A general route to the synthesis of 1,5-methano- and 1,5-ethano-2, 3,4,5-tetrahydro-1h-3-benzazepines

Article abstract of DOI:10.1021/jo049122q

A general approach to preparing 1,5-methano-(1) and l,5-ethano-2,3,4,5- tetrahydro-lff-3-benzazepine (2) is discussed. This strategy involves converting an indanone or tetralone (4) to a cyanohydrin (3) which is subjected to hydrogenolysis followed by lac

Full text of DOI:10.1021/jo049122q

SCHEME 1. Ma zzocch i’s Str a tegy to Ben za zep in e 11
A Gen er a l Rou te to th e Syn th esis of
1,5-Meth a n o- a n d 1,5-Eth a n o-
2,3,4,5-tetr a h yd r o-1H-3-ben za zep in es
Christopher J . O’Donnell,*,† Robert A. Singer,‡
J ason D. Brubaker,† and J ason D. McKinley‡
Pfizer Global Research and Development, Pfizer, Inc.,
Eastern Point Road,
Groton, Connecticut 06340
christopher_j_odonnell@groton.pfizer.com
Received May 25, 2004
SCHEME 2. Wa lter ’s Str a tegy to Ben za zep in e 22
Abstr a ct: A general approach to preparing 1,5-methano-
(1) and 1,5-ethano-2,3,4,5-tetrahydro-1H-3-benzazepine (2)
is discussed. This strategy involves converting an indanone
or tetralone (4) to a cyanohydrin (3) which is subjected to
hydrogenolysis followed by lactamization and reduction to
provide bicyclic aryl piperidine (1) and bicyclic aryl homopi-
peridine (2).
We recently desired an efficient and general route for
the preparation of 1,5-methano- (1) and 1,5-ethano-
2,3,4,5-tetrahydro-1H-3-benzazepine (2). Both 1 and 2
have been prepared and studied as potential morphine-
type analgesics; however, both were accessed by different
synthetic routes and neither route was generally ap-
plicable to the respective homologue.1,2
Hydrogenation of the olefin was followed by reduction
using LiAlH4 to give 2. This synthesis produced 2 in
seven steps and 21% overall yield. Due to the mechanistic
requirement of the C3-C4 olefin of 9 for the rearrange-
ment of 9 f 10, this approach is not applicable to the
corresponding cyclopropane acyl azide derived from in-
dene that would be required for the synthesis of 1 via
this route. Additionally, it has been reported that treat-
ment of structurally related cyclopropane acyl azides
derived from indenes under similar conditions proceeds
to give the expected Curtius rearrangement products.9
We sought an alternative approach to both 1 and 2 that
would avoid the problematic benzyne chemistry.10 Ad-
ditionally, we hoped to avoid the low-yielding, sequential
oxidation process used in the Mazzochi synthesis as well
as the reported improvements in this process that involve
the use of heavy metals.11 We also sought a route that
would be generally applicable to this class of compounds.
We recognized that commercially available indanone-
3-carboxylic acid (11) should be a viable precursor to 1
through homologation with cyanide or nitromethane
(Scheme 3). This strategy was initiated by converting
indanone 11 to methyl ester 4a in excellent yield.12 Ester
4a was treated with TMSCN (1.2 equiv) and ZnI2 (0.01
equiv) in toluene at 50 °C for 5 h to afford silylated
The previous preparation of 1 is shown in Scheme 1.1
The Diels-Alder reaction between cyclopentadiene and
benzyne provided benzonorbornadiene 5.3 Solvolysis of
the alkene with acetic acid followed by saponification
provided exo-benzonorbornenol (6)4 from which sequential
oxidation to the corresponding ketone,5 diketone,6 and
finally dicarboxylic acid (7) proceeded in low yield. The
conversion of 7 to the cyclic imide in two steps followed
by reduction provided 1. This synthesis produced 1 in
nine steps and 1.2% overall yield. This benzyne Diels-
Alder based approach is not well suited to the preparation
of the ethylene-bridged homologue 2 as the 1,4-cyclo-
hexadiene/benzyne cycloaddition gives an inseparable,
complex mixture and proceeds in low yield.7
The reported synthesis of 2 is shown in Scheme 2.2
Methyl-1-benzonorcaradienecarboxylate (8) was gener-
ated by heating methyl diazoacetate with an excess of
naphthalene. Saponification to the acid followed by
generation of the corresponding acid chloride and treat-
ment with sodium azide provided acyl azide 9. Heating
9 in benzyl alcohol affected rearrangement to product 10.8
(9) DeMarinis, R. M.; Bryan, W. M.; Shah, D. H.; Hieble, J . P.;
Pendleton, R. G. J . Med. Chem. 1981, 24, 1432.
