Synthesis of 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones by addition of Grignard reagents to derivatives of o-aminobenzonitrile

Article abstract of DOI:10.1039/b819260j

Addition of organometallics to N-(α-haloacyl)-o-aminobenzonitrile resulted in the formation of 2,5-disubstituted 1,4-benzodiazepin-3-ones, whereas N-(β-haloacyl)-o-aminobenzonitrile gave 2,6-disubstituted 1,5-benzodiazocin-4-ones under similar conditions.

Full text of DOI:10.1039/b819260j

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of 1,4-benzodiazepin-3-ones and 1,5-benzodiazocin-4-ones by
addition of Grignard reagents to derivatives of o-aminobenzonitrile
Birgitta Pettersson, Anna Rydbeck† and Jan Bergman*
Received 30th October 2008, Accepted 12th December 2008
First published as an Advance Article on the web 5th February 2009
DOI: 10.1039/b819260j
Addition of organometallics to N-(a-haloacyl)-o-aminobenzonitrile resulted in the formation of
2,5-disubstituted 1,4-benzodiazepin-3-ones, whereas N-(b-haloacyl)-o-aminobenzonitrile gave
2,6-disubstituted 1,5-benzodiazocin-4-ones under similar conditions. Initial cylization of
N-(b-haloacyl)-o-aminobenzonitrile to obtain the corresponding lactam (e.g. a,a-dimethyl-
N-(2-cyanophenyl)-b-lactam) increased the yield of 1,5-benzodiazocin-4-ones significantly.
Somewhat surprisingly, addition of lithium reagents to N-(b-haloacyl)-o-aminobenzonitrile
gave 4,4-disubstituted quinazolines via Grob fragmentation.
the last decade, usually involving intermolecular nucleophilic
Introduction
aromatic substitution.5,6 It should be noted that these rare 1,4-
Several 1,4-benzodiazepines have during a long period of time
benzodiazepin-3-ones also have biological activities. The potent
antithrombotic agent Lotrafiban (E) provides an example (Fig. 2).6
been used as drugs. The psychoactive drugs Librium (A), Valium
(B), Ativan (C) and Xanax (D) are perhaps the most well known
(Fig. 1). Further extensive investigations of this class of seven-
membered N-heterocycles have also led to development of a
number of pharmacologically active agents directed against other
diseases such as cancer, HIV and cardio-arrhythmia in addition
to the well-known anxiolytic and sedative effects.1,2
Moreover, alkaloids containing the 1,4-benzodiazepine moiety
have been found among secondary metabolites derived from
anthranilic acid. Most of the naturally occurring benzodiazepines
are biologically active; however, molecules with tranquilizing
properties have not been found.3
Despite the number and immense diversity of synthetic 1,4-
benzodiazepines, especially the 1,4-benzodiazepin-2-ones, there
are only a few studies available concerning 1,4-benzodiazepin-
3-ones with the general formulas 1 and 2 (Fig. 2).4 1,4-
Benzodiazepin-3-ones have lately attracted attention as pep-
tidomimetics, thus a few synthetic methods have appeared during
Fig. 2
Previous studies have shown that treatment of o-amino-
benzonitrile (3), or its N-acylated derivatives (4), with Grig-
nard reagents can result in the formation of the unusual 1,4-
benzodiazepin-3-ones (1 and 2) often formed together with the
quinazolines 5 (Scheme 1).7a,b Initially, the organometallic reagent
Karolinska Institute, Department of Biosciences at Novum, Unit of Organic
Chemistry, SE-141 57, Huddinge, Sweden. E-mail: jabe@biosci.ki.se
† Ne`e Brynolf; present address, Amersham Health R & B AB, Medeon
SE-205 12 Malmo¨, Sweden
Fig. 1
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Scheme 1 Overview of Routes A and B toward 1,4-benzodiazepines 1 and 2. M = MgBr, R = aryl, R1 = alkyl, R2 = alkyl or H, X = Br.
adds to the nitrile function, leading to the formation of an imine
dianion 6, which in some cases can be isolated. The reactivity
of these anions and Route A to yield 1,4-benzodiazepine-3-ones
1 has recently been investigated in our group.8 Compound 1
(R = Ph, R1 = R2 = Me) could also be separated into two
crystalline conformers (A and B), whose structures (Fig. 3) have
been determined by X-ray crystallography.7b
N-bromoacetylanthranilate gave 1,4-benzodiazepin-2,5-dione
(10) under the same reaction conditions (Scheme 2). In order to
favour the formation of the desired benzodiazepine 1 we used the
bromo-substituted starting material 4.
Scheme 2 The influence of the substituent on the cyclization.9
Addition of alkyl Grignard reagents and lithium regents (BuLi,
PhLi) to 4 failed to give benzodiazepines, and instead 4-amino-
2-quinolinones were formed, via halogen-metal exchange at the
a-carbon as previously reported by Bergman et al.10 Addition of
LiCl or TMEDA did not change the outcome of this reaction.
A side reaction in the synthesis of 1,4-benzodiazepin-3-ones
is the addition of a second equivalent of the Grignard reagent
which occurred when isomerisation of 1 was possible, i.e. R2 =
H (Scheme 3). It is reasonable to assume that 2,3-dihydro-
1H-1,4-benzodiazepin-3-one is initially formed, which thereafter
rapidly undergoes intramolecular hydride transfer to 4,5-dihydro-
1,4-benzodiazepin-3-one 2. In fact when such an isomerisation
was possible (R2 = H), only the 4,5-dihydro compound 2a–f,
and in some cases the 2,2,5-trisubstituted derivative 11, could
be isolated. It is known that the imine bond is susceptible to
nucleophiles, and accordingly we have observed hydrolytic ring
opening and also addition of phenylmagnesium bromide to 2-
phenyl-1,4-benzodiazepin-5-one.11 The proposed mechanism is
also supported by the fact that 2a could be converted to 11 by
addition of phenylmagnesium bromide (the structures of 2 (R1 =
Et) and 11(R1 = Et, R2 = Ph) have been confirmed by X-ray
crystallography).12 It is noteworthy that the addition of a second
equivalent of the Grignard reagent did not occur in any cases
except when R1 = Et, R2 = H. For example, when R1 = i-propyl
or i-butyl only the 2,5-disubstituted 1,4-benzodiazepin-3-ones (2)
could be isolated, probably due to steric hindrance exerted by the
R1 group. The 1,4-benzodiazepin-3-ones prepared via Route B are
summarised in Table 1.
Fig.
3
The two isolable conformers (A and B) of 1,2-dihy-
dro-2,2-dimethyl-5-phenyl-3H-1,4-benzodiazepin-3-one (1)7b.
Herein, we will take a closer look at Route B toward these
intriguing products (Scheme 1) starting from N-(a-haloacyl)-o-
anthranilonitrile (4). Furthermore, the methodology was also
applied to obtain a higher homologue of 1,4-benzodiazepine-3-
ones 1 and 2, namely the 1,5-benzodiazocin-4-one 7 from N-(b-
haloacyl)-o-aminobenzonitrile 8 (Scheme 5).
