Synthesis and diversification of 1,2,3-triazole-fused 1,4-benzodiazepine scaffolds

Article abstract of DOI:10.1021/ol1028404

A substituted heterocyclic scaffold comprising a 1,4-benzodiazepine fused with a 1,2,3-triazole ring has been synthesized and diversified via a variety of refunctionalizations. The strategy features the rapid assembly of the scaffold by combining 3-4 reac

Full text of DOI:10.1021/ol1028404

ORGANIC
LETTERS
2011
Vol. 13, No. 5
852–855
Synthesis and Diversification of 1,2,3-
Triazole-Fused 1,4-Benzodiazepine
Scaffolds
James R. Donald and Stephen F. Martin*
Department of Chemistry and Biochemistry, The Texas Institute for Drug and
Diagnostic Development, The University of Texas at Austin, Austin, Texas 78712,
United States
sfmartin@mail.utexas.edu
Received November 23, 2010
ABSTRACT
A substituted heterocyclic scaffold comprising a 1,4-benzodiazepine fused with a 1,2,3-triazole ring has been synthesized and diversified via a
variety of refunctionalizations. The strategy features the rapid assembly of the scaffold by combining 3-4 reactants in an efficient
multicomponent assembly process, followed by an intramolecular Huisgen cycloaddition.
Privileged scaffolds are uniquely suited to the prepara-
tion of molecular libraries for lead development in medic-
inal chemistry.1 Such frameworks are attractive for drug
discovery because of the high hit rates and the pharmaco-
logical profiles of their derivatives relative to those of other
ring systems. By varying substitutents on these privileged
scaffolds, one can often identify potent and selective
binders for multiple biological targets from a single library.
Indeed, a retrospective analysis of all known drugs reveals
that nearly 25% can be traced back to a mere 41 sub-
structures that have since been catagorized as privileged.2
The 1,4-benzodiazepine ring system present in 1 is the
archetypal privileged structure as defined by Evans more
than 20 years ago.3 Compounds derived from the 1,4-
benzodiazepine ring system, which has been suggested
to serve as a structural mimic of peptide β-turns4 and
R-helices,5 bind to a multitude of targets, including G-
protein coupled receptors, ligand-gated ion channels, and
enzymes.1a Accordingly, it is hardly surprising that 1,4-
benzodiazepines are found in a large number of pharma-
ceutical agents.2 Biologically active natural products such
(3) 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.; Lotti, V. J.; Cerino, D. J.; Chen,
T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J. Med.
Chem. 1988, 31, 2235–2246.
(4) Ripka, W. C.; De Lucca, G. V.; Bach, A. C., II; Pottorf, R. S.;
Blaney, J. M. Tetrahedron 1993, 49, 3593–3608.
(1) For reviews, see: (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893–930. (b) DeSimone, R. W.; Currie, K. S.;
Mitchell, S. A.; Darrow, J. W.; Pippin, D. A. Comb. Chem. High T. Scr.
2004, 7, 473–493. (c) Costantino, L.; Barlocco, D. Curr. Med. Chem.
2006, 13, 65–85. (d) Duarte, C. D.; Barreiro, E. J.; Fraga, C. A. M. Mini-
Rev. Med. Chem. 2007, 7, 1108–1119. (e) Welsch, M. E.; Snyder, S. A.;
Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347–361.
(5) Grasberger, B. L.; Lu, T.; Schubert, C.; Parks, D. J.; Carver, T. E.;
Koblish, H. K.; Cummings, M. D.; LaFrance, L. V.; Milkiewicz, K. L.;
Calvo, R. R.; Maguire, D.; Lattanze, J.; Franks, C. F.; Zhao, S.;
Ramachandren, K.; Bylebyl, G. R.; Zhang, M.; Mathney, C. L.; Petrella,
E. C.; Pantoliano, M. W.; Deckman, I. C.; Spurlino, J. C.; Maroney, A. C.;
Tomczuk, B. E.; Molloy, C. J.; Bone, R. F. J. Med. Chem. 2005, 48, 909–
912.
(2) Bemis, G. W.; Murcko, M. A. J. Med. Chem. 1996, 39, 2887–2893.
r
10.1021/ol1028404
Published on Web 01/28/2011
2011 American Chemical Society