(10) For recent advances in benzyne-mediated protocols for the
formation of benzonorbornadienes, see: Coe, J . W.; Wirtz, M. C.;
Bashore, C. G.; Candler, J . Org. Lett. 2004, 6, 1589.
† Neurosciences Medicinal Chemistry.
‡ Chemical Research and Development.
(1) For the preparation of 1, see: Mazzocchi, P. H.; Stahly, B. C. J .
Med. Chem. 1979, 22, 455.
(2) For the preparation of 2, see: Walter, L. A.; Chang, W. K. J .
Med. Chem. 1975, 18, 206.
(11) An improvement in this oxidation strategy has been used that
involved osmium-catalyzed dihdroxylation of 5, NaIO4 cleavage of the
resulting diol to a dialdehyde intermediate, and reductive amination
with benzylamine to close the benzazepine ring; see: Brooks, P. R.;
Caron, S.; Coe, J . W.; Ng, K. K.; Singer, R. A.; Vazquez, E.; Vetelino,
M. G.; Watson, H. H.; Whritenour, D. C.; Wirtz, M. C. Synthesis 2004,
(11), 1755. For related examples, see: (a) Coe, J . W. Org. Lett. 2000,
2, 4205. (b) Bashore, C. G.; Samardjiev, I. J .; Bordner, J .; Coe, J . W. J .
Am. Chem. Soc. 2003, 125, 3268.
(3) Wittig, G.; Knauss, E. Chem. Ber. 1958, 91, 895.
(4) Cristol, S. J .; Caple, R. J . Org. Chem. 1966, 31, 2741.
(5) Bartlett, P. D.; Giddings, W. P. J . Am. Chem. Soc. 1960, 82, 1240.
(6) Tanida, H.; Hata, Y. J . Am. Chem. Soc. 1966, 88, 4289.
(7) Crews, P.; Beard, J . J . Org. Chem. 1973, 38, 522 and references
therein.
(8) Doering, W. von E.; Goldstein, M. J . Tetrahedron 1959, 5, 53.
10.1021/jo049122q CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/29/2004
5756
J . Org. Chem. 2004, 69, 5756-5759

SCHEME 3. Rou te to 1 via In d a n on e-3-ca r boxylic
Acid (11)
SCHEME 4. Rou te to 2 via Tetr a lon e-4-ca r boxyla te
Meth yl Ester
methyl ester 4b (Scheme 4).19 2-Phenylglutaric anhydride
(14) was heated in sulfuric acid producing tetralone-4-
carboxylate,20 and this mixture was conveniently con-
verted to ester 4b in 80% yield by pouring the resulting
acidic mixture into cold methanol and warming to room
temperature. Ester 4b was treated with TMSCN and
ZnI2 to give silylated cyanohydrin 3b as a 1.2:1 mixture
of diastereomers.21 Hydrogenolysis of the crude cyano-
hydrin 3b using Pearlman’s catalyst and 3 M HCl (aq)
provided the corresponding primary amine which, after
filtration to remove the catalyst, was treated with sodium
tert-butoxide to give 15.22 Lactam 15 was reduced with
lithium aluminum hydride and 2 was isolated in 75%
yield from 4b. This route produced 2 in five steps and
60% overall yield.
In summary, we have provided a new, common strat-
egy for the preparation of 1 and 2. This strategy involves
homologating readily available indanone and tetralone
starting materials to their corresponding cyanohydrins.
Hydrogenolysis of the cyanohydrin intermediates with
concomitant reduction of the nitrile followed by lactam-
ization and reduction of the resulting lactams provides
the desired bicyclic aryl piperidine 1 and bicyclic aryl
homopiperidine 2. This sequence represents an efficient,
high-yielding, general route to both of these benzazepine
structures.
cyanohydrin 3a as a 2:1 mixture of diastereomers after
aqueous workup.13 The crude cyanohydrin was subjected
to hydrogenolysis using Pearlman’s catalyst and p-
toluenesulfonic acid (1.5 equiv) to provide 12 as a 10:1
mixture of diastereomers.14,15 There were two critical
factors for the success of the hydrogenolysis. First, the
excess cyanide needed to be removed prior to the hydro-
genolysis step, and this was accomplished with the
aqueous workup. Second, it was crucial to use excess acid
(>1 equiv) to facilitate the hydrogenolysis of 3a . Under
these acidic conditions, the nitrile was reduced relatively
rapidly and 1 equiv of acid was needed to prevent
deactivation of the catalyst with the resulting free amine.
