A simple route to tetrahydro-1,4-benzodiazepin-3-ones bearing diverse N1, N4, and C10 functionalization

Article abstract of DOI:10.1016/j.tetlet.2005.03.171

We describe an efficient synthesis of enantiopure tetrahydro-1,4- benzodiazepine-3-ones derived from l-alanine. Diverse substitution at N1, N4, and C10 can be achieved by coupling various N-alkyl derivatives of l-alanine and N-allyl-(2-fluoro-5-nitro)benzylamine. Cyclization of this intermediate proceeds in high yield and without racemization, providing diversity at N1. The NO₂ group was easily transformed into other functional groups or removed, providing diversity at C10. Finally, oxidative deallylation allows diverse substitution to be installed at N4.

Full text of DOI:10.1016/j.tetlet.2005.03.171

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3633–3635
A simple route to tetrahydro-1,4-benzodiazepin-3-ones
bearing diverse N1, N4, and C10 functionalization
Ella C. Clement and Paul R. Carlier*
Department of Chemistry, Virginia Tech, Blacksburg, VA 24061, USA
Received 17 March 2005; revised 23 March 2005; accepted 23 March 2005
Available online 11 April 2005
Abstract—We describe an efficient synthesis of enantiopure tetrahydro-1,4-benzodiazepine-3-ones derived from L-alanine. Diverse
substitution at N1, N4, and C10 can be achieved by coupling various N-alkyl derivatives of L-alanine and N-allyl-(2-fluoro-5-
nitro)benzylamine. Cyclization of this intermediate proceeds in high yield and without racemization, providing diversity at
N1. The NO2 group was easily transformed into other functional groups or removed, providing diversity at C10. Finally, oxidative
deallylation allows diverse substitution to be installed at N4.
Ó 2005 Elsevier Ltd. All rights reserved.
The tetrahydro-1,4-benzodiazepine-3-one scaffold has
been found to be useful for the preparation of fibrinogen
receptor antagonists 1–2,1–3 angiotensin analogs 3,4 and
protein kinase C activators 4.5 Inspection of compounds
1–4 demonstrates the importance of substitution at N1,
N4, C2, and C10 on this scaffold. In this letter we
describe an efficient route to diversely functionalized
tetrahydro-1,4-benzodiazepin-3-ones 5 derived from
alanine that bear this substitution pattern (Scheme 1).
intramolecular nucleophilic aromatic substitution. To
accelerate substitution, a carboxyl ester1–3 or nitro3,4
group is most often placed para to the leaving group.6
We envisioned performing a cyclization of an intermedi-
ate (e.g., 9–11) that already incorporated the desired N1
substituent R1 and an allyl group at N4 that could be
subsequently deprotected and alkylated. The nitro
group was chosen to facilitate nucleophilic substitution,
since subsequent functional group transformation
would provide diversity at C10. To assemble the cycliza-
tion precursor, we adopted the basic strategy of Miller
et al.1 However, at the outset it was not clear whether
The key step in most syntheses of tetrahydro-1,4-benzo-
diazepin-3-ones is closure of the heterocyclic ring by
Scheme 1. Medicinally important tetrahydro-1,3-benzodiazepin-3-ones 1–4 and target scaffold 5.
Keywords: Benzodiazepine; Scaffold; Nucleophilic aromatic substitution.
*
Corresponding author. Tel.: +1 5402319219; fax: +1 4259848099; e-mail: pcarlier@vt.edu
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.03.171

3634
E. C. Clement, P. R. Carlier / Tetrahedron Letters 46 (2005) 3633–3635
non-racemizing cyclization could be achieved with a
secondary amine; the two published relevant examples
(i.e., p-NO2)3,4 feature primary amines (i.e., R1 = R2 = H).
Furthermore, yields are sometimes low (e.g., 18%),3
and the basic reaction conditions might promote
racemization during the long reaction times reported
(12–72 h).4
benzodiazepin-3-ones from intermediates like 9 feature
removal of the N1 protecting group (Boc, FMOC) in a
separate step prior to cyclization under basic
conditions.3,4 However, we found that simple heating
of (S)-9 and 10 to 200 °C in DMSO (without base) for
30 min caused thermolysis of the Boc group and cycliza-
tion, affording (S)-12 (67%) and (S)-13 (92%). Thus,
cyclization of (S)-9 and 10 can be carried out directly
without a separate deprotection step. Cyclization of
N-i-Pr analog (S)-11 proceeded in 61% yield, despite the
steric hindrance provided by the secondary alkyl group.
These reactions of 10 and 11 represent the first published
syntheses of N1-substituted tetrahydro-1,4-benzodiaze-
pin-3-ones by direct cyclization. Finally, as hoped, chiral
stationary phase HPLC indicated that no racemization
had occurred during the high temperature cyclizations
to 12–14.
Our syntheses began with commercially available 6
(Scheme 2); treatment with NBS in CCl4 afforded 7 as
off-white, needle-like crystals in 66% yield. Subsequent
reaction with excess allylamine in THF gave 8 in 87%
yield. Note that reaction of 7 with methylamine is less
selective, giving significant amounts of the undesired
nucleophilic aromatic substitution product. Compound
8 was then coupled with either (S)-N-Boc-Ala-OH,
(S)-N-Boc-N-methyl-Ala-OH,7 or (S)-N-i-Pr-Ala-OH8
(DCC, HOBT in CH2Cl2) to afford (S)-9 (86%), (S)-10
(86%), and (S)-11 (68%), respectively. Apparently, the
i-Pr group is large enough to prevent significant self-
condensation of the unprotected N-i-Pr-Ala-OH under
these conditions. Previous syntheses of tetrahydro-1,4-
Nitro compounds 13 and 14 can easily be reduced to pri-
mary aromatic amines 15 and 16 accordingly by reflux-
ing in CH3OH for 3 h in the presence of Fe powder and
aq NH4Cl.9 The corresponding amines were deaminated
Scheme 2. Synthesis of diversely functionalized tetrahydro-1,4-benzodiazepin-3-ones. Reagents and conditions: (i) NBS, CCl4, hm, 18 h (66%); (ii)
allyl amine (3.0 equiv), THF, rt, 16 h (87%); (iii) (S)-Boc-Ala-OH or (S)-Boc-N-Me-Ala-OH or (S)-N-i-Pr-Ala-OH, DCC, HOBT, CH2Cl2, rt, 4 h, 9
(86%), 10 (86%), 11 (68%); (iv) DMSO, 200 °C, 30 min, 12 (67%), 13 (92%, 3 h), 14 (61%, 3 h); (v) Fe/NH4Cl(aq), CH3OH, reflux, 3 h, 15 (97%), 16
(92%); (vi) H2SO4/AcOH, NaNO2/H2O, FeSO4Æ7H2O/DMF, 10% NaOH, 17 (57%), 18 (44%); (vii) NaBH4/THF, formaldehyde/H2SO4, 0 °C,
NaOH(s), 19 (89%), or phthalic anhydride, AcOH, reflux, 1.5 h, 20 (80%); (vii) 10 mol % K2OsO4Æ2H2O, NMO (3 equiv), NaIO4 (3 equiv), dioxane–
H2O, 21 (6 h, 60 °C, 64%), 22 (18 h, 60 °C, 75%).

