Rearrangement of 2-hydroxyalkylazetidines into 3-fluoropyrrolidines

Article abstract of DOI:10.1055/s-2008-1072770

Upon treatment with DAST (diethylaminosulfur trifluoride) enantiopure 2-hydroxyalkylazetidines rearrange into 3-fluoropyrrolidines. The reaction is stereospecific and involves a bicyclic 1-azoniabicyclo[2.1.0]pentane intermediate which is regioselectively opened by a fluoride anion. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072770

LETTER
1345
Rearrangement of 2-Hydroxyalkylazetidines into 3-Fluoropyrrolidines
Rearrangement
o
r
2-Hydr
u
oxyalkylazet
n
idines into 3
o
-FluoropyrrolidinesDrouillat, François Couty,* Olivier David, Gwilherm Evano, Jérome Marrot
UniverSud Paris, Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles Saint Quentin en Yvelines,
45 avenue des Etats-Unis, 78035 Versailles Cedex, France
Fax +33(1)39254452; E-mail: couty@chimie.uvsq.fr
Received 6 February 2008
rangement. Secondly, the nonregioselective opening of
this putative intermediate by the fluoride anion may lead
to mixtures of fluorinated pyrrolidines 7 and azetidines, as
reported by Cossy with pyrrolidinols who obtained mix-
tures of 3 and 4.
Abstract: Upon treatment with DAST (diethylaminosulfur trifluo-
ride) enantiopure 2-hydroxyalkylazetidines rearrange into 3-fluoro-
pyrrolidines. The reaction is stereospecific and involves a bicyclic
1-azoniabicyclo[2.1.0]pentane intermediate which is regioselec-
tively opened by a fluoride anion.
Key words: fluorination, DAST, pyrrolidines, azetidines
F
R'
R"
The replacement of a hydrogen atom by a fluorine atom in
a molecule deeply modifies its electronic and lipophilic
properties while maintaining its overall geometry. This
strategy is now commonly used in medicinal chemistry
since up to 18% of the new drugs released contain at least
one fluorine atom; this percentage has increased to 30%
for agrochemicals.1 New methods for the selective intro-
duction of a fluorine atoms into pyrrolidines, a ubiquitous
skeleton in bioactive molecules are therefore highly desir-
able. Up to now, most 3-fluoro (or difluoro) pyrrolidines
have been prepared by electrophilic fluorination of avail-
able 3-hydroxy (or oxo) pyrrolidines,2 nucleophilic open-
ing of suitably functionalized 3,4-epoxypyrrolidines,3
reduction of the corresponding pyrrolidinone,4 1,3-dipolar
cycloaddition with 3-fluoroacrylates,5 or radical
cyclization6 and they have found application in medicinal
chemistry after their incorporation in bioactive molecules
such as ACE inhibitors,7 antibacterials,8 calcium-sensing
receptor antagonists,9 di- and tripeptidyl peptidase inhibi-
tors,10 or antitumour agents.11 Therefore, a general synthe-
sis of stereodefined enantiomerically pure 3-
fluoropyrrolidines with additional substituents on the ni-
trogen ring would certainly find applications in medicinal
chemistry.
N
R
+
3
R'
R"
F
R"
DAST
R'
N
N
R
R"
OH
R'
R
F
2
N
R
1
4
R"
R"
F
R"
F
DAST
?
R'
N
R'
N
R
5
R
R'
N
R
OH
7
6
regioselectivity ?
Scheme 1 Can the DAST-induced rearrangement of pyrrolidinols
be transposed to azetidinols?
Ph
Ph
EtOH, H2SO4
67%
CN
CO2Et
N
N
Bn 8
Bn 9
Ph
LiAlH4, THF, r.t.
92%
OH
N
Bn 12
Stimulated by the recent report from Cossy and co-
workers12 describing the rearrangement of 2-hydroxy-
alkylpyrrolidines 1 to 3-fluoropiperidines 3 via aziridini-
um intermediate 2 (Scheme 1) and in continuation of our
studies related to the ring expansions of azetidines,13 we
decided to investigate whether such a transformation
would be possible starting from 2-hydroxyalkylazetidines
5. The success of this reaction involving azetidinols
would mostly depend on two parameters. First, the energy
of strained 1-azoniabicyclo[2.1.0]pentane 6 should be
much higher than that of 2 and a competing SN1 process
could in this case hamper the stereospecificity of the rear-
Scheme 2 Synthesis of azetidinol 12
A set of representative azetidinols bearing a primary, sec-
ondary or tertiary alcohol function and presenting various
substitution patterns on the azetidine ring was thus pre-
pared following our reported procedure.14 Primary alco-
hols 10–14 were obtained in excellent yields by LiAlH4-
mediated reduction of the corresponding ethyl ester, itself
prepared from the corresponding 2-cyano azetidine.
