Synthesis of masked vicinal amino aldehydes of pyrrolizine and pyrrolo [1,2-c]thiazole series

Article abstract of DOI:10.1055/s-0028-1088029

Acylation of (1,3-dihydro-1,3-dimethyl-2H-benzimidazol-2-ylidene) acetonitrile with mixed anhydrides of N-Boc proline and 4-thiazolidinecarboxylic acid was found to proceed at the exocyclic carbon atom yielding the corresponding C-acyl derivatives. Remova

Full text of DOI:10.1055/s-0028-1088029

PAPER
1265
Synthesis of Masked Vicinal Amino Aldehydes of Pyrrolizine and Pyrrolo
[1,2-c]thiazole Series
A
mino Aldehydes
n
of Pyrrolizin
t
e
and P
o
yrrolo[1,2-
c
n
]thiazole V. Tverdokhlebov,*a Alexander V. Denisenko,b Andrey A. Tolmachev,a,b Yulian M. Volovenko,b
Svetlana V. Shishkina,c Oleg V. Shishkinc
a
Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
Fax +38(044)5373253; E-mail: atver@univ.kiev.ua
Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
STC ‘Institute for Single Crystals’, NAS of Ukraine, 60 Lenina ave., 61001 Kharkiv, Ukraine
b
c
Received 29 September 2008; revised 8 January 2009
ine series. To the best of our knowledge, there are only 5
papers dealing with these compounds,6 while more than
50 publications are devoted to other aldehydes of this
structural framework. The single relatively general ap-
Abstract: Acylation of (1,3-dihydro-1,3-dimethyl-2H-benzimida-
zol-2-ylidene)acetonitrile with mixed anhydrides of N-Boc proline
and 4-thiazolidinecarboxylic acid was found to proceed at the exo-
cyclic carbon atom yielding the corresponding C-acyl derivatives.
Removal of the protecting group with equimolar amount of hydro- proach to pyrrolizine-2(6)-carboxaldehydes is the reac-
tion of 2-acylpyrrole derivatives with acrolein6a,b or its
chloric acid effected simultaneous cyclization affording 2-(3-ami-
equivalents.6c Evidently, this method is incompatible with
no-5,6,7,7a-tetrahydro-1-oxo-1H-pyrrolizin-2-yl)- and 2-(5-amino-
7,7a-dihydro-7-oxo-1H,3H-pyrrolo[1,2-c]thiazol-6-yl)-1,3-dimeth-
the presence of an amino group. A few less common syn-
ylbenzimidazolium chlorides. Reduction of the prepared salts with
theses known6d,e also do not tolerate amine functionality.
sodium borohydride resulted in 3-amino-2-(2,3-dihydro-1,3-di-
Hence, the 3-aminopyrrolizine-2-carboxaldehyde moiety
represents a synthetic challenge we decided to meet.
methyl-1H-benzimidazol-2-yl)-5,6,7,7a-tetrahydro-1H-pyrrolizin-1-
one and 5-amino-6-(2,3-dihydro-1,3-dimethyl-1H-benzimidazol-2-
yl)-1,7a-dihydro-3H,7H-pyrrolo[1,2-c]thiazol-7-one, respectively.
These compounds were shown to be masked aldehydes. Their reac-
tions with phenylhydrazine and hydroxylamine yielded correspond-
ing hydrazones and oximes, whereas condensation with
malononitrile furnished 2-amino-5a,6,7,8-tetrahydro-5-oxo-5H-py-
N,N¢-Dimethylbenzimidazolium moiety is an equivalent
of the aldehyde functionality.7 Its reduction to 2,3-dihydro
derivative provides the masked formyl group,7 which can
be liberated by hydrolytic cleavage, if necessary.7a Re-
rido[3,2-b]pyrrolizine-3-carbonitrile and 2-amino-5a,6-dihydro- cently we have applied such an approach to the prepara-
5H,8H-thiazolo[3¢,4¢:1,5]pyrrolo[2,3-b]pyridine-3-carbonitrile.
tion of 2-aminopyrrole-3-carboxaldehyde derivatives 1
(Figure 1) by reduction of the corresponding benzimida-
zolium salt precursors 2.8 The latter were obtained in two
steps from the nitrile 3 (Scheme 1) by means of C-acyla-
tion with chloroacetyl chloride followed by amination
with primary amines.8 As a continuation of our research in
this field, the utility of the compound 3 for the synthesis
of vicinal amino aldehyde derivatives of fused pyrroles
has been studied, and the results obtained are reported
herein.
Key words: acylations, amino aldehydes, heterocycles, nitriles, re-
duction
Vicinal (hetero)aromatic amino aldehydes are powerful
synthons in heterocyclic chemistry.1 However, within the
pyrrole series these derivatives are poorly represented,2
whereas for the fused pyrroles like pyrrolizine they are
hitherto unknown. Among all isomeric aminopyrroliz-
ines, the 3(5)-substituted derivatives are of especial inter-
est because of their structural relation to jenamidines
alkaloid family.3 At the same time the 3(5)-aminopyr-
rolizines are the least investigated in comparison with oth-
er amines of this structural framework. Only a few
syntheses have been reported,3–5 and most of them includ-
ed various intramolecular nucleophilic additions of nitro-
gen or carbon to the nitrile group.3,4 Furthermore, attempts
of electrophilic introduction of nitrogen functionalities
into the pyrrolizine were examined,5 but sometimes it was
complicated with formation of a mixture of positional iso-
mers.5a
Cl–
+
Me
Me
N
N
O
O
N
N
Me
Me
H2N
H2N
N
N
R
R
2
1
Figure 1 3-Carboxaldehyde derivatives 1 and their precursors 2 (R
is alkyl or substituted phenyl)
In turn, 2(6)-formylpyrrolizines are the least studied de-
rivatives among all the isomeric aldehydes of the pyrroliz-
Compound 3 reacts with certain electrophiles at the exo-
cyclic carbon atom.8,9 Its reaction with mixed anhydrides
of Boc-protected proline (4a, n = 1) and pipecolic acid
(4b, n = 2) occurs smoothly affording derivatives 5a,b in
70–80% yields. The anhydrides 4a,b were generated in
situ from the appropriate acids and ethyl chloroformate. It
SYNTHESIS 2009, No. 8, pp 1265–1270
x
x
.
