1,3-dipolar cycloaddition of difluoro(methylene)cyclopropanes with nitrones: Efficient synthesis of 3,3-difluorinated tetrahydropyridinols

Article abstract of DOI:10.1055/s-2008-1077966

Difluoro-substituted spirocyclopropaneisoxazolidines were formed by 1,3-dipolar cycloaddition of difluoro(methylene)cyclopropanes (F ₂MCPs) with nitrones in high yields. The [3+2]-cycloaddition reactions exhibited good regioselectivity and high

Full text of DOI:10.1055/s-2008-1077966

LETTER
1989
1,3-Dipolar Cycloaddition of Difluoro(methylene)cyclopropanes with
Nitrones: Efficient Synthesis of 3,3-Difluorinated Tetrahydropyridinols
Efficient
S
ynthesis
i
of 3,3
a
o
ted Tetrahyd
-
ropyridi
C
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Road, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: jchxiao@mail.sioc.ac.cn
Received 19 April 2008
of F2MCP could react with cyclic dienes with high regio-
and stereoselectivity.9 Considering the importance of 1,3-
dipolar cycloaddition of MCPs in the construction of aza-
heterocyclic skeletons and the bioactivity of the fluorinat-
Abstract: Difluoro-substituted spirocyclopropaneisoxazolidines
were formed by 1,3-dipolar cycloaddition of difluoro(methyl-
ene)cyclopropanes (F2MCPs) with nitrones in high yields. The
[3+2]-cycloaddition reactions exhibited good regioselectivity and
high stereoselectivity. The cycloadducts could rearrange further to ed analogues, we investigated the [3+2]-cycloaddition of
form highly substituted 3,3-difluorinated tetrahydropyridinols.
F2MCP with nitrones and found that a series of highly
substituted gem-difluorinated tetrahydropyridinols could
be readily prepared.
Key words: fluorine, difluoro(methylene)cyclopropanes, 3,3-di-
fluorinated tetrahydropyridinols, ring rearrangement, 1,3-dipolar
cycloaddition, nitrone
Treatment of F2MCP 1 with phenyl-N-methylnitrone (2a)
in toluene at 50 °C for eight hours in a sealed tube gave a
good yield of 3a (81%) together with a small amount of
other isomers 3a¢ (Table 1, entry 1). High yields of ex-
pected 3a could be obtained in 1,4-dioxane with 2–3% in-
separable isomers 3a¢, which was determined by 19F NMR
spectroscopy (entry 3). Fortunately, reaction in petroleum
ether afforded 3a as the only product in 95% yield (entry
7). In the case of 4-nitrophenyl-N-methylnitrone (2b),
which does not dissolve well in nonpolar solvents, 3b was
formed as the sole cycloadduct when 1,4-dioxane was
used as a co-solvent in petroleum ether (entry 8). The con-
Methylenecyclopropane derivatives (MCPs), which are
relatively stable but highly strained molecules, have at-
tracted chemists’ attention over the past decades.1 With
regard to the cycloaddition reaction of these compounds,
there is a great deal of interest in the 1,3-dipolar cycload-
dition of nitrones. In most cases, the corresponding 1,3-di-
polar cycloadducts could rearrange further to form N-
heterocyclic six-membered-ring compounds at high tem-
perature, such as 4-pyridones or 4-pyridinols.2 This syn-
thetic methodology has been demonstrated as a useful
strategy to synthesize azaheterocyclic skeletons,3 which Table 1 Optimization of the Reaction Conditions for the 1,3-Dipo-
lar Cycloaddition
exist widely in natural products and pharmaceutical inter-
mediates.4
F
F
F
H
F
It is well known that the incorporation of fluorine into or-
ganic molecules could have profound effects on their
physical and biological properties.5 For the purpose of ex-
ploiting new efficient bioactive structures, fluorine chem-
ists made great efforts in synthesizing such fluorine-
containing azaheterocyclic skeletons.6 For example, Qing
designed and synthesized several nojirimycin analogues
(gem-4,4-difluorinated iminosugars). The biological eval-
uation of these azaheterocyclic structures revealed that the
gem-difluoromethylene group generally reduced the inhi-
bition of glycosidases.7 However, multiple reaction steps
are always required for the synthesis of these compounds.
