Synthesis of β-disubstituted β-amino isoxazolyl ketones by addition of ketimines with isoxazolyl methyl ketone enolates

Article abstract of DOI:10.1016/j.tetlet.2014.02.053

A series of β-disubstituted N-sulfinyl β-amino isoxazolyl ketones has been prepared by addition of tert-butanesulfinyl ketimines with the n-BuLi-generated enolates of isoxazolyl methyl ketones.

Full text of DOI:10.1016/j.tetlet.2014.02.053

Tetrahedron Letters 55 (2014) 2134–2137
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Tetrahedron Letters
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Synthesis of b-disubstituted b-amino isoxazolyl ketones by addition
of ketimines with isoxazolyl methyl ketone enolates
Jason Guernon, Lawrence Marcin, Mendi Higgins, Fukang Yang, Jianliang Shi, Lawrence Snyder,
⇑
Lorin A. Thompson, Yong-Jin Wu
Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of b-disubstituted N-sulfinyl b-amino isoxazolyl ketones has been prepared by addition of tert-
butanesulfinyl ketimines with the n-BuLi-generated enolates of isoxazolyl methyl ketones.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 28 January 2014
Revised 10 February 2014
Accepted 16 February 2014
Available online 24 February 2014
Keywords:
N-Sulfinyl b-amino isoxazolyl ketone
tert-Butanesulfinyl ketimine
1-(3,5-Dimethylisoxazol-4-yl)ethanone
b-Aryl-b-methyl aminoalcohol
In a recent medicinal chemistry program, we required easy
access to enantiomerically pure b-aryl-b-methyl aminoalcohol 1
(Fig. 1). Our initial approach involved the diastereoselective
addition of the titanium enolate of methyl acetate to tert-butane-
sulfinyl ketimine 2 to give b-disubstituted N-sulfinyl-b-amino
ester 3 (Scheme 1).1,2 This ester was converted to aldehyde 4 in
two steps. However, a poor yield of the desired alcohol 5 was
obtained from addition of either (3,5-dimethylisoxazol-4-yl)mag-
nesium bromide or (3,5-dimethylisoxazol-4-yl)lithium to the
aldehyde 4. We also envisioned preparation of aminoalcohol 1 by
stereoselective reduction of the corresponding ketone 7, which
would be prepared by addition of metallated dimethyl isoxazole
to the Weinreib amide 6 (Scheme 2). Unfortunately, we were
unable to find conditions to effect this transformation in an
acceptable yield.3 More specifically, no addition was observed
when 5 was exposed to (3,5-dimethylisoxazol-4-yl)magnesium
bromide or (3,5-dimethylisoxazol-4-yl)lithium at temperatures
up to À40 °C. At higher temperature, decomposition of the isoxaz-
ole reagent occurred. As a result of the apparent challenge in using
the metallated dimethyl isoxazole species, we decided to change
the disconnection to avoid using these reagents. As shown in
Scheme 3, an alternate disconnection would involve addition of
the metal enolate of 1-(3,5-dimethylisoxazol-4-yl)ethanone (5) to
ketimine 2, which would provide a direct approach to the pro-
tected b-amino ketone 7 (Scheme 3). While ester enolate addition
OH
H2N
Br
N
O
F
F
1
Figure 1.
to sulfinyl aldimine/ketimine has become one of the most reliable
routes to enantiomerically pure b-substituted N-sulfinyl-b-amino
esters as demonstrated by the formation of adduct 3 from ketimine
2,2 the corresponding ketone enolate addition has been rarely uti-
lized presumably due to self aldol condensation of ketones under
reaction conditions. In 2003, Davis et al. reported a highly diaste-
reoselective addition of p-toluenesulfinyl aldimine with ketone
enolates.4–6 However, to our knowledge, there have been no exam-
ples involving ketimines to give b-dialkyl substituted b-amino ke-
tones such as 7. Moreover, all three methyl groups of ketone 8 are
prone to deprotonation, and selective enolate formation could be
challenging. This Letter describes our studies on the selective eno-
late formation of
ketimines.