x
x
.2
0
0
9
Advanced online publication: 25.03.2009
DOI: 10.1055/s-0028-1088029; Art ID: P10808SS
© Georg Thieme Verlag Stuttgart · New York

1266
A. V. Tverdokhlebov et al.
PAPER
( )n
N
( )n
N
Boc
EtO
O
( )n
NC
N
NC
N
N
H2N
Me
O
O
O
O
Boc
Me
Me
+
Me
Me
Me
N
4a,b
N
N
N
HCl
Cl–
a: n = 1
b: n = 2
3
5a,b
6a,b
S
EtO
Me
O
S
N
O
O
N
Boc
7
H2N
Me
O
CN
N
HCl
+
Me
Cl–
N
N
S
N
N
O
Me
Boc
8
9
Scheme 1
is noteworthy that previously the mixed anhydrides of ing nitrile 3. However, in the case of indolizine derivative
protected proline were used for acylation of diazomethane 6b even traces of the appropriate products like 10 and 11
only.10 Other C-acyl derivatives were prepared by either were not detected in the reaction mixture and the starting
Claisen type condensation of proline esters11 and salt 6b was completely recovered.17 The reason for the
imidazolides12 or addition of organometallics to appropri- different behavior of compound 6b is unclear. Neverthe-
ate esters,13 Weinreb amides,14 and carboxylates.15 Fur- less, we have noted the difference in the chemical shifts of
thermore, the carbodiimide assisted acylation of certain 2-C of benzimidazolium moiety in derivatives 6a, 9 and
phosphorus ylides was reported.16 Thus, the present reac- 6b. Thus, in the 13C NMR spectra of compounds 6a and 9
tion has revealed applicability of mixed anhydrides of a- this signal was observed at 170.8 and 170.6 ppm, respec-
amino acids for acylation of the enamine type carbon.
tively, whereas for the derivative 6b it appeared at 162.6
ppm. So far as the chemical shift value could be consid-
ered as indirect measure of electrophilicity of the appro-
priate carbon atom, these data showed lower reactivity of
compound 6b compared to 6a and 9 thus agreeing with the
experiment. Perhaps, another geometry of the molecule
6b results in different conjugation degree between the two
bicyclic parts, thus influencing the reactivity. For more
detailed conclusions the quantum chemical calculations
are required.
Deprotection of the compounds 5a,b with an equimolar
amount of hydrochloric acid furnished the benzimidazoli-
um salts 6a,b in nearly quantitative yield. Obviously, de-
rivatives 6 are formed through the hydrogen chloride
assisted intramolecular addition of the liberated amine to
the nitrile, which is accompanied by the transfer of charge
to the benzimidazole moiety. Moreover, the sequence was
successfully extended to the cysteine derived anhydride 7,
thus leading to the salt 9 via the intermediate compound 8.
The S,N-acetal fragment in the derivatives 8 and 9 sur-
vived completely the hydrolytic conditions of deprotec-
tion-cyclization step.
The structure of the compounds prepared 6 and 9 was ini-
1
tially deduced from their H and 13C NMR spectra and
then confirmed unambiguously by X-ray crystallographic
study carried out for the derivative 6a (Figure 2).
Further, reduction of the quaternary salts 6 and 9 was ex-
amined (Scheme 2). Treatment of compounds 6a and 9
with excess sodium borohydride in methanol resulted in
the masked amino aldehyde derivatives of pyrrolizine 10
and pyrrolo[1,2-c]thiazole 11 in moderate yields (30–
40%). It should be noted that in the case of pyrroles 2 the
yield of the reduction was at least twice higher.8 Nonethe-
less, at the expense of the good yields on the previous
steps, the method allows preparation of the target com-
pounds 10 and 11 in 20–25% overall yield from the start-
Figure 2 X-ray molecular structure of compound 6a·2H2O with the
atom numbering used in the crystallographic analysis
Synthesis 2009, No. 8, 1265–1270 © Thieme Stuttgart · New York

PAPER
Amino Aldehydes of Pyrrolizine and Pyrrolo[1,2-c]thiazole
1267
corrected. Elemental analyses were performed at the microanalyti-
cal department of the Institute of Organic Chemistry, NAS, Kiev,
Ukraine. 1H and 13C NMR spectra were recorded on a Varian Unity
6a, 9
NaBH4
X
1
plus 400 spectrometer (400 MHz for H and 100 MHz for 13C) in
X
DMSO-d6. Chemical shifts (d) are given in ppm downfield from in-
N
ternal Me4Si. J values are in Hz. The purity of all compounds ob-
N
1
H2N
O
tained was checked by H NMR and LC/MS on an Agilent 1100
i
H2N
Me
O
instrument.
N
Me
N
N
Nitriles 5a,b and 8; General Procedure
NH
Ph
Ethyl chloroformate (0.77 g, 7.1 mmol) was added dropwise to an
ice-cooled and stirred solution of the appropriate N-Boc amino acid
(7.1 mmol) and Et3N (0.98 mL, 7.1 mmol) in anhyd dioxane (15
mL). After the addition was complete, the mixture was stirred at 10–
15 °C for 1h. Then compound 3 (1.02 g, 5.5 mmol) was added in one
portion and resulting mixture was slowly heated up to the boiling
point and stirred at reflux for 1 h. Upon cooling the precipitated
Et3N·HCl was removed by filtration and the dioxane was evaporat-
ed to dryness in vacuo. The residue was triturated with H2O (20
mL), filtered, and recrystallized from aq i-PrOH to give derivatives
5a,b and 8.
12, 13
ii
10, 11
X
N
iii
X
H2N
O
N
N
O
N
OH
H2N
16, 17
14, 15
NC
2-[Cyano(1,3-dihydro-1,3-dimethyl-2H-benzimidazol-2-
ylidene)acetyl]-1-pyrrolidinecarboxylic Acid t-Butyl Ester (5a)
Yield: 1.64 g (78%); mp 128 °C (H2O–i-PrOH).