E. C. Clement, P. R. Carlier / Tetrahedron Letters 46 (2005) 3633–3635
3635
by use of NaNO2 and Fe2SO4 in DMF10 to yield (S)-17
and (S)-18, respectively; HPLC analysis of (S)-17
indicated 99% ee. The primary aromatic amine (S)-16
was converted to the corresponding N,N-dimethylamine
(S)-19 in 89% yield in the presence of NaBH4 and form-
aldehyde in THF.11 HPLC analysis of (S)-19 indicated
99% ee. Refluxing (S)-16 with phthalic anhydride
in acetic acid for 1.5 h12 afforded (S)-20 in 80% yield;
HPLC analysis indicated 98% ee.
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of such activating functional groups: (a) Ma, D.; Zhang,
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Removal of the N4-allyl group from the tetrahydro-
1,4-benzodiazepin-3-ones proved more difficult than
anticipated. Traditional Pd(PPh3)4 catalyzed deallylation
methods, either with N,N0-dimethylbarbaturic acid,13 or
with the Et3N/HCO2H system recommended for
imides,14 proved completely unsuccessful. Catalysis
15
by RhCl(PPh3)3
also proved ineffectual, and
RuCl2(PPh3)3 catalyzed deallylation16 proceeded only
in low to moderate yields. In the end acceptable yields
were obtained with Bundleꢀs oxidative deallylation pro-
tocol.17 Treatment of (S)-13 and (S)-19 with catalytic
potassium osmate in the presence of N-methyl morphol-
ine N-oxide and sodium periodate gave (S)-22 and (S)-
21 in 75% and 64% yield, respectively. Chiral stationary
phase HPLC indicated that no racemization had
occurred during the deallylation. Since alkylation of
tetrahydro-1,4-benzodiazepin-3-ones at N4 is facile,18
a variety of alkyl groups can now be installed at this
position of 21–22.
7. Schutkowski, M.; Mrestani-Klaus, C.; Neubert, K. Int. J.
Pept. Protein Res. 1995, 45, 257–265.
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Synthesis 1980, 743–746.
In summary, enantiomerically pure tetrahydro-1,4-benzo-
diazepin-3-ones (12–22) were synthesized from deriva-
tives of L-alanine. The key cyclization step proceeded
quickly and easily without racemization, even in the case
of 2° amines (cf. 13, 14). Our choice of 8 as a precursor
allows differential functionalization of N1, N4, and the
C10-amino group. This method could be trivially ex-
tended to other amino acids and should thus facilitate
synthesis of diversely functionalized 1,4-benzodiazepin-
3-ones.
12. Perry, C. J.; Parveen, Z. J. Chem. Soc., Perkin Trans. 2
2001, 512–521.
13. Garro-Helion, F.; Merzouk, A.; Guibe, F. J. Org. Chem.
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Acknowledgements
14. Koch, T.; Hesse, M. Synthesis 1992, 931–932.
15. Doi, H.; Sakai, T.; Yamada, K.-i.; Tomioka, K. Chem.
Commun. 2004, 1850–1851.
We thank the NSF (CHE-0213525) and the Virginia
Tech Department of Chemistry for financial support.
16. Hu, Y.-J.; Dominique, R.; Das, S. K.; Roy, R. Can.
J. Chem. 2000, 78, 838–845.
References and notes
17. Kitov, P. I.; Bundle, D. R. Org. Lett. 2001, 3, 2835–
2838.
18. Ali, F. E.; Yuan, C. C. K.; Ross, S. T.; Hall, L. B. Mol.
Divers. 2000, 5, 1–5.
1. Miller, W. H.; Ku, T. W.; Ali, F. E.; Bondinell, W. E.;
Calvo, R. R.; Davis, L. D.; Erhard, K. F.; Hall, L. B.;
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