Polycyclic N-heterocyclic compounds. Part 61: A novel Truce-Smiles type rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give cycloalkeno[1,2-d]furo[2,3-b]pyridines

Article abstract of DOI:10.1016/j.tetlet.2009.12.010

The cycloalkeno[1,2-d]furo[2,3-b]pyridine skeleton was conveniently synthesized from fused 4-(2-cyanovinyloxy)butanenitriles in one step through sequential intramolecular Michael addition, β-elimination and intramolecular nucleophilic addition. This sequence thus consists of a novel Truce-Smiles type rearrangement followed by cyclization. The 5-amino derivatives were transformed further to lactams in good yields.

Full text of DOI:10.1016/j.tetlet.2009.12.010

Tetrahedron Letters 51 (2010) 903–906
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Polycyclic N-heterocyclic compounds. Part 61: A novel Truce–Smiles type
rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give
cycloalkeno[1,2-d]furo[2,3-b]pyridines q
b
b
b,
Kensuke Okuda a, , Norimasa Watanabe , Takashi Hirota , Kenji Sasaki
*
*
a Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
b Faculty of Pharmaceutical Sciences, Okayama University, 1-1-1 Tsushima-naka, Kita-Ku, Okayama 700-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The cycloalkeno[1,2-d]furo[2,3-b]pyridine skeleton was conveniently synthesized from fused 4-(2-cyano-
vinyloxy)butanenitriles in one step through sequential intramolecular Michael addition, b-elimination
and intramolecular nucleophilic addition. This sequence thus consists of a novel Truce–Smiles type rear-
rangement followed by cyclization. The 5-amino derivatives were transformed further to lactams in good
yields.
Received 8 November 2009
Revised 29 November 2009
Accepted 3 December 2009
Available online 5 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Truce–Smiles rearrangement
Michael addition
Cyanovinyl ether
Estervinyl ether
Cycloalkeno[1,2-d]furo[2,3-b]pyridine
Heterocycle
1. Introduction
takes place, the resulting oxyanion could be trapped by intramolec-
ular nitrile groups sequentially to give 5-aminocycloalkeno
Rearrangement reactions are powerful tools in organic synthe-
sis because simple, readily obtained precursors frequently produce
molecules of much higher complexity. Among the many name
rearrangement reactions that have been developed is the Truce–
Smiles rearrangement, a useful procedure that involves formation
of carbon–carbon bonds of an aryl ring with concomitant breaking
of a carbon–heteroatom bond.2,3
[1,2-d]furo[2,3-b]pyridines (4). A Truce–Smiles rearrangement
As a part of our continuing program on the synthesis of polycy-
clic N-heterocyclic compounds for medicinal applications, we have
developed a general one step preparation of aromatic ring-fused
furo[2,3-b]pyridines (2) from aryl-1-carbonitriles having a 3-
cyanopropoxy group adjacent to the cyano (carbonitrile) group
(1). This transformation of 1 to 2 is carried out by the action of
potassium tert-butoxide on 1 and corresponds to a Truce–Smiles
rearrangement reaction followed by an intramolecular cyclization
(Scheme 1).4–7
Scheme 1.
We have now explored the extension of this reaction sequence to
2-(3-cyanopropoxy)cycloalkene-1-carbonitriles (3). One can assume
that a base-generated carbanion nucleophile adjacent to a nitrile
group will undergo Michael addition (Scheme 2). If b-elimination
q
See Ref. 1.
* Corresponding authors. Tel.: +81 58 237 3931x228; fax: +81 58 237 8571 (K.O.).