Additionally, the reduction of the benzylic alcohol was
sluggish and did not proceed to completion unless excess
acid was employed. The observed increase in diastereo-
selectivity during the hydrogenolysis is consistent with
initial elimination of the benzyl alcohol to an indene
intermediate that is reduced from the least hindered face
providing the cis isomer as the major product.16 Removal
of the catalyst by filtration followed by treatment of the
filtrate containing 12 with sodium tert-butoxide at room
temperature led to formation of 13, which was isolated
by recrystallization in 65% yield from 4a . A minor side
product that formed during the lactam cyclization was
the amino acid hydrolysis product of 12, which failed to
cyclize to 13 under all conditions examined. Lactam 13
was reduced with borane (generated in situ), and the
tosylate salt of 1 was isolated in 81% yield.17 In summary,
this route produced 1 in five synthetic steps and 51%
overall yield.18
Exp er im en ta l Section
3-Oxoin d a n -1-ca r boxylic Acid Meth yl Ester (4a ). A solu-
tion of 10.0 g of 3-oxoindan-1-carboxylic acid (56.8 mmol, 1.0
equiv) and 0.25 mL of concentrated sulfuric acid in 20 mL of
methanol was heated to reflux for 4 h. The reaction mixture was
then cooled to room temperature and diluted with 100 mL of
methyl tert-butyl alcohol. The organic solution was washed twice
with 60 mL of a saturated aqueous sodium bicarbonate solution
and once with 50 mL of a saturated aqueous sodium chloride
solution. The organic layer was dried over anhydrous sodium
sulfate and concentrated. The product, 3-oxoindan-1-carboxylic
acid methyl ester, crystallized as a white solid upon concentra-
tion (10.4 g, 96%): mp 46-47 °C; 1H NMR (400 MHz, CDCl3) δ
7.74 (d, J ) 7.6 Hz, 1H), 7.68 (d, J ) 7.6 Hz, 1H), 7.62 (t, J )
7.6 Hz, 1H), 7.44 (t, J ) 7.6 Hz, 1H), 4.29 (dd, J ) 8.0, 3.4 Hz,
1H), 3.76 (s, 3H), 3.13 (dd, J ) 19.1, 3.4 Hz, 1 H), 2.86 (dd, J )
Utilizing the same strategy, the ethylene bridge ho-
mologue (2) was prepared from tetralone-4-carboxylate
(12) House, H. O.; Sauter, F. J .; Kenyon, W. G.; Riehl, J .-J . J . Org.
Chem. 1968, 33, 957.
(13) (a) Gassman, P. G.; Talley, J . J . Tetrahedron Lett. 1978, 19,
3773. (b) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. Chem. Commun.
1973, 55. (c) Lidy, W.; Sundermeyer, W. Chem. Ber. 1973, 106, 587.
(14) Ratio determined by HPLC and GC-MS. The major component
was determined to be the cis-isomer as it is rapidly consumed in the
subsequent cyclization, whereas the minor isomer is consumed more
slowly.
(15) The diastereoselectivity approaches 1:1 upon increased reaction
time, suggesting acid-catalyzed isomerization of the ester.
(16) Support for this presumed intermediate has been reported in
similar systems; see: Trivedi, B. K.; Blankley, C. J .; Bristol, J . A.;
Hamilton, H. W.; Patt, W. C.; Kramer, W. J .; J ohnson, S. A.; Bruns,
R. F.; Cohen, D. M.; Ryan, M. J . J . Med. Chem. 1991, 34, 1043.
(17) (a) Brown, H. C.; Heim, P.; Yoon, N. M. J . Am. Chem. Soc. 1970,
92, 1637. (b) Brown, H. C.; Korytnyk, N. J . Am. Chem. Soc. 1960, 82,
3866.
(19) For an alternative synthesis of tetralone 4b, see: Oh, S.-H.;
Sato, T. J . Org. Chem. 1994, 59, 3744.
(20) Horning, E. C.; Finelli, A. F. J . Am. Chem. Soc. 1949, 71, 3204.
