Synthesis of l-Boc-3-fluoroazetidine-3-carboxylic acid

Article abstract of DOI:10.1021/jo802791r

Synthetic strategies toward 3-fluoroazetidine-3-carboxylic acid, a new cyclic fluorinated β-amino acid with high potential as building block in medicinal chemistry, were evaluated. The successful pathway includes the bromoflu-orination of N-(diphenylmethy

Full text of DOI:10.1021/jo802791r

recognized as exciting building blocks for the synthesis of
ꢀ-peptides and antibiotics, as enzyme inhibitors, and as thera-
peutic agents.7,8 Nevertheless, very little is known about the
chemistry of their cyclic counterparts.7 Only very recently,
Fustero et al. reported the synthesis of various cyclic fluorinated
ꢀ-amino acid derivatives, using a cross-metathesis reaction of
suitable fluorinated imidoyl chlorides and acrylates as a key
step.9
Furthermore, fluoroazetidines exhibit interesting biological
activities, such as dipeptidyl peptidase IV inhibitors,10 canna-
binoid receptor modulators,11 and antibiotics.12 In addition, the
patents concerning fluorinated azetidines emphasize the pos-
sibilities of these compounds as substituents to modulate the
activity of different active compounds.13 Since cyclic secondary
amines can easily be incorporated in compounds of pharma-
ceutical interest, the synthesis of N-deprotected 3-fluoroaze-
tidines is of concern. In continuation of our interest in fluorinated
azetidines,14 we herein describe an optimized procedure for the
Synthesis of 1-Boc-3-fluoroazetidine-3-carboxylic
Acid
Eva Van Hende,† Guido Verniest,†,§ Frederik Deroose,‡
Jan-Willem Thuring,‡ Gregor Macdonald,‡ and
Norbert De Kimpe*,†
Department of Organic Chemistry, Faculty of Bioscience
Engineering, Ghent UniVersity, Coupure Links 653,
B-9000 Ghent, Belgium, and Johnson & Johnson
Pharmaceutical Research & DeVelopment, a DiVision of
Janssen Pharmaceutica NV, Turnhoutseweg 30,
B-2340 Beerse, Belgium
norbert.dekimpe@ugent.be
ReceiVed December 22, 2008
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Synthetic strategies toward 3-fluoroazetidine-3-carboxylic
acid, a new cyclic fluorinated ꢀ-amino acid with high
potential as building block in medicinal chemistry, were
evaluated. The successful pathway includes the bromoflu-
orination of N-(diphenylmethylidene)-2-(4-methoxyphe-
noxymethyl)-2-propenylamine, yielding 1-diphenylmethyl-
3-hydroxymethyl-3-fluoroazetidine after reduction of the
imino bond, ring closure, and removal of the 4-methoxy-
benzyl group. Changing the N-protecting group to a Boc-
group allows further oxidation to 1-Boc-3-fluoroazetidine-
3-carboxylic acid, a new fluorinated heterocyclic amino acid.
(4) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. ReV.
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The beneficial effects of fluorine as a substituent in organic
compounds stimulated the intense research in organofluorine
chemistry in the past decade. This is reflected by the numerous
papers in this area in recent years and the commercial applica-
tions of organofluorine compounds in pharmaceutical chemistry
and agrochemistry.1-6 As a specific class of fluorine-containing
biologically active compounds, fluorinated ꢀ-amino acids are
† Ghent University.
§ Postdoctoral Fellow of the Research Foundation
Vlaanderen).
- Flanders (FWO-
(14) Van Brabandt, W.; Verniest, G.; De Smaele, D.; Duvey, G.; De Kimpe,
N. J. Org. Chem. 2006, 71, 7100.
‡ Johnson & Johnson Pharmaceutical Research & Development.
