A novel and efficient iodine(III)-mediated access to 1,4-benzodiazepin-2-ones

Article abstract of DOI:10.1016/S0040-4039(02)02019-1

A novel access to 1,4-benzodiazepin-2-ones starting from glycine and alanine derivatives is described. The key cyclization step was performed by the action of phenyliodine(III)bis(trifluoroacetate) (PIFA) on the corresponding methoxyamide derivatives lead

Full text of DOI:10.1016/S0040-4039(02)02019-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8273–8275
A novel and efficient iodine(III)-mediated access to
1,4-benzodiazepin-2-ones
M. Teresa Herrero, Imanol Tellitu,* Esther Dom´ınguez,* Isabel Moreno and Rau´l SanMart´ın
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencias, Universidad del Pa´ıs Vasco—Euskal Herriko Unibertsitatea
(UPV/EHU), PO Box 644, 48080 Bilbao, Spain
Received 4 September 2002; accepted 16 September 2002
Abstract—A novel access to 1,4-benzodiazepin-2-ones starting from glycine and alanine derivatives is described. The key
cyclization step was performed by the action of phenyliodine(III)bis(trifluoroacetate) (PIFA) on the corresponding methoxyamide
derivatives leading to the C(9a)ꢀN(1) bond construction. This strategy avoids the necessity of additional functionalization on the
phenyl ring and facilitates the access to a number of 1,4-benzodiazepine derivatives. Additionally, no racemization in the
cyclization step was observed starting from optically pure (S)-alanine ester. © 2002 Elsevier Science Ltd. All rights reserved.
1,4-Benzodiazepine derivatives have varied biological
activities and are one of the most important classes of
bioavailable therapeutic agents.1 Examples have been
reported that act as anxiolytic, anticonvulsant, and
antihypnotic agents,2 selective cholecystokinin (CCK)
receptor subtype A or B antagonists,3 k-selective opioid
antagonists,4 platelet-activating factor antagonists,5
human immunodeficiency virus (HIV) transactivator
Tat antagonists,6 GPIIbIIIa inhibitors,7 and reverse
transcriptase inhibitors.8 This broad biological activity
is the reason for the profound attention that the scien-
tific community has paid to the synthesis of this kind of
heterocycles.9
2-oxo derivatives13 in contrast with the more widely
studied benzodiazepin-2,5-diones.
In recent years, our group has been concerned with the
development of hypervalent iodine reagents for the
synthesis of heterocyclic compounds. The clean trans-
formations achieved, the mild conditions employed,
and the low toxicity associated with it, prompted us to
include PIFA in our synthetic plans. Therefore, we
have taken advantage of the known14 ability of PIFA
to generate N-acylnitrenium ions from N-alkoxyamides
of type 2b which, eventually, could be trapped
intramolecularly by arene rings, as shown in Scheme 2,
to afford the desired heterocycles.15
In particular, most of the strategies directed toward the
preparation of 1,4-benzodiazepin-2-ones of type 1 can
be summarized by route A depicted in Scheme 1. They
all require an aminophenyl group (or any other related
nitrogen containing functional group) and a carbonyl
functionality, such as COOH,10 COOR11 and COX,12
as shown in precursor 2a. This assumption may limit
the access to a series of the target heterocycles with
different substitution patterns on the benzene ring.
Because aminoacids are one of the most useful building
blocks for the preparation of 1,4-benzodiazepines, we
Therefore, we considered that the design of a novel
access to benzodiazepine series by the construction of
the C(9a)ꢀN(1) bond on simple non-functionalized ben-
zene rings would be most desirable. On the other hand,
the projected synthesis (vide infra) will provide the
Scheme 1. Retrosynthetic analysis for 1,4-benzodiazepin-2-
ones.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02019-1

