Synthesis of alkyl 5,6-dialkyl-2-amino-3-cyanopyridine-4-carboxylates

Article abstract of DOI:10.1023/A:1017503015471

An unusual route has been found for the hydrolysis of 3-amino-1,1-dialkoxy-6,7-dialkyl-4-aryl-3a, 4, 5, 7a-tetrahydro-1H-pyrrolo[3,4-c]pyridine-3a, 7a-dicarbonitriles in acidic medium which leads to the formation of alkyl 5,6-dialkyl-2-amino-3-cyanopyridi

Full text of DOI:10.1023/A:1017503015471

Chemistry of Heterocyclic Compounds, Vol. 37, No. 3, 2001
SYNTHESIS OF ALKYL 5,6-DIALKYL-
2
-AMINO-3-CYANOPYRIDINE-
-CARBOXYLATES
4
A. N. Vasiliev, Ya. S. Kayukov, O. E. Nasakin, A. N. Lyshchikov,
V. N. Nesterov, O. V. Kayukova, and O. V. Poulkherovskaya
An unusual route has been found for the hydrolysis of 3-amino-1,1-dialkoxy-6,7-dialkyl-4-aryl-
3
a,4,5,7a-tetrahydro-1H-pyrrolo[3,4-c]pyridine-3a,7a-dicarbonitriles in acidic medium which leads to
the formation of alkyl 5,6-dialkyl-2-amino-3-cyanopyridine-4-carboxylates.
Keywords:
a,7a-dicarbonitriles, alkyl 2-amino-5,6-dialkyl-3-cyanopyridine-4-carboxylates.
3-amino-1,1-dialkoxy-6,7-dialkyl-4-aryl-3a,4,5,7a-tetrahydro-1H-pyrrolo[3,4-c]pyridine-
3
By studying the addition reaction of nucleophiles at the cyano group of 1,1,2,2-tetracyano-substituted
cyclic systems it has been shown that the process occurs selectively at one of the cyano groups with subsequent
cyclization and formation of 2-amino-5,5-dialkoxypyrroline or 2-aminopyrrolin-5-one fragment [1-4]. The
hydrolysis reaction of compounds containing these fragments has been studied for many substances. In the
majority of cases the hydrolysis in the presence of mineral acids occurs without affecting the remaining cyano
groups and leads to the formation of imides [4, 5]. Examples are also known where the hydrolysis reaction
occurs more extensively, but in these cases it has been proposed that imides are formed in the intermediate
stages [5, 6].
For 1,1-dialkoxy-6,7-dialkyl-3-amino-4-aryl-3a,4,5,7a-tetrahydro-1H-pyrrolo[3,4-c]pyridine-3a,7-
dicarbonitriles 1a-i [7] we have discovered an unusual route for the hydrolysis using dilute sulfuric acid in
which alkyl 5,6-dialkyl-2-amino-3-cyanopyridine-4-carboxylates (9) are formed instead of the expected imides
2
. Their structures are based on a series of experimental facts and on their physico-chemical analytical data.
Hence compounds 1a and 1f, which differ only in their alkoxy groups give different compounds in the course of
the reaction and hence the alkoxy groups are wholly or partially retained in the structure. Among the reaction
products aromatic aldehydes are found. The hydrolysis of compounds 1a and 1e, which have different aryl
substituents, leads to one and the same compound 9a, i.e. in the hydrolysis process elimination of fragment
containing the aromatic substituent occurs and this is converted to the aldehyde under the reaction conditions.
-1
Absorption bands at 3300-3200 and 1660 cm corresponding to the stretching and bending vibrations of
-1
the NH group and strong absorption bands of the conjugated cyano group at 2230-2240 cm are observed in the
2
IR spectra of the compounds obtained (Table 1).
The nature of the absorption bands of the cyano and amino groups allows one to suppose the presence of
enaminonitrile fragment in the hydrolysis product molecule. The presence of a strong absorption band in the
-
1
region of 1705-1725 cm points to the occurrence of carbonyl group in the synthesized compounds. The mass
____________________________________________________________________________________________
I. N. Ul'yanov Chuvash State University, Cheboksary 428015, Russia e-mail: intruder@chuvsu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 338-343, March, 2001. Original article
submitted February 3, 2000.
0009-3122/01/3703-0309$25.00©2001 Plenum Publishing Corporation
309