(21) The solvent change to methylene chloride was made to expedite
removal upon workup. The reaction works in identical yield and
diastereoselectivity when run in toluene.
(22) Both p-toluenesulfonic acid and 3 M HCl could be used in this
reaction without noticeable differences in the overall yield. Use of
aqueous HCl for the conversion of 3a f 12 in Scheme 3 was efficient
for the hydrogenolysis but led to increased hydrolysis of the ester.
(18) For an alternative synthesis of benzazepine 1, see: Singer, R.
A.; McKinley, J . D.; Barbe, G.; Farlow, R. A. Org. Lett. 2004, 6, 2357.
J . Org. Chem, Vol. 69, No. 17, 2004 5757

19.1, 8.0 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ 204.4, 172.5,
151.3, 136.5, 135.2, 129.1, 126.7, 124.1, 52.9, 43.8, 39.7; IR (neat,
cm-1) 2954, 1710, 1602, 1462, 1435, 1403, 1319, 1241, 1206,
1168, 1092, 1044, 1014, 986, 881, 837, 760, 686, 580, 538.
3-Cya n o-3-tr im eth ylsila n yloxyin d a n -1-ca r boxylic Acid
Meth yl Ester (3a ). To a solution of 3.80 g of 3-oxoindan-1-
carboxylic acid methyl ester (20.0 mmol, 1 equiv) in 6 mL of
toluene and 2 mL of acetonitrile was added 192 mg of zinc iodide
(0.600 mmol, 0.03 equiv) followed by 3.47 mL of trimethylsilyl
cyanide (26.0 mmol, 1.3 equiv). The reaction mixture was heated
to 50 °C for 5 h. The reaction mixture was then cooled to room
temperature and diluted with 12 mL of toluene and 8 mL of a
saturated aqueous sodium bicarbonate solution. After the mix-
ture was stirred for 1 h, the layers were separated. The organic
layer was washed with another 8 mL of a saturated aqueous
sodium bicarbonate solution followed by 8 mL of a saturated
aqueous sodium chloride solution. The organic layer was dried
over anhydrous sodium sulfate and concentrated in vacuo to give
3-cyano-3-trimethylsilanyloxyindan-1-carboxylic acid methyl es-
ter as an oil (5.61 g, 97%). The silylated cyanohydrin product
was obtained as a mixture of two diastereomers in a 2:1 ratio:
1H NMR (400 MHz, CDCl3) (major isomer) δ 7.54-7.50 (m, 1H),
7.42-7.38 (m, 3H), 4.14 (t, J ) 7.7 Hz, 1H), 3.78 (s, 3H), 3.01
(dd, J ) 13.3, 7.5 Hz, 1H), 2.79 (dd, J ) 13.3, 7.5 Hz, 1H), 0.26
(s, 9H); (minor isomer) δ 7.59-7.55 (m, 1H), 7.48-7.44 (m, 3H),
4.29 (t, J ) 7.5 Hz, 1H), 3.78 (s, 3H), 3.03 (dd, J ) 13.7, 7.5 Hz,
1H), 2.70 (dd, J ) 13.7, 7.5 Hz, 1H), 0.14 (s, 9H); 13C NMR (100
MHz, CDCl3) (unassigned) δ 172.3, 172.0, 142.3, 142.1, 140.1,
138.8, 130.8, 130.5, 129.1, 128.9, 125.8, 125.6, 124.7, 124.3, 120.8,
120.6, 75.4, 75.3, 52.7, 52.7, 47.4, 46.8, 45.6, 45.3, 1.4, 1.3; IR
(neat, cm-1) 2956, 1739, 1477, 1436, 1253, 1197, 1169, 1135,
7.31 (d, J ) 7.6 Hz, 1H), 7.22 (t, J ) 7.6 Hz, 1H), 7.18 (t, J ) 7.6
Hz, 1H), 5.62 (s, 1H), 3.68 (dd, J ) 11.2, 4.1 Hz, 1H), 3.55 (d, J
) 3.7 Hz, 1H), 3.43-3.37 (m, 1H), 3.18 (d, J ) 11.2 Hz, 1H),
2.52-2.45 (m, 1H), 2.32 (d, J ) 11.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 173.6, 144.7, 144.6, 128.0, 127.7, 123.2, 122.9,
49.3, 47.9, 39.1, 38.4; IR (neat, cm-1) 3218, 2949, 2872, 1666,
1485, 1459, 1400, 1328, 1303, 1288, 1250, 1215, 1122, 1104,
1045, 1004, 946, 910, 756, 730, 643, 613. Anal. Calcd for C11H11
-
NO: C, 76.28; H, 6.40; N, 8.09. Found: C, 75.94; H, 6.27; N,
7.99.
