New synthesis of 1,3-dihydro-1,4-benzodiazepin-2(2H)-ones and 3-amino-1,3-dihydro-1,4-benzodiazepin-2(2H)-ones: Pd-catalyzed cross-coupling of imidoyl chlorides with organoboronic acids

Article abstract of DOI:10.1021/jo026860a

A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic reagent as the key step, is described. A five-step synthesis of a

Full text of DOI:10.1021/jo026860a

New Syn th esis of 1,3-Dih yd r o-1,4-ben zod ia zep in -2(2H)-on es a n d
3-Am in o-1,3-d ih yd r o-1,4-ben zod ia zep in -2(2H)-on es: P d -Ca ta lyzed
Cr oss-Cou p lin g of Im id oyl Ch lor id es w ith Or ga n obor on ic Acid s
Alan Nadin,* J ose´ M. Sa´nchez Lo´pez, Andrew P. Owens, Dean M. Howells,
Adam C. Talbot, and Timothy Harrison
Department of Medicinal Chemistry, Merck Sharp & Dohme Research Laboratories,
The Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK
alan_nadin@merck.com
Received December 17, 2002
A new approach to the synthesis of 1,4-benzodiazepines and 3-amino-1,4-benzodiazepines, which
employs the Pd-catalyzed cross-coupling reaction of an imidoyl chloride with an organometallic
reagent as the key step, is described. A five-step synthesis of a key intermediate is described and
it is shown that in only four further steps (three couplings and a TFA-mediated BOC-deprotection)
a wide variety of N1-, C3-amino-, C5-carbon-, or nitrogen-substituted 1,4-benzodiazepines can be
synthesized.
In tr od u ction
The 1,4-benzodiazepine skeleton (I, Figure 1) is one of
medicinal chemistry’s most widely used motifs. First
discovered in the 1960s,1 there are many marketed
pharmaceutical agents (e.g. Diazepam) that contain a 1,4-
benzodiazepine. These function principally as GABA
receptor agonists for CNS clinical indications such as
anxiety, insomnia, muscle spasm, epilepsy and convul-
sions.
The slightly more functionalized 3-amino-1,4-benzo-
diazepine skeleton (II, Figure 1), first highlighted as a
component of a nonpeptidic CCK antagonist,2 has gained
recognition as a “privileged structure”3 and has been used
in a number of medicinal chemistry programs in many
therapeutic settings (for example, CCK,4 bradykinin,5
farnesyl transferase,6 PDE IV,7 and IKS-mediated cardiac
arythmia8). Most recently, several publications,9 includ-
F IGURE 1. 1,4-Benzodiazepin-2(2H)-ones and 3-amino-1,4-
benzodiazepin-2(2H)-ones.
(1) Fryer, R. I. Bicyclic Diazepines, The Chemistry of Heterocyclic
Compounds; Wiley: New York, 1991; Chapter 7.
(2) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.;
Anderson, P. S.; Chang, R. S. L.; Loti, V. J .; Cerino, D. J .; Chen, T. B.;
Kling, P. J .; Kunkel, K. A.; Springer, J . P.; Hirschfield, J . J . Med. Chem.
1988, 31 2235.
ing our own,10 have described the use of acylated 3-amino-
benzodiazepines (e.g. III, Figure 1) as highly potent
γ-secretase inhibitors (with potential for the nonpalliative
treatment of Alzheimer’s Disease11).
(3) Patchett, A. A.; Nargund, R. P. Ann. Rep. Med. Chem. 2000,
35, 289.
(4) Castro, J . L.; Broughton, H. B.; Russell, M. G. N.; Rathbone,
D.; Watt, A. P.; Ball, R. G.; Chapman, K. L.; Patel, S.; Smith, A. J .;
Marshall, G. R.; Matassa, V. G. J . Med. Chem. 1997, 40, 2491 and
references therein.
(8) Selnick, H. G.; Liverton, N. J .; Baldwin, J . J .; Butcher, J . W.;
Claremon, D. A.; Elliott, J . M.; Freidinger, R. M.; King, S. A.; Libby,
B. E.; McIntyre, C. J .; Pribush, D. A.; Remy, D. C.; Smith, G. R.;
Tebben, A. J .; J urkiewicz, N. K.; Lynch, J . J .; Salata, J . J .; Sanguinetti,
M. C.; Siegl, P. K.; Slaughter, D. E.; Vyas, K. J . Med. Chem. 1997, 40,
3865.
(5) Amblard, M.; Daffix, I.; Berge, G.; Calmes, M.; Dodey, P.;
Pruneau, D.; Paquet, J .-L.; Luccarini, J .-M.; Belichard, P.; Martinez,
J . J . Med. Chem. 1999, 42 (20), 4193-4201.
(6) J ames, G. L.; Goldstein, J . L.; Brown, M. S.; Rawson, T. E.;
Somers, T. C.; McDowell, R. S.; Crowley, C. W.; Lucas, B. K.; Levinson,
A. D.; Marsters, J . C., J r. Science (Washington, D.C.) 1993, 260 (5116),
1937-42.
(7) Pascal, Y.; Andrianjara, C. R.; Auclair, E.; Avenel, N.; Bertin,
B.; Calvet, A.; Feru, F.; Lardon, S.; Moodley, I.; Ouagued, M.; Payne,
A.; Pruniaux, M.-P.; Szilagyi, C. Bioorg. Med. Chem. Lett. 2000, 10
(1), 35-38.
(9) (a) Athena-Elan: e.g.: Thompson, R. C.; Wilkie, S.; Stack, D.
R.; Vanmeter, E. E.; Shi, Q.; Britton, T. C.; Audia, J . E.; Reel, J . K.;
Mabry, T. E.; Dressman, B. A.; Cwi, C. L.; Henry, S. S.; Mcdaniel, S.
L.; Stucky, R. D.; Porter, W. J . WO 9967221. (b) DuPont: e.g.: Olson,
R. E. WO 0192235.
(10) (a) Castro Pineiro, J . L.; Churcher, I.; Guiblin, A. R.; Harrison,
T.; Kerrad, S.; Madin, A.; Nadin, A. J .; Owens, A. P.; Sparey, T. J .;
Teall, M. R.; Williams, S. WO 0190084. (b) Churcher, I.; Ashton, K.;
Butcher, J . W.; Clarke, E. E.; Harrison, T.; Lewis, H. D.; Owens, A.
P.; Teall, M. R.; Williams, S.; Wrigley, J . D. J . Bioorg. Med. Chem.
Lett. 2003, 13, 179.
10.1021/jo026860a CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/07/2003
2844
J . Org. Chem. 2003, 68, 2844-2852

Synthesis of 1,4-Benzodiazepines
F IGURE 3. Retrosynthesis of 1,4-benzodiazepin-2(2H)-ones
and 3-amino-1,4-benzodiazepin-2(2H)-ones.
F IGURE 2. General strategies for the synthesis of 1,4-
benzodiazepin-2(2H)-ones and 3-amino-1,4-benzodiazepin-
2(2H)-ones.12
sp2 coupling of an imidoyl triflate with 2-pyridylzinc
chloride has been investigated by Shiraishi and co-
workers20 and Davis has reported a single example of a
Kumada coupling of a Grignard reagent with an imidoyl
chloride, although even a slight variation to the structure
of the imidoyl chloride caused the reaction to fail.21 In
contrast, a number of examples of Pd(0)-catalyzed cross-
couplings of the isomeric lactam-derived ketene aminal
triflates22 and phosphates23 have been reported. In this
contribution, we describe the successful execution of the
retrosynthesis described in Figure 3 and present a new
and efficient route to a very versatile intermediate from
which almost any N1-, N3-, C5-substituted benzo-
diazepine can be made in only four additional steps.
There are a number of commonly employed and ef-
ficient synthetic routes to 1,4-benzodiazepines and
3-amino-1,4-benzodiazepines,12 which are broadly sum-
marized in Figure 2. The major limitation with these
routes is that the C-5 substituent and, to a lesser extent,
the N-1 substituent are established at an early stage in
the synthesis. This is clearly not ideal for the preparation
of analogues containing diversity at either of these
positions. One exception related to the work described
in this article is contained in a Sanofi patent,13 which
describes the nucleophilic addition of two organo-
manganese reagents (cyclohexylmanganese and phenyl-
manganese) to the C-5 imidoyl chloride of a simple 1,4-
benzodiazepine.
Accordingly, it was surmized that a more convergent
approach to 1,4-benzodiazepines and 3-amino-1,4-benzo-
diazepines may well be realized through a Pd(0)-
catalyzed sp2 cross-coupling reaction of an imidoyl halide
(haloimidate) or triflate with a suitable organometallic
C-5 substituent (stannane, organozinc, or boronic acid)
(2 f 1, Figure 3). In principle, 2 should be available by
functionalization of bis(lactam) 3.
Resu lts a n d Discu ssion
As a model substrate for the key cross-coupling reac-
tion, 5 was prepared from 425 following the efficient
procedure described by Wade and co-workers (eq 1).24
Examples of carbon-carbon bond formations involving
Pd(0)-catalyzed reactions of imidoyl halides or triflates
are surprisingly rare, given the vast numbers of examples
that involve alkenyl halides or triflates, or 2-halo- (or
triflyl-) pyridines. A few examples of sp2-sp couplings
of imidoyl chlorides with alkynyl stannanes,14,15 alkynyl
cuprates,16 and alkynes17 are known, including an elegant
approach to the synthesis of the semicorrins.18,19 The sp2-
The cross-coupling reaction of 5 with a representative
arylborane [2-(3-pyridyl)-1,3,2-dioxaborinane] to make 6
(Table 1) was investigated under a variety of conditions
utilized for the Suzuki reaction. Initial results with the
(16) (a) Ukhin, L. Y.; Orlova, Z. I. Zh. Org. Chem. 1987, 23, 2185.
