Convenient preparation of optically pure 3-aryloxy-pyrrolidines

Article abstract of DOI:10.1080/00397910701796691

Chiral 3-methanesulfonyl-1-Boc-pyrrolidine and piperidine were reacted with sodium phenolates, resulting in a mixture of displacement and elimination products. Following carbamate deprotection and pH adjustment, the 3-pyrroline and tetrahydropyridine by-products resulting from elimination were easily removed through aqueous partitioning and/or concentration. Although the pyrrolidines were formed with a high degree of optical purity, slight racemization was observed for the piperidine case because elevated temperatures were required to effect displacement. Copyright Taylor & Francis Group, LLC.

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Convenient Preparation of Optically Pure
3‐Aryloxy‐pyrrolidines
Christophe Bénard a , Rahim Mohammad a , Neerja Saraswat a , Rudong Shan
a , Samarendra N. Maiti a , Peter G. M. Wuts b , Michael Stier b , Teresa Lints
b , James Bradow b & Jacob B. Schwarz b
a Naeja Pharmaceutical Research and Development, Edmonton, Alberta,
Canada
b Pfizer Global Research and Development, Groton, Connecticut, USA
Published online: 27 Feb 2008.
To cite this article: Christophe Bénard , Rahim Mohammad , Neerja Saraswat , Rudong Shan , Samarendra N.
Maiti , Peter G. M. Wuts , Michael Stier , Teresa Lints , James Bradow & Jacob B. Schwarz (2008): Convenient
Preparation of Optically Pure 3‐Aryloxy‐pyrrolidines, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 38:4, 517-524
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Synthetic Communicationsw, 38: 517–524, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701796691
Convenient Preparation of Optically Pure
3-Aryloxy-pyrrolidines
1
1
1
´
Christophe Benard, Rahim Mohammad, Neerja Saraswat,
Rudong Shan,1 Samarendra N. Maiti,1 Peter G. M. Wuts,2
Michael Stier,2 Teresa Lints,2 James Bradow,2 and
Jacob B. Schwarz2
1Naeja Pharmaceutical Research and Development, Edmonton, Alberta,
Canada
2Pfizer Global Research and Development, Groton, Connecticut, USA
Abstract: Chiral 3-methanesulfonyl-1-Boc-pyrrolidine and piperidine were reacted
with sodium phenolates, resulting in a mixture of displacement and elimination
products. Following carbamate deprotection and pH adjustment, the 3-pyrroline and
tetrahydropyridine by-products resulting from elimination were easily removed
through aqueous partitioning and/or concentration. Although the pyrrolidines were
formed with a high degree of optical purity, slight racemization was observed
for the piperidine case because elevated temperatures were required to effect
displacement.
Keywords: aryl ethers, pyrrolidines, piperidines
The 3-aryloxypyrrolidine moiety has been incorporated into various biologi-
cally active agents, as exemplified by the factor Xa inhibitor DX-9065a 1[1]
and the 5HT2c antagonist Org 37684 2.[2] Typically, a Mitsunobu reaction
between a hydroxypyrrolidine and a phenol is used to construct the basic
framework.[3,4] Recognizing the need to ultimately conduct such a
process on a large scale, we desired a synthetic approach that would be
Received in the USA August 21, 2007
Address correspondence to Jacob B. Schwarz, Pfizer Global Research and Develop-
ment, Groton Laboratories, Eastern Point Road, Groton, CT 06340. E-mail: jacob.
schwarz@pfizer.com
517

