Preparation of 3,4-fused-spiro[furan-5(5H),4′-piperidin]-2-one

Article abstract of DOI:10.1016/j.tetlet.2009.07.035

A general method for the preparation of various 3,4-fused-spiro[furan-5(5H),4′-piperidin]-2-one with high yield is reported. The formation of spiro[furanone-piperidine] structure was achieved by a Suzuki coupling, followed by an iodolactonization reaction

Full text of DOI:10.1016/j.tetlet.2009.07.035

Tetrahedron Letters 50 (2009) 5228–5230
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Tetrahedron Letters
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Preparation of 3,4-fused-spiro[furan-5(5H),40-piperidin]-2-one
*
Jian Liu , Tianying Jian, Liangqin Guo, Tzvetomira Atanasova, Ravi P. Nargund
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
A general method for the preparation of various 3,4-fused-spiro[furan-5(5H),40-piperidin]-2-one with
high yield is reported. The formation of spiro[furanone-piperidine] structure was achieved by a Suzuki
coupling, followed by an iodolactonization reaction.
Article history:
Received 13 May 2009
Revised 29 June 2009
Accepted 1 July 2009
Available online 10 July 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Spiro piperidine
Suzuki coupling
Iodolactonization
Spiro piperidines are commonly used structure motifs in drug
discoveries. One successful example is 1-(methylsulfonyl)-
spiro[indoline-3,40-piperidine] (1) employed by Merck scientists
in the discovery of MK-0677 which is one of the most potent pep-
tidomimetic growth hormone secretagogues and entered Phase III
clinical trials.1 Recently we reported the synthesis of a close ana-
logue to 1, (2-methylsulfonyl)-2,3-dihydro-1H-spiro[isoquinoline-
4,40-piperidine] 2, as an interesting intermediate for a medicinal
chemistry program.2
Wehavehadcontinuinginterestinspiropiperidines, whichledto
the study of 3,4-pyridine fused-spiro[furan-5(5H),40-piperidin]-2-
one 3, especially the structure 4, 3-chloro-2-methyl-5H-spiro
[furo[3,4-b]pyridine-7,40-piperidin]-5-one (Fig. 1). We discovered
4 as an important common intermediate for the SAR study in one
of our medicinal chemistry programs. Thus effort was invested in
looking for a general synthesis of 3,4-fused-spiro[furan-5(5H),40-
piperidin]-2-one analogues.
Methyl 5-chloro-6-methyl-2-triflatepyridine-3-carboxylate 5,4
was coupled with tert-butyl 4-(4,4,5,5-tetramethyl-1,2,3-dioxa-
borolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 65 via a pal-
ladium-mediated high yield Suzuki cross-coupling to form 7. Then
the ester in 7 was hydrolyzed to acid to afford compound 8 in an
excellent yield. An iodine initialized lactonization6 under a basic
condition in acetonitrile and water generated the spiro lactone
structure 9. Finally the iodo was removed by a radical type reduction
using tributyltin hydride to provide 3-chloro-2-methyl-5H-spiro
[furo[3,4-b]pyridine-7,40-piperidin]-5-one 4 in 70% yield over four
steps from compound 5.7
The same synthetic route as for compound 4 was applied to
different aromatic ortho halide or triflate carboxylic ester, or nitrile
substrates for the preparation of different 3,4-fused-spiro[furan-
5(5H),40-piperidin]-2-ones. The reaction conditions for each step
H
N
The synthesis of 3,4-fused-spiro[furan-5(5H),40-piperidin]-2-
one was reported with benzo, pyridino, and thiopheno as fused
rings.3 Halogen-metal exchange or direct lithiation generates ortho
carboxylate dianion, which is then added to N-protected 4-piperid-
inone, followed by acidic treatment to form the spiro lactone. This
excellent chemistry provides one-pot reaction to form the 3,4-
fused-spiro[furan-5(5H),40-piperidin]-2-one in moderate yield.
However, this method is limited to simple systems with no aromatic
substitutions. Here we are reporting a general syntheticroute we de-
rived from the synthesis of compound 4, utilizing a Suzuki coupling,
followed by an iodolactonization reaction to form the spiro struc-
ture. The synthetic route for compound 4 is shown in Scheme 1.
P
N
P
N
O
NH2
O
N
O
O
S
O
N
O
N
N
S
S
O
O
O
2
1
MK-0677
P
N
P
N
N
N
O
O
Cl
O
O
3
4
P = H or Boc
* Corresponding author. Tel.: +1 732 594 9600; fax: +1 732 594 3007.
