Diastereoselective synthesis of enantiopure (αR)-2-methyl-4-(α- phenylethyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones

Article abstract of DOI:10.1016/j.tetasy.2003.11.033

(αR,2R)- and (αR,2S)-2-methyl-4-(α-phenylethyl)-1,2,3,4- tetrahydro-benzo[e][1,4]diazepin-5-ones 7 and 8 were synthesised by an intramolecular azide cycloaddition followed by stereoselective reduction of a bicyclic ketimine.

Full text of DOI:10.1016/j.tetasy.2003.11.033

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 687–692
Diastereoselective synthesis of enantiopure (aR)-2-methyl-4-
(a-phenylethyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones
Egle Beccalli,a Gianluigi Broggini,b,* Giuseppe Paladino,b Tullio Pilatic
and Guido Pontremolia
aIstituto di Chimica Organica ‘A. Marchesini’, Facoltꢀa di Farmacia, Universitꢀa di Milano, via Venezian 21, 20133 Milano, Italy
bDipartimento di Scienze Chimiche, Fisiche e Matematiche, Universitꢀa dell’Insubria, via Valleggio 11, 22100 Como, Italy
cConsiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Molecolari, via Golgi 19, 20133 Milano, Italy
Received 6 November 2003; accepted 18 November 2003
Abstract—(aR,2R)- and (aR,2S)-2-methyl-4-(a-phenylethyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones 7 and 8 were synthes-
ised by an intramolecular azide cycloaddition followed by stereoselective reduction of a bicyclic ketimine.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Several strategies of access to 1,4-benzodiazepin-5-ones
are known,5 but the structural variety within this class of
drugs justifies continuing work on novel synthetic
methodologies, particularly if they lead to enantiopure
products.6 In this context, we have previously reported a
synthetic approach to 1,4-benzodiazepin-5-ones where
the construction of the seven-membered ring relies upon
an intramolecular cycloaddition of the azido group onto
a multiple C–C bond.7 We herein report a convenient
extension of the same approach, which leads to
2-methyl-4-(a-phenylethyl)-1,2,3,4-tetrahydro-benzo[e][1,
4]diazepin-5-ones in enantiomerically pure form. To this
end, we used as key intermediates N,N-disubstituted
2-azidobenzamides bearing both an ethylenic bond and
the (R)-phenylethyl unity.
The 1,4-benzodiazepin-5-one skeleton is of interest be-
cause of its frequent presence in molecules with phar-
macological activity.1 Their use mainly concerns the
pharmacotherapy of allergies (i.e., tarpane),2 anxiety
(i.e., diazepam and oxazepam),3 epilepsy, convulsive
states and emotional disorder (i.e., flumazenil).4
Cl
Me
H
N
O
N
N
N
Cl
O
Ph
NMe2
diazepam
tarpane
N
N
O
COOEt
H
N
2. Results and discussion
OH
N
Cl
The (R)-N-allyl-2-amino-N-(a-phenylethyl)-benzamides
3a–c were synthesised by allylation of the amides 1a–c
and reduction of the nitroderivatives 2a–c according to
the procedure already reported for compound 3a.8 We
previously found that diazotisation of 3a, followed by
treatment with sodium azide and subsequent reflux in
toluene, gave the bicyclic ketimine 6a.9 We have now
isolated the intermediate azido compound 4a and
proven the general feasibility of the sequence with
the substrates 3b and c. Curiously, as revealed by
NMR spectroscopy, compounds 4a–c exist at room
N
F
Ph
Me
O
oxazepam
flumazenil
Keywords: Benzo[e][1,4]diazepin-5-ones; Diastereoselective synthesis;
Ketimine reduction; Diffractometric X-ray analysis.
* Corresponding author. Tel.: +39-031-2386441; fax: +39-031-23864-
49; e-mail: gianluigi.broggini@uninsubria.it
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.033

688
E. Beccalli et al. / Tetrahedron: Asymmetry 15 (2004) 687–692
NO2
Br
NO2
Cl
Ph
toluene, ∆
K2CO3, NaOH
H
X
NH
H3C
H N
2
_
+
+
X
Bu4N HSO4
toluene, ∆
K2CO3
O
CH3
O
Ph
H
1
NO2
NH2
1) NaNO2/HCl
2) NaN3
Fe/EtOH
AcOH
X
N
X
N
O
H3C
O
H3C
Ph
Ph
H
H
2
3
N
N
N
N
N3
toluene
N
N
X
X
∆
N
X
Ph
O
H3C
O
Ph
Ph
O
H
H3C
H3C
H
H
4
6
5
c
entry
a
b
X
H
Cl
F
Scheme 1. Preparation and intramolecular cycloaddition of azides 4a–c.
temperature as a 4:3 mixture of two conformers,
probably due to restricted rotation around the amide
bond. The conversion of 4a–c to 6a–c, carried out in
refluxing toluene, proceeded in 54–72% yields. Since it
is well known that the 4,5-dihydro-1,2,3-triazoles can
thermally lose nitrogen,10 the intermediacy of the intra-
molecular cycloadducts 5a–c is reasonable (Scheme 1).
reducing agent gave the same diastereoselectivity as the
one observed with NaBH4.
CH3
H
CH3
H
H
N
H
N
NaBH4
6a-c
+
N
N
X
X
THF, EtOH
-40°C
Ph
Ph
O
O
At this point, having in hand optically active substrates,
we saw an opportunity of manipulating them to create a
new stereocentre hopefully in a selective manner. The
reaction of 6a with NaBH4 actually gave two products,
which were isolated in their pure state by column
chromatography in 53% and 9% yield. According to the
1H NMR, their ratio in the crude mixture was 75:25.