(b) Kazankova, M. A.; Trostyanskaya, I. G.; Lutsenko, S. V.; Efimova,
I. V.; Beletskaya, I. P. Russ. J . Org. Chem. 1999, 35, 1273.
(17) Lin, L.-Y.; Sheng, H.-Y.; Huang, Y.-Z. Synthesis 1991, 235.
(18) J acobi, P. A.; Liu, H. J . Am. Chem. Soc. 1999, 121, 1958.
(19) J acobi, P. A.; Liu, H. Org. Lett. 1999, 1, 341.
(20) Yamamoto, S.; Hashiguchi, S.; Miki, S.; Igata, Y.; Watanabe,
T.; Shiraishi, M. Chem. Pharm. Bull. 1996, 44, 734.
(21) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael, Y.
W. Org. Lett. 2000, 2, 3901.
(22) (a) Luker, T.; Hiemstra, H.; Speckamp, W. N. J . Org. Chem.
1997, 62, 8131. (b) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J . Org.
Chem. 2001, 66, 2459 and references therein.
(23) (a) Nicolaou, K. C.; Namoto, K. Chem. Commun. (Cambridge)
1998, 16, 1757-1758. (b) J iang, J .; DeVita, R. J .; Doss, G. A.; Goulet,
M. T.; Wyvratt, M. J . J . Am. Chem. Soc. 1999, 121, 593.
(24) Wade, P. C.; Vogt, B. R.; Toeplitz, B.; Puar, M. S.; Gougoutas,
J . Z. J . Org. Chem. 1979, 44, 88.
(11) VanDenBerg, C. M.; Kazmi, Y.; J ann, M. W. Drugs Aging 2000,
162, 123-38.
(12) (a) Sternbach, L. H. Angew. Chem., Int. Ed. Engl. 1971, 10,
34. (b) Bock, M. G.; DiPardo, R. M.; Evans, B. E.; Rittle, K. E.; Veber,
D. F.; Freidinger, R. M. Tetrahedron Lett. 1987, 28, 939. (c) Shi, Y.-J .;
Wells, K. M.; Pye, P. J .; Choi, W.-B.; Churchill, H. W. O.; Lynch, J . E.;
Maliakal, A.; Sager, J . W.; Rossen, K.; Volante, R. P.; Reider, P. J .
Tetrahedron 1999, 55, 909. (d) Bock, M. G.; DiPardo, R. M.; Evans, B.
E.; Rittle, K. E.; Veber, D. F.; Freidinger, R. M.; Hirschfield, J .;
Springer, J . P. J . Org. Chem. 1987, 52, 3232. (e) Bourrain, S.; Showell,
G. A. Synthesis 1994, 5, 505. (f) Sherrill, R. G.; Sugg, E. E. J . Org.
Chem. 1995, 60, 730.
(13) Bouisset, M.; Bousquet, A.; Heymes, A. DE 3831533 1988.
(14) Kobayashi, T.; Sakakura, T.; Tanaka, M. Tetrahedron Lett.
1985, 26, 3463.
(15) Faust, R.; Go¨belt, B. Tetrahedron Lett. 1997, 38, 8017.
(25) Available from Maybridge, Ltd, UK.
J . Org. Chem, Vol. 68, No. 7, 2003 2845

Nadin et al.
TABLE 1. Rea ction of Im id oyl Ch lor id e 5 w ith Bor on ic Acid s u n d er Va r iou s Con d ition se
entry
Pd (equiv)
ligand/base (equiv)
reaction conditions
product (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (0.01)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.01)
Pd(OAc)2 (0.1)
Pd2(dba)3 (0.1)
Pd(PPh3)4 (0.1)
Pd(PPh3)4 (0.1)
Pd(PPh3)4 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
La (0.02), KF (3)
La (0.2), KF (3)
THF, rt, 20 h
THF, rt, 24 h
6 (0)
6 (0)
6 (0)
6 (0)
6 (31)
6 (87)
6 (89)
6 (91)
6 (95)
7 (44)
8 (22)
9 (0)
La (0.02), K3PO4 (2)
La (0.2), K3PO4 (2)
PtBu3(0.2), Cs2CO3 (2)
K3PO4 (2)
toluene, 100 °C, 24 h
toluene, 100 °C, 20 h
dioxane, 80 °C, 24 h
DMF, 100 °C, 3 h
H2O-DME, 100 °C, 0.5 h
H2O-DME, RT, 10 d
DMF, 100 °C, 2 h
DMF, 100 °C, 2 h
DMF, 100 °C, 2 h
DMF, 100 °C, 2 h
Na2CO3 (2)
Na2CO3 (2)
PPh3 (0.2), Cs2CO3 (2)
PPh3 (0.2), Cs2CO3 (2)
PPh3 (0.2), Cs2CO3 (2)
PPh3 (0.2), Cs2CO3 (2)
10b
11c
12d
a
b
d
L
) 2-(di-tert-butylphosphino)biphenyl. 2-Fluorobenzeneboronic acid was used. c 3-Fluorobenzeneboronic acid was used. 4-
Fluorobenzeneboronic acid was used. e Reactions were performed on a 1 mmol scale with 2-(3-pyridyl)-1,3,2-dioxaborinane; yields are
based on isolated, purified material.
TABLE 2. Rea ction of Im id oyl Ch lor id e 5 w ith Va r iou s
catalyst/ligand system employed by Buchwald26 for the
Or ga n om eta llicsf
cross-coupling of aryl chlorides were not encouraging
(entries 1-4), with either starting material being recov-
ered unchanged or decomposition occurring. Under con-
ditions first described by Fu,27 an isolated yield of 31%
was obtained (entry 5). However, with Pd(PPh3)4 and
either K3PO428 (entry 6) or aqueous Na2CO329 as the base,
the yield of 6 was increased greatly with essentially clean
and complete conversion occurring rapidly at 100 °C
(entry 7). The success of the latter reaction was somewhat
surprising as imidoyl chlorides are normally unstable to
aqueous conditions. The reaction with Na2CO3/H2O-DME
(entry 8) also went to completion at room temperature
but required a reaction time of over 10 days. From this
entry
organometallica
product (%)
1
2
3
4
5
6
7
8
9
2-fluorobenzeneboronic acid
3-fluorobenzeneboronic acid
4-fluorobenzeneboronic acid
3-methoxybenzeneboronic acid
4-methoxybenzeneboronic acid
4-nitrobenzeneboronic acid
2-thiopheneboronic acid
7 (99)
8 (95)
9 (97)
10 (90)
11 (82)
12 (66)
13 (94)
14 (98)
15 (68)
16 (76)
17e
30
initial screen, palladium(II) acetate-PPh3-Cs2CO3 ap-
peared to be the best conditions, yielding 6 in 95%
isolated yield. However, this yield was not reproducible
and on changing the structure of the boronic acid even
modestly (entries 10-12) the isolated yields of 7-9 were
disappointingly low.
benzo[b]thiophene-2-boronic acid
phenylacetyleneb
10
11
6-ethoxy-6-oxohexylzinc bromidec
tri(n-butyl)vinylstannaned
a
Reaction conditions: Na2CO3 (2 equiv), Pd(PPh3)4 (0.01 equiv),
Fortunately, the original conditions29 for the Suzuki
coupling (entry 7) worked reliably with a wide variety of
aromatic and heteroaromatic boronic acids to give com-
pounds 7-14 (entries 1-8, Table 2), even with a reduced
amount of Pd(PPh3)4 (1 mol %). It was also pleasing to
find that the Castro-Stevens sp-sp2 coupling of 5 with
phenylacetylene worked well to give 15 and an sp2-sp3
coupling with an organozinc reagent afforded 16 (Table
2, entries 9 and 10). The Stille reaction of 5 with tri(n-
butyl)vinyltin (entry 11) also proceeded well to give the
1-azadiene 17, but this was unstable to chromatography.
Unfortunately, attempts to form an organometallic spe-
cies from 5 were unsuccessful: bis(pinacolato)diboron,
80 °C, DME-H2O unless otherwise stated. Reaction conditions:
b
PdCl2(PPh3)2, CuI, Et3N, PPh3, 90 °C. c Reaction conditions:
d
PdCl2(PPh3)2, THF, rt. Reaction conditions: Pd2(dba)3, PtBu3,
CsF, dioxane, 100 °C. e Reaction product unstable to chromatog-
raphy. f Reactions were performed on a 1 mmol scale; yields are
based on isolated, purified material.
(dppf)PdCl2, KOAc, dioxane, 80 °C31 gave the 5-acetoxy
derivative; and pinacolborane, (dppf)PdCl2, AsPh3, Et3N32
led to reduction. Attempts to form the organozinc with
commercially available Rieke zinc were also unsuccessful.
Having defined reliable conditions for the Suzuki
coupling and demonstrated the effectiveness of a range
of other cross-coupling reactions on chloroimidate 5, we
next turned our attention to applying the same reaction
conditions to the more challenging 3-amino-1,4-benzo-
diazepines.
(26) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38,
2413.
(27) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 1998, 3724,
3387.
(28) Shieh, W.-C.; Carlson, J . A. J . Org. Chem. 1992, 57, 379.
(29) Suzuki, A. Acc. Chem. Res. 1982, 15, 178.
(30) Showell, G. A.; Bourrain, S.; Neduvelil, J . G.; Matassa, V. G.;
Matheson, S.; Patel, S.; Smith, A. J .; Chapman, K. L.; Marquis-Omer,
D.; Ball, R. G. Med. Chem. Res. 1996, 65, 312-317.
