One-pot, two-step cascade synthesis of quinazolinotriazolobenzodiazepines

Article abstract of DOI:10.1021/ol301592z

An operationally simple, one-pot, two-step cascade method has been developed to afford quinazolino[1,2,3]triazolo[1,4]benzodiazepines. This unique, atom-economical transformation engages five reactive centers (amide, aniline, carbonyl, azide, and alkyne) and employs environmentally benign iodine as a catalyst. The method proceeds via sequential quinazolinone-forming condensation and intramolecular azide-alkyne 1,3-dipolar cycloaddition reactions. Substrate scope, multicomponent examples, and mechanistic insights are discussed.

Full text of DOI:10.1021/ol301592z

ORGANIC
LETTERS
2012
Vol. 14, No. 14
3732–3735
One-Pot, Two-Step Cascade Synthesis of
Quinazolinotriazolobenzodiazepines
Kathryn G. Guggenheim, Hannah Toru, and Mark J. Kurth*
Department of Chemistry, University of California, One Shields Avenue, Davis,
California 95616, United States
mjkurth@ucdavis.edu
Received June 8, 2012
ABSTRACT
An operationally simple, one-pot, two-step cascade method has been developed to afford quinazolino[1,2,3]triazolo[1,4]benzodiazepines. This
unique, atom-economical transformation engages five reactive centers (amide, aniline, carbonyl, azide, and alkyne) and employs environmentally
benign iodine as a catalyst. The method proceeds via sequential quinazolinone-forming condensation and intramolecular azideꢀalkyne 1,3-
dipolar cycloaddition reactions. Substrate scope, multicomponent examples, and mechanistic insights are discussed.
Quinazolinones, benzodiazepines, and triazoles are con-
sidered privileged heterocycles and are found in many
bioactive compounds.1ꢀ3 The quinazolinone core is a
ubiquitous pharmacophore appearing in natural and syn-
thetic products.1a Natural products (Figure 1) with the
quinazolinone moiety include rutaecarpine (1,1aꢀc a Chinese
herbal medication isolated from the fruit of Evodia rutae-
carpa with applications in the treatment of headache,
cholera, and dysentery) and febrifugine (2,1a a Chinese herb
used in the treatment of malaria). Methaqualone (3,Figure1)
was once a commonly prescribed synthetic drug (on the
market in the U.S. since the 1960s) that exhibits hypnotic and
sedative effects.1a,d Pharmaceuticals derived from the benzo-
diazepine core, binding to GABAA receptors at the benzo-
diazepine site,2a emerged in many marketed drugs during the
1970s. Two of these are alprazolam (4, Xanax)2b and
diazepam (5, Figure 1, Valium),2c which continue to be
Figure 1. Natural and synthetic examples of bioactive quinazo-
prescribed today for the treatment of anxiety and insomnia.
Compounds such as 6 (plus analogues, Figure 1), derived
linones, benzodiazepines, and triazoles.
(1) (a) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787–826.
(b) Zhou, J.; Fang, J. J. Org. Chem. 2011, 76, 7730–36. (c) Granger,
B. A.; Kaneda, K.; Martin, S. F. Org. Lett. 2011, 13, 4542–45. (d)
Rostamizadeh, S.; Amani, A. M.; Aryan, R.; Ghaieni, H. R.; Shadjou,
N. Synth. Commun. 2008, 38, 3567–76.
(2) (a) Sigel, E. Med. Chem. Rev.;Online 2005, 2, 251–56. (b) Hester,
J. B., Jr. U.S. Patent No. 3,987,052, 1969. (c) Keller, O.; Steiger, N.;
Sternbach, L. H. U.S. Patent No. 3,442,946, 1969.
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2006, 1, 525–38. (b) Mohapatra, D. K.; Maity, P. K.; Shabab, M.; Khan,
M. I. Bioorg. Med. Chem. Lett. 2009, 19, 5241–45.
from the further elaborated [1,2,3]triazolo[1,4]benzodiazepine
skeleton, display activity as protease inhibitors.3
The pharmacological records of these privileged motifs
prompted us to develop an atom-economical, one-pot,
two-step cascade method for the production of com-
pounds incorporating the three aforementioned hetero-
cycles. Many procedures have appeared in the literature
for the synthesis of quinazolinones; these generally utilize
r
10.1021/ol301592z
Published on Web 06/29/2012
2012 American Chemical Society