1,5-Meth a n o-2,3,4,5-tetr a h yd r o-1H-3-ben za zep in e Tosy-
la te (1). To a solution of 1.38 g of 1,5-methano-2,3,4,5-tetrahy-
dro-2-oxo-1H-3-benzazepine (8.00 mmol, 1 equiv) in 8 mL of
tetrahydrofuran was added 603 mg of sodium borohydride (16.0
mmol, 2.0 equiv) followed by slow addition of 2.77 mL of boron
trifluoride diethyl etherate (21.6 mmol, 2.7 equiv). Once the
effervescence subsided, the reaction mixture was heated to 50
°C for 5 h. The reaction was then cooled to room temperature
for addition of 10 mL of methanol (added dropwise at first) and
0.125 mL of concentrated hydrochloric acid. Heating was
resumed at a reflux for 12 h. The reaction mixture was then
cooled to room temperature and concentrated in vacuo. The
residue was diluted with 20 mL of 20% aqueous sodium
hydroxide followed by 30 mL of methyl tert-butyl ether. The
mixture was stirred for 30 min, and then the aqueous layer was
extracted with another 30 mL of methyl tert-butyl ether. The
combined organic layers were washed with 40 mL of a saturated
aqueous sodium chloride solution and dried over anhydrous
sodium sulfate. After concentration in vacuo, 1.67 g of p-
toluenesulfonic acid monohydrate (8.80 mmol, 1.1 equiv) was
added with 20 mL of 2-propanol. The solution was heated until
homogeneous and then allowed to gradually cool to room
temperature with stirring. White crystals of the tosylate salt of
1,5-methano-2,3,4,5-tetrahydro-1H-3-benzazepine formed which
were collected by filtration (2.17 g, 81%): mp 207-208 °C; 1H
NMR (400 MHz, CD3OD) δ 7.69 (d, J ) 7.9 Hz, 2H), 7.43-7.32
(m, 4H), 7.23 (d, J ) 7.9 Hz, 2H), 3.37 (d, J ) 11.2 Hz, 4H), 3.30
(bs, 2H), 3.15 (d, J ) 12.4 Hz, 2H), 2.36 (s, 3H), 2.40-2.35 (m,
1H), 2.08 (d, J ) 11.2 Hz, 1H); 13C NMR (100 MHz, CD3OD) δ
140.8, 140.5, 139.1, 127.2, 127.2, 124.3, 122.3, 45.1, 39.7, 37.3,
18.7; IR (KBr, cm-1) 3438, 3021, 2958, 2822, 2758, 2719, 2683,
2611, 2424, 1925, 1606, 1497, 1473, 1428, 1339, 1302, 1259,
1228, 1219, 1176, 1160, 1137, 1122, 1087, 1078, 945, 914, 876,
847, 829, 818, 801, 710, 492. Anal. Calcd for C18H21NO3S: C,
65.23; H, 6.39; N, 4.23; Found: C, 65.05; H, 6.48; N, 4.26.
4-Oxo-1,2,3,4-tetr a h yd r on a p h th a len e-1-ca r boxylic Acid
Meth yl Ester (4b). 2-Phenylglutaric anhydride (52.2 g, 0.274
mol) and concentrated sulfuric acid (274 mL) were heated in an
oil bath at 70 °C for a period of 1.5 h. The resulting mixture
was allowed to cool to rt and was added to a cooled solution (ice/
water bath) of MeOH (550 mL) over a period of 30 min. Upon
complete addition, the mixture was allowed to warm to rt and
stirred for 20 h. The mixture was poured over 1 L of ice. Brine
(500 mL) and water (500 mL) were added, and the resulting
mixture was extracted with EtOAc (4 × 500 mL). The combined
organics were washed successively with satd NaHCO3 (500 mL),
water (500 mL), and brine (500 mL). The organics were dried
(Na2SO4), filtered, and concentrated to provide 44.8 g (80%) of
the title compound as a brown oil which was used without
further purification: 1H NMR (CDCl3, 400 MHz) δ 8.02 (dd, 1H,
J ) 7.9, 1.3 Hz), 7.48 (td, 1H, J ) 7.5, 1.3 Hz), 7.35 (td, 1H, J )
7.5, 1.3 Hz), 7.29 (1H, d, J ) 7.9 Hz), 3.96, (t, 1H, J ) 5.0 Hz),
3.69 (s, 3H), 2.87 (ddd, 1H, J ) 17.4, 11.6, 5.0 Hz), 2.60 (dt, 1H,
J ) 17.4, 5.0 Hz), 2.51-2.43 (m, 1H), 2.36-2.27 (m, 1H); 13C
NMR (CDCl3, 100 MHz) δ 197.2, 173.3, 140.4, 133.8, 132.4, 129.4,
128.2, 127.6, 52.6, 44.6, 35.8, 26.0; GCMS m/z 204 (M+); HRMS
(ES) calcd for M + H + CH3CN 246.1130, found 246.1131.
