A concise synthesis of (S)-2-(fluorodiphenylmethyl)pyrrolidine: A novel organocatalyst for the stereoselective epoxidation of α,β-unsaturated aldehydes

Article abstract of DOI:10.1055/s-0029-1218636

A concise synthesis of (S)-2-(fluorodiphenylmethyl)pyrrolidine from cheap, commercially available starting materials is described. Pertinent features of this synthetic route include ease of synthesis, facile purification steps, and an operationally simple deoxy?fluorination step to install the C-F bond. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0029-1218636

1394
PRACTICAL SYNTHETIC PROCEDURES
A Concise Synthesis of (S)-2-(Fluorodiphenylmethyl)pyrrolidine:
A Novel Organocatalyst for the Stereoselective Epoxidation of
a,b-Unsaturated Aldehydes
Synthesis of
(
S
)-2
h
-(Fluorodiph
r
enylme
i
thyl)py
srrolidine tof Sparr, Eva-Maria Tanzer, Julia Bachmann, Ryan Gilmour*
Laboratory for Organic Chemistry, Department of Chemistry and Applied Biosciences,
Swiss Federal Institute of Technology (ETH) Zurich, Wolfgang-Pauli-Str. 10, 8093 Zurich,
Switzerland
Fax +41(44)6331235; E-mail: ryan.gilmour@org.chem.ethz.ch
Received 16 October 2009; revised 23 November 2009
PSP
No182
Abstract: A concise synthesis of (S)-2-(fluorodiphenylmethyl)pyrrolidine from cheap, commercially available starting materials is de-
scribed. Pertinent features of this synthetic route include ease of synthesis, facile purification steps, and an operationally simple deoxy-
fluorination step to install the C–F bond.
Key words: diethylaminosulfur trifluoride, fluorination, organocatalyst, proline, synthesis
BnBr, i-Pr2NEt
toluene
SOCl2
MeOH
O
O
O
+
N
H
N
N
H2
97%
2 steps
reflux
Bn
OH
OMe
OMe
Cl–
3
L-proline
2
PhBr, Mg
THF, 93%
DAST
H2, HCl (aq)
Pd/C, EtOH
Ph
Ph
Ph
Ph
CH2Cl2
Ph
OH
Ph
OH
N
H
N
H
N
96%
54%
Bn
F
1
5
4
Scheme 1 A short synthesis of (S)-2-(Fluorodiphenylmethyl)pyrrolidine (1)
clude its limited commercial availability, high cost and
difficulties associated with its preparation.5 To date, the
Introduction
As part of our research programme investigating the con- only reported synthesis of (S)-2-(fluorodiphenylmeth-
formational effects of organofluorine compounds,1,2 we yl)pyrrolidine (1) is that of O’Hagan et al. (Scheme 3).6
recently reported on the fluorine-iminium ion gauche ef- This elegant strategy relies on the decarboxylative hydro-
fect; a conformational change caused by the charge-dipole fluorination of oxazolidinone 6 to furnish the title com-
effect that is induced upon condensation of aldehydes and pound in a single step.
secondary b-fluoroamines.1 Furthermore, we demonstrat-
ed that this effect could be exploited in the design of a
highly selective catalyst3 for the epoxidation of a,b-unsat-
urated aldehydes.4 Consequently, the proline derivative
(S)-2-(fluorodiphenylmethyl)pyrrolidine (1) was found to
be a highly competent epoxidation catalyst furnishing the
desired products with excellent stereoselectivities and
yields (Scheme 2).
