4-fluoropyrrolidine-2-carbonyl fluorides: Useful synthons and their facile preparation with 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride

Article abstract of DOI:10.1021/jo1025783

4-Fluoropyrrolidine derivatives are useful in medicinal chemistry applications such as dipeptidyl peptidase IV inhibitors. As attractive synthons for these, N-protected (2S,4S)-4-fluoropyrrolidine-2-carbonyl fluorides were synthesized in high yield by double fluorination of N-protected (2S,4R)-4-hydroxyproline with 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride (Fluolead). The 4-fluoropyrrolidine-2-carbonyl fluorides were converted to useful intermediates such as 4-fluoropyrrolidine-2-carboxamides, -N-methoxy-N-methylcarboxamide (Weinreb amide), -carboxylate methyl esters, and -carbonitriles in excellent yields. The crystalline N-Fmoc-cis-4- fluoropyrrolidine-2-carbonyl fluoride 2a is a particularly useful synthon due to its high yield of preparation and easy isolation as an enantiomerically pure compound by crystallization. Thus, the methodology using the synthons prepared by the stereospecific double fluorination has enabled a significant decrease in the synthetic steps needed for the preparation of the 4-fluoropyrrolidine derivatives useful for medicinal applications.

Full text of DOI:10.1021/jo1025783

ARTICLE
pubs.acs.org/joc
4-Fluoropyrrolidine-2-carbonyl Fluorides: Useful Synthons and Their
Facile Preparation with 4-tert-Butyl-2,6-dimethylphenylsulfur Trifluoride†
Rajendra P. Singh and Teruo Umemoto*
IM&T Research, Inc., 6860 North Broadway, Suite B, Denver, Colorado 80221, United States
S Supporting Information
b
ABSTRACT: 4-Fluoropyrrolidine derivatives are useful in
medicinal chemistry applications such as dipeptidyl peptidase
IV inhibitors. As attractive synthons for these, N-protected
(2S,4S)-4-fluoropyrrolidine-2-carbonyl fluorides were synthe-
sized in high yield by double fluorination of N-protected
(2S,4R)-4-hydroxyproline with 4-tert-butyl-2,6-dimethylphe-
nylsulfur trifluoride (Fluolead). The 4-fluoropyrrolidine-2-
carbonyl fluorides were converted to useful intermediates such
as 4-fluoropyrrolidine-2-carboxamides, -N-methoxy-N-methylcarboxamide (Weinreb amide), -carboxylate methyl esters, and -
carbonitriles in excellent yields. The crystalline N-Fmoc-cis-4-fluoropyrrolidine-2-carbonyl fluoride 2a is a particularly useful
synthon due to its high yield of preparation and easy isolation as an enantiomerically pure compound by crystallization. Thus, the
methodology using the synthons prepared by the stereospecific double fluorination has enabled a significant decrease in the
synthetic steps needed for the preparation of the 4-fluoropyrrolidine derivatives useful for medicinal applications.
’ INTRODUCTION
Fluorine has an increasingly important role in medicinal
chemistry and drug design, as it often imparts enhanced biolo-
gical activity, metabolic stability, binding interaction, or other
desirable traits in the physical properties of drug molecules.1
Therefore, research into the biochemical applications of fluori-
nated compounds has been conducted extensively and actively.1
Recently, 4-fluoropyrrolidine derivatives A,2 B,3 C,4 and D5 as
shown in Figure 1 have been developed as potent dipeptidyl
peptidase (DPP) IV inhibitors for diabetes treatment. 4-Fluor-
opyrrolidine derivatives I, II, III, IV, and V as shown in Figure 2
have been used as key intermediates for the preparation of these
DPP IV inhibitors.2ꢀ6 In particular, carboxamide IV and carbo-
nitrile V are important intermediates for the preparation of DPP
inhibitors having a substituted acetyl group at the N-position
such as C and D.
Figure 1. Potent DPP-IV inhibitors.
The conventional methodologies have been limited by the fact
that the carboxyl group in 4-hydroxyprolines must be protected
VIII, which was then (iii) fluorinated with DAST2,8ꢀ10 to give IX.
or changed to another functional group inactive to fluorination,
Next, step (iv) was a careful hydrolysis of IX with lithium hydroxide
such as a methoxycarbonyl or cyano, before fluorination of the
giving Xwith the possibility of racemization. Acid Xwas transformed
4-hydroxy group with a deoxofluorinating agent. Therefore,
to carboxamide I in two steps, (v) a reaction with di-tert-butyldi-
many synthetic steps have been required as illustrated below.
carbonate followed by (vi) ammonium bicarbonate. Compound I
In addition, diethylaminosulfur trifluoride (DAST) has been
was dehydrated to give carbonitrile II. Weinreb amide III (R = Boc)
used as the deoxofluorinating agent of choice in most cases of
was prepared by (viii) treating X with N,O-dimethylhydroxylamine
conventional synthesis schemes. However, DAST has low ther-
hydrochloride/EDC/HOBt/Et3N/DMF.3,6b (2S,4S)-N-Haloace-
mal stability, is potentially explosive, and is not easily handled due
tyl-4-fluoropyrrolidine-2-carboxamide IV was prepared by (ix)
to fuming in air and vigorous reaction on contact with water.7
N-deprotection of carboxamide I, followed by (x) haloacetylation.
Thus, (2S,4S)-4-fluoropyrrolidine derivatives IꢀV have been
prepared as shown in Scheme 1.2,3 A starting material, (2S,4R)-4-
hydroxyproline (VI), was (i) esterified and (ii) N-protected with a
group such as tert-butoxycarbonyl (Boc) group to give compound
Received: December 28, 2010
Published: March 29, 2011
r
2011 American Chemical Society
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Scheme 1. Conventional Preparation of Useful Intermediates IꢀV
Scheme 2. Reaction of trans-4-Hydroxy-L-proline Deriva-
tives with ArSF3
Figure 2. Useful 4-fluoropyrrolidine intermediates for DPP IV
inhibitors.
alcohols provide stereoselective deoxofluoroarylsulfinylation
products.19a Here, with Fluolead, we have developed a stereo-
specific double fluorination of (2S,4R)-4-hydroxypyrrolines as
another example of bifunctional compounds, giving (2S,4S)-4-
fluoropyrrolidine-2-carbonyl fluorides, as a new synthetic strat-
egy, which significantly decreases the necessary reaction steps for
the preparation of useful 4-fluorinated pyrrolidine intermediates
for medicinal applications.
Compound IV was dehydrated (xi) to give (2S,4S)-N-haloacetyl-4-
fluoropyrrolidine-2-carbonitrile V.2,11
4-Fluoropyrrolidine-2-carbonitrile II was prepared alternatively.2
The starting material VI was converted to N-Boc-4-hydroxyproline,
which was followed by three steps, treatments with ClCOOEt/
Et3N, ammonia, and then trifluoroacetic anhydride to give N-Boc-4-
hydroxypyrrolidine-2-carbonitrile. Fluorination of the carbonitrile
with DAST afforded II.