o-aminobenzamides and aldehydes or ketones as starting
materials and Bronsted/Lewis acids or Bronsted bases as
catalysts to effect imine formation and subsequent ring
closure (Scheme 1a).4aꢀi The quinazolinone synthesis
methodology developed by Wang et al. is attractive be-
cause it is environmentally benign, and inexpensive mole-
cular iodine is used catalytically (5 mol %) at 50 °C to
promote product formation.4d Furthermore, the thermally
driven intramolecular azideꢀalkyne 1,3-dipolar cycload-
dition is well-documented, usually employing elevated
temperatures (80ꢀ120 °C is common) to afford the 1,5-
fused-1,2,3-triazole (Scheme 1b).1c,3,5
Scheme 2. Proposed Mechanism
Scheme 1. Classic Methods for the Synthesis of Quinazolinones
(a) and 1,5-Fused 1,2,3-Triazoles (b)
Scheme 3. One-Pot Cascade Synthesis of Quinazolino-
[1,2,3]triazolo[1,4]benzodiazepine 9a
The method described herein (Scheme 2) draws on these
ideas to explore the use of molecular iodine to promote a
cascade sequence of reactions. Step one consists of anili-
noꢀketo condensation to form Schiff base 10 and subse-
quent nucleophilic attack by the amide nitrogen onto the
imine to form an aminal (quinazolinone 11). These two
iodine-promoted condensations preorganize the alkyne
and azide for an intramolecular 1,3-dipolar cycloaddition
(step two) to form the complex pentacyclic system 9.6
These transformations were demonstrated by reacting
o-amino-N-(prop-2-yn-1-yl)benzamide (7) with o-azidoace-
tophenone (8a) in MeOH using 10 mol % of I2 at 50 °C
(open to the atmosphere). This one-pot, two-step cascade
reaction delivered pure quinazolino[1,2,3]triazolo[1,4]-
benzodiazepine 9, which precipitated from the reaction
mixture in 70% isolated yield (Scheme 3).
a Product characterized by 1H and 13C NMR, IR, and HRMS.
This method affords many advantageous features. For
instance, exploiting inexpensive, nontoxic, air-stable io-
dine as catalyst4h in a one-pot, two-step cascade process
characterizes this as an operationally simple procedure.
Additionally, this is a highly atom-economical reaction
engaging five reactive centers (aniline, amide, carbonyl,
azide, and alkyne) spanning two starting materials. An-
other attractive aspect is that each starting material can be
accessed in one straightforward step from commercial
reagents. o-Amino-N-(prop-2-yn-1-yl)benzamide (7) was
prepared by the chemoselective nucleophilic opening of
isatoic anhydride (12) with propargylamine and subse-
quent decarboxylation of the in situ formed carbamic acid,
providing the propargylated amide/free aniline in 88%
yield in pure form (Scheme 4a; no column chromatogra-
phy necessary).7 The second starting material, o-azidoace-
tophenone (8a: R2 = Me; R3 = H), was obtained in one
pot by diazotization of o-aminoacetophenone (13a) and
subsequent displacement with sodium azide in high yield
(Scheme 4b; 8bꢀd were also prepared in this fashion; 8b:
R2 = Me; R3 = [3,4]dioxole; 8c: R2 = Ph; R3 = H; 8d:
R2 = Ph; R3 = p-Cl).8 Substituted isatoic anhydrides are
an ideal starting point for this method but, unfortunately,
(4) (a) Shaabani, A.; Maleki, A.; Mofakham, H. Synth. Commun.
2008, 38, 3751–59. (b) Wang, M.; Dou, G.; Shi, D. J. Comb. Chem. 2010,
12, 582–86. (c) Roy, A. D.; Jayalakshmi, K.; Dasgupta, S.; Roy, R.;
Mukhopadhyay, B. Magn. Reson. Chem. 2008, 46, 1119–26. (d) Wang,
X.-S.; Yang, K.; Zhou, J.; Tu, S.-J. J. Comb. Chem. 2010, 12, 417–21. (e)
Cheng, X.; Vellalath, S.; Goddard, R.; List, B. J. Am. Chem. Soc. 2008,
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130, 15786–87. (f) Miklos, F.; Fulop, F. Eur. J. Org. Chem. 2010, 5, 959–
65. (g) Mohiuddin, G.; Reddy, P. S.; Ahmed, K.; Ratnam, C. V. J. Chem.
Res., Synop. 1987, 224–25. (h) Parvatkar, P. T.; Parameswaran, P. S.;
Tilve, S. G. Chem.;Eur. J. 2012, 18, 5460–89. (i) Xu, W.; Jin, Y.; Liu,
H.; Jiang, Y.; Fu, H. Org. Lett. 2011, 13, 1274–77.
(5) (a) Majumdar, K. C.; Ray, K. Synthesis 2011, 23, 3767–83. (b)
Donald, J. R.; Martin, S. F. Org. Lett. 2011, 13, 852–55. (c) Arigela,
R. K.; Mandadapu, A. K.; Sharma, S. K.; Kumar, B.; Kundu, B. Org.
Lett. 2012, 14, 1804–07.
(6) Iodine may also play a role in the click reaction as the effective
temperature (50 °C) is lower than that generally required (80ꢀ120 °C)
for intramolecular azideꢀalkyne 1,3-dipolar cycloadditions. It is, how-
ever, difficult to probe this mechanistic aspect as intermediate azidoalk-
yne 11 is not isolable.
(7) Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913–16.
(8) Stokes, B. J.; Vogel, C. V.; Urnezis, L. K.; Pan, M.; Driver, T. G.
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Org. Lett., Vol. 14, No. 14, 2012
3733