1H NMR: d = 1.41 (s, 9 H, t-C4H9), 1.84–1.94 (m, 3 H, 3,3,4-H),
2.31 (m, 1 H, 4-H), 3.39–3.49 (m, 2 H, 5-CH2), 3.74 (s, 6 H, 2
NCH3), 4.73 (m, 1 H, 2-H), 7.40 (m, 2 H, HAr), 7.61 (m, 1 H, HAr),
7.67 (m, 1 H, HAr).
13C NMR: d = 24.0 (4-CH2), 28.6 [C(CH3)3], 31.1 (3-CH2), 33.3 (2
NCH3), 47.2 (5-CH2), 56.9 (CCN), 61.7 (2-CH), 78.7 [C(CH3)3],
112.1 (4,7-CBim), 121.9 (CN), 125.1 (5,6-CBim), 132.3 (3a,7a-CBim),
153.0 (2-CBim), 153.8 (COO), 189.7 (C=O).
Scheme 2 X = CH2 (10, 12, 14, 16); S (11, 13, 15, 17). Reagents
and conditions: (i) PhNHNH2·HCl, EtOH, reflux; (ii) NH2OH·HCl,
EtOH, reflux; (iii) cat. NH4Cl, CH2(CN)2, EtOH, reflux.
The amino aldehyde nature of the derivatives 10 and 11
was demonstrated by several transformations. Thus, their
treatment with phenylhydrazine afforded the correspond-
ing hydrazones 12 and 13. Similarly, the oximes 16 and 17
were obtained by reaction with hydroxylamine. Finally,
the ammonium chloride catalyzed condensation with ma-
lononitrile yielded derivatives of tricyclic systems 14 and
15. It is noteworthy that compound 15 is the representa-
tive of the novel hitherto unknown heterocyclic skeleton
of thiazolo[3¢,4¢:1,5]pyrrolo[2,3-b]pyridine. At the same
Anal. Calcd for C21H26N4O3: C, 65.95; H, 6.85; N, 14.65. Found: C,
66.01; H, 6.82; N, 14.50.
2-[Cyano(1,3-dihydro-1,3-dimethyl-2H-benzimidazol-2-
ylidene)acetyl]-1-piperidinecarboxylic Acid t-Butyl Ester (5b)
time the pyrido[3,2-b]pyrrolizine system 14 is little Yield: 1.59 g (73%); mp 119 °C (H2O–i-PrOH).
1H NMR: d = 1.47 (s, 9 H, t-C4H9), 1.67–1.76 (m, 4 H, 4,5-CH2),
1.92 (m, 1 H, 3-H), 2.33 (m, 1 H, 3-H), 3.46 (m, 1 H, 6-H), 3.79 (s,
6 H, 2 NCH3), 3.96 (m, 1 H, 6-H), 5.23 (m, 1 H, 2-H), 7.44 (m, 4 H,
HAr).
known. To the best of our knowledge only four deriva-
tives of this structural framework have been reported to
date.18
In summary, the present investigation has resulted in the
preparation of the first examples of vicinal amino alde-
hydes of the pyrrolizine and pyrrolo[1,2-c]thiazole series.
Moreover, during the synthesis the acylation of the enam-
ine type carbon with mixed anhydrides of N-protected a-
amino acids has been carried out for the first time, thus re-
vealing the principal applicability of the mixed anhy-
drides for C-acylations. Compound 3 turned out to be
suitable starting material for the synthesis of amino alde-
hyde derivatives of monocyclic8 and fused pyrroles. How-
ever, some limitations of the method have been also
13C NMR: d = 19.9 (4-CH2), 24.9 (5-CH2), 28.1 (3-CH2), 28.6
[C(CH3)3], 33.3 (2 N CH3), 42.1 (6-CH2), 43.0 (2-CH), 56.2 (CCN),
78.9 [C(CH3)3], 112.1 (4,7-CBim), 121.8 (CN), 125.2 (5,6-CBim),
132.4 (3a,7a-CBim), 153.1 (2-CBim), 155.6 (COO), 191.0 (C=O).
Anal. Calcd for C22H28N4O3: C, 66.65; H, 7.12; N, 14.13. Found: C,
66.60; H, 7.30; N, 14.20.
4-[Cyano(1,3-dihydro-1,3-dimethyl-2H-benzimidazol-2-
ylidene)acetyl]-3-thiazolidinecarboxylic Acid t-Butyl Ester (8)
Yield: 1.87 g (85%); mp 103 °C (H2O–i-PrOH).
1H NMR: d = 1.48 (s, 9 H, t-C4H9), 3.28 (dd, 2J = 11.5 Hz, 3J = 5.5
found. At present the dependence of the reduction of the Hz, 1 H, 5-H), 3.57 (m, 1 H, 5-H), 3.81 (s, 6 H, 2 NCH3), 4.61 (d,
salts of type 6,9 on the size and nature of the fused ring re-
mains vague. Therefore, further research in the field is in
progress.
J = 6.5 Hz, 1 H, 2-H), 4.75 (m, 1 H, 4-H), 5.28 (d, J = 6.5 Hz, 1 H,
2-H), 7.45–7.48 (m, 4 H, HAr).
13C NMR: d = 28.5 [C(CH3)3], 33.3 (2 NCH3), 35.3 (5-CH2), 50.0
(4-CH), 57.2 (CCN), 64.3 (2-CH2), 80.1 [C(CH3)3], 112.2 (4,7-
C
C
Bim), 121.6 (CN), 125.3 (5,6-CBim), 132.3 (3a,7a-CBim), 152.5 (2-
Bim), 153.1 (COO), 186.9 (C=O).
The starting nitrile 3 was prepared according to the described pro-
cedure.9a N-Boc proline, pipecolic acid, and 4-thiazolidinecarboxy-
lic acid were obtained as reported.19 All melting points were
determined in open capillary tubes in a Thiele apparatus and are un-
Anal. Calcd for C20H24N4O3S: C, 59.98; H, 6.04; N, 13.99; S, 8.01.