solvent
Ts
R1
R1
N
O
isomers
50 °C, 12 h
Ts
O
N
H
2a: R1 = Ph
2b: R1 = 4-O2NC6H4
1
3'
3
Entry Nitrone Solvent
Product Yield (%)a 3:3¢b
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2b
toluene
3a
3a
3a
3a
3a
3a
3a
3b
81
51
99
73
73
56
95
55
20:1
20:1
[bmim][PF6]c
1,4-dioxane
Et2O
40:1
16:1
Difluoro(methylene)cyclopropanes (F2MCPs), the fluori-
nated analogues of MCPs, have been less studied over the
past decades due to the difficulties in synthesis.8 Recently,
we disclosed a route to prepare sulfonyl difluoro(methyl-
ene)cyclopropanes (F2MCPs) by the reaction of difluoro-
carbene with 1,2-allenic sulfones, and found that this kind
MeCN
11:1
MeOH
100:0
100:0
100:0
PE
co-solventd
a Total yield of 3 and 3¢.
b Determined by 19F NMR.
SYNLETT 2008, No. 13, pp 1989–1992
Advanced online publication: 15.07.2008
DOI: 10.1055/s-2008-1077966; Art ID: W06408ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
8
c 1-Butyl-3-methylimidazoliumhexafluorophosphate.
d PE–1,4-dioxane (2:1).

1990
X.-C. Hang et al.
LETTER
1
figuration of 3b was confirmed by H NMR and 2D gen on the benzene ring (entries 2 and 3). As for the alkyl-
NOESY experiments. The proton Ha appeared at d = 3.93 or alkenyl-substituted nitrones 2h and 2i, higher amounts
ppm as a doublet, and was coupled to proton Hb (J = 4.1 of isomers (5% and 12%) were observed and the efforts to
Hz), which indicated that the two protons were placed at obtain pure products failed (entries 6 and 7). Changing the
the adjacent carbon atoms (Figure 1). Although NOE ef- substituents on the nitrogen atom from methyl to phenyl
fects of Ha–Hc, Ha–Hd, Hb–Hd, and Hb–Hc were unambig- or isopropyl resulted in no reaction (entries 8 and 9),
uously detected, there was no observable correlation which demonstrated that the steric hindrance of the sub-
between Hd and Hc in its 2D NOESY spectrum, which in- stituents on the nitrogen had a significant effect on the re-
dicated that the tosyl group is situated anti to the 4-nitro- activity.
phenyl group.
Thermal rearrangement of the difluoro-substituted spiro-
cyclopropaneisoxazolidines was then investigated. When
3a was heated in tert-butanol at 100 °C in a sealed tube for
Hc
O
four hours, the signals of 3a (d = –144.9, –158.2 ppm; J =
O
S
151 Hz) in 19F NMR disappeared and a new AB peak sig-
F
F
Hc
no NOE
Ha
Hd
nal appeared at d = –109.9 and –125.6 ppm with a cou-
pling constant of 269 Hz, indicating the opening of the
difluorocyclopropane ring. After column chromatography
and recrystallization in CHCl3, 4a was obtained in 40%
yield and its structure was confirmed by single crystal X-
ray analysis.11 As shown in Figure 2, a tetrahydropyridi-
nol structure was formed. Due to the presence of the adja-
cent strong electron-withdrawing CF2 and tosyl groups,
the 4-carbonyl group in 4a adopts the enol form. The ther-
mal instability of the cycloadducts 3 encouraged us to try
a one-pot procedure for the synthesis of difluorinated tet-
rahydropyridinols. Treatment of nitrone 2a with 1.02–
1.05 equivalents of 1 in petroleum ether at 100 °C for
eight hours afforded 4a in nearly quantitative yield as de-
termined by 19F NMR (Table 3). Further investigation re-
vealed that this enol structure decomposed upon column
Hb
NO2
O
N
Hd
Figure 1 Configuration of 3b
With the optimized reaction conditions in hand, we ex-
