Synthesis of 6,6-difluorocyclopropa[b]furo[2,3-c]pyrrole and 7-fluorofuro[3,2-c]pyridine derivatives via 1,5-electrocyclization of carbene-derived azomethine ylides

Article abstract of DOI:10.1055/s-2005-864820

Reaction of N(5-R-furan-2-ylmethylidene)anilmes with difluorocarbene, generated in CF₂Br₂/Pb*/Bu₄NBr/ultrasound system proceeds via 1,5-electrocyclization of intermediate azomethine ylides to give 6,6-difluorocyclopropa[b]furo[2,3-c]pyrrol-4(5H)-one or/and 4,4,6,6-tetrafluorocyclopropa[b]furo[2,3-c]pyrrole derivatives. Thermolysis of these compounds under solvent-free conditions gives rise to 2,5-disubstituted 7-fluoro-4,5-dihydrofuro[3,2-c]pyridine-4(5H)-ones in high yields.

Full text of DOI:10.1055/s-2005-864820

1006
LETTER
Synthesis of 6,6-Difluorocyclopropa[b]furo[2,3-c]pyrrole and 7-Fluoro-
furo[3,2-c]pyridine Derivatives via 1,5-Electrocyclization of Carbene-Derived
Azomethine Ylides
S
ynthesi
g
s of 6,6-Diflu
o
orocyclopro
r
pa[
b
]furo[2,3-
V
]
pyrrole
D
erivativ
.
es Voznyi, Mikhail S. Novikov,* Alexander F. Khlebnikov
Department of Chemistry, St. Petersburg State University, Universitetskii pr. 26, Petrodvorets, St. Petersburg 198504, Russia
Fax +7(812)428639; E-mail: MSN@MN10151.spb.edu
Received 21 November 2004
R1
O
Abstract: Reaction of N-(5-R-furan-2-ylmethylidene)anilines with
difluorocarbene, generated in CF2Br2/Pb*/Bu4NBr/ultrasound sys-
tem proceeds via 1,5-electrocyclization of intermediate azomethine
ylides to give 6,6-difluorocyclopropa[b]furo[2,3-c]pyrrol-4(5H)-
one or/and 4,4,6,6-tetrafluorocyclopropa[b]furo[2,3-c]pyrrole de-
rivatives. Thermolysis of these compounds under solvent-free con-
ditions gives rise to 2,5-disubstituted 7-fluoro-4,5-dihydrofuro[3,2-
c]pyridine-4(5H)-ones in high yields.
N
R2
CF2Br2
1
Pb*, Bu4NBr
ultrasound
:CF2
O
R1
O
R2
N
R1
N
R2
CF2
Key words: ylides, carbenes, cylizations, fused heterocycles
F
F
2
5
:CF2
Furo[3,2-c]pyridines have attracted considerable attention
due to their diverse biological activity, e.g., analgetic,
antipyretic, anti-inflammatory, and anticoagulatory.1
Fluoro-substituted furo[3,2-c]pyridine derivatives may
present special interest. It is well known that introduction
of fluorine into biologically active molecules often pro-
duces significant changes in the physical properties,
biological activity, and metabolic profile of these com-
pounds. Various methods have been employed to con-
struct the furo[3,2-c]pyridine backbone, starting either
from substituted pyridines2 or furans.3 However, these
methods have never been used to prepare fluoro-substitut-
ed furo[3,2-c]pyridine derivatives. Over the past years
certain fluoro-substituted nitrogenous heterocycles have
been successfully synthesized by a domino reaction of di-
fluorocarbene with the C=N bond of acyclic and cyclic
Schiff bases.4 The basic principle of construction of a
cyclic system, employed in this approach, consists in
generation in situ of an unstable gem-difluoroazomethine
ylide and its subsequent 1,3-dipolar cycloaddition to elec-
tron-deficient C=C, C≡C, and C=O bonds5 or ylide-ylide
isomerization.6
F
F
F
F
O
O
+
R2
N
O
R1
R2
N
R1
F
F
4
3
SiO2/H2O
Scheme 1
heterocyclic compounds are limited to derivatives of 3-
quinolyl-substituted azomethine ylides generated by the
decarboxylation method.10
We found that azomethine ylides 2 generated in situ from
N-furfurylideneanilines and difluorocarbene undergo 1,5-
electrocyclization into a furan ring. Diflurocarbene was
generated by reduction of dibromodifluoromethane with
active lead in the presence of tetrabutylammonium bro-
mide under ultrasound irradiation. The active lead (Pb*)
was prepared before use by reduction of Pb(OAc)2 with
sodium borohydride in aqueous acetic acid.4d
In the present work we propose a facile two-stage synthe-
sis of 7-fluorofuro[3,2-c]pyridin-4-ones, based on a new
1,5-electrocyclization reaction of fluorinated azomethine
ylides generated from substituted N-furfurylideneanilines
1 and diflurocarbene. 1,5-Cyclization reactions of ortho-
substituted pyridinium ylides7 and azomethine ylides, in-
Imines 1a,b and 1e,f react with difluorocarbene to give,
after chromatographic purification, 6,6-difluoro-5a,6-di-
hydro-3aH-cyclopropa[b]furo[2,3-c]pyrrol-3(3aH)-ones
4 (Scheme 1, Table 1).11 The primary cyclization products
of ylides 2, compounds 5, have a highly reactive pyrroline
double bond and under the reaction conditions undergo
fast difluorocyclopropanation to form tetrafluorides 3.
When applied to silica gel, the latter readily hydrolyzed to
difluorides 4. In the case of 1c,d, intermediate tetrafluo-
rides 3 could be isolated, that quantitatively hydrolyzed
on silica gel to compounds 4 within a day. The optimal
imine-to-carbene source ratio (CF2Br2/Pb*/Bu4NBr) for
8
volving the C=C and C=O bonds of alkenyl and aroyl
substituents are well known.9 The examples of application
of this reaction of azomethine ylides for annelation of
SYNLETT 2005, No. 6, pp 1006–1008
0
6.
0
4.
2
0
0
5
Advanced online publication: 23.03.2005
DOI: 10.1055/s-2005-864820; Art ID: G45004ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 6,6-Difluorocyclopropa[b]furo[2,3-c]pyrrole Derivatives
1007
Table 1 Reaction of Imines 1a–f with Difluorocarbene
Imine
1a
R1
R2
Reaction time (h)
Yield of 3 (%)
Yield of 4 (%)
Ph
H
5
5
53
36
6
1b
4-BrC6H4
Ph
Me
1c
4-EtO2CC6H4
2-FC6H4
Br
14
12
6
36
51
1d
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
1e
50
34
1f
4-NCC6H4
4
F
F
preparing compounds 3/4 is about 1:3. Decrease of the
carbene excess in the reaction mixture decreases the con-
version of the starting imine, whereas its increase gives
rise to difluorocyclopropanation of the furan double bond
in compounds 3. Thus, for example, with a 1:8:6:6
1g:CF2Br2:Pb*:Bu4NBr ratio, a mixture of compounds 3g
and 6 (1:0.8) was obtained (Scheme 2). Keeping this
mixture on silica gel at room temperature for a day result-
ed in formation of a mixture of compounds 4g and 7 in the
same ratio.
F
O
O
160 °C
–HF
R2
R2
N
R1
N
R1
X
X
O
8
3 X = F
4 X + X = O
Scheme 3
Table 2 Thermolysis of Cyclopropa[b]furo[2,3-c]pyrroles 3, 4
Heating of compounds 4a,b,f in the absence of solvent at
160 °C for 10 minutes is accompanied by HF release and
formation of 7-fluoro-4,5-dihydrofuro[3,2-c]pyridine-4-
ones 8a,b,f in isolable yields of 80–93%.12 Thermolysis of
tetrafluoride 3c gives the same result (Scheme 3, Table 2).
Compound R1
R2
Yield of 8 (%)
4a
4b
3c
4f
Ph
H
83
80
86
93
4-BrC6H4
Ph
Me
4-EtO2CC6H4
4-NCC6H4
R
4-MeOC6H4
O
N
R
In summary, this paper describes a simple two-stage pro-
tocol for preparing 7-fluorofuro[3,2-c]pyridine-4(5H)-
ones from cheap and readily available starting materials,
based on a new conversion of gem-difluoroazomethine
ylides, viz. 1,5-electrocyclization into the furan ring.
1g
6-fold excess of
CF2Br2, Pb*, Bu4NBr
F
F
F
F
F
Acknowledgment
O
R
F
O
N
R
+
R
N
R
We gratefully acknowledge the Russian Foundation for Basic
Research (project 05-03-33257).
F
F
F
F
6
3g
References
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SiO2/H2O
F
SiO2/H2O
F
F
F
O
R
O
+
N
O
R
R
N
R
F
F
O
4g
7
R = 4-BrC6H4
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1974, 81, 316131.
Scheme 2
Synlett 2005, No. 6, 1006–1008 © Thieme Stuttgart · New York

1008
I. V. Voznyi et al.
LETTER
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(11) General Procedure for Preparation of Compounds 3 and
4.
A flask containing active lead (1.2 g, 5.8 mmol) and CH2Cl2
(7 mL) was charged with Bu4NBr (2.0 g, 6.0 mmol), imine
1a–f (2.7 mmol), and CBr2F2 (1.95 g, 9.3 mmol). The flask
was tightly stopped, and the mixture was irradiated with
ultrasound at 40 °C until the lead was completely consumed.
Chromatography (hexane–EtOAc, 4:1) followed by
recrystallization provided compounds 4 or/and 3.
5-(4-Bromophenyl)-4,4,6,6-tetrafluoro-2-(2-fluoro-
phenyl)-4,5,5a,6-tetrahydro-3aH-cyclo-propa[b]fu-
ro[2,3-c]pyrrole (3d): mp 135–140 °C dec. (hexane–Et2O).
1H NMR (300 MHz, CDCl3): d = 3.88 (t, JHF = 7.3 Hz, 1 H,
5a-H), 4.60 (dddd, J = 13.3, 6.4, 3.9, 2.6 Hz, 1 H, 3a-H), 5.93
(dd, J = 3.9, 2.6 Hz, 1 H, 3-H), 7.01–7.69 (m, 8 H, Ar-H). 13C
NMR (75 MHz, CDCl3): d = 50.5 (t, JCF = 15.5 Hz, 1a-C),
58.4 (t, JCF = 32.1 Hz, 3a-C), 70.0 (m, 6a-C), 98.0 (d,
JCF = 14.4 Hz, 3-C), 109.7 (ddd, JCF = 320, 302, 9.4 Hz, 6-
C), 115.3, 115.6 (d, JCF = 21.6 Hz), 116.6 (d, JCF = 11.6 Hz),
118.4, 123.9 (d, JCF = 3.9 Hz), 127.3 (d, JCF = 1.7 Hz, CAr),
128.6 (ddd, JCF = 260, 247, 5.5 Hz, 4-C), 130.9 (d, JCF = 8.8
Hz), 131.8, 137.7 (d, JCF = 5.0 Hz, CAr), 152.7 (2-C), 159.9
(d, JCF = 254 Hz, CAr-F). Anal. Calcd for C19H11BrF5NO: C,
51.38; H, 2.50; N 3.15. Found: C, 51.41; H, 2.75; N, 2.92.
6,6-Difluoro-5-phenyl-5a,6-dihydro-3aH-cyclo-
propa[b]furo[2,3-c]pyrrol-4 (5H)-one (4a): mp 87–88 °C
(hexane–Et2O). IR (CHCl3): 1725 (C=O) cm–1. 1H NMR
(300 MHz, CDCl3): d = 3.96 (dd, 3J HF = 8.2, 1.7 Hz, 1 H, 5a-
H), 4.22 (dd, J = 4.5, 2.6 Hz, 1 H, 3a-H), 5.54 (dd, J = 4.5,
2.6 Hz, 1 H, 3-H), 6.62 (t, J = 2.6 Hz, 1 H, 2-H), 7.23–7.54
(m, 5 H, Ph-H). 13C NMR (75 MHz, CDCl3): d = 49.5 (dd,
JCF = 17.7, 15.5 Hz, 5a-C), 51.6 (d, JCF = 1.7 Hz, 3a-C), 68.2
(dd, JCF = 19.4, 11.1 Hz, 6a-C), 100.4 (d, JCF = 1.1 Hz, 3-C),
108.5 (dd, JCF = 319, 301 Hz, 6-C), 120.7, 125.7, 128.8,
137.3 (CPh), 147.5 (2-C), 170.8 (dd, JCF = 3.9, 3.2 Hz, 4-C).
Anal. Calcd for C13H9F2NO2: C, 62.65; H, 3.64; N, 5.62.
Found: C, 62.64; H, 3.82, N, 5.73.
(4) (a) Khlebnikov, A. F.; Novikov, M. S.; Kostikov, R. R. Russ.
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Kostikov, R. R. Eur. J. Org. Chem. 1998, 133.
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(12) General Procedure for Preparation of Compounds 8.
Compound 3 or 4 (0.52 mmol) is placed to a dry, 10 mL, one-
necked round-bottomed flask and is heated at 160 °C for 10
min. Upon cooling to r.t. a brown solid forms;
recrystallization from CH2Cl2–Et2O mixture gives furo[3,2-
c]pyridine 8 as a colorless solid.
7-Fluoro-5-phenylfuro[3,2-c]pyridine-4 (5H)-one (8a):
mp 120–121 °C (CH2Cl2–Et2O). IR (CHCl3): 1630 (C=C),
1705 (C=O) cm–1. 1H NMR (300 MHz, CDCl3): d = 7.07
(dd, JHH = 2.0 Hz, JHF = 2.3 Hz, 1 H, 3-H), 7.28 (d, JHF = 5.9
Hz, 1 H, 6-H), 7.39–7.52 (m, 5 H, Ar-H), 7.63 (d, 1 H,
JHH = 2.0 Hz, 2-H). 13C NMR (75 MHz, CDCl3): d = 108.2
(d, JCF = 2.2 Hz, 3-C), 117.5 (d, JCF = 3.3 Hz, 3a-C), 119.7
(d, JCF = 32.6 Hz, 6-C), 126.5, 128.1, 129.0 (CAr), 137.8 (d,
(8) (a) Romashin, Y. N.; Liu, M. T. H.; Bonneau, R. Chem.
Commun. 1999, 447. (b) Romashin, Y. N.; Liu, M. T. H.;
Ma, W.; Moss, R. A. Tetrahedron Lett. 1999, 40, 7163.
J
J
CF = 239 Hz, 7-C), 140.0 (CAr), 144.6 (2-C), 148.9 (d,
CF = 15.5 Hz, 7a-C), 156.9 (4-C). Anal. Calcd for
C13H8FNO2: C, 68.12; H, 3.52; N 6.11. Found: C, 67.96; H,
3.55; N 6.08.
Synlett 2005, No. 6, 1006–1008 © Thieme Stuttgart · New York