Scheme 1. Synthesis of Scaffolds 4 and 7
Figure 1. Derivatives of the 1,4-benzodiazepine ring system.
as asperlicin (2)6 and anthramycin (3)7 also possess a 1,4-
benzodiazepine substructure (Figure 1).
Scheme 2. Diversification of Scaffolds 4 and 7
We recently developed a general approach for preparing
a variety of substituted scaffolds of possible medical rele-
vance by a strategy that involves sequencing multicompo-
nent assembly processes (MCAPs) with subsequent cycli-
zations.8,9 During the course of these investigations, we
developed an expedient route to a compound bearing the
1,2,3-triazolo-1,4-benzodiazepine scaffold 4.10 Although
compounds derived from 4 are known to bind weakly to
the benzodiazepine receptor11 and also to inhibit serine
proteases,12 little else is known regarding the biological
activity of compounds having this substructure. We now
report some extensions of our initial discovery that have
led to the facile synthesis of a number of novel members of
this intriguing structural subclass of benzodiazepines, in-
cluding more complex analogs possessing additional fused
heterocyclic rings.
We first explored a simple variant of our original
MCAP-cyclization approach in accord with the plan out-
lined in Scheme 1. The parent 1,2,3-triazolo-1,4-benzodia-
zepine scaffold 4 was prepared from known aldehyde 513
employing a reductive amination, followed by a thermally
induced, intramolecular Huisgen cycloaddition. This entry
to 4 is both shorter and higher yielding than the reported
method.14 The brominated scaffold 7 was accessed in a
similar fashion from the known aldehyde 6.15
With an efficient route to amine 4 in hand, N-diversifica-
tion was undertaken to afford various analogs. Representa-
tive examples of urea formation, reductive amination and
cross-coupling using conditions developed by the Buchwald
group are given in Scheme 2.16 The aryl bromide 7 is also a
useful intermediate that can be used in diverse cross-coupling
reactions. For example, biphenyl substrates are found in
many biologically active compounds.1,2 It therefore occurred
to us that hybrid biphenyl-benzodiazepine scaffolds might
be of use in lead discovery. We found that 7 underwent a
facile Suzuki cross-coupling to give the biaryl 11 in 84%
yield. The bromide 7 could also be coupled with secondary
amines under Buchwald conditions as exemplified by the
use of morpholine to give the aniline derivative 12.16
We envisioned that the triazolobenzodiazepine 14,
which bears an R-amino nitrile function, would be a useful
point of embarkation for the preparation of a number of
tricyclic and tetracyclic analogs. The benzodiazepine scaf-
fold 14 was thus prepared in 69% overall yield from
(6) Chang, R. S. L.; Monaghan, R. L.; Birnbaum, J.; Stapley, E. O.;
Goetz, M. A.; Albersschonberg, G.; Patchett, A. A.; Liesch, J. M.;
Hensens, O. D.; Springer, J. P. Science 1985, 230, 177–179.
(7) (a) Leimgruber, W.; Stefanovic, V.; Schenker, F.; Karr, A.;
Berger, J. J. Am. Chem. Soc. 1965, 87, 5791–5793. (b) Leimgruber, W.;
Batcho, A. D.; Schenker, F. J. Am. Chem. Soc. 1965, 87, 5793–5795.
(8) For the first example of this process, see: Martin, S. F.; Benage,
B.; Geraci, L. S.; Hunter, J. E.; Mortimore, M. J. Am. Chem. Soc. 1991,
113, 6161–6171.
(9) For a review of related strategies, see: Sunderhaus, J. D.; Martin,
S. F. Chem.;Eur. J. 2009, 15, 1300–1308.
(10) (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Org. Lett.
2007, 9, 4223–4226. (b) Sunderhaus, J. D.; Dockendorff, C.; Martin,
S. F. Tetrahedron 2009, 65, 6454–6469.
(11) Bertelli, L.; Biagi, G.; Giorgi, I.; Livi, O.; Manera, C.; Scartoni,
V.; Martini, C.; Giannaccini, G.; Trincavelli, L.; Barili, P. L. Farmaco
1998, 53, 305–311.
(12) Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan, M. I.
Bioorg. Med. Chem. Lett. 2009, 19, 5241–5245.
(13) Pelkey, E. T.; Gribble, G. W. Tetrahedron Lett. 1997, 38, 5603–
5606.
(14) Alajarın, M.; Cabrera, J.; Pastor, A.; Villalgordo, J. M. Tetra-
´
hedron Lett. 2007, 48, 3495–3499.
(15) Main, C. A.; Petersson, H. M.; Rahman, S. S.; Hartley, R. C.
Tetrahedron 2008, 64, 901–914.
(16) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem. 2000, 65, 1144–1157.
Org. Lett., Vol. 13, No. 5, 2011
853