Results and discussion
In this study a few factors were observed to affect the course of
the reaction when organometallics, RM, reacted with N-haloacyl-
o-aminobenzonitrile 4 (Scheme 1, Route B). These factors are:
the nature of the halide (X) in the starting material (4), the
organometallic reagent (RM) and the substituents at the a-
position (R1, R2). The nature of the halide (X) has turned out
to influence the size of the ring formed in the reaction. Thus,
in some cases, quinazolines were obtained from the reaction
via intramolecular attack on the amide anion. This should be
disfavoured because of the low electrophilicity of the carbonyl
functionality, but in the case where X = Cl, this was nevertheless
the preferred outcome of the reaction. A similar precedent
has previously been reported9 by Pa´rka´nyi, who found that
methyl N-chloroacetylanthranilate cyclized to N-chloromethyl-
4-quinazolinone (9) when treated with ammonia, while methyl
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Scheme 3 Reagents and conditions: Compound 1: PhMgBr (2 eq), THF, reflux 12 h; General procedure for compound 2a–f: a) RMgBr (2 eq), THF,
reflux, 3 h; Compound 11: PhMgBr (4,5 eq), THF, reflux.
Table 1 1,4-Benzodiazepin-3-ones obtained via Route B, Scheme 3
Compound
R
R1
R2
Yield (%)
1
Ph
Ph
Ph
Ph
Me
Et
Et
i-Pr
i-Bu
Et
Me
Ph
H
H
H
H
H
H
83
80
68
65
69
74
61
63
11
2a
2b
2c
2d
2e
2f
Ph
2-Thienyl
2-Thienyl
2-Thienyl
i-Pr
i-Bu
Obviously, formation of 1,4-benzodiazepin-3-ones of type 1, 2
and 11 proceeds via a rearrangement. One might speculate that the
mechanism could involve an intermediate aziridinone (12). This
hypothesis is however not supported by the fact that N-methyl-
1,4-benzodiazepin-3-ones has been isolated from the reaction of
N-methylated o-aminobenzonitrile 3 via Route A (Scheme 1).
Another suggested mechanism, which also is supported by the for-
mation of quinazolines 5, involves the intermediate 13 (Scheme 1).8
It is noteworthy that the non-rearranged isomer of 1, i.e. 1,4-
benzodiazepin-2-one 14, was never observed (Scheme 4).
Although the 3-membered intermediate 12 does not seem to be
on the reaction pathway to 1, we became interested in the following
question: can the 4-membered molecule 15 be transformed into
the next higher homologue of 1,4-benzodiazocin-3-one, i.e. 1,5-
benzodiazocin-4-one 7 (Scheme 5)? A similar ring expansion
reaction of N-arylated b-lactams recently has been reported by
Buchwald et al. using a copper-mediated coupling reaction.13
Moreover, this is a convenient strategy for obtaining these rather
unfavoured rings, as a nitrogen nucleophile is formed in situ
which induces an intramolecular cyclization with a neighboring
electrophile. These 8-membered heterocycles (7a–g) crystallized
nicely, and the structure of 7f has previously been determined in
detail by X-ray methods.14
Scheme 4 Proposed mechanisms involved in the formation of benzodi-
azepine-3-ones 1, 2a–f and 11. R = aryl, R1 = alkyl or H, R2 = alkyl, M =
MgBr, X = Br.
primarily due to the formation of quinazolines 16, which were
isolated in two cases, namely 2-(2-chloro-1,1-dimethylethyl)-
4-butylquinazoline (16a) and 2-(2-chloro-1,1-dimethylethyl)-4-
isopropylylquinazoline (16b) (25–33%, Scheme 5). Obviously,
Route B is much more favourable and convenient; most products
were isolated directly after work-up, without further purification
(Table 2).
Although it is known that organometal reagents such as RLi
and RCeCl2 can add twice to nitriles, the outcome of the reaction
between 8 and RLi was unexpected, as outlined in Scheme 6.15,16
The proposed mechanism involves a Grob fragmentation that
results in the formation of the previously unknown quinazolinones
17.17 The 3,3,6-trisubstituted benzodiazocines 7a and 7c were
also isolated from this reaction, but in low yields (≤30%).
Molecule 17b (R = Ph) could be independently prepared from
reaction of o-aminotriphenylcarbinol 18 (readily available from
Compound 7 could also be obtained directly from the N-
acylacetanilide 8 (Scheme 5, Route C), albeit in lower yields,
Scheme 5 Reagents and conditions: a) RMgBr (2 eq), THF, reflux, 3 h; b) NaH, DMF, 70 ◦C, 3.5 h; c) RMgBr (2 eq), THF, reflux, 3 h.
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Scheme 6 Grob fragmentation.17 Reagents and conditions: a) PhLi or BuLi (5 eq), THF, 1.5 h, -78 ◦C to RT; b) NaOCN, AcOH/H2O (2:1), 3 h, 60 ◦C.
Table 2 1,5-Benzodiazocin-4-ones 7a–g obtained via Routes C and D
to give an colourless oil. Addition of hexane gave 7.21 g (27 mmol,
90%) of 4a as a white crystalline material after several hours, mp
68–69 ◦C (lit.10 mp 61 ◦C); IR nmax: 3350, 2205, 1690, 1580, 1530,
1450, 1300, 1160 and 760 cm-1; dH: 2.01 (6H, s), 7.43 (2H, m),
7.77 (1H, m), 7.86 (1H, m), 10.26 (1H, s); dC: 30.9 (q), 59.6 (s),
109.7 (s), 116.6 (s), 126.8 (d), 127.1 (d), 133.2 (d), 133.8 (d),
139.8 (s), 170.2 (s).
Yield (%)
Compound
R
Route C
Route D
7a
7b
7c
7d
7e
7f
Ph
2-Thienyl
Bu
i-Pr
Pr
Et
Me
44
35
46
40
42
42
28
91
70
74
70
73
85
39
N-(a-Bromobutyryl)-2-cyanoanilide (4b) (general procedure for
N-(a-bromoalkyl)-2-cyanoanilides 4b–d)
7g
To a well-stirred 2-phase system composed of K2CO3 (7.00 g,
50 mmol) in H2O (50 mL) and o-aminobenzonitrile (5.90 g,
50 mmol) in CH2Cl2 (50 mL)) a-bromobutyryl bromide (5.9 mL,
50 mmol) in CH2Cl2 (25 mL) was added dropwise at 0–5 ◦C. After
stirring for 20 h at room temperature the water phase was extracted
with CH2Cl2. The combined organic phases were washed with
aqueous NaHCO3 (10%), dried (MgSO4) and concentrated in
vacuo to give 12.2 g (46 mmol, 91%) of 4b as a white solid, mp:
104 ◦C (lit.10 105 ◦C); IR nmax: 3240, 2970, 2230, 1670, 1580, 1535,
1450, 1300, 1170 and 770 cm-1; dH: 1.00 (3H, t, J 14.6 and 7.3),
1.97 (1H, m), 2.08 (1H, m), 4.57 (1H, t, J 14.6, 7.3), 7.41 (1H,
m), 7.56 (1H, m), 7.72 (1H, m), 7.86 (1H, m), 10.56 (1H, s); dC:
11.8 (q), 28.0 (t), 50.2 (d), 107.8 (s), 116.5 (s), 125.7 (d), 126.4 (d),
133.4 (d), 133.9 (d), 139.3 (s), 167.7 (s).
o-aminobenzoic acid methyl ester) and NaOCN under acidic
conditions (Scheme 6).18
Conclusions
The addition of organometallics to derivatives of o-amino-
benzonitrile was investigated. This resulted in a convenient route
toward several unusual 1,4-benzodiazepine-3-ones (Table 1) by
addition of Grignard reagents to N-(a-haloacyl) derivatives of
readily available anthranilonitrile. The methodology was also
successfully applied to obtain the next higher homologue 1,5-
benzodiazocine-4-one (Table 2) in high yields.
