Copper catalyzed β-difluoroacetylation of dihydropyrans and glycals by means of direct C-H functionalization

Article abstract of DOI:10.1021/ol401483j

A copper catalyzed direct functionalization of dihydropyrans and glycals has been developed. This method affords a new and straightforward access to C-2-CF₂ dihydropyrans and glycosides in a single step starting from readily available starting

Full text of DOI:10.1021/ol401483j

ORGANIC
LETTERS
2013
Vol. 15, No. 13
3428–3431
Copper Catalyzed β‑Difluoroacetylation
of Dihydropyrans and Glycals by Means
of Direct CÀH Functionalization
Marie-Charlotte Belhomme, Thomas Poisson,* and Xavier Pannecoucke*
ꢀ
Normandie Universite, COBRA, UMR 6014 et FR 3038; Universite de Rouen;
INSA Rouen; CNRS, 1 rue Tesniere, 76821 Mont Saint-Aignan Cedex, France
ꢀ
ꢁ
thomas.poisson@insa-rouen.fr; xavier.pannecoucke@insa-rouen.fr
Received May 26, 2013
ABSTRACT
A copper catalyzed direct functionalization of dihydropyrans and glycals has been developed. This method affords a new and straightforward
access to C-2-CF2 dihydropyrans and glycosides in a single step starting from readily available starting materials. This new copper based catalytic
system, probably involving a Cu(III) species as supported by experiments, allows the formation of the valuable fluorinated glycosides in good
yields.
Molecules containing a fluorine atom represent a re-
markable class of compounds; the unique properties of the
fluorine atom push it to the forefront of agrochemicals and
drugs discovery. Its electronegativity, its small size, and the
high energy of the CÀF bond afford it the impressive
ability to change the physical and biological properties of
molecules.1,2 On the other hand, fluorine is well recognized
as a metabolically stable analog and/or surrogate of the
hydrogen atom.2 As a result, more than 20% of pharma-
ceuticals and 30% of agrochemicals bear at least one
fluorine atom.1 Thus, many synthetic efforts have been
recently devoted to achieving the introduction of fluorine
or fluorinated building blocks in an efficient manner3 and
particularly by means of CÀH bond functionalization.4
Quite recently, the introduction of fluorine and a CF3
moiety onto aromatic and aliphatic backbones has at-
tracted much attention, offering a wide range of elegant
and efficient processes.5 Surprisingly, the catalyzed direct
introduction of a functionalized fluorinated moiety has
been less explored, and such processes have remained
scarce despite the high level of functionalization of the
resulting products.6 Among these fluorinated moieties, the
CF2CO2Et moiety is extremely appealing due to the huge
possibility of postfunctionalization. However, the intro-
duction of the difluoroacetyl moiety onto an alkene or
aromaticmoietyusually focuses on (1) aradicaladdition of
€
(1) (a) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b)
O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (c) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (d) Jeschke,
P. ChemBioChem 2004, 5, 570.
€
(2) Bohm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
€
Muller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637.
(3) For review, see: (a) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
2011, 473, 470. (b) Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011,
111, 4475. (c) Prakash, G. K. S.; Wang, F. Chim. Oggi 2012, 5, 30. For an
early report on the radical of the fluorinated moiety on alkenes, see: (d)
Chen, Q.-Y.; Yang, Z.-Y. J. Fluorine Chem. 1985, 28, 399. (e) Chen,
Q.-Y.; He, Y.-B.; Yang, Z.-Y. J. Fluorine Chem. 1986, 34, 255. (f) Chen,
Q.-Y.; Yang, Z.-Y.; Zhao, C.-X.; Qiu, Z.-M. J. Chem. Soc., Perkin
Trans. 1 1988, 563. (g) Chen, Q.-Y.; Yang, Z.-Y. J. Chem. Soc., Chem.
Commun. 1986, 498. For selected examples, see: (h) Zhu, J.; Zhang, W.;
Zhang, L.; Liu, J.; Zheng, J.; Hu, J. J. Org. Chem. 2010, 75, 5505. (i) Zhu,
J.; Wang, F.; Huang, W.; Zhao, Y.; Ye, W.; Hu, J. Synlett 2011, 899. (j)
Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett. 2011, 13,
5560.
