Development of one-pot synthesis of α-hydroxy α-trifluoromethyl amides

Article abstract of DOI:10.1016/j.tetlet.2013.07.064

An efficient one-pot-three-step method has been developed to assemble readily available aryl or heteroaryl halides, methyl trifluoropyruvate, and amines into biologically important α-hydroxy α-trifluoromethyl amides without isolation of any intermediates.

Full text of DOI:10.1016/j.tetlet.2013.07.064

Accepted Manuscript
Development of one-pot synthesis of α-hydroxy α-trifluoromethyl amides
Zhaoyang Meng, William E. Butcher
PII:
S0040-4039(13)01213-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.07.064
TETL 43262
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 June 2013
9 July 2013
10 July 2013
Please cite this article as: Meng, Z., Butcher, W.E., Development of one-pot synthesis of α-hydroxy α-
trifluoromethyl amides, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.07.064
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Abstract
Development of one-pot synthesis of α-hydroxy
α-trifluoromethyl amides
Zhaoyang Meng*, William E. Butcher
Leave this area blank for abstract info.

Development of one-pot synthesis of α-hydroxy α-trifluoromethyl amides
Zhaoyang Meng*, William E. Butcher†
Department of Medicinal Chemistry, Merck Research Laboratories, 770 Sumneytown
Pike, PO Box 4, West Point, PA 19486, USA
This is where the receipt/accepted dates will go; Received Month XX, 2013; Accepted
Month XX, 2013
Abstract—
An efficient one-pot-three-step method has been developed to assemble readily available
aryl or heteroaryl halides, methyl trifluoropyruvate and amines into biologically
important α-hydroxy α-trifluoromethyl amides without isolation of any intermediates.
©2013 Elsevier Science Ltd. All rights reserved
Keywords:
One-pot
α-Hydroxy α-trifluoromethyl amides
Halogen-magnesium exchange reaction
Bodroux reaction
2

Although rarely found in nature,1 organofluorine compounds account for
approximately 20% of pharmaceuticals on the markets, including some of the top selling
drugs.2 Selective installation of fluorine atom(s) or fluorinated group(s) into drug
candidates often results in remarkable changes in pharmacokinetic and physicochemical
properties as well as biological activities.3
Figure 1. Examples of biologically active α-hydroxy α-trifluoromethyl amides
α-Hydroxy α-trifluoromethyl amides constitute an interesting sub-class of
organofluorine containing compounds and have been widely studied as potential
pharmaceutical agents (Figure 1); for example, anesthetic 1,4 hGPR91 antagonist 2,5 11β-
HSD1 inhibitor 3,6 and androgen receptor modulator 4.7
Route 1.
O
R
1
R
R
R
OH
R
1
1. TBAF(cat.), TMSCF
1
N
3
O
HN
+
R
2
N
R
R
F C
3
R
2
2
O
2. aq. HCl
O
OH
O
O
Route 2.
R
1
OMe
R
R
HN
R
F C
3
OH
R
1
OH
MgX
OH
X
R
LiOH
2
O
N
OH
OMe
R
R
F C
3
F C
3
R
F C
3
2
PyBOP
O
O
O
Scheme 1. Known synthetic routes of α-hydroxy α-trifluoromethyl amides
∗ Corresponding author. Tel.: +1 215 652 6199. E-mail address: zhaoyang.meng@merck.com (Z. Meng).
†
Merck Summer Intern (2012).
3

Therefore, several methods have been developed for the preparation of this class
of compounds (Scheme 1). One route involves the TBAF-catalyzed nucleophilic
trifluoromethylation of α-keto amides with TMS-CF3 followed by acidic hydrolysis of
the resultant silyl ether.8 However, this procedure is limited by the availability of α-keto
acids. α-Hydroxy α-trifluoromethyl amides can also be made by a four-step sequence
from substituted halides: Grignard reagent preparation, addition to methyl
trifluoropyruvate, ester saponification, and PyBOP-mediated amide bond formation.9
Although the second approach is more general because of the readily available halides, it
requires a number of tedious work-up steps and purification of intermediates.
Scheme 2. Rationale of one-pot-three-step synthesis
These factors prompted us to search for a more general and efficient methodology
to overcome these limitations. One-pot, multi-step reactions allows the construction of
several bonds in one-pot manner without the need for any intermediate isolations and is a
valuable tool to improve synthetic efficiency.10 As shown in Scheme 2, the selective
halogen-magnesium exchange reaction promoted by an alkyl Grignard reagent such as
iPrMgCl is a widely utilized method for the generation of highly functionalized
organomagnesium reagents.11 Reaction of the in situ formed arylmagnesium reagent I
with the highly electrophilic methyl trifluoropyruvate 6a results in a rapid and
regioselective addition to the α-keto functional group. We envisioned that without
purification, subsequent reaction of the methyl ester intermediate II with an appropriate
amine in the presence of a Grignard reagent would afford directly the desired amide (the
Bodroux reaction).12 Herein, we present the discovery and development of this one-pot-
three-step reaction towards the α-hydroxy α-trifluoromethyl amide scaffold, its scope and
limitations.
4

