A novel synthesis of pyrrolo[1,2-d][1,4]diazocines from tetrahydropyrrolo[1,2-a] pyrazines using activated alkynes in pyrazine ring expansion

Article abstract of DOI:10.1016/j.tet.2010.04.104

A novel and efficient one-pot synthesis of pyrrolo[1,2-d][1,4]diazocines based on tandem transformation of tetrahydropyrazine ring was elaborated.

Full text of DOI:10.1016/j.tet.2010.04.104

Tetrahedron 66 (2010) 5140e5148
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A novel synthesis of pyrrolo[1,2-d][1,4]diazocines from tetrahydropyrrolo[1,2-a]
pyrazines using activated alkynes in pyrazine ring expansion
,
a
a
a
Leonid G. Voskressensky a , Alexander A. Titov , Tatiana N. Borisova , Anna V. Listratova ,
*
Roman S. Borisov b, Larisa N. Kulikova a, Alexey V. Varlamov a
a Organic Chemistry Department of the Russian Peoples’ Friendship University, 6, Miklukho-Maklaia St., Moscow 117198, Russia
b A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Science, 29, Moscow 119991, Leninsky ave., Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient one-pot synthesis of pyrrolo[1,2-d][1,4]diazocines based on tandem transformation
of tetrahydropyrazine ring was elaborated.
Received 2 February 2010
Received in revised form 6 April 2010
Accepted 26 April 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Available online 22 May 2010
Keywords:
Pyrrolopyrazines
Pyrrolo[1,4]diazocines
Activate alkynes
Ring expansion
Michael addition
1. Introduction
We have previously developed an original and efficient
method for the synthesis of tetrahydropyrrolo[3,2-d]azocines
Among numerous biologically active aryl- and heteroaryl-fused
six and seven-membered 1,4-diazaheterocyclesdpiperazines1 and
diazepines,2 their eight- and nine-membered congeners represent
an apparently underexplored group with immense therapeutic
potential. In many cases their structures strongly resemble the
whole composition of low-membered analogues in accordance to
the fundamental bioisosteric rules.3
based on the transformation of tetrahydropyrrolo[3,2-c]pyridines
under the action of activated alkynes.7 Subsequent research of the
tandem transformations of tetrahydropyrrolo[1,2-a]pyrimidines,8
tetrahydro-
b and g
-carbolines,9 tetrahydrothieno[3,2-c] and
[2,3-c]pyridines and their benzo analogues10 showed that this
reaction is a general one for the annulated tetrahydropyridine
system.
The few pathways towards benzoannulated pyrrolodiazocines
include Ugi-type reaction and Dieckman condensation4 of ade-
quately substituted pyrroles and a multi-step synthesis of fully
hydrogenated pyrrolo[1,2-a][1,4]diazocines and pyrrolo[1,2-a][1,5]
diazocines starting from proline and pyroglutamic acid.5 It was
shown that pyrrolo[1,2-a][1,4]diazocines could be used as di-
peptide reverse-turn mimetics6 exhibiting cognition enhancing
activity.
In this paper we report on the reactivity of 1-methyl-2-aryl-6-R-
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines in the reaction with ac-
tivated alkynes. The main goal of this study was to elaborate a new
method for the synthesis of pyrrolo[1,2-d][1,4]diazocines.
2. Results and discussion
Based on the obtained data we could presume that the pathway
of the reaction is defined by different factors: (a) the nature of the
solvent; (b) the electronic effects of the substituents both on the
tetrahydropyridines fragment and on the fused aromatic ring; (c)
the type of the linkage between tetrahydropyridine and aromatic
rings.
* Corresponding author. Tel.: þ7 495 955 0757; fax: þ7 495 955 0779; e-mail
address: lvoskressensky@sci.pfu.edu.ru (L.G. Voskressensky).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.104

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
5141
R1
R1
In aprotic solvents tetrahydropyrrolo[3,2-c]pyridines produce
R2I
mixtures containing tetrahydropyrrolo[2,3-d]azocines 1 and 3-vi-
nyl substituted pyrroles 2 in the various ratio. In the case of re-
actions in methanol the main products are 3-alkoxy(hydroxy)
alkyl-pyrroles 3, the latter compounds can be cyclized into pyr-
roloazocine by the action of electrophilic agents (yield 70e75%)
(Scheme 1).
N
R2
N
N
MeCN
N
I
6-8
NaBH4
R1
NaBH4
S
R2
N
N
OMe
N
R1
R1
Y
N
12
H
9-11
R1
X
R
X
R2
or
(CF3CO)2O
Py
N
R2
POCl3
DMF
1)Ac2O
2) LiAlH4
R
N
H
N
N
H
R1
R1
3
S
Y
POCl3,DMF
R2
N
N
O
R1
or
N
N
Y
Et
(CF3CO)2O,Py
R3 14-21
R
X
13
N
+
R2
R2
N
H
N
Scheme 3.
R1
N
H
R
X
Y
R1
R=R1=R1=Me
1
2
Table 1
Pyrrolo[1,2-a]pyrazines 14e21
X=Y=CO2Me
X=H, Y=CO2Me
R3=CH=CH2,
R1=R1=H R=Bn
R2=CHO, COCF3,
COMe, C=C(CN)2
Compound
R1
R2
R3
CH(Me)OMe(Et), CH(Me)OH
9
Ph
Ph
Me
Et
Me
Me
Et
Me
Et
Me
Et
d
d
d
H
H
H
10
11
14
15
16
17
18
19
20
21
Scheme 1.
p-MeeC6H4
Ph
Ph
p-MeeC6H4
Th
Ph
Ph
Tetrahydropyrrolo[1,2-a]pyrimidines under the action of al-
kynes in protic solvents undergo the cleavage process of tetrahy-
dropyrimidine ring thus forming only substituted pyrroles 4 and 5
(Scheme 2).
H
CF3
CF3
CF3
CF3
p-MeeC6H4
Th
Me
Et
COCF3
Me
N
Me
N
H
both in methanol and in acetonitrile require an excess of the alkyne
(from 2 upto 10-fold molar excess) and more forcing conditions
(reflux). At room temperature reactions proceeded very slowly. In
the case of reactions with acetylacetylene pyrrolopyrazines 14 and
16 reacted smoothly at 30 ꢀC but pyrrolopyrazine 15 required
reflux. However in all cases tandem transformation leads to the
enlargement of tetrahydropyrazine ring yielding pyrrolodiazocines
22e27 (Scheme 4, Table 2). The time of the reactions varies from 4
to 100 h.
Y
Me
Me
X
COCF3
X
4
N
Y
+
N
Me
Me
Me
COCF3
N
R1
Me
5
Y
R1
X=Y=CO2Me, R=H, CH2OMe
X=H, Y=CO2Me, R=H
O
R1
O
N
Y
N
R1=H, CH2-N(Me)-CH=CH-CO2Me
H
H
N
R2
N
Scheme 2.
R2
14-16
22-27
The synthesis of starting tetrahydropyrrolo[1,2-a]pyrazines
14e21 required for the present study is shown in Scheme 3.
Dihydropyrrolopyrazines 6e8 were obtained according to the
previously described procedure.11 The subsequent quaternization
of compounds 6 and 7 by methyl or ethyl iodide and reduction of
the obtained quaternary salts by the action of NaBH4 led to the
formation of N-alkyl substituted intermediate tetrahydropyrrolo
[1,2-a]pyrazines 9e11. N-Ethyl tetrahydropyrrolopyrazine 13 were
synthesized via acylation of corresponding dihydropyrrolopyrazine
12 followed by reduction with LiAlH4 in THF. The required pyrro-
lopyrazines 14e21 were obtained by formylation or tri-
fluoroacylation of corresponding tetrahydropyrrolopyrazines 9e11
and 13 (Scheme 3, Table 1).
Scheme 4.
Table 2
Tetrahydropyrrolo[1,2-d][1,4]diazocines 22e27
Compound
R1
R2
Y
22
23
24
25
26
27
Ph
Ph
Me
Et
Me
Me
Et
CO2Me
CO2Me
CO2Me
COMe
COMe
COMe
p-MeeC6H4
Ph
Ph
p-MeeC6H4
Me
Unlike pyrrolopyridines and pyrrolopyrimidines reactions of
formyl substituted pyrrolopyrazines 14e16 with methyl propiolate
Reaction of compound 14 with DMAD in refluxing acetonitrile
for 3 weeks yielded only a multi-component mixture.

5142
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
The reaction of compounds 16 with DMAD in methanol led to
the cleavage process involving one molecule of the solvent thus
S
giving substituted pyrrole 28 in yield 65% (Scheme 5).
R
N
Y
Y
S
R
N
N
N
Et
Et
MeOH
E
4'
3'
37 39
-
17, 21
R
O
H
R
E
Scheme 7.
N
N
O
H
Me
O
N
MeOH
Me
Table 4
Tetrahydropyrrolo[1,2-d][1,4]diazocines 37e39
N
E
16
Me
Compound
R
Y
E
R=p-Me-C6H4
28
37
38
39
CHO
CHO
COCF3
CO2Me
COMe
CO2Me
E = CO2Me
Scheme 5.
Trifluoroacetyl substituted pyrrolopyrazines 18e20 do not react
with activated alkynes in acetonitrile even under reflux. In the case
of reactions with methyl propiolate and acetylacetylene in reflux-
ing methanol two concurrent processesdenlargement and cleav-
age of tetrahydropyrazine ringdtook place producing the mixtures
of pyrrolodiazocines 29e34 and methoxyalkyl substituted pyrroles
35 and 36 (Scheme 6 and Table 3).
singlets at
d
¼7.43e7.69 ppm. In the 1H NMR spectra of pyrroles 28,
35, 36 characteristic protons resonate: as singlets for three protons
at
d
¼4.75e5.32 ppm from methoxy group and as singlet at
d¼4.77e5.39 ppm (28) or two broad singlets at ¼4.64e5.09 and
d
d¼7.27e7.53 ppm (35 and 36) from enamine fragment.
We presume that the tandem transformation starts with the
formation of zwitterion A. Intramolecular substitution in the
zwitterion A leads to the enlargement of the tetrahydropyrazine
fragment thus forming 1,2,3,6-tetrahydropyrrolo[1,2-d][1,4]diazo-
cines 22e27, 29e34 and 37e39. In the case of reactions in
methanol intermediate, B could be stabilized by the nucleophilic
assistance of the solvent resulting into the cleavage of the pyrazine
ring (Scheme 8).
