Practical preparation of 3,3-difluoropyrrolidine

Article abstract of DOI:10.1021/jo050591h

A practical and cost-effective synthesis of 3,3-difluoropyrrolidine is reported. The synthesis involves the isolation of two intermediates, which are prepared via two efficient through processes: (1) a Claisen rearrangement followed by a Ru(VIII)-catalyzed oxidation to prepare the 2,2-difluorosuccinic acid and (2) an efficient cyclization to form N-benzyl-3,3-difluoropyrrolidinone followed by BH₃·Me₂S reduction.

Full text of DOI:10.1021/jo050591h

In this paper, we describe a practical synthesis of 3,3-
difluoropyrrolidine (Scheme 1). This synthesis features
two efficient through processes: (1) a Claisen rearrange-
ment of 1 followed by a Ru(VIII)-catalyzed oxidation of
2 to prepare 2,2-difluorosuccinic acid (3) and (2) an
efficient cyclization to form N-benzyl-3,3-difluoropyrro-
lidinone (5) followed by BH3‚Me2S reduction. In compari-
son to the literature synthesis,4 this chromatography-free
route only requires isolating two crystalline solid inter-
mediates 3 and 6, employs inexpensive and readily
available starting materials, and avoids using expensive
and unstable fluorinating reagents such as DAST.
Practical Preparation of
3,3-Difluoropyrrolidine
Feng Xu,* Bryon Simmons, Joseph Armstrong III, and
Jerry Murry
Department of Process Research, Merck Research
Laboratories, Rahway, New Jersey 07065
feng_xu@merck.com
Received March 23, 2005
2,2-Difluorosuccinic acid6 (3) is an expensive com-
mercial product (Lancaster, $165/5 g) and is not available
in large quantity. The literature-known preparation7 of
2,2-difluorosuccinic acid is also not suitable for large-scale
preparation and requires using 1,1-dichloroethene and
1-chloro-1,2,2-trifluoroethene gas. We envisioned that 3
is a suitable intermediate for the preparation of 3,3-
difluoropyrrolidine. As reported, 2 could be prepared from
ester 1.8
To overcome the workup issues associated with the
volatile intermediates (1 and 2,2-difluoropent-4-enoic acid
from hydrolysis of 2, vide infra) and avoid isolation of 1
and 2, we first developed an efficient through process to
A practical and cost-effective synthesis of 3,3-difluoropyr-
rolidine is reported. The synthesis involves the isolation of
two intermediates, which are prepared via two efficient
through processes: (1) a Claisen rearrangement followed by
a Ru(VIII)-catalyzed oxidation to prepare the 2,2-difluoro-
succinic acid and (2) an efficient cyclization to form N-benzyl-
3,3-difluoropyrrolidinone followed by BH3‚Me2S reduction.
In recognition of the high electronegativity of fluorine,
the strong C-F bond, and its unique capabilities such
as increasing lipid solubility and inhibiting the enzymatic
recognition process by C-F bonding, etc., it has become
popular in the pharmaceutical industry to introduce/
incorporate fluorine into an organic molecule in attempts
to significantly improve the drug candidates’ biological
activities and metabolic stability.1 Although the applica-
tion of small building blocks containing gem-difluoro
moieties continues to receive attention,2 the preparation
of these small molecules is not always efficient and
practical. Specifically, the 3,3-difluoropyrrolidine moiety
has recently been incorporated in pharmacologically
active substances;3 however, the literature synthesis4
involves DAST fluorination of 3-pyrrolidinone, the latter
of which is derived from the expensive chiral 3-hydroxy-
pyrrolidine. Neither of these compounds are ideal for
large-scale preparation in terms of cost and safety issues.5
For our specific research interests, we required a cost-
effective, safe synthesis of 3,3-difluoropyrrolidine that
was amenable to large-scale preparation.
(3) For recent examples, see: (a) Wilson, D. M.; Termin, A. P.;
Neubert, T. D. PCT Int. Appl. WO2005014558, 2005. (b) Hennequin,
L. F. A. PCT Int. Appl. WO2005013998, 2005. (c) Nelson, M. L.;
Ohemeng, K.; Amoo, V.; Kim, O.; Abato, P.; Assefa, H.; Berniac, J.;
Bhatia, B.; Bowser, T.; Chen, J.; Grier, M.; Hohos, A.; Honeyman, L.;
Ismail, M. Y.; Mechiche, R.; Nihlawi, M.; Sizensky, E. PCT Int. Appl.
