A Weinreb amide approach to the synthesis of trifluoromethylketones

Article abstract of DOI:10.1039/c2cc35037h

A novel route to access trifluoromethylketones (TFMKs) from Weinreb amides is reported. This represents the first documented case of the Ruppert-Prakash reagent (TMS-CF₃) reacting in a constructive manner with an amide and enables synthesis of TMFKs without risk of over-trifluoromethylation.

Full text of DOI:10.1039/c2cc35037h

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COMMUNICATION
A Weinreb amide approach to the synthesis of trifluoromethylketonesw
a
a
DiAndra M. Rudzinski,z Christopher B. Kellyz and Nicholas E. Leadbeater*ab
Received 13th July 2012, Accepted 8th August 2012
DOI: 10.1039/c2cc35037h
A novel route to access trifluoromethylketones (TFMKs) from
Weinreb amides is reported. This represents the first documented
case of the Ruppert–Prakash reagent (TMS–CF3) reacting in a
constructive manner with an amide and enables synthesis of
TMFKs without risk of over-trifluoromethylation.
Trifluoromethylation of an activated carbonyl derivative
with TMS–CF3 via nucleophilic substitution is another viable
option to access TFMKs. While acid chlorides and anhydrides
are known to be too reactive for mono-trifluoromethylation,
Prakash9 and Shreeve10 have published independent reports
detailing procedures for direct acyl substitution of esters using
TMS–CF3. While significant achievements, both methods
have drawbacks. Prakash’s hinges on the use of anhydrous
reaction conditions to avoid quenching the –CF3 anion.
Additionally, prolonged reaction times and very low temperatures
are necessary to avoid double-addition.9 Shreeve improved
on this by using CsF as an initiator and conducting most
reactions solvent-free.10 However, problems with exotherms
limit its scalability.
The trifluoromethyl group (–CF3) is of great interest to the
medicinal chemistry community due to its ability to drastically
alter the physiological and chemical properties of compounds.1
While many methods for the introduction of this functionality
into organic molecules have been developed, few compare to the
versatile nature of the Ruppert–Prakash reagent (TMS–CF3).2
This reagent has been used in the construction of many
trifluoromethylated synthons including a-trifluoromethyl
alcohols,3 benzotrifluorides,4a trifluoromethyl heteroarenes,4b
trifluoromethylamines,4c aryltrifluoromethyl-sulfides,4c and
trifluoromethyl alkanes,4c alkenes4d and alkynes.4e One moiety
that is relatively difficult to access directly using TMS–CF3 is
the trifluoromethylketone (TFMK). TMFKs are highly valuable
species as synthons in the construction of other fluorinated
compounds5 and as potent enzyme inhibitors.6
In 1981, Weinreb and co-workers reported a method for
using N-methoxy-N-methylamides (now known as Weinreb
amides) to prepare ketones directly without the risk of over
alkylation.14 The importance of this discovery has become
clear based on the regularity in which they are used in
synthesis and the numerous methods developed for their
preparation.15 A lesser-known report detailed the successful
synthesis of a TFMK using the Weinreb amide of trifluoroacetic
acid when treated with a Grignard reagent.16 This demonstrated
that in an acyl substitution reaction, the N-methoxy-N-methyl-
amine group will be eliminated preferentially over the CF3
moiety. With this important precedent, we theorised that Weinreb
amides could serve as viable candidates for trifluoromethylation
to synthesise TFMKs directly using TMS–CF3, despite the
established lack of reactivity of amides with TMS–CF3.17 Here
we detail the results of our investigation.
Current methods for the preparation of TFMKs utilize
three major routes: alkylation of trifluoroacetic acid (TFA)
derivatives (via organometallic reagents),7 oxidation of a-CF3
alcohols,8 or, more recently, nucleophilic substitution of
carbonyl derivatives utilizing TMS–CF3.9,10 Alkylation is the
more traditional route and, while several successful strategies
have been developed, concomitant exhaustive alkylation or
Meerwein–Ponndorf–Verley type reductions can lead to
complications. Conditions to avoid some of these problems
have recently been developed.7e Routes exploiting oxidation can
also prove difficult. a-Trifluoromethyl alcohols are notoriously
difficult substrates to oxidize and, while periodinane-based
methods are successful,11 attempts using standard oxidants
(metal-based or DMSO-based) are often met with poor yields
or failure.8,12,13
We began our investigation by screening the reaction
between 1a and TMS–CF3 using a variety of fluoride initiators
(Table 1). Initially we used 1.3 equivalents of TMS–CF3, this
being the typical loading for the trifluoromethylation of
carbonyl compounds.3 Less aggressive fluoride sources, NaF
and KF were not effective initiators for the reaction, likely due
to solubility issues (entries 1 and 2). However, use of more
aggressive initiators, TBAF and CsF, did lead to the desired
TFMK 3a, albeit in suboptimal conversion (entries 3 and 4).
