Stereoselective synthesis of ambiphilic alkenes via regioselective methylation of α-trifluoromethanesulfonyl carbonyl compounds with trimethylsilyldiazomethane

Article abstract of DOI:10.1016/j.tetlet.2011.05.015

α-Trifluoromethanesulfonyl esters, ketones and amides are C-H acids capable of reacting with trimethylsilyldiazomethane to afford the corresponding ambiphilic alkenes. While esters were found to be non-selective, ketones were highly regioselective for O-methylation and displayed variable E/Z stereoselectivity. Amides were observed to be both highly regio- and stereoselective, affording O-methylation with exclusive formation of the Z-alkene.

Full text of DOI:10.1016/j.tetlet.2011.05.015

Tetrahedron Letters 52 (2011) 3714–3717
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Stereoselective synthesis of ambiphilic alkenes via regioselective methylation
of a-trifluoromethanesulfonyl carbonyl compounds with
trimethylsilyldiazomethane
⇑
Han Il Kong, Jennifer E. Crichton, Jeffrey M. Manthorpe
Carleton University, Department of Chemistry, 1125 Colonel By Drive, 203 Steacie Building, Ottawa, ON, Canada K1S 5B6
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-Trifluoromethanesulfonyl esters, ketones and amides are C–H acids capable of reacting with trimeth-
Received 15 March 2011
Revised 3 May 2011
Accepted 4 May 2011
Available online 14 May 2011
ylsilyldiazomethane to afford the corresponding ambiphilic alkenes. While esters were found to be
non-selective, ketones were highly regioselective for O-methylation and displayed variable E/Z stereose-
lectivity. Amides were observed to be both highly regio- and stereoselective, affording O-methylation
with exclusive formation of the Z-alkene.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ambiphilic alkenes
C–H acids
Stereoselective alkene synthesis
Trifluoromethyl sulfones (triflones)
Trimethylsilyldiazomethane
As part of a research program toward exploring the chemistry of
-sulfonyl carbonyl compounds, we required a route to -disub-
stituted -trifluoromethanesulfonyl (triflyl, Tf) esters that would
be amenable to the installation of various -substituents. While
several potential avenues were envisaged, the most reasonable ap-
proach appeared to be alkylation of -triflyl esters (Scheme 1);
unfortunately this reaction is non-trivial. The conjugate bases of
-triflyl esters are extremely stable and potentially challenging
a
a,a
a
a
a
a
to alkylate. The pKa of ethyl trifluoromethanesulfonylacetate is
6.4 in DMSO;1 by comparison, acetic acid has a pKa of 12.6 in
DMSO.2 Indeed, a battery of conditions led only to recovery of
starting material and/or decomposition by nucleophilic attack of
the halide byproduct on the ester alkyl group. This in turn leads
to decarboxylation and a host of other side-products, as reported
by Langlois and co-workers3 (Eq. 1).
Scheme 1. Potential alkylation of a-triflyl esters.
In order to evaluate the applicability of this premise, we pre-
pared cyclohexyl triflylacetate 1 from the corresponding bromide
and sodium trifluoromethanesulfinate,5 a commercially available
nucleophilic triflyl source.6 Treatment of 1 with the commercially
available diazomethane synthon trimethylsilyldiazomethane7
(10 equiv) in MeOH at room temperature for 1 h resulted in a mix-
ture of three major methylation products: a 1.5:1 ratio of C-methyl-
ation (2) to O-methylation (3) (Eq. 2).8 The bis-C,O- and bis-C,
Given the highly acidic nature of a-triflyl esters, we next consid-
ered the viability of alkylation with diazoalkanes. While diazoalk-
anes are ‘hard’ reagents,4 it is not immediately clear whether the
hard site in
a-triflyl esters is the enolate oxygen or carbon, given
the triflyl group’s extraordinary electron withdrawing character
and ability to stabilize negative charge, which is comparable to that
of the nitro group.1 Thus, there are six potential reaction products,
arising from mono- or bis-C-methylation, E- or Z-selective O-meth-
ylation, and C-methylation followed by O-methylation.
ð1Þ
⇑
Corresponding author. Tel.: +1 613 520 2600x1711; fax: +1 613 520 3749.
E-mail address: jeffrey_manthorpe@carleton.ca (J.M. Manthorpe).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.015