tended the [3+2] cycloaddition to other nitrones. All aryl-
substituted N-methylnitrones 2c–2g reacted smoothly
with 1 to give the corresponding difluorinated spirocyclo-
propaneisoxazolidines in moderate to good yields
(Table 2). As for the more polar nitrones like 2f, a small
portion of 1,4-dioxane should also be added to facilitate
the solubilization (entry 4). Small amounts of isomers (2–
3%) were still found in the case of 2d and 2e with a halo-
Table 2 Reaction of F2MCP 1 with Nitrones10
F
F
F
H
F
R2
petroleum ether
50 °C, 12 h
Ts
R1
other isomers
R1
N
O–
Ts
O
N
H
R2
1
2c–k
3c–k
3'
Entry
Nitrone
2c
R1
R2
3 (%)a
3c, 63
3d, 75
3e, 85
3f, 90c
3g, 87
3h, 80d
3i, 69d
3j, –e
3¢ (%)
b
1
2
3
4
5
6
7
8
9
4-MeOC6H4
Me
Me
Me
Me
Me
Me
Me
Ph
–
2d
2e
4-BrC6H4
4-ClC6H4
4-HOC6H4
3
2
b
2f
–
b
2g
1-naphthyl-C6H4
–
2h
2i
PhCH=CH
5
i-Pr
Ph
12
b
2j
–
b
2k
Ph
i-Pr
3k, –e
–
a Isolated yield.
b No isomers were formed.
c 1,4-Dioxane was used as co-solvent.
d The crude yield was determined by 19F NMR.
e No reaction was observed.
Synlett 2008, No. 13, 1989–1992 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of 3,3-Difluorinated Tetrahydropyridinols
1991
OH
chromatography. Pure crystals of 4 could be obtained in
moderate to high yields after precipitation, filtration and
recrystallization. It should be noted that N-phenylnitrone
2j, which did not afford the cycloadduct 3j at 50 °C
(Table 2, entry 8) reacted well with 1 at 65 °C within six
hours to give 4j in one step (Table 3, entry 7). The cy-
cloadduct 3j was never detected by 19F NMR during the
reaction process, which indicated that 3j was not as stable
as other adducts and would rearrange immediately. The
mechanism of the rearrangement was considered to be a
diradical process as proposed initially by Brandi.2 Cy-
cloadduct 3a was chosen as the model compound to illus-
trate the process (Scheme 1). The cleavage of N–O bond
occurred upon heating to give a diradical intermediate 5,
followed by ring opening to form a new diradical 6, which
cyclized readily into the difluorinated tetrahydropyridinol
4a.11
F
F
F
Ts
H
F
t-BuOH
Ts
Ph
100 °C, 8 h
N
Ph
O
N
H
4a
3a
O
F
F
F
Ts
H
F
Ts
Ph
.N
.O
Ph
H
.N
6
5
Scheme 1 Thermal rearrangement of 3a
the corresponding adducts. It seems likely that a number
of difluorinated azaheterocycles could be synthesized by
this method from readily available starting materials.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Figure 2 Crystal structure of 4a
We thank the Chinese Academy of Sciences (Hundreds of Talents
Program), the National Natural Science Foundation (20772147) and
the Scientific Research Foundation for the Returned Overseas Chi-
nese Scholars, State Education Ministry for financial support.
Table 3 One-Pot Synthesis of Pyridinol Compounds 412
OH
F
F
Ts
R1
F
R2
F
petroleum ether
100 °C, 8 h
R1
N
O–
References and Notes
Ts
N
R2
(1) For recent reviews, see: (a) Goti, A.; Cordero, F. M.;
Brandi, A. Top. Curr. Chem. 1996, 178, 1. (b) Brandi, A.;
Goti, A. Chem. Rev. 1998, 98, 589. (c) Brandi, A.; Cicchi,
S.; Cordero, F. M.; Goti, A. Chem. Rev. 2003, 103, 1213.
(d) Nakamura, I.; Yamamoto, Y. Adv. Synth. Catal. 2002,
344, 111. (e) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem.
Rev. 2007, 107, 3117.
(2) (a) Brandi, A.; Guarna, A.; Goti, A.; De Sarlo, F.