Spectroscopic and analytical investigations were con-
sistent with two diastereoisomeric structures (Scheme 2),
but did not allow the assignment of the configuration of
the new stereocentre. Since both compounds 7a and 8a
were oily materials, we converted the secondary amine
group of the major diastereoisomer 7a into the benz-
amide 9 with the aim of carrying out X-ray crystal
structure analysis. The latter revealed an (R)-configu-
ration at the stereocentre at position 2 (Fig. 1) thus
allowing the absolute configurations (aR,2R) and
(aR,2S) to be assigned to 7a and 8a, respectively. The
same reaction occurred with the ketimines 6b and c to
give 7-chloro- and 7-fluoro-substituted 2-methyl-4-(a-
phenylethyl)-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-
ones 7b and c and 8b and c, whose absolute configura-
tions were inferred from their NMR spectra when
compared to the 7a and 8a. It is noteworthy that the
treatment of the ketimine 6a with DIBALH as the
H3C
H
H3C
H
7a-c
8a-c
PhCOCl
pyridine
Ph
O
CH3
H
N
N
Ph
entry
X
a
c
b
O
H3C
H
H
Cl
F
9
Scheme 2. Reduction of the ketimines 6a–c.
3. Conclusion
A set of new enantiopure 1,4-benzodiazepin-5-ones has
been made available utilising an intramolecular azide
cycloaddition as a key step in building a bicyclic system.
The synthetic interest is enhanced by their close struc-
tural analogy with those of widely used drugs.

E. Beccalli et al. / Tetrahedron: Asymmetry 15 (2004) 687–692
689
4.3. General procedure for the preparation of (R)-N-
allyl-2-nitro-N-(a-phenylethyl)-benzamides 2b,c
The compounds were prepared as described in the lit-
erature for compound 2a.8
20
Compound 2b: 95% yield; oil; ½aꢀ ¼ +144.1 (c 0.34,
D
CHCl3); IR (neat): m 1644 cmꢁ1
;
1H NMR (CDCl3):
d ¼ 1:60 (3H, d, J ¼ 6.9 Hz), 4.65 (2H, d, J ¼ 5.0 Hz),
5.37 (1H, d, J ¼ 10.6 Hz), 5.44 (1H, d, J ¼ 17.3 Hz), 6.03
(1H, tdd, J ¼ 5.0, 10.6, 17.3 Hz), 6.12 (1H, q,
J ¼ 6.9 Hz), 6.97 (1H, d, J ¼ 9.2 Hz), 7.30–7.42 (6H, m),
8.19 (1H, d, J ¼ 9.2 Hz); 13C NMR (CDCl3): d ¼ 19:6
(q), 46.0 (t), 58.1 (d), 113.5 (d), 114.2 (d), 114.7 (d), 115.3
(d), 115.4 (d), 116.2 (d), 116.4 (d), 119.3 (t), 128.2 (d),
128.9 (d), 136.2 (s), 138.5 (s), 141.3 (s), 163.4 (s), 168.5
(s); MS: m=z 344 (Mþ). Anal. Calcd for C18H17ClN2O3:
C, 62.70; H, 4.97; N, 8.12. Found: C, 62.73; H, 5.18; N,
7.97.
Figure 1. ORTEP plot of 9 (molecule A); for clarity, only hydrogen
atoms bonded to chiral carbon atoms are reported. Thermal ellipsoids
at 50% probability level; hydrogen atoms not to scale.
4. Experimental section
4.1. General
20
Compound 2c: 71% yield; oil; ½aꢀ ¼ +82.4 (c 0.65,
CHCl3); IR (neat): m 1648 cmꢁ1
;
1DH NMR (CDCl3):
€
Melting points were measured on a Buchi B-540 heating
unit and are uncorrected. 1H and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively, on an
Avance 400 Bruker. Mass spectra were determined on a
WG-70EQ instrument. IR spectra were taken on a
FT-IR Perkin–Elmer 1725X spectrophotometer. Optical
rotations were measured on a Perkin–Elmer 343 plus
polarimeter at the sodium D line.
d ¼ 1:72 (3H, d, J ¼ 7.1 Hz), 4.35–4.80 (2H, m), 5.32
(1H, d, J ¼ 10.5 Hz), 5.48 (1H, d, J ¼ 17.1 Hz), 6.03 (1H,
tdd, J ¼ 5.0, 10.5, 17.1 Hz), 6.11 (1H, q, J ¼ 7.1 Hz), 6.98
(1H, dd, J ¼ 2.7, 9.2 Hz), 7.19 (1H, dd, J ¼ 2.7, 7.7 Hz),
7.35–7.53 (5H, m), 8.25 (1H, dd, J ¼ 4.7, 9.2 Hz); 13C
NMR (CDCl3): d ¼ 19:5 (q), 48.5 (t), 52.4 (d), 115.0 (dd,
JC–F ¼ 24.1 Hz), 116.7 (dd, JC–F ¼ 23.6 Hz), 117.6 (t),
126.8 (d), 128.0 (d), 128.2 (d), 128.4 (dd, JC–F ¼ 6.9 Hz),
129.0 (d), 136.4 (d, JC–F ¼ 133.4 Hz), 139.9 (s), 163.4 (s),
164.4 (s), 167.1 (s); MS: m=z 328 (Mþ). Anal. Calcd for
C18H17FN2O3: C, 65.85; H, 5.22; N, 8.53. Found: C,
65.99; H, 5.28; N, 8.71.