Scheme 3. Synthesis of Scaffold 14 and Direct Access to
Amide 15
Scheme 5. Amide Derived Diversification of Scaffold 14
Scheme 4. N-Diversification of Scaffold 14
and methyl iodide respectively (Scheme 5). The fused
β-lactam 24 was prepared by sequential N-acylation of 14
with chloroacetyl chloride to give 20 and treatment of the
intermediate amide with sodium hydride in DMF. The β-
lactam motif is alsoa privilegedsubstructure thatis present
in several pharmaceutical agents and numerous biologi-
cally activecompounds.2,17 Under the same conditions, the
2-fluorobenzamide derivative21affordedisoindolinone25
in 76% yield. To the best of our knowledge, this is the first
example wherein a nitrile R-anion participates in an in-
tramolecular ipso-substitution; this sequence also repre-
sents a new entry to isoindolinones, compounds that have
also been identified as privileged scaffolds.18 For example,
1,4-benzodiazepine-fused isoindolinones are of interest as
potassium channel antagonists in the treatment of cardiac
arrhythmia19 and Meniere’s disease.20
1,2,5-Trisubstituted pyrroles can be synthesized from N-
acyl-R-aminoacetonitriles.21 Recognizing that pyrrole-
fused 1,4-benzodiazepines have been reported as HIV-1
reverse transcriptase inhibitors,22 we were attracted to the
possible application of this underutilized methodology to
the synthesisof suchcompounds. Inthe event, treatment of
the anions generated upon deprotonation of 15 or 26 with
NaH with vinyltriphenylphosphonium bromide (Schweizer’s
reagent) delivered the pyrroles 28 and 29 in 72 and 85%
yields, respectively(Scheme6). Notably, pyrroleformation
was complete at ambient temperature within an hour,
conditions significantly milder than the high temperatures
aldehyde 5 via a facile two-step sequence that involved a
Strecker reaction as the MCAP, followed by a dipolar
cycloaddition (Scheme 3). Careful control of temperature
in this conversion is essential because elimination of hydro-
gen cyanide to produce the known imine 1614 is observed at
temperatures above 60 °C. N-Acetylation of the R-amino-
nitrile 13 gives an amide that undergoes dipolar cycloaddi-
tion at room temperature to afford benzodiazepine 15 in
96% yield; the marked difference in the reactivities of the
amine 13 and its derived amide is notable. A “one-pot”,
four-component reaction was also developed that furn-
ished benzodiazepine 15 in 49% yield.
The N-diversification of 14 using a variety of different
electrophiles was straightforward and generally proceeded
in excellent yields (Scheme 4). Representative examples of
N-diversification include N-acylation of 14 to give amide
17 and N-sulfonylation to provide sulfonamide 18. Re-
ductive amination of 14 led to a variety of tertiary amines
of the general type 19.
ꢀ
(17) del Pozo, C.; Macıas, A.; Lopez-Oritz, F.; Maestro, M. A.;
´
ꢀ
Alonso, E.; Gonzalez, J. Eur. J. Org. Chem. 2004, 535–545.
(18) Salcedo, A.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 3600–
3603.
(19) Baldwin J. J.; Claremon, D. A.; Elliott, J. M.; Liverton, N.;
Remy, D. C.; Selnick, H. G. Merck & Co. Inc., World Patent WO
9514471 (A1), 1995.
(20) Lynch Jr. J. J.; Salata, J. J. Merck & Co. Inc., World Patent WO
9800405 (A1), 1998.
(21) (a) Cooney, J. V.; McEwen, W. E. J. Org. Chem. 1981, 46, 2570–
2573. (b) Cooney, J. V.; Beaver, B. D.; McEwen, W. E. J. Het. Chem.
1985, 22, 635–642.
(22) De Lucca, G. V.; Otto, M. J. Bioorg. Med. Chem. Lett. 1992, 2,
1639–1644.
The nitrile function in 14 was incorporated at the outset
to serve as a functional handle for introducing additional
substituents and to facilitate the formation of other rings.
We first exploited the acidic character of the proton adja-
cent to the nitrile to prepare benzodiazepine derivatives 22
and 23 through intermolecular alkylation of the anion
generated by deprotonation of 15, with benzyl bromide
854
Org. Lett., Vol. 13, No. 5, 2011