(4) Selected examples: (a) Nagib, D. A.; MacMillan, D. W. C. Nature
2011, 480, 224. (b) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter,
R. D.; Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S.
J. Am. Chem. Soc. 2012, 134, 1494. (c) Mejıa, E.; Togni, A. ACS Catal.
2012, 2, 521.
(5) Selected examples: (a) Cho, E. J.; Senecal, T. D.; Kinzel, T.;
Zhang, Y.; Watson, D. A.; Buchwald, S. L. Science 2010, 328, 1679. (b)
Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2012, 134, 9034. (c) Novak, P.;
Lishchynskyi, A.; Grushin, V. V. J. Am. Chem. Soc. 2012, 134, 16167. (d)
Hu, M.; Ni, C.; Hu, J. J. Am. Chem. Soc. 2012, 134, 15257. (e) Wang, X.;
Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520.
(6) Surapanich, N.; Kuhakarn, C.; Pohmakotr, M.; Reutrakul, V.
Eur. J. Org. Chem. 2012, 5943.
r
10.1021/ol401483j
Published on Web 06/21/2013
2013 American Chemical Society

a halogenated or selenium based reagent on electron-rich
olefins or electron-rich arenes;7aÀc (2) the copper-bronze
mediated reductive coupling of aryl or vinyl iodide withthe
copper species derived from the corresponding bromo,
iodo, or trimethylsilyl difluoroacetate;7dÀe (3) a copper
mediated cross-coupling reaction of boronic acid with
iododifluoroacetate in the presence of a stoichiometric
amount of copper metal;7f or (4) a nickel catalyzed cross-
coupling of vinyl zirconium species with bromodifluoroa-
cetyl compounds.7g To the best of our knowledge no catalytic
approach to the direct introduction of BrCF2CO2Et by
means of CÀH bond functionalization has been reported
to date. Thus, as our group is always interested in the
preparation of fluorinated carbohydrates analogues, we
report herein a catalytic radical free introduction of the
CF2CO2Et moiety onto the C-2 position of dihydropyrans
and glycals derivatives by means of direct copper catalyzed
CÀH functionalization (Scheme 1).
Table 1. Optimization of the Reaction Conditions
yield
(%)a
entry
metal
Pd(PPh3)4
base
solvent
1b,c
2c
Cs2CO3
Cs2CO3
Cs2CO3
À
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMF
DMF
DMF
19
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
À
39
3
47
4c
NRd
NRd
21f
4f
5c
À
6
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuI
Et3N
7
K3PO4
K2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
8
9e
10e
11e
12e
13e
49
73
65
70
Scheme 1. Previous Examples of Difluoroacetylation Reactions
[Cu(OTf)]2 C6H6
62f
52f
3
Cu(PF6) (CH3CN)4
3
a Isolated yield. b Reaction was performed at 110 °C for 24 h.
c Without 3. d Starting material was fully recovered. e Reaction was
performed under an air atmosphere. f Determined by 19F NMR using
R,R,R-trifluorotoluene as an internal standard. 3: 1,10-phenanthroline.
