A Magnesium-Based Diastereoselective Preparation of Pyridylic 1,3-Amino Alcohols Using the tert -Butyl Sulfinamide Auxiliary

Article abstract of DOI:10.1055/s-0034-1378854

1,3-Amino alcohols were prepared by using a two-step approach and an interesting reversal in diastereoselectivity is discussed.

Full text of DOI:10.1055/s-0034-1378854

SYNTHESIS
0
0
3
9
-
7
8
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1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 3231–3240
paper
3231
K. Fjelbye et al.
Paper
Synthesis
A Magnesium-Based Diastereoselective Preparation of Pyridylic
1,3-Amino Alcohols Using the tert-Butyl Sulfinamide Auxiliary
O
Kasper Fjelbye
S
O
S
Niels Svenstrup
Ask Püschl*
t-Bu
N
OTBS
NH2 OH
• HCl
I
t-Bu
NH
OTBS
HCl (4 M, dioxane)
MeOH
CF3
CF3
i-PrMgCl.LiCl
N
CF3
O
N
H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark
ASKP@Lundbeck.com
O
2-MeTHF–CH2Cl2 (1:6)
–10 °C
N
O
40%
89%
Received: 30.04.2015
Accepted after revision: 26.05.2015
Published online: 22.07.2015
O
∗
NH2 OH
2*
S
Ar-Mg
t-Bu
NH OTBS
∗
DOI: 10.1055/s-0034-1378854; Art ID: ss-2015-z0281-op
Ar
∗
Ar
Abstract 1,3-Amino alcohols were prepared by using a two-step ap-
1a–c
3a–c
proach and an interesting reversal in diastereoselectivity is discussed.
Key words organometallic addition, diastereoselectivity, sulfin-
amides, halogen-metal exchange, amino alcohol
O
∗
S
t-Bu
N
OTBS
In a recent medicinal chemistry project we needed ac-
cess to 1,3-amino alcohols (S)-1a–c, and (R)-1a–c (Scheme
1 and Table 4). Although trifluoroethoxy derivative (R)-1c
has previously been prepared through a nine-step synthe-
sis,1 we decided to investigate a shorter route utilizing the
diastereoselective addition of an organometallic reagent to
the TBS-protected chiral sulfinylimine shown in Scheme 1.
Both enantiomers of 2 and their reactions have been de-
scribed in a patent,2 and the diastereoselective addition of
an ester enolate to some closely related reagents have been
described.3
The optically active tert-butyl sulfinamide auxiliary de-
scribed by Ellman,4 provides a feasible way to prepare a
wide range of primary amines, including amino alcohols,
diastereoselectively.5–11 Both enantiomers of the tert-butyl
sulfinamide are commercially available and are readily con-
densed with aldehydes or ketones to provide the corre-
sponding aldimines or ketimines, which can function as
common precursors for the preparation of optically active
amines after nucleophilic addition and deprotection.
Whereas the preparation of chiral 1,2-amino alcohols
has been described in detail,5,9,11–13 syntheses of 1,3-amino
alcohols using a common precursor are much less abun-
dant. Our first approach towards the synthesis of 1c using
lithium-based chemistry did not afford any of the desired
product, likely as a result of the elimination of HF from the
2* = (RS)-2 or (SS)-2
Scheme 1 Preparation of 1,3-amino alcohols employing reagent 2*.
The structures of 3a–c are shown in Table 3; the structures of 1a–c are
shown in Table 4.
trifluoroethoxy functionality, which has often been not-
ed;14 thus, the development of a milder magnesium-based
protocol was desired. Halogen–Li exchange is usually per-
formed at very low temperatures (e.g., –78 °C), whereas
halogen–magnesium exchange can be carried out at higher
temperatures (e.g., room temperature).
The enantiomeric imines (RS)-2 and (SS)-2 were pre-
pared as described in Scheme 2, based on reported proce-
dures,5,15,16 and were stable for several months at room
temperature.
In the search for an optimized protocol for the construc-
tion of pyridylic 1,3-amino alcohols, the preparation of
Grignard reagents from deactivated (e.g., alkoxylated) io-
dopyridines was examined using different magnesium
sources (Table 1). The lower reactivity of the corresponding
alkoxylated bromopyridines, made those substrates less at-
tractive as precursors of Grignard reagents.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3231–3240

3232
K. Fjelbye et al.
Paper
Synthesis
cially available (s-Bu)2Mg·LiCl complex solution led to the
rapid and exclusive formation of A. The optimized condi-
tions summarized in entry 4 were then used to prepare 6 to
validate the method by using the simple electrophile benz-
aldehyde (Scheme 3).
NaH
TBSCl
OH OTBS
HO
O
OH
88%
Swern
oxidation
66%
O
∗
∗
N
S
S
Ph
OH
I
t-Bu
NH2
O
OTBS
t-Bu
OTBS
1) i-PrMgCl⋅LiCl
O
2) work-up
(RS or SS)
+
N
2-MeTHF
93%
(RS)-2 68%
N
(SS)-2 100%
OMe
OMe
Scheme 2 Preparation of (RS)-2 and (SS)-2 enantiomers from propane-
1,3-diol
6
4
Scheme 3 Studying the applicability of the organometallic addition
protocol with benzaldehyde as a simple electrophile
Table 1 Iodine–Magnesium Exchange of a Deactivated Iodopyridine
at Room Temperature
The optimized conditions were used in the following
addition to 2. Exploring a small series of solvents, and their
influence on the diastereoselective addition, led to the
somewhat surprising results that the most commonly em-
ployed ethereal solvents, Et2O and THF provided the adduct
(RS,R)-3a in only 2–8% yield (Table 2). The study was per-
formed by preparing the Grignard species and allowing it to
react with (RS)-2 in the solvent indicated (Table 2). An in-
crease in both yield and selectivity was observed when the
reaction was performed in 2-methyltetrahydrofuran (2-
MeTHF). The improved outcome of organometallic reac-
tions in 2-MeTHF has also been noted by Zhang et al.19 and
by Aycock.20
OMe
I
H
N
1) Mg source (0.93 equiv)
2) MeOH quench
+
N
N
OMe
OMe
N
OMe
4
A
B
Entry
Solvent
Mg source
Time
A/B (%)a
1
2
3
4
5
6
THF
THF
THF
Mg(0)
2 h
10:0
71:3
32:21
61:0
47:43
71:0
Table 2 Screening of Ethereal Solventsa
i-PrMgCl
n-PrMgCl
90 min
48 h
O
I
O
S
S
2-MeTHF
2-MeTHF
2-MeTHF
i-PrMgCl LiCl
i-PrMgCl LiCl
(s-Bu)2Mg LiCl
75 min
24 h
t-Bu
NH OTBS
(RS)-2
+
t-Bu
N
N
solvent, r.t.
10 min
a Determined by LC (UV) MS analysis.