R1
O
N
F3C
N
R2
18-20
Y
MeOH
R1
3'
4'
O
R1
O
N
Y
R1
R
N
O
O
F3C
N
Y
Me
N
+
R2
22-27, 29-34, 37-39
F3C
N
R2
35, 36
3
N
R2
2
29-34
Y
Y
Scheme 6.
R1
O
O
R1
R2
Y
N
N
N
Table 3
Tetrahydropyrrolo[1,2-d][1,4]diazocines 29e34 and pyrrole 35e36
N
R
R
N
MeOH
R2
A
Compound
R1
R2
Y
14-21
29
30
31
32
33
34
35
36
Ph
Ph
Me
Et
Me
Me
Et
Me
Me
Me
CO2Me
CO2Me
CO2Me
COMe
COMe
COMe
CO2Me
COMe
CH3
O
R1
O
R1
p-MeeC6H4
O
H
Ph
Ph
N
F3C
O
Me
R
N
Y
p-MeeC6H4
R2
B
Ph
Ph
N
R2
Y
35, 36
1-Thienyl substituted tetrahydropyrrolo[1,2-a]pyrazines 17
and 21 did not react with alkynes even in refluxing acetonitrile
and with the use of excess of the reagent. In methanol at 55 ꢀC
formyl pyrrolopyrazine 17 reacted with methyl propiolate and
acetylacetylene smoothly in 48 and 32 h, respectively, yielding
only pyrrolodiazocines 37 and 38. Analogously, under the same
conditions trifluoroacetyl substituted pyrrolopyrazine 21 in the
presence of methyl propiolate gave pyrrolodiazocine 39 (Scheme
7, Table 4).
Scheme 8.
In the case of reaction with DMAD we consider the possibility of
delocalization of anionic center between two ester groups. This
process diminishes nucleophilicity of anionic center facilitating the
cleavage process of tetrahydropyrazine ring via the intermediate B
(Scheme 9).
3. Conclusion
The structures of pyrrolodiazocines 22e27, 29e34 and 37e39
and pyrroles 28, 35, 36 were confirmed by spectral data. The 1H
NMR spectra of pyrrolodiazocines 22e27, 29e34 and 37e39 have
similar characteristic signals: the enamine protons resonate as
We have elaborated a new method for the synthesis of tetra-
hydropyrrolodiazocines based on tandem cleavage-cyclization re-
action of easy available tetrahydropyrrolpyrazine derivatives.

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
5143
E
hexane); [Found: C, 79.3; H, 7.9; N, 12.2. C15H18N2 requires C, 79.61;
H, 8.02; N, 12.38%]; Rf (1:2 ethyl acetate/hexane) 0.36; dH (400 MHz,
CDCl3) 7.40e7.29 (5H, m, Ph), 6.57e6.56 (1H, m, 6-H), 6.08 (1H, dd, J
3.4, 2.8 Hz, 7-H), 5.37e5.36 (1H, m, 8-H), 4.49 (1H, s, 1-H), 4.21 (1H,
td, J 11.2, 4.4 Hz, 4-CH2), 4.05 (1H, ddd, J 11.6, 3.9, 2.9 Hz, 4-CH2),
3.31 (1H, ddd, J 12.1, 4.3, 2.9 Hz, 3-CH2), 2.75 (1H, ddd, J 12.1, 11.1,
3.9 Hz, 3-CH2), 2.72e2.64 (1H, m, NCH2Me), 2.26 (1H, qd, J 13.8,
7.0 Hz, NCH2Me), 1.05 (3H, t, J 7.0 Hz, NCH2Me); dC (150.9 MHz,
CDCl3) 142.5, 131.6, 128.8 (2C), 128.2 (2C), 127.3, 118.1, 108.0, 105.3,
65.6, 47.9, 47.7, 44.6, 11.7; m/z (EI, 70 eV) 226 (9, Mþ), 225 (10), 168
(17), 167 (10), 149 (100), 94 (10), 91 (11), 77 (20), 56 (9), 51 (22), 42
(25), 41 (17), 39 (18%).
O
R1
R1
O
E
N
N
R
N
R
E
N
MeOH
Me
A
Me
16
E
E = CO2Me
H3C
R1
R1
O
O
H
N
H
E
O
O
N
N
Me
Me
E
R
N
B
E
Me
28
4.2.3. 2-Methyl-1-(4-methylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]
pyrazine (11). Yield 2.06 g (91%), as brown oil; [Found: C, 79.4; H,
8.3; N, 12.2. C15H18N2 requires C, 79.61; H, 8.02; N, 12.38%]; Rf
(silufol, ethyl acetate) 0.46; dH (400 MHz, CDCl3) 7.21 (2H, d, J
7.8 Hz, CHeAr), 7.11 (2H, d, J 7.8 Hz, CHeAr), 6.52 (1H, s, 6-H), 6.02
(1H, t, J 2.6 Hz, 7-H), 5.28 (1H, s, 8-H), 4.20 (1H, td, J 11.7, 4.3 Hz, 4-
CH2), 4.09 (1H, s,1-H), 4.00e3.95 (1H, m, 4-CH2), 3.12 (1H, dd, J 11.9,
2.9 Hz, 3-CH2), 2.77 (1H, dd, J 11.9, 3.8 Hz, 3-CH2), 2.33 (3H, s, NMe),
2.18 (3H, s, C6H4eMe-p); dC (150.9 MHz, CDCl3) 138.9, 137.1, 131.8,
128.9 (2C), 128.8 (2C), 118.2, 108.1, 105.1, 68.1, 53.0, 44.7, 43.5, 21.1;
m/z (EI, 70 eV) 226 (2, Mþ), 211 (11), 210 (100), 209 (53), 208 (5),195
(27),182 (13),181 (7),168 (8), 167 (9), 91 (7), 65 (9), 42 (7), 41 (7), 39
(7%).
E
Scheme 9.
4. Experimental section
4.1. General
All solvents were distilled and dried before use, DMAD, acetyla-
cetylene and methyl propiolate were purchased from ACROC OR-
GANICS and were used without any additional purification. Column
chromatography was performed with aluminium oxide, activated,
neutral, Brockmann I purchased from ACROS ORGANIC. 1H and 13
C
NMR spectra were recorded in CDCl3 solutions, at 25 ꢀC, using a 400
or 600 MHz NMR spectrometer, peak positions are given in parts per
4.3. 1-(2-Thienyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
(12)
million (d) with tetramethylsilane used as the internal standard.
Mass-spectra were registered using ESI or EI techniques. IR spectra
were recorded with a PerkineElmer Spectrum One instrument. Only
noteworthy IR absorptions [cmꢁ1] are listed. Melting points were
determined in capillary tube and are uncorrected.
To a stirred solution of pyrrolopyrazine 8 (5.8 g, 219 mmol) in
methanol (20 mL), NaBH4 (2.7 g, 73 mmol) was added in small
portions. The stirring was continued for 48 h at 50 ꢀC (TLC moni-
toring). After completion of the reaction, the solvent was evapo-
rated in vacuo, the residue was dissolved in water (15 mL) and
extracted with ether (3ꢂ20 mL). The combined organic layers were
dried with MgSO4. The solvent was evaporated in vacuo to give
pyrrolopyrazine 12 (2.23 g, 45%) as yellow solid, mp 92e93 ꢀC
(ethyl acetate/hexane); [Found: C, 64.5; H, 5.8; N, 13.5. C11H12N2S
requires C, 64.67; H, 5.92; N, 13.71%]; Rf (alufol, 20:1, i-PrOH/NH3)
0.69; dH (400 MHz, CDCl3) 7.21 (1H, d, J 4.9 Hz, CHeTh), 7.01 (1H, d, J
3.0 Hz, 6-H), 6.92 (1H, dd, J 4.9, 3.7 Hz, CHeTh), 6.55 (1H, s, CHeTh),
6.09 (1H, t, J 3.0 Hz, 7-H), 5.77e5.76 (1H, m, 8-H), 5.39 (1H, s, 1-H),
4.04e3.88 (2H, m, 4-CH2), 3.37e3.29 (1H, m, 3-CH2), 3.24e3.15 (1H,
m, 3-CH2), 2.10 (1H, s, NH); dC (150.9 MHz, CDCl3) 144.4, 141.0,
126.5, 126.2, 125.7, 116.1, 106.1, 104.0, 55.7, 47.9, 46.7; m/z (EI, 70 eV)
204 (57, Mþ), 203 (75),174 (18),121 (65), 94 (20), 92 (26), 67 (18), 65
(20), 51 (17), 45 (41), 42 (20), 41 (39), 39 (100), 38 (18%).
4.2. General procedure for the synthesis of
tetrahydropyrrolopyrazines 9e11
A solution of alkyl iodide (12 mmol) in acetonitrile (5 mL) was
added dropwise to a stirred solution of dihydropyrrolopyrazine
(10 mmol) in acetonitrile (7 mL). The reaction mixture was heated
at reflux for 3 h (TLC monitoring). After completion of the reaction
the solvent was evaporated in vacuo to give the corresponding salt.
The salt (12 mmol) was dissolved in methanol (17 mL) and the
resulting solution was stirred. NaBH4 (1.89 g, 50 mmol) was added
to the stirred solution by small portions. The stirring was continued
for 5 days (TLC monitoring). The solvent was evaporated in vacuo.
The resulting mixture was dissolved in water (30 mL) and extracted
with ether (3ꢂ50 mL). The combined organic layers were dried
with MgSO4. The solvent was evaporated in vacuo to give the target
tetrahydropyrrolopyrazines 9e11.
4.4. 2-Ethyl-1-(2-thienyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]
pyrazine (13)
4.2.1. 2-Methyl-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
(9). Yield 1.63 g (77%) as white solid, mp 73e75 ꢀC (ethyl acetate/
hexane); [Found: C, 78.9; H, 7.9; N, 13.1. C14H16N2 requires C, 79.21;
H, 7.60; N, 13.20%]; Rf (1:1, ethyl acetate/hexane) 0.70; dH (400 MHz
CDC13) 7.39e7.29 (5H, m, Ph), 6.57 (1H, s, 6-H), 6.07 (1H, t, J 2.7 Hz,
7-H), 5.33e5.31 (1H, m, 8-H), 4.25 (1H, td, J 11.8, 4.3 Hz, 4-CH2), 4.16
(1H, s, 1-H), 4.04e4.00 (1H, m, 3-CH2), 3.19e3.14 (1H, m, 4-CH2),
2.82 (1H, td, J 11.8, 3.9 Hz, 3-CH2), 2.22 (3H, s, NMe); dC (150.9 MHz,
CDCl3) 141.9, 131.5, 128.9 (2C), 128.2 (2C), 127.6, 118.3, 108.1, 105.2,
68.4, 53.0, 44.7, 43.6; m/z (EI, 70 eV) 212 (14, Mþ), 211 (17), 168 (15),
167 (10), 135 (100), 77 (24), 51 (16), 42 (33), 39 (10%).
