A convenient preparation of diversely substituted fused 2-amino- and 2-alkylthionicotinonitriles under microwave irradiation

Article abstract of DOI:10.1016/j.tetlet.2014.09.067

We describe a convenient and operationally simple protocol to prepare nicotinonitriles fused to either a cycloalkane or a saturated heterocycle, containing diverse substituents at position 2 of the nicotinonitrile core, under microwave irradiation. The protocol is useful for rapid and automated synthesis of the target compounds. An unusual case of the loss of a tert-butyl group is observed when tert-butylamine was used to bring about the pyridine ring formation.

Full text of DOI:10.1016/j.tetlet.2014.09.067

Accepted Manuscript
A convenient preparation of diversely substituted fused 2-amino- and 2-alkylth-
ionicotinonitriles under microwave irradiation
Mikhail Krasavin, Alexander Sapegin, Mikhail Dorogov
PII:
S0040-4039(14)01568-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.09.067
TETL 45161
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 July 2014
29 August 2014
11 September 2014
Please cite this article as: Krasavin, M., Sapegin, A., Dorogov, M., A convenient preparation of diversely substituted
fused 2-amino- and 2-alkylthionicotinonitriles under microwave irradiation, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.09.067
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A convenient preparation of diversely substituted fused 2-amino-
and 2-alkylthionicotinonitriles under microwave irradiation
Mikhail Krasavin, Alexander Sapegin, Mikhail Dorogov

A convenient preparation of diversely substituted fused 2-amino-
and 2-alkylthionicotinonitriles under microwave irradiation
Mikhail Krasavin,a, b* Alexander Sapegin,c Mikhail Dorogov c
a
Department of Chemistry, St. Petersburg State University, 26 Universitetskyi Prospekt,
Peterhof 198504, Russian Federation
b
Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland 4111,
Australia
c The Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl,
150000, Russian Federation
* Corresponding Author; phone: + 7 931 3617872, fax: +7 812 428 6939.
E-mail: m.krasavin@hotmail.com
Abstract: We describe a convenient and operationally simple protocol to prepare
nicotinonitriles fused to either a cycloalkane or a saturated heterocycle, containing diverse
substitutuents at position 2 of the nicotinonitrile core, under microwave irradiation. The
protocol is useful for rapid and automated synthesis of the target compounds. An unusual
case of the loss of a tert-butyl group is observed when tert-butylamine was used to bring
about the pyridine ring formation.
Keywords: “Push-pull” 1,3-butadienes, pyridine synthesis, microwave irradiation, parallel
chemistry, nucleophilic substitution, ammonia equivalent, retro-ene reaction
Treatment of 4-dialkylamino-1,3-butadiene-1,1-dicarbonitriles 1, which could be
incorporated into a more complex polycyclic system, with various nucleophiles (such as
ammonia) leads to the formation of a pyridine nucleus.1 The resulting pyridines 2 (as well as
their ester analogs obtained in a similar manner) are appropriately functionalized to enable
further extension of the heteropolycyclic system (e.g., via the fusion of a new pyrimidine
ring).2 Taken alone, pyridines 2 represent an important scaffold that has found utility in
kinase inhibitors3 and mGluR1 antagonists.4 Perhaps the most remarkable success of this
chemotype in the area of drug design was the development of AZD1283,5 a potent P2Y12
receptor antagonist, recently advanced into human trials as an antithrombotic agent (Figure

