Development of an enantioselective hydrogenation route to (S)-1-(2-(methylsulfonyl)pyridin-4-yl)propan-1-amine

Article abstract of DOI:10.1021/op5001513

A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation employing the in-house-developed ligand MeO-BIBOP, and a mild epimerization-free deprotection of a propionamide using Koenig's procedure.

Full text of DOI:10.1021/op5001513

Article
pubs.acs.org/OPRD
Development of an Enantioselective Hydrogenation Route to (S)‑1-
(2-(Methylsulfonyl)pyridin-4-yl)propan-1-amine
Jonathan T. Reeves,* Zhulin Tan, Diana C. Reeves, Jinhua J. Song, Zhengxu S. Han, Yibo Xu,
Wenjun Tang, Bing-Shiou Yang, Hossein Razavi, Christian Harcken, Daniel Kuzmich, Paige E. Mahaney,
Heewon Lee, Carl A. Busacca, and Chris H. Senanayake
Departments of Chemical Development and Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road,
P.O. Box 368, Ridgefield, Connecticut 06877-0368, United States
S
* Supporting Information
ABSTRACT: A highly enantioselective enamide hydrogenation route to the title amine was developed. Highlights of the
synthesis include an efficient two-step synthesis of a 2-sulfonyl 4-pyridyl ethyl ketone, a simple enamide synthesis by direct
condensation of propionamide with a ketone, catalytic asymmetric enamide hydrogenation employing the in-house-developed
ligand MeO-BIBOP, and a mild epimerization-free deprotection of a propionamide using Koenig’s procedure.
workup, the product was obtained in 72% yield. The synthesis
of 6 from the analogous nitrile, 2-chloroisonicotinitrile, was also
possible but proceeded in lower yield with formation of larger
amounts of impurities.2 The installation of the methyl sulfone
group was initially accomplished by an SNAr reaction of
chloride 6 with aqueous NaSMe and catalytic Bu4NBr in
toluene to give an intermediate sulfide 7, which was not isolated
but directly oxidized by addition of AcOOH to give 3 in 69%
yield after crystallization.3 Other oxidants such as NaBO3·
4H2O/AcOH, MMPP, and H2O2/Na2WO4 were either less
effective or required tedious workup and isolation procedures.
While this route effectively provided initial quantities of 3,
the use of NaSMe, even as the more convenient aqueous
solution, was not desirable due to its potent stench, which
proved difficult to eliminate even with the most rigorous
containment procedures. A “stench-free” protocol was sub-
sequently explored in which NaSMe was replaced with thiourea
and iodomethane.4 Thus, heating chloride 6 with thiourea in
EtOH at 65 °C resulted in an SNAr reaction to give the
thiouronium salt 8 in 95% yield (Scheme 3). Conveniently, the
thiouronium salt was isolated simply by direct filtration of the
cooled reaction mixture. Treatment of a water solution of 8
with aqueous NaOH and MeI resulted in hydrolysis of the
thiouronium salt to the 2-mercaptopyridine sodium salt and
urea, with subsequent S-methylation to give the sulfide 7.
Again, 7 was not isolated but was directly oxidized by AcOOH
to give sulfone 3 in 70% yield after crystallization. This process
avoided the stench associated with the NaSMe process, as
thiourea and the thiouronium salt 8 were odorless solids.
Although the thiouronium route to 3 solved the odor issue of
the NaSMe route, it required two additional steps.
Furthermore, the oxidation with AcOOH posed a safety
concern for large-scale use.5 The introduction of the sulfone
group by an SNAr reaction with MeSO2Na was therefore
investigated.6 The reaction was initially attempted by heating
INTRODUCTION
■
As part of a recent drug development program, we required an
efficient synthesis of the intermediate chiral amine 1. The
retrosynthetic analysis of 1 is shown in Scheme 1. To set the
Scheme 1. Retrosynthetic analysis of 1
stereocenter, asymmetric hydrogenation of an N-acylated
enamide 4 was planned. Deacylation of the hydrogenation
product 5 would provide the target amine 1. The N-acylated
enamide 4 was planned to derive from ketone 3, which in turn
would ideally be derived from an inexpensive starting material,
such as 2-chloroisonicotinic acid 2. It was also desired to install
the sulfone moiety by an SNAr reaction, thereby avoiding
transition metal-catalyzed coupling processes.
