A scalable synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5- dihydrooxazole ((S)-t-BuPyOx) ligand

Article abstract of DOI:10.3762/bjoc.9.187

An efficient method for the synthesis of the (S)-4-(tert-butyl)-2-(pyridin- 2-yl)-4,5-dihydrooxazole ((S)-t-BuPyOx) ligand has been developed. Inconsistent yields and tedious purification in known routes to (S)-t-BuPyOx suggested the need for an efficient, dependable, and scalable synthetic route. Furthermore, a route suitable for the synthesis of PyOx derivatives is desirable. Herein, we describe the development of a three-step route from inexpensive and commercially available picolinic acid. This short procedure is amenable to multi-gram scale synthesis and provides the target ligand in 64% overall yield.

Full text of DOI:10.3762/bjoc.9.187

A scalable synthesis of the
(S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole
((S)-t-BuPyOx) ligand
Hideki Shimizu1,2, Jeffrey C. Holder1 and Brian M. Stoltz*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1637–1642.
1The Warren and Katharine Schlinger Laboratory for Chemistry and
doi:10.3762/bjoc.9.187
Chemical Engineering, Division of Chemistry and Chemical
Engineering, California Institute of Technology, Pasadena, California
Received: 06 June 2013
Accepted: 15 July 2013
Published: 12 August 2013
91125, USA and 2Shionogi & Co., Ltd. 1-3, Kuise Terajima 2-chome
Amagasaki, Hyogo 660-0813, Japan
Email:
Associate Editor: J. P. Wolfe
Brian M. Stoltz* - stoltz@caltech.edu
©
2013 Shimizu et al; licensee Beilstein-Institut.
*
Corresponding author
License and terms: see end of document.
Keywords:
asymmetric catalysis; diamine ligands; optimization; synthesis
Abstract
An efficient method for the synthesis of the (S)-4-(tert-butyl)-2-(pyridin-2-yl)-4,5-dihydrooxazole ((S)-t-BuPyOx) ligand has been
developed. Inconsistent yields and tedious purification in known routes to (S)-t-BuPyOx suggested the need for an efficient,
dependable, and scalable synthetic route. Furthermore, a route suitable for the synthesis of PyOx derivatives is desirable. Herein,
we describe the development of a three-step route from inexpensive and commercially available picolinic acid. This short proce-
dure is amenable to multi-gram scale synthesis and provides the target ligand in 64% overall yield.
Introduction
Pyridinooxazoline (PyOx) ligands represent a growing class of scale synthesis of (S)-t-BuPyOx was known (a number of
bidentate dinitrogen ligands used in asymmetric catalysis syntheses are known, including [26]). We sought to address this
[
1-23]. Recently, our laboratory reported the catalytic asym- shortcoming by developing an efficient route starting from a
metric conjugate addition of arylboronic acids to cyclic, cheap, commercially available precursor to pyridinooxazoline
β,β-disubstituted enones utilizing (S)-t-BuPyOx (1) as the chiral ligands. Herein, we report an efficient, highly scalable syn-
ligand (Figure 1) [24]. This robust reaction is insensitive to thesis of (S)-t-BuPyOx.
oxygen atmosphere, highly tolerant of water [25], and provides
cyclic ketones bearing β-benzylic quaternary stereocenters in Results and Discussion
high yields and enantioselectivities. While the reaction itself Initially, (S)-t-BuPyOx (1) was synthesized by methanolysis of
proved to be amenable to multi-gram scale, the ligand is not yet 2-cyanopyridine (2) to afford methoxyimidate 3, and subse-
commercially available and no reliable method for the large- quent acid-catalyzed cyclization to afford the (S)-t-BuPyOx
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Beilstein J. Org. Chem. 2013, 9, 1637–1642.
Figure 1: Initial PyOx synthesis and revised plan.
ligand (Figure 1) [27]. We found the yields of this reaction Satisfied with our ability to generate amide 4 on gram-scale
sequence to be highly variable, and the purification by silica gel with good yield, we turned our attention to the completion of
chromatography to be tedious. In the revised retrosynthesis, the synthesis. The cyclization of amide 4 to (S)-t-BuPyOx (1)
picolinic acid (5) was identified as a comparably priced, proved more challenging than anticipated. Activation of alcohol
commonly available surrogate for cyanopyridine 2. Amidation 4 as mesylate 9 (Table 2, entries 1,2) and tosylate 10 (Table 2,
