Synthesis of conformationally constrained spirohydantoins with a dibenzo[a,d]heptadiene ring

Article abstract of DOI:10.1055/s-2000-7108

Conformationally constrained dibenzo[a,d]cycloheptadiene-based spirohydantoins were prepared from dibenzosuberone via the transformation of the α-hydroxy ester to the azido ester, followed by its reduction to the amino ester, and cyclization of the carbomethoxy N,N'-asymmetric ureas, derived from the amino ester with triphosgene and a variety of amines. A novel ring expansion reaction was also observed in the process.

Full text of DOI:10.1055/s-2000-7108

PAPER
1449
Synthesis of Conformationally Constrained Spirohydantoins with a
Dibenzo[a,d]heptadiene Ring
Bin Tao, Jack W. Timberlake*
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Fax +1(504)2806860; E-mail: jtimberl@uno.edu
Received 29 February 2000
O
Abstract: Conformationally constrained dibenzo[a,d]cycloheptadi-
1). Na/DME
ene-based spirohydantoins were prepared from dibenzosuberone
HO
CO2Me
2). OC(OMe)2
3). H +
via the transformation of the a-hydroxy ester to the azido ester, fol-
lowed by its reduction to the amino ester, and cyclization of the car-
2
bomethoxy N,N’-asymmetric ureas, derived from the amino ester
with triphosgene and a variety of amines. A novel ring expansion re-
action was also observed in the process.
66%
1
NaN3/TFA
CH2Cl2
98%
N3
H2N
CO2Me
CO2Me
Key words: spirohydantions, triphosgene, N,N’-asymmetric ureas,
6-carbomethoxy-11,12-dihydrodibenz[b,f]azocine, ring expansion
reaction
Zn/HOAc 73%
Mg/MeOH 70%
4
3
1). OC(OCCl3)2
2). NH2R
Hydantoins have long been known for their biological ac-
tivities,1-3 such as anticonvulsants and herbicidants, etc.,4
and recently have even been found as natural products.5,6
Although a large number of hydantoins have been pre-
pared,7-11 only a few synthetic examples of conformation-
ally constrained hydantoins have been reported.12 We
wish to report here a synthesis of conformationally con-
strained 3’-substituted spirohydantions with a diben-
zo[a,d]cycloheptadiene ring from dibenzosuberone in
short steps via the conversion of the a-hydroxy ester to the
azido ester, followed by reduction to the corresponding
amino ester and cyclization of the a-carbomethoxy ureas,
derived from the amino ester with triphosgene13-17 and
various amines.
R
O
N
RHN(O)CHN
CO2Me
O
HN
NaH/THF
a, R = H
b, R = Et
c, R = n-Bu
d, R = c-Pentyl
e, R = Ph
5a- f
6a- f
f, R = CH2CH2PhOH-p
Scheme 1
high yield (96%) when it was subjected to TFA in meth-
ylene chloride. Thus, 7 can be obtained either from 2 via
3 or directly from 2. It is noted that this reaction may pro-
vide a direct synthetic route to imines from some tertiary
alcohols although the scope of the reaction would need
additional investigation.
The target spirohydantoins were synthesized from diben-
zosuberone (1) as outlined in Scheme 1. Dibenzosuberone
was first converted to the corresponding a-hydroxy ester
218 by reacting with sodium in DME and quenching with
dimethyl carbonate. Taking advantage of the nucleophi-
licity of hydrazoic acid, the “Ritter” type reaction of 2
with sodium azide would give compound 3.