DISCUSSION AND RESULTS
■
Installation of the Methyl Sulfone. The conversion of 2-
chloroisonicotinic acid to the corresponding ethyl ketone 6 was
accomplished by treatment of a cold THF solution of 2 with 2.2
equiv of EtMgCl (Scheme 2).1 Warming of the solution from
−20 to 20 °C effected complete consumption of the starting
material. After quenching with aqueous HCl and extractive
Received: May 12, 2014
© XXXX American Chemical Society
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Scheme 2. Synthesis of ethyl ketone 6 and sulfone 3
Scheme 3. Thiouronium route to methyl sulfone 3
chloride 6 and MeSO2Na in NMP. The conversion to sulfone 3
was slow under these conditions, however, reaching only 25%
conversion after 24 h at 130 °C (Table 1, entry 1).
and subsequent reductive acylation, most commonly with Fe as
the reductant.8 While oxime formation from 3 proceeded
smoothly, the reductive acetylation using either Fe powder or
Fe(OAc)2 proceeded in 11−28% yield with formation of
significant impurities (Scheme 4).
Table 1. SNAr Reaction of 6 with MeSO2Na
Scheme 4. Formation of enamide 10a via oxime formation/
reductive acylation
conversion
yield
b
a
entry
conditions
NMP, 130 °C, 24 h
CuI (1 equiv), NMP, 130 °C, 24 h
Bu4NCl (0.3 equiv), HCl (1 equiv), DMAc,
130 °C, 24 h
(%)
(%)
1
2
3
25
<5
50
−
−
−
We recently developed a titanium-mediated enamide
formation using ammonia in place of hydroxylamine.9 Treat-
ment of the ketone with Ti(Oi-Pr)4 and methanolic NH3
effects formation of an imine which is subsequently N-
acetylated on addition of Et3N and Ac2O. This process
unfortunately gave only a 35% yield of 10a, consistent with
our observation that highly electron-deficient ketones give
decreased yields (Scheme 5).
4
5
6
Bu4NCl (0.3 equiv), DMAc, 130 °C, 48 h
H2O/AcOH (5:1 v/v), 110 °C, 46 h
AcOH, 110 °C, 5 h
95
97
95
b
52
80
66
a
Conversion of 6 to 3 as measured by HPLC analysis. Isolated yield
of 3 after crystallization from the reaction mixture.
Interestingly, the addition of stoichiometric CuI to the reaction
resulted in almost complete suppression of the displacement
(entry 2). Application of the conditions developed by Maloney
and Kuethe (Bu4NCl, DMAc, MeSO2Na, HCl) gave an
improved conversion of 50% after 24 h at 130 °C but with
concomitant formation of several impurities (entry 3).7 By
omitting the HCl, however, the reaction proceeded more
cleanly, and a 95% conversion was achieved after 48 h at 130
°C (entry 4). The product could be isolated in 52% yield by
crystallization upon addition of water to the reaction mixture.
The use of a water/AcOH (5:1 v/v) mixture as solvent led to a
similar acceleration of the displacement compared to the
Bu4NCl conditions, and the product could be isolated in 80%
yield after crystallization (entry 5). These conditions were
optimal in terms of yield and also because they avoided the use
of costly Bu4NCl. Interestingly, switching to pure AcOH as
solvent (entry 6) dramatically accelerated the reaction, but
caused the formation of impurities which reduced the overall
yield.
Scheme 5. Titanium-mediated formation of enamide 10a
with NH3 and Ac2O
The direct condensation of acetamide with ketones is
perhaps the simplest and most direct route to N-acetyl
enamides. Unfortunately, this reaction generally proceeds in
very low yields for the majority of ketones.10 Notable
exceptions are 2-tetralone and 3-chromanone substrates,
which have been shown to give the corresponding N-acetyl
enamides in high yields.11 Despite the discouraging precedent
for efficient enamide formation via this avenue, the
condensation of 3 with acetamide was explored. Refluxing a
mixture of 3, acetamide, and 0.1 equiv of TsOH in toluene with
azeotropic removal of water, a 94% conversion to 10a was
achieved after 8 days. During this time, it was noted that
Enamide Preparation. With the ketone 3 in hand, the
synthesis of the requisite enamide was investigated. The
traditional approach to N-acetyl enamides from ketone starting
materials involves the conversion of the ketone to a ketoxime,
B
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Table 2. Condensation of Amides with Ketone 3
a
b
c
Conversion of 3 to 10 as measured by HPLC analysis. Isolated yield after crystallization. Crystallization yield not optimized.
acetamide was collecting in the receiver. Consequently,
additional acetamide was added to the reaction mixture
periodically to compensate for the quantities lost by apparent
sublimation or codistillation with toluene. While the reaction
was very slow, it was nonetheless quite clean, and this
encouraged further exploration of the reaction. It was reasoned
that the use of higher-molecular weight amides might result in a
faster reaction by avoiding the codistillation with toluene
(Table 2). Thus, propionamide (entry 2), isobutyramide (entry
3), and pivalamide (entry 4) were tested in the enamide
formation. All three of these amides gave much faster
conversions to their respective enamides, reaching 86−92%
conversion after 24−48 h. Propionamide gave a 62% isolated
yield of 10b after crystallization as a single Z-olefin isomer.