OMe
MeO
N
4
(RS,R)-3a
5
Compound 4 was included in a slight excess to fully con-
sume the magnesium source (0.93 equiv) and the reaction
was followed by LC MS until complete conversion. The pres-
ence of the dehalogenated starting material 2-methoxypyr-
idine A, after MeOH quench, supports the assumption that
the C–metal bond had formed. Initial attempts to prepare
the Grignard species was performed by using magnesium
insertion with magnesium(0), which only allowed forma-
tion of 10% A, under the activation of 1,2-diiodoethane. Ap-
plying i-PrMgCl significantly increased the amount of A
formed, although a small amount of 6,6′-dimethoxy-3,3′-
bipyridine B, was also detected. Conducting the exchange
by using n-PrMgCl over the course of 48 h led to the forma-
tion of A and B in 32 and 21%, respectively. Employing the
TurboGrignard reagent i-PrMgCl·LiCl17,18, led to exclusive
formation of A if prolonged reaction times were avoided
(Table 1, entries 4 and 5). Furthermore, the use of commer-
Entry
Solvent
Molarity
[M]
dr
Yield of
(crude)b
(RS,R)-3a (%)c
1
2
3
4
5
THF
0.15
0.15
0.15
0.15
0.05
–
8
2
Et2O
–
dioxane
2-MeTHF
2-MeTHF
–
7
81:19
87:13
23
35
a Reaction conditions: i-PrMgCl·LiCl.
b The dr was determined by LC (UV) MS analysis of the crude reaction mix-
ture.
c The yields are based on the isolated major isomer.
The lower yields observed when the reaction was con-
ducted in THF and Et2O may be explained by the increased
formation of an elimination product 5, in these solvents.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3231–3240

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K. Fjelbye et al.
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Synthesis
When the second generation TurboGrignard conditions (Ta-
ble 1, entry 6) were employed on 2, compound 5 was
formed as the major product, which can be attributed to
the increased basicity of the magnesium species [Ar2Mg or
Ar(s-Bu)Mg] formed in situ.
When the reaction between 4 and a TBDPS O-protected
aldimine 7,21 which is closely related to 2, was performed, it
was possible to isolate 5 in 23% yield, thereby confirming
the identity of the byproduct. To suppress the formation of
5 and increase the yield of the adduct, the temperature was
decreased to 0 °C and the Grignard reagent in 2-MeTHF was
diluted with ice-cold CH2Cl2 prior to the addition of 2. Dilu-
tion by the chlorinated solvent was found to improve the
outcome significantly, and the method was applied to het-
eroaromatic analogues of interest (Table 3), affording a
small series of protected 1,3-amino alcohols 3a–c. Under
these conditions, it was also possible to prepare 3d from 5-
bromo-2-(trifluoromethyl)pyridine, being slightly activated
to organometallic exchange reactions. In the case of 3d, it
was not possible to separate the two diastereomers (RS,R)-
3d and (RS,S)-3d by using silica gel chromatography.
To gain access to both enantiomers of 3a and 3c, both
enantiomers of 2 were employed. The diastereoselective
outcome of the addition for the 2-halopyridines was in ac-
cordance with the transition-state model proposed by
Barrow et al.5 for related additions forming 1,2-amino alco-
hols. This selectivity is opposite to that predicted by Ellman
for aldimines without additional heteroatoms on the ali-
phatic chain, and isomerization of the C–N double bond is
believed to occur prior to the addition.7 The formation of
so-called ‘anti-Ellman’ products has also been recognized
by Davis et al.,22 where chelating effects overrule the tradi-
tional chair-like transition-state model. On the basis of the
experimentally observed selectivity, and confirmed by X-
ray crystallography of the products (see below), we have
proposed a bicyclic transition state (Figure 1) that resem-
bles that proposed by Barrow et al.5 for 1,2-amino alcohols.
Table 3 Optimized Magnesium-Based Protocol Using Aromatic Start-
ing Materials
O
O
S
*
S
i-PrMgCl.LiCl
2-MeTHF–CH2Cl2 (1:6)
*
t-Bu
NH OTBS
Ar-X
+
t-Bu
N
OTBS
*
Ar
3a–d
OPG
2
Ar
O
S
H
M
t-Bu
N
S
OPG
N
Producta Ar-X
Absolute
Yield (R)-3a–d Yield (S)-3a–d
t-Bu
M
Ar
O
config. of 2 (%)b
(%)b
anti-Ellman TS
MeO
N
N
Ellman TS
3a
S
–
40
Figure 1 Proposed transition-state models accounting for the ob-
served selectivity. The ‘Ellman TS’ (left) reflects the selectivity observed
for the 3-halopyridines, whereas the ‘anti-Ellman TS’ (right) is in agree-
ment with the experimental observations for the formation of 3b.
I
I
MeO
3ac
3b
3c
R
S
R
52
52
–
–
The acidic deprotection of 3a–c (Table 4) was facilitated
by HCl in MeOH/dioxane, and, in contrast to the carbamate-
based tert-butoxycarbonyl protecting group that forms vol-
atile products upon acidic treatment, the OTBS and Ellman
auxiliary produces nonvolatile compounds (i.e., tert-butyl-
methylsulfinate and tert-butyldimethylmethoxysilane),
which are easily recognized in the 1H NMR spectra.24–28 The
purity of the hydrochloride salts are thus highly dependent
on the precipitation of the products upon deprotection.
The enantiopure products 1a and 1b were found to be
dihydrochloride salts, whereas (R)-1c was a monohydro-
chloride salt, as determined by elemental analysis. In the
case of (S)-1a (Figure 2) and (R)-1b (Figure 3), it was possi-
ble to confirm the absolute configurations of the stereogen-
ic centers through X-ray crystallographic analysis of the di-
hydrochloride salts.
N
3
I
O
N
44
CF3
I
O
N
3cd
3d
S
40
–
–
CF3
F3C
I
N
R
39e
Br
a The major isomer formed for the 3-halopyridines was opposite to that of
the 2-halopyridines.
b Isolated yield of the major diastereomer.
c A dr of 80:20 was determined by 1H NMR spectroscopic analysis of the
crude reaction mixture.
The optimized procedure for preparation of pyridylic
1,3-amino alcohols was used in the formation of the de-
sired trifluoroethoxylated compound 1c (Scheme 4). 2-Bro-
mo-5-hydroxypyridine was alkylated in 91% yield with tri-
d A dr of 82:18 was determined by LC MS UV analysis of the crude reaction
mixture.
e Contaminated by the minor isomer; a dr of 77:23 was determined by 1
NMR spectroscopic analysis.
H
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3231–3240

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K. Fjelbye et al.
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Synthesis
Table 4 Deprotection of Diastereomers 3a–c
O
∗
NH2 OH
∗
HCl
S
t-Bu
NH OTBS
MeOH–dioxane (1:1)
∗
Ar
Ar
3a–c
1a–c
Starting ma- Ar
terial
Product
Yield (%)
75
(S)-3a
(S)-1a
N
N
Figure 3 X-ray crystal structure of (R)-1b obtained from EtOH. The
green circles represent the chlorine, blue nitrogen and red oxygen.
Mercury software was used for the ORTEP representation.
MeO
(R)-3a
(R)-1a
90
deprotection to yield the desired enantiopure amino alco-
hol (R)-1c in 89% yield (Scheme 4). The absolute configura-
tion of (R)-1c is tentatively assigned based on the biological
activity of some derivatives (see Eskildsen et al.23) and by
analogy with the stereochemistry of 1b.
MeO
N
(S)-3b
(R)-3b
(R)-3c
(S)-1b
(R)-1b
(R)-1c
82
84
89
TfO
N
N
Br
CF3
N
Br
a
O
91%
N
HO
CF3
b
O
S
O
8
90%
t-Bu
NH OTBS
(SS)-2
CF3
N
I
N
c
O
40%
O
(SS,R)-3c
CF3
CF3
9
d
89%
NH2 OH
N
. HCl
O
Figure 2 X-ray crystal structure of (S)-1a obtained from EtOH/Et2O.
