Diastereoselective synthesis of substituted 2,3,4,5-tetrahydro-1H-1- benzazepine-5-carboxylic esters by a tandem reduction-reductive amination reaction

Article abstract of DOI:10.1002/jhet.5570410413

An efficient, diastereoselective synthesis of substituted and unsubstituted 2,3,4,5-tetrahydro-1H-1-benzazepine-5-carboxylic esters has been developed based on the tandem reduction-reductive animation reaction. Catalytic hydrogenation of a series of 2-(2-nitrophenyl)-5-oxoalkanoic esters initiates a reaction sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the N-hydroxylamino (or amino) nitrogen with the side chain carbonyl, and (3) reduction of the seven-membered cyclic imine. Cyclizations that produce 2-alkyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-carboxylic esters are diastereoselective for the product having the C2 alkyl and the C5 ester groups cis. In these reactions, the transannular ester group exerts a strong seediest effect on the reduction of the cyclic imine intermediate, though not as strong as that observed in previous closures of 2-alkyl-1,2,3,4-tetrahydroquinoline-4- carboxylic esters. This decrease in diastereoselectivity is attributed to (1) the greater distance between the ester and the imine double bond and (2) the increased conformational mobility of the larger ring, both of which diminish the stereodirecting effect of the ester. Finally, formation of the seven-membered ring is sufficiently slow that reaction with the side chain ester group competes with heterocycle formation in several of the reactions.

Full text of DOI:10.1002/jhet.5570410413

Jul-Aug 2004
563
Diastereoselective Synthesis of Substituted 2,3,4,5-Tetrahydro-1H-1-
benzazepine-5-carboxylic Esters by a Tandem Reduction-Reductive
Amination Reaction
Richard A. Bunce*, Lara B. Johnson and Elizabeth M. Holt [1]
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
Received February 11, 2004
An efficient, diastereoselective synthesis of substituted and unsubstituted 2,3,4,5-tetrahydro-1H-1-ben-
zazepine-5-carboxylic esters has been developed based on the tandem reduction-reductive amination reac-
tion. Catalytic hydrogenation of a series of 2-(2-nitrophenyl)-5-oxoalkanoic esters initiates a reaction
sequence involving (1) reduction of the aromatic nitro group, (2) condensation of the N-hydroxylamino (or
amino) nitrogen with the side chain carbonyl, and (3) reduction of the seven-membered cyclic imine.
Cyclizations that produce 2-alkyl-2,3,4,5-tetrahydro-1H-1-benzazepine-5-carboxylic esters are diastereose-
lective for the product having the C2 alkyl and the C5 ester groups cis. In these reactions, the transannular
ester group exerts a strong stereodirecting effect on the reduction of the cyclic imine intermediate, though
not as strong as that observed in previous closures of 2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic
esters. This decrease in diastereoselectivity is attributed to (1) the greater distance between the ester and the
imine double bond and (2) the increased conformational mobility of the larger ring, both of which diminish
the stereodirecting effect of the ester. Finally, formation of the seven-membered ring is sufficiently slow that
reaction with the side chain ester group competes with heterocycle formation in several of the reactions.
J. Heterocyclic Chem., 41, 563 (2004).
Introduction.
furnished alkene 2 in 60% yield. Ozonolysis of alkene 2
followed by reductive workup in the presence of catalytic
acid afforded acetal 3 which was hydrolyzed with 3%
We recently reported a tandem reduction-reductive ami-
nation reaction for the diastereoselective synthesis of (±)-
2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic esters
from 2-(2-nitrophenyl)-4-oxoalkanoic ester derivatives
[2]. In this sequence, it was found that the side chain car-
boxylic ester exerted a strong stereodirecting effect on the
reductive cyclization to give exclusively the cis-2,4-disub-
stituted product. The current project sought to extend this
reaction to the synthesis of (±)-2-alkyl-2,3,4,5-tetrahydro-
1H-1-benzazepine-5-carboxylic esters [3,4,5] with the
added goal of ascertaining the ability of a similarly posi-
tioned ester group to control stereochemistry in seven-
membered ring closures.
Tetrahydro-1H-1-benzazepine derivatives substituted at
C2 and C5 have been found to selectively inhibit the V2
receptor of the hormone arginine vasopressin. This hor-
mone exerts its actions through three receptor subtypes
with the V2 receptor (present in the collecting duct of the
kidney) controlling blood pressure, blood volume, and
plasma osmolality. Thus, inhibitors of the arginine vaso-
pressin V2 receptor may have applications in the treatment
of disorders such as diabetes, congestive heart failure, and
hypertension [6]. The 2-indolinones, which are also possi-
ble products from these reactions, have been investigated
as drugs for managing chronic conditions involving the
muscarinic M3 receptor, which most notably include
obstructive pulmonary disease, bronchitis, and asthma [7].
Results and Discussion.
The cyclization substrates required for this study were
prepared in 1-3 steps from methyl 2-nitrophenylacetate (1)
(Scheme 1). Alkylation [8] of 1 with 4-iodo-1-butene [9]

564
R. A. Bunce, L. B. Johnson and E. M. Holt
Vol. 41
aqueous perchloric acid in tetrahydrofuran [10] to give
nitro aldehyde 4 in 93% yield. Substrates 5-8 were gener-
ated by adapting the alkylation procedure above [8] for the
conjugate addition of the methyl 2-nitrophenylacetate
anion to methyl vinyl ketone, ethyl vinyl ketone, phenyl
vinyl ketone [11] and methyl acrylate, respectively. The
addition products were isolated in 71-94% yields.