4.2. General procedure for the preparation of the
(R)-2-nitro-N-(a-phenylethyl)-benzamides 1b,c
This compound was prepared as described in the liter-
ature for compound 1a.8
4.4. General procedure for the preparation of (R)-N-
allyl-2-amino-N-(a-phenylethyl)-benzamides 3b,c
Compound 1b: 74% yield; mp 167–168 ꢁC (from diiso-
20
propyl ether); ½aꢀ ¼ +61.0 (c 0.20, CHCl3); IR (nujol): m
D
1
3320, 1646 cmꢁ1; H NMR (CDCl3): d ¼ 1:63 (3H, d,
The compounds were prepared as described in the lit-
erature for the compound 3a.8
J ¼ 7.4 Hz), 5.30 (1H, dq, J ¼ 7.0, 7.4 Hz; after deuteri-
ation: q, J ¼ 7.4 Hz), 6.10 (1H, br d, J ¼ 7.0 Hz, missing
after deuteriation), 7.29–8.11 (8H, m); 13C NMR
(CDCl3): d ¼ 21:3 (q), 50.2 (d), 126.3 (d), 126.5 (d),
126.8 (d), 128.3 (d), 129.3 (d), 130.4 (d), 130.8 (d), 133.0
(d), 134.9 (s), 138.4 (s), 140.9 (s), 142.3 (s), 164.5 (s); MS:
m=z 304 (Mþ). Anal. Calcd for C15H13ClN2O3: C, 59.12;
H, 4.30; N, 9.19. Found: C, 58.96; H, 4.41; N, 9.25.
20
Compound 3b: 78% yield; oil; ½aꢀ ¼ +59.7 (c 0.16,
D
CHCl3); IR (neat): m 3342, 1622 cmꢁ1
;
1H NMR
(CDCl3): d ¼ 1:62 (3H, d, J ¼ 7.0 Hz), 3.12 (2H, d,
J ¼ 4.8 Hz), 4.44–4.66 (2H, m), 4.77 (2H, br s, missing
after deuteriation), 5.90–6.00 (1H, m), 6.13 (1H, q,
J ¼ 7.0 Hz), 7.22–7.54 (7H, m), 8.19 (1H, d, J ¼ 8.8 Hz);
13C NMR (CDCl3): d ¼ 18:5 (q), 58.0 (d), 66.2 (t), 113.5
(d), 115.2 (t), 116.7 (d), 118.3 (d), 118.7 (d), 126.2 (d),
127.8 (d), 128.5 (d), 138.2 (s), 140.4 (s), 151.3 (s), 161.7
(s), 169.9 (s); MS: m=z 314 (Mþ). Anal. Calcd for
C18H19ClN2O: C, 68.67; H, 6.08; N, 8.90. Found: C,
68.81; H, 5.88; N, 8.95.
Compound 1c: 70% yield; mp 136–137 ꢁC (from diiso-
20
propyl ether); ½aꢀ ¼ +14.6 (c 0.28, CHCl3); IR (nujol): m
D
1
3325, 1642 cmꢁ1; H NMR (CDCl3): d ¼ 1:59 (3H, d,
J ¼ 6.9 Hz), 5.25 (1H, dq, J ¼ 6.6, 6.9 Hz; after deuteri-
ation: q, J ¼ 6.9 Hz), 6.45 (1H, br d, J ¼ 6.6 Hz, missing
after deuteriation), 7.08 (1H, dd, J ¼ 2.4, 7.6 Hz), 7.19
(1H, ddd, J ¼ 2.4, 7.6, 9.0 Hz), 7.25–7.39 (5H, m), 8.08
(1H, dd, J ¼ 4.6, 9.0 Hz); 13C NMR (CDCl3): d ¼ 21:4
(q), 50.1 (d), 116.6 (dd, JC–F ¼ 23.6 Hz), 117.5 (dd,
JC–F ¼ 22.1 Hz), 126.8 (d), 127.8 (dd, JC–F ¼ 7.7 Hz),
128.1 (d), 129.2 (d), 136.2 (d, JC–F ¼ 135.7 Hz), 142.5 (s),
164.0 (s), 164.7 (s), 166.6 (s); MS: m=z 288 (Mþ). Anal.
Calcd for C15H13FN2O3: C, 62.50; H, 4.55; N, 9.72.
Found: C, 62.49; H, 4.71; N, 9.52.
20
Compound 3c: 91% yield; oil; ½aꢀ ¼ +129.7 (c 0.50,
D
CHCl3); IR (neat): m 3328, 1630 cmꢁ1
;
1H NMR
(CDCl3): d ¼ 1:64 (3H, d, J ¼ 7.0 Hz), 3.48–3.58 (1H,
m), 3.89–4.36 (3H, m, after deuteriation 1H, m), 4.94–
5.06 (2H, m), 5.30–5.61 (1H, m), 5.64–5.83 (1H, m),
6.64–6.95 (5H, m), 7.24–7.42 (3H, m); 13C NMR
(CDCl3): d ¼ 19:1 (q), 58.8 (d), 70.1 (t), 113.6 (d), 117.0
(t), 117.5 (dd, JC–F ¼ 24.8 Hz), 118.2 (d), 118.4 (dd,

690
E. Beccalli et al. / Tetrahedron: Asymmetry 15 (2004) 687–692
JC–F ¼ 21.8 Hz), 127.7 (d), 128.0 (dd, JC–F ¼ 7.0 Hz),
128.9 (d), 140.6 (d, JC–F ¼ 138.9 Hz), 141.4 (s), 154.4 (s),
156.8 (s), 170.5 (s); MS: m=z 298 (Mþ). Anal. Calcd for
C18H19FN2O: C, 72.46; H, 6.42; N, 9.39. Found: C,
72.48; H, 6.59; N, 9.28.