´
C. Benard et al.
518
efficient and atom economical, without the generation of phosphine oxide
and hydrazide by-products.[5]
Toward this end, it had been reported in this journal that 3R-1-benzyl-3-
methanesulfonyloxy-pyrrolidine 3 underwent smooth displacement by the
sodium anion of 5-methoxy-4-indanol to afford a precursor (4) to Org 37684
(Scheme 1).[2] However, because the conditions required to effect N-debenzyla-
tion would likely be incompatible with certain functionalities (e.g., chloro), we
chose instead to examine etherification of the N-Boc-protected mesylate 5.
Several displacement reactions of 5 had been previously reported, including
the use of cyanide,[6] enolates,[7] nucleobases,[8] and pyrrolopyrimidines,[9]
but phenols seemed to be absent from the range of nucleophilic partners.
Our initial investigation of the displacement of mesylate 5 with the sodium
salt of m-cresol was at first glance disappointing, as a significant amount (.30%)
of elimination by-product was formed (Scheme 2). The by-products were of
similar polarity and as a consequence could not be easily separated following
the addition step. As a result, the mixture was exposed to anhydrous HCl to
deprotect the carbamates in the hope that the by-product could be removed chro-
matographically at this stage. However, we were delighted to find, after adjusting
the pH of the solution to 8 with aqueous NaHCO3, extraction, and concentration,
that only amine (2)-8a was obtained in 69% yield from 5 in more than 95%
chemical purity. Apparently, the elimination by-product 7 on deprotection
afforded 3-pyrroline, which either partitioned into the aqueous phase or was
evaporated on concentration (bp ¼ 90–918C at 748 mmHg). Similar results
were obtained for displacement of 5 with o-cresol, although the steric
hindrance afforded by the ortho substituent resulted in slightly attenuated yield.
As a further test of this method, we turned our attention to the
3-hydroxypiperidine system. In our hands, the Mitsunobu reaction of N-Boc-
protected (R)-3-hydroxypiperidine 10 (Aldrich) under standard conditions
(DIAD, Ph3P, THF, rt or 608C) afforded the corresponding piperidine aryl
Scheme 1. Synthesis of Org 37684 (2).[2]

Optically Pure 3-Aryloxy-pyrrolidines
519
Scheme 2. Formation of pure (3R)-m-tolyloxy-pyrrolidine ( 2 )-8.
ethers 11 in low yield (,30%) and contaminated with inseparable triphenylpho-
sphine oxide.[10–12] However, when mesylate (R)-(þ)-12[13] was subjected to
displacement with the sodium anion of m-cresol or 3-fluorophenol, a ca. 2:1
mixture of displacement and elimination products 11 and 13 was obtained
(Scheme 3). Noteworthy is that higher temperatures were required than for
the pyrrolidine case to effect usable conversion of starting material to
products, which in turn resulted in lower isolated yields because of some
decomposition (at 608C, only starting mesylate 12 and elimination product
13 were observed). Fortunately, as observed previously for the pyrrolidine
case, deprotection, aqueous basification, and concentration led to the
formation of amines (2)-14a and (2)-14b in more than 92% chemical purity.
Table 1 contains chemical purity (HPLC) and optical rotation data for chiral
mesylates 5 and 12, as well as m-aryloxy substituted heterocycles 8 and 14.
Chemical purity for all crude pyrrolidines and piperidines on concentration was
greater than 92%. The sign and magnitude of optical rotation was consistent for
the mesylate pairs and also for several final products. In cases where chemical
purity was significantly reduced compared to the enantiomeric product
(ꢀ2.8%), the magnitude (but not the sign) of rotation was also smaller. Chiral
HPLC analysis confirmed that 3-aryloxypyrrolidines 8 were formed with a high
degree of optical purity as expected. However, we were surprised to find that
slight (ca. 10%) racemization occurred in the case of piperidines 14, presumably
owing to competing displacement by mesylate anion at the elevated temperatures
required to effect conversion. Conditions for HPLC optical purity assessment: pyr-
rolidines 8b, Chiracel OD-H 0.46 ꢁ 25-cm column, mobile phase A CO2, mobile