a Department of Chemistry, University of Connecticut,
55 North Eagleville Road, Storrs, CT 06269, USA
b Department of Community Medicine & Health Care, University of
Connecticut Health Center, The Exchange, 263 Farmington Ave,
Farmington, CT 06030, USA.
1
Extended reaction times failed to improve conversion. H-NMR
spectroscopy of the crude reaction mixture showed the formation
of intermediate 2a. We postulated that 2a could either eliminate to
give the desired ketone or revert to the starting material.18 We
decided to optimise the conditions for formation of 2a then follow
with a cleavage step to yield the TFMK. We screened several
solvents with varying polarities (entries 5–7), theorising that
E-mail: nicholas.leadbeater@uconn.edu
w Electronic supplementary information (ESI) available: Representa-
tive experimental procedure and characterisation of reaction products.
See DOI: 10.1039/c2cc35037h
z These authors contributed equally to this work.
c
9610 Chem. Commun., 2012, 48, 9610–9612
This journal is The Royal Society of Chemistry 2012

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Table 1 Optimisation of reaction conditionsa
Table 2 Trifluoromethylation of Weinreb amidesa
Entrya Solvent Initiator TMS–CF3 (eq.) Time (h) 2a (%) 3a (%)
Entry R
Yieldb (%) Entry R
Yieldb (%)
1
THF
THF
THF
THF
MeCN CsF
CH2Cl2 CsF
Toluene CsF
Toluene CsF
Toluene CsF
Toluene CsF
Toluene CsF
Toluene CsF
NaF
KF
TBAF 1.3
1.3
1.3
17
17
17
17
17
17
17
17
17
17
17
24
—
—
—
—
—
11
70
63
84
90
91
95 (81)e
—
—
12
55
—
—
—
—
—
—
—
—
2
3b
4
1
81
78
14
15
76
51
CsF
1.3
1.3
1.3
1.3
1.0
2.0
3.0
6.0
2.0
5c
6c
7c
8c
9c
10c
11c
12d
2
3
72
16
84
a
Reaction conditions: 1a (1.0 mmol), initiator (20 mol%), TMS–CF3,
b
c
d
solvent (1.5 mL) at rt. 5 mol% initiator. 0.5 mL solvent. Performed
on a 5 mmol scale in 2.5 mL solvent, cooled 0 1C to rt. e Isolated yield.
4
5
88
—
17
18
63
90d
altering the solvent polarity could shift the reaction pathway to
favour 2a. A nonpolar solvent, toluene, gave the best conversion to
the silylated intermediate (entry 7). Next, variation of the
TMS–CF3 loading was examined to improve the overall conversion
to 2a (entries 8–11). While 2 eq. did not give the highest conversion
(entry 9 vs. entries 10 and 11) it was the most practical for scale up.
We were pleased to find that, upon scale up and at slightly extended
reaction times, we achieved near quantitative conversion to 2a
(entry 12). This intermediate proved stable enough to be isolated in
excellent yield and characterised (see ESIw).
Seeking to obtain the TFMK from this compound, we next
attempted to cleave 2a to give 3a by elimination of the amino
substituent. Believing this silyl ether to be difficult to cleave
because of its surprising inherent stability and steric bulk, we
initially used a stoichiometric loading of TBAF in THF. We also
added an equal volume of water to serve as a proton source for the
departing amino group. However, we found that we obtained
minimal conversion to the TFMK. Upon heating to 50 1C, we
obtained complete conversion to the desired TFMK in 2 h.
However, we wanted to see if we could reduce the loading of
TBAF and the amount of water used without compromising the
rapidity and completeness of cleavage. In the case of 2a, 10 mol%
TBAF with an equal volume of water could be used without loss
in conversion. These reduced loadings were later found not to be
compatible with all intermediates screened; hence we utilised
stoichiometric conditions for this study.
6
—
19
99
c
7
8
9
—
75
66
20
21
22
59
—
61
10
81
61
23
24
48
11
12
Decomp.