Experimental
N-(a-Bromo-3-methylbutanoyl)-2-cyanoanilide (4c)
All starting materials and solvents were obtained from commercial
sources and used without further purification. THF was distilled
from sodium and benzophenone. Chromatography was performed
using silica gel (40–63 mm). Melting points were determined in
open capillary tubes on a Bu¨chi-B545 melting point apparatus.
IR spectra were recorded on Thermo Nicolet Avatar 330 FT-IR
instrument. NMR spectra were recorded on a Bruker DPX 300
operating at 300.1 MHz for 1H and 75.5 MHz for 13C in DMSO-
D6. Chemical shifts are reported in ppm downfield to TMS. The
elemental analyses was performed by H. Kolbe Mikroanalytisches
Laboratorium, Mu¨lheim an der Ruhr, Germany.
Compound 4c as prepared according to the procedure given for
4b on a 50 mmol scale, using 6.8 mL (50 mmol) a-bromo-3-
methylbutanoyl bromide. After evaporation 4c was collected as
a off white solid. Yield: 13.5 g (48 mmol, 96%), mp 125 ◦C (from
2-propanol); Ir nmax: 3241, 2973, 2231, 1666, 1521, 1490, 1439,
1189, 753, 713 cm-1; dH: 1.04 (3H, d, J 6.1), 1.11 (3H, d, J 6.1),
2.24 (1H, m), 4.43 (1H, d, J 8.6), 7.42 (1H, m), 7.53 (1H, m),
7.77 (1H, m), 7.85 (1H, m), 10.54 (1H, s); dC: 19.5 (q), 20.19 (q),
31.9 (d), 57.0 (d), 107.9 (s), 116.6 (s), 125.8 (d), 126.5 (d), 133.4 (d),
134.0 (d), 139.2 (s), 167.5 (s).
N-(a-Bromohexanoyl)-2-cyanoanilide (4d)
N-(a-Bromoisobutyryl)-2-cyanoanilide (4a)
Compound 4d was prepared according to the procedure given
for 4b on a 50 mmol scale, using 7.6 mL (50 mmol) of a-
bromohexanoyl bromide. After evaporation 4d was collected as a
white solid. Yield: 13.3 g (90%), mp 107 ◦C (from 2-propanol); Ir
To a CH2Cl2 (50 mL) solution of o-aminobenzonitrile (3.54 g,
30 mmol) and pyridine (3.6 mL, 45 mmol), a-bromoisobutyryl
bromide (36 mmol, 4.4 mL) was added dropwise at room
temperature. After stirring for 20 h, the reaction mixture was
washed with water several times, dried (MgSO4) and evaporated
n
max: 3241, 2965, 2228, 1669, 1523, 1334, 1174, 960, 757, 670 cm-1;
dH : 0.91 (3H, d, J 6.6), 0.96 (3H, d, J 6.6), 1.73 (1H, m),
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1.92 (2H, m), 4.75 (1H, t, J 15.2 and 7.6), 7.41 (1H, m), 7.59
(1H, m), 7.72(1H, m), 7.85 (1H, m), 10.56 (1H, s); dC : 21.7 (q),
22.0 (q), 26.05 (d), 42.9 (t), 47.1 (d), 107.4 (s), 116.4 (s), 125.5 (d),
126.3 (d), 133.4 (d), 133.9 (d), 139.2 (s), 167.8 (s).
separated off and the water phase was extracted several times with
EtOAc. The combined organic layers were dried (MgSO4) and
concentrated in vacuo. Purification by column chromatography
(EtOAc/heptane, 1:4) gave a off-white solid 2b, 0.90 g (65%) which
could be recrystallised from 2-propanol to give white prisms, mp
142 ◦C, (Found C, 77.78; H, 6.44; N, 10.12. C18H18N2O requires C,
77.67; H, 6.52; N, 10.06%); Ir nmax: 3215, 2969, 1651, 1623, 1589,
1449, 1050, 761, 725, 697 cm-1; dH (353 K): 0.60 (3H, d, J 6.8),
1.04 (3H, d, J 6.8), 2.92–3.03 (1H, m), 5.39 (1H, d, J 7.6), 7.11–
7.25 (2H, m), 7.28–7.34 (6H, m), 7.42–7.47 (1H, m), 9.14 (1H, d, J
7.5); dC (353 K): 19.0 (q), 19.8 (q), 33.7 (d), 56.0 (d), 126.1 (d),
126.9 (d), 127.2 (d), 127.2 (d), 128.1 (d), 128.3 (d), 128.7 (d),
132.5 (s), 138.6 (s), 145.8 (s), 163.4 (s), 171.4 (s).
1,2-Dihydro-2,2-dimethyl-5-phenyl-3H-1,4-benzodiazepin-3-one
(1) and 2-(1-bromo-1-methylethyl)-4-phenylquinazoline (5)
N-(a-Bromoisobutyryl)-2-cyanoanilide 4a (1.33 g, 5 mmol) was
dissolved in THF (10 mL) and added dropwise to a stirred
THF (10 mL) solution of phenylmagnesium bromide (11 mmol,
prepared by general procedure). After 12h at reflux, aqueous
NH4Cl (20 mL, 20%) was added cautiously and the mixture was
stirred for 1h. The aqueous layer was extracted with EtOAc and the
combined organic layers were washed (water and brine) and dried
(NaSO4). Evaporation of the solvent gave a yellow solid material
which was recrystallised from◦ethanol to give 1.10 g (83%) of 1, as
a yellow fine powder, mp 197 C (lit.8 197◦C). Ir umax: 3300, 3000,
2-Phenyl-2-isobutyl-4,5-dihydro-[3H]-1,4-benzodiazepin-3-
one (2c)
Compound 2c was prepared according to the procedure given
for 2b on a 5 mmol scale using N-(a-bromo-3-hexanoyl)-2-
cyanoanilide 4d. The crude product was purified by column
chromatography (EtOAc/heptane, 1:4) to afford 1.01 g (69%) of
2c as a yellow solid. The product could be recrystallised from 2-
propanol to afford a yellow powder solid, mp 156–157 ◦C, (Found
C, 78.05; H, 6.89; N, 9.58. C19H20N2O requires C, 78.05; H, 6.89;
N, 9.58%); Ir nmax: 3203, 3062, 2957, 1656, 1626, 1449, 1384, 749,
724, 696 cm-1; dH (353 K): 0.65 (d, 3H, J 6.61), 0.73 (d, 3H, J
6.61), 1.84–1.93 (1H, m), 2.19–2.26 (1H, m), 2.50–2.57 (1H, m;
appear in CDCl3 at 2.8 (1H, brs)), 5.39 (1H, d, J 7.0), 7.13–7.15
(m, 2H), 7.24–7.32 (6H, m), 7.41–7.46 (1H, m), 9.90 (1H, m, J 6.5);
dH (353 K): 21.7 (q), 21.9 (q), 24.3 (d), 44.7 (t), 55.5(d), 125.7 (d),
125.9 (d), 126.8 (d), 126.9 (d), 127.8 (d), 127.8 (d), 128.2 (d),
132.6 (s), 138.3 (s), 145.2 (s), 163.0 (s), 166.1 (s).