typical Heck selectivity, which provides predominantly the
R-product.8 Thus, we hypothesized that the reaction might
go through a different pathway: an electrophilic metala-
tion. We next thought a more electrophilic metal, such
as copper, might improve this chemical transformation,
through a Cu(III) species, as a d8 metal intermediate of the
reaction.9
Pleasingly, the use of Cu(OTf)2 affords a significant
enhancement of the yield from 19% to 39% under milder
conditions (entry 2). Moreover, a lower temperature and
lower reaction time were required to ensure a full conver-
sion along with a better isolated yield. The addition of a
ligand (1,10-phenanthroline3) was beneficial, and the yield
was improved to 47% (entry 3).10 Noteworthy, control
experiments revealed that the reaction did not occur in the
absence of base11 or copper catalyst (entries 4 and 5). The
At the outset of the project, dihydropyran (DHP) was
used as the model substrate to optimize the reaction
conditions. Surprisingly, initial attempts using Pd catalysts
led to the exclusive formation of the β-adduct 2a albeit in
low yield. Encouraged by these exciting results, we decided
to improve this transformation. After extensive investiga-
tions, the corresponding adduct 2a was obtained in 19%
yield using Pd(PPh3)4 as a catalyst (Table 1, entry 1). The
complete β-selectivity of the reaction contrasts with the
(8) For examples of complete R-selectivity: (a) Gøgsig, T. M.;
Kleimark, J.; Lill, S. O. N.; Korsager, S.; Lindhardt, A. T.; Norrby,
P.-O.; Skrydstrup, T. J. Am. Chem. Soc. 2012, 134, 443. (b) Mo, J.; Xiao,
J. Angew. Chem., Int. Ed. 2006, 45, 4152. (c) Larhed, M.; Hallberg, A.
J. Org. Chem. 1997, 62, 7858. For examples and discussions regarding
the R/β regioselectivity: (d) Andersson, C.-M.; Hallberg, A. J. Org.
Chem. 1987, 52, 3529. (e) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am.
Chem. Soc. 2001, 123, 8217. (f) Cabri, W.; Candiani, I.; Bedeschi, A.
J. Org. Chem. 1993, 58, 7421. (g) Datta, G. K.; von Schenck, H.;
Hallberg, A.; Larhed, M. J. Org. Chem. 2006, 71, 3896.
(7) (a) Murakami, S.; Ishii, H.; Tajima, T.; Fuchigami, T. Tetrahedron
2006, 62, 3761. For a photocatalytic approach, see: (b) Wallentin, C.-J.;
Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc. 2012,
134, 8875. (c) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org.
Lett. 2011, 13, 5560. (d) Taguchi, T.; Kitagawa, O.; Morikawa, T.;
Nishiwaki, T.; Uehara, H.; Endo, H.; Kobayashi, Y. Tetrahedron 1986,
27, 6103. (e) Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Wallace, D. J.;
Davies, A. J.; Kennedy, D. J.; Dolling, U. H. Tetrahedron Lett. 2002, 43,
9271. (f) Qi, Q.; Shen, Q.; Lu, L. J. Am. Chem. Soc. 2012, 134, 6548. (g)
Schwaebe, M. K.; McCarthy, J. R.; Whitten, J. P. Tetrahedron Lett. 2000,
41, 791.
(9) (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (b) Gigant,
N.; Chausset-Boissarie, L.; Belhomme, M.-C.; Poisson, T.; Panne-
coucke, X.; Gillaizeau, I. Org. Lett. 2013, 15, 278. For well-defined
ꢁ
Cu(III) species: (c) Casitas, A.; Canta, M.; Sola, M.; Costas, M.; Ribas,
X. J. Am. Chem. Soc. 2011, 133, 19386.
(10) See Supporting Information for details.
(11) Starting material was fully recovered, precluding an additionÀ
elimination process which would have afforded the R-bromo-β-CF2CO2Et
pyran derivative.