-1
TABLE 1. IR Spectral Characteristics (cm ) of Compounds 9a-h
Com-
νNH
δNH
νC=N
νC=O
pound
9
9
9
9
9
9
9
9
a
b
c
d
e
f
3190, 3315, 3400, 3420
3190, 3323, 3387, 3412
3170, 3250, 3330, 3380
3165, 3250, 3320, 3383
3150, 3240, 3335, 3410
3120, 3220, 3330, 3400
3160, 3330, 3387, 3405
3175, 3315, 3369, 3415
1635
1640
1640
1639
1640
1662
1649
1645
2227
2232
2230
2223
2229
2232
2230
2227
1705
1723
1705
1698
1722
1715
1710
1707
g
h
Fig. 1. Molecular structure of
methyl 2-amino-3-cyano-5,6-dimethylpyridine-4-carboxylate 9b.
spectroscopic data for the product of hydrolysis of compound 1a allow to suppose that the starting compound
adds a molecule of water in the course of the reaction but also eliminates molecules of benzaldimine, methanol,
and hydrogen cyanide. X-ray structural investigation of the single crystal of compound 9b was carried out to
provide an unambiguous proof of the structure of the reaction products (see Fig. 1).
A comparative analysis of compounds containing 5,5-dialkoxy-2-amino-3,4-dicyanopyrroline fragment
hydrolysis of which gives the corresponding imides) and pyrrolo[3,4-c]pyridines 1 discussed here has shown
(
that one of the significant differences in the latter is the presence of the multiple bond (having an enamine
character) in direct proximity to the pyrroline fragment. Thanks to this disposition of the multiple bond it is able
to provide anchimeric assistance to the fission of the pyrroline ring [8]. On the other hand, addition of the
amidine group formed in this way to the electrophilic carbon atom of the enamine provides the possibility of
subsequent stabilization to give the aromatic system of the end product. In our view, these factors predetermine
the reaction course and are the most likely reason for its anomalous character. Hence we propose the following
scheme for the reaction.
3
10

OR
O
NC
OR
N
RO
NC
H
N
RO
1NC
H
N
+
R1
R1
O
CN
NH2
NH2
CN
R
H+
CN
H
2
H
Ar
2
R
H
2
R
N
H
2
R
N
H
N
H
Ar
Ar
1a–i
+
RO
H
OR
CN
+
RO OR
RO
OR
CN
NH
NH
CN
R1
1
CN
NH
R1
H
NH2
R
NH2
Ar
CN
H
CN
H
2
R
NH
2
R
2
R
N
H
4
N
H
N
H
+
Ar
Ar
5
3
+
H O
2
–
–
ROH
OR
CN
O
+
OR
CN
H
O
1
H
O
H
OR
CN
R1
CN
R
CN
R1
CN
NH
2
R
H
N
NH2
–ArCH=NH
2
R
Ar
NH
N H
N
NH2
H
2
R
CHAr
N
H
7
6
–
HCN
OR
–
ArCH=NH
OR
O
OR
CN
O
O
1
1
H
R
CN
CN
H
1
H
R
CN
R
CN
Ar
–
ArCH=NH
2
R
NH
–HCN
2
R
2
NH2
N
NH2
R
N
NH2
N
H
9
a–h
8
1
2
1
2
1
a R ,R = (CH
2
)
4
, R = CH
, R = H, R = CH
, R = CH
3
, Ar = Ph; b R = R = CH
3
, R = CH
3
, Ar = Ph;
, Ar = Ph;
1
2
1
2
c R = CH
3
3
, Ar = Ph; d R ,R = (CH
2
)
3
, R = CH
3
1
2
1
2
e R ,R = (CH
2
)
4
3
, Ar = 4-MeOC
6
H
4
; f R ,R = (CH
2
)
4
, R,R = (CH ) , Ar = Ph;
2
2
1
2
1
2
g R = R = CH
3
, R,R = (CH
2
)
2
, Ar = Ph; h R = CH
3
, R = H, R,R = (CH
2
)
2
, Ar = Ph;
1
2
1
2
1
2
i R ,R = (CH
2
)
4
, R = C
2
H
5
, Ar = Ph; 9 a R = CH
3
, R ,R = (CH
2
)
4
; b R = R = R = CH
3
;
1
2
1
2
1
2
c R = R = CH
3
, R = H; d R = CH
3
, R ,R = (CH
2
)
3
; e R = HOCH
2
CH
, R = CH
2
, R ,R = (CH
2
)
4
;
1
2
1
2
f R = HOCH
2
CH
2
, R = R = CH
h R = C
3
; g R = HOCH
, R ,R = (CH
2
2 4
)
CH
2
3
, R = H;
1
2
2
H
5
Initially the protonated substrate undergoes fission of the pyrroline fragment to form intermediate 3.
Evidently in the latter, an additional stabilization is possible due to the interaction of the carbocationic center
with a π-orbital of the double bond and this can be represented by the Lewis structure 4. This must result in an
increase in the partial positive charge on atom C(6) of the tetrahydropyridine ring which favors the
intramolecular addition of the amidine group. The carbocation 5 formed as a result of these reactions is further
stabilized by the formation of the ester group and subsequent fission of aldimine and hydrogen cyanide. For the
intermediate 6 two routes can be proposed for the elimination of aldimine, i.e. staged fission via the
intermediate 7 or an simultaneous cycloelimination via the tautomeric form 8.
3
11