H. I. Kong et al. / Tetrahedron Letters 52 (2011) 3714–3717
3715
C-methylation products were not observed. Ethyl triflylacetate 4
was also examined under the same conditions and afforded a
8:4:4:1:1 mixture of products arising from C-methylation (5),
non-selective O-methylation (6 and 7), and non-selective bis-C,O-
methylation (8 and 9, Scheme 2). This served to confirm the ambi-
guity of the hard site in the conjugate base of triflylacetyl esters.
While the product mixture was not ideal, we did achieve the neces-
sary level of reactivity and surmised that if the reactivity could be
tuned in either direction the products would be useful. C-alkylation
would move us toward our desired products and O-alkylation
would afford ambiphilic alkenes with clearly defined nucleophilic
and electrophilic termini.
ð2Þ
Scheme 3. Steric and electronic effects in the methylation of
compounds.
a-triflyl carbonyl
Given that the amount of charge borne by the enolate oxygen
varies with the nature of the substituent adjacent to the carbonyl,
we postulated that carbonyl compounds other than esters would
be more selective in their reaction with trimethylsilyldiazome-
anticipated to be subject to both steric effects, which would favour
the Z-enolate if the alkoxide is smaller than the Y group (NR2 in
amides or alkyl/aryl group in ketones), and electronic effects,
which would favour the E-alkene via a minimization of dipoles. It
was expected that the amides would fall under steric control, as
virtually all acyclic monosubstituted amide enolates favour the Z
configuration, due to minimization of A1,3-strain.9 Ketones were
anticipated to be more substrate-dependent, with larger Y groups
promoting the Z geometry.
thane. Accordingly, we elected to explore the methylation of a-tri-
flyl ketones and amides (Scheme 3) with the anticipation that
these should afford predominantly O-methylation due to increased
electron density on the enolate oxygen. E/Z stereochemistry was
A selection of
a-triflyl amides was prepared from 2 equiv of
the corresponding amine and bromoacetyl bromide or 2-bromo-
propionyl bromide, followed by SN2 reaction with sodium triflu-
oromethanesulfinate in DMA (Table 1). While the preparation of
a
-triflyl esters and ketones has been reported previously,3 to the
best of our knowledge this is the first report of the synthesis of
a-triflyl tertiary acetamides.
We also prepared a selection of
a-triflyl ketones (Scheme 4).
The requisite
a-halo ketones 16 and 18 were commercially avail-
able, while 22 and 24 were prepared by
a
-bromination of the ke-
tone.10 Since cyclohexyl methyl ketone is not commercially
available, the carboxylic acid chloride was converted to the bromo-
methyl ketone 20 by reaction with trimethylsilyldiazomethane,
followed by treatment with HBr.11 Several of the ketones exhibited
significant enol content, a phenomenon previously observed anec-
dotally in
a
-perfluoro sulfonyl ketones.12 We are currently com-
pleting a thorough study of this phenomenon and these results
Scheme 2. Methylation of ethyl triflylacetate.
will be reported shortly.13
Table 1
Synthesis of
a
-triflyl amides
Entry
R1, R2
R3
NaO2SCF3 equiv
Step 2 temp, time
Product
Yield (%, 2 steps)
1
2
3
4
5
6
(CH2)4
(C2H4)2O
i-Pr2
Et2
Bu, H
(CH2)4
H
H
H
H
H
CH3
1.5
2.0
1.5
1.5
60 °C, 2 d
70 °C, 3 d
70 °C, 3 d
70 °C, 3 d
70 °C, 4 d
70 °C, 7 d
10
11
12
13
14
15
90
52
54
86
72
41
1.2 + 0.5 after 2 d
1.5 + 0.85 after 4 d