78
73
25
26
—
66
With optimised conditions in hand for both the conversion
of the Weinreb amide to the silyl intermediate and its subsequent
cleavage, we next explored the substrate scope of our protocol. An
array of aryl Weinreb amides (Table 2, entries 1–4, 16, 19) were
compatible with our reaction conditions giving good to excellent
yield of their corresponding TFMKs. Three exceptions were rings
bearing o-substituents to the Weinreb functionality (entries 5–7).
Since 1g and 1f (entries 6 and 7) are electronic antagonists, we
concluded that their lack of reactivity can be attributed to the
steric bulk of these groups. This was confirmed by placement of a
nonpolar group at the ortho position (entry 5). Ortho-substitution
likely deters coordination of the amide to TMS–CF3.2,19
By distancing the amide away from the ortho-substitutent
13
a
Reaction conditions: Addition: Weinreb amide (1 eq.), TMS–CF3
(2 eq.), CsF (0.2 eq.), toluene (2 M or 0.5 M), 24 h. Cleavage: TBAF
(1 eq., 1 M in THF), H2O (equal vol. with respect to TBAF) 50 1C, 2 h.
b
c
Isolated yield after purification. 25% conversion by 1H-NMR to
d
TFMK. Isolated yield of stable hydrate.
reactivity was returned and we obtained a good yield of the
corresponding TFMK (entry 8).
Various aliphatic (entries 9–15, 20–25) and heterocyclic
Weinreb amides (entries 17, 18 and 26) were then screened. Those
with a-substitution proved incompatible (entries 21 and 25),
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9610–9612 9611

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Table 3 Trifluoromethylation of a,b-unsaturated Weinreb amidesa
This work was supported by the National Science Foundation
(CAREER Award CHE-0847262). We wish to thank Dr You-Jun
Fu, Trevor Hamlin, Michael Mercadante and Adam McShane for
technical and editorial assistance.
Notes and references
Entry
R
Yield of 3 (%)
22
Ratio of 3 : 4
25 : 75b
1 For examples, see: (a) K. Muller, C. Faeh and F. Diederich,
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Science, 2007, 317, 1881; (b) S. Purser, P. R. Moore, S. Swallow
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1
2 For reviews: (a) G. K. S. Prakash and M. Mandal, J. Fluorine
Chem., 2001, 112, 123; (b) J. Gawronski, N. Wascinska and
J. Gajewy, Chem. Rev., 2008, 108, 5227; (c) R. P. Singh and
J. M. Shreeve, Tetrahedron, 2000, 56, 7613.
3 R. Krishnamurti, D. R. Bellew and G. K. S. Prakash, J. Org.
Chem., 1991, 56, 984.
4 (a) T. D. Senecal, A. T. Parsons and S. L. Buchwald, J. Org. Chem.,
2011, 76, 1174; (b) L. Chu and F.-L. Qing, J. Am. Chem. Soc., 2012,
134, 1298; (c) Trifluoromethyltrimethylsilane. e-Encyclopedia of
Reagents for Organic Synthesis, Wiley, New York, 2010;
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2
3
47
41
55 : 45b
41 : 59b
4
5
a
51
—
71 : 29b
—
Reaction conditions: Addition: Weinreb amide (1 eq.), TMS–CF3
(2 eq.), CsF (0.2 eq.), toluene (2 M), 24 h. Cleavage: TBAF (1 eq., 1 M
b
in THF), H2O (equal vol. with respect to TBAF) rt, 2 h. Ratio
1
determined by H-NMR spectroscopy.
´
A. Krasovskiy, U. Majumder, V. E. Trepanier and D. Y. K. Chen,
J. Am. Chem. Soc., 2009, 131, 3690.
which likely can be explained using a similar steric argument
as the o-substituted substrates. By moving the substituent
to the b-position (entry 23), restricting its conformation
(entry 22), or removing it entirely (entry 20), the reaction
proceeds easily, giving fair to good yields of the desired
TFMKs. Of note is the a-phenyl substituted substrate (entry 24)
whose decomposition could be attributed to the enhanced
acidity of its a-protons. Furyl, thiophenyl, and pyridyl systems
were all compatible with our optimised conditions, affording
good yields of the corresponding TFMKs (entries 15, 26, 17,
and 18 respectively).