WO2005009943, 2005. (d) Kadereit, D.; Defossa, E.; Schoenafinger, K.;
Klabunde, T.; Herling, A. German patent DE10335092, 2005. (e) Chan,
C. K.; Zhang, M.-Q.; Moinet, C.; Proulx, M.; Reddy, T. J.; Courchesne,
M. PCT Int. Appl. WO2005007656, 2005. (f) 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, 1265-1268. (g) Duffy,
J. L.; Mathvink, R. J.; Weber, A. E.; Xu, J. PCT Int. Appl. WO200405-
0022, 2004. (h) Hulin, B. PCT Int. Appl. WO2004046106, 2004. (i)
Colandrea, V. J.; Edmondson, S. D.; Mathvink, R. J.; Mastracchio, A.;
Weber, A. E.; Xu, J. PCT Int. Appl. WO2004043940, 2004. (j) Ancliff,
R.; Eldred, C. D.; Fogden, Y. C.; Hancock, A. P.; Heightman, T. D.;
Hobbs, H.; Hodgson, S. T.; Lindon, M. J.; Wilson, D. M. PCT Int. Appl.
WO2004035556, 2004. (k) Churcher, I.; Harrison, T.; Kerrad, S.;
Oakley, P. J.; Shaw, D. E.; Teall, M. R.; Williams, S. PCT Int. Appl.
WO2004031137, 2004. (l) Shiraishi, M.; Hara, T.; Kusaka, M.; Kanzaki,
N.; Yamamoto, S.; Miyawaki, T. PCT Int. Appl. WO2004016576, 2004.
(m) Gonzales, J. E., III; Wilson, D. M.; Termin, A. P.; Grootenhuis, P.
D. J.; Zhang, Y.; Petzoldt, B. J.; Fanning, L. T. D.; Neubert, T. D.;
Tung, R. D.; Martinborough, E.; Zimmermann, N. PCT Int. Appl.
WO2004078733, 2004.
(4) Giardina, G.; Dondio, G.; Grugni, M. Synlett 1995, 55-57.
(5) For a recent review, see: Tozer, M. J.; Herpin, T. F. Tetrahedron
1996, 52, 8619-8683.
(1) For recent reviews, see: (a) Bo¨hm, H.-J.; Banner, D.; Bendels,
S.; Kansy, M.; Kuhn, B.; Mu¨ller, K.; Obst-Sander, U.; Stahl, M.
ChemBioChem 2004, 5, 637-643. (b) Houben-Weyl Methods of Organic
Chemistry, workbench edition; Georg Thieme Verlag: Stuttgart,
Germany, 2000; Vols. E10a-c. (c) Hiyama, T. Organofluorine Com-
pounds; Springer: Berlin, Germany, 2000. (d) Banks, R. E.; Smart, B.
E.; Tatlow, J. C. Organofluorine Chemistry: Principles and Commercial
Applications; Plenum Press: New York, 1994.
(2) For recent examples, see: (a) Mae, M.; Hong, J. A.; Hammond,
G. B.; Uneyama, K. Tetrahedron Lett. 2005, 46, 1787-1789. (b) Boydell,
A. J.; Vinader, V.; Linclau, B. Angew. Chem., Int. Ed. 2004, 43, 5677-
5679. (c) Suzuki, A.; Mae, M.; Amii, H.; Uneyama, K. J. Org. Chem.
2004, 69, 5132-5134. (d). Wu, Y.-Y.; Zhang, X.; Meng, W.-D.; Qing,
F.-L. Org. Lett. 2004, 6, 3941-3944. (e) Uneyama, K.; Tanaka, H.;
Kobayashi, S.; Shioyama, M.; Amii, H. Org. Lett. 2004, 6, 2733-2736.
(f) Sekiguchi, T.; Sato, K.; Ishihara, T.; Konno, T.; Yamanaka, H. Chem.
Lett. 2004, 33, 666-667.
(6) ,2-Difluorosuccinic acid is also a useful building block. For recent
applications, see: (a) Boros, E. E.; Samano, V.; Ray, J. A.; Thompson,
J. B.; Jung, D. K.; Kaldor, I.; Koble, C. S.; Martin, M. T.; Styles, V. L.;
Mook, R. A., Jr.; Feldman, P. L.; Savarese, J. J.; Belmont, M. R.;
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10.1021/jo050591h CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/24/2005
J. Org. Chem. 2005, 70, 6105-6107
6105

SCHEME 1. Synthesis of 3,3-Difluoropyrrolidinea
a Reagents and conditions: (a) allyl alcohol, hexane, reflux; (b) TMSCl, Zn dust, MeCN/hexane, 60 °C; (c) 2 mol % of RuCl3, H5IO6,
MeCN/water, 0-20 °C; (d) (CF3CO)2O, i-PrOAc; then, BnNH2; (e) SOCl2, i-PrOAc; (f) BH3‚Me2S, THF/toluene, 55 °C; (g) 5% Pd-C, H2,
45 psi, MeOH.