3716
H. I. Kong et al. / Tetrahedron Letters 52 (2011) 3714–3717
Table 3
Reaction of trimethylsilyldiazomethane with a-triflyl carbonyl compounds
Entry
1
S.M.
Product
Conv. (%)a
100
Yield (%)
74
Z/E ratiob
OCH3
Tf
10
100:0
N
26
OCH3
Tf
N
2
11
100
80
100:0
100:0
O
28
OCH3
Tf
29 (12 h)
63 (48 h)
N
N
3
4
12
13
22
29
OCH3
Tf
65 (12 h)
100 (18 h)
44 (86)c
100:0
100:0
30
OCH3
Tf
25 (12 h)
45 (60 h)
16 (12 h)
23 (60 h)
Pr
N
H
31
5
6
14
15
Scheme 4. Preparation of a-triflyl ketones.
0d 0e
Table 2
Optimization of the reaction of trimethylsilyldiazomethane with pyrrolidinyl trifly-
lacetamide
OCH3
Tf
66
7
17
100
100:0
89f
33
Entry Me3SiCHN2
(equiv)
Solvent
Conc.
(M)
Time
(h)
Conv.
(%)a
OCH3
Tf
8
19
21
23
10
92
68
77
100:0
100:0
25:75
Cy
Ph
1
2
3
4
10
10
10
5
MeOH
EtOH
i-PrOH
MeOH
EtOH
i-PrOH
MeOH
EtOH
EtOH
EtOH
EtOH/THF
EtOH/Et2O
EtOH/
EtOAc
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1
1
1
1
1
3
3
3
100
100
68
100
100
86
27
OCH3
24
24
24
12
12
12
12
12
12
12
Tf
9
100
100
5
5
6
5
34
7
8
9
10
11
12
13
2.5
2.5
2.5
1.5
2.5
2.5
2.5
50
100
100
47
90
94
10
91
11
25
82
48
n.d.
a
Determined by integration of the 1H NMR spectrum of the crude reaction
mixture.
a
Determined by integration of the 1H NMR spectrum of the crude reaction
With an array of substrates in hand, we selected amide 10 as
mixture.
b
Assigned via 2D NOESY experiment.
our prototype. Treatment with 10 equiv of trimethylsilyldiazome-
thane at 0.5 M in MeOH for 3 h resulted in 100% conversion (Table
2). Gratifyingly, the Z-alkene 26 was the only observed product. No
C-methylation or bis-methylation products were found. We then
c
d
e
f
Crude yield.
Under standard conditions.
5 equiv Me3SiCHN2, 1 M in EtOH, rt, 5 d.
10 equiv Me3SiCHN2, 1 M in MeOH, rt, 3 h.

