On the mechanism and stereochemistry of the formation of β-lactam derivatives of 2,4-disubstituted-2,3-dihydro-benzo[1,4]diazepines

Article abstract of DOI:10.1002/jhet.5570380503

2-Chloro-4-phenyl-2a-(4′-methoxyphenyl)-3,5-dihydroazatetracylic [1,2-d]benzo[1,4]diazepin-1-one (III_a) and 2-chloro-4-phenyl-2a-(4′-methoxyphenyl)-3,5-dihydroazatetracyclic [1,2-d]benzo[1,4]diazepin-1-one(III_b) were synthesized. 1-B

Full text of DOI:10.1002/jhet.5570380503

On the Mechanism and Stereochemistry of the Formation of β-Lactam
Sep-Oct 2001
1031
Derivatives of 2,4-Disubstituted-2,3-dihydro-benzo[1,4]diazepines
Hong-zhong Wang* [a], Xin Zhou [a], Jia-xi Xu [a],
Sheng Jin [a], Yue-ming Li [b] and Albert S. C. Chan* [b]
[a] College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People's Republic of China
[b] Open Laboratory of Chirotechnology and Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, People's Republic of China
Received July 11, 2000
2-Chloro-4-phenyl-2a-(4'-methoxyphenyl)-3,5-dihydroazatetracyclic[1,2-d]benzo[1,4]diazepin-1-one
(III ) and 2-chloro-4-methyl-2a-(4'-methoxyphenyl)-3,5-dihydroazatetracyclic[1,2-d]-benzo[1,4]diazepin-
a
1-one (III ) were synthesized. 1-Benzoyl-2-phenyl-4-(4'-methoxyphenyl)[1,4]-benzodiazepine (II ) was
b
a
formed through benzoylation of starting material 2-phenyl-4-(4'-methoxyphenyl)-[1,4]benzodiazepine (I )
a
with the inversion of seven-member ring boat conformation. The thus formed β-lactams should have four
pairs of stereoisomers. However, only one pair of enantiomers (2S,2aR,4R) and (2R,2aS,4S) was obtained.
The mechanism and stereochemistry of the formation of these compounds were studied on the basis of nmr
spectroscopy and further confirmed by X-ray diffraction.
J. Heterocyclic Chem., 38, 1031 (2001).
Diazepines are compounds showing high bioactivity,
give an unstable complex intermediate, followed by loss of a
proton at the α position of the chloroacetyl group. A
cycloaddition reaction then occurred after the intramolecular
rearrangement of the intermediate. Alternatively, the reaction
may have proceeded via stepwise [2 + 2] cycloaddition of the
substrate with ketene, which was formed from chloroacetyl
chloride by the action of triethyl amine present in the reaction
mixture. The same intermediate, however, should be formed
no matter which way the reaction proceeded. The ring
closure step was governed by the conformation of both the
intermediate and the product; the R product can only be
formed through conrotatory counter-clockwise rotation
(Scheme 2).
and studies on the synthesis of β-diazepine lactams have
been reported [1,2]. However, there have been few reports
so far on the mechanism and stereochemistry of the forma-
tion of diazepine β-lactams. In our previous study, a series
of cycloaddition reactions of dihydrodiazepine and
dihydrobenzothiazepine compounds were carried out, and
interesting results obtained [3-7].
Results and Discussion.
In order to facilitate the cycloaddition process, the N-H
group in the starting material 2-phenyl-(or 2-methyl)-4-(4'-
methoxyphenyl)-benzo[1,4]diazepine (I) was protected. A
benzoyl group was used as the protective group, and nmr
signals from the benzoylated product II differed
significantly from those of the starting material I.
Table 1
Chemical Shifts and Coupling Constants of the Proton
H , H and H on the Seven-member Ring of I, II and III
a
b
c
H
H
H
J
J
J
bc
a
b
c
ab
ac
I
I
II
II
3.04
2.62
3.15
2.48
3.23
2.94
3.34
3.09
5.20
4.20
6.20
5.35
13.36
13.39
13.36
13.32
8.84
8.08
13.85
11.8
3.92
4.04
4.50
5.04
a
b
a
Theoretically, the [2 + 2] cycloaddition reaction should
give four pairs of β-lactam derivatives, but only one pair of
diastereomers were obtained in the presence of triethylamine.
After thorough study on the reaction mechanism and the
stereochemistry of both the starting material and the product,
it was proposed that chloroacetyl chloride at first reacted
with the imine functional group of 1-benzoyl-2-methyl(or
phenyl)-4-(4'-methoxyphenyl)-benzo[1,4]diazepine (II) to
b
As shown in table 1, three protons on C-2 and C-3 of I
a
form an AMX spin system, and show three quadruplets
with coupling constants of J = 13 Hz, J = 9 Hz and J
bc
ab
ac
= 4 Hz. After benzoylation, the coupling constants of these
three protons are: J = 13 Hz, J = 14 and J = 5 Hz.
ab
ac
bc

