Novel access to 1,4-benzodiazepin-2-ones via the Buchwald reaction and application to the synthesis of novel heterocyclics

Article abstract of DOI:10.1016/j.tetlet.2011.12.045

A new two step strategy for the preparation of 1,4-benzodiazepin-2-ones has been developed starting from the 2-halogenobenzophenone under Buchwald conditions (Pd(OAc)₂, XantPhos, Cs₂CO₃, dioxane 100 °C). This strategy has

Full text of DOI:10.1016/j.tetlet.2011.12.045

Tetrahedron Letters 53 (2012) 1033–1035
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Tetrahedron Letters
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Novel access to 1,4-benzodiazepin-2-ones via the Buchwald reaction
and application to the synthesis of novel heterocyclics
⇑
Christophe Salomé , Martine Schmitt, Jean-Jacques Bourguignon
Laboratoire d’Innovation Thérapeutique, UMR 7200, Faculté de Pharmacie, 74 route du Rhin, BP 60024, 67401 Illkirch, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2011
Revised 8 December 2011
Accepted 12 December 2011
Available online 20 December 2011
A new two step strategy for the preparation of 1,4-benzodiazepin-2-ones has been developed starting
from the 2-halogenobenzophenone under Buchwald conditions (Pd(OAc)2, XantPhos, Cs2CO3, dioxane
100 °C). This strategy has been extended to two 2-halogeno-3-benzoyl-azines (pyridines, pyridazines).
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Buchwald
Pd crosscoupling
1,4-Benzodiazepin-2-one
Pyridine
Pyridazine
PG
In an earlier medicinal chemistry program dealing with the
development of novel cyclic nucleotide phosphodiesterase inhibi-
tors, differently substituted and functionalized 1,4-benzodiazepin-
2-ones 1 were prepared following numerous literature methods as
summarized in Scheme 1. They generally start from a title substi-
tuted benzophenone 2, which was reacted with a glycine derivative.
The use of the ethyl ester 3 (method 1)1 suffered from important for-
mation of piperazine-2,5-dione and was not satisfactory, when
OH
N
H
R
N
PG
ii)
O
N
H
4
PG: Protecting group
O
O
Method 2a
Classical peptidic
coupling conditions
5
Ar
PG deprotection
using chiral a-aminoacids (less nucleophilic) toward the relatively
R
N
R
NH
OEt
O
hindered benzophenone carbonyl group. By another way, the use
of N-protected glycine 4 needed a first step of N-acylation leading
to amide 5 (method 2a).2 However this approach showed limitation
associated with a fair nucleophilicity of the aniline NH group of 2, in
particular when it was substituted (R – H), or if the benzo ring of 2
was bearing electron-deficient groups (NO2, Cl, CN). Finally, to by-
pass the poor reactivity of both reactants, the use of the highly elec-
trophilic bromacetic bromide was efficiently used to build 3-
unsubstituted 1,4-benzodiazepin-2-ones with an additional amina-
tion step of the bromomethyl intermediate 6 (method 2b).3
The specific aim of this Letter deals with novel strategies em-
ployed for building 1,4-benzodiazepin-2-ones leading to novel
scaffolds, in particular those resulting from the replacement of
the benzo ring of 1 by other six-membered ring azines (pyridine,
pyridazine, pyrimidine,. . .).
i)
H2N
3
O
O
Method 1
toluene, reflux
N
Ar
Ar
1
MeOH, NH3,
then
2
MeOH, reflux.
Br
R
N
iii)
Br
4
Br
O
O
Method 2b
toluene, 2, 6-lutidine, rt
O
Ar
6
Scheme 1. Literature methods for preparation of substituted 1,4-benzodiazepin-2-
ones starting from o-aminobenzophenone 2.
Thus the methods 1 and 2a were first selected, and 2-aminopyr-
idine and 3-aminopyridazine derivatives 7a and 7b were used,
respectively as reference systems. However in both cases and in
various experimental conditions (DCC, EDCI, HATU, HBTU, BTBO),4
no reaction could be observed, as the result of the presence of azine
⇑
Corresponding author. Tel.: +33 (0) 3 68 85 42 31/18; fax: +33 (0) 3 68 85 43 10.