´
C. Benard et al.
520
Scheme 3. Formation of pure (3S)-m-tolyloxy-piperidine (2)-14.
phase B MeOH þ 0.2% isopropylamine, gradient 95% A to 40% A in 15 min,
flow rate 4.0 mL/min, injection volume 27 mL, detection DAD 254 nm; piper-
idines 14b, Chiracel OD-H 0.46 ꢁ 25-cm column, mobile phase A 95% CO2,
mobile phase B 5% MeOH þ 0.2% isopropylamine, flow rate 4.0 mL/min,
injection volume 30 mL, detection DAD 254 nm.
Table 1. Chemical and optical purity of crude pyrrolidines and piperidines
Entry
Compound
Ar
HPLC puritya
aDb
1
2
(S)-5
(R)-5
94.8%
94.5%
96.7%
96.7%
95.4%
92.6%
96.8%
96.8%
96.5%
96.9%
92.8%
95.8%
þ22.5
221.0
22.92
þ2.87
219.9c
þ11.3c
22.08
þ2.68
þ7.88
27.39
þ3.17d
26.43d
3
(R)-8a
(S)-8a
(R)-8b
(S)-8b
(S)-12
(R)-12
(R)-14a
(S)-14a
(R)-14b
(S)-14b
3-Me
3-Me
2-Me
2-Me
4
5
6
7
8
9
3-Me
3-Me
3-F
10
11
12
3-F
aConditions: ACE_4 5 mm C18, 60 ꢁ 150-mm column, acetonitrile with 95% to
10% A gradient over 10 min (A ¼ 0.1 M aq. phosphoric acid), detection 200–400 nm).
bJasco DIP-1000 polarimeter, 589 nm, c ¼ 0.3–1.0 in CH2Cl2.
c
ꢂ
Enantiomeric ratio . 98:2; see .
d
ꢂ
Enantiomeric ratio 90:10; see .
ꢂConditions for HPLC optical purity assessment; pyrrolidines 8b, Chiracel OD-H
0.46 ꢁ 25 cm column, mobile phase A CO2, mobile phase B MeOH þ 0.2% isopropy-
lamine, gradient 95% A to 40% A in 15 min, flow rate 4.0 mL/min, injection volume
27 mL, detection DAD 254 nm: piperidines 14b, Chiracel OD-H 0.46 ꢁ 25 cm
column, mobile phase A 95% CO2, mobile phase B 5% MeOH þ 0.2% isopropyla-
mine, flow rate 4.0 mL/min, injection volume 30 mL, detection DAD 254 nm.

Optically Pure 3-Aryloxy-pyrrolidines
521
In conclusion, we have developed a phenolate displacement reaction of
secondary mesylates situated on carbamate-protected pyrrolidine and piper-
idine templates. The formation of elimination products in the displacement
step was of no consequence with regard to isolation of the free aminoethers.
Following deprotection, the by-products were easily removed because of
their volatility and/or aqueous solubility. As a result, the 3-aryloxy-pyrroli-
dines and piperidines were obtained in 29–69% yield with more than 92%
chemical purity as well as high optical purity. Slightly reduced optical
purity was observed in the piperidine case because of the more demanding
conditions to effect displacement. Currently, optimization to effect this trans-
formation under milder conditions to provide enantiopure piperidines is
ongoing and will be reported in due course.
EXPERIMENTAL
(S)-3-Methanesulfonyloxy-pyrrolidine-1-carboxylic Acid
tert-Butyl Ester 5
To a solution of (S)-3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester
(10.8 g, 57.41 mmol) in CH2Cl2 (80 mL) were added triethylamine (8.8 mL,
63.15 mmol) and methanesulfonyl chloride (4.9 mL, 63.15 mmol). The
reaction mixture was stirred at rt for 1 h, then quenched with water
(100 mL) and extracted with CH2Cl2 (3 ꢁ 200 mL). The organic phase was
separated, dried (MgSO4), and concentrated to afford 5 (15.2 g, quantitative)
1
as an amber oil: H NMR (400 MHz, CDCl3): d 5.27 (s, 1H), 3.68–3.50
(m, 4H), 3.05 (s, 3H), 2.29 (m, 1H), 2.17 (m, 1H), 1.47 (s, 9H). 13C NMR
(100 MHz, DMSO-d6): d 154.0 (Cq), 81.7–80.9 (d, CH), 79.4 (Cq),
52.7–52.5 (d, CH2), 44.1–44.0 (d, CH2), 38.3 (CH3), 32.5–31.6 (d, CH2),
28.8 (CH3). MS m/z 266 [C10H19NO5S þ 1].
(R)-3-m-Tolyloxy-pyrrolidine 8a
To a solution of m-cresol (0.39 mL, 3.77 mmol) in DMF (5 mL) was added
sodium hydride (60% in oil, 150 mg, 3.77 mmol), and the mixture was
stirred at rt for 30 min. A solution of (S)-3-methanesulfonyloxy-pyrrolidine-
1-carboxylic acid tert-butyl ester 5 (1.0 g, 3.77 mmol) in DMF (5 mL) was
then added dropwise, and the mixture was heated to 608C overnight. The
mixture was cooled and diluted with EtOAc (10 mL). The organic phase
was separated, washed with brine (3 ꢁ 50 mL) and 3 N KOH (1 ꢁ 30 mL),
dried (MgSO4), and concentrated to give 6a and eliminated product 7 (same
1
polarity, ratio 2:1, 1.01 g, 64% in 6a) as a brown oil. H NMR (400 MHz,
CDCl3): d 7.19–7.12 (m, 1H), 6.80–6.68 (m, 3H), 4.89 (br.s, 1H),
3.64–3.52 (m, 4H), 2.33 (s, 3H), 2.17–2.09 (m, 2H), 1.48 (s, 9H). MS m/z