2940, 1685, 1575, 1450, 1255, 1105, 770, 700 cm-1 dH: 1.29 (6H,
;
s), 6.72 (1H, t, J 7.4), 6.74–7.20 (2 H, m), 7.28 (1H, s), 7.38 (1H, t,
J 7.4), 7.50–7.60 (5H, m); dC: 24.1 (q), 62.4(s), 116.7 (d), 117.8 (s),
120.1 (d), 128.4 (d), 129.4 (d), 130.7 (d), 132.6 (d), 132.8 (d),
138.9 (s), 147.0 (s), 166.2 (s), 173.7 (s).
The structure has been established by X-ray crystallography and
separated into two crystalline conformers.7b
Compound 5 was collected as white needles 65.4 mg (4%) from
the filtrate, mp 136 ◦C (lit.8 mp 136 ◦C); IR umax: 1609, 1561, 1540,
1485, 1464, 1390, 1164, 782, 621, 596, 522 cm -1; dH: 2.23 (6H, s),
7.63–7.69 (3H, m), 7.74–7.80 (1H, m), 7.82–7.86 (2H, m), 8.03–
8.14 (3H, m); dC: 32.4 (q), 66.1 (s), 120.7 (s), 126.8 (d), 128.8 (d),
128.8 (d), 130.1 (d), 130.3 (d), 134.6 (d), 135.6 (s), 150.3 (s),
166.0 (s), 168.0 (s).
2-Ethyl-5-phenyl-4,5-dihydro-[3H]-1,4-benzodiazepin-3-one (2a)
2-Ethyl-5-(2-thienyl)-4,5-dihydro-[3H]-1,4-benzodiazepin-3-
one (2d)
N-(a-Bromobutyryl)-2-cyanoanilide 4b (2.67 g, 10 mmol) was
dissolved in 20 mL dry THF and added dropwise to a THF-
solution of phenylmagnesium bromide (22 mmol in 20 mL).
After 4h at reflux aqueous NH4Cl (30 mL, 20%) was added
and the mixture was stirred for one hour. The organic layer was
separated off and the water phase was extracted several times
with EtOAc. The combined organic layers were dried (MgSO4)
and concentrated in vacuo. The residue crystallized from ethanol
to give 1.82 g (68%) of 2a as a yellow crystalline solid, mp 183–
185 ◦C; Ir nmax: 3167, 3032, 1662, 1630, 1479, 1447, 1132, 771, 733,
695 cm-1; dH 348 K: 0.71 (3H, t, J 7.5), 2.34–2.57 (2H, m) (appear
in CDCl3 at 2.73 (2H, brs)), 5.46 (1H, d, J 7.4), 7.09–7.11 (2H, m,),
7.25–7.33 (6H, m), 7.41–7.46 (1H, m), 10.59 (s, 1H); dC: 9.36 (s),
29.31 (t), 55.49 (d), 126.18 (d), 127.2 (d), 128.1 (d), 128.8 (d),
145.38 (s), 163.4 (s), 168.3 (s). The structure of this compound has
previously been determined by X-ray crystallography.12
Compound 2d was prepared according to the procedure given for
2b on a 5 mmol scale using N-(a-bromo-butyryl)-2-cyanoanilide
4b. The crude product was purified by column chromatography
(EtOAc/heptane, 1:3) to afford 1.01 g (74%) of 2d as a pale yellow
solid, 168–169 ◦C (from 2-propanol); Ir nmax: 3169, 2980, 1661,
1629, 1450, 1229, 1119, 769, 708 cm-1; dH (353 K): 0.82 (3H, t, J
7.4), 2.39–2.73 (2H, m; appear in CDCl3 at 2.77–2.81 (2H, m)), 5.56
(1H, d, J 6.8), 6.64 (1H, brs), 6.90–6.93 (1H, m), 7.25–7.32 (2H, m),
7.37–7.38 (1H, m), 7.41–7.48 (2H, m), 9.25 (1H, brs); dC: 9.5 (q),
29.5 (t), 53.0 (d), 125.2 (d), 125.3 (d), 126.3 (d), 126.8 (d), 127.5 (d),
128.3 (d), 129.2 (d), 132.9 (s), 144.1 (s), 145.4 (s), 163.4 (s), 168.2 (s).
2-Isopropyl-5-(2-thienyl)-4,5-dihydro-[1H]-1,4-benzodiazepin-3-
one (2e)
Compound 2e was prepared according to the procedure given
for 2b on a 5 mmol scale using N-(a-bromo-3-methylbutanoyl)-
2-cyanoanilide 4c. The crude product was purified by column
chromatography (EtOAc/heptane, 1:3) to afford 0.87 g (61%) of
2e as a yellow solid. The product could be recrystallised from
2-propanol to afford of a pale yellow crystalline solid, mp 135–
2-Phenyl-2-isopropyl-4,5-dihydro-[3H]-1,4-benzodiazepin-3-
one (2b)
N-(a-Bromo-3-methylbutanoyl)-2-cyanoanilide 4c (1.4 g, 5 mmol)
was dissolved in THF (20 mL) and added dropwise to a THF
solution (10 mL) of phenylmagnesium bromide (11.5 mmol). After
20h at reflux aqueous NH4Cl (20 mL, 20%) was added and the
reaction mixture was stirred for one hour. The organic layer was
◦
137 C; (Found C, 67.68; H, 5.58; N, 9.92. C16H16N2OS requires
C, 67.58; H, 5.67; N, 9.85%); Ir nmax: 3172, 2966, 1651, 1623, 1287,
1027, 841, 799, 760, 703 cm-1; dH (353 K): 0.71 (3H, d, J 6.8),
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1.09 (3H, d, J 6.8), 2.97–3.06 (1H, m), 5.55 (1H, d, J 7.4), 6.63
(1H, brs), 6.90–6.92 (1H, m), 7.26–7.33 (2H, m), 7.37–7.40 (2H,
m), 7.43–7.45 (1H, m), 9.20 (1H, d, 7.1); dC (353 K): 19.0 (q),
20.0 (q), 33.6 (d), 52.8 (d), 125.3 (d), 125.5 (d), 126.3 (d), 126.6 (d),
127.5 (d), 128.3 (d), 129.1 (d), 132.1(s), 143.6 (s), 145.3 (s), 163.3 (s),
171.1 (s).
