The reaction of tetrahydrochromeno[3,4-c]pyridines with activated alkynes. the first synthesis of tetrahydrochromeno[4,3-d]azocines

Article abstract of DOI:10.1016/j.tetlet.2011.06.012

The first synthesis of tetrahydrochromeno[4,3-d]azocines via an alkyne-induced expansion reaction is described.

Full text of DOI:10.1016/j.tetlet.2011.06.012

Tetrahedron Letters 52 (2011) 4189–4191
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Tetrahedron Letters
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The reaction of tetrahydrochromeno[3,4-c]pyridines with activated alkynes.
The first synthesis of tetrahydrochromeno[4,3-d]azocines
Leonid G. Voskressensky a, , Larisa N. Kulikova a, Sergey V. Gozun b, Victor N. Khrustalev c,
⇑
Tatiana N. Borisova a, Anna V. Listratova a, Maxim V. Ovcharov a, Alexey V. Varlamov a
a Organic Chemistry Department of the Russian Peoples’ Friendship University, 6 Miklukho-Maklaya St., Moscow 117198, Russia
b OOO ‘Bioskrining’, 1 Mruzovskiy St., Moscow 105120, Russia
c A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Moscow, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
The first synthesis of tetrahydrochromeno[4,3-d]azocines via an alkyne-induced expansion reaction is
Received 4 April 2011
Revised 20 May 2011
Accepted 3 June 2011
Available online 13 June 2011
described.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Coumarins
Ring-expansion
Domino-reaction
Azocine
Coumarins have been found to exhibit a wide range of biological
and controlled therapeutic activities. They occur extensively in
nature and exhibit low toxicity.1,2 In many cases, the type of bio-
logical action is predetermined by the substituents present on
the main benzopyran skeleton.
dihydro-1H-chromeno[3,4-c]pyridin-5(2H)-one (2), prerequisite
for this study, was prepared via Pechmann condensation of 3-car-
boethoxy-4-piperidone with resorcinol according to the published
procedure.16 To avoid possible side-reactions with alkynes, the
phenolic OH was transformed into OAc by reaction with acetic
anhydride to yield 8-acetoxychromenopyridine 3 (Scheme 1).
The reaction of 3 with methyl propiolate (MP) or acetyl acety-
lene in dry dichloromethane at room temperature17 yielded the
unexpected products, dienes 4 and 5 in 80% and 70% yields, respec-
tively. A plausible mechanism for this transformation is shown in
Scheme 2. Michael addition of the N atom to the triple bond of
the alkyne to form the zwitterionic intermediate A is followed by
tetrahydropyridine ring cleavage and a 1,5-proton shift. The driv-
ing force for this unusual transformation is most likely the creation
of extended conjugation in the resulting products.
Fused 3,4-heterocyclic coumarin derivatives2,3 also show a wide
range of biological activity. Specifically, those bearing a benzopy-
ranone–pyridine or piperidine skeleton were found to: interact
with DNA,4 transfer energy in photophysical processes,5 act as po-
tential platelet activating factor antagonists,6 depressant or hypo-
tensive activators7 and potent antipsychotic agents,8 whereas
others exhibited antibacterial,9 antitumor,10 anticholinergic,11
antiinflammatory12 and antimicrobial13 activities. Much less is
known about coumarins fused with medium-sized azacycles, that
is, azocines. To the best of our knowledge, the only example re-
ported is [1]benzopyrano[3,4-c]azocine 1 ( Fig. 1), formed via a
multi-component reaction between 2-oxo-2H-1-benzopyran-3-
carboxamide and ethyl 3-aminocrotonate.14
The structure of 4 was elucidated unambiguously by the X-ray
diffraction analysis of a single crystal18 (Fig. 2). The molecule of 4
contains two planar fragments, a 2H-chromen-2-one and a vinyla-
mino-2-propenoate (–CH@CH–N–CH@CH–COOMe). The dihedral
The lack of synthetic approaches obviously hampers the biolog-
ical evaluation of this promising heterocyclic system. As part of a
research program related to the development of medium-sized
azacycle synthesis via the alkyne-induced ring-expansion dom-
ino-reaction,15 we herein report the first synthesis of the previ-
ously unknown chromeno[4,3-d]azocine system from readily
available chromenopyridine derivatives. 3-Benzyl-8-hydroxy-3,4-
H2N
O
O
HN
1
O
O
⇑
Corresponding author. Tel.: +7 495 955 07 57; fax: +7 495 955 07 79.
E-mail address: lvoskressensky@sci.pfu.edu.ru (L.G. Voskressensky).
Figure 1.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.012