δ–
Ph
S
Ph
Ph
F
O
N
CHO
Ph
H
+
N
F
1
H
O
H2O2
Ph
Nu
92% yield
96% ee
Ph
Whilst the synthetic utility of compound 1 has been dem-
onstrated, we envisaged that a number of issues may limit
its use by the synthetic community. Pertinent examples in-
Scheme 2 The stereoselective epoxidation of trans-cinnamalde-
hyde mediated by (S)-2-(fluorodiphenylmethyl)pyrrolidine (1)
Whilst this synthetic route is concise, there are some
drawbacks when operating on large scale such as the use
of hazardous reagents (HF·pyridine), the modest yield of
the fluorination step, and the risk of elimination subse-
SYNTHESIS 2010, No. 8, pp 1394–1397
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218636; Art ID: T20109SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
0

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of (S)-2-(Fluorodiphenylmethyl)pyrrolidine
1395
O’Hagan et al. (2000)
[(R)-7] was detected, further underscoring the synthetic
utility of this approach (Figure 1).9
O
Ph
Ph
OH
In conclusion, we report a high-yielding, five-step synthe-
sis of (S)-2-(fluorodiphenylmethyl)pyrrolidine (1) from
commercial L-proline. The need for column chromatogra-
phy has been minimised, thus rendering this approach
amenable to scale-up.
N
H
N
H
OH
triphosgene
Et3N
L-proline
5
80–90%
H
Ph
Ph
HF⋅pyridine
Ph
Ph
N
H
N
31%
F
O
All reactions were performed under an atmosphere of argon unless
stated otherwise. All chemicals were reagent grade and used as sup-
plied. Solvents for extractions and chromatography were technical
grade and distilled prior to use. Analytical TLC was performed on
precoated Merck silica gel 60 F254 plates (0.25 mm) and visualised
by UV 254 nm and ninhydrin stain. TLC plates were deactivated by
dipping the plates in silica gel pretreated with 1.0% NH4OH (25%
aq solution) prior to use. Flash column chromatography was carried
out on Fluka silica gel 60 (230–400 mesh). Concentration in vacuo
was performed at ~10 mbar and 40 °C, and drying was accom-
O
1
6
Scheme 3 The synthesis of (S)-2-(fluorodiphenylmethyl)pyrroli-
dine (1) reported by O’Hagan and co-workers6
quent to C–F bond formation.6 Herein we report an alter-
native strategy for the synthesis of (S)-2-
(fluorodiphenylmethyl)pyrrolidine (1) featuring facile pu-
rification steps, high yields, and an operationally simple
deoxyfluorination process (Scheme 1). Treatment of com-
mercially available L-proline with thionyl chloride in
methanol under reflux conditions furnished the hydro-
chloride salt 2 as a colourless solid. This material was im-
mediately subjected to benzylation conditions to furnish
the fully protected proline scaffold 3 as a colourless oil
following a modification of the procedure reported by
Heimgartner.7 A double addition of phenylmagnesium
bromide to methyl ester 3 proceeded smoothly to generate
the carbinol 4 in excellent yield.8 Hydrogenolytic cleav-
age of the benzyl group catalysed by Pd/C gave diphenyl
prolinol 5 as a beige solid in 96% yield. Finally, incorpo-
1
plished at ~10–2 mbar and r.t. H NMR, 19F NMR, and 13C NMR
spectra were recorded on a Bruker AV 400 MHz spectrometer.
Chemical shifts (d) are reported in ppm relative to residual solvent
peaks. Melting points were measured on a Büchi B540 melting
point apparatus and are uncorrected. IR spectra were measured on a
Perkin-Elmer Spectrum 100 FTIR spectrometer and reported in
cm–1. Optical rotations were obtained by using a JASCO P-2000 po-
larimeter. High-resolution mass spectra were measured by the MS
service at the Laboratory for Organic Chemistry, ETH Zurich.
Methyl (S)-1-Benzylpyrrolidine-2-carboxylate (3)
A 250 mL round-bottomed flask was charged with L-proline (5.76
g, 50.0 mmol) and MeOH (100 mL). The solution was cooled to
0 °C and SOCl2 (4.38 mL, 60.0 mmol) was added dropwise over 15
ration of fluorine by a DAST-mediated deoxyfluorination min. The solution was warmed to r.t. and then heated at reflux for 2
h. The solvent was removed in vacuo and co-evaporated with tolu-
reaction produced the title compound 1 in 54% yield
ene (3 × 20 mL). The residue, L-proline methyl ester hydrochloride
(2), was dissolved in toluene (50 mL) and DIPEA (42.7 mL, 247
mmol) was added at r.t. The resulting solution was cooled to 0 °C
and BnBr (6.54 mL, 55.0 mmol) was added over a period of 15 min.
