Regioselective double Boekelheide reaction: First synthesis of 3,6-dialkylpyrazine-2,5-dicarboxaldehydes from dl-alanine

Article abstract of DOI:10.1016/j.tetlet.2012.05.057

Pyrazine-2,5-dicarboxaldehyde was synthesized on a multi-gram scale by MnO₂ oxidation of 2,5-bis(hydroxymethyl)pyrazine, which in turn was obtained from 2,5-dimethylpyrazine employing double Boekelheide reaction as a key step as reported previously. This reaction was subsequently utilized in a regioselective fashion as a key step to synthesize efficiently, for the first time, 3,6-di(long-chain)alkylpyrazine-2,5-dicarboxaldehydes starting from dl-alanine. These monomers are certain to have importance as electron deficient and chemically versatile components for new materials development.

Full text of DOI:10.1016/j.tetlet.2012.05.057

Tetrahedron Letters 53 (2012) 3869–3872
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regioselective double Boekelheide reaction: first synthesis of
3,6-dialkylpyrazine-2,5-dicarboxaldehydes from DL-alanine
⇑
⇑
Sajal Kumar Das , Joseph Frey
Department of Chemistry and Institute for Nanotechnology and Advanced Materials, Bar Ilan University, Ramat Gan 52900, Israel
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 March 2012
Revised 7 May 2012
Accepted 11 May 2012
Available online 17 May 2012
Pyrazine-2,5-dicarboxaldehyde was synthesized on a multi-gram scale by MnO2 oxidation of 2,5-
bis(hydroxymethyl)pyrazine, which in turn was obtained from 2,5-dimethylpyrazine employing double
Boekelheide reaction as a key step as reported previously. This reaction was subsequently utilized in a
regioselective fashion as a key step to synthesize efficiently, for the first time, 3,6-di(long-chain)alkylpyr-
azine-2,5-dicarboxaldehydes starting from DL-alanine. These monomers are certain to have importance as
electron deficient and chemically versatile components for new materials development.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Aromatic dialdehydes
Conjugated systems
Pyrazine dialdehydes
Boekelheide reaction
Regioselective
Aromatic or heteroaromatic dialdehydes have been at the fore-
front of material science research due to the broad synthetic scope
of aldehyde chemistry. Specifically, these bifunctional intermedi-
ates can serve as key precursors for making conjugated oligo-
and polymers utilizing Wittig or Horner–Wadsworth–Emmons
olefination, Knoevenagel condensation, Corey–Fuchs alkynation,
and imine formation reaction.1 Also, their use in the syntheses of
conjugated systems containing benzimidazole, benzoxazole, and
benzothiazole are well documented in the literature.2 They have
also recently been used to prepare non-conjugated poly(benzo-
ins).3 While these applications are diverse, the majority of dialde-
hydes constitute only limited range of families. Classic examples
include the extensively studied and widely used benzene-1,4-dial-
dehydes4 and thiophene-2,5-dialdehydes.5 To the best of our
knowledge, there is no research involved in the design, synthesis,
and applications of 3,6-di(long-chain)alkylpyrazine-2,5-carboxal-
dehydes.6 On the other hand, the presence of an electron deficient
azaheterocycle ring like pyrazine in a conjugated backbone can
significantly change the polymer property.7 However, due to the
difficulty in preparing functionalized pyrazine monomers, materi-
als containing pyrazine in the conjugated chain have been scarcely
reported.8 In this Letter, we report the synthesis of pyrazine-2,5-
dicarboxaldehydes 1 and 20a–c (Fig. 1) which is certain to have
importance as electron deficient and chemically versatile compo-
nents for materials development.
N
N
OHC
R
R
CHO
1
20a
R = H ( ), n-hexyl ( ), n-octyl (20b) and 2-ethylhexyl (20c)
Figure 1. Pyrazine-2,5-dicarboxaldehydes 1 and 20a–c.