2980, 2229, 1662, 1509, 1448, 1301, 1189, 926, 757, 719cm-1; dH
1.31 (s, 6H), 3.85 (s, 2H), 7.42 (m, 2H), 7.68 (m, 1H), 7.83 (m, 1H),
9.78 (m, 1H); dC : 23.0 (q), 44.4 (t), 52.2 (s), 109.5 (s), 116.6 (s),
126.3 (d), 127.1 (d), 132.9 (d), 133.6 (d), 140.2 (s), 173.5 (s).
a,a-Dimethyl-N-(2-cyanophenyl)-b-lactam (15)
3-Chloro-N-(2-cyanophenyl)-2,2-dimethylpropanamide 8 (7.8 g,
33 mmol) was dissolved in DMF (20 mL) and added at to a
suspension of NaH (0.79 g, 33 mmol) in DMF (30 mL) under
nitrogen atmosphere in room temperature. After ~30 min, when
H2 ceased to evolve, the mixture was heated to 70 ◦C and left
for 3.5 h with stirring. The reaction mixture was cooled room
temperature and then poured into cold water. A white precipitate
was formed and collected by filtration after a few minutes. Washing
with several portions of water gave 6.01 g (91%) of 15 as a white
2-Isobutyl-5-(2-thienyl)-4,5-dihydro-[1H]-1,4-benzodiazepin-3-
one (2f)
Compound 2f was prepared according to the procedure given
for 2b on a 5 mmol scale using N-(a-bromo-3-hexanoyl)-2-
cyanoanilide 4d. The product was purified by column chromatog-
raphy (EtOAc/heptane, 1:3) to afford 0.94 g (63%) of 2f as a pale
yellow solid. The product could be recrystallised from 2-propanol
to give white needles, mp 179–180 ◦C; (Found C, 68.54; H, 6.12;
◦
N, 9.45. C17H18N2OS requires C, 68.43; H, 6.08; N, 9.39%); Ir nmax
:
solid material, mp: 86–87 C (found C, 71.79; H, 6.10; N, 13.92.
3161, 3044, 2866, 1663, 1627, 1428, 1286, 1176, 1094, 759, 719,
710 cm-1; dH (353 K): 0.71 (3H, d, J 6.6), 0.78 (3H, d, J 6.6),
1.91–2.04 (1H, m), 2.25–2.32 (1H, m), 2.49–2.59 (1H, m; appear
in CDCl3 at 2.82–2.89 (1H, m)), 5.54 (1H, d, J 6.0), 6.65 (1H, brs),
6.90–6.93 (1H, m), 7.24–7.32 (2H, m), 7.35–7.42 (2H, m), 7.43–
7.48 (1H, m), 9.18 (1H, brs); dC (353K): 22.1 (q), 22.4 (q), 24.4 (d),
45.1 (t), 53.1 (d), 124.9 (d), 125.3 (d), 126.5 (d), 127.0 (d), 127.8 (d),
128.4 (d), 129.3 (d), 132.7 (s), 144.5 (s), 145.3 (s), 163.4 (s), 166.2 (s).
C12H12N2O required C, 71.98; H, 6.04; N, 13.99%); Ir nmax: 2968,
2217, 1735, 1488, 1449, 1358, 1151, 1074, 756 cm-1; dH: 1.33 (s,
6H), 3.92 (s, 2H), 7.24 (m, 1H), 7.68 (m, 1H), 7.76 (m, 1H), 8.05
(m, 1H); dC: 20.8 (q), 50.7 (s), 55.5 (t), 98.7 (s), 117.3 (s), 120.2 (d),
124.0 (d), 134.1 (d), 134.2 (d), 140.4 (s), 172.0 (s).
6-Phenyl-3, 3-dimethyl-1,2,3,4-tetrahydro-1, 5-benzodiazocin-4-
one (7a). General procedure for compound 7a–7g (Routes C and D)
Route D. A THF solution (20 mL) of lactam 15 (1.3 g,
6.5 mmol) was added to phenyl magnesium bromide (13 mmol) in
THF (10 mL). After 3 h at reflux, the reaction was quenched by
addition of NH4Cl (20 mL, 20%). Solid material was filtered off
and the phases were separated. The water phase was washed with
EtOAc and the combined organic layers were washed with water
and brine and dried (Na2SO4). Evaporation of the solvent in vacuo
gave a yellow solid which was recrystallised from ethanol to afford
1.65 g (91%) of 7a as a fine yellow powder solid, mp 197–199 ◦C;
(Found C, 77.78; H, 6.44; N, 10.12. C18H18N2O required C, 77.67;
H, 6.52; N, 10.06%); Ir nmax: 3374, 2923, 1661, 1626, 1485, 1303,
1178, 934, 751, 698, 626 cm-1; dH: 7.64 (m, 2H), 7.52 (m, 3H), 7.10
(m, 1H), 6.91 (m, 1H), 6.69 (m, 2H), 6.41 (m, 1H), 3.61 (dd, 1H,
J = 14.7, 6.9 Hz), 2.90 (dd, 1H, J = 14.7, 6.9 Hz), 1.19 (s, 3H),
1.09 (s, 3H); dC: 21.8 (q), 26.0 (q), 38.2 (t),. 52.1 (s), 114.3 (d),
114.7 (s), 117.5 (d), 128.4 (d), 129.4 (d), 139.0 (s), 132.2 (d),
131.3 (d), 130.9 (d), 146.3 (s), 164.4 (s).
2,5-Diphenyl-2-ethyl-1,2,4,5-tetrahydro-[3H]-1,4-benzodiazepin-3-
one (11)
N-(a-Bromobutyryl)-2-cyanoanilide 4b (5.9 g, 22 mmol) was
dissolved in THF (100 mL) and added dropwise to a stirred
solution of phenylmagnesium bromide (0.1 mol) in THF (100 mL).
The reaction mixture was refluxed overnight and thereafter
quenched by addition of aqueous NH4Cl (100 mL). The layers
were separated and the water phase was extracted with EtOAc. The
combined organic phases were washed with water and brine, dried
(MgSO4) and concentrated in vacuo. The residue was recrystallised
from 2-propanol to give 6.02 g (80%) of 11 as a yellow crystalline
solid, mp 198–199 ◦C; Ir nmax: 3180, 3050, 2980, 1650, 1600, 1495,
1450, 1415, 745, 725, 715 cm-1; dH: 0.85 (3H, t, J 7.4), 1.82–1.89
(1H, m), 2.24–2.33 (1H, m), 5.10 (1H, s), 5.42 (1H, d, J 6.5), 6.91–
6.95 (2H, m), 7.06–7.08 (2H, m), 7.01–7.16 (5H, m), 7.02–7.23
(5H, m), 8.40 (1H, d, J 6.5); dC: 8.2 (q), 31.5 (t), 57.9 (d), 70.2 (s),
121.1 (d), 123.2 (d), 126.3 (d), 126.4 (d), 126.5 (d), 127.2 (d),
127.5 (d), 127.6 (d), 128.3 (d), 128.7 (d), 133.6 (s), 142.4 (s),
142.6 (s), 145.6 (s), 174.3 (s). The structure of this compound
has previously been determined by X-ray crystallography.11
Route C. 3-Chloro-N-(2-cyanophenyl)-2-methanbutanamide
8 (2.36 g, 10 mmol) was dissolved in THF (30 mL) and added to a
THF solution (20 mL) of phenyl magnesium bromide (25 mmol).