8 and its addition to tert-butanesulfinyl
At the outset of this work, we explored the addition using the
titanium enolate of ketone 8 based on the precedent of the success-
ful addition of the titanium enolate of methyl acetate to ketimine
2.1 Treatment of ketone 8 with 2 equivalents (equiv) of LDA at
À78 °C generated the lithium enolate, and in situ transmetalation
with chlorotitanium triisopropoxide (2 equiv) presumably gave
⇑
Corresponding author. Tel.: +1 203 677 7485; fax: +1 203 677 7702.
E-mail address: yong-jin.wu@bms.com (Y.-J. Wu).
http://dx.doi.org/10.1016/j.tetlet.2014.02.053
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

J. Guernon et al. / Tetrahedron Letters 55 (2014) 2134–2137
2135
Table 1
Optimization of the addition of 2 to metal enolate of 8
O
S
HN
S
N
F
O
O
O
a
b,c
Br
Br
O
O
S
HN
S
N
O
N
F
O
8
O
F
F
F
Br
Br
F
2
N
3
base, THF
O
F
F
2
7
O
O
S
HN
S
HN
O
OH
d
Entry
Conditions
Isolated yield (%)
Br
Br
H
N
1
2
3
4
4
5
6
LDA, ClTi(Oi-Pr)3, À78 °C
0
0
O
F
F
F
F
LDA, ClTi(Oi-Pr)3, À78 °C to À40 °C
LDA, À78 °C
5
4
15
25
27
31
59
LDA, À78 °C to À40 °C
KHMDS, À78 °C
e
1
KHMDS, À78 °C to À40 °C
n-BuLi, À78 °C to À40 °C
Scheme 1. Reagents and conditions: (a) LDA (2 equiv), THF, À78 °C, ClTi(Oi-Pr)3
(2 equiv), À78 °C, 72%; (b) LiAlH4, ether, 0 °C, 82%; (c) Swern oxidation, 74%; (d) 4-
bromo-3,5-dimethylisoxazole, n-BuLi, À78 °C or magnesium, iodine, rt, THF; (e) 4 N
HCl, dioxane, <5% yield.
prepare the amine-free lithium enolate of ketone 8. Treatment of 8
with 1.05 equiv of n-BuLi in THF at À78 °C brought about enoliza-
tion with no appreciable formation of the adduct due to nucleo-
philic addition of n-BuLi. Reaction of this lithium enolate with
ketimine 2 at À78 °C for 30 min and then at À40 °C for 30 min gave
adduct 7 in 59% yield, a significant improvement over the reaction
with LDA or KHMDS.10 Again, the addition proceeded with high
diastereoselectivity (>20:1). The addition of the lithium enolate
to ketimine 2 was sluggish at À78 °C, so it was necessary to warm
the reaction mixture to À40 °C and maintain at that temperature
for 30 min. Also worth noting is the impact of the concentration.
In the studies reported by Davis et al., dilute concentration
(0.02 M) was typically used in the ketone enolate addition to aldi-
mines (to minimize self aldol condensation of ketones). This would
limit its applications on large scale reactions. In our case, similar
yields were obtained when the reaction was run between 0.02
and 0.5 M. Presumably, self condensation was minimized due to
complete enolate formation. The high concentration conditions al-
lowed us to make adduct 7 on a large scale (20 g).
O
O
S
HN
S
HN
O
O
b
a
Br
F
Br
F
3
N
OMe
N
O
F
F
7
6
Scheme 2. Reagents and conditions: (a) N,O-dimethyl-hydroxylamine hydrochlo-
ride (5 equiv), n-BuLi (10 equiv), THF, À60 °C, 60%; (b) 4-bromo-3,5-dimethylisox-
azole, n-BuLi or magnesium, iodine, <3%.
O
S
HN
S
O
N
F
O
+
O
N
base
Br
F
Br
N
O
O
F
F
8
7
2
In order to demonstrate the scope of the method, the n-BuLi-
generated lithium enolate of ketone 8 was added to a variety of
ketimines derived from aryl methyl ketones, and the results are
summarized in Table 2. In most cases, these reactions were run
only once as a sufficient quantity was obtained for our medicinal
chemistry analog purposes, and the yields were not optimized.
