Synthesis of 3,3-difluoroazetidines

Article abstract of DOI:10.1055/s-2006-948186

A high-yield synthesis of 3,3-difluoroazetidines was developed by a monochlorohydroalane reduction of 3,3-difluoroazetidin-2-ones. The latter compounds were conveniently synthesized by a Reformatsky-type reaction of aldimines with ethyl bromo-difluoroacet

Full text of DOI:10.1055/s-2006-948186

LETTER
2039
Synthesis of 3,3-Difluoroazetidines
S
ynthesis of 3,3-Difluor
i
oazetid
l
ines lem Van Brabandt, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent University, Coupure links 653, 9000 Ghent, Belgium
Fax +32(9)2646243; E-mail: norbert.dekimpe@UGent.be
Received 19 April 2006
3,3-Difluoroazetidin-2-ones can be prepared by con-
densation of b,b-difluoro ester enolates with imines or
oxazolidines and by ring-closure of 3-hydroxy-2,2-di-
fluoropropionamides or a,a-difluoro-b-alaninates.22 In
the present report, 3,3-difluoro-4-phenylazetidin-2-ones
4–6 were synthesized in good yields (77–87%) via a Re-
formatsky-type reaction using ethyl bromodifluoroacetate
and different benzaldimines 1–3.23,26 Therefore, ethyl bro-
modifluoroacetate was reacted with freshly activated Zn
and an aldimine in THF under reflux during one hour. Per-
forming the same reaction with N-(2-methylpropylidene)-
2-propenyl-1-amine (8) afforded 3,3-difluoroazetidin-2-
one (9) in 55% yield, next to a small amount (5%) of b-
amino-a,a-difluoroester 10. Debenzylation of 3,3-difluo-
ro-1-(4-methoxybenzyl)azetidin-2-one (4) was achieved
using three equivalents of ceric ammonium nitrate (CAN)
in a mixture of acetonitrile and water in a 9:1 ratio. In this
way, the deprotected 3,3-difluoroazetidin-2-one 7 was
obtained in 83% yield (Scheme 1).
Abstract: A high-yield synthesis of 3,3-difluoroazetidines was de-
veloped by a monochlorohydroalane reduction of 3,3-difluoroazeti-
din-2-ones. The latter compounds were conveniently synthesized
by a Reformatsky-type reaction of aldimines with ethyl bromo-
difluoroacetate.
Key words: 3,3-difluoroazetidines, 3,3-difluoroazetidin-2-ones,
aldimines, Reformatsky, monochlorohydroalane
Recently, fluorine chemistry has received a great deal of
interest. Due to the peculiar properties of fluorine (high
electronegativity; relatively small size; very low polariz-
ability; tightly bound, three non-bonding electron pairs
and excellent overlap between 2s an 2p orbitals of fluorine
with the corresponding orbitals of other second period
elements), its presence induces modifications to the phys-
iological activity of bioactive compounds by introducing
lipophilic, hydrogen bonding and steric effects.1,2 At
present, a rapidly growing interest in 3-fluorinated aze-
tidines exists, as these compounds possess interesting
biological activities. The medicinal importance of 3,3-di-
fluoroazetidines is emphasized by recent patents which
relate fluorinated azetidines to new therapeutically active
and selective inhibitors of the enzyme dipeptidyl pepti-
dase-IV (DPP-IV).3–7 The inhibition of this enzyme is
emerging as a new therapeutic approach for the treatment
of type 2 diabetes.8 In addition, the recent patents concern-
ing fluorinated azetidines highlight the possibilities of
these compounds as substituents to modulate the activity
of different active compounds.9–17 In the latter publica-
tions, 3,3-difluoroazetidines are mainly synthesised by
treatment of 3-azetidinones with diethylaminosulphur tri-
fluoride (DAST), but no examples of the synthesis of 2-
functionalized 3,3-difluoroazetidines via this method are
known. Furthermore, perfluoroazetidines have been pre-
pared by thermolysis of the corresponding perfluoro-1,2-
oxazines or by photolysis of perfluorinated triazines, but
these perfluoroazetidines constitute a peculiar class of
compounds.18–21 In conclusion, no general pathway to-
wards 3,3-difluoroazetidines is available, although the
medicinal potential of this new class of compounds is very
promising. As a result, new syntheses towards the highly
attractive 3,3-difluoroazetidines are of considerable inter-
est towards organic and medicinal chemists.
