F- Nucleophilic-Addition-Induced Allylic Alkylation

Article abstract of DOI:10.1021/jacs.6b11205

Herein we present a novel strategy based on palladium-catalyzed allylic alkylation by taking advantage of the nucleophilic addition of external fluoride onto gem-difluoroalkenes as the initiation step. The merit of this protocol is highly appealing, as it enables a formal allylation of trifluoroethylarene derivatives through the in situ generation of β-trifluorocarbanions, which otherwise are deemed to be problematic in deprotonative allylation. Furthermore, this strategy distinguishes itself by high modularity, operational simplicity, and wide substrate scope with respect to allyl carbonates, giving rise to a broad array of homoallyltrifluoromethane derivatives, which otherwise would not be easily obtained using existing synthetic methods.

Full text of DOI:10.1021/jacs.6b11205

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Communication
-
F Nucleophilic Addition Induced Allylic Alkylation
Panpan Tian, Cheng-Qiang Wang, Sai-Hu Cai, Shengjin Song, Lu Ye, Chao Feng, and Teck-Peng Loh
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b11205 • Publication Date (Web): 28 Nov 2016
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F- Nucleophilic Addition Induced Allylic Alkylation
Panpan Tian,†, § Cheng-Qiang Wang,†,§ Sai-Hu Cai,† Shengjin Song,† Lu Ye,† Chao Feng,*,† and
Teck-Peng Loh*,‡,¶
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†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic In-
novation Center for Advanced Materials, Nanjing Tech University, 30 South Puzhu Road, Nanjing 211816, P.R. China
‡Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, P.R. China
¶Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Techno-
logical University. Singapore 637616
Supporting Information Placeholder
ABSTRACT: Herein, we present a novel strategy based on palladium-catalyzed allylic alkylation by taking advantage of
the nucleophilic addition of external fluoride onto gem-difluoroalkenes as the initiation step. The merit of this protocol is
highly appealing as it enables a formal allylation of trifluoroethylarene derivatives through the in situ generation of β-
trifluorocarbanions, which otherwise are deemed to be problematic via deprotonative allylation manners. Furthermore,
this strategy distinguishes itself by high modularity, operational simplicity and wide substrate scope with respect to allyl
carbonates, giving rise to a broad array of homoallyltrifluoromethane derivatives, which otherwise would not be easily
obtained using the existing synthetic methods.
Transition-metal-catalyzed allylic alkylation (AA as ab-
breviation) reaction represents one of the most important
and fundamental C-C bond formation reactions in mod-
ern synthetic organic chemistry.1 By enabling straightfor-
ward introduction of synthetically versatile allyl frag-
ments to a great diversity of pro-nucleophiles, these reac-
tions find broad applications in natural product synthesis,
medicinal chemistry and materials science.2 In this con-
text, the palladium-catalyzed variant, also widely known
as the Tsuji-Trost reaction, was particularly well explored
and met with a great success during the past several dec-
ades (Scheme 1a).3 However, the majority of reported ex-
amples were restricted to the creation of only one C(sp3)-
C(sp3) bond, with only sporadic cases, which enables a
nucleophilic addition induced allylic alkylation (NAAA as
abbreviation), being reported.4 By making use of the vinyl
epoxide or aziridine as amphiphilic precursors under pal-
ladium catalysis, Yamamoto, Aggarwal et al. have success-
fully achieved the NAAA reaction with external Michael
acceptors.5 Moreover, an elegant example of three-
components NAAA reaction was also disclosed by Yama-
moto and coworkers, although the employment of doubly
activated Michael acceptor was found to be a prerequisite
(Scheme 1b).6a To be noted, by using this strategy Plietker
and coworkers have successfully developed an efficient
protocol based on nucleophilic ferrate system, which al-
lowed the smooth alkoxy- and trifluoromethylation-
allylation of doubly activated alkenes.6b,6c Considering the
challenges and potential problems associated with NAAA
reactions, for example the competing premature AA reac-
tion of pro-nucleophile or simple conjugate addition of
pro-nucleophile with Michael acceptor, it is thus quite
understandable for their slow advance.