The reaction sequence to produce the 2,3,4,5-tetrahy-
dro-1H-1-benzazepines likely follows the same path as our
earlier 1,2,3,4-tetrahydroquinoline synthesis [2]—reduc-
tion of the aromatic nitro group followed by reductive ami-
nation of the N-hydroxylamino (or amino) group with the
side chain carbonyl (Scheme 3). Diastereoselection in the
tetrahydroquinoline ring closures occurs during hydro-
genation of the final cyclic imine intermediate. In this
step, steric shielding of the top face of the imine by the
transannular ester group serves to direct the incoming
hydrogen to the opposite side of the molecule giving a cis
relationship between the C2 alkyl and the C4 ester groups.
The reactions to produce 2-alkyl (or phenyl)-2,3,4,5-
tetrahydro-1H-1-benzazepine-5-carboxylic esters show a
similar preference for the cis products [12], but to a lesser
degree than in the tetrahydroquinolines. Two major fac-
tors likely contribute to this reduced diastereoselectivity.
First, the C5 ester in 20a is further away from the imine
double bond and thus exerts less influence in the final
reduction step. Second, the more flexible seven-mem-
bered cyclic imine can place the ester group in a pseudo-
equatorial position (as in 20b) where it would be unable to
block the top face of the imine double bond. Thus, forma-
tion of at least minor quantities of the trans products
would be expected.
The results of our study are summarized in Scheme 2.
Reduction of nitro aldehyde 4 under 4 atmospheres of
hydrogen in methanol at 30˚ using 20 weight percent of 5%
palladium-on-carbon gave methyl 2,3,4,5-tetrahydro-1H- 1 -
benzazepine-5-carboxylate (9) in 60% yield. Similar
reduction of nitro ketones 5 and 6 produced mixtures of the
c i s - and t r a n s- 2 - a l k y l - 2 , 3 , 4 , 5 - t e t r a h y d r o - 1 H- 1 - b e n-
zazepine-5-carboxylic esters in 98% and 76% yields,
respectively. The ratio of c i s:trans products 1 0:11 from 5
was 10:1; the ratio of c i s:trans products 1 2:13 from 6 was
8.5:1. Reduction-reductive amination of the phenyl-substi-
tuted substrate 7 gave cis- and trans-2-phenyl-2,3,4,5-
tetrahydrobenzazepines 14 and 15 in a ratio of 5:1, but only
20% yield; the major product was indolinone 16 in 32%
yield. Finally, attempted reduction-lactamization of nitro
diester 8 under hydrogenation conditions gave the uncy-
clized amino diester 17 in 97% yield. All products were
easily separated and purified by chromatographic methods.

Jul-Aug 2004
Substituted 2,3,4,5-Tetrahydro-1H-1-benzazepine-5-carboxylic Esters
565
ucts were easily isolated in good to excellent yields.
F i n a l l y, attempted reduction-lactamization of a nitro
diester cyclization substrate gave the amino diester, which
required further heating for ring closure.
EXPERIMENTAL
Commercial reagents and solvents were used as received.
Potassium carbonate was ground into a fine powder, dried under
vacuum for 24 hours at 120˚, and stored in an oven at 120˚ until
needed. Methyl (2-nitrophenyl)acetate (1) was prepared as
described previously [2]. Commercially available 4-bromo-1-
butene was converted to the iodide by treatment with sodium
iodide in acetone [9]. Phenyl vinyl ketone was prepared by the
method of Reich and co-workers [11].
All reactions were run under dry nitrogen in oven-dried glass-
ware. The sodium bicarbonate (saturated) and sodium chloride
(saturated) used in various work-up procedures were aqueous
solutions. Reactions were monitored by thin layer chromatogra-
phy on silica gel GF plates (Analtech no. 21521) with ultraviolet
detection. Preparative separations were performed by one of the
following methods: (1) flash column chromatography [17] on
silica gel (grade 62, 60-200 mesh) containing ultraviolet-active
phosphor (Sorbent Technologies, UV-5) packed into quartz
columns or (2) preparative thin layer chromatography on 20-cm x
20-cm silica gel GF plates (Analtech, no. 02015). Band elution
for both methods was monitored using a hand-held ultraviolet
lamp. Melting points were uncorrected. Infrared spectra were
run as thin films on sodium chloride disks and referenced to poly-
styrene. H and C Nuclear magnetic resonance spectra were
measured in deuteriochloroform at 300 MHz and 75 MHz,
respectively, using tetramethylsilane as an internal standard;
coupling constants (J) are given in Hz. High-resolution mass
spectra (electron impact/direct probe) were obtained at 70 elec-
tron volts.
While cyclizations in the tetrahydroquinoline series [2]
did not give any appreciable side reactions, closure of the
seven-membered rings was sufficiently slow to allow com-
peting processes to occur [13]. This was apparent in the
cyclization of 7 where reduction of the phenyl-conjugated
ketone [14] forced reaction of the N-hydroxylamino (or
amino) nitrogen with the side chain ester to give
indolinone 16 in preference to tetrahydrobenzazepines 14
and 15. The use of lower hydrogen pressure (1.5 atmos-
pheres) and temperature (20˚) did not significantly alter
this result. These findings stand in contrast to a related
eight-membered ring closure, performed under identical
conditions in ethanol, which showed a marked temperature
dependence, with phenyl ketone reduction favored at 45-
50˚ and reductive cyclization favored at 20˚ [15].