The mixture was heated at reflux and the biphasic mixture was vig-
orously stirred for 24 h. The reaction was quenched at r.t. by the ad-
dition of sat. aq NaHCO3 (50 mL). The mixture was extracted with
EtOAc (2 × 50 mL) and the combined organic extracts were washed
with brine (50 mL). The combined organic layers were dried
(Na2SO4) and evaporated in vacuo to yield a brown oil (10.7 g,
97%). An analytical sample was obtained by distillation (bp 125 °C/
10–1 mbar; Lit.7a bp 115–120 °C/8 × 10–2 mbar) as a colourless oil;
(Scheme 1; DAST = F3SNEt2). To ensure that the optical
purity had not been compromised during the synthetic se-
quence, compound 1 was acylated and subsequently anal-
ysed by HPLC. Gratifyingly, no trace of the R-enantiomer
20
Rf = 0.50 (MeOH–CH2Cl2, 1:70); [a]D –69.7 (c 1.05, CHCl3)
{Lit.7a [a]D –79.2 (c 1.20, CHCl3)}.
IR (neat): 3630w, 3062w, 3028w, 2951m, 2878w, 2800m, 2182w,
1747s, 1732s, 1604w, 1495m, 1435m, 1454m, 1376m, 1276m,
1195s, 1168s, 1133s, 1087m, 1075m, 1037m, 1029m, 1005m,
932m, 912m, 889m, 845w, 822w, 741s, 698s cm–1.
1H NMR (400 MHz, CDCl3): d = 7.16–7.35 (5 H, m, C6H5), 3.85 (1
H, d, 2J = 12.8 Hz, PhCHH), 3.60 (3 H, s, CH3), 3.54 (1 H, d, 2J =
12.8 Hz, PhCHH), 3.22 (1 H, dd, 3J = 6.3 Hz, 3J = 8.9 Hz, CHN),
2.95–3.05 (1 H, m, NCHHCH2), 2.30–2.39 (1 H, m, NCHHCH2),
2.00–2.18 (1 H, m, NCHCHH), 1.80–1.85 (2 H, m, NCHCHH and
NCH2CHH), 1.65–1.78 (1 H, m, NCH2CHH).
13C NMR (100 MHz, CDCl3): d = 174.5 (CO2Me), 138.3 (C6H5),
129.2 (C6H5), 128.2 (C6H5), 127.1 (C6H5), 65.3 (NCH), 58.7
(CH2Ph), 53.2 (NCH2CH2), 51.6 (CH3), 29.4 (NCHCH2), 23.0
(NCH2CH2).
HRMS (ESI): m/z [M + H]+ calcd for C13H18NO2: 220.1332; found:
220.1326.
Figure 1 HPLC trace of (S)-7 and its enantiomer (R)-7 prepared by
the procedure described above9
Synthesis 2010, No. 8, 1394–1397 © Thieme Stuttgart · New York

1396
C. Sparr et al.
PRACTICAL SYNTHETIC PROCEDURES
(S)-(1-Benzylpyrrolidin-2-yl)diphenylmethanol (4)
13C NMR (100 MHz, CDCl3): d = 148.1 (C6H5), 145.4 (C6H5),
128.3 (C6H5), 128.0 (C6H5), 126.5 (C6H5), 126.4 (C6H5), 125.9
(C6H5), 125.6 (C6H5), 77.1 (CPh2), 64.5 (CHN), 46.8 (CH2N), 26.3
(NCHCH2), 25.5 (NCH2CH2).
HRMS (ESI): m/z [M + H]+ calcd for C17H20NO: 254.1539; found:
254.1537.
