the NCCN dihedral angle, which may differ in the
isomers C-F from those observed for A and B. Note that
structures D1 and D2 are identical, and structures C1 and
C2 are enantiomers (and therefore need not to be consid-
ered separately as long as the compounds are racemic).
Only those two product diastereoisomers are formed that
result from recombination of two benzyl radicals adopting
both the conformation designated as conformation a. In
contrast, the non-observed diastereoisomers would require
one or both radicals to adopt conformation b. In both of
these conformations, the aryl ring attached to the radical
center may be assumed to be essentially coplanar with this
carbon atom to maximize resonance stabilization. The
indolinyl group, while not necessarily truly planar, comes
nevertheless reasonably close to this description, with the
exception of the pivaloyloxymethyl subsituent which pro-
jects out of the approximate plane. We assume that, to max-
imize radical stabilization by the nitrogen lone pair and to
render the approach of a second radical to the radical center
sterically possible, the indolinyl group, too, will be approx-
imately coplanar with the radical carbon atom. In confor-
mation b, one ortho hydrogen atom of the aryl group suf-
fers a severe steric interaction with H-7 of the indoline moi-
ety. There is no similar interaction with the groups attached
to C-2 in conformation a as these groups are oriented out-
of-plane. Radical recombination occurs therefore exclu-
sively between two radicals of equal or opposite absolute
configuration in conformation a by way of the face oppo-
site to the pivaloyloxymethyl substituent.
The dependence of the product ratio on the aryl sub-
stituent is less readily understood. Statistically, A and B
isomers would be expected to be formed in a 1:1 ratio.
Subtle differences in the energies of the gauche interac-
tions between the three combinations of aryl and indolinyl
groups appear to be at work. In compound 11B containing
a 4-substituted phenyl group, the two indolinyl groups and
the two aryl groups are each arranged in a gauche relation-
ship. This compound predominates over its isomer 11A,
indicating that the sum of the steric interaction energies
between two phenyl and two indolinyl groups is smaller
than twice the steric interaction energy between a phenyl
and an indolinyl group as long as no bulky ortho-sub-
stituent is present. It may be assumed that the introduction
of such a substituent as in compounds 12 and 13 increases
the steric interaction energy between the two aryl groups,
thus favoring the A isomer in which the orientation of
these groups is anti-periplanar while two gauche interac-
tions occur between the indolinyl and aryl substituents.
Finally, we note that the homochiral nature of the start-
ing material 1 renders an A-type structure, which is a meso
form, impossible for compound 8. It is therefore likely that
this compound possesses a B-type structure with the

898
I. Nowak and C. George
Vol. 39
meter. The Mo-K source was equipped with an incident beam
graphite monochromator. Lattice parameters were determined
using SAINT [15] from 5003 reflections within 4.9° < 2θ <
absolute stereochemistry opposite to that depicted in
Figures 1 and 3. The high degree of stereochemical induc-
tion observed for the present reaction may find application
in a simple synthesis of homochiral ligands of the 1,2-
diamino-1,2-diarylethane class potentially useful in enan-
tioselective catalysis.
α
58.1°. The data collection range had a {(sin θ)/λ}
= 0.68. A
max
set of 7554 reflections was collected in the φ and ω scan mode.
There were 4799 unique reflections. Corrections were applied
for Lorentz, polarization, and absorption effects. The structure
was solved with SHELXTL [16] and refined with the aid of the
SHELX97 system of programs. The full-matrix least-squares
EXPERIMENTAL
2
refinement on F varied 253 parameters: atom coordinates and
anisotropic thermal parameters for all non-H atoms. H atoms
were included using a riding model [coordinate shifts of C
applied to attached H atoms, C-H distances set to 0.96 to 0.93 Å,
Thin-layer chromatography was performed in a solvent-vapor-
saturated chamber on silica gel 60 F plates. Spots were visual-
254
ized by UV light. Melting points (uncorrected) were determined
in open capillaries on a Thomas-Hoover Unimelt apparatus.