4-Cya n o-4-tr im eth ylsila n yloxy-1,2,3,4-tetr a h yd r on a p h -
th a len e-1-ca r boxylic Acid Meth yl Ester (3b). 4-Oxo-1,2,3,4-
tetrahydronaphthalene-1-carboxylic acid methyl ester (28.0 g,
0.137 mol) was dissolved in CH2Cl2 (138 mL). ZnI2 (0.22 g, 0.69
mmol) and I2 (0.21 g, 0.82 mmol) were added, and then TMSCN
(32.95 mL, 0.247 mol) was added dropwise over 15 min. The
resulting mixture was heated at reflux for 20 h. The mixture
1092, 1033, 1011, 880, 843, 756, 623. Anal. Calcd for C15H19
-
NO3Si: C, 62.25; H, 6.62; N, 4.84. Found: C, 62.20; H, 6.53; N,
4.92.
3-Am in om eth ylin d a n -1-ca r boxylic Acid Meth yl Ester
(12). To a solution of 5.79 g of 3-cyano-3-trimethylsilanyloxyin-
dan-1-carboxylic acid methyl ester (20.0 mmol, 1.0 equiv) in 25
mL of methanol was added 5.71 g of p-toluensulfonic acid
monohydrate (30.0 mmol, 1.5 equiv). The solution was stirred
for 15 min, and then 4.21 g of 20% palladium hydroxide on
carbon, 50% wet by weight (3.00 mmol, 0.15 equiv), was added.
The reaction mixture was subjected to hydrogenolysis at 50 psi
of hydrogen at 50 °C over 24 h. After this time, the reaction
mixture was filtered through Celite, and typically the filtrate
was used in the next step without further purification. The
product could be isolated by concentrating the filtrate in vacuo.
The residue was partitioned between 30 mL of methylene
chloride and 20 mL of a saturated aqueous solution of sodium
carbonate. The aqueous layer was extracted with another 15 mL
of methylene chloride. The combined organic layers were washed
with 40 mL of a saturated aqueous solution of sodium chloride.
The organic solution was dried over anhydrous sodium sulfate
and concentrated to afford 3-aminomethylindan-1-carboxylic acid
methyl ester as an oil (3.65 g, 89%) with approximately a 10:1
ratio of diastereomers (major diastereomer): 1H NMR (400 MHz,
CDCl3) δ 7.43 (dd, J ) 6.9, 1.6 Hz, 1H), 7.29-7.25 (m, 3H), 4.09
(t, J ) 8.1 Hz, 1H), 3.80 (s, 3H), 3.31-3.24 (m, 1H), 3.14 (dd, J
) 12.8, 4.7 Hz, 1H), 2.98 (dd, J ) 12.8, 7.3 Hz, 1H), 2.62-2.52
(m, 1H), 2.31-2.42 (m, 1H), 1.3 (bs, 2H).