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M. T. Herrero et al. / Tetrahedron Letters 43 (2002) 8273–8275
(30% yield). Conversely, trifluoroacetic acid was the
reagent of choice to transform amide 7b into benzodi-
azepine-2-one 8b (70% yield) instead of BF3·OEt2 (30%
yield). In addition, the enantiomeric excess of benzodi-
azepine 8b was measured to be >98% (HPLC).22
In summary, a novel entry to the 1,4-benzodiazepin-2-
one skeleton by a PIFA mediated intramolecular
cyclization has been described. The efficiency, and lack
of racemization throughout the synthesis when starting
from (S)-alanine methyl ester, characterize the reported
novel approach.
Scheme 2. Generation of the electrophilic N-acylnitrenium
species and intramolecular attack.
employed the commercially available N-benzylglycine
(3) and the known16 N-benzyl-a-aminoester 4 as start-
ing materials of our synthesis. Following the route
depicted in Scheme 3, derivative 6a was prepared
directly from 3 by N-acylation with ethyl chloroformi-
ate, and derivative 6b was prepared17 in a two-step
sequence by protection of aminoester 418 followed by
basic hydrolysis19 of the resulting derivative 5.20 After a
number of assays, the optimal transformation into
amides 7a,b was accomplished using methoxylamine
hydrochloride and a combination of EDC, HOBt and
triethylamine in CH2Cl2.
Acknowledgements
This research was supported by the University of the
Basque Country (Project UPV 170.310G37/98), the
Spanish Ministry of Education and Culture (PB97-
0600), and the Basque Government (GV 170.310-
G0053/96). M.T.H. thanks the Ministry of Science and
Technology (MCT) for a predoctoral scholarship.
References
As mentioned above, and in order to promote the key
cyclization step, PIFA was selected as the source of
hypervalent iodine to generate electrophilic N-
acylnitrenium ions from amides 7a,b. At this point, the
action of the required additive was studied in both
cases and, therefore, an optimization of the standard
conditions was carried out. Cyclization of 7a to yield
benzodiazepine-2-one 8a was best performed21 using
boron trifluoride etherate (60% yield) instead of TFA
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9. Some review articles on the synthesis of 1,4-benzodi-
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Scheme 3. Synthesis of 1,4-benzodiazepin-2-ones 8a,b.
Reagents and conditions: (i) NaOH, ClCOOEt, THF/H2O, rt
(quantitative); (ii) NaOH, ClCOOEt, THF/H2O, rt (98%); (iii)
LiOH, THF/H2O, rt (96%); (iv) NH2OMe·HCl, Et3N, EDC,
HOBt, CH2Cl2, rt (87% for 7a; 75% for 7b); (v) PIFA,
BF3·OEt2, CH2Cl2, −20°C (60% for 8a); (v) PIFA, TFA,
CH2Cl2, 0°C (70% for 8b).
10. Ku, T. W.; Ali, F. E.; Bondinell, W. E. Tetrahedron Lett.
1997, 38, 3131–3134.
11. See for example: Karp, G. M. J. Org. Chem. 1995, 60,
5814–5819.