Org. Lett., Vol. 15, No. 13, 2013
3429

nature of the base was crucial to achieve the transforma-
tion in good yield. Organic bases such as Et3N were less
efficient (entry 6), and a survey of inorganic bases high-
lighted K2CO3 as the most efficient base for this transfor-
mation (entry 8).10 Then, a solvent screening showed that
DMF and NMP were the most adequate solvents.10
Nicely, a simple change from an argon to an air atmo-
sphere led to the formation of 2a in 73% yield (entry 9),12
while the Cu(OTf)2/Cs2CO3/NMP system gave a slightly
lower yield (65%, entry 10). Another pertinent result is the
effectiveness of Cu(I) catalysts as depicted in entries
Scheme 3. Evidence of the Reaction Mechanism
11À13. To our delight, both CuI and [Cu(OTf)]2 C6H6 led
3
to the formation of 2a in fairly decent yield, 70% and 62%
respectively (entries 11 and 12), while CuPF6 (CH3CN)4
3
gave a moderate yield along with unidentified side products
(52%, entry 13). These last results clearly point out the
fact that Cu(I) species might be the real active catalyst13
involved in a Cu(I)/Cu(III) cycle. Next, functionalized dihy-
dropyran derivatives 1b and 1c were engaged in the reaction,
and pleasingly both benzyl and pivaloyl protecting groups
were compatible affording the corresponding products 2b
and 2c in 72% and 60% isolated yield respectively using
ether 4. Under standard conditions an isomerization of the
double bond of the product was observed, supporting the
presence of an oxonium intermediate. Indeed, two sites of
deprotonation are available, and it occurred on the less
hindered position affording the trisubstituted enol ether 5 as
the sole product (Scheme 3, eq 2). According to these results,
we proposed the following mechanism. The in situ generated
Cu(I) complex12 is involved in an oxidative addition into the
CÀhalogen bond of BrCF2CO2Et leading to the formation
of an highly electrophilic Cu(III) species.14a Then, the last
one reacts with DHP forming an oxonium species, which is
then released as an enol ether by the base. A final reductive
elimination delivers the desired product and regenerates the
copper catalyst (Scheme 3).14b
Cu(PF6) (CH3CN)4 as a catalyst instead of Cu(OTf)2
(Scheme 2).
3
Scheme 2. Scope of Dihydropyran Derivativesa
Finally, in order to highlight this new reactivity, we
turned our attention tothe functionalization ofmuchmore
complex and challenging substrates: carbohydrate deriva-
tives. Indeed, fluorinated carbohydrates are extremely
appealing,15 as the feature of the fluorine atom or fluori-
nated group to enhance the stability or to mimic the
glycosidic linkage might afford metabolically stable
carbohydrate-based drugs.14 Thus, the design and synth-
esis of in vivo stable glycomimetic compounds appear as a
real challenge toward the discovery of new biologically
active compounds. In addition, to the best of our knowledge
no catalytic CÀH-bond functionalization of the glycosidic
a Cu(OTf)2 was used.
On the basis of this new transformation mechanism,
mechanistic experiments were carried out. First, in order to
rule out a radical pathway, the addition of radical inhibi-
tors or radical scavengers to the reaction mixture was
performed (Scheme 3, eq 1).
Interestingly, the addition of radical inhibitors or radical
scavengers had a negligible effect on the yield of the reaction.
In the presence of 20 mol % of TEMPO, TBHT, benzoqui-
none, or diphenylethene, a slight drop in the reaction yield
was observed. Noteworthy, the reaction carried out with 1
equiv of TEMPO still proceeded smoothly although a
longer reaction time was required (66%, 36 h). Additional
evidence of the reaction mechanism was obtained with enol
(14) (a) Ethyl bromoacetate does not react, even at higher tempera-
ture. We suppose that the CF2 moiety strengthens the electrophilicity of
the Cu(III) intermediate, supporting the hypothesis of a nucleophilic
attack of the DHP ring on the electrophilic metal center. All our
attempts to characterize the Cu(III) species were unsuccessful. (b) We
cannot rule out that the reductive elimination proceeds before the proton
abstraction.
(12) The use of an oxygen atmosphere supressed the reaction.
(13) The active Cu(I) can be generated through either the reduction
or the disproportionation of Cu(II). For reduction, see: (a) Phipps, R. J.;
Grimster, N. P.; Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 8172. For
disproportion, see: (b) Ribas, X.; Calle, C.; Poater, A.; Casitas, A.;
Gomez, L.; Xifra, R.; Parella, T.; Benet-Buchholz, J.; Schweiger, A.;
Mitrikas, G.; Sola, M.; Llobet, A.; Stack, T. D. P. J. Am. Chem. Soc.
2010, 132, 12299 and references herein.
ꢁ
(15) For a review, see: Leclerc, E.; Pannecoucke, X.; Etheve-Quel-
quejeu, M.; Sollogoub, M. Chem. Soc. Rev. 2013, 42, 4270.