E-mail address: salome@unistra.fr (C. Salomé).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.045

1034
C. Salomé et al. / Tetrahedron Letters 53 (2012) 1033–1035
Methods 1, 2a
O
O
NH2
H
N
O
NH2
H
N
No Reaction
O
Cl
N
Cl
N
NH
Cl
N
X
O
N
O
X
H
N
O
Br
N
NH2
N
X
NH3
N
NH
Method 2b
X
Cl
X
Cl
Cl
MeOH
O
15
15a
16
O
N
X
NH3
then
Scheme 4. Possible prototropic system secondary amide favoring an internal H-
MeOH reflux
MeOH
bond.
then
MeOH reflux
ations may account for the high stability of 15 toward cycloconden-
sation (MeOH, reflux or HBr/AcOH, room temperature). First, the
trans geometry of the secondary amide in 15 strongly disfavors
the intramolecular attack of the amino group onto the benzophe-
none carbonyl. In addition, this feature is probably stabilized
through an internal H bond interaction, as illustrated in Scheme 4
(structure 15a).
These two structural behaviors are no more possible with ter-
tiary amides instead of a secondary amide. Both cis and trans
geometries are present in equilibrium with tertiary amides. In
addition, N-substitution avoids the existence of a prototropic sys-
tem favoring the internal H bonding.
For validation of this hypothesis, the reaction with 13 was per-
formed with the N-protected N-methylglycine carboxamide
(Scheme 5). The N-methyl intermediates 17a and 17b were ob-
tained in moderate yields (40% by HPLC, 30–35%). All the attempts
with the newly described system with secondary amide ([(al-
lyl)PdCl]2, JackiePhos in toluene)10 or by Pd(OAc)2 activation11 did
7a, X = CH
7b, X = N
6a, X = CH, 95%
6b, X = N, 99%
8a, X = CH
8b, X = N
Scheme 2. Attempts to prepare diazepin-2-ones 8 using literature methods.
emphasizing dramatic decrease in the reactivity of additional elec-
tron-withdrawing effects in both pyridine and pyridazine systems.
Thus, the method 2b (Scheme 2) led to the expected bromo-
methyl intermediates 6a and 6b in a good yield (95%). However,
when treated with ammonia, the starting materials 7a and 7b were
recovered quantitatively. Again, the presence of the electron-defi-
cient azines favored the nucleophilic attack onto the most electro-
philic center, the N-acyl carbonyl group in 6a and 6b. In conclusion,
the classical methods used for building regular 1,4-benzodiazepin-
2-ones could not be used for the construction of their correspond-
ing aza-benzodiapin-2-ones 8a and 8b.
Finally we developed an alternative way, using an umpollung
method based on the Buchwald reaction with a weak nucleophile.5
The aniline of the heterocyclic system showing a very low nucleo-
philicity, we were expecting that the corresponding o-halogeno-
benzophenone will be enough electrophilic to react with an N-
protected aminoamide, as illustrated in Scheme 3.
Table 1
Buchwald reaction with 2,6-dichloro-3-benzoylpyridine 13 by means of different N-
protected glycinamide 10.
For pharmacological purposes, we first prepared a series of 6,7-
diethoxybenzodiazepin-2-ones.6 Thus, the starting 6-bromo-3,4-
diethoxybenzophenone 9 was used for the prototypical reaction.
The palladium-catalyzed amidation following the Buchwald exper-
imental conditions7 was performed on 9 by means of N-benzyloxy-
carbonyl glycinamide 10 in a good yield (70%, non-optimized).8
Moreover, N-deprotection followed by cyclization afforded the de-
sired compound 12 in quantitative overall yield ((i), (ii), and (iii)).