A 250 mL round-bottomed flask was charged with Mg turnings
(610 mg, 25.0 mmol), THF (10 mL), and I2 (2.00 mg). PhBr (842
mL, 8.00 mmol) was added by a syringe and the flask was warmed
with a heat gun until the reaction started. The remaining PhBr (1.79
mL, 17.0 mmol) was added over a period of 30 min and the reaction
mixture was heated at reflux for a further 30 min. The mixture was
cooled to 5–10 °C and a solution of compound 3 (2.19 g, 10.0
mmol) in THF (4.0 mL) was added dropwise over 10 min. The mix-
ture was stirred at r.t. for 16 h, cooled to 0 °C, and quenched by the
addition of concd HCl (20 mL). The mixture was stirred for 2 h,
concentrated in vacuo, and then Et2O (40 mL) was added. Vigorous
stirring for 2 h resulted in the formation of a white precipitate,
which was isolated by filtration and washed with Et2O (20 mL). The
solid was then dissolved in a mixture of EtOAc (120 mL) and aq
NaOH (1.00 mol/L, 80 mL, pH 10–11). The phases were separated
and the aqueous layer was then extracted with EtOAc (2 × 20 mL).
The combined organic layers were washed with brine (20 mL),
dried (Na2SO4), and concentrated in vacuo to give a colourless solid
(3.19 g, 93%). An analytical sample was recrystallised from EtOH;
(S)-2-(Fluorodiphenylmethyl)pyrrolidine (1)
A 50 mL round-bottomed flask was charged with compound 5 (253
mg, 1.00 mmol) and CH2Cl2 (11 mL). The solution was cooled to
0 °C and DAST (245 mL, 2.00 mmol) was added over a period of 2
min. The reaction was gradually warmed to r.t. over a period of 6.5
h and quenched with sat. aq NaHCO3 (18 mL). The layers were sep-
arated and the aqueous phase was back-extracted with CH2Cl2
(3 × 20 mL). The combined organic phases were dried (MgSO4)
and concentrated in vacuo. The residue was purified by flash col-
umn chromatography [gradient elution CH2Cl2–MeOH–NH4OH
(aq 25%), 800:4:0.25 to 400:4:0.25] to afford 1 as a yellow oil (141
mg, 54%);6,12 Rf = 0.75 (MeOH–CH2Cl2 1:5, deactivated SiO2);
[a]D20 –24.9 (1.00 CHCl3) {Lit.13 [a]D –25.0 to –29.0 (c 1, CHCl3)}.
mp 118.8–119.6 °C (Lit.10 mp 120–122 °C); Rf = 0.35 (MeOH–
IR (neat): 3361w, 3060w, 3028w, 2964m, 2871m, 1948w, 1810w,
1600w, 1493m, 1448m, 1412w, 1318w, 1284w, 1260w, 1233m
1202m, 1158w, 1111m, 1064m, 1033m, 987m, 895m, 803w, 747s,
695s, 656m, 637s cm–1.
20
CH2Cl2, 1:20, deactivated SiO2); [a]D +86.6 (c 1.00, CHCl3)
{Lit.10[a]D29 +73.7 (c 1.0, CHCl3)}.
IR (neat): 3435m, 3052w, 2962w, 2894w, 2802m, 1599w, 1492m,
1447m, 1356m, 1306m, 1250m, 1179m, 1128m, 1100m, 1032m,
997m, 971m, 865m, 764m, 748m, 726m, 699s, 673m and 639s
cm–1.
1H NMR (400 MHz, CDCl3): d = 7.40–7.50 (2 H, m, C6H5), 7.30–
7.38 (2 H, m, C6H5), 7.10–7.30 (6 H, m, C6H5), 4.10 (1 H, dt, 3JH,F
=
27.8 Hz, 3J = 6.9 Hz, NCH), 2.94–3.5 (1 H, m, NCHH), 2.74–2.85
(1 H, m, NCHH), 1.50–1.80 (4 H, m, NCHCH2 and NCH2CH2).