As an alternative pathway towards N-substituted 3,3-di-
fluoroazetidin-2-ones, it was found that functionalization
of 1-unsubstituted 3,3-difluoroazetidin-2-one 7 under
phase-transfer conditions was possible. Therefore, differ-
ent bromides were used in the presence of 0.1 equivalent
of sodium iodide, 0.4 equivalent of tetrabutylammonium
hydrogensulfate and 2 equivalents of potassium hydrox-
ide in THF (Scheme 2).24,27 In the case of allyl bromide,
the reaction was complete after one hour of stirring at
room temperature. Substitution of 3,3-difluoroazetidin-2-
one 7 with 1-bromobutane turned out to be more difficult
as one hour and a half of reflux in THF was required to
complete the reaction.
Finally, 3,3-difluoroazetidin-2-ones 4–7 and 9 were con-
verted towards the corresponding new 3,3-difluoroaze-
tidines 12–16 in high yields. An excess of six equivalents
of monochlorohydroalane in diethyl ether at 0 °C for four
hours proved to be an excellent reductive agent to perform
these reactions (Scheme 3).25,28 After work-up, no further
purification was necessary, leading to high yields of 3,3-
difluoroazetidines 12–16.
In conclusion, a straightforward methodology toward
new 3,3-difluoroazetidines was developed via reduction
of 3,3-difluoroazetidin-2-ones with an excess of
monochloroalane.
Acknowledgment
SYNLETT 2006, No. 13, pp 2039–2042
1
7
.0
8
.2
0
0
6
Advanced online publication: 09.08.2006
DOI: 10.1055/s-2006-948186; Art ID: G14206ST
© Georg Thieme Verlag Stuttgart · New York
The authors are indebted to Ghent University (GOA) for financial
support.

2040
W. Van Brabandt, N. De Kimpe
LETTER
R
2 equiv
N
R = 4-MeOC6H4CH2
3 equiv CAN
F
F
BrCF2CO2Et
F
F
5 equiv Zn
H
MeCN, H2O (9:1)
0 °C to r.t., 18 h
N
NH
THF, ∆, 1 h
O
R
O
7 (83%)
4 R = 4-MeOC6H4CH2 (77%)
5 R = Bn (82%)
1 R = 4-MeO-C6H4CH2
2 R = Bn
6 R = allyl (87%)
3 R = allyl
F
F
F
2 equiv BrCF2CO2Et
5 equiv Zn
N
H
F
+
EtO
HN
N
THF, ∆, 1 h
O
O
10 (5%)
8
9 (53%)
Scheme 1
(9) Ge, P.; Horvath, R. F.; Zhang, L. Y.; Yamaguchi, Y.; Kaiser,
B.; Zhang, X.; Zhang, S.; Zhao, H.; John, S.; Moorcroft, N.;
Shutske, G. WO 2005023806 A2, 2005; Chem. Abstr. 2005,
142, 261783.
(10) Brooks, D. P. WO 2005000311 A1, 2005; Chem. Abstr.
2005, 142, 114098.
F
F
1.1 equiv RBr
0.1 equiv NaI
0.4 equiv n-Bu4NHSO4
KOH, THF
F
F
N
NH
O
O
R
6 R = allyl (86%)
11 R = Bu (45%)
(11) Flohr, A.; Norcross, R. D. US 2004204584 A1, 2004; Chem.
Abstr. 2004, 141, 350158.
7
(12) Churcher, I.; Harrison, T.; Kerrad, S.; Oakley, P. J.; Shaw,
D. E.; Teall, M. R.; Williams, S. WO 2004031137 A1, 2004;
Chem. Abstr. 2004, 140, 321108.
Scheme 2
(13) Collins, I. J.; Cooper, L. C.; Harrison, T.; Keown, L. E.;
Madin, A. R.; Mark, P. WO 2003093252 A1, 2003; Chem.
Abstr. 2003, 139, 16965.
(14) Provins, L.; Van Keulen, B. J.; Surtees, J.; Talaga, P.;
Christophe, B. WO 2003087064 A1, 2003; Chem. Abstr.