The additions worked well for ketimines bearing both electron-
withdrawing and electron-donating groups. The reaction condi-
tions are mild enough to tolerate a variety of functional groups
including nitro (entry 11) and nitrile (entries 6–7 and 15).
We also applied the addition of the n-BuLi-generated lithium
enolate of ketone 5 to ketimines derived from heteroaryl methyl
ketones (Table 3). The ketimines bearing all isomeric pyridyl
groups gave 39–51% yields (entries 1, 2, 4–9) with the exception
of 2-fluoro-pyridin-3-yl (19%, entry 3). The ketimine derived from
1-(pyrazin-2-yl)ethanone furnished the desired adduct in moder-
ate yield (31%, entry 10). Ketimines bearing halogen-substituted
thiophenes gave various yields: the highest (43%, entry 13) ob-
tained from 3-chloro-thiophen-2-yl, while the lowest from 2,5-
di-chloro-thiophen-3-yl (9%, entry 12). The N-protected pyrrole
heteroaryl also gave a moderate yield (32%, entry 15). Both oxa-
zole-4-yl (entry 16) and thiazol-4-yl (entry 17) delivered the best
yields in the heteroaryl series (56% and 63%, respectively). How-
ever, the unsubstituted isoxazole (entry 19) failed to provide any
desired adduct due to decomposition under basic conditions.
1,2,3-Thiadiazol-4-yl worked (8%, entry 20), but the yield was
low again due to a stability issue.
Scheme 3.
the more covalent titanium enolate. When ketimine 2 was added
to this enolate solution at À78 °C or À40 °C, no formation of the de-
sired adduct 7 was observed, and only the starting materials were
recovered. At higher temperatures, significant decomposition of
ketone 8 occurred.
We next turned to the lithium and potassium enolates which
were successfully added to aldimines in the studies reported by
Davis et al.4–6 Reaction of ketone 8 with KHMDS at À78 °C followed
by addition of ketimine 2 gave the desired adduct in 27–31% iso-
lated yields along with some recovered ketimine (Table 1). A some-
what lower yield (15–25%) was obtained when LDA was used to
generate the lithium enolate. Nevertheless, the addition was highly
diastereoslective as the other diastereomer was virtually undetect-
able by both LC/MS and 1H NMR analysis of the crude reaction mix-
ture. We speculated that the poor yield may partially result from
the proton transfer from the diisopropylamine or bis(trimethyl-
silyl)amine (HMDS) (released from the enolate formation) to the
metal enolate. This problem can be obviated by treatment of an
LDA-generated enolate with another equiv of n-BuLi to remove
the problematic NH proton.7 This methodology has been used to
improve the efficiency of enolate reactions such as alkylation8
and phenylselenation.9 Another approach is to generate amine-free
metal enolates. In many reactions with electrophiles, use of amine-
free enolates gives better results.7 With this in mind, we sought to

2136
J. Guernon et al. / Tetrahedron Letters 55 (2014) 2134–2137
Table 2
Table 4
Additions of ketimines derived from aryl methyl ketones with lithium enolate of 8
Additions of ketimines derived from alkyl methyl ketones with lithium enolate of 8
O
O
O
S
HN
O
S
HN
N
O
N
O
8
8
O
O
S
S
Ar
R
N
O
N
O
N
N
n-BuLi, THF
O
O
n-BuLi, THF
Ar
R
Entry
Ar
Ph
Isolated yield (%)
Entry
R
Isolated yield (%)
1
2
3
4
5
6
7
8
36
38
48
37
31
58
58
59
41
47
41
35
32
35
51
40
40
48
1
2
3
Methyl
Cyclohexyl
1-Methylcyclopropyl
35
13
10
o-F-phenyl
m-F-phenyl
p-F-phenyl
p-Cl-phenyl
m-CN-phenyl
p-CN-phenyl
3,5-Di-F-phenyl
3-F-5-Br-phenyl
o-F-m-Br-phenyl
o-NO2-p-F-phenyl
o-F-p-CF3-phenyl
o-F-p-CF3-phenyl
p-F-p-OMe-phenyl
p-F-m-CN-phenyl
2,3-Di-F-5-Br-phenyl
3,4-Di-F-5-Cl-phenyl
3,4,5-Tri-F-phenyl
N
Table 5
Additions of ketimines with lithium enolates of un- or mono-substituted isoxazolyl
methyl ketones
9
10
11
12
13
14
15
16
17
18
O
O
S
HN
N
O
O
R
S
Ar
N
O
N
n-BuLi, THF
O
Ar
R
Entry
Ar
R
Isolated yield (%)
1
2
3
4
5
2,4-Di-F-5-Br-phenyl
2,4-Di-F-5-Br-phenyl
o,p-Di-F-phenyl
o,p-Di-F-phenyl
o,p-Di-F-phenyl
H
Me
Me
Ph
0
47
58
58
45
N
19
46
F
F
o-Cl-Ph
The addition of the n-BuLi-generated lithium enolate of ketone
5 was extended to the ketimines derived from alkyl methyl
ketones (Table 4). In all these cases, the desired adducts were
obtained, but the yields were somewhat lower than the ketimines
derived from both aryl and heteroaryl ketones.