Encouraged by this preliminary result, the same strategy was
applied to heteroaromatic 2-iminochlorides. The highly reactive
2,6-dichloro-3-(3-chlorobenzoyl)pyridine 13 was synthesized fol-
lowing the Haimova procedure9 and was first reacted with differ-
ently N-protected glycine amides (see Table 1). The yields leading
to intermediates 14 were satisfactory (42–80%) but were still not
optimized because of the failure of the next step of the reaction.
Easy N-deprotection of 14 gave the free amino intermediate 15.
A relatively easy cyclization of 15 should yield the expected bicyclic
compound 16. However, both geometric and electronic consider-
O
PG
N
H
Cl
N
Cl
Cl
Pd(OAc)2, XantPhos
N
NH
O
O
H
N
O
+
Cs2CO3, dioxane
100 C
H2N
PG
Cl
Cl
10
13
14
PG = Protecting Group
Entry
Protecting groups R
Product
Yield (%)
1
2
3
4
Cbz
Fmoc
N(Bn)Boc
N(PMB)2
14a
14b
14c
14d
50
42
80
50
O
Cbz
H
N
O
N
H
EtO
EtO
Br
Pd(OAc)2, XantPhos,
Cs2CO3,
EtO
EtO
EtO
NH
H2 (1 atm), Pd/C,
MeOH,
dioxane 100 °C
O
O
N
EtO
Then MeOH, reflux
Z-NHCH2C(O)NH2
10
9
11,
70%
12, quant.
Cbz =
O
O
Scheme 3. Synthesis of 1,4-benzodiazepine-2-ones via the Buchwald reaction.

C. Salomé et al. / Tetrahedron Letters 53 (2012) 1033–1035
1035
R
HN
O
Pd(OAc)2, XantPhos,
Cs2CO3,
Cl
N
Cl
O
N
Cl
N
N
O
Cl
N
dioxane 100 °C,
HBr/AcOH
N
R = Cbz
80%
O
Fmoc-NHCH2C(O)NHMe
or
Cl
Cbz-NHCH2C(O)NHMe
Cl
13
Cl
18
17a R = Fmoc (35%)
17b R = Cbz (30%)
Cbz
HN
Pd(OAc)2, XantPhos,
Cs2CO3,
dioxane 100 °C,
O
N
Cl
N
O
N
N
N
O
N
N
Cl
N
Cl
N
Cbz-NHCH2C(O)NHMe
O
72%
Cl
20
21
19
Scheme 5. Buchwald reaction with N0-Protected-N-methyl glycinamide onto 2,6-dichloro-3-benzoylpyridine 13 and 3,6-dichloro-4-benzoylpyridazine 20 yielding the
diazepin-2-ones 18 and 19, respectively.
not work. These last conditions provided very complex mixtures.
However these results are in good agreement with data and re-
marks of Buchwald when he developed palladium catalyzed amida-
tion reactions with fairly reactive non-cyclic secondary amides.12
However, after easy N-deprotection (HBr for Cbz13 and piperi-
dine for Fmoc), the cyclization step afforded the novel functional-
ized pyridodiazepin-2-one 18 (80%). In a similar manner, the
pyridazinodiazepin-2-one 19 could be prepared in satisfactory
overall yield (72%). In this case, the diazepin-2-one ring spontane-
ously cyclized during the Buchwald reaction. It resulted from the
highly electrophilic character of the benzoyl carbonyl in 21 facili-
tating the Cbz deprotection.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.045.
References and notes
1. Boruah, R. C.; Sandhu, J. S. J. Heterocycl. Chem. 1988, 25, 459.
2. Stempel, A.; Landgraf, F. W. J. Org. Chem. 1962, 27, 4675.
3. Bolli, M. H.; Marfurt, J.; Grisostomi, C.; Boss, C.; Binkert, C.; Hess, P.; Treiber, A.;
Thorin, E.; Morrison, K.; Buchmann, S.; Bur, D.; Ramuz, H.; Clozel, M.; Fischli,
W.; Weller, T. J. Med. Chem. 2004, 47, 2776.