Found: C, 59.92; H, 6.17; N, 13.90; S, 7.77.
Synthesis 2009, No. 8, 1265–1270 © Thieme Stuttgart · New York

1268
A. V. Tverdokhlebov et al.
PAPER
Benzimidazolium Chlorides 6a,b and 9; General Procedure
A solution of the appropriate compound 5a,b, 8 (3 mmol) and concd
HCl (0.33 mL) in i-PrOH (10 mL) was refluxed for 30–40 min. Af-
ter cooling, the solid formed was filtered and washed with cold
i-PrOH (5 mL) yielding pure derivatives 6a,b, 9. i-PrOH filtrate was
evaporated to dryness in vacuo and the residue was crystallized
from anhyd MeCN affording additional portion of compounds 6a,b,
9.
13C NMR: d = 31.4 (1-C), 32.8 (NCH3), 33.1 (NCH3), 50.7 (3-C),
71.0 (7a-C), 80.0 (6-C), 113.1 (4-CBim), 113.3 (7-CBim), 126.2 (5-
CBim), 126.3 (6-CBim), 132.3 (3a-CBim), 132.5 (7a-CBim), 146.5 (5-C),
170.6 (2-CBim), 189.5 (7-C=O).
Anal. Calcd for C15H17ClN4OS: C, 53.49; H, 5.09; N, 16.63; Cl,
10.52; S, 9.52. Found: C, 53.68; H, 4.87; N, 16.70; Cl, 10.54; S,
9.31.
Pyrrolizine 10 and Pyrrolo[1,2-c]thiazole 11; General Proce-
dure
2-(3-Amino-5,6,7,7a-tetrahydro-1-oxo-1H-pyrrolizin-2-yl)-1,3-
dimethyl-3H-benzimidazolium Chloride (6a)
Yield: 0.92 g (96%); mp >300 °C (i-PrOH).
1H NMR: d = 1.60 (m, 1 H, 6-H), 2.10–2.17 (m, 3 H, 6,7,7-H), 3.37
(m, 2 H, 5-CH2), 3.79 (s, 3 H, NCH3), 3.83 (s, 3 H, NCH3), 4.11 (dd,
J = 9.5, 6.5 Hz, 1 H, 7a-H), 7.57 (m, 2 H, HAr), 7.91 (m, 2 H, HAr),
8.41 (s, 1 H, NH2), 8.62 (s, 1 H, NH2).
NaBH4 (0.45 g, 14 mmol) was added in portions to a stirred and ice-
cooled solution of the salts 6a or 9 (3.5 mmol) in MeOH (15 mL).
After the addition was complete, the stirring was continued for 1 h
and then the mixture was left overnight. The precipitate formed was
filtered, washed with H2O (10 mL) and recrystallized from i-PrOH
to give derivatives 10, 11.
13C NMR: d = 26.9 (6-C), 27.9 (7-C), 32.8 (NCH3), 33.2 (NCH3),
47.9 (5-C), 70.5 (7a-C), 79.5 (2-C), 112.8 (4-CBim), 113.1 (7-CBim),
125.9 (5-CBim), 126.0 (6-CBim), 132.3 (3a-CBim), 132.5 (7a-CBim),
147.3 (3-C), 170.8 (2-CBim), 191.3 (1-C=O).
3-Amino-2-(2,3-dihydro-1,3-dimethyl-1H-benzimidazol-2-yl)-
5,6,7,7a-tetrahydro-1H-pyrrolizin-1-one (10)
Yield: 0.32 g (32%); mp 185 °C (i-PrOH).
1H NMR: d = 1.38 (m, 1 H, 6-H), 1.96 (m, 3 H, 6,7,7-H), 2.45 (s, 3
H, NCH3), 2.48 (s, 3 H, NCH3), 3.16 (m, 2 H, 5-CH2), 3.70 (m, 1 H,
7a-H), 4.58 (s, 1 H, 2-CHBim), 6.41 (m, 2 H, HAr), 6.58 (m, 2 H, HAr),
7.59 (br s, 2 H, NH2).
13C NMR: d = 27.3 (6-C), 27.4 (7-C), 33.6 (NCH3), 33.7 (NCH3),
47.8 (5-C), 69.2 (7a-C), 84.7 (2-CBim), 88.3 (2-C), 106.8 (4-CBim),
107.2 (7-CBim), 119.3 (5-CBim), 119.6 (6-CBim), 143.0 (3a-CBim),
143.3 (7a-CBim), 174.5 (3-C), 195.2 (1-C=O).
Anal. Calcd for C16H19ClN4O: C, 60.28; H, 6.01; N, 17.57; Cl,
11.12. Found: C, 60.09; H, 5.82; N, 17.38; Cl, 11.37.
X-ray Crystal Structure20
Suitable crystals of 6a were grown from aq EtOH in the form of hy-
drate with two molecules of H2O. Intensities of 28391 reflections
(5137 independent, Rint = 0.038) were measured with ‘Xcalibur-3’
diffractometer operating in the w-2Q scan mode, 2Qmax = 60°, and
using graphite monochromated MoKa radiation (l = 0.71073 Å).
Crystal data: C16H19ClN4O·2H2O, Mr = 354.83, monoclinic,
a = 13.820(1), b = 9.191(1), c = 13.976(1) Å, b = 97.43(1)°,
V = 1760.4(1) Å3, T = 293 K, space group P21/n, Z = 4,
m(MoKa) = 0.239 mm–1. The structure was solved by direct method
using SHELXTL program package.21 Positions of hydrogen atoms
were located from electron density difference maps and refined by
riding model with Uiso = nUeq of the carrier atom (n = 1.5 for methyl
groups and n = 1.2 for the rest of hydrogens). Hydrogen atoms par-
ticipating in hydrogen bonds were refined isotropically. Full-matrix
least-squares refinement against F2 in anisotropic approximation for
nonhydrogen atoms using 5061 reflections was converged to
R1 = 0.038, wR2 = 0.105 [for 2504 reflections with F>4s(F)],
S = 0.851.
Anal. Calcd for C16H20N4O: C, 67.58; H, 7.09; N, 19.70. Found: C,
67.81; H, 7.10; N, 19.70.