Trifluoroacetamide (entry 5) gave no detectable product,
presumably due to the low nucleophilicity of the amide.
Due to its superior performance in both the hydrogenation
and deprotection reactions (vide infra), propionamide-derived
10b was deemed the optimal substrate. A screen of alternative
acid catalysts for the enamide formation (H2SO4, HCl, HBr,
H3PO4, TfOH, Tf2NH, Amberlyst 15 resin) showed H2SO4 to
be most effective. The optimum process involved azeotropically
distilling a mixture of 3, propionamide (2 equiv), concentrated
H2SO4 (0.1 equiv), and toluene for 24−48 h (85−94%
conversion). On addition of i-PrOH, Et3N (0.2 equiv) and
water to the cooled reaction mixture, the product directly
crystallized out in 70% yield (Scheme 6).
Scheme 6. Optimized conditions for synthesis of N-
propionyl enamide 10b
pressure of 450 psi (31 bar) were employed for the screening
studies. Using N-propionyl enamide 10b as substrate, the
patent-free ligands dipamp (11), skewphos (12), and norphos
(13) (Figure 1) were examined in CH2Cl2 as solvent (entries
1−3), with dipamp providing the best selectivity (68% ee
favoring the R-enantiomer). We have developed the BIBOP
series of ligands and demonstrated their efficiency in the
catalytic asymmetric hydrogenation of a variety of substrates,
including N-acetyl enamides.13 When MeO-BIBOP (14) was
employed, a dramatic increase in ee to >99.9% in favor of the
desired S-enantiomer was observed, keeping CH2Cl2 as solvent
(entry 4). Application of the same conditions to the analogous
N-acetyl (entry 5), N-isobutyryl (entry 6), and N-pivaloyl
(entry 7) enamides resulted in high ee’s for the acetyl and
isobutyryl enamides, but a drop to 87% ee was observed for the
more sterically demanding pivaloyl enamide.
Since the propionyl enamide 10b was the optimal substrate
for enamide formation, its hydrogenation was further
optimized. On lowering the catalyst loading below 5 mol %
with CH2Cl2 as solvent, the ee dropped significantly. We
subsequently found that the catalyst loading could be reduced
without sacrificing enantioselectivity by switching the solvent to
MeOH. In this case, even at 0.05 mol % catalyst, a 97% ee was
Enantioselective Hydrogenation of Enamide and
Deprotection. The enamides were then subjected to catalytic
asymmetric hydrogenation.12 Selected screening results for the
effects of different ligands, solvents, and catalyst loadings on
enantioselectivity are shown in Table 3. The precatalyst
rhodium bis(norbornadiene) tetrafluoroborate and a hydrogen
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Table 3. Enamide hydrogenation screening results
Table 4. Deprotection of 15b under acidic conditions
time
(h)
loss in ee
a
b
entry
1
conditions
conversion (%)
(%)
50% aq HCl, 90 °C
18
no product
formation
−
R
mol %
ee (%) of
product
a
entry (substrate) Rh(nbd)2BF4
ligand
solvent
CH2Cl2
2
3
4
5
50% aq H3PO4, 90 °C
50% aq H2SO4, 90 °C
48% aq HBr, 80 °C
MeOH, 50% aq HCl,
90 °C
24
18
67
29
>95
>95
92
34
22
2
b
1
2
Et (10b)
Et (10b)
5
5
(S,S)-dipamp
(11)
68
b
(R,R)-
skewphos
(12)
CH2Cl2
53
97
8
b
3
Et (10b)
Et (10b)
Me (10a)
i-Pr (10c)
t-Bu (10d)
Et (10b)
Et (10b)
Et (10b)
Et (10b)
5
(S,S)-norphos
(13)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOH
MeOH
MeOH
MeOH
37
6
7
n-PrOH, 50% aq HCl,
90 °C
i-PrOH, 50% aq HCl,
90 °C
16
22
95
93
20
13
4
5
MeOBIBOP
>99.9
97
(14)
a
b
5
5
MeOBIBOP
Conversion as measured by HPLC. [% ee of 15b] − [% ee of 1].
(14)
6
5
MeOBIBOP
96
(14)
requiring 67 h to reach complete conversion (entry 4). The use
of an alcohol cosolvent with HCl was explored. It was found
that an equal volume of MeOH with 50% HCl gave a clean,
albeit slow, conversion to 1 with about 8% loss in ee (entry 5).
Using n-PrOH or i-PrOH, however, gave much more
epimerization (entries 6−7).
7
5
MeOBIBOP
87
(14)
8
1
MeOBIBOP
98
(14)
9
0.1
0.05
0.01
MeOBIBOP
98
(14)
10
11
MeOBIBOP
97
The optimal conditions for deprotection still posed
significant challenges. The product amine was highly water
soluble, and recovering it from the aqueous solution was
tedious. As a result, the isolated yield of 1 was low (25−30%).