4190
L. G. Voskressensky et al. / Tetrahedron Letters 52 (2011) 4189–4191
O
O
H+
OH
O
+
N
OH
Bn
Bn
N
Bn
N
Ac2O
O
O
O
O
HO
AcO
3 (82%)
2 (65%)
Figure 2. The ORTEP plot of 4.
Scheme 1. Synthesis of the starting compound 3.
γ
X
X
Bn
Bn
N
Bn
δ
N
X
N
X
H
Bn
O
β
H
[1,5]-shift
N
α
O
CH2Cl2, rt
O
O
O
O
O
O
A
AcO
AcO
AcO
4
5
(80%) X = COOMe
(70%) X = COMe
3
AcO
Scheme 2. Reactions of compound 3 with activated terminal alkynes.
CO2Me
Bn
O
N
Bn
CO2Me
Bn MeOH
N
+δ2
N
CO2Me
+δ1
MeOH/CH2Cl2
pathway b
H
O
O Me
O
AcO
O
AcO
AcO
O
O
A
MeOH
a
pathway
Bn
Bn
N
CO2Me
O
CO2Me
Bn
N
N
MeO2C
MeO2C
1'
MeO
α
H2O
H
Bn
N
O
O
β
-MeOH
O
O
O
AcO
O
O
6 (45%)
AcO
AcO
7
B
(15%)
HO
Scheme 3. Reactions of compound 3 with methyl propiolate in MeOH.
angle between the corresponding planes is 43.1°. The acetyl group
is almost perpendicular to the plane of the 2H-chromen-2-one (the
interplanar angle is 76.8°), and the benzyl group is almost perpen-
dicular to the plane of the vinylamino-2-propenoate (the interpla-
nar angle is 87.7°). The N1 nitrogen atom has a trigonal-planar
configuration. In the crystal state, molecules of 4 are arranged at
van-der-Waals distances.
When the reaction of 3 with MP was carried out in a protic sol-
vent (MeOH/CH2Cl2, 1:1 mixture),19 surprisingly no trace of 4 was
detected in the reaction mixture, and the only products isolated in
this case were the target chromeno[4,3-d]azocine derivative 620
(45%) and 4-vinylchromene 721 (15%) (Scheme 3).
The difference in reactivity can most likely be explained by the
crucial role methanol plays in this reaction. This reaction again
starts with formation of the zwitterion A.
The anionic part of the latter accepts a proton from methanol
(pathway a), thus producing a potent base (methoxide anion), that
causes Hofmann-like cleavage of the tetrahydropyridine ring,
yielding derivative B, which undergoes hydrolysis during column
chromatography, providing 7. The alternative pathway b consti-