Freshly distilled acetic anhydride (5.4 g, 53 mmol) was added to
pyrrolopyrazine 12 (2.2 g, 11 mmol). The reaction mixture was
stirred for 2 h (TLC monitoring). After completion of the reaction,
the pH was adjusted to 9e10 by addition of 40% aqueous Na2CO3.
The resulting solution was extracted with CH2Cl2 (3ꢂ20 mL). The
combined organic layers were dried with MgSO4. The solvent was
evaporated in vacuo to give intermediate N-acetyl substituted
pyrrolopyrazine (1.8 g, 68%) as white solid, mp 100e102 ꢀC.
To a stirred suspension of LiAlH4 (2.34 g, 61.6 mmol) in THF
(100 mL) N-acetyl substituted pyrrolopyrazine (1.9 g, 7.7 mmol)
was added by small portions. The reaction was carried out under an
argon atmosphere. The reaction completed in 3 h (TLC monitoring).
After completion ethyl acetate (10 mL), water (7 mL) and 30%
aqueous solution of NaOH (25 mL) were added to the stirred
4.2.2. 2-Ethyl-1-phenyl-1,2,3,4-tetrahydropyrrolopyrazine
(10).
Yield 1.47 g (65%), as yellowish solid, mp 52e53 ꢀC (ethyl acetate/

5144
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
reaction mixture. The resulting solution was poured into a funnel
and extracted with ethyl acetate (3ꢂ100 mL). The combined or-
ganic layers were dried with MgSO4. The solvent was evaporated in
vacuo to give pyrrolopyrazine 13 (1.0 g, 59%) as white solid, mp
45e46 ꢀC (ethyl acetate/hexane); [Found: C, 66.9; H, 6.8; N, 11.9.
C13H16N2S requires C, 67.20; H, 6.94; N, 12.06%]; Rf (sorbfil, 2:3,
ethyl acetate/hexane) 0.73; dH (400 MHz, CDCl3) 7.25 (1H, d, J
4.9 Hz, CHeTh), 7.03 (1H, d, J 2.9 Hz, 6-H), 6.94 (1H, dd, J 4.9, 3.2 Hz,
CHeTh), 6.55 (1H, s, CHeTh), 6.10 (1H, t, J 2.9 Hz, 7-H), 5.64e5.63
(1H, m, 8-H), 4.92 (1H, s, 1-H), 4.13e3.99 (2H, m, 4-CH2), 3.31 (1H,
td, J 12.4, 4.3 Hz, 3-CH2), 2.85e2.72 (2H, m, 3-CH2 and NCH2Me),
2.38 (1H, qd, J 13.7, 7.0 Hz, NCH2Me), 1.10 (3H, t, J 7.0 Hz, NCH2Me);
dC (150.9 MHz, CDCl3) 146.8, 143.3, 126.0, 125.8, 125.3, 118.3, 108.0,
105.4, 59.7, 47.6, 47.2, 44.0, 12.0; m/z (EI, 70 eV) 232 (46, Mþ), 231
(38), 203 (9), 174 (34), 149 (100), 121 (14), 97 (20), 94 (20), 77 (11),
65 (13), 56 (17), 51 (14), 45 (30), 42 (48), 41 (31), 39 (71%).
13.5, 3.0 Hz, 4-CH2), 4.40e4.31 (1H, m, 4-CH2), 4.17 (1H, s, 1-H), 3.19
(1H, dd, J 11.8, 3.9 Hz, 3-CH2), 2.78 (1H, td, J 11.8, 4.0 Hz, 3-CH2), 2.35
(3H, s, NMe), 2.21 (3H, s, C6H4eMe-p); dC (100.6 MHz, CDCl3) 178.9,
141.7, 137.8, 137.5, 130.4, 129.2 (2C), 128.7 (2C), 123.8, 108.3, 67.8,
52.2, 45.3, 43.4, 21.1; m/z (EI, 70 eV) 254 (40, Mþ), 253 (35), 225
(26), 210 (6), 196 (7), 167 (6), 164 (11), 163 (100), 132 (9), 112 (6), 42
(7%).
4.5.4. 2-Ethyl-1-(2-thienyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azine-6-carbaldehyde (17). Yield 1.0 g (78%), yellow oil; [Found: C,
64.3; H, 6.0; N, 10.6. C14H16N2OS requires C, 64.58; H, 6.19; N,
10.76%]; Rf (silufol, 1:2, ethyl acetate/hexane) 0.73; nmax (KBr)
1663 cmꢁ1
; dH (400 MHz, CDCl3) 9.46 (1H, s, CHO), 7.28e7.26 (1H,
m, CHeTh), 7.04 (1H, d, J 3.5 Hz, CHeTh), 6.95 (1H, dd, J 5.1, 3.5 Hz,
CHeTh), 6.81 (1H, d, J 4.0 Hz, 7-H), 5.76 (1H, d, J 4.0 Hz, 8-H), 4.95
(1H, s, 1-H), 4.64 (1H, td, J 13.6, 4.0 Hz, 4-CH2), 4.32 (1H, ddd, J 13.7,
9.5, 4.5 Hz, 4-CH2), 3.31 (1H, td, J 12.6, 4.3 Hz, 3-CH2), 2.82e2.69
(2H, m, 3-CH2 and NCH2Me), 2.36 (1H, qd, J 13.8, 7.0 Hz, NCH2Me),
1.09 (3H, t, J 7.0 Hz, NCH2Me); dC (150.9 MHz, CDCl3) 179.1, 144.7,
140.2, 130.4, 126.6, 126.1, 126.0, 123.8, 108.4, 59.8, 47.7, 46.6, 44.9,
11.8; m/z (EI, 70 eV) 260 (75, Mþ), 231 (100), 202 (40), 177 (94), 174
(10), 147 (8), 122 (10), 108 (13), 97 (18), 56 (8%).
4.5. General procedure for the synthesis of pyrrolo[1,2-a]
pyrazines 14e17
Freshly distilled POCl3 (1.54 g, 10 mmol) was added dropwise to
cooled (ꢁ5 ꢀC) DMF (2.31 ml, 30 mmol) maintaining the tempera-
ture. The resulting solution was stirred for 40 min at room tem-
perature and pyrrolopyrazine (5 mmol) dissolved in DMF (3 mL)
was added. The stirring was continued for 8 h (TLC monitoring).
The pH of the reaction mixture was adjusted to 9e10 (10% aqueous
NaOH). The resulting solution was extracted with ether (3ꢂ20 mL).
The combined organic layers were dried with MgSO4. The solvent
was evaporated in vacuo to give the target pyrrolopyrazines 14e17.
4.6. General procedure for the synthesis of pyrrolo[1,2-a]
pyrazines 18e21
Trifluoroacetic anhydride (2.78 ml, 20 mmol) was added drop-
wise to a stirred solution of pyrrolopyrazine (10 mmol) and pyri-
dine (2.00 ml, 25 mmol) in dry CH2Cl2 (40 mL). The stirring was
continued at 35 ꢀC (TLC monitoring). After completion, the pH of
the reaction mixture was adjusted to 9e10 by addition of 40%
aqueous Na2CO3. The resulting solution was extracted with CH2Cl2
(3ꢂ50 mL). The combined organic layers were dried with MgSO4.
The solvent was evaporated in vacuo to crude product, which was
purified by column chromatography or recrystalization to give
pyrrolopyrazines 18e21.
4.5.1. 2-Methyl-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-
6-carbaldehyde (14). Yield 0.60 g (50%), yellowish solid, mp
138e139 ꢀC (ethyl acetate/hexane); [Found: C, 74.7; H, 6.6; N, 11.5.
C15H16N2O requires C, 74.97; H, 6.71; N, 11.66%]; Rf (alufol, 1:3, ethyl
acetate/hexane) 0.49; nmax (KBr) 1646 cmꢁ1
; dH (400 MHz, CDCl3)
9.46 (1H, s, CHO), 7.37e7.32 (5H, m, Ph), 6.78 (1H, d, J 4.1 Hz, 7-H),
5.48 (1H, d, J 4.1 Hz, 8-H), 4.75 (1H, dd, J 13.5, 2.5 Hz, 4-CH2),
4.42e4.32 (1H, m, 4-CH2), 4.21 (1H, s, 1-H), 3.20 (1H, ddd, J 12.1, 4.4,
1.3 Hz, 3-CH2), 2.80 (1H, td, J 12.1, 4.0 Hz, 3-CH2), 2.23 (3H, s, NMe);
dC (150.9 MHz, CDCl3) 179.1, 141.4, 140.5, 130.4, 128.8 (2C), 128.6
(2C),128.1,124.0,108.3, 68.1, 52.2, 45.5, 43.5; m/z (EI, 70 eV) 240 (31,
Mþ), 239 (16), 211 (17),196 (8),167 (6),164 (9),163 (100), 77 (12), 51
(7), 42 (19%).
4.6.1. 2,2,2-Trifluoro-1-(2-methyl-1-phenyl-1,2,3,4-tetrahy-
dropyrrolo[1,2-a]pyrazin-6-yl)ethanone (18). Purified by column
chromatography (ethyl acetate/hexane, 1:8), yield 1.66 g (54%), as
yellowish solid, mp 111e113 ꢀC (ethyl acetate/hexane); [Found: C,
62.0; H, 4.8; N, 8.9. C16H15F3N2O requires C, 62.33; H, 4.90; N,
9.09%]; Rf (sorbfil, 1:2, ethyl acetate/hexane) 0.64; nmax (KBr)
1651 cmꢁ1
; dH (400 MHz, CDCl3) 7.37e7.32 (5H, m, Ph), 7.09e7.06
4.5.2. 2-Ethyl-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-6-
carbaldehyde (15). Yield 0.61 g (48%), yellow solid, mp 87e89 ꢀC
(ether); [Found: C, 75.9; H, 7.1; N, 10.7. C16H18N2O requires C, 75.56;
H, 7.13; N, 11.01%]; Rf (alufol, 1:3, ethyl acetate/hexane) 0.55; nmax
(1H, m, 7-H), 5.55 (1H, d, J 4.5 Hz, 8-H), 4.73 (1H, dd, J 13.7, 2.7 Hz,
4-CH2), 4.45e4.35 (1H, m, 4-CH2), 4.22 (1H, s, 1-H), 3.24 (1H, dd, J
12.2, 4.6 Hz, 3-CH2), 2.81 (1H, dd, J 12.2, 4.0 Hz, 3-CH2), 2.24 (3H, s,
2
NMe); dC (100.6 MHz, CDCl3) 169.4 (q, JC,F 35 Hz), 144.4, 140.0,
(KBr) 1654 cmꢁ1
;
dH (400 MHz, CDCl3) 9.46 (1H, s, CHO), 7.35e7.30
128.8 (2C), 128.7 (2C), 128.4, 123.6 (q, 3JC,F 4 Hz), 123.5, 117.2 (q, 1JC,F
291 Hz), 109.5, 68.3, 52.1, 46.3, 43.4; m/z (EI, 70 eV) 308 (17, Mþ),
307 (10), 232 (10), 231 (100), 211 (9), 134 (8), 118 (7), 91 (6), 77 (16),
69 (7), 51 (9), 42 (21%).
