Silver-catalyzed vinylogous fluorination of vinyl diazoacetates

Article abstract of DOI:10.1021/ol403017e

A silver-catalyzed vinylogous fluorination of vinyl diazoacetates to generate γ-fluoro-α,β-unsaturated carbonyls is presented. Application of this method to the fluorination of farnesol and steroid derivatives was achieved.

Full text of DOI:10.1021/ol403017e

ORGANIC
LETTERS
2
013
Vol. 15, No. 24
152–6154
Silver-Catalyzed Vinylogous Fluorination
of Vinyl Diazoacetates
6
Changming Qin and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta,
Georgia 30322, United States
hmdavie@emory.edu
Received October 21, 2013
ABSTRACT
A silver-catalyzed vinylogous fluorination of vinyl diazoacetates to generate γ-fluoro-r,β-unsaturated carbonyls is presented. Application of this
method to the fluorination of farnesol and steroid derivatives was achieved.
The development of new methods for achieving selective
1
relevant compounds such as steroids, amino acids and
3
metalloprotease inhibitors. Traditional approaches for
fluorination is a current research area of intense interest.
Organofluorine compounds display broad utility as valu-
ablepharmaceuticals, agrochemicals, materialsand tracers
the synthesis of γ-fluoro-R,β-unsaturated carbonyls
mainly rely on electrophilic fluorination of conjugated
2
4
for positron emission tomography. γ-Fluoro-R,β-unsatu-
rated carbonyls represent a versatile class of intermediates
inorganicsynthesis andareprevalentmotifsinbiologically
enolethers and Wittig-type reaction ofR-fluoro aldehydes
5
6
7
or ketones. Recently, we and others have described that
metal-stabilized vinylcarbenes derived from vinyl diazo-
acetates can selectively display electrophilic reactivity at the
vinylogous position instead of the carbene site. This type of
behavior is especially favorable when silver catalysts are
(
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1
0.1021/ol403017e r 2013 American Chemical Society
Published on Web 11/14/2013

6
c,d,7h
used.
vinylogous fluorination to generate highly functionalized
In this paper, we report a silver-catalyzed
a
8
Table 1. Vinylogous Fluorination Optimization
γ-fluoro-R,β-unsaturated carbonyls (eq 1).
b
entry
catalyst
fluoride
TMAF
yield (%)
Our fluorination study began with examination of dif-
ferent fluoride sources using the styryl diazoacetate 1 asthe
model substrate. Among fluoride sources examined, many
of the standard nucleophilic sources of fluoride failed to
give any fluorinated products (Table 1, entries 1À6), but
1
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgSbF6
AgOTf
<5
<5
<5
<5
<5
<5
44
55
90
88
90
c
2
TBAF
TBABF
3
d
4
KHF
2
5
Fluolead
TASF
9
6
Deoxo-Fluor and DAST can provide the desired product 2
7
deoxo-Fluor
DAST
in 44% and 55% yield, respectively (Table 1, entries 7 and 8).
8
10
The use of triethylamine trihydrogen fluoride dramatically
improved the yield to 90% (Table 1, entry 9). After
determining the effect of different silver salts (Table 1,
entries 9À11), we chose silver acetate and triethylamine
trihydrogen fluoride in dichloromethane as our standard
fluorination conditions. In all of these reactions, the ratio
of vinylogous versus carbenoid fluorination is >20/1.
Having developed the optimized conditions, the scope of
the vinylogous fluorination was examined with a variety of
vinyldiazo derivatives. The reaction was found to be quite
general as illustrated in Scheme 1. The size of ester group
9
Et
3
NÀ3HF
10
11
Et NÀ3HF
3
Et
3
NÀ3HF
a
Vinyl diazoacetate (0.4 mmol, 1.0 equiv), silver catalyst (10 mol %),
and fluoride source (2.0 mmol, 5.0 equiv) under reflux in dichloro-
methane. Isolated yield; <5 refers to no observation of product 2 from
b
1
c
d
H NMR analysis prior to chromatography. 1.0 M in THF. Dry DMF
as solvent at 90 °C.
a
Scheme 1. Synthesis of Secondary Allylic Fluorides
(
tert-butyl to methyl) did not affect the efficiency of this
reaction, affording the desiredproducts4aÀc in high yields
92À94%). A particularly interesting example is the sub-
strate 3d with a substituted allyl ester. The desired product
d was isolated in 85% yield and no intramolecular
(
4
cyclopropanation was observed. Moreover, when an
amide was used as the acceptor group, the reaction can
still afford the desired product 4e in 60% isolated yield.
(
6) (a) Davies, H. M. L.; Saikali, E.; Clark, T. J.; Chee, E. H.
Tetrahedron. Lett. 1990, 31, 6299. (b) Davies, H. M. L.; Hu, B.; Saikaki,
E.; Bruzinski, P. R. J. Org. Chem. 1994, 59, 4535. (c) Sevryugina, Y.;
Weaver, B.; Hansen, J.; Thompson, J.; Davies, H. M. L.; Petrukina,
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Chem. Sci. 2011, 2, 457. (e) Morton, D.; Dick, A. R.; Ghosh, D.; Davies,
H. M. L. Chem. Commun. 2012, 48, 5838. (f) Valette, D.; Lian, Y.;
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135, 14516.
(7) (a) Wang, X.; Xu, X.; Zavalji, P. Y.; Doyle, M. P. J. Am. Chem.
Soc. 2011, 133, 16402. (b) Xu, X.; Zavalij, P. Y.; Hu, W.; Doyle, M. P. J.
Org. Chem. 2013, 78, 1583. (c) Qian, Y.; Zavalij, P. J.; Hu, W.; Doyle,
M. P. Org. Lett. 2013, 15, 1564. (d) Wang, X.; Abrahams, Q. M.; Zavalij,
P. Y.; Doyle, M. P. Angew. Chem., Int. Ed. 2012, 51, 5907. (e) Qian, Y.;
Xu, X.; Wang, X.; Zavalij, P. J.; Hu, W.; Doyle, M. P. Angew. Chem.,
Int. Ed. 2012, 51, 5900. (f) Barluenga, J.; Lonzi, G.; Riesgo, L.; Lopez,
L. A.; Tomas, M. J. Am. Chem. Soc. 2010, 132, 13200. (g) Pagar, V. V.;
Jadhav, A. M.; Liu, R. S. J. Am. Chem. Soc. 2011, 133, 20728. (h) Yue,
Y.; Wang, Y.; Hu, W. Tetrahedron Lett. 2007, 48, 3975.
(8) Previous transformations on carbenoid fluorination of diazo
compounds have been achieved under acidic conditions: (a) Olah,
G. A.; Welch, J. T. Synthesis 1974, 896. (b) Setti, E. L.; Mascaretti,
O. A. J. Chem. Soc., Perkin Trans. 1 1988, 2059. (c) Pasceri, R.; Bartrum,
H. E.; Hayes, C. J.; Moody, C. J. Chem. Commun. 2012, 48, 12077.
(9) (a) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 17, 2561. (b)
a
Middleton, W. J. J. Org. Chem. 1975, 40, 574. (c) Lal, G. S.; Pez, G. P.;
Pesaresi, R. J.; Prozonic, F. M. Chem. Commun. 1999, 215. (d) Lal, G. S.;
Pez, G. P.; Pesaresi, R. J.; Prozonic, F. M.; Cheng, H. J. Org. Chem.
Vinyl diazoacetate (0.4 mmol, 1.0 equiv), silver catalyst (10 mol %),
triethylamine trihydrogen fluoride (322 mg, 5.0 equiv) under reflux in
dichloromethane. NMR yield using dibromomethane as internal stan-
b
1
999, 64, 7048.
dard due to product decomposition upon silica gel chromatography.
c
(
10) (a) Haufe, G. J. Prakt. Chem. 1996, 338, 99. (b) Nelson, T. D.;
AgOTf (20 mol %) and 10 equiv of Et
NÀ3HF.
3
Crouch, R. D. Synthesis 1996, 1031.
Org. Lett., Vol. 15, No. 24, 2013
6153