Scheme 2 exemplifies the synthesis of novel alcohol 12,
starting from (1R,2S)-norephedrine as chiral source.14e
The anti secondary alcohols 19–21 were prepared as pre-
viously reported,14b from the diastereoselective reduction
of the corresponding ketone, itself prepared by addition of
SYNLETT 2008, No. 9, pp 1345–1348
Advanced online publication: 07.05.2008
DOI: 10.1055/s-2008-1072770; Art ID: D04808ST
x
x.
x
x.
2
0
0
8
© Georg Thieme Verlag Stuttgart · New York

1346
B. Drouillat et al.
LETTER
Table 1 Fluorination of 2-Hydroxyalkylazetidines (continued)
the appropriate organometallic reagent onto the corre-
sponding 2-cyano azetidine. Scheme 3 highlights the
preparation of novel compounds 19–21. Finally, tertiary
alcohols 23–25 were prepared by addition of phenyl- or
methylmagnesium bromide onto the corresponding ester.
Entry Substrate
Product(s)
Yield (%)a
69
Ph
Ph
F
F
F
F
OH
6
N
N
N
N
N
Ph
Ph
MeLi, BuLi or CyMgCl,
THF, r.t.
O
19
31
Ph
CN
Ph
N
N
R
15
16 (R = Me) 78%
17 (R = Bu) 87%
18 (R = Cy) 81%
OH
7
78b
n-Bu
N
n-Bu
Ph
N
NaBH4, ZnBr2
EtOH
OH
R
20
32
Ph
Ph
19 (R = Me) 69%
20 (R = Bu) 93%
21 (R = Cy) 75%
OH
Cy
8
80
Cy
N
Scheme 3 Synthesis of azetidinols 19–21
21
33
Ph
Ph
Having in hand a representative set of azetidinol sub-
strates, they were treated under standardized conditions
with DAST (1.5 equiv, CH2Cl2, 0 °C 1 h, then r.t., 1 h),
followed by alkaline workup. Results are given in
Table 1.
OH
Ph
9
62
Ph
N
34
22
Ph
Ph
N
Table 1 Fluorination of 2-Hydroxyalkylazetidines
10
37c
N
OH
OH
F
F
Entry Substrate
Product(s)
Yield (%)a
23
35
F
Ph
Ph
N
N
OH
OH
1
81
32d
N
11
N
Ph
Ph
26
F
10
24
36
25
Ph
Ph
Ph
e
N
12
–
2
58
N
N
OH
Ph
Ph
27
Ph
11
25
a Yield of isolated products.
Ph
F
F
F
b This compound was contaminated with 12% of unrearranged isomer
37 (see text).
3
68
45
79
N
N
OH
c Elimination product 38 (37%) was isolated in this experiment (see
text).
d An unseparable elimination product 39 (40%) was produced in this
experiment.
12
28
Ph
Ph
e A complex crude mixture was obtained in which starting material
was the major product. No characteristic signals of a rearranged 3-
fluoropyrrolidine could be detected.
4
N
N
OH
OH
13
29
Ph
As depicted in the Table 1, all primary and secondary al-
cohols rearranged into 3-fluoropyrrolidines in fair to good
yields (entries 1–9). In all cases, only one diastereoisomer
was produced, as proven by examination of the 19F NMR
spectra. The identity of the rearranged product could be
easily determined by analysis of the coupling constants in
both 19F and 1H NMR spectra. For example, in compound
26, the 1H NMR spectrum displayed a characteristic sig-
nal at d = 5.13 (dt, 2JHF = 54.0 Hz, 3JHH = 6.0 Hz) while the
Ph
5
N
N
Bn
Bn
14
30
Synlett 2008, No. 9, 1345–1348 © Thieme Stuttgart · New York

LETTER
Rearrangement of 2-Hydroxyalkylazetidines into 3-Fluoropyrrolidines
1347
19F NMR spectrum showed one sharp signal at d = –168.2 formation of an intermediate carbonium ion (supported by
(app sept, 2JHF = 80.7 Hz, 3JHF = 30.0 Hz), in accordance the competitive formation of elimination products 41 and
with a CH2CHFCH2 pattern. In only one case (entry 7, 42), that is faster than the initial nucleophilic displace-
substrate 20) 12% of a minor inseparable compound con- ment leading to the bicyclic ammonium ion.