After 3h at reflux NH4Cl (20 mL, 20%) was added and followed by
the work-up described above (for 7a from lactam 15) The organic
layer was evaporated to afford a yellow oil which was purified by
column chromatography (EtOAc/heptane, 1:4) which gave 1.22 g
(44%) of 7a as a yellow crystalline solid.
3-Chloro-N-(2-cyanophenyl)-2,2-dimethylpropananamide (8)
To a CH2Cl2 suspension (50 mL) of anthranilonitrile (5.9 g,
50 mmol) and pyridine (4.9 mL, 60 mmol) b-chloropivaloyl
◦
chloride (5 mL, 60 mmol) was slowly added at 0 C. After 20 h
stirring at room temperature, the reaction mixture was washed
with water several times and dried (Na2SO4). Crystalline material
appeared after a few minutes and the mixture was capped and left
over night in room temperature. The crystals was filtered off and
carefully washed with cold CH2Cl2 to give 9.6 g (81%) of 8 as pale
pink needles, mp: 97–98 C (Found C, 60.89; H, 5.54; N, 11.83.
C12H13ClN2O requires C, 60.89; H, 5.54; N, 11.83%); Ir nmax: 3310,
6-(2-Thienyl)-3,3-dimethyl-1,2,3,4-tetrahydro-1,5-benzodiazocin-
4-one (7b)
Compound 7b was prepared by the same procedure as described
for 7a (Route D) on a 10 mmol scale using a,a-dimethyl-N-
(2-cyanophenyl)-b-lactam (15) and thienyl magnesium bromide
(20 mmol) to give 1.99 g (70%) of 7b as a yellow powder
◦
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solid, mp 228–230 ◦C (2-propanol), (Found C, 67.52; H, 5.62;
N, 9.78. C16H16N2OS required C, 67.58; H, 5.67; N, 9.85%);
Ir nmax: 3370, 3333, 2965, 1654, 1632, 1600, 1486, 1231, 1160,
1045, 849, 727 cm-1; dH: 1.12 (s, 3H), 1.16 (s, 3H), 2.72–2.98 (m,
1H), 3.57–3.79 (m, 1H), 6.34–6.59 (m, 1H), 6.60–6.74 (m, 1H),
6.76–6.95 (m, 1H), 7.28–6.98 (m, 2H), 7.33–7.36 (m, 1H), 7.75–
7.93 (m, 1H); dC: 21.4 (q), 26.1 (q), 38.9 (t), 51.7 (s), 114.3 (d),
117.5 (d), 128.2 (d), 131.4 (d), 131.6 (d), 132.3 (d), 133.5 (d),
143.9 (s), 145.3 (s), 158.4 (s), 191.52 (s). Alternatively, 7b could
be obtained via Route C according to the procedure described
for 7a on a 10 mmol scale using 3-chloro-N-(2-cyanophenyl)-2-
methanbutanamide 8 and thienyl magnesium bromide (25 mmol).
Evaporation gave a yellow oil which was purified by column
chromatography (EtOAc/heptane, 1:4) to give 0.99 g (35%) of
7b as a yellow crystalline solid.
7.02–7.08 (1H, m)), 6.66–6.68 (1H, m), 6.59–6.64 (1H, m), 6.49–
6.53 (1H, m), 7.20–7.23 (1H, m); dC: 20.0 (q), 21.7 (q), 22.2 (q),
25.8 (q), 35.5 (d), 38.0 (t), 52.1 (s), 115.1 (d), 116.5 (s), 117.4 (d),
129.1 (d), 130.8 (d), 145.0 (s), 171.7 (s), 191.4 (s).
Alternatively, 7d could be obtained via Route C according to the
procedure described for 7a on a 5 mmol scale using 3-chloro-N-(2-
cyanophenyl)-2-methanbutanamide 8 and isopropyl magnesium
bromide (12.5 mmol). Evaporation gave a yellow oil which was
purified by flushing through a short silica plug, EtOAc:heptane
(1:4), gave 0.49 g (40%) of 7d as a yellow crystalline solid. 16b was
also isolated as a pale yellow oil. Yield: 0.33 g (25%); Ir nmax: 2968,
2864, 1614, 1556, 1494, 1389, 1336, 1188, 1108, 926, 762 cm-1;
dH: 1.33 (6H, d, J 6.8), 1.48 (6H, s), 3.94–4.03 (1H, m), 4.11 (2H,
s), 7.65–7.70 (1H, m), 7.92–7.94 (2H, m), 8.30–8.33 (1H, m); dC:
21.6 (q), 25.0 (q), 30.2 (d), 44.4 (t), 54.8 (s), 120.5 (s), 124.4 (d),
128.6 (d), 127.1 (d), 133.5 (d), 149.6 (s), 168.0 (s), 175.0 (s).
6-Butyl-3, 3-dimethyl-1,2,3,4-tetrahydro-1, 5-benzodiazocin-4-one
(7c) and 2-(2-chloro-1,1-dimethylethyl)-4-butylquinazoline (16a)
6-Propyl-3,3-dimethyl-1,2,3,4-tetrahydro-1, 5-benzodiazocin-4-
one (7e)
Compound 7c was prepared by the same procedure as described
for 7a (Route D) on a 10 mmol scale using a,a-dimethyl-N-
(2-cyanophenyl)-b-lactam (15) and butyl magnesium bromide
(20 mmol) to give 1.91 g (74%) of a colourless crystalline material,
mp: 118–119 ◦C (2-propanol), (Found C, 74.44; H, 8.53; N, 10.88
C16H22N2O required C, 74.38; H, 8.58; N, 10.84%); Ir nmax: 3316,
2926, 2866, 1655, 1604, 1491, 1337, 1191, 1148, 970, 746, 736 cm-1;
dH: 0.92 (3H, m), 1.13 (6H, s), 1.38–1.45 (2H, m), 1.64–1.57 (2H,
m), 2.77–2.89 (3H, m), 3.47 (1H, dd, J 14.4 and 6.9), 6.48–6.53
(1H, m), 6.58–6.61 (1H, m), 6.66–6.68 (1H, m), 7.02–7.07 (1H, m),
7.23–7.26 (1H, m); dC: 13.8 (q), 21.8 (q), 21.9 (t), 28.7 (t), 25.7 (q),
37.8 (t), 38.0 (t), 52.3(s), 115.2 (d), 116.7 (s), 117.5 (d), 129.6 (d),
130.9 (d), 145.0 (s), 167.0 (s), 191.1 (s) Alternatively, 7c could
be obtained via Route C according to the procedure described
for 7a on a 10 mmol scale using 3-chloro-N-(2-cyanophenyl)-2-
methanbutanamide 8 and butyl magnesium bromide (25 mmol).
Evaporation gave a yellow oil which was purified by column
chromatography (EtOAc/heptane, 1:4) to give 1.19 g (46%) 7c
as a yellow crystalline solid.