(5H, m, Ph), 6.78 (1H, d, J 4.1 Hz, 7-H), 5.50 (1H, dd, J 4.1, 0.5 Hz, 8-
H), 4.76e4.71 (1H, m, 4-CH2), 4.51 (1H, s, 1-H), 4.33 (1H, ddd, J 13.6,
11.1, 4.5 Hz, 4-CH2), 3.33 (1H, ddd, J 12.4, 4.5, 2.6 Hz, 3-CH2), 2.72
(1H, ddd, J 12.4, 11.1, 4.0 Hz, 3-CH2), 2.70e2.61 (1H, m, NCH2Me),
2.26 (1H, qd, J 13.7, 7.0 Hz, NCH2Me), 1.03 (3H, t, J 7.0 Hz, NCH2Me);
dC (100.6 MHz, CDCl3) 178.9, 141.6, 140.9, 130.3, 128.8 (2C), 128.5
(2C), 127.9, 123.8, 108.5, 65.5, 47.7, 47.2, 45.5, 11.5; m/z (EI, 70 eV)
254 (16, Mþ), 253 (7), 225 (9), 196 (7), 178 (11), 177 (100), 167 (5), 91
(5), 77 (8), 56 (6), 42 (10%).
4.6.2. 1-(2-Ethyl-1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-
6-yl)-2,2,2-trifluoroethanone (19). Purified by recrystallization
(ethyl acetate/hexane), yield 1.64 g (51%), as yellowish solid, mp
74e75 ꢀC (ethyl acetate/hexane); [Found: C, 63.1; H, 5.2; N, 8.5.
C17H17F3N2O requires C, 63.35; H, 5.32; N, 8.69%]; Rf (sorbfil, 1:2,
ethyl acetate/hexane) 0.59; nmax (KBr) 1661 cmꢁ1
;
dH (600 MHz,
5
4.5.3. 2-Methyl-1-(4-methylphenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]
pyrazine-6-carbaldehyde (16). Yield 0.80 g (63%), white solid, mp
134e135 ꢀC (ethyl acetate/hexane); [Found: C, 75.4; H, 7.3; N, 10.9.
C16H18N2O requires C, 75.56; H, 7.13; N, 11.01%]; Rf (silufol, ethyl
CDCl3) 7.37e7.31 (5H, m, Ph), 7.07 (1H, dd, J 4.4, JH,F 1.7 Hz, 7-H),
5.57 (1H, d, J 4.4 Hz, 8-H), 4.73 (1H, td, J 13.7, 2.9 Hz, 4-CH2), 4.51
(1H, s, 1-H), 4.38e4.33 (1H, m, 4-CH2), 3.37 (1H, ddd, J 12.4, 4.7,
2.9 Hz, 3-CH2), 2.74e2.70 (1H, m, 3-CH2), 2.69e2.63 (1H, m,
NCH2Me), 2.25 (1H, qd, J 13.5, 6.9 Hz, NCH22Me), 1.03 (3H, t, J 6.9 Hz,
NCH2Me); dC (100.6 MHz, CDCl3) 169.3 (q, JC,F 35 Hz), 144.7, 140.4,
128.8 (2C), 128.7 (2C), 128.2, 123.5 (q, 3JC,F 4 Hz), 123.4, 117.2 (q, 1JC,F
acetate) 0.66; nmax (KBr) 1645 cmꢁ1
; dH (400 MHz, CDCl3) 9.45 (1H,
s, CHO), 7.20 (2H, d, J 8.0 Hz, CHeAr), 7.15 (2H, d, J 8.0 Hz, CHeAr),
6.77 (1H, d, J 4.0 Hz, 7-H), 5.48 (1H, d, J 4.0 Hz, 8-H), 4.73 (1H, dd, J

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
5145
290 Hz), 109.7, 65.8, 47.7, 47.2, 46.4, 11.5; m/z (EI, 70 eV) 322 (7, Mþ),
246 (11), 245 (100), 225 (9), 168 (8), 167 (15), 166 (9), 148 (9), 147
(11), 127 (7), 119 (7), 104 (8), 91 (25), 77 (13), 69 (8), 56 (17), 51 (7),
42 (14%).
4.8. Experimental procedure for the synthesis of
pyrrolodiazocine 24 in acetonitrile
Methyl propiolate (920 mg, 10.9 mmol) was added to a solution
of pyrrolopyrazine 16 (400 mg, 1.6 mmol) in acetonitrile (20 mL).
The reaction was heated for 14 days at reflux (TLC monitoring).
After completion the solvent was evaporated in vacuo to give crude
product, which was purified by recrystallization (ethyl acetate/
hexane) to give pyrrolodiazocine 24.
4.6.3. 2,2,2-Trifluoro-1-[2-methyl-1(4-methylphenyl)-1,2,3,4-tetra-
hydropyrrolo[1,2-a]pyrazin-6-yl]ethanone (20). Purified by column
chromatography (ethyl acetate/ether, 1:1), yield 1.80 g (56%), as
white solid, mp 108e109 ꢀC (ethyl acetate/hexane); [Found: C,
63.0; H, 5.2; N, 8.5. C17H17F3N2O requires C, 63.35; H, 5.32; N,
8.69%]; Rf (sorbfil, 1:2, ethyl acetate/hexane) 0.57; nmax (KBr)
4.8.1. Methyl 9-formyl-3-methyl-6-(4-methylphenyl)-1,2,3,6-tetra-
hydropyrrolo[1,2-d][1,4]diazocine-5-carboxylate (24). Yield 290 mg
(55%) as white solid, mp 193e195 ꢀC (ethyl acetate/hexane); [Found:
C, 70.6; H, 6.4; N, 8.0. C20H22N2O3 requires C, 70.99; H, 6.55; N, 8.28%];
1658 cmꢁ1
; dH (400 MHz, CDCl3) 7.21 (2H, d, J 8.2 Hz, CHeAr), 7.16
5
(2H, d, J 8.2 Hz, CHeAr), 7.08 (1H, dd, J 4.3, JH,F 2.0 Hz, 7-H), 5.56
(1H, d, J 4.3 Hz, 8-H), 4.72 (1H, dd, J 13.9, 2.8 Hz, 4-CH2), 4.44e4.34
(1H, m, 4-CH2), 4.19 (1H, s, 1-H), 3.23 (1H, ddd, J 12.2, 4.6, 1.6 Hz, 3-
CH2), 2.79 (1H, td, J 12.2, 4.1 Hz, 3-CH2), 2.36 (3H, s, NMe), 2.23 (3H,
s, eC6H4eMe-p); dC (100.6 MHz, CDCl3) 169.4 (q, 2JC,F 35 Hz), 144.7,
Rf (silufol, ethyl acetate) 0.69; nmax (KBr) 1686, 1654, 1602 cmꢁ1
; dH
(400 MHz, CDCl3) 9.47 (1H, s, CHO), 7.49 (1H, s, 4-H), 7.08 (2H, d, J
7.8 Hz, CHeAr), 6.98 (1H, d, J 3.9 Hz, 8-H), 6.82 (2H, d, J 7.8 Hz, CHeAr),
6.44 (1H, s, 6-H), 6.23 (1H, d, J 3.9 Hz, 7-H), 5.49 (1H, td, J15.0, 5.2 Hz, 1-
CH2), 3.77 (1H, td, J 15.8, 5.2, Hz, 2-CH2), 3.77 (1H, dd, J 15.0, 3.8 Hz,1-
CH2), 3.04 (3H, s, CO2Me), 2.88 (1H, dd, J 15.8, 5.2 Hz, 2-CH2), 2.35 (3H,
s, NMe), 2.29 (3H, s, C6H4eMe-p); dC (100 MHz, CDCl3) 179.3, 170.3,
152.9,144.8,142.0,135.9,133.4,129.7 (2C),126.7,125.8 (2C),114.1, 96.8,
51.6, 49.6, 46.2, 43.6, 41.9, 21.0; m/z (EI, 70 eV) 338 (100, Mþ), 307 (15),
295 (13), 279 (90), 249 (16), 247 (15), 222 (30), 42 (11%).
3
138.2, 137.0, 129.4 (2C), 128.8 (2C), 123.6 (q, JC,F 4 Hz), 123.4, 117.2
(q, 1JC,F 290 Hz),109.5, 68.0, 52.2, 46.3, 43.4, 21.2; m/z (EI, 70 eV) 322
(35, Mþ), 321 (28), 232 (11), 231 (100), 225 (14), 132 (7), 42 (6%).
4.6.4. 1-[2-Ethyl]-1-(2-thienyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyr-
azin-6-yl]-2,2,2-trifluoroethanone (21). Purified by column chro-
matography (ethyl acetate, 1:15), yield 2.62 g (80%), as yellow oil;
[Found: C, 54.7; H, 4.8; N, 8.4. C15H15F3N2OS requires C, 54.87; H,
4.90; N, 8.53%]; Rf (sorbfil,1:7, ethyl acetate/hexane) 0.54; nmax
4.9. Experimental procedure for the synthesis of
pyrrolodiazocine 25 in acetonitrile
(KBr) 1660 cmꢁ1
; dH (600 MHz, CDCl3) 7.30 (1H, d, J 5.2 Hz,
5
CHeTh), 7.12 (1H, dd, J 4.3, JH,F 2.0 Hz, 7-H), 7.07 (1H, d, J 3.5 Hz,
CHeTh), 6.97 (1H, dd, J 5.2, 3.5 Hz, CHeTh), 5.81 (1H, d, J 4.3 Hz,
8-H), 4.96 (1H, s, 1-H), 4.65 (1H, td, J 13.9, 4.0 Hz, 4-CH2), 4.36
(1H, ddd, J 13.9, 9.6, 5.0 Hz, 4-CH2), 3.36 (1H, td, J 12.9, 4.0 Hz, 3-
CH2), 2.81e2.73 (2H, m, 3-CH2 and NCH2Me), 2.36 (1H, qd, J 13.7,
6.90 Hz, NCH2Me), 1.10 (3H, t, J 6.9 Hz, NCH2Me); dC (150.9 MHz,
Acetylacetylene (260 mg, 3.9 mmol) was added to a solution of
pyrrolopyrazine 14 (74 mg, 0.32 mmol) in acetonitrile (8 mL). The
reaction was heated for 3 days at reflux (TLC monitoring). After
completion the solvent was evaporated in vacuo to give crude
product, which was purified by recrystallization (ethyl acetate/
hexane) to give pyrrolodiazocine 25.