(31) Ishiyama, T.; Murata, M.; Miyaura, N. J . Org. Chem. 1995,
60, 7508.
(32) Murata, M.; Oyama, T.; Watanbe, S.; Masuda, Y. Synthesis
2000, 778.
2846 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of 1,4-Benzodiazepines
TABLE 3. Rea ction of Im id oyl Ch lor id es 22-24 w ith
SCHEME 1. Syn th esis of Im id oyl Ch lor id e 20
Va r iou s Bor on ic Acid sb
SCHEME 2. Syn th esis a n d Rea ction of
3-Am in o-5-ch lor o-1,4-ben zod ia zep in es
a
Overall yield following deprotection of the BOC group with
b
TFA-DCM. Yields are based on isolated, chromatographically
pure material. Noncommercially available boronates were made
from the corresponding bromides or triflates by the Miyaura
protocol (ref 31).
a
Prepared by alkylation of 3 (ref 12) and imidoyl chloride
formation (64%) (see Experimental Section).
converted to the imidoyl chloride 20 in high yield by
treatment with POCl3 and N,N-dimethylaniline at reflux
for 5 h, followed by an aqueous workup and chromatog-
raphy. Alternatively the reaction can be performed in
only a few minutes by refluxing 19 in neat POCl3,
although on a practical scale the workup is more difficult.
Once pure, 20 was stable in a stoppered flask at room
temperature for several months. Although the cyclization
reaction was efficient on a small scale (56% isolated
yield), attempts to scale it up or optimize the reaction
conditions were repeatedly unsuccessful. In particular,
the reaction always failed when the N1 substituent was
a hydrogen atom. Given that the N1 position is a valuable
point of diversity, we sought an alternative solution.
Surprisingly, the 3-amino-5-chloro-1,4-benzodiazepine
or, at the inception of this work, 3-amino-1,4-benzo-
diazepin-2,5-dione frameworks were not known com-
pounds.33 Our first generation synthesis of a 3-amino-
1,4-benzodiazepin-2,5-dione is shown in Scheme 1. Re-
action of N-methyl anthranilamide with the acid chloride
of R-benzotriazolyl-CBZ-glycine under conditions de-
scribed by Sherrill and Sugg12f gave 18, which underwent
thermal cyclization (180 °C, DMSO) with the elimination
of benzotriazole to form 19. Bis(lactam) 19 was selectively
(33) A synthesis of 3-amino-3,4-dihydro-1-methyl-1H-1,4-benzodi-
azepine-2,5-dione is described by Wu et al., WO 9828268.
J . Org. Chem, Vol. 68, No. 7, 2003 2847

Nadin et al.
TABLE 4. Rea ction of Im id oyl Ch lor id es 22-24 w ith
Va r iou s Am in esa
entry
R1
amine
product (%)
1
2
3
H
H
morpholine
azetidine
piperidine
morpholine
36 (76)
37 (81)
38 (64)
39 (84)
Me
CH2CONH2
4
a
Yields are based on isolated, chromatographically pure mate-
rial.
Our second generation approach, based on the electro-
philic azidation of 5 (R ) Me) or 21 (R ) PMB), was more
reliable and is shown in Scheme 2. The azidation8 of 5
proceeded well to give the azide in good isolated yield.
Reduction of the azide functionality to give 22 was
achieved by hydrogenation with PtO2 under a slight
pressure of hydrogen in the presence of a modest excess
of (BOC)2O. Other methods (PPh3-H2O-MeOH; TMSI) or
hydrogenation in the absence of (BOC)2O were unsuc-
cessful.
Application to the synthesis of 21 worked equally well
and on removal of the PMB protecting group with ceric
ammonium nitrate at -10 °C 23 was obtained reliably
(and on a multigram scale) in 60-80% yield. Imidoyl
chloride 23 can be selectively alkylated at the N1 position
with iodoacetamide (and with other simple alkylating
agentssdata not shown) to give 24.
Con clu sion
A new approach to the synthesis of 1,4-benzodiazepines
and 3-amino-1,4-benzodiazepines, which utilizes the
cross-coupling reaction of an imidoyl chloride as the key
step, has been described. A five-step synthesis of 23
allows access to virtually any N1-, C3-acylamino, C5-
carbon-, or nitrogen-substituted benzodiazepine from
commercially available starting materials via four further
transformations (a Pd(0)-catalyzed cross-coupling, an
alkylation, a TFA-mediated BOC-deprotection, and an
acylation). We believe this work refreshes the benzodi-
azepine field by the application of modern cross-coupling
reactions and will assist in the future preparation of
biologically active benzodiazepines.41
A variety of cross-coupling reactions were performed
on imidoyl chlorides 22-24 with use of the conditions
defined in our earlier study, and the results are shown
in Table 3. From these results, it can be seen that the
yields of 25-33 are generally good, even with unusual
and functionalized boronic acids (entries 1-11). It is
noteworthy that the cross-coupling reaction proceeds well
either with or without functionality at the N1 position,
thereby allowing the N1 and C5 substituents to be
introduced in either order.
In a further exploration of the reactivity of imidoyl
chlorides 22-24, a variety of simple secondary amines
were reacted with 22-24 to give 36-39 as shown in
Table 4. The products, amidinobenzodiazepines, are often
more water-soluble and brain penetrant than typical
benzodiazepines.30,34 Previous syntheses of amidino-
benzodiazepines have involved formation of the C3-
unsubstituted amidine, followed by electrophilic amina-
tion and reduction;35 this new route would appear to be
an attractive, more convergent, alternative.
Exp er im en ta l Section
Gen er a l Con sid er a tion s. Melting points are uncorrected.
Unless otherwise noted, all reactions were performed in oven-
dried glassware under an atmosphere of dry nitrogen. Solu-
tions were evaporated under reduced pressure with a rotary
evaporator. Flash column chromatography was performed on
silica gel (40-63 µm mesh). Starting materials were obtained
commercially and used as received.
2H -1,4-Ben zod ia zep in -2-on e, 5-ch lor o-1,3-d ih yd r o-1-
m eth yl- (5):36 A solution of 4 (25 g, 0.13 mol), N,N-dimethyl-
aniline (33 mL, 0.26 mol), POCl3 (12.2 mL, 0.13 mol), and
benzene (250 mL) was refluxed for 7 h, then allowed to cool
overnight. The reaction mixture was cooled to 0 °C, treated
with ice water (100 mL), and stirred for 30 min until the
reaction mixture reached room temperature. The reaction
mixture was poured into more water and ether. The organic
layer was separated, washed with water and brine, dried
(MgSO4), filtered, and evaporated. Trituration with ether gave
5 (21.8 g, 80%) as a white solid: mp 185-187 °C. 1H NMR
(400 MHz, CDCl3) 7.82 (1H, dd, J ) 7.8, 1.5 Hz), 7.58 (1H,
ddd, J ) 7.4, 7.4, 0.8 Hz), 7.32-7.27 (2H, m), 4.63 (1H, br s),
3.27 (1H, br s), 3.41 (3H, s). 13C NMR (90 MHz, CDCl3): 37.2,
Finally, to illustrate the use of these new strategies in
preparing biologically active benzodiazepines, the BOC
group was readily removed from 31 with TFA, and
acylation with a representative phenylacetic acid pro-
ceeded uneventfully to give 40 in high yield (eq 2).
(36) Baldwin, J . J .; Claremon, D. A.; Elliott, J . M.; Liverton, N.;
Remy, D. C.; Selnick, H. G. WO 9514473 1995.
(37) Reeder, E.; Sternbach, L. H. US patent 3270053, 1966.
(38) Wang, J . K. T.; Morgan, J . I.; Spector, S. Proc. Natl. Acad. Sci.
U.S.A. 1984, 81, 753.
(39) Hagashita, Y.; Seno, K.; Myakoshi, M.; Tsushima, T.; Ishihara,
Y. J P 07097371, 1995.
(40) Shove, L. T.; Chen, S.-W.; Beatty, M.; et al. Bioorg. Med. Chem.
1995, 3, 1547.
(41) Owens, A. P.; Nadin, A.; Talbot, A. C.; Harrison, T. Bioorg. Med.
Chem. Lett. Submitted for publication.
(34) Showell, G. A.; Bourrain, S.; Neduvelil, J . G.; Fletcher, S. R.;
Baker, R.; Watt, A. P.; Fletcher, A. E.; Freedman, S. B.; Kemp, J . A.;
Marshall, G. R.; Patel, S.; Smith, A. J .; Matassa, V. G. J . Med. Chem.
1994, 37, 719.
(35) Reference 12e and references therein.
2848 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of 1,4-Benzodiazepines
58.1, 123.0, 126.6, 129.1, 131.2, 134.6, 144.2, 159.3, 170.6.
MS: 209 (M + H)+. Anal. Calcd for C10H9OClN2: C 57.57, H
4.35, N 13.43. Found: C 57.25, H 4.48, N 13.39.
obtained in 66% yield as a white solid: mp 196-200 °C. 1H
NMR (360 MHz, CDCl3): 8.24 (2H, d, J ) 9.1), 7.83 (2H, d, J
) 9.1 Hz), 7.66-7.61 (1H, m), 7.43 (1H, d, J ) 8.4 Hz), 7.27-
7.24 (2H, m), 4.89 (1H, d, J ) 10.5 Hz), 3.84 (1H, d, J ) 10.5
Hz), 3.45 (3H, s). 13C NMR (90 MHz, CDCl3): 171.5, 170.1,
150.7, 146.2, 146.0, 133.9, 132.3, 131.7, 129.5, 126.0, 125.2,
Gen er a l P r oced u r e for th e Cr oss-Cou p lin g of Im id oyl
Ch lor id es w ith Bor on ic Acid s (Gen er a l P r oced u r e A).