The green circles represent the chlorine, blue nitrogen and red oxygen.
Mercury software was used for the ORTEP representation.
(R)-1c
CF3
Scheme 4 Optimized preparation of compound (R)-1c in four steps
from 2-bromo-5-hydroxypyridine. Reagents and conditions: (a) CsCO3,
DMF; (b) NaI (3 equiv), cat. CuI, cat. diamine ligand, MeCN, 100 °C;
(c) 2-MeTHF–CH2Cl2 (1:6), –10 °C; (d) HCl, MeOH–dioxane (1:1).
fluoroethyl triflate by using CsCO3 in N,N-dimethylform-
amide (DMF) to afford 8. Attempts to install the
trifluoroethyl group by using the iodide or the mesylate
leaving groups were unsuccessful. The subsequent trans-
halogenation employing aromatic Finkelstein conditions,
described by Buchwald et al.29 for the conversion of aryl
bromides into iodides, furnished 9 in 90% yield. Halogen–
metal exchange of 9 in 2-MeTHF followed by dilution with
an excess volume of CH2Cl2 and reaction with the aldimine
(SS)-2 afforded (R)-1c in 40% yield, followed by acidic
We have thus developed a short stereodivergent synthe-
sis of 1,3-amino alcohols that tolerates base-labile groups,
for example (R)-1c.
GC MS data was obtained with a Varian gas chromatograph equipped
with an EI mass spectrometer. Melting points were measured with a
Büchi apparatus and are uncorrected. TLC was performed on Silica
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3231–3240

3235
K. Fjelbye et al.
Paper
Synthesis
Gel 60 F254 from Merck visualized under UV at 254 nm. Starting mate-
rials that were not synthesized by the author were purchased from
Sigma–Aldrich, Chemetall GmbH or Across Chemicals. All reaction
solvents were HPLC grade and dried over 4 Å molecular sieves. All re-
actions were carried out under a nitrogen or argon atmosphere. LC-
MS data were acquired with a Waters Acquity UPLC-MS consisting of
a Waters Acquity system including column manager, binary solvent
manager, sample organizer, PDA detector (operating at 254 nm), ELS
detector, and TQ-MS equipped with APPI-source operating in positive
ion mode. LC-conditions: The column was Acquity UPLC BEH C18
1.7 μm; 2.1 × 50 mm operating at 60 °C with 1.2 mL/min binary gra-
dient consisting of H2O+0.05% trifluoroacetic acid (TFA) (A) and
MeCN+5% H2O+0.05% TFA (B). Gradient: 0.00 min: 10% B; 1.00 min:
100% B; 1.01 min: 10% B; 1.15 min: 10% B. The retention times pro-
vided in the experimental section shall be compared to the total run
time of 1.15 min. HRMS data were acquired with a Bruker Daltonic
MicroTOF with internal calibration using ESI in the positive mode.
NMR data were collected with a Bruker 600-Avance-III spectrometer
equipped with a 5 mm TCI cryoprobe operating at 600 and 151 MHz
for 1H and 13C, respectively. 19F NMR spectra were recorded with a
Bruker 500-Avance spectrometer equipped with a 5 mm QNP probe
operating at 470.6 Hz, using CFCl3 as point-zero. The solvents used for
(S)-3-Amino-3-(6-methoxypyridin-3-yl)propan-1-ol Dihydrochlo-
ride [(S)-1a]
To a flask containing (SS,S)-3a (143 mg, 0.357 mmol) in MeOH (0.9
mL) was added HCl (4 M in dioxane, 0.9 mL) at r.t. and the reaction
mixture was stirred overnight, after which it was placed at 2–8 °C for
1 h. The suspension was then transferred to a frit funnel by using a
syringe and triturated with Et2O (3 × 10 mL) to give (S)-1a.
Yield: 82 mg (0.321 mmol, 90%); white powder; mp 134.4–141.0 °C;
[α]D20 = 22.42 (MeOH).
1H NMR (600 MHz, DMSO-d6): δ = 8.52 (br, 3 H), 8.25 (d, J = 2.5 Hz,
1 H), 7.90 (dd, J = 8.6, 2.5 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 6.11 (br,
3 H), 4.37–4.31 (m, 1 H), 3.86 (s, 3 H), 3.39 (dt, J = 11.0, 5.5 Hz, 1 H),
3.20 (ddd, J = 11.0, 8.1, 5.5 Hz, 1 H), 2.15 (ddt, J = 12.0, 8.1, 5.9 Hz,
1 H), 1.98–1.91 (m, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 163.61, 146.68, 138.35, 126.29,
110.65, 56.70, 53.40, 49.29, 36.51.
Anal. Calcd for C9H16Cl2N2O2: C, 42.37; H, 6.32; N, 10.98. Found: C,
41.99; H, 6.37; N, 10.67.
(R)-3-Amino-3-(6-methoxypyridin-3-yl)propan-1-ol Dihydrochlo-
ride [(R)-1a]
1
NMR were CDCl3, with reference signals for CHCl3 (δ = 7.26 ppm, H)
and (δ = 77.16 ppm, 13C), and DMSO-d6 with the reference signals for
residual DMSO (δ = 2.50 ppm, 1H) and (δ = 39.51 ppm, 13C) using TMS
as internal reference.30 The chemical shifts are provided in ppm and
broad proton signals are labeled (br). Organometallic reagents were
purchased from Chemetall as THF solutions; i-PrMgCl·LiCl and (s-
Bu)2Mg·LiCl (0.6 M) were titrated with molecular iodine in anhydrous
THF prior to use.
To a flask containing (SS,R)-3a (41 mg, 0.102 mmol) in MeOH (0.3 mL)
was added HCl (4 M in dioxane, 0.3 mL) at r.t. and the reaction mix-
ture was stirred for 3 h while precipitation occurred. The suspension
was then transferred to a frit funnel and triturated with Et2O (3 × 30
mL) to give (R)-1a.
Yield: 19.6 mg (0.077 mmol, 75%); white solid; mp 137.8–144.4 °C;
[α]D20 –19.5 (MeOH).
1H NMR (600 MHz, DMSO-d6): δ = 8.50 (br, 3 H), 8.25 (d, J = 2.5 Hz,
1 H), 7.89 (dd, J = 8.6, 2.5 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 1 H), 5.93 (br,
3 H), 4.37–4.31 (m, 1 H), 3.85 (s, 3 H), 3.39 (dt, J = 11.0, 5.5 Hz, 1 H),
3.23–3.18 (m, 1 H), 2.18–2.11 (m, 1 H), 1.98–1.91 (m, 1 H).
13C NMR (151 MHz, DMSO-d6): δ = 163.63, 146.69, 138.32, 126.27,
110.65, 56.70, 53.39, 49.30, 36.50.
Crystal Structure of (S)-1a
Crystals were prepared by dissolving (S)-1a (6 mg) in EtOH (1.5 mL) in
an open Pyrex glass vial placed in a closed blue cap flask surrounded
by excess Et2O. After two weeks, colorless crystals of (S)-1a appeared.
The colorless crystals of (S)-1a [(C9H16N2O2)2+, (Cl–)2] are orthorhom-
bic. At 298 K a = 8.3763(3), b = 8.5964(3), c = 17.6648(6) Å;
Anal. Calcd for C9H16Cl2N2O2·1/4 H2O: C, 41.63; H, 6.41; N, 10.79.