5-Amino-6-(2,3-dihydro-1,3-dimethyl-1H-benzimidazol-2-yl)-
1,7a-dihydro-3H,7H-pyrrolo[1,2-c]thiazol-7-one (11)
Yield: 0.43 g (41%); mp 172–173 °C (i-PrOH).
1H NMR: d = 2.44 (s, 3 H, NCH3), 2.47 (s, 3 H, NCH3), 2.94 (dd,
2J = 11.5 Hz, 3J = 3.5 Hz, 1 H, 1-H), 3.17 (dd, 2J = 11.5 Hz, 3J = 9.5
3
Hz, 1 H, 1-H), 3.95 (dd, J = 3.5, 9.5 Hz, 1 H, 7a-H), 4.10 (d,
J = 11.0 Hz, 1 H, 3-H), 4.57 (s, 1 H, 2-CHBim), 4.77 (d, J = 11.0 Hz,
1 H, 3-H), 6.43 (m, 2 H, HAr), 6.59 (m, 2 H, HAr), 6.74 (br s, 1 H,
NH2), 7.94 (br s, 1 H, NH2).
13C NMR: d = 32.2 (1-C), 33.5 (NCH3), 33.8 (NCH3), 51.7 (3-C),
69.7 (7a-C), 84.4 (2-CBim), 90.5 (6-C), 107.0 (4-CBim), 107.2 (7-
2-(3-Amino-1,5,6,7,8,8a-hexahydro-1-oxo-2-indolizin-yl)-1,3-
dimethyl-3H-benzimidazolium Chloride (6b)
Yield: 0.99 g (99%); mp 245–246 °C (MeCN).
1H NMR: d = 1.36 (m, 2 H, 7-CH2), 1.52 (m, 1 H, 6-H), 1.73 (m, 1
H, 6-H), 1.85 (m, 1 H, 8-H), 2.06 (m, 1 H, 8-H), 3.04 (m, 1 H, 5-H),
4.32 (m, 1 H, 5-H), 4.72 (m, 7 H, 2 NCH3, 8a-H), 7.59 (m, 2 H, HAr),
7.91 (m, 2 H, HAr), 8.19 (s, 2 H, NH2).
CBim), 119.4 (5-CBim), 119.6 (6-CBim), 142.9 (3a-CBim), 143.3 (7a-
CBim), 173.6 (5-C), 193.5 (7-C=O).
Anal. Calcd for C15H18N4OS: C, 59.58; H, 6.00; N, 18.53; S, 10.60.
Found: C, 59.60; H, 5.84; N, 18.33; S, 10.46.
Phenylhydrazones 12, 13 and Oximes 16, 17; General Proce-
dure
13C NMR: d = 22.8 (7-C), 25.9 (8-C), 28.9 (6-C), 33.0 (2 NCH3),
41.9 (5-C), 64.2 (8a-C), 76.9 (2-C), 113.0 (4-CBim), 113.1 (7-CBim),
125.9 (5-CBim), 126.0 (6-CBim), 132.4 (3a-CBim), 132.5 (7a-CBim),
147.6 (3-C), 162.6 (2-CBim), 189.9 (1-C=O).
A solution of compound 10, 11 (2 mmol) and phenylhydrazine hy-
drochloride (0.37 g, 2.6 mmol) or hydroxylamine hydrochloride
(0.18 g, 2.6 mmol) in EtOH (5 mL) was refluxed for 0.5 h. Upon
cooling, the solid precipitated was filtered, washed with H2O (5 mL)
and recrystallized from the appropriate solvent yielding derivatives
12, 13 or 16, 17.
Anal. Calcd for C17H21ClN4O: C, 61.35; H, 6.36; N, 16.83; Cl,
10.65. Found: C, 61.45; H, 6.22; N, 16.93; Cl, 10.53.
3-Amino-5,6,7,7a-tetrahydro-1-oxo-1H-pyrrolizine-2-carbox-
aldehyde Phenylhydrazone (12)
Yield: 0.34 g (66%); mp 229–230 °C (i-PrOH).
1H NMR: d = 1.35 (m, 1 H, 6-H), 1.98 (m, 3 H, 6,7,7-H), 3.21 (m,
1 H, 5-H), 3.26 (m, 1 H, 5-H), 3.74 (m, 1 H, 7a-H), 6.61 (t, J = 7.0
Hz, 1 H, 4-HPh), 6.81 (d, J = 7.0 Hz, 2 H, 2,6-HPh), 7.13 (t, J = 7.0
Hz, 2 H, 3,5-HPh), 7.58 (s, 1 H, NH2), 7.67 (s, 1 H, N=CH), 8.22 (s,
1 H, NH2), 9.46 (s, 1 H, NH).
2-(5-Amino-7,7a-dihydro-7-oxo-1H,3H-pyrrolo[1,2-c]thiazol-6-
yl)-1,3-dimethyl-3H-benzimidazolium Chloride (9)
Yield: 0.96 g (95%); mp 302 °C (i-PrOH).
2
3
1H NMR: d = 3.10 (dd, J = 11.5 Hz, J = 6.0 Hz, 1 H, 1-H), 3.30
(dd, 2J = 11.5, 3J = 9.0 Hz, 1 H, 1-H), 3.82 (s, 6 H, 2 NCH3), 4.32
(d, J = 10.5 Hz, 1 H, 3-H), 4.38 (dd, 3J = 6.0 Hz, 3J = 9.0 Hz, 1 H,
7a-H), 5.04 (d, J = 10.5 Hz, 1 H, 3-H), 7.59–7.62 (m, 2 H, HAr),
7.92–7.94 (m, 2 H, HAr), 8.74 (s, 1 H, NH2), 9.13 (s, 1 H, NH2).
Synthesis 2009, No. 8, 1265–1270 © Thieme Stuttgart · New York

PAPER
Amino Aldehydes of Pyrrolizine and Pyrrolo[1,2-c]thiazole
1269
13C NMR: d = 26.9 (6-C), 27.7 (7-C), 47.7 (5-C), 69.5 (7a-C), 93.1
(2-C), 111.7 (2,6-CPh), 117.7 (4-CPh), 129.5 (3,5-CPh), 135.1 (1-
CPh), 146.6 (N=CH), 172.0 (3-C), 192.5 (1-C=O).