NaN3 / 4 eq TFA
However, during this process, we found that the amount
of trifluoroacetic acid (TFA) used was critical to the suc-
cessful transformation of compound 2 to 3. Using a
known procedure,19 the reaction with a large excess of
TFA did not give the desired compound 3, but instead, af-
forded the ring expansion product 7 (Scheme 2), likely the
rearrangement product of 3 in the acidic condition. We
reasoned that lowering the amount of the TFA used in the
reaction might prevent the rearrangement and found that
the reaction of 2 with 4 equivalents of TFA, by addition
dropwise at 0 °C, and stirring for 2 days at room temper-
2
3
CH2Cl2
98 %
NaN3
TFA
96 %
95 %
excess TFA
CH2Cl2
CH2Cl2
MeO2C
N
7
ature with occasional additions of methylene chloride to Scheme 2
dilute the mixture, yielded the azido ester 3 in nearly
quantitative yield. Furthermore, 3 was converted to 7 in
Synthesis 2000, No. 10, 1449–1453 ISSN 0039-7881 © Thieme Stuttgart · New York

1450
B. Tao, J. W. Timberlake
PAPER
R
O
N
O=C=N
CO2Me
O
HN
(CCl3O)2CO
RNH2
4
8
6a- f
Scheme 3
(d = 0.00 ppm). Infrared spectra (cm-1) were obtained from KBr
pellets on a Magna-IR 550 instrument. HRMS data were obtained
The next step was to reduce the resulting azido ester to the
corresponding amino compound. One of the convenient
methods for this transformation is catalytic hydrogena- on a MicroMass autospec mass spectrometer or from Iowa State
University (ionization energy 70 eV). Combustion elemental anal-
yses were performed by Oneida Research Services, Inc., Whites-
boro, New York.
tion. However, reduction of 3 with HCO2NH4 over Pd/C
in methanol20,21 proved to be problematic, showing sever-
al spots on a TLC plate. No efforts were made to separate
them. The reaction with Mg in MeOH22 afforded the de-
Methyl 10,11-dihydro-5-hydroxydibenzo[a,d]cycloheptene-5-
carboxylate (2)
sired amino ester 4 in 70% yield, but it was difficult to
separate the product from the gelatinous reaction system.
A similar reaction with Zn powder in acetic acid23 pro-
ceeded well to furnish 4 in 73% yield after normal work-
up.
A mixture of dibenzosuberone (10.4 g, 50 mmol) and Na (2.8 g,
122 mmol, washed with dry Et2O) in DME (100 mL) was stirred
overnight under a N2 atm at r.t. Dimethyl carbonate (6.0 mL, 71
mmol) in DME (20 mL) was then added to the reaction flask. The
mixture was stirred for an additional 24 h and quenched with cold
H2O (20 mL) and with sat. NH4Cl until pH 8. The resulting mixture
was extracted with Et2O (3 ¥ 50 mL) and the combined organic
With the amino ester in hand, triphosgene was used to
convert 4 to the N,N’-asymmetric ureas 5 in one pot after
quenching the reaction with different amines. The advan- layers were washed with brine (2 ¥ 30 mL) and dried (Na2SO4). Re-
moval of the solvent and crystallization (hexane/EtOAc, 2:1) yield-
tage in using triphosgene is that the isocyanate 8, generat-
ed in situ (Scheme 3), can react with a variety of amines,
even aromatic ones and those containing hydroxyl groups,
to yield a variety of N,N’-asymmetric ureas, which can
ed the final product as a white solid. Yield: 8.9 g, 66%; mp: 134-
136 ∞C (Lit.18 mp: 134-135 ∞C).
1H NMR (CDCl3): d = 7.76 (m, 2H, arom), 7.26-7.23 (m, 4H,
arom), 7.16-7.14 (m, 2H, arom), 3.93 (s, 1H, D2O exchangeable,
subsequently be converted to the 3’-substituted hydanto-
OH), 3.73 (s, 3H, OCH3), 3.36-3.26 (m, 2H, CH2CH2), 3.05-2.97
ins 6. For example, the intermediate 8, generated from the
reaction of 4 with triphosgene, was quenched with ethy-
lamine, cyclopentylamine, aniline, even 4-hydroxyphen-
ethylamine, to produce the corresponding N,N’-
asymmetric ureas in good yields (72-87%). Finally, cy-
clization of these carbomethoxy ureas 5 with NaH in THF
readily provided the 3’-substituted spirohydantoins 6 with
a dibenzo[a,d]cycloheptadiene ring.
(m, 2H, CH2CH2).
13C NMR (CDCl3): d = 175.1 (CO2CH3), 139.3, 139.2, 130.2,
128.1, 126.2, 126.1 (6C, arom), 79.8 (Ar2-C), 53.4 (OCH3), 33.7
(CH2CH2).