Tetrahedron Lett. 1986, 27, 1727. (b) Brandi, A.; Garro, S.;
Guarna, A.; Goti, A.; Cordero, F.; De Sarlo, F. J. Org. Chem.
1988, 53, 2430. (c) Brandi, A.; Cordero, F. M.; De Sarlo, F.;
Goti, A.; Guarna, A. Synlett 1993, 1. (d) Brandi, A.; Durust,
Y.; Cordero, F. M.; De Sarlo, F. J. Org. Chem. 1992, 57,
5666. (e) Goti, A.; Anichini, B.; Brandi, A. J. Org. Chem.
1996, 61, 1665. (f) Ghosh, A. K.; Bilcer, G.; Schiltz, G.
Synthesis 2001, 2203. (g) List, B.; Castello, C. Synlett 2001,
1687.
(3) (a) Cordero, F. M.; Brandi, A.; Querci, C.; Goti, A.;
De Sarlo, F.; Guarna, A. J. Org. Chem. 1990, 55, 1762.
(b) Cordero, F. M.; Cicchi, S.; Goti, A.; Brandi, A.
Tetrahedron Lett. 1994, 35, 949. (c) Cicchi, S.; Goti, A.;
Brandi, A. J. Org. Chem. 1995, 60, 4743.
(4) For recent reviews, see: (a) Buffat, M. G. P. Tetrahedron
2004, 60, 1701. (b) Felpin, F.-X.; Lebreton, J. M. Eur. J.
Org. Chem. 2003, 3693. (c) Weintraub, P. M.; Sabol, J. S.;
Kane, J. M.; Borcherding, D. R. Tetrahedron 2003, 59,
2953.
1
2
4
Entry
Nitrone
2a
R1
Ph
R2
4 (%)a
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Me
Ph
4a (70)
4b (79)
4c (82)
4d (75)
4e (69)
4h (70)
4j (58)b
2b
4-O2NC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
PhCH=CH
Ph
2c
2d
2e
2h
2j
a Isolated yield.
b Reaction performed in 1,4-dioxane at 65 °C.
In summary, we have developed an efficient one-pot pro-
cedure for the synthesis of 3,3¢-difluorinated tetrahydro-
pyridinols by combining the 1,3-dipolar cycloaddition of
F2MCPs and nitrones with subsequent rearrangement of
Synlett 2008, No. 13, 1989–1992 © Thieme Stuttgart · New York

1992
X.-C. Hang et al.
LETTER
(5) (a) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, 2004. (b) Chambers, R. D. Fluorine in
Organic Chemistry; Blackwell: Cambridge, 2004.
(6) (a) Arnone, A.; Bravo, P.; Donadelli, A.; Resnati, G.
J. Chem. Soc., Chem. Commun. 1993, 984. (b) Reymond,
J.-L.; Pinkerton, A. A.; Vogel, P. J. Org. Chem. 1991, 56,
2128. (c) Kim, D.-K.; Kim, G.; Kim, Y.-W. J. Chem. Soc.,
Perkin Trans. 1. 1996, 803. (d) Kilonda, A.; Compernolle,
F.; Hoornaert, G. J. J. Org. Chem. 1995, 60, 5820.
was purified by chromatography on a silica gel column (PE–
EtOAc, 10:1) to yield 3a as a viscous oil (70 mg, 95%). 1H
NMR (300 MHz, CDCl3): d = 1.38 (s, 3 H), 1.53 (s, 3 H),
2.48 (s, 3 H), 2.55 (s, 3 H), 3.89 (d, J = 4.8 Hz, 1 H), 4.06 (d,
J = 4.8 Hz, 1 H), 6.91–6.97 (m, 2 H), 7.15–7.25 (m, 3 H),
7.33 (d, J = 8.2 Hz, 2 H), 7.72 (d, J = 8.2 Hz, 2 H). 19F NMR
(282 MHz, CDCl3): d = –144.9 (d, J = 151 Hz, 1 F), 158.2
(d, J = 151 Hz, 1 F). IR (film): 3066, 3035, 3008, 2969, 2933,
2878, 1597, 1496, 1479, 1457, 1436, 1325, 1305, 1249,
1209, 1188, 1149, 1125, 1087, 1078 cm–1. MS (ESI): m/z =
430.0 [M + Na+]. Anal. Calcd for C21H23F2NO3S: C, 61.90;
H, 5.69; N, 3.44. Found: C, 61.87; H, 5.80; N, 3.05.