1).6 Numerous examples of converting compounds 1 into pyridines 2 have been documented
in the literature and now constitute a classical method to form pyridines. Still, various novel
facets of this chemistry continue to appear in the literature, including the recently described
solventless method to make pyridines 2 from 1 and primary amines,7 and an interesting
application of this methodology to the preparation of structurally intriguing pyridine-fused
lactones developed by the same group.8 Moreover, on reviewing the literature on this popular
pyridine synthesis, the lack of a general method that is practically simple (from the standpoint
of reaction format and the ease of product isolation) and amenable to parallel (better yet,
automated) synthesis of arrays of pyridines 2, became apparent.
In one of our drug discovery projects, we required a rapid synthesis of nicotinonitriles 3 fused
to either a cycloalkane or a saturated heterocycle, containing diverse substitutuents at position
2 of the nicotinonitrile core. Both the nitrogen- and sulfur-linked side chains in that position
were envisioned for systematic exploration of structure-activity relationships. Compounds 3
were quite naturally disconnected into the respective “push-pull” 4-(morpholin-1-yl)-1,3-
butadiene-1,1-dicarbonitriles 4 which, in turn, could be disconnected into the respective
cyclic ketones 5 (via enamine retrosynthesis) and ethoxymethylene malononitrile (Scheme
1).9 Synthons 4 were indeed quite conveniently prepared by a modified two-step protocol
adopted from the literature,10 via the gram-scale preparation of enamine 6 followed by its
condensation with ethoxymethylene malononitrile. Good yields of crystalline compounds 4a-
d were obtained after simple crystallization (Scheme 2). However, when we attempted the
conversion of 4 into the target nicotinonitriles 3 on treatment with various amines (primary
and secondary) in EtOH for 12-24 hours at ambient temperature (as was described in the
literature11), we found the conversions as well as the purities and yields of the desired
compounds 3 to be unsatisfactory. Moreover, the results of subsequent chromatographic
purification also turned out to be overly sensitive to the nature of the amine used. Increasing
the reaction temperature incrementally up to reflux did improve the conversion rate (the
starting material disappeared within 10 min at 50 °C), but led to significant formation of side
products, according to TLC analysis. In this communication, we report our findings that
under brief microwave irradiation, precursors 4 are converted cleanly and rapidly into target
compounds 3. The general applicability of this finding to the synthesis of 2-amino- and 2-
alkylthio-substituted nicotinonitriles is discussed below.
Even preliminary experimentation under microwave irradiation indicated the apparent
advantages of this method, such as the purity of the resultant crude products and the short

reaction times. Therefore, we proceeded to test the practicality of this method in a
combinatorial format. Sixteen test reactions comprising a range of amines (Scheme 3) were
performed on 0.5 mmol scale and were conducted in 5 mL septum-capped microwave vials
using a Biotage InitiatorTM microwave reactor (operating at 100 W) equipped with a robotic
sample handling arm. The starting materials 4 were weighed out in each vial, anhydrous
EtOH was added followed by an amine (0.5 mmol, added neat or as a solution in a minimum
volume of EtOH). The vials were capped and placed on a sample rack. Each sample was
programmed to be irradiated at 100 °C for 15 minutes. Upon completion of the reaction array,
each vial was de-capped and the contents were analyzed by LC-MS. In all the cases studied,
the crude reaction mixtures were found to contain a significant amount of the target
compound, except for the reaction of 4b with t-BuNH2, where instead of compound 3h, a
product lacking the tert-butyl group was obtained, as judged by the m/z value observed for
the main product peak. The identity of 3h as N-dealkylated 2-aminonicotinonitrile was
confirmed by 1H and 13C NMR spectroscopy. The reaction mixtures were concentrated under
a stream of nitrogen using a multi-channel blow-drying head and the resulting dark brown
oils purified on silica gel cartridges using a gradient of 0ꢀ5% MeOH in CH2Cl2 to provide
good to excellent yields of compounds 3a-p (Table 1).
The unexpected removal of the tert-butyl group in 3h was somewhat puzzling. Similar
dealkylation reactions are commonplace under acidic treatment.12 However, considering the
apparently basic to neutral medium in our experiments, a possible justification would be to
invoke some participation from a neighboring nitrogen atom that could trigger the
dealkylation via a pericyclic (retro-ene) reaction. The only plausible explanation we have at
the moment is that for the sterically demanding tert-butylamine, the reaction might have
taken an alternative course13 and the observed de-tert-butylation might be the only pathway
to restoring the aromaticity of the pyridine nucleus in 3h (Scheme 4).14 To our knowledge,
this is the first example of the facile thermal removal of a tertiary alkyl group from nitrogen
under basic or neutral conditions. We obtained similar results (compounds 3q-s) with the
other three precursors (4a, 4c and 4d), thereby confirming tert-butylamine to have acted as an
ammonia equivalent in these reactions (Scheme 5).
We were also happy to find that our method was applicable to the preparation of 2-
alkylthionicotinonitriles. Precursors 4a-d were treated, in combinatorial fashion, with four
different thiols. Under the same conditions (EtOH, 100 °C, 15 min), good to excellent yields
of the products 3t-y were obtained after chromatographic purification (Scheme 6, Table 2).

