A robust protocol for the synthesis of quinoxalines and 5 H -benzo[ e ][1,4]diazepines via the acidless Ugi reaction

Article abstract of DOI:10.1055/s-0033-1339135

Concise two-step, one-pot protocols for the syntheses of quinoxalines and 5H-benzo[e][1,4]diazepines are reported. An 'acidless' Ugi reaction followed by a Boc-deprotection-cyclization sequence is shown to produce arrays of both functionalized scaffolds in good yield. Mono-N-Boc-protected diamines are employed to access quinoxalines and an analogous benzylic amine affords access to 5H-benzo[e][1,4]diazepines in conjunction with supporting reagents in the 'acidless' Ugi reaction. Both methodologies are robust, straightforward, and allow installation of at least three points of diversity in the resulting scaffolds. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339135

1680▌
LETTER
lAetteRr obust Protocol for the Synthesis of Quinoxalines and 5H-Benzo[e][1,4]di-
azepines via the Acidless Ugi Reaction
Quinoxalines and 5H-Benzo[e][1,4]diazepines
Muhammad Ayaz,a Guillermo Martinez-Ariza,a Christopher Hulme*a,b
a
Department of Pharmacology and Toxicology, College of Pharmacy, BIO5 Oro Valley, The University of Arizona, 1580 E. Hanley Blvd.,
Oro Valley, AZ 85737, USA
Fax +1(520)6260794; E-mail: hulme@pharmacy.arizona.edu
b
Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721, USA
Received: 07.04.2014; Accepted: 30.04.2014
bedded masked amino nucleophile/s in combination with
Abstract: Concise two-step, one-pot protocols for the syntheses of
suitably located electrophilic moieties in the Ugi four-
quinoxalines and 5H-benzo[e][1,4]diazepines are reported. An ‘ac-
component reaction (U-4CR) where after acid treatment
and cleavage of the protecting group, intramolecular cy-
idless’ Ugi reaction followed by a Boc-deprotection–cyclization se-
quence is shown to produce arrays of both functionalized scaffolds
in good yield. Mono-N-Boc-protected diamines are employed to ac- clization leads to the synthesis of a variety of heterocyclic
cess quinoxalines and an analogous benzylic amine affords access
to 5H-benzo[e][1,4]diazepines in conjunction with supporting re-
scaffolds.
An analogous variant of the Ugi-4CR makes use of water
agents in the ‘acidless’ Ugi reaction. Both methodologies are ro-
in place of a carboxylic acid as the fourth component of
the reaction (denoted the ‘acidless’ Ugi reaction), howev-
er, the original protocol as described by Ugi1 had a limited
substrate scope with generally low yields unless the em-
ployed carbonyl and amine inputs were formaldehyde and
a secondary amine, respectively. However, List and
coworkers6 were able to improve the scope of the three-
component reaction (3CR) through catalysis with
phenylphosphinic acid 7 to afford α-amino amides 8
(Scheme 1). Mechanistically, water (5) acts as an acid
equivalent7 trapping the nitrilium ion B.
bust, straightforward, and allow installation of at least three points
of diversity in the resulting scaffolds.
Key words: multicomponent reaction, combinatorial chemistry,
Ugi, quinoxalines, benzodiazepines
The Ugi reaction1 is the most widely explored multicom-
ponent reaction with applications found in a number of
heterocylic ring-forming processes and the total synthesis
of biologically active natural products.2 A typical proce-
dure involves the condensation of an aldehyde 1, amine 2,
isocyanide 3, and carboxylic acid 4 to form α-amido am-
ides 6 (Scheme 1). Since water is the only byproduct ob-
served during this reaction the transformation is highly
atom-economical.3 Furthermore the simplicity of the reac-
tion has driven chemists to exploit the Ugi product
through post-Ugi transformations affording many unique
scaffolds with multiple points of diversity derived from
the four Ugi reagents.4 In this context, a commonly used
strategy called ‘Ugi–deprotect–cyclize’ (UDC)5 uses em-
With improved scope of reaction, we set about using the
100% atom-economic 3CR to generate quinoxalines 10
and 5H-benzo[e][1,4]diazepines 13, consistent with group
goals to generate concise methodologies toward pharma-
cologically relevant molecules to augment the molecular
libraries small molecule repository (MLSMR).8,9 There
are a few multicomponent approaches followed by sec-
ondary transformations to access quinoxalines exempli-
fied by the Ugi–Smiles reaction,10a the Groebke–
R2
N
O
Ugi-4CR
R
R3
O
N
H
–O
R
O
O
R1
R3NC
R2
4
6
R1
H
3
R1
N
1
HX
C
N+ R3
O
P
R1
H
R2NH2
R2HN
– H2O
Ph
B
A
2
OH
NHR2
H
NHR3
7
H2O
R1
acid-free
Ugi reaction
O
5
8
Scheme 1 Ugi four-component and Ugi three-component acid-free reactions
SYNLETT 2014, 25, 1680–1684
Advanced online publication: 03.06.2014
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339135; Art ID: st-2014-d0296-l
© Georg Thieme Verlag Stuttgart · New York

LETTER
Quinoxalines and 5H-Benzo[e][1,4]diazepines
1681
OMe
O
NH2
O
O
solvent, r.t.