Found: C, 41.68; H, 6.31; N, 10.76.
V = 1271.97(8) Å3; M = 255.14; Z = 4; space group
P
212121,
F(000) = 536. Intensities of 2225 reflections. CuKα radiation. The
structure was solved using SHELXL-2014/4 and the absolute stereo-
chemistry was determined with the stereocenter at C6 assigned as S
with a Flack parameter of –0.003(16).
(S)-3-Amino-3-(pyridin-2-yl)propan-1-ol Dihydrochloride [(S)-1b]
To a flask containing (SS,S)-3b (0.065 g, 0.175 mmol) in MeOH (0.4
mL) was added HCl (4 M in dioxane, 0.4 mL, 47.7 mmol) and the reac-
tion mixture was stirred at r.t. overnight. The precipitated salt was
placed on a filter and triturated with Et2O (4 × 5 mL) followed by
evaporation of excess volatiles in vacuo at 60 °C overnight. The anhy-
drous material afforded (S)-1b.
Crystal Structure of (R)-1b
The crystals were prepared by recrystallization from boiling EtOH.
The colorless crystals of (R)-1b [(C8H14N2O)2+, (Cl–)2] are orthorhom-
bic. At 293 K, a = 6.7297(6), b = 9.3506(9), c = 17.5779(13) Å;
Yield: 32.3 mg (0.143 mmol, 82%); white powder; [α]D20 +2.7 (c 1.00,
V = 1106.12(16) Å3; M = 225.11;
Z
=
4; space group
P 212121;
MeOH).
F(000) = 472. Intensities of 2323 reflections, Final R1, (I
>
1H NMR (600 MHz, DMSO-d6): δ = 8.67 (ddd, J = 4.9, 1.6, 0.8 Hz, 1 H),
8.64 (br, 2 H), 8.01–7.97 (m, 1 H), 7.65 (d, J = 7.8 Hz, 1 H), 7.51 (dd,
J = 7.4, 5.1 Hz, 1 H), 6.54 (br, 3 H), 4.56–4.50 (m, 1 H), 3.43 (dt, J = 11.9,
6.2 Hz, 1 H), 3.34–3.29 (m, 1 H), 2.09 (td, J = 13.4, 6.2 Hz, 1 H), 2.00–
1.94 (m, 1 H).
2σ(I)) = 2.51%. CuKα radiation. The structure was solved by direct
methods using the SHELXL-2013 package. The absolute stereochem-
istry was determined with the stereocenter assigned as R with a Flack
parameter of –0.007(5). The Flack equivalent and its uncertainty are
calculated to be –0.003(6).
13C NMR (151 MHz, DMSO-d6): δ = 155.88, 148.20, 138.57, 124.09,
123.19, 56.55, 51.81, 36.69.
HRMS (ESI): m/z [M + H]+ calcd for C8H13N2O: 153.1022; found:
153.1016.
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K. Fjelbye et al.
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Synthesis
(R)-3-Amino-3-(pyridin-2-yl)propan-1-ol Dihydrochloride [(R)-
1b]
action mixture was stirred at r.t. overnight and then filtered. The sol-
vent was removed in vacuo and the crude product was purified by sil-
ica gel chromatography (EtOAc–heptanes, 5–100%) to provide (RS)-2.
To a flask containing (SS,R)-3b (1.79 g, 4.83 mmol) in MeOH (12 mL)
was added HCl (4 M in dioxane, 11.93 mL, 47.7 mmol) and the reac-
tion mixture was stirred at r.t. overnight. The precipitated salt was
placed on a filter and triturated with Et2O (4 × 75 mL) followed by
evaporation of excess volatiles in vacuo at 60 °C for 3 h. The anhy-
drous material afforded (R)-1b (0.912 g, 4.05 mmol, 84% yield) as a
white powder. Recrystallization from boiling EtOH (5.5 mL) provided
very large transparent crystals that were analyzed by X-ray crystal-
lography.
Yield: 0.48 g (1.65 mmol, 100%); yellow oil; TLC: Rf = 0.6 (EtOAc–hep-
tanes, 50%).
1H NMR (600 MHz, CDCl3): δ = 8.09 (t, J = 4.7 Hz, 1 H), 3.96–3.90 (m,
2 H), 2.76–2.68 (m, 2 H), 1.19 (s, 9 H), 0.87 (s, 9 H), 0.05 (s, 6 H).
13C NMR (151 MHz, CDCl3): δ = 167.93, 59.61, 56.61, 39.46, 25.88,
22.37, 18.29, –5.35.
LCMS: m/z = 292.3 [M + H]+ (tR 0.95 min; UV).
Mp 148–158 °C (decomp); [α]D20 –3.4 (c 1.00, MeOH).
HRMS (ESI): m/z [M + H]+ calcd for C13H30NO2SSi: 292.1761; found:
292.1763.
1H NMR (600 MHz, DMSO-d6): δ = 8.72–8.66 (m, 4 H), 8.04–8.00 (m,
1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.53 (ddd, J = 7.5, 5.0, 0.7 Hz, 1 H), 6.93
(br, 2 H), 4.58–4.52 (m, 1 H), 3.43 (dt, J = 11.8, 6.0 Hz, 1 H), 3.34–3.29
(m, 1 H), 2.11 (td, J = 13.5, 6.0 Hz, 1 H), 1.98 (td, J = 13.5, 6.0 Hz, 1 H).
(SS)-N-{3-[(tert-Butyldimethylsilyl)oxy]propylidene}-2-methyl-
propane-2-sulfinamide [(SS)-2]
13C NMR (151 MHz, DMSO-d6): δ = 155.72, 147.86, 138.97, 124.24,
123.33, 56.55, 51.70, 36.66.
HRMS (ESI): m/z [M + H]+ calcd for C8H13N2O: 153.1022; found:
153.1022.
A round-bottom flask was charged with (S)-2-methylpropane-2-sul-
finamide (5.02 g, 41.5 mmol), pyridinium p-toluenesulfonate (0.521
g, 2.07 mmol), and magnesium sulfate (24.95 g, 207 mmol) in CH2Cl2
(83 mL, 0.5 M). A solution of 3-[(tert-butyldimethylsilyl)oxy]propanal
(9.37 g, 49.8 mmol) in CH2Cl2 (35 mL) was added dropwise at r.t. and
the reaction mixture was stirred overnight followed by filtration. The
solvent was removed in vacuo and the crude product was purified by
silica gel chromatography (EtOAc–heptanes, 5–100%) to provide (SS)-
2.
Anal. Calcd for C8H14Cl2N2O2·1/4 H2O: C, 41.85; H, 6.37; N, 12.20.
Found: C, 42.13; H, 6.26; N, 12.20.
(R)-3-Amino-3-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]propan-1-ol
Hydrochloride [(R)-1c]
Yield: 8.25 g (28.3 mmol, 68%); yellow oil; Rf = 0.60 (EtOAc–heptanes,
A round-bottom flask was charged with (R)-3c (0.85 g, 1.81 mmol) in
MeOH (4.5 mL) followed by the dropwise addition of HCl (4 M in di-
oxane, 4.5 mL, 17.92 mmol). The yellow mixture was stirred over-
night, followed by concentration in vacuo to provide a crude oily
amorphous mass. The crude material was transferred by using a spat-
ula onto a filter where it was triturated with Et2O (10 × 80 mL) and
stored in vacuo at 60 °C overnight. The resulting solid was identified
as being (R)-1c (0.464 g, 1.62 mmol, 89% yield) as a pale solid that was
recrystallized from first MeOH/MTBE then MeCN to afford a white
powder; mp 168.9–169.3 °C.