1H NMR (400 MHz, CDCl3): d = 7.65 (2 H, dd, 3J = 8.2 Hz, 4J = 1.0
Hz, C6H5), 7.51 (2 H, dd, 3J = 8.30 Hz,4J = 1.1 Hz, C6H5), 6.85–7.30
(11 H, m, C6H5), 4.85 (1 H, br s, OH), 3.90 (1 H, dd, 3J = 9.40 Hz,
3J = 4.68 Hz, CHN), 3.16 (1 H, d, 3J = 12.6 Hz, PhCHH), 2.95 (1 H,
2
13C NMR (100 MHz, CDCl3): d = 143.1 (d, JC,F = 23.5 Hz,
C6H5ipso), 142.6 (d,2JC,F = 23.5 Hz, C6H5ipso), 128.4 (C6H5meta), 128.2
(d, JC,F = 1.1 Hz, C6H5meta), 127.5 (d, JC,F = 1.2 Hz, C6H5para), 127.3
(d, JC,F = 1.0 Hz, C6H5para), 125.6 (d, 3JC,F = 9.2 Hz, C6H5ortho), 124.9
(d, 3JC,F = 9.3 Hz, C6H5ortho), 100.1 (d, 1JC,F = 182.4 Hz, CF), 64.5
3
d, J = 12.6 Hz, PhCHH), 2.80–2.85 (1 H, m, NCHHCH2), 2.20–
2.45 (1 H, m, NCHHCH2), 1.80–1.95 (1 H, m, NCHCHH), 1.65–
1.75 (1 H, m, NCHCHH), 1.50–1.65 (2 H, m, NCH2CH2).
2
3
(d, JC,F = 22.2 Hz, NCH), 47.5 (NCH2), 26.5 (d, JC,F = 3.4 Hz,
NCHCH2), 26.0 (NCH2CH2).
13C NMR (100 MHz, CDCl3): d = 148.1 (C6H5), 146.7 (C6H5),
139.7 (C6H5), 128.6 (C6H5), 128.2 (C6H5), 128.2 (C6H5), 128.1
(C6H5), 128.1 (C6H5), 126.8 (C6H5), 126.4 (C6H5), 126.2 (C6H5),
125.6 (C6H5), 125.6 (C6H5), 77.9 (CPh2), 70.7 (CHN), 60.6
(PhCH2), 55.5 (NCH2CH2), 29.8 (NCHCH2), 24.1 (NCH2CH2).
19F NMR (376 MHz, CDCl3): d = –170.1 (d, 3JH,F = 27.8 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C17H19FN: 256.1496; found:
256.1489.
HRMS (ESI): m/z [M + H]+ calcd for C24H26NO: 344.2009; found:
344.1999.
Acknowledgment
We acknowledge generous financial support from the Alfred
Werner Foundation (Assistant Professorship to R.G.), the Roche
Research Foundation (Fellowship to C.S.), Novartis (doctoral fel-
lowship to C.S.), and the Laboratory for Organic Chemistry, ETH
Zurich.
(S)-Diphenyl(pyrrolidin-2-yl)methanol (5)
A 100 mL round-bottomed flask was charged with compound 4
(1.03 g, 3.00 mmol), EtOH (25 mL), concd HCl (365 mL, 12.0
mmol) and 10% Pd/C (450 mg). The flask was carefully evacuated
and flushed three times with H2. The mixture was stirred under a
reservoir of H2 (balloon) at r.t. for 18 h. The reaction mixture was
then filtered over a pad of Celite, washed with EtOH (100 mL), and
the solvent was removed in vacuo. To the residue was added EtOAc
(100 mL) and aq NaOH (1.0 mol/L, 100 mL, pH >11). The layers
were separated and the aqueous phase was back-extracted with
EtOAc (3 × 80 mL). The combined organic phases were washed
with brine (100 mL), dried (Na2SO4), and the solvent was removed
in vacuo to afford an off-white solid (729 mg, 96%); mp 78.3–
79.5 °C (Lit.11 mp 80–82 °C); Rf = 0.50 (MeOH–CH2Cl2, 1:5, deac-
References
(1) Sparr, C.; Schweizer, W. B.; Senn, H. M.; Gilmour, R.
Angew. Chem. Int. Ed. 2009, 48, 3065; Angew. Chem. 2009,
121, 3111.
(2) Bucher, C.; Sparr, C.; Schweizer, W. B.; Gilmour, R. Chem.
Eur. J. 2009, 15, 7637.
(3) List, B.; Lifchits, O. Synfacts 2009, 673.