cat. 7 (10 mol%)
O
MeO
NHBoc
O
NHBu
1a
2a
NH
NC
3a
NHBoc
8a
P
Ph
OH
H
7
TFA–DCE
temperature
time
O
O
N
H
NHBu
N
NHBu
N
N
OMe
OMe
10a
9a
Scheme 2 Acidless Ugi model reaction toward quinoxalines 10
Blackburn–Bienaymé reaction,10b the Petasis reaction,10c ‘acidless’ Ugi reaction towards this end is unreported.
and a recently reported highly original indole-based mul- Furthermore, only a few routes11 toward 5H-ben-
ticomponent reaction (MCR).10d However, the use of the zo[e][1,4]diazepines are reported and none are amenable
O
O
O
N
N
N
H
N
N
N
N
NHBu
NHBu
OMe
Br
F
10a, 50%
10b, 55%
10c, 48%
O
O
N
N
N
N
O
NHBu
NHBu
N
N
N
H
OCF3
NHBu
Br
10d, 57%
10e, 53%
10f, 40%
O
O
N
N
N
O
N
H
N
NHBu
N
N
O
O
Br
10g, 44%
10h, 41%
10i, 59%
O
O
O
N
N
N
N
N
NHBu
NHBu
NHBu
N
F
CF3
Br
F
10j, 44%
10k, 57%
10l, 46%
Figure 1 Solvent screening for the synthesis of 8a. Yields are based on the ‘area under the curve’ of the desired product (A%) observed in
LC–MS at UV (λ = 254 nm).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 1680–1684

1682
M. Ayaz et al.
LETTER
to high-throughput production. The pharmacological ac-
tivity profiles of both scaffolds 10 and 13 are widespread
adding further impetus to discovery of highly concise
preparations.12,13 Building on the findings of Ugi1 and
List,6 herein we report an acidless Ugi reaction combined
with a one-pot deprotection–cyclization step ultimately
leading to an array of diverse quinoxaline- and 5H-ben-
zo[e][1,4]diazepine-containing compounds.
In a typical reaction, 4-methoxyphenylglyoxal (1a) and
Boc-protected amine 2a is mixed with n-butyl isonitrile
(3a) in the presence of 10 mol% phenylphosphinic acid 7
to generate the acidless Ugi product 8a (Scheme 2). Mod-
el reactions were carried out at room temperature in dif-
ferent solvents, and product formation was monitored by
LC–MS at 1, 6, and 16 hour intervals (Figure 1). Optimal
yields were observed using CH2Cl2 (Figure 1, entry 7;
85% yield of 8a as judged by LC–MS). Interestingly,
methanol, which is generally believed to be the solvent of
choice for the classical Ugi reaction, proved a poor choice
in the acidless version (25% yield, 16 h, Figure 1, entry 4).
Thus, after using optimal conditions (CH2Cl2, r.t., 16 h,
Figure 1), the solvent was then removed under reduced
pressure to afford crude 8a which was dissolved in a 20%
solution of TFA in DCE. Heating this reaction via micro-
wave irradiation at 140 °C for 20 min afforded the desired
quinoxaline 10a exclusively (99% yield as judged by LC–
MS ‘area% under the curve’) derived from a Boc-remov-
al, oxidative–cyclization sequence (overall 50% isolated
yield; Scheme 2). Note that at lower temperatures (80 °C,
20 min), oxidation of intermediate 9a (Scheme 2) to 10a
proved to be only ca. 30% complete.
Figure 2 Quinoxalines 10 assembled via the acid-free Ugi–deprot-
ection–cyclization pathway
To evaluate the generality of the two-step, one-pot proce-
dure we thus evaluated the sequence with eight glyoxalde-
hydes 1, two amines 2, and four isonitriles 3 (Scheme 3).