Methyl 5-azido-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-
carboxylate (3)
To a stirred suspension of 2 (2.01 g, 7.5 mmol) and sodium azide
(1.00 g, 15.0 mmol) in CH2Cl2 (20 mL), cooled in an ice-bath, was
added dropwise a solution of trifluoroacetic acid (TFA, 2.31 mL,
30.0 mmol) in CH2Cl2 (10 mL) under a N2 atm. The mixture was al-
lowed to reach r.t. after the addition of TFA and stirred for 48 h, dur-
ing which time additional CH2Cl2 (60 mL) was added to dilute the
suspension. Cold H2O was carefully added to the reaction flask,
cooled in an ice-bath, followed by the addition of concd ammonium
hydroxide until pH 8. The mixture was extracted with CH2Cl2
(2 ¥ 50 mL) and the combined organic layers were washed with
H2O (2 ¥ 30 mL) and dried (Na2SO4). Evaporation of the solvent
in vacuo yielded product 3 (2.15 g, 98%) as a white solid: mp:
79.5-81 ∞C (hexane/EtOAc).
1H NMR (CDCl3): d = 7.55 (t, 2H, J = 5.0, 7.5 Hz, arom), 7.27-
7.24 (m, 4H, arom), 7.18-7.15 (m, 2H, arom), 3.81 (s, 3H, OCH3),
3.26-3.15 (m, 2H, CH2CH2), 3.12-3.02 (m, 2H, CH2CH2).
13C NMR (CDCl3): d = 171.0 (CO2CH3), 139.0, 136.50, 130.7,
128.5, 126.7, 126.5 (6C, arom), 76.0 (Ar2-C), 53.2 (OCH3), 33.2
(CH2CH2).
In conclusion, we have shown a synthetic route to confor-
mationally constrained 3’-substituted spirohydantoins
with a dibenzo[a,d]heptadiene ring by conversion of the
a-hydroxy ester to the corresponding azido ester, fol-
lowed by reduction to the amino ester and cyclization of
the carbomethoxy N,N’-asymmetric ureas, derived from
the amino ester with triphosgene and amines. A novel ring
expansion reaction to cyclic imines was also observed.
Dimethoxyethane (DME), tetrahydrofuran (THF) were distilled
from Na and benzophenone before use. CH2Cl2 and Et3N were dis-
tilled from CaH2. MeOH was distilled from Mg. Unless otherwise
stated, all the reagents used were purchased from Aldrich Chemical
Company and used without purification. Mps were determined in an
open capillary tube on an Unimelt or a Mel-temp apparatus and are
uncorrected. TLC was performed using silica gel 60 F254 (E. Merck,
Darmstadt, Germany) and flash column chromatography was car-
ried out on silica gel (60-200 mesh). 1H and 13C NMR spectra were
recorded on a Varian-Gemini 300 MHz spectrometer (75 MHz
for 13C). Chemical shifts are reported in ppm and referenced to TMS
Anal. Calcd for C17H15N3O2 (293.32): C, 69.60; H, 5.16; N, 14.33.
Found: C, 69.46; H, 5.01; N, 14.37.
Synthesis 2000, No. 10, 1449–1453 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Conformationally Constrained Spirohydantoins
1451
6-Carbomethoxy-11,12-dihydrodibenz[b,f]azocine (7)
Method A (from 2)
evaporated under reduced pressure. The residue was taken up to
EtOAc (30 mL) and washed with sat. NaHCO3 (30 mL) and the
aqueous layer was extracted two more times with EtOAc (2 ¥ 30
mL). The combined organic layers were washed with brine (2 ¥ 20
mL) and dried (Na2SO4). The residue, after evaporation of the sol-
vent, was purified by flash chromatography to yield 4 (0.98 g, 73%)
as a white solid. The NMR indicated that the final product was
identical to that prepared with Method B above.