L. G. Voskressensky et al. / Tetrahedron Letters 52 (2011) 4189–4191
4191
17. Methyl(E)-3-benzyl[(E)-2-(3-methyl-7-methylcarbonyloxy-2-oxo-2H-4- chromen
yl)-1-ethenyl]amino-2-propenoate (4): To solution of 8-acetoxychromen
tutes a 6-membered ring-expansion reaction, facilitated by the
nucleophilic assistance of MeOH as depicted in Scheme 3.
In conclusion, we have demonstrated, that the reaction of chro-
meno[3,4-c]pyridine with activated alkynes is solvent-dependent
and yields either [(2-oxo-2H-chromen-4-yl)vinyl]amines 4 and 5
(aprotic solvent) or chromeno[4,3-d]azocine 6 and 4-vinylchrom-
ene 7 (protic solvent). Further work aimed at exploring the scope
and limitations of this reaction is underway and the results will
be reported in due course.
a
opyridine 3 (160 mg, 0.46 mmol) in dry CH2Cl2 (5 mL) was added methyl
propiolate (0.05 mL, 0.55 mmol). The reaction mixture was stirred at room
temperature for 3 d (TLC monitoring). After completion, the solvent was
evaporated in vacuo. The residue was purified by recrystallization (EtOAc).
Yield 143 mg, (80%), yellow solid, mp 166–168 °C (EtOAc); Anal. Calcd for
C
25H23NO6: C, 69.27; H, 5.35; N 3.23. Found C, 69.4; H, 5.3; N 3.3. Rf (silufol,
EtOAc/hexane, 1:1) 0.64; mmax (KBr) 1752, 1709, 1614 cmꢀ1; dH (400 MHz,
CDCl3) 7.66 (1H, s, -CH) 7.22–7.37 (4H, m, CH-Ar), 7.12–7.17 (2H, m, CH-Ar),
6.98 (1H, s, 8-H), 6.84 (1H, d, J 8.7 Hz, 6-H), 6.76 (1H, d, J 14.3 Hz, b-CH), 5.56
(1H, d, J 14.3 Hz, -CH), 5.12 (1H, d, J 13.7 Hz, d-CH), 4.76 (2H, s, CH2-Ar), 3.64
c
a
(3H, s, CO2CH3), 2.24 (3H, s, COCH3), 2.04 (3H, s, 3-CH3); dC (100 MHz, CDCl3)
168.8, 168.5, 161.9, 152.8, 152.1, 148.3, 148.0, 144.3, 140.1, 135.2, 134.2, 129.3,
128.8, 128.1, 126.7, 126.5, 126.3, 126.1, 117.8, 110.2, 100.9, 93.9, 51.3, 21.1,
14.7; m/z (LC–MS) 434 [M+H].
Acknowledgments
This work was supported by a Grant of the RF President (MR-
1048.2010.3) and The Russian Foundation for Basic Research
(Grant 11-03-00164)
18. The crystal of
4
(C25H23NO6, M = 433.44) is triclinic, space group P-1, at
= 108.001(1)o,
= 117.401(1)o, V = 1065.70(9) Å3, Z = 2, dcalc = 1.351 g/cm3,
= 0.097 mmꢀ1
13745 total reflections (6225 unique
T = 100 K: a = 9.8565(4) Å, b = 10.6047(4) Å, c = 12.3764(8) Å,
a
b = 92.462(1)o,
F(0 0 0) = 456,
c
l
;
reflections, Rint = 0.024) were measured on a three-circle Bruker SMART APEX
II CCD diffractometer (k(MoK )-radiation, graphite monochromator, / and
x
References and notes
a
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displacement parameters [Uiso(H) = 1.5 Ueq(C) for the CH3-groups and
Uiso(H) = 1.2 Ueq(C) for the other groups]. The final divergence factors were
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19. Experimental procedure for the synthesis of chromenoazocine 6 and chromene 7:
To
a solution of 8-acetoxychromenopyridine 3 (130 mg, 0.37 mmol) in a
mixture of MeOH/CH2Cl2 (10 mL, 1:1) was added methyl propiolate (0.42 mL,
0.45 mmol). The mixture was stirred at room temperature for 1 d (TLC
monitoring). After completion the solvent was evaporated in vacuo. The
residue was purified by column chromatography to give chromenoazocine 6 as
a white solid and chromene 7 as a yellow oil.
20. Methyl3-benzyl-10-methylcarbonyloxy-7-oxo-1,3,6,7-tetrahydro-2H-chromeno[4,
3-d]azocine-5-carboxylate (6): Purified by column chromatography (SiO2,
MeOH/CHCl3, 1:50), yield 72 mg, (45%), as a white solid, mp 273–274 °C
(EtOAc); Anal. Calcd for C25H23NO6: C, 69.27; H, 5.35; N 3.23. Found: C, 69.2; H,
5.1; N 3.3. Rf (silufol, EtOAc/hexane, 1:1) 0.67; mmax (KBr) 1763, 1709, 1613
cmꢀ1; dH (400 MHz, CDCl3) 7.60 (1H, s, 4-H) 6.95–7.00 (7H, m, CH-Ar), 6.80 (1H,
dd, J 2.4, 8.8 Hz, 12-H), 4.22 (2H, s, 2-CH2), 3.97 (2H, s, CH2-Ar), 3.82 (2H, t, J
6.5 Hz, 2-CH2) 3.70 (3H, s, CO2CH3), 2.98 (2H, t, J 6.5 Hz, 1-CH2), 2.26 (3H, s,
COCH3); dC (100 MHz, CDCl3) 169.9, 168.8, 161.2, 152.4, 152.2, 152.0, 145.6,
137.1, 128.8 (2C), 128.2, 127.5 (2C), 124.9, 124.5, 188.4, 117.6, 110.0, 95.1, 62.0,
51.5, 48.8, 31.1, 23.7, 21.2; m/z (LC–MS) 434 [M+H]+.
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21. Methyl (E)-3-benzyl(7-hydroxy-2-oxo-4-vinyl-2H-3-chromenylmethyl)amino-2-
propenoate (7): Purified by column chromatography (SiO2, MeOH/CHCl3,
1:20), yield 24 mg, (15%), as
70.58; H, 5.41; N 3.58. found C, 70.4; H, 5.5; N, 3.7. Rf (silufol, EtOAc/hexane,
1:1) 0.25;
max (KBr) 1720, 1612 cmꢀ1; dH (400 MHz, CDCl3) 9.80 (1H, br s, OH),
7.61 (1H, d, J 13.1 Hz, N-CH@CH), 6.64–7.26 (6H, m, CH-Ar), 6.63 (1H, t, J 2.4 Hz,
6-H), 6.61 (1H, d, J 2.1 Hz, 8-H), 6.58 (1H, dd, J 11.8, 17.8 Hz, -CH), 5.77 (1H,
a yellow oil; Anal. Calcd for C23H21NO5: C,
m
a
dd, J 1.2, 11.8 Hz, b-CH), 5.41 (1H, d, J 17.8 Hz, b-CH), 4.62 (1H, d, J 13.1 Hz, N–
CH@CH), 4.46 (2H, s, CH2-Ar), 4.24 (2H, s, 10-CH2), 3.57 (3H, s, COCH3); m/z (LC–
MS) 392 [M+H]+
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