2
CDCl3) 169.4 (q, JC,F 36 Hz), 143.9, 143.2, 126.8, 126.2 (2C), 123.5
3
1
(q, JC,F 4 Hz), 123.4, 117.1 (q, JC,F 290 Hz), 109.6, 60.0, 47.7, 46.6,
45.9, 11.7; m/z (EI, 70 eV) 328 (28, Mþ), 327 (26), 270 (16), 245
(100), 231 (74), 202 (19), 200 (15), 174 (19), 147 (18), 110 (18), 97
(56), 89 (15), 69 (59), 57 (15), 56 (45), 45 (36), 42 (77), 41 (22), 39
(69%).
4.9.1. 5-Acetyl-3-methyl-6-phenyl-1,2,3,6-tetrahydropyrrolo[1,2-d]
[1,4]diazocine-9-carbaldehyde (25). Yield 290 mg (55%) as brown
solid, mp 170e171 ꢀC (ethyl acetate/hexane); [Found: C, 73.7; H,
6.4; N, 8.9. C19H20N2O2 requires C, 74.00; H, 6.54; N, 9.08%]; Rf
(silufol,1:1, ethyl acetate/hexane) 0.30; nmax (KBr) 1658,1580 cmꢁ1
;
dH (600 MHz, CDCl3) 9.43 (1H, s, CHO), 7.45 (1H, s, 4-H), 7.22 (2H, t, J
7.7 Hz, CHeAr), 7.13e7.11 (1H, m, CHeAr), 6.93 (1H, d, J 3.9 Hz, 8-H),
6.88 (2H, d, J 8.3 Hz, CHeAr), 6.45 (1H, s, 6-H), 6.18 (1H, d, J 3.9 Hz,
7-H), 5.44 (1H, ddd, J 15.3, 13.7, 5.7 Hz, 1-CH2), 3.90e3.85 (1H, m, 2-
CH2), 3.70 (1H, ddd, J 15.3, 4.4, 1.3 Hz, 1-CH2), 3.00 (3H, s, COMe),
2.81 (1H, ddd, J 15.7, 5.7, 1.3 Hz, 2-CH2), 2.31 (3H, s, NMe); dC
(100 MHz, CDCl3) 194.3, 179.3, 154.8, 144.8, 144.6, 133.4, 129.0 (2C),
126.8, 126.2, 125.8 (2C), 114.4, 111.3, 49.4, 46.0, 43.8, 40.1, 25.1; m/z
(EI, 70 eV) 308 (45, Mþ), 265 (37), 222 (5), 115 (5), 82 (5), 78 (5), 43
(100), 42 (28%).
4.7. Experimental procedure for the synthesis of
pyrrolodiazocine 22 in acetonitrile
Methyl propiolate (440 mg, 5.3 mmol) was added to a solution
of pyrrolopyrazine 14 (370 mg, 1.5 mmol) in acetonitrile (15 mL).
The reaction was heated for 5 days at reflux (TLC monitoring). After
completion the solvent was evaporated in vacuo to give crude
product, which was purified by recrystallization (ethyl acetate/
hexane) to give pyrrolodiazocine 22.
4.10. General procedure for the synthesis of
pyrrolodiazocines 25 and 34 in methanol
4.7.1. Methyl 9-formyl-3-methyl-6-phenyl-1,2,3,6-tetrahydropyrrolo
[1,2-d][1,4]diazocine-5-carboxylate (22). Yield 250 mg (51%) as yel-
lowish solid, mp 163e164 ꢀC (ethyl acetate/hexane); [Found: C, 70.0; H,
6.1; N, 8.5. C19H20N2O3 requires C, 70.35; H, 6.21; N, 8.64%]; Rf (silufol,
Acetylacetylene (177 mg, 2.6 mmol) was added to a stirred so-
lution of pyrrolopyrazine 14 or 20 (2 mmol) in methanol (20 mL).
The stirring was continued at 30 ꢀC (TLC monitoring). After com-
pletion the solvent was evaporated in vacuo to give crude product,
which was purified by recrystallization (ethyl acetate/hexane) to
give the target pyrrolodiazocine 25 or 34.
1:1, ethyl acetate/hexane) 0.87; nmax (KBr) 1683, 1653, 1600 cmꢁ1
; dH
(400 MHz, CDCl3) 9.47 (1H, s, CHO), 7.68 (1H, s, 4-H), 7.31e7.01 (5H, m,
Ph), 6.98 (1H, d, J3.8 Hz, 8-H), 6.25 (1H, d, J3.8 Hz, 7-H), 6.17 (1H, s, 6-H),
5.42 (1H, ddd, J14.9,13.1, 5.4 Hz,1-CH2), 3.90e3.71 (5H, m, 2-CH2 and 1-
CH2 andCO2Me), 2.99 (3H, s, NMe), 3.82 (1H, dd, J15.4, 4.6 Hz, 2-CH2); dC
(100 MHz, CDCl3) 179.4,170.3,153.0,145.1,144.6,133.5,129.7 (2C),126.8,
126.4, 126.0 (2C), 114.2, 96.7, 51.7, 49.5, 46.3, 43.7, 42.3; m/z (EI, 70 eV)
324 (60, Mþ), 293 (5), 281 (7), 265 (30), 235 (6), 208 (14), 192 (8), 180
(11),167 (8),154 (9),152 (12),115 (12), 91 (9), 78 (9), 77 (2), 59 (100), 57
(23), 52 (12), 43 (14), 42 (93), 41 (12%).
4.10.1. 5-Acetyl-3-methyl-6-phenyl-1,2,3,6-tetrahydropyrrolo[1,2-d]
[1,4]diazocine-9-carbaldehyde (25). Yield 120 mg (31%).
4.10.2. 1-[5-Acetyl-3-methyl-6-(4-methylphenyl)-1,2,3,6-tetrahy-
dropyrrolo[1,2-d][1,4]diazocin-9-yl]-2,2,2-trifluoroethanone
(34).

5146
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
Yield 270 mg (70%) as white solid, mp 112e114 ꢀC (ethyl acetate/
hexane); [Found: C, 64.4; H, 5.3; N, 7.0. C21H21F3N2O2 requires C,
64.61; H, 5.42; N, 7.18%]; Rf (sorbfil, 1:1, ethyl acetate/hexane) 0.63;
C, 55.0; H, 4.5; N, 6.6. C19H19F3N2O3S requires C, 55.33; H, 4.64; N,
6.79%]; Rf (sorbfil, 1:7, ethyl acetate/hexane) 0.22; nmax (KBr) 1664,
1606 cmꢁ1
; dH (400 MHz, CDCl3) 7.72 (1H, s, 4-H), 7.31 (1H, dd, J 4.3,
nmax (KBr) 1662, 1590 cmꢁ1
;
dH (600 MHz, CDCl3) 7.50 (1H, s, 4-H),
5JH,F 2.0 Hz, 8-H), 7.16 (1H, d, J 5.0 Hz, CHeTh), 6.91 (1H, dd, J 5.0,
3.7 Hz, CHeTh), 6.61e6.60 (1H, m, CHeTh), 6.31 (1H, d, J 4.3 Hz, 7-H),
6.30 (1H, s, 6-H), 5.20 (1H, ddd, J 15.4, 12.3, 5.1 Hz, 1-CH2), 4.20 (1H,
td, J 15.4, 3.4 Hz, 1-CH2), 4.05 (1H, ddd, J 16.1,12.3, 3.4 Hz, 2-CH2), 3.76
(3H, s, CO2Me), 3.32e3.19 (2H, m, NCH2Me), 3.14 (1H, ddd, J 16.1, 5.1,
3.4 Hz, 2-Ha), 1.13 (3H, t, J 7.2 Hz, NCH2Me); dC (100.6 MHz, CDCl3)
7.32e7.31 (1H, m, 8-H), 7.07 (2H, d, J 7.7 Hz, CHeAr), 6.80 (2H, d, J
7.7 Hz, CHeAr), 6.51 (1H, s, 6-H), 6.27 (1H, d, J 4.4 Hz, 7-H), 5.39 (1H,
ddd, J 15.2, 13.4, 5.5 Hz, 1-CH2), 4.07e4.01 (1H, m, 2-CH2), 3.81 (1H,
ddd, J 15.2, 4.4, 1.7 Hz, 1-CH2), 3.05 (3H, s, CO2Me), 2.88 (1H, ddd, J
15.7, 5.5, 1.7 Hz, 2-CH2), 2.35 (3H, s, NMe), 2.29 (3H, s, C6H4eMe-p);
2
2
dC (100 MHz, CDCl3) 194.2, 169.5 (q, JC,F 34 Hz), 154.8, 147.8, 141.3,
170.0, 169.4 (q, JC,F 38 Hz), 152.2, 149.6, 146.7, 127.3, 126.0, 125.5 (q,
136.0, 129.8 (2C), 126.2, 125.9 (q, 3JC,F 4 Hz), 125.6 (2C), 117.5 (q, 1JC,F
290 Hz), 115.4, 110.9, 49.6, 46.9, 43.9, 40.0, 25.1, 21.0; m/z (EI, 70 eV)
390 (45, Mþ), 347 (27), 271 (4), 43 (100), 42 (21%).
3JC,F 4 Hz), 124.3, 122.7, 117.3 (q, JC,F 291 Hz), 114.3, 96.6, 52.1, 51.6,
1
48.5, 48.1, 38.8, 14.8; m/z (EI, 70 eV) 412 (55, Mþ), 354 (13), 353 (72),
352 (11), 282 (10), 255 (14), 226 (13), 200 (20), 199 (17), 198 (13), 186
(16), 172 (15), 160 (14), 154 (21), 142 (17), 140 (25), 121 (16), 111 (13),
97 (31), 98 (15), 84 (15), 82 (19), 71 (18), 69 (19), 68 (14), 59 (100), 58
(43), 56 (63), 54 (15), 53 (17), 45 (29), 42 (25), 41 (13), 39 (23%).