’ RESULTS AND DISCUSSION
Since the fluorination with DAST involves a potentially serious
safety issue,7 methods have been reported using other deoxofluor-
inating agents such as morpholinosulfur trifluoride (Morpho-
DAST),12 Yarovenko reagent (ClCHFCF2NEt2),13 Ishikawa
reagent (CF3CHFCF2NEt2),13,14 and 2,2-difluoro-1,3-dimethyli-
midazolidine (DFI).15 Morpho-DAST and DFI are more stable
than DAST. The fluorinations with C8F17SO2F/DBU16 and with
Tf2O/pyridine followed by treatment with tetrabutylammonium
fluoride17 have also been reported. Fluorination of a related
compound, N-benzyl-4-hydroxypyrrolidine, with Deoxo-Fluor
reagent [(MeOCH2CH2)2NSF3] that is more thermally stable
than DAST has been reported.18
Recently, we have developed 4-tert-butyl-2,6-dimethylphenyl-
sulfur trifluoride (Fluolead) as a novel new and versatile deoxo-
fluorinating agent that has high thermal stability and ease of
handling.19a Fluolead reagent fluorinates alcohols,19aꢀe alde-
hydes, ketones, and carboxylic acids, giving the corresponding
CF, CF2, and CF3 compounds in high yields.19a It also reacts with
thiocarbonyl, thioester, and dithiocarbonate compounds to give
the corresponding CF2, CF2O, and CF3O compounds.19a Reac-
tions with bifunctional compounds such as diols and amino
Based on literature researching we have found that there are no
reports on double deoxofluorination of 4-hydroxyprolines to
achieve 4-fluoropyrrolidine-2-carbonyl fluorides. The double
deoxofluorination has been found by us to be a very useful
methodology for reducing the number of steps required for the
production of pharmaceutically useful 4-fluoropyrrolidine deriva-
tives. This is based on 4-tert-butyl-2,6-dimethylphenylsulfur tri-
fluoride (Fluolead), which has recently been developed as a
deoxofluorinating reagent.19 Fluolead is versatile, relatively highly
safe, shelf-stable, and easily handled in comparison to DAST,
Deoxo-Fluor, and other related deoxofluorinating agents.19a
With (2S,4R)-N-Fmoc-4-hydroxyproline (1a) as a substrate,
the reaction of Fluolead reagent proceeded smoothly in dichlor-
omethane at ice bath temperature (∼0 °C) to room temperature
to produce (2S,4S)-N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluor-
ide (2a) in 90% NMR yield (78% isolated yield), as shown in
Scheme 2 and Table 1 (run 1). The fluorination of the hydroxyl
group at the 4-positon proceeded in an inversion manner.
Monitoring the reaction by 19F NMR indicated that the formation
of the carbonyl fluoride moiety was fast (<0.5 h), but the
fluorination of the hydroxyl group was slow (about 60 h at rt).
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Table 1. Synthesis of 4-Fluoropyrrolidine-2-carbonyl Fluoride Derivatives with ArSF3
a
run
substrate
ArSF3
solvent
T (°C), time (h)
additiveb
product
yieldc (%)
1
2
1a
1a
1a
1a
1a
1b
1c
1d
1d
1d
1d
Fluolead
Fluolead
Fluolead
C6H5SF3
p-ClC6H4SF3
Fluolead
Fluolead
Fluolead
Fluolead
Fluolead
Fluolead
CH2Cl2
∼0 °C to rt, 1 h; rt, 60 h
∼0 °C to rt, 1 h; rt, 22 h
∼0 °C to rt, 1 h; rt, 5 h
∼0 °C to rt, 1 h; rt, 60 h
∼0 °C to rt, 1 h; rt, 60 h
∼0 °C to rt, 1 h; rt, 60 h
∼0 °C to rt, 1 h; rt, 72 h
∼0 °C to rt, 1 h; rt, 45 h
∼0 °C to rt, 1 h; rt, 45 h
∼0 °C to rt, 1 h; rt, 60 h
∼0 °C to rt, 1 h; rt, 20 h
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2d
90 (78)
100 (88)
92 (84)
68
CH2Cl2
HFꢀpy, 0.1 equiv
HFꢀpy, 0.4 equiv
3
CH2Cl2
4
CH2Cl2
5
CH2Cl2
54
6
CH2Cl2
90 (75)
90 (76)
27
7
CH2Cl2
8
CH2Cl2
9
CH2Cl2
pyridine, 0.5 equiv
Et3N, 0.25 equiv
90
10
CH2Cl2
77
11
CH2Cl2/Et2O(9/1)
56
a The amount of ArSF3 used was a 2.5 equimolar amount relative to a substrate except for runs 4 and 10, in which 3.8 and 3.0 equimolar amounts of ArSF3
were used, respectively. Fluolead = 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride. b The amount of an additive used is shown relative to a substrate.
HF-py (py = pyridine) (density 1.1) (available from commercial suppliers) is a 7:3 w/w of anhydrous HF and pyridine, and its molecular weight is
considered to be 263 as C5H5N(HF)9.2 c Yields are based on 19F NMR using fluorobenzene as a standard, and yields in parentheses are isolated yields.
Phenylsulfur trifluoride and p-chlorophenylsulfur trifluoride in
place of Fluolead under the same reaction conditions provided
68% and 54% yields of the product 2a, respectively (runs 4 and 5,
Table 1). Thus, Fluolead is superior to unsubstituted and chlorine
atom-substituted phenylsulfur trifluorides since multialkylated
Fluolead is reactive, while electron-withdrawing group-substituted
phenylsulfur trifluoride is deactivated. When HFꢀpyridine (7:3
w/w) was used as a catalyst, the double fluorination reaction of 1a
with Fluolead was found to be accelerated. With addition of 0.1
equiv of HFꢀpyridine, the reaction was complete in quantitative
yield in less than 22 h (run 2). With 0.4 equiv of HFꢀpyridine, the
reaction was greatly accelerated and almost completed around 5 h
(run 3).
Similarly to 1a, (2S,4R)-N-Cbz- and -N-chloroacetyl-4-hydro-
xyproline (1b) and (1c) reacted with Fluolead to give (2S,4S)-N-
Cbz- and -N-chloroacetyl-4-fluoropyrroline-2-carbonyl fluoride
(2b and 2c) in excellent yields, respectively (runs 6 and 7).
However, reaction of (2S,4R)-N-Boc-4-hydroxyproline (1d)
with Fluolead gave (2S,4S)-N-Boc-4-fluoropyrroline-2-carbonyl
fluoride (2d) in very low yield (27%, run 8). The low yield was
due to deprotection of the acid-sensitive tert-butoxycarbonyl
(Boc) group occurring under the reaction conditions, as 19F
NMR of the reaction mixture showed tert-butyl fluoride, a Boc-
cleavage product, was formed in 43% yield. The yield of 2d was
greatly improved when a 0.5 equimolar amount of pyridine
relative to a substrate was added as a HF-trap agent (90% in
run 9). The reaction was slow or incomplete when pyridine was
used in more than 0.5 equiv amounts, while the deprotection
reaction occurred when less than 0.5 equiv of pyridine was used.
When a 0.25 equimolar amount of triethylamine was used, the
yield was 77% (run 10). When a 9:1 v/v mixture of dichlor-
omethane and diethyl ether was used as a solvent instead of
dichloromethane alone, the yield was increased to 56% from
27%, indicating the ether can serve as a HF-trap agent (run 11).
Compounds 2a and 2b were identified by spectral and
elemental analyses of the purified products. As we failed to get
a pure sample of 2c, it was derived to known compounds 5d and
6c as discussed below. Compound 2d was identified by the
comparison with the spectral data of an authentic sample, which
was prepared by fluorination of (2S,4S)-N-Boc-4-fluoroproline.
For further comparison, the other stereoisomers at 4-position,
(2S,4R)-N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluoride (2a0)
and (2S,4R)-N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride
(2d0) were prepared by fluorination of (2S,4R)-N-Fmoc-4-
fluoroproline and (2S,4R)-N-Boc-4-fluoroproline, respectively.
Thus, the structural identification of 2a and 2d was furthermore
comfirmed due to the observed definite differences in 19F NMR
between 2a and 2a0, and 2d and 2d0.
In the fluorination with Fluolead, 4-tert-butyl-2,6-dimethylphe-
nylsulfinyl fluoride is formed as a byproduct which is derived from
Fluolead. Crystalline product 2a was easily isolated by crystallization
from dichloromethane/pentane, as the byproduct is soluble in a
hydrocarbon (pentane) while 2a is insoluble in a hydrocarbon.
As shown in Scheme 3, when 1a was allowed to react with
DAST or Deoxo-Fluor, the yields of the double fluorination
product 2a were low (40% and 41%, respectively), and byproduct
amides 3 and 4 were formed in 45% and 39% yields. The
byproducts were isolated and confirmed by comparison with
authentic samples, which were synthesized by the reaction of 2a
with diethylamine and bis(2-methoxyethyl)amine, respectively.