We first focused on the synthesis of the known dialdehyde, that
is, pyrazine-2,5-dicarboxaldehyde 1. The synthesis of 1 has been
accomplished by two different routes; one was by the vapor phase
catalytic oxidation of 2,5-dimethylpyrazine9 and the other method
utilized ozonolysis of 2,5-distyrylpyrazine (Scheme 1).10 However,
both these methods are difficult to conduct at a laboratory viable
level particularly on large scale. Additional disadvantages of these
two methods are unwanted formation of 5-methylpyrazine-2-car-
boxaldehyde, commercial unavailability and instability of 2,5-
distyrylpyrazine, and more importantly, the tedious isolation of
highly water soluble 1 from aqueous solution.
Our initial attempts to obtain 1 by LAH or DIBAL reduction of
diester 4 or diamide 5 were unsuccessful (Scheme 1).
A possible explanation might be that a highly electron deficient
pyrazine ring is normally susceptible to nucleophilic attack. This
effect is even more pronounced in the presence of the two electron
withdrawing groups, resulting in the formation of mainly by-prod-
ucts with reduced pyrazine ring or the decomposition of starting
materials. Consequently, we chose to synthesize 2,5-bis(hydroxy-
methyl)pyrazine 6 (Scheme 2) which could be oxidized to 1. Syn-
thesis of compound 6 was reported more than 50 years ago11 but
⇑
Tel.: +972 3 531 7682; fax: +972 3 738 4053.
E-mail addresses: sajalkdas@gmail.com (S.K. Das), Joseph.Frey@biu.ac.il (J. Frey).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.057

3870
S. K. Das, J. Frey / Tetrahedron Letters 53 (2012) 3869–3872
N
It is a well known fact that for better solubility of oligomers and
OHC
N
V2O5, MoO3
oxidation
polymers in common organic solvents, the monomer must contain
long-chain alkyl groups. Commonly used alkyl groups are n-hexyl,
n-octyl, 2-ethylhexyl etc. So, we then turned our attention to syn-
thesize 3,6-di(long-chain)alkylpyrazine-2,5-dicarboxaldehydes. In
1999, Zhang and Tour synthesized 3,6-diodopyrazine-2,5-diketals
by neopentylketal-directed lithiation of pyrazine ring.13 In this
context, we were very much interested to synthesize a similar
compound, namely, 3,6-diodopyrazine-2,5-di(neopentyl)acetal 10
(Scheme 3) as the subsequent introduction of two long chain alkyl
groups on the pyrazine ring was planned to achieve by Kumada
coupling strategy. Toward that objective, dialdehyde 1 was first
treated with neopentyl glycol in a refluxing benzene–acetonitrile
solvent system in the presence of a catalytic amount of TsOH to
furnish diacetal 9 in good yield. Unfortunately, crystalline com-
pound 9 was completely insoluble in THF and ether at low temper-
ature and hence, Tour’s reaction condition of diodination of
pyrazine nucleus by LTMP mediated lithiation did not work in
our case. We could recover almost all the unreacted starting mate-
rial and running the reaction from 0 °C to rt resulted in complete
decomposition of 9.
As the above route for the synthesis of 3,6-di(long-chain)alkyl-
pyrazine-2,5-carboxaldehydes was unsuccessful, we then turned
our attention again to the double Boekelheide reaction strategy
for which synthesis of 3,6-dimethyl-2,5-di(long-chain)alkylpyra-
zines was essential. Toward that objective, DL-alanine 12 was con-
verted into the corresponding Weinreb amide 14 following a
reported two-step reaction sequence (Scheme 4).14 Next, addition
of freshly prepared n-hexylmagnesium bromide to 14 at 15–
20 °C in dry THF provided ketone 15a in high yield. It is very impor-
tant to mention that there was no reaction at À78 °C and negligible
conversion took place at 0 °C. Ketones 15b,c were similarly synthe-
sized. When ketones 15a,b were subjected to standard hydrogena-
tion reaction using hydrogen balloon and 10% Pd-C, the products
were surprisingly the corresponding pyrazine derivatives 16a–b
N
2
N
(10%)
CHO
1
N
ozonolysis
1
(30%)
N
3
O
O
N
N
N
N
MeO
LiAlH4 or
DIBAL-H
N
O
O
N
or
1
X
OMe
O
O
5
4
Scheme 1. Literature synthetic routes and our initial unsuccessful attempts to 1.
surprisingly, to the best of our knowledge, there is no precedence
for the synthesis of 1 by using this approach.
