[5C+1N] Annulations: Two novel Routes to Substituted Dihydrofuro[3,2-c] Pyridines

Article abstract of DOI:10.1021/ol302314c

Two novel routes based on [5C + 1N] annulations for the synthesis of 2,3-dihydrofuro[3,2-c]pyridines are described. Ammonium acetate (NH ₄OAc) is used as an ammonia source in both routes. The first route utilizes 1-acyl-1-[(dimethylamino)alkenoyl]cyclopropanes as a five-carbon 1,5-bielectrophilic species and combines the [5C + 1N] annulation and regioselective ring-enlargement of cyclopropyl ketone into one pot, whereas the second route utilizes 3-acyl-2-[(dimethylamino)alkenyl]-4,5-dihydrofurans as the five-carbon synthons, which involves a sequential intermolecular aza-addition, intramolecular aza-nucleophilic addition/elimination, and dehydration reaction.

Full text of DOI:10.1021/ol302314c

ORGANIC
LETTERS
2012
Vol. 14, No. 20
5196–5199
[5C þ 1N] Annulations: Two Novel
Routes to Substituted
Dihydrofuro[3,2‑c]pyridines
Peng Huang, Rui Zhang, Yongjiu Liang, and Dewen Dong*
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun,
130022, China
dwdong@ciac.jl.cn
Received August 19, 2012
ABSTRACT
Two novel routes based on [5C þ 1N] annulations for the synthesis of 2,3-dihydrofuro[3,2-c]pyridines are described. Ammonium acetate (NH4OAc)
is used as an ammonia source in both routes. The first route utilizes 1-acyl-1-[(dimethylamino)alkenoyl]cyclopropanes as a five-carbon 1,5-
bielectrophilic species and combines the [5C þ 1N] annulation and regioselective ring-enlargement of cyclopropyl ketone into one pot, whereas
the second route utilizes 3-acyl-2-[(dimethylamino)alkenyl]-4,5-dihydrofurans as the five-carbon synthons, which involves a sequential
intermolecular aza-addition, intramolecular aza-nucleophilic addition/elimination, and dehydration reaction.
Furo[3,2-c]pyridines play an important role in organic
chemistry for their presence in numerous natural products
and synthetic organic compounds along with diverse bio-,
physio-, and pharmacological activities.1,2 In addition,
furo[3,2-c]pyridines are common organic ligands in transi-
tionmetal complexes.3 Extensiveworkhasgeneratedmany
synthetic approaches to furo[3,2-c]pyridine derivatives,4
starting either from preformed furans or pyridines.5,6
However, most of the existing methods require multistep
procedures to generate the pyridine and furan rings in-
dividually, and suffer from limited substrate scope and
harsh reaction conditions. So far, there are only very few
methods reported on the synthesis of furo[3,2-c]pyridines
by construction of the furan and pyridine nuclei in a single
step.7 Therefore, to match the increasing scientific and
pharmaceutical demands, it is still of continued inter-
est and great importance to develop facile and efficient
(1) For natural products, see: (a) Sakemi, S.; Bordner, J.; DeCosta,
D. L.; Dekker, K. A.; Hirai, H.; Inagaki, T.; Kim, Y.-J.; Kojima, N.;
Sims, J. C.; Sugie, Y.; Sugiura, A.; Sutcliffe, J. A.; Tachikawa, K.;
Truesdell, S. J.; Wong, J. W.; Yoshikawa, N.; Kojima, Y. J. Antibiot.
2002, 55, 6–18. (b) Fukuda, T.; Yamaguchi, Y.; Masuma, R.; Tomoda,
H.; Omura, S. J. Antibiot. 2005, 58, 309–314.