4.53 (1H, br s), 4.84 (1H, br s), 5.94–6.10 (1H, m), 6.23
(1H, q, J ¼ 7.0 Hz), 7.07–7.48 (8H, m); 13C NMR
(CDCl3): major conformer: d ¼ 18:9 (q), 45.0 (t), 52.2
(d), 115.9 (dd, JC–F ¼ 22.9 Hz), 117.2 (t), 119.7 (dd,
JC–F ¼ 21.6 Hz), 121.0 (dd, JC–F ¼ 8.4 Hz), 126.9 (d),
127.8 (d), 128.4 (d), 129.0 (d), 133.1 (s), 134.5 (d,
JC–F ¼ 139.2 Hz), 158.5 (s), 161.0 (s), 167.3 (s); minor
conformer: d ¼ 18:7 (q), 48.1 (t), 57.6 (d), 114.0 (dd),
114.8 (dd), 116.7 (t), 122.4 (dd), 127.0 (d), 127.8 (d),
128.4 (d), 128.9 (d), 131.3 (s), 134.7 (d), 158.8 (s), 161.3
(s), 168.1 (s); MS: m=z 324 (Mþ). Anal. Calcd for
C18H17FN4O: C, 66.65; H, 5.28; N, 17.27. Found: C,
66.72; H, 5.16; N, 17.39.
4.5. General procedure for the preparation of (R)-N-
allyl-2-azido-N-(a-phenylethyl)-benzamides 4a–c
HCl (12 M, 2.2 mL, 27 mmol) was added to a solution of
3a–c (0.27 mmol) in Et2O (4 mL). After cooling at 0 ꢁC,
NaNO2 (37 mg, 0.54 mmol) was added and the mixture
was stirred for 30 min. NaN3 (88 mg, 1.35 mmol) was
then added and the solution stirred at room temperature
for 40 min. After separation, the organic layer was
washed with aqueous NaHCO3 and dried over Na2SO4.
The solvent was removed under reduced pressure to give
4a–c as a 4:3 mixture of two conformers.
4.6. General procedure for the preparation of (R)-2-
methyl-4-(a-phenylethyl)-3,4-dihydro-benzo[e][1,4]diaze-
pin-5-ones 6a–c
A solution of 4a–c (0.21 mmol) in toluene (4 mL) was
refluxed for 3 h. The evaporation of the solvent under
reduced pressure left a residue, which was chromato-
graphed on a silica gel column using hexane/AcOEt 1:2
as eluent to give 6a–c as a white solid.
20
Compound 4a: 75% yield; oil; ½aꢀ ¼ +71.4 (c 0.23,
D
CHCl3); IR (neat): m 2120, 1660 cmꢁ1
;
1H NMR
(CDCl3): major conformer: d ¼ 1:56 (3H, br s), 3.30–3.61
(2H, m), 4.72 (1H, br s), 4.91–5.08 (1H, m), 5.35 (1H, br
s), 5.81 (1H, br s), 7.00–7.45 (9H, m); minor conformer:
d ¼ 1:56 (3H, br s), 3.30–3.61 (2H, m), 4.51 (1H, br s),
4.74 (1H, br s), 4.91–5.08 (1H, m), 6.07 (1H, br s), 7.00–
7.45 (9H, m); 13C NMR (CDCl3): major conformer:
d ¼ 18:5 (q), 44.9 (t), 51.7 (d), 116.7 (t), 118.5 (d), 124.8
(d), 125.3 (d), 126.6 (d), 127.6 (d), 127.9 (d), 128.5 (d),
130.3 (d), 131.3 (s), 138.3 (s), 140.3 (s), 168.6 (s); minor
conformer: d ¼ 18:3 (q), 47.8 (t), 57.1 (d), 116.3 (t), 119.0
(d), 125.0 (d), 126.5 (d), 127.1 (d), 127.3 (d), 128.1 (d),
128.3 (d), 130.2 (d), 131.3 (s), 138.3 (s), 140.3 (s), 169.4
(s); MS: m=z 306 (Mþ). Anal. Calcd for C18H18N4O: C,
70.57; H, 5.92; N, 18.29. Found: C, 70.72; H, 6.04; N,
18.18.
Compound 6a: see literature.9
Compound 6b: 72% yield; mp 109–111 ꢁC (from diiso-
20
propyl ether); ½aꢀ ¼ +307.1 (c 0.40, CHCl3); IR
D
(CH2Cl2): m 1622 cmꢁ1
;
1H NMR (CDCl3): d ¼ 1:54–
1.63 (6H, m), 3.36, 3.43 (2H, AB system, J ¼ 14.0 Hz),
6.23 (1H, q, J ¼ 7.1 Hz), 7.20–7.48 (7H, m), 8.08 (1H,
dd, J ¼ 1.5, 7.4 Hz); 13C NMR (CDCl3): d ¼ 15:6 (q),
21.1 (q), 43.6 (t), 50.5 (d), 126.8 (d), 128.1 (d), 128.3 (d),
128.7 (d), 128.9 (d), 129.9 (d), 132.9 (s), 133.8 (s), 137.2
(s), 139.3 (s), 164.6 (s), 173.9 (s); MS: m=z 312 (Mþ).