1H NMR (600 MHz, DMSO-d6): δ = 8.45 (d, J = 2.9 Hz, 1 H), 7.63 (dd,
J = 8.6, 2.9 Hz, 1 H), 7.54 (d, J = 8.6 Hz, 1 H), 4.93 (q, J = 8.8 Hz, 2 H),
4.44 (dd, J = 12.5, 5.9 Hz, 1 H), 3.53 (br, 1 H), 3.40 (dt, J = 11.3, 5.8 Hz,
1 H), 3.27 (dt, J = 11.3, 6.7 Hz, 1 H), 2.10–2.02 (m, 1 H), 1.92 (td,
J = 13.6, 5.9 Hz, 1 H).
50%).
1H NMR (600 MHz, CDCl3): δ = 8.09 (t, J = 4.7 Hz, 1 H), 3.93 (td, J = 6.2,
1.7 Hz, 2 H), 2.75–2.71 (m, 2 H), 1.19 (s, 9 H), 0.88 (s, 9 H), 0.05 (s,
3 H), 0.05 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 168.05, 59.73, 39.58, 26.00, 22.49,
–5.24, –5.24.
LCMS: m/z = 292.3 [M + H]+ (tR 1.00 min; UV).
(SS)-N-{(S)-3-[(tert-Butyldimethylsilyl)oxy]-1-(6-methoxypyridin-
3-yl)propyl}-2-methylpropane-2-sulfinamide [(SS,S)-3a]
To a solution of 4 (0.594 g, 2.53 mmol) in 2-MeTHF (6 mL) was added
i-PrMgCl·LiCl (0.73 M in THF, 3.23 mL, 2.36 mmol) at –10 °C. Genera-
tion of the active nucleophile was followed by LCMS analysis and, af-
ter 1 h, the solution was diluted with CH2Cl2 (30 mL) at –10 °C, then
(SS)-2 (0.491 g, 1.69 mmol) in CH2Cl2 (5 mL) was added. The reaction
mixture was stirred for 2.5 h followed by the addition of half-saturat-
ed aq NH4Cl (10 mL) and the phases were separated. The aqueous
phase was extracted with CH2Cl2 (35 mL) and the organic phases were
combined and concentrated in vacuo to provide a colorless oil that
was subjected to purification by silica gel chromatography (40 g SiO2;
EtOAc–heptanes, 10–80%; eluting at 63%) followed by examination of
the UV-active fractions by LCMS analysis. The desired fractions were
combined and concentrated in vacuo to provide the major isomer
(SS,S)-3a.
13C NMR (151 MHz, DMSO-d6): δ = 153.10, 149.89, 137.31, 123.87 (q,
J = 277.9 Hz), 123.45, 122.68, 64.81 (q, J = 34.2 Hz), 56.55, 51.56,
36.70.
19F NMR (471 MHz, DMSO-d6): δ = –72.97.
LCMS: m/z = 251.1 [M + H]+ (tR = 0.31 min; UV).
HRMS (ESI): m/z [M + H]+ calcd for C10H14F3N2O2: 251.1002; found:
251.1007.
Anal. Calcd for C10H14ClF3N2O2: C, 41.90; H, 4.92; N, 9.77. Found: C,
42.44; H, 5.09; N, 9.40.
Yield: 272 mg (0.679 mmol, 40%); colorless oil.
(RS)-N-{3-[(tert-Butyldimethylsilyl)oxy]propylidene}-2-methyl-
propane-2-sulfinamide [(RS)-2]
1H NMR (600 MHz, CDCl3): δ = 8.11 (d, J = 2.5 Hz, 1 H), 7.59 (dd,
J = 8.6, 2.5 Hz, 1 H), 6.74 (d, J = 8.6 Hz, 1 H), 4.58–4.54 (m, 1 H), 3.93
(s, 3 H), 3.71 (d, J = 5.1 Hz, 1 H), 3.62 (ddd, J = 10.5, 6.6, 5.4 Hz, 1 H),
3.52 (ddd, J = 10.4, 6.7, 5.3 Hz, 1 H), 2.18 (dtd, J = 11.9, 6.6, 5.5 Hz,
1 H), 1.97–1.90 (m, 1 H), 1.20 (s, 9 H), 0.87 (s, 9 H), 0.01 (s, 3 H), 0.00
(s, 3 H).
A round-bottom flask was charged with (RS)-2-methylpropane-2-sul-
finamide (0.20 g, 1.65 mmol), pyridinium p-toluenesulfonate (0.02 g,
0.08 mmol), and magnesium sulfate (0.99 g, 8.23 mmol) in CH2Cl2 (4
mL) at r.t. A solution of 3-[(tert-butyldimethylsilyl)oxy]propanal (0.62
g, 3.29 mmol) in CH2Cl2 (2 mL) was then added dropwise and the re-
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Synthesis
13C NMR (151 MHz, CDCl3): δ = 163.93, 145.81, 138.03, 130.48,
111.12, 59.70, 56.04, 54.13, 53.64, 39.37, 26.04, 22.72, 18.30 –5.24,
–5.28.
J = 10.6, 6.1, 4.5 Hz, 1 H), 3.67–3.62 (m, 1 H), 2.18 (dtd, J = 13.0, 7.4,
5.5 Hz, 1 H), 2.11 (dtd, J = 13.0, 5.5, 4.5 Hz, 1 H), 1.18 (s, 9 H), 0.88 (s,
9 H), 0.04 (s, 3 H), 0.02 (s, 3 H).
LCMS: m/z = 401.1 [M + H]+ (tR 0.92 min; UV).
13C NMR (151 MHz, CDCl3): δ = 161.67, 149.51, 136.53, 122.35,
122.11, 61.15, 59.63, 55.88, 39.72, 26.13, 22.83, 18.57, –5.22, –5.24.
HRMS (ESI): m/z [M + H]+ calcd for C18H35N2O2SSi: 371.2183; found:
HRMS (ESI): m/z [M + H]+ calcd for C19H37N2O3SSi: 401.2289; found:
401.2285.
371.2181.
(RS)-N-{(R)-3-[(tert-Butyldimethylsilyl)oxy]-1-(6-methoxypyridin-
3-yl)propyl}-2-methylpropane-2-sulfinamide [(RS,R)-3a]
Minor Isomer (SS,S)-3b
To a solution of 4 (470 mg, 2.00 mmol) in 2-MeTHF (5 mL) was slowly
added i-PrMgCl·LiCl (0.73 M in THF, 2.56 mL, 1.87 mmol) at r.t. Gener-
ation of the active nucleophile was followed by LCMS analysis and, af-
ter 1 h, the solution was cooled to –10 °C and diluted with CH2Cl2 (25
mL), then (RS)-2 (389 mg, 1.33 mmol) in CH2Cl2 (5 mL) was added. The
mixture was stirred for 5 h when LCMS indicated full conversion of
the electrophile (RS)-2. The mixture became clear yellow, sat. aq.
NH4Cl (5 mL) was added and the phases were separated. The aqueous
phase was extracted with CH2Cl2 (2 × 50 mL) and the organic layers
were combined, concentrated in vacuo, and purified by silica gel
chromatography (120 g SiO2; EtOAc–heptanes, 10–100%; eluting at ca.