prepare 3 in high yield. Thus, the ester 1 was efficiently
prepared by condensation of 1.3 equiv of allyl alcohol and
difluorochloroacetic acid in hexane. Without workup and
isolation, the crude ester 1 (bp 110 °C) was directly
treated with 1.5 equiv of Zn dust in the presence of 1.5
equiv of TMSCl in MeCN/hexane at 60 °C to afford 2.
The preactivation of Zn dust was not required. In contrast
to the reported procedure,8 the reaction was carried out
at much lower reaction temperature to avoid using a
sealed tube without diminishing the yield.
Without further purification and isolation, the filtered
crude rearrangement product 2 was concentrated to
remove hexane as well as the excess TMSCl before
oxidation. Removal of hexane improved the efficiency of
the subsequent oxidation reaction. Isolation of the cor-
responding hydrolyzed acid, which is formed as soon as
2 is subjected to aqueous conditions, is not recommended,
since this volatile acid can be partially lost during
concentration.
concentration. After several attempts, we were pleased
to find out that formation of 2,2-difluorosuccinic anhy-
dride can be completed cleanly by using 1.2 equiv of (CF3-
CO)2O in i-PrOAc. Treatment of the above crude anhy-
dride solution with only 1.5 equiv of BnNH2 gave the
desired amic acid 4 in 95% assay yield. In this case, the
amide formation can be achieved even in the presence of
excess CF3CO2H. Although other dehydrating reagents
such as (CF3CO)2O, AcCl, Ac2O, etc. could be used for
formation of the imide 5, the cyclization of the crude 4
in the presence of 2 equiv of SOCl2 at 60 °C in i-PrOAc
proceeded very smoothly and cleanly.
After aqueous work up, the crude 5 was reduced with
BH3‚Me2S in THF/toluene at 55 °C. The reaction was
quenched with dry MeOH followed by HCl(g) to destroy
the amine-boron complex as well as convert the volatile
free base of 6 to the crystalline HCl salt. The HCl salt 6
was isolated from i-PrOH as a white solid in 84% yield
over three steps.
After optimization, the crude 2 was directly oxidized
with 2 mol % RuCl3 in the presence of H5IO6 in aqueous
MeCN at 0-20 °C to give the desired diacid 3. Controlling
the reaction temperature below 20 °C and applying only
2 mol % Ru(III) proved to be crucial to achieve a clean
oxidation.9 The use of H5IO6 rather than NaIO4 avoided
formation of a heavy slurry during the reaction. The
water-soluble diacid 3 was best extracted in the organic
phase by a mixture of MeCN/i-PrOAc (2:3), which pro-
vided high efficiency for extraction and clean phase
separation. However, part of the iodic acid was also
extracted to the organic phase and had to be reduced.
Otherwise, a brown to dark color would develop upon
storage or during concentration. This was simply over-
come by treating the organic phase with thiosulfate.
Finally, 3 was isolated as an off-white solid from toluene
in 72% overall yield over three steps.
Hydrogenolysis of the HCl salt of 6 at room tempera-
ture in the presence of 5% Pd-C in MeOH under 45 psi
of H2 gave the desired 3,3-difluoropyrrolidine. However,
the use of a catalytic amount of acid such as HOAc or
HCl improved the reaction rate and helped to achieve a
full conversion. Therefore, in a typical experiment, 0.5
equiv of HOAc was used. Finally, 3,3-difluoropyrrolidine
was isolated as its white crystalline HCl salt in 98% yield.
In summary, a practical synthesis of 3,3-difluoropyr-
rolidine was developed. The overall yield for this chro-
matography-free synthesis is 59%.
Experimental Section
2,2-Difluorosuccinic Acid (3). A 1-L three-necked round-
bottom flask was equipped with a thermometer, a N2 inlet, a
Dean-Stark distillation head, and an overhead stirrer. Chlo-
rodifluoroacetic acid (100 g, 0.766 mol), allyl alcohol (57.8 g, 0.996
mol), and hexane (100 mL) were added at ambient temperature.
The reaction solution was heated to 70-75 °C (internal tem-
perature). After 10 h, the reaction solution was allowed to cool
to ambient temperature. MeCN (300 mL) and Zn dust (70.1 g,
1.072 mol) were added. TMSCl (600 mL, 1.149 mol) was added
dropwise over 30 min. The slurry was stirred at 60 °C (internal
temperature) for 3 days. Then, the slurry was cooled to 5 °C.