Anal. Calcd for C18H17ClN2O: C, 69.12; H, 5.48; N,
8.96. Found: C, 69.29; H, 5.39; N, 9.09.
20
Compound 4b: 64% yield; oil; ½aꢀ ¼ +122.9 (c 0.18,
D
CHCl3); IR (neat): m 2112, 1633 cmꢁ1
;
1H NMR
Compound 6c: 54% yield; mp 126–127 ꢁC (from diiso-
20
(CDCl3): major conformer: d ¼ 1:67 (3H, d, J ¼ 6.6 Hz),
3.42–3.68 (2H, m), 4.12–4.36 (1H, m), 4.76–4.99 (1H,
m), 5.06–5.20 (1H, m), 5.98 (1H, br s), 7.08–7.70 (8H,
m); minor conformer: d ¼ 1:57 (3H, d, J ¼ 6.6 Hz), 3.42–
3.68 (2H, m), 4.53–4.71 (1H, m), 4.76–4.99 (1H, m),
5.29–5.51 (1H, m), 6.14 (1H, br s), 7.08–7.70 (8H, m);
13C NMR (CDCl3): major conformer: d ¼ 18:9 (q), 45.4
(t), 52.2 (d), 112.4 (d), 117.4 (t), 121.2 (d), 125.6 (d),
128.2 (d), 128.5 (d), 128.9 (d), 130.5 (d), 130.8 (s), 137.4
(s), 140.4 (s), 162.5 (s), 167.4 (s); minor conformer:
d ¼ 18:8 (q), 48.2 (t), 57.6 (d), 109.0 (d), 116.9 (t),
122.9 (d), 126.9 (d), 128.2 (d), 128.5 (d), 128.8 (d), 130.6
(d), 131.0 (s), 137.4 (s), 140.5 (s), 162.5 (s), 168.8 (s); MS:
m=z 340 (Mþ). Anal. Calcd for C18H17ClN4O: C,
63.44; H, 5.03; N, 16.44. Found: C, 63.29; H, 4.88; N,
16.59.
propyl ether); ½aꢀ ¼ +339.0 (c 0.30, CHCl3); IR
D
(CH2Cl2): m 1634 cmꢁ1
;
1H NMR (CDCl3): d ¼ 1:58–
1.65 (6H, m), 3.32, 3.42 (2H, AB system, J ¼ 14.3 Hz),
6.22 (1H, q, J ¼ 7.2 Hz), 7.11–7.58 (7H, m), 7.77 (1H,
dd, J ¼ 1.7, 8.8 Hz); 13C NMR (CDCl3): d ¼ 16:5 (q),
25.7 (q), 43.0 (t), 51.9 (d), 117.2 (dd, JC–F ¼ 25.0 Hz),
119.4 (dd, JC–F ¼ 24.7 Hz), 128.2 (d), 128.5 (dd,
JC–F ¼ 8.1 Hz), 128.8 (d), 129.2 (d), 140.8 (d,
JC–F ¼ 131.6 Hz), 142.8 (s), 159.3 (s), 161.7 (s), 166.4 (s),
169.7 (s); MS: m=z 296 (Mþ). Anal. Calcd for
C18H17FN2O: C, 72.96; H, 5.78; N, 9.45. Found: C,
73.01; H, 5.89; N, 9.66.
4.7. General procedure for the reaction of 6a–c with
NaBH4
20
Compound 4c: 68% yield; oil; ½aꢀ ¼ +136.6 (c 0.60,
D
CHCl3); IR (neat): m 2121, 1646 cmꢁ1
;
1H NMR
A solution of NaBH4 (7.6 mg, 0.20 mmol) in water
(0.4 mL) was added dropwise at )20 ꢁC to a solution of
4a–c (0.14 mmol) in THF (0.3 mL) and EtOH (0.3 mL).
After cooling for 1 h at )40 ꢁC and for 15 h at )20 ꢁC,
the mixture was poured in water (20 mL), adjusted to
(CDCl3): major conformer: d ¼ 1:66 (3H, br s), 3.38–3.58
(2H, m), 4.80 (1H, br s), 5.04–5.11 (1H, m), 5.79–5.92
(1H, br s), 6.13 (1H, q, J ¼ 7.0 Hz), 7.07–7.48 (8H, m);
minor conformer: d ¼ 1:66 (3H, br s), 3.38–3.58 (2H, m),

E. Beccalli et al. / Tetrahedron: Asymmetry 15 (2004) 687–692
691
pH 11 with 40% aqueous NaOH and extracted with
Et2O (30 mL · 3). The organic layer was dried over
Na2SO4 and the solvent removed under reduced pres-
sure. The residue was chromatographed on a silica gel
column to give 7a–c and 8a–c.
4.7.4. (aR,2S)-7-Chloro-2-methyl-4-(a-phenylethyl)-1,2,
3,4-tetrahydro-benzo[e][1,4]diazepin-5-one 8b. Oil;
20
D
½aꢀ ¼ +108.1 (c 0.38, CHCl3); IR (CH2Cl2): m 3061,
1620 cmꢁ1
;
1H NMR (CDCl3): d ¼ 0:85 (3H, d,
J ¼ 6.3 Hz), 1.56 (3H, q, J ¼ 7.0 Hz), 3.02 (1H, tq,
J ¼ 6.3, 6.4 Hz), 3.19 (2H, d, J ¼ 6.4 Hz), 3.58 (1H, br s,
missing after deuteriation), 6.24 (1H, q, J ¼ 7.0 Hz), 6.50
(1H, d, J ¼ 8.0 Hz), 7.15 (1H, dd, J ¼ 7.4, 7.6 Hz), 7.28–
7.36 (5H, m), 7.88 (1H, d, J ¼ 1.3 Hz); 13C NMR
(CDCl3): d ¼ 19:0 (q), 21.4 (q), 50.9 (d), 52.8 (d), 52.9
(t), 113.5 (d), 119.7 (s), 122.0 (s), 126.8 (d), 128.1 (d),
128.2 (d), 128.3 (d), 130.7 (d), 137.2 (s), 140.1 (s), 166.1
(s); MS: m=z 314 (Mþ). Anal. Calcd for C18H19ClN2O:
C, 68.67; H, 6.08; N, 8.90. Found: C, 68.51; H, 5.93; N,
9.06.