2003, 139, 337980.
(15) Borthwick, A. D.; Hatley, R. J.; Hickey, D. M. B.; Liddle, J.;
Livermore, D. G. H.; Mason, A. M.; Miller, N. D.; Nerozzi,
F.; Sollis, S. L.; Szardenings, A. K.; Wyatt, P. G. WO
2003053433A1, 2003; Chem. Abstr. 2003, 139, 85377.
(16) Selnick, H. G.; Barrow, J. C.; Nantermet, P. G.; Williams, P.
D.; Stauffer, K. J.; Sanderson, P. E.; Rittle, K. E.; Morissette,
M. M.; Wiscount, C. M.; Tran, L. O.; Lyle, T. A.; Staas, D.
D. WO 2002050056 A1, 2002; Chem. Abstr. 2002, 137,
63475.
F
F
R2
R1
F
R2
R1
F
6 equiv AlH2Cl
Et2O, 0 °C, 4 h
N
N
O
4 R1 = 4-MeO-Bn, R2 = Ph
5 R1 = Bn, R2 = Ph
6 R1 = allyl, R2 = Ph
7 R1 = H, R2 = Ph
9 R1 = allyl, R2 = i-Pr
12 R1 = 4-MeOC6H4CH2
R2 = Ph (87%)
13 R1 = Bn, R2 = Ph (84%)
14 R1 = allyl, R2 = Ph (87%)
15 R1 = H, R2 = Ph (82%)
16 R1 = allyl, R2 = i-Pr (85%)
Scheme 3
(17) Carling, W. R.; Mitchinson, A. R.; Michail, G. N.; Street, L.
J. WO 2000047582 A1, 2000; Chem. Abstr. 2000, 133,
177176.
(18) Banks, R. E.; Barlow, M. G.; Haszeldine, R. N. J. Chem.
Soc. 1965, 6149.
(19) Banks, R. E.; Haszeldine, R. N.; Matthews, V. J. Chem. Soc.
1967, 2263.
(20) Yamamoto, T.; Yasuhara, A.; Shiraishi, F.; Kaya, K.; Abe,
T. Chemosphere 1997, 35, 643.
References and Notes
(1) Smart, B. J. Fluorine Chem. 2001, 109, 3.
(2) Welch, J. T. Tetrahedron 1987, 43, 3123.
(3) Parker, J. C.; Hulin, B. US 2005043292 A1, 2005; Chem.
Abstr. 2005, 142, 261783.
(4) Li, W.; Oliver, E. Jr.; Rojas, C.; Kalish, V.; Belyakov, S.
WO 2004071454 A2, 2004; Chem. Abstr. 2004, 141,
225299.
(5) Duffy, J. L.; Mathvink, R. J.; Weber, A. E.; Xu, J. WO
2004050022 A2, 2004; Chem. Abstr. 2004, 141, 54612.
(6) Colandrea, V. J.; Edmondson, S. D.; Mathvink, R. J.;
Mastracchio, A.; Weber, A. E.; Xu, J. WO 2004043940 A1,
2004; Chem. Abstr. 2004, 141, 7438.
(7) Hulin, B.; Parker, J. C. WO 2003101958 A2, 2003; Chem.
Abstr. 2003, 140, 16965.
(8) Weber, A. J. Med. Chem. 2004, 47, 4135.
(21) Chambers, R. D.; Shepherd, T.; Tamura, M. J. Chem. Soc.,
Perkin Trans. 1 1990, 975.
(22) Lacroix, S.; Chequillaume, A.; Gérard, S.; Marchand-
Brynaert, J. Synthesis 2003, 2483; and references cited
therein.
(23) Marcotte, S.; Pannecoucke, X.; Feasson, C.; Quirion, J.-C. J.
Org. Chem. 1999, 64, 8461.
(24) Duboc, R.; Hénaut, C.; Savignac, M.; Genet, J.-P.;
Bhatnagar, N. Tetrahedron Lett. 2001, 42, 2461.
(25) Ojima, I.; Zhao, M.; Yamato, T.; Nakahashi, K. J. Org.
Chem. 1991, 56, 5263.