E-mail address: okuda@gifu-pu.ac.jp (K. Okuda).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.010

904
K. Okuda et al. / Tetrahedron Letters 51 (2010) 903–906
Scheme 3.
occurs by an intramolecular nucleophilic aromatic substitution at an
ipso position,2 but to date there has been no precedent for this type of
rearrangement for aliphatic alkenes such as 3. We wish to report
herein the details of a novel Truce–Smiles type rearrangement reac-
tion for a series of cycloalkenyl substrates 3.
propoxy group was simply substituted with ethoxide to give 2-eth-
oxycyclopentene-1-carbonitrile (6a)10 in 33% yield. Similar results
were obtained for 3b (runs 5–8) and 3c (runs 9–12), respectively.
The best yields were obtained when NaH was used as base in
DME under reflux condition. In none of the reactions did we detect
the Thorpe–Zieglar reaction product, that is, 5-amino-2,3-
dihydrocycloalkeno[1,2-b]oxepin-4-carbonitrile (4’). Thus we have
demonstrated a novel sequence for cyanovinyl ether (3) that in-
volves a Truce–Smiles type rearrangement followed by an intra-
molecular cyclization.
We next explored transformation of the amino group of 4 to lac-
tam 7 for further derivatization at the 5-position. Thus, 4a was diaz-
otized with sodium nitrite in dioxane/sulfuric acid and then treated
with water (Scheme 4). The amino group of 4a was easily trans-
formed to the hydroxy group under these conditions and the tauto-
meric lactam (7a) was isolated in 80%. In the 1H NMR spectrum of 7a,
one deuterium oxide exchangeable lactam proton appeared at
10.44 ppm and the amino group disappeared. In the IR spectrum
of 7a, lactam bands at 3440 cmÀ1 (NH) and 1640 cmÀ1 (CO) were
present and the amino band had disappeared. Similar reactions
were performed with 4b and 4c to give 7b (83%) and 7c (73%),
respectively.11 Finally, the bronchodilatory activities of 4 and 7 were
evaluated on the basis of their relaxation activity to tracheal con-
traction induced by carbamylcholine chloride as a primary in vitro
assay.12 None of the compounds showed promising activity.
2. Results and discussion
The starting 2-oxocycloalkanecarbonitriles (5a–c) were readily
prepared from the corresponding commercially available alkanedi-
carbonitriles by Thorpe–Ziegler condensation, followed by an acid
hydrolysis of the resulting enamine.8,9 Reaction of 5 with 4-chlo-
robutyronitrile in the presence of potassium carbonate in DMF
gave 2-(3-cyanopropoxy)cycloalkene-1-carbonitrile (3a–c) in
moderate yield (Scheme 3). In the IR spectrum of 3, two cyano
absorption bands at 2200–2270 cmÀ1 appeared and the carbonyl
band disappeared, strongly suggesting that 3 is an O-alkyl rather
than a C-alkyl derivative.
The initial attempt to react 3a with potassium tert-butoxide in
dioxane at reflux temperature gave 4a as a sole product in 18%
yield (Table 1, run 1). In the 1H NMR spectrum of 4a, two methy-
lene protons of the dihydrofuran appeared at 3.04 and 4.55 ppm
as triplet with a coupling constant 8.6 Hz. The two deuterium
oxide exchangeable protons of the amino group appeared at
4.12 ppm. In the IR spectrum of 4a, amino bands at 3500 and
3350 cmÀ1 were present and the cyano band had disappeared.
These data are consistent with the structure of 4a and were sup-
ported by FAB-MS and elemental analysis. The relative low yield
may be due to the harsh reaction conditions, but attempting the
reaction at a more moderate temperature of 80 °C for 48 h gave
only recovered starting material. Changing the base from potas-
sium tert-butoxide to NaH gave no improvement in the product
yield (run 2) but a solvent change from dioxane to 1,2-dimethoxy-
ethane (DME) gave a slightly improved yield of 4a (25%) (run 3).
When sodium ethoxide was used as a base in ethanol, the cyano-
Scheme 4.