Scheme 6. Preparation of Pyrrole and Tetrazole-Fused 1,4-
Benzodiazepines
Scheme 7. Diversification using the Bruylants Reaction
corresponding organozinc species in order to obviate com-
peting deprotonation alpha to the cyano function.
and extended reaction times previously reported in the
literature for related cyclizations.21
In summary, we have demonstrated the synthesis of a
number of diversely substituted 1,2,3-triazolo 1,4-benzo-
diazepines based upon scaffolds prepared using our ap-
proach to diversity oriented synthesis that features an
MCAP involving imines followed by various cyclization
reactions. A more efficient route to the parent scaffold 4was
developed, and representative derivatives of 4 were pre-
pared. Brominated analogues of 4 are also readily available
and may be used in a variety of cross-coupling reactions.
Employing the Strecker reaction as the MCAP introduced
an R-amino nitrile into the scaffold as a versatile functional
handle. The nitrile functionality present in scaffold 14 can
be exploited to enable the introduction of additional sub-
stituents by Bruylants reaction, R-alkylation or arylation
reactions. The nitrile group was also used in ring-forming
reactions to give pyrroles and tetrazoles. Extensions of
these discoveries to the efficient syntheses of novel targeted
libraries are the subject of current investigations.
Tetrazole-fused 1,4-benzodiazepines are known benzo-
diazepine receptor binders23 and glycoprotein GPIIb/IIIb
antagonists.24 Toward preparing such compounds, we
found that 27, which was readily prepared from 14 by
acylation with 2-azidobenzoyl chloride,25 underwent an
intramolecular dipolar cycloaddition upon heating to give
the hexacylic fused-tetrazole 30; a related approach to
tetrazole-fused 1,4-benzodiazepines has been reported by
Garanti.26
The capability of the nitrile function to serve as a leaving
group was exploited to synthesize compounds via the
Bruylants reaction (Scheme 7). Displacement of the nitrile
from 19 under “Reformatsky-type” conditions afforded
ester 32 in 75% yield.27 Amines 33 and 34 were also pre-
pared using a variant of the Bruylants reaction wherein
organozinc reagents were used as nucleophiles. It was
necessary to transmetallate the Grignard reagents to the
Acknowledgment. We thank the National Institutes of
Health (GM 86192) and the Robert A. Welch Foundation
(F-0652) for their generous support of this work.
(23) Boulouard, M.; Gillard, A. C.; Guillaumat, P. O.; Daoust, M.;
Legrand, E.; Quermonne, M. A.; Rault, S. Pharm. Pharmacol. Commun.
1998, 4, 43–46.
(24) Robarge, K. D.; Dina, M. S.; Somers, T. C.; Lee, A.; Rawson,
T. E.; Olivero, A. G.; Tischler, M. H.; Webb, R. R., II; Weese, K. J.;
Aliagas, I.; Blackburn, B. K. Bioorg. Med. Chem. 1998, 6, 2345–2381.
Supporting Information Available. Experimental pro-
1
~
ꢀ
(25) Cledera, P.; Avendano, C.; Menendez, J. C. Tetrahedron 1998,
54, 12349–12360.
cedures, spectral data and copies of H and 13C NMR
(26) Broggini, G.; Garanti, L.; Molenti, G.; Zecchi, G. Heterocycles
1999, 51, 1295–1301.
spectra for all new compounds and an improved method
for preparing 4. This material is available free of charge
via the Internet at http://pubs.acs.org.
ꢁ
(27) Bernardi, L.; Bonini, B. F.; Capito, E.; Dessole, G.; Fochi, M.;
Comes-Franchini, M.; Ricci, A. Synlett 2003, 1778–1782.
Org. Lett., Vol. 13, No. 5, 2011
855