To a stirred suspension of 2 (1.34 g, 5.0 mmol) and sodium azide
(0.65 g, 10.0 mmol) in dry CH2Cl2 (30 mL), cooled in an-ice bath,
was added dropwise TFA (10 mL) over 10 min. After addition, the
solution was allowed to warm to r.t. and stirred for an additional
48 h. CH2Cl2, H2O (30 mL each) and concd ammonia were subse-
quently added to the reaction flask, cooled in an ice-bath, until
pH 8. The mixture was extracted with CH2Cl2 (2 ¥ 30 mL) and the
combined organic layers were washed with H2O (2 ¥ 20 mL). Evap-
oration of the solvent and purification by flash chromatography
(hexane/EtOAc, 3:1) afforded pure 7 (1.26 g, 95%) as a yellow
solid: mp: 98.5-100 ∞C (hexane/EtOAc).
1H NMR (CDCl3): d = 7.38-7.13 (m, 1H, arom), 7.09-7.02 (m, 5H,
arom), 6.92 (t, 1H, J = 7.3 Hz, arom), 6.83 (d, 1H, J = 8.0 Hz,
arom), 3.96 (s, 3H, OCH3), 3.20-3.10 (m, 2H, CH2CH2), 2.97-2.78
(m, 2H, CH2CH2).
13C NMR (CDCl3): d = 164.8 (CO2CH3), 163.2 (C = N), 148.8,
138.3, 132.9, 129.9, 129.3, 129.2, 128.5, 126.7, 126.5, 125.3, 124.7
(11C, arom), 53.0 (OCH3), 34.9 (CH2CH2), 29.8 (CH2CH2).
N,N’-Asymmetric Ureas 5a-f; General Procedure
To a stirred solution of triphosgene (0.22 g, 0.70 mmol) in THF
(30 mL) was added a solution of 4 (0.54 g, 2.0 mmol) and Et3N
(0.60 mL, 4.4 mmol) in dry THF (10 mL) at r.t. The mixture was
stirred for 20 min and a solution of amine or amine hydrochloride
(2.0 mmol) with Et3N (2.0 mmol) in THF (10 mL), except for 5a,
where anhyd ammonia was bubbled through the reaction system for
15 min, was added into the system. The mixture was kept stirring
for an additional 30 min. The solvent was removed under reduced
pressure and the residue was passed through a column (hexane/
EtOAc, 1:1 or EtOAc) and crystallized to yield the products.
Anal. Calcd for C17H15NO2 (265.30): C, 76.96; H, 5.66; N, 5.24.
Found: C, 76.66; H, 5.74; N, 5.20.
1-{5-Carbomethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohep-
tene-5}urea (5a)
White solid (80%); mp: 220-222 ∞C.
Method B (from 3)
1H NMR (DMSO-d6): d = 7.80 (br s, 1H, NHCO), 7.37 (d, 2H,
J = 7.3 Hz, arom), 7.15-7.11 (m, 6H, arom), 5.70 (br s, 2H,
CONH2), 3.43 (s, 3H, OCH3), 3.10 (s, 4H, CH2CH2).
13C NMR (DMSO-d6): d = 174.3 (CO2CH3), 157.1 (NHCONH2),
143.0, 141.5, 130.7, 129.0, 127.8, 126.9 (6C, arom), 69.7 (Ar2-C),
53.9 (OCH3), 36.2 (CH2CH2).
Compound 3 (0.47 g, 1.60 mmol) in dry CH2Cl2 (10 mL) was treat-
ed with TFA (4 mL) in an ice-bath and stirred for 24 h at r.t. After
the above workup (half the amount of the corresponding reagents
used), product 7 (0.41 g, 96%) was obtained.
Methyl 5-amino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-
5-carboxylate (4)
HRMS: m/z calcd for C18H18N2O3 (M)+: 310.1317. Found:
Method A
310.1316.
A mixture of 3 (0.88 g, 3.0 mmol) and 10% Pd/C (150 mg) in dry
MeOH (30 mL) was kept under 40 psi of H2 in a Parr apparatus for
20 h. Filtration and evaporation of the solvent gave crude product
which displayed 5 spots on a TLC plate (hexane/EtOAc, 3:1). The
residue was redissolved in MeOH (30 mL) and 10% Pd/C (150 mg)
was added to the solution. The mixture was again subjected to the
above conditions for an additional 40 h. The composition of the
mixture showed no change (determined by TLC) after normal work-
up.