2-Amino-5a,6-dihydro-5-oxo-5H,8H-thiazolo-[3¢,4¢:1,5]pyrro-
lo[2,3-b]pyridine-3-carbonitrile (15)
Yield: 0.32 g (68%); mp 207 °C (DMF–H2O).
Anal. Calcd for C14H16N4O: C, 65.61; H, 6.29; N, 21.86. Found: C,
65.49; H, 6.07; N, 21.80.
1H NMR: d = 2.92 (m, 1 H, 6-H), 3.28 (m, 1 H, 6-H), 4.33 (m, 2 H,
5a-H, 8-H), 4.94 (d, J = 9.0 Hz, 1 H, 8-H), 8.04 (s, 1 H, 4-H), 8.18
(br s, 2 H, NH2).
5-Amino-7,7a-dihydro-7-oxo-1H,3H-pyrrolo[1,2-c]thiazole-6-
carboxaldehyde Phenylhydrazone (13)
Yield: 0.37 g (67%); mp 257–258 °C (EtOH).
13C NMR: d = 31.5 (6-C), 49.6 (8-C), 71.4 (5a-C), 85.2 (3-C), 106.5
(4a-C), 117.2 (CN), 140.6 (4-C), 164.5 (2-C), 172.5 (9a-C), 193.7
(5-C=O).
1H NMR: d = 2.92 (m, 1 H, 1-H), 3.18 (m, 1 H, 1-H), 4.00 (m, 1 H,
7a-H), 4.20 (d, J = 11.5 Hz, 1 H, 3-H), 4.81 (d, J = 11.5 Hz, 1 H, 3-
H), 6.63 (t, J = 6.5 Hz, 1 H, 4-HPh), 6.85 (d, J = 6.5 Hz, 2 H, 2,6-
HPh), 7.14 (t, J = 6.5 Hz, 2 H, 3,5-HPh), 7.67 (s, 1 H, N=CH), 7.79
(s, 1 H, NH2), 8.57 (s, 1 H, NH2), 9.61 (s, 1 H, NH).
13C NMR: d = 31.8 (1-C), 51.6 (3-C), 70.0 (7a-C), 94.4 (6-C), 111.8
(2,6-CPh), 118.0 (4-CPh), 129.5 (3,5-CPh), 133.8 (1-CPh), 146.3
(N=CH), 171.2 (5-C), 191.0 (7-C=O).
Anal. Calcd for C10H8N4OS: C, 51.71; H, 3.47; N, 24.12; S, 13.80.
Found: C, 51.70; H, 3.64; N, 24.19; S, 13.94.
References
(1) For a review, see: Caluwe, P. Tetrahedron 1980, 36, 2359.
(2) Eger, K.; Pfahl, J. G.; Folkers, G.; Roth, H. J. J. Heterocycl.
Chem. 1987, 24, 425.
Anal. Calcd for C13H14N4OS: C, 56.92; H, 5.14; N, 20.42; S, 11.69.
Found: C, 56.74; H, 4.97; N, 20.27; S, 11.60.
(3) (a) Snider, B. B.; Duvall, J. R.; Sattler, I.; Huang, X.
Tetrahedron Lett. 2004, 45, 6725. (b) Snider, B. B.; Duvall,
J. R. Org. Lett. 2005, 7, 4519. (c) Duvall, J. R.; Wu, F.;
Snider, B. B. J. Org. Chem. 2006, 71, 8579.
(4) (a) Volovenko, Yu. M.; Shokol, T. V.; Babichev, F. S.
Dopov. Akad. Nauk Ukr. RSR, Ser. B. 1986, 2, 35; Chem.
Abstr. 1987, 107, 163331. (b) Volovenko, Yu. M. Chem.
Heterocycl. Compd. (Engl. Transl.) 1997, 33, 854; Khim.
Geterotsikl. Soedin. 1997, 975. (c) Hartke, K.; Radau, S.
Liebigs Ann. Chem. 1974, 2110. (d) Fares, V.; Flamini, A.;
Poli, N. J. Am. Chem. Soc. 1995, 117, 11580.
3-Amino-5,6,7,7a-tetrahydro-1-oxo-1H-pyrrolizine-2-carbox-
aldehyde Oxime (16)
Yield: 0.22 g (60%); mp 220–221 °C (i-PrOH).
1H NMR: d = 1.33 (m, 1 H, 6-H), 1.97 (m, 3 H, 6,7,7-H), 3.16 (m,
1 H, 5-H), 3.22 (m, 1 H, 5-H), 3.73 (m, 1 H, 7a-H), 7.17 (s, 1 H,
NH2), 7.66 (s, 1 H, N=CH), 8.20 (s, 1 H, NH2), 10.00 (s, 1 H, OH).
13C NMR: d = 26.9 (6-C), 27.8 (7-C), 47.6 (5-C), 69.7 (7a-C), 90.3
(2-C), 142.9 (N=CH), 172.2 (3-C), 192.4 (1-C=O).
(e) Bonamico, M.; Fares, V.; Flamini, A.; Imperatori, P.;
Poli, N. Angew. Chem., Int. Ed. Engl. 1989, 28, 1049.
(f) Fares, V.; Flamini, A.; Poli, N. J. Chem. Res., Synop.
1995, 228. (g) Bonamico, M.; Fares, V.; Flamini, A.;
Giuliani, A. M.; Imperatori, P. J. Chem. Soc., Perkin Trans.
2 1988, 1447. (h) Collange, E.; Flamini, A.; Poli, R. J. Phys.
Chem. 2002, A106, 200. (i) Flamini, A.; Fares, V.;
Capobianchi, A.; Valentini, V. J. Chem. Soc., Perkin Trans.
1 2001, 3069.
Anal. Calcd for C8H11N3O2: C, 53.03; H, 6.12; N, 23.19. Found: C,
52.87; H, 6.19; N, 23.20.