The formation of 3 can be explained by reaction of product 2a
with diethylamine generated from decomposition of Et2NS(O)F
derived from DAST during the reaction. Similarly, the formation
of 4 can be explained by reaction of 2a with bis(2-methox-
yethyl)amine generated from the decomposition of (MeOCH2-
CH2)2NS(O)F during the reaction. Thus, the reactions with
DAST and Deoxo-Fluor are compromised by such side reactions,
which are attributed to the weak and labile NꢀS bonding of
DAST and Deoxo-Fluor. It was reported that a similar byproduct,
N,N-bis(methoxyethyl)benzamide, was obtained in 67% yield
when Deoxo-Fluor was reacted with benzoic acid in the presence
of N,N-diisopropylethylamine. The benzamide was presumed to
be formed by reaction of benzoyl fluoride with bis(2-methox-
yethyl)amine resulting from Deoxo-Fluor.20 Similar amide pro-
ducts, PhCOCONR2 (R = Et and MeOCH2CH2), were reported
to be formed when DAST and Deoxo-Fluor reacted with
phenylpyruvic acid.21
Another deoxofluorinating agent, 2,2-difluoro-1,3-dimethy-
limidazolidine (DFI), was examined. Reaction of 1a with DFI
provided product 2a in 68% NMR yield (50% isolated) under
the same reaction conditions as for Fluolead (conditions of run 1,
Table 1). The yield was much less than with Fluolead.
As shown in Scheme 4, fluorination of the cis-isomer,
(2S,4S)-N-Fmoc-4-hydroxyproline (1a0), with Fluolead was
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Scheme 3. Reactions of trans-4-Hydroxy-L-proline Derivative with DAST and Deoxo-Fluor Reagent
Scheme 4. Reaction of cis-4-Hydroxy-L-proline Derivative
with Fluolead Reagent
Table 2. Reactions of 4-Fluoropyrrolidine-2-carbonyl Fluor-
ides with Nucleophiles
entry substrate
NuH
solvent T (°C) time (h) product yielda (%)
1
2
3
4
5
6
2a
2a
NH3
CH2Cl2 rt
1
1
1
1
1
1
5a
95
70
94
85
94
95
HN(OMe)Me CH2Cl2 rt
5b
2b NH3
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
CH2Cl2 rt
5cb
5dc
5ed
5fb
2c
2a
NH3
MeOH
2b MeOH
a Yields are isolated yields. b Chen, H.; Chen, Y. Patent No. CN
101318922. c See refs 4 and 11d. d Tran, T. T.; Patino, N.; Frogier, T.;
Guedj, R. J. Fluorine Chem. 1997, 82, 125ꢀ130.
Scheme 5. Reactions of 4-Fluoropyrrolidine-2-carbonyl
Fluorides with Nucleophiles
(N-protection, double fluorination, and then amidation) from
the starting material VI by means of our new method, while six or
five steps were required to reach I or III according to the
conventional methods (see Scheme 1).
The synthesis of carboxamides, Weinreb amides, and carbox-
ylate esters may also be performed directly in a one-pot proce-
dure by the reaction of 4-hydroxyproline 1 with Fluolead in
dichloromethane followed by the addition of amines or metha-
nol. In these cases, byproducts, 4-tert-2,6-dimethylphenylsulfina-
mides or -sulfinate methyl ester, may be formed by reaction of
4-tert-butyl-2,6-dimethylphenylsulfinyl fluoride, derived from
Fluolead, with the amine or methanol. Therefore, it may be
needed to remove the byproducts from the reaction mixture. As
there is a significant difference in polarity between them, the
separation of byproducts from the desired products may easily be
achieved by such a method as standard chromatography on
silica gel.
Carboxamides 5a, 5c, and 5d were converted into the corre-
sponding carbonitriles 6a, 6b,23 and 6c,4,11d respectively, in high
yields by using 1.5 equiv of trifluoroacetic anhydride as a
dehydrating agent in anhydrous THF6a (Scheme 6). Carboni-
triles 6a, 6b, and 6c were colorless solids and purified by
crystallization from dichloromethane/pentane mixture.
N-Fmoc-4-fluoropyrrolidine-2-carboxamide (5a) was easily
deprotected using a suitable deprotecting reagent as shown in
Scheme 7. Reaction of 5a with diethylamine in dichloromethane
led to the formation of deprotected 7, which was then treated
with HCl in ether to give the stable hydrochloride salt 86a in
excellent yield.
also studied. This reaction produced the trans-isomer, (2S,4R)-
N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluoride (2a0), in 36%
NMR yield. Fluoride 2a0 was identified by comparison with an
authentic sample. The low yield of 2a0 may be explained by
possible side reaction of 1a0 by the cis-conformation of
2-COOH and 4-OH groups although we did not examine its
byproducts.
The 4-fluoropyrrolidine-2-carbonyl fluorides are useful syn-
thons. Reactions of carbonyl fluorides 2aꢀc with ammonia, N,O-
dimethylhydroxylamine, and methanol led to the formation of
the corresponding carboxamides 5a,c,d, Weinreb amide22 5b,
and carboxylates 5e,f in excellent isolated yields, respectively, as
shown in Scheme 5 and Table 2. 19F NMR showed that products
5a,b,e,f were not contaminated with any diastereomers, while 5c
and d were contaminated with a small amount (ca. 4%) of the
diastereomers. Thus, our new methodology using synthons 2
greatly decreases the necessary steps for the preparation of the
useful 4-fluoropyrrolidine intermediates. For example, carboxa-
mide 5a and Weinreb amide 5b were prepared in only three steps
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Scheme 6. Conversion of Carbamides to Carbonitriles
(2a) as white powder. An analytically pure sample of 2a was obtained
by thin-layer chromatography on silica gel using a 2:1 mixture of Et2O
and hexane as an eluent.
2a: mp 127ꢀ128 °C; 19F NMR (CDCl3) δ (a 56:44 mixture of two
rotamers) 28.53 (s, 0.56F) and 28.34 (s, 0.44F), ꢀ172.92 (m, 1F); 1H
NMR (CDCl3) δ (a mixture of two rotamers) 2.2ꢀ2.8 (m, 2H),
3.5ꢀ4.0 (m, 2H), 4.1ꢀ4.8 (m, 4H), 5.1ꢀ5.4 (m, 1H), 7.2ꢀ7.9 (m,
8H); 13C NMR (CDCl3) (a mixture of two rotamers) δ 30.8, 31.2, 35.8
(d, J = 21.7 Hz), 36.8 (d, J = 21.0 Hz), 47.2, 53.1 (d, J = 24.6 Hz), 53.5 (d,
J = 25.3 Hz), 55.8 (d, J = 66.5 Hz), 56.3 (d, J = 66.5 Hz), 68.0, 68.1, 90.9
(d, J = 177.0 Hz), 92.0 (d, J = 177.7 Hz), 120.2, 125.0, 125.1, 125.2,
127.3, 128.0, 141.3, 141.4, 141.5, 141.7, 143.8, 143,9, 153.9, 154.5, 161.3
(d, J = 371.3 Hz); IR (Nujol, KBr) 1855 (COF), 1839 (COF), 1694
(NCOO) cmꢀ1; HRMS/ESI-APCI method (solvent; methanol) (M þ
Na)þ calcd for C20H17F2NNaO3 380.1070, found 380.1069. Anal.
Calcd for C20H17F2NO3: C, 67.22; H, 4.80; N, 3.92. Found: C, 67.23;
H, 5.04; N, 3.89.
Scheme 7. Deprotection of Carboxamide 5a
(2S,4S)-N-Cbz-4-fluoropyrrolidine-2-carbonyl Fluoride (2b).
