Facile synthesis of 4-vinyl- and 4-fluorovinyl-1,2,3-triazoles via bifunctional "click-olefination" reagents

Article abstract of DOI:10.1039/c0cc05083k

Modular synthesis of vinyl and fluorovinyl triazoles can be achieved from bifunctional propargyl and fluoropropargyl sulfones by Cu-catalyzed azide-alkyne ligation and Julia-Kocienski olefination. Competitive click reactions of the protio and fluoropropar

Full text of DOI:10.1039/c0cc05083k

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COMMUNICATION
Facile synthesis of 4-vinyl- and 4-fluorovinyl-1,2,3-triazoles via
bifunctional ‘‘click-olefination’’ reagentsw
Rakesh Kumar, Padmanava Pradhan and Barbara Zajc*
Received 21st November 2010, Accepted 25th January 2011
DOI: 10.1039/c0cc05083k
Modular synthesis of vinyl and fluorovinyl triazoles can be
achieved from bifunctional propargyl and fluoropropargyl
sulfones by Cu-catalyzed azide–alkyne ligation and Julia–
Kocienski olefination. Competitive click reactions of the protio
and fluoropropargyl sulfones show higher reactivity of the latter,
and a preliminary DFT analysis was performed.
Formation of triazoles via the Huisgen ligation of azides and
alkynes is an efficient, atom-economical process.1 Furthermore,
the Cu-catalyzed azide–alkyne click ligation has yielded facile
and efficient access to triazoles, often with high regioselectivity.2,3
Using the fluorinated building block approach,4 we5,6 and
others7 have been developing syntheses of regiospecifically
fluorinated molecules via the Julia–Kocienski olefination.5–7
Since both the triazole moiety8 and the fluorine atom9
are widely prevalent in pharmacological agents, a modular
Scheme
1 Synthesis and click reactions of BT-propargyl and
methodology allowing facile assembly of triazole rings as well
as the fluorovinyl moiety, would be of high interest. This
communication describes such an approach.
fluoropropargyl sulfones.
of the sulfide (Scheme 1).12 Metalation–fluorination of 1
yielded the unknown fluoro derivative 2 (63%). Although
deprotection of the TMS group in 2 proceeded cleanly,
chromatographic purification of 2 gave a mixture of alkyne
and the corresponding rearranged allene. An in situ alkyne
deprotection-click reaction route was therefore investigated.
Conditions for the deprotection-click reaction were evaluated
using p-methoxyphenyl azide and fluoropropargyl sulfone 2. Use
of AgBF4, CuSO4 and Na ascorbate in the biphasic CH2Cl2/H2O
led to low conversion to desired triazole after 72 h, at room
temperature (Table 1, entry 1). Conditions recently reported for
one-pot synthesis of triazoles from TMS-protected alkynes were
then evaluated.13 Reaction in the presence of AgBF4, CuSO4/Na
ascorbate in tBuOH/H2O at 35 1C resulted in an incomplete
reaction even after 72 hours, with 16% conversion to triazole 4
(entry 2). On the other hand, fast, efficient alkyne deprotection
and azide ligation could be achieved with AgBF4 and
Cu(CH3CN)4PF6 in CH2Cl2/MeOH (entry 3).13 No further
optimizations were performed.
We hypothesized that a bifunctionalizable building block
containing a ‘‘clickable’’ unit and an olefination handle, would
offer great flexibility in accessing regioselectively difunctionalized
triazoles, wherein both the N1 and vinyl substituents can be
readily varied. Although conversion of enynes to 4-vinyl-1,2,3-
triazoles has been reported,10 to the best of our knowledge, the
combination of click chemistry and Julia–Kocienski reaction
has not been used for synthesis of either unfluorinated or
fluorinated vinyl triazoles. Hence, we decided to explore
such a route for the synthesis of N-substituted 4-vinyl and
4-(a-fluorovinyl)-1,2,3-triazoles.
For this approach, appropriate propargyl and a-fluoro-
propargyl heteroaryl (benzothiazole or phenyltetrazole)11 sulfones
were required. Benzothiazol-2-yl (BT) propargyl sulfone 1 was
prepared by reaction of TMS-protected propargyl bromide
and sodium salt of BT-thiol, followed by m-CPBA oxidation
Department of Chemistry, The City College and The City University
of New York, New York, New York 10031-9198, USA.
E-mail: barbaraz@sci.ccny.cuny.edu; Fax: +1 212-650-6107;
Tel: +1 212-650-8926
With AgBF4/Cu(CH3CN)4PF6, reactions of sulfones 1
and
2 with alkyl and aryl azides in CH2Cl2/MeOH
w Electronic supplementary information (ESI) available: Synthetic
procedures and spectral data for 1–8, general synthetic procedure
for 9–26, HRMS data of 9–26, 19F NMR data of 18–26, data from the
DFT calculations, copies of 1H spectra of 1–26 and 13C spectra of 1–8.