60% EtOAc). The fractions containing the major isomer (as indicated
by LCMS) were collected and evaporation of volatiles in vacuo at 60 °C
afforded the major isomer (RS,R)-3a.
Yield: 0.098 g (0.26 mmol, 3%).
1H NMR (600 MHz, CDCl3): δ = 8.51 (d, J = 4.6 Hz, 1 H), 7.61 (td, J = 7.7,
1.7 Hz, 1 H), 7.28 (d, J = 7.7 Hz, 1 H), 7.13 (ddd, J = 7.7, 4.6, 0.8 Hz,
1 H), 4.88 (d, J = 7.5 Hz, 1 H), 4.59 (q, J = 7.5 Hz, 1 H), 3.68 (dt, J = 10.3,
6.4 Hz, 1 H), 3.56–3.52 (m, 1 H), 1.98–1.93 (m, 2 H), 1.23 (s, 9 H), 0.87
(s, 9 H), 0.01 (s, 3 H), –0.01 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 161.41, 149.22, 136.75, 122.41,
122.05, 59.46, 57.88, 56.03, 40.89, 26.00, 22.86, 18.32, –5.26, –5.27.
LCMS: m/z = 371.3 [M + H]+ (tR 0.75 min; UV).
(RS)-N-{(S)-3-[(tert-Butyldimethylsilyl)oxy]-1-[5-(2,2,2-trifluoro-
ethoxy)pyridin-2-yl]propyl}-2-methylpropane-2-sulfinamide
[(RS,S)-3c]
Yield: 275 mg (0.69 mmol, 52%); yellow oil; dr 80:20% (determined
by LCMS; UV).
To a solution of 9 (0.303 g, 1.00 mmol) in 2-MeTHF (2.5 mL) was add-
ed dropwise i-PrMgCl·LiCl (0.73 M in THF, 1.28 mL, 0.93 mmol)
at –10 °C. The exchange reaction was followed by LCMS analysis and,
after 45 min, the mixture was diluted with CH2Cl2 (10 mL). A solution
of (RS)-2 (0.194 g, 0.67 mmol) in CH2Cl2 (5 mL) was then added slowly
and the mixture was stirred for 4 h at –10 °C after which sat. aq NH4Cl
(5 mL) was added. The mixture was diluted with CH2Cl2 (35 mL), the
phases were separated, and the aqueous phase was extracted with
CH2Cl2 (2 × 35 mL). The combined organic phases were washed with
brine and the organic volatiles were removed in vacuo to provide a
yellow oil that was subjected to silica gel chromatography (120 g SiO2;
EtOAc–heptanes, 10–100%) followed by examination of the UV-active
fractions by LCMS. Combination of the desired fractions and removal
of solvents in vacuo provided (RS,S)-3c.
1H NMR (600 MHz, CDCl3): δ = 8.09 (d, J = 2.5 Hz, 1 H), 7.58 (dd,
J = 8.5, 2.5 Hz, 1 H), 6.73 (d, J = 8.5 Hz, 1 H), 4.56–4.53 (m, 1 H), 3.91
(s, 3 H), 3.72 (d, J = 5.3 Hz, 1 H), 3.61 (ddd, J = 10.5, 6.6, 5.3 Hz, 1 H),
3.51 (ddd, J = 10.5, 6.8, 5.3 Hz, 1 H), 2.17 (dtd, J = 12.2, 6.6, 5.3 Hz,
1 H), 1.92 (dtd, J = 12.2, 6.8, 5.3 Hz, 1 H), 1.18 (s, 9 H), 0.86 (s, 9 H),
0.00 (s, 3 H), –0.01 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 163.89, 145.78, 137.99, 130.46,
111.09, 59.67, 56.04, 54.12, 53.61, 39.33, 26.02, 22.69, 18.34, –5.27,
–5.31.
LCMS: m/z = 401.4 [M + H]+ (tR 0.92 min; UV).
HRMS (ESI): m/z [M + H]+ calcd for C19H37N2O3SSi: 401.2289; found:
401.2280.
Yield: 0.137 g (0.29 mmol, 44%); colorless oil.
1H NMR (600 MHz, CDCl3): δ = 8.29 (d, J = 2.8 Hz, 1 H), 7.30 (d,
J = 8.5 Hz, 1 H), 7.22 (dd, J = 8.5, 2.8 Hz, 1 H), 4.70 (dt, J = 7.5, 5.4 Hz,
1 H), 4.61 (d, J = 5.4 Hz, 1 H), 4.39 (q, J = 8.0 Hz, 2 H), 3.69 (ddd,
J = 10.4, 5.9, 4.4 Hz, 1 H), 3.62 (ddd, J = 10.6, 8.0, 4.4 Hz, 1 H), 2.14
(dtd, J = 14.2, 7.5, 4.4 Hz, 1 H), 2.09–2.03 (m, 1 H), 1.17 (s, 9 H), 0.87
(s, 9 H), 0.03 (s, 3 H), 0.01 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 155.79, 152.68, 137.54, 123.12 (q,
J = 278.0 Hz), 122.62, 122.42, 66.23 (q, J = 36.0 Hz), 61.17, 58.91,
39.59, 26.10, 22.78, –5.24, –5.26.
19F NMR (471 MHz, CDCl3): δ = –74.39.
LCMS: m/z = 469.1 [M + H]+ (tR 0.94 min; UV).
HRMS (ESI): m/z [M + H]+ calcd for C20H36F3N2O3SSi: 469.2163; found:
469.2157.
(SS)-N-{(R)-3-[(tert-Butyldimethylsilyl)oxy]-1-(pyridin-2-yl)pro-
pyl}-2-methylpropane-2-sulfinamide (3b)
To a solution of 2-iodopyridine (2.67 g, 13.01 mmol) in 2-MeTHF (23
mL) was slowly added i-PrMgCl·LiCl (0.73 M in THF, 16.56 mL, 12.09
mmol) at –10 °C. Generation of the active nucleophile was followed
by LCMS analysis and, after 1 h, the solution was diluted with ice-cold
CH2Cl2 (200 mL), which was transferred by using a cannula followed
by the addition of (SS)-2 (2.71 g, 9.30 mmol) in CH2Cl2 (20 mL). The
reaction mixture was stirred for 5 h then sat. aq. NH4Cl (30 mL) was
added, the phases were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (2 × 100 mL). The combined organic phases were
concentrated in vacuo and purified by silica gel chromatography
(330 g SiO2; EtOAc–heptanes, 10–100%; eluting at ca. 60% EtOAc–hep-
tanes). Examination of the UV-active fractions by LCMS followed by
evaporation of volatiles in vacuo afforded (SS,S)-3b and (SS,R)-3b.
(SS)-N-{(R)-3-[(tert-Butyldimethylsilyl)oxy]-1-[5-(2,2,2-trifluoro-
ethoxy)pyridin-2-yl]propyl}-2-methylpropane-2-sulfinamide
[(SS,R)-3c]
Major Isomer (SS,R)-3b
Yield: 1.79 g (4.83 mmol, 52%); yellow oil.
To a solution of 9 (2.21 g, 7.29 mmol) in 2-MeTHF (20 mL) was added
dropwise i-PrMgCl·LiCl (0.73 M in THF, 9.35 mL, 6.81 mmol) at –10 °C.