The alkylthio compounds 3t-y, in contrast to their amino counterparts 3a-s obtained in a
similar manner, contained noticeably less colored contamination (quite visible, in the case of
3a-s, but not detectable as impurities in the 1H NMR spectrum). Mindful of the potential for
2-alkylthiopyridines to act as precursors to 2-aminopyridines via aromatic nucleophilic
substitution (directly15 or via preliminary activation by S-oxidation16), we tested such a
possibility. Compound 3v (selected based on the lower volatility of the benzyl thiol that
would be released as the result of the substitution) was synthesized on large scale and
subjected to treatment with a set of amines (Scheme 7) in EtOH at 120 °C. To achieve full
conversion, longer reaction times (1 h) were required, however, product purification was very
straightforward. The respective products 7a-e were obtained in good yields and contained
much fewer colored impurities compared to compounds 3a-s prepared without the
intermediacy of the 2-thioalkylnicotinonitrile. Preliminary oxidation of 3v with m-CPBA (3
equiv) led to a noticeably easier substitution with amines (only 10 min at 100 °C for
morpholine). However, the purity of the product mixture decreased and the S-
oxidation/substitution protocol was discarded.
In summary, we have described a convenient and operationally simple protocol to prepare
nicotinonitriles 317 fused to either a cycloalkane or a saturated heterocycle, containing diverse
substitutuents at position 2 of the nicotinonitrile core, under microwave irradiation. The
protocol appears to be superior to hitherto reported methods employing conventional heating
and is distinctly useful for the rapid and automated preparation of arrays of compounds 3,
with a possibility for parallel work-up and purification. An unusual case of the loss of a tert-
butyl group (which we think proceeds via a retro-ene step) was observed when tert-
butylamine was used to bring about the pyridine ring formation. This is in sharp contrast to
typical de-tert-butylation that in a similar context requires acidic treatment. The scope of this
transformation will be investigated and the results reported in due course.
Acknowledgements
Mikhail Krasavin acknowledges support from Griffith University.
References and notes
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3. Anderson, David R.; Stehle, Nathan W.; Kolodziej, Stephen A.; Reinhard, Emily J. PCT
Int. Appl. WO 2004055015A1; Chem. Abstr. 2004, 141, 534203.
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Klochkova, A.; Pyatkin, I.; Kazyulkin, D.; Aksenova, E.; Shulepin, S.; Timonina, O.;
Haasis, A.; Gutcaits, A.; Parsons, C. G.; Kauss, V.; Weil, T. J. Med. Chem. 2008, 51,
634-647.
5. Giordanetto, F.; Bach, P.; Zetterberg, F.; Antonsson, T.; Bylund, R.; Johansson, J.;
Sellén, M.; Brown, D.; Hideståhl, L.; Berntsson, P.; Hovdal, D.; Zachrisson, H.;
Björkman, J.-A.; van Giezen, J. J. J. Bioorg. Med. Chem. Lett. 2014, 24, 2963-2968.
6. Andersen, S. M.; Aurell, C.-J.; Zetterberg, F.; Bollmark, M.; Ehrl, R.; Schuisky, P.; Witt,
A. Org. Process Res. Dev. 2013, 17, 1543-1551.
7. Villemin, D.; Belhadj, Z.; Cheikh, N.; Choukchou-Braham, N.; Bar, N.; Lohier, J.-F.
Tetrahedron Lett. 2013, 54, 1664-1668.
8. Cheikh, N.; Villemin, D.; Bar, N.; Lohier, J.-F.; Choukchou-Braham, N.; Mostefa-Kara,
