Cyclopropanation of 3,4-dihydro-1 H-benzo[e][1,4]diazepine-2,5-diones

Article abstract of DOI:10.1016/j.tetlet.2005.09.096

A two step parallel synthesis protocol for the preparation of 1N-substituted spirobenzodiazepineones is described. Treatment of 4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating prot

Full text of DOI:10.1016/j.tetlet.2005.09.096

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8207–8211
Cyclopropanation of 3,4-dihydro-1H-benzo[e][1,4]diazepine-
2,5-diones
Oliver Lack and Rainer E. Martin*
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division, CH-4070 Basel, Switzerland
Received 22 August 2005; revised 13 September 2005; accepted 16 September 2005
Available online 11 October 2005
Abstract—A two step parallel synthesis protocol for the preparation of 1N-substituted spirobenzodiazepineones is described. Treat-
ment of 4-methyl-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione with a series of alkyl halides using a microwave-assisted heating
protocol provided N-derivatized compounds, which were transformed to the corresponding cyclopropylamines employing modified
Kulinkovich-type reaction conditions. X-ray structural analysis gave conclusive evidence of the newly created spiro centre and
revealed a significant flattening of the seven-membered ring system compared with the benzodiazepinedione system providing a
characteristically different pattern of bond exit vectors. The physicochemical parameters logD, pKa, solubility and membrane
permeability of both cyclopropanated and precursor compounds were assessed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The cyclopropyl group has gained considerable interest
in medicinal chemistry over recent years due to its inter-
esting bond characteristics,1 the ability to orient vectors
in a unique three dimensional fashion,2 the potential to
control local conformation by restricting the number of
rotational degrees of freedom and the possibility to fine-
tune physicochemical properties. There has also been a
continuing interest in the cyclopropyl group as an
important synthetic intermediate especially for the syn-
thesis of condensed structures and molecules of higher
complexity.3 A recent literature survey revealed more
than 200 patents of pharmaceutically active compounds
that contain a cylopropylamine moiety demonstrating
this class to be of outstanding interest to the medicinal
chemist.4
antibiotic Chicamycin-A8 or the cholecystokinin antago-
nist Asperlicin,9 respectively. The number of publica-
tions on benzodiazepines in general and the recurrent
interest in novel synthetic routes towards benzodiaze-
pine backbones underlines the continuing interest in this
enduring compound class.10 Herein, we describe the
merger of these two structurally appealing compound
classes into one single molecule, namely cyclopropa-
nated benzodiazepineones, and the exploration of their
potentially interesting physicochemical properties.
In 1996 de Meijere et al. described the extension of the
classical Kulinkovich reaction11 transforming alkyl
esters into cyclopropanols to amides using stoichiome-
tric amounts of titanium reagent allowing corresponding
cyclopropylamines to be synthesized in a convenient
one-step procedure.12 Not surprisingly, it was reported
that this reaction does not work on primary and second-
ary amides as well as on a,b-unsaturated systems.13 We
thus speculated that the Kulinkovich-type reaction
applied to benzodiazepinediones would occur in a regio-
selective fashion exclusively at the acetamide moiety,
leaving the benzamide group unaffected due to its a,b-
unsaturated character.
Over the last decades, benzodiazepinones have emerged
as a particularly fascinating class of scaffolds in medici-
nal chemistry and have been viewed repeatedly as the
prototype of a Ôprivileged structureÕ as they hit various
classes of pharmacologically relevant targets such as
GPCRs, ion channels and enzymes.5 Prominent exam-
ples include the GABAA agonists Diazepam6 (sedative)
or Zolpidem7 (nonaddictive hypnotic), the antitumour
Condensation of isatoic acid anhydride (1) and glycine
(2) or sarcosine (N-methylglycine, 3) at 120 ꢁC in a 1:1
mixture of acetic acid and DMF afforded the unpro-
tected benzodiazepinedione 4 or the N-methylbenzamide
derivative 5, respectively, which were used as the first
Keywords: Benzodiazepineone; Kulinkovich reaction; Combinatorial
chemistry; Medicinal chemistry.