(2) For biological activities, see: (a) Kim, J. T.; Hamilton, A. D.;
Bailey, C. M.; Domoal, R. A.; Wang, L.; Anderson, K. S.; Jorgensen,
W. L. J. Am. Chem. Soc. 2006, 128, 15372–15373. (b) Miyazaki, Y.;
Nakano, M.; Sato, H.; Truesdale, A. T.; Stuart, J. D.; Nartey, E. N.;
Hightower, K. E.; Kane-Carson, L. Bioorg. Med. Chem. Lett. 2007, 17,
250–254. (c) Naylor, A.; Judd, D. B.; Scopes, D. I. C.; Hayes, A. G.;
Birch, P. J. J. Med. Chem. 1994, 37, 2138–2144. (d) Koike, T.; Takai, T.;
Hoashi, Y.; Nakayama, M.; Kosugi, Y.; Nakashima, M.; Yoshikubo,
S.; Hirai, K.; Uchikawa, O. J. Med. Chem. 2011, 54, 4207–4218.
(4) For reviews, see: (a) Shiotani, S. Heterocycles 1997, 45, 975–1011.
(b) Sherman, A. R. In Comprehensive Heterocyclic Chemistry III:
Bicyclic 5ꢀ6 Systems: Two Heteroatoms 1:1; Katritzky, A. R., Ramsden,
C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier: Oxford, 2008, Vol. 10,
pp 263ꢀ337.
(5) From furans: (a) Herz, W.; Tocker, S. J. Am. Chem. Soc. 1955, 77,
3554–3556. (b) Molina, P.; Fresneda, P. M.; Hurtado, F. Synthesis 1987,
45–48. (c) Eloy, F.; Deryckere, A. J. Heterocycl. Chem. 1971, 8, 57–60.
(d) Maruoka, H.; Okabe, F.; Yamasaki, K.; Masumoto, E.; Fujioka, T.;
Yamagata, K. Heterocycles 2010, 82, 867–880.
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Tetrahedron Lett. 1998, 39, 5375–5376. (c) Lechel, T.; Dash, J.;
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1672.
r
10.1021/ol302314c
Published on Web 10/01/2012
2012 American Chemical Society

approaches for the preparation of furo[3,2-c]pyridines from
readily available and simple starting materials.
was obtained in 36% yield and characterized as 4-phenyl-
2,3-dihydrofuro[3,2-c]pyridine 2a.14
On the other hand, cyclopropanes are extremely versa-
tile synthetic intermediates due to their ready accessibility
and good reactivity.8,9 During the course of our studies on
the chemistry of cyclopropanes,10 we developed an effi-
cient synthesis of 2,3-dihydrofurans via ring-enlargment
of 1-benzoyl/carbamoyl-1-dimethylaminoalkenoyl cyclo-
propanes11 in which a dual role of dimethylamino group in
the transformation was noted as (i) a strong electron-
donating group to direct the ring-enlargement reaction of
cyclopropyl ketone and (ii) a good leaving group when
subjected to a nucleophilic vinylic substitution (SNV) re-
action. In light of these findings, we recently achieved
divergent synthesis of 2,3-dihydrofuro[3,2-c]pyridin-4(5H)-
ones and 2,3-dihydrothieno[3,2-c]pyridin-4(5H)-ones from
1-carbamoyl-1-[(dimethylamino)alkenoyl]cyclopropanes in
the presence of Vilsmeier-type reagent (Tf2O/DMF) and
Lawesson’s reagent, respectively.12 Inspired by these re-
sults and as a continuation of our interest in the synthesis
of highly valuable heterocycles from cyclopropanes, we
envisioned that 1-acyl-1-dimethylaminoalkenoyl cyclo-
propanes 1 might serve as a five-carbon 1,5-bielectrophilic
species and undergo a formal [5C þ 1N] annulation13 with
ammonia, and their cyclopropane ring might open new
pathways for further and useful synthetic elaborations of
the pyridinone skeleton. We report herewith the results on
the synthesis of furo[3,2-c]pyridines based on the formal
[5C þ 1N] annulations.