H. I. Kong et al. / Tetrahedron Letters 52 (2011) 3714–3717
3717
sought to optimize the reaction conditions. In order to ensure
complete desilylation, we elected initially to limit our solvents to
simple alcohols. Though trimethylsilyldiazomethane is commonly
used in the presence of methanol,14 we observed that ethanol
was the superior solvent for the formation of 26, as it enabled
the reduction of the number of equivalents of trimethylsilyldia-
zomethane from 10 to 2.5. Further experimentation demonstrated
that THF, Et2O, or EtOAc could be effectively used with EtOH in a
1:1 ratio. Notably, changing the reaction concentration from 0.5
to 1.0 M was inconsequential for amide 10, but was required to
achieve full conversion of ketone 21 (Eq. 3).
Scheme 5. Potential application of ambiphilic alkenes.
Research Fund, and Carleton University for financial support. The
authors thank Prof. Jeff Smith and Matthew Huebsch (Carleton
University) for performing mass spectrometric analysis.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.015.
ð3Þ
References and notes
With our optimized reaction conditions in hand, we began to
explore other substrates (Table 3).15 The methylation of
a-triflyl
1. Goumont, R.; Magnier, E.; Kizilian, E.; Terrier, F. J. Org. Chem. 2003, 68, 6566.
2. (a) Kolthoff, I. M.; Chantooni, M. K.; Bhowmik, S. J. Am. Chem. Soc. 1968, 90, 23;
(b) Bordwell, F. G.; Algrim, D. J. Org. Chem. 1976, 41, 2507.
3. Eugene, F.; Langlois, B.; Laurent, E. J. Fluorine Chem. 1994, 66, 301.
4. For a related example of O–methylation of acetone dicarboxylic acid anhydride,
see: Ray, J. A.; Harris, T. M. Tetrahedron Lett. 1982, 23, 1971.
5. (a) Hendrickson, J. B.; Judelson, D. A.; Chancellor, T. Synthesis 1984, 320; (b)
Hendrickson, J. B.; Bair, K. W.; Skipper, P. L.; Sternbach, D. D.; Wareing, J. Org.
Prep. Proced. Int. 1977, 9, 173; (c) Hendrickson, J. B.; Skipper, P. L. Tetrahedron
1976, 32, 1627.
amides was affected by the nature of the nitrogen substituents.
Methylation of the secondary amide 14 was poor (entry 5) and
while the reaction conditions had been optimized for the methyla-
tion of pyrollidinyl amide 10, more sterically hindered amides were
not as effectively methylated (entries 3 and 4). As expected, only
the Z-alkene was observed for all tertiary amide substrates. Inter-
estingly, a secondary amide, which lacks the A1,3-strain of the ter-
tiary amides, also afforded the Z-alkene exclusively (entry 5).
6. Sodium trifluoromethanesulfinate was purchased from TCI America and used
as received.
7. Trimethylsilyldiazomethane was purchased from Aldrich Chemical Corp. as a
2 M solution in diethyl ether and used as received.
8. E/Z stereochemistry of 3 was not assigned but the isomer ratio was found to be
1.8:1.
Notably, a-methyl amide 15 was completely unreactive, indicative
of the increased A1,3-interactions and likely lack of overlap of the C–
H bond and the carbonyl p⁄ orbital.16
9. (a) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233; (b) Evans, D. A.;
Takacs, J. M.; McGee, L. R.; Ennis, M. D.; Mathre, D. J.; Bartroli, J. Pure Appl. Chem.
1981, 53, 1109.
10. Pravst, I.; Zupan, M.; Stavber, S. Tetrahedron Lett. 2006, 47, 4707.
11. For a related preparation of ketone 22, see: Wagner, R. B.; Moore, J. A. J. Am.
Chem. Soc. 1950, 72, 2884.
Akin to
effective O-methylation for all substrates tested. In the cyclic and
-methylene substrates, the Z isomer was obtained exclusively
(entries 7–9). Contrary to our results with -substituted amides,
-substituted ketones were reactive but afforded E/Z mixtures
(entries 10–11).
In conclusion, we have developed a facile method for the stere-
oselective synthesis of -triflyl enol ethers and -triflyl ketene
aminals, both of which can be classified as ambiphilic alkenes.
We are currently exploring the chemistry of these compounds as
electrophiles and substrates for cycloadditions, including cyclo-
propanation to afford a new class of donor-acceptor cyclopropanes,
(Scheme 5)17 and results will be reported in due course.
a-triflyl amides, a-triflyl ketones demonstrated
a
a
a
12. For two examples of cyclic
a-perhalosulfonyl ketones exhibiting keto-enol
tautomerism, see: (a) Kobayashi, Y.; Yoshida, T.; Kumadaki, I. Tetrahedron Lett.
1979, 3865; (b) Wang, X.-J.; Liu, J.-T. Chin. J. Chem. 2007, 25, 649.
13. Kong, H. I.; Crichton, J. E.; Manthorpe, J. M. Manuscript in Preparation.
14. Trimethylsilyldiazomethane. e-Encyclopedia of Reagents for Organic Synthesis
[Online]; Wiley-InterScience, Posted September 15, 2006. http://
a
a
www.mrw.interscience.wiley.com/eros/articles/rt298/frame.html
March 2, 2011).
(accessed
15. See Supplementary data for full experimental details.
16. For a example of a similar decrease in acidity due to amide A1,3-interactions,
see: Evans, D. A.; Clark, J. S.; Metternich, R.; Novack, V. J.; Sheppard, G. S. J. Am.
Chem. Soc. 1990, 112, 866.
17. For recent reviews on donor-acceptor cyclopropanes, see: (a) Lebold, T. P.; Kerr,
M. A. Pure App. Chem. 2010, 82, 1797; (b) Davies, H. M. L.; Denton, J. R. Chem.
Soc. Rev. 2009, 38, 3061.
Acknowledgments
J.M.M. thanks NSERC (Discovery and RTI programs), Canada
Foundation for Innovation (Leaders Opportunity Fund), Ontario