taminated the pyrrolidine product. On the basis of MS and
NMR spectroscopy, the structure of this minor compound
37 was shown to be the nonrearranged fluoroazetidine.
Particularly relevant signals indicative of this structure
are: (i) a doublet in the 13C NMR spectrum at d = 30.6
(3JCF = 21.0 Hz) indicative of a CH2CHF pattern and, (ii)
1
a doublet of multiplets in the H NMR spectrum at d =
4.45, also in accordance with this feature. On the other
hand, tertiary alcohols 23–25 did not rearrange at all. The
only fluorinated compound produced were determined to
be 35 and 36 and these products were accompanied by sig-
nificant amounts of elimination products 38 and 39 (ratios
35:38 and 36:39 ca. 6:4). The yield and ratio remained ex-
actly the same when 23 was reacted with Deoxofluor in-
stead of DAST. Finally, an attempt to treat 2-acylazetidine
40 (Figure 1) under the same conditions (DAST, CH2Cl2,
r.t.) aiming to produce a 3,3-difluoropyrrolidine15 failed
and the starting material was recovered.
Figure 2 ORTEP structure of fluoropyrrolidine 30
Ph
F
DAST, – HF
NEt2
14
S
N
O
F
41
Bn
Ph
Ph
N
O
F
– Et2N
– F–
S
N
F
n-Bu
37
38
Ph
N
O
+N
30
Bn
Ph
N
n-Bu
H
F–
42
Ph
40
39
Scheme 4 Mechanism of the rearrangement
Figure 1 Structure of compounds 37–40
In summary, we have developed an efficient and straight-
forward synthesis of stereodefined 3-fluoropyrrolidines18
in enantiomerically pure form, that takes advantage of the
reactivity of functionalized azetidines based on the strain
in this heterocycle.19
The relative configuration of the substituents in the pro-
duced 3-fluoropyrrolidines was unambiguously deter-
mined by X-ray crystallography of compound 30, whose
ORTEP diagram is depicted in Figure 2.16 The 2,3-trans
relationship between the fluorine atom and the adjacent
phenyl group and the observed stereospecificity of the re-
arrangement is fully consistent with the mechanism out-
lined in Scheme 4 starting with 14 and involving an
intermediate 1-azoniabicyclo[2.1.0]pentane 42. Consider-
ing the poor nucleofugacity of the fluoride anion, this re-
action is expected to be under kinetic control17 and the
chemoselectivity (2-fluoroalkylazetidine vs. rearranged
3-fluoropyrrolidine) arises from the regioselective attack
of the fluoride anion at the C-2 carbon in the intermediate
azetidinium ion 42. This high regioselectivity contrasts
with the results obtained by Cossy for the higher homo-
logues (Scheme 1), since in this case, the regioselectivity
was poorer and was found to depend on the substitution
pattern of the starting 2-hydroxyalkylpyrrolidine. The
highly strained nature of intermediate 42 probably dis-
criminates here to a larger extent between the two possible
attacks of the fluoride anion. The absence of rearrange-
ment in the case of tertiary alcohols can be ascribed to the
Acknowledgment
The authors thank the CNRS for financial support.
References and Notes
(1) Humphreys, A. Med Ad News 2006, 25 (6), 20.
(2) (a) Demange, L.; Ménez, A.; Dugave, C. Tetrahedron Lett.
1998, 39, 1169; and references cited therein. (b) Singh, R.
P.; Shreeve, J. M. J. Fluorine Chem. 2002, 116, 23.
(c) Burger, K.; Rudolph, M.; Fehn, S.; Sewald, N. J.
Fluorine Chem. 1994, 66, 87.