Furthermore, the loss of ee necessitated an upgrade in chiral
purity. The HCl salt of 1 was a hygroscopic solid, however, and
was not amenable to recrystallization. In 2009, Koenig and co-
workers reported a mild deprotection of secondary acetamides
via conversion to the corresponding imidoyl chlorides and
subsequent in situ alcoholysis.15 This procedure is run at mild
temperatures (0 °C to rt) and was shown to avoid
epimerization in sensitive substrates. Gratifyingly, application
of Koenig’s protocol to propionamide 15b resulted in a fast
(<20 min) and clean deprotection reaction. After addition of
propylene glycol and warming to rt, the product crystallized out
and was isolated by direct filtration in 86% yield (Scheme 7).
Interestingly, the product 1a was obtained as a 1:1 cocrystal
with pyridinium hydrochloride. The stoichiometry of the
cocrystal was consistent with elemental analysis data. In
contrast to the hygroscopic HCl salt of 1 obtained by acid
hydrolysis of 15b, the pyridinium hydrochloride cocrystal 1a
was a nonhygroscopic white solid. Furthermore, the product
was obtained with no loss in chiral purity: 98% ee starting
propionamide provided 98% ee amine. Notably, application of
(14)
MeOBIBOP
94
(14)
a
b
Ratio of ligand to catalyst = 1.1:1. The R-enantiomer of 15b was the
major enantiomer.
achieved (entry 10). Further reduction of the loading to 0.01
mol % (entry 11) resulted in a 94% ee. Thus, for substrate 10b,
a loading of 0.05 to 0.1 mol % was deemed optimal.
The final step was the deprotection of the propionyl group to
give the free amine. Traditionally this conversion is
accomplished by acidic or basic hydrolysis at elevated
temperatures.14 Attempted hydrolysis of 15b under basic
conditions quickly led to hydrolytic displacement of the
sulfone moiety under all conditions. Efforts were therefore
focused on acidic conditions (Table 4). The use of 50%
aqueous HCl at 90 °C led to complete decomposition of the
starting material, due to hydrolysis of the sulfone group (entry
1). With 50% aqueous H3PO4, deprotection occurred but was
accompanied by pronounced epimerization, with a 34% loss in
enantiomeric excess (entry 2). Sulfuric acid also caused a
significant amount of epimerization (entry 3). Aqueous HBr at
80 °C caused little loss in ee, but the reaction was quite slow,
Figure 1. Ligand structures.
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mm × 150 mm, column temperature 25 °C, isocratic 90:10
heptane/1-propanol, 2 mL/min; (R)-enantiomer: 5.82 min,
(S)-enantiomer: 8.83 min. Chiral purity determination of 1 was
done using the following method: Chirosil SCA (−) column,
4.6 mm × 250 mm, 20 °C, 95:5 0.5% HClO4/methanol, 1 mL/
min; (S)-enantiomer: 4.68 min, (R)-enantiomer: 6.14 min.
1-(2-Chloropyridin-4-yl)propan-1-one (6). A slurry of 2-
chloroisonicotinic acid 2 (115.0 g, 730.0 mmol) in THF (460
mL) was cooled to −20 °C. EtMgCl solution (800.0 mL, 2.0 M
in THF, 1600 mmol, 2.2 equiv) was added at a rate to control
the internal temperature at ≤5 °C. The reaction mixture was
warmed to 20 °C and stirred for 4 h. The reaction mixture was
cooled to 0 °C and treated over 10 min with EtOAc (75 mL) to
quench residual EtMgCl (CAUTION: ethane gas evolution;
explosion danger), followed by a solution of conc. HCl (230
mL) in water (460 mL). The resultant mixture was
concentrated under vacuum at 45−50 °C to remove THF,
and the residual aqueous phase was extracted with EtOAc (2 ×
460 mL). The combined organic phases were concentrated
under vacuum at 45−50 °C to give a solution of 6 in EtOAc
(143.5 g, 62.3 wt % purity by assay, 72% yield) which was used
directly in the next step. A pure sample of 6 was obtained by
concentration to dryness of the EtOAc solution followed by
crystallization from cold (0 °C) heptane to give 6 as an off-
Scheme 7. Mild Deprotection of 15b using Koenig’s Method
these deprotection conditions to isobutyramide 15c and
pivalamide 15d gave 1 in 16% and 0% yield, respectively.
The presence of at least two α-protons in the amide appears
critical to the success of the imidoyl chloride formation. This is
in concurrence with the observation of Koenig that benzamides
were unchanged under the reaction conditions. The presence of
the equivalent of pyridinium hydrochloride was tolerated in
subsequent reactions.