5-Amino-7,7a-dihydro-7-oxo-1H,3H-pyrrolo[1,2-c]thiazole-6-
carboxaldehyde Oxime (17)
Yield: 0.25 g (63%); mp 242–243 °C (EtOH).
1H NMR: d = 2.88 (m, 1 H, 1-H), 3.17 (m, 1 H, 1-H), 4.00 (m, 1 H,
7a-H), 4.17 (d, J = 10.5 Hz, 1 H, 3-H), 4.75 (d, J = 10.5 Hz, 1 H, 3-
H), 7.43 (s, 1 H, NH2), 7.67 (s, 1 H, N=CH), 8.56 (s, 1 H, NH2),
10.22 (s, 1 H, OH).
(5) (a) Yang, Z.; Zhang, S. J. Indian Chem. Soc. 2002, 79, 698.
(b) Sun, G.; Yang, Z.; Zhang, S. J. Indian Chem. Soc. 2003,
80, 851.
13C NMR: d = 31.7 (1-C), 51.2 (3-C), 70.2 (7a-C), 91.6 (6-C), 142.1
(N=CH), 171.5 (5-C), 190.8 (7-C=O).
(6) (a) Varlamov, A. V.; Borisova, T. N.; Bonifas, N.;
Chernyshev, A. I.; Alexandrov, G. G.; Voskresensky, L. G.
Chem. Heterocycl. Compd. (Engl. Transl.) 2004, 40, 166;
Khim. Geterotsikl. Soedin. 2004, 201. (b) Clare, B. W.;
Ferro, V.; Skeleton, B. W.; Stick, R. V.; White, A. H. Aust.
J. Chem. 1993, 46, 805. (c) Abbiati, G.; Casoni, A.;
Canevari, V.; Nava, D.; Rossi, E. Org. Lett. 2006, 8, 4839.
(d) Hamersma, J. A. M.; Nossin, P. M. M.; Speckamp, W. N.
Tetrahedron 1985, 41, 1999. (e) Dannhardt, G.; Lehr, M.
Arch. Pharm. (Weinheim, Ger.) 1988, 321, 545.
(7) (a) Craig, J. C.; Ekwuribe, N. N.; Fu, C. C.; Walker,
K. A. M. Synthesis 1981, 303. (b) Ramos, J. M.; Tarazi, M.;
Wuest, J. D. J. Org. Chem. 1987, 52, 5437. (c) Katritzky,
A. R.; Aslan, D. C.; Oniciu, D. C. Tetrahedron: Asymmetry
1998, 2245. (d) Lee, I.-S. H.; Jeoung, E. H.; Kreevoy, M. M.
J. Am. Chem. Soc. 1997, 119, 2722. (e) Lee, I.-S. H.;
Jeoung, E. H. J. Org. Chem. 1998, 63, 7275.
Anal. Calcd for C7H9N3O2S: C, 42.20; H, 4.55; N, 21.09; S, 16.09.
Found: C, 42.16; H, 4.79; N, 21.10; S, 16.24.
Pyrido[3,2-b]pyrrolizine 14 and Thiazolo[3¢,4¢:1,5]pyrrolo[2,3-
b]pyridine 15; General Procedure
A solution of compound 10, 11 (2 mmol), malononitrile (0.17 g, 2.6
mmol) and NH4Cl (0.01 g, 0.2 mmol) in EtOH (5 mL) was refluxed
for 1 h. After cooling, the precipitate formed was filtered, washed
with H2O (10 mL) and recrystallized from aq DMF affording deriv-
atives 14,15.
2-Amino-5a,6,7,8-tetrahydro-5-oxo-5H-pyrido[3,2-b]pyrroliz-
ine-3-carbonitrile (14)
Yield: 0.17 g (40%); mp 260 °C (DMF–H2O).
1H NMR: d = 1.25 (m, 1 H, 7-H), 2.20 (m, 3 H, 7,6,6-H), 3.09 (m,
1 H, 8-H), 3.28 (m, 1 H, 8-H), 4.53 (dd, J = 10.0, 6.0 Hz, 1 H, 5a-
H), 8.00 (s, 1 H, 4-H), 8.16 (s, 1 H, NH2), 8.27 (s, 1 H, NH2).
13C NMR: d = 24.1 (7-C), 27.1 (6-C), 47.2 (8-C), 74.6 (5a-C), 83.1
(3-C), 108.3 (4a-C), 117.4 (CN), 141.7 (4-C), 163.9 (2-C), 173.8
(9a-C), 193.6 (5-C=O).
(8) Tverdokhlebov, A. V.; Denisenko, A. V.; Tolmachev, A. A.;
Volovenko, Yu. M. Synthesis 2007, 1811.
(9) (a) Rudnev, M. I.; Kurbatov, V. P.; Chub, N. K.; Osipov,
O. A. J. Gen. Chem. USSR (Engl. Transl.) 1988, 58, 2077;
Zh. Obshch. Khim. 1988, 58, 2334. (b) Zakhs, E. R.;
Ponyaev, A. I.; Subbotina, M. A.; El’tsov, A. V. Russ. J.
Anal. Calcd for C11H10N4O: C, 61.67; H, 4.71; N, 26.15. Found: C,
61.53; H, 4.73; N, 26.20.
Synthesis 2009, No. 8, 1265–1270 © Thieme Stuttgart · New York

1270
A. V. Tverdokhlebov et al.
PAPER
(13) (a) Chen, P.; Cheng, P. T. N.; Spergel, S. H.; Zahler, R.;
Gen. Chem. (Engl. Transl.) 2001, 71, 1076; Zh. Obshch.
Khim. 2001, 71, 1142. (c) Zakhs, E. R.; Subbotina, M. A.;
El’tsov, A. V. J. Org. Chem. USSR (Engl. Transl.) 1979, 15,
178; Zh. Org. Khim. 1979, 15, 200.
Wang, X.; Thottathil, J.; Barrish, J. C.; Polniaszek, R. P.
Tetrahedron Lett. 1997, 38, 3175. (b) De Luca, L.;
Giacomelli, G.; Porcheddu, A. Org. Lett. 2001, 3, 1519.