´
C. Benard et al.
522
222 [C16H23NO3-55]. To the crude mixture of 6a and 7 (1.01 g) was added 4
M HCl in dioxane (10 mL). The mixture was stirred at rt for 30 min at which
time water (20 mL) was added, and the pH of the solution was adjusted to 8 by
addition of NaHCO3 in small portions. The mixture was extracted with
CH2Cl2 (3 ꢁ 50 mL), and the organic phase was dried (MgSO4) and concen-
trated to furnish 8a (0.46 g, 69% from 5) as an amber oil: 1H NMR (400 MHz,
CDCl3): d 7.18–7.09 (m, 1H), 6.78–6.61 (m, 3H), 4.85 (br.s, 1H), 3.25–2.96
(m, 4H), 2.32 (2s, 3H), 2.13–1.99 (m, 2H), 1NH not seen. 13C NMR
(100 MHz, CDCl3): d 157.3 (Cq), 139.9 (Cq), 129.5 (CH), 122.2 (CH),
116.6 (CH), 112.5 (CH), 70.8 (CH), 52.6 (CH2), 45.4 (CH2), 32.7 (CH2),
21.8 (CH3). MS m/z 178 [C11H15NO þ 1].
(S)-3-o-Tolyloxy-pyrrolidine 8b
Prepared from o-cresol (0.39 mL, 3.77 mmol) and (R)-3-methanesulfonyloxy-
pyrrolidine-1-carboxylic acid tert-butyl ester 5 (1.0 g, 3.77 mmol) by the
procedure outlined previously to yield 8b (0.39 g, 58% from 5) as an amber
1
oil: H NMR (400 MHz, CDCl3): d 7.14 (dd, 2H), 6.86 (dd, 1H), 6.77 (dd,
1H), 4.88 (br. s, 1H), 3.63 (br. s, 1H), 3.29–3.02 (m, 4H), 2.20 (s, 3H), 2.09
(m, 2H). 13C NMR (100 MHz, CDCl3): d 154.3 (Cq), 131.8 (CH), 128.1
(Cq), 127.0 (CH), 122.0 (CH), 112.0 (CH), 75.1 (CH), 50.3 (CH2), 44.1
(CH2), 31.5 (CH2), 16.7 (CH3). MS m/z 178 [C11H15NO þ 1].
(S)-3-Methanesulfonyloxy-piperidine-1-carboxylic Acid tert-Butyl
Ester 12
To a solution of (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester
(4.0 g, 19.9 mmol) in dichloromethane (30 mL) were added triethylamine
(3.0 mL, 21.9 mmol) and methanesulfonyl chloride (1.7 mL, 21.86 mmol).
The reaction mixture was stirred at rt for 1 h, then quenched with water
(20 mL) and extracted with CH2Cl2 (3 ꢁ 50 mL). The organic phase was
separated, dried (MgSO4), and concentrated to provide 12 (5.6 g, quantitative)
1
as a colorless oil that solidified on standing: H NMR (400 MHz, CDCl3): d
4.72 (br.s, 1H), 3.69–3.61 (m, 2H), 3.49–3.29 (m, 2H), 3.06 (s, 3H),
2.02–1.77 (m, 3H), 1.58–1.46 (m, 1H), 1.46 (s, 9H). 13C NMR (100 MHz,
CDCl3): d 154.9 (Cq), 80.3 (Cq), 75.6 (CH), 39.0 (CH3), 30.6 (2CH2), 28.5
(2CH2), 21.8 (CH3). MS m/z 224 [C11H21NO5S-55].
(R)-3-m-Tolyloxy-piperidine 14a
To a solution of m-cresol (0.78 g, 7.16 mmol) in DMF (5 mL) was added sodium
hydride (60% in oil, 0.29 g, 7.16 mmol) portionwise at 08C. The mixture was