The synthesis starts from the commercially available 2,5-
dimethylpyrazine 2 which we treated with m-CPBA in ethyl ace-
tate to furnish corresponding N,N-dioxide derivative 6 in 90% yield.
Isolation of the pure product by mere filtration of the reaction mix-
ture prompted us to choose m-CPBA over the literature known
H2O2–AcOH system in this reaction. Next, heating a suspension
of 6 in acetic anhydride at 158 °C for 7 h resulted in a diacetate
derivative 7 in 20% yield. The reaction was run for a longer time
to minimize the formation of the monoacetate product in this dou-
ble Boekelheide reaction,12 and by a modified work-up of the crude
product, the yield of the reaction was improved slightly. The low
product yield in this reaction was due to the formation of large
amount of black polymeric materials.12 Nevertheless, the reaction
on large scale could provide multi-gram quantities of 7.
Next, deacetylation of 7 by NaOMe in dry methanol afforded
compound 8 in high yield. This compound is highly polar and insol-
uble at low or room temperature in all the organic solvents which
are generally used for alcohol to aldehyde oxidation reactions.
However, activated MnO2 could effectively oxidize compound 8
into 1 in dry 1,4-dioxane at 96 °C. This reaction was high yielding
(85%) and did not produce any side product; thus enabling the iso-
lation of the pure product just by filtration of the reaction mixture.
Although, the synthesis of dialdehyde 1 from 2 is a four-step
reaction sequence with an overall yield of 8%, it has several notice-
able advantages. First, all the steps were operationally very simple,
reproducible and could be performed on a large scale and multi-
gram quantities of dialdehyde 1 were easily accessible from a
single batch. Second, two of the synthetic steps produced pure
reaction products which did not require column chromatography.
And most importantly, water soluble 1 was isolated very easily un-
der anhydrous condition.
rather than simple a-amino-ketone derivatives. The reactions were
very clean and we could not detect any intermediate compounds
despite close monitoring by TLC. However, hydrogenation of ke-
tone 15c provided mainly the corresponding
a-amino-ketone
derivative which was then kept in open flask for 12 h to get pyra-
zine 16c in moderate yield. In this case, the presence of ethyl side
group might have put some difficulty in the auto-condensation
reaction. Pyrazines 16a–c were then converted to corresponding
N,N-dioxide derivatives 17a–c by treating with m-CPBA in high
yields.
With compound 17a–c in hand, the stage was then set for dou-
ble Boekelheide reaction. It is well known that acetoxylation in the
Boekelheide rearrangement of N-oxides of pyridine or pyrazine
derivatives can take place both at methyl and methylene carbons
attached to the heterocyclic rings. Thus, tetraalkylpyrazine-N,N-
dioxides 17a–c have four Boekelheide rearrangement sites which
O
OAc
N
N
O
N
N
(i) Ac2O, 158 °C, 7 h
m-CPBA, EtOAc
rt, 24 h
(ii) rt, 12 h
20%
6
N
N
OAc
90%
2
7
OH
OHC
N
N
N
NaOMe, dry MeOH
rt, 3 h
MnO2, dry 1,4-dioxane
96 C, 45 min
°
CHO
N
8
94%
1
OH
85%
Scheme 2. Synthesis of pyrazine-2,5-carboxaldehyde 1.