The reaction can tolerate a variety of functionality on the
aryl group as illustrated by 4fÀo (63À96%). Furthermore,
the reaction can also be expanded to alkyl-substituted
vinyldiazoacetates as seen from 4pÀr (81À86%).
Scheme 3. Late-Stage Fluorination of Steroids
To further evaluate the fluorination method, we de-
signed and synthesized disubstituted vinyl diazoacetates
5
aÀg. Whenthese vinyl diazoacetatesweresubjectedtothe
standard conditions, the fluorinated products 6aÀg con-
taining quaternary carbon centers were readily formed
in good to excellent yields (75À91%) with a variety of
aryl- and alkyl-substituted vinyl diazoacetates (Scheme 2).
A particularly interesting example is the synthesis of the
fluorinated farnesol derivative 6g.
a
Scheme 2. Synthesis of Tertiary Allylic Fluorides
1
8
18
12
F labeling, F half-life: 110 min). Metal-catalyzed
1
3
reactions of diazo compounds can be extremely fast
and accordingly we explored the possibility of achieving fast
fluorination. Indeed, fluorination of vinyl diazoacetate 3c
in 80% isolated yield was achieved in 5 min when 20 mol %
of silver triflate was used as catalyst (Scheme 4).
Scheme 4. Rapid Fluorination Conditions
a
Vinyl diazoacetate (0.4 mmol, 1.0 equiv), silver catalyst (10 mol %),
triethylamine trihydrogen fluoride (322 mg, 5.0 equiv) under reflux in
dichloromethane.
In summary, we have developed a silver-catalyzed viny-
logous fluorination of vinyl diazoacetates. This novel
methodology is operationally simple and provides a di-
verse range of γ-fluoro-R,β-unsaturated carbonyl building
blocks. The method offers a strategy for rapid late-stage
generation of fluorinated compounds that may be used in
the synthesis PET radioligands. Future work will be
directed toward developing an enantioselective version of
this fluorination methodology.
Fluorinated steroids constitute an important class of
1
1
molecules with significant biological activity. Therefore,
we sought to apply this method to late-stage fluorination
of steroids (Scheme 3). The steroidal diazo derivatives 7
and 9 were readily formed by a diazo transfer reaction on
the corresponding steroids. Under slightly modified reac-
tion conditions using silver triflate, diazo 7 and 9 can be
converted to the desired fluorinated steroids 8 and 10
in 56% and 60% yield, respectively. An intriguing feature
of this fluorination process is the selective formation of
the 6-β-fluoro isomer. A similar selectivity has been seen
in vinylogous hydroxylation of steroidal diazo via silver
catalysis and has been rationalized to be due to stereoelec-
Acknowledgment. This work was supported by the
National Institutes of Health (GM099142).
Supporting Information Available. Experimental pro-
cedures and characterization and spectral data for new
compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
6
e
tronic effects from the conformation of the steroid used.
Considerable interest has been shown in developing fast
fluorination methods because they may be useful in devel-
oping positron emission tomography (PET tracers with
(
12) (a) Lee, E.; Hooker, J. M.; Ritter, T. J. Am. Chem. Soc. 2012,
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(
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A. S., Jr. Science 1995, 270, 283.
9
The authors declare no competing financial interest.
6
154
Org. Lett., Vol. 15, No. 24, 2013