4.11. General procedure for the synthesis of pyrrolodiazocines
22e24, 31 and 39
Methyl propiolate (420 mg, 5 mmol) was added to a solution of
pyrrolopyrazine 14e16, or 20, 21 (2 mmol) in methanol (20 mL).
The reaction was heated at reflux (TLC monitoring). After comple-
tion the solvent was evaporated in vacuo to give crude product,
which was purified by recrystallization (ethyl acetate/hexane) to
give pyrrolodiazocines 22e24, 31 or 39.
4.12. General procedure for the synthesis of pyrrolodiazocine
26 and 33
Acetylacetylene (272 mg, 4 mmol) was added to a solution of
pyrrolopyrazine 15 or 19 (2 mmol) in methanol (20 mL). The re-
action was heated at reflux (TLC monitoring). After completion the
solvent was evaporated in vacuo to give crude product, which was
purified by recrystallization (ethyl acetate/hexane) to give pyrro-
lodiazocines 26 or 33.
4.11.1. Methyl 9-formyl-3-methyl-6-phenyl-1,2,3,6-tetrahydropyrrolo
[1,2-d][1,4]diazocine-5-carboxylate (22). Yield 240 mg (57%).
4.11.2. Methyl 3-ethyl-9-formyl-6-phenyl-1,2,3,6-tetrahydropyrrolo
[1,2-d][1,4]diazocine-5-carboxylate (23). Yield 340 mg (71%) as
yellowish solid, mp 154e156 ꢀC (ethyl acetate/hexane); [Found: C,
70.8; H, 6.5; N, 8.1. C20H22N2O3 requires C, 70.99; H, 6.55; N, 8.28%];
Rf (sorbfil, 1:2, ethyl acetate/hexane) 0.43; nmax (KBr) 1656,
4.12.1. 5-Acetyl-3-ethyl-6-phenyl-1,2,3,6-tetrahydropyrrolo[1,2-d]
[1,4]diazocine-8-carbaldehyde (26). Yield 406 mg (63%), as yellow
solid, mp 182e183 ꢀC (ethyl acetate/hexane); [Found: C, 74.2; H,
6.7; N, 8.5. C20H22N2O2 requires C, 74.51; H, 6.88; N, 8.69%]; Rf
(sorbfil,1:1, ethyl acetate/hexane) 0.45; nmax (KBr) 1650,1578 cmꢁ1
;
1604 cmꢁ1
;
dH (600 MHz, CDCl3) 9.46 (1H, s, CHO), 7.72 (1H, s, 4-H),
dH (600 MHz, CDCl3) 9.46 (1H, s, CHO), 7.53 (1H, s, 4-H), 7.29e7.25
(2H, m, CHeAr), 7.19e7.15 (1H, m, CHeAr), 6.97e6.95 (3H, m,
CHeAr and 8-H), 6.49 (1H, s, 6-H), 6.23 (1H, d, J 4.0 Hz, 7-H), 5.50
(1H, ddd, J 14.9, 13.3, 6.1 Hz, 1-CH2), 3.80 (1H, ddd, J 15.3, 13.3,
5.0 Hz, 2-CH2), 3.75e3.70 (1H, m, 1-CH2), 3.27 (2H, qd, J 13.9, 7.2 Hz,
NCH2Me), 2.99 (1H, ddd, J 15.3, 6.1, 0.9 Hz, 2-CH2), 2.36 (3H, s,
COMe), 1.14 (3H, t, J 7.2 Hz, NCH2Me); dC (100 MHz, CDCl3) 194.3,
179.3, 154.3, 144.8, 144.6, 133.1, 129.0 (2C), 126.9, 126.2, 126.0 (2C),
114.2, 111.7, 52.2, 48.1, 46.6, 40.2, 25.2, 15.0; m/z (EI, 70 eV) 322 (33,
Mþ), 279 (30), 249 (7), 208 (8), 56 (11), 43 (100%).
7.29 (2H, t, J 7.7 Hz, CHeAr), 7.20e7.17 (1H, m, CHeAr), 7.06e7.04
(2H, m, CHeAr), 6.97 (1H, d, J 3.9 Hz, 8-H), 6.25 (1H, d, J 3.9 Hz, 7-H),
6.16 (1H, s, 6-H), 5.44 (1H, ddd, J 16.2, 14.7, 6.1 Hz, 1-CH2), 3.75 (3H,
s, CO2Me), 3.75e3.69 (2H, m, 2-CH2 and 1-CH2), 3.28e3.23 (1H, m,
NCH2Me), 3.18e3.12 (1H, m, NCH2Me), 2.96 (1H, dd, J 14.7, 5.5 Hz, 2-
CH2), 1.08 (3H, t, J 7.2 Hz, NCH2Me); dC (100 MHz, CDCl3) 179.3,
170.3, 152.5, 144.9, 144.7, 133.1, 129.0 (2C), 126.8, 126.4, 126.1 (2C),
114.0, 96.9, 51.9, 51.6, 48.1, 46.9, 42.2, 15.0; m/z (EI, 70 eV) 338 (14,
Mþ), 279 (9), 115 (4), 91 (4), 77 (17), 59 (100), 56 (12%).
4.11.3. Methyl 9-formyl-3-methyl-6-(4-methylphenyl)-1,2,3,6-tetra-
hydropyrrolo[1,2-d][1,4]diazocine-5-carboxylate (24). Yield 230 mg
(44%).
4.12.2. 1-(5-Acetyl-3-methyl-6-phenyl-1,2,3,6-tetrahydropyrrolo[1,2-
d][1,4]diazocin-9-yl)-2,2,2-trifluoroethanone (33). Yield 164 mg
(21%) as white solid, mp 137e139 ꢀC (ethyl acetate/hexane);
[Found: C, 64.3; H, 5.3; N, 7.0. C21H21F3N2O2 requires C, 64.61; H,
5.42; N, 7.18%]; Rf (sorbfil, 1:3, ethyl acetate/hexane) 0.38; nmax
4.11.4. Methyl
3-methyl-6-(4-methylphenyl)-9-(trifluoroacetyl)-
1,2,3,6-tetrahydropyrrolo[1,2-d][1,4]diazocine-5-carboxylate (31).
Yield 276 mg (34%) as yellow solid, mp 95e97 ꢀC (ethyl acetate/
hexane); [Found: C, 61.9; H, 5.1; N, 6.7. C21H21F3N2O3 requires C,
62.06; H, 5.21; N, 6.89%]; Rf (sorbfil, 1:2, ethyl acetate/hexane) 0.56;
(KBr) 1661, 1580 cmꢁ1
; dH (400 MHz, CDCl3) 7.55 (1H, s, 4-H),
7.34e7.27 (3H, m, 8-H and CHeAr), 7.21e7.17 (1H, m, CHeAr),
6.96e6.94 (2H, m, CHeAr), 6.57 (1H, s, 6-H), 6.28 (1H, d, J 4.3 Hz, 7-
H), 5.43 (1H, ddd, J 15.1, 13.2, 6.0 Hz, 1-CH2), 3.88 (1H, ddd, J 15.7,
13.2, 4.7 Hz, 2-CH2), 3.78 (1H, ddd, J 15.1, 4.7, 1.4 Hz, 1-CH2),
3.35e3.21 (2H, m, NCH2Me), 3.01 (1H, ddd, J 15.7, 6.0, 1.4 Hz, 2-
CH2), 2.36 (3H, s, COMe), 1.14 (3H, t, J 7.2 Hz, NCH2Me); dC (100 MHz,
nmax (KBr) 1686, 1666, 1597 cmꢁ1
; dH (400 MHz, CDCl3) 7.68 (1H, s,
4-H), 7.34e7.32 (1H, m, 8-H), 7.10 (2H, d, J 7.9 Hz, CHeAr), 6.90 (2H,
d, J 7.9 Hz, CHeAr), 6.30 (1H, d, J 4.2 Hz, 7-H), 6.18 (1H, s, 6-H), 5.33
(1H, ddd, J 15.0, 13.1, 5.4 Hz, 1-CH2), 4.01e3.90 (1H, m, 2-CH2), 3.81
(1H, ddd, J 15.0, 3.4, 1.6 Hz, 1-CH2), 3.75 (3H, s, CO2Me), 3.00 (3H, s,
NMe), 2.85 (1H, ddd, J 15.8, 5.4, 1.6 Hz, 2-CH2), 2.31 (3H, s,
C6H4eMe-p); dC (100 MHz, CDCl3) 170.1, 169.5 (q, 2JC,F 35 Hz), 153.0,
2
CDCl3) 194.2, 169.5 (q, JC,F 35 Hz), 154.3, 147.6, 144.1, 129.1 (2C),
3
126.4, 126.0 (q, JC,F 4 Hz), 125.9, 125.8 (2C), 117.4 (q, 1JC,F 290 Hz),
115.2, 110.9, 52.1, 48.0, 47.3, 40.3, 25.1, 14.9; m/z (EI, 70 eV) 390 (24,
Mþ), 347 (23), 165 (5), 115 (8), 91 (10), 77 (7), 56 (8), 43 (100), 42
(11%).
3
147.7, 141.4, 136.1, 129.8 (2C), 126.2, 125.8 (q, JC,F 4 Hz), 125.7 (2C),
117.1 (q, 1JC,F 290 Hz), 115.1, 96.2, 51.7, 49.7, 47.1, 43.7, 42.1, 21.0; m/z
(EI, 70 eV) 406 (21, Mþ), 347 (20), 91 (10), 69 (6), 59 (100), 42 (59%).
4.13. Experimental procedure for the synthesis of
pyrrolodiazocine 27
4.11.5. Methyl 3-ethyl-6-(2-thienyl)-9-(trifluoroacetyl)-1,2,3,6-tetra-
hydropyrrolo[1,2-d][1,4]diazocine-5-carboxylate (39). Yield 140 mg
(22%) as white solid, mp 88e90 ꢀC (ethyl acetate/hexane); [Found:
Acetylacetylene (290 mg, 3.4 mmol) was added to a stirred so-
lution of pyrrolopyrazine 16 (350 mg, 1.4 mmol) in methanol

L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
5147
(20 mL). The stirring was continued for 3 days at 30 ꢀC (TLC mon-
itoring). After completion the solvent was evaporated in vacuo to
give crude product, which was purified by recrystallization (ethyl
acetate/hexane) to give pyrrolodiazocine 27.