of (S)-tert-leucinol (6) and picolinic acid (5) would generate entry 3) followed by in situ cyclization gave the desired prod-
amide 4, which upon cyclization would generate the ligand uct in low yield and incomplete conversion. This could poten-
framework.
tially result from ligand hydrolysis under the given reaction
conditions [29]. As an alternative to insitu cyclization of an
Initial efforts focused on the amidation reaction between activated intermediate, alcohol 4 was reacted with thionyl chlo-
(
(
S)-tert-leucinol and picolinic acid (5) via acid chloride 7 ride (Table 2, entries 4–10) to yield chloride 11, which was
Table 1), which was generated in situ by treatment of acid 5 isolated as the hydrochloric acid salt and dried under vacuum.
with a number of chlorinating agents. Oxalyl chloride (Table 1, This compound proved to be bench stable and was spectroscop-
entries 1,2) provided reasonable yields of amide 4, however bis- ically unchanged after being left open to oxygen atmosphere
acylation of (S)-tert-leucinol was observed as a common side and adventitious moisture for more than one week. Further-
product. Importantly, temperature control of this reaction more, chloride 11 proved to be a superior cyclization substrate.
(
Table 1, entry 2) allowed the isolation of 75% of desired A series of bases were screened. Organic amine bases (Table 2,
alcohol 4 in acceptable purity without the use of column chro- entries 4,5) and sodium hydride (Table 2, entry 6) provided
matography. Use of diphenyl chlorophosphate (Table 1, entries inadequate conversion and low yields, whereas hydroxide and
3
,5,6) also resulted in noticeable quantities of over-acylation alkoxide bases proved superior (Table 2, entries 7–10). Finally,
products, as well as the generation of a small amount of phos- sodium methoxide was chosen to be optimal, as slower rates of
phorylation of amide 4. These results encouraged us to explore hydrolysis of chloride 11 were observed when compared to the
alternative activation strategies to generate the desired amide use of potassium hydroxide.
bond. Adapting a procedure from Sigman, activation of acid 5
by treatment with isobutylchloroformate and N-methylmorpho- Attempts to purify ligand 1 via salt formation failed due to
line (anhydride 8) facilitated the desired transformation with the instability of the generated products [30]. Purification by silica
highest overall yield, with amide 4 being isolated in 92% yield, gel chromatography also proved challenging as up to 10% of
albeit requiring column chromatography [28].
crude ligand 1 was observed to decompose, even with the addi-
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Beilstein J. Org. Chem. 2013, 9, 1637–1642.
Table 1: Amidation reactions of picolinic acid.
entry
reagent
solvent 1/2
temp (°C)a
base
time (h)b
yield (%)c
1
2
3
4
5
6
7
(COCl)2
(COCl)2
DPCP
THF/THF
50
Et3N
Et3N
Et3N
none
none
Et3N
NMM
1
7
6
5
2
3
3
55
THF/THF
0 to rt
0 to rt
rt
75d
72
THF/THF
SOCl2
toluene/THF
THF/THF
trace
30
DPCP
50
DPCP
THF/THF
0 to rt
0 to rt
65d
92
iBuOCOCl, NMM
CH2Cl2/CH2Cl2
DPCP = diphenyl chlorophosphate, NMM = N-methylmorpholine. aTemperature for second step; bTime for second step; cIsolated yield; dPurification
by flash chromatography not required.
Table 2: Cyclization screen.
entry
conditions
R
temp (°C)
base
time (h)
yield (%)a
1
2
3
4
5
6
7
8
9
MsCl, Et3N, CH2Cl2
OMs
OMs
OTs
Clc
0 to 40
0 to 80
0 to 80
rt
Et3N
12
12
12
18
12
18
11
11
10
3
N.D.b
N.D.b
N.D.b
38
MsCl, Et3N, ClCH2CH2Cl
Et3N
TsCl, DMAP, Et3N, ClCH2CH2Cl
Et3N
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
SOCl2
DABCO
Clc
50
DBU
59
Clc
0 to 50
50
NaH, THF
5% KOH/EtOH
5% KOH/MeOH
25% NaOMe/MeOH
25% NaOMe/MeOH
60
Clc
58
Clc
50
62
Clc
50
71
10
Clc
50
72
MsCl = methanesulfonyl chloride, TsCl = 4-toluenesulfonyl chloride, DMAP = 4-dimethylaminopyridine, DABCO = 1,4-diazabicyclo[2.2.2]octane,
DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene. aIsolated yield; bIncomplete conversion; cIntermediate 11 isolated as HCl salt and dried under high
vacuum before use in cyclization reactions.
tion of triethylamine to the eluent. Finally, the use of neutral Conclusion
silica gel (American International Chemical ZEOprep ECO In conclusion, we have developed a concise, highly efficient