Synlett 2006, No. 13, 2039–2042 © Thieme Stuttgart · New York

LETTER
Synthesis of 3,3-Difluoroazetidines
2041
(26) Synthesis of 3,3-Difluoroazetidines 4–6 and 9 via the
Reformatsky-Type Reaction.
NMR (282 Hz, CDCl3): d = –113.96 (dd, J = 223.4, 9.5 Hz),
–124.56 (d, J = 223.4 Hz). IR (NaCl): nC=O = 1794, nmax
=
As an example, the synthesis of 1-benzyl-3,3-difluoro-4-
phenylazetidin-2-one(5) is described. To a refluxing
suspension of freshly activated Zn dust (1.63 g, 25 mmol) in
dry THF (10 mL) was added a solution of 2 (0.98 g, 5 mmol)
and ethyl bromodifluoroacetate (1.52, 7.5 mmol) in THF at
such a rate so as to maintain vigorous reflux. After 1 h of
reflux, the reaction mixture was cooled and extracted with
CH2Cl2 (2 ꢀ 20 mL). The combined organic extracts were
dried (MgSO4) and concentrated under vacuum. The residue
was then purified by flash column chromatography over
silica gel.
2971, 2938, 1645, 1473 cm–1. MS (70 eV): m/z (%) = 190
(100) [M+ + 1]. Anal. Calcd for C9H13F2NO: C, 57.13; H,
6.93; N, 7.40. Found: C, 57.29; H, 7.14; N, 7.68.
Ethyl 3-(Allylamino)-2,2-difluoro-4-methylpentanoate
(10): 5% yield; TLC: Rf = 0.25 (PE–EtOAc, 10:1). 1H NMR
(300 MHz, CDCl3): d = 0.98 and 1.06 [6 H, 2 d, J = 6.88 Hz,
CH(CH3)2], 1.35 (3 H, t, J = 7.15 Hz, CH2CH3), 2.03 [1 H,
septd, J = 6.9, 4.4 Hz, CH(CH3)2], 3.01 (1 H, ddd, J = 20.6,
9.4, 4.4 Hz, NHCH), 3.32 [1 H, dd, J = 14.0, 5.8 Hz,
NHC(H)H], 3.39 [1 H, dd, J = 14.0, 6.3 Hz, NHC(H)H],
4.31 (2 H, q, J = 7.2 Hz, OCH2), 5.03–5.20 (2 H, m,
CH2=CH), 5.73 (1 H, m, CH2=CH). 13C NMR (75 MHz,
CDCl3): d = 13.99 (CH3CH2O), 17.62 and 21.10
[CH(CH3)2], 28.00 [CH(CH3)2], 52.14 (NHCH2), 62.51
(OCH2), 63.32 (dd, J = 24.2, 20.8 Hz, NHCH), 115.88
(CH2=CH), 117.66 (t, J = 257.29 Hz),136.82 (CH2=CH),
164.77 (t, J = 32.31 Hz, C=O). 19F NMR (282 Hz, CDCl3):
d = –107.19 (dd, J = 254.9, 9.5 Hz), –117.44 (dd, J = 254.9,
20.8 Hz). IR (NaCl): nC=O = 1773, 1758, nmax = 2966, 1468
cm–1. MS (70 eV): m/z (%) = 236 (100) [M+ + 1]. Anal.
Calcd for C11H19F2NO2: C, 56.16; H, 8.14; N, 5.95. Found:
C, 55.82; H, 8.31; N, 5.75.
Preparation of Activated Zn Dust.
Nitrogen gas was bubbled through a mixture of 100 g (1.53
mol) of zinc and 250 mL of distilled H2O. After 15 min of
stirring, 7.5 g (46 mmol) of CuSO4 was added, and the
resulting mixture was stirred for 45 min under nitrogen
atmosphere. At the same time, 500 mL of distilled H2O and
500 mL of acetone were degassed by stirring under a
nitrogen atmosphere during 45 min. In order to remove the
formed ZnSO4, the Zn–Cu couple was filtered off and
washed with 500 mL of degassed H2O and 500 mL of
degassed acetone (to remove the water). After evaporation of
the solvent in vacuo, the activated Zn thus obtained was used
immediately in the cyclocondensation reaction above.