Infrared spectra were obtained on an ATI Mattson Genesis Series
H angles idealized, U (H) were set to 1.2 to 1.5 U (C). Final
iso
eq
residuals were R1 = 0.038 for the 3976 observed data with F
o
>4σ( F ) and 0.050 for all data. Final difference Fourier excur-
1
13
o
spectrometer in KBr pellets. H and C NMR spectra were
acquired at a field strength corresponding to a proton frequency
of 300 MHz. Elemental Analyses were performed by Micro-
Analysis, Inc. Mass spectra were obtained on a Shimadzu QP-
5000 mass spectrometer using a direct inlet probe and an electron
beam energy of 70 eV. Optical rotations were measured with a
Rudolph Research Automatic Polarimeter.
-3
sions were 1.07 and -0.82 eÅ . The molecule sits on an inversion
center and has C symmetry.
i
(S)-(-)-2-(Hydroxymethyl)indoline.
This compound was prepared from (S)-(-)-indoline-2-car-
boxylic acid following the published general procedure; [17] col-
orless plates, mp 59-61 ºC; ir: 3278, 3195, 1608, 1463, 1077,
-1
1
1047, 828, 778, 744 cm ; H nmr (CDCl ): δ 2.39 (br s, 2H),
Single-crystal X-ray Diffraction Analysis of Compounds 11B
and 12A.
3
2.85 (dd, 1H, J = 8.0, 15.8 Hz), 3.12 (dd, 1H, J = 9.2, 16.1 Hz),
3.59 (dd, 1H, J = 6.3, 10.8 Hz), 3.74 (dd, 1H, J = 3.8, 11.0 Hz),
Compound 11B: C
H N O Br , F.W. = 892.64, mono-
42 44 4 8 2
13
4.06 (m, 1H), 6.65-6.76 (m, 2H); 7.01-7.11 (m, 2H); C nmr
clinic space group C2/c, a = 27.884(1), b = 10.274(1), c =
(CDCl ): δ 31.7, 60.1, 65.1, 109.7, 118.8, 124.5, 127.1, 128.4,
3
3
17.559(1) Å, β = 126.23(1)°, V = 4057.45(8) Å , Z = 4, ρ
=
calc
-1
25
150.1; ms: m/z 149 (53), 118 (100), 91 (55); [α]
= +49.4 (c =
D
-3
1.461 mg mm , λ(Cu K ) = 1.54178 Å, µ = 3.010 mm , F
α
0.88, MeOH).
(000) = 1832, T = 293 K. A yellow 0.40 x 0.07 x 0.04-mm crys-
tal was used for data collection with a Bruker SMART [15] 6K
CCD detector on a Platform goniometer. The Rigaku rotating Cu
anode source was equipped with an incident beam Gobel mirror.
Lattice parameters were determined using SAINT [15] from
5003 reflections within 7.9<2θ < 133.7°. The data collection
(S)-(-)-2-(Acetoxymethyl)-N-(ethoxycarbonyl)indoline.
To a suspension of (S)-(-)-2-(hydroxymethyl)indoline (4.5 g,
30 mmol) and Na CO (3.8 g, 36 mmol) in water (100 mL) were
2
3
added EtOCOCl (4.6 mL, 48 mmol) and EtOAc (5 mL) in one
portion. The mixture was stirred at room temperature for 4 hours
and extracted with AcOEt (4 x 50 mL). The organic layer was
range had a {(sin θ)/λ}
= 0.59. A set of 9139 reflections was
max
collected in the ω scan mode. There were 3302 unique reflec-
tions. Corrections were applied for Lorentz, polarization, and
absorption effects. The structure was solved with SHELXTL [16]
and refined with the aid of the SHELX97 system of programs.
dried over Na SO and evaporated to give an oil which was dis-
2
4
solved in Et N (8.3 mL, 60 mmol) and Ac O (3.4 mL, 60 mmol).