E-mail address: jian_liu@merck.com (J. Liu).
Figure 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.035

J. Liu et al. / Tetrahedron Letters 50 (2009) 5228–5230
5229
Boc
Boc
b
N
N
Boc
a
O
CO2Me
OTf
N
a
OTf
COOMe
N
N
b
+
O
+
B
O
O
B
O
CO2Me
Cl
COOMe
Cl
16
17
6
6
7
5
Boc
N
Boc
N
Boc
N
Boc
N
Boc
Boc
N
N
I
N
N
d
e
N
c
c,d
I
O
O
O
O
O
O
Cl
Cl
CO2Me
COOH
Cl
O
O
4
8
9
18
19
20
Scheme 1. Synthesis of 4. Reagents and conditions: (a) Pd(dppf), Na2CO3, DMF/H2O,
100 °C, microwave, 89%; (b) NaOH (5 N)/MeOH, then HCl, 95%; (c) I2, KI, NaHCO3,
H2O/CH3CN (5/1), 85%; (d) Bu3SnH, AIBN, toluene, 80 °C, 97%.
Scheme 2. Synthesis of 20. Reagents and conditions: (a) Tf2O, NaH, Et2O, 0 °C, 97%;
(b) Pd(dppf), Na2CO3, DMF/H2O, 90 °C, 3 h, 94%; (c) NaOH(5 N)/MeOH, then HCl; (d)
I2, KI, NaHCO3, H2O/CH3CN, 48% two steps; (d) Bu3SnH, AIBN, toluene, 80 °C, 85%.
of all compounds were exactly the same as those for 4, and the
overall yields were from moderate to good. The yields varied sig-
nificantly on the step of iodolactonization which was sensitive to
the substrates.7 All final products as white solids were purified
by chromatography and were characterized by LC–MS and 1H
NMR.8 Table 1 lists the different commercially available or readily
prepared substrates and the corresponding spiro piperidine prod-
ucts. The synthesis can tolerate different heterocyclic rings with
various substitutions. In addition, we have applied this synthetic
route to prepare a spiro[furan-5(5H)-40-piperidin]-3-one with an
olefinic fused ring such as compound 20 (Scheme 2). Ethyl 2-oxo-
cyclopentanecarboxylate 16 was converted to enol triflate 17 when
treated by triflic anhydride in ether with sodium hydride as a base.
Suzuki coupling of 17 with 6 catalyzed by Pd(dppf) generated
product 18. Hydrolysis of ester in 18 followed by iodo lactonization
converted it to a spiro compound 19. Finally, the iodo was reduced
by tributyltin hydride under radical condition to form the spiro
compound 208 with an unsaturated fused ring.
Table 1
3,4-Fused-spiro[furan-5(5H),40-piperidin]-2-ones prepared from their corresponding
aromatic substrates
Substrates
OTf
CO2Me
Products (yields)a
Substrates
Br
CO2Me
Products (yields)a
Boc
N
Boc
N
N
N
N
b
a
O
O
N
O
O
3a (85%)
3b (48%)
Br
Boc
N
Cl
Boc
N
N
N
CO2Me
CO2Me
N
c
d
O
O
N
Effort to expand thefuran ring to a six-memberedlactonewas not
successful. Homologationof acid8 led to anaryl aceticacid. However
to our disappointment, iodolactonization on this homologated acid
to form the six-membered lactone did not work. Presumably the for-
mation of a six-membered lactone is much slower than the forma-
tion of a five-membered ring, which led to a complicated mixture
of iodination products unable to be characterized.
In summary, we have demonstrated that the biologically inter-
esting 3,4-fused-spiro[furan-5(5H),40-piperidin]-2-one can be pre-
pared from aromatic ortho halide or triflate carboxylic ester, or
nitrile via a Suzuki coupling and an iodolactonization as key steps.
This methodology allows for a variety of aromatic or olefinic fused
rings with various substitutions. The piperidine nitrogen and the
lactone functional groups in the spiro structures can be used as
handles for further derivatizations for the preparation of biologi-
cally active molecules.
O
O
3c (30%)
3d (43%)
OTf
Boc
N
N
Boc
N
N
F3C
Cl
CN
CO2Me
F
F3C
N
N
f
e
O
O
F
O
O
10 (70%)
11 (31%)
N
Boc
N
OTf
CO2Me
Boc
N
Cl
CO2Me
F3C
S
N
g
h
O
O
F3C
S
O
O
Acknowledgments
12 (45%)
13 (30%)
We would like to thank Ms. Ningning Guan and Ms. Ellen Craw-
ford in Merck Outsourcing Department for coordinating scale up
synthesis at WuXi PharmaTech of several compounds reported
herein.
