A rapid and efficient method for the reduction of quinoxalines

Article abstract of DOI:10.1002/jhet.5570420546

Mono and di-substituted alkyl and aryl quinoxalines are rapidly reduced in high yield to their respective 1,2,3,4-tetrahydro-derivatives by borane in THF solution. In the case of the 2,3-di-substituted compounds, reduction is stereoselective yielding excl

Full text of DOI:10.1002/jhet.5570420546

Jul-Aug 2005
A Rapid and Efficient Method for the Reduction of Quinoxalines
1031
Andrew M. McKinney, Kevin R. Jackson, Ralph Nicholas Salvatore†
Western Kentucky University, Bowling Green, KY, 42101
University of Massachesetts Boston, Boston, MA, 02125
†ralph.salvatore@wku.edu
Elena-Maria Savrides, Mary Jane Edattel, Terrence Gavin*
Iona College, New Rochelle, NY 10801
*(tgavin@iona.edu)
Received November 9, 2004
Mono and di-substituted alkyl and aryl quinoxalines are rapidly reduced in high yield to their respective
1,2,3,4-tetrahydro-derivatives by borane in THF solution. In the case of the 2,3-di-substituted compounds,
reduction is stereoselective yielding exclusively the cis-isomers. Sodium borohydride in acetic acid also
reduces alkyl and aryl quinoxalines, but proceeds with lower yields and often produces side products.
Sodium borohydride in ethanol reduces quinoxaline and 2-methylquinoxaline in high yield; however, the
reaction is very slow, whereas 2,3-dialkyl and 2-aryl quinoxalines are not efficiently reduced by sodium
borohydride in ethanol.
J. Heterocyclic Chem., 42, 1031 (2005).
General interest in tetrahydroquinoxaline derivatives is
methanol [12] effectively reduced 1a but were accompa-
due to their biological activities. Compounds that possess
this ring system have recently been studied as potential
vasorelaxants [1], anticonvulsants [2] and anti-HIV
agents [3]. One approach to obtaining these compounds
is direct reduction of the parent quinoxalines. Classical
reagents for the conversion of quinoxalines to 1,2,3,4-
tetrahydroquinoxalines include lithium aluminum
hydride [4] and catalytic hydrogenation [4, 5]. Both
methods proceed with moderate to good yields but
require substantial purification procedures and extended
reaction times. In fact, we found a significant amount of
starting quinoxaline unconsumed by LAH even after
increasing the stipulated reaction time to six to twelve
hours. More recently, the use of titanium chloride [6] or
indium powder [7], yields mixtures of stereoisomers and
offer no experimental improvement. We were consider-
ably more intrigued by sporadic reports over the last
three decades that featured the use of various boron
reagents for the reduction of the diazine ring in the
quinoxaline system. However, results from these prior
studies were somewhat difficult to interpret. For exam-
ple, pyridine-borane in acetic acid solution at room tem-
perature after seven hours was shown to reduce 1a in
95% yield, while trimethylamine-borane was apparently
ineffective [8]. Subsequently, 2-aminopyrimidine-borane
was used for this same transformation [9] but the
reported yield was only 54%. Use of the borohydride ion
has a similar history. In 1973, Rao stated [10] that
quinoxaline was unaffected by sodium borohydride in
methanol, but showed that this reagent in acetic acid
reduced quinoxalines in moderate to good yields, in the
presence of an electron-withdrawing substituent on the
fused benzene ring. Later papers demonstrated that both
potassium borohydride in carboxylic acid media [11] and
sodium cyanoborohydride with benzyl chloroformate in
nied by, respectively, alkyaltion or acylation at nitrogen.
Scheme 1
We report herein that borane in THF rapidly converts
1a-f to 2a-f (Scheme 1). As demonstrated in Table I, the
reactions proceed in excellent yields and the reductions
involving 1c and 1f are highly stereoselective, resulting in
the syn addition of hydrogen to give 2c and 2f. We also
examined sodium borohydride as a reducing agent for 1a-f
and are now able to clarify prior ambiguities. In ethanol,
sodium borohydride slowly reduces 1a and 1b to give
excellent yields of 2a and 2b. In addition, we have
extended the procedure of Rao [10] by using sodium boro-
hydride in acetic acid to reduce simple alkyl and aryl
quinoxalines in moderate to good yields. Data for the
sodium borohydride reductions is summarized in Table II.
High yields and fast reaction times render borane-THF
a superior reagent for the transformation of 1 to 2.
Solutions of borane-THF can be generated from the
addition of iodomethane to lithium borohydride [13] and
this technique (Method A) produces products that are
indistinguishable from those obtained from commer-
cially available borane-THF solutions (Method B). In
the two cases examined (Table I) the non-optimized
yields of 2c and 2f prepared using Method A are margin-
ally higher than those obtained for the identical products

1032
A. M. McKinney, K. R. Jackson, R. N. Salvatore, E.-M. Savrides, M. J. Edattel, and T. Gavin
Vol. 42
Table I
Reduction of Quinoxalines 1a-f with BH -THF (Methods A and B)
3
1
2
+
Compound
R
R
Yield (%) [a]
M (m/z)
Mp (°C)
2a
2b
2c
2d
2e
2f
H
H
91
134 (C H N )
96-97
68-69
8
10 2
CH
CH
H
99
148 (C H N )
9 12 2
3
CH
H
88 (79) [b]
81
162 (C
210 (C
216 (C
286 (C
H N )
103-104 [c]
65-66
3
3
10 14 2
Phenyl
H N )
14 14 2
2-Thienyl
Phenyl
H
90
H
N S)
81-82
12 12
2
Phenyl
81 (74) [b]
H
N )
145-146
20 18
2
[a] isolated products from Method A, yields from Method B in parenthesis; [b] product was exclusively the cis isomer; [c] for product from Method B,
mp 109-111 °C
Table II
Reduction of Quinoxalines 1a-f with NaBH in Various Solvents
4
1
2
Compound
R
R
EtOH [a]
(% Yield)
AcOH [b]
(% Yield)
2a
2b
2c
2d
2e
3
H
CH
CH
Phenyl
2-Thienyl
Phenyl
H
H
CH
H
H
99
92
25 [c,d]
30 [d]
30 [d]
-
77
81
71 [c]
66
79
3
Addition of one equivalent of acetic acid to sodium or
lithium borohydride in ethereal solvents yields hydrogen
and either MB(OAc) or MBH(OAc) [13]. The latter was
considered to be the active reducing agent in prior studies
involving conditions similar to those described in Table II
[14]. In any case, it is obvious from the difference in stere-
3
3
4
3
Phenyl
77 [e]
[a] Method C;[b] Method D;[c] product contains both cis and trans iso-
mers;[d] estimated from product mixture by H NMR;[e] isolated
product is 3.
1
ochemical outcomes for the reduction of 1c, that NaBH in
4
glacial acetic acid is a considerably different reagent than
borane-THF. It is possible that quinoxaline is protonated
by acetic acid prior to reduction in a manner resembling
that suggested by Gribble [15] for the reduction of indole
in this medium. Like 1f in this study, the reduction of
indole was accompanied by alkylation at nitrogen when
using Method B. The high purity (> 97%) of all products
isolated from the borane-THF reductions using either
method is confirmed by GC/MS analysis with one
exception. Compound 2c, when prepared by Method A,
shows starting material to be present (ca. 10%). This
problem is not encountered when using Method B. It
should be noted, that in either case 2c is identical to cis-
1,2,3,4-tetrahydro-2,3-dimethylquinoxaline prepared by
reduction with LAH using the procedure of DeSelms and
Mosher [4].
NaBH -HOAc was used. No alkylated products are
4
formed when borane-THF is used as the reducing agent.
Reaction of 1a or 1b with sodium borohydride in ethanol
(Method C) is extremely slow, requiring five days and a
large excess of reducing agent for the complete consump-
tion of the starting material in both cases. It is not a useful
method for the reduction of 1c-e. Reaction of 1c is incom-
1
The use of sodium borohydride in acetic acid (Method
D) is complicated by the fact that reduction of 1c under
these conditions led to a mixture of stereoisomers. The
plete after five days. The H NMR spectrum indicates only
25% of the staring material is converted to products, which
include both cis and trans stereoisomers in this case.
Treatment of 1d with excess borohydride for five days
1
isomers are readily distinguished in the H NMR spec-
1
trum by the methine protons, which occur at δ 3.1
(trans) and δ 3.5 (cis). Integration of these signals indi-
cates that the mixture is predominantly composed of the
cis-isomer (87%). Moreover, reduction of 1f in acetic
acid media did not lead to 2f, but rather gave rise to 3, in
77% yield. The nonequivalence of the ethylene protons
leads to a mixture at least three components. The H NMR
spectrum shows signals characteristic of 1,2-dihydro-3-
phenylquinoxaline, 4 [16], and 2d, as well as, the starting
1
in the H NMR spectrum of this compound is presum-
ably due to slow conformational changes caused by the
bulky substituents.

Jul-Aug 2005
Communication to the Editor
1033
nmr: δ 49.5, 50.7, 114.9, 119.2, 124.2, 125.0, 126.8, 128.6, 129.2,
material. Analogous results are produced by the reaction of
1e under these conditions. We did not attempt to separate
the mixtures, nor did we attempt to use 1f as a substrate.
In conclusion, borane-THF, either generated in-situ from
iodomethane and lithium borohydride, or from commer-
cially available solutions in THF is a rapid, efficient and
stereoselective reagent for the complete reduction of the
diazine ring in the quinoxaline system.
+
+
130.0, 133.1, 145.7; ms: m/z 216 (M ), 133 (M - C H S), 97
4
3
(C H S).
5
5
Anal. Calcd. for C
H N S: C, 66.63; H, 5.59; N, 12.95.
12 12 2
Found: C, 66.26; H, 5.23; N, 12.57.
General Procedure for the Reduction of Quinoxalines Using
Sodium Borohydride in Ethanol.
Method C.
Solid sodium borohydride (2.5 mmol) was added to a stirred
mixture of the quinoxaline (1.0 mmol) in ethanol (10 ml). The
reaction was purged with nitrogen, attached to mineral oil bub-
bler and stirred for three days at ambient temperature. A second
portion of sodium borohydride (2.5 mmol) was added along with
10 ml of ethanol. The mixture was purged with nitrogen and stir-
ring was continued for an additional 2-3 days. The solvent was
evaporated and the residue partitioned between aqueous NaOH (3
M, 30 ml) and dichloromethane (15 ml). The aqueous layer was
extracted with dichloromethane (4 x 15 ml) and the combined
EXPERIMENTAL
Quinoxalines were purchased from the Aldrich Chemical Co.
and used as received with the exception of 1e which was prepared
from 2-thienylglyoxal [17] by the method of Billman [18]. NMR
spectra were obtained from a JEOL spectrometer nominally oper-
ating at 500 MHz for hydrogen and 125 MHz for carbon 13.
FTIR spectra were obtained as solutions in CH Cl using a
Nicolet Impact 400 spectrometer. Mass Spectra were obtained
using a Hewlett-Packard 5973 MSD instrument.
2
2
organic layers were dried, filtered and evaporated. The residue
1
was dissolved in CDCl and evaluated by H NMR spectroscopy.
3
General Procedure for the Reduction to 1,2,3,4-Tetrahydro-
quinoxalines (2a-f) Using Borane-THF.
Method D.
Reductions using sodium borohydride in acetic acid generally
Method A.
followed the procedure of Rao [10], but CH Cl rather than chlo-
2
2
Under a nitrogen atmosphere, iodomethane (3.1 mmol) was
added to a stirred mixture of lithium borohydride (3.4 mmol) and
anhydrous THF (5 ml) in a water bath at room temperature. After 10
minutes vigorous effervescence had completely ceased and 1 (1.0
mmol) in anhydrous THF (10 ml) was added via syringe and stirred
for 10-15 minutes. To the resulting solution, methanol (5 ml) was
added (vigorous effervescence) and the solution was stirred for an
additional 30 minutes. The solvents were evaporated and the
residue was dissolved in methanol (10 ml) and evaporated. The
residue was taken up in dichloromethane (15 ml) and aqueous
NaOH (3 M, 30 ml). After separation, the aqueous layer was thor-
oughly extracted with additional dichloromethane (4 x 15 ml). The
combined organic layers were dried with potassium carbonate, fil-
tered and evaporated. The materials obtained were either solids,
which were not further purified, or viscous oils, which crystallized
upon triturating with pentane. Compounds were then analyzed by
GC/MS and part of this data is presented in Table I. The physical
and spectroscopic properties of compounds 2a [19], 2b [20], 2c [4],
2d [16] and 2f [4] are consistent with those previously reported.
roform was used for extractions and aqueous acetic acid solutions
were made basic prior to extraction. Product identity was con-
firmed by comparison of physical and spectroscopic data with lit-
erature values.
1,4-Diethyl-2,3-diphenyl-1,2,3,4-tetrahydroquinoxaline (3).
Sodium borohydride was added in small portions to a well-
stirred solution 1f (0.232 g, 0.82 mmol) in glacial acetic acid (20
ml) at 10-15 °C until TLC (CH Cl /EtOAc, 3:1) indicated the
2
2
starting material was completely consumed. Water (80 ml) was
added and the solution was extracted with CH Cl (30 ml). The
2
2
aqueous layer was made basic with solid NaOH and extracted (3
x 15 ml). The combined organic layers were dried and the solvent
was evaporated. The residue was purified by silica gel chro-
matography (eluted with hexanes/EtOAc, 10:1) to give 0.214 g of
1
a waxy solid (77%), mp 130-133; H nmr (deuteriochloroform):
δ 0.90-1.00 (m, 6H, N-Et), 3.09-3.10 (m, 2H, N-Et), 3.37-3.38
(m, 2H, N-Et), 4.21 (s, 2H, cis CH), 6.75-7.26 (m, 14H, ArH);
13
C nmr: δ 11.0, 43.2, 64.9, 111.8, 118.0, 127.3, 127.5, 129.5,
+
+
135.2, 139.3; ms: m/z 342 (M ), 313 (M - C H ), 91 (C H ).
2
5
7 7
Method B.
Anal. Calcd. for C
H N : C, 84.17; H, 7.65; N, 8.18. Found:
24 26 2
To a stirred THF (5 ml) solution of 1 (1.0 mmol) under a nitro-
gen atmosphere in a water bath at ambient temperature was added
borane THF solution (2.5 ml, 1.0 M). After 15 minutes methanol
(5 ml) was added (vigorous effervescence) and the clear solution
was stirred for 30 minutes. Further treatment was identical to that
given above in Method A. Characterization of compounds 2c and
2d [21] prepared by this method is fully consistent with data
obtained using Method A.
C, 84.35; H, 7.35; N, 8.05.
Acknowledgement.
Partial support for this work was provided by the National
Science Foundation's Department of Undergraduate Education
through grant #0127193 and the National Science Foundation-
Kentucky EPSCoR grant #596208. In addition, the authors wish
to thank the Materials Characterization Center, Western
Kentucky University for providing elemental analysis.
1,2,3,4-Tetrahydro-2-(2'-thienyl)quinoxaline (2e).
This compound, prepared by Method A, was shown to be 97.5 %
pure by gc/ms, mp 86-87 °C; ir: NH 3390 cm ; H nmr (deuteri-
-1
1
REFERENCES AND NOTES
ochloroform): δ 3.41-3.43 (dd, 1H, trans 3-H, J = 7.5, 12.5 Hz),
3.53-3.55 (dd, 1H, cis 3-H, J = 2.9, 12.5 Hz), 3.95 (br s, 2H, N-H),
[1] Y. Matsumoto, R. Tsuzuki, A. Matssuhisa, T. Yoden, Y.
Yamagiwa, I. Yanagisawa, T. Shibanuma and H. Nohira, Bioorg. Med.
13
4.82-4.84 (dd, 1H, 2-H, J = 2.9, 7.5 Hz), 6.5-7.3 (m, 7H, ArH);
C

1034
A. M. McKinney, K. R. Jackson, R. N. Salvatore, E.-M. Savrides, M. J. Edattel, and T. Gavin
Vol. 42
Chem., 8, 393 (2000).
[2] B. Pouw, M. Nour and R. R. Matsumoto, Eur. J. Pharmacol.,
386, 181 (1999).
[3] M. Patel, R. J. McHugh Jr., B. C. Cordova, R. M. Klabe, S.
Erickson-Vitanen, G. L. Trainor and J. D. Rogers, Bioorg. Med. Chem.
Lett., 10, 1729 (2000).
[4] R. C. DeSelms and H. S. Mosher, J. Am. Chem. Soc., 82, 3762
(1960).
[5] R. C. DeSelms, R. J. Greaves and W. R. Schleigh, J.
Heterocyclic Chem., 11, 595 (1974).
Heterocyclic Chem., 16, 973 (1979).
[12] J. R. Russell, C. D. Garner and J. A. Joule, J. Chem. Soc.
Perkin Trans. I, 409 (1992).
[13] T. E. Cole, R. K. Bakshi, M. Srebnik, B. Singaram and H. C.
Brown, Organometallics, 5, 2303 (1986).
[14] P. Marchini, G. Liso and A. Reho, J. Org. Chem., 40, 3453
(1975)
[15] G. W. Gribble, P. D. Lord, J. Skotnicki, S. E. Dietz, J. T. Eaton
and J. L. Johnson, J. Am. Chem. Soc., 96, 7812 (1974).
[16] J. Figueras, J. Org. Chem., 31, 803 (1966).
[17] J. W. Watthey, T. Gavin, M. Desai, B. Finn, R. K. Rodebaugh
and S. Patt, J. Med. Chem., 26, 1116 (1983).
[6] J. Armand and K. Chekir, J. Heterocyclic Chem., 17, 1237
(1980).
[7] C. J. Moody and M. R. Pitts, M, Synlett, 1029 (1998).
[8] Y. Kikugawa, K. Saito and S. Yamada, Synthesis, 447 (1978).
[9] Y. Okamoto, T. Osawa, Y. Kurasawa, T. Kinoshita, and K.
Takagi, J. Heterocyclic Chem., 23, 1383 (1986).
[10] K. V. Rao and D. J. Jackman, J. Heterocyclic Chem., 10, 213
(1973).
[18] J. H. Billman and J. L. Rendall, J. Am. Chem. Soc., 66, 540
(1944).
[19] J. Hamer and R. E. Holliday, J. Org. Chem., 28, 2488 (1963).
[20] G. H. Fisher and H. P. Schultz, J. Org. Chem., 39, 635 (1974).
[21] For example, compound 2d was prepared by Method B in
74% yield, mp 145 °C. Anal. Calcd. for C
H N : C, 83.88; H, 6.34; N,
14 14 2
[11] J.-M. Cosmao, N. Collignon, and G. Queguiner, J.
9.78. Found: C, 83.47; H, 6.02; N, 9.37.