Synthesis of 3-fluoroazetidines

Article abstract of DOI:10.1021/jo061095b

N-(Alkylidene or 1-arylmethylidene)-2-propenylamines were regiospecifically functionalized to novel N-(alkylidene or 1-arylmethylidene)-3-bromo-2- fluoropropylamines, which were proven to be excellent precursors for 3-fluoroazetidines.

Full text of DOI:10.1021/jo061095b

tidines have been synthesized via a ring opening of 1-azabicyclo-
[1.1.0]butanes with Olah’s reagent (pyridine.10 HF) or liquid
hydrogen fluoride.12 Although good yields were obtained for
the ring opening, the drawback of this synthesis is the use of a
multistep preparation of the labile starting material, that is,
1-azabicyclo[1.1.0]butanes. A very peculiar example of a
reduction of a 3-fluorinated â-lactam with diisobutyl aluminum
hydride toward the corresponding 3-fluoro-2-azetidinol is also
known.13 At present, a rapidly growing interest in 3-fluorinated
azetidines exists, as these compounds apparently possess
interesting biological activities. The inhibition of specific
enzymes such as dipeptidyl peptidase IV constitutes a promising
feature of fluorinated azetidines which can be applied in the
treatment of type 2 diabetes.14-18 In addition, the recent patents
concerning fluorinated azetidines emphasize the possibilities of
these compounds as substituents to modulate the activity of
different active compounds.19-22 In the latter publications,
3-fluorinated azetidines are mainly synthesized by treatment of
3-azetidinols or 3-azetidinones with diethylaminosulfur trifluo-
ride (DAST). Until now, this synthetic method is the only
procedure to obtain 3-fluorinated azetidines. However, no
examples of the synthesis of 3- or 4-substituted 3-fluoroaze-
tidines via this method are known. As a result, new syntheses
toward the highly attractive 3-fluoroazetidines are of consider-
able interest for organic, agrochemical, and medicinal chemists.
Synthesis of 3-Fluoroazetidines
Willem Van Brabandt, Guido Verniest,† Dirk De Smaele,
Guillaume Duvey, and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience
Engineering, Ghent UniVersity, Coupure links 653, B-9000
Ghent, Belgium
norbert.dekimpe@UGent.be
ReceiVed May 29, 2006
N-(Alkylidene or 1-arylmethylidene)-2-propenylamines were
regiospecifically functionalized to novel N-(alkylidene or
1-arylmethylidene)-3-bromo-2-fluoropropylamines, which
were proven to be excellent precursors for 3-fluoroazetidines.
Introduction
The selective fluorination of biologically important com-
pounds often results in a profound modification of their
biological activity.1-3 These distinctive properties of specifically
fluorinated compounds have significantly contributed to the
growing interest in the field of organofluorine chemistry in the
past decade. Although â-fluorinated amines have been the
subject of considerable attention because of their interesting
pharmaceutical properties,1-3 their small ring heterocyclic
analogues have barely been described in the literature. 3-Mono-
fluorinated azetidines are very rare compounds, the chemistry
of which is virtually unknown, apart from some isolated
transformations. Perfluoroazetidines have been prepared by
thermolysis of the corresponding perfluoro-1,2-oxazines or by
photolysis of perfluorinated triazines,4-7 while 3-fluoroazetidine
N-oxides have been involved in the synthesis of isoxazolidines
via thermal ring enlargement.8 Photofluorination of azetidines
with fluoroxytrifluoromethane has been used in the preparation
of L-cis-3-fluoroazetidine-2-carboxylic acid.9-11 3-Fluoroaze-
Results and Discussion
In the present article, we report an efficient and facile three-
step procedure for the synthesis of 3-fluoroazetidines 4 and 11
using N-(alkylidene or 1-arylmethylidene)-γ-bromo-â-fluoro-
amines 3. Imines bearing reactive halogens in the side chain
have not been frequently used in organic synthesis because of
the lability of this type of bifunctional compounds. However,
(9) Kollonitsch, J.; Barash, L.; Doldouras, G. A. J. Am. Chem. Soc. 1970,
92, 7494.