*
Corresponding author. Tel.: +41 61 688 7350; fax: +41 61 688
8714; e-mail: rainer_e.martin@roche.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.096

8208
O. Lack, R. E. Martin / Tetrahedron Letters 46 (2005) 8207–8211
substrates to investigate the cyclopropanation reaction
(Scheme 1). As expected, using starting material,
Ti(OiPr)4 and CH3CH2MgBr in a ratio of 1:1:2 did
not show any signs of conversion to the desired products
of both the doubly unprotected compound 4 and the
benzamide methylated derivative 5 according to analyti-
cal HPLC, which can be attributed to the presence of
acidic amide protons. Interestingly, the acetamide pro-
tected compound 6 containing a free benzamide moiety
did provide the corresponding cyclopropanated reaction
product 7, albeit in very poor yields of only 10%.14
However, most of the starting material was recovered.
Conducting the reaction with the doubly alkylated com-
pound 8a, which can be obtained by either benzylation
of acetamide 5 or methylation of benzamide 6, Ti(OiPr)4
and CH3CH2MgBr in a ratio of 1:1:2 resulted in a signi-
ficant increase of the desired cyclopropanated product
9a to 35% isolated yield. However, the main product
obtained was Grignard-adduct 10a.
cyclopropanated product 9a yielding still considerable
amounts of undesired addition product 10a in all cases.
A considerable improvement in terms of product to
starting material ratio was observed when the reaction
was conducted with CH3Ti(OiPr)3 instead of Ti(OiPr)4,
consistent with previous observations.15 Increasing the
ratio of titanium versus Grignard reagent improves
product ratios in favour of the cyclopropanated product
(Table 1).16 For instance, changing the ratio of benzyl-
ated compound 8b/CH3Ti(OiPr)3/CH3CH2MgBr from
1:1:1 to 1:2:1 resulted in a significant increase of the
ratio of desired product 9b relative to Grignard adduct
10b from 0.76 to 25, although the ratio of combined
products 9b + 10b to starting material 8b dropped
slightly from 0.79 to 0.58 (Table 1, entries 1 and 3). Most
importantly, the use of CH3Ti(OiPr)3 enabled both the
complex formation as well as the cyclopropanation reac-
tion to be carried out at rt rather than ꢀ78 ꢁC, simplify-
ing considerably the synthetic protocol and making it
amenable to parallel synthesis. In contrast, performing
the reaction with Ti(OiPr)4 at rt resulted in decomposi-
tion of the entire starting material.
Systematic variation of the reaction conditions including
time, temperature and sequence of reagent addition and
ratio had only a minor influence on the yield of the
In order to elucidate the structural impact of the cyclo-
propyl group on the benzodiazepine scaffold we con-
ducted single crystal X-ray analysis studies on both
starting material 8c and the corresponding cyclopropa-
nated product 9c (Fig. 1).17,18
H
N
O
H
O
N
O
a
H
N
+
R1
O
HO
N
R1
R1
R1
O
O
2
= H
R1
R1
1
3
= CH3
4
5
= H
= CH3
b
R2
N
R2
N
R2
N
O
OH
R1
c
+
N
N
N
R1
R1
O
O
O
R1 = H, R2 = 3,4-DMB
11
7
6
2 = 3,4-DMB
2 = Bn
10a
10b
9a
9b
8a R1 = CH3, R
R1 = CH3, R
8b
Scheme 1. Synthesis of cyclopropanated benzodiazepinones. Reagents
and conditions: (a) CH3COOH/DMF (1:1), 120 ꢁC, 18 h, 4: 82%, 5:
84%; (b) R2Cl/R2Br, K2CO3, DMF, MW 140 ꢁC, 20 min, 8a: 65%, 8b:
83%; (c) (i) Ti(OiPr)4, CH3CH2MgBr, THF, ꢀ78 ꢁC ! rt, 16 h, 7:
10%, 9a: 35%; (ii) CH3Ti(OiPr)3, CH3CH2MgBr, THF, rt, 16 h, 9b:
75%. DMB = 3,4-di-methoxybenzyl; Bn = benzyl.
Figure 1. Single crystal X-ray diffraction analysis of parent and cyclo-
propanated benzodiazepinones 8 c and 9c, respectively. The ORTEP
drawing depicts thermal ellipsoides at a 30% probability level.
Table 1. Reaction conditions, yields and ratios obtained for the optimization of the cyclopropanation reaction of benzodiazepinedione 8b
Entry
Starting material (SM)
SM/CH3Ti(OiPr)3/CH3CH2MgBra
Ratio (9b+10b)/8bb
Ratio 9b/10bc
1
2
3
4
8b
8b
8b
8b
1:1:1
1:1:2
1:2:1
1:2:2
0.79
0.68
0.58
0.66
0.76
0.54
25
2.3
a Complex formation 1 h at rt, reaction at rt.
b Ratio determined by analyt. HPLC.
c Estimated by quantitative TLC spot analysis.