1
13
Caution: Though we never experienced any problems, addi-
tion of 5% palladium-on-carbon to methanol can cause fires.
This operation should be performed under a nitrogen atmosphere.
Catalytic hydrogenation of nitro diester 8 using our stan-
dard protocol gave the uncyclized amino diester 17 in
nearly quantitative yield. This result matches an earlier
report [4b] that also described the isolation of an amino
ester from a nitro ester substrate under catalytic hydro-
genation conditions. Closure to the lactam, in this case,
required additional heating in 1:1 ethanol:water. The cur-
rent system has two esters positioned to generate either a
five-membered or a seven-membered lactam upon cycliza-
tion with the amino group. Mild heating of 17 at 50˚ in
benzene for 5 days gave the expected [13,16] five-mem-
bered lactam 18 as the only product in 76% yield.
In conclusion, an efficient synthesis of 2,3,4,5-tetrahy-
dro-1H-1-benzazepine derivatives has been developed
using a tandem reduction-reductive amination strategy.
Cyclizations that produce 2-alkyl-2,3,4,5-tetrahydro-1H-
1-benzazepine-5-carboxylic esters gave products having
the C2 alkyl and the C5 ester groups predominantly cis,
though selectivity was not as good as in analogous clo-
sures to tetrahydroquinolines. Despite this reduced
diastereoselectivity, most of the cis-2,5-disubstituted prod-
Methyl (±)-2-(2-Nitrophenyl)-5-hexenoate (2).
The general procedure of Makosza and Tyrala [8] was used. A
250-mL, three-necked, round-bottomed flask equipped with an
addition funnel, a reflux condenser, and a magnetic stir bar was
charged with 100 mL of dry acetonitrile, 11.6 g (84 mmole) of
anhydrous potassium carbonate, and 12 mg of 18-crown-6.
Stirring was initiated and 1.95 g (10.0 mmole) of 1 was added
dropwise over 10 minutes. The resulting blue solution was
stirred for 10 minutes and 2.27 g (12.5 mmole) of 4-iodo-1-
butene was added dropwise. The mixture was warmed to 55-60˚
and the reaction was allowed to proceed until thin layer chro-
matography indicated complete consumption of 1 (18 hours).
After cooling to room temperature, the crude reaction mixture
was diluted with ether, vacuum filtered, and concentrated under
reduced pressure. The resulting yellow oil was purified by flash
chromatography on a 30 cm x 2.5 cm silica gel column eluted
with 5-15% ether in hexanes to give 1.49 g (60%) of 2 as a light
-1
1
yellow oil; ir: 1734, 1528, 1358 cm ; H nmr: δ 7.88 (dd, 1H, J
= 8.1, 1.4), 7.55 (m, 2H), 7.42 (ddd, 1H, J = 8.8, 7.0, 1.8), 5.77
(ddt, 1H, J = 17.7, 9.8, 6.5), 5.02 (m, 1H), 4.97 (m, 1H), 4.20 (t,

566
R. A. Bunce, L. B. Johnson and E. M. Holt
Vol. 41
1H, J = 7.2), 3.67 (s, 3H), 2.28 (m, 1H), 2.07 (m, 2H), 1.95 (m,
13
1H); C nmr: δ 173.1, 149.3, 137.0, 133.5, 133.0, 129.9, 128.1,
This compound (2.62 g, 94%) was isolated as a light yellow
-1 1
oil; ir: 1744, 1716, 1530, 1356 cm ; H nmr: δ 7.89 (dd, 1H, J =
7.9, 1.4), 7.60 (ddd, 1H, J = 7.9, 7.2, 1.4), 7.51 (dd, 1H, J = 7.9,
1.6), 7.43 (ddd, 1H, J = 8.2, 7.2, 1.6), 4.19 (t, 1H, J = 7.0), 3.66 (s,
3H), 2.46 (m, 3H), 2.39 (q, 2H, J = 7.4), 2.13 (m, 1H), 1.04 (t, 3H,
124.7, 115.6, 52.3, 45.4, 32.0, 31.6.
Anal. Calcd. for C H NO : C, 62.64; H, 6.07; N, 5.62.
13 15
Found: C, 62.41; H, 6.01; N, 5.75.
4
13
J = 7.4); C nmr: δ 210.1, 172.7, 149.4, 140.9, 133.2, 130.0,
128.3, 124.7, 52.3, 45.2, 39.7, 35.9, 26.7, 7.7.
Anal. Calcd. for C H NO : C, 60.21; H, 6.09; N, 5.02.
Methyl (±)-2-(2-Nitrophenyl)-5-oxopentanoate (4).
A solution of 1.20 g (4.82 mmole) of 2 in 125 mL of methanol
was cooled to –78º and treated with ozone until thin layer chor-
matography indicated complete consumption of the starting
material. Excess ozone was purged with a stream of dry nitrogen
and the reaction was quenched at –78˚ by addition of 5.08 g (84.9
mmole) of dimethyl sulfide and 200 mg of p-toluenesulfonic
acid. The resulting solution was warmed to room temperature
and stirred for 8 hours, then concentrated under reduced pressure.