See DOI: 10.1039/c0cc05083k
yielded the corresponding triazoles (Scheme 1). Both
BT-sulfones 1 and 2 gave high yields of the triazole sulfones
3–8 (74%–84% in reactions of 1 and 68%–93% in reactions
of 2, Fig. 1).
c
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Table 1 Conditions tested for deprotection-click reaction of 2
Entry Click catalyst (molar equiv.)
AgBF4 (molar equiv.) Solvent; T/1C; t/h
CH2Cl2–H2O 1.7 : 1; rt; 72
%Ratio of 4 : 2 : 2aa or yield
1
2
3
CuSO4Á5H2O (0.05); Na ascorbate (0.1) 0.2
5 : 77 : 18
CuSO4Á5H2O (0.1); Na ascorbate (0.2)
Cu(CH3CN)4ÁPF6 (0.2)
0.2
0.2
t-BuOH–H2O 9.5 : 0.5; 35 1C; 72 16 : 0 : 84
CH2Cl2–CH3OH 4 : 1; rt; 2
93b
a
In case of incomplete conversion, product was not isolated. Relative ratio of 4 : 2 : 2a determined by 19F NMR. The ratio takes into
b
consideration the molar excess of 2. Yield of isolated, purified 4.
These calculations showed little difference between the
HOMO energies of 2a and 1a, whereas the LUMO energy of
2a is lower than that of 1a by 3.7 kcal molÀ1 (Table 2 in
the ESIw). The NBO bond order of the triple bond was
similar in 1a and 2a (1.932 and 1.926, respectively). Interesting
differences emerged upon comparing the NBO analyzed
natural charges at the triple bond (Table 3 in the ESIw). In 1a
there is higher electron density at the terminal alkynyl carbon
atom as compared to 2a. On the other hand, electron density at
the internal alkynyl carbon in fluoro analogue 2a is higher as
compared to protio 1a. The alkynyl proton is slightly more
electropositive in 2a than in 1a. The ability of the fluorine atom
to stabilize accumulating negative charge at the terminal alkynyl
carbon in the course of the ligation reaction may be an important
contributor to the enhanced reactivity of 2a compared to 1a. In
this context, a stepwise mechanism for the azide–alkyne ligation
has been proposed,2b and has been supported by computation17a,c
and kinetic studies.17b In this mechanism, formation of a copper
metallacycle is described as the rate-limiting step, with an increase
in electron density at the terminal alkynyl carbon. A second
copper atom in close proximity to the terminal alkynyl carbon has
been proposed to stabilize the transition state.17b,c In our case, the
fluorine atom in 2a may additionally contribute to such charge
stabilization, which is absent in protio analogue 1a. These
reactions are complex and clearly additional studies will be needed
in order to fully understand the reactivity differences.
Fig. 1 Structures of the triazolyl Julia reagents.
Table 2 Competitive click reactions of 1 and 2 with various azides
%Ratio of productsa
X = H
X = F
Entry
R=
1
2
3
p-MeO–C6H4–
Ph(CH2)3–
CH3(CH2)9–
3 : 8
5 : 17
7 : 28
4 : 92
6 : 83
8 : 72
a
1
Relative ratio of products determined by H NMR.
To assess whether the fluorine atom exerted any influence
on the click reactions of propargyl sulfone 2, competitive
reactions of 1 and 2 with p-methoxyphenyl, 3-phenylpropyl
and decyl azides were performed (Table 2).
The protio Julia–Kocienski reagents 3 and 5, as well as the
fluoro analogues 4 and 6 were next tested in olefination
reactions (Table 3). These olefinations were performed under
reaction conditions that were previously shown to favor a
trans disposition of aryl and alkyl substituents, i.e. E-isomer in
reactions of the unfluorinated Julia–Kocienski reagents18 and
Z-isomer with a-fluorobenzyl BT-sulfones.6a
Yields and stereoselectivities in olefinations with the protio
reagents 3 and 5 depended on both the carbonyl compound as
well as the R group on the triazolyl moiety (entries 1–8). Yields
were lowest in condensations of N-(3-phenylpropyl) substituted
triazole 5 with alkanals (entries 6 and 8). Olefinations with
fluoro analogues 4 and 6 were Z-selective in every case tested
(entries 10–17). Product yields in reactions with the fluorinated
building blocks 4 and 6 were generally higher in comparison to
those with protio derivatives 3 and 5. Reactions of the ketone,
N-benzylpiperidone with protio reagent 5 and fluoro reagent 4
a-Fluoro-substituted propargyl sulfone 2 was more reactive
in the azide–alkyne ligation reactions, than the unfluorinated
propargyl sulfone 1. This is consistent with results from
uncatalyzed and catalyzed azide ligation reactions with
fluoro-substituted cyclooctyne14,15 and diynes,16 respectively.