O. Lack, R. E. Martin / Tetrahedron Letters 46 (2005) 8207–8211
8209
As anticipated the benzodiazepinedione 8c structure
shows a perfect boat-like conformation of the seven-
membered ring system. In contrast, the cyclopropanated
compound 9c does not exhibit a twist-like conformation
as observed for benzazepinone derivatives, indicating
that conjugation of the anilinic nitrogen with the aro-
matic system is strong enough to maintain coplanarity
about the endocyclic C4–N2 bond with the aryl system.19
The exocyclic C11–N2 bond deviates somewhat from
planarity causing a slight pyrimidalization at the aniline
nitrogen atom. The stronger conjugation of this nitro-
gen atom with the phenyl group in 9c is also evidenced
by a significant shortening of the C4–N2 bond lengths
The physicochemical data of compound library 8a–l and
9a–l including aniline basicity (pKa), solubility (Lysa),
passive membrane permeation (Pampa)21 and distribu-
tion coefficients (logD) are summarized in Table 2.
The cyclopropanated compounds 9a–l display pKa
values between 3.0 and 3.9. Compared with amide coun-
terparts 8a–l, the solubility of all cyclopropanated com-
pounds investigated decreases considerably, with the
only exception being compound pair 8f/9f where nearly
identical solubilities for both starting material and prod-
uct were obtained.
Interestingly, permeabilities increase from amide to
cyclopropanated compounds with short alkyl substitu-
ents 8g–i/9g–i whereas in compound pairs with aromatic
and more bulky alkyl substituents such as 8a–e/9a–e and
8j–l/9j–l a trend towards lower permeability values is
observed. Again the thiazole pair 8f/9f is an exception,
following the trend of the shorter alkyl substituents
rather than the aromatic side chains, showing a higher
permeability of the cylopropanated compound 9f com-
pared with the corresponding amide 8f. The conversion
of amides to the corresponding cyclopropanated amines
on average increases the lipophilicity logD by about
1.2 units. However, for thiazole compound pair 8f/9f
only a minor increase of 0.2 units and for isopropyl
counterparts 8i/9i, a significant higher than average
increase of 1.7 units is observed. The exception of
compounds 8f/9f from the general trend with respect
to Lysa, Pampa or logD indicates that the thiazole side
chain dominates the overall physicochemical properties
of the molecule.
˚
from 1.44 to 1.39 A, typical for alkyl-substituted aniline
derivatives, accompanied by a concomitant lengthening
2
3
˚
˚
of the N –C bond from 1.37 A in 8c to 1.44 A in struc-
ture 9c, respectively. The resulting conformation might
best be described as an Ôenvelope-typeÕ conformation
with five atoms in plane and two atoms (N1, C2) forming
a twisted flap. This flattening of the seven-membered
ring system upon cyclopropanation is interesting from
a structural and medicinal chemistry point of view as
it gives access to a characteristically distinct pattern of
bond exit vectors emanating from the benzoyl lactam
nitrogen (N1) and the methylene carbon (C2).
The preparation of a cyclopropanated benzodiazepi-
none compound library using the optimized Kulinko-
vich-type reaction protocol is outlined in Scheme 2.
Alkylation of building block 5 with a series of different
alkyl and benzyl halides using K2CO3 as a base in
DMF under microwave-assisted heating to 140 ꢁC for
20 min provided benzodiazepinediones 8a–l in good to
excellent yields after purification by preparative
HPLC.20 Treatment of library 8a–l with a 2.5-fold
excess of a preformed 2:1 complex of CH3Ti(OiPr)3
and CH3CH2MgBr at rt for 16 h provided the expected
compounds 9a–l after isolation by preparative HPLC in
moderate yields (Table 2). The cyclic methylene group
in benzodiazepinediones 8a–l display two diastereo-
topic protons giving rise to a classical AB system in the
1H NMR spectra. Interestingly, these two distinctly dif-
ferent protons merge to a singlet for all products 9a–l,
indicating an increased conformational flexibility of
the cyclopropanated framework compared to the more
rigid benzodiazepinediones 8a–l. Similarly, the excocy-
clic methylene groups present in compounds 8a–f, which
also display a pair of doublets, merge to a single signal
for the cyclopropanated analogues 9a–f.