B.; Sopkova, J. Tetrahedron 2013, 69, 1234-1247.
9. Kurihara, H.; Mishima, H. J. Heterocycl. Chem. 1977, 14, 1077-1079.
10. The procedure was adopted from: Oganisyan, A. Sh.; Noravyan, A. S.; Grigoryan, M.
Zh. Chem. Heterocycl. Compd. 2001, 37, 763-765. Enamines 6 were prepared by
condensation of the respective ketones 5 (25 mmol) with morpholine (26.3 mmol,
toluene reflux with a Dean-Stark trap in the presence of a catalytic amount of p-TSA),
followed by high-vacuum distillation. Equimolar amounts of 6 and ethoxymethylene
malononitrile were combined in MeOH (2 mL/mmol) and stirred at r.t. while the color of
the solution gradually darkened and a crystalline material formed. The reaction flask was
stored in a freezer overnight; the crystalline product was collected by filtration, washed
with ice-cold MeOH and air-dried to provide analytically pure 4.
11. Golovko, T. V.; Smirnova, O. B.; Solov´eva, N. P.; Anisimova, O. S.; Granik, V. G.
Russ. Chem. Bull. 2007, 56, 1032-1040.
12. (a) Sharp, P. P.; Banwell, M. G.; Renner, J.; Lohmann, K.; Willis, A. C. Org. Lett. 2013,
15, 2616-2619; (b) Cho, S. Y.; Han, S.-Y.; Ha, J. D.; Ryu, J. W.; Lee, C. O.; Jung, H.;
Kang, N. S.; Kim, H. R.; Koh, J. S.; Lee, J. Bioorg. Med. Chem. Lett. 2010, 20, 4223-
4227.
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14. We prepared compound 3h′ (Scheme 4) by an alternative method4 and exposed it to the
microwave conditions in which 3h formed. No de-tert-butylation was observed after 1 h,
strongly suggesting that the loss of the tert-butyl group was dictated by the course of the
reaction leading to 3h.
15. Ibrahim, D. A.; Ismail, N. S. M. Eur. J. Med. Chem. 2011, 46, 5825-5832.
16. (a) Venkatesh, C.; Sundaram, G. S. M.; Ila, H.; Junjappa, H. J. Org. Chem. 2006, 71,
1280-1283; (b) Panda, K.; Siddiqui, I.; Mahata, P. K.; Ila, H.; Junjappa, H. Synlett 2004,
449-452.
17. Characterization data for representative compounds: 3d – grey solid, mp = 282 °C (dec.);
1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.30-7.38 (m, 5H), 6.76 (br s, 2H), 5.13
(s, 2H), 4.47 (s, 2H), 3.73 (t, J = 7.2 Hz, 4H), 3.67 (t, J = 5.2 Hz, 2H), 3.27 (t, J = 7.2
Hz, 4H), 2.68 (t, J = 5.2 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) δ 161.4, 157.3, 155.2,
136.5, 136.2, 128.3, 127.9, 127.7, 124.8, 115.3, 95.0, 67.5, 66.2, 50.1, 44.2, 42.3, 32.6;
LC-MS m/z calcd for C21H23N4O3 ([M+H]+) 379.2, found 379.4; Anal Calcd for
C21H23N4O3: C, 66.65; H, 5.86; N, 14.81; found C, 66.82; H, 5.93; N, 14.73; 3h – beige
solid, mp = 186-188 °C; 1H NMR (300 MHz, DMSO-d6) δ 7.73 (s, 1H), 6.28 (br s, 2H),
5.36 (s, 2H), 3.36 (t, J = 6.2 Hz, 2H), 2.63 (t, J = 6.2 Hz, 2H); 13C NMR (75 MHz,
DMSO-d6) δ 156.3, 155.0, 137.0, 124.1, 115.7, 106.7, 72.6, 64.6, 32.6; LC-MS m/z calcd
for C9H10N3O ([M+H]+) 176.3, found 176.4; Anal Calcd for C9H9N3O: C, 61.70; H, 5.18;
N, 23.99; found C, 61.56; H, 5.03; N, 24.13; 3t - grey solid, mp = 163-165 °C; 1H NMR
(300 MHz, DMSO-d6) δ 7.61 (s, 1H), 4.12 (s, 2H), 3.61 (s, 3H), 3.35 (t, J = 6.3 Hz, 2H),
3.17 (t, J = 6.5 Hz, 2H), 2.12 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 168.3, 166.3,
153.2, 139.4, 133.3, 118.0, 105.5, 51.3, 35.6, 29.3, 29.9, 21.4; LC-MS m/z calcd for
C12H13N2O2S ([M+H]+) 248.3, found 248.1; Anal Calcd for C12H12N2O2S: C, 58.05; H,
4.87; N, 11.28; found C, 57.92; H, 4.79; N, 11.13.