N-{5-Carbomethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohep-
tene-5}-N’-ethylurea (5b)
White solid (87%); mp: 200-202 ∞C.
1H NMR (DMSO-d6): d = 7.67 (s, 1H, Ar2C-NH), 7.34 (d, 2H,
J = 8.0 Hz, arom), 7.16-7.10 (m, 6H, arom), 6.42 (m, 1H, CON-
HEt), 3.42 (s, 3H, OCH3), 3.11-3.08 (m, 4H, CH2CH2), 2.82-2.77
(m, 2H, CH2CH3), 0.87-0.84 (t, 3H, J = 6.8 Hz, CH2CH3).
13C NMR (DMSO-d6): d = 173.2 (CO2CH3), 155.2 (NHCONH2),
141.9, 140.5, 129.7, 127.9, 126.8, 125.9 (6C, arom), 68.7 (Ar2-C),
53.1 (OCH3), 35.3 (CH2CH2), 33.6 (NHCH2), 15.4 (CH2CH3).
Method B
A suspension of 3 (0.62 g, 2.13 mmol) and magnesium (0.22 g,
9.3 mmol) in dry MeOH (20 mL) was refluxed for 30 h. The mixture
was then cooled and diluted with sat. NH4Cl (30 mL) and extracted
with CH2Cl2 (3 ¥ 60 mL). The combined organic layers were
washed with brine (3 ¥ 30 mL) and dried (Na2SO4). Evaporation of
the solvent under reduced pressure yielded the product 4 (0.40 g,
70%) as a slightly yellow solid: mp: 118.5-120 ∞ C (hexane/
EtOAc).
1H NMR (CDCl3): d = 7.63 (m, 2H, arom), 7.20-7.08 (m, 6H,
arom), 3.72 (s, 3H, OCH3), 3.37-3.26 (m, 2H, CH2CH2), 3.19-2.98
(m, 2H, CH2CH2), 1.93 (br s, 2H, NH2).
HRMS: m/z calcd for C20H22N2O3 (M)+: 338.1630. Found:
338.1650.
N-n-Butyl-N’-{5-carbomethoxy-10,11-dihydro-5H-diben-
zo[a,d]cycloheptene-5}urea (5c)
White solid (86%); mp: 218-219∞C.
1H NMR (DMSO-d6): d = 7.68 (s, 1H, Ar2C-NH), 7.34 (d, 2H,
J = 8.0 Hz, arom), 7.16-7.10 (m, 6H, arom), 6.44 (m, 1H, CONH-
Bu-n), 3.42 (s, 3H, OCH3), 3.11-3.08 (m, 4H, CH2CH2Ar), 2.77-
2.75 (m, 2H, NHCH2Pr), 1.18-1.16 (m, 4H, CH2CH2CH2CH3),
0.80-0.77 (t, 3H, J = 6.4 Hz, CH3 of Bu).
13C NMR (DMSO-d6): d = 173.2 (CO2CH3), 155.3 (NHCONH),
141.9, 140.5, 129.7, 127.9, 126.8, 125.9 (6C, arom), 68.7 (Ar2-C),
53.1 (OCH3), 35.3 (CH2CH2), 31.9 (NHCH2), 19.4, 13.6 (CH2CH3).
13C NMR (CDCl3): d = 176.6 (CO2CH3), 140.4, 138.0, 130.6,
127.7, 126.2, 124.1 (6C, arom), 65.2 (Ar2-C), 52.9 (OCH3), 32.3
(CH2CH2).
HRMS: m/z calcd for C15H14N (M-CO2CH3)+: 208.1126. Found:
208.1120.
HRMS: m/z calcd for C22H26N2O3 (M)+: 366.1943. Found:
366.1980.
Method C
A suspension of 3 (1.47 g, 5.00 mmol) and Zn powder (2.0 g) in
HOAc (30 mL) was stirred for 24 h at r.t. under a N2 atm. The
suspension was filtered, washed with EtOAc and the filtrate was
N-{5-Carbomethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohep-
tene-5}-N’-cyclopentylurea (5d)
White solid (78%); mp: 200-202 ∞C.