Table 1
Reaction of dinitriles 3 with bases
Run
Compd
Base (1.4–1.5 equiv)
Solvent
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
3a
3a
3a
3a
3b
3b
3b
3b
3c
3c
3c
3c
tert-BuOK
NaH
Dioxane
Dioxane
DME
Ethanol
Dioxane
Dioxane
DME
Ethanol
Dioxane
Dioxane
DME
2
2
10
6
3
2
8
6
3
2
4a
4a
4a
6a
4b
4b
4b
6b
4c
4c
4c
6c
18
18
25
33
15
15
43
37
15
15
21
31
NaH
NaOEt*
tert-BuOK
NaH
NaH
NaOEt*
tert-BuOK
NaH
10
11
12
NaH
8
6
NaOEt*
Ethanol
All reactions were carried out under reflux condition.
*
2 equiv was used.

K. Okuda et al. / Tetrahedron Letters 51 (2010) 903–906
905
benzene to give 4a (2.00 g, 25%) as pale brown plates, mp 154–
156 °C. IR (KBr): 3500, 3350 (NH); 1H NMR (200 MHz, CDCl3): d
2.12 (2H, quint, J = 7.0 Hz, H-7), 2.62, 2.75 (each 2H, each t,
J = 7.0 Hz, H-6 and 8), 3.04 (2H, t, J = 8.6 Hz, H-1), 4.12 (2H, br s,
D2O exchangeable, NH2), 4.55 (2H, t, J = 8.6 Hz, H-2); FABMS: m/z
177 (MH+). Anal. Calcd for C10H12N2O: C, 68.16; H, 6.86; N, 15.90.
Found: C, 68.14; H, 6.83; N, 15.64.
3. Conclusion
In summary, reaction of 2-(3-cyanopropoxy)cycloalkene-1-car-
bonitrile (3) with a base gave 5-aminocycloalkeno[1,2-d]furo[2,3-
b]pyridines (4) via a Truce–Smiles type rearrangement followed
by an intramolecular cyclization. We are currently exploring their
further derivatization at the 5-position for development of poten-
tial pharmaceutics.
4.4. 5-Amino-1,2,6,7,8,9-hexahydrofuro[2,3-c]isoquinoline (4b)
4. Experimental
4.1. General
To a solution of 3b (10.0 g, 52.6 mmol) in dry DME (400 mL)
was added NaH (1.90 g, 79.2 mmol) and the mixture was refluxed
for 8 h under stirring. After the evaporation of the solvent, ice
water (400 mL) was added and the aqueous solution was extracted
with ethyl acetate (200 mL Â 3). The organic layer was washed
with sat. brine, dried over Na2SO4, and evaporated in vacuo. The
residue was recrystallized from benzene to give 4b (4.30 g, 43%)
as pale brown plates, mp 177–179 °C. IR (KBr): 3450, 3350 (NH);
1H NMR (200 MHz, CDCl3): d 1.70–1.90 (4H, m, H-7 and 8), 2.33,
2.53 (each 2H, each t, each J = 5.9 Hz, H-6 and 9), 2.99 (2H, t,
J = 8.6 Hz, H-1), 4.17 (2H, br s, D2O exchangeable, NH2), 4.55 (2H,
t, J = 8.6 Hz, H-2); FABMS: m/z 191 (MH+). Anal. Calcd for
C11H14N2O: C, 69.45; H, 7.42; N, 14.73. Found: C, 69.47; H, 7.28;
N, 14.66.
All melting points were determined on a Yanagimoto micro-
melting point apparatus, and are uncorrected. Elemental analyses
were performed on a Yanagimoto MT-5 CHN Corder elemental ana-
lyzer. The FAB-mass spectra were obtained on a VG 70 mass spec-
trometer and m-nitrobenzyl alcohol was used as a matrix. The IR
spectra were recorded on a Japan Spectroscopic IRA-102 diffraction
grating infrared spectrophotometer or FT/IR-200 spectrophotome-
ter and frequencies are expressed in cmÀ1. The 1H NMR spectra
were recorded on a Hitachi R-1500, Varian VXR-200 or VXR-500
instrument each operating at 60, 200, and 500 MHz with tetra-
methylsilane as an internal standard. Column chromatography
was performed on silica gel (IR-60-63-210-W, Daiso). TLC was car-
ried out on Kieselgel 60F254 (Merck) or silica gel 70FM (Wako).