F
F
Br
Boc
N
Br
Boc
N
CO2Me
CO2Me
S
F
F
i
O
j
O
O
References and notes
O
S
14 (64%)
1. (a) Patchett, A. A.; Nargund, R. P.; Tata, J. R.; Chen, M.-H.; Barakat, K. J.; Johnston,
D. B. R.; Cheng, K.; Chan, W. W.-S.; Butler, B.; Hickey, G.; Jacks, T.; Schleim, K.;
Pong, S.-S.; Chaung, L.-Y. P.; Chen, H. Y.; Frazier, E.; Leung, K. H.; Chiu, S.-H. L.;
Smith, R. G. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7001; (b) Nargund, R. P.;
Patchettt, A. A.; Bach, M. A.; Murphy, M. G.; Smith, R. G. J. Med. Chem. 1998, 41,
3103.
15 (54%)
a
Overall yields are for four steps from substrates to spiro piperidines. Each
product was prepared at the scale of 400 mg to multi grams.
2. Liu, J.; Jian, T.; Sebhat, S.; Nargund, R. Tetrahedron Lett. 2006, 47, 5115.

5230
J. Liu et al. / Tetrahedron Letters 50 (2009) 5228–5230
3. (a) Marxer, A.; Rodriguez, H. R.; McKenna, J. M.; Tsai, H. M. J. Org. Chem. 1975, 40,
1427; (b) Parham, W. E.; Egberg, D. C.; Sayed, Y. A.; Traikill, R. W.; Keyser, G. E.;
Neu, N.; Montgomery, W. C.; Jones, L. J. Org. Chem. 1976, 41, 2628; (c) Sauter, F.;
Stanetty, P.; Frohlich, H.; Ramer, W. Heterocycles 1987, 26, 2639; d Sagara, T.;
Itoh, S.; Nakashima, H.; Goto, Y.; Shimizu, A.; Iwasawa, Y.; Okamoto, O. PCT Int.
Appl., WO2002088089, 2002.
4. Compound 5 was readily prepared from commercially available 2-hydroxy-6-
methyl-nictinic acid by chlorination, esterification and conversion of 2-hydroxy
to triflate: Cale, A. D.; Gero, T. W.; Walker, K. R.; Lo, Y. S.; Welstead, W. J.; Jaques,
L. W.; Johnson, A. F.; Leonard, C. A.; Nolan, J. C.; Johnson, D. N. J. Med. Chem. 1989,
32, 2178.
was stirred for 20 min and became colorless. The organic layer was separated
and the aqueous layer was extracted with ethyl acetate (3 ꢀ 100 mL). The
combined organic phases were washed with water, brine, dried over MgSO4,
filtered, and concentrated to afford light color product 9 5.00 g (85%, Rf = 0.4 in
ethyl acetate:hexanes = 1:4). C17H20ClIN2O4: LC–MS, ESI (M+Na)+: 501.0; 1H
NMR (CDCl3, 500 MHz): d 8.11 (1H, s), 2.78 (3H, s), 2.38 (1H, dd, J = 12.5, 9.0 Hz),
4.62 (1H, br), 4.42 (1H, dd, J = 12.0, 4.5 Hz), 4.02–4.30 (3H, br), 3.82 (1H, br),2.15
(1H, d, J = 6.5 Hz), 1.53 (9H, s) ppm; (d) reduction of iodo in 9 to 4: To a 500 mL
one-necked round-bottomed flask was charged 9 (5.00 g, 10.44 mmol), AIBN
(0.086 g, 0.052 mmol), and toluene (40 mL). The mixture was heated to 80 °C
and stirred while Bu3SnH (9.00 g, 30.93 mmol) was added by syringe dropwise
under nitrogen. The mixture was stirred and heated in an oil bath of 80 °C for
3 h, and then concentrated. The residue was purified by MPLC (330 g silica gel,
0–25% ethyl acetate in hexanes) to afford white solid product 4 3.56 g (96.6%,
Rf = 0.3 in ethyl acetate:hexanes = 1:4). C17H21ClN2O4: LC–MS, ESI (M+Na)+:
375.2; 1H NMR (CDCl3, 500 MHz): d 8.07 (1H, s), 4.20 (2H, br, 3.28 (2H, br), 2.75
(3H, s), 2.23 (2H, td, J = 13.5, 5.0 Hz), 1.64 (2H, d, J = 12.0 Hz), 1.49 (9H, s) ppm.