(10) Kollonitsch, J. U.S. Patent 4030994 21/06/1977; Chem. Abstr. 1977,
88, 83904.
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Abstr. 1972, 76, 154488.
(12) Alvernhe, G.; Laurent, A.; Touhami, K.; Bartnik, R.; Mloston, G.
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(14) Parker, J. C.; Hulin, B. U.S. Pat. Appl. Publ. US 2005043292 A1
24/02/2005; Chem. Abstr. 2005, 142, 261783.
(15) Li, W.; Oliver, E., Jr.; Rojas, C.; Kalish, V.; Belyakov, S. PCT Int.
Appl. WO 2004071454 A2 26/08/2004; Chem. Abstr. 2004, 141, 225299.
(16) Duffy, J. L.; Mathvink, R. J.; Weber, A. E.; Xu, J. PCT Int. Appl.
WO 2004050022 A2 17/06/2004; Chem. Abstr. 2004, 141, 54612.
(17) Colandrea, V. J.; Edmondson, S. D.; Mathvink, R. J.; Mastracchio,
A.; Weber, A. E.; Xu, J. PCT Int. Appl. WO 2004043940 A1 27/05/2004;
Chem. Abstr. 2004, 141, 7438.
(18) Hulin, B.; Parker, J. C. PCT Int. Appl. WO 2003101958 A2 11/
12/2003; Chem. Abstr. 2003, 140, 16965.
(19) Ge, P.; Horvath, R. F.; Zhang, L. Y.; Yamaguchi, Y.; Kaiser, B.;
Zhang, X.; Zhang, S.; Zhao, H.; John, S.; Moorcroft, N.; Shutske, G. PCT
Int. Appl. WO 2005023806 A2 17/03/2005; Chem. Abstr. 2005, 142,
261783.
* To whom correspondence should be addressed. Tel: +32 (0)9 264 59 50.
Fax: +32 (0)9 264 62 43.
† Postdoctoral Fellow of the Research Foundation Flanders (FWO-Vlaan-
deren).
(1) Welch, J. T. Tetrahedron 1987, 43, 3123.
(2) Welch, J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
John Wiley & Sons: New York, 1991.
(3) Smart, B. J. Fluorine Chem. 2001, 109, 3.
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10.1021/jo061095b CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/05/2006
7100
J. Org. Chem. 2006, 71, 7100-7102

SCHEME 1. Synthesis of 3-Fluoroazetidines
SCHEME 2. Attempts of Bromofluorination Reactions
TABLE 1. Synthesis of N-(Alkylidene)- and
N-(1-Arylmethylidene)-3-bromo-2-fluoropropylamines 3a-f and
3-Fluoroazetidines 4a-f
The methodology described above was also evaluated for the
synthesis of interesting 3-bromo-3-fluoroazetidines (Scheme 2).
However, the bromofluorination of N-(benzylidene)-2-bromo-
2-propenylamine 5 proved unsuccessful and yielded mainly
benzaldehyde owing to hydrolysis during the aqueous workup
(Scheme 2). This lack of reactivity can be attributed to the low
nucleophilicity of the vinyl bromide unit and the higher
reactivity of the imino function toward N-bromination, the latter
resulting in hydrolysis during aqueous workup. Different
attempts to perform a functionalization of 2-methyl-2-pro-
penylamine hydrochloride 7 did not give any constructive result,
demonstrating the need to perform an imination of the amine
7. In other words, the imino function is a suitable protective
group for alkenylamines which undergo electrophilic addition
reactions.
yield
of 3
bp of 3
°C/mmHg
yield
of 4
R1
C6H5
4-MeC6H4
4-MeOC6H4
CHEt2
R2
a
b
c
d
e
f
Me
Me
Me
Me
Me
C6H5
76%
78%
71%
68%
73%
77%
69-71/0.05
70%
61%
65%
61%
59%
60%
73-75/0.05
51-55/0.03
t-Bu
C6H5
former research demonstrated the synthetic potential of N-(ω-
haloalkyl)imines in the synthesis of azaheterocycles.23,24 Here
we describe the first functionalization of olefinic imines into
novel bromofluorinated imines 3, which are easily converted
to 3-fluoroazetidines 4.