3
2
The mixture was stirred for 4 hours at room temperature and then
partitioned between CH Cl (100 mL) and water (100 mL). The
2
2
2
The full-matrix least-squares refinement on F used 3 restraints
organic layer was extracted with CH Cl (2 x 100 mL) and dried
2
2
and varied 267 parameters: atom coordinates and anisotropic
thermal parameters for all non-H atoms. H atoms were included
using a riding model [coordinate shifts of C applied to attached H
atoms, C-H distances set to 0.96 to 0.93 Å, H angles idealized,
over Na SO . Evaporation and column chromatography (silica
2
4
gel, ethyl acetate:hexane = 1:2) provided 7.1 g (90 %) of the
-1
product, ir: 2985, 1746, 1709, 1486, 1410, 1194, 1057, 755 cm ;
1
H nmr (CDCl ): δ 1.37 (t, 3H, J = 7.0 Hz), 1.94 (s, 3H), 2.90 (d,
3
U
(H) were set to 1.2 to 1.5 U (C). Final residuals were R1 =
1H, J = 16.6 Hz), 3.33 (dd, 1H, 9.9, 16.2 Hz), 4.20 (m, 2H), 4.30
iso
eq
13
0.041 for the 2932 observed data with F >4σ(F ) and 0.045 for
(q, 2H, J = 7.0 Hz), 4.71 (br s, 1H), 6.92-7.01 (m, 1H); C nmr
o
o
all data. Final difference Fourier excursions were 0.47 and -0.48
(CDCl ): δ 14.5, 20.5, 31.3, 57.4, 61.6, 64.6, 115.2, 122.8, 124.6,
3
-3
eÅ . The t-butyl moiety is disordered over two sites at occupan-
127.4, 129.6, 141.8, 153.0, 170.7; ms: m/z 263 (7), 203 (15), 190
25
cies of 79:21. The bond and next nearest neighbor distances of
the t-butyl carbons for the lower occupancy positions were
restrained to those of the higher occupancy positions. The mole-
(18), 130 (28), 118 (100), 91 (20); [α]
= -56.6 (c = 1.25,
D
CHCl ).
3
Anal. Calcd for C
H NO : C, 63.87; H, 6.51; N, 5.32.
14 17 4
cule sits on an inversion center and has C symmetry.
Found: C, 63.54; H, 6.63; N, 5.51.
i
Compound (12A): C
H N O Br , F.W. = 892.64, triclinic
42 44 4 8 2
(S)-(-)-2-(Acetoxymethyl)-N-(ethoxycarbonyl)-5-nitroindoline.
To a solution of (S)-(-)-2-(acetoxymethyl)-N-(ethoxycar-
space group P1bar, a = 9.326(2), b = 9.327(2), c 13.592(2) Å,
α = 74.632(3), β = 71.321(3), and γ = 63.166(3)°. V =
3
-3
989.3(3) Å , Z = 1, ρ
= 1.498 mg mm , λ(Mo K ) =
bonyl)indoline (15.8 g, 60 mmol) in Ac O (250 mL) was added
calc
-1
α
2
0.71073 Å, µ = 2.108 mm , F(000) = 458, T = 93 K. A yellow
0.32 x 0.16 x 0.08-mm crystal was used for data collection with a
Bruker SMART [15] 1K CCD detector on a four-circle gonio-
nitric acid (35 mL, 275 mmol) dropwise at -15 ºC. The mixture
was allowed to warm to 0 ºC within 30 minutes and was poured
onto crushed ice (500 g). After warming to ambient temperature,

Sep-Oct 2002
Stereoselective Dimerization of Benzylic Amines Derived from Indoline
899
the product was extracted into EtOAc (5 x 100 mL), and the com-
bined organic phases were dried over Na SO and evaporated.
Anal. Calcd for C H N O : C, 67.59; H, 5.67; N, 9.85.
16 16 2 3
Found: C, 67.32; H, 5.91; N, 9.53.
2
4
Column chromatography (500 g of silica gel, ethyl
acetate:hexane = 1:2) followed by crystallization from methanol
provided pure product (12.0 g, 65%), mp 94-96 ºC; ir: 1743,
(S)-(+)-N-Benzyl-2-[[[N-(tert-butoxycarbonyl)-L-valyl]oxy]-
methyl]-5-nitroindoline (1).