Entry a: elution with AcOEt/hexane 2:1 gave 8a (9%)
and 7a (53%).
4.7.1.
(aR,2R)-2-Methyl-4-(a-phenylethyl)-1,2,3,4-
20
tetrahydro-benzo[e][1,4]diazepin-5-one 7a. Oil; ½aꢀ
¼
D
)24.1 (c 0.34, CHCl3); IR (CH2Cl2): m 3058, 1629 cmꢁ1
;
1H NMR (CDCl3): d ¼ 1:06 (3H, d, J ¼ 6.3 Hz), 1.62
(3H, d, J ¼ 7.0 Hz), 2.97 (1H, dd, J ¼ 4.0, 15.2 Hz), 3.04
(1H, dd, J ¼ 9.2, 15.2 Hz), 3.57 (1H, br s, missing after
deuteriation), 3.76 (1H, ddq, J ¼ 4.0, 6.3, 9.2 Hz), 6.26
(1H, q, J ¼ 7.0 Hz), 6.58 (1H, dd, J ¼ 1.1, 8.1 Hz), 6.87
(1H, ddd, J ¼ 1.1, 7.7, 8.1 Hz), 7.18–7.36 (6H, m), 7.88
(1H, dd, J ¼ 1.8, 7.7 Hz); 13C NMR (CDCl3): d ¼ 16:8
(q), 20.3 (q), 47.7 (t), 51.3 (d), 56.7 (d), 119.4 (d), 119.7
(d), 122.8 (s), 127.1 (d), 128.4 (d), 128.7 (d), 132.4 (d),
132.5 (d), 141.0 (s), 143.9 (s), 170.0 (s); MS: m=z 280
(Mþ). Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N,
9.99. Found: C, 76.92; H, 7.21; N, 9.86.
Entry c: elution with AcOEt/hexane 3:1 gave 8c (12%)
and 7c (45%).
4.7.5. (aR,2R)-7-Fluoro-2-methyl-4-(a-phenylethyl)-1,2,
3,4-tetrahydro-benzo[e][1,4]diazepin-5-one
7c.
Oil;
20
D
½aꢀ ¼ )23.1 (c 0.01, CHCl3); IR (CH2Cl2): m 3045,
1634 cmꢁ1
;
1H NMR (CDCl3): d ¼ 1:05 (3H, d,
J ¼ 6.3 Hz), 1.66 (3H, d, J ¼ 7.0 Hz), 2.96–3.04 (2H, m),
3.42 (1H, br s, missing after deuteriation), 3.77 (1H,
ddq, J ¼ 4.1, 6.3, 8.9 Hz), 6.24 (1H, q, J ¼ 7.0 Hz), 6.60
(1H, dd, J ¼ 4.5, 8.7 Hz), 6.98 (1H, ddd, J ¼ 3.0, 8.7,
9.4 Hz), 7.28–7.42 (5H, m), 7.58 (1H, dd, J ¼ 3.0,
9.4 Hz); 13C NMR (CDCl3): d ¼ 17:1 (q), 20.9 (q), 47.7
(t), 51.8 (d), 57.4 (d), 118.0 (dd, JC–F ¼ 23.5 Hz), 119.5
(dd, JC–F ¼ 22.8 Hz), 121.8 (dd, JC–F ¼ 7.0 Hz), 127.6 (d),
127.8 (d), 129.0 (d), 139.9 (d, JC–F ¼ 134.9 Hz), 141.2 (s),
156.4 (s), 158.8 (s), 169.2 (s); MS: m=z 298 (Mþ). Anal.
Calcd for C18H19FN2O: C, 72.46; H, 6.42; N, 9.39.
Found: C, 72.51; H, 6.63; N, 9.51.
4.7.2. (aR,2S)-2-Methyl-4-(a-phenylethyl)-1,2,3,4-tetra-
20
D
hydro-benzo[e][1,4]diazepin-5-one 8a. Oil; ½aꢀ ¼ +155.0
1
(c 0.36, CHCl3); IR (CH2Cl2): m 3054, 1622 cmꢁ1; H
NMR (CDCl3): d ¼ 0:77 (3H, d, J ¼ 6.3 Hz), 1.49 (3H,
d, J ¼ 7.0 Hz), 2.79 (1H, tq, J ¼ 6.3, 6.4 Hz), 2.99 (2H, d,
J ¼ 6.4 Hz), 3.49 (1H, br s, missing after deuteriation),
6.24 (1H, q, J ¼ 7.0 Hz), 6.54 (1H, d, J ¼ 8.0 Hz), 6.86
(1H, dd, J ¼ 7.4, 7.6 Hz), 7.15–7.46 (6H, m), 7.88 (1H,
dd, J ¼ 1.3, 7.6 Hz); 13C NMR (CDCl3): d ¼ 15:9 (q),
21.0 (q), 46.8 (t), 51.5 (d), 55.5 (d), 119.1 (d), 119.5 (d),
122.6 (s), 127.5 (d), 128.2 (d), 128.7 (d), 131.8 (d), 132.2
(d), 139.9 (s), 143.8 (s), 169.6 (s); MS: m=z 280 (Mþ).