4.5. 5-Amino-1,2,7,8,9,10-hexahydro-6H-cyclohepta[1,2-
d]furo[2,3-b]pyridine (4c)
4.2. General procedure of 2-(3-cyanopropoxy)cycloalkene-1-
carbonitrile (3)
To a solution of 3c (10.0 g, 49.0 mmol) in dry DME (400 mL) was
added NaH (1.70 g, 70.8 mmol) and the mixture was refluxed for
8 h under stirring. After the evaporation of the solvent, ice water
(400 mL) was poured into the residue and the solution was ex-
tracted with ethyl acetate. The organic layer was washed with
sat. brine, dried over Na2SO4, and evaporated in vacuo. The residue
was recrystallized from benzene to give 4c (2.10 g, 21%) as pale
brown plates, mp 141–143 °C. IR (KBr): 3450, 3350 (NH); 1H
NMR (200 MHz, CDCl3): d 1.52–1.90 (6H, m, H-7, 8, and 9), 2.53,
2.63 (each 2H, each m, H-6 and 10), 3.07 (2H, t, J = 8.6 Hz, H-1),
4.17 (2H, br s, D2O exchangeable, NH2), 4.53 (2H, t, J = 8.6 Hz, H-
2); FABMS: m/z 205 (MH+). Anal. Calcd for C12H16N2O: C, 70.56;
H, 7.90; N, 13.71. Found: C, 70.55; H, 7.81; N, 13.60.
To a solution of 2-oxocycloalkanecarbonitriles 5 (0.120 mol) in
dry DMF (400 mL) were added 4-chlorobutyronitrile (15.4 g,
0.149 mol) and potassium carbonate (51.4 g, 0.372 mol) and the
mixture was then stirred at 80 °C for 6 h. After the evaporation of
the solvent in vacuo, 400 mL of ice water was poured into the res-
idue and the aqueous solution was extracted with ethyl acetate
(300 mL Â 3). The organic layer was washed with sat. brine, dried
over Na2SO4, and evaporated in vacuo. The residue was chromato-
graphed on silica gel. The eluate of benzene–ethyl acetate (4:1)
was evaporated in vacuo to give a viscous pale yellow oil (3). 3a
(65%); IR (CHCl3): 2250, 2200 (CN); 1H NMR (200 MHz, CDCl3): d
1.94 (2H, quint, J = 7.6 Hz, H-4), 2.09 (2H, quint, J = 6.1 Hz, H-2’),
2.46–2.66 (6H, m, H-3, 5, and CH2CN), 4.41 (2H, t, J = 6.1 Hz,
OCH2); FABMS: m/z 177 (MH+); FABHRMS m/z: Calcd. for
C10H13N2O: 177.1028. Found: 177.1037. 3b (73%); IR (CHCl3):
2270, 2220 (CN); 1H NMR (60 MHz, CDCl3): d 1.50–2.00 (6H, m,
H-4, 5, and 2’), 2.00–2.45 (4H, m, H-3 and 6), 2.59 (2H, t,
J = 5.6 Hz, CH2CN), 4.12 (2H, t, J = 5.6 Hz, OCH2); FABMS: m/z 191
(MH+); FABHRMS m/z: Calcd. for C11H15N2O: 191.1184. Found:
191.1203. 3c (64%); IR (CHCl3): 2250, 2210 (CN); 1H NMR
(200 MHz, CDCl3): d 1.45–1.85 (8H, m, H-4, 5, 6, and 2’), 1.80–
2.15 (6H, m, H-3, 7, and CH2CN), 4.20 (2H, t, J = 5.9 Hz, OCH2); FAB-
MS: m/z 205 (MH+); FABHRMS: m/z Calcd. for C12H17N2O:
205.1341. Found: 205.1351.
4.6. 1,2,4,5,7,8-Hexahydro-6H-cyclopenta[1,2-d]furo[2,3-
b]pyridin-5-one (7a)
To a suspension of 4a (3.00 g, 17.0 mmol) in dioxane (80 mL)
and concd H2SO4 (0.2 mL) was added dropwise a solution of NaNO2
(2.40 g, 34.8 mmol in 1.5 mL H2O) with cooling under 5 °C. After
the end point of the reaction was confirmed with KI-starch paper,
water (200 mL) was poured into the mixture and the solution was
stirred at rt for 0.5 h. The precipitated solid was collected on filter
in vacuo and recrystallized from dioxane to give 7a (2.40 g, 80%) as
colorless needles, mp 237–239 °C. IR (KBr): 3440 (NH), 1640 (CO);
1H NMR (500 MHz, DMSO-d6): d 2.00 (2H, quint, J = 7.3 Hz, H-7),
2.61, 2.72 (each 2H, each t, each J = 7.3 Hz, H-6 and 8), 3.01 (2H,
t, J = 8.6 Hz, H-1), 4.50 (2H, t, J = 8.6 Hz, H-2), 10.44 (1H, br s, D2O
exchangeable, NH); FABMS: m/z 178 (MH+). Anal. Calcd for
C10H11NO2: C, 67.78; H, 6.26; N, 7.90. Found: C, 67.48; H, 6.04; N,
7.84.
4.3. 5-Amino-1,2,7,8-tetrahydro-6H-cyclopenta[1,2-d]furo
[2,3-b]pyridine (4a)
To a solution of 3a (8.00 g, 45.4 mmol) in dry 1,2-dimethoxy-
ethane (DME) (400 mL) was added NaH (1.60 g, 66.7 mmol) and
the reaction mixture was then refluxed for 10 h. After the evapora-
tion of the solvent, ice water (400 mL) was poured into the residue
and the solution was extracted with ethyl acetate (200 mL Â 3).
The organic layer was washed with sat. brine, dried over Na2SO4,
and evaporated in vacuo. The residue was recrystallized from
4.7. 1,2,4,5,6,7,8,9-Octahydrofuro[2,3-c]isoquinolin-5-one (7b)
To a suspension of 4b (3.00 g, 15.8 mmol) in dioxane (80 mL)
and concd H2SO4 (0.2 mL) was added dropwise a solution of NaNO2
(2.20 g, 31.9 mmol in 1.5 mL H2O) under 5 °C. After the end point of
the reaction was confirmed with KI-starch paper, water (200 mL)

906
K. Okuda et al. / Tetrahedron Letters 51 (2010) 903–906
was poured into the mixture and the solution was stirred at rt for
0.5 h. The precipitated solid was collected by filtration in vacuo and
recrystallized from dioxane to give 7b (2.50 g, 83%) as colorless
needles, mp 217–219 °C. IR (KBr): 3480 (NH), 1640 (CO); 1H
NMR (200 MHz, DMSO-d6): d 1.63–1.73 (4H, m, H-7 and 8), 2.30–
2.42, 2.44–2.58 (each 2H, each m, H-6 and 9), 2.96 (2H, t,
J = 8.6 Hz, H-1), 4.48 (2H, t, J = 8.6 Hz, H-2), 10.55 (1H, br s, D2O
exchangeable, NH); FABMS: m/z 192 (MH+). Anal. Calcd for
C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 69.07; H, 6.81;
N, 7.27.
Acknowledgments
We are grateful to the SC-NMR Laboratory of Okayama Univer-
sity for 200 and 500 MHz 1H NMR experiments. We also thank Dr.