S. K. Das, J. Frey / Tetrahedron Letters 53 (2012) 3869–3872
3871
in this case also, we note the substantial contribution of the alkyl
chains to the successful outcome of this synthetic step as we con-
sider the limiting low reaction yield in the corresponding reaction
of the parent pyrazine system 6. Similarly, compound 17b–c fur-
nished the corresponding diacetates 18b–c without the formation
of undesired isomeric products. Next, 3,6-di(long-chain)alkylpyr-
azine-2,5-dicarboxaldehydes 20a–c was obtained by deacetylation
of 18a–c and MnO2 oxidation of the resulting alcohols 19a–c. Dial-
dehydes 20a–c could be synthesized on gram scale from a single
batch and stored for long time without decomposition in the free-
zer in N2 flushed container.
Next, we were very much interested to explore the reactivity of
dialdehydes 20a–c in Wittig olefination as we were very much
curious about the tolerance of the highly electron deficient pyra-
zine ring to strong basic and nucleophilic reaction conditions pres-
ent in the Wittig reaction. Toward this direction, phosphonium
salt15 21 (4.0 equiv) was treated with potassium tert-butoxide
(3.0 equiv) in dry THF at 0 °C to generate the corresponding ylide
which was subsequently reacted with aldehyde 20a (Scheme 7).
We were pleased to see that the reaction led to the formation of
the desired diolefin compound 22 in moderate yield.
O
(i) LTMP, THF-ether,
-78 °C
N
Neopentyl glycol,
O
1
O
O
(ii) I /THF, -25 C
°
TsOH, benzene-MeCN,
reflux, overnight,
2
N
O
9
(70%)
O
O
R
RMgX
N
I
N
R
O
O
Kumada coupling
O
O
I
N
N
11
10
O
Not formed
Scheme 3. Attempted synthesis of diacetal 10.
raise the issue of regioselectivity (Scheme 5). For example, com-
pound 17a on heating with acetic anhydride might produce four
possible products. In order to obtain 18a, Boekelheide rearrange-
ment of 17a must occur regioselectively on two methyl groups.
To know the outcome, compound 17a was heated at 158 °C for
7 h in acetic anhydride and we were delighted to see that the reac-
tion led to the formation of the desired product 18a in 45% yield
(Scheme 6). The product was easily isolated by column chromatog-
raphy and recrystallization. The absence of any signal correspond-
ing to methyl groups on the pyrazine ring in the 1H NMR of the
crude product confirmed the formation of 18a as the sole
Boekelheide rearrangement product. Although, there was forma-
tion of a significant amount of brown colored polymeric material
It is very important to mention that the phosphonium salt was
taken in excess to ensure the complete consumption of base. We
observed that the presence of excess base resulted in lower yield
of 22 possibly due to cleavage of the pyrazine ring. Compound
22, related diene compounds, and other triblock monomers which
could be synthesized easily from 20a–c should be useful in the
synthesis of several donor–acceptor copolymers incorporating
pyrazine acceptor and well-known donors like thiophene,
CbzHN
O
NHCbz
NH2
CO2H
Cbz-Cl, Na2CO3
MeNHOMe.HCl, EDC
N
CO2H
(95%)
THF-H2O, 0 °C-rt, 2 h
anh.Et3N, dry CH2Cl2,
0 °C-rt, 5 h
O
13
12
14 (94%)
(i) H2, 10% Pd-C, 6 h
CbzHN
R
N
N
RMgBr, dry THF
0-20 oC, 10 h
EtOAc (for 16a-c)
m-CPBA
R
(ii) air, overnight (for 16c)
EtOAc, rt,
24 h
R
O
15a (92%),
16a
16b
(75%),
(75%)
15b
15c
(94%
(90)%
O
16c (56%)
R
N
N
O
R =
n-hexyl
(a)
n-octyl
(b)
2-ethylhexyl
17a
17b
17c
(91%),
(93%)
(92%)
R
(c)
Scheme 4. Synthesis of 3,6-dimethyl-2,5-di(longchain)alkylpyrazine-N,N-dioxides 17a–c.
N
AcO
R
R
OAc
O
N
N
18a
R
Ac2O, heat
R = n-pentyl
desired product
R
OAc
R
N
OAc
N
OAc
R
N
N
N
AcO
R
R
O
R
N
R
17a
N
OAc
OAc
undesired products
Scheme 5. Probable products in the Boekelheide rearrangement of 17a.