The crude reaction mixture was diluted with ether, washed with
sodium bicarbonate and sodium chloride, and dried (magnesium
sulfate). Vacuum filtration and concentration under reduced
pressure gave the dimethyl acetal 3 containing 5-10% of alde-
hyde 4. This mixture was dissolved in 25 mL of tetrahydrofuran,
cooled to 0˚, and 25 mL of 3% aqueous perchloric acid was
added dropwise with stirring [10]. The solution was stirred at 0˚
for 1 hour and at room temperature for 4 hours, then extracted
with dichloromethane (three times). The combined organic
extracts were washed with sodium bicarbonate (two times) and
sodium chloride, dried (magnesium sulfate), vacuum filtered, and
concentrated under reduced pressure to yield 1.14 g (94%) of 4,
which was used without further purification; ir: 1737, 1527,
14 17
5
Found: C, 60.14; H, 6.15; N, 5.04.
Methyl (±)-2-(2-Nitrophenyl)-5-oxo-5-phenylpentanoate (7).
This compound (3.18 g, 90%) was isolated as a light yellow
-1
oil; ir: 1736, 1687, 1530, 1353 cm ; H nmr: δ 7.91 (m, 3H),
1
7.57 (m, 3H), 7.44 (m, 3H), 4.32 (t, 1H, J = 7.4), 3.67 (s, 3H),
13
3.07 (m, 2H), 2.64 (m, 1H), 2.30 (m, 1H); C nmr: δ 198.8,
172.7, 149.4, 136.6, 133.3, 133.2, 133.1, 130.0, 128.6, 128.3,
128.0, 124.8, 52.3, 45.4, 36.3, 27.2.
Anal. Calcd. for C H NO : C, 66.06; H, 5.20; N, 4.28.
18 17
5
Found; C, 65.92; H, 5.24; N, 4.31.
Dimethyl (±)-2-(2-Nitrophenyl)pentanedioate (8).
This compound (1.99 g, 71%) was isolated as a light yellow
-1
1
oil; ir: 1739, 1530, 1357 cm ; H nmr: δ 7.91 (dd, 1H, J = 8.1,
1.6), 7.60 (ddd, 1H, J = 7.9, 7.3, 1.6), 7.49 (dd, 1H, J = 7.9, 1.6),
7.44 (ddd, 1H, J = 8.1, 7.3, 1.6), 4.27 (t, 1H, J = 7.3), 3.67 (2 s,
13
6H), 2.54 (m, 1H), 2.37 (m, 2H), 2.19 (m, 1H); C nmr: δ 172.9,
172.5, 149.4, 133.2, 132.9, 130.0, 128.4, 124.9, 52.4, 51.7, 45.2,
31.6, 27.9.
Anal. Calcd. for C H NO : C, 55.52; H, 5.34; N, 4.98.
-1
1
1353 cm ; H nmr: δ 9.76 (s, 1H), 7.91 (dd, 1H, J = 8.1, 1.4),
7.61 (ddd, 1H, J = 8.0, 7.5, 1.4), 7.49 (dd, 1H, J = 8.0, 1.4), 7.45
(ddd, 1H, J = 8.0, 7.5, 1.4), 4.21 (t, 1H, J = 7.2), 3.67 (s, 3H), 2.53
13 15
6
Found: C, 55.37; H, 5.40; N, 5.05.
13
Methyl (±)-2,3,4,5-Tetrahydro-1H-1-benzazepine-5-carboxylate
(9).
(m, 3H), 2.18 (m, 1H); C nmr: δ 200.8, 172.5, 149.3, 133.3,
132.9, 129.9, 128.5, 124.9, 52.4, 45.3, 41.6, 25.1.
To a solution of 570 mg (2.27 mmole) of 4 in 200 mL of
methanol was added 125 mg of 5% palladium-on-carbon and the
mixture was hydrogenated in a stainless steel hydrogenation ves-
sel under 4 atmospheres of hydrogen for 3 hours at 30˚. The
crude reaction mixture was concentrated, diluted with ether, and
Representative Procedure for Conjugate Addition Reactions:
Methyl (±)-2-(2-Nitrophenyl)-5-oxohexanoate (5).
The general procedure of Makosza and Tyrala [8] was adapted.
A 250-mL, three-necked, round-bottomed flask equipped with an
addition funnel, a reflux condenser, and a magnetic stir bar was
charged with 100 mL of dry acetonitrile, 11.6 g (84 mmole) of
anhydrous potassium carbonate, and 12 mg of 18-crown-6.
Stirring was initiated and 1.95 g (10.0 mmole) of 1 was added
dropwise over 10 minutes. The resulting blue solution was
stirred for 10 minutes and 0.92 g (13.2 mmole) of methyl vinyl
ketone was added dropwise. The mixture was warmed to 55-60˚,
and the reaction was allowed to proceed until thin layer chro-
matography indicated complete consumption of 1 (48 hours).
After cooling to room temperature, the mixture was diluted with
ether, vacuum filtered, and concentrated under reduced pressure.