2250 J. Org. Chem. 2009, 74, 2250–2253
10.1021/jo802791r CCC: $40.75 2009 American Chemical Society
Published on Web 02/13/2009

SCHEME 1. Retrosynthetic Analysis for the Synthesis of
1-Boc-3-fluoroazetidine 1
SCHEME 2. Synthesis of 1-Boc-3-fluoro-3-phenylazetidine 9
via Bromofluorination of N-(Diphenylmethylidene)allylamine 6
synthesis of 3-fluoro-3-phenylazetidines 2 (R2 ) Ph). In
addition, the first synthesis of 1-Boc-3-fluoroazetidine-3-car-
boxylic acid 1 (R1 ) Boc), an interesting amino acid building
block, is described (Scheme 1).
Because of the above-described importance of 3-fluoroaze-
tidine-3-carboxylic acids, a synthetic strategy was designed for
their synthesis via bromofluorination of suitable imines, followed
by reductive ring closure (Scheme 1). In that respect, the
synthesis of 3-aryl-3-fluoroazetidines (2, R2 ) aryl), which could
be used as substrates for the synthesis of the corresponding
fluorinated ꢀ-amino acids via oxidative cleavage of the aryl
moiety, was envisaged. At first, attempts were directed toward
synthesizing 1-alkyl-3-fluoro-3-phenylazetidines via our recently
disclosed method that involves the bromofluorination of aldi-
mines.14 Unfortunately, this pathway proved unsuitable for the
large scale preparation of the required fluoroazetidines 2 due
to the unavoidable hydrolysis of the starting imines during
the bromofluorination reaction. During this reaction, most
probably a N-halogenation takes place causing rapid hy-
drolysis. It was reasoned that a more stable protecting group
on the imine nitrogen was required. Toward this end,
N-(diphenylmethylidene)amines 6 were considered, which
were synthesized via transimination of benzophenone imine
4 with 2-phenyl-2-propenylamine 5 (Scheme 2).
This moist-stable N-(diphenylmethylidene)-2-phenyl-2-pro-
penylamine 6 was very smoothly bromofluorinated with tri-
ethylamine trihydrofluoride and N-bromosuccinimide (NBS) in
dichloromethane at 0 °C in high yield (90%). The resulting
N-(diphenylmethylidene)-(3-bromo-2-fluoro-2-phenylpropyl)-
amine 7, which was pure enough to use without chromatographic
purification, was reacted with sodium cyanoborohydride in
methanol under reflux for 16 h. The resulting reaction mixture
already contained the desired 3-fluoroazetidine 8 at this stage,
together with equal amounts of the intermediate γ-bromoamine.
After workup, this mixture was refluxed in DMSO in the
presence of K2CO3 to complete the ring-closing reaction. In this
way, 1-(diphenylmethyl)-3-fluoro-3-phenylazetidine 8 was ob-
tained in 57% yield after chromatographic purification. N-
Deprotection of the 3-fluoroazetidine 8 by hydrogenation over
Pd/C afforded the corresponding 1-unsubstituted azetidine,
which could not easily be isolated and purified. Therefore, this
azetidine was in situ trapped with Boc2O to yield the corre-
sponding 1-Boc-azetidine 9. It was found that 3-fluoro-3-
phenylazetidine could easily be obtained as the hydrochloride
or trifluoroacetate after reaction of azetidine 9 with the corre-
sponding acid and subsequent precipitation of the formed
ammonium salts from Et2O (Scheme 2). Using the above-
described optimized method, the new 3-fluoroazetidines 8 and
9 could be prepared on a gram scale, which makes these
compounds of interest for use in medicinal chemistry. In order
to establish a convenient route to the new 3-fluoroazetidine-3-
carboxylic acid, attempts were performed to transform the
phenyl group of 9 into a carboxylic group via oxidative cleavage
using NaIO4/RuCl3 ·3H2O. Unfortunately, these oxidation reac-
tions failed to yield any fluorinated azetidine-3-carboxylic acid.
In addition, experiments to synthesize 3-fluoroazetidines bearing
a more electron-rich aromatic substituent at the 3-position
revealed that this strategy is not suitable, due to the tedious
synthesis of the necessary 2-(methoxyaryl)-2-propenylamines,
as was experienced for 2-(3,4-dimethoxyphenyl)-2-propenyl-
amines.15
Although the above-described method cleanly resulted in
interesting new fluorinated azetidines 10 and 11, these com-
pounds proved unsuitable for the synthesis of the corresponding
3-fluoroazetidine-3-carboxylic acid, due to failure of the oxida-
tive cleavage of the phenyl group into a carboxylic acid.