3872
S. K. Das, J. Frey / Tetrahedron Letters 53 (2012) 3869–3872
OAc
OH
N
R
(i) Ac2O, 158 °C, 7 h
(ii) rt, 12 h
NaOMe, dry MeOH
rt, 3 h
N
N
R
17a-c
R
N
R
OAc
18a
OH
(45%)
19a (98%)
19b (96%)
19c (97%)
18b (42%)
18c (43%)
OHC
R
N
N
R
MnO2, dry 1,4-dioxane
96 °C, 45 min
CHO
20a
(88%)
20b (85%)
20c (83%)
R =
n-hexyl
(a)
n-octyl
(b)
2-ethylhexyl
(c)
Scheme 6. Synthesis of 3,6-di(long-chain)alkylpyrazine-2,5-carboxaldehydes 20a–c.
(i) KOBut, THF, 0 oC
Supplementary data
PPh3Br
20a
(ii)
Br
S
21
Supplementary data (experimental procedures, copies of 1H and
13C NMR spectra of all new compounds) associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.05.057.
Br
N
N
S
S
Br
References and notes
22
(55%)
1. (a) Grimsdale, A. C.; Chan, K. L.; Martin, R. E.; Jokisz, P. G.; Holmes, A. B. Chem.
Rev. 2009, 109, 897; (b) Cheng, Y. J.; Yang, S. H.; Hsu, C. S. Chem. Rev. 2009, 109,
5868.
Scheme 7. Wittig olefination of 20a leading to 22.
2. (a) Rabbani, M. G.; El-Kaderi, H. M. Chem. Mater. 2011, 23, 1650. and references
cited therein.; (b) Ebara, K.; Shibasaki, Y.; Ueda, M. J. Polym. Sci., Part A: Polym.
Chem. 2002, 40, 3399; (c) United States Patent 3681297, 1972.
3. Pinaud, J.; Vijayakrishna, K.; Taton, D.; Gnanou, Y. Macromolecules 2009, 42,
4932.
4. For some recent examples, see: (a) Makowski, B. T.; Lott, J.; Valle, B.; Singer, K.
D.; Weder, C. J. Mater. Chem. 2012, 22, 5190; (b) Nguyen, T. H.; Zhang, C.; Li, R.;
Sun, S. S. J. Polym. Sci., Part A: Polym. Chem. 2012, 50, 1197; (c) Lloveras, V.;
Gancedo-Vidal, J.; Figueira-Duarte, T. M.; Nierengarten, J. F.; Novoa, J. J.; Mota,
F.; Ventosa, N.; Rovira, C.; Veciana, J. J. Am. Chem. Soc. 2011, 133, 5818; (d)
Zhang, W.; Zhu, L.; Qin, J.; Yang, C. J. Phys. Chem. B 2011, 115, 12059; (e) Bounos,
G.; Ghosh, S.; Lee, A. K.; Plunkett, K. N.; DuBay, K. H.; Bolinger, J. C.; Zhang, R.;
Friesner, R. A.; Nuckolls, C.; Reichman, D. R.; Barbara, P. F. J. Am. Chem. Soc.
2011, 133, 10155.
5. For some recent examples, see: (a) Speros, J. C.; Paulsen, B. D.; White, S. P.; Wu,
Y.; Jackson, E. A.; Slowinski, B. S.; Frisbie, C. D.; Hillmyer, M. A. Macromolecules
2012, 45, 2190; (b) Barik, S.; Bletzacker, T.; Skene, W. G. Macromolecules 2012,
45, 1165; (c) Franco, S.; Garin, J.; Martinez, P. T. R.; Orduna, J.; Yu, Y.; Lira-Cantu,
M. Org. Lett. 2012, 14, 752; (d) Delgado, P. A.; Liu, D. Y.; Kean, Z.; Wagener, K. B.
Macromolecules 2011, 44, 9529; (e) Mike, J. F.; Nalwa, K.; Makowski, A. J.;
Putnam, D.; Tomlinson, A. L.; Chaudhary, S.; Jeffries-El, M. Phys. Chem. Chem.