1-Benzyl-3,3-difluoro-4-phenylazetidin-2-one (5): 82%
yield; TLC: Rf = 0.15 (PE–EtOAc, 10:1). 1H NMR (300
MHz, CDCl3): d = 3.93 (1 H, dd, J = 14.6, 2.2 Hz, NCH),
4.72 [1 H, dd, J = 7.4, 2.2 Hz, NC(H)H], 4.95 [1 H, d,
(27) Synthesis of 3,3-Difluoroazetidines 6 and 11 via
N-Alkylation of Difluoro-b-lactam (7).
As an example, the synthesis of 1-allyl-3,3-difluoro-4-
phenylazetidin-2-one(6) is described. 3,3-Difluoroazetidin-
2-one 7 (0.18 g, 1 mmol) was added to a solution of allyl
bromide (0.15 g, 1.1 mmol), NaI (0.013 g, 0.1 mmol), n-
Bu4NHSO4 (0.14 g, 0.4 mmol) and KOH (0.11 g, 2 mmol) in
THF (10 mL). In the case of 3,3-difluoroazetidine 6, 1 h
stirring at r.t. proved to be sufficient to complete the
reaction. Then, 1.5 h of reflux was needed to complete the
reaction in the case of azetidin-2-one 11. Subsequently, the
mixture was poured in H2O (20 mL), and the reaction
mixture was extracted three times with Et2O (20 mL). The
organic extracts were combined, dried over MgSO4 and
concentrated under vacuum. The residue was then purified
by flash column chromatography.
J = 14.6 Hz, NC(H)H], 7.09–7.45 (10 H, m, 2 ꢀ C6H5). 13
NMR (75 MHz, CDCl3): d = 44.22 (NCH2), 68.00 (dd,
C
J = 26.5, 24.2 Hz, NCH), 120.59 (dd, J = 292.6, 290.2 Hz,
CF2), 128.08, 128.44, 128.60, 129.06, 129.09 and 129.84 (2
ꢀ CC5H5), 129.99 and 133.38 (2 ꢀ CC5H5), 160.94 (t,
J = 30.6 Hz, C=O). 19F NMR (282 Hz, CDCl3): d = –114.18
(dd, J = 223.7, J = 7.0 Hz), –120.78 (d, J = 223.7 Hz). IR
(NaCl): nmax = 3034, 2926, 1789, 1496, 1457 cm–1. MS (70
eV): m/z (%) = 274 (10) [M+ + 1]. Anal. Calcd for
C16H13F2NO: C, 70.32; H, 4.79; N, 5.13. Found: C, 70.51; H,
4.91; N, 4.89.
1-Butyl-3,3-difluoro-4-phenylazetidin-2-one (11): 45%
yield; TLC: Rf = 0.15 (PE–EtOAc, 20:1). 1H NMR (300
MHz, CDCl3): d = 0.90 (3 H, t, J = 7.3 Hz, CH3), 1.26–1.39
(2 H, m, CH3CH2), 1.52 (2 H, quint, J = 7.4 Hz, NCH2CH2),
2.94–3.03 [1 H, m, NC(H)H], 3.56–3.80 [1 H, m, NC(H)H],
4.91 (1 H, dd, J = 7.2, 2.2 Hz, NCH), 7.26–7.33 and 7.44–
7.47 (5 H, 2 m, C6H5). 13C NMR (75 MHz, CDCl3): d =
13.48 (CH3), 20.08 (CH3CH2), 29.06 (NCH2CH2), 40.16
(NCH2), 68.74 (t, J = 24.8 Hz, NCH), 120.50 (dd, J = 293.1,
289.6 Hz, CF2), 128.01, 129.05 and 129.86 (CC5H5), 130.45
(CC5H5), 161.22 (t, J = 30.0 Hz, C=O). 19F NMR (282 Hz,
CDCl3): d = –114.38 (dd, J = 223.7, 7.8 Hz), –121.77 (d,
J = 223.7 Hz). IR (NaCl): nC=O = 1788 cm–1. MS (70 eV):
m/z (%) = 240 (100) [M+ + 1]. Anal. Calcd for C13H15F2NO:
C, 65.26; H, 6.32; N, 5.85. Found: C, 65.04; H, 6.39; N, 5.68.
(28) Synthesis of 3,3-Difluoroazetidines 12–16.