(16) For examples of CÀH functionalization of glycosides, see: (a)
Frihed, T. G.; Heuckendorff, M.; Pedersen, C. M.; Bols, M. Angew.
Chem., Int. Ed. 2012, 51, 12285. (b) Bai, Y.; Zeng, J.; Cai, S.; Liu, X.-W.
Org. Lett. 2011, 13, 4394. (c) Farr, R . N.; Outten, R. A.; Cheng, J. C.-Y.;
Daves, G. D. Organometallics 1990, 9, 3151.
3430
Org. Lett., Vol. 15, No. 13, 2013

equivalents from 4 to 8 equiv, and enhancement of the
reaction temperature to 110 °C furnish the corresponding
tri-O-Bn-D-glucal 2d in 62% yield (Scheme 4). The same
protocol was used for glucal derivatives 2e, 2f, and 2g
affording the CF2 glycosides in 50%, 65%, and 51% yield
respectively.18 Galactal derivatives reacted smoothly under
our optimized conditions furnishing the fluoroglycosides 2i,
2j, and 2k in moderate yield. The 6-deoxy-L-glucal deriva-
tives 1l, 1m, and 1n were submitted to the reaction condi-
tions. The benzyl protected glycomimetic 2l and the
pivaloyl-protected CF2 derivatives 2m were obtained in
51% and 50% yield respectively, while the methyl protected
fluorinated glycoside 2m was isolated in 60% yield. We then
turned our attention to the arabinal derivatives; surprisingly
the methyl and benzyl protected glycals 2o and 2p gave
lower yields compared to the previous glycosides, 39% and
42% respectively.18b
Scheme 4. Synthesis of Fluorinated Glycal Derivativesa
In conclusion we report herein an unsual nonradical
addition of BrCF2CO2Et to dihydropyran and glycal
derivatives. This straightforward methodology based on
a copper catalyzed CÀH bond functionalization process
afforded an easy access to C-2 CF2-dihydropyrans and C-2
CF2-glycosides. Mechanistic studies support a plausible
Cu(I)/Cu(III) catalytic cycle involving a highly electrophi-
lic organometallic species. This new methodology was
successfully applied to a broad range of glycal derivatives
giving an easy access to a new class of fluorinated com-
pounds with potential applications as glycomimetics.
Further applications of this new intriguing reactivity is
currently underway in our laboratory.
a Reaction conditions: 1 (0.24 mmol), BrCF2CO2Et (8 equiv,
1.92 mmol), Cu(PF6) (MeCN)4 (0.024 mmol), 3 (0.029 mmol), K2CO3
3
b
c
(0.48 mmol), DMF (1.2 mL), 110 °C. 110 °C, 30 h. The isolated
product contained some impurities. d CuI was used.
Acknowledgment. This work has been partially sup-
ꢀ
ported by INSA de Rouen, Universite de Rouen, CNRS,
and LABEX SynOrg (ANR-11-LABX-0029). M.-C.B.
thanks the MESR for a doctoral fellowship.
moiety by a fluorinated building block has been reported
to date.16 This new site selective introduction of the
CF2CO2Et moiety applied to glycal derivatives could
provide a straightforward and practical access to the un-
studied C-2-CF2 glycomimetics.17 Initial attempts revealed
that further optimizations were required to ensure a full
conversion and decent yields as well. After optimizations,
Supporting Information Available. Experimental proce-
dures along with spectroscopic data. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(18) (a) The PMB protected glucal 1e gave a lower yield, probably
due to a partial deprotection of the PMB ether. p-Anisaldehyde was
detected by 1H NMR of the crude product. (b) We suspect that the ring
conformation and particularly the C-4 center might affect the reactivity
and stability of the resulting product.
we found that the use of Cu(PF6) (CH3CN)4 instead of
3
Cu(OTf)2, an increase in the number of BrCF2CO2Et
(17) For an example of introduction of a fluorinated moiety at the C2
position of the carbohydrate, see: Wegert, A.; Miethchen, R.; Hein, M.;
Reinke, H. Synthesis 2005, 1850 and references herein.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 13, 2013
3431