CHeAr), 6.31 (1H, d, J 4.4 Hz, 7-H), 6.24 (1H, s, 6-H), 5.34 (1H, ddd, J
15.1, 13.0, 5.4 Hz, 1-CH2), 3.98e3.78 (2H, m, 1-CH2 and 2-CH2), 3.76
(3H, s, CO2Me), 3.01 (3H, s, NMe), 3.87 (1H, ddd, J 15.8, 5.4, 1.6 Hz, 2-
2
CH2); dC (100 MHz, CDCl3) 170.2, 169.7 (q, JC,F 35 Hz), 153.1, 147.5,
144.6, 129.3 (2C), 126.6, 126.3, 126.0 (2C), 125.9 (q, 3JC,F 4 Hz), 117.5
(q, 1JC,F 290 Hz),115.3, 96.1, 51.8, 49.6, 47.2, 43.8, 42.5; m/z (EI, 70 eV)
392 (86, Mþ), 377 (7), 261 (11), 333 (100), 315 (14), 302 (7), 276 (21),
235 (7), 229 (7), 180 (7), 115 (10), 42 (14%).
4.13.1. 5-Acetyl-3-methyl-6-(4-methylphenyl)-1,2,3,6-tetrahy-
dropyrrolo[1,2-d][1,4]diazocine-9-carbaldehyde (27). Yield 130 mg
(30%) as white solid, mp 175e176 ꢀC (ethyl acetate/hexane);
[Found: C, 74.3; H, 6.8; N, 8.6. C20H22N2O2 requires C, 74.51; H, 6.88;
N, 8.69%]; Rf (silufol, ethyl acetate) 0.48; nmax (KBr) 1661,
4.15.2. Methyl
(2E)-3-[{2-[2-[methoxy(phenyl)methyl]-5-(tri-
1589 cmꢁ1
;
dH (600 MHz, CDCl3) 9.45 (1H, s, CHO), 7.47 (1H, s, 4-H),
fluoroacetyl)-1H-pyrrol-1-yl]ethyl}(methyl)amino]acrylate (35).
7.04 (2H, d, J 7.6 Hz, CHeAr), 6.95 (1H, d, J 3.9 Hz, 8-H), 6.78 (2H, d, J
7.6 Hz, CHeAr), 6.41 (1H, s, 6-H), 6.19 (1H, d, J 3.9 Hz, 7-H), 5.46 (1H,
ddd, J 14.8, 13.7, 5.5 Hz, 1-CH2), 3.97e3.92 (1H, m, 2-CH2), 3.73 (1H,
ddd, J 14.8, 4.4, 1.3 Hz, 1-CH2), 3.02 (3H, s, COMe), 2.84 (1H, ddd, J
15.7, 5.5, 1.3 Hz, 2-CH2), 2.33 (3H, s, NMe), 2.27 (3H, s, C6H4eMe-p);
dC (100 MHz, CDCl3) 194.4, 179.3, 154.9, 144.9, 141.8, 135.7, 133.4,
129.7 (2C), 126.8, 125.8 (2C), 114.4, 111.5, 49.6, 46.0, 43.9, 39.9, 25.2,
21.0; m/z (EI, 70 eV) 322 (100, Mþ), 293 (6), 279 (39), 248 (9), 223
(10), 203 (9), 167 (9), 129 (5), 105 (6), 57 (5), 43 (56), 42 (18)%.
Yield 51 mg (15%), white solid, mp 115e117 ꢀC (ethyl acetate/hex-
ane); [Found: C, 59.1; H, 5.3; N, 6.4. C21H23F3N2O4 requires C, 59.43;
H, 5.46; N, 6.60%]; Rf (sorbfil, 1:3, ethyl acetate/hexane) 0.27; nmax
(KBr) 1670, 1612 cmꢁ1
; dH (400 MHz, CDCl3) 7.47e7.31 (6H, m, Ph
and 3-H), 7.21 (1H, dd, J 4.3, 5JH,F 2.1 Hz, 40-H), 6.07 (1H, d, J 4.3 Hz,
30-H), 5.32 (1H, s, CH(OMe)Ph), 4.61 (1H, d, J 13.6 Hz, 2-H),
4.46e4.31 (2H, m,
b
-CH2), 3.69 (3H, s, CO2Me), 3.42 (3H, s, CH(OMe)
-CH2), 2.83 (3H, s, NMe); dC (100.6 MHz,
CDCl3) 170.0 (q, JC,F 35 Hz), 169.6, 152.1, 145.6, 137.7, 129.1 (2C),
Ph), 3.30e3.18 (2H, m,
a
2
3
1
128.8, 127.2 (2C), 125.8, 125.4, 124.1 (q, JC,F 4 Hz), 117.0 (q, JC,F
291 Hz), 112.7, 85.5, 78.4, 57.2, 56.0, 50.5, 45.2; m/z (EI, 70 eV) 424
(6, Mþ), 409 (10), 393 (13), 392 (40), 378 (7), 377 (41), 294 (7), 129
(6), 128 (100), 45 (11%).
4.14. Experimental procedure for the synthesis of pyrrole 28
DMAD (690 mg, 4.7 mmol) was added to a stirred solution of
pyrrolopyrazine 16 (400 mg, 1.6 mmol) in methanol (20 mL). The
reaction was heated at reflux (TLC monitoring). After completion the
solvent was evaporated in vacuo to give crude product, which was
purifiedbyrecrystallization(ethyl acetate/hexane)togivepyrrole28.
4.16. Experimental procedure for the synthesis of
pyrrolodiazocine 30
Methyl propiolate (310 mg, 3.7 mmol) was added to a solution of
pyrrolopyrazine 19 (400 mg, 1.2 mmol) in methanol (20 mL). The
reaction was heated for 6 h at reflux (TLC monitoring). After com-
pletion the solvent was evaporated in vacuo to give crude product,
which was purified by recrystallization (ethyl acetate/hexane) to
give diazocine 30.
4.14.1. Dimethyl (2E)-2-[(2-{2-formyl-5-[methoxy(4-methylphenyl)
methyl]-1H-pyrrol-1-yl}ethyl)(methyl)amino]but-2-enedioate (28).
Yield 440 mg (65%) as white solid, mp 125e127 ꢀC (ethyl acetate/
hexane); [Found: C, 64.2; H, 6.6; N, 6.4. C23H28N2O6 requires C,
64.47; H, 6.59; N, 6.54%]; Rf (sorbfil, 1:4 ethyl acetate/hexane) 0.32;
nmax (KBr) 1738, 1683, 1664, 1578 cmꢁ1
; dH (400 MHz, DMSO-d6)
9.48 (1H, s, CHO), 7.27 (2H, d, J 7.9 Hz, CHeAr), 7.19 (2H, d, J 7.9 Hz,
4.16.1. Methyl
3-ethyl-6-phenyl-9-(trifluoroacetyl)1,2,3,6-tetrahy-
CHeAr), 6.88 (1H, d, J 4.0 Hz, 30-H), 5.98 (1H, d, J 4.0 Hz, 40-H), 5.31
dropyrrolo[1,2-a][1,4]diazocine-5-carboxylate (30). Yield 240 mg
(49%) as yellow solid, mp 126e127 ꢀC (ethyl acetate/hexane);
[Found: C, 61.8; H, 5.1; N, 6.7. C21H21F3N2O3 requires C, 62.06; H,
5.21; N, 6.89%]; Rf (sorbfil, 1:3, ethyl acetate/hexane) 0.64; nmax
(1H, s, CH(OMe)Ph), 4.76 (1H, s, 3-H), 4.53e4.35 (2H, m,
3.97 (3H, s, CO2Me), 3.66 (3H, s, CO2Me), 3.48 (2H, t, J 6.7 Hz,
b
a
-CH2),
-CH2),
3.38 (3H, s, CH(OMe)Ph), 2.74 (3H, s, NMe), 2.36 (3H, s, C6H4eMe);
dC (100.6 MHz, CDCl3) 179.4, 168.0, 166.0, 154.6, 143.6, 138.3, 135.1,
132.4, 129.4 (3C), 127.7 (2C), 124.9, 111.5, 85.1, 77.5, 56.9, 53.1, 50.8,
43.8, 38.0, 21.2; m/z (EI, 70 eV) 428 (8, Mþ), 412 (11), 325 (100), 293
(9), 281 (9), 266 (15), 265 (58), 247 (13), 235 (12), 234 (10), 186 (36),
167 (16), 154 (9), 129 (11), 104 (10), 91 (26), 82 (22), 81 (12), 80 (11),
78 (10), 77 (16), 68 (11), 59 (78), 58 (18), 57 (26), 51 (11), 45 (13), 42
(55), 41 (18%).
(KBr) 1656, 1604 cmꢁ1
;
dH (600 MHz, CDCl3) 7.73 (1H, s, 4-H), 7.33
5
(1H, dd, J 4.3, JH,F 2.2 Hz, 8-H), 7.30 (2H, t, J 7.7 Hz, CHeAr), 7.20
(1H, t, J 7.2 Hz, CHeAr), 7.04 (2H, d, J 7.7 Hz, CHeAr), 6.30 (1H, d, J
4.3 Hz, 7-H), 6.22 (1H, s, 6-H), 5.39e5.32 (1H, m, 1-CH2), 3.81e3.75
(2H, m, 1-CH2 and 2-CH2), 3.75 (3H, s, CO2Me), 3.21 (2H, qd, J 14.3,
7.2 Hz, NCH2Me), 2.99e2.96 (1H, m, 2-CH2), 1.08 (3H, t, J 7.2 Hz,
2
NCH2Me); dC (100 MHz, CDCl3) 170.1, 169.5 (q, JC,3F 35 Hz), 152.5,
147.5, 144.3, 129.1 (2C), 126.5, 125.9 (3C), 125.8 (q, JC,F 4 Hz), 117.4
(q, 1JC,F 290 Hz), 114.9, 96.2, 51.8, 51.7, 48.0, 47.5, 42.3, 14.8; m/z (EI,
70 eV) 406 (15, Mþ), 347 (37), 276 (11), 220 (9), 205 (10), 192 (18),
180 (18), 154 (20), 139 (19), 115 (39), 91 (38), 77 (60), 69 (28), 59
(100), 42 (80%).
4.15. Experimental procedure for the synthesis of
pyrrolodiazocine 29 and pyrrole 35
Methyl propiolate (140 mg, 1.6 mmol) was added to a solution of
pyrrolopyrazine 18 (250 mg, 0.8 mmol) in methanol (8 mL). The
reaction was heated for 7 h at reflux (TLC monitoring). After com-
pletion the solvent was evaporated in vacuo. The residue was pu-
rified by column chromatography (ethyl acetate/hexane, 1:3) to
give pyrrolodiazocine 29 (100 mg, 31%) as white solid and pyrrole
35 (50 mg, 32%) as white solid.