Scheme 1. Reaction of 1a with NH4OAc in DMSO
The above result encouraged us to optimize the reaction
conditions, including the ratio of NH4OAc to 1a, reaction
temperature, and solvents. Itwas observed that 2acould be
obtained in 50% yield by raising the ratio of NH4OAc/1a
to 10:1, but a further increase of the amount of NH4OAc
had no significant effect on the reaction. Higher tempera-
ture, for example, 120 °C, would result in lower yield. The
reaction could proceed in other reaction media, such as
N,N-dimethylformamide, toluene, and glycerol, but the yield
of 2a was lower than in DMSO. Other ammonia sources,
such as NH3 H2O, NH3/ethanol, and NH4Cl, were inves-
3
tigated in the reaction; however, no efficient result was
achieved. A series of experiments revealed that the optimal
results were obtained when the reaction of 1a and 10.0
equiv of NH4OAc was performed in DMSO at 110 °C
for 3.0 h, whereby the yield of 2a reached 55% (Table 1,
entry 1).
Having established the optimal conditions for the 2,3-
dihydrofuro[3,2-c]pyridine synthesis, we intended to de-
termine its scope and limitation. Thus, a series of reaction
of 1-acyl-1-[(dimethylamino)alkenoyl]cyclopropanes 1 and
NH4OAc were carried out under the conditions as for
entry 1, Table 1. All the reactions of cyclopropanes 1bꢀi
bearing varied R1 and R2 groups proceeded smoothly to
afford the corresponding 2,3-dihydrofuro[3,2-c]pyridines
2bꢀi in moderate to good yields (Table 1, entries 2ꢀ9). The
efficiency of the 2,3-dihydrofuro[3,2-c]pyridine synthesis
was evaluated by subjecting cyclopropanes 1jꢀl with R3 as
methyl group to the above conditions, and the correspond-
ing 2jꢀl were obtained, but in lower yields (Table 1, entries
10ꢀ12). It is worth noting that the ring-enlargement
reaction of substrates 1 containing an additional R1 sub-
stituent on the cyclopropane ring occurred in a highly
regioselective manner (Table 1, entries 2ꢀ8, 11, and 12).
Aactually, such regioselectivity was observed in the pre-
vious work achieved by us11,12 and other researchers9b on
the ring-enlargement reactions of cyclopropane. There-
fore, we provide here a novel route for the synthesis of 2,3-
dihydrofuro[3,2-c]pyridines that combines the construc-
tion of furan and pyridine ring in a single step.
The reaction of 1-benzoyl-1-[(dimethylamino)alkenoyl]-
cyclopropane 1a with NH4OAc (6.0 equiv) was initially
tested in dimethyl sulfoxide (DMSO) at 100 °C, which
proceeded as indicated by TLC (Scheme 1). A main product
(8) For reviews, see: (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003,
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Zhang, L. J. Am. Chem. Soc. 2008, 130, 1814–1815. (c) Zhang, Z.;
Zhang, Q.; Sun, S.; Xiong, T.; Liu, Q. Angew. Chem., Int. Ed. 2007, 46,
1726–1729. (d) Wei, Y.; Lin, S.; Zhang, J.; Niu, Z.; Fu, Q.; Liang, F.
Chem. Commun. 2011, 47, 12394–12396. (e) Wei, Y.; Lin, S.; Xue, H.;
Liang, F.; Zhao, B. Org. Lett. 2012, 14, 712–715.
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Liu, Q. Org. Lett. 2007, 9, 2421–2423. (b) Wang, K.; Xiang, D.; Liu, J.;
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14, 370–373. (b) Huang, P.; Zhang, R.; Liang, Y.; Dong, D. Org. Biomol.
Chem. 2012, 10, 1639–1644.
(13) For the synthesis of pyridines via [5C þ 1N] annulation, see:
(a) Craig, D.; Henry, G. D. Tetrahedron Lett. 2005, 46, 2559–2562.