13C NMR (CDCl3, 125 MHz): d 168.2, 165.8, 163.0, 153.9, 133.4, 132.2, 118.0,
84.8, 79.4, 40.3 (br), 39.8 (br), 33.4, 28.0, 23.4 ppm.
5. Compound
6 was prepared following the literatures: (a) Eastwood, P. R.
Tetrahedron Lett. 2000, 41, 3705; (b) Wustrow, D. J.; Wise, L. D. Syntheis 1991,
993.
6. (a) Mali, R. S.; Patil, S. R. Synth. Commun. 1990, 20, 167; (b) Reich, S. H.; Melnick,
M.; Pino, M. J.; Fuhry, M. M.; Trippe, A. J.; Appelt, K.; Davies, J. F.; Wu, B.-W.;
Musick, L. J. Med. Chem. 1996, 39, 2781.
7. General procedures for the preparation of 4: (a) Suzuki cross-coupling to 7: A dried
heavy-wall pyrex vessel was charged with 5 (2.68 g, 8.04 mmol), Pd(dppf)
(0.294 g, 0.4 mmol),
24.1 mol), H2O (4 mL), and DMF (12 mL). The reaction mixture was flushed
with nitrogen and the vessel was sealed before mixing with Biotage
6
(2.487 g, 8.04 mmol), sodium carbonate (2.588 g,
8. Compound 3a:C16H20N2O4: LC–MS, ESI (M+Na)+: 327.1; 1H NMR (CDCl3,
500 MHz) d: 8.77 (1H, dd, J = 6.0, 1.0 Hz), 8.12 (1H, dd, J = 7.0, 1.5 Hz), 7.43
(1H, dd, J = 7.5, 5.0 Hz), 4.12 (2H, m), 3.21 (2H, m), 2.19 (2H, m), 1.61 (2H, d,
J = 14.0 Hz)), 1.42 (9H, s) ppm; 3b: C16H20N2O4: LC–MS, ESI (M+Na)+: 327.1; 1H
NMR (CDCl3, 500 MHz) d: 8.89 (1H, d, J = 4.5 Hz), 7.79 (1H, dd, J = 8.0, 1.0 Hz),
7.56 (1H, dd, J = 8.0, 4.5 Hz), 4.19 (2H, br), 3.27 (2H, br), 2.07 (2H, m), 1.69 (2H, d,
J = 13.5 Hz), 1.48 (9H, s) ppm; 3c: C16H20N2O4: LC–MS, ESI (M+Na)+: 327.1; 1H
NMR (CDCl3, 500 MHz) d: 8.88 (1H, d, J = 4.5 Hz), 8.86 (1H, s), 7.79 (1H, d,
4.5 Hz), 4.23 (2H, br), 3.28 (2H, br), 2.15 (2H, m), 1.76 (2H, d, J = 14.0 Hz), 1.51
(9H, s) ppm; 3d: C16H20N2O4: LC–MS, ESI (M+Na)+: 327.1; 1H NMR (CDCl3,
500 MHz) d: 9.20 (1H, s), 8.98 (1H, s, J = 2.0 Hz), 7.39 (1H, d, J = 2.0 Hz), 4.21 (2H,
br), 3.25 (2H, br), 2.08 (2H, m), 1.72 (2H, d, J = 13.5 Hz), 1.49 (9H, s) ppm; 10:
C17H19F3N2O4: LC–MS, ESI (M+Na)+: 395.1; 1H NMR (CDCl3, 400 MHz) d: 8.39
(1H, 8.0 Hz), 7.88 (1H, d, 8.0 Hz), 4.25 (2H, br), 3.31 (2H, br), 2.33 (2H, m), 1.72
(2H, d, J = 13.6 Hz), 1.50 (9H, s) ppm; 11: C17H21FN2O4: LC–MS, ESI (M+Na)+:
359.2; 1H NMR (CDCl3, 500 MHz) d: 7.72 (1H, d, J = 7.5 Hz), 4.19 (2H, br), 3.28
(2H, br), 2.65 (3H, s), 2.25 (2H, m), 1.64 (2H, br), 1.49 (9H, s) ppm; 12:
C17H22N2O4: LC–MS, ESI (M+Na)+: 341.2; 1H NMR (CDCl3, 500 MHz) d: 8.64 (1H,
s), 7.95 (1H, s), 4.19 (2H, br), 3.29 (2 h, br), 2.46 (3H, s), 2.22 (2H, m), 1.62 (2H, d,
a
microwave reactor. The reaction mixture was exposed to microwave
irradiation for 1 h at 100 °C. After cooled down to room temperature, the
mixture was partitioned between ethyl acetate (20 mL) and water (10 mL). The
organic layer was separated and the aqueous layer was extracted with ethyl