4. DCC, N,N0-Dicyclohexylcarbodiimide; EDCI, N-(3-Dimethylaminopropyl)-N0-
ethylcarbodiimide hydrochloride HATU, O-(7-Azabenzotriazol-1-yl)-N,N,N0,N0-
tetramethyluronium hexafluorophosphate; HBTU, O-(benzotriazol-1-yl)-
In conclusion, an alternative and original approach leading to
1,4-benzodiazepin-2-ones and two novel functionalized heterocy-
clic systems, difficult to obtain using the literature known meth-
ods, has been stepped up via a Buchwald reaction. The key step
N,N,N0,N0-tetramethyluronium
(trifluoromethyl)benzotriazolyl] oxalate.
hexafluorophosphate;
BTBO,
1,10-Bis[6-
5. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
6. Bourguignon, J.-J.; Lagouge, Y.; Lugnier, C.; Klotz, E.; Macher, J.-P.; Raboisson, P.;
Schultz, D. WO patent 098865, 2002.
needs the use of secondary amide of glycine (or other chiral a-ami-
7. Salomé, C.; Schmitt, M.; Bourguignon, J.-J. Tetrahedron Lett. 2009, 50, 3798.
no acids) allowing easy cyclocondensation step to provide the ex-
pected bi-cyclic systems (compds 12, 18, 19). Numerous
pharmacologically active 1,4-benzodiazepin-2-ones are N-substi-
tuted. However, in the specific case of a NH-free derivative would
have to be synthesized, the N-benzyl carboxamide of glycine could
be introduced and removed at the final step. The limiting rate of
this approach still remains as the moderate yields that were previ-
ously observed by Buchwald with acyclic secondary amides onto
regular aromatics4 and by us onto heteroaromatics.6 The study of
the optimization of the Pd-catalyzed reaction with other catalysts
and other ligands are ongoing to increase the yield of this key step.
Allover, this method is straightforward and might be applied to a
wide range of electron poor systems. Such functionalized bicyclic
scaffolds have not been previously described. Their biological
activities are currently under investigation.
8. In
a flame-dried Schlenk tube, palladium acetate (0.017 mmol, 0.1 equiv),
Xantphos (0.035 mmol, 0.1 equiv) and Cs2CO3 (0.530 mmol, 1.5 equiv) were
introduced under Argon. The Schlenk tube was purged few minutes with
Argon. A solution of benzophenone (0.350 mmol, 1 equiv) and the glycinamide
(0.420 mmol, 1.2 equiv) in dioxane (1 mL) was added. The mixture was stirred
at 100 °C (16 h). The solution was filtered through a pad of celite. The pad was
washed with CH2Cl2. The organic layers were combined and the solvents were
evaporated. The residue was purified by silica gel column chromatography
(cyclohexane/EtOAc) to obtain the coupled compound.
9. Radinov, R.; Chanev, J. C.; Haimova, M. J. Org. Chem. 1991, 56, 4793.
10. Hicks, Jacqueline D.; Hyde, Alan M.; Cuezva, Alberto Martinez; Buchwald,
Stephen L. J. Am. Chem. Soc. 2009, 131, 16720.
11. Fors, B. P.; Krattiger, P.; Strieter, E.; Buchwald, S. L. Org. Lett. 2008, 10, 3505;
Dooleweerdt, K.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2010, 12, 2350.
12. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101.
13. An HBr solution in acetic acid (30%, 600
acid solution of benzylcarbamate derivatives (0.5 mmol). The solution was
stirred at room temperature (5 h). The volatiles were evaporated and
lL) was added dropwise to an acetic
a
saturated aqueous Na2CO3 solution was added. The aqueous layer was
extracted with CH2Cl2 (3 ꢀ 10 mL). The organic layers were combined, dried
(MgSO4), and concentrated under vacuum. The residue was purified by silica
gel column chromatography (cyclohexane/EtOAc) to obtain diazepin-2-one
derivatives 18.
Acknowledgment
Financial support from Neuro3D is gratefully acknowledged.