(11) The single-crystal X-ray structural data for 4a have been
deposited at the Cambridge Crystallographic Data Centre
and allocated the deposition number CCDC 684886.
(12) Preparation of 3,3-Difluoro-1,2,2-trimethyl-6-phenyl-5-
tosyl-1,2,3,6-tetrahydropyridin-4-ol (4a): Into a 5-mL
sealed tube were added 1 (50 mg, 0.184 mmol), phenyl-N-
methylnitrone (2a; 24 mg, 0.184 mmol) and PE (2.5 mL).
The mixture was stirred at 100 °C for 8 h. After cooling to
r.t., 3,3-difluoro-1,2,2-trimethyl-6-phenyl-5-tosyl-1,2,3,6-
tetrahydropyridin-4-ol (4a) was precipitated. After
(e) Arnone, A.; Bravo, P.; Donadelli, A.; Resnati, G.
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Pacini, B.; Filippo, M. D.; Altamura, S. J. Med. Chem. 2005,
48, 4547. (g) Fabio, R. D.; Giovannini, R.; Bertani, B.;
Borriello, M.; Bozzoli, A. Bioorg. Med. Chem. Lett. 2006,
16, 1749.
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(b) Wang, R.-W.; Qiu, X.-L.; Bols, M.; Ortega-Caballero,
F.; Qing, F.-L. J. Med. Chem. 2006, 49, 2989.
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Drach, J. C.; Zemlicka, J. J. Med. Chem. 2001, 44, 4019.
(b) Taguchi, T.; Okada, M. J. Fluorine Chem. 2000, 105,
279. (c) Dolbier, W. R. Jr.; Burkholder, C. R.; Chaves, A. L.;
Green, A. J. Fluorine Chem. 1996, 77, 31. (d) Dolbier, W.
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Xiao, J.-C. Eur. J. Org. Chem. 2008, 1101.
(10) Preparation of 1,1-Difluoro-2,2,5-trimethyl-6-phenyl-7-
tosyl-4-oxa-5-azaspiro[2.4]heptane (3a): Into a 5-mL
sealed tube were added 1 (50 mg, 0.184 mmol), phenyl-N-
methylnitrone (2a; 30 mg, 0.22 mmol) and PE (1.5 mL). The
mixture was stirred at 50 °C for 12 h. After cooling to r.t., the
solvent was removed under reduced pressure. The residue
removing the solvent by filtration, the residue was
recrystallized in CHCl3 by slow evaporation. Yield: 52 mg,
70%. 1H NMR (300 MHz, CDCl3): d = 1.16 (s, 3 H), 1.30 (s,
3 H), 1.93 (s, 3 H), 2.32 (s, 3 H), 4.11 (d, J = 9.8 Hz, 1 H),
6.87–7.01 (m, 9 H), 10.6 (s, 1 H). 19F NMR (282 MHz,
CDCl3): d = –109.0 (dd, J = 9.7, 269 Hz, 1 F), –125.6 (d, J =
269 Hz, 1 F). 13C NMR (75 MHz, CDCl3): d = 12.7, 20.2 (d,
JFC = 4 Hz), 21.4, 32.1, 59.0 (dd, JFC = 15, 18 Hz), 62.7,
113.9 (m), 115.4 (t, JFC = 184 Hz), 126.3, 127.7, 127.9,
129.4, 130.3, 137.8, 138.3 (d, JFC = 2 Hz), 143.8, 152.3 (t,
JFC = 19 Hz). IR (film): 3235, 2995, 2821, 1643, 1598, 1496,
1456, 1369, 1317, 1289, 1276, 1249, 1217, 1175, 1148,
1125, 1101, 1070, 1057, 1017, 994 cm–1. MS (ESI): m/z =
408.1 [M + H+].
Synlett 2008, No. 13, 1989–1992 © Thieme Stuttgart · New York