acetate (3 ꢀ 15 mL). The combined organic phases were washed with water,
brine, dried over MgSO4, filtered, and concentrated. The residue was purified by
MPLC (40 g silica gel, 0–20% ethyl acetate in hexanes) to afford white solid
product 7 2.63 g (89%, Rf = 0.2 by ethyl acetate:hexanes = 1:4). C18H23ClN2O4:
LC–MS, ESI (M+H)+: 367.2; 1H NMR (CDCl3, 500 MHz): d 7.99 (1H, s), 5.71 (1H, s),
4.03 (2H, d, J = 2.5 Hz), 3.83 (3H, s), 3.63 (2H, br), 2.63 (3H, s), 2.46 (2H, d,
J = 1.5 Hz), 1.46 (9H, s) ppm. 13C NMR (CDCl3, 125 MHz): d 164.8, 163.3, 158.9,
154.1, 153.8, 152.0, 137.9, 130.5, 123.9, 82.5, 52.3, 43.6, 28.1, 27.9, 27.7,
22.5 ppm; (b) hydrolysis of ester to acid 8: To a 100 mL one-necked round-
bottomed flask was charged 7 (4.55 g, 12.40 mmol) along with MeOH (15 mL)
and NaOH (5 N, 8 mL). The resulting reaction mixture was stirred and heated to
60 °C for 1 h. Then the reaction mixture was concentrated to half volume. After
the mixture was acidified to pH 3 by concentrated HCl, the mixture was
extracted with ethyl acetate (3 ꢀ 100 mL). The combined organic phases were
washed with water, brine, dried over MgSO4, filtered, and concentrated to afford
light colored solid product 8 4.376 g (100%). C17H22ClN2O4: LC–MS, ESI (M+H)+:
353.2; (c) iodolactonization to 9: To a 500 mL one-necked round-bottomed flask
was charged 8 (4.376 g, 12.40 mol) and CH3CN (30 mL), NaHCO3 (satd, 150 mL).
Most of the acid dissolved. Under stirring, a solution of I2 (4.092 g, 16.124 mmol)
and KI (10.295 g, 62.015 mmol) in water (60 mL) was added dropwise in 10 min.
The resulting reaction mixture was stirred at room temperature for 18 h
overnight. Most of the iodine color paled away. To the flask, ethyl acetate
(100 mL) was added, followed by a solution of NaS2O3 (15%, 60 mL). The solution
J = 13.5 Hz), 1.46 (9H, s) ppm; 13: C16H18F3NO4S: LC–MS, ESI (M+Na)+: 400.1; 1
H
NMR (CDCl3, 500 MHz) d: 7.35 (1H, s), 4.09 (2H, br), 3.31 (2H, br), 2.02 (2H, m),
1.80 (2H, d, J = 13.0 Hz), 1.47 (9H, s) ppm; 14: C17H19F2NO4: LC–MS, ESI
(M+Na)+: 362.2; 1H NMR (CD3OD, 500 MHz) d: 7.79 (1H, dd, J = 8.5, 7.0 Hz), 7.70
(1H, 9.0, 7.0 Hz), 4.22 (2H, d, J = 13.0 Hz), 3.21 (2H, br), 2.20 (2H, m), 1.71 (2H, d,
J = 13.5 Hz), 1.51 (9H, s) ppm; 15: C15H19NO4S: LC–MS, ESI (M+Na)+: 332.1; 1H
NMR (CDCl3, 500 MHz) d: 7.83 (1H, d, J = 5.0 Hz), 6.98 (1H, d, 5.0 Hz), 4.06 (2H,
br), 3.34 (2H, br), 2.02 (2H, m), 1.80 (2H, d, J = 14.0 Hz), 1.49 (9H, s) ppm; 20:
C16H23NO4: LC–MS, ESI (M+Na)+: 316.1; 1H NMR (CDCl3, 500 MHz) d: 4.06 (2H,
br), 3.21 (2H, br), 2.52 (4H, br), 2.46 (2H, br), 1.83 (2H, m), 1.58 (2H, d,
J = 13.0 Hz), 1.46 (9H, s) ppm.