Oil; isolated yield 75%; 19F-NMR (CDCl3) δ (a 47:53 mixture of two
rotamers) 28.50 (s, 0.47F), 28.36 (s, 0.53F), ꢀ173.0 (m, 1F); 1H NMR
(CDCl3) δ 2.25ꢀ2.7 (m, 2H), 3.6ꢀ4.05 (m, 2H), 4.65ꢀ4.8 (m, 1H),
5.1ꢀ5.4 (m, 3H), 7.3ꢀ7.4 (m, 5H); 13C NMR (CDCl3) δ (mixture of
two rotamers) 35.9 (d, J = 23.8 Hz), 36.8 (d, J = 23.8 Hz), 53.1 (d, J =
26.1 Hz), 53.3 (d, J = 26.0 Hz), 55.9 (d, J = 67.2 Hz), 56.3 (d, J = 67.2
Hz), 67.9, 68.0, 90.8 (d, J = 177.5 Hz), 91.8 (d, J = 177.7 Hz), 128.2,
128.5, 128.7, 135.9, 136.0, 153.9 154.5, 161.4 (d, J = 371.0 Hz),
161.6 (d, J = 371.3 Hz); IR (neat, KBr) 1855 (COF), 1712
(NCOO) cmꢀ1; HRMS/ESI-APCI method (solvent; methanol)
(M ꢀ F þ OCH3 þ Na)þ calcd for C14H16FNNaO4 304.0956, found
304.0959. Anal. Calcd for C13H13F2NO3: C, 57.99; H, 4.87; N, 5.20.
Found: C, 57.78; H, 5.27; N, 5.51. An analytically pure sample of 2b was
obtained by thin-layer chromatography on silica gel using a 2:1 mixture
of Et2O and hexane as an eluent.
(2S,4S)-N-Chloroacetyl-4-fluoropyrrolidine-2-carbonyl
fluoride (2c): oil; isolated yield 76%; 19F NMR (CDCl3) δ 28.58 (s,
1F, COF), ꢀ173.37 (m, 1F, CHF); 1H NMR (CDCl3) δ 2.2ꢀ2.8 (m,
2H), 3.7ꢀ4.2 (m, 4H), 4.7ꢀ5.0 (m 1H), 5.1ꢀ5.5 (m, 1H); 13C NMR
(CDCl3) δ 34.9 (d, J = 21.6 Hz), 41.6, 53.3 (d, J = 23.8 Hz), 56.1 (d,
J = 66.5 Hz), 58.2, 91.3 (d, J = 178.4 Hz), 160.5 (d, J = 369.9 Hz), 165.9;
HRMS/ESI-APCI method (solvent; methanol) (M ꢀ F þ OCH3 þ
Na)þ calcd for C8H11ClFNNaO3 246.0304, found 246.0308.
Preparation of (2S,4S)-N-Boc-4-fluoropyrrolidine-2-car-
bonyl Fluoride (2d) as an Authentic Sample. (2S,4S)-N-Boc-
4-fluoroproline (1.17 g, 5 mmol) and sodium fluoride (0.63 g, 15 mmol)
were placed in a fluoropolymer vessel, and 10 mL of dry dichloro-
methane was added into the vessel. The mixture was cooled with an ice
bath. A solution of 2,2-difluoro-1,3-dimethylimidazolidine (817 mg, 6
mmol) in 2 mL of dry dichloromethane was added slowly. After the
addition, the mixture was stirred for 5 min. The ice bath was removed
and the mixture warmed to room temperature. The reaction mixture was
stirred for a total of 20 min. 19F NMR analysis of the reaction mixture
showed that (2S,4S)-N-Boc-4-fluoropyrrolidine-2-carbonyl fluoride
(2d) was produced in 85% yield. The mixture was diluted with 10 mL
of dichloromethane and washed with water. The organic layer was dried
over anhydrous magnesium sulfate and filtered. Removal of solvent
followed by washing with a small amount of water and then drying gave
846 mg (yield 72%) of 2d: oil; 19F NMR (CDCl3) (a 6:4 mixture of two
rotamers) δ 28.22 (s, 0.6F, COF), 28.14 (s, 0.4F, COF), ꢀ173.18 (m,
1F, CF); 1H NMR (CDCl3) δ (mixture of two rotamers) 1.40 (s, 0.55 ꢁ
9H, t-Bu), 1.43 (s, 0.45 ꢁ 9H, t-Bu), 2.2ꢀ2.6 (m, 2H), 3.45ꢀ3.95 (m,
2H), 4.5ꢀ4.7 (m, 1H), 5.22 (br d, J = 51.9 Hz, 1H, CHF); 13C NMR
(CDCl3) δ (mixture of two rotamers) 90.9 (d, J = 177.0 Hz, 1H, CF),
92.0 (d, J = 177.0 Hz, CF), 153.1 (s, CON), 153.8 (s, CON), 161.5 (d,
J = 372.1 Hz, COF), 161.7 (d, J = 372.8 Hz, COF); IR (neat, KBr) 1849
’ CONCLUSION
By employment of the stereospecific double fluorination of
4-hydroxypyrolines with Fluolead reagent, we have succeeded in
synthesizing the useful synthons, N-protected 4-fluoropyrroli-
dine-2-carbonyl fluorides 2, which can serve through very
straightforward methodology in the synthesis of optically active
4-fluoropyrrolidine derivatives having different functional groups
at the 2-postion, such as a carbamoyl, cyano, alkoxycarbonyl, and
N-methoxy-N-methylcarbamoyl group. Significantly, N-Fmoc-
cis-4-fluoropyrrolidine-2-carbonyl fluoride 2a is a particularly
useful synthon due to its high yield synthesis, convenient
purification as a crystalline solid, and its utility in providing
enantiomerically highly pure pharmaceutical intermediates or
final products.
’ EXPERIMENTAL SECTION
General Methods. All experiments were performed under anhy-
drous conditions in an atmosphere of nitrogen with oven-dried glass-
ware or fluoropolymer (PFA) vessels. Chemicals were purchased and
used without prior purification unless otherwise noted. Solvents were
dried by standard procedures. H, 19F, and 13C NMR spectra were
1
recorded at 300.53, 282.78, and 75.57 MHz, respectively. 19F chemical
shifts are reported in ppm with CFCl3 (δ = 0.00).
Double Fluorination of 4-Hydroxyproline Derivatives
1aꢀd with Fluolead Reagent. Typical Procedure. A solution of
9.03 g (36.1 mmol) of 4-tert-butyl-2,6-dimethylphenylsulfur trifluoride
(Fluolead) in 10 mL of dry dichloromethane was slowly added over
20 min into a stirred solution of 5.10 g (14.4 mmol) of (2S,4R)-N-Fmoc-
4-hydroxyproline (1a) in 20 mL of dry dichloromethane in a fluoropo-
lymer vessel cooled in an ice bath. After complete addition, the reaction
mixture was stirred for 0.5 h, and then the ice bath was removed. It took
about 1 h for the temperature of the reaction solution to get to room
temperature after starting the reaction at ice bath temperature. Stirring
was continued at room temperature for 60 h. Analysis of the reaction
mixture by 19F NMR using fluorobenzene added as a standard showed
that the yield of product was 90%. After the solvent was removed at
reduced pressure, diethyl ether (20 mL) and then pentane (20 mL) were
added to the resulting residue. Stirring the mixture well gave a solid,
which was then obtained by filtration followed by washing with pentane
(25 mL ꢁ 2). The solid was dissolved in dichloromethane and
precipitated out by adding pentane to the solution, giving 3.86 g
(78%) of (2S,4S)-N-Fmoc-4-fluoropyrrolidine-2-carbonyl fluoride
3117
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The Journal of Organic Chemistry
ARTICLE
(COF), 1694 (NCOO) cmꢀ1; HRMS/ESI-APCI method (solvent;
methanol) (M ꢀ F þ OCH3 þ Na)þ calcd for C11H18FNNaO4
270.1112, found 270.1109. Anal. Calcd for C10H15F2NO3: N, 5.95.
Found: N, 6.07.24
Preparation of (2S,4S)-N-Fmoc-4-fluoropyrrolidine-4-N,N-
bis(20-methoxyethyl)carbamide (4) as an Authentic Sample.
Bis(2-methoxyethyl)amine (133 mg, 1.0 mmol) was added into a stirred
solution of 178 mg (0.50 mmol) of 2a in 1 mL of dry dichloromethane.