Table
5 describes additions involving unsubstituted and
monosubstituted isoxazolyl methyl ketones. The unsubstituted
1-(isoxazol-4-yl)ethanone failed to give the desired adduct due
to the fragmentation of the corresponding heteroaryl lithium re-
agent under the reaction conditions (entry 1). The monosubsti-
tuted isoxazolyl methyl ketones (entries 2–5) gave comparable
yields to those obtained with dimethyl isoxazolyl methyl ketone
8. This suggests that the deprotonation of the methyl ketone occurs
prior to that of the C3 hydrogen of the isoxazole ring system.
Table 6 describes additions involving other disubstituted isox-
azolyl methyl ketones. In general, the yields were comparable or
even superior to those obtained with 1-(3,5-dimethylisoxazol-4-
yl)ethanone. The advantage of using n-BuLi as the base is amply
demonstrated in the addition to the ketimine derived from 1-
(2,4-difluoro-5-(pyrimidin-5-yl)phenyl)ethanone (entry 6). When
LDA or KHMDS was added to 1-(3-methyl-5-(trifluoromethyl)iso-
xazol-4-yl)ethanone, only a negligible amount of the desired ad-
duct was formed. In contrast, the use of n-BuLi brought about
clean addition to give the desired adduct in 76% yield.
We also later found that diethyl ether is an acceptable solvent
for these additions, as a reaction of the lithium enolate of 8 with
the ketimine derived from 2,3-di-fluoro-5-bromophenylmethyl ke-
tone in diethyl ether gave the desired product in 98% yield on 10 g
scale (cf. 40% yield was obtained in THF on 5 g scale, Table 2, entry
16).
Having identified conditions for the preparation of the desired
ketone 7, we returned our attention to the production of the de-
sired aminoalcohol 1 (Scheme 4). The N-sulfinyl b-amino ketone
7 underwent highly stereoselective reduction with lithium tri-
tert-butoxyaluminum hydride in ether to give syn-1,3-N-sulfinyl-
Table 3
Additions of ketimines derived from heteroaryl methyl ketones with lithium enolate
of 8
O
O
S
HN
N
O
8
O
S
Het
N
O
N
O
n-BuLi, THF
Het
Entry
Het
Isolated yield (%)
1
2
3
4
5
6
7
8
3-Pyridyl
4-Pyridyl
2-F-pyridin-3-yl
48
57
19
47
46
51
39
44
39
31
15
9
43
23
32
56
63
33
0
6-F-pyridin-3-yl
6-CF3-pyridin-3-yl
5-Me-6-F-pyridin-3-yl
4-Br-pyridin-2-yl
3-F-pyridin-4-yl
4-Br-pyridin-2-yl
Pyrazin-2-yl
5-Cl-thiophen-3-yl
2,5-Di-Cl-thiophen-3-yl
3-Cl-thiophen-2-yl
5-Br-3-Cl-thiophen-2-yl
1-TMS(CH2)2OCH2-1H-pyrrol-2-yl
Oxazol-4-yl
9
10
11
12
13
14
15
16
17
18
19
20
b-amino alcohol
5
in 91% yield,11,12 and the sulfinyl group
Thiazol-4-yl
Thiazol-5-yl
Isoxazol-4-yl
1,2,3-Thiadiazol-4-yl
was removed to give syn-1,3-amino alcohol 1.13 Treatment of 1
with CDI gave cyclic carbamate 8. The syn-1,3-aminoalcohol
relative stereochemistry of 1 was determined by an NOE effect
8

J. Guernon et al. / Tetrahedron Letters 55 (2014) 2134–2137
2137
Table 6
In summary, we have developed a direct approach to the N-sul-
finyl b-amino isoxazolyl ketones by addition of tert-butanesulfinyl
ketimines with the n-BuLi-generated enolate of isoxazolyl methyl
ketones. This methodology provides easy access to a variety of
enantiomerically pure b-dialkyl substituted syn-1,3-b-amino alco-
hols bearing various isoxazoles, which are versatile building blocks
for medicinal chemistry research.