K. L. Kirk (NIDDK, NIH) for helpful suggestions.
References and notes
1. Part 60 Okuda, K.; Tagata, T.; Kashino, S.; Hirota, T.; Sasaki, K. Chem. Pharm. Bull.
2009, 57, 1296–1299.
2. For a leading review, see Snape, T. J. Chem. Soc. Rev. 2008, 37, 2452–2458.
3. For recent reports on Truce–Smiles rearrangement, see: (a) Erickson, W. R.;
McKennon, M. J. Tetrahedron Lett. 2000, 41, 4541–4544; (b) Kimbaris, A.; Cobb,
J.; Tsakonas, G.; Varvounis, G. Tetrahedron 2004, 60, 8807–8815; (c) Mitchell, L.
H.; Barvian, N. C. Tetrahedron Lett. 2004, 45, 5669–5671; (d) Snape, T. J. Synlett
2008, 2689–2691.
4.8. 1,2,4,5,7,8,9,10-Octahydro-6H-cyclohepta[1,2-d]furo[2,3-
b]pyridin-5-one (7c)
4. Hirota, T.; Matsushita, T.; Sasaki, K.; Kashino, S. Heterocycles 1995, 41, 2565–
2574.
5. Sasaki, K.; Rouf, A. S. S.; Hirota, T. J. Heterocycl. Chem. 1996, 33, 49–52.
6. Hirota, T.; Tomita, K.; Sasaki, K.; Okuda, K.; Yoshida, M.; Kashino, S. Heterocycles
2001, 55, 741–752.
7. Okuda, K.; Yoshida, M.; Hirota, T.; Sasaki, K. Chem. Pharm. Bull. 2010, 58, in
press.
8. Rodríguez-Hahn, L.; Parra, M.; Martínez, M. Synth. Commun. 1984, 14, 967–972.
9. Liu, H.-J.; Ly, T.-W.; Tai, C.-L.; Wu, J.-D.; Liang, J.-K.; Guo, J.-C.; Tseng, N.-W.;
Shia, K.-S. Tetrahedron 2003, 59, 1209–1226.
To a suspension of 4c (3.00 g, 14.7 mmol) in dioxane (80 mL)
and concd H2SO4 (0.2 mL) was added dropwise a solution of NaNO2
(2.00 g, 29.0 mmol in 1.5 mL H2O) while the solution was cooled
under 5 °C. After the end point of the reaction was confirmed with
KI-starch paper, water (200 mL) was poured into the reaction mix-
ture which was then stirred at rt for 0.5 h. The precipitated solid
was collected on filter in vacuo and recrystallized from dioxane
to give 7c (2.20 g, 73%) as colorless needles, mp 204–206 °C. IR
(KBr): 3460 (NH), 1630 (CO); 1H NMR (200 MHz, DMSO-d6): d
1.36–1.68 (6H, m, H-7, 8, and 9), 2.56–2.68 (4H, m, H-6 and 10),
3.04 (2H, t, J = 8.6 Hz, H-1), 4.46 (2H, t, J = 8.6 Hz, H-2), 10.25 (1H,
br s, D2O exchangeable, NH); FABMS: m/z 206 (MH+). Anal. Calcd
for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.37; H,
7.64; N, 6.88.
10. Lamant, M. Compt. Rend. 1959, 248, 3714–3716.
11. Compound 7 was also accessible from ethyl 2-(3-cyanopropoxy)cycloalken-1-
carboxylate, which was prepared from ethyl 2-oxocycloalkanecarboxylate and
chlorobutyronitrile in the presence of K2CO3 in DMF, using strong bases
directly. But the yield was relatively low (ꢀ20%). In this case, intramolecular
Claisen type condensation products were not isolated either.
12. Sasaki, K.; Rouf, A. S. S.; Hirota, T.; Nakaya, N. J. Heterocycl. Chem. 1999, 36, 461–
465.