CONCLUSION
■
The optimal route to 1a is shown in Scheme 8. Highlights of
the route are (1) the use of inexpensive 2-chloroisonicotinic
acid as starting material; (2) a direct incorporation of the
methyl sulfone via an SNAr reaction of chloride 6 with sodium
methanesulfinate; (3) a simple synthesis of enamide 10b by
direct condensation with propionamide; (4) a highly
enantioselective hydrogenation of N-propionyl enamide 10b
using the novel in-house developed ligand 14; (5) the efficient
and epimerization-free deprotection of the propionyl group
using Koenig’s procedure. The use of propionamide or other
primary amides instead of acetamide for enamide formation by
direct condensation with ketones is a variation which may
prove useful for other electron-poor ketone substrates.
1
white solid. Mp 33−35 °C; H NMR (400 MHz, CDCl3) δ
8.49 (d, J = 5.1 Hz, 1 H), 7.69 (s, 1 H), 7.60 (dd, J = 1.3, 5.1
Hz, 1 H), 2.94 (q, J = 7.1 Hz, 2 H), 1.17 (t, J = 7.1 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ 198.6, 152.8, 150.9, 145.6,
122.3, 119.9, 32.5, 7.7; HRMS: calcd for C8H9ClNO [M + H]:
170.0367. Found: 170.0374.
1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-one (3). A
flask was charged with 6 (50.0 g, 294.8 mmol), Bu4NBr (4.75 g,
14.7 mmol) and toluene (200 mL). To the resultant solution
was added aqueous NaSMe solution (179.0 g, 15.0 wt % in
water, 383.2 mmol, 1.3 equiv), and the reaction mixture was
heated at 75 °C for 8 h. After cooling to rt, the lower aqueous
phase was separated and discarded. The remaining toluene
solution was cooled to 0 °C and treated slowly with AcOOH
solution (136.4 mL, 32 wt % in AcOH, 648.6 mmol, 2.2 equiv).
The reaction mixture was allowed to warm to rt and stirred at rt
overnight. EtOAc (200 mL) and brine (200 mL) were added,
and the lower aqueous phase was removed. The organic phase
was washed with saturated aqueous NaHCO3 (200 mL). The
organic phase was concentrated by distillation under vacuum to
a volume of about 200 mL. Water (50 mL) and heptane (250
EXPERIMENTAL SECTION
■
General Information. HPLC analysis for reaction mon-
itoring and purity determination was performed on an Agilent
1100 LC system with the following method: TSK-gel
SuperODS column (ID 4.6 mm, length 5.0 cm), detection at
220 nm, run time 5 min, mobile phase A = water with 0.05%
TFA, mobile phase B = MeCN with 0.05% TFA, ramp from
10% B to 90% B in 3.5 min, hold at 90% B until 5 min, column
temperature 25 °C. Chiral purity determination of 15b was
done using the following method: Chiralpak AD-3 column, 4.6
Scheme 8. Optimized Route to 1a
E
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mL) were added, and the mixture was cooled to 0−5 °C. After
1 h, the resultant solid was filtered, washed with water and
heptane, and dried under vacuum at 25 °C to give 3 (43.3 g,
the solid was washed with water and dried under vacuum at 55
°C to give 9 (8.86 g, 92% yield) as a white solid. Mp 179−180
°C; 1H NMR (400 MHz, DMSO d6) δ 12.06 (br s, 1 H), 8.80
(d, J = 5.1 Hz, 1 H), 8.23−8.22 (m, 1 H), 7.91 (dd, J = 1.5, 5.1
Hz, 1 H), 3.30 (s, 3 H), 2.76 (q, J = 7.6 Hz, 2 H), 1.04 (t, J =
7.6 Hz, 3 H); 13C NMR (100 MHz, DMSO d6) δ 158.0, 155.5,
151.0, 145.5, 123.8, 116.3, 39.7, 17.6, 10.4; HRMS: calcd for
C9H13N2O3S [M + H]: 229.2735. Found: 229.2730.
1
69% yield) as white crystals. Mp 53−54 °C; H NMR (400
MHz, DMSO d-6) δ 9.03 (dd, J = 0.7, 5.1 Hz, 1 H), 8.33−8.32
(m, 1 H), 8.19 (dd, J = 0.7, 4.9 Hz, 1 H), 3.35 (s, 3 H), 3.19 (q,
J = 7.1 Hz, 2 H), 1.12 (t, J = 7.1 Hz, 3 H); 13C NMR (100
MHz, DMSO d6) δ 199.2, 158.7, 151.7, 144.9, 125.4, 117.8,
39.8, 32.0, 7.4; HRMS: calcd for C9H12NO3S [M + H]:
214.0532. Found: 214.0543.
(Z)-N-(1-(2-(Methylsulfonyl)pyridin-4-yl)prop-1-en-1-
yl)acetamide (10a). A mixture of ketone 3 (10.0 g, 46.9
mmol), acetamide (5.50 g, 93.1 mmol), TsOH·H2O (0.88 g,
4.64 mmol) and toluene (50 mL) was heated at 130 °C with
azeotropic removal of water for 8 days (192 h). The reaction
mixture was cooled to rt, diluted with CH2Cl2 (100 mL), and
washed with a solution of saturated aqueous NaHCO3 (50
mL). The organic phase was concentrated to dryness, and the
resultant solid was recrystallized from EtOAc/hexanes to give
2-(4-Propionylpyridin-2-yl)isothiouronium Chloride
(8). A flask was charged with 6 (100.0 g, 589.6 mmol),
thiourea (47.1 g, 619.1 mmol), and absolute EtOH (300 mL).
The mixture was heated at 65 °C for 18 h and cooled to rt. The
solid was filtered, washed with EtOAc, and dried under vacuum
at 25 °C to give 8 (137.5 g, 95% yield) as a tan solid. Mp 195−
1
198 °C; H NMR (400 MHz, DMSO d6) δ 9.66 (br s, 4 H),
1
8.84 (dd, J = 0.7, 5.1 Hz, 1 H), 8.12−8.11 (m, 1 H), 7.90 (dd, J
= 1.5, 5.1 Hz, 1 H), 3.11 (q, J = 7.1 Hz, 2 H), 1.08 (t, J = 7.1
Hz, 3 H); 13C NMR (100 MHz, DMSO d6) δ 199.7, 166.7,
152.0, 150.4, 144.7, 125.6, 121.7, 32.0, 7.5; HRMS: calcd for
C9H12N3OS [M − Cl]: 210.0696. Found: 210.0689.
10a (3.41 g, 29% yield, ∼95:5 mixture of Z: E isomers by H
NMR) as a white solid. Mp 141−144 °C; 1H NMR (500 MHz,
DMSO d-6) δ 9.44 (s, 1 H), 8.67 (d, J = 5.1 Hz, 1 H), 7.87 (s, 1
H), 7.68 (d, J = 5.1 Hz, 1 H), 6.38 (q, J = 6.9 Hz, 1 H), 3.28 (s,
3 H), 2.05 (s, 3 H), 1.77 (d, J = 6.9 Hz, 3 H); 13C NMR (125
MHz, DMSO d6) δ 168.5, 158.0, 150.2, 148.4, 132.4, 126.2,
123.2, 115.9, 39.7, 22.5, 13.8; HRMS: calcd for C11H15N2O3S
[M + H]: 255.0798. Found: 255.0807.
1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-one (3)
from 8. A flask was charged with 8 (100.0 g, 407.0 mmol)
and water (250 mL). A solution of NaOH (34.18 g, 854.5
mmol, 2.1 equiv) in water (200 mL) was prepared. One half of
this solution was charged to the reaction followed by MeI (27.9
mL, 447.7 mmol, 1.1 equiv). Then the remainder of the
aqueous NaOH solution was charged dropwise. The reaction
mixture was stirred at rt for 1 h, resulting in complete
conversion of 8 to 7 as determined by HPLC analysis. Toluene
(400 mL) was charged, and the lower aqueous phase was
removed. The toluene solution was then cooled to about 0 °C.
AcOOH solution (188.3 mL, 32 wt % in AcOH, 895.4 mmol,
2.2 equiv) was added slowly. The reaction mixture was allowed
to warm to rt and stirred at rt for 3 h. A solution of Na2SO3 (50
g) in water (200 mL) was charged. After 30 min, a solution of
NaOH (50 g) in water (50 mL) was added. The mixture was
extracted with EtOAc (2 × 400 mL). The combined organic
phases were concentrated by distillation under vacuum to a
volume of about 400 mL. Water (50 mL) and heptane (400
mL) were added, and the mixture was cooled to 0−5 °C. After
1 h, the resultant solid was filtered, washed with water and
heptane, and dried under vacuum at 25 °C to give 3 (60.8 g,
70% yield) as white crystals. Spectral data for 3 obtained by this
route were consistent with those listed above.
1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-one (3)
from 6. A flask was charged with 6 (10.0 g, 59.0 mmol),
MeSO2Na (14.2 g, 85 wt %, 117.9 mmol, 2.0 equiv), AcOH
(5.0 mL) and water (25 mL). The reaction mixture was heated
at 110 °C for 46 h. After cooling to rt, water (40 mL) and
heptane (5 mL) were added, and the mixture was cooled to 0
°C and held at this temperature for 1 h. The resultant solid was
filtered, washed with water and heptane, and dried under
vacuum at 25 °C to give 3 (10.1 g, 80% yield) as white crystals.
Spectral data for 3 obtained by this route were consistent with
those listed above.