Scheme 1. Tsuji-Trost reaction and nucleophilic
addition induced allylic alkylation
Due to the unique intrinsic nature of fluorine atom, the
development of effective synthetic strategies for the in-
troduction of fluorine or fluorine-containing functional
groups to organic frameworks is of vital importance in
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pharmaceutical and
agrochemical research,7 among
tiveness of trifluoroethylarene in this transformation is in
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which the discovery of novel synthetic approaches for the
introduction of trifluoromethyl group has particularly
gained much attention.8 With our recent success of using
gem-difluoroalkene as electrophile for the introduction of
monofluoroalkene moiety,9 we envisage the possibility of
uncovering an unprecedented strategy for the modular
construction of homoallyltrifluoromethane derivatives by
taking advantage of palladium-catalyzed NAAA reaction
(Scheme. 1c).10 It needs to be pointed out that Hu and
coworkers have recently reported a novel synthetic route
full agreement with the current notion of allylic alkylation
of organofluorine compounds, with only substrates that
possess sufficiently acidic protons being competent.16 In
the present scenario, the carbanion is generated in situ
via nucleophilic addition, thus bypassing the convention-
al strong base mediated deprotonation protocol.
Table 1. Optimization of reaction condition
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to
trifluoromethylated
compounds
with
gem-
difluoroalkene as α-trifluoromethylated carbon-centered
radical precursor.10a The rationales of this envisioned
NAAA reaction are based on the following considerations:
i) the α-carbon atom of gem-difluoroalkenes are particu-
larly electron-deficient because of the electron-
withdrawing abilities of the two fluorine atoms, thus
making them susceptible to external nucleophiles (here as
the fluoride);11 ii) while the addition and elimination of
fluoride is a reversible process, the ensuing C-C bond
formation could dramatically drive such process forward;
iii) the potential side reactions such as allylic fluorination
may not pose significant problem provided that the allyl
fluorides could also be ionized by palladium catalyst, thus
serving as a bifurcated allyl donor.12 In addition, the kinet-
ically more favored formation of C-C bond compared with
that of C-F bond in palladium-catalyzed allylic substitu-
tion could be another factor that would guarantee the
execution of this multi-component reaction. Despite rea-
sonability of rationales envisioned, challenges associated
with this proposal still remain, among which the inhibi-
tion of expected allylation by premature quenching of the
in situ generated β-trifluorocarbanion is of concern.13
entry
solvent
Acetone
DCE
ligand
X-Phos
X-Phos
X-Phos
X-Phos
X-Phos
XantPhos
bpy
additive
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuOAc
CuF2
3a (%)a
23
1
trace
trace
67
88b
85b
0b
99b
96b
65b
2
3
MeCN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
4
5
6
7
8
9
10
11
12
X-Phos
X-Phos
X-Phos
-
Cu(OTf)2
-
CuOAc
CuOAc
traceb
0c
X-Phos
Experiments were performed with 1a (0.15 mmol), 2a (0.3
mmol), CsF (0.45 mmol), additive (0.015mmol), Pd(OAc)2
(0.0075 mmol), monodentate ligand (0.015 mmol)/bidentate
ligand (0.0075 mmol) in solvent (1.0 mL) stirring at 60 oC for
10 hours. Isolated yields. Using Pd(MeCN)4(BF4)2 as cata-
lyst. cNo palladium catalyst was added.
a
b
To challenge our hypothesis, the palladium-catalyzed
NAAA reaction of methyl 4-(2,2-difluorovinyl)benzoate 1a
and allyl tert-butyl carbonate 2a was examined with ex-
ternally added fluoride salt as the nucleophile and repre-
sentative results were shown in Table 1. After systematic
examination of various parameters, the optimized reac-
tion conditions was obtained: using CsF as fluoride
source, Pd(MeCN)2(BF4)2, X-Phos or XantPhos as the cata-
lyst and assisting ligand in the presence of CuF2 as addi-
tive and DMF as the solvent(see the Supporting Infor-
mation for details of reaction optimization).14 Although
not mandatory, the addition of catalytic amount copper
salt was revealed to have appreciable enhancement on the
reaction efficiency. While the exact role of copper salt in
this transformation requires further in-depth investiga-
tion, its beneficial effect could be rationalized by assum-
ing its ability to stabilize the carbanion generated in situ.15
Furthermore, control experiments demonstrated the in-
dispensability of both palladium catalyst and phosphine
ligand on this NAAA reaction, without either, no desired
product could be obtained. It is also worth mentioning