The resulting yellow oil was purified by flash chromatography on
a 30 cm x 2.5 cm silica gel column eluted with 5-15% ether in
hexanes to give 2.40 g (91%) of 5 as a light yellow oil; ir: 1744,
®
vacuum filtered through a pad of Celite 545 topped with a layer
of magnesium sulfate to remove the catalyst. Concentration of
the filtrate produced a light yellow oil that was purified by
preparative thin layer chromatography eluted with increasing
concentrations of ether in hexanes (25-50%) to give 280 mg
-1
1
(60%) of 9 as a light yellow oil; ir: 3366, 1730 cm ; H nmr: δ
7.10 (td, 1H, J = 7.7, 1.6), 7.03 (ddd, 1H, J = 7.5, 1.9, 1.0), 6.87
(td, 1H, J = 7.5, 1.2), 6.75 (d, 1H, J = 7.7, 1.2), 3.86 (dd, 1H, J =
7.4, 2.2), 3.72 (br s, 1H), 3.70 (s, 3H), 3.11 (ddd, 1H, J = 12.8,
7.9, 3.2), 2.96 (ddd, 1H, J = 12.8, 8.0, 3.3), 2.20 (m, 1H), 1.93-
13
1.76 (complex, 3H);
C nmr: δ 174.4, 149.9, 130.4, 130.1,
127.7, 121.0, 120.2, 51.8, 50.2, 48.0, 28.5, 28.2; hrms: m/z
Calcd. for C H NO : 205.1103; Found: 205.1101.
Anal. Calcd. for C H NO : C, 70.24; H, 7.32; N, 6.83.
12 15
2
12 15
2
-1
1
1716, 1530, 1358 cm ; H nmr: δ 7.89 (dd, 1H, J = 8.1, 1.5),
7.60 (ddd, 1H, J = 8.2, 7.4, 1.6), 7.51 (dd, 1H, J = 8.0, 1.5), 7.44
(ddd, 1H, J = 8.1, 7.3, 1.5), 4.16 (t, 1H, J = 7.3), 3.66 (s, 3H),
Found: C, 70.39; H, 7.39; N, 6.75.
Reductive Cyclization of 5.
13
2.60-2.42 (complex, 3H), 2.12 (s, 3H), 2.11 (m, 1H); C nmr: δ
To a solution of 1.00 g (3.77 mmole) of 5 in 200 mL of
methanol was added 200 mg of 5% palladium-on-carbon and the
mixture was hydrogenated as described for the preparation of 9.
The crude product was purified by preparative thin layer chro-
matography eluted with 25-50% ether in hexanes to give two
major bands. Band 1 (fastest moving) gave 11; band 2 gave 10.
207.3, 172.6, 149.5, 140.4, 133.2, 129.9, 128.3, 124.7, 52.3, 45.1,
41.1, 29.9, 26.6.
Anal. Calcd. for C H NO : C, 58.87; H, 5.66; N, 5.28.
13 15
5
Found: C, 58.80; H, 5.72; N, 5.33.
Methyl (±)-2-(2-Nitrophenyl)-5-oxoheptanoate (6).

Jul-Aug 2004
Substituted 2,3,4,5-Tetrahydro-1H-1-benzazepine-5-carboxylic Esters
567
Methyl (±)-(2S * , 5S *)-2-Methyl-2,3,4,5-tetrahydro-1 H- 1 - b e n-
zazepine-5-carboxylate (11).
13
J = 7.4);
C nmr: δ 173.8, 148.6, 130.9, 130.5, 127.9, 121.2,
120.8, 59.7, 51.8, 50.2, 32.7, 30.1, 28.0, 10.8; hrms: m/z Calcd.
for C H NO : 233.1416; Found: 233.1414.
Anal. Calcd. for C H NO : C, 72.10; H, 8.15; N, 6.01.
14 19
2
This compound (70 mg, 9%) was isolated as a light yellow oil
that crystallized on standing at 0˚. The crystals were triturated at
0˚ with 1% ether in petroleum ether to give a white solid, mp 45-
14 19
2
Found: C, 72.27; H, 8.23; N, 5.91.
-1
1
47˚; ir: 3353, 1735 cm ; H nmr: δ 7.07 (td, 1H, J = 7.5, 1.4),
6.94 (dd, 1H, J = 7.6, 1.4), 6.85 (td, 1H, J = 7.5, 1.2), 6.73 (dd,
1H, J = 7.6, 1.2), 3.84 (dd, 1H, J = 8.5, 2.0), 3.75 (s, 3H), 3.33 (br
Reductive Cyclization of 7.
To a solution of 510 mg (1.56 mmole) of 7 in 200 mL of
methanol was added 125 mg of 5% palladium-on-carbon and the
mixture was hydrogenated as described for the preparation of 9.
The crude product was purified by preparative thin layer chro-
matography eluted with 25-50% ether in hexanes to give three
major bands. Band 1 (fastest moving) gave 15; band 2 gave 14;
band 3 gave 16.
s, 1H), 3.05 (m, 1H), 2.15 (m, 1H), 1.88 (m, 2H), 1.51 (m, 1H),
13
1.20 (d, 3H, J = 6.4);
C nmr: δ 175.3, 148.3, 129.7, 128.8,
127.4, 121.0, 120.3, 52.5, 51.8, 48.9, 36.2, 27.5, 23.3; hrms: m/z
Calcd. for C H NO : 219.1259; Found: 219.1257.
Anal. Calcd. for C H NO : C, 71.23; H, 7.76; N, 6.39.
13 17
2
13 17
2
Found: C, 71.42; H, 7.82; N, 6.31.
Methyl (±)-(2R*,5S*)-2-Phenyl-2,3,4,5-tetrahydro-1 H- 1 - b e n-
zazepine-5-carboxylate (15).