(Z)-N-(1-(2-(Methylsulfonyl)pyridin-4-yl)prop-1-en-1-
yl)isobutyramide (10c). A mixture of ketone 3 (5.00 g, 23.4
mmol), isobutyramide (3.06 g, 35.2 mmol), TsOH·H2O (445
mg, 2.34 mmol) and toluene (30 mL) was heated at 130 °C
with azeotropic removal of water for 24 h. The reaction mixture
was cooled to rt, and water (20 mL) was added dropwise. After
stirring for 3 h at rt, the solid was filtered, washed with water
and heptane, and dried under vacuum at 45 °C to give 10c
(3.77 g, 57% yield, ∼98:2 mixture of Z: E isomers by 1H NMR)
1
as a tan solid. Mp 169−170 °C; H NMR (400 MHz, DMSO
d6) δ 9.36 (s, 1 H), 8.70 (d, J = 5.1 Hz, 1 H), 7.88 (d, J = 1.3
Hz, 1 H), 7.69 (dd, J = 1.7, 5.1 Hz, 1 H), 6.44 (q, J = 7.0 Hz, 1
H), 3.29 (s, 3 H), 2.69 (sept, J = 6.8 Hz, 1 H), 1.79 (d, J = 7.0
Hz, 3 H), 1.14 (d, J = 6.8 Hz, 6 H); 13C NMR (100 MHz,
DMSO d6) δ 175.4, 158.1, 150.2, 148.4, 132.2, 126.4, 122.9,
115.9, 39.7, 33.9, 19.5, 13.7; HRMS: calcd for C13H19N2O3S
[M + H]: 283.1111. Found: 283.1127.
(Z)-N-(1-(2-(Methylsulfonyl)pyridin-4-yl)prop-1-en-1-
yl)pivalamide (10d). A mixture of ketone 3 (5.00 g, 23.4
mmol), pivalamide (4.70 g, 46.5 mmol), TsOH·H2O (445 mg,
2.34 mmol) and toluene (30 mL) was heated at 130 °C with
azeotropic removal of water for 48 h. The reaction mixture was
cooled to rt, and EtOAc (10 mL) was added followed by
dropwise addition of water (20 mL). After stirring for 1 h at rt,
the solid was filtered, washed with water and heptane, and dried
under vacuum at 45 °C to give 10d (3.95 g, 57% yield, >99:1
mixture of Z: E isomers by 1H NMR) as a tan solid. Mp 174−
176 °C; 1H NMR (400 MHz, DMSO d6) δ 9.01 (s, 1 H), 8.68
(d, J = 5.2 Hz, 1 H), 7.86 (d, J = 1.5 Hz, 1 H), 7.67 (dd, J = 1.7,
5.2 Hz, 1 H), 6.52 (q, J = 6.9 Hz, 1 H), 3.28 (s, 3 H), 1.75 (d, J
= 6.9 Hz, 3 H), 1.24 (s, 9 H); 13C NMR (100 MHz, DMSO d6)
δ 176.8, 158.1, 150.3, 148.7, 132.4, 127.3, 122.7, 115.7, 39.7,
38.6, 27.2, 13.7; HRMS: calcd for C14H21N2O3S [M + H]:
297.1267. Found: 297.1286.
(E)-1-(2-(Methylsulfonyl)pyridin-4-yl)propan-1-one
oxime (9). A flask was charged with 3 (9.00 g, 42.2 mmol),
NH2OH·HCl (3.52 g, 50.6 mmol, 1.2 equiv) and EtOH (50
mL). To the resultant slurry was added 2 N aqueous NaOH
solution (23.2 mL, 46.4 mmol, 1.1 equiv). The reaction mixture
was stirred at rt for 20 h. The resultant slurry was filtered, and
Optimized Process for Propionyl Enamide Formation.