1-Allyl-3,3-difluoro-4-phenylazetidin-2-one (6): 87%
yield; TLC: Rf = 0.25 (PE–EtOAc, 10:1). 1H NMR (300
MHz, CDCl3): d = 3.47–3.55 [1 H, m, NC(H)H], 4.29 [1 H,
dd, J = 15.4, 5.2 Hz, NC(H)H], 4.94 (1 H, dd, J = 7.4, 2.2
Hz, NCH), 5.11–5.26 (2 H, m, CH=CH2), 5.67–5.80 (1 H, m,
CH=CH2), 7.27–7.32 and 7.42–7.46 (5 H, 2 m, C6H5). 13
NMR (75 MHz, CDCl3): d = 42.78 (NCH2), 68.37 (t,
J = 24.8 Hz, NCH), 120.31 (CH2=CH), 120.62 (dd,
J = 293.1, 289.6 Hz, CF2), 128.02, 129.05 and 129.86
(CC5H5), 129.49 (CH=CH2), 130.21 (CC5H5), 160.93 (t,
C
J = 30.6 Hz, C=O). 19F NMR (282 Hz, CDCl3): d = –114.13
(dd, J = 223.7, 7.4 Hz), –121,43 (d, J = 223.7 Hz). IR
(NaCl): nC=O = 1688, 1684 cm–1. MS (70 eV): m/z (%) = 224
(100) [M+ + 1]. Anal. Calcd for C12H11F2NO: C, 64.57; H,
4.97; N, 6.27. Found: C, 64.40; H, 5.15; N, 6.41.
1-Allyl-3,3-difluoro-4-isopropylazetidin-2-one (9): 53%
yield; TLC: Rf = 0.1 (PE–EtOAc, 10:1). 1H NMR (300 MHz,
CDCl3): d = 1.02 [3 H, dd, J = 6.9, 0.8 Hz, CH(CH3)CH3],
1.07 [3 H, d, J = 6.9 Hz, CH(CH3)CH3], 2.03 [1 H, octet,
J = 6.9 Hz, CH(CH3)2], 3.66–3.77 [2 H, m, NC(H)H and
NCH], 4.27 [1 H, ddt, J = 15.7, 5.0, 1.7 Hz, NC(H)H], 5.24–
As an example, the synthesis of 1-allyl-3,3-difluoro-4-
phenylazetidine (14) is described. LiAlH4 (0.57 g, 0.015
mmol) was added to AlCl3 (2.01 g, 0.015 mmol) in Et2O (30
mL) at 0 °C. After 30 min stirring at r.t., 3,3-difluoro-
azetidin-2-one 6 (1.12 g, 0.005 mmol) was added to the
reaction mixture. After 4 h of stirring at r.t., H2O was added
until all LiAlH4 was neutralized. The solvent was decanted
and the resulting suspension was extracted three times with
Et2O (20 mL). The organic layers were combined, dried over
MgSO4 and concentrated under vacuum, yielding pure
1-allyl-3,3-difluoro-4-phenylazetidine (14).