Anal. Calcd for C18H20N2O: C, 77.11; H, 7.19; N, 9.99.
Found: C, 77.17; H, 7.03; N, 9.82.
4.7.6. (aR,2S)-7-Fluoro-2-methyl-4-(a-phenylethyl)-1,2,
3,4-tetrahydro-benzo[e][1,4]diazepin-5-one
8c.
Oil;
20
D
½aꢀ ¼ +81.7 (c 0.14, CHCl3); IR (CH2Cl2): m 3092,
1625 cmꢁ1
;
1H NMR (CDCl3): d ¼ 0:85 (3H, d,
J ¼ 6.3 Hz), 1.58 (3H, d, J ¼ 7.0 Hz), 2.06 (1H, br s,
missing after deuteriation), 2.81–3.04 (3H, m), 6.21 (1H,
q, J ¼ 7.0 Hz), 6.55 (1H, dd, J ¼ 4.5, 8.7 Hz), 6.72 (1H,
dd, J ¼ 4.4, 8.4 Hz), 7.32–7.48 (6H, m); 13C NMR
(CDCl3): d ¼ 16:2 (q), 20.9 (q), 46.4 (t), 51.9 (d), 56.2
Entry b: elution with AcOEt/hexane 3:1 gave 8b (11%)
and 7b (48%).
4.7.3. (aR,2R)-7-Chloro-2-methyl-4-(a-phenylethyl)-1,2,
(d),
117.9
(dd,
JC–F ¼ 23.3 Hz),
119.6
(dd,
3,4-tetrahydro-benzo[e][1,4]diazepin-5-one
7b.
Oil;
JC–F ¼ 22.6 Hz), 122.8 (dd, JC–F ¼ 7.2 Hz), 127.7 (d),
128.4 (d), 129.1 (d), 138.1 (d, JC–F ¼ 136.1 Hz), 140.1 (s),
140.8 (s), 159.1 (s) 169.3 (s); MS: m=z 298 (Mþ). Anal.
Calcd for C18H19FN2O: C, 72.46; H, 6.42; N, 9.39.
Found: C, 72.38; H, 6.53; N, 9.22.
20
D
½aꢀ ¼ )18.7 (c 0.24, CHCl3); IR (CH2Cl2): m 3054,
1622 cmꢁ1
;
1H NMR (CDCl3): d ¼ 1:09 (3H, d,
J ¼ 6.3 Hz), 1.64 (3H, d, J ¼ 7.0 Hz), 3.03 (1H, dd,
J ¼ 4.0, 15.2 Hz), 3.57 (1H, br s, missing after deuteria-
tion), 3.75 (1H, dd, J ¼ 9.2, 15.2 Hz), 4.24 (1H, ddq,
J ¼ 4.0, 6.3, 9.2 Hz), 6.27 (1H, q, J ¼ 7.0 Hz), 6.54 (1H,
dd, J ¼ 1.1, 8.1 Hz), 7.25 (1H, dd, J ¼ 1.1, 7.7 Hz), 7.18–
7.40 (5H, m), 7.89 (1H, d, J ¼ 2.5 Hz); 13C NMR
(CDCl3): d ¼ 19:8 (q), 20.6 (q), 50.7 (d), 52.2 (t), 53.9
(d), 113.7 (d), 119.5 (s), 122.3 (s), 126.7 (d), 128.6 (d),
128.7 (d), 129.0 (d), 130.5 (d), 138.3 (s), 140.2 (s), 166.5
(s); MS: m=z 314 (Mþ). Anal. Calcd for C18H19ClN2O:
C, 68.67; H, 6.08; N, 8.90. Found: C, 68.70; H, 5.88; N,
8.79.
4.8. (aR,2R)-1-Benzoyl-2-methyl-4-(a-phenylethyl)-
1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one 9
Benzoyl chloride (5.0 mL, 4.31 mmol) was dropped into
a solution, previously cooled to 0 ꢁC, of 7a (0.54 g,
1.93 mmol) in pyridine (10 mL). After stirring at rt for
2 days, the mixture was poured into 5% aqueous HCl
and extracted with CH2Cl2 (20 mL · 3). The organic

692
E. Beccalli et al. / Tetrahedron: Asymmetry 15 (2004) 687–692
layer was washed with aqueous NaHCO3 (20 mL · 2)
and dried over Na2SO4. The solvent was removed under
reduced pressure and the crude solid chromatographed
on a silica gel column using light petroleum/AcOEt (1:1)
CCDC, 2 Union Road, Cambridge CB2 1EZ, UK,
e-mail: deposit@ccdc.cam.ac.uk.
as the eluent to give 630 mg of 9 (85%). Mp 156–157 ꢁC
Acknowledgements
20
(from diisopropyl ether); ½aꢀ ¼ )362.9 (c 0.28, CHCl3);
D
IR (nujol): m 1638, 1629 cmꢁ1
;
1H NMR (CDCl3):
We are grateful to MURST and CNR for financial
support.
d ¼ 1:12 (3H, d, J ¼ 6.3 Hz), 1.72 (3H, d, J ¼ 7.2 Hz),
2.84 (1H, dd, J ¼ 12.6, 15.2 Hz), 3.11 (1H, dd, J ¼ 5.3,
15.5 Hz), 5.11 (1H, ddq, J ¼ 5.3, 6.3, 12.6 Hz), 6.24 (1H,
q, J ¼ 7.2 Hz), 6.62 (1H, d, J ¼ 7.8 Hz), 7.15–7.41 (12H,
m), 7.85 (1H, dd, J ¼ 1.3, 7.7 Hz); 13C NMR (CDCl3):
d ¼ 15:8 (q), 18.4 (q), 47.9 (t), 51.3 (d), 57.3 (d), 127.6
(d), 128.0 (d), 128.4 (d), 128.6 (d), 128.9 (d), 129.1 (d),
129.2 (d), 130.2 (d), 130.4 (d), 131.8 (d), 135.2 (s), 135.8
(s), 136.4 (s), 140.8 (s), 169.4 (s), 171.0 (s); MS: m=z 384
(Mþ). Anal. Calcd for C25H24N2O2: C, 78.10; H, 6.29;
N, 7.29. Found: C, 78.22; H, 6.10; N, 7.36.