are not generally available. Fortunately, substituted o-
amino-N-(prop-2-yn-1-yl)benzamides (15aꢀc; 15a: R1 =
o-OMe; 15b: R1 = m-OMe; 15c: R1 = p-Br) can also be
prepared by 1,10-carbonyldiimidazole (CDI)-mediated
coupling of substituted anthranilic acids (14aꢀc) with
propargylamine (Scheme 4c; note that aniline protection
is unnecessary).9 o-Azidobenzaldehyde (17) can also serve
as the electrophilic carbonyl center in this methodology.
Direct displacement of the nitro group of o-nitrobenzalde-
hyde (16) with sodium azide affords 17 (Scheme 4d).8
Scheme 4. Preparation of Starting Materials
Figure 2. Substrate scope; isolated yields shown. Note: all
products were characterized by 1H and 13C NMR, IR, and
HRMS.
The versatility/limitations of this method were evaluated
by examining substrate scope (Figure 2, isolated yields
listed) using the conditions outlined in Scheme 3. These
results show that R-group substitution can have a signifi-
cant effect on product yield. For instance, electron-donat-
ing substituents in both the R1 (o-OMe and m-OMe with
respect to the aniline: 19, 20, 22, and 23) and R3 (dioxole:
21ꢀ23) positions are well tolerated by this system. One
explanation for this ꢀOMe tolerance at R1 is that the
donating character of the methoxy group enhances aniline
nucleophilicity and in turn facilitates imine formation. It is
also interesting to note that when R1 is substituted with a
halogen (Br), the yield drops substantially (18 = 30%; the
inductively withdrawing character of the Br may have had
the opposite effect of the -OMe group). Not surprisingly,
when R2 is a phenyl group, the lowest yields are obtained
(24 = 25%, 25 = 11%, and 26 = 11%) as a consequence
of steric congestion. Furthermore, when an aldehyde (17;
R2 = R3= H) is employed in place of a ketone, the final
quinazolino[1,2,3]triazolo[1,4]benzodiazepine is delivered
Scheme 5. Oxidation of 27a to 27ba,b
a Product characterized by 1H and 13C NMR, IR, and HRMS.
b Isolated yield after silica gel column chromatography.
in good yield (27a = 62%) together with the air- or
I2-oxidized side product 27b (16%).
Formation of quinazolinones27a and 27bwasintriguing
and prompted us to explore the possibility of converting
27a to 27b under oxidative conditions. Indeed, the facile
(9) Mizutani, T.; Nagase, T.; Ito, S.; Miyamoto, Y.; Tanaka, T.;
Takenaga, N.; Tokita, S.; Sato, N. Bioorg. Med. Chem. Lett. 2008, 18,
6041–45.
3734
Org. Lett., Vol. 14, No. 14, 2012