Compound 7e was prepared by the same procedure as described
for 7a (Route D) on a 10 mmol scale using a,a-dimethyl-N-
(2-cyanophenyl)-b-lactam (15) and propyl magnesium bromide
(20 mmol) to give 1.78 g (73%) of 7e as a colourless crystalline
solid, mp 111–112 ◦C; Ir nmax: 3323, 2923, 2866, 1655, 1598, 1491,
1334, 1197, 1154, 978, 836, 762, 744 cm-1; dH: 0.97–1.02 (3H,
m), 1.13 (6H, s), 1.25–1.06 (m, 1H), 1.59–1.69 (2H, m),2.73–2.28
(3H, m), 3.45 (1H, dd, J 14.62 and 6.92), 6.48–6.53 (1H, m),
6.58–6.61 (1H, m), 6.68–6.71 (1H, m), 7.01–7.08 (1H, m), 7.23
(1H, m); dC:13.7 (q), 19.86 (t), 21.8 (q), 25.7 (q), 37.8 (t), 40.3
(t), 52.3 (s), 115.2 (d), 116.8 (s), 117.5 (d), 129.6 (d), 130.9 (d),
144.9 (s), 166.9 (s), 191.1 (s).
Alternatively, 7e could be obtained via Route C according to the
procedure described for 7a on a 5 mmol scale using 3-chloro-N-
(2-cyanophenyl)-2-methanbutanamide 8 and propyl magnesium
bromide (12.5 mmol). Evaporation gave a yellow oil which was
purified by flushing through a short silica plug, EtOAc:heptane
(1:4), gave 0.51 g (42%) of 7e as a crystalline solid.
16a was also isolated from the column as white needles. Yield:
0.91 g (33%), mp 45 ◦C, (Found C, 69.56; H, 7.61; N, 10.09
C15H21ClN2 required C, 69.43; H, 7.65; N, 10.12%); Ir nmax: 2954,
2869, 1615, 1552, 1416, 1397, 1383, 1186, 934, 791, 760, 622 cm-1;
dH: 0.93 (3H, t, J 7.3), 1.36–1.46 (2H, m), 1.48 (6H, s), 1.78–1.83
(2H, m), 3.27 (2H, t, J 7.6), 4.11 (2H, s), 7.64–7.70 (1H, m), 7.92–
7.94 (2H, m), 8.25–8.28 (1H, m); dC: 13.8 (q), 21.8 (t), 25.0 (q),
29.8 (t), 33.0 (t), 44.3 (t), 54.8 (s), 121.4 (s), 125.0 (d), 127.2 (d),
128.4 (d), 133.7 (d), 149.2 (s), 167.9 (s), 171.0 (s).
6-Ethyl-3,3-dimethyl-1,2,3,4-tetrahydro-1, 5-benzodiazocin-4-
one (7f)
Compound 7f was prepared by the same procedure as described
for 7a (Route D) on a 10 mmol scale using a,a-dimethyl-N-
(2-cyanophenyl)-b-lactam (15) and ethyl magnesium bromide
(20 mmol) to give 1.96 g (85%) of 7f as a pale yellow crystalline
solid, mp 166 ◦C; Ir nmax: 3367, 2970, 1673, 1650, 1602, 1492,
1385, 1334, 1197, 1020, 955, 751 cm-1; dH:1.13–1.18 (9H, m), 2.78–
2.95 (3H, m), 3.46 (1H, dd, J 14.7 and 6.8), 6.50–6.54 (1H, m),
6.60–6.62 (1H, m), 6.67–6.72 (1H, m), 7.03–7.08 (1H, m), 7.24–
7.27 (1H, m); dC:11.2 (q), 21.8 (q), 25.8 (q), 31.4 (t), 37.9 (t),
52.4 (s), 115.2 (d), 116.8 (s), 117.4 (d), 129.5 (d), 130.9 (d), 145.0 (s),
167.8 (s), 191.1 (s).
Alternatively, 7f could be obtained via Route C according to
the procedure described for 7a on a 5 mmol scale using 3-chloro-
N-(2-cyanophenyl)-2-methanbutanamide 8 and ethyl magnesium
bromide (12.5 mmol). Evaporation gave a yellow oil which was
purified by flushing through a short silica plug, EtOAc:heptane
6-Isopropyl-3,3-dimethyl-1,2,3,4-tetrahydro-1, 5-benzodiazocin-
4-one (7d) and 2-(2-chloro-1,1-dimethylethyl)-4-
isopropylylquinazoline (16b)
Compound 7d was prepared by the same procedure as described
for 7a (Route D) on a 10 mmol scale using a,a-dimethyl-N-(2-
cyanophenyl)-b-lactam (15) and isopropyl magnesium bromide
(20 mmol) to give 1.71 g (70%) of 7d as a crystalline solid, mp
117–118 ◦C, Ir nmax: 3318, 2973, 2935, 1660, 1529, 1486, 1196,
1162, 973, 736 cm-1; dH: 1.14 (6H, s), 1.16–1.22 (6H, m), 2.69 (1H,
dd, J 14.7 and 7.3), 3.26 (1H, m), 3.47 (1H, dd, J 14.7 and 7.3),
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(1:4), gave 0.48 g (42%) of 7f as a pale yellow solid. The structure of
1599, 1446, 1416, 1262, 750, 696 cm-1; dH: 6.46–6.47 (m, 1H),
6.82–6.90 (m, 2H), 7.11–7.21 (m, 5H), 7.27–7.35 (m, 6H), 8.14
(s, 1H), 9.38 (s, 1H); dC: 66.2 (s), 114.0 (d), 120.6 (d), 125.4 (s),
127.2 (d), 127.4 (d), 127.8 (d), 128.0 (d), 128.1 (d), 137.3 (s),
145.0 (s), 154.1 (s). Compound 17b could be alternatively obtained
from reaction of NaOCN with o-amino-triphenylcarbinol (18):
NaOCN (0.65 g, 10 mmol) was dissolved in a hot solution of
acetic acid and water (2:1) (20 mL) and added to o-amino-
triphenylcarbinol (2.75 g, 10 mmol) in 100 mL acetic acid and
water (2:1). After stirring at 60 ◦C for 3 h solid material was
filtered off to afford 17b as a white solid. Yield: 1.35 g (4.5 mmol,
45%).
this compound has been established by X-ray chrystallagrophy.14
6-Methyl-3,3-dimethyl-1,2,3,4-tetrahydro-1,
5-benzodiazocin-4-one (7g)
Compound 7g was prepared by the same procedure as described
for 7a (Route D) on a 10 mmol scale using a,a-dimethyl-N-
(2-cyanophenyl)-b-lactam (15) and methyl magnesium bromide
(20 mmol) to give 0.84 g (39%) of 7g as a solid, mp 218 ◦C, (Found
C, 72.28; H, 7.42; N, 13.03 C13H16N2O required C, 72.19; H, 7.46;
N, 12.95%); Ir nmax: 3363, 2970, 1675, 1660, 1601, 1489, 1335, 1220,
1146, 962, 747 cm-1; dH: 1.14 (6H, m), 2.24–2.05 (3H, m; appear at
2.55 in CDCl3 (3H, s)), 2.86 (1H, dd, J 7.2), 3.52 (1H, dd, J 6.8),
6.49–6.54 (1H, m), 6.59–6.62 (1H, m), 6.71–6.75 (1H, m), 7.03–
7.09 (1H, m), 7.38–7.31 (1H, m); dC : 22.0 (q), 25.6 (q), 26.7 (q),
37.7 (t), 52.5 (s), 115.2 (d), 116.8 (s), 117.4 (d), 130.0 (d), 131.1 (d),
145.1 (s), 163.5 (s), 190.4 (s).