The solid was removed through a Celite plug filtration. The wet
cake was washed with cold (5-10 °C) dry MeCN (150 mL). The
After screening various conditions, the formation of
amic acid 4 was best achieved via 2,2-difluorosuccinic
anhydride. However, 2,2-difluorosuccinic anhydride is a
volatile intermediate and can be easily lost during
(9) Oxidation by using bleach/cat. RuCl3 was tried under various
conditions with controlled pH at acidic, or basic, or near neutral
conditions. However, the reaction profiles were not as clean as the use
of NaIO4 or H5IO6.
6106 J. Org. Chem., Vol. 70, No. 15, 2005

filtrate was concentrated to about 300 mL and diluted to 400
mL with MeCN.
the solvent switched to toluene (150 mL). Any insoluble solids
were removed through filtration (Celite). THF (150 mL) and
BH3‚Me2S (2.0 M in THF, 648 mL) were added at ambient
temperature. The reaction mixture was stirred at 55 °C for 3 h.
A light slurry was formed during the reaction. The reaction was
then cooled to 0-5 °C and quenched with dry MeOH (200 mL)
dropwise followed by saturation with HCl (g). The reaction
solution was stirred at 0-10 °C for 1 h and at 55 °C for 1 h. The
solvents were switched in a vacuum to i-PrOH (about 250 mL),
which allowed the product to crystallize as a white solid. The
slurry was aged at 0 °C for 2 h before filtration. The wet cake
was washed with cold 50% i-PrOH in i-PrOAc (2 × 100 mL) to
yield 64 g of 6 as a white solid; 84% yield over three steps.
2,2-Difluorosunnic anhydride: 1H NMR (CDCl3, 400 MHz)
δ 3.38 (t, J ) 12.8 Hz, 2 H). 19F NMR (CDCl3, 376 MHz) δ
-105.2.
Water (400 mL) followed by RuCl3 (3.18 g, 15.3 mmol) were
added to the above crude reaction solution at ambient temper-
ature. The reaction mixture was then cooled to 5 °C. Periodic
acid (627 g, 2.76 mol) was added portion-wise over 2-3 h while
the reaction temperature was maintained below 20 °C with
external cooling. By 19F and 1H NMR: >95% conversion was
achieved. 19F NMR (d4-MeOH): 2,2-difluoropent-4-enoic acid,
-107.7 ppm; 2,2-difluorosuccinic acid, -106.2 ppm. 1H NMR (d4-
MeOH): 2,2-difluoropent-4-enoic acid, 2.82 (dt) ppm; 2,2-difluo-
rosuccinic acid, 3.24 (t) ppm. Then, i-PrOH (10 mL) was added
in one portion and the reaction mixture was aged at ambient
temperature for 1 h. i-PrOAc (300 mL) was added and the
organic phase was separated. The aqueous phase was extracted
with a solution of i-PrOAc and MeCN (300 mL, i-PrOAc/MeCN
) 3:2). The combined organic phase was mixed with 20%
Na2S2O3 (100 mL) until the organic phase turned light yellow.
The reaction solution was acidified with concentrated HCl to
pH 1 before phase separation. The aqueous phase was back-
extracted with a solution of i-PrOAc and MeCN (200 mL,
i-PrOAc/MeCN ) 3:2). The combined organic phase was washed
with brine (100 mL). Concentration in a vacuum and solvent
switch to toluene (300 mL) gave the desired 3 as a slurry before
filtration. The wet cake was washed with toluene (2 × 100 mL)
to yield 85 g of 37,10 as an off-white crystalline solid; 72% yield
over three steps.
N-Benzyl-3,3-difluoropyrrolidine (6). To a solution of 2,2-
difluorosuccinic acid (50 g, 0.324 mol) in i-PrOAc (500 mL) was
added trifluoroacetic anhydride (81.1 g, 0.389 mol) in one portion
at ambient temperature. The reaction solution was stirred at
50 °C for 1 h. By 19F NMR: >98% conversion.19F NMR (CDCl3):
2,2-difluorosunnic anhydride, -105.2 ppm. Then, the reaction
solution was allowed to cool to 5 °C. BnNH2 (52 g, 0.486 mol)
was added dropwise while the reaction temperature was main-
tained below 20 °C. Then, the slurry was stirred at ambient
temperature for 1 h. The reaction was quenched with water (200
mL) followed by saturated Na2CO3 to pH 8-9. The separated
organic phase was discarded. The aqueous phase was acidified
with 5 N HCl to pH 1 and extracted with i-PrOAc (2 × 500 mL).