Methyl (±)-(2R*,5S *)-2-Methyl-2,3,4,5-tetrahydro-1H-1-ben-
zazepine-5-carboxylate (10).
This compound (14 mg, 3%) was isolated as a white solid, mp
This compound (740 mg, 90%) was isolated as a white solid,
1
-1
1
-1
mp 102-104˚ (ether-petroleum ether); ir: 3359, 1737 cm ;
68-70˚ (ether-petroleum ether); ir: 3349, 1733 cm ; H nmr: δ
7.38-7.25 (complex, 5H), 7.12 (m, 2H), 6.92 (td, 1H, J = 7.3, 1.2),
6.74 (d, 1H, J = 7.6), 3.94 (dd, 1H, J = 5.8, 3.3), 3.85 (dd, 1H, J =
11.2, 1.7), 3.70 (s, 3H), 3.59 (br s, 1H), 2.52 (m, 1H), 2.16 (m,
H
nmr: δ 7.10 (td, 1H, J = 7.5, 1.6), 7.03 (dd, 1H, J = 7.4, 1.6), 6.87
(td, 1H, J = 7.4, 1.3), 6.74 (dd, 1H, J = 7.5, 1.3), 3.84 (dd, 1H, J =
6.0, 2.3), 3.65 (s, 3H), 3.27 (br s, 1H), 2.91 (m, 1H), 2.42 (m,
13
13
1H), 1.97-1.72 (complex, 2H); C nmr: δ 173.5, 148.4, 145.7,
131.3, 130.4, 128.7, 128.1, 127.5, 126.4, 121.6, 121.0, 63.4, 51.9,
1H), 1.69 (m, 3H), 1.21 (d, 3H, J = 6.5); C nmr: δ 173.7, 148.6,
131.2, 130.3, 127.9, 121.2, 120.8, 53.6, 51.8, 50.3, 34.9, 28.1,
50.1, 35.2, 28.1; hrms: m/z Calcd. for C H NO : 281.1416;
18 19
24.0; hrms: m/z Calcd. for C
219.1258.
H
13 17
NO : 219.1259; Found:
2
2
Found: 281.1415.
Anal. Calcd. for C H NO : C, 76.87; H, 6.76; N, 4.98.
Found: C, 77.04; H, 6.83; N, 4.89.
Anal. Calcd. for C H NO : C, 71.23; H, 7.76; N, 6.39.
18 19
2
13 17
Found: C, 71.45; H, 7.84; N, 6.29.
2
Methyl (±)-(2S* , 5S* )-2-Phenyl-2,3,4,5-tetrahydro-1H-1-ben-
zazepine-5-carboxylate (14).
Reductive Cyclization of 6.
To a solution of 1.00 g (3.58 mmole) of 6 in 200 mL of
methanol was added 200 mg of 5% palladium-on-carbon and the
mixture was hydrogenated as described for the preparation of 9.
The crude product was purified by preparative thin layer chro-
matography eluted with 25-50% ether in hexanes to give two
major bands. Band 1 (fastest moving) gave 13; band 2 gave 12.
This compound (73 mg, 17%) was isolated as a white solid, mp
-1
1
82-84˚ (ether-petroleum ether); ir: 3343, 1732 cm ; H nmr: δ
7.42-7.27 (complex, 5H), 7.10 (td, 1H, J = 7.2, 1.7), 6.99 (dd, 1H,
J = 7.6, 1.7), 6.92 (td, 1H, J = 7.2, 1.3), 6.76 (dd, 1H, J = 7.6, 1.3),
3.96 (m, 2H), 3.79 (s, 3H), 3.63 (br s, 1H), 2.22 (m, 1H), 1.95
13
(overlapping m, 3H);
C nmr: δ 175.5, 148.1, 145.5, 134.2,
Methyl (±)-(2S*, 5S*)-2-Ethyl-2, 3, 4, 5-tetrahydro-1 H-1-ben -
zazepine-5-carboxylate (13).
130.6, 128.8, 128.1, 127.6, 126.4, 121.7, 120.8, 62.4, 51.9, 48.6,
36.9, 27.8; hrms: m/z Calcd. for C H NO : 281.1416; Found:
18 19
2
281.1414.
Anal. Calcd. for C H NO : C, 76.87; H, 6.76; N, 4.98.
Found: C, 76.99; H, 6.84; N, 4.88.
This compound (67 mg, 8%) was isolated as a light yellow oil
that crystallized on standing at 0˚. The crystals were triturated at
0˚ with 1% ether in petroleum ether to give a white solid, mp 46-
18 19
2
-1
1
48˚; ir: 3365, 1735 cm ; H nmr: δ 7.05 (td, 1H, J = 7.4, 1.5),
6.95 (dd, 1H, J = 7.6, 1.5), 6.85 (td, 1H, J = 7.4, 1.2), 6.73 (dd,
1H, J = 7.6, 1.2), 3.85 (dd, 1H, J = 8.3, 2.3), 3.74 (s, 3H), 3.42 (br
s, 1H), 2.81 (m, 1H), 2.16 (m, 1H), 1.92 (m, 2H), 1.58-1.42 (com-
(±)-3-(3-Phenylpropyl)-2-indolinone (16).