To our delight, the methodology proved general with
varying reaction inputs, rendering the quinoxalines 10a–
l14 in good isolated yields (Figure 2).
At this stage, it was envisioned that utilizing an alternate
benzylic amine 11 would unlock access to 5H-ben-
zo[e][1,4]diazepines 1315 after the formation of the acid-
1) PhPO2H2 (10 mol%)
CH2Cl2, 16 h
2) TFA–DCE (20%)
MW 140 °C, 20 min
O
O
R2
R3
N
R2
R3
NH2
NHR4
O
R4NC
R1
40–59%
one-pot two-step
R1
1
N
NHBoc
2
3
10
Scheme 3 Two-step, one-pot sequence towards quinoxalines 10a–l
O
R2NC
3
PhPO2H2 (10 mol%)
CH2Cl2, 16 h
R1
O
R2
TFA–DCE
MW 140 °C
20 min
N
H
R1
R2
N
O
N
H
NH
N
NHBoc
12
13a–c
O
NH2
NHBoc
O
NHBoc
NC
R1
1
11
BocHN
R1
O
14
TFA–DCE
MW 140 °C
20 min
N
PhPO2H2 (10 mol%)
CH2Cl2, 16 h
N
O
N
N
H
H
NH
R1
N
NHBoc
15
13d
Scheme 4 Acid-free Ugi assembly for the synthesis of 5H-benzo[e][1,4]diazepines 11
Synlett 2014, 25, 1680–1684
© Georg Thieme Verlag Stuttgart · New York

LETTER
Quinoxalines and 5H-Benzo[e][1,4]diazepines
1683
(4) (a) Banfi, L.; Basso, A. Synthesis of Heterocycles via
less Ugi product 12 with subsequent acid treatment
(Scheme 4). In addition, employing two internal Boc-pro-
tected amine nucleophiles via the use of 14 and 11 would
set up the possibility of a double deprotection–cyclization
cascade process forming benzimidazole-embedded ben-
zodiazepines 13d (Scheme 4).5
Multicomponent Reactions I, In Topics in Heterocyclic
Chemistry; Orru, R. V. A.; Ruijter, E., Eds.; Springer: Berlin
Heidelberg, 2010, 1–39. (b) Kalinski, C.; Lemoine, H.;
Schmidt, J.; Burdack, C.; Kolb, J.; Umkehrer, M.; Ross, G.
Synthesis 2008, 4007. (c) Zhu, J. Eur. J. Org. Chem. 2003,
1133.
(5) (a) Hulme, C.; Dietrich, J. Mol. Diversity 2009, 13, 195.
(b) Ayaz, M.; De Moliner, F.; Dietrich, J.; Hulme, C. In
Isocyanide Chemistry: Applications of Isocyanides in
IMCRs for the Rapid Generation of Molecular Diversity;
Wiley-VCH: Weinheim, 2012, 335–384. (c) Dömling, A.
Chem. Rev. 2006, 106, 17. (d) Hulme, C.; Peng, J.; Louridas,
B.; Menard, P.; Krolikowski, P.; Kumar, N. V. Tetrahedron
Lett. 1998, 39, 8047. (e) Hulme, C.; Peng, J.; Tang, S.;
Burns, C. J.; Morize, I.; Labaudiniere, R. J. Org. Chem.
1998, 63, 8021. (f) Rhoden, C. R. B.; Rivera, D. G.; Kreye,
O.; Bauer, A. K.; Westermann, B.; Wessjohann, L. A.
J. Comb. Chem. 2009, 11, 1078.
As expected, using similar conditions to those optimized
for quinoxalinone formation furnished the final benzodi-
azepine chemotype in good isolated yields, exemplified
by 13a–d (Figure 3).
O
O
NH
NH
N
N
N
N
(6) Pan, S. C.; List, B. Angew. Chem. Int. Ed. 2008, 47, 3622.
(7) El Kaïm, L.; Grimaud, L. In Isocyanide Chemistry: Ugi and
Passerini Reactions with Carboxylic Acid Surrogates;
Wiley-VCH: Weinheim, 2012, 159–194.
Br
13b, 56%
13a, 39%
(8) (a) Xu, Z.; De Moliner, F.; Cappelli, A. P.; Ayaz, M.;
Hulme, C. Synlett 2014, 25, 225. (b) Shaw, A. Y.; McLaren,
J. A.; Nichol, G. S.; Hulme, C. Tetrahedron Lett. 2012, 53,
2592.