1032
Vol. 38
H. Wang, X. Zhou, J. Xu, S. Jin, Y. Li and A. S. C. Chan
Figure 1. ORTEP drawing of compound I .
a
According to the literature [8], proton H of I is in +sc
c
a
relation with H and H and this has been changed after the
a
b
benzoylation. In the benzoylated compound 1-benzoyl-2-
phenyl-4-(4'-methoxyphenyl)-benzo[1,4]diazepine (II ),
a
H and H are in +ap relation, while H and H are in a +sc
c
a
c
b
relation. This means that the seven-member ring was
inverted to a chair or boat conformation during the
benzoylation process. The chair conformation is the high
energy one, since the ring system contains a C=C double
bond. Also, the benzoyl group and the neighboring phenyl
group are in +sp relation, while the inversion to the boat
Figure 2. ORTEP drawing of compound II .
a
conformation needs only a little energy [9]. In the boat
conformation, the benzoyl group and the neighboring
phenyl are in +ap relation. This was further confirmed by
the X-ray crystal structure of compound II .
a

On the Mechanism and Stereochemistry of the Formation of β-Lactam Derivatives
1033
Sep-Oct 2001
seven-member ring. This conformation has a high energy
and is sterically hindered, and is thus difficult to form.
However, IV may exist when R and R have comparable
B
3
4
size, (2R*,2aR*,4R*) diastereomers will be obtained when
R-IV undergoes counter-clockwise conrotatory, and
B
S-IV undergoes clockwise conrotatory ring closure. It is
B
impossible to form the (2S*,2aS*,4R*) diastereomer. This
can then provide a reasonable explanation of Szollosy's
two diastereomers that resulted from the reaction of
O=C=C(Br)CH with dihydrobenzo[1,4]thiazepine. The
3
nmr spectrum of the mixture formed showed that two
compounds were present. The major component was
(2S*,2aR*,4R*) and the minor one (2R*,2aR*,4R*).
The related configurations of these compounds were
further confirmed through X-ray diffraction studies of
I , II and 2-chloro-4-phenyl-2a-(4'-methoxyphenyl)-
a
a
3,5-dihydro-azatetracyclic[1,2-d]benzo[1,4]diazepin-1-
one (III ). The seven-member ring of III possessed a
a
a
slightly twisted boat conformation with H and H in sp
a
c
relation, while H and H were in +sc relation. The four-
c
b
member ring of the β-lactam and the three atoms of the
boat bottom remained co-planar. The methoxy group and
benzoyl group were at the boat bottom, the phenyl group
and the boat head resided on the same side, thus
allowing the most favorable arrangement of the
functional group (Figure 3).
Figure 3. The ORTEP drawing of III .
a
Szollozy et al. studied the stereochemistry of the forma-
tion of β-lactam derivatives via the reaction of
benzo[1,4]thiazepine with ketene compounds bearing
different substituents [10]. They usually obtained the
(2S*,2aR*,4R*) product as the only diastereomer. But
when the α-substituents on the ketene have comparable
size, another diastereomer (2R*,2aR*,4R*) could also be
obtained in small amount. They did not provide any
explanation for this result. A previous study on the [2 + 1]
cycloaddition of benzo[1,4]diazepine with ethoxy
carbonyl carbene [11] showed that the factor governing the
product stereochemistry was the conformation of the
reaction intermediate. The [2 + 2] reaction seems to be a
similar case. The chloroacetyl chloride or ketene molecule
approaches the lone pair electron of the imine nitrogen
atom from the less hindered direction, and the thus formed
EXPERIMENTAL
Melting points were measured on a Yanaco micro melting
point apparatus and were uncorrected. Infrared spectra were
recorded on Carlzearl Zeiss Jena Specord 75-IR instrument and
1
H nmr spectra on Brucker ARX-400 spectrometer using
deuteriochloroform as solvent and tetramethylsilane as internal
standard. Mass spectra were obtained on a VG ZAB-HS mass
spectrometer. Microanalysis were carried out on a Perkin-Elmer
240C analyzer. X-ray diffraction data were obtained on a
Rigaku AFC6S diffractometer. All solvents were dried and
distilled before use.
4-(4-Methoxyphenyl)-2-phenyl-2,3-dihydro-1H-benzo[b][1,4]-
diazepine (I ).
a
intermediate IV may have two conformations: IV or IV .
A
B
o-Phenylenediamine (18 g, 0.16 mmol) and 1-(4-Methoxy-
phenyl)-3-phenylpropenone (38.1 g, 0.16 mmol) were
dissolved in 225 ml of anhydrous ethanol. To this solution was
added 5 ml of piperidine and the reaction mixture was refluxed
for 9 hours. The reaction mixture was then concentrated and
left standing to allow the crystallization of the product;
28 grams of yellowish solid was obtained in 77% yield, mp
When R = H and R = Cl, IV is more stable than IV .
3
4
A
B
When undergoing 4π- cycloaddition reaction, there could
be two different stereoisomers due to the rigidity and
asymmetry of IV. (2S,2aR,4R) isomer will then be
obtained when R-IV undergoes counter-clockwise
A
conrotatory ring closure, while S-IV will give
A
-1
102-4°; ir: ν 1605 (C=N) cm .
(2R,2aS,4S) isomer via clockwise conrotatory ring closure.
And (2R*,2aS*,4R*) isomers will be obtained when
Anal. Calcd. for C
H ON (266): C, 76.69; H, 6.77; N,
17 18 2
10.53. Found: C, 77.10; H, 6.90; N, 10.62.
R-IV undergoes clockwise conrotatory and S-IV
A
A
4-(4-Methoxy-phenyl)-2-methyl-2,3-dihydro-1H-benzo[b][1,4]-
undergoes counter-clockwise conrotatory ring closure.
diazepine (I ).
Due to the rigidity and asymmetry of II , the four-member
b
a
ring of the (2R*,2aS*,4R*) will reside perpendicular to the
boat bottom of the seven-member ring. The N-5 benzoyl
group will also reside at the boat bottom of the
The reaction was carried out according to a procedure similar
to that described for the preparation of I . The product was
a
received in 65% yield, mp 103-104°; ir: ν 3330, 1590 (C=N)