The mixture was stirred at room temperature for 45 min. After some
amount of dichloromethane was added, the mixture was washed with
water, dried over anhydrous magnesium sulfate, and filtered. Solvent was
removed at reduced pressure, and the resulting residue was thin-layer
chromatographed on silica gel using ethyl acetate as an eluent to give 211
mg (90%) of 4: oil; 19F NMR (CDCl3) (a 4:6 mixture of rotamers) δ
ꢀ171.71 (m, 0.4F), ꢀ172.68 (m, 0.6F); 1H NMR (CDCl3) δ 2.2ꢀ2.7
(m, 2H), 3.1ꢀ4.1 (multiplets with singlet of methyl groups, 16H),
4.2ꢀ4.5 (m, 3H), 4.8ꢀ4.9 (m, 1H), 5.1ꢀ5.4 (m, 1H), 7.2ꢀ7.8 (m, 8H);
13C NMR (CDCl3) (mixture of rotamers) δ 36.8 (d, J = 21.7 Hz), 38.1
(d, J = 22.4 Hz), 46.6, 47.0, 47.2, 47.5, 48.5, 48.7, 53.2 (d, J = 26.0 Hz),
53.9 (d, J = 26 Hz), 56.2, 59.0, 59.1, 59.3, 67.7, 70.4, 70.5, 71.0, 90.6 (d, J
= 179.2 Hz), 91.4 (d, J = 181.3 Hz), 119.9, 120.0, 125.2, 125.3, 127.1,
127.2, 127.7, 127.8, 141.3, 141.4, 143.8, 144.2, 144.4, 154.4, 154.7, 171.2,
171.4; HRMS/ESI-APCI method (solvent; methanol) (M þ H)þ calcd
for C26H31FN2O5 471.2290, found 471.2289. Anal. Calcd for
C26H31FN2O5: N, 5.95. Found: N, 5.75.24
Preparation of (2S,4R)-N-Boc-4-fluoropyrrolidine-2-car-
bonyl Fluoride (2d0) as an Authentic Sample. Compound 2d0
was prepared in 90% isolated yield using (2S,4R)-N-Boc-4-fluoroproline
in the same way as for 2d. Compound 2d0: oil; 19F NMR (CDCl3) (a 4:6
mixture of rotamers) δ 28.66 (s, 0.4F, COF), 28.10 (s, 0.6F, COF),
ꢀ177.16 (m, 0.4F, CF), ꢀ177.83 (m, 0.6F, CF); 1H NMR (CDCl3) (a
mixture of rotamers) δ 1.42 (s, 0.6 ꢁ 9H, t-Bu), 1.44 (s, 0.4 ꢁ 9H, t-Bu),
2.0ꢀ2.8 (m, 2H), 3.45ꢀ4.0 (m, 2H), 4.51 (m. 1H), 5.22 (dm, 1H, J =
51.6 Hz); 13C NMR (CDCl3) (mixture of two rotamers) δ 90.7 (d, J =
179.9 Hz, CF), 91.6 (d, J = 179.9 Hz, CF), 153.1 (s, CON), 154.2 (s,
CON), 161.9 (d, J = 368.4 Hz, COF), 162.1 (d, J = 368.4 Hz, COF); IR
(neat, KBr) 1849 (COF), 1702 (NCOO), 1664 (NCOO) cmꢀ1
;
HRMS/ESI-APCI method (solvent; methanol) (M ꢀ F þ OCH3 þ
Na)þ calcd for C11H18FNNaO4 270.1112, found 270.1114. Anal. Calcd
for C10H15F2NO3: C, 51.06; H, 6.43; N, 5.95. Found: C, 50.79; H, 6.64;
N, 5.97.
Reaction of (2S,4R)-N-Fmoc-4-hydroxyproline (1a) with
Diethylaminosulfur Trifluoride (DAST). A solution of 591 mg
(3.67 mmol) of diethylaminosulfur trifluoride (DAST) in 2 mL of dry
dichloromethane was slowly added to a stirred solution of 518 mg (1.47
mmol) of 1a in 3 mL of dry dichloromethane in a fluoropolymer vessel
cooled in an ice bath. After complete addition, the reaction mixture was
stirred for 1 h in an ice bath, and then the ice bath was removed and the
reaction mixture was stirred for 60 h at room temperature. 19F NMR
analysis of the reaction mixture showed that 2a and 3 were formed in
40% and 45% yield, respectively. After some amount of dichloromethane
was added into the reaction mixture, the mixture was washed with water,
dried over anhydrous magnesium sulfate, and filtered. Removal of solvent
at reduced pressure gave a residue, which was then thin-layer chromato-
graphed onsilicagel using ethylacetate asaneluent togive2a and 3, which
were identified by comparison with each of authentic samples.
Reaction of (2S,4R)-N-Fmoc-4-hydroxyproline (1a) with
Bis(2-methoxyethyl)aminosulfur Trifluoride (Deoxo-Fluor).
The reaction was carried out in the same way as that of 1a with DAST as
shown above except that Deoxo-fluor was used in place of DAST. After
the reaction, 19F NMR analysis of the reaction mixture showed that 2a
and amide 4 were formed in 41% and 39% yield, respectively. Products
2a and 4 were isolated in the same way as with DAST and identified by
comparison with each of authentic samples.
Preparation of (2S,4R)-N-Fmoc-4-fluoropyrrolidine-2-car-
bonyl Fluoride (2a0) as an Authentic Sample. A solution of
Fluolead (10.5 mmol) in 5 mL of dry dichloromethane was added slowly
to a stirred solution of (2S,4R)-N-Fmoc-4-fluoroproline (7 mmol) in
15 mL of dry dichloromethane in a fluoropolymer vessel cooled in an ice
bath. After complete addition, the ice bath was removed and the reaction
mixture was stirred at room temperature for 0.5 h. 19F NMR analysis of
the reaction mixture showed that 2a0 was produced in 97% yield. All of
the volatiles were removed at reduced pressure, and dichloromethane
(2 mL) was added to the residue, followed by the addition of pentane
(30 mL). After stirring well, the supernatant liquid was removed and the
residue (solid) was washed with pentane (25 mL ꢁ 2). Product 2a0 (1.75
g, 70% yield) was obtained as white powder by dissolving the solid in
dichloromethane and precipitating with pentane. 2a0: mp 110ꢀ111 °C;
19F NMR (CDCl3) (a 6:4 mixture of two rotamers) δ 29.69 (s, 0.6F,
COF), 29.39 (s, 0.6F, COF), ꢀ177.05 (m, 0.6F, CF), ꢀ177.99 (m, 0.4F,
1
CF); H NMR (CDCl3) δ (mixture of rotamers) 2.0ꢀ2.9 (m, 2H),
3.4ꢀ4.8 (m, 6H), 5.1ꢀ5.45 (m, 1H), 7.2ꢀ8.0 (m, 8H); 13C NMR
(CDCl3) (mixture of two rotamers) δ 35.9 (d, J = 22.4 Hz), 37.0 (d, J =
22.4 Hz), 47.1, 53.1 (d, J = 22.4 Hz), 53.6 (d, J = 23.1 Hz), 55.9 (d, J =
66.5 Hz), 56.5 (d, J = 66.5 Hz), 57.9, 68.3, 90.4 (d, J = 177.9 Hz), 91.4 (d,
J = 180.6 Hz), 120.2, 124.8, 124.9, 127.3, 128.0, 141.4, 143.7, 154.2,
154.8, 161.5 (d, J = 367.8 Hz); IR (Nujol, KBr) 1855 (COF), 1840
(COF), 1695 (NCOO) cmꢀ1; HRMS/ESI-APCI method (solvent;
methanol) (M ꢀ F þ OCH3 þ Na)þ calcd for C21H20FNNaO4
392.1269, found 392.1272. Anal. Calcd for C20H17F2NO3: C, 67.22;
H, 4.80; N, 3.92. Found: C, 66.92; H, 4.98; N, 3.84.