6 (a) Y.-M. Shao, W.-B. Yang, T.-H. Kuo, K.-C. Tsai, C.-H. Lin,
A.-S. Yang, P.-H. Liang and C.-H. Wong, Bioorg. Med. Chem.,
2008, 16, 4652; (b) C. A. Veale, J. R. Damewood, Jr.,
G. B. Steelman, C. Bryant, B. Gomes and J. Williams, J. Med.
Chem., 1996, 38, 86.
7 (a) J.-P. Begue and D. Bonnet-Delpon, Tetrahedron, 1991,
´ ´
47, 3207; (b) K. T. Dishart and R. Levine, J. Am. Chem. Soc.,
1956, 78, 2268; (c) X. Creary, J. Org. Chem., 1987, 52, 5026;
(d) J.-T. Lin, T. Yamazaki and T. Kitazume, J. Org. Chem., 1987,
52, 3211; (e) T. Yamazaki, T. Terajima and T. Kawasaki-Takasuka,
Tetrahedron, 2008, 64, 2419.
8 Examples of this strategy: (a) F. Grellepois, F. Chorki, B. Crousse,
M. Ourevitch, D. Bonnet-Delpon and J.-P. Begue, J. Org. Chem.,
´ ´ ´
2002, 67, 1253; (b) H. Lebel, M. Davi and G. T. Stok"osa, J. Org.
Chem., 2008, 73, 6828; (c) H. Lebel and V. Paquet, Org. Lett.,
2002, 4, 1671.
Finally, a,b-unsaturated Weinreb amides were explored as
substrates. Using 1aa as a model substrate, we obtained a low
yield of the desired TFMK 3aa (Table 3, entry 1). However,
19F and 1H NMR analysis revealed an additional TFMK
product, namely 4aa. Formation of 4aa can be rationalised
by Michael addition of the displaced N,O-dimethylhydroxyl-
amine anion into the highly electrophilic alkene of 3aa. Other
a,b-unsaturated Weinreb amides showed similar reactivity
with differences in the ratio of 3 : 4 (entries 2–4). Interestingly,
non-conjugated a,b-unsaturated Weinreb amide 1ee afforded
no reaction (entry 5).
9 J. Wiedemann, T. Heiner, G. Mloston, G. K. S. Prakash and
G. A. Olah, Angew. Chem., Int. Ed., 1998, 37, 820.
10 R. P. Singh, G. Cao, R. L. Kirchmeier and J. M. Shreeve, J. Org.
Chem., 1999, 64, 2873.
11 R. J. Linderman and D. M. Graves, J. Org. Chem., 1989, 54, 661.
´ ´
12 V. Kesavan, D. Bonnet-Delpon, J.-P. Begue, A. Srikanth and
S. Chandrasekaran, Tetrahedron Lett., 2000, 41, 3327.
13 We have recently developed an effective alternative to this oxidation
problem by using an oxoammonium salt: C. B. Kelly, M. A.
Mercadante, T. A. Hamlin, M. H. Fletcher and N. E. Leadbeater,
manuscript submitted.
14 S. Nahm and S. Weinreb, Tetrahedron Lett., 1981, 22, 3815.
15 For reviews: (a) V. K. Khlestkin and D. G. Mazhukin, Curr. Org.
Chem., 2003, 7, 967; (b) J. Singh, N. Satyamurthi and I. S. Aidhen,
J. Prakt. Chem., 2000, 342, 340.
16 D. A. Shaw and T. C. Tuominen, Synth. Commun., 1985, 15, 1291.
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56, 7613.
18 In fact, if left for extended reaction times in THF, 2a would slowly
revert back to 1a. We attribute this to the Lewis basicity of THF
which has been observed previously to influence the decomposition
of similar tetrahedral intermediates. See ref. 7e.
In conclusion, we have disclosed the first example of
TMS–CF3 reacting with an amide functionality to furnish a
TFMK. The reaction is compatible with a range of Weinreb
amides, affording moderate to excellent yields of the TFMK
products without formation of the over-trifluoromethylated
products. While most Weinreb amides react readily, sterically
encumbered amides fail to react appreciably, if at all. The
use of a,b-unsaturated Weinreb amides is complicated by
the formation of the Michael adduct of the TFMK and
N,O-dimethylhydroxylamine, but the TFMK and this adduct
are separable and can be isolated in fair yield.
19 R. P. Singh and J. M. Shreeve, J. Org. Chem., 2000, 65, 3241.
c
9612 Chem. Commun., 2012, 48, 9610–9612
This journal is The Royal Society of Chemistry 2012