(b) Tyvorskii, V. I.; Bobrov, D. N.; Kulinkovich, O. G.; Tehrani, K. A.;
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2445. (e) Bezensek, J.; Prek, B.; Groselj, U.; Kasunic, M.; Svete, J.;
Stanovnik, B. Tetrahedron 2012, 68, 4719–4731. (f) Yuan, F.-Q.; Han,
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Liu, Q. J. Org. Chem. 2009, 74, 899–902.
On the basis of the above experimental results together
with some literature reported, a plausible mechanism for
the synthesis of 2,3-dihydrofuro[3,2-c]pyridines 2 from
cyclopropanes 1 is proposed as depicted in Scheme 2.
The attack of ammonia on the carbonꢀcarbon double
ꢀ
ꢀ
ꢀ
(14) 2a is a known compound; see ref 7.
Org. Lett., Vol. 14, No. 20, 2012
5197

with ammonia, GuareschiꢀThorpe condensation, or
Hantzsch reaction.16
Table 1. Synthesis of 2,3-Dihydrofuro[3,2-c]pyridines 2 from
1-Acyl-1-[(dimethylamino)alkenoyl]cyclopropanes 1a
The above successful expansion of the formal [5C þ 1N]
synthetic strategy tofused heterobicyclic systems17 and our
continued interest in exploring novel [5 þ 1] annula-
tion reaction prompted us to search for new five-carbon
precursors. One system that attracted our atention is
3-[(dimethylamino)alkenoyl]-4,5-dihydrofurans, which is
analogous to R-alkenoyl ketene-S,S-acetals used in our
previously reported [5 þ 1] annulations as five-carbon 1,5-
bielectrophilic species.18
entry
1
R1
R2
R3
2
yieldb (%)
1
2
1a
H
Ph
Ph
Ph
Ph
Me
Me
H
H
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
55
57
52
53
61
64
56
50
58
46
43
45
1b Ph
1c 4-ClC6H4
1d 4-MeC6H4
Scheme 3. Reaction of 3a with DMFDMA
3
4
5
1e
1f
Ph
6
4-MeC6H4
7
1g 4-t-BuC6H4 Me
1h Ph styryl
2g
2h
2i
8
9
1i
1j
H
H
cyclopropyl
10
11
12
Ph
Ph
Me
Me 2j
Me 2k
Me 2l
1k Ph
1l Ph
Thus, the condensation reaction of easily accessible
3-acetyl-2-methyl-5-phenyl-4,5-dihydrofuran 3a19 and
N,N-dimethylformamide dimethyl acetal (DMFDMA)
at 120 °C was conducted.11,12 The reaction furnished a
product in 80% isolated yield, which was characterized
as3-acetyl-2-dimethylaminovinyl-5-phenyl-4,5-dihydrofuran
5a instead of 3-[(dimethylamino)alkenoyl]-2-methyl-5-
phenyl-4,5-dihydrofuran 4a based on its analytical and
spectra data (Scheme 3). Comparison of the 13C NMR
spectra between 3a and 5a let us establish the structure of
5a without difficulty. In the 13C NMR spectra, 3a dis-
played two peaks at δ 14.9 and 29.4 ppm, which were
assigned to the carbon signals of 2-methyl of dihydrofuran
ring and the methyl group of 3-acetyl, respectively. The
disappearance of peak at δ 14.9 ppm along with appearance
of two peaks at δ85.8 and 149.3 ppm in the 13C NMR spectra
of 5a indicated that the 2-methyl is more reactive than acetyl
group of 3a in its condensation with DMFDMA.20
a Reagents and conditions: 1 (1.0 mmol), NH4OAc (10.0 mmol),
DMSO (4.0 mL), 110 °C, 2.5ꢀ4.0 h. b Isolated yield.
