Imidazo[l,2-a]quinoxalines accessed via two sequential isocyanide-based multicomponent reactions

Article abstract of DOI:10.1021/jo900050k

A novel synthetic protocol toward imidazo[l,2-a]quinoxa-lines has been developed. It includes two isocyanide-based multicomponent reactions sequentially introducing four diversity elements to the final products

Full text of DOI:10.1021/jo900050k

SCHEME 1. Synthesis of Quinoxalines by IMCR of
Substituted o-Phenylenediamines10 and IMCR/IMCR
Coupling Strategy Explored in This Work
Imidazo[1,2-a]quinoxalines Accessed via Two
Sequential Isocyanide-Based Multicomponent
Reactions
Mikhail Krasavin,* Sergey Shkavrov, Vladislav Parchinsky,
and Konstantin Bukhryakov
Chemical DiVersity Research Institute, 2a Rabochaya Street,
Khimki, Moscow Region, 141400, Russia
myk@chemdiV.com
ReceiVed January 9, 2009
Additionally, various premeditated post-IMCR events have
allowed reaching even higher levels of molecular complexity
in a few chemical events.8 Of particular interest is such an
IMCR/post-IMCR tandem design that would allow the product
of initial IMCR to be a substrate for another IMCR and so on,
thus multiplying the diversity and/or complexity of resulting
compounds. This strategy has been reduced to practice in recent
work by Wessjohann9 in which sequential Ugi reactions led to
biologically active peptoid structures containing as many as eight
amide units.
Recently we described a novel IMCR process involving
aromatic 1,2-diamines 1, aldehydes, and isocyanides that led
to redox-unstable 1,4-dihydroquinoxalines 2. These were quickly
oxidized with DDQ into stable quinoxalines 3 contaning three
elements of diversity resulting from the three reactants.10 This
two-step sequence represented a conceptually new method for
preparing substituted quinoxalines. We reasoned that if we use
a convertible isocyanide, such as tert-butylisocyanide11 or
1,1,3,4-tetramethylbutylisocyanide (Walborsky reagent12), to
construct quinoxalines 4 using the same two-step sequence, then
the Rconv group could be removed (still leaving behind two
diversity elements from the first IMCR) and the resulting
2-aminoquinoxalines 5 could serve as substrates for GB-MCR,
i.e., the second IMCR in a row (Scheme 1). Herein we report
our results on the feasibility of the above strategy.
A novel synthetic protocol toward imidazo[1,2-a]quinoxa-
lines has been developed. It includes two isocyanide-based
multicomponent reactions sequentially introducing four
diversity elements to the final products.
Isocyanide-based multicomponent reactions (IMCRs) con-
tinue to unveil their potential as a powerful tool for constructing
skeletally diverse drug-like compounds.1 The broad range of
molecular scaffolds that have been crafted via IMCRs extends
from classical linear “Ugi” compounds2 through a variety of
cyclic peptoid compounds resulting from the use of bifunctional
(e.g., tethered carboxy carbonyl3) reagents, and to novel bicyclic
heterocycles (such as imidazo[1,2-x]azines and -azoles,4 or
tetrahydropyrazines5) that have sprung up from applications of
the Groebke-Blackburn reaction (GB-MCR)6 and versions
thereof.7
(8) Recent reviews on post-IMCR chemistries: (a) Akritopoulou-Zanze, I.;
Djuric, S. W. Heterocycles 2007, 73, 125-147. (b) Akritopoulou-Zanze, I. Curr.
Opin. Chem. Biol. 2008, 12, 324–331.
(9) Wessjohann, L. A.; Tran Thi Phuong, T.; WestermannB.,PCT Int. Appl.
WO2008022800 (Chem. Abstr. 2008, 148, 285479). For recent examples on
relevant methodology by the same group on multiple multicomponent macro-
cyclizations including bifunctional building blocks (MiBs), see: (a) Rivera, D. G.;
Vercillo, O. E.; Wessjohann, L. A. Org. Biomol. Chem. 2008, 6, 1787–1795.
(b) Leon, F.; Rivera, D. G.; Wessjohann, L. A. J. Org. Chem. 2008, 73, 1762–
1767.
(10) Krasavin, M.; Parchinsky, V. Synlett 2008, 645–648.
(11) Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.; Sandulenko, Y.; Bukhry-
akov, K. Tetrahedron Lett. 2008, 49, 7318–7321.