References and notes
1. (a) Vida, J. A. In Medicinal Chemistry Part III; Wolf,
M. V., Burger, A., Eds.; Wiley: New York, 1981; (b)
Landquist, J. K. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford,
1984; Vol. 1, Chapter 1/06; (c) Sharp, J. T. In Compre-
hensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon: Oxford, 1984; Vol. 7, Chapter 5/18;
(d) Baldessarini, R. J. In The Pharmacologic Basis of
Therapeutics; Gilman, A. G., Goodman, L. S., Ralland,
T. W., Murad, F., Eds.; Macmillan: New York, 1985; pp
391–413.
2. (a) Hanze, A. R.; Strube, R. E.; Greig, M. E. J. Med.
Chem. 1963, 6, 767; (b) Waldvogel, E.; Schwarb, G.;
Bastian, J.-M.; Bourquin, J.-P. Helv. Chim. Acta 1976, 59,
866.
3. Reeder, E.; Sternbach, L. U.S. Patent 3,109,843, 1963;
Chem. Abstr. 1964, 60, 2994a.
4.9. X-ray crystallographic analysis of 9
Single-crystal X-ray diffraction measurements were
performed on a Bruker SMART-APEX diffractometer,
equipped with a Bruker KRIOFLEX low temperature
device; graphite monochromator, Mo-Ka radiation
ꢁ
(k ¼ 0:71073 A). C25H24N2O2, Mr ¼ 384:46, monoclinic,
space group P21, a ¼ 11:895ð2Þ, b ¼ 8:7488ð11Þ,
3
ꢁ
ꢁ
c ¼ 29:595ð4Þ A, b ¼ 95:163ð8Þꢁ, V ¼ 3067:4ð8Þ A , Z ¼
6, Dc ¼ 1:249 g cmꢁ3, l(Mo-Ka) ¼ 0.080 mmꢁ1. Data
were collected at T ¼ 90 K, because the crystals were
very poorly diffracting at room temperature; 24233
collected data up to 2h ¼ 55ꢁ; 7401 unique [5633 with
I0 > 2rðI0Þ], Rave ¼ 0:0526. Structure solved by SIR-9211
and refined by SHELX9712; final disagreement factors
for all (observed) reflections: RwðF 2Þ ¼ 0:0891ð0:0839Þ
and R ¼ 0:0612ð0:0417Þ, goodness-of-fit ¼ 0.991. The
asymmetric unit contains three independent molecules
signed as A, B and C. Figure 1 shows a projection of
molecule A; the numbering scheme of the three mole-
cules is exactly the same. The cyclic nucleus of the three
molecules is very similar, while large differences are
found for the torsion angles around the bonds C12–C14
and C21–C23; for example, the torsion angles N4–C21–
C23–C24 and O13–C12–C14–C19 are 127.2(7), 112.0(6),
165.1(2) and )128.1(3), )146.5(2), )131.9(3)ꢁ for mole-
cules A, B and C, respectively. All crystallographic data
(excluding structure factors) were deposited at the
Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC 223466. Copies of the
data can be obtained free of charge on application to
€
^
4. Frostl, W.; Maıtre, L. Pharmacopsych 1989, 22, 54.
5. Walser, A.; Fryer, R. I. In Bicyclic Diazepines; Wiley: New
York, 1991; Chapter VII.
6. (a) Sunjic, W.; Lisini, A.; Segar, A.; Kovac, T.; Kojtez, F.;
Ruscic, B. J. Heterocycl. Chem. 1979, 16, 757; (b) Herrero,
ꢂ
S.; Garcıa-Lopez, M. T.; Cenarruzabeitia, E.; Del Rio, J.;
Herranz, R. Tetrahedron 2003, 59, 4491; (c) Herrero, S.;
ꢂ
Garcıa-Lopez, M. T.; Herranz, R. J. Org. Chem. 2003, 68,
ꢂ
ꢂ
4582.
7. (a) Broggini, G.; Molteni, G.; Zecchi, G. Synthesis 1995,
647; (b) Broggini, G.; Molteni, G.; Zecchi, G. Gazz. Chim.
Ital. 1997, 127, 809.
8. Broggini, G.; Garanti, L.; Molteni, G.; Pilati, T.; Ponti,
A.; Zecchi, G. Tetrahedron: Asymmetry 1999, 10, 2203.
9. Broggini, G.; Molteni, G.; Pilati, T. Tetrahedron: Asym-
metry 2002, 13, 2491.
10. (a) Bourgois, J.; Bourgois, M.; Texier, F. Bull. Soc. Chim.
Fr. 1978, 485; (b) Patai, S. The Chemistry of the Azido
Group; Interscience: London, 1971.
11. Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, G. J. Appl.
Crystallogr. 1994, 27, 435.
12. Sheldrick, G. M. SHELX97. Program for the Refinement
€
of Crystal Structures, University of Gottingen, Germany,
1997.