(3) (a) Hulin, B.; Cabral, S.; Lopaze, M. G.; Van Volkenburg,
M. A.; Andrews, K. M.; Parker, J. C. Bioorg. Med. Chem.
Lett. 2005, 15, 4770. (b) Ayad, T.; Génisson, Y.; Broussy,
S.; Baltas, M.; Gorrichon, L. Eur. J. Org. Chem. 2003, 2903.
(4) Xu, F.; Simmons, B.; Armstrong, J., III; Murry, J. J. Org.
Chem. 2005, 70, 6105.
(5) Bonini, F. B.; Boschi, F.; Franchini, M. C.; Fochi, M.; Fini,
F.; Mazzanti, A.; Ricci, A. Synlett 2006, 543.
Synlett 2008, No. 9, 1345–1348 © Thieme Stuttgart · New York

1348
B. Drouillat et al.
LETTER
(17) The kinetic control invoked here is also supported by the
(6) Li, Y.; Hu, J. Angew. Chem. Int. Ed. 2007, 46, 2489.
(7) Smith, E. M.; Swiss, G. F.; Neustadt, B. R.; Gold, E. H.;
Sommer, J. A.; Brown, A. D.; Chiu, P. J. S.; Moran, R.;
Sybertz, E. J.; Baum, T. J. Med. Chem. 1988, 31, 875.
(8) Inagaki, H.; Miyauchi, S.; Miyauchi, R. N.; Kawato, H. C.;
Ohki, H.; Matsuhachi, N.; Kawakami, K.; Takahashi, H.;
Takemura, M. J. Med. Chem. 2003, 46, 1005.
(9) Yang, W.; Wang, Y.; Roberge, J. Y.; Ma, Z.; Liu, Y.;
Lawrence, R. M.; Rotella, D. P.; Seethala, R.; Feyen, J. H.
M.; Dickson, J. K., Jr. Bioorg. Med. Chem. Lett. 2005, 15,
1225.
(10) (a) Xu, J.; Wei, L.; Mathwink, R.; He, J.; Park, Y.-J.; He, H.;
Leiting, B.; Lyons, K. A.; Marsillo, F.; Patel, R. A.; Wu, J.
K.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem.
Lett. 2005, 15, 2533. (b) Ganelin, C. B.; Bisop, P. B.;
Bambal, R. B.; Chan, S. M. T.; Leblond, B.; Moore, A. N. J.;
Zhao, L.; Bourgeat, P.; Rose, C.; Vargas, F.; Schwartz, J.-C.
J. Med. Chem. 2005, 48, 7333. (c) Caldwell, C. G.; Chen,
P.; He, J.; Parmee, E. R.; Leiting, B.; Marsilio, F.; Patel, R.
A.; Wu, J. K.; Eiermann, G. J.; Petrov, A.; He, H.; Lyons, K.
A.; Thornberry, N. A.; Weber, A. E. Bioorg. Med. Chem.
Lett. 2004, 14, 1265.
chemical stability of 36, which does not rearrange when
heated at 100 °C in toluene for 8 h.
(18) General Procedure for the Reaction of Azetidinols with
DAST: To a solution of the required 2-hydroxyalkyl-
azetidine (1 mmol) in anhyd CH2Cl2 (7 mL) cooled at 0 °C
under argon was added dropwise diethylaminosulfur
trifluoride (245 mL, 2 mmol). The resulting solution was
allowed to reach r.t. (1 h) and was stirred for 1 h. The
reaction mixture was then basified with 1 M NaOH (5 mL).
The layers were separated and the aqueous layer was
extracted with CH2Cl2 (2 × 10 mL). Drying over MgSO4,
filtration, and evaporation of the solvent under reduced
pressure gave a residue that was purified by flash
chromatography.