(Z)-N-(1-(2-(Methylsulfonyl)pyridin-4-yl)prop-1-en-1-yl)-
propionamide (10b). A mixture of ketone 3 (100.0 g, 469.0
mmol), propionamide (63.1 g, 863.0 mmol), and toluene (500
F
dx.doi.org/10.1021/op5001513 | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Article
mL) was treated with concentrated H2SO4 (2.56 mL, 46.4
mmol) at rt. The reaction mixture was then heated at 130 °C
with azeotropic removal of water for 48 h. The reaction mixture
was cooled to 60 °C, and isopropanol (60 mL) and water (60
mL) were added successively. The reaction mixture was cooled
to rt, stirred at rt for 1h, and the solid was filtered. The solid
was washed with isopropanol followed by toluene, and dried
under vacuum at 45 °C to give 10b (88.1 g, 70% yield, >99:1
enantiomer: 4.68 min, (R)-enantiomer: 6.14 min). Mp 184−
1
185 °C; H NMR (400 MHz, DMSO d6) δ 9.19 (br s, 3 H),
8.98−8.96 (m, 2 H), 8.85 (d, J = 5.0 Hz, 1 H), 8.67−8.62 (m, 1
H), 8.30 (s, 1 H), 8.13−8.09 (m, 2 H), 8.04 (dd, J = 1.6, 5.0
Hz, 1 H), 4.45 (br s, 1 H), 3.32 (s, 3 H), 2.14−2.04 (m, 1 H),
1.94−1.83 (m, 1 H), 0.78 (t, J = 7.6 Hz, 3 H), 0.88 (t, J = 7.4
Hz, 3 H); 13C NMR (100 MHz, DMSO d6) δ 158.1, 150.5,
149.9, 146.2, 141.6, 127.3, 126.7, 119.5, 54.3, 39.8, 27.0, 9.7;
HRMS: calcd for C9H15N2O2S [M − pyridinium HCl − HCl +
H]: 215.0849. Found: 215.0859. Anal. Calcd for
C14H21Cl2N3O2S: C, 45.90; H, 5.78; Cl, 19.36; N, 11.47; S,
8.75. Found: C, 45.67; H, 5.58; Cl, 19.24; N, 11.36; S, 8.60.
1
mixture of Z: E isomers by H NMR) as a white solid. Mp
123.5−124.5 °C; 1H NMR (400 MHz, DMSO d6) δ 9.39 (s, 1
H), 8.69 (dd, J = 0.5, 5.1 Hz, 1 H), 7.89 (d, J = 1.2 Hz, 1 H),
7.69 (dd, J = 1.8, 5.1 Hz, 1 H), 6.44−6.39 (m, 1 H), 3.30 (s, 3
H), 2.37 (q, J = 7.6 Hz, 2 H), 1.79 (d, J = 7.0 Hz, 3 H), 1.11 (t,
J = 7.6 Hz, 3 H); 13C NMR (100 MHz, DMSO d6) δ 172.3,
158.0, 150.2, 148.5, 132.3, 126.2, 123.1, 115.9, 39.7, 28.4, 13.8,
9.9; HRMS: calcd for C12H17N2O3S [M + H]: 269.0954.
Found: 269.0963.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(S)-N-(1-(2-(Methylsulfonyl)pyridin-4-yl)propyl)-
propionamide (15b). A 100 mL hydrogenation vessel was
charged with 10b (10.0 g, 37.3 mmol) and MeOH (20 mL). In
a glovebox, a vial was charged with rhodium bis-
(norbornadiene) tetrafluoroborate (13.9 mg, 0.0373 mmol,
0.1 mol %) and ligand 14 (18.3 mg, 0.041 mmol, 0.11 mol %).
MeOH (5 mL) was added to the vial, and the contents were
stirred for 30 min. The resultant solution was charged to the
hydrogenation vessel, and the vessel was then evacuated and
filled with hydrogen. The reaction mixture was hydrogenated
under 450 psi of hydrogen at 22 °C for 14 h. By HPLC analysis,
the starting material was fully consumed to product 15b. The
product was formed in 98% ee by chiral HPLC analysis
(Chiralpak AD-3 column, 4.6 mm × 150 mm, 25 °C, 90:10
heptane/1-propanol, 2 mL/min; (R)-enantiomer: 5.82 min,
(S)-enantiomer: 8.83 min). The solution was filtered through a
thin pad of Celite, and the pad was rinsed with additional
MeOH. The combined MeOH filtrates were concentrated
under vacuum to a thick oil (10.6 g, 95.0 wt %, quantitative
yield), which was generally used directly in the next step. A
pure sample of 15b was obtained by crystallization of the crude
oil from EtOAc/heptane. Mp 72−74 °C; 1H NMR (400 MHz,
DMSO d6) δ 8.72 (d, J = 4.9 Hz, 1 H), 8.42 (d, J = 7.9 Hz, 1
H), 8.00 (s, 1 H), 7.66 (dd, J = 1.2, 4.9 Hz, 1 H), 4.83 (q, J =
7.6 Hz, 1 H), 3.30 (s, 3 H), 2.26−2.12 (m, 2 H), 1.78−1.62 (m,
2 H), 1.01 (t, J = 7.6 Hz, 3 H), 0.88 (t, J = 7.3 Hz, 3 H); 13C
NMR (100 MHz, DMSO d6) δ 173.0, 158.0, 156.4, 150.1,
125.6, 117.9, 53.3, 39.6, 28.5, 28.4, 10.7, 9.9; HRMS: calcd for
C12H19N2O3S [M + H]: 271.1111. Found: 271.1120.
AUTHOR INFORMATION
Corresponding Author
*jonathan.reeves@boehringer-ingelheim.com
Notes
■
The authors declare no competing financial interest.
REFERENCES
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