TABLE 2. The Characteristics of the Synthesized Compounds 9a-h
Found, %
Com-
Empirical
——————
Calculated, %
mp, °C
Yield, %
pound formula
C
H
N
9
9
9
9
9
9
9
9
a
b
c
d
e
f
C
C
12
10
H
13
11
N
3
3
O
2
2
62.30
5.71
5.66
18.15
18.17
195-196
171-172
188-189
219-220
143-144
225-226
185-186
155-156
56
78
51
58
42
57
82
75
6
2.33
H
N
O
58.55
5.43
20.45
5
8.59
5.40
20.41
C
9
H
9
N
3
O
2
56.51
4.77
4.74
21.95
21.98
5
6.54
C
C
C
C
C
11
13
11
10
13
H
11
H
15
H
13
H
11
H
15
N
N
N
N
N
3
O
O
O
O
O
2
60.78
5.15
19.31
6
0.82
59.79
9.77
5.11
19.34
3
3
3
3
3
3
3
2
5.76
5.74
16.15
16.09
5
56.17
5.53
17.85
5
6.17
5.56
17.88
g
h
54.27
4.96
4.97
19.05
19.00
5
4.29
68.15
6.56
18.32
6
8.12
6.55
18.34
TABLE 3. Bond Lengths (d) and Bond Angles (ω) in the Molecule 9b
Bond
d, Å
Angle
ω, deg.
O(41)–C(41)
O(42)–C(42)
N(l)–C(2)
N(31)–C(31)
C(3)–C(4)
C(4)–C(5)
С(5)–С(6)
C(6)–C(61)
O(42)–C(41)
N(1)–C(6)
N(21)–C(2)
C(2)–C(3)
C(3)–C(31)
C(4)–C(41)
C(5)–C(51)
1.190(5)
1.458(5)
1.348(4)
1.148(5)
1.402(5)
1.372(5)
1.419(5)
1.496(5)
1.310(5)
1.340(4)
1.339(5)
1.415(5)
1.435(5)
1.514(5)
1.518(5)
C(41)–O(42)–C(42)
N(21)–C(2)–N(1)
N(1)–C(2)–C(3)
C(4)–C(3)–C(31)
N(31)–C(31)–C(3)
C(5)–C(4)–C(41)
O(41)–C(41)–O(42)
O(42)–C(41)–C(4)
C(4)–C(5)–C(51)
N(1)–C(6)–C(5)
C(5)–C(6)–C(61)
C(6)–N(1)–C(2)
N(21)–C(2)–C(3)
C(4)–C(3)–C(2)
C(2)–C(3)–C(31)
C(5)–C(4)–C(3)
C(3)–C(4)–C(41)
O(41)–C(41)–C(4)
C(4)–C(5)–C(6)
C(6)–C(5)–C(51)
N(1)–C(6)–C(61)
115.5(4)
116.6(3)
120.6(3)
122.4(3)
178.0(4)
120.5(3)
125.2(4)
111.8(3)
122.4(3)
123.0(3)
120.8(3)
120.0(3)
122.8(3)
118.4(3)
119.2(3)
121.2(3)
118.3(3)
123.0(4)
116.8(3)
120.8(4)
116.2(3)
EXPERIMENTAL
Monitoring of the reaction course and the purity of the synthesized compounds was carried out by TLC
on Silufol UV-254 plates with UV or iodine vapor visualization. IR spectra were obtained for thin layers
(
suspensions in vaseline oil) on UR-20 instrument. High- and low-resolution mass spectra were recorded on a
Varian MAT-212 instrument with an ionization energy of 70 eV.
3
12