-1
1
1716, 1513, 1487, 1341, 1301, 1273, 1236, 1055, 1045 cm ; H
To a stirred solution of (S)-(-)-N-benzyl-2-(hydroxymethyl)-5-
nmr (CDCl ): δ 1.38 (t, 3H, J = 7.1 Hz), 1.90 (s, 3H), 9.04 (dd,
nitroindoline (11.0 g, 38.7 mmol) and triethylamine (10.8 mL,
3
1H, J = 2.1, 16.7 Hz), 3.41 (dd, 1H, J = 10.1, 16.7 Hz), 4.18 (dd,
1H, J = 3.7, 11.5 Hz), 3.29-4.40 (m, 3H), 4.80(m, 1H), 7.80 (br s,
1H), 8.00 (s, 1H), 8.10 (dd, 1H, J = 2.3, 8.9 Hz); C nmr
77.4 mmol) in dry CH Cl (150 mL) was added N-(tert-butoxy-
2 2
carbonyl)-L-valyl fluoride [18] (12.7 g, 58.1 mmol) under nitro-
gen. The reaction mixture was left for 11 hours at room tempera-
ture, then evaporated to dryness, and the residue was purified by
column chromatography on silica gel (ethyl acetate:hexane = 1:4)
to give the product (9.9 g, 53%), ir: 3408, 1742, 1716, 1708, 1609,
13
(CDCl ): δ 14.3, 20.4, 30.6, 58.6, 62.5, 64.4, 114.3, 120.2, 124.5,
3
131.1, 143.0, 147.7, 152.4, 170.6; ms: m/z 308 (2), 248 (12), 235
25
(6), 175 (7), 117 (44), 43 (100); [α]
= -49.0 (c = 1.12, MeOH).
D
-1
1
Anal. Calcd for C
H
N O : C, 54.54; H, 5.23; N, 9.09.
1498, 1385, 1317, 1174 cm ; H nmr (CDCl ): δ 0.77 (d, 3H, J =
14 16
2
6
3
6.8 Hz), 0.87 (d, 3H, J = 6.8 Hz), 1.43 (s, 3H), 1.91 (m, 1H), 2.96
(d, 1H, J = 5.7, 16.7 Hz), 3.34 (d, 1H, J = 10.1, 16.7 Hz), 4.08-4.25
(m, 2H), 4.32-4.40 (m, 1H), 4.47 (d, 1H, J = 16.7 Hz), 4.64 (d, 1H,
Found: C, 54.67; H, 5.43; N, 9.34.
(S)-(-)-N-(Ethoxycarbonyl)-2-(hydroxymethyl)-5-nitroindoline.
To a vigorously stirred mixture of (S)-(-)-2-(acetoxymethyl)-
N-(ethoxycarbonyl)-5-nitroindoline (10.0 g, 32.5 mmol) in
J = 16.7 Hz), 4.86 (d, 1H, J = 9.0 Hz), 6.31 (d, 1H, J = 8.8 Hz),
13
7.22-4.38 (m, 5H), 7.92 (s, 1H), 8.03 (dd, 1H, J = 2.2, 8.8 Hz);
C
MeOH (1.5 L) and THF (100 mL) was added Na CO (24.1 g,
nmr (CDCl ): δ 17.3, 19.0, 28.2, 30.8, 31.1, 49.6, 58.5, 62.0, 65.2,
2
3
3
227 mmol) in water (500 mL). After stirring for 1.5 hour, the
organic solvents were evaporated under reduced pressure, and the
residue was brought with HCl to pH 7. Ethyl acetate extraction
and drying followed by concentration provided an oil which was
chromatographed on silica gel (ethyl acetate:hexane = 1:2) to
provide a pale yellow solid (7.7 g, 89%). An analytically pure
sample was obtained by crystallization from toluene, mp 115-117
79.9, 104.2, 120.6, 126.6, 126.8, 127.7, 128.9, 136.3, 138.7,
155.6, 156.8, 172.2; ms: m/z 483 (10), 410 (10), 266 (31), 253
25
(100), 91 (93); [α]
= +126.6 (c = 1.25, MeOH).
D
Anal. Calcd for C
H N O : C, 64.58; H, 6.88; N, 8.69.
26 33 3 6
Found: C, 64.42; H, 7.11; N, 8.56.
Dimerization Reaction of Compound (1).