Therefore, the 4-methoxyphenoxymethyl group at C-3 was
chosen as a latent hydroxymethyl and carboxylic acid function.
In our strategy, the allylamine 14 was identified as a key
intermediate. A large-scale preparation of allylamine 14 was
performed via initial reaction of 3-chloro-2-chloromethylpropene
12 with 4-methoxyphenol (PMP-OH) in the presence of KOtBu
in DMF at room temperature during 15 h, and subsequent reaction
of the obtained 3-chloro-2-(4-methoxyphenoxymethyl)propene
13with ammonia in methanol in a pressure vessel at 130 °C for
4 h. This procedure can be used to prepare 2-(4-methoxyphe-
noxymethyl)-2-propenylamine 14 on a 20 g scale without the
need for chromatographic purification. Subsequent transimina-
tion of N-(diphenylmethylene)amine 4 with the obtained allyl-
amine 14 afforded imine 15, which was regioselectively
bromofluorinated using triethylamine trihydrofluoride and NBS
in dichloromethane.16 It should be noted that it was necessary
to purify NBS prior to use by recrystallization from benzene
(15) Bargar, T. M.; McCowan, J. R.; McCarthy, J. R.; Wagner, E. R. J. Org.
Chem. 1987, 52, 678.
(16) Alvernhe, G.; Laurent, A.; Haufe, G. Synthesis 1987, 6, 562.
J. Org. Chem. Vol. 74, No. 5, 2009 2251

SCHEME 3. Synthesis of 1-Diphenylmethyl-3-fluoro-3-
hydroxymethylazetidine 18
SCHEME 4. Synthesis of 1-Boc-3-fluoroazetidine-3-
carboxylic Acid 22 via Oxidation of the Corresponding
Alcohol 21 with NaIO4/RuCl3
water17 could be accomplished and resulted in the envisaged
1-Boc-3-fluoroazetidine-3-carboxylic acid 22 (Scheme 4).
It should be noted that an apparent direct route toward
analogous 3-fluoroazetidines via deprotonation of the com-
mercially available 1-diphenylmethyl-3-cyanoazetidine followed
by electrophilic fluorination does not result in the corresponding
3-fluoroazetidine-3-carbonitirile. This reaction was evaluated
using a range of bases (NaH, LiHMDS, LDA, n-BuLi, t-BuLi)
in acetonitrile or THF followed by quenching with N-fluoro-
dibenzenesulfonimide (NFSI) or 1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor).
Although deuteration experiments proved that deprotonation can
be accomplished using LDA as a base in THF at 0 °C in 1 h,
all fluorination reactions failed, yielding only starting material.
In conclusion, the first synthesis of 3-fluoroazetidine-3-
carboxylic acid, a cyclic fluorinated ꢀ-amino acid derivative
with high potential as building block in medicinal chemistry,
is disclosed. The synthetic pathway includes the bromoflu-
orination of N-(diphenylmethylidene)-2-(4-methoxyphenoxy-
methyl)prop-2-enylamine, yielding 1-diphenylmethyl-3-fluoro-
3-hydroxymethylazetidine after reduction, ring closure, and
cleavage of the O-(4-methoxyphenyl) group. After hydrogenoly-
sis of the N-protecting group and reaction with Boc2O, the
successful oxidation of 1-Boc-3-fluoro-3-hydroxymethylazeti-
dine using NaIO4/RuCl3 ·3H2O toward 1-Boc-3-fluoroazetidine-
3-carboxylicacid,anewfluorinatedaminoacid,wasaccomplished.
and drying over P2O5 to prevent hydrolysis of the imine during
reaction. Reaction of the fluorinated imine 16 with 2 equiv of
sodium cyanoborohydride in the presence of HOAc gave rise
to pure 1-diphenylmethyl-3-fluoro-3-(4-methoxyphenoxymethyl)-
azetidine 17 in 74% yield after recrystallization from diethyl
ether and hexane (1:3). Subsequently, the O-protecting group
was easily removed via oxidation with ceric ammonium nitrate
(CAN), yielding 1-diphenylmethyl-3-fluoro-3-hydroxymethyl-
azetidine 18 in 61% yield. This fluorinated 3-(hydroxymethyl)-
azetidine 18 represents an unknown class of compounds with
considerable potential as building blocks for pharmaceutical
applications (Scheme 3).