2H-1,4-Ben zod ia zep in -2-on e, 5-(3-p yr id yl)-1,3-d ih yd r o-1-
m eth yl- (6): A mixture of the imidoyl chloride 5 (200 mg, 0.96
mmol) was treated with 2-(3-pyridyl)-1,3,2-dioxaborinane (188
mg, 1.15 mmol), Pd(PPh3)4 (11.1 mg, 0.01 mmol), 2 N aqueous
Na2CO3 (1.5 mL), and DME (2.5 mL), degassed with nitrogen,
and heated at 80 °C for 120 min. The reaction mixture was
cooled, extracted with ethyl acetate, washed with brine, dried,
filtered, and evaporated to give the crude product. Purification
by flash column chromatography (5% MeOH-CH2Cl2) gave 6
123.3, 59.2, 36.8. MS: 296 (M
295.09569((0.001).
+
H)+. Measured M+
2H-1,4-Ben zod ia zep in -2-on e, 5-(2-th ien yl)-1,3-d ih yd r o-
1-m eth yl-(13):40 Following general procedure A, 13 was
obtained in 94% yield. 1H NMR (CDCl3, 360 MHz): 7.58-7.22
(7H, m), 4.73 (1H, d, J ) 10.9 Hz), 3.77 (1H, d, J ) 10.9 Hz),
3.39 (3H, s). 13C NMR (100 MHz, CDCl3), 170.6, 164.9, 143.6,
141.5, 131.3, 130.0, 129.02, 129.00, 128.1, 125.8, 123.9, 121.0,
56.6, 34.8. MS: 257 (M + 1)+. Anal. Calcd for C14H12ON2S: C
65.60, H 4.72, N 10.93, S 12.51. Found: C 65.82, H 5.12, N
10.57, S 12.30.
1
(219 mg, 91%) as a white powder: mp 240-242 °C. H NMR
(400 MHz, CDCl3): 8.79 (1H, d, J ) 1.4 Hz), 8.68 (1H, dd, J )
4.8, 1.4 Hz), 8.03 (1H, ddd, J ) 7.9, 1.9. 1.9 Hz), 7.59 (1H,
ddd, J ) 7.3, 7.3, 1.7 Hz), 7.38 (1H, d, J ) 8.3 Hz), 7.37-7.34
(1H, m), 7.31 (1H, dd, J ) 7.8, 1.7), 7.24 (1H, dd, J ) 7.9, 7.9
Hz), 4.86 (1H, d, J ) 10.6 Hz), 4.12 (1H, d, J ) 10.6 Hz), 3.43
(3H, s). 13C NMR (100 MHz, CDCl3): 169.6, 168.0, 151.5, 150.2,
144.1, 137.0, 134.4, 132.4, 130.0, 127.7, 124.5, 123.9, 122.2,
57.3, 34.8. MS: 252 (M + H)+.
2H-1,4-Ben zodiazepin -2-on e, 5-(2- ben zo[b]th ioph en yl)-
1,3-d ih yd r o-1-m eth yl- (14): Following general procedure A,
14 was obtained in 98% yield. 1H NMR (400 MHz, CDCl3):
7.87-7.26 (9H, m), 4.79 (1H, d, J ) 10.9 Hz), 3.84 (1H, d, J )
10.9 Hz), 3.41 (3H, s). 13C NMR (100 MHz, CDCl3): 170.5,
164.5, 144.3, 143.6, 141.2, 139.5, 131.7, 129.9, 128.4, 127.6,
126.1, 124.7, 124.6, 124.2, 122.5, 121.3, 56.9, 34.9. MS: 307
(M + 1)+. Anal. Calcd for C18H14ON2S (0.1H2O): C 70.15, H
4.58, N 9.09, S 10.40. Found: C 69.97, H 4.85, N 8.71, S 10.06.
2H-1,4-Ben zod ia zep in -2-on e, 5-(p h en yla lk yn yl)-1,3-d i-
h yd r o-1-m eth yl- (15): A solution of chloroimidate 5 (250 mg,
1.20 mmol), phenylacetylene (147 mg, 1.44 mmol), CuI (6 mg),
PPh3 (84 mg), and PdCl2(PPh3)2 (42 mg) in triethylamine (2
mL) was stirred at 90 °C overnight. The reaction mixture was
partitioned between ethyl acetate and water. The organic
phase was washed with brine, dried (MgSO4), filtered, and
evaporated in vacuo. Purification by column chromatography
(hexane/ethyl acetate 6:4) gave 15 (224 mg, 68%) as a white
2H-1,4-Ben zod ia zep in -2-on e, 5-(2-flu or op h en yl)-1,3-d i-
h yd r o-1-m eth yl- (7):37 Following general procedure A, 7 was
obtained in 99% yield. 1H NMR (400 MHz, CDCl3): 7.67-7.01
(8H, m), 4.86 (1H, d, J ) 10.7 Hz), 3.81 (1H, d, J ) 10.7 Hz),
3.44 (3H, s). MS: 269 (M + H)+. Anal. Calcd for C16H13ON2F:
C 71.63, H 4.83, N 10.13. Found: C 71.48, H 4.88, N 10.44.
2H-1,4-Ben zod ia zep in -2-on e, 5-(3-flu or op h en yl)-1,3-d i-
h yd r o-1-m eth yl-(8): Following general procedure A, 8 was
obtained in 95% yield. 1H NMR (400 MHz, CDCl3): 7.59-7.13
(8H, m), 4.82 (1H, d, J ) 10.7 Hz), 3.78 (1H, d, J ) 10.7 Hz),
3.42 (3H, s). 13C NMR (100 MHz, CDCl3): 170.2, 169.0 (d, J )
2.5 Hz), 162.6 (d, J ) 246.5 Hz), 144.1, 140.9 (d, J ) 6.9 Hz),
131.6, 130.24, 129.8 (d, J ) 8.1 Hz), 128.2, 125.4 (d, J ) 3.2
Hz), 124.0, 121.2, 117.3 (d, J ) 21.5 Hz), 116.3 (d, J ) 22.8
1
foam. H NMR (360 MHz, CDCl3): 7.94-7.91 (1H, m), 7.59-
7.54 (3H, m), 7.40-7.26 (5H, m), 4.8 (1H, br s), 3.8 (1H, br s),
3.41 (1H, s). 13C NMR (90 MHz, CDCl3): 170.9, 158.0, 144.4,
134.1, 133.8, 131.6, 131.3, 130.9, 130.3, 126.3, 123.1, 123.0,
93.5, 89.5, 59.2, 37.0. MS: 275 (M + H)+. Measured M+
274.11061((0.0021).
Hz), 57.0, 34.8. MS: 269 (M + H)+. Anal. Calcd for C16H13
-
ON2F: C 71.63, H 4.83, N 10.13. Found: C 71.05, H 4.69, N
10.17.
2H-1,4-Ben zod ia zep in -2-on e, 5-(4-flu or op h en yl)-1,3-d i-
h yd r o-1-m eth yl- (9):38 Following general procedure A, 9 was
obtained in 97% yield. 1H NMR (360 MHz, CDCl3): 7.64-7.05
(8H, m), 4.79 (1H, d, J ) 10.7 Hz), 3.76 (1H, d, J ) 10.7 Hz),
3.42 (3H, s). 13C NMR (100 MHz, CDCl3): 170.3, 168.9, 164.2
(d, J ) 250.6 Hz), 144.1, 134.99, 134.96, 131.64, 131.55, 131.53,
130.3, 128.5, 123.9, 121.1, 115.3, 115.1, 56.9, 34.8. MS: 269
(M + H)+. Anal. Calcd for C16H13ON2F‚0.1H2O: C 71.15, H
4.85, N 10.37. Found: C 71.32, H 4.79, N 10.15.
2H-1,4-Ben zod ia zep in -2-on e, 5-(6-eth oxy-6-oxoh exyl )-
1,3-d ih yd r o-1-m eth yl- (16): A solution of 5 (250 mg, 1.20
mmol) in THF (3 mL) was treated with Pd(PPh3)2Cl2 (84 mg,
0.12 mmol) and 6-ethoxy-6-oxohexylzinc bromide (0.5 M in
THF, 3.6 mL) and stirred at room temperature for 20 h. The
reaction mixture was partitioned between ethyl acetate and
water. The organic layer was washed with brine, dried
(MgSO4), filtered, and evaporated in vacuo. Purification by
column chromatography (hexane/ethyl acetate 1:1 f 3:7) gave
16 (186 mg, 49%), and unchanged starting material (95 mg,
38%). 1H NMR (360 MHz, CDCl3): 7.51-7.21 (4H, m), 4.56
(1H, d, J ) 10.9 Hz), 4.10 (1H, q, J ) 7.2 Hz), 3.61 (1H, d, J
) 10.9 Hz), 3.36 (3H, s), 2.79 (2H, m), 2.24 (2H, m), 2.24 (2H,
t, J ) 7.5 Hz), 1.58 (4H, m), 1.33 (2H, m), 1.23 (3H, t, J ) 7.2
Hz). MS: 317 (M + H)+.