(4) For seminal examples, see: (a) Marigo, M.; Franzén, J.;
Poulsen, T. B.; Zhuang, W.; Jørgensen, K. A. J. Am. Chem.
Soc. 2005, 127, 6964. (b) Lee, S.; MacMillan, D. W. C.
Tetrahedron 2006, 62, 11413. (c) Wang, X.; List, B. Angew.
Chem. Int. Ed. 2008, 47, 1119; Angew. Chem. 2008, 120,
1135.
(5) (S)-2-(Fluorodiphenylmethyl)pyrrolidine (1) (98% ee
HPLC, 97%) (500 mg = 348.50 CHF) and its R-enantiomer
(500 mg = 332.16 CHF) are available from Sigma-Aldrich.
20
20
tivated SiO2); [a]D –76.3 (c 1.00, CH2Cl2) {Lit.11 [a]D –87.5 (c
1.16, CH2Cl2)}.
IR (neat): 3326m, 3028w, 2967m, 2868w, 1598w, 1490m, 1446m,
1400m, 1270m, 1173m, 1070m, 1029w, 985m, 916w, 873m, 805w,
749s, 696s, 628s cm–1.
1H NMR (400 MHz, CDCl3): d = 7.60–7.65 (2 H, m, C6H5), 7.53–
7.59 (2 H, m, C6H5), 7.15–7.35 (6 H, m, C6H5), 4.30 (1 H, t, 3J = 7.6
Hz, CHN), 3.02–3.15 (1 H, m, NCHH), 2.90–3.02 (1 H, m, NCHH),
1.55–1.85 (4 H, m, NCHCH2 and NCH2CH2).
Synthesis 2010, No. 8, 1394–1397 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Synthesis of (S)-2-(Fluorodiphenylmethyl)pyrrolidine
1397
(6) O’Hagan, D.; Royer, F.; Tavasli, M. Tetrahedron:
Asymmetry 2000, 11, 2033.
(10) Shen, Y.; Feng, X.; Li, Y.; Zhang, G.; Jiang, Y. Eur. J. Org.
Chem. 2004, 129.
(7) (a) Bucher, C. B.; Linden, A.; Heimgartner, H. Helv. Chim.
Acta 1995, 78, 935. (b) Palomo, C.; Landa, A.; Mielgo, A.;
Oiarbide, M.; Puente Á, ; Vera, S. Angew. Chem. Int. Ed.
2007, 46, 8431; Angew. Chem. 2007, 119, 8583.
(8) Nakano, K.; Nozaki, K.; Hiyama, T. J. Am. Chem. Soc. 2003,
125, 5501.
(9) For this analysis (R)-7 was prepared from D-proline
following the procedure described in this manuscript.
HPLC: Derivatisation with Ac2O (1.2 equiv) and DMAP
(1.2 equiv) in CH2Cl2 at r.t. for 2 h. Removal of the solvent
and purification by flash column chromatography (SiO2,
EtOAc). HPLC on a Reprosil Chiral-OM, 5 mm column
(1.0 mL/min, i-PrOH–n-hexane, 1:6): (S)-7 tR = 6.56 min
and (R)-7 tR = 6.21 min.
(11) Enders, D.; Kipphard, H.; Gerdes, P.; Brena-Valle, L.;
Bhushan, V. Bull. Soc. Chem. Belg. 1988, 97, 691.
(12) Whilst the product is identical to known material,6 the
yellow colouration may be removed by the following simple
procedure to yield a clear, colourless oil: To the yellow oil
(100 mg) was added HCl in MeOH (500 mL, 1.25 mol/L).
The resulting suspension was filtered and the solid was
washed with Et2O. The solid was dissolved in a mixture of
EtOAc (5.0 mL) and NaOH (5.0 mL, 2.0 mol/L, pH >9). The
layers were separated, the organic phase was washed with
brine (5.0 mL), dried (Na2SO4) and concentrated in vacuo to
give a colourless oil (98.5 mg).
(13) Sigma Aldrich Specification Sheet (Product Number
552569, CAS Number 274674-23-6).
Synthesis 2010, No. 8, 1394–1397 © Thieme Stuttgart · New York