Preparation of (2S,4S)-N-Fmoc-4-fluoropyrrolidine-4-N,N-
diethylcarbamide (3) as an Authentic Sample. Diethylamine
(73 mg, 1.0 mmol) was added into a stirred solution of 178 mg (0.50
mmol) of 2a in 1 mL of dry dichloromethane. The mixture was stirred at
room temperature for 45 min. After some additional amount of
dichloromethane was added, the mixture was washed with water, dried
over anhydrous magnesium sulfate, and filtered. Solvent was removed at
reduced pressure, and the resulting residue was thin-layer chromato-
graphed on silica gel using ethyl acetate as an eluent to give 174 mg
(85%) of 3: oil; 19F NMR (CDCl3) (a 36:64 mixture of rotamers)
Preparation of (2S,4S)-N-Fmoc-4-fluoropyrrolidine-2-car-
boxamide (5a). Compound 2a (355 mg, 1 mmol) was dissolved in
5 mL of dichloromethane. Into the solution was added an aqueous
28ꢀ30% ammonia solution (NH3, 2.2 mmol) dropwise at room
temperature. The reaction mixture was stirred at room temperature
for 0.5 h. The mixture was extracted with dichloromethane. The organic
layer was separated, washed with water, dried over anhydrous magne-
sium sulfate, and filtered. Removal of solvent at reduced pressure gave a
solid, which was then crystallized from a 1:3 mixture of dichloromethane
and pentane to give 335 mg (95%) of 5a as white crystals: mp
106ꢀ107 °C; 19F NMR (CDCl3) δ (a 52:48 mixture of two rotamers)
1
δ ꢀ171.90 (m, 0.36F), ꢀ172.52 (m, 0.64F); H NMR (CDCl3) δ
1.0ꢀ1.4 (m, 6H), 2.1ꢀ2.7 (m, 2H), 3.1ꢀ4.8 (m, 10H), 5.1ꢀ5.4 (m,
1H), 7.2ꢀ7.9 (m, 8H); 13C NMR (CDCl3) (mixture of rotamers) δ
13.0, 14.3, 36.7 (d, J = 21.7 Hz), 37.9 (d, J = 22.4 Hz), 40.4, 40.6, 41.2,
41.5, 47.2, 47.5, 53.1 (d, J = 26.0 Hz), 53.8 (d, J = 25.3 Hz), 56.2, 56.4,
67.3, 67.7, 90.5 (d, J = 179.9 Hz), 91.5 (d, J = 180.6 Hz), 120.0, 125.2,
125.4, 127.1, 127.2, 127.8, 141.3, 141.4, 143.8, 144.3, 144.4, 154.4,
154.7, 169.6, 169.8; HRMS/ESI-APCI method (solvent; methanol)
(M þ Na)þ calcd for C24H27FN2NaO3 433.1898, found 433.1899.
Anal. Calcd for C24H27FN2O3: C, 70.22; H, 6.63; N, 6.82. Found: C,
69.91; H, 6.74; N, 6.72.
1
δ ꢀ174.50 (m, 0.52F), ꢀ173.02 (m, 0.48F); H NMR (CDCl3) δ
2.0ꢀ2.8 (m, 2H), 3.35ꢀ3.9 (m, 2H), 4.1ꢀ4.7 (m, 4H), 5.16 (d, 1H, J =
52.3 Hz), 5.9ꢀ6.4 (m, 2H), 7.2ꢀ7.9 (m, 8H); 13C NMR (CDCl3) δ
(mixture of two rotamers) δ 35.6 (d, J = 21.0 Hz), 37.5 (d, J = 19.5 Hz),
47.3, 53.9 (d, J = 25.3 Hz), 54.3 (d, J = 23.8 Hz), 59.6, 67.7, 68.0, 91.6 (d,
3118
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The Journal of Organic Chemistry
ARTICLE
J = 175.5 Hz), 92.2 (d, J = 177.0 Hz), 120.2, 124.9, 125.0, 127.2, 127.3,
128.0, 141.5, 143.6, 143.7, 155.3, 155.8, 173.8, 174.3; HRMS/ESI-APCI
method (solvent; methanol) (M þ Na)þ calcd for C20H19FN2NaO3
(CD3CN) δ 2.2ꢀ2.6 (m, 2H), 3.6ꢀ4.25 (m, 4H), 4.45 (m, 1H),
5.1ꢀ5.4 (m, 1H), 5.8ꢀ6.7 (m, 2H); 13C NMR (CD3CN) (a major
rotamer) δ 35.6 (d, J = 21.0 Hz), 42.9, 53.5 (d, J = 23.8 Hz), 59.7, 93.2 (d,
J = 175.6 Hz), 166.1, 173.1. 19F NMR showed that 5d was contaminated
with a small amount (ca. 4%) of its diastereomer, as a small peak
at ꢀ178.6 ppm (m) which may correspond to the diastereomer was
observed in the 19F NMR of 5d.
377.1272, found 377.1277. Anal. Calcd for C20H19FN2O3 1/4H2O: C,
3
66.93; H, 5.48; N, 7.81. Found: C, 66.88; H, 5.41; N, 7.91.
Preparation of (2S,4S)-N-Fmoc-4-fluoropyrrolidine-2-N-
methoxy-N-methylcarboxamide (5b). Compound 2a (714 mg,
2.0 mmol) was dissolved in 5 mL of dichloromethane. The solution was
cooled in an ice bath. Into the solution was added a dichloromethane
solution of N,O-dimethylhydroxylamine (in situ prepared from 4.0
mmol of N,O-dimethylhydroxylamine hydrochloride and 4.0 mmol of
diisopropylethylamine in 5 mL of dichloromethane at ice bath
temperature). The reaction mixture was stirred at ice bath temperature
for 1 h. The mixture was washed with water, dried over anhydrous
magnesium sulfate, and filtered. Removal of solvent at reduced pressure
gave a solid, which was then chromatographed on silica gel using ethyl
acetate as an eluent to give 589 mg (74%) of 5b: mp 64ꢀ65 °C; 19F
NMR (CDCl3) δ ꢀ171.39 (m, 1F); 1H NMR (CDCl3) δ (a 6:4 mixture
of two rotamers) 2.22ꢀ2.6 (m, 2H), 3.13 (s, 0.4 ꢁ 3H, NCH3), 3.24 (s,
0.6 ꢁ 3H, NCH3), 3.48 (s, 0.4 ꢁ 3H, OCH3), 3.77 (s, 0.6 ꢁ 3H,
OCH3), 3.7ꢀ4.9 (m, 6H except a peak at 3.77), 5.18 (dm, J = 53.3 Hz,
Preparation of Methyl (2S,4S)-N-Fmoc-4-fluoropyrroli-
dine-2-carboxylate (5e). Compound 2a (1 mmol) was dissolved
in 5 mL of dichloromethane. Into the reaction, an excess of methanol
was added at room temperature. The reaction mixture was stirred at
room temperature for 1 h. After addition of some amount of dichlor-
omethane, the reaction mixture was washed with water, dried over
anhydrous magnesium sulfate and filtered. Removal of solvent at
reduced pressure gave a solid, which was then crystallized from a 1:3
mixture of dichloromethane and pentane to give 345 mg (94%) of 5e as
white crystals: mp 120ꢀ121 °C; 19F NMR δ (CDCl3) ꢀ172.70 (m, 1F);
1H NMR (CDCl3) (a 54:46 mixture of two rotamers) δ 2.2ꢀ2.7 (m,
2H), 3.6ꢀ4.0 (m, 5H; including two CH3 singlets at 3.67 as a minor
rotamer and 3.76 as a major rotamer), 4.15ꢀ4.7 (m, 4H), 5.20 (dm, J =
52.3 Hz, 0.46H), 5.25 (dm, J = 52.6 Hz, 0.54H), 7.2ꢀ7.9 (m, 8H); 13C
NMR (CDCl3) (a mixture of two rotamers) δ 36.7 (d, J = 21.7 Hz), 37.8
(d, J = 21.7 Hz), 47.3, 52.7, 53.3 (d, J = 24.6 Hz), 53.6 (d, J = 24.6 Hz),
57.5, 57.8, 67.6, 67.8, 91.2 (d, J = 177.7 Hz), 92.2 (d, J = 177.7 Hz),
120.1, 127.2, 127.9, 141.4, 143.8, 144.1, 154.4, 155.6, 171.8; HRMS/
ESI-APCI method (solvent; methanol) (M þ Na)þ calcd for
C21H20FNNaO4 392.1269, found 392.1272. Anal. Calcd for
C21H20FNO4: N, 3.79. Found: N, 3.78.24
0.4H, CHF), 5.27 (dm, J = 53.3 Hz, 0.6H, CHF), 7.25ꢀ7.8 (m, 8H); 13
C
NMR (CDCl3) δ (mixture of two rotamers) 32.5, 36.2 (d, J = 21.7 Hz),
37.3 (d, J = 22.4 Hz), 47.3, 47.5, 53.3 (d, J = 25.3 Hz), 53.9 (d, J = 25.3
Hz), 56.6, 56.8, 61.0, 61.2, 66.8, 67.7, 90.8 (d, J = 179.2 Hz), 91.8 (d, J =
179.9 Hz), 119.9, 120.1, 125.0, 125.1, 125.4, 127.1, 127.2, 127.6, 127.7,
127.8, 141.3, 141.4, 143.9, 144.2, 144.2, 154.4, 154.7, 171.1, 171.3.