This compound (125 mg, 32%) was isolated as a white pow-
der, mp 82-83˚ (ether-petroleum ether); lit mp 84-85˚ [18]; ir:
-1
1
3217, 1708 cm ; H nmr: δ 8.70 (br s, 1H), 7.28-7.10 (complex,
13
plex, 3H), 0.98 (t, 3H, J = 7.4); C nmr: δ 175.2, 148.2, 129.5,
129.1, 127.4, 120.8, 120.3, 58.3, 51.8, 49.0, 33.5, 29.5, 26.9,
7H), 7.01 (t, 1H, J = 7.5), 6.88 (d, 1H, J = 7.5), 3.48 (t, 1H, J =
5.9), 2.61 (overlapping m, 2H), 2.00 (m, 2H), 1.78-1.60 (com-
10.7; hrms: m/z Calcd. for C H NO : 233.1416; Found:
14 19 2
233.1413.
13
plex, 2H);
127.8, 125.8, 124.1, 122.3, 109.7, 45.9, 35.8, 30.1, 27.5; hrms:
C nmr: δ 180.4, 141.8, 141.5, 129.6, 128.3 (2),
Anal. Calcd. for C H NO : C, 72.07; H, 8.21; N, 6.00.
14 19
Found: C, 72.16; H, 8.25; N, 5.89.
2
m/z Calcd. for C H NO: 251.1310; Found: 251.1307.
17 17
Anal. Calcd. for C H NO: C, 81.27; H, 6.77; N, 5.58.
17 17
Found: C, 80.96; H, 6.87; N, 5.54.
Methyl (±)-(2R*,5S*)-2-Ethyl-2, 3, 4, 5-tetrahydro-1H-1-ben-
zazepine-5-carboxylate (12).
Dimethyl (±)-2-(2-Aminophenyl)pentanedioate (17).
This compound (566 mg, 68%) was isolated as a white solid,
-1
1
To a solution of 750 mg (2.66 mmole) of 8 in 200 mL of
methanol was added 180 mg of 5% palladium-on-carbon and the
mixture was hydrogenated as described for the preparation of 9.
The crude product was purified by preparative thin layer chro-
matography eluted with 25-50% ether in hexanes to give 650 mg
mp 74-76˚ (ether-petroleum ether); ir: 3360, 1728 cm ; H nmr:
δ 7.11 (td, 1H, J = 7.4, 1.6), 7.03 (dd, 1H, J = 7.7, 1.6), 6.88 (td,
1H, J = 7.4, 1.2), 6.76 (dd, 1H, J = 7.7, 1.2), 3.85 (dd, 1H, J = 6.3,
2.2), 3.66 (s, 3H), 3.39 (br s, 1H), 2.65 (m, 1H), 2.42 (m, 1H),
1.79-1.63 (complex, 3H), 1.52 (quintet, 2H, J = 7.4), 0.99 (t, 3H,

568
R. A. Bunce, L. B. Johnson and E. M. Holt
Vol. 41
[a] J. G. Topliss, E. P. Shapiro and R. I. Taber, J. Med. Chem., 10, 642
(1967); [b] T. Fukuyama, L. Xu and S. Goto, J. Am. Chem. Soc., 114, 383
(1992).
[6a] M. Qadir, R. E. Priestley, T. W. D. F. Rising, T. Gelbrich, S. J.
Coles, M. B. Hursthouse, P. W. Sheldrake, N. Whittall and K. K. Hii,
Tetrahedron Lett., 44, 3675 (2003); [b] K. Kondo, K. Kan, Y. Tanada, M.
Bando, T. Shinohara, M, Kurimura, H. Ogawa, S. Nakamura, T. Hirano,
Y. Yamamura, M. Kido, T. Mori and M. Tominaga, J. Med. Chem., 45,
3805 (2002).
(97%) of 17 as a yellow oil that darkened on exposure to air; ir:
-1
3453, 3378, 3263, 1732 cm ; H nmr: δ 7.07 (overlapping t and
1
d, 2H, J = 7.5), 6.74 (td, 1H, J = 7.5, 1.1), 6.69 (d, 1H, J = 7.5),
4.11 (br s, 2H), 3.78 (t, 1H, J = 7.4), 3.68 (s, 3H), 3.67 (s, 3H),
13
2.35 (m, 3H), 2.19 (m, 1H);
C nmr: δ 174.0, 173.9, 144.9,
128.2, 127.9, 122.7, 118.9, 116.7, 52.2, 51.7, 45.4, 31.4, 25.8;
hrms: m/z Calcd. for C H NO : 251.1157; Found: 251.1155.
Anal. Calcd. for C H NO : C, 62.15; H, 6.77; N, 5.58.
13 17
4
13 17
4
Found; C, 62.47; H, 6.85; N, 5.44.
[7] T. Ohno, M. Miura and H. Aizawa, Japanese Patent JP 98-
370262; Chem. Abstr., 133, 99576 (2000).
[8] M. Makosza and A. Tyrala, Synth. Commun., 16, 419 (1986).
[9] This compound was prepared using the general halide
exchange procedure reported in R. A. Bunce and J. C. Allison, Synth.
Commun., 29, 2175 (1999).
[10] T. Hudlicky, B. C. Ranu, S. M. Narqvi and A. Srnak, J. Org.
Chem., 50, 123 (1985).
[11] H. J. Reich, J. M. Renga and I. L. Reich, J. Am. Chem. Soc.,
97, 5434 (1975).
Methyl (±)-3-(2-Oxoindolin-3-yl)propanoate (18).