The exchange reaction was followed by LCMS analysis and, after 1 h,
the mixture was diluted with CH2Cl2 (110 mL). Subsequently, (SS)-2
1H NMR (600 MHz, CDCl3): δ = 8.57–8.55 (m, 1 H), 7.65 (td, J = 7.7,
1.8 Hz, 1 H), 7.33 (d, J = 7.7 Hz, 1 H), 7.17 (ddd, J = 7.7, 4.8, 0.9 Hz,
1 H), 4.72 (q, J = 5.5 Hz, 1 H), 4.68 (d, J = 5.5 Hz, 1 H), 3.70 (ddd,
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3238
K. Fjelbye et al.
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Synthesis
(1.42 g, 4.86 mmol) in CH2Cl2 (5 mL) was added slowly and the mix-
ture was stirred for 5.5 h at –10 °C. The reaction was quenched by the
addition of H2O (30 mL), then the mixture was diluted with CH2Cl2
(75 mL), the phases were separated, and the aqueous phase was ex-
tracted with CH2Cl2 (2 × 100 mL). The combined organic phases were
washed with brine, filtered, and the volatiles were removed in vacuo
to provide a yellow oil. The oil was purified by silica gel chromatogra-
phy (330 g SiO2; EtOAc–heptanes, 10–100%) followed by examination
of the UV-active fractions by LCMS. Collection of the desired fractions
and removal of solvent provided the major isomer (SS,R)-3c.
mmol) was added and the mixture was stirred for 30 min at 0 °C then
for 1 h at r.t. Sat. aq NH4Cl (5 mL) was then added, and the phases
were separated. The aqueous phase was extracted with EtOAc (2 × 75
mL) and the combined organic layers were dried over MgSO4, filtered,
and concentrated in vacuo. The resulting crude product was purified
by silica gel chromatography (EtOAc–heptanes, 5–80%) to afford 4.
Yield: 1.34 g (5.72 mmol, 81%); colorless oil.
1H NMR (600 MHz, CDCl3): δ = 8.33 (dd, J = 2.4, 0.7 Hz, 1 H), 7.77 (dd,
J = 8.7, 2.4 Hz, 1 H), 6.59 (dd, J = 8.7, 0.7 Hz, 1 H), 3.90 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 163.61, 152.84, 146.41, 113.52, 82.23,
53.76.
LCMS: m/z = 236.0 [M + H]+.
The spectroscopic data are in good accordance with literature.31
Yield: 0.900 g (1.92 mmol, 40%); colorless oil.
1H NMR (600 MHz, CDCl3): δ = 8.30 (d, J = 3.0 Hz, 1 H), 7.31 (d,
J = 8.6 Hz, 1 H), 7.23 (dd, J = 8.6, 3.0 Hz, 1 H), 4.73–4.69 (m, 1 H), 4.60
(d, J = 5.1 Hz, 1 H), 4.39 (q, J = 8.0 Hz, 2 H), 3.72–3.67 (m, 1 H), 3.65–
3.61 (m, 1 H), 2.15 (dtd, J = 12.0, 7.7, 4.4 Hz, 1 H), 2.10–2.04 (m, 1 H),
1.18 (s, 9 H), 0.88 (s, 9 H), 0.04 (s, 3 H), 0.02 (s, 3 H).
(R)-N-Allylidene-2-methylpropane-2-sulfinamide (5)
13C NMR (151 MHz, CDCl3): δ = 155.85, 152.69, 137.58, 122.63, 122.41
(coupling to fluorine not detected), 122.21, 66.26 (q, J = 36.0 Hz, 1C),
61.19, 58.92, 55.83, 39.62, 26.13, 22.82, –5.21, –5.23.
19F NMR (471 MHz, CDCl3): δ = –74.39.
LCMS: m/z = 469.1 [M + H]+ (tR 0.94 min; UV).
To a stirred solution of 3 (0.470 g, 2.00 mmol) in 2-MeTHF (30 mL)
was added i-PrMgCl·LiCl (0.73 M in THF, 2.56 mL, 1.88 mmol) drop-
wise at r.t. Generation of the active nucleophile was followed by LCMS
analysis by monitoring the dehalogenation after quenching in a vial of
MeOH. After 75 min, 7 (554 mg, 1.33 mmol) in 2-MeTHF (1.6 mL) was
added and the reaction mixture was stirred until the electrophile dis-
appeared on LCMS (ca. 1.5 h; the solution became clear yellow), after
which half-saturated aq NH4Cl (10 mL) was added and the phases
were separated. The aqueous phase was extracted with EtOAc (2 × 50
mL) and the organic layers were combined, washed with brine, dried
over MgSO4, concentrated in vacuo and purified by silica gel chroma-
tography (40 g SiO2; EtOAc–heptanes, 5–100%) followed by examina-
tion of the UV-active fractions by LCMS. Combination of UV-active
fractions provided the byproduct 5.
(RS)-N-{(R)-3-[(tert-Butyldimethylsilyl)oxy]-1-[6-(trifluorometh-
yl)pyridin-3-yl]propyl}-2-methylpropane-2-sulfinamide [(RS,R)-
3d]
To a solution of 5-bromo-2-(trifluoromethyl)pyridine (452 mg, 2.00
mmol) in 2-MeTHF (5 mL) was slowly added i-PrMgCl·LiCl (0.73 M in
THF, 2.56 mL, 1.87 mmol) at r.t. Generation of the active nucleophile
was followed by LCMS analysis and, after 1.25 h, the solution was
cooled to –10 °C and diluted with CH2Cl2 (25 mL), after which (RS)-2
(389 mg, 1.33 mmol) in CH2Cl2 (5 mL) was added. The mixture was
stirred for 5 h until complete conversion was observed, then aq NH4Cl
(5 mL) was added and the phases were separated. The aqueous phase
was extracted with CH2Cl2 (2 × 50 mL) and the organic layers were
combined, concentrated in vacuo and purified by silica gel chroma-
tography (120 g SiO2; EtOAc–heptanes, 10–100%) followed by exam-
ination of the UV-active fractions by LCMS. The desired fractions were
combined and concentrated in vacuo to afford (R)-3d contaminated
with the minor isomer (77:23).
Yield: 0.048 g (0.30 mmol, 23%); colorless oil.
1H NMR (600 MHz, CDCl3): δ = 8.20 (d, J = 9.3 Hz, 1 H), 6.70–6.61 (m,
1 H), 6.00–5.99 (m, 1 H), 5.98–5.96 (m, 1 H), 1.18 (s, 9 H).
13C NMR (151 MHz, CDCl3): δ = 164.39, 134.68, 131.76, 57.49, 22.54.
LCMS: m/z = 160.1 [M + H]+ (tR 0.52 min; UV).
The spectroscopic data are in accordance with literature.32
(6-Methoxypyridin-3-yl)(phenyl)methanol (6)
To a stirred solution of 3 (0.470 g, 2.00 mmol) in 2-MeTHF (30 mL)
was added i-PrMgCl·LiCl (0.73 M in THF, 2.56 mL, 1.88 mmol) drop-
wise at r.t. Generation of the active nucleophile was followed by LCMS
analysis by monitoring the dehalogenation after quenching in a vial of
MeOH. After 75 min, benzaldehyde (0.251 g, 0.24 mL, 2.36 mmol) in
2-MeTHF (2 mL) was added and the mixture was immediately ana-
lyzed by LCMS, which showed full conversion of 3. Sat. aq. NH4Cl (5
mL) was then added followed by H2O (20 mL) and the phases were
separated. The aqueous phase was extracted with EtOAc (2 × 50 mL)
and the organic layers were combined, washed with brine, dried over
MgSO4, concentrated in vacuo, and purified by silica gel chromatogra-
phy (40 g SiO2; EtOAc–heptanes, 10–100%) followed by examination
of the UV-active fractions by LCMS. The desired fractions were com-
bined and concentrated to afford 6.