Additions of ketimines with lithium enolates of disubstituted isoxazolyl methyl
ketones
R2
O
O
S
HN
N
R2
N
O
O
R1
S
Ar
N
O
n-BuLi, THF
O
R1
Ar
Acknowledgments
Entry
Ar
R1
R2
Isolated yield (%)
We thank Dr. Xiaohua Huang for carrying out the NOE experi-
ments on carbamate 9 and Dr. John Macor for support.
1
2
3
o,p-Di-F-phenyl
o,p-Di-F-phenyl
o,p-Di-F-phenyl
N
Me
Et
CHF2
Et
Et
Me
54
42
41
References and notes
N
4
5
Me
Et
Et
Et
49
87
1. Audia, J. D.; Mergott. D. J.; Sheehan, S. M.; Watson, B. M. WO 2009/134617.
2. Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600–3740.
3. Davis, A. D.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang, B.; Bowen, K.; Lee, S.
H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
4. Davis, F. A.; Yang, B. Org. Lett. 2003, 5, 5011.
5. Davis, F. A.; Santhanaraman, N. J. Org. Chem. 2006, 71, 4222.
6. Davis, F. A.; Yang, B. J. Am. Chem. Soc. 2005, 127, 8398.
7. Seebach, D. Angew. Chem., Int. Ed. 1988, 27, 1624.
8. Aebi, J. D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1507.
F
F
F
F
N
N
F
N
9. Clive, D. L. J.; Tao, Y.; Khodabocus, A.; Wu, Y.-J.; Angoh, A. G.; Bennett, S. M.;
Boddy, C. N.; Bordeleau, L.; Kellner, D.; Kleiner, G.; Middleton, D. S.; Nichols, C.
J.; Richardson, S. R.; Vernon, P. G. J. Am. Chem. Soc. 1994, 116, 11275.
10. Representative procedure: To a solution of 8 (3.9 g, 27.7 mmol) in THF (36 mL) at
À78 °C was added n-BuLi (2.5 M solution in THF, 11.07 mL, 27.7 mmol), and
the reaction mixture was stirred at À78 °C for 20 min. A solution of ketimine 2
(5.2 g, 15.37 mmol) in THF (15 mL) was added dropwise over a period of 5 min,
and the reaction mixture was stirred at À78 °C for 30 min. The reaction
mixture was warmed up to À40 °C over 20 min period and stirred at À40 °C for
30 min. Water was added, the aqueous layer was extracted with ethyl acetate
(3 Â 100 mL). The combined organic layers were washed with brine, dried over
anhydrous sodium sulfate, and filtered, and the filtrate was evaporated in
vacuo to give the crude product. The crude product was purified by silica gel
chromatography eluting with 1–40% ethyl acetate/hexanes to give adduct 7
(4.3 g, 59% yield). 1H NMR (500 MHz, CDCl3) d 7.81 (t, J = 8.2 Hz, 1H), 6.82 (dd,
J = 12.2, 7.9 Hz, 1H), 5.48 (s, 1H), 3.95–3.84 (m, 1H), 3.64 (dd, J = 18.3, 2.9 Hz,
1H), 2.65 (s, 3H), 2.41 (s, 3H), 1.80 (s, 3H), 1.34 (s, 9H). MS (M+H) 479.2.
