Tetrahydropyridine (THP) ring expansion under the action of activated terminal alkynes. The first synthesis and X-ray crystal structure of tetrahydropyrimido[4,5-d]azocines

Article abstract of DOI:10.1016/j.tetlet.2005.11.136

Tetrahydropyridopyrimidines (THPPm) 1-3 underwent tandem cleavage-cyclization piperidine ring enlargement under the action of terminal activated alkynes to produce tetrahydropyrimido[4,5-d]azocines 4-7 in good preparative yields. The latter compounds are representatives of a new heterocyclic system.

Full text of DOI:10.1016/j.tetlet.2005.11.136

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 999–1001
Tetrahydropyridine (THP) ring expansion under the action
of activated terminal alkynes. The first synthesis and X-ray
crystal structure of tetrahydropyrimido[4,5-d]azocines
Leonid G. Voskressensky,* Tatiana N. Borisova, Innokenti S. Kostenev,
Larisa N. Kulikova and Alexey V. Varlamov
Organic Chemistry Department of the Russian People’s Friendship University, 6, Miklukho-Maklaya St, Moscow 117198, Russia
Received 28 October 2005; revised 16 November 2005; accepted 24 November 2005
Available online 15 December 2005
Abstract—Tetrahydropyridopyrimidines (THPPm) 1–3 underwent tandem cleavage–cyclization piperidine ring enlargement under
the action of terminal activated alkynes to produce tetrahydropyrimido[4,5-d]azocines 4–7 in good preparative yields. The latter
compounds are representatives of a new heterocyclic system.
ꢀ 2005 Elsevier Ltd. All rights reserved.
Medium-sized N-containing heterocycles, in particular
eight-membered rings, are key structures of various
structurally remarkable natural products.1–3 They are
also frequently used as precursors in syntheses of biolo-
gically active compounds. Annulated azocines have
recently been demonstrated to possess substantial
bioactivity as preventatives of urinary disturbance,4
AChE inhibitors5 and 17-b-hydroxysteroid dehydroge-
nase inhibitors.6 As the direct formation of these ring
sizes from acyclic precursors is entropically and enthalpi-
cally disfavored, the efficient construction of medium-
sized cycles is a challenge and has therefore attracted
considerable attention during the past years. We have
recently reported THP ring enlargement in tetrahydro-
pyrrolopyridines and tetrahydrocarbolines7 and unusual
Stevens rearrangement in benzo[b]naphthyridines under
the action of dimethyl acetylenedicarboxylate (DMAD).8
Fused pyrimidines are common sources for the develop-
ment of new therapeutic agents and due to the fact that
only a few examples of pyrimidoazocines are known,9,10
we were interested in developing an efficient synthetic
procedure for the synthesis of pyrimidoazocine deriva-
tives. We now report a new one-pot procedure for the
synthesis of previously unknown tetrahydropyri-
mido[4,5-d]azocines starting from readily available
tetrahydropyridopyrimidines (THPPm) derivatives.
Tetrahydropyrido[4,3-d]pyrimidines 1–3 were synthe-
sized according to the procedure previously described11
(Scheme 1).
Compounds 1–3 were treated12 with ethyl propiolate or
methyl propiolate in dry methanol at 25 ꢁC. In all
cases the reaction proceeded smoothly, giving azocines
4–613–15 as the only products (Scheme 2).
The structure of compound 5 was investigated by X-ray
diffraction.16 Suitable crystals were obtained by recrys-
tallization from methanol by slow evaporation at room
temperature. The refined X-ray crystal structure of 5 is
shown in Figure 1. The conformation of the eight-mem-
bered ring is a twisted bath, in which the C(1), C(4),
N(1), and C(7) atoms are almost coplanar, whilst the
C(2), C(3), C(8), and C(9) atoms are located in the same
O
O
COOEt
R
OH-
NH2
HN
N
NH
R1
+
N
R
R1
N
1 R=Me, R1=Ph (59%)
2 R=Bn, R1=Ph (79%)
3 R=Bn, R1=Me (62%)
*
Corresponding author. Fax: +7 095 9550779; e-mail: lvoskressensky@
sci.pfu.edu.ru
Scheme 1.
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.136