quinazolino[1,2,3]triazolo[1,4]benzodiazepines 9 and
27a;are delineated in Scheme 6. In these two examples,
propargylamine, isatoic anhydride (12), o-azidoacetophe-
none (8a), or o-azidobenzaldehyde (17), and 20 mol % I2
(at 0.2 M MeOH) were simultaneously combined in one pot.
The in situ formed o-amino-N-(prop-2-yn-1-yl)benzamide
(7; Scheme 6) went on to deliver the targeted heterocycles,
albeit in lower yields compared to the two-component
versions.
Scheme 6. Multicomponent Examplesa
In conclusion, an atom-economical, cascade, five-cen-
tered, one-pot, two-step method has been developed, ex-
ploiting the inexpensive, environmentally friendly catalyst
I2. The substrate scope has been examined showing that
this method is tolerant of various functional groups and
aryl substitutions. We have also shown that multicompo-
nent examples of this method are possible. All final
compounds have been sent to the Molecular Libraries
Small Molecule Repository (MLSMR) with the goal of
identifying biologically active molecules.
a Isolated yields after silica gel column chromatography.
conversion of 27a to 27b can be achieved with DDQ
(Scheme 5) in good isolated yield (70%).
Multicomponent reactions are important because they
deliver complex, diverse final products from relatively
simple starting materials in one operational step.10 We
were interested in investigating the possibility of develop-
ing a multicomponent version of this method (Scheme 6);if
successful, a starting material synthetic step would be cir-
cumvented. Indeed, multicomponent preparations of quina-
zolinones have been reported, which typically utilize isatoic
anhydride (12), ammonium acetate, and an aldehyde.1d,11
Two successful multicomponent experiments;delivering
Acknowledgment. We thank the National Science
Foundation (CHE-0910870) and the National Institutes
of Health (GM089153) for generous financial support. We
also thank Ms. Kelli M. Farber (University of California)
for assistance in the collection of HRMS data.
Supporting Information Available. Full experimental
details and characterization data (1H NMR, 13C NMR,
IR, HRMS, and mp) of all new compounds. This material
is available free of charge via the Internet at http://pubs.
acs.org.
(10) Ruijter, E.; Scheffelaar, R.; Orru, V. A. Angew. Chem., Int. Ed.
2011, 50, 6234–46.
(11) (a) Chen, J.; Su, W.; Wu, H.; Liu, M.; Jin, C. Green Chem. 2007,
9, 972–75. (b) Zeng, L.-Y.; Cai, C. J. Heterocycl. Chem. 2010, 47, 1035–
39. (c) Mohammadi, A. A.; Dabiri, M.; Qaraat, H. Tetrahedron 2009, 65,
3804–08.
The authors declare no competing financial interest.
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