4
TABLE 4. Coordinates of Non-hydrogen Atoms (×10 ) and Coefficients of
2
3
Equivalent Isotropic Shift (Å ×10 ) for Compound 9b
Atom
O(41)
O(42)
N(l)
N(21)
N(31)
C(2)
C(3)
C(31)
C(4)
C(41)
C(42)
C(5)
C(51)
C(6)
C(61)
O(4lA)
O(42A)
O(41')
O(42')
N(IA)
N(21A)
N(31A)
C(2A)
C(3A)
C(31A)
C(4A)
C(41A)
C(42A)
C(42')
C(5A)
C(51A)
C(6A)
C(61A)
x
y
z
U
(eq)
463(4)
2788(3)
4301(3)
5245(5)
3863(5)
4392(4)
3629(4)
3740(5)
2750(4)
1848(5)
2028(8)
2645(4)
1738(5)
3472(4)
3425(5)
1010(6)
569(6)
8142(4)
8795(3)
5558(3)
7537(4)
10577(4)
6989(4)
7847(4)
9366(4)
7168(4)
8074(4)
9739(7)
5711(4)
4950(5)
4934(4)
3340(4)
6368(5)
7849(5)
8466(7)
6924(7)
4346(3)
6345(4)
9373(4)
5786(4)
6656(4)
8183(5)
6001(5)
6928(8)
8734(12)
8021(14)
4519(5)
3691(9)
3733(5)
2135(5)
-68(4)
-701(2)
1727(2)
2935(3)
2075(3)
2035(3)
1417(3)
1771(3)
493(3)
-130(3)
-1298(5)
180(3)
-830(3)
834(3)
560(3)
2650(3)
4102(3)
3759(5)
3389(6)
5679(2)
6883(3)
5999(4)
5957(3)
5297(3)
5659(4)
4366(3)
3679(4)
3440(9)
2889(11)
4083(3)
3099(4)
4775(3)
4524(4)
83(1)
43(1)
26(1)
53(1)
45(1)
27(1)
25(1)
30(1)
27(1)
32(1)
52(1)
26(1)
38(1)
23(1)
28(1)
23(1)
18(1)
60(2)
60(2)
27(1)
37(1)
59(1)
26(1)
34(1)
43(1)
39(1)
76(2)
32(2)
47(3)
45(1)
83(2)
34(1)
49(1)
2281(8)
71(9)
3314(4)
4279(4)
3364(5)
3484(4)
2814(5)
3086(5)
1949(5)
1240(7)
-161(13)
-627(16)
1787(5)
858(9)
2507(5)
2419(7)
Alkyl 5,6-Dialkyl-2-amino-3-cyanopyridine-4-carboxylates (9a-h). (General Method). Compound 1
0.01 mol) was suspended in mixture of water and 2-propanol (1:1, 5 ml) and sulfuric acid (1.1 g, 0.011 mol)
(
was added as 15% aqueous solution. A large excess of acid led to some difficulties in the separation of the final
material. The mixture obtained was brought to boiling and then cooled. It was neutralized with sodium
bicarbonate to neutral reaction and the precipitate formed was filtered, washed with 2-propanol, and purified by
recrystallization from ethyl acetate or sublimation in vacuo. The melting point, yield, and elemental analysis
data are given in Table 2. The mass spectrum of compound 9a showed the following m/z (Irel, %): 231 (42),
2
16 (100), 200 (14), 188 (7), 172 (10), 170 (22), 157 (9), 143 (8), 77 (14), 63 (9), 43 (10) (the molecular ion
peak and 10 strongest fragment ions are referred).
X-ray Diffraction Investigation of Compound 9b. Crystals of 9b (C10
H
11
N
3
O , M = 205.22) at 20°C
2
are triclinic; the space group P1; a = 8.479 (2), b = 9.491 (2), c = 12.939 (3) Å; α = 98.62 (2), β = 92.64 (3),
3
3
γ = 97.37 (3)°; V = 1018.7 (4) Å ; Z = 4 (two crystallographically independent molecules), dcalc = 1.338 g/cm .
The unit cell parameters and intensities of 4780 reflections were measured on a Siemens P3/PC automatic four-
circle diffractometer (293 K, λMoKα, graphite monochromator, θ/2θ scanning, θmax = 27°) (Table 3). The
3
13

structure was solved by direct method and refined by full-matrix, least-squares analysis in the anisotropic
approximation for non-hydrogen atoms (Table 4). The hydrogen atoms were localized directly by Fourier
difference synthesis and refined in the isotropic approximation. A disordering of the methoxycarbonyl group in
one of the crystallographically independent molecules was observed. The final divergence factors were
R
1
= 0.083 for 4412 independent reflections with I>2σ (I) and wR = 0.264 for all 4473 independent reflections.
2
Calculations were performed using the SHELXTL PLUS; SHELXL-93 programs.
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1
.
A. B. Zolotoi, O. A. D'yachenko, S. V. Konovalikhin, L. O. Atovmyan, O. E. Nasakin, P. M. Lukin,
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Khim., 1818 (1987).
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Chernogolovka (1987), p. 39.
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S. V. Lindenman, Yu. T. Struchkov, and A. Kh. Bulai, Zh. Org. Khim., 31, 370 (1995).
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R. H. Boyd, J. Amer. Chem. Soc., 83, 4288 (1961).
Ya. S. Kayukov, O. E. Nasakin, Ya. G. Urman, V. N. Khrustalev, V. N. Nesterov, M. Yu. Antipin,
A. N. Lyshchikov, and P. M. Lukin, Khim. Geterotsikl. Soedin., 367 (1997).
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3
14