1034
Vol. 38
H. Wang, X. Zhou, J. Xu, S. Jin, Y. Li and A. S. C. Chan
-1
+
Anal. Calcd. for C H O N Cl (508): C, 73.23; H, 4.92; N,
31 25 3 2
5.51. Found: C, 73.21; H, 4.76; N, 5.46.
cm ; ms: m/z 328 (M , 80.2), 313(47.7), 224(100), 133(41.4);
1
H nmr (deuteriochloroform): δ 3.03 (dd, 1H), 3.22 (dd, 1H),
3.85 (s, 3H), 5.15 (dd, 1H), 6.84-7.87(m, 13H).
2-Chloro-4-methyl-2a-(4-methoxyphenyl)-3,5-dihydro-
Anal. Calcd. for C
H ON (328): C, 80.49; H, 6.10; N, 8.54.
22 20 2
azatidino[1,2-d]benzo[b][1,4]diazepin-1-one (III ).
b
Found: C, 80.62; H, 5.97; N, 8.43.
The reaction was carried out by using the procedure described
1-Benzoyl-4-(4-methoxyphenyl)-2-phenyl-2,3-dihydro-1H-
above for the synthesis of III ; the product was isolated in 67%
a
benzo[b][1,4]diazepine (II ).
a
-1
+
yield, mp: 236-7°. ir: ν 1760, 1620 cm ; ms: m/z 446 (M ), 411,
265, 105 (100), 77; H nmr (deuteriochloroform): δ 1.24 (d, 3H),
1
To a mixture of 17.0 g (0.054 mol) I and 7.5 ml triethyl amine in
a
260 ml of anhydrous benzene was added dropwise 6.8 ml
(0.054 mol) of benzoyl chloride under reflux. The mixture was
refluxed for another 6 hours after completing the addition, and then
cooled and filtered to give 16.3 g of yellowish solid (yield 70%), mp
239-240° (ethanol). A single crystal suitable for X-ray diffraction
analysis was obtained after recrystallizing twice from anhydrous
2.22 (dd, 1H), 3.24 (dd, 1H), 3.70 (s, 3H), 4.94 (s, 1H), 5.26
(m, 1H), 6.24-8.48 (m, 14H).
Anal. Calcd. for C
H O N Cl (446): C, 69.88; H, 5.15; N,
26 23 3 2
6.27. Found: C, 73.21; H, 5.22; N, 6.22.
Acknowledgements.
-1
+
ethanol. ir: 1640 (C=N) cm ; ms: m/z 432 (M , 23.4), 327 (62.0),
This work was supported by National Natural Scientific
Foundation of China (29972001) and ASD Fund of the Hong
Kong Polytechnic University.
1
312 (10.9), 236 (10.7), 105 (100); H nmr (deuteriochloroform): δ
3.15 (t, 1H), 3.33 (dd, 1H), 6.20 (dd, 1H), 6.66-8.13 (m, 18H).
Anal. Calcd. for C
H O N (432): C, 80.56; H, 5.56; N,
29 24 2 2
6.48. Found: C, 80.55; H, 5.39; N, 6.30.
REFERENCES AND NOTES
1-Benzoyl-2-methyl-4-(4-methoxyphenyl)-2,3-dihydro-1H-
benzo[b][1,4]diazepine (II ).
b
[*] The authors now is affiliated with Department of Biological