A solution of 650 mg (2.59 mmole) of 17 in 25 mL of benzene
was heated at 50˚ until thin layer chromatography indicated com-
plete conversion of the starting material (5 days). The solution
was concentrated under reduced pressure and purified by prepar-
ative thin layer chromatography eluted with 50% ether in hexa-
nes. The major band afforded 430 mg (76%) of 18 as a light yel-
low oil that crystallized upon standing. Recrystallization from
ether-petroleum ether gave 18 as a white solid, mp 76-77˚; lit mp
[12] The cis stereochemistry of the major products was determined
1
by analysis of H nmr coupling constants and was confirmed by a single
-1
1
79-80˚ [19]; ir: 3259, 1733, 1711 cm ; H nmr: δ 9.51 (br s,
1H), 7.22 (overlapping t and d, 2H, J = 7.6), 7.03 (td, 1H, J = 7.5,
crystal X-ray structure of compound 10. Intensity data were measured on
a Brucker P4 diffractometer with MoKα radiation (λ = 0.71073 Å) at
room temperature [XSCANS Users Manual; Siemens Analytical X-ray
Instruments, Inc. Madison, WI, USA (1991)]. All non-hydrogen posi-
tions were determined using the SHELXS structure solution program [G.
M. Sheldrick, Acta Cryst., A46, 467 (1990)] and refined by full matrix
1.1), 6.93 (d, 1H, J = 7.5), 3.63 (s, 3H), 3.55 (t, 1H, J = 6.2), 2.58-
13
2.21 (complex, 4H);
C nmr: δ 180.2, 173.3, 141.7, 128.5,
128.1, 124.0, 122.3, 109.9, 51.6, 44.9, 29.9, 25.3; hrms: m/z
Calcd. for C H NO : 219.0895; Found: 219.0892.
Anal. Calcd. for C H NO : C, 65.75; H, 5.94; N, 6.39.
12 13
3
2
least squares methods on the basis of F using the SHELXL97 refinement
12 13
3
program [G. M. Sheldrick, SHELXL97 Program for the Refinement of
Crystal Structures; University of Gottingen, Germany (1997)]. Hydrogen
atoms were placed in calculated positions using idealized geometry and
Found: C, 65.89; H, 6.01; N, 6.28.
Acknowledgement.
constrained to those positions during final refinements. C
H NO , for-
13 17 2
mula weight: 219.28, a = 9.312(13), b = 14.805(11), c = 9.373(6) Å, β =
We wish to thank the NIH (GM54256) and the Oklahoma
Center for the Advancement of Science and Technology (HR01-
015) for support of this research. Funds for the 300 and 400 MHz
NMR spectrometers of the Oklahoma Statewide Shared NMR
Facility were provided by NSF (BIR-9512269), the Oklahoma
State Regents for Higher Education, the W. M. Keck Foundation,
and Conoco, Inc. Partial support for our mass spectrometer by
the NIH and the Oklahoma Center for the Advancement of
Science and Technology is also appreciated.
3
102.48(4)˚, V = 1262(2) Å , Z = 4, monoclinic space group P2 /c, den-
1
3
sity(calculated) = 1.154 Mg/m , 2241 observed reflections (F˚ > 2.0(σF)),
R = 0.0628.
[13a] F. C. Lightstone and T. C. Bruice, Bioorg. Chem., 2 6, 193
(1998); [b] See also G. Illuminati and L. Mandolini, Acct. Chem. Res.,
14, 95 (1981); [c] F. A. Carey and R. J. Sundberg, Advanced Organic
Chemistry, Part A, 4th Ed.; Kluwer Academic/Plenum Press: New York,
NY, 2000; pp 166-171; [d] E. L. Eliel, S. H. Wilen, L. N. Mander,
Stereochemistry of Organic Compounds; J. Wiley and Sons: New York,
NY, 1994; pp 678-682.
[14a] P. N. Ry l a n d e r , Catalytic Hydrogenation in Org a n i c
Syntheses; Academic Press: New York, NY, 1979; pp 100-102; [b] M.
Hudlicky, Reductions in Organic Chemistry, 2nd ed.; American
Chemical Society: Washington, DC, 1996; pp 155-156; [c] Reduction of
phenyl ketones has been observed under 1 atmosphere of hydrogen in
ethanol at 20˚ using 5% palladium-on-carbon, see S. R. Angle and J. D.
Rainier, J. Org. Chem., 57, 6883 (1992).
[15a] See reference 5a; [b] It should be pointed out that the mass
balances for the reactions described in this reference were relatively low
(44-66%) and other unreported products could have been present.
[16] R. Besse, P. J. Garratt, C. J. Hobbs, H. M. Rogers, A. M.
Sueleiman, C. S. J. Walpole and R. Wigglesworth, Tetrahedron, 46, 7803
(1990).
[17] W. C. Stille, M. Kahn and A. Mitra, J. Org. Chem., 43, 2923
(1978).
[18] G. Tacconi and F. Marione, Recirca Scientifica, 38, 1239
(1968); Chem. Abstr., 71, 101641 (1971).
[19a] P. J. Julian and H. C. Printy, J. Am. Chem. Soc., 7 5, 5301 (1953);
[b] A second report gave the mp of 18 as 75-78˚, see R. B. Labroo, V. M.
Labroo, M. M. King and L. A. Cohen, J. Org. Chem., 5 6, 3637 (1991).
REFERENCES AND NOTES
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