The ratio of fluoro/protio substituted triazole products in the
competitive reactions of 1 and 2 with 3-phenylpropyl and
n-decyl azide was 4.9 and 2.6, respectively. A higher difference
in reactivity between 1 and 2 was observed in the reaction with
p-methoxyphenyl azide, where the ratio of fluoro/protio
substituted triazole derivatives was 11.5 (Table 2).
In order to obtain insight into the difference in reactivity
between 1 and 2 in click reactions, preliminary DFT calculations
were performed at the B3LYP/6-311++G(2d,2p) level on BT
fluoropropargyl sulfone 2a (shown in the scheme above Table 1)
and on BT propargyl sulfone 1a (the protio analogue of 2a).
c
3892 Chem. Commun., 2011, 47, 3891–3893
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Table 3 Synthesis of vinyl and fluorovinyl triazoles
triazoles, and can potentially find broad applicability in
organic synthesis as well as in high-throughput methodology.
This work was supported by PSC CUNY awards.
Infrastructural support was provided by NIH RCMI Grant
5G12 RR03060. We thank Prof Michael Green (CCNY) for
advice on the DFT computational analysis and Dr Andrew
Poss (Honeywell) for a sample of NFSI.
Entry Carbonyl
X= BT-sulfone Yield,a E/Z ratiob
1
2
H
H
3
5
9 : 73%, 33/67
10 : 85%, 15/85
Notes and references
1 (a) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 565;
(b) R. Huisgen, Angew. Chem., Int. Ed. Engl., 1963, 2, 633.
2 (a) C. W. Tornøe, C. Christensen and M. Meldal, J. Org. Chem.,
2002, 67, 3057; (b) V. V. Rostovtsev, L. G. Green, V. V. Fokin and
K. B. Sharpless, Angew. Chem., Int. Ed., 2002, 41, 2596.
3 For reviews see: (a) H. C. Kolb, M. G. Finn and K. B. Sharpless,
Angew. Chem., Int. Ed., 2001, 40, 2004; (b) M. V. Gil,
M. J. Arevalo and O. Lopez, Synthesis, 2007, 1589.
3
4
H
H
5
5
11 : 65%, 72/28
12 : 44%, 83/17
5
6
H
H
3
5
13 : 67%, 86/14
14 : 41%, 77/23
4 Fluorine-Containing Synthons, ed. V. A. Soloshonok, American
Chemical Society, Washington, DC, 2005.
5 For a review see: B. Zajc and R. Kumar, Synthesis, 2010,
1822.
7
8
H
H
3
5
15 : 71%, 72/28
16 : 31%, 7/93
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9c
H
F
5
6
17 : 59%
10
18 : 47%, 26/74
11
12
F
F
4
6
19 : 72%, 14/86
20 : 90%, 7/93
13
F
6
21 : 76%, 38/62
14
15
16
F
F
F
4
6
4
22 : 60%, 15/85
23 : 57%, 19/81
24 : 68%, 34/66
8 W.-Q. Fan and A. R. Katritzky, in Comprehensive Heterocyclic
Chemistry II, ed. A. R. Katritzky, C. W. Rees and E. F. V. Scriven,
Elsevier Science, Oxford, 1996, vol. 4, p. 1.
17
18c
F
F
6
4
25 : 63%, 36/64
26 : 87%
9 J.-P. Begue and D. Bonnet-Delpon, Bioorganic and Medicinal
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a
b
Yields of isolated, purified products. Relative ratio of diastereomers
determined in the crude reaction mixture either by 1H or by 19F NMR.
c
Conditions: LHMDS, THF, 0 1C.
11 For reviews see: (a) P. R. Blakemore, J. Chem. Soc., Perkin Trans.
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gave the corresponding vinyl triazoles in 59% and 87% yields,
respectively (entries 9 and 18).
In summary, facile and previously unprecedented access to
vinyl and fluorovinyl triazoles is possible from the bifunctional
propargyl and fluoropropargyl benzothiazolyl sulfones. The
fluoropropargyl derivative is readily obtained via metalation–
fluorination of propargyl benzothiazolyl sulfone. Synthesis of
triazoles from TMS-protected propargyl and fluoropropargyl
sulfones can be accomplished in a single step by in situ TMS
deprotection and Cu-catalyzed azide–alkyne ligation (68–93%
yields). In competitive experiments a higher reactivity of the
fluoropropargyl sulfone 2 was observed, compared to the
protio analogue. DFT calculations show lower electron
density at the terminal alkynyl carbon atom in 2a compared
to the protio analogue. This may be a contributor to the higher
reactivity of the fluoropropargyl sulfone in the azide–alkyne
ligation. This highly modular approach offers rapid access to
diversely functionalized N-substituted vinyl and fluorovinyl
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3891–3893 3893