HRMS/ESI-APCI method (solvent; methanol) (M þ H)þ calcd for
C22H24FN2O4 399.1715, found 399.1714. Anal. Calcd for
C22H23FN2O4: C, 66.32; H, 5.82; N, 7.03. Found: C, 66.18; H, 5.86;
N, 6.96.
Preparation of Methyl (2S,4S)-N-Cbz-4-fluoropyrrolidine-
2-carboxylate (5f). Into a solution of 269 mg (1.0 mmol) of 2b in
5 mL of dichloromethane was added 320 mg (10 mmol) of methanol at
room temperature, followed by the addition of 152 mg (1.5 mmol) of
triethylamine. The mixture was stirred at room temperature for 1 h. After
addition of some amount of dichloromethane, the reaction mixture
was washed with water, dried over anhydrous magnesium sulfate, and
filtered. Removal of solvent at reduced pressure gave 266 mg (95%) of
Preparation of (2S,4S)-N-Cbz-4-fluoropyrrolidine-2-car-
boxamide (5c). Compound 2b (807 mg, 2 mmol) was dissolved in
5 mL of dichloromethane. Into the solution was added an aqueous
28ꢀ30% ammonia solution (NH3, 6.6 mmol) dropwise at room
temperature. The mixture was stirred at room temperature for 0.5 h.
The reaction mixture was extracted with dichloromethane, and the
organic layer was separated, washed with water, dried over anhydrous
magnesium sulfate, and filtered. Removal of solvent at reduced pressure
gave a solid, which was then crystallized from a 1:3 mixture of
dichloromethane and pentane to give 751 mg (94%) of 5c as white
crystals: 19F NMR (CDCl3) δ (a 1:1 mixture of two rotamers) ꢀ172.75
(m, 0.5F), ꢀ174.32 (m, 0.5F); 1H NMR (CDCl3) δ 2.0ꢀ2.8 (m, 2H),
3.4ꢀ4.0 (m, 2H), 4.43 (m, 1H), 4.8ꢀ5.4 (m, 3H), 6.2ꢀ6.7 (m, 2H),
7.2ꢀ7.5 (m, 5H); 13C NMR (CDCl3) δ (mixture of two rotamers) 35.7
(d, J = 20.2 Hz), 37.5 (d, J = 21.8 Hz), 54.1(m), 59.7, 67.8, 91.7 (d, J =
176.3 Hz), 92.3 (d, J = 178.4 Hz), 128.1, 128.4, 128.7, 136.1, 155.3,
155.8, 174.1, 174.7. 19F NMR showed that 5c was contaminated with a
small amount (ca. 4%) of its diastereomer, as two small peaks at ꢀ176.8
(m) and ꢀ177.8 (m) with a 2:3 ratio that may correspond to two
rotamers of the diastereomer were observed in the 19F NMR of 5c.
Preparation of (2S,4S)-N-Chloroacetyl-4-fluoropyrroli-
dine-2-carboxamide (5d). An aqueous 28ꢀ30% ammonia solution
(NH3, 10 mmol) was added to a stirred solution of 1.06 g (5.0 mmol) of
2c in 10 mL of dichloromethane cooled in an ice bath. After 10 min, the
ice bath was removed, and stirring was continued for another 20 min at
room temperature. Water (10 mL) was added to the reaction mixture.
The reaction mixture was shaken well and then the dichloromethane
layer removed. The aqueous layer was mixed with a saturated brine
aqueous solution and extracted with ethyl acetate (25 mL ꢁ 3). Ethyl
acetate layers were combined, dried over anhydrous magnesium sulfate,
and filtered. Removal of solvent at reduced pressure gave 886 mg (85%)
of 5d as a white solid: 19F NMR (CD3CN) (a 1:3 mixture of two
rotamers) δ ꢀ173.20 (m, 0.25F), ꢀ173.85 (m, 0.75F); 1H NMR
1
5f: oil; 19F NMR (CDCl3) δ ꢀ172.8 (m, 1F); H NMR (CDCl3) δ
(a 53:47 mixture of two rotamers) 2.2ꢀ2.6 (m, 2H), 3.6ꢀ4.0 (m, 5H,
including two CH3 singlet peaks at 3.63 as a minor rotamer and 3.74 as a
major rotamer), 4.53 (d, J = 9.3 Hz, 0.47H), 4.60 (d, J = 9.6 Hz, 0.53H),
5.0ꢀ5.4 (m, 3H), 7.2ꢀ7.5 (m, 5H); 13C NMR (CDCl3) (mixture of two
rotamers) δ 36.5 (d, J = 21.7 Hz), 37.5 (d, J = 21.7 Hz), 52.3, 52.4, 53.2
(d, J = 31.1 Hz), 53.5 (d, J = 30.3 Hz), 57.5, 57.8, 67.1, 67.2, 91.3 (d, J =
177.0 Hz), 92.2 (d, J = 177.0 Hz), 127.9, 128.0, 128.1, 128.2, 128.5,
128.6, 136.6, 154.2, 154.6, 171.6, 171.9.
Preparation of (2S,4S)-N-Fmoc-4-fluoropyrrolidine-2-car-
bonitrile (6a). Into a solution of 354 mg (1.0 mmol) of 5a in 3 mL of
dry tetrahydrofuran (THF) cooled in an ice bath was slowly added
trifluoroacetic anhydride (315 mg, 1.5 mmol). The reaction mixture was
stirred under ice bath cooling for 2 h. After reaction, all the volatiles were
removed on vacuum to give a solid, which was then crystallized from an
ether/pentane mixture to give 250 mg (75%) of 6a: mp 106ꢀ107 °C;
19F NMR (CDCl3) δ ꢀ174.70 (m, 1F); 1H NMR (CDCl3) δ 2.15ꢀ2.75
(m, 2H), 3.4ꢀ4.0 (m, 2H), 4.15ꢀ4.85 (m, 4H), 5.30 (d, J = 51.6 Hz,
1H), 7.2ꢀ7.9 (m, 8H); 13C NMR (CDCl3) (mixture of two rotamers) δ
37.0 (d, J = 21.7 Hz), 38.0 (d, J = 21.7 Hz), 45.4, 45.8, 47.1, 52.9 (d, J =
23.8 Hz), 53.3 (d, J = 23.8 Hz), 68.2, 68.6, 90.9 (d, J = 179.9 Hz), 91.9 (d,
J = 179.9 Hz), 117.9, 118.1, 120.2, 125.0, 125.2, 127.3, 128.0, 141.5,
143.6, 143.7, 143.8, 153.5, 154.0; IR (neat, KBr) 2243 (CN), 1714
(NCOO) cmꢀ1; HRMS/ESI-APCI method (solvent; methanol) (M þ
Na)þ calcd for C20H17FN2NaO2 359.1166, found 359.1164. Anal.
Calcd for C20H17FN2O2: N, 8.33. Found: N, 8.32.24
Preparation of (2S,4S)-N-Cbz-4-fluoropyrrolidine-2-car-
bonitrile (6b). Dehydration of 5c (266 mg, 1 mol) was conducted
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The Journal of Organic Chemistry
ARTICLE
in the same manner as that of 5a with trifluoroacetic anhydride in THF,
as mentioned above. The solid obtained by removal of all the volatiles
was crystallized from an ether/pentane mixture to give 211 mg (85%) of
(m, 9H), 0.19 (m, 9H), 1.8ꢀ2.4 (m, 2H), 3.3ꢀ3.8 (m, 2H), 3.8ꢀ4.0 (m,
2H), 4.2ꢀ4.6 (m, 2H); 13C NMR (CDCl3) δ ꢀ0.3, ꢀ0.1, 37.9, 41.8,
55.3, 59.2, 70.3, 165.1, 171.8.