In summary, a convenient protocol for the regioselec-
tive cyclopropanation of benzodiazepinediones was
developed using a modified Kulinkovich-type reaction
protocol. The use of CH3Ti(OiPr)3 allowed the cyclo-
propanation to be carried out at rt, which greatly facili-
tated the rapid assembly of a compound library in a
parallel fashion. The successful incorporation of a
cyclopropyl group exclusively at the acetamide moiety
was confirmed by 1H NMR, 13C NMR, HRMS as
well as single crystal X-ray diffraction analysis. Assess-
ment of the physicochemical properties of 9a–l
revealed interesting trends with respect to solubility
and lipophilicity in comparison to their amide precur-
sors 8a–l. The spirocyclic benzodiazepinone backbone
represents an interesting novel template that offers sev-
eral possibilities for further modification, which may
result in new biological activity.
General procedure: Compound library 8a–l: To a solu-
tion of building block 5 (0.095 g, 0.5 mmol, 1.0 equiv)
in DMA (1.0 mL) was added Cs2CO3 (0.65 g,
2.5 mmol, 5.0 equiv) and the corresponding alkylbro-
mide/chloride (0.75 mmol, 1.5 equiv). After micro-
wave-assisted heating to 140 ꢁC for 20 min (Emrys
Optimizer, Personal Chemistry) the reaction mixture
was concentrated under reduced pressure, a solution
of satd NaHCO3 (1 mL) added and the mixture
extracted with ethyl acetate (3 · 1 mL). The organic
phases were combined and the organic solvent
removed under reduced pressure, the residues dissolved
R
R
O
O
H
N
N
N
a
b
N
N
N
O
O
O
5
8a-l
9a-l
Scheme 2. Parallel synthesis of cyclopropanated benzodiazepinones.
Reagents and conditions: (a) RCl/RBr, K2CO3, DMF, MW 140 ꢁC,
20 min; (b) CH3Ti(OiPr)3, CH3CH2MgBr, THF, rt, 16 h.

8210
O. Lack, R. E. Martin / Tetrahedron Letters 46 (2005) 8207–8211
Table 2. Isolated yields and physicochemical data of both starting materials 8a–l and cyclopropanated analogues 9a–l
Yielda (%)
pKa
Lysac (lg/mL)
Pampa Ped (10ꢀ6 cm/s)
logDe
b
Compound
R
O
O
8a
9a
31
8
—
3.2
53
14
7.7
2.9
1.8
3.1
8b
9b
23
43
—
3.1
>326
23
9.3
4.1
1.9
2.9
8c22
9c23
41
20
—
3.0
208
49
7.6
5.7
1.4
2.6
O
O
8d
9d
42
15
—
3.2
326
71
8.5
4.2
1.5
2.6
O
O
8e
9e
31
8
—
3.2
53
14
7.7
2.9
1.8
3.1
Cl
N
8f
9f
22
24
—
3.4
>378
>352
5.4
6.4
1.9
2.1
S
8g
9g
30
16
—
3.1
208
123
2.4
6.0
0.1
1.4
CH3
8h
9h
31
15
—
3.4
>290
121
3.9
9.3
0.5
1.9
8i
9i
44
25
—
3.4
>262
71
6.1
8.3
0.9
2.6
8j
9j
74
32
—
3.9
>255
76
5.3
3.1
0.7
2.1
8k
9k
33
20
—
3.4
>292
168
7.4
6.2
0.9
2.3
8l
9l
53
33
—
3.4
>307
122
9.0
7.3
1.4
2.7
a After preparative HPLC purification.
b pKa values were determined spectrophotometrically on a ProfilerSGA instrument in a SGA buffer system containing 10% (v/v) methanol at an ionic
strength of 150 mM.
c Lyophilization solubility assay. Solubility was measured from lyophilized DMSO stock solutions spectrophotometrically at pH = 6.5 in a 50 mM
phosphate buffer.
d Parallel Artificial Membrane Permeation Assay: low: Pe < 0.1, medium: 0.1 < Pe < 1.0, high: Pe > 1.0.
e logD values were measured spectrophotometrically at pH = 7.4 in a 1-octanol/50 mM TAPSO buffer system containing 5% (v/v) DMSO.
in DMSO, filtered and purified by preparative HPLC
affording compounds 8a–l. Compound library 9a–l:
To 12 solutions of CH3Ti(OiPr)3 (0.12 g, 0.5 mmol,
5.0 equiv) in dry THF (2 mL) at 0 ꢁC was added in
parallel slowly a solution of 1.0 M CH3CH2MgBr in
THF (0.25 mL, 0.25 mmol, 2.5 equiv), which immedi-
ately resulted in the formation of a dark brown sus-
pension. After stirring for 1 h, compounds 8a–l
(0.1 mmol, 1.0 equiv), dissolved in dry THF (2 mL),
were added and the reaction mixtures shaked at rt
for 16 h. Addition of a solution of 1.0 M NH4Cl
(1 mL), extraction with diethyl ether (3 · 1 mL) and
combination of the organic phases provided after
removal of the organic solvent under reduced pressure
the crude reaction products. Dissolution in DMSO, fil-
tration and purification by preparative HPLC gave
compounds 9a–l.