-1
1
ºC; ir: 3257, 1701, 1516, 1484, 1319, 1260 cm ; H nmr
Compound 1 (12.0 g, 24.8 mmol), N-methylmorpholine (17.6
g, 173.9 mmol) and dry THF (450 mL) were placed in a 1 L
round bottom flask under nitrogen. The flask was cooled to -78
ºC, and sodium hexamethyldisilazide (124 mL of a 1 M solution
in THF) was added slowly with vigorous stirring. After the addi-
tion was completed (35 minutes), the solution was allowed to
(CDCl ): δ 1.43 (t, 1H, J = 7.1 Hz), 2.43 (br s, 1H), 3.12 (d, 1H,
3
J = 16.8 Hz), 3.43 (dd, 1H, J = 10.3, 16.8 Hz), 3.84 (m, 2H), 4.39
(q, 2H, J = 7.1 Hz), 4.73 (m, 1H), 7.78 (br s, 1H), 8.04 (s, 1H),
8.12 (dd, 1H, J = 2.3, 8.9 Hz); ms: m/z 266 (37), 235 (100), 163
13
(45), 145 (36), 130 (32), 117 (60), 84 (31); C nmr (CDCl ): δ
3
14.3, 30.3, 61.5, 62.6, 64.1, 114.4, 120.4, 124.0, 131.8, 143.0,
warm to 0 ºC within 3.3 hours. Then saturated aqueous NH Cl
4
25
147.8, 153.3; [α]
= -100.3 (c = 0.955, MeOH).
(150 mL) and water (150 mL) were added. The layers were sepa-
rated, and the aqueous phase was extracted with ethyl acetate (4 x
100 mL). The combined organic phases were evaporated to dry-
ness, and the residue was chromatographed on silica gel (ethyl
acetate:hexane = 1:10, then 1:5) to provide compound 1 as a yel-
low oil (6.15 g, 51%), ir: 3427, 1742, 1716, 1707, 1604, 1499,
D
Anal. Calcd for C
H N O : C, 54.13; H, 5.30; N, 10.52.
12 14 2 5
Found: C, 53.96; H, 5.47; N, 10.38.
(S)-(-)-N-Benzyl-2-(hydroxymethyl)-5-nitroindoline.
A round bottom flask fitted with a dropping funnel was
charged with NaH (5.2 g, 216 mol) and benzyl bromide (22.2 g,
130 mmol) and cooled to -30 ºC. DMF (100 mL) was added with
stirring under a nitrogen atmosphere. Then (S)-(-)-N-(ethoxycar-
bonyl)-2-(hydroxymethyl)-5-nitroindoline (19.9 g, 86.5 mmol) in
DMF (200 mL) was slowly added within 30 minutes to the result-
ing suspension. The reaction mixture was allowed to warm to
room temperature, and water (50 mL) was added cautiously to
destroy the excess of NaH. Addition of more water (600 mL) was
followed by neutralization with 6 M HCl and extraction with
ethyl acetate (4 x 200 mL). The combined organic extracts were
concentrated, and the residue was purified by column chromatog-
raphy on silica gel (ethyl acetate:hexane = 1:2) to give 16.3 g
-1
1
1385, 1322, 1173 cm ; H nmr (CDCl ): δ 0.72 (d, 6H, J = 6.6
3
Hz), 0.82 (d, 6H, J = 6.6 Hz), 1.43 (s, 18H), 1.85 (m, 2H), 2.06
(dd, 2H, J = 10.0, 16.1 Hz), 2.51 (d, 2H, J = 16.6 Hz), 2.93 (dd,
2H, J = 8.6, 10.5 Hz), 3.29 (d, 2H, J = 9.0 Hz), 3.95-4.06 (m, 4H),
4.81 (d, 2H, J = 8.5 Hz), 5.92 (s, 2H), 6.94 (d, 2H, J = 8.8 Hz),
7.20-7.45 (m, 10H), 7.81 (s, 2H), 8.16 (dd, 2H, J = 1.7, 8.8 Hz);
13
C nmr (CDCl ): δ 17.4, 18.9, 28.3, 30.9, 31.3, 57.4, 58.0, 58.3,
3
64.7, 80.0, 103.5, 121.4, 126.6, 127.8, 128.2, 129.0, 129.3, 136.8,
139.0, 155.4, 155.5, 172.1; ms: m/z 482 (5), 426 (3), 91 (8), 56
25
(31), 41 (100); [α]
= -260.8 (c = 0.365, MeOH).
D
Anal. Calcd. for C
H N O : C, 64.58; H, 6.88; N, 8.69.
26 33 3 6
Found: C, 64.33; H, 7.09; N, 8.81.