Step 3. Anhydrous HF gas with nitrogen gas was bubbled into a stirred
solution of 4.70 g (15.0 mmol) of the product of step 2 in 20 mL of dry
acetonitrile in a fluoropolymer vessel [HF was generated by heating 10 g
1
6b: 19F NMR (CDCl3) δ ꢀ174.93 (m, 1F); H NMR (CDCl3) δ
2.1ꢀ2.7 (m, 2H), 3.4ꢀ4.0 (m, 2H), 4.69 (t, J = 10.3 Hz, 1H), 5.05ꢀ5.4
(m, 3H), 7.2ꢀ7.5 (m, 5H); 13C NMR (CDCl3) (mixture of two
rotamers) (major rotamer) δ 36.9 (d, J = 21.7 Hz), 45.9, 52.9 (d, J =
23.8 Hz), 68.0, 92.2 (d, J = 178.5 Hz), 118.3, 128.3, 128.5, 128.7, 135.9,
154.1, (minor rotamer) δ 37.8 (d, J = 20.9 Hz), 45.4, 53.3 (d, J = 24.6
Hz), 68.1, 91.2 (d, J = 178.5 Hz), 118.4, 128.2, 128.5, 128.7, 135.9, 153.4.
Praparation of (2S,4S)-N-Chloroacetyl-4-fluoropyrroli-
dine-2-carbonitrile (6c). Into a solution of 209 mg (1.0 mmol) of
5d in 4 mL of dry THF was slowly added 315 mg (1.5 mmol) of
trifluoroacetic anhydride at room temperature. The reaction mixture was
stirred for 0.5 h at room temperature and evaporated to dryness under
vacuum. The resulting solid was crystallized from a dichloromethane/
pentane mixture, giving 164 mg (86% yield) of 6c as a white solid: mp
139ꢀ140 °C (lit.4 mp 140ꢀ141 dec); 19F NMR (CDCl3) δ ꢀ174.63
(m, 1F); 1H NMR (CDCl3) (mixture of rotamers) δ 2.2ꢀ2.9 (m, 2H),
3.65ꢀ4.35 (m, 4H), 4.9ꢀ5.1 (m, 1H), 5.25ꢀ5.6 (m, 1H); 13C NMR
(CDCl3) (major rotamer) δ 36.5 (d, J = 21.7 Hz), 41.3, 45.5, 53.2 (d, J =
24.6 Hz), 92.0 (d, J = 182.0 Hz), 117.0, 165.3.
(100 mmol) of NaF HF at 215 °C in a fluoropolymer vessel and carried
3
with nitrogen flow into the solution]. After that, the reaction mixture was
stirred at room temperature for 15 h and then evaporated to dryness in
vacuum. The resulting solid was washed with 100 mL of dry ether and
dried in vacuum to give 2.67 g (92%) of 1c as a off-white solid: mp
1
123ꢀ124 °C dec; H NMR (D2O) δ 1.9ꢀ2.4 (m, 2H), 3.4ꢀ3.7 (m,
2H), 3.9ꢀ4.2 (m, 2H), 4.3ꢀ4.5 (m, 2H); 13C NMR (CDCl3) (mixture
of two rotamers) major rotamer δ 36.7, 41.9, 54.9, 58.4, 69.8, 168.3,
175.3; IR (Nujol, KBr) 3310 (OH), 1713 (COOH), 1644
(CON) cmꢀ1; HRMS/ESI-APCI method (solvent; methanol) (M þ
H)þ calcd for C7H11ClNO4 208.0371, found 208.0369; (M þ Na)þ
calcd for C7H10ClNNaO4 230.0191, found 230.0189. Anal. Calcd for
C7H10ClNO4: C, 40.50; H, 4.85; N, 6.75. Found: C, 40.51; H, 4.94;
N, 6.59.
’ ASSOCIATED CONTENT
Preparation of (2S,4S)-4-Fluoropyrrolidine-2-carboxa-
mide hydrochloride (8). Compound 5a (354 mg, 1 mmol) was
dissolved in 12 mL of a 1:1 mixture of diethylamine and dichloro-
methane at room temperature. After the mixture was stirred for 1.5 h, all
the volatiles were removed under reduced pressure. To the resulting
residue was added 10 mL of ethyl acetate and 5 mL of water, and the
mixture was stirred well and left standing. The aqueous layer was
separated, washed with 10 mL of ethyl acetate, and evaporated to
dryness by a vacuum pump. The residue was dissolved in 2 mL of
2-propanol and mixed with ether. The resulting precipitates were
collected, washed with ethyl acetate, and dried in vacuum to give 119
mg (90%) of (2S,4S)-4-fluoropyrrolidine-2-carboxamide (7) as crystals:
19F NMR (D2O) δ ꢀ172.40 (m, 1F); 1H NMR (D2O) δ 2.0ꢀ2.5 (m,
2H), 2.8ꢀ3.35 (m, 2H), 3.80 (dd, J = 14.1, 4.1 Hz, 1H), 5.16 (dt, J =
53.2, 4.1 Hz, 1H); 13C NMR (D2O) δ 37.5 (d, J = 21.7 Hz), 52.7 (d, J =
23.1 Hz), 58.5, 94.6 (d, J = 171.2 Hz), 177.7.
Compound 7 (119 mg, 0.90 mmol) was dissolved in 5 mL of
2-propanol, and 1.5 mL (HCl 1.5 mmol) of 1.0 M HCl in ether was
added into the solution. After the mixture was stirred for 10 min, all of
the volatiles were removed under reduced pressure. The resulting solid
was dried in vacuum at 50 °C for 2 h, giving 148 mg (98%) of 8 as solid
powder. The product was identified by comparison with an authentic
sample (OmegaChem).
Preparation of (2S,4R)-N-(Chloroacetyl)-4-hydroxypyrro-
lidine-2-carboxylic Acid (1c). Step 1. A flask with a condenser was
charged with 20.0 g (152 mmol) of (2S,4R)-4-hydroxyproline and
130 mL (517 mmol) of N,O-bis(trimethylsilyl)acetamide, and the
mixture was heated at 90ꢀ100 °C under nitrogen atmosphere for 6 h,
during which time the initial slurry became a clear solution. A byproduct,
O-(trimethylsily)acetamide, was completely removed from the reaction
mixture by distillation under 4 mmHg at a maximum temperature of
150 °C (oil bath). The resulting residue was 45.6 g (86%) of trimethyl-
silyl (2S,4R)-N-trimethylsilyl-4-(trimethylsilyloxy)pyrrolidine-2-carbo-
xylate25 as a clear yellow oil.
Step 2. Into a stirred solution of 5.22 g (15.0 mmol) of the product of
step 1 in 15 mL of dry dichloromethane was added dropwise a solution
of 1.45 g (15.0 mmol) of chloroacetyl fluoride26 in 5 mL of dry
dichloromethane at room temperature. Exothermic reaction occurred
with liberation of Me3SiF. The reaction mixture was stirred at room
temperature for 2 h. Complete removal of solvent in vacuum gave 5.02 g
(95%) of trimethylsilyl (2S,4R)-N-(chloroacetyl)-4-(trimethylsilyloxy)-
pyrrolidine-2-carboxylate as off-white solid: 1H NMR (CDCl3) δ 0.02
Supporting Information. 19F, 1H, and 13C NMR spectra
S
b
of new compounds 1c, 2aꢀd, 2a0,d0, 3, 4, 5a,b, and 6a. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: teruoumemoto@comcast.net.
Notes
†Synthesis of 4-fluoropyrrolidine-2-carbonyl fluorides with Fluo-
lead has been published as our patent, WO/2010/081014 A1.
’ ACKNOWLEDGMENT
We thank UBE Industries, Ltd., Japan, for research funding for
this work. We thank Lloyd Garrick for technical contributions.
We thank Dr. Hideya Yoshitake and Dr. Shigeyoshi Nishino of
UBE Industries, Ltd., for support of this project.
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