silica gel, 40–63 micron, $18/kg) allowed isolation of ligand 1 and scalable synthesis of the chiral ligand (S)-t-BuPyOx (1)
in high purity and with no observed decomposition.
(Figure 2). Efforts to further refine the synthesis by telescoping
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Beilstein J. Org. Chem. 2013, 9, 1637–1642.
Figure 2: Scale-up synthesis of (S)-t-BuPyOx.
the procedure and removing chromatographic purifications are 4.02–3.96 (m, 2H), 3.69 (m, 1H), 2.72 (br t, J = 6.5 Hz, -OH),
currently underway.
1.05 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 165.6, 149.7,
48.2, 137.6, 126.4, 122.6, 63.7, 60.6, 33.9, 27.1; IR (neat film,
NaCl): 3375, 2962, 1669, 1591, 1570, 1528, 1465, 1434, 1366,
289, 1244, 1088, 1053, 998 cm−1; HRMS (MultiMode
1
Experimental
1
ESI/APCI) m/z: [M + H]+ calcd for C12H19N2O2, 223.1447;
found, 223.1448; [α]25D −8.7 (c 1.17, CHCl3, >99% ee).
(
S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)picolinamide (4):
To a 200 mL round bottom flask was added picolinic acid
2.46 g, 20.0 mmol, 1.00 equiv), 50 mL CH2Cl2, and N-methyl-
(
morpholine (3.03 g, 30.0 mmol, 1.50 equiv). The reaction mix- (S)-N-(1-chloro-3,3-dimethylbutan-2-yl)picolinamide hydro-
ture was cooled to 0 °C in an ice bath and isobutyl chlorofor- chloride (11): A 500 mL 3-neck round bottom flask was
mate (3.14 g, 23.0 mmol, 1.15 equiv) was added dropwise over charged with a stir bar, amide alcohol 4 (8.89 g, 40.0 mmol,
3
0 min. Following complete addition, the reaction mixture was 1.00 equiv) and toluene (140 mL). The resulting clear solution
stirred for 30 min at 0 °C. In a separate flask, (S)-tert-leucinol was warmed to 60 °C. In a separate flask, SOCl2 (9.25 g,
(
(
2.58 g, 22.0 mmol, 1.10 equiv) was dissolved in CH2Cl2 80.0 mmol, 2.00 equiv) was diluted with toluene (20 mL). This
25 mL), and N-methylmorpholine (2.43 g, 24.0 mmol, solution was transferred slowly, dropwise, over 20 min to the
1
.20 equiv) was added. This solution was transferred dropwise vigorously stirring reaction mixture at 60 °C. The reaction mix-
over the course of 1 h to the cooled reaction mixture using a ture was stirred at 60 °C for 4 h, at which time the slurry was
syringe pump. The cooling bath was removed and the reaction cooled to ambient temperature, concentrated on a rotary evapo-
mixture was allowed to warm to room temperature and stirred rator under reduced pressure (40 °C, 40 mmHg), and dried
for 2 h. The mixture was quenched with an aqueous solution of under vacuum (0.15 mmHg) to give a white powder of amide
NH4Cl (10 g in 50 mL H2O) and the aqueous phase was chloride hydrochloric salt 11 (10.80 g, 98% yield). This ma-
extracted with CH2Cl2 (20 mL). The combined organic phase terial was used in the following step without purification.
was dried over Na2SO4 (5 g), filtered, and concentrated under 1H NMR (500 MHz, DMSO-d6) δ 8.70 (ddd, J = 4.8, 2.0,
reduced pressure. The residue was purified with flash silica gel 1.0 Hz, 1H), 8.66 (br d, J = 9.9 Hz, -NH), 8.10 (dt, J = 8.0,
column chromatography (4:1 hexanes/acetone) to afford amide 1.0 Hz, 1H), 8.06 (td, J = 7.5, 1.4 Hz, 1H), 7.66 (ddd, J = 7.4,
alcohol 4 as a white solid (4.10 g, 92% yield). Rf 0.32 with 4.8, 1.4 Hz, 1H), 4.08 (td, J = 9.9, 3.7 Hz, 1H), 3.97–3.90 (m,
3
:2 hexanes/acetone; mp 79.6–79.9 °C; 1H NMR (500 MHz, 2H), 0.93 (s, 9H); 13C NMR (125 MHz, DMSO-d6) δ 163.6,
CDCl3) δ 8.56 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.32 (br d, 149.0, 147.8, 138.1, 126.5, 122.0, 59.0, 44.9, 35.0, 26.3; IR
J = 8.9 Hz, -NH), 8.19 (dt, J = 7.8, 1.1 Hz, 1H), 7.85 (td, (neat film, NaCl): 3368, 2963, 1680, 1520, 1465, 1434, 1369,
J = 7.7, 1.7 Hz, 1H), 7.43 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 1285, 1239, 1087, 998 cm−1; HRMS (MultiMode ESI/APCI)
1640

Beilstein J. Org. Chem. 2013, 9, 1637–1642.
m/z: [M + H]+ calcd for C12H18ClN2O, 241.1108; found, Acknowledgements
This publication is based on work supported by NIH-NIGMS
R01GM080269-01), and the authors additionally thank
2
41.1092; [α]25D +39.4 (c 0.96, MeOH, >99% ee).
(
Amgen, Abbott, Boehringer Ingelheim, and Caltech for finan-
cial support. J.C.H. thanks the American Chemical Society
Division of Organic Chemistry for a graduate research fellow-
ship. We also thank Shionogi & Co., Ltd. for a research grant
and fellowship to H.S.
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