-
(66%) of the product, ir: 3427, 1609, 1509, 1496, 1314, 1267 cm
The syntheses of the racemic amines 3-8 were carried out in a
similar way as that of 1. The products were only partially charac-
1
1
; H nmr (CDCl ): δ 3.04 (dd, 1H, J = 7.3, 16.6 Hz), 3.22 (dd,
3
1
1H, J = 10.4, 16.5 Hz), 3.68 (dd, 1H, J = 4.0, 11.6 Hz), 3.81 (dd,
1H, J = 3.9, 11.7 Hz), 4.05 (m, 1H), 4.50 (d, 1H, J = 16.4 Hz),
4.59 (d, 1H, J = 16.4 Hz), 6.30 (d, 1H, J = 8.8 Hz), 7.21-7.38 (m,
terized ( H nmr, ms) and then subjected to the action of base.
Representative Example for the Synthesis of the Dimers (9-13).
13
5 Hz), 7.86 (s, 1H), 7.98 (dd, 1H, J = 1.7, 8.8 Hz); C nmr
To a solution of amine 5 (30 mg, 0.08 mmol) and N-methyl-
morpholine (58 mg, 0.57 mmol) in dry THF (2 mL) was added a
1 M solution of NaHMDS in THF (0.41 mL) at -78 °C under
nitrogen. The reaction mixture was allowed to warm to 0 °C
(CDCl ): δ 30.1, 49.2, 62.8, 64.8, 103.7, 120.5, 126.5, 126.8,
3
127.5, 128.6, 136.6, 137.7, 157.4; ms: m/z 284 (25), 253 (100),
25
91 (97); [α]
= +155.7 (c = 0.61, MeOH).
D

900
I. Nowak and C. George
Vol. 39
within 1.5 hour and then quenched with saturated NH Cl (10
4H), 7.65 (dd, 2H, J = 1.4, 7.8 Hz), 7.70 (s, 2H), 7.83 (d, 2H, J =
4
13
mL). Extraction with ethyl acetate (4 x 20 mL) followed by
preparative TLC on silica gel (ethyl acetate:hexane = 1:3) pro-
vided a mixture of the dimers 10A and 10B (20 mg, 67%) as a
yellow oil, ms: m/z 367, 265, 219, 57.
8.0 Hz), 7.93 (dd, 2H, J = 2.3, 9.0 Hz); C nmr (CDCl ): δ 27.0;
3
31.9; 38.7; 59.0; 64.8; 67.6; 102.4; 108.3; 120.4; 125.2; 129.0;
129.0; 129.3; 131.0; 138.6; 139.3; 140.5; 155.2; 178.1; ms: m/z
493, 391, 178, 57.
Anal. Calcd. for C
Found: C, 51.03; H, 4.34; N, 5.50.
H I N O : C, 51.13; H, 4.50; N, 5.68.
42 44 2 4 8
Dimers (9A) and (9B).
These compounds gave ms: m/z 387, 176, 179, 105.
Dimer (11B).
REFERNCES AND NOTES
This compound was obtained as yellow prisms after several
[1] Giese, B. Radicals in Organic Synthesis: Formation of
Carbon-Carbon Bonds. Pergamon Press, Oxford, 1986, pp 113-119.
[2] R. B. Bates and C. A. Ogle, Carbanion Chemistry,
Springer-Verlag, Berlin, 1983, p 64.
[3] R. B. Guthrie in T. Durst and E. Burcel, Comprehensive
Carbanion Chemistry pt A, Elsevier, New York, 1980, pp 197-269.
[4] B. M. Trost and I. Fleming, Comprehensive Organic
Synthesis, Pergamon Press, Oxford, 1991, Vol 3, pp 413-702.
[5] F. N. Jones, M. F. Zinn and C. R. Hauser, J. Org. Chem.
28, 663, (1963).
recrystallizations from MeOH-CH Cl , mp 292-294 ºC; ir: 1730,
2
2
-1
1
1603, 1493, 1315, 1271, 1152 cm ; H nmr (CDCl ): δ 1.00 (s,
3
18H), 2.12 (dd, 2H, J = 9.9, 16.2 Hz), 2.55 (d, 2H, J = 16.1 Hz),
2.89 (dd, 2H, J = 7.8, 10.5 Hz), 3.49 (dd, 2H, J = 2.7, 8.5 Hz),
3.93 (m, 2H), 5.80 (s, 2H), 6.90 (s, 2H, J = 9.0 Hz), 7.23-7.45 (m,
13
8H), 7.82 (s, 2H), 8.16 (dd, 2H, J = 2.2, 8.8 Hz); C nmr
(CDCl ): δ 26.9; 31.3; 38.6; 56.9; 58.2; 64.2; 103.5; 121.4;
3
123.1; 126.2; 128.1; 129.8; 132.5; 136.0; 139.2; 155.3; 178.2;
ms: m/z 445, 417, 178, 57.