(12) (a) Walborsky, H. M.; Niznik, G. E. J. Am. Chem. Soc. 1969, 91, 7778–
7780. (b) Walborsky, H. M.; Niznik, G. E. J. Org. Chem. 1972, 37, 187–191.
(1) Do¨mling, A. Chem. ReV. 2006, 106, 17–89.
(2) Ugi, I. Peptides 1980, 2, 365–381.
(3) Ilyn, A. P.; Loseva, M. V.; Vvedensky, V. Y.; Putsykina, E. B.;
Tkachenko, S. E.; Kravchenko, D. V.; Khvat, A. V.; Krasavin, M. Y.;
Ivachtchenko, A. V. J. Org. Chem. 2006, 71, 2811–2819.
(4) Hulme, C.; Lee, Y.-S. Mol. DiVersity 2008, 12, 1–15.
(5) Kysil, V.; Tkachenko, S.; Khvat, A.; Williams, C.; Tsirulnikov, S.;
Churakova, M.; Ivachtchenko, A. Tetrahedron Lett. 2007, 48, 6239–6244.
(6) (a) Groebke, K.; Weber, L.; Mehlin, F. Synlett 1998, 66, 1–663. (b)
Blackburn, C.; Guan, B.; Fleming, P.; Shiosaki, K.; Tsai, S. Tetrahedron Lett.
1998, 39, 3635–3638.
(7) (a) Shaabani, A.; Maleki, A.; Moghimi-Rad, J. J. Org. Chem. 2007, 72,
6309–6311. (b) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. J. Comb.
Chem. 2008, 10, 323.
10.1021/jo900050k CCC: $40.75
Published on Web 02/12/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 2627–2629 2627

TABLE 1. TMSCl-Promoted GB-MCR of Aminoquinoxalines 5a-c
SCHEME 2. Preparation of 5a-c as Substrates for the
Groebke-Blackburn Reaction
promoted GB-MCR and versions thereof both in pure acetoni-
trile14 and methanol.5 When attempting GB-MCR with 5a-c,
we found that these substrates were poorly soluble in pure
acetonitrile, thus giving only partial conversions.
Acetonitrile-methanol mixtures, however, dissolve amino-
quinoxalines and we used this reaction medium throughout the
study. To our delight, the products with the desired molecular
weight were present in the reaction mixtures as single isomer
(as evidenced by a single product LCMS peak and verified by
1H NMR analysis of the crude products giving only one set of
signals corresponding to the target imidazo[1,2-a]quinoxalines),
thus confirming that the reaction was free from the regiochemi-
cal ambiguity noted for such processes by us15 and others.16
The products 6a-k were isolated chromatographically in
satisfactory yields (Table 1). Their identity as the target
1
imidazo[1,2-a]quinoxalines was further confirmed by H and
13C NMR and elemental analyses and single-crystal X-ray
analysis of a representative compound (6f, see the Supporting
Information).
Between the two convertible isocyanides that proved to work
well in GB-MCR (vide supra), we chose the Walborsky reagent
for our studies. Although it is more expensive than tert-
butylisocyanide, its removal requires only brief exposue to
mineral acid (such as 4 N HCl in dioxane13) while removing
t-BuNC with TFA involves inevitable (albeit sometimes use-
ful11) intermediacy of the respective trifluoroacetamides and the
need to hydrolyze the latter that limits the process’s functional
group tolerance. The three isooctylamino quinoxalines 4a-c
were synthesized in good yields as described earlier.10 Treatment
of 4a-c with 4 N HCl in dioxane led to nearly quantitative
yields of the primary amines 5a-c (Scheme 2).
The latter were now used as substrates for GB-MCR. Among
the range of conditions described for this reaction, we narrowed
our choice to the protocol involving TMSCl as a promoter, that
has given us14 and others5 superior results compared to other
catalysts or promoters such as lanthanide Lewis acids6b or
mineral acids.6a An equimolar amount of TMSCl effictively
Crystallographic information was particularly important in
confirming that the GB-MCR had taken the desired regiochemi-
cal course (6 vs 7). This is further confirmed by NOESY
information obtained for compounds 6c (Figure 1).
In conclusion, we developed a synthetic strategy to prepare
substituted imidazo[1,2-a]quinoxalines 6 that have not been
described in the literature. The conceptually new protocol
includes two coupled IMCR processes: the earlier described
synthesis of quinoxalines from o-phenylenediamines and the
Groebke-Blackburn multicomponent reaction. The simplicity
of the reaction design and the possibility to synthesize novel
heterocycles 6 with four diversity elements in only four chemical
operations (including two chromatographic purifications) makes
the described methodology a tool of choice to construct these
(15) Parchinsky, V. Z.; Shuvalova, O.; Ushakova, O.; Kravchenko, D. V.;
Krasavin, M. Tetrahedron Lett. 2006, 47, 947–951.
(16) (a) Mandair, G. S.; Light, M.; Russell, A.; Hursthouse, M.; Bradley,
M. Tetrahedron Lett. 2002, 43, 4267–4269. (b) Craballares, S.; Cifuentes, M. M.;
Stephenson, G. A. Tetrahedron Lett. 2007, 48, 2041–2045.
(13) Sandulenko, Y.; Komarov, A.; Rufanov, K.; Krasavin, M. Tetrahedron
Lett. 2008, 49, 5990–5993.
(14) Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.; Kysil, V.; Ivachtchenko,
A. Tetrahedron Lett. 2008, 49, 5241–5243.
2628 J. Org. Chem. Vol. 74, No. 6, 2009

2.39 (s, 3H), 1.96 (s, 2H), 1.57 (s, 6H), 0.93 (s, 9H); 13C NMR (75
MHz, CDCl3) δ 149.3, 145.8, 139.8, 138.8, 137.2, 134.6, 133.0,
128.8, 128.1, 127.8, 125.6, 55.5, 51.1, 31.3, 31.1, 28.8, 19.8, 19.4;
LCMS (M + H) 362. Anal. Calcd for C24H31N3: C, 79.73; H, 8.64;
N, 11.62. Found: C, 79.69; H, 8.60; N, 11.59.
Typical Procedure 2: Isooctyl Group Removal To Prepare
5. Isooctylaminoquinoxalines 4 (5 mmol) were dissolved in 4 N
HCl in dioxane and the solution was stirred at rt for 3 h. The
reaction mixture was carefully added to ice-cold sat. aq NaHCO3
solution and, when CO2 evolution seized, the mixture was extracted
with ethyl acetate (3 × 50 mL). Combined organic extracts were
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
1
The products were at least 90% pure as judged by H NMR and
were used in the next step without further purification.
1
5b: white solid, mp 171-173 °C (methanol); H NMR (300
MHz, CDCl3) δ 7.79 (dd, J ) 8.0, 1.5 Hz, 2H), 7.72 (s, 1H), 7.52
(m, 3H), 7.45 (s, 1H), 5.16 (s, 2H), 2.38 (s, 3H), 2.44 (s, 3H); 13
C
NMR (75 MHz, CDCl3) δ 149.8, 144.2, 139.8, 139.3, 137.0, 136.6,
134.6, 129.0, 128.7, 128.0, 124.7, 20.0, 19.5; LCMS (M + H) 250.
ANal. Calcd for C16H15N3: C, 77.08; H, 6.06; N, 16.85. Found: C,
77.13; H, 6.11; N, 16.89.
FIGURE 1. Possible regiochemical outcomes15,16 of the GB-MCR of
5 and through-space interactions observed in the NOESY spectrum of
6c.
Typical Procedure 3: The Groebke-Blackburn Reaction
To Prepare 6. A solution of 5 (1 mmol) in 50:50 MeOH/MeCN
(10 mL) was treated with an aldehyde (1 mmol) and the mixture
was stirred at rt for 3 h. To the resulting solution (often cloudy)
was added TMSCl (1 mmol) in a minimum volume of DCM, then
the mixture was stirred for an additional 30 min, an isocyanide (1
mmol) was added, and the mixture was heated at 50 °C over 20-72
h. When the reaction was complete (as judged by TLC and LCMS
analyses), the mixture was cooled to rt and partitioned between
sat. aq NaHCO3 (25 mL) and ethyl acetate (25 mL). The aqueous
layer was further extracted with ethyl acetate (2 × 25 mL). The
combined organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. Chromatography on silica gel
with an appropriate gradient (0-10%) of methanol in DCM
provided the target compounds 6a-k in yields indicated in Table
1.
medicinally relevant17 compounds. Biological profiling of the
described compounds is currently underway in our laboratories.
The results of these studies will be disclosed in due course.
Experimental Section
Typical Procedure 1: Synthesis of Quinoxalines 4. The starting
o-phenylenediamine (10 mmol) was dissolved in anhydrous metha-
nol (50 mL) and the solution was thoroughly degassed by
freeze-thaw technique. To the solution were added concentrated
HCl (10 mmol) and equimolar amounts of the aldehyde and the
isocyanide. The reaction mixture was stirred in argon atmosphere
at rt for 18 h. The methanol was evaporated in vacuo. The resi-
due was partitioned between sat. aq NaHCO3 and chloroform and
the aqueous layer was further extracted with chloroform. The
combined organic extracts were dried over anhydrous MgSO4,
filtered, and concentrated in vacuo. The crude product was taken
up in dry benzene (the amount of benzene was such that the mixture
is transparent to slightly cloudy, usually e50 mL on the scale
described) and a solution of DDQ in a small amount of benzene
was added dropwise. The resulting mixture was stirred at rt for
1-3 h. The precipitate of hydroquinone was filtered off and washed
with toluene. The combined filtrate and washings were concentrated
in vacuo and the quinoxalines 4 were isolated chromatographically
(SiO2) with ethyl acetate-hexane mixtures as eluent.
1
6e: brown sticky solid; H NMR (300 MHz, d6-DMSO) δ 9.29
(s, 1H), 8.86 (s, 1H), 8.75 (d, J ) 7.9 Hz, 2H), 8.56 (d, J ) 3.8
Hz, 1H), 8.45 (d, J ) 7.9 Hz, 1H), 7.76 (s, 1H), 7.53 (m, 4H),
5.24 (t, J ) 5.3 Hz, 1H), 3.47 (t, J ) 6.0 Hz, 2H), 3.34 - 3.42 (m,
2H), 3.11 (q, J ) 6.1 Hz, 2H), 2.43 (s, 3H), 2.38 (s, 3H), 1.86 (m,
2H), 1.08 (t, J ) 6.9 Hz, 3H); 13C NMR (75 Hz, d6-DMSO) δ
147.6, 147.5, 137.0, 136.1, 134.8, 134.5, 134.4, 133.6, 133.4, 133.3,
129.9, 129.6, 127.8, 126.1, 123.7, 116.0, 95.6, 67.8, 65.4, 45.9,
29.7, 20.2, 19.3, 15.1; LCMS (M + H+) 452. Anal. Calcd for
C28H29N5O: C, 74.48; H, 6.47; N, 15.51. Found: C, 74.54; H, 6.49;
N, 15.55.
4b: gray solid, mp 143-145 °C; 1H NMR (300 MHz, CDCl3) δ
7.64 (d, J ) 5.9 Hz, 3H), 7.52 (m, 4H), 4.98 (s, 1H), 2.45 (s, 3H),
Acknowledgment. We would like to thank Dr. Alexander
Manaev of the Chemical Diversity Research Institute for his
help in obtaining X-ray crystallography data.
(17) Imidazo[1,2-a]quinoxaline fragment is present in a variety of biologically
active compounds with various types of activity, e.g.: (a) Moarbess, G.; Deleuze-
Masquefa, C.; Bonnard, V.; Gayraud-Paniagua, S.; Vidal, J.-R.; Bressolle, F.;
Pinguet, F.; Bonnet, P.-A. Bioorg. Med. Chem. 2008, 16, 6601–6610. (b)
Moarbess, G.; El-Hajj, H.; Kfoury, Y.; El-Sabban, M. E.; Lepelletier, Y.;
Hermine, O.; Deleuze-Masquefa, C.; Bonnet, P.-A.; Bazarbachi, A. Blood 2008,
111, 3770–3777. (c) Belema, M.; Bunker, A.; Nguyen, V. N.; Beaulieu, F.;
Ouellet, C.; Qiu, Y.; Zhang, Y.; Martel, A.; Burke, J. R.; McIntyre, K. W.; Pattoli,
M. A.; Daloisio, C.; Gillooly, K. M.; Clarke, W. J.; Brassil, P. J.; Zusi, F. C.;
Vyas, D. M. Bioorg. Med. Chem. Lett. 2007, 17, 4284–4289. (d) Deleuze-
Masquefa, C.; Gerebtzoff, G.; Subra, G.; Fabreguettes, J.-R.; Ovens, A.; Carraz,
M.; Strub, M.-P.; Bompart, J.; George, P.; Bonnet, P.-A. Bioorg. Med. Chem.
2004, 12, 1129–1139.
Supporting Information Available: Characterization data
for the newly synthesized compounds (4a-c, 5a-c, 6a-k) and
an X-ray crystallographic file (CIF) for compound 6f. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO900050K
J. Org. Chem. Vol. 74, No. 6, 2009 2629