The reaction of the functionalized imines 3a-f with sodium
borohydride in methanol under reflux afforded the corresponding
3-fluoroazetidines 4a-f, which were purified by flash chroma-
tography (Table 1). No change in reactivity was observed when
N-alkylidene- (3d,e) or N-(1-arylmethylidene)amines (3a-c,f)
were used as substrates for the cyclization reaction toward
azetidines 4. As almost no side products were formed during
the hydride induced cyclization, the moderate yields are due to
the affinity of 3-fluoroazetidines 4 toward silica gel in the
purification step, a classical problem in the purification of
N-containing heterocycles (while the use of alumina did not
result in the separation of the minor amounts of impurities from
the azetidines 4).
Imination of aromatic and aliphatic aldehydes 1a-e with
2-substituted 2-propenylamines afforded the corresponding
imines 2a-f, which were subsequently regiospecifically bro-
mofluorinated to N-(1-arylmethylidene)- or N-(alkylidene)-3-
bromo-2-fluoropropylamines 3a-f using triethylamine trihy-
drofluoride and N-bromosuccinimide in dichloromethane (Scheme
1, Table 1). This is the first report on the tolerance of an imino
functionality to the bromination and fluorinating reagent, which
has been shown previously to halogenate olefins.25 Although
all compounds 3a-f were pure enough (>95%) to be used in
further reactions, imines 3a and 3c,d could be distilled easily
at high vacuum to remove the minor amounts of impurities. It
should be noted that, based on 1H NMR analysis, no R-bromi-
nation took place during bromofluorination of aldimine 2d.
To investigate the regioselectivity of the bromofluorination,
attempts were made to perform the functionalization of N-
(benzylidene)allylamine. As the only reactivity observed was
the decomposition of the starting compound because of pro-
longed reaction times, the suitability of the more stable
(23) De Kimpe, N.; De Smaele, D. Tetrahedron Lett. 1994, 35, 8023.
(24) De Kimpe, N.; De Smaele, D. Tetrahedron 1995, 51, 5465.
(25) Alvernhe, G.; Laurent, A.; Haufe, G. Synthesis 1987, 562.
J. Org. Chem, Vol. 71, No. 18, 2006 7101

SCHEME 3. Regioselectivity of Bromofluorination of 9
* Isolated yield after column chromatography.
Hz), 65.83 (d, J ) 25.6 Hz), 93.72 (d, J ) 177.0 Hz), 127.9, 128.2,
130.6, 135.4, 163.1. IR (NaCl, cm-1): 1649. MS (70 eV) m/z (%):
257/9(M+, 3), 178(4), 158(1), 149(3), 118(100), 117(12), 104(5),
91(70), 90(11), 89(11), 77(9), 65(9), 63(6), 59(9), 51(10), 41(7).
Anal. Calcd for C11H13BrFN: C, 51.18; H, 5.08; N, 5.43. Found:
C, 51.05; H, 5.23; N, 5.30.
General Procedure for the Synthesis of 3-Fluoroazetidines
4a-f. At 0 °C, 0.1 mol of sodium borohydride was added to a
solution of 0.05 mol of imine 3a-f in 50 mL of methanol. After
reflux for 2 h, the resulting mixture was triturated with water and
three times extracted with dichloromethane. The combined organic
extracts were dried (MgSO4), and, after evaporation of the solvent,
3-fluoroazetidines 4a-f were obtained. Further purification was
performed by flash chromatography over silica gel.