11. Davis, F. R.; Gaspari, P. M.; Nolt, B. M.; Xu, P. J. Org. Chem. 2008, 73, 9619.
12. To a solution of 7 (9.9 g, 20.7 mmol) in ether (46.1 mL) at À78 °C was added
lithium tri-tert-butoxyaluminum hydride (1.0 M solution in THF, 83.0 mL,
83.0 mmol) dropwise, and the reaction mixture was stirred at À78 °C for
10 min and then warmed to À20 °C over a period of 1 h. The reaction mixture
was diluted with 100 mL ether, and crystals of sodium sulfate decahydrate
(0.5 g) were added, and the reaction mixture was stirred at rt for 12 h and then
filtered. The filtrate was evaporated in vacuo to give 5 (29.0 g, 91% yield) as a
white foam. 1H NMR (500 MHz, CDCl3) d 7.68 (t, J = 8.0 Hz, 1H), 6.88 (dd,
J = 11.8, 8.0 Hz, 1H), 5.41 (s, 1H), 5.11–5.01 (m, 1H), 4.28 (d, J = 3.2 Hz, 1H), 2.59
(dd, J = 14.8, 10.4 Hz, 1H), 2.39 (s, 3H), 2.30 (s, 3H), 2.04 (s, 3H), 1.94–1.88 (m,
1H), 1.28 (s, 9H). MS (MÀH) 479.2.
N
6
7
CF3
Me
Me
Ph
76
65
F
O
Et
N
Et
8
9
o,p-Di-F-phenyl
o,p-Di-F-phenyl
p-F-phenyl
o,p-Di-F-phenyl
o,p-Di-F-phenyl
o,p-Di-F-phenyl
p-F-phenyl
o,p-Di-F-phenyl
o,p-Di-F-phenyl
o,p-Di-F-phenyl
Me
Me
Me
Me
Me
Me
Me
Ph
p-Tolyl
p-F-Ph
p-F-Ph
p-OMe-Ph
m-Cl-Ph
o-Cl-Ph
o-Cl-Ph
Me
56
70
81
72
52
71
59
64
64
66
10
11
12
13
14
15
16
17
p-F-Ph
p-CF3-Ph
Me
Me
O
HN
O
H
Br
c
b
a
O
N
7
5
1
Me
F
13. To a solution of 5 (9 g, 18.8 mmol) in methanol (75 mL) at rt was added
hydrogen chloride in dioxane (46.9 mL, 188 mmol), and the reaction mixture
was stirred at rt for 10 min. The solvents were removed completely to give a
yellow foam. Saturated sodium bicarbonate was added, and the aqueous layer
was extracted with CH2Cl2 (3 Â 100 mL). The combined organic layers were
washed with brine, dried over anhydrous sodium sulfate, and filtered, and the
filtrate was evaporated in vacuo to give the crude product. The crude product
was purified by silica gel chromatography eluting with 95% CH2Cl2/5% MeOH/
0.5% ammonium hydroxide to give 1 (7.0 g, 99% yield) as a foam. 1H NMR
(500 MHz, CDCl3) d 7.52 (dd, J = 8.5, 7.6 Hz, 1H), 6.93 (dd, J = 12.0, 8.0 Hz, 1H),
5.09 (dd, J = 11.1, 2.3 Hz, 1H), 2.42 (s, 3H), 2.31 (s, 3H), 2.23–2.13 (m, 1H), 1.82
(dd, J = 14.4, 2.4 Hz, 1H), 1.74 (s, 3H). MS (M+H) 377.2.
F
nOe
9
Scheme 4. Reagents and conditions: (a) LiAlH(Ot-Bu)3, ether, À78 to À30 °C, 91%;
(b) 4 N HCl in dioxane, MeOH, 99%; (c) CDI, THF, 85%.
between the methyl group and the hydrogen attached to the carba-
mate oxygen. The absolute stereochemistry of 1 was confirmed by
X-ray analysis of its derivatives, and these data will be disclosed in
due course.