Alternatively, 7g could be obtained via Route C according to the
procedure described for 7a on a 5 mmol scale using 3-chloro-N-
(2-cyanophenyl)-2-methanbutanamide 8 and methyl magnesium
bromide (12.5 mmol). Evaporation gave a yellow oil which was
purified by flushing through a short silica plug, EtOAc:heptane
(1:4), gave 0.30 g (28%) of 7g as a yellow crystalline solid.
References
1 (a) K. Leonard, J. J. Marugan, P. Maboisson, R. Calvo, J. M. Gushe,
H. K. Koblish, J. Lattance, S. Zhao, M. D. Cummings, M. Player, A. C.
Maroney and T. Lu, Bioorg. Med. Chem. Lett., 2006, 16, 3463–3468;
(b) M.-C. Hsu, A. D. Schutt, M. Holly, L. W. Slice, M. I. Sherman, D. D.
Richman, M. J. Potash and D. J. Volsky, Science, 1991, 254, 1799–1802;
(c) H. G. Selnick, N. J. Liverton, J. J. Baldwin, J. W. Butcher, D. A.
Claremon, J. M. Elliott, R. M. Freidinger, S. A. King, B. E. Libby, C. J.
McIntyre, D. A. Pribush, D. A. Remy, D. C. Smith, A. J. Tebben, N. K.
Juriewicz, J. J. Lynch, J. J. Salata, M. C. Sanguinetti, P. K. S. Siegl, D. E.
Slaughter and K. J. Vyas, J. Med. Chem., 1997, 40, 3865–3868.
2 B. E. Evans, K. E. Rittle, M. G. Bock, R. M. DiPardo, R. M. Freidinger,
W. L. Whitter, G. F. Lundell, D. F. Veber, P. S. Anderson, R. S. L.
Chang, V. J. Lotti, D. J. Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel,
J. P. Springer and J. Hirshfield, J. Med. Chem, 1988, 31, 2235–2246.
3 W. Roos, The Alkaloids, 1990, 39, 63–97.
4,4-Dibutyl-3,4-dihydroquinazoline (17a)
To a solution of 3-chloro-N-(2-cyanophenyl)-2-methanbutana-
mide 8 (1.36 g, 5.8 mmol) in THF (50 mL), BuLi (18.1 mL,
29 mmol) was added at -78 ◦C. The temperature was slowly
allowed to rise until room temperature was reached (~30 min).
After stirring for 1.5 h aqueous NH4Cl (15 mL, 20%) was carefully
added and a white solid appeared. The reaction mixture was
allowed to stir for a few minutes and thereafter the solid material
was filtered off to give of 17a. Additional white material (17a)
appeared in the filtrate, which was collected after a few hours
to give a total of 0.91 g (61%) of 17a. The product could be
recrystallised from ethanol to give white needles, mp: 179 ◦C; IR
4 H. Quast, S. Ivanova, E.-M. Peters and K. Peters, Eur. J. Org. Chem.,
2000, 8, 1577–1578.
5 U. Rosenstro¨m, C. Sko¨ld, G. Lindeberg, M. Botros, F. Nyberg, A.
Karlen and A. Hallberg, J. Med. Chem., 2004, 47, 859–870.
6 J. M. Samanen, F. E. Ali, L. S. Barton, W. E. Bondinell, J. L. Burgess,
J. F. Callahan, R. R. Calvo, W. Chen, L. Chen, K. Erhard, G. Feuerstein,
R. Heys, S. M. Hwang, D. R. Jakas, R. M. Keenan, T. W. Ku, C. Kwon,
C.-P. Lee, W. H. Miller, K. A. Newlander, A. Nichols, M. Parker, C. E.
Peishoff, G. Rhodes, S. Ross, A. Shu, R. Simpson, D. Takata, T. O.
Yellin, I. Uzsinskas, J. W. Venslavsky, C. K. Yuan and W. F. Huffman,
J. Med. Chem., 1996, 39, 4867–4870.
7 (a) J. Bergman, A. Brynolf and B. Elman, Heterocycles, 1983, 11, 2141–
2145; (b) J. Bergman and A. Brynolf, Heterocycles, 1983, 11, 2145–
2148.
8 P. Wiklund and J. Bergman, Org. Biomol. Chem., 2002, 1, 367–372.
9 N. S. Cho, K. Y. Song and C. Pa´rka´nyi, J. Het. Chem, 1989, 26, 1807–10.
10 J. Bergman, A. Brynolf, A. Elman and E. Vuorinen, Tetrahedron, 1986,
42, 3689–3696.
n
max: 3211, 3116, 3068, 2956, 2930, 2859, 1685 cm-1; dH: 0.74–0.79
(6H, m), 0.88–0.90 (2H, m), 1.13–1.25 (6H, m), 1.52–155 (2H, m),
1.72–1.77 (2H, m), 6.62 (1H, s), 6.69–6.72 (1H, m), 6.81–6.85 (1H,
m), 7.02–7.06 (2H, m), 8.89 (1H, s); dC: 14.0 (q), 22.3 (t), 25.7 (t),
43.1 (t), 60.5 (s), 113.4 (d), 120.9 (d), 122.6 (s), 124.7 (d), 127.3 (d),
138.0 (s), 153.2 (s).
11 A. Brynolf, Synthetic studies of 1,4-benzodiazepines, quinazolines and
quinazolinones, Ph.D. Thesis, Dept. of Organic Chemistry, 1991, Royal
Institute of Technology (KTH): Stockholm, Sweden.
12 K.-W. Toernroos, Acta. Cryst. Section C, 1988, 44, 550–553.
13 A. Klapars, S. Parris, K. W. Anderson and S. L. Buchwald, J. Am.
Chem. Soc., 2004, 126, 3529–3533.
4,4-Diphenyl-3,4-dihydroquinazoline (17b)
14 K.-W. Toernroos, Acta. Cryst. Section C, 1987, 43, 2447–2448.
15 G. Alvernhe and A. Laurent, Tetrahedron Lett., 1973, 13, 1057–1060.
16 E. Ciganek, J. Org. Chem., 1992, 57, 4521–4527.
17 C. A. Grob and P. W. Schiess, Angew. Chem., 1967, 6, 1–106.
18 A. Baeyer and V. Villiger, Ber., 1904, 37, 3191–3193.
Compound 17b was prepared according to the procedure de-
scribed for 17a on a 5 mmol scale using appropriate amount of
reagents and solvents. 0.95 g (63%) of 17b was filtered off as a white
solid, mp 276 ◦C (ethanol), IRnmax: 3335, 3191, 3055, 2969, 1669,
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