{Ben zotr ia zol-2-yl-[(2-ca r ba m oyl-p h en yl)-m eth yl-ca r -
ba m oyl]-m eth yl}-ca r ba m ic a cid ben zyl ester (18): A so-
lution of 2-(benzotriazol-1-yl)-N-(benzyloxycarbonyl)glycine
(Katritzky et al.42) (50 g, 0.15 mol) in THF (300 mL) at 0 °C
was treated slowly with oxalyl chloride (2.0 M in CH2Cl2, 81
mL, 0.16 mol) and DMF (1 mL). The reaction mixture was
stirred at 0 °C for 2 h, then treated with a solution of
2-(methylamino)benzamide (23 g, 0.15 mol) and 4-methyl-
morpholine (38 mL, 0.35 mol) in THF (100 mL). The reaction
mixture was stirred overnight at 40 °C, then filtered. The
residue was partitioned between water and warm ethyl
acetate. The aqueous layer was extracted three times with
ethyl acetate. The combined extracts were combined with the
original filtrate, dried (MgSO4), filtered and evaporated in
2H-1,4-Ben zod ia zep in -2-on e, 5-(3-m eth oxyp h en yl)-1,3-
d ih yd r o-1-m eth yl- (10):39 Following general procedure A, 10
1
was obtained in 90% yield. H NMR (400 MHz, CDCl3): 7.55
(1H, ddd, J ) 7.4, 7.4, 1.6 Hz), 7.53-7.26 (4H, m), 7.21-7.14
(1H, m), 7.10 (1H, ddd, J ) 7.7, 7.7, 1.2 Hz), 7.02-6.99 (1H,
m), 4.81 (1H, d, J ) 10.7 Hz), 3.84 (3H, s), 3.77 (1H, d, J )
10.7 Hz), 3.41 (3H, s). 13C NMR (100 MHz, CDCl3): 169.8,
169.5, 159.5, 144.0, 140.2, 132.0, 130.2, 129.8, 128.3, 124.3,
122.4, 122.0, 116.6, 114.4, 57.1, 55.6, 34.6. MS: 281 (M + H)+.
Measured M+ 280.12117((0.0016).
2H-1,4-Ben zod ia zep in -2-on e, 5-(4-m eth oxyp h en yl)-1,3-
d ih yd r o-1-m eth yl- (11): Following general procedure A, 11
was obtained in 82% yield as a white solid: mp 151-152 °C.
1H NMR (360 MHz, CDCl3): 7.59-7.52 (3H, m), 7.35-7.32
(2H, m), 7.21-7.17 (1H, m), 6.92-6.89 (2H, m), 4.76 (1H, d, J
) 10.7 Hz), 3.85 (3H, s), 3.74 (1H, d, J ) 10.7 Hz), 3.41 (3H,
s). 13C NMR (100 MHz, CDCl3): 170.1, 168.9, 161.4, 144.0,
131.9, 131.3, 131.2, 130.3, 128.4, 124.3, 122.0, 114.1, 56.9, 55.8,
34.6. MS: 281 (M + H)+. Anal. Calcd for C17H16O2N2: C 72.84,
H 5.75, N 9.99. Found: C 72.48, H 5.88, N 9.57. Measured
M+ 280.12117((0.0013).
2H-1,4-Ben zod ia zep in -2-on e, 5-(4-n itr op h en yl)-1,3-d i-
h yd r o-1-m eth yl- (12): Following general procedure A, 12 was
(42) Katritzky, A. R.; et al. J . Org. Chem. 1990, 55, 2206
J . Org. Chem, Vol. 68, No. 7, 2003 2849

Nadin et al.
vacuo. Trituration with ethyl acetate gave 18 as a white
powder (23 g, 33%), mp 68-75 °C. The mother liquors were
evaporated and purified by column chromatography to give a
further quantity of 18 (21 g, 30%). 1H NMR (400 MHz,
DMSO): 9.3 (1H, d), 8.8 (1H, d), 8.15-6.90 (15H, m), 4.92-
4.75 (2H, m), 3.12 (3H, d, J ) 4.2 Hz).
(1-Meth yl-2,5-d ioxo-2,3,4,5-tetr a h yd r o-1H-ben zo[e][1,4]-
d ia zep in -3-yl)-ca r ba m ic a cid ben zyl ester (19): Compound
18 (23 g, 0.05 mol) was added to DMSO (500 mL) at 180 °C.
The reaction mixture was stirred at 180 °C for 20 min, cooled
to room temperature, and diluted with 1 M NaOH (aq) and
ether. The aqueous phase was extracted with ethyl acetate
(five times) and the combined organic phases were washed
with brine, dried, filtered and evaporated. Purification by
column chromatography gave 19 (5.8 g, 34%) as a yellow solid,
mp 143-145 °C. 1H NMR (400 MHz, DMSO): 8.74 (1H, br d),
7.74-7.32 (10H, m), 5.21 (1H, dd, J ) 7.8, 4.7), 5.07 (2H, s),
3.39 (3H, s). 13C NMR (100 MHz, DMSO): 35.9, 59.5, 66.6,
123.1, 126.4, 128.3, 128.5, 128.9, 129.0, 129.9, 133.1, 137.0,
140.4, 155.6, 166.4, 168.1. MS: 340 (M + H)+. Anal. Calcd for
(1-Meth yl-5-ch lor o-2-oxo-2,3,4,5-tetr a h yd r o-1H-ben zo-
[e][1,4]d ia zep in -3-yl)-ca r b a m ic a cid ter t-b u t yl est er
(22): Step 1. A solution of 5 (3.4 g, 0.016 mol) (WO 9514473)
was dissolved in dry THF (120 mL) and cooled to -78 °C. A
solution of KOtBu (1.0 M in THF, 19 mL) was added dropwise.
The solution was warmed to -30 °C, held at that temperature
for 5 min, then re-cooled to -78 °C. The reaction mixture was
treated with a solution of trisyl azide (5.56 g, 0.018 mol) in
THF (60 mL). After 5 min, glacial acetic acid (8.5 mL) was
added and the reaction mixture was left to warm to room
temperature overnight. The solvent was partially removed in
vacuo and the residue was taken up in ethyl acetate-brine-
water. The organic layer was separated, washed with brine,
dried, filtered, and evaporated. Purification by flash column
chromatography (hexane/ethyl acetate 7:3) gave the azide (2.3
g, 57%). 1H NMR (400 MHz, CDCl3): 7.84 (1H, dd, J ) 7.9,
1.4 Hz), 7.64 (1H, ddd, J ) 7.5, 7.5, 1.5 Hz), 7.37-7.31 (2H,
m), 4.41 (1H, s), 3.47 (3H, s).
Step 2. A solution of the foregoing azide (0.67 g, 2.69 mmol)
in dioxane (20 mL) was treated with BOC2O (0.63 g, 2.96
mmol) and PtO2 (20.6 mg, 0.13 mmol) and hydrogenated at
40 psi at room temperature for 4 h. The reaction mixture was
filtered through Hyflo, washing with ethyl acetate. The reac-
tion mixture was evaporated in vacuo and purified by column
chromatography (5% ethyl acetate-CH2Cl2) to give 22 (0.58
g, 67%) as a white powder: mp 197-200 °C. 1H NMR (360
MHz, CDCl3): 7.84 (1H, dd, J ) 7.9, 1.4 Hz), 7.62-7.58 (1H,
m), 7.35-7.28 (2H, m), 6.32 (1H, d, J ) 8.8 Hz), 5.20 (1H, d,
J ) 8.8 Hz), 3.45 (3H, s), 1.44 (9H, s). 13C NMR (90 MHz,
CDCl3) 166.7, 155.2, 153.7, 141.8, 134.2, 128.9, 127.1, 125.8,
122.9, 79.4, 69.2, 35.9, 28.5. Anal. Calcd for C15H18ClN3O3: C
55.64, H 5.60, N 12.98. Found: C 54.94, H 5.58, N 12.87. MS:
324 (M + H)+. Measured M+ 323.10366 ((0.0014).
(5-Ch lor o-2-oxo-2,3,4,5-t et r a h yd r o-1H -b en zo[e][1,4]-
d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl ester (23): Step
1. A solution of 21 (24 g, 0.08 mol) was dissolved in THF (500
mL), cooled to -78 °C, and treated with a solution of KOtBu
(1.0 M in THF, 122 mL, 0.122 mol). The reaction mixture was
stirred for 30 min at -78 °C, then was treated with a solu-
tion of trisyl azide (28 g, 0.096 mol) in THF (100 mL) and
stirred at -78 °C for 40 min. The reaction mixture was treated
with acetic acid (70 mL), warmed to room temperature, and
stirred overnight. The reaction mixture was evaporated par-
tially in vacuo, taken up in ethyl acetate-water, washed, dried
(MgSO4), filtered, and evaporated in vacuo. Purification by
chromatography gave the azide (25 g, 92%). 1H NMR (360
MHz, CDCl3): 7.77 (1H, d, J ) 8.5 Hz), 7.67-7.64 (2H, m),
7.40-7.35 (1H, m), 6.96 (2H, d, J ) 6.6 Hz), 6.82 (2H, d, J )
6.6 Hz), 5.33 (1H, d, J ) 15.5 Hz), 4.97 (1H, d, J ) 15.5 Hz),
3.68 (3H, s), 3.35 (1H, s).
Step 2. A solution of the foregoing azide (25 g, 0.70 mol) in
dioxane (300 mL) was treated with BOC2O (25 g, 0.105 mol)
and PtO2 (2.5 g, 0.011 mol) and hydrogenated at 40 psi at room
temperature for 3.5 h. The reaction mixture was filtered
through Hyflo and purified by column chromatography to give
the BOC-carbamate (22 g, 73%). 1H NMR (360 MHz NMR, d6-
DMSO) 7.95 (1H, d, J ) 8.7 Hz), 7.78-7.68 (3H, m), 7.41-
7.36 (1H, m), 6.93 (2H, d, J ) 8.6 Hz), 6.78 (2H, d, J ) 8.6
Hz), 5.37 (1H, d, J ) 15.5 Hz), 5.10 (1H, d, J ) 8.7 Hz), 4.89
(1H, d, J ) 15.5 Hz), 3.67 (3H, s), 1.39 (9H, s).