Anal. Calcd. for C
H Br N O : C, 56.51; H, 4.97; N, 6.28.
42 44 2 4 8
[6] F. N. Jones, R. L. Vaulx and C. R. Hauser, J. Org. Chem.
28, 3461, (1963).
Found: C, 56.04; H, 4.88; N, 6.05.
[7] K. P. Klein and C. R. Hauser, J. Org. Chem. 32, 1479,
(1967).
[8] P. Beak and W. J. Reitz, Chem. Rev., 78, 275, (1978).
[9] A. I. Meyers and J. M. Marra, Tetrahedron Lett., 26, 5863,
(1985).
Dimer (12A).
This compound was obtained as yellow prisms after several
recrystallizations from MeOH-CH Cl , mp 250-252 ºC; ir: 1729,
1603, 1492, 1318, 1259, 1150 cm ; H nmr (CDCl ): δ 1.01 (s,
2
2
-1
1
3
[10] A. I. Meyers, M. Boes and D. A. Dickman, Org. Synth. 67,
60, (1988).
[11] A. I. Meyers, K. B. Kunnen and W. C. Still, J. Am. Chem.
Soc. 109, 4405, (1987).
[12] D. Seebach, J.-J. Lohmann and M. A. Syfrig, Angew.
Chem., Int. Ed. Engl., 23, 2481, (1984).
[13] A. R. Katritzky and K. Akatugawa, Tetrahedron, 42, 257,
(1986).
[14] J. A. Monn and K. C. Rice, Tetrahedron Lett., 30, 911,
(1989).
[15] Bruker (1995) SMART and SAINT Data Collection and
Reduction Software for the SMART system. Bruker-AXS, Madison,
Wisconsin, USA.
[16] G. M. Sheldrick, (1997). SHELXTL Version 5.1 Bruker
Analytical X-ray Instruments, Madison, Wisconsin, USA.
[17] M. J. McKennon, A. I. Meyers, K. Drauz and M.
Schwarm, J. Org. Chem. 58, 3568, (1993).
[18] L. A. Carpino, L.-S. M. E. Mansour and D. Sadat-Aalaee,
J. Org. Chem., 56, 2611, (1991).
18H), 3.67 (d, 2H, J = 16.2 Hz), 2.90 (dd, 2H, J = 10.0, 16.4 Hz),
3.78 (dd, 2H, J = 6.2, 11.2 Hz), 3.76 (dd, 2H, J = 2.7, 11.2 Hz),
4.23 (m, 2H), 6.16 (s, 2H), 6.82 (d, 2H, J = 8.8 Hz), 7.08-7.20 (m,
4H), 7.56 (dd, 2H, J = 1.5, 7.8 Hz), 7.65 (dd, 2H, J = 1.7, 7.8 Hz),
13
7.70 (s, 2H), 7.95 (dd, 2H, J = 2.2, 8.8 Hz); C nmr (CDCl ): δ
3
26.9, 31.9, 38.7, 58.9, 61.7, 64.9, 107.5, 120.4, 125.4, 125.5,
128.2, 128.9, 129.3, 130.8, 133.6, 135.6, 139.4, 155.3, 178.1; ms:
m/z 445, 207, 178, 57.
Anal. Calcd. for C
H Br N O : C, 56.51; H, 4.97; N, 6.28.
42 44 2 4 8
Found: C, 56.34; H, 4.71; N, 6.12.
Dimer (13A).
This compound was obtained as yellow needles after several
recrystallizations from MeOH-CH Cl , mp 253-255 ºC; ir: 1728,
2
2
-1
1
1603, 1487, 1318, 1257, 1147 cm ; H nmr (CDCl ): δ 1.01 (s,
3
18H), 2.69 (d, 2H, J = 16.2 Hz), 2.96 (dd, 2H, J = 9.8, 16.1 Hz),
3.35 (dd, 2H, J = 6.2, 11.2 Hz), 3.74 (dd, 2H, J = 2.7, 11.2 Hz),
4.26 (m, 2H), 5.95 (s, 2H), 6.91 (d, 2H, J = 9.0 Hz), 6.90-7.25 (m,