Several attempts to oxidize the hydroxymethyl function of
18 to the corresponding carboxylic acid failed, probably due to
the presence of the basic amino group in azetidine 18. Therefore,
the nitrogen atom of 18 was rendered less-basic by treatment
of 1-diphenylmethyl-3-fluoro-3-(4-methoxyphenoxymethyl)-
azetidine 17 with ethyl chloroformate in dichloromethane in a
pressure vessel to give 1-ethoxycarbonylazetidine 19 as a
suitable substrate for further oxidation reactions (Scheme 4).
However, it was observed that a higher yield of N-alkoxycar-
bonylazetidine could be obtained by hydrogenolysis of the
diphenylmethyl group and in situ protection of the free N-H
using Boc2O toward N-Boc-azetidine 20 in 62% yield.
Subsequently, 4-methoxyphenylether 20 was successfully
cleaved with CAN in acetonitrile/water (1/1) at -10 °C yielding
3-fluoro-3-hydroxymethylazetidine 21 in 74% yield. Next, the
oxidation with 5 equiv NaIO4 in the presence of catalytic
amounts of ruthenium(III) chloride trihydrate in acetonitrile/
Experimental Section
1-Boc-3-fluoro-3-(4-methoxyphenoxymethyl)azetidine (20).
The synthesis of azetidine 20 is given as a representative example
for the synthesis of azetidine 9. To a solution of 0.60 g (1.6 mmol)
of 3-fluoroazetidine 17 and 0.35 g (1.6 mmol, 1 equiv) of Boc2O
in 2 mL of dry ethyl acetate was added 0.15 g of Pd/C (20% w/w).
The solution was stirred at room temperature under hydrogen
(17) Hanselmann, R.; Zhou, J.; Ma, P.; Confalone, P. N. J. Org. Chem. 2003,
68, 8739.
2252 J. Org. Chem. Vol. 74, No. 5, 2009

atmosphere (4 bar). After 48 h, the solution was filtered, and the
solvent was evaporated yielding a clear oil. The obtained azetidine
20 was separated from diphenylmethane by flash chromatography
on silicagel using hexane/EtOAc/Et3N (90:9:1) as the solvent
mixture, yielding 0.31 g of azetidine 20. Rf ) 0.1. White crystals.
Yield: 62%. Mp. 53 °C. 1H NMR (CDCl3): δ 1.46 (9H, s, C(CH3)3);
3.77 (3H, s, CH3O); 4.13 (4H, d, J ) 19.0 Hz, (CH2)2N); 4.15
(2H, d, J ) 19.0 Hz, CH2O); 6.82-6.88 (4H, m, 4 × CHar). 19F
NMR (CDCl3): δ -158.42 (septet, J ) 18.9 Hz). 13C NMR
(CDCl3): δ 28.5 (3 × CCH3); 55.9 (CH3O); 57.8 (d (br), J ) 23.1
Hz, (CH2)2N); 70.0 (d, J ) 27.7 Hz, CH2O); 80.4 (C(CH3)3); 90.0
(d, J ) 210.0 Hz, CF); 114.9 (2 × CHar); 116.0 (2 × CHar); 152.6
(Cq,ar); 154.7 (Cq,ar); 156.4 (d, J ) 2.3 Hz, CdO). IR (ATR, cm-1):
ν ) 2975; 1700 (CdO); 1508. GC-MS (EI): m/z 311 (M+, 45);
255 (14); 211 (38); 124 (100); 109 (34); 57 (60). Anal. Calcd for
C16H22FNO4: C, 61.7; H, 7.1; N, 4.5. Found: C, 61.9; H, 7.0; N,
4.5.
1-Boc-3-fluoro-3-(hydroxymethyl)azetidine (21). A solution of
0.34 g (1.1 mmol) of azetidine 20 in 3 mL of CH3CN was cooled
to -10 °C. During stirring, a solution of 1.8 g (3.3 mmol, 3 equiv)
of ceric ammonium nitrate (CAN) in 3 mL of destilled water was
added during 5 min using a syringe. Stirring was continued at -10
°C. After 1.5 h, the reaction mixture was poured in 10 mL of water
and extracted with EtOAc (3 × 10 mL). The obtained 3-hydroxym-
ethylazetidine 21 was purified by flash chromatography on silica
gel using hexane/EtOAc (80:20) as the solvent mixture, yielding
0.18 g of azetidine 21. Rf ) 0.01. The spots on silicagel are only
visible for a short moment after treatment of the TLC plate with
KMnO4. Yellow oil. Yield ) 74%. 1H NMR (CDCl3): δ 1.44 (9H,
s, C(CH3)3); 2.89 (1H, s(br), OH); 3.84 (2H, d, J ) 21.2 Hz, CH2O);
3.95-4.10 (4H, m, (CH2)2N). 19F NMR (CDCl3): δ -161.15 (septet,
J ) 19.3 Hz). 13C NMR (CDCl3): δ 28.3 (C(CH3)); 57.3 (d (br), J
) 25.4 Hz, (CH2)2N); 64.4 (d, J ) 26.5 Hz, CH2OH); 80.4
(C(CH3)3); 91.2 (d, J ) 208.8 Hz, CF); 156.4 (d, J ) 3.5 Hz,
COOtBu). IR (ATR, cm-1): ν ) 3408; 2977; 1678; 1407. MS
(ES+): m/z 150 (M + H+-t-Bu, 100). Anal. Calcd for C9H16FNO3:
C, 52.7; H, 7.9; N, 6.8. Found: C, 52.4; H, 7.8; N, 6.9.
1-Boc-3-fluoroazetidine-3-carboxylic Acid (22). To a solution
of 0.20 g (1.0 mmol) of azetidine 21 in 2 mL of CH3CN/water
(1/1) was added 13.1 mg (0.05 mmol, 0.05 equiv) of ruthenium(III)
chloride trihydrate and 1.10 g (5 mmol, 5 equiv) of NaIO4. After
being stirred for 16 h at room temperature, the mixture was poured
in 4 mL of 1 M HCl and extracted with dichloromethane (3 × 5
mL). After drying (MgSO4), filtration, and evaporation of the
solvent, 0.10 g of 1-Boc-3-fluoroazetidine-3-carboxylic acid 22 was
obtained as a crystalline compound. White crystals. Yield 47%.
Mp: 86 °C. 1H NMR (CDCl3): δ 1.46 (9H, s, C(CH3)3); 4.21 (2H,
dd, J ) 10.5 Hz, J ) 21.1 Hz, (C(H)H)2N); 4.43 (2H, dd, J ) 10.5
Hz, J ) 18.2 Hz, (CH(H))2N); 8.99 (1H, s(br), COOH). 19F NMR
(CDCl3): δ -163.19 (pentet, J ) 19.5 Hz). 13C NMR (CDCl3): δ
28.5 (C(CH3)3); 59.3 (d (br), J ) 24.2 Hz, (CH2)2N); 81.7
(C(CH3)3); 87.0 (d, J ) 220.4 Hz, CF); 156.6 (d, J ) 2.3 Hz,
COOtBu); 170.8 (d, J ) 28.8 Hz, COOH). IR (ATR, cm-1): ν )
2979; 1753; 1636. MS (ES-): m/z 218 (M - H+, 100). Anal. Calcd
for C9H14FNO4: C, 49.3; H, 6.4; N, 6.4. Found: C, 49.0; H, 6.1; N,
6.5.
Acknowledgment. We are indebted to the Research Founda-
tion - Flanders (FWO-Flanders), Ghent University (GOA, BOF),
and Johnson & Johnson Pharmaceutical Research & Develop-
ment, a Division of Janssen Pharmaceutica NV, for financial
support.
Supporting Information Available: General experimental
conditions and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JO802791R
J. Org. Chem. Vol. 74, No. 5, 2009 2253