N-(diphenylmethylidene)allylamine 9 was evaluated (Scheme
3). Hydride induced cyclization of the reaction mixture, obtained
by bromofluorination of ketimine 9, led to the formation of
1-benzhydryl-2-(fluoromethyl)aziridine 10 and 1-benzhydryl-
3-fluoroazetidine 11 in a 1:3 ratio, respectively, as determined
1
by H NMR. 2-(Fluoromethyl)aziridine 10 originates from the
formation of N-(2-bromo-3-fluoropropyl)-N-(diphenylmethyli-
dene)amine during the bromofluorination reaction of imine 9,
which proves the lack of regioselectivity of this reaction in this
particular case. Upon chromatographic separation by column
chromatography, 17% of the novel 1-(benzhydryl)-2-(fluoro-
methyl)aziridine 10 and 38% of 1-(benzhydryl)-3-fluoroazetidine
11 were isolated.
1-Benzyl-3-fluoro-3-methylazetidine 4a. Yield: 70%. 1H NMR
(270 MHz, CDCl3): δ 1.58 (3H, d, J ) 22.4 Hz), 3.25 (2H, d ×
d, J ) 22.8 Hz, J ) 8.4 Hz), 3.35 (2H, d × d × d, J ) 13.3 Hz,
J ) 8.4 Hz, J ) 1.9 Hz), 3.66 (2H, s), 7.23-7.33 (5H, m). 13C
NMR (68 MHz, CDCl3): δ 23.1 (d, J ) 25.7 Hz), 63.5, 65.3 (d,
J ) 20.7 Hz), 89.8 (d, J ) 203.9 Hz), 127.1, 128.3, 128.4, 137.9.
IR (NaCl, cm-1): 1381, 1364, 1323, 1271, 1230, 938. MS (70 eV)
m/z (%): 179 (M+, 7), 178(8), 164(3), 119(3), 118(5), 104(3), 102-
(3), 91(100), 65(10), 44(6), 42(5), 41(5). Anal. Calcd for C11H14-
FN: C, 73.71; H, 7.87; N, 7.81. Found: C, 73.58; H, 7.99; N,
7.73.
In conclusion, a new and efficient three-step synthesis of
3-fluoroazetidines was developed from aldehydes via hitherto
unknown bromofluoroimines.
Experimental Section
General Procedure for the Bromofluorination of N-(Al-
kylidene- or 1-Arylmethylidene)-2-propenylamines 2a-f. At 0
°C, 4.4 mmol of triethylamine tris(hydrofluoride) and 2.2 mmol of
N-bromosuccinimide were added to a solution of 2 mmol of
N-(allyl)imine 2a-f in dichloromethane under nitrogen atmosphere.
After 4 h of stirring at room temperature, the solvent was
evaporated, and the residue was washed three times with 10 mL of
pentane. After evaporation of the solvent, N-(3-bromo-2-fluoro-
propyl)imines 3a-f were obtained, sufficiently pure (>95%) for
further use in the next step. Imines 3a,c,d were distilled under
vacuum.
Acknowledgment. The authors are indebted to the Research
Foundation-Flanders (FWO-Flanders), the I.W.T. (Institute for
the promotion of innovation by science and technology in
Flanders) and Ghent University (GOA) for financial support.
N-Benzylidene-3-bromo-2-fluoro-2-methylpropylamine 3a.
Yield: 76%. Boiling point: 69-71 °C/0.05 mmHg. 1H NMR (270
MHz, CDCl3): δ 1.51 (3H, d, J ) 21.5 Hz), 3.59 (2H, d, J ) 16.8
Hz), 3.70-3.88 (2H, m), 7.31-7.73 (5H, m), 8.18 (1H, s). 13C NMR
(68 MHz, CDCl3): δ 22.1 (d, J ) 22.0 Hz), 37.07 (d, J ) 26.9
Supporting Information Available: Experimental procedures
and full spectroscopic data for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
JO061095B
7102 J. Org. Chem., Vol. 71, No. 18, 2006