1000
L. G. Voskressensky et al. / Tetrahedron Letters 47 (2006) 999–1001
R2
R2
R2
O
R2
O
N
NH
R1
R
1-3
N
NH
R1
1-3
N
MeOH
R
N
MeOH
4 R=Me, R1=Ph, R2=CO2Et (57%)
5 R=Bn, R1=Ph, R2=CO2Me (81%)
6 R=Bn, R1=Me, R2=CO2Et (67%)
A
Scheme 2.
R2
Me
O
R2
O
H
NH
R1
O
+δ1
N
R
N
+δ
N
NH
R1
R
N
4-6
B
Scheme 4.
O
MeOOC
O
Bn
MP
N
N
N
MeOH
N
N
Bn
N
8
9 (72%)
Figure 1.
Scheme 5.
direction from this plane within 1.11, 1.25, 1.27, and
1.26 A, respectively.
˚
To see whether this piperidine ring enlargement is gen-
eral for the THPPm family, we carried out the reaction
of a trycyclic derivative 818 with methyl propiolate (MP)
in methanol (Scheme 5).
In order to determine the scope and limitations of this
reaction, we examined the reactivity of three other ter-
minal alkynes (phenylacetylene, propiolaldehyde diethyl
acetal, and 3-butyn-2-one) toward compound 2. While
the first two alkynes were unreactive (only tar-like prod-
ucts and unreacted 2 were isolated even after 24 h of
refluxing in methanol), the reaction with 3-butyn-2-one
proceeded smoothly, providing azocine 717 in 65% yield
(Scheme 3).
Analogous to the above results, azocine 917 was isolated
in 72% yield.
In conclusion, using a new, alkyne-induced piperidine
ring enlargement reaction, we have elaborated an effec-
tive synthetic pathway toward the previously unknown
tetrahydropyrimido[4,5-d]azocine system.
Our attempts to use other solvents (MeCN, THF, and
DMF) in this reaction failed, in all cases multicompo-
nent unseparable reaction mixtures were formed. We
presume, that the reaction proceeds via the intermediate
zwitterion A, resulting from Michael addition of the ter-
tiary nitrogen to the alkyne. Cleavage of the C(1)–N
bond occurs via the formation of six-membered transi-
tion state B in which a molecule of alcohol facilitates
the SN reaction (Scheme 4).
Acknowledgements
Financial support from the Russian Foundation for
Basic Researches (Grant # 05-033211) is gratefully
acknowledged.
References and notes
O
1. Lunt, E. In Comprehensive Organic Chemistry; Barton, D.,
Ollis, W. D., Eds.; Pergamon Press, 1974; Vol. 4, p 493.
2. Brown, J. D. In Comprehensive Heterocyclic Chemistry;
Katrizky, A. R., Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984; Vol. 3, p 57.
O
O
NH
2
N
MeOH
Bn
N
Ph
3. Clercq, E. D.; Beraaerts, R. J. Biol. Chem. 1987, 262,
14905.
4. Khalifan, R. WO2004019889, 2004; Chem. Abstr. 2004,
140, 229478.
7 (65%)
Scheme 3.