Synthesis 2000, No. 10, 1449–1453 ISSN 0039-7881 © Thieme Stuttgart · New York

1452
B. Tao, J. W. Timberlake
PAPER
1H NMR (DMSO-d6): d = 7.59 (s, 1H, Ar2C-NH), 7.34 (d, 2H,
J = 8.4 Hz, arom), 7.17-7.10 (m, 6H, arom), 6.51 (d, 1H, J = 7.6
Hz, CONH-c-C5H9), 3.59-3.56 (m, 1H, c-CH), 3.42 (s, 3H, OCH3),
3.09 (s, 4H, CH2CH2Ar), 1.61-1.50 (m, 4H, c-CH2, c-CH2), 1.45-
1.39 (m, 2H, c-CH2), 1.18-1.13 (m, 2H, c-CH2).
13C NMR (DMSO-d6): d = 173.3 (CO2CH3), 154.9 (NHCONH2),
141.9, 140.5, 129.7, 127.9, 126.8, 125.9 (6C, arom), 68.7 (Ar2-C),
53.1 (OCH3), 50.6 (NCH-c), 35.3 (CH2CH2Ar), 33.0 (c-CH2), 23.1
(c-CH2).
Spiro{10,11-dihydro-9H-dibenzo[a,d]cycloheptene-9,5’-imidia-
zolidine}-3’-ethyl-2’,4’-dione (6b)
Colorless crystals (85%); mp: 183-185 ∞C.
1H NMR (DMSO-d6): d = 9.47 (s, 1H, Ar2C-NH), 7.43-7.40(m,
2H, arom), 7.28-7.25 (m, 6H, arom), 3.58-3.52 (m, 2H, CH2CH3),
3.43-3.39 (m, 2H, CH2CH2), 2.98-2.94 (m, 2H, CH2CH2), 1.04 (t,
3H, J = 7.2 Hz, CH3).
13C NMR (DMSO-d6): d = 174.2 (CONH), 155.6 (NHCONH),
142.9, 135.8, 130.9, 128.5, 127.5, 126.6 (6C, arom), 70.7 (Ar2-C),
34.5 (CH2CH2), 33.0 (CH2CH3), 13.1 (CH3).
HRMS: m/z calcd for C23H26N2O3 (M)+: 378.1943. Found:
378.1930.
HRMS: m/z calcd for C19H18N2O2 (M)+: 306.1368. Found:
306.1380.
N-{5-Carbomethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohep-
tene-5}-N’-phenylurea (5e)
Spiro{10,11-dihydro-9H-dibenzo[a,d]cycloheptene-9,5’-imidia-
zolidine}-3’-n-butyl-2’,4’-dione (6c)
Colorless crystals (80%); mp: 157-159 ∞C.
White solid (72%); mp: 216-217 ∞C.
1H NMR (DMSO-d6): d = 9.06 (s, 1H, Ar2C-NH), 8.20 (s, 1H,
arom), 7.40 (d, 2H, J = 7.2 Hz, arom), 7.19-7.09 (m, 10H, arom),
6.81 (t, 1H, J = 7.2 Hz, NHAr), 3.46 (s, 3H, OCH3), 3.20-3.09 (m,
4H, CH2CH2).
13C NMR (DMSO-d6): d = 173.2 (CO2CH3), 152.3 (NHCONH),
142.4, 140.1, 139.8, 129.8, 128.6, 128.1, 127.0, 126.2, 121.1, 117.2
(10C, arom), 68.9 (Ar2-C), 53.4 (OCH3), 35.6 (CH2CH2).
1H NMR (DMSO-d6): d = 9.48 (s, 1H, Ar2C-NH), 7.44-7.42(m,
2H, arom), 7.28-7.25 (m, 6H, arom), 3.60-3.56 (m, 2H, NCH2),
3.39-3.33 (m, 2H, CH2CH2), 2.97-2.91 (m, 2H, CH2CH2), 1.48-
1.41 (m, 2H, NCH2CH2), 1.20-1.12 (m, 2H, CH2CH2CH3), 0.81 (t,
3H, J = 7.2 Hz, CH3).