4.17. Experimental procedure for the synthesis of
pyrrolodiazocine 32 and pyrrole 36
Acetylacetylene (180 mg, 2.6 mmol) was added to a solution of
pyrrolopyrazine 18 (400 mg, 1.3 mmol) in methanol (15 mL). The
reaction was heated for 7 h at reflux (TLC monitoring). After com-
pletion the solvent was evaporated in vacuo. The residue was pu-
rified by column chromatography (ethyl acetate/hexane, 1:15) to
give pyrrolodiazocine 32 (120 mg, 23%) as yellow solid and pyrrole
36 (100 mg, 19%) as yellow solid.
4.15.1. Methyl 3-methyl-6-phenyl-9-(trifluoroacetyl)-1,2,3,6-tetrahy-
dro[1,2-d][1,4]diazocine-5-carboxylate (29). Yield 100 mg (32%),
white solid, mp 159e161 ꢀC (ethyl acetate/hexane); [Found: C, 61.0;
H, 4.8; N, 7.0. C20H19F3N2O3 requires C, 61.22; H, 4.88; N, 7.14%]; Rf
(sorbfil, 1:3, ethyl acetate/hexane) 0.34; nmax (KBr) 1666,
1620 cmꢁ1
;
dH (400 MHz, CDCl3) 7.70 (1H, s, 4-H), 7.33e7.28 (3H, m,
4.17.1. 1-(5-Acetyl-3-methyl-6-phenyl-1,2,3,6-tetrahydropyrrolo[1,2-
CHeAr and 8-H), 7.21 (1H, t, J 7.3 Hz, CHeAr), 7.02 (2H, d, J 8.1 Hz,
a][1,4]diazocin-9-yl)-2,2,2-trifluoroethanone (32). Yield 120 mg

5148
L.G. Voskressensky et al. / Tetrahedron 66 (2010) 5140e5148
(23%) as yellow solid, mp 184e186 ꢀC (ethyl acetate/hexane);
[Found: C, 63.5; H, 5.0; N, 7.3. C20H19F3N2O2 requires C, 63.82; H,
5.09; N, 7.44%]; Rf (sorbfil, 1:3, ethyl acetate/hexane) 0.42; nmax
recrystallization (ethyl acetate/hexane) to give pyrrolodi-
azocine 38.
(KBr) 1660, 1589 cmꢁ1
;
dH (400 MHz, CDCl3) 7.52 (1H, s, 4-H),
4.19.1. 5-Acetyl-3-ethyl-6-(2-thienyl)-1,2,3,6-tetrahydropyrrolo[1,2-
d][1,4]diazocine-9-carbaldehyde (38). Yield 160 mg (38%) as yel-
low solid, mp 134e136 ꢀC (ethyl acetate/hexane); [Found: C,
65.5; H, 6.0; N, 8.3. C18H20N2O2S requires C, 65.83; H, 6.14; N,
8.53%]; Rf (sorbfil, 1:2, ethyl acetate/hexane) 0.33; nmax (KBr)
7.33e7.26 (4H, m, 8-H and CHeAr), 6.93e6.90 (1H, m, CHeAr), 6.92
(2H, d, J 7.8 Hz, CHeAr) 6.57 (1H, s, 6-H), 6.28 (1H, d, J 4.3 Hz, 7-H),
5.40 (1H, ddd, J 15.2, 13.8, 5.5 Hz, 1-CH2), 4.06e3.95 (1H, m, 2-CH2),
3.80 (1H, dd, J 15.2, 2.5 Hz,1-CH2), 3.06 (3H, s, COMe), 2.88 (1H, dd, J
15.9, 4.2 Hz, 2-CH2), 2.36 (3H, s, NMe); dC (150.9 MHz, CDCl3) 194.1,
1650, 1579 cmꢁ1
; dH (400 MHz, CDCl3) 9.46 (1H, s, CHO), 7.51
2
169.5 (q, JC,F 35 Hz), 154.8, 147.4, 144.3, 129.1 (2C), 126.3, 126.2,
(1H, s, 4-H), 7.11 (1H, d, J 5.1 Hz, CHeTh), 6.94 (1H, d, J 4.0 Hz, 8-
H), 6.88 (1H, dd, J 5.1, 3.5 Hz, CHeTh), 6.54 (1H, s, 6-H),
6.53e6.50 (1H, m, CHeTh), 6.23 (1H, d, J 4.0 Hz, 7-H), 5.45e5.33
(1H, m, 1-CH2), 4.13e4.04 (2H, m, 1-CH2 and 2-CH2), 3.37e3.19
(2H, m, NCH2Me), 3.17e3.10 (1H, m, 2-CH2), 2.32 (3H, s, COMe),
1.16 (3H, t, J 7.2 Hz, NCH2Me); dC (100 MHz, CDCl3) 193.7, 179.5,
154.0, 150.0, 144.1, 133.3, 127.3, 126.6, 124.0, 122.6, 113.7, 112.1,
52.4, 48.2, 47.6, 36.8, 25.1, 15.0; m/z (EI, 70 eV) 328 (100, Mþ),
299 (7), 285 (45), 257 (8), 240 (11), 214 (17), 178 (10), 140 (10), 97
(12), 71 (7), 43 (23%).
3
1
125.8 (q, JC,F 4 Hz), 125.7 (2C), 117.4 (q, JC,F 292 Hz), 115.4, 110.6,
49.4, 46.8, 43.9, 40.2, 25.0; m/z (EI, 70 eV) 376 (100, Mþ), 361 (6),
333 (83), 285 (8), 276 (14), 271 (8), 229 (9), 193 (8), 180 (7), 115 (7),
91 (7), 43 (16), 42 (11%).
4.17.2. (3E)-4-[{2-[2-[Methoxy(phenyl)methyl]-5-(trifluoroacetyl)-
1H-pyrrol-1-yl]ethyl}(methyl)amino]but-3-en-2-one
(36). Yield
101 mg (19%), yellow solid, mp 120e122 ꢀC (ethyl acetate/hexane);
[Found: C, 61.5; H, 5.6; N, 6.7. C21H23F3N2O3 requires C, 61.76; H,
5.68; N, 6.86%]; Rf (sorbfil, 1:3, ethyl acetate/hexane) 0.25; nmax
(KBr) 1668, 1569 cmꢁ1
; dH (400 MHz, CDCl3) 7.44e7.32 (6H, m, Ph
Acknowledgements
and 3-H), 7.22e7.21 (1H, m, 40-H), 6.09 (1H, d, J 4.3 Hz, 30-H), 5.32
(1H, s, CH(OMe)Ph), 5.08 (1H, d, J 13.7 Hz, 2-H), 4.46e4.30 (2H, m,
The financial support of the Russian Foundation for Basic Re-
search (grant # 08-03-00226-a) is gratefully acknowledged.
b-CH2), 3.42 (3H, s, CH(OMe)Ph), 3.30e3.18 (2H, m, a-CH2), 2.85
(3H, s, NMe), 2.11 (3H, s, COMe); dC (100.6 MHz, CDCl3) 195.2, 170.0
(q, 2JC,F 35 Hz), 151.7, 145.4, 137.7, 128.9 (2C), 128.8, 127.0 (2C), 125.6,
124.1 (q, 3JC,F 4 Hz),116.9 (q, 1JC,F 291 Hz),112.8, 98.2, 78.3, 57.2, 56.6,
45.5, 35.8, 27.9; m/z (EI, 70 eV) 408 (31, Mþ), 393 (100), 294 (16),
287 (17), 277 (8), 112 (80), 84 (8), 70 (11) 43 (10%).
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.04.104. These data include
MOL files and InchIkeys of the most important compounds
described in this article.
4.18. Experimental procedure for the synthesis of
pyrrolodiazocine 37
References and notes
Methyl propiolate (170 mg, 2.0 mmol) was added to a stirred
solution of pyrrolopyrazine 17 (310 mg, 1.2 mmol) in methanol
(15 mL). The stirring was continued for 6 days at 55 ꢀC (TLC mon-
itoring). After completion the solvent was evaporated in vacuo to
give crude product, which was purified by recrystallization (ethyl
acetate/hexane) to give pyrrolodiazocine 37.
1. (a) Askew, B. C.; Bednar, R. A.; Bednar, B.; Claremon, D. A.; Cook, J. J.;
McIntyre, C. J.; Hunt, C. A.; Gould, R. J.; Lynch, R. J.; Lynch, J. J., Jr.; Gaul, S. L.;
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L. M.; Prueksaritanont, T.; Baldwin, J. J.; Hartman, G. D. J. Med. Chem. 1997,
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4.18.1. Methyl 3-ethyl-9-formyl-6-(2-thienyl)-1,2,3,6-tetrahydropyrrolo
[1,2-d][1,4]diazocine-5-carboxylate (37). Yield 240 mg (57%) as yellow
solid, mp 125e127 ꢀC (ethyl acetate/hexane); [Found: C, 62.5; H, 5.8;
N, 8.0. C18H20N2O3S requires C, 62.77; H, 5.85; N, 8.13%]; Rf (sorbfil,
1:4, ethyl acetate/hexane) 0.50; nmax (KBr) 1653, 1610 cmꢁ1
; dH
(400 MHz, CDCl3) 9.47 (1H, s, CHO), 7.71 (1H, s, 4-H), 7.16e7.14 (1H,
m, CHeTh), 6.95 (1H, d, J 4.0 Hz, 8-H), 6.90 (1H, dd, J 5.1, 3.5 Hz,
CHeTh), 6.60e6.59 (1H, m, CHeTh), 6.26 (1H, d, J 4.0 Hz, 7-H), 6.23
(1H, s, 6-H), 5.29 (1H, ddd, J 14.9, 12.7, 5.3 Hz, 1-CH2), 4.13 (1H, ddd, J
14.9, 4.2, 2.5 Hz, 1-CH2), 3.99 (1H, ddd, J 15.8,12.7, 4.2 Hz, 2-CH2), 3.75
(3H, s, CO2Me), 3.35e3.33 (2H, m, NCH2Me), 3.11 (1H, ddd, J 15.8, 5.3,
2.5 Hz, 2-CH2), 1.12 (3H, t, J 7.2 Hz, NCH2Me); dC (100 MHz, CDCl3)
179.4, 169.9, 152.2, 150.3, 144.0, 133.2, 127.2, 126.4, 124.1, 122.6, 113.3,
97.2, 52.1, 51.5, 48.2, 47.8, 38.7, 14.9; m/z (EI, 70 eV) 344 (85, Mþ), 312
(9), 285 (100), 255 (22), 240 (15), 214 (27), 186 (15), 173 (12), 140 (16),
97 (17), 71 (15), 56 (11%).
4.19. Experimental procedure for the synthesis of
pyrrolodiazocine 38
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vacuo to give crude product, which was purified by
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