L. G. Voskressensky et al. / Tetrahedron Letters 47 (2006) 999–1001
1001
5. Voskressensky, L. G.; Borisova, T. N.; Kulikova, L. N.;
Varlamov, A. V.; Catto, M.; Altomare, C.; Carotti, A Eur.
J. Org. Chem. 2004, 3128.
6. Waehaelae, K.; Lilienkampf, A.; Alho, S.; Huhtinen, K.;
Johansson, N.; Koskimies, P.; Vihko, K. WO2004110459,
2004; Chem. Abstr. 2005, 142, 74590.
7. Voskressensky, L. G.; Borisova, T. N.; Soklakova, T. A.;
Kulikova, L. N.; Borisov, R. S.; Varlamov, A. V. Lett.
Org. Chem. 2005, 2, 18.
8. Voskressensky, L. G.; Borisova, T. N.; Kostenev, I. S.;
Vorobiev, I. V.; Varlamov, A. V. Tetrahedron Lett. 2005,
46, 1975.
15. Ethyl 8-benzyl-2-methyl-4-oxo-3,4,5,8,9,10-hexahydropyri-
mido[4,5-d]azocine-6-carboxylate 6: White crystals, mp
209 ꢁC. 1H NMR (400 MHz, CDCl3): d 8.50 (br s, 1H),
7.62 (s, 1H), 7.30–7.10 (m, 5H), 4.32 (s, 2H), 4.17 (q,
J = 7.0 Hz, 2H), 3.96 (s, 2H), 3.75 (t, J = 6.4 Hz, 2H), 3.07
(t, J = 6.4 Hz, 2H), 2.36 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H).
EIMS: m/z (%): 353 (M+, 10), 279 (25), 216 (12), 188 (12),
161 (15), 91 (100). IR (KBr) 1692, 1655 and 1608 cmꢀ1
.
Anal. Calcd for C20H23N3O3: C, 67.97; H, 6.56; N, 11.89.
Found: C, 67.83; H, 6.48; N, 11.75.
16. Crystal structure analysis for 5: C24H23N3O3, Mr =
401.45 g molꢀ1, triclinic, space group P-1, a = 8.5060
˚
9. Schwan, T. J.; Miles, N. J. J. Heterocycl. Chem. 1982, 19,
1257.
10. Boger, D. L.; Patel, M.; Mullican, M. D. Tetrahedron Lett.
1982, 23, 4559.
(17), b = 11.060(2), c = 11.261(2) A, a = 89.41(3)ꢁ, b =
3
˚
79.27(3)ꢁ, c = 86.66(3)ꢁ, V = 1039.1(4) A , Z = 2, q =
1.283 g cm3, l = 0.086 cmꢀ1, F(000) = 424, crystal size:
0.43 · 0.27 · 0.14 mm. Crystal data was collected on a
Cad-4 diffractometer (kMoKa radiation, graphite mono-
chromator; x scanning, 2hmax = 50ꢁ). A total of 3649
reflections (1.84ꢁ < h < 25.17ꢁ) were collected of which
3627 were unique (R(int) = 0.0958). The structure was
11. Cook, A. H.; Reed, K. J. J. Heterocycl. Chem. 1945, 399.
12. General experimental procedure: To a stirred solution of
pyridopyrimidine 1–3 (1 mmol) in 15 mL of methanol at
25 ꢁC, 1.2 mmol of ethyl propiolate was added and stirring
was continued for an additional 3 h (TLC monitoring).
Methanol was evaporated under reduced pressure and the
resulting residues were recrystallized from ethanol to give
compounds 4–6.
13. Ethyl 8-methyl-4-oxo-2-phenyl-3,4,5,8,9,10-hexahydropyri-
mido[4,5-d]azocine-6-carboxylate 4: Pale yellow crystals,
mp 133 ꢁC. 1H NMR (400 MHz, CDCl3): d 8.50 (br s,
1H), 8.30 (d, J = 7.2 Hz, 2H), 7.68 (m, 2H), 7.54 (m, 1H),
7.43 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 4.06 (s, 2H), 3.80 (t,
J = 6.4 Hz, 2H), 3.40 (t, J = 6.4 Hz, 2H), 3.00 (s, 3H), 1.16
(t, J = 7.2 Hz, 3H). EIMS: m/z (%): 339 (M+, 5), 309 (20),
295 (100), 267 (25), 142 (45), 114 (30), 104 (45), 84 (22), 70
(25), 59 (20), 42 (60), 29 (50). Anal. Calcd For
C19H21N3O3: C, 67.24; H, 6.24; N, 12.38. Found: C,
66.94; H, 6.12; N, 12.27.
14. Methyl 8-benzyl-4-oxo-2-phenyl-3,4,5,8,9,10-hexahydropy-
rimido[4,5-d]azocine-6-carboxylate 5: Yellow crystals, mp
245 ꢁC. 1H NMR (400 MHz, CDCl3): 8.26 (d, J = 7.8 Hz,
2H), 7.68 (m, 2H), 7.66 (s, 1H), 7.56 (m, 1H), 7.21–7.15
(m, 5H), 4.35 (s, 2H), 4.08 (s, 2H), 3.81 (t, J = 7.1 Hz, 2H),
3.66 (s, 3H), 3.20 (t, J = 7.1 Hz, 2H). EIMS: m/z (%): 401
(M+, 15), 341 (15), 310 (15), 91 (100), 65 (25). 13C NMR
(100 MHz, DMSO-d6): d 165.2, 162.2, 152.8, 151.8, 148.2,
137.2, 132.1, 131.5, 129.1 (2CH), 128.8, 127.9 (2CH), 127.7
(2CH), 127.5 (2CH), 103.1, 95.6, 61.0, 51.1, 48.4, 39.4,
20.2. IR (KBr) 1632 and 1575 cmꢀ1. Anal. Calcd for
C24H23N3O3: C, 71.80; H, 5.77; N, 10.47. Found: C, 71.75;
H, 5.78; N, 10.40.
19
solved with the program SHELXS-97 and refined using
SHELXL-9720 to R1 = 0.0520 and wR(F2) = 0.1284 for 1740
reflections with I > 2r(I); maxnmin residual electron
density 0.279 and ꢀ0.221 e Aꢀ3. Crystallographic data
˚
(excluding structure factors) for compound 5 have been
deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
287968.
17. Huber, I.; Fulop, F.; Bernath, G. J. Heterocycl. Chem.
1987, 24, 1473.
18. Methyl 3-(1,5-cyclohexadienylmethyl)-9-methyl-7-oxo-1,3,
6,7-tetrahydro-2H-pyrido[10,20:1,2]pyrimido[4,5-d]azocine-
5-carboxylate 9: Yellow crystals, mp 248 ꢁC. 1H NMR
(400 MHz, DMSO-d6): d 7.50 (s, 1H), 7.50 (m, 1H), 7.19–
7.11 (m, 6H), 6.78 (m, 1H), 4.37 (s, 2H), 3.87 (s, 2H), 3.78
(t, J = 6 Hz, 2H), 3.56 (s, 3H), 3.14 (t, J = 6 Hz, 2H), 2.88
(s, 3H). 13C NMR (100 MHz, DMSO-d6): d 169.1, 164.3,
161.7, 160.5, 152.6, 142.8, 138.6, 135.2, 132.6, 129.2
(2CH), 128.1 (2CH), 125.1, 118.2, 115.8, 95.8, 59.7, 50.9,
48.8, 40.9, 24.4, 21.3. ESI MS: 390 (M++1). IR (KBr)
1648 and 1597 cmꢀ1. Anal. Calcd for C23H23N3O3: C,
70.93; H, 5.95; N, 10.79. Found: C, 70.83; H, 5.96; N,
10.67.
19. Sheldrick, G. M. SHELXS, Program for Crystal Structure
Solution; University of Go¨ttingen: Germany, 1997.
20. Sheldrick, G. M. SHELXL, Program for Crystal Struc-
ture Refinement; University of Go¨ttingen: Germany,
1997.