Phys. 2011, 13, 1338.
6. 3,6-Dimethylpyrazine-2,5-dicarboxaldehyde was synthesized by SeO2
oxidation of tetramethylpyrazine. Schumann, H.; Luo, H. K. Zeit für
Naturforsch. B: Chem. Sci. 2005, 60, 22.
7. (a) Hebbar, N.; Fiol-Petit, C.; Ramondenc, Y.; Ple, G.; Ple, N. Tetrahedron 2011,
67, 228; (b) Saito, R.; Matsumura, Y.; Suzuki, S.; Okazaki, N. Tetrahedron 2010,
66, 8273; (c) Tian, Y. H.; Kertesz, M. Macromolecules 2009, 42, 2309.
8. Pieterse, K.; Lauritsen, A.; Schenning, A. P. H. J.; Vekemans, J. A. J. M.; Meijer, E.
W. Chem. Eur. J. 2003, 9, 5597. and references cited therein.
9. Kastron, V. V.; Iovel, I. G.; Skrastins, I.; Gol’dberg, Yu. Sh.; Shymanskaya, M. V.;
Dubur, G. Ya. Khim. Geterotsikl. Soedin. 1986, 8, 1124.
10. Stadler, A. M.; Puntoriero, F.; Campagna, S.; Kyritsakas, N.; Welter, R.; Lehn, J.
M. Chem. Eur. J. 2005, 11, 3997.
ethylenedioxythiophene, dialkoxylphenylene, carbazole, phenothi-
azine etc. utilizing Suzuki and Sonogashira coupling reactions. In
this communication while we describe the first synthesis of
3,6-dialkyl-2,5-pyrazinedicarboxaldehydes and monomer 22, our
future efforts will be in the applications of 22 and related mole-
cules in organic materials.
In summary, we have synthesized pyrazine-2,5-dicarboxalde-
hyde on
a multi-gram scale by MnO2 oxidation of 2,5-
bis(hydroxymethyl)pyrazine, which in turn was obtained from
2,5-dimethylpyrazine employing double Boekelheide rearrange-
ment as a key step as reported previously. Subsequently, 3,6-di
(long-chain)alkylpyrazine-2,5-dicarboxaldehydes were synthe-
sized starting from DL-alanine by utilizing the Boekelheide reac-
tion in a regioselective fashion. Special features of the synthetic
route are the ease of the reaction sequence and the cheap com-
mercial availability of the starting materials. Despite having
attractive symmetry in 2,5-disubstituted pyrazines, they have
been somewhat neglected in polymer science due to the difficulty
in preparing functionalized pyrazines. It is anticipated that this
new family of monomers will find applications as electron defi-
cient and chemically versatile components for new materials
development. Work in this direction is currently in progress and
will be published in the future. In addition, functionalized diazinyl
heterocycles have been widely used to synthesize a large number
of biologically important molecules; therefore, the new synthetic
strategies described here would likely have applications far be-
yond the scope of material science.
11. Koelsch, C. F.; Gumprecht, W. H. J. Org. Chem. 1958, 23, 1603.
12. Klein, B.; Berkowitz, J.; Hetman, N. E. J. Org. Chem. 1961, 26, 126.
13. Zhang, C. Y.; Tour, J. M. J. Am. Chem. Soc. 1999, 121, 8783.
14. Kano, S.; Yokomatsu, T.; Iwasawa, H.; Shiroshi, S. Chem. Pharm. Bull. 1988, 36,
3341.
Acknowledgments
15. Yang, F.; Xu, X. L.; Gong, Y. H.; Qiu, W. W.; Sun, Z. R.; Zhou, J. W.; Audebert, P.;
Tang, J. Tetrahedron 2007, 63, 9188.
This work was supported by the Israel Science FoundationGrant
No. 1019/07, and the Bar Ilan Institute for Nanotechnology and Ad-
vanced Materials to whom we are indebted.