O
N
NH
NH
N
N
(9) Xu, Z.; De Moliner, F.; Cappelli, A. P.; Hulme, C. Angew.
Chem. Int. Ed. 2012, 51, 8037.
N
N
CF3
Br
13c, 14%
13d, 41%
(10) (a) Oble, J.; El Kaïm, L.; Gizzi, M.; Grimaud, L.
Heterocycles 2007, 73, 503. (b) Krasavin, M.; Parchinsky,
V. Synlett 2008, 645. (c) Heravi, M. M.; Baghernejad, B.;
Oskooie, H. A. Tetrahedron Lett. 2009, 50, 767. (d) Ayaz,
M.; Dietrich, J.; Hulme, C. Tetrahedron Lett. 2011, 52,
4821. (e) Martinez-Ariza, G.; Ayaz, M.; Hulme, C.
Tetrahedron Lett. 2013, 54, 6719.
Figure 3 5H-Benzo[e][1,4]diazepines assembled from the acid-free
Ugi–deprotection–cyclization sequence
In conclusion, a MCR-based novel one-pot, two-step ap-
proach has been successfully applied towards the synthe-
sis of quinoxalines 10 and 5H-benzo[e][1,4]diazepines
13. The acidless three-component Ugi reaction catalyzed
with phenylphosphinic acid provides three points of di-
versity with 100% atom economy. Subsequently, a Boc-
deprotection–cyclization–oxidation sequence is triggered
under acidic conditions forming arrays of the desired
products 10 and 13.
(11) (a) Attanasi, O. A.; De Crescentini, L.; Favi, G.; Mantellini,
F.; Nicolini, S. J. Org. Chem. 2011, 76, 8320.
(b) Wasserman, H. H.; Long, Y. O.; Parr, J. Tetrahedron
Lett. 2003, 44, 361. (c) Randles, K. R.; Storr, R. C. J. Chem.
Soc., Chem. Commun. 1984, 22, 1485.
(12) (a) Fonseca, T.; Gigante, B.; Marques, M. M.; Gilchrist, T.
L.; De Clercq, E. Bioorg. Med. Chem. 2004, 12, 103.
(b) Zarranz, B.; Jaso, A.; Aldana, I.; Monge, A.; Maurel, S.;
Deharo, E.; Jullian, V.; Sauvain, M. Arzneimittelforsch.
Drug Res. 2011, 55, 754. (c) Gazit, A.; Yee, K.; Uecker, A.;
Böhmer, F.; Sjöblom, T.; Östman, A.; Waltenberger, J.;
Golomb, G.; Banai, S.; Heinrich, M. C.; Levitzki, A. Bioorg.
Med. Chem. 2003, 11, 2007.
(13) (a) Bauer, A.; Danneberg, P.; Weber, K. H.; Minck, K. J.
Med. Chem. 1973, 16, 1011. (b) Sternbach, L. H. J. Med.
Chem. 1979, 22, 1. (c) Aastha, P.; Navneet, K.; Anshu, A.;
Pratima, S.; Dharma, K. Res. J. Chem. Sci. 2013, 3, 90.
(14) Preparation of Quinoxaline 10c; Typical Procedure
4-Fluorophenylglyoxaldehyde (1.0 equiv, 1.0 mmol, 152
mg) and tert-butyl (2-aminophenyl)carbamate (1.0 equiv,
1.0 mmol, 208 mg) were combined in CH2Cl2 (2 mL). n-
Butyl isocyanide (1.0 equiv, 1.0 mmol, 83 mg, 0.104 mL)
and phenylphosphinic acid (0.1 equiv, 0.1 mmol, 14 mg)
were added, and the reaction was stirred for 16 h at r.t. The
progress of the reaction was monitored by LC–MS and TLC.
Upon completion, the solvent was evaporated in vacuo, the
residue was dissolved in 20% TFA–DCE (3.0 mL), and the
reaction mixture was heated in a microwave (Biotage
InitiatorTM) at 140 °C for 20 min. The reaction was allowed
to cool to r.t. at which time the mixture was diluted with
EtOAc (15 mL), and the organic layer was washed with sat.
Acknowledgment
Financial support from the National Institutes of Health (Grant
P41GM086190) and CONACyT-University of Arizona (doctoral
scholarship 215981/311412 for G.M.A.) is appreciatively acknow-
ledged.
References and Notes
(1) (a) Ugi, I. Angew. Chem., Int. Ed. Engl. 1962, 1, 8.
(b) Marcaccini, S.; Torroba, T. Nat Protoc. 2007, 2, 632.