Acknowledgements
We are very much indebted to Professor Klaus Muller
¨
and Dr. Mark Rogers-Evans for seeding the ideas of this
study as well as to Drs. Konrad Bleicher and Luke
Green for many helpful discussions. We are also grateful
to the Analytical Services and the Molecular Properties
Group for providing spectroscopic and physicochemical
´
data, respectively, as well as to Mr. Andre Alker for
solving the single crystal X-ray structures.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2005.09.096.

O. Lack, R. E. Martin / Tetrahedron Letters 46 (2005) 8207–8211
8211
cabinet using the UV image processing software Video-
Scan TLC/HPTLC 1.0.01 and Video Store 2.25ꢀ from
Synoptics Ltd, Camag.
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22. Spectroscopic data for compound 8c: 1H NMR (300 MHz,
DMSO): d 3.14 (s, 3H), 3.68 (s, 3H), 3.76 (d, J = 14.8 Hz,
1H), 4.15 (d, J = 14.8 Hz, 1H), 4.90 (d, J = 15.7 Hz, 1H),
5.25 (d, J = 15.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 7.01
(d, J = 8.7 Hz, 2H), 7.24–7.65 (m, 4H). 13C NMR
(75 MHz, DMSO): d 35.16, 48.16, 52.33, 54.94, 113.87,
121.98, 125.40, 128.07, 128.91, 129.52, 129.94, 131.68,
139.29, 158.26, 166.32, 167.97. FTIR (ATR, cmꢀ1): 2934
(w), 2839 (w), 1672 (s), 1632 (s), 1601 (s), 1512 (s), 1466
(m), 1397 (m), 1240 (s), 1213 (m), 1174 (m). HRMS (EI
POS) m/z calculated for C18H18N2O3 (M)+: 310.1317,
found: 310.1317.
23. Spectroscopic data for compound 9c: 1H NMR (300 MHz,
CDCl3): d 0.65 (t, J = 6.6 Hz, 2H), 0.92 (t, J = 6.6 Hz,
2H), 3.08 (s, 3H), 3.31 (s, 2H), 3.70 (s, 3H), 4.40 (s, 2H),
6.65 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.6 Hz, 2H), 6.89
(t, J = 7.9 Hz, 1H), 7.01 (d, J = 8.6 Hz, 2H), 7.14
(td, J = 8.0 Hz, J = 1.7 Hz, 1H), 8.11 (dd, J = 7.9 Hz,
J = 1.7 Hz, 1H). 13C NMR (75 MHz, CDCl3): d 14.01,
37.91, 45.66, 55.24, 56.58, 58.98, 113.97, 120.66, 120.86,
126.42, 127.67, 131.46, 131.74, 133.14, 148.62, 158.68,
169.28. FTIR (ATR, cmꢀ1): 2923 (w), 2853 (w), 1621 (s),
1595 (s), 1587 (m), 1507 (s), 1482 (s), 1455 (m), 1389 (m),
1284 (m), 1241 (s), 1212 (s), 1167 (s). HRMS (EI POS) m/z
calculated for C20H22N2O2 (M)+: 322.1681, found:
322.1681.
13. Lee, J.; Cha, J. K. J. Org. Chem. 1997, 62, 1584–1585.
14. Compound 6 was prepared in 75% yield by reaction of 3,4-
dimethoxy-benzyl-protected isatoic acid anhydride with
glycine at 125 ꢁC for 3 h followed by stirring at rt
overnight in concd acetic acid.
15. (a) Chaplinski, V.; Winsel, H.; Kordes, M.; de Meijere, A.
Synlett 1997, 111–114; (b) de Meijere, A.; Winsel, H.;
Stecker, B. Organic Syntheses Annual Vol. 81, p. 14
(available online at http://www.orgsyn.org/).
16. To guide the optimization process, the ratio of products 9b
and 10b to starting material 8b was assessed by analyt.
HPLC. Due to the inability to resolve the reaction
products 9b and 10b by HPLC they were quantified via
TLC spot analysis conducted by a Camag Reprostar 3 UV