Sciences and Biotechnology, Tsinghua University, Beijing 100084,
People’s Republic of China.
[1] E. Cortes and R. Martines, J. Heterocyclic Chem., 20, 161
(1983).
[2] E. Cortes, R. Martines and I. Carollos, J. Heterocyclic Chem.,
26, 119 (1989).
[3] R. X. Lan and S. Jin, Chinese Chem. Lett., 3, 179 (1992).
[4] X. Y. Zhang and S. Jin, Chinese Chem. Lett., 3, 181 (1992).
[5] J. X. Xu, H. T. Wu and S. Jin, Chinese J. Chem., 17, 84
(1999).
The reaction was carried out using the procedure described
above for the preparation of II . The product was isolated in 75%
yield, mp 163-4°. A single crystal suitable for X-ray diffraction
a
analysis was obtained after recrystallizing twice from anhydrous
+
1
ethanol. ms: m/z 370 (M ), 265, 251, 105 (100); H nmr
(deuteriochloroform): δ 1.40 (d,3H), 2.48 (t,1H), 3.09 (dd, 1H),
3.87 (s, 3H), 5.35 (m, 1H), 6.65-8.03 (m, 13H).
Anal. Calcd. for C
H O N (370): C, 77.84; H, 5.95; N,
24 22 2 2
7.57. Found: C, 77.83; H, 6.15; N, 7.53.
2-Chloro-4-phenyl-2a-(4-methoxyphenyl)-3,5-dihydroaze-
tidino[1,2-d]benzo[b][1,4]diazepin-1-one (III ).
[6] B. Y. Mi and S. Jin, Chinese Chem. Lett., 2, 925 (1991).
[7] D. Yao, B. Y. Mi, S. Jin and X. L. Jin, Synthetic Chemistry, 6,
272 (1998).
[8] Y. C. Lu, P. Liu, S. Jin and Q. Y. Xing, Scientia Sinica(B), 4,
339 (1987).
[9] Y. C. Lu and S. Jin, J. Mol. Struct. (Thro Chem), 167, 253
(1988).
[10] A. Syollosy and G. Kotorych, Can. J. Chem., 66, 279
(1988).
a
To a solution containing 1.30 g (3 mmol) of II and 0.34 ml
a
(6 mmol) of chloroacetyl chloride in 80 ml of anhydrous benzene
was added a solution of 0.84 ml (6 mmol) triethylamine in 80 ml
anhydrous benzene in 2 hours under reflux. The reaction mixture
was then concentrated and separated via chromatography using
cyclohexane:ethyl acetate (5:4) as the eluant to give 0.66 g of
-1
solid product in 43% yield, mp 224-5°; ir: ν 1770, 1630 cm ; ms:
+
1
m/z 508 (M ), 473, 427, 312, 105 (100), 77; H nmr (deuterio-
chloroform): δ 2.90 (dd, 1H), 3.37 (dd, 1H), 3.72 (s, 3H), 5.03
(s, 1H), 6.10 (dd, 1H), 6.24-8.48 (m, 18H).
[11] H. Z. Wang, B. H. Huang, Z. Chun and S. Jin, Chinese J. of
Organic Chemistry, 20, 218 ( 2000).