that no detectable amount of 3a was observed when sub-
jecting 4-(2,2,2-trifluoroethyl)benzoate to the optimized
reaction conditions, which firmly rules out its potential as
a reaction intermediate in the catalytic cycle. The ineffec-
With the optimized reaction conditions in hand, the
reaction generalities as well as the limitations with re-
spect to both gem-difluoroalkene and allyl carbonate were
surveyed and the results were summarized in Table 2. In
general, gem-difluoroalkenes with electron-withdrawing
substituents reacted smoothly to afford the desired
homoallyltrifluoromethane products in good to excellent
yields, whereas those with electron-donating groups were
reluctant to participate in such transformation, which was
ascribed to the low electrophilicity of the substrates or
the instability of the resulting β-trifluorocarbanions,
which quickly collapsed without further engaging in al-
lylation process. gem-Difluoroalkenes containing a variety
of synthetically useful functionalities such as CO2Me, CN,
CF3, Ac and NO2 were amenable to this reaction and the
locations of substituents were found to have appreciable
influence on the reaction efficiency (3a-3l). To our pleas-
ure, pyridine derived gem-difluoroalkene reacted smooth-
ly without obvious deleterious effect on the reaction, thus
giving rise to product 3g in synthetically useful yield. For
allyl carbonate, substrates with alkyl, aryl or ester substit-
uents on the internal alkene moiety were compatible with
the reaction conditions (3h-3o). Also of note was the nice
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carbonates containing substituents on the allylic posi-
Table 2. Reaction scope of NAAA reaction
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tions, the allylic alkylation could potentially lead to the
formation of both region- and diastereoisomers. Within
our experiments, moderate to high selectivity were ob-
served depending on the substrates employed. The sub-
strate scope with respect to 1-arylallyl carbonate was quite
broad, with electronically differentiated functional groups
such as halogen, CF3, CN, OMe and ester being well
adapted regardless of their substitution locations (3q-
3aa). The nice tolerance of halogen substituents provides
a synthetic handle for further elaboration through tradi-
tional cross-coupling strategies. In addition, extended
aromatic entity such as naphthyl derived substrate also
uneventfully underwent this reaction and provided prod-
uct 3ab in 50% yield. Also of note, the reaction efficiency
was not inhibited by heteroaryl containing allyl car-
bonates and when pyridine based substrate was applied,
the adduct 3ac was produced in 64% yield. Besides 1-
arylallyl carbonate, alkyl and alkenyl based congeners
could also be employed as effective allyl donors, for ex-
ample product 3ae could be isolated in 78% yield when 1-
cyclohexylallyl carbonate was used, while in the case of
diallyl carbinol counterpart, product 3ad was produced in
81% yield, albeit with moderate stereoselectivity. It also
needs to be pointed out that the present allylation proto-
col could also be readily extended to ketone based gem-
difluoroalkene derivatives, allowing the expedient con-
struction of architectures containing quaternary carbon
centers with one substituent being the trifluoromethyl
group (3af-3ao). In this respect, by making use of tetra-
hydronaphthalene derived gem-difluoroalkene as sub-
strate, we were able to obtain the densely functionalized
product 3aj in 51% yield. Because of the electron delocali-
zation ability of ester group, further electronic activation
was not required in the case of gem-difluoroacrylate de-
rivatives and related allylation products could be obtained
in moderate to good yields (3ak, 3al). It is noteworthy
that when gem-difluoroalkene derived from trifluoroace-
tophenone was employed, the reaction occurred readily
to produce product 3am in 80% yield, thus providing an
efficient method for the synthesis of gem-trifluoromethyl
homoallylbenzene derivatives. Furthermore, the con-
struction of quaternary carbon center also proved to be
feasible via two-fold allylation processes, provided that
substrates contain functionalities that are electron-
withdrawing strong enough for assisting further deproto-
nation after introduction of the first allyl group (3an,
3ao). Finally, while it is quite appealing to extend this
NAAA reaction into asymmetric version, preliminary ef-
fort in this direction was unfortunately less rewarding
with only marginal enantiomeric excess observed (see the
Supporting Information for the details).15 Continuing en-
deavor aiming at realizing asymmetric NAAA reaction is
still underway in our lab.
R2
R3
R3
FF2C R2
R4
F
OBoc
Pd(CH3CN)4(BF4)2/L
R1
+
R1
R4
CuF2, CsF, DMF
60 oC, N2, 10h
F
1
2
3
CF2F
CF2F
CF2F
CF2F
MeO2C
F3C
NC
Ac
3a, 99%*
CF2F
3b, 94%*
3c, 82%*
3d, 67%
CF2FMe
CF2F
CF2FCO2Me
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N
NO2
3e, 81%*
CO2Me
3f, 78%*
NO2
3g, 51%
3h, 92%
CF2FMe
CF2FMe
CF2FMe
CF2FMe
CO2Me
MeO2C
NC
NO2
3l
, 60%
3i, 93%
3j, 93%
CF2F
3k, 96%
CF2FCO2Me
CF2F
NO2
NC
NC
F
3o, 92%
CF2F
3n
, 75%
3m, 74%
F
CF2F
CF2F
Ph
Cl
NC
NO2
NO2
3p
, 46%
3q
3r
, 59%
, 70%
CF3
CF3
CF2F
CF2F
CF2F
NO2
3s, 77%
MeO2C
CF3
NC
3t, 56%
CF2F
3u, 66%
CF2F
CO2Me
CF3
CF2F
CO2Me
3v
NO2
3w
NO2
3x
, 91%
, 65%
, 48%
CN
CF2F
CF2F
CF2F
OMe
OMe
NO2
NO2
NO2
3y, 48%
3z, 76%
3aa, 66%
CF2F
CF2F
CF2F
NO2
N
NO2
NO2
3ad, 81%†
3ab
3ac
, 64%
, 50%
CF3
FF2C Me
CF2F
FF2C Me
O2N
NO2
O2N
3ae, 78%
FF2C Me
3af, 99%
3ag, 99%
FF2C Et
FF2C
CO2Me
FF2C Me
CO2Me
EtO2C
MeO2C
F3C
MeO2C
3ah
3ai
3aj
3ak
, 78%
, 95%
, 55%
, 51%
R
CF2F
CF2F
CO2Me
CO2Me
FF2C Ph
EtO2
FF2C Ph
F3C
C
O2N
R
O2N
R = 4ꢀOMeꢀC6H4,
*,‡
*,‡
3al
3am
, 80%
, 51%
3an
3ao
, 62%
, 95%
Experiments were performed with 1 (0.15 mmol), 2 (0.3
mmol), CsF (0.45 mmol), CuF2 (0.015mmol),
Pd(MeCN)4(BF4)2 (0.0075 mmol), XantPhos (0.0075 mmol) in
DMF (1.0 ml) stirring at 60 C for 10 hours. Using X-Phos
(0.015 mmol) as ligand. †Linear/Branched = 3/1. ‡2 (0.45
mmol) was employed.
o
*
In conclusion, by making use of palladium-catalyzed
nucleophilic addition induced allylic alkylation manifold,
we have successfully developed a strategically novel syn-
thetical protocol that allows a step-economic and expedi-
ent construction of homoallyltrifluoromethane deriva-
compatibility of alkynyl functionalities, for example, by
using this strategy, trifluoromethyl incorporated enyne
product 3p could be selectively obtained, albeit with
somewhat compromised reaction efficiency. For allylic
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(4) (a) Shim, J.-G.; Nakamura, H.; Yamamoto, Y. J. Org. Chem.
tives without resorting to the deprotonative functionali-
zation manner.17 This three-component transformation is
characterized by its well organized reaction sequence,
thus obviating the potential side pathways which would
otherwise occur between either of two reaction partners
employed. It is also worth mentioning that by making use
of such strategy, the reaction boundary, which restricts
the allylic alkylation of trifluoromethyl-containing mole-
cules to those with relative low pKa values, is skillfully
overridden.16
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ASSOCIATED CONTENT
Supporting Information
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(b) Gillis, E. P., Eastman, K. J., Hill, M. D., Donnelly, D. J.;
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O’Hagan, D. J. Fluorine Chem. 2014, 167, 16.
Detailed experiment procedures and compound characteri-
zation deta. “This material is available free of charge via the
Internet at http://pubs.acs.org.”
(8) (a) Alonso, C.; de Marigorta, E. M.; Rubiales, G.; Palacios, F.
Chem. Rev. 2015, 115, 1847. (b) Studer, A. Angew. Chem. Int. Ed.
2012, 51, 8950. (c) Yang, X.; Wu, T.; Phipps, R. J.; Toste, F. D.
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(9) Tian, P.; Feng, C.; Loh, T.-P. Nat. Commun. 2015, 6, 7472.
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AUTHOR INFORMATION
Corresponding Author
iamcfeng@njtech.edu.cn
teckpeng@ntu.edu.sg
Author Contributions
§
P. T. and C.-Q. W. contributed equally to this work.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the “1000-Youth Talents Plan”, a Start-up Grant
(39837110) from Nanjing Tech University. We also thank the
funding support of the State Key Program of National Natu-
ral Science Foundation of China (21432009) for generous
financial support.
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such as Rh, Ir, Ni and Mo-based systems were not effective for
this transformation; using nitrogenous or NHC ligands only led
to formation of premature protonation byproducts, see the sup-
porting information for details.
(15) We appreciate one reviewer’s comments on a possible role of
CuF2 by assuming the in situ formation of fluoride cluster with
CsF, which acts as a “soft” nucleophile and also the difficulty for
asymmetric induction using chiral ligands as result of Cu-
stabilized carbanion with considerable covalent bond character.
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(17) (a) Sha, S.-C.; Zhang, J.; Carroll, P. J.; Walsh, P. J. J. Am.
Chem. Soc. 2013, 135, 17602. (b) Trost, B. M.; Thaisrivongs, D. A. J.
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