Yield: 230 mg (0.523 mmol, 39%); yellow oil.
1H NMR (600 MHz, CDCl3): δ = 8.64 (d, J = 2.1 Hz, 1 H), 7.90 (dd,
J = 8.1, 2.1 Hz, 1 H), 7.62 (d, J = 8.1 Hz, 1 H), 4.70 (dt, J = 13.2, 6.8 Hz,
1 H), 4.24 (d, J = 6.8 Hz, 1 H), 3.63–3.58 (m, 1 H), 3.56–3.51 (m, 1 H),
2.12–2.06 (m, 1 H), 2.01–1.95 (m, 1 H), 1.15 (s, 9 H), 0.83 (s, 9 H),
–0.03 (s, 3 H), –0.04 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 149.14, 147.25 (q, J = 34.8 Hz), 141.42,
136.51, 124.70–118.66 (m), 61.59, 59.33, 56.37, 55.03, 39.35, 25.89,
22.55, 18.22, –5.42, –5.46.
LCMS: m/z = 439.4 [M + H]+ (tR 0.97 min; UV).
HRMS (ESI): m/z [M + H]+ calcd for C19H34F3N2O2SSi: 439.2057; found:
439.2055.
Yield: 0.372 g (1.73 mmol, 93%); yellow oil.
5-Iodo-2-methoxypyridine (4)
1H NMR (600 MHz, CDCl3): δ = 8.14 (d, J = 2.5 Hz, 1 H), 7.54 (ddd,
J = 8.6, 2.5, 0.4 Hz, 1 H), 7.39–7.32 (m, 4 H), 7.31–7.25 (m, 1 H), 6.73–
6.68 (m, 1 H), 5.82 (s, 1 H), 3.91 (s, 3 H), 2.37 (br, 1 H).
13C NMR (151 MHz, CDCl3): δ = 163.87, 145.27, 143.35, 137.54,
132.26, 128.77, 127.92, 126.41, 111.11, 73.94, 53.64.
To an ice-cooled solution of isopropylmagnesium chloride (1.61 M in
THF, 4.64 mL, 7.47 mmol) in THF (20 mL) was slowly added n-BuLi
(1.5 M in hexane, 4.98 mL, 7.47 mmol). The mixture was then stirred
for 5 min to give a yellow solution, then 5-bromo-2-methoxypyridine
(1.405 g, 0.98 mL, 7.10 mmol, 95%) was added and the resulting solu-
tion was stirred for 45 min at 0 °C. Molecular iodine (3.79 g, 14.94
LCMS: m/z = 216.0 [M + H]+ (tR 0.50 min; UV).
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Synthesis
The spectroscopic data are in good accordance with literature.33
Yield: 3.8 g (12.54 mmol, 90%); white crystals; mp 51.7–53.4 °C.
1H NMR (600 MHz, CDCl3): δ = 8.15 (d, J = 3.1 Hz, 1 H), 7.65 (dd,
J = 8.6, 0.4 Hz, 1 H), 6.98 (dd, J = 8.6, 3.1 Hz, 1 H), 4.38 (q, J = 7.9 Hz,
2 H).
(RS)-N-{3-[(tert-Butyldiphenylsilyl)oxy]propylidene}-2-methyl-
propane-2-sulfinamide (7)
13C NMR (151 MHz, CDCl3): δ = 154.14, 138.89, 135.26, 124.94, 122.91
(q, J = 278.1 Hz), 108.48, 66.21 (q, J = 36.3 Hz).
19F NMR (471 MHz, CDCl3): δ = –74.27.
A round-bottom flask was charged with (R)-2-methylpropane-2-sul-
finamide (1.68 g, 13.87 mmol), pyridinium p-toluenesulfonate (0.174
g, 0.69 mmol) and MgSO4 (8.35 g, 69.3 mmol) as a suspension in
CH2Cl2 (50 mL). To this mixture, a solution of 3-[(tert-butyldiphenylsi-
lyl)oxy]propanal (6.5 g, 20.80 mmol) in CH2Cl2 (15 mL) was added
dropwise at r.t. and the reaction mixture was stirred overnight then
filtered. The solute was concentrated in vacuo and subjected to puri-
fication by silica gel chromatography (120 g SiO2; EtOAc–heptanes,
10–80%). Investigation of the UV-active fractions by LCMS followed by
combination of those desired and concentration in vacuo afforded 7.
LCMS: m/z = 304.0 [M + H]+ (tR 0.68 min; UV).
Anal. Calcd for C7H5F3INO: C, 27.75; H, 1.66; N, 4.62. Found: C, 27.60;
H, 1.66; N, 4.49.
Acknowledgment
Yield: 4.16 g (10.01 mmol, 72%); colorless oil.
We would like to acknowledge The Process Department of H. Lund-
beck A/S, especially Mikkel Fog Jacobsen, PhD; Martin Juhl, PhD and
Anders E. Håkansson, PhD for insightful suggestions. Furthermore, we
would like to thank Heidi Lopez de Diego, PhD for helpful discussions,
Andrew Bond (Department of Pharmacy – UCPH) and Pharmorphix
for X-ray structure determinations.
1H NMR (600 MHz, CDCl3): δ = 8.14 (t, J = 4.7 Hz, 1 H), 7.68–7.63 (m,
4 H), 7.47–7.41 (m, 2 H), 7.41–7.37 (m, 4 H), 3.96 (td, J = 6.1, 1.4 Hz,
2 H), 2.77–2.73 (m, 2 H), 1.19 (s, 9 H), 1.03 (s, 9 H).
13C NMR (151 MHz, CDCl3): δ = 167.97, 135.68, 133.45, 129.89,
127.88, 60.56, 56.72, 39.38, 26.89, 22.49, 19.25.
LCMS: m/z = 416.3 [M + H]+ (tR 1.11 min; UV).
HRMS (ESI): m/z [M + H]+ calcd for C23H34NO2SSi: 416.2074; found:
416.2067.
Supporting Information
The spectroscopic data are in accordance with literature.21
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1378854.
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2-Bromo-5-(2,2,2-trifluoroethoxy)pyridine (8)
To a solution of 6-bromopyridin-3-ol (2.30 g, 13.23 mmol) in DMF (18
mL) was added Cs2CO3 (4.74 g, 14.55 mmol) in small portions. The re-
action mixture was stirred for 10 min after which 2,2,2-trifluoroethyl
trifluoromethanesulfonate (3.38 g, 14.55 mmol) in DMF (5 mL) was
added slowly. After stirring for 1 h at r.t., the suspension was poured
into H2O and the aqueous mixture was extracted with EtOAc (75 mL).
The organic phase was then washed with brine and dried over MgSO4
followed by removal of the volatiles in vacuo. The resulting crude ma-
terial was subjected to silica gel chromatography (120 g SiO2; EtOAc–
heptanes, 5–100%) followed by analysis of the UV active fractions by
LCMS. Combination of the desired fractions followed by concentra-
tion in vacuo provided 8.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 3231–3240