5.34 (2 H, m, CH=CH2), 5.70–5.83 (1 H, m, CH=CH2). 13
NMR (75 MHz, CDCl3): d = 18.21 and 18.25 (2 ꢀ CH3),
18.84 [CH(CH3)2], 44,34 (NCH2), 70.87 (t, J = 22.5 Hz,
C
NCH), 119.73 (CH2=CH), 120.62 (dd, J = 290.8, 283.8 Hz,
CF2), 130.39 (CH=CH2), 161.28 (t, J = 30.6 Hz, C=O). 19
F
Synlett 2006, No. 13, 2039–2042 © Thieme Stuttgart · New York

2042
W. Van Brabandt, N. De Kimpe
LETTER
3,3-Difluoro-1-(4-methoxybenzyl)-4-phenylazetidine
(12): 87% yield. 1H NMR (300 MHz, CDCl3): d = 3.21 [1 H,
ddd, J = 15.7, 13.5, 9.5 Hz, NC(H)HCF2], 3.48 [1 H, dd,
J = 12.8, 2.2 Hz, NC(H)HC6H4], 3.65–3.74 [1 H, m,
NC(H)HCF2], 3.78 (3 H, s, CH3O), 3.95 [1 H, d, J = 12.9 Hz,
NC(H)HC6H4], 4.44 (1 H, dd, J = 14.9, 10.5 Hz, NCH),
6.82–6.87 (2 H, m, 2 ꢀ MeOCCH), 7.21–7.49 (7 H, m, C6H5
and 2 ꢀ NCH2CCH). 13C NMR (75 MHz, CDCl3): d = 55.26
(CH3O), 60.32 (NCH2C6H4), 61.42 (t, J = 22.6 Hz, CH2CF2),
76.68 (t, J = 32.3 Hz, NCH), 113.81 (2 ꢀ CH3OCCH),
117.03 (t, J = 279.8 Hz, CF2), 127.87, 128.33, 128.44 and
129.90 (CC5H5 and 2 ꢀ MeOCCHCH), 129.09 and 134.07
(NCHC and NCH2C), 159.02 (MeOC). 19F NMR (282 Hz,
CDCl3): d = –116.65 (ddt, J = 190.7, 15.6, 10.4 Hz), –91.78
(dtd, J = 190.7, 14.3, 6.5 Hz). IR (NaCl): nmax = 2959, 2935,
2838, 1613, 1513, 1454, 1331 cm–1. MS (70 eV): m/z (%) =
290 (10) [M+ + 1], 121 (100). Anal. Calcd for C17H17F2NO:
C, 70.57; H, 5.92; N, 4.84. Found: C, 70.71; H, 5.78; N, 4.60.
1-Benzyl-3,3-difluoro-4-phenylazetidine (13): 84% yield.
1H NMR (300 MHz, CDCl3): d = 3.24 [1 H, ddd, J = 15.7,
13.5, 9.5 Hz, NC(H)HCF2], 3.47 [1 H, dd, J = 13.1, 1.9 Hz,
NC(H)HC6H5], 3.68 [1 H, tdd, J = 9.6, 6.6, 1.5 Hz,
7.25–7.46 (5 H, m, C6H5). 13C NMR (75 MHz, CDCl3): d =
60.26 (NCH2CH=CH2), 61.80 (dd, J = 24.2, 20.8 Hz,
CH2CF2), 77.03 (t, J = 22.5 Hz, NCH), 116.95 (t, J = 279.8
Hz, CF2), 118.04 (CH=CH2), 127.90, 128.31 and 128.44
(CC5H5), 133.79 (CH=CH2), 134.21 (NCHC). 19F NMR
(282 Hz, CDCl3): d = –116.33 (ddt, J = 190.7, 15.6, 10.4
Hz), –91.63 (dtd, J = 190.7, 14.7, 6.9 Hz). IR (NaCl):
nmax = 3067, 3031, 2977, 2925, 2857, 2807, 1644, 1497,
1459, 1452 cm–1. MS (70 eV): m/z (%) = 210 (20) [M+ + 1],
190 (80), 88 (100). Anal. Calcd for C12H13F2N: C, 68.88; H,
6.26; N, 6.69. Found: C, 69.09; H, 6.10; N, 6.53.
3,3-Difluoro-4-phenylazetidine (15): 82% yield. 1H NMR
(300 MHz, CDCl3): d = 3.79 [1 H, ddd, J = 22.0, 10.5, 1.7
Hz, NC(H)HCF2], 4.04 [1 H, ddd, J = 14.9, 13.5, 10.5 Hz,
NC(H)HCF2], 5.14 (1 H, dd, J = 14.9, 10.5 Hz, NCH), 7.22–
7.44 (5 H, m, C6H5). 13C NMR (75 MHz, CDCl3): d = 56.08
(t, J = 24.2 Hz, NHCH2), 71.04 (t, J = 23.7 Hz, NHCH),
119.21 (t, J = 282.1 Hz, CF2), 127.29, 128.34 and 128.40
(CC5H5), 135.46 (NHCHC). 19F NMR (282 Hz, CDCl3): d =
–91.22 (dq, J = 189.9, 12.9 Hz), –110.18 (ddt, J = 189.9,
14.7, 11.3 Hz). IR (NaCl): nmax = 3347, 2948, 2879, 1514,
1497, 1459 cm–1. MS (70 eV): m/z (%) = 170 (100) [M+ + 1].