M. T. Herrero et al. / Tetrahedron Letters 43 (2002) 8273–8275
8275
12. See for example: Blackburn, B. K.; Lee, A.; Baier, M.;
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D.; McDowell, R. S. J. Med. Chem. 1997, 40, 717–729.
13. The widely prescribed diazepam, among others, has the
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14. (a) Kikugawa, Y.; Kawase, M. Chem. Lett. 1990, 581–
582; (b) Wardrop, D. J.; Basak, A. Org. Lett. 2001, 7,
1053–1056 and references cited therein.
15. (a) For a recent contribution of our group referred to the
synthesis of quinolinones employing this strategy, see:
Herrero, M. T.; Tellitu, I.; Herna´ndez, S.; Dom´ınguez,
E.; Moreno, I.; SanMart´ın, R. ARKIVOC 2002, v, 31–37;
(b) For a different application, see also: Romero, A. G.;
Darlington, W. H.; McMillan, M. W. J. Org. Chem.
1997, 62, 6582–6587.
16. Spectroscopic data of compound 4 can be found in:
Szila´gyi, L.; Gyo¨rgydea´k, Z. J. Am. Chem. Soc. 1979,
101, 427–432.
mmol) in 8 mL of CH2Cl2 was added at 0°C to a solution
of amide 7b (100 mg, 0.36 mmol) in 7 mL of the same
solvent, and the new solution was stirred until total
consumption of the starting material (tlc, Hex/EtOAc,
7/3). Then, the mixture was washed with Na2CO3 (10%
aq.) (1×4 mL), dried over Na2SO4, filtered and the sol-
vent was evaporated at reduced pressure. The resulting
residue was purified by column chromatography (Hex/
EtOAc, 7/3) to afford benzodiazepine 8b as a yellowish
1
oil (70%). H NMR (32°C): l 1.03 (d, J=7.0, 3H), 1.26
(t, J=7.1, 3H), 3.81 (s, 3H), 4.16 (q, J=7.1, 2H), 4.25 (d,
J=14.5, 1H), 4.82 (d, J=14.5, 1H), 4.95 (q, J=7.0, 1H),
7.21–7.40 (m, 2H), 7.43–7.50 (m, 2H). 13C NMR: l 14.5,
17.4, 46.4, 57.8, 61.9, 61.9, 120.4, 127.1, 128.3, 129.4,
129.6, 138.6, 154.3, 165.7. IR (neat): w 1698, 1683 cm−1
.
MS (EI) m/z (%): 278 (M+, 44), 250 (76), 235 (41), 220
(13), 219 (82), 135 (41), 132 (49), 130 (24), 120 (93), 106
(55), 105 (100), 104 (39). HRMS calcd for C14H18N2O4
278.1255, found 278.1266. [h]2D0 −238 (c 0.2, CH2Cl2). Ee:
99% (Chiralcel OJ, Hex/EtOAc, 98/2, 0.7 mL/min, tR=
43.35 min).
17. For an alternative synthesis of 6b including spectroscopic
information, see: Buckley, T. F., III; Rapoport, H. J.
Am. Chem. Soc. 1981, 103, 6157–6163.
4-Ethoxycarbonyl-1-methoxy-1,3,4,5-tetrahydro-2H-[1,4]-
benzodiazepin-2-one (8a): Compound 8a was obtained in
60% yield from 7a following the procedure described for
8b but using BF3·OEt2 instead of TFA and working at
−20°C. Purification was carried out by column chro-
matography (Hex/EtOAc, 7/3) to afford benzodiazepine
18. This substrate was prepared following standard proce-
dures by reductive amination of benzaldehyde with (S)-
alanine methyl ester.
19. LiOH in a mixture of THF/H2O was employed to avoid,
as detected under other conditions, racemization at this
stage.
20. N,N-Dibenzyl substituted precursors of type 4 were also
prepared but the corresponding final cyclization step
proceeded with limited success (20% yield for the corre-
1
8a as a yellowish oil (70%). H NMR: l 1.26 (t, J=6.7,
3H), 3.80 (s, 3H), 4.02 (s, 2H), 4.16 (q, J=6.7, 2H), 4.54
(s, 2H), 7.28–7.37 (m, 2H), 7.42–7.52 (m, 2H). 13C NMR:
l 14.5, 47.6, 48.3, 62.1, 62.5, 120.6, 127.3, 127.6, 127.7,
130.3, 138.9, 154.8, 162.7. IR (neat): w 1698 cm−1. MS
(EI) m/z (%): 264 (M+, 22), 236 (40), 205 (100), 177 (33),
161 (18), 133 (24), 132 (41), 120 (58), 106 (47), 105 (48),
104 (41). HRMS calcd for C13H16N2O4 264.1115, found
264.1110.
sponding
N-benzyl-N-methoxy-3-methyl-1,4-benzodi-
azepin-2-one). This and other ancillary studies that
facilitated the synthesis’ achievement will be reported
elsewhere.
21. (3S)-4-Ethoxycarbonyl-1-methoxy-3-methyl-1,3,4,5-tetra-
hydro-2H-[1,4]benzodiazepin-2-one (8b): A solution of
TFA (0.07 mL, 0.91 mmol) and PIFA (169 mg, 0.39
22. Chiralcel OJ, Hex/iPrOH (98/2), 0.7 mL/min.