Optically Pure 3-Aryloxy-pyrrolidines
523
stirred at rt for 1 h, at which time a solution of (S)-3-methanesulfonyloxy-piper-
idine-1-carboxylic acid tert-butyl ester 12 (2.0 g, 7.16 mmol) in DMF (5 mL)
was added dropwise. The mixture was heated to 1208C overnight, then
cooled and poured into EtOAc (50 mL), washed with 3 N KOH (30 mL)
and brine (2 ꢁ 50 mL), dried (Na2SO4), and concentrated to afford 11a and
eliminated product 13 (same polarity, ratio 2: 1, 1.29 g, 41% in 11a) as a
brown oil. MS m/z 236 [C17H25NO3-55]. To the crude mixture of 11a and
13 (1.29 g) was added 4 M HCl in dioxane (5 mL). The mixture was stirred
at rt for 1 h, at which time water (10 mL) was added and the pH of the
solution adjusted to 8 by addition of NaHCO3 in small portions. The
mixture was extracted with CH2Cl2 (3 ꢁ 30 mL), and the organic phase was
dried (MgSO4) and concentrated to provide 14a (0.40 g, 29% from 12) as a
1
brown oil: H NMR (400 MHz, CDCl3): d 7.20–7.16 (dd, 1H), 6.78–6.72
(m, 3H), 4.38–4.32 (m, 1H), 4.22–4.00 (br.s, 1H), 3.22–3.20 (m, 1H),
2.95–2.80 (m, 3H), 2.30 (s, 3H), 2.05–1.50 (m, 4H). 13C NMR (100 MHz,
CDCl3): d 157.2 (Cq), 140.0 (Cq), 129.8 (CH), 122.0 (CH), 117.0 (CH),
112.9 (CH), 71.8 (CH), 50.3 (CH2), 46.0 (CH2), 29.9 (CH2), 23.7 (CH2),
21.9 (CH3). MS m/z 192 [C12H17NO þ 1].
(R)-3-(3-Fluoro-phenoxy)-piperidine 14b
Prepared from 3-fluorophenol (0.8 g, 7.16 mmol) and (S)-3-methanesulfony-
loxy-piperidine-1-carboxylic acid tert-butyl ester 12 (2.0 g, 7.16 mmol) by
the procedure outlined previously to give 14b (0.48 g, 34% from 12) as a
1
brown oil: H NMR (400 MHz, CDCl3): d 7.22–7.17 (m, 1H), 6.74–6.70
(dd, 1H), 6.68–6.62 (m, 2H), 4.32–4.26 (m, 1H), 3.43–3.25 (br.s, 1H),
3.21–3.18 (m, 1H), 2.95–2.78 (m, 3H), 2.05–1.50 (m, 4H). 13C NMR
(100 MHz, CDCl3): d 165.5–162.8 (d (C-F), Cq), 159.0 (Cq), 130.3 (CH),
111.8 (CH), 108.0 (CH), 103.9 (CH), 72.2 (CH), 50.1 (CH2), 46.0 (CH2),
29.9 (CH2), 23.9 (CH2). MS m/z 196 [C11H14FNO þ 1].
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