C
18H17O4N3: C 63.71, H 5.05, N 12.38. Found: C 63.25, H 5.01,
N 12.26. Measured M+ 339.121 ((0.0002).
(1-Meth yl-5-ch lor o-2-oxo-2,3,4,5-tetr a h yd r o-1H-ben zo-
[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ben zyl ester (20): A
solution of 19 (1.1 g, 3.24 mmol) in POCl3 (3 mL) was heated
at 90 °C for 10 min. The reaction mixture was cooled, diluted
with ethyl acetate, and poured into ice-cold NaHCO3 solution.
The organic phase was washed with NaHCO3 solution (twice)
and brine (twice), dried (MgSO4), filtered, and evaporated in
vacuo. Flash column chromatography (hexane/ethyl acetate
2:1) gave 20 as a white foam (950 mg, 82%). 1H NMR (360
MHz, CDCl3) 7.84 (1H, d, J ) 7.9 Hz), 7.60 (1H, t, J ) 7.3
Hz), 7.36-7.26 (7H, m), 6.59 (1H, d, J ) 8.3 Hz), 5.22 (1H, d,
J ) 8.3 Hz), 5.13 (1H, d, J ) 12.3 Hz), 5.09 (1H, d, J ) 12.3
Hz), 3.44 (3H, s). 13C NMR (90 MHz, CDCl3): 37.8, 69.0, 70.3,
123.5, 127.4, 129.7, 129.9, 130.0, 130.3, 131.2, 135.2, 137.9,
142.9, 156.1, 157.4, 167.8. MS: 380 (M + Na)+. Anal. Calcd
for C18H16O3N3Cl: C 60.42, H 4.51, N 11.74. Found: C 60.40,
H 4.44, N 11.23. Measured M+ 357.08801((0.0010).
2H-1,4-Ben zod ia zep in -2-on e, 5-ch lor o-1,2-d ih yd r o-1-(4-
m eth oxyben zyl)- (21): Step 1. A suspension of 3 (30 g, 0.17
mol), 4-methoxybenzyl chloride (23 mL, 0.17 mol), and Cs2CO3
(165 g, 0.51 mol) in DMF (750 mL) was stirred overnight at
room temperature. The reaction mixture was filtered. The
filtrate was evaporated in vacuo and the resulting residue
partitioned between water and ethyl acetate. The aqueous
layer was extracted with ethyl acetate, and the combined
organic layers were dried, filtered, and evaporated in vacuo.
Trituration with hexane gave the alkylated lactam (25 g).
Further product was obtained by column chromatography
(2.5% MeOH-CH2Cl2) of the mother liquors to give a total
1
yield of 35 g (69%). H NMR (400 MHz, CDCl3) 8.75 (1H, t, J
) 5.6 Hz), 7.63 (1H, dd, J ) 1.6, 7.8 Hz), 7.54-7.46 (2H, m),
7.29-7.25 (1H, m), 7.03 (2H, d, J ) 6.6 Hz), 6.80 (2H, d, J )
6.6 Hz), 5.25 (1H, br d, J ) 10 Hz), 4.87 (1H, br d, J ) 10 Hz),
3.85-3.77 (1H, m), 3.68 (3H, s), 3.59-3.50 (1H, m). MS: 439
(M + H)+.
Step 2. A solution of the foregoing compound (4.3 g, 0.014
mol), N,N-dimethylaniline (3.7 mL, 0.029 mol), POCl3 (1.35
mL, 0.014 mol), and benzene (30 mL) was refluxed for 7 h,
then allowed to cool overnight. The reaction mixture was cooled
to 0 °C, treated with ice water (15 mL), and stirred for 30 min
until the reaction mixture reached room temperature. The
reaction mixture was poured into more water and ether. The
organic layer was separated, washed, dried, filtered, and
evaporated. Purification by chromatography (CH2Cl2/hexane/
ethyl acetate 1:1:0.1) gave 21 (3.5 g, 77%). 1H NMR (360 MHz
NMR, d6-DMSO): 7.73 (1H, d, J ) 7.5 Hz), 7.61-7.57 (2H,
m), 7.34-7.30 (1H, m), 6.99 (2H, d, J ) 8.6 Hz), 6.81 (2H, d,
J ) 8.6 Hz), 5.3 (1H, br d), 4.9 (1H, br d), 4.45 (1H, br d), 3.85
(1H, br d), 3.68 (3H, s).
Step 3. A solution of the foregoing compound (5 g, 0.012
mol) was dissolved in acetonitrile (225 mL) and water (85 mL)
and cooled to -15 °C. A solution of ceric ammonium nitrate
(50 g, 0.091 mol) in water was added in three portions and
the reaction mixture was stirred for 2 h, then diluted with
ethyl acetate and water. The organic layer was washed with
water and brine. Purification by a combination of trituration
and chromatography (CH2Cl2/hexane/ethyl acetate 1:1:0.3)
gave the deprotected chloroimidate 23 (2.7 g, 74%) as a white
solid, mp 204-206 °C. 1H NMR (400 MHz NMR, DMSO) 11.03
(1H, s), 7.85-7.82 (2H, m), 7.68-7.64 (1H, m), 7.37-7.33 (1H,
m), 7.24-7.22 (1H, m), 4.98 (1H, d, J ) 8.7 Hz), 1.39 (9H, s).
2850 J . Org. Chem., Vol. 68, No. 7, 2003

Synthesis of 1,4-Benzodiazepines
13C NMR (100 MHz, CDCl3) 166.7, 155.2, 153.7, 138.0, 134.1,
129.8, 125.3, 124.7, 121.8, 79.3, 69.1, 28.5. Anal. Calcd for
) 7.5 Hz), 6.91 (1H, d, J ) 8.1 Hz), 6.75-6.60 (2H, m), 5.90
(1H, d, J ) 8.4 Hz), 4.79 (1H, d, J ) 8.4 Hz), 2.58 (2H, d, J )
6.3 Hz), 2.17 (2H, t, J ) 5.8 Hz), 0.94 (9H, s). 13C NMR (90
MHz, CDCl3): 207.9, 170.2, 168.6, 156.6, 156.3, 145.6, 139.7,
139.0, 133.7, 132.2, 130.5, 129.4, 128.5, 125.5, 124.6, 123.0,
81.6, 70.1, 37.8, 29.6, 27.0. MS: 406 (M + H)+. Measured M+
405.16885((0.0004).
C
14H16O3N3Cl: C 54.29, H 5.21, N 13.57. Found: C 54.20, H
5.26, N 13.44. Measured M+ 309.08801((0.0015).
(1-(E t h ylca r b oxa m id o)-5-ch lor o-2-oxo-2,3,4,5-t e t r a -
h yd r o-1H-ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-
bu tyl ester (24): A solution of 23 (600 mg, 1.94 mmol) in DMF
(10 mL) was treated with iodoacetamide (394 mg, 2.12 mmol)
and cesium carbonate (1.9 g, 5.83 mmol) and stirred at room
temperature for 1 h. The reaction mixture was diluted with
ethyl acetate and brine, washed, dried, filtered, and evapo-
rated. Purification by column chromatography (CH2Cl2/ethyl
acetate 1:1) gave the alkylated chloroimidate 24 (620 mg, 87%)
as a white solid :mp 204-207 °C. 1H NMR (400 MHz NMR,
DMSO): 7.91-7.83 (2H, m), 7.77-7.72 (1H, m), 7.65 (1H, s),
7.48-7.43 (2H, m), 7.20 (1H, s), 5.08 (1H, d), 4.46 (1H, d), 4.33
(1H, d), 1.38 (9H, s). 13C NMR (100 MHz, DMSO): 169.3, 166.0,
155.2, 141.3, 134.1, 128.8, 127.6, 126.1, 123.1, 79.5, 68.9, 51.5,
28.5. MS: 367 (M + H)+. Anal. Calcd for C16H19O4N4Cl: C
52.39, H 5.22, N 15.27. Found: C 51.63, H 5.07, N 15.50.
(5-(5-(1-ter t-Bu toxyca r bon yl)in d olyl)-2-oxo-2,3,4,5-tet-
r ah ydr o-1H-ben zo[e][1,4]diazepin -3-yl)-car bam ic acid ter t-
bu tyl ester (30): Following general procedure A, 30 was
obtained in 77% yield as a white solid: mp 155-159 °C. 1H
NMR (360 MHz, CDCl3): 9.86 (1H, s), 8.10 (1H, d, J ) 8.8
Hz), 7.75 (1H, s), 7.60 (1H, d, J ) 3.5 Hz), 7.49 (2H, d, J ) 8.1
Hz), 7.33 (1H, d, J ) 7.7 Hz), 7.21 (1H, d, J ) 8.1 Hz), 7.14
(1H, t, J ) 7.5 Hz), 6.55 (1H, d, J ) 3.5 Hz), 6.50 (1H, d, J )
8.4 Hz), 5.34 (1H, d, J ) 8.4 Hz), 1.66 (9H, s), 1.50 (9H, s). 13
C
NMR (90 MHz, CDCl3): 171.4, 170.0, 157.2, 151.3, 139.6,
138.3, 135.3, 133.8, 133.3, 132.2, 129.9, 128.7, 128.1, 125.7,
124.9, 123.4, 116.5, 109.5, 85.9, 81.9, 70.5, 30.2, 30.0. MS: 491
(M + H)+. Measured M+ 490.22161((0.0018).