The organic phase was washed with 2 N HCl brine (200 mL).
The azeotropically dried solution of the crude 4 in i-PrOAc (800
mL) was directly used in the next step without further purifica-
tion. HPLC assay: 95% yield.
4: 1H NMR (d4-MeOH, 400 MHz) δ 9.16 (s, br, 1 H), 7.35-
7.22 (m, 5 H), 4.46 (m, 2 H), 3.27 (t, J ) 14.4 Hz). 19F NMR
(d4-MeOH, 376 MHz) δ -105.3. 13C NMR (d4-MeOH, 100 MHz)
δ 168.3 (t, J ) 8.0 Hz), 164.4 (t, J ) 28.1 Hz), 137.6, 128.2, 127.1,
127.0, 115.5 (t, J ) 252.2 Hz), 42.7, 38.7 (t, J ) 26.5 Hz). Anal.
Calcd for C11H11F2NO3: C, 54.32; H, 4.56; N, 5.76. Found: C,
54.82; H, 4.15; N, 5.80.
5: 1H NMR (CDCl3, 400 MHz) δ 7.40-7.32 (m, 5 H), 4.72 (s,
2 H), 3.14 (t, J ) 12.6 Hz, 2 H). 19F NMR (CDCl3, 376 MHz) δ
-107.44. 13C NMR (CDCl3, 100 MHz) δ 168.4 (t, J ) 8.0 Hz),
166.0 (t, J ) 31.2 Hz), 134.1, 128.9, 128.8, 128.5, 114.0 (t, J )
253.1 Hz), 42.9, 38.9 (t, J ) 24.4 Hz). Anal. Calcd for C11H9F2-
NO2: C, 58.67; H, 4.03; F, 16.87; N, 6.22. Found: C, 58.56; H,
3.80; F, 17.16; N, 6.18.
6: 1H NMR (d4-MeOH, 400 MHz) δ 7.53 (m, 5 H), 4.05 (s, 2
H), 3.88 (t, J ) 11.6 Hz, 2 H), 3.69 (s, br, 2 H), 2.9 (s, br, 2 H).
13C NMR (d6-DMSO, 100 MHz) δ 131.2, 130.9, 129.8, 129.1, 127,7
(t, J ) 241.9 Hz), 57.8 (t, J ) 34.4 Hz), 51.2, 33.9 (t, J ) 24.8
Hz). Anal. Calcd for C11H14ClF2N: C, 56.54; H, 6.04; N, 5.99.
Found: C, 56.45; H, 6.05; N, 5.91.
3,3-Difluoropyrrolidine HCl Salt. A slurry of 6 (50 g, 0.213
mol), 5% Pd-C (contained 50% water, 5.0 g), and HOAc (6.5 g,
0.1065 mol) in MeOH (500 mL) was agitated under 45 psi of H2
pressure at ambient temperature for 7 h. After filtration through
a Celite plug to remove catalysts, the filtrate was solvent
switched to toluene (200 mL) in a vacuum. The desired HCl salt
was collected through filtration. The wet cake was washed with
toluene (2 × 100 mL) to give 30.0 g of 3,3-difluoropyrrolidine
HCl salt4,10 as a white solid; 98% yield. 1H NMR (d4-MeOH, 400
MHz) δ 3.73 (m, 2 H), 3.62 (m, 2 H), 2.59 (m, 2 H). 19F NMR
(d4-MeOH, 376 MHz) δ -100.9. 13C NMR (d4-MeOH, 100 MHz)
δ 128.9 (t, J ) 247. 5 Hz), 51.8 (t, J ) 34.4 Hz), 45.3 (t, J ) 4.0
Hz), 34.3 (t, J ) 24.8 Hz).
SOCl2 (77 g, 0.648 mol) was added to the above solution at
ambient temperature. The reaction solution was agitated at 50-
55 °C for 4 h. The reaction was cooled to 0-5 °C. Half saturated
brine (200 mL) was added slowly to quench the excess SOCl2.
The organic phase was washed with brine (200 mL) then brine
and 5% Na2CO3 (about 300 mL) to pH 8-9. After a final brine
wash (200 mL), the organic phase was azeotropically dried and
Supporting Information Available: NMR spectra for
compounds 3-6 and 3,3-difluoropyrrolidine. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) The spectroscopic data and mp were in full agreement with the
reported data.
JO050591H
J. Org. Chem, Vol. 70, No. 15, 2005 6107