Palladium-catalyzed anti-markovnikov hydroalkylation of homoallylic alcohols bearing β-fluorines

Article abstract of DOI:10.1021/ol402032a

A palladium-catalyzed anti-Markovnikov hydroalkylation of β,β-difluorinated homoallylic alcohols with alkylzinc reagents has been developed. This method affords a wide range of synthetically useful gem-difluorinated compounds with good functional group compatibility.

Full text of DOI:10.1021/ol402032a

ORGANIC
LETTERS
2013
Vol. 15, No. 17
4478–4481
Palladium-Catalyzed Anti-Markovnikov
Hydroalkylation of Homoallylic Alcohols
Bearing β‑Fluorines
Xiaowei Lin† and Feng-Ling Qing*,†,‡
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China, and College of
Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North
Renmin Lu, Shanghai 201620, China
flq@mail.sioc.ac.cn
Received July 19, 2013
ABSTRACT
A palladium-catalyzed anti-Markovnikov hydroalkylation of β,β-difluorinated homoallylic alcohols with alkylzinc reagents has been developed.
This method affords a wide range of synthetically useful gem-difluorinated compounds with good functional group compatibility.
Transition-metal-catalyzed cross-coupling reactions of
organic electrophiles and organometallic reagents are
widely used for carbonꢀcarbon formation.1 Historically,
development of the efficient cross-coupling of alkyl halides
or pseudohalides with alkyl organometallics to form the
C(sp3)ꢀC(sp3) bonds has been much slower than the
related C(sp2)ꢀC(sp2) coupling. This was probably due
to the slow oxidative addition of alkyl electrophiles with
low-valent metal complexes, and the resultant alkylꢀmetal
complexes may suffer from competitive side reactions (β-
hydride elimination, hydrodehalogenation). In the past
four decades, since the pioneering works by Kochi and
Tamura,2 Suzuki et al.,3 and Knochel et al.,4 many efficient
cross-coupling catalyst systems have been developed for
the C(sp3)ꢀC(sp3) bond formation.5 Very recently, Sig-
man and co-workers havereported analternative substrate
control tactic to formally construct a new C(sp3)ꢀC(sp3)
bond using alkenes, including styrenes,6 allylic amines,7
allylic alcohols, and homoallylic alcohols,8 as surrogates
for alkyl electrophiles. However, the substitution at the
allylic position of homoallylic alcohols was essentialfor the
formation of the anti-Markovnikov product in high yield
and selectivity (Scheme 1a). For example, a protected
homoallylic alcohol, lacking substitution at the allylic
position, was used as a coupling partner to afford a 2.8:1
mixture of anti-Markovnikov (I) and Markovnikov (II)
products in low yield (<20%) (Scheme 1b).8
† Chinese Academy of Sciences
‡ Donghua University
(1) (a) De Meijere, A., Diederich, F., Eds. Metal-Catalyzed Cross-
Coupling Reactions; Wiley-VCH: Weinheim, Germany, 2004. (b) Beller, M.,
Bolm, C., Eds. Transition Metals for Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2004.
(2) (a) Tamura, M.; Kochi, J. K. J. Organomet. Chem. 1972, 42, 205.
(b) Kochi, J. K.; Tamura, M. J. Am. Chem. Soc. 1971, 93, 1485. (c)
Kochi, J. K.; Tamura, M. J. Am. Chem. Soc. 1971, 93, 1483.
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M. S. Chem. Rev. 2011, 111, 1417. (c) Rudolph, A.; Lautens, M. Angew.
Chem., Int. Ed. 2009, 48, 2656. (d) Terao