(1-Met h yl-5-(3-p yr id yl)-2-oxo-2,3,4,5-t et r a h yd r o-1H -
ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl es-
ter (25): Following general procedure A, 25 was obtained in
88% yield as a white solid: mp 238-240 °C. 1H NMR (360
MHz, DMSO) 8.69 (2H, br s), 7.91 (1H, d, J ) 8.0 Hz), 7.85
(1H, d, J ) 7.5 Hz), 7.78-7.66 (2H, m), 7.49 (1H, dd, J ) 4.9,
7.8 Hz), 7.36-7.34 (2H, m), 5.07 (1H, d, J ) 7.5 Hz), 3.38 (3H,
s), 1.39 (9H, s). 13C NMR (90 MHz, DMSO) 30.4, 37.2, 71.7,
80.9, 124.6, 125.7, 126.8, 129.7, 131.6, 134.7, 135.5, 138.9,
145.1, 152.1, 153.6, 157.1, 166.7, 169.8. MS: 367 (M + H)+.
Anal. Calcd for C20H22O3N4: C 65.56, H 6.05, N 15.29. Found:
C 65.34, H 6.06, N 15.05. Measured M+ 366.16918((0.0014).
(1-Met h yl-5-(7-ch r om a n oyl)-2-oxo-2,3,4,5-t et r a h yd r o-
1H-ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl
ester (26): Following general procedure A and deprotection
of the BOC group with TFA-CH2Cl2, 26 was obtained in 77%
yield as a pale yellow solid: mp 162-165 °C. 1H NMR (360
MHz, DMSO) 8.34 (1H, d, J ) 6.1 Hz), 8.13 (1H, d, J ) 8.7
Hz), 7.76-7.65 (4H, m), 7.37-7.31 (2H, m), 6.41 (1H, d, J )
6.1 Hz), 4.6 (1H, vbr s), 4.54 (1H, s), 3.40 (3H, s). 13C NMR
(100 MHz, DMSO) 176.5, 169.8, 163.8, 157.9, 156.0, 143.46,
143.45, 132.7, 129.7, 128.0, 126.2, 125.7, 125.5, 124.7, 122.6,
119.7, 113.0, 71.1, 35.2. MS: 333 (M + H)+. Measured M+
333.11134((0.0017).
(5-(4-Ch lor oph en yl)-2-oxo-2,3,4,5-tetr ah ydr o-1H-ben zo-
[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl ester (27):
Following general procedure A, 27 was obtained in 70% yield
as a white solid: mp 189-191 °C. 1H NMR (400 MHz,
CDCl3): 9.03 (1H, s), 7.56-7.48 (3H, m), 7.35 (1H, s), 7.33 (1H,
s), 7.31 (1H, dd, J ) 7.4, 1.2 Hz), 7.19 (2H, t, J ) 7.6 Hz), 6.37
(1H, d, J ) 8.6 Hz), 5.31-5.29 (1H, m), 1.49 (9H, s). 13C NMR
(100 MHz, CDCl3): 169.0, 166.6, 155.3, 137.5, 137.0, 136.9,
132.3, 131.2, 131.0, 128.5, 127.3, 124.2, 121.6, 80.3, 68.7, 28.4.
MS: 330 (M - tBu + H)+. Measured M+ 385.11931((0.0004).
(5-(5-Qu in olyl)-2-oxo-2,3,4,5-t et r a h yd r o-1H -b en zo[e]-
[1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl ester (28):
Following general procedure A, 28 was obtained in 72% yield
as a white solid: mp 211-214 °C. 1H NMR (360 MHz,
CDCl3): 10.10 (1H, s), 9.11 (1H, d, J ) 1.1 Hz), 8.29 (1H, s),
8.13 (1H, d, J ) 8.4 Hz), 7.79 (1H, d, J ) 8.1 Hz), 7.75 (1H, t,
J ) 8.1 Hz), 7.55 (2H, t, J ) 7.7 Hz), 7.35 (1H, d, J ) 7.7 Hz),
7.29 (1H, d, J ) 8.1 Hz), 7.19 (1H, t, J ) 7.5 Hz), 6.56 (1H, d,
J ) 8.4 Hz), 5.41 (1H, d, J ) 8.4 Hz), 1.51 (9H, s). 13C NMR
(360 MHz, CDCl3): 170.9, 167.3, 157.2, 152.6, 150.4, 139.8,
139.7, 134.4, 133.0, 132.8, 132.5, 131.0, 130.5, 129.1, 128.81,
128.76, 126.2, 123.8, 82.2, 70.9, 30.2. MS: 403 (M + H)+.
Measured M+ 402.16918((0.0002).
(5-(3,4-Meth ylen edioxyph en yl)-2-oxo-2,3,4,5-tetr ah ydr o-
1H-ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl
ester (31): Following general procedure A, 31 was obtained
1
in 77% yield as a white solid: mp 206-207 °C. H NMR (400
MHz, CDCl3): 9.01 (1H, s), 7.53-7.49 (1H, m), 7.38 (1H, dd,
J ) 6.7, 1.2 Hz), 7.20-7.14 (3H, m), 6.98 (1H, dd, J ) 1.8, 8.0
Hz), 6.76 (1H, d, J ) 8.2 Hz), 6.35 (1H, d, J ) 8.6 Hz), 6.01
(2H, dd, J ) 1.4, 8.0 Hz), 5.27 (1H, d, J ) 8.6 Hz), 1.48 (9H,
s). 13C NMR (90 MHz, CDCl3) 169.3, 166.8, 155.3, 149.8, 147.8,
137.5, 133.0, 132.0, 131.3, 127.7, 125.2, 124.0, 121.4, 109.8,
107.7, 101.5, 80.1, 68.5, 28.4. MS: 396 (M + H)+, 418 (M +
t
Na)+, 340 (M - Bu + H)+. Anal. Calcd for C21H21O5N3: C
63.79, H 5.35, N 10.63. Found: C 63.45, H 5.41, N 10.37.
Measured M+ 395.14811((0.0014).
(5-(3,4-Eth ylen ed ioxyp h en yl)-2-oxo-2,3,4,5-tetr a h yd r o-
1H-ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl
ester (32): Following general procedure A, 32 was obtained
1
in 67% yield as a white solid: mp 162-164 °C. H NMR (360
MHz, CDCl3): 9.89 (1H, s), 7.45 (1H, t, J ) 7.5 Hz), 7.35 (1H,
d, J ) 7.7 Hz), 7.17-7.14 (2H, m), 7.09 (1H, d, J ) 1.8 Hz),
7.03 (1H, dd, J ) 2.1, 8.4 Hz), 6.81 (1H, d, J ) 8.4 Hz), 6.49
(1H, d, J ) 8.4 Hz), 5.26 (1H, d, J ) 8.4 Hz), 4.23 (4H, d, J )
7.0 Hz), 1.47 (9H, s). 13C NMR (90 MHz, CDCl3): 171.4, 168.7,
157.2, 147.7, 145.0, 139.6, 133.9, 133.7, 133.0, 129.4, 125.6,
125.4, 123.3, 120.9, 118.7, 81.8, 70.4, 66.4, 66.0, 30.2. MS:
410 (M
409.16376((0.0006).
+ - +
H)+, 354 (M tBu H)+. Measured M+
(5-(4-R-Tetr olyl)-2-oxo-2,3,4,5-tetr a h yd r o-1H-ben zo[e]-
[1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl ester (33):
Following general procedure A, 33 was obtained in 52% yield
as a white solid: mp 241-244 °C. 1H NMR (360 MHz,
CDCl3): 9.29 (1H, s), 8.00 (1H, d, J ) 8.1 Hz), 7.56 (2H, s),
7.35-7.30 (1H, m), 7.23 (1H, s), 7.20 (1H, s), 6.43 (1H, d, J )
8.1 Hz), 5.33 (1H, d, J ) 8.4 Hz), 2.97 (2H, d, J ) 5.3 Hz),
2.68 (2H, t, J ) 6.1 Hz), 2.15 (2H, d, 6.0), 1.49 (9H, s). 13C
NMR (90 MHz, CDCl3): 199.9, 170.6, 169.1, 157.2, 146.3,
144.6, 139.4, 135.6, 134.2, 132.9, 132.0, 130.0, 129.1, 128.9,
126.1, 123.4, 82.2, 70.7, 41.0, 31.5, 30.2, 24.9. MS: 420 (M +
t
H)+, 364 (M - Bu + H)+. Measured M+ 419.1845((0.0004).
(5-(4-(Tr iflu or om eth yl)ph en yl)-2-oxo-2,3,4,5-tetr ah ydr o-
1H-ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl
ester (34): Following general procedure A, 34 was obtained
1
in 44% yield as a white solid: mp 236-238 °C. H NMR (360
MHz, CDCl3) 9.11 (1H, s), 7.12 (4H, q, J ) 8.4 Hz), 7.00 (1H,
t, J ) 7.4 Hz), 6.74-6.63 (3H, m), 5.87 (1H, d, J ) 8.4 Hz),
4.80 (1H, d, J ) 8.1 Hz), 0.95 (9H, s). 13C NMR (90 MHz,
CDCl3) 170.3, 167.3, 156.6, 143.1, 139.0, 133.7, 133.6 (q, J )
33.0 Hz), 132.1, 131.5, 128.3, 126.5 (q, 3.4), 126.4, 125.1 (q,
272.8), 125.5, 123.0, 81.6, 70.1, 29.6. MS: 420 (M + H)+, 364
(5-(5-(1-In d a n oyl))-2-oxo-2,3,4,5-tetr a h yd r o-1H-ben zo-
[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl ester (29):
Following general procedure A, 29 was obtained in 51% yield
as a white solid: mp 233-234 °C. 1H NMR (360 MHz,
CDCl3): 9.20 (1H, s), 7.17 (1H, s), 7.15 (1H, s), 6.99 (1H, t, J
t
(M - Bu + H)+. Anal. Calcd for C21H20F3O3N3: C 60.14, H
4.81, N 10.02. Found: C 60.31, H 4.84, N 9.82. Measured M+
419.14567((0.0027).