(c) Heathcock, C. H.; von Geldern, T. W. Heterocycles
1987, 25, 75. (d) Elliott, R. L.; Kopecka, H.; Lin, N.-H.; He,
Y.; Garvey, D. S. Synthesis 1995, 772.
(10) (a) Gavai, A. V.; Vaz, R. J.; Mikkilineni, A. M.; Roberge,
J. Y.; Liu, Y.; Lawrence, R. M.; Corte, J. R.; Yang, W.;
Bednarz, M.; Dickson, J. K.; Ma, Z.; Seethala, R.; Feyen,
J. H. M. Bioorg. Med. Chem. Lett. 2005, 15, 5478.
(b) Bures, F.; Kulhanek, J. Tetrahedron: Asymmetry 2005,
16, 1347. (c) Bernard, E.; Vanderesso, R. Tetrahedron Lett.
2004, 45, 8603. (d) Vasanthakumar, G.-R.; Patil, B. S.;
Suresh Babu, V. V. J. Chem. Soc., Perkin Trans. 1 2002,
2087. (e) Lakeev, S. N.; Mullagalin, I. Z.; Galin, F. Z.;
Majdanova, I. O.; Abdullin, M. F. Russ. Chem. Bull. 2002,
51, 2230; Izv. Akad. Nauk Ser. Khim. 2002, 2071.
(14) (a) De Luca, L.; Giacomelli, G.; Taddei, M. J. Org. Chem.
2001, 66, 2534. (b) Knight, J. G.; Ley, S. V. Tetrahedron
Lett. 1991, 32, 7119.
(15) (a) Overman, L. E.; Lesuisse, D. Tetrahedron Lett. 1985, 26,
4167. (b) Evans, D. A.; Nelson, J. V.; Vogel, E.; Taber, T. R.
J. Am. Chem. Soc. 1981, 103, 3099. (c) Goldstein, S. W.;
Overman, L. E.; Rabinowitz, M. H. J. Org. Chem. 1992, 57,
1179.
(f) Wallen, E. A. A.; Christiaans, J. A. M.; Saario, S. M.;
Forsberg, M. M.; Venäläinen, J. I.; Paso, H. M.; Männistö,
P. T.; Gynther, J. Bioorg. Med. Chem. 2002, 10, 2199.
(g) Harrison, J. R.; O’Brien, P.; Porter, D. W.; Smith, N. M.
J. Chem. Soc., Perkin Trans. 1 1999, 3623. (h) Plucinska,
K.; Liberek, B. Tetrahedron 1987, 43, 3509. (i) Fujimoto,
K.; Iwano, Y.; Hirai, K.; Sugawara, S. Chem. Pharm. Bull.
1986, 34, 999.
(16) (a) Aitken, R. A.; Karodia, N.; Massil, T.; Young, R. J.
J. Chem. Soc., Perkin Trans. 1 2002, 533. (b) Aitken, R. A.;
Karodia, N. J. Chem. Soc., Chem. Commun. 1996, 2079.
(17) To be precise, the material recovered from the reaction
exhibited the same 1H and 13C NMR spectra as that of
compound 6b, but differed in melting point and elemental
analysis, having significant lack of Cl. Probably, it was a
mixture of the salts 6b with different counterions, namely
chloride, hydroxide, and, maybe, borate. Treatment of this
material with HCl afforded compound 6b identical with the
authentic sample in all parameters.
(18) (a) Nomura, Y.; Bando, T.; Takeuchi, Y.; Tomoda, S. Bull.
Chem. Soc. Jpn. 1984, 57, 1271. (b) Laduree, D.; Robba, M.
Heterocycles 1984, 22, 303.
(19) (a) Harris, B. D.; Bhat, K. L.; Joullie, M. Heterocycles 1986,
24, 1045. (b) Swarbrick, M. E.; Gosselin, F.; Lubell, W. D.
J. Org. Chem. 1999, 64, 1993. (c) Oiry, J.; Pue, J. Y.;
Fatome, M.; Sentenac-Roumanou, H.; Lion, C.; Imbach,
J. L. Eur. J. Med. Chem. 1992, 27, 809.
(11) (a) Wada, C. K.; Holms, J. H.; Curtin, M. L.; Dai, Y.;
Florjancic, A. S.; Garland, R. B.; Guo, Y.; Heyman, H. R.;
Stacey, J. R.; Steinman, D. H.; Albert, D. H.; Bouska, J. J.;
Elmore, I. N.; Goodfellow, C. L.; Marcotte, P. A.; Tapang,
P.; Morgan, D. W.; Michaelides, M. R.; Davidsen, S. K.
J. Med. Chem. 2002, 45, 219. (b) Koskinen, A. M. P.;
Kallatsa, O. A. Tetrahedron 2003, 59, 6947. (c) Verbicky,
C. A.; Zercher, C. K. J. Org. Chem. 2000, 65, 5615.
(d) Yuste, F.; Ortiz, B.; Carrasco, A.; Peralta, M.; Quintero,
L.; Sanchez-Obregon, R.; Walls, F.; Garcia Ruano, J. L.
Tetrahedron: Asymmetry 2000, 11, 3079. (e) Wittenberger,
S. J. J. Org. Chem. 1996, 61, 356.
(20) Full crystallographic parameters have been deposited at the
Cambridge Crystallographic Data Centre under reference
number CCDC 702208. These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44(1223)336-
033; e-mail: deposit@ccdc.cam.ac.uk].
(12) (a) Bal, G.; Van der Veken, P.; Antonov, D.; Lambeir,
A.-M.; Grellier, P.; Croft, S. L.; Augustyns, A.; Halmers, A.
Bioorg. Med Chem. Lett. 2003, 13, 2875. (b) Hoffman,
R. V.; Tao, J. J. Org. Chem. 1999, 64, 126.
(21) Sheldrick, G. M. SHELXTL PLUS. PC version. A System of
Computer Programs for the Determination of Crystal
Structure from X-ray Diffraction Data. Rev. 5.1.; University
of Göttingen: Germany, 1998.
Synthesis 2009, No. 8, 1265–1270 © Thieme Stuttgart · New York