(2) (a) Hulme, C.; Gore, V. Curr. Med. Chem. 2003, 10, 51.
(b) Tempest, P. Curr. Opin. Drug Discovery Devel. 2005, 8,
776. (c) Ruijter, E.; Orru, R. V. A. Drug Discovery Today
Technol. 2013, 10, e15. (d) Dömling, A.; Wang, W.; Wang,
K. Chem. Rev. 2012, 112, 3083. (e) Slobbe, P.; Ruijter, E.;
Orru, R. V. A. Med. Chem. Commun. 2012, 3, 1189.
(f) Akritopoulou-Zanze, I. Curr. Opin. Chem. Biol. 2008,
12, 324.
(3) Trost, B. Science 1991, 254, 1471.
© Georg Thieme Verlag Stuttgart · New York
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LETTER
aq NaHCO3 (2 × 20 mL) and brine (2 × 20 mL). The organic
phase was dried over MgSO4 and concentrated under
reduced pressure, and the crude was purified by flash
chromatography (hexane–EtOAc, 0–100%) using an
ISCO™ purification system to afford N-butyl-3-(4-
fluorophenyl)quinoxaline-2-carboxamide as a beige solid
(155 mg, 48% yield). 1H NMR (400 MHz, CDCl3): δ = 8.18–
8.06 (m, 2 H), 7.96–7.66 (m, 4 H), 7.55 (s, 1 H), 7.16 (m, 2
H), 3.48–3.43 (m, 2 H), 1.68–1.53 (m, 2 H), 1.50–1.34 (m, 2
H), 0.96 (t, J = 7.3 Hz, 3 H). 13C NMR (100 MHz, CDCl3):
δ = 164.5, 162.2, 152.6. 144.9, 142.3, 139.2, 134.5, 131.6,
130.9, 130.7, 130.5, 129.2, 129.1, 115.2, 115.0, 39.5. 31.5,
20.1, 13.7. ESI-MS: m/z = 324 [M + H]+.
and TLC. Upon completion, the solvent was evaporated in
vacuo, the residue was dissolved in 20% TFA–DCE (3.0
mL), and the reaction mixture was heated in microwave at
140 °C for 20 min. After cooling the reaction to r.t., the
reaction mixture was diluted with EtOAc (15 mL), and the
organic layer was washed with sat. aq NaHCO3 (2 × 20 mL)
and brine (2 × 20 mL). The organic phase was dried over
MgSO4 and concentrated under reduced pressure, and the
crude was purified by flash chromatography (hexane–
EtOAc, 0–100%) using an ISCO™ purification system to
afford 3-(3-bromophenyl)-N-(2,6-dimethylphenyl)-5H-
benzo[e][1,4]diazepine-2-carboxamide as a yellow solid
(250 mg, 56% yield). 1H NMR (400 MHz, CDCl3): δ = 8.48
(br s, 1 H), 7.99–7.96 (m, 1 H), 7.83–7.81(m, 1 H), 7.61–
7.53 (m, 2 H), 7.50–7.44 (m, 1 H), 7.41 (dd, J = 7.7, 1.5 Hz,
1 H), 7.37–7.28 (m, 2 H), 7.10–6.98 (m, 3 H), 4.88 (d, J =
(15) Preparation of 5H-Benzo[e][1,4]diazepine 13b; Typical
Procedure
3-Bromophenylglyoxaldehyde (1.0 equiv, 1.0 mmol, 213
mg) and tert-butyl 2-aminobenzylcarbamate (1.0 equiv,
1.0 mmol, 223 mg) were combined in CH2Cl2 (2 mL). 2-
Isocyano-1,3-dimethylbenzene (1.0 equiv, 1.0 mmol, 131
mg) and phenylphosphinic acid (0.1 equiv, 0.1 mmol, 14
mg) were added, and the reaction was stirred for 16 h at r.t.
while regularly monitoring the reaction progress by LC–MS
10.5 Hz, 1 H), 4.01 (d, J = 10.5 Hz, 1 H), 2.15 (s, 6 H). 13
NMR (100 MHz, CDCl3): δ = 161.4, 160.5, 155.6, 147.2,
139.9, 135.2, 133.7, 132.7, 130.2, 130.1, 129.2, 128.6,
C
128.2, 128.1, 127.6, 127.4, 126.8, 125.7, 122.8, 54.4, 18.6.
ESI-MS: m/z = 446 [M + H]+.
Synlett 2014, 25, 1680–1684
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