Initially, as shown in Table 1, we carried out a model study using iodobenzene 5a,
methyl trifluoropyruvate 6a and piperidine 7a as substrates. Thus, treatment of a solution
of iodide 5a in THF with iPrMgCl at 0 oC for 1 hour was followed by cooling to -78 oC
and pyruvate 6a was added to trap the newly formed Grignard reagent. Once the
transformation was completed, the α-hydroxy α-trifluoromethyl ester intermediate was
not isolated but immediately reacted with amine 7a and excess iPrMgCl at 0 oC. The
reaction mixture was then warmed to room temperature and stirred overnight to provide
the desired amide 8a in 78% isolated yield.
Table 1 Optimization of the one-pot reaction
Entry
R'MgX
iPrMgCl
ToC
Yielda of 8a (%)
1
-78 oC
-78 oC
-78 oC
0 oC
78
64
75
26
2
iPrMgBr
3
iPrMgCl.LiCl
iPrMgCl
4
a Isolated yield.
Next, the alkyl Grignard reagent was optimized and iPrMgCl was found to give
the best yield (Table 1). A temperature survey then revealed that a higher yield was
obtained when addition of the Grignard trapping reagent, methyl trifluoropyruvate, was
carried out at lower temperature (-78 oC, entry 1). Possibly due to its reactive
electrophile nature, addition of methyl trifluoropyruvate at higher temperature (0 oC,
entry 4) didn't improve the yield and the crude material contained extensive impurities.
With optimal reaction conditions established, we then studied the scope and
limitations of this one-pot-three-step transformation with respect to the halides and
amines employed in the process, and the results are summarized in Table 2. The
5

generality of this method was first tested using various primary and secondary, aliphatic
and aromatic amines (entries 1-5) and all cases provided moderate to good yield. Next,
instead of using phenyl iodide 5a, a range of functionalized aryl and heteroaryl halides
were selected for evaluation. Clearly, this one-pot process's overall yield is highly
dependent on the halide-magnesium exchange rate at the first step. Arylbromides are
known to undergo exchange more slowly than the corresponding iodides11 and a reaction
starting from phenyl bromide 5c gave no desired product (entry 7). However, electron-
poor aryl bromides, such as 1-bromo-3, 5-difluorobenzene 5d (entry 8), did provide the
amide in 46% yield. It is noteworthy that from heteroaryl halides containing pyridine,
thiophene, and isoxazole, the corresponding amides were also obtained (entries 11, 12
and 14).
Table 2 One-pot synthesis of α-hydroxy α-trifluoromethyl amides
Entry
1
Halides 5
Amines 6
Yielda of 8 (%)
74 (8b)
HN
O
6b
5a
5a
5a
2
3
65 (8c)
72 (8d)
6c
6d
4
5
6
71 (8e)
70 (8f)
56 (8g)
5a
5a
6e
6f
6a
5b
6

7
8
0
6a
6a
5c
F
Br
46 (8h)
F
5d
9
52 (8i)
6a
5e
5f
10
11
12
56 (8j)
59 (8k)
27 (8l)
F
I
6a
6a
6a
S
I
5g
5h
13
63 (8m)
6g
5i
14
15
53 (8n)
47 (8o)
41 (8p)
6h
5j
F
I
6i
5f
16
5k
6j
a Isolated yield.
Furthermore, as shown in Table 3, besides methyl trifluoropyruvate, this one-pot-
three-step protocol could also be successfully applied to other types of α-keto esters, such
as 7b and 7c (Table 3).
Table 3 One-pot synthesis of α-hydroxy α-non-trifluoromethyl amides
7

Entry
1
Amines 6
Yielda of 9 (%)
48 (9a)
α-Keto ester 7
O
OMe
6a
O
7b
O
HN
OMe
2
3
4
5
72 (9b)
53 (9c)
46 (9d)
50 (9e)
66 (9f)
O
6b
O
7b
O
OMe
S
6a
6e
O
7c
O
OMe
S
O
7c
O
OMe
S
6f
O
7c
O
OMe
S
6
6d
O
7c
a Isolated yield.
In conclusion, we have developed a general and efficient one-pot-three-step
approach to assemble readily available aryl or heteroaryl halides, methyl
trifluoropyruvate and amines into biologically important α-hydroxy α-trifluoromethyl
amides without isolation of any intermediates. Moreover, this methodology has been
successfully extended to use non-CF3 containing keto esters as trapping reagents.
Acknowledgments
We are grateful to Drs. Michael T. Rudd and D. Jonathan Bennett for support of this
work. We thank Merck West Point Mass Spectrometry facility for assistance with
8