Anal. Calcd for C9H9F2N: C, 63.90; H, 5.36; N, 8.28. Found:
C, 64.14; H, 5.25; N, 8.43.
1-Allyl-3,3-difluoro-4-isopropylazetidine (16): 53% yield.
1H NMR (300 MHz, CDCl3): d = 0.92 and 0.95 (6 H, 2 d,
J = 6.7 Hz, 2 ꢀ CH3), 1.96–2.08 [1 H, m, CH(CH3)2], 2.89–
3.01 [2 H, m, NCH and NC(H)HCH=CH2], 3.10 [1 H, td,
J = 15.4, 10.2 Hz, NC(H)HCF2], 3.51 [1 H, ddt, J = 13.4,
5.1, 1.5 Hz, NC(H)HCH=CH2], 3.70 [1 H, tdd, J = 10.5,
10.2, 1.5 Hz, NC(H)HCF2], 5.12–5.24 (2 H, m, CH=CH2),
5.74–5.87 (1 H, m, CH=CH2). 13C NMR (75 MHz, CDCl3):
d = 18.54 and 18.76 (2 ꢀ CH3), 28.83 [CH(CH3)2], 61.94 (dd,
J = 25.4, 20.8 Hz, CH2CF2), 62.28 (NCH2CH=CH2), 80.37
(dd, J = 21.9, 19.6 Hz, NCH), 117.7 (t, J = 278.1 Hz, CF2),
118.21 (CH=CH2), 133.81 (CH=CH2). 19F NMR (282 Hz,
CDCl3): d = –117.80 (dtd, J = 197.7, 16.5, 8.7 Hz), –88.64
(ddt, J = 197.7, 14.7, 10.0 Hz). IR (NaCl): nmax = 2964,
2931, 2875, 2803, 1645, 1472, 1458 cm–1. MS (70 eV):
m/z (%) = 176 (100) [M+ + 1]. Anal. Calcd for C9H15F2N: C,
61.69; H, 8.63; N, 7.99. Found: C, 61.53; H, 8.69; N, 7.89.
NC(H)HCF2], 3.96 [1 H, d, J = 13.1 Hz, NCH(H)C6H5],
4.44 (1 H, dd, J = 14.9, 10.5 Hz NCH), 7.18–7.49 (10 H, m,
2 ꢀ C6H5). 13C NMR (75 MHz, CDCl3): d = 60.94
(NCH2C6H5), 61.65 (dd, J = 24.2, 20.8 Hz, CH2CF2), 76.87
(t, J = 22.5 Hz, NCH), 117.01 (t, J = 279.2 Hz, CF2), 127.43,
127.87, 128.31, 128.39, 128.45 and 128.62 (2 ꢀ CC5H5),
133.96 (NCHC), 137.08 (NCH2C). 19F NMR (282 Hz,
CDCl3): d = –117.00 (ddt, J = 190.7, 15.6, 10.4 Hz), –91.82
(dtd, J = 190.7, 13.9, 6.9 Hz). IR (NaCl): nmax = 3064, 3031,
2970, 2925, 2855, 2802, 1604, 1496, 1453 cm–1. MS (70
eV): m/z (%) = 260 (20) [M+ + 1], 120 (100), 91 (20). Anal.
Calcd for C16H15F2N: C, 74.11; H, 5.83; N, 5.40. Found: C,
74.01; H, 6.11; N, 5.27.
1-Allyl-3,3-difluoro-4-phenylazetidine (14): 87%yield. 1H
NMR (300 MHz, CDCl3): d = 3.13 [1 H, ddd, J = 13.4, 9.5,
1.0 Hz, NC(H)HCH=CH2], 3.31 [1 H, ddd, J = 15.6, 13.5,
9.5 Hz, NC(H)HCF2], 3.42 [1 H, ddt, J = 13.4, 5.5, 1.4 Hz,
NC(H)HCH=CH2], 3.84 [1 H, tdd, J = 9.5, 6.9, 1.5 Hz,
NC(H)HCF2], 4.44 (1 H, ddd, J = 15.1, 10.2, 0.8 Hz, NCH),
5.08–5.26 (2 H, m, CH=CH2), 5.72–5.85 (1 H, m, CH=CH2),
Synlett 2006, No. 13, 2039–2042 © Thieme Stuttgart · New York