J . Org. Chem, Vol. 68, No. 7, 2003 2851

Nadin et al.
(1-Eth ylca r boxa m id o-5-(3,4-(d iflu or om eth ylen ed ioxy)-
ph en yl)-2-oxo-2,3,4,5-tetr ah ydr o-1H-ben zo[e][1,4]diazepin -
3-yl)-ca r ba m ic a cid ter t-bu tyl ester (35): Following general
procedure A and deprotection of the BOC group with TFA-
CH2Cl2, 35 was obtained in 82% yield. 1H NMR (400 MHz,
DMSO): 7.66-7.60 (1H, m), 7.56 (1H, s), 7.53-7.46 (3H, m),
7.35 (1H, dd, J ) 8.4, 1.7 Hz), 7.31-7.26 (2H, m), 7.12 (1H, s),
4.47 (1H, d, J ) 16.8 Hz), 4.42 (1H, d, J ) 16.8 Hz), 4.36 (1H,
s), 2.6 (2H, br s). 13C NMR (100 MHz, DMSO) 167.62, 167.61,
140.62, 133.8, 130.0, 127.39, 127.32, 124.6, 122.7, 120.6,
108.8, 108.0, 68.4, 47.9. MS: 389 (M + H)+. Measured M+
388.09831((0.0004).
obtained in 84% yield as a white solid: mp 267-269 °C. 1H
NMR (360 MHz, DMSO): 7.60-7.47 (4H, m), 7.36-7.32 (1H,
m), 7.11-7.06 (2H, m), 4.87 (1H, d, J ) 8.6 Hz), 4.52 (1H, d,
J ) 16.8 Hz), 4.32 (1H, d, J ) 16.8 Hz), 3.69-3.57 (4H, m),
3.25-3.15 (4H, m), 1.35 (9H, s). 13C NMR (90 MHz, DMSO)
30.4, 50.1, 51.5, 68.0, 68.2, 80.6, 125.3, 127.5, 128.6, 130.6,
133.8, 144.2, 156.9, 162.8, 171.2, 171.5. MS: 418 (M + H)+.
Anal. Calcd for C20H27O5N5: C 57.54, H 6.52, N 16.68. Found:
C 57.40, H 6.29, N 16.12. Measured M+ 417.20121((0.0009).
(5-(3,4-Meth ylen edioxyph en yl)-2-oxo-2,3,4,5-tetr ah ydr o-
1H -b en zo[e][1,4]d ia zep in -3-yl)-2,4,5-(t r iflu or op h en yl)-
a ceta m id e (40): Step 1. A solution of benzodiazepine 31 (100
mg, 0.25 mmol) in DCM (5 mL) and TFA (1 mL) was stirred
at room temperature for 2 h, evaporated in vacuo, azeotroped
with toluene, and purified by ion exchange chromatography
to give the amine in quantitative yield. 1H NMR (360 MHz,
DMSO):10.62 (1H, br s), 7.57 (1H, t, J ) 7.1 Hz), 7.31-6.84
(6H, m), 6.08 (2H, d, J ) 3.1 Hz), 4.20 (1H, s), 2.7 (2H, vbr s).
13C NMR (90 MHz, DMSO) 72.4, 103.9, 110.0, 110.9, 123.5,
125.1, 126.8, 129.0, 132.4, 133.9, 135.2, 141.1, 149.7, 151.3,
166.1, 172.8. MS: 296 (M + H)+.
Gen er a l P r oced u r e for th e Rea ction of Im id oyl Ch lo-
r id es w ith Am in es (Gen er a l P r oced u r e B). (5-Mor p h o-
linyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)-
ca r ba m ic a cid ter t-bu tyl ester (36): A solution of the
chloroimidate 23 (0.9 g, 2.90 mmol) was treated with morpho-
line (3 mL) and heated in a sealed tube for 2 h at 100 °C. The
reaction mixture was evaporated in vacuo. Purification by
column chromatography gave the amidine 36 (0.8 g, 76%) as
1
a white solid: mp 244-246 °C. H NMR (400 MHz, DMSO):
10.46 (1H, s), 7.60-7.53 (2H, m), 7.28-7.14 (3H, m), 4.73 (1H,
d, J ) 9.5 Hz), 3.72-3.54 (4H, m), 3.13-2.99 (4H, m), 1.36
(9H, s). 13C NMR (100 MHz, DMSO): 172.8, 163.0, 157.1,
141.1, 134.1, 131.4, 126.1, 125.5, 124.2, 80.6, 68.7, 68.1, 50.6,
30.4. MS: 361 (M + H)+. Anal. Calcd for C18H24O4N4: C 59.99,
H 6.71, N 15.55. Found: C 59.83, H 6.56, N 15.18. Measured
M+ 360.17975((0.0009).
Step 2. A solution of the foregoing amine (75 mg) in DMF
(4 mL) was treated with EDC (58 mg), HOBT (41 mg), and
2,3,5-trifluorophenylacetic acid (53 mg) and stirred at room
temperature for 2 h. The reaction mixture was diluted with
ethyl acetate, washed with citric acid solution, sodium bicar-
bonate solution, and brine, and dried (MgSO4). Evaporation
and purification by column chromatography gave 40 as a white
solid (118 mg, 82%): mp 251-254 °C. 1H NMR (400 MHz,
DMSO): 10.82 (1H, s), 9.44 (1H, d, J ) 7.8 Hz), 7.62 (1H, t, J
) 7.3 Hz), 7.44-6.89 (9H, m), 6.11 (2H, d, J ) 2.6 Hz), 5.19
(1H, d, J ) 7.8 Hz), 3.81 (2H, s). 13C NMR (100 MHz, DMSO):
35.1, 68.5, 102.1, 104.4 (d, J ) 20 Hz), 104.7 (d, J ) 21 Hz),
108.2, 109.0, 113.6 (d, J ) 24 Hz), 121.8, 123.6, 125.2, 126.8,
127.3, 127.4, 130.8, 132.5, 132.7, 139.1, 147.9, 149.8, 166.4,
168.3, 168.8. 19F NMR (400 MHz, DMSO): -116.43 (d, J )
15.5 Hz), -135.54 (d, J ) 23.3 Hz), -147.29 (dd, J ) 15.5,
23.3 Hz). MS: 468 (M + H)+. Anal. Calcd for C24H16O4N3F3:
C 61.67, H 3.45, N 8.99. Found: C 61.64, H 3.51, N 8.75.
Measured M+ 467.10929((0.0011).
(5-Azetid in yl-2-oxo-2,3,4,5-tetr a h yd r o-1H-ben zo[e][1,4]-
d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl ester (37): Fol-
lowing general procedure B, 37 was obtained in 81% yield as
a white solid: mp 222-224 °C. 1H NMR (400 MHz, CDCl3):
8.52 (1H, s), 7.48-7.42 (2H, m), 7.18 (1H, t, J ) 7.4 Hz), 7.09
(1H, d, J ) 7.4 Hz), 6.01 (1H, d, J ) 8.5 Hz), 5.12 (1H, d, J )
8.5 Hz), 4.08 (2H, q, J ) 7.9 Hz), 3.71 (2H, q, J ) 7.9 Hz), 2.23
(2H, qn, J ) 7.9 Hz), 1.42 (9H, s). 13C NMR (100 MHz,
CDCl3): 171.4, 161.4, 155.3, 136.7, 131.6, 129.1, 124.4, 123.2,
121.7, 79.7, 66.0, 51.7, 28.3, 16.0. MS: 331 (M + H)+. Anal.
Calcd for C17H22O3N4: C 61.80, H 6.71, N 16.96. Found: C
61.69, H 6.70, N 16.41. Measured M+ 330.16918((0.0016).
(1-Met h yl-5-p ip er id in yl-2-oxo-2,3,4,5-t et r a h yd r o-1H -
ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-bu tyl es-
ter (38): Following general procedure B, 38 was obtained in
64% yield as a white solid: mp 230-232 °C. 1H NMR (400
MHz, DMSO: 7.65-7.60 (1H, m), 7.56-7.51 (2H, m), 7.37-
7.33 (1H, m), 7.09 (1H, d, J ) 8.6 Hz), 4.74 (1H, d, J ) 8.6
Hz), 3.30 (3H, s), 3.23-3.13 (4H, m), 1.66-1.52 (4H, m), 1.50-
1.35 (2H, m), 1.36 (9H, s). 13C NMR (100 MHz, DMSO) 24.5,
25.5, 28.5, 34.7, 48.5, 66.7, 66.7, 78.7, 122.9, 125.4, 126.4, 128.7,
131.9, 142.9, 155.0, 160.6, 170.4. MS: 373 (M + H)+. Anal.
Calcd for C20H28O3N4: C 64.49, H 7.58, N 15.04. Found: C
63.99, H 7.55, N 14.62. Measured M+ 372.21613((0.0012).
(1-Eth ylcar boxam ido-5-m or ph olin yl-2-oxo-2,3,4,5-tetr a-
h yd r o-1H-ben zo[e][1,4]d ia zep in -3-yl)-ca r ba m ic a cid ter t-
bu tyl ester (39): Following general procedure B, 39 was
Ackn owledgm en t. We thank Professor Istva´n Marko´
(Universite´ Catholique de Louvain, Belgium) for useful
discussions, Drs. Ute Gerhard and Steve Thomas for
measuring the high-resolution mass spectral data, and
Dr. Russell Mortishire-Smith for assistance in preparing
the Supporting Information.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra of 5, 6, 10-12, 15, 19, 20, and 22-40. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O026860A
2852 J . Org. Chem., Vol. 68, No. 7, 2003