Scheme 2. Plausible Mechanism for the Reaction of 1 with
NH4OAc
(16) For reviews of synthesis and applications of pyridine derivatives,
see: (a) Jones, G. In Comprehensive Heterocyclic Chemistry II: Six-
membered Rings with One Heteroatom and Fused Carbocyclic Deriva-
tives; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., McKillop, A., Eds.;
Pergamon: Oxford, 1996; Vol. 5, pp 167ꢀ243. (b) Henry, G. D. Tetra-
hedron 2004, 60, 6043–6061.
bond of 1 at high temperature triggers the transfor-
mation13e and induces a regioselective ring-enlargement
to generate intermediate A,11,12b followed by an intramo-
lecular aza-nucleophilic addition and elimination to form
bicyclic intermediate B,15 which then undergoes dehydration
reaction to give rise to the final product 2,3-dihydrofuro-
[3,2-c]pyridine of type 2. It should be noted that the added
cyclopropane ring of 1 makes it possible to construct
pyridine skeleton in the presence of amonia in this work,
which is different from the traditional formal [5C þ 1N]
annulation of 1,5-dicarbonyl compounds and their equivalents
(17) For reviews on the construction of heterofused pyridines, see:
ꢁ
(a) Varela, J. A.; Saa, C. Chem. Rev. 2003, 103, 3787–3801. (b) Shaaban,
M. R.; El-Sayed, R.; Elwahy, A. H. M. Tetrahedron 2011, 67, 6095–6130.
For selected reports, see: (c) Arcadi, A.; Cacchi, S.; Giuseppe, S. D.;
Fabrizi, G.; Marinelli, F. Org. Lett. 2002, 4, 2409–2412. (d) Engstrom,
K. M.; Baize, A. L.; Franczyk, T. S.; Kallemeyn, J. M.; Mulhern, M. M.;
Rickert, R. C.; Wagaw, S. J. Org. Chem. 2009, 74, 3849–3855. (e) Zheng,
X.; Kerr, M. A. Org. Lett. 2006, 8, 3777–3779.
(18) For our previous work on [5 þ 1] annulations, see: (a) Bi, X.;
Dong, D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127,
4578–4579. (b) Dong, D.; Bi, X.; Liu, Q.; Cong, F. Chem. Commun. 2005,
3580–3582. (c) Bi, X.; Dong, D.; Li, Y.; Liu, Q.; Zhang, Q. J. Org. Chem.
2005, 70, 10886–10889.
(19) For the synthesis and utilization of 3-acetyl-2,3-dihydrofurans,
see: (a) Baciocchi, E.; Ruzziconi, R. J. Org. Chem. 1991, 56, 4772–4778.
(b) Bowman, R. K.; Johnson, J. S. Org. Lett. 2006, 8, 573–576. (c) Lau,
M.; Langer, P. Tetrahedron Lett. 2008, 49, 5618–5619. (d) Lau, M.; Sher,
M.; Villinger, A.; Fischer, C.; Langer, P. Eur. J. Org. Chem. 2010, 3743–
3753.
(15) (a) Church, R.; Trust, R.; Albright, J. D.; Powell, D. W. J. Org.
Chem. 1995, 60, 3750–3758. (b) Wang, Y.; Xin, X.; Liang, Y.; Lin, Y.;
Duan, H.; Dong, D. Adv. Synth. Catal. 2009, 351, 2217–2223.
5198
Org. Lett., Vol. 14, No. 20, 2012

Actually, 3-acetyl-2-dimethylaminovinyl-5-phenyl-4,5-
dihydrofuran 5a can also be regarded as a five-carbon
1,5-bielectrophilic species.21 Then, the reaction of 5a and
NH4OAc (10.0 equiv) was attempted in DMSO at 110 °C.