Selected data: Compound 26: yield (from 10): 81%;
colorless oil; Rf 0.75 (EtOAc); [a]D25 –46.1 (c = 0.57,
CHCl3). 1H NMR (300 MHz): d = 1.40 (d, J = 6.6 Hz, 3 H,
Me), 1.80–2.15 (m, 2 H, H4, H4¢), 2.50–3.75 (m, 3 H, H2,
H5, H5¢), 2.79 (dd, J = 12.0, 30.0 Hz, 1 H, H2¢), 3.21 (q, J =
6.6 Hz, 1 H, CHMe), 5.13 (dt, 2JHF = 54.0 Hz, 3JHH = 6.0 Hz,
1 H, H3), 7.13–7.28 (m, 5 H, Ar). 13C NMR (75 MHz): d =
23.1 (Me), 32.8 (d, 3JC–F = 23.0 Hz, C2), 50.9 (C4), 59.6 (d,
3JCF = 23.0 Hz, C4), 65.4 (CHMe), 92.5 (d, 2JCF = 176.0 Hz,
C3), 127.0, 128.1, 128.4 (CHAr), 145.1 (CqAr). 19F NMR
(188 MHz): d = –168.2 [qd (false hept), 2JHF = 80.7 Hz,
3JHF = 30.0 Hz, 1 F]. MS (CI, NH3 gas): m/z = 194 (100)
[MH+]. Compound 30: yield (from 14): 79%; colorless solid;
mp 69 °C; Rf 0.85 (EtOAc–pentane, 1:9); [a]D25 +119.8 (c =
0.5, CHCl3). 1H NMR (300 MHz): d = 1.29 (d, J = 6.0 Hz, 3
H, Me), 2.48–2.72 (m, 2 H, H2, H5), 3.16 (ddd, 3JHH = 3.0,
9.0 Hz, 3JHF = 36.0 Hz, 1 H, H5¢), 3.27 (d, J = 12.0 Hz, 1 H,
NCHHPh), 3.35 (dd, 3JHH = 12.0 Hz, 3JHF = 21.0 Hz, 1 H,
(11) O’Neil, I. A.; Thompson, S.; Kalindjan, B.; Jenkins, T.
Tetrahedron Lett. 2003, 44, 7809.
(12) (a) Déchamps, I.; Gomez Pardo, D.; Cossy, J. Synlett 2007,
263. (b) Déchamps, I.; Gomez Pardo, D.; Cossy, J. Eur. J.
Org. Chem. 2007, 4224.
(13) (a) Couty, F.; Durrat, F.; Prim, D. Tetrahedron Lett. 2003,
44, 5209. (b) Vargas-Sanchez, M.; Couty, F.; Evano, G.;
Prim, D.; Marrot, J. Org. Lett. 2005, 7, 5861. (c) Couty, F.;
Durrat, F.; Evano, G.; Marrot, J. Eur. J. Org. Chem. 2006,
4214.
(14) (a) Agami, C.; Couty, F.; Evano, G. Tetrahedron:
Asymmetry 2002, 13, 297. (b) Couty, F.; Prim, D.
Tetrahedron: Asymmetry 2002, 13, 2619. (c) Couty, F.;
Durrat, F.; Evano, G.; Prim, D. Tetrahedron Lett. 2004, 45,
7525. (d) Couty, F.; Evano, G.; Vargas-Sanchez, M.;
Bouzas, G. J. Org. Chem. 2005, 70, 9028. (e) Couty, F.;
Evano, G.; Rabasso, N. Tetrahedron: Asymmetry 2003, 14,
2407.
(15) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(16) Crystal structure has been deposited at the Cambridge
Crystallographic Data Centre and allocated the deposition
number CCDC 676883.
H3), 4.22 (d, J = 12.0 Hz, 1 H, NCHHPh), 5.10 (dm, 2JHF
=
57.0 Hz, 1 H, H4), 7.22–7.41 (m, 10 H, Ar). 13C NMR (75
MHz): d = 16.0 (Me), 57.4 (NCH2Ph), 60.3, 60.8 (d, 3JCF
23.0 Hz, C3, C5), 67.2 (d, 4JCF = 2.2 Hz, C2), 98.3 (d, 2JCF
182.0 Hz, C4), 127.1, 127.2, 127.4, 128.1, 128.4, 128.8,
=
=
128.9 (CHAr), 138.4, 140.5 (CqAr). 19F NMR (188 MHz):
d = –164.4 to –165.2, (m, 1 F). MS (ESI, +ve): m/z = 270.3
(100) [MH+].
(19) Couty, F.; Durrat, F.; Evano, G. Targets in Heterocyclic
Systems – Chemistry and Properties, Vol. 9; Attanasi, O. A.;
Spinelli, D., Eds.; Italian Society of Chemistry: Rome, 2005,
186.
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