1,5-Me t h a n o-2-oxo-2,3,4,5-t e t r a h yd r o-1H -3-b e n za ze -
p in e (13). To a solution of 3-aminomethylindan-1-carboxylic acid
methyl ester (assume 20.0 mmol, 1 equiv) in 50 mL of methanol
(this was the crude reaction mixture from the prior step) was
added 3.84 g of NaO-t-Bu (40.0 mmol, 2.0 equiv). The reaction
mixture was heated to reflux for 2 h. The reaction was cooled to
room temperature and concentrated in vacuo. The residue was
partitioned between 60 mL of ethyl acetate and 40 mL of 5%
aqueous solution of sodium bicarbonate. The aqueous layer was
extracted twice more with 50 mL of ethyl acetate. The combined
organic layers were dried over anhydrous sodium sulfate and
concentrated to provide a solid. The solid was recrystallized from
10 mL of toluene to obtain white crystals of 1,5-methano-2-oxo-
2,3,4,5-tetrahydro-1H-3-benzazepine (1.78 g, 51%): mp ) 172-
1
173 °C; H NMR (400 MHz, CDCl3) δ 7.33 (d, J ) 7.6 Hz, 1H),
5758 J . Org. Chem., Vol. 69, No. 17, 2004

was cooled to rt, satd NaHCO3 (100 mL) was added, and the
resulting mixture was stirred for 30 min. The mixture was
partitioned, and the organic layer was washed successively with
satd NaHCO3 (100 mL), water (100 mL), and brine (100 mL).
The organic layer was dried (Na2CO3), filtered, and concentrated
to afford 34.5 g (83%) of the title compound as a brown oil which
was used without further purification: 1H NMR (CDCl3, 400
MHz) δ 7.72-7.68 (m, 1H), 7.37-7.31 (m, 2H), 7.29-7.26 (m,
1H), 3.86-3.83 (m, 1H), 3.717/3.715 (s, 3H), 2.60-2.20 (m, 4H),
0.212/0.189 (9H); GCMS m/z 303 (M+).
1,5-Eth an o-2,3,4,5-tetr ah ydr o-1H-3-ben zazepin e (2). Pearl-
man’s catalyst (20% Pd(OH)2-C (50% water), 17.22 g, 12.3
mmol) was added to a solution of 4-cyano-4-trimethylsilanyloxy-
1,2,3,4-tetrahydronaphthalene-1-carboxylic acid methyl ester
(24.8 g, 81.2 mmol) in MeOH (400 mL) and 3 M aq HCl (41 mL).
This mixture was shaken under an atmosphere of hydrogen (50
psi) at 50 °C for a period of 20 h. The resulting solution was
filtered through a pad of Celite and washed with MeOH (300
mL). Sodium tert-butoxide (27.5 g, 286 mmol) was added, and
the resulting solution was stirred at rt for 20 h. The mixture
was concentrated, and the residue was dissolved in EtOAc (500
mL) and water (200 mL). The layers were partitioned, and the
aqueous layer was extracted with EtOAc (3 × 200 mL). The
combined organics were washed with brine, dried (Na2SO4),
filtered, and concentrated to afford 11.2 g of 1,5-ethano-2-oxo-
2,3,4,5-tetrahydro-1H-3-benzazepine (15) as a white solid (GCMS
m/z 187). Tetrahydrofuran (160 mL) was added to this white
solid, and the resulting slurry was heated in an oil bath at 45
°C. A solution of LiAlH4 in THF (1 M, 120 mmol, 120 mL) was
added dropwise to this mixture over a period of 60 min. The
resulting mixture was heated at 45 °C for 20 h. Upon cooling to
rt, a solution of water (8.65 mL) in THF (50 mL) was added
dropwise to the mixture over a period of 120 min and the
resulting mixture was allowed to stir for 20 h. The solids were
removed by filtration through a pad of Celite, and the filter cake
was washed with additional THF (200 mL). The filtrate was
concentrated to afford 9.32 g (90%) of the title compound as an
oil: 1H NMR (CDCl3, 400 MHz) δ 7.19 (dd, 2H, J ) 5.4, 3.3 Hz),
7.08 (dd, 2H, J ) 5.4, 3.3 Hz), 2.99-2.95 (m, 4H), 2.81-2.76 (m,
2H), 2.04-1.99 (m, 2H), 1.87-1.80 (m, 2H); 13C NMR (CDCl3,
100 MHz) δ 142.2, 126.8, 126.6, 52.9, 41.9, 27.1; APCI MS m/z
174.2 (M + 1); HRMS (ES) calcd for M + H 174.1283, found
174.1275.
Ack n ow led gm en t. We thank Mr. Steve Massett for
recommending the use of indane 11 for the preparation
of 1. We thank Mr. J amison Tuttle for the initial supply
of tetralone 4b. We also thank Drs. J otham Coe,
Christopher Helal, and Angel Guzman-Perez for their
helpful discussions in the preparation of this manuscript.
J O049122Q
J . Org. Chem, Vol. 69, No. 17, 2004 5759