Figure 1. Construction of 2-aminonicotinonitriles 2 and the structure of the antithrombotic
clinical candidate AZD1283.
Scheme 1. Retrosynthesis of target nicotinonitriles 3 studied in this work.
NC
CN
CN
Z
X
Y
X
Y
+
ZH
N
N
3
4
O
O
X
Y
=
EtO
CN
CN
OBn
O
X
Y
O
N
+
O
O
HN
5
O
Z = SR, NR1R2
Scheme 2. Preparation of the “push-pull” 1,3-butadienes 4.10
EtO
CN
CN
NC
CN
morpholine
cat. p-TSA
X
Y
X
Y
X
Y
toluene, reflux
12 h
(Dean-Stark trap)
MeOH, r. t.
8-12 h
N
O
N
O
O
5a-d
4a-d
6a-d
56-71%
after distillation
OBn
N
O
X
O
O
=
O
Y
a
d
b
c

Scheme 3. Preparation of 2-aminonicotinonitriles 3a-p.
NC
CN
R1
R2
N
H
CN
X
Y
X
Y
R1
EtOH
N
N
N
MW irradiation
100 oC, 15 min
R2
O
3a-p
4
Scheme 4. Plausible mechanism for the formation of 3h and the loss of a t-Bu group.
Expected course:
N
NC
CN
N
O
H2N
O
O
N
H
HN
N
N
H
N
O
N
O
4b
3h'
Postulated actual course:
N
NC
N
CN
N
CN
H2N
O
O
O
O
N
NH2
N
NH
H
NH
- morpholine
N
-
O
3h
4b
Scheme 5. General character of the de-tert-butylation.
NC
CN
NH2
CN
NH2
X
X
Y
Y
EtOH
N
N
MW irradiation
100 oC, 15 min
O
3q-s
4
OBn
O
O
X
Y
O
N
=
q (56%)
r (44%)
s (66%)

Scheme 6. Formation of pyridines 3t-y triggered by thiols.
Scheme 7. Direct nucleophilic substitution of the benzylthio group in 3v with various amines.
R1
R2
O
O
CN
S
N
CN
H
O
O
R1
N
EtOH
N
N
R2
MW irradiation
120 oC, 1 h
3v
7a-e
Table 1. Compounds 3a-p prepared in this work.a
Product
Isolated
yield (%)
63
72
3a
NH2
O
3b
NH2
76
45
47
3c
NH
3d
O
NH
3e
3f
N
H
NH
78
81
3g
3h
NH
47b
NH2

42
39
3i
3j
O
F
NH2
NH2
73
81
3k
3l
NH2
HN
47
59
63
49
3m
3n
3o
H2N
HN
NH2
3p
H2N
a Crude products were at least 85% pure according to LC-MS analysis throughout, except for
3a, 3d, 3i, 3j, 3m, 3p (where >65% purity was observed).
b The isolated yield of the de-tert-butylated product is shown (see Scheme 5).
Table 2. Alkylthio compounds 3t-y prepared in this work.a
R1
Product
Isolated
yield (%)
SH
46
3t
MeOOC
HO
SH
66
71
76
59
3u
3v
3w
3x
SH
SH
SH
SH
64
3y
SH
a
Isolated yields. Crude products were at least 85% pure according to LC-MS analysis
throughout.