HRMS analyses. W.E.B. thanks Merck Future Talent Program for support of a summer
internship.
References and notes
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2008, 51, 4359. (c) Hodgetts, K. J.; Combs, K. J.; Elder, A. M.; Harriman, G. C. Annu.
Rep. Med. Chem. 2010, 45, 429.
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Ellena, J.; Cafiso, D. S.; Brown, M. L. J. Med. Chem. 2003, 46, 2494. (b) Schenck, H. A.;
Lenkowski, P. W.; Choudhury-Mukherjee, I.; Ko, S.-H.; Stables, J. P.; Patel, M. K.;
Brown, M. L. Bioorg. Med. Chem. 2004, 12, 979.
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Shaikh, N. S.; Shitole, P. Kurhade, S.; De, S.; Majumdar, S.; Reddy, S. B.; Tambe, S.;
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Saiah, E. WO 2010/141550 A2, 2010.
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A1, 2007.
8. (a) Singh, R. P.; Kirchmeier, Robert L.; Shreeve, Jean'ne M. J. Org. Chem. 1999, 64,
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Chem. 1998, 98, 127.
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2008/048540 A2, 2008.
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7134.
9

11. Knochel, P.; Dohle, W.; Gommermann, N.; Kneisel, F. F; Kopp, F.; Korn, T.;
Sapountzis, I; Vu V. A. Angew. Chem. Int. Ed. Engl. 2003, 42, 4302.
12. (a) Bassett, H. L.; Thomas, C. R. J. Chem. Soc. 1954, 1188. (b) Williams, J. M.;
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Tetrahedron Lett. 1995, 36, 5461.
13. Representative procedure for the synthesis of α-hydroxy α-trifluoromethyl amides 8:
preparation of 3,3,3-trifluoro-2-hydroxy-1-morpholino-2-phenylpropan-1-one 8b (Table
2, entry 1). To a solution of phenyl iodide 5a (300 uL, 2.68 mmol) in THF (4 mL) at 0 oC,
isopropylmagnesium chloride in THF (1338 µL, 2.68 mmol, 2M) was added dropwise.
After stirring at 0 oC for 1h, a solution of methyl trifluoropyruvate 7a (273 uL, 2.68
mmol) in THF (3 mL) was added dropwise at -78 oC. The mixture was stirred at -78 oC
for 1h and then warmed to 0 oC, morpholine 6b (350 µL, 4.01 mmol) and
isopropylmagnesium chloride (2.0 mL, 4.01 mmol, 2 M) were added dropwise. At the
end of the addition, the external cooling was removed, and the reaction was aged at room
temperature overnight. At 0 oC, the reaction mixture was quenched with slow addition of
sat. NH4Cl and extracted with EtOAc. The combined organic layers were dried over
anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash
chromatography (0-60% EtOAc/hexane) provided the desired amide 8b (479.9 mg, 62%).
1H-NMR (DMSO-d6) δ: (ppm) 7.46-7.41 (m, 5H), 5.39 (s, 1H), 4-2.9 (m, 8H). HRMS
calcd for [M+H]: 290.0999. Found: 290.0999.
14. Representative procedure for the synthesis of α-hydroxy α-non-trifluoromethyl
amides 9: preparation of 2-hydroxy-1-morpholino-2,2-diphenylethanone 9a (Table 3,
entry 1). To a solution of phenyl iodide 5a (300 uL, 2.68 mmol) in THF (4 mL) at 0 oC,
isopropylmagnesium chloride in THF (1338 µL, 2.68 mmol, 2M) was added dropwise.
After stirring at 0 oC for 1h, a solution of ethyl 2-oxo-2-phenylacetate 7b (477 mg, 2.68
mmol) in THF (3 mL) was added dropwise at -78 oC. The mixture was stirred at -78 oC
for 1h and then warmed to 0 oC, morpholine 6b (350 µL, 4.01 mmol) and then
isopropylmagnesium chloride (2007 µL, 4.01 mmol, 2 M) were added dropwise. At the
end of the addition, the external cooling was removed, and the reaction was aged at room
temperature overnight. At 0 oC, the reaction mixture was quenched with slow addition of
sat. NH4Cl and extracted with EtOAc. The combined organic layers were dried over
10

anhydrous Na2SO4, filtered and concentrated in vacuo. Purification by flash
chromatography (0-60% EtOAc/hexane) provided the desired amide 9a (570 mg, 72%).
1H-NMR (DMSO-d6) δ: (ppm) 7.44-7.30 (m, 10H), 5.76 (s, 1H), 3.72-3.08 (m, 8H).
HRMS calcd for [M+H]: 298.1438. Found: 298.1431.
11