13C NMR (DMSO-d6): d = 174.1 (CONH), 155.6 (NHCONH),
142.6, 135.5, 131.7, 128.2, 127.2, 126.3 (6C, arom), 70.4 (Ar2-C),
37.5 (NCH2), 34.3 (CH2CH2), 29.3 (NCH2CH2), 18.9 (CH2CH3),
12.1 (CH3).
HRMS: m/z calcd for C24H22N2O3 (M)+: 386.1630. Found:
386.1620.
HRMS: m/z calcd for C21H22N2O2 (M)+: 334.1681. Found:
334.1680.
N-{5-Carbomethoxy-10,11-dihydro-5H-dibenzo[a,d]cyclohep-
tene-5}-N’-(4-hydroxyphenylethyl)urea (5f)
White solid (82%); mp: 176-178 ∞C.
1H NMR (DMSO-d6): d = 9.16 (s, 1H, Ar2C-NH), 7.75 (s, 1H, OH),
7.33 (d, 2H, J = 7.6 Hz, arom), 7.17-7.10 (m, 6H, arom), 6.89 (d,
2H, J = 7.6 Hz, arom), 6.66 (d, 2H, J = 7.6 Hz, arom), 6.44 (m, 1H,
NHAr), 3.41 (s, 3H, OCH3), 3.10 (s, 4H, CH2CH2), 2.97-2.94 (m,
2H, CH2NH), 2.41-2.38 (m, 2H, CH2Ar).
13C NMR (DMSO-d6): d = 173.2 (CO2CH3), 155.5 (NHCONH2),
155.2, 141.9, 140.5, 129.7, 129.5, 128.0, 126.8, 125.9, 115.0, 114.9
(10C, arom), 68.7 (Ar2-C), 53.1 (OCH3), 35.3 (ArCH2CH2Ar), 35.0
(NHCH2CH2).
Spiro{10,11-dihydro-9H-dibenzo[a,d]cycloheptene-9,5’-imidia-
zolidine}-3’-cyclopentyl-2’,4’-dione (6d)
Colorless crystals (79%); mp: 176-178 ∞C.
1H NMR (DMSO-d6): d = 9.45 (s, 1H, Ar2C-NH), 7.40-7.25 (m,
8H, arom), 4.33-4.30(m, 1H, c-CH), 3.57-3.51 (dd, 2H, J = 14.8,
9.6 Hz, CH2CH2), 2.97-2.91 (dd, 2H, J = 14.8, 9.6 Hz, CH2CH2),
1.82-1.75 (m, 6H, c-3CH2), 1.50-1.49 (m, 2H, c-CH2).
13C NMR (DMSO-d6): d = 174.2 (CONH), 153.8 (NHCONH),
142.9, 135.8, 130.3, 128.1, 127.4, 126.4 (6C, arom), 69.9 (Ar2-C),
34.4 (CH2CH2), 28.3 (c-CH2), 24.5 (c-CH2).
HRMS: m/z calcd for C26H26N2O4 (M)+: 430.1893. Found:
430.1880.
HRMS: m/z calcd for C22H22N2O2 (M)+: 346.1681. Found:
346.1690.
3’-Substituted Spirohydantoins 6a-f; General Procedure
Compounds 5 (1.0 mmol) were refluxed with NaH (30 mg, 1.2
equiv for 5a-e; 60 mg, 2.5 equiv for 5f) in THF (30 mL) for 2-6 h
(monitored by TLC). The mixture was cooled to r.t. and H2O (1-2
mL) was added. The solvent was removed under reduced pressure
and the resulting residue was passed through a column to yield
the crude products, which were crystallized to give the pure spiro-
hydantoins 6.
Spiro{10,11-dihydro-9H-dibenzo[a,d]cycloheptene-9,5’-imidia-
zolidine}-3’-phenyl-2’,4’-dione (6e)
Colorless crystals (90%): mp: 224-226 ∞C.
1H NMR (DMSO-d6): d = 9.81 (s, 1H, Ar2C-NH), 7.61-7.48 (m,
2H, arom), 7.47-7.28 (m, 11H, arom), 3.57-3.51 (dd, 2H, J = 15.2,
9.6 Hz, CH2CH2), 2.97-2.91 (dd, 2H, J = 15.2, 9.6 Hz, CH2CH2).
13C NMR (DMSO-d6): d = 173.4 (CONH), 154.5 (NHCONH),
143.0, 135.7, 131.6, 131.1, 129.0, 128.7, 128.2, 127.9, 126.9, 126.8
(10C, arom), 70.7 (Ar2-C), 34.6 (CH2CH2).
Spiro{10,11-dihydro-9H-dibenzo[a,d]cycloheptene-9,5’-imidia-
zolidine}-2’,4’-dione (6a)
Colorless crystals (82%); mp: 314-316 ∞C (dec.).
IR (KBr): 3365, 3120, 3085, 1775, 1718, 1413, 795, 719 cm-1.
HRMS: m/z calcd for C23H18N2O2 (M)+: 354.1368. Found:
354.1340.
1H NMR (DMSO-d6): d = 10.82 (br s, 1H, Ar2C-NH), 9.16 (s, 1H,
CONHCO), 7.56-7.53 (m, 2H, arom), 7.31-7.24 (m, 6H, arom),
3.67-3.59 (m, 2H, CH2CH2), 2.96-2.88 (m, 2H, CH2CH2).
13C NMR (DMSO-d6): d = 177.1 (CONH), 157.7 (NHCOCH),
144.0, 137.2, 132.0, 129.5, 128.8, 127.7 (6C, arom), 73.2 (Ar2-C),
35.7 (CH2CH2).
Spiro{10,11-dihydro-9H-dibenzo[a,d]cycloheptene-9,5’-imidia-
zolidine}-3’-(4-hydroxyphenylethyl)-2’,4’-dione (6f)
Off white solid (73%); mp: 220-222 ∞C.
1H NMR (DMSO-d6): d = 9.36, 9.20(s, 1H, Ar2C-NH), 7.27-7.22
(m, 8H, arom), 6.86 (d, 2H, J = 8.4 Hz, arom), 6.59 (d, 2H, J = 8.4
Hz, arom), 3.57 (t, 2H, J = 6.8 Hz, NCH2), 3.53-3.47 (dd, 2H,
J = 15.2, 9.2 Hz, CH2CH2), 2.96-2.91 (dd, 2H, J = 15.2, 9.2 Hz,
CH2CH2), 2.71 (t, 2H, J = 6.8 Hz, ArCH2), 2.07 (s, 1H, OH).
HRMS: m/z calcd for C17H14N2O2 (M)+: 278.1055. Found:
278.1054.
Synthesis 2000, No. 10, 1449–1453 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Conformationally Constrained Spirohydantoins
1453
13C NMR (DMSO-d6): d = 174.3 (CONH), 155.7 (NHCONH),
155.5, 142.8, 135.7, 130.8, 129.7, 128.4, 127.8, 126.5, 115.1, 115.0
(10C, arom), 70.7 (Ar2-C), 34.5 (ArCH2CH2Ar), 32.0 (NCH2), 30.7
(NCH2CH2).
(10) Dressman, B. A.; Spangle, L. A.; Kaldor, S. W. Tetrahedron
Lett. 1996, 37, 937.
(11) Xiao, X.; Ngu, K.; Chao, C.; Patel, D. V. J. Org. Chem. 1997,
62, 6968.
(12) DuPriest, M. T.; Conrow, R. E.; Kuzmich, D. Tetrahedron
Lett. 1990, 31, 2959.
(13) Eckert, H.; Foster, B. Angew. Chem., Int. Ed. Engl. 1987, 26,
894.
HRMS: m/z calcd for C25H22N2O3 (M)+: 398.1630. Found:
398.1670.
(14) Zhao, X.; Chang, Y. -L.; Fowler, F. W.; Lauher, J. W. J. Am.
Chem. Soc. 1990, 112, 6627.
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Article Identifier:
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Synthesis 2000, No. 10, 1449–1453 ISSN 0039-7881 © Thieme Stuttgart · New York