To our delight, the reaction proceeded smoothly as indi-
cated by TLC and furnished a product which was char-
acterized as 4-methyl-2-phenyl-2,3-dihydrofuro[3,2-c]pyridine
(Table 2, entry 1). In the same fashion, a range of reactions
of selected 3-acyl-2-[(dimethylamino)alkenyl]-4,5-dihy-
drofurans 5bꢀe bearing varied R1 and R2 substituents on
the dihydrofuran ring were carried out, and the corre-
sponding 2,3-dihydrofuro[3,2-c]pyridines 2 were obtained
in good to high yields (Table 2, entries 2ꢀ5). It should be
noted that the cyclization proved to be suitable for sub-
strate 5f with R3 as methyl group to afford the correspond-
ing 2,3-dihydrofuro[3,2-c]pyridine 2o in moderate yield
(Table 2, entry 6). The results shown above have demon-
strated the efficiency and synthetic interest of the formal
[5C þ 1N] annulation for the synthesis of 2,3-dihydrofuro-
[3,2-c]pyridines 2 with respect to the five-carbon precur-
sors 5 bearing variable substituted groups, i.e., R1, R2, and
R3. Thus, we provided an alternative route to the synthesis
of 2,3-dihydrofuro[3,2-c]pyridine of type 2.
As shown in Scheme 4, the reaction commences from the
1,6-addition of ammonia to 5 at high temperature,5d,13e,21
followed by intramolecular tandem aza-nucleophilic addi-
tion and elimination reactions to afford the product 2,3-
dihydrofuro[3,2-c]pyridine of type 2.15
Scheme 4. Plausible Mechanism for the Reaction of 5 with
NH4OAc
In summary, two novel routes for the synthesis of 2,3-
dihydrofuro[3,2-c]pyridine of type 2 based on the formal
[5C þ 1N] annulations are developed. The first route uses
1-acyl-1-dimethylaminoalkenoylcyclopropanes as a five-
carbon 1,5-bielectrophilic species, which involves intermo-
lecular addition of ammonia, regioselective ring-enlarge-
ment of cyclopropylketone, intramolecular aza-addition/
elimination, and dehydration reactions. The second route
utilizes 3-acyl-2-[(dimethylamino)alkenyl]-4,5-dihydrofur-
ans as the five-carbon synthons, which involves a sequential
intermolecular 1,6-addition of ammonia, intramolecular
aza-addition/elimination, and dehydration reaction. Both
routes allow the construction of the fused heterobicyclic
system in a single step, and are associated with readily
available starting materials, mild conditions, and flexible
substitution patterns. Further work on the utilization and
extension of the scope of the protocols is currently under
investigation in our laboratory.
Table 2. Synthesis of 2.3-Dihydrofuro[3,2-c]pyridines 2 from
3-Acyl-2-[(dimethylamino)alkenyl]-4,5-dihydrofurans 5a
entry
5
R1
R2
R3
2
yieldb (%)
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
Ph
Me
Me
Me
Me
CF3
CF3
H
2e
2f
83
85
80
81
70
63
4-MeC6H4
4-t-BuC6H4
4-ClC6H4
Ph
H
H
2g
2m
2n
2o
H
H
Ph
Me
a Reagents and conditions: 3 (1.0 mmol), NH4OAc (10.0 mmol),
DMSO (4.0 mL), 110 °C, 3.0ꢀ4.0 h. b Isolated yield.
Acknowledgment. Financial support of this research by
the National Natural Science Foundation of China
(51073150 and 21172211) is greatly acknowledged.
Based on the above results, a mechanism for the syn-
thesis of 2,3-dihydrofuro[3,2-c]pyridines 2 from 3-acyl-2-
[(dimethylamino)alkenyl]-4,5-dihydrofurans 5 is proposed.
Supporting Information Available. Experimental de-
tails, full characterization data, and copies of NMR
spectra for new compounds 1ꢀ5. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(20) Mukhanova, T. I.; Alekseeva, L. M.; Granik, V. G. Chem.
Heterocycl. Compd. 1990, 26, 739–742.
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The authors declare no competing financial interest.
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