An unusual reaction of benzalaminoacetals in trifluoroacetic acid: Facile synthesis of 2-benzylpyrazines

Article abstract of DOI:10.1021/jo702448a

(Chemical Equation Presented) Benzalaminoacetals (1), upon refluxing with trifluoroacetic acid, lead to 2-benzylpyrazines, rather than the expected isoquinolines. This unusual reaction represents another useful way to prepare a variety of 2-benzylpyrazines from the corresponding benzaldehydes.

Full text of DOI:10.1021/jo702448a

a larger scale, due to inconsistent yields. As a measure to
improve the yield, we decided to investigate the use of reagents
alternative to concentrated sulfuric acid or PPA that could
promote the cyclization of benzalaminoacetals using 1a as a
model compound. The reagents employed in the study included
neat trifluoromethane sulfonic acid, propionic acid, acetic acid,
and trifluoroacetic acid. While trifluoromethane sulfonic acid
afforded unidentified tarry material, anhydrous acetic acid and
propionic acid were found to be inefficient in promoting the
cyclization, even at refluxing temperatures. To our surprise,
when neat trifluoroacetic acid was employed as the cyclization
medium, benzylpyrazine 2a was isolated instead of the expected
isoquinoline 3a. This result drew our attention to the reaction
mechanism and its application in the synthesis of substituted
pyrazines.
An Unusual Reaction of Benzalaminoacetals in
Trifluoroacetic Acid: Facile Synthesis of
2-Benzylpyrazines
John Kallikat Augustine,*,†,‡ Yanjerappa Arthoba Naik,‡
Ashis Baran Mandal,† and Umesha Kundapur†
Syngene International Ltd., Biocon Park, Plot Nos. 2 and 3,
Bommasandra IV Phase, Jigani Link Road, Bangalore 560 100,
India, and Department of Chemistry, KuVempu UniVersity,
Shankaraghatta Post, Shimoga 577 451, India
john.kallikat@syngeneintl.com
ReceiVed NoVember 15, 2007
In initial studies, we treated the Schiff’s base 1a with an
excess (10 equiv) of neat trifluoroacetic acid at reflux for 25
min and obtained 2a and 4-isopropyl benzaldehyde in equimolar
quantities. Intrigued by this result, we examined the reaction
under various conditions to optimize the reaction. The employ-
ment of solvent-free conditions proved to be particularly
convenient; for instance, when the experiment of entry 1 (Table
1) was repeated in dichloromethane (25 mL) with an excess of
CF3COOH (10 equiv) at reflux, 13 h were required for the
Benzalaminoacetals (1), upon refluxing with trifluoroacetic
acid, lead to 2-benzylpyrazines, rather than the expected
isoquinolines. This unusual reaction represents another useful
way to prepare a variety of 2-benzylpyrazines from the
corresponding benzaldehydes.
The structural diversity and biological importance of nitrogen-
containing heterocycles have made them attractive targets for
synthesis over many years. They are found in various natural
products and have been identified as products of chemical and
biological importance.1 In the course of our studies directed
toward the synthesis of nitrogen-containing heterocycles as
pharmaceutical intermediates, we were in need of several
isoquinoline analogues. To this end, we had occasion to explore
the Pomeranz-Fritsch isoquinoline synthesis, wherein an
aromatic aldehyde is condensed with aminoacetaldehyde dim-
ethyl acetal to Schiff’s base, which is further cyclized in the
presence of sulfuric acid or polyphosphoric acid (PPA) to
provide the isoquinoline.2
However, the Pomeranz-Fritsch reaction is substrate de-
pendent. Electron-donating substituents on the substrate are
found to accelerate the isoquinoline formation, while electron-
withdrawing groups retard the reaction. The yields with methoxy
as substituents are reported to be good, while with the nitro
group, oxazoles are produced as byproduct.3 In our hands, we
found this reaction sequence to be problematic, particularly on
1
complete conversion of 1a as confirmed by H NMR of the
crude reaction mixture. Similarly, when toluene at reflux was
employed as the reaction medium in place of dichloromethane,
11 h were required for the complete disappearance of 1a. Under
solvent-free conditions, we examined the reaction by decreasing
the amount of CF3COOH in a step-by-step approach. This
experimentation revealed that reducing the trifluoroacetic acid
to a stoichiometric amount (4 equiv) was also effective in
providing the pyrazine 2a without any loss of yield.4
Next, we studied the outcome of this reaction in various acids
under solvent-free conditions. A side-by-side comparison of
trifluoroacetic acid, trichloroacetic acid, tribromoacetic acid,
methanesulfonic acid, acetic acid, and formic acid was carried
out with 1a as a test compound. The results are depicted in
Table 2. While the reaction of 1a in anhydrous trichloroacetic
acid afforded 2a in 44% yield in 2 h, the reaction was too
sluggish in anhydrous tribromoacetic acid, even at elevated
temperatures. Formic acid and methane sulfonic acid failed to
produce 2a, rather providing 4-isopropylbezaldehyde due to the
decomposition of 1a. Anhydrous trifluoroacetic acid was found
to be the most suitable reaction medium to yield 2-benzylpyra-
zines in good yields.
* Address correspondence to this author. Phone: +91 80 2808 3131. Fax:
+91 80 2808 3150.
† Syngene International Ltd., Bangalore 560 100.
Apparently, the formation of pyrazine 2a was mediated by
CF3COOH. With the optimal reaction conditions in hand,
‡ Kuvempu University.
(1) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R. Heterocycles
in Life and Society; John Wiley and Sons: Chichester, UK, 1997.
(2) (a) Pomeranz, C. Monatsch. Chem. 1894, 15, 299. (b) Fritsch, P.
Chem. Ber. 1893, 26, 419. (c) Gensler, W. J. Org. React. 1951, 6, 191-
206. (d) Bobbitt, J. M.; Roy, D. N.; Marchand, A.; Allen, C. W. J. Org.
Chem. 1967, 32, 2225-2227.
(3) (a) Cass, W. E. J. Am. Chem. Soc. 1942, 64, 785. (b) Brown, E. V.
J. Org. Chem. 1977, 42, 3208.
(4) The reaction did not proceed at room temperature even after 6 h
with stirring.
10.1021/jo702448a CCC: $40.75 © 2008 American Chemical Society
Published on Web 01/10/2008
1176
J. Org. Chem. 2008, 73, 1176-1179

TABLE 1. Synthesis of 2-Benzylpyrazines from Benzalaminoacetals
a Substrates are prepared from the commercial aldehydes by refluxing with aminoacetaldehyde dimethyl acetal in toluene. b Isolated by column
chromatography. c Yields are calculated relative to the theoretical yield of benzylpyrazines. d The acetylene group is hydrated under acidic conditions to the
acetyl group.
J. Org. Chem, Vol. 73, No. 3, 2008 1177

TABLE 2. Comparison of Efficiency of Various Acids in
Promoting 1a into 2a
SCHEME 1. Proposed Mechanism of the Reaction between
Two Molecules of Schiff’s Base in Trifluoroacetic Acid to
Produce 2-Benzylpyrazine
yield of
2a (%)
entry
solventa
temp (°C)
time (h)
1
2
3
4
5
6
7
CF3COOH
CCl3COOH
CBr3COOH
MeSO3H
HCOOH
AcOH
75
75
0.5
2
2
0.5
0.5
3
90
44
125
100
100
100
100
17b
0c
0c
NRd
47e
H2SO4
0.5
a Anhydrous acids (4-5 equiv) were used as solvent. b 4-Isopropylben-
zaldehyde was the major byproduct. c 4-Isopropylbenzaldehyde was the only
product isolated. d No reaction. e Isolated as isoquinoline 3a.
subsequently, we investigated the scope of this reaction. Various
benzalaminoacetals (1b-p) were subjected to the reaction under
the standard conditions to obtain corresponding 2-benzyl
pyrazines in good yields. We now wish to report that such a
transformation is general in scope among the reactions we
examined and the results are summarized in Table 1.
In general, the treatment of benzalaminoacetals 1 with neat
trifluoroacetic acid (4-5 equiv) at reflux for 20-40 min affords
2-benzylpyrazines in good yields (Table 1), while sulfuric acid
provides isoquinolines. The aldimines could be readily obtained
on refluxing the corresponding aldehydes with aminoacetalde-
hyde dimethyl acetal in toluene under a Dean-Stark trap.5 As
illustrated in Table 1, pyrazines are formed mostly in good yields
and electron-withdrawing or electron-donating groups on the
substrate did not affect the yield of benzylpyrazine. From Table
1, we can discern that this reaction tolerated a wide scope of
functional groups, such as alkyl, nitro, halo, cyano, carboxylate,
methoxy, trifluoromethyl, hydroxy, allyloxy, and substituted
amine (entry 15, Table 1), and provided the corresponding
pyrazines in moderate to good yields. A substrate possessing
an acetylene group on the ring (entry 10, Table 1) provided the
corresponding acetophenone due to hydration of the acetylene
group under acidic conditions.6 Thus, compound 1j afforded
exclusively 2j, along with the byproduct 4-formyl acetophenone.
As evidenced by us, the byproduct of this reaction was the
corresponding aromatic aldehyde, which was found in equimolar
quantities relative to the pyrazine as observed by the 1H NMR
of the crude reaction mixture. This observation suggested that
two molecules of Schiff’s base were involved in the reaction
to produce 1 mol of 2-benzylpyrazine and aldehyde. Conse-
quently, a postulate for the formation of 2-benzylpyrazines is
outlined in Scheme 1. The first step of the reaction is initiated
by trifluoroacetic acid to produce enol 3. Addition of the enol
3 to a second molecule of enol gives the self-condensation
species 4. The dimerization of 3 into 4 is probably acid
catalyzed, where protonation of the nitrogen atom of the
electrophile facilitates the nucleophilic attack. The sequential
loss of a molecule of aldehyde and water provides 7. The
protonation of the NH-group in 7 will facilitate the breakdown
of the C-N bond with double bond rearrangement and expulsion
of a proton from the OH-group to form 8. Finally, 8 undergoes
ring closure to provide 2-benzylpyrazine 10. The formation of
2-benzylpyrazine is spontaneous and we did not find any of
the postulated intermediates by LCMS or 1H NMR of the crude
reaction mass during the progress of reaction. However, we
found starting material, benzylpyrazine, and byproduct benzal-
dehyde by H NMR. This indicates that as soon as the acetal
protection is lost, the intermediate undergoes self-dimerization
to afford benzylpyrazine.
1
In conclusion, an unusual reaction for the synthesis of
2-benzylpyrazines from benzalaminoacetals is unveiled. This
novel finding provides an interesting insight into the effect of
trifluoroacetic acid on the reaction outcome and represents
another useful way to prepare 2-substituted pyrazines, since the
starting materials are readily available. Furthermore, substituted
pyrazines are extremely useful intermediates in the pharmaceuti-
cal and food industry. Further application of this reaction for
the construction of substituted pyrazines from ketones and
(5) For a general procedure, see: (a) Perchonock, C. D.; Lantos, I.;
Finkelstein, J. A.; Holden, K. A. J. Org. Chem. 1980, 45, 10, 1950-1953.
(b) Abramovitch, R. A.; Struble, D. L. Tetrahedron 1968, 24, 705-716.
(6) Modena, G.; Rivetti, F.; Scorrano, G.; Tonellato, U. J. Am. Chem.
Soc. 1977, 99, 3392-3395.
1178 J. Org. Chem., Vol. 73, No. 3, 2008

oil. This compound was immediately used in the next step without
any further purification.
heteroaromatic and aliphatic aldehydes is underway in our
laboratory and will be reported in due course.
Representative Procedure for the synthesis of 2-Benzylpyra-
zines from Benzalaminoacetals. A mixture of 1a (15.2 g, 0.064
mol) and CF3COOH (29 g, 0.254 mol) was heated to 75 °C under
nitrogen atmosphere for a given period of time (entry 1, Table 1).
The completion of reaction was confirmed by TLC. Upon comple-
tion of reaction, we found only two products on TLC (10% EtOAc/
hexane). The polar compound corresponds to benzylpyrazine. The
brown reaction mixture was concentrated under vacuum and the
residue was diluted with CH2Cl2 (100 mL) and washed with a
saturated solution of sodium bicarbonate (2 × 20 mL) and water
(2 × 25 mL) and dried over sodium sulfate. The organic phase
was evaporated under vacuum and the residue was directly loaded
onto a silica gel column. Eluting with 5% ethyl acetate in hexanes
afforded 6.2 g (90%) of 2-(4-isopropylbenzyl)pyrazine 2a as a
yellow oil.
Experimental Section
General. 1H NMR and 13C NMR spectra were recorded on 400-
MHz and 100-MHz Bruker spectrometers, respectively. Elemental
analysis was performed on a Thermo Finnigan FLASH EA 1112
CHN analyzer. Melting points were recorded (uncorrected) on a
Buchi Melting Point B-545 apparatus. All the substrates (1a-p)
were synthesized in-house from the corresponding commercially
available aldehydes by refluxing with aminoacetaldehyde dimethyl
acetal on a Dean-Stark setup with toluene as the solvent. The crude
benzalaminoacetals were immediately used in the next reaction
without further purification. The products were characterized by
1H NMR, 13C NMR, LCMS, and elemental analysis. The structure
of compound 2b was further confirmed by single-crystal X-ray
analysis (see the Supporting Information).
Representative Procedure for the Synthesis of Benzalami-
noacetals from Benzaldehydes. A mixture of 4-isopropylbenzal-
dehyde (10 g, 0.067 mol) and aminoacetaldehyde dimethyl acetal
(7.75 g, 0.073 mol) in toluene (100 mL) was refluxed under a
Dean-Stark trap with azeotropic removal of water for 4 h. The
reaction was monitored by TLC (10% EtOAc/hexane). The solvent
was removed under vacuum to give N-[(4-isopropylphenyl)-
methylene]-2,2-dimethoxyethanamine7 1a (15.2 g, 96%) as a yellow
Acknowledgment. The authors thank Dr. Suresh Joghee and
Dr. Sathya Shanker for helpful discussions and gratefully
acknowledge Dr. Goutam Das, COO, Syngene International Ltd
for his invaluable support.
Supporting Information Available: 1H NMR and 13C NMR
and LCMS report for compounds 2a-p, single-crystal X-ray report
(CIF and ORTEP) for compound 2b, and 1H NMR for new
substrates 1d, 1h, and 1i-p. This material is available free of charge
via the Internet at http://pubs.acs.org.
(7) Applied Research Systems, patent WO2007/48788, 2007; Appl. No.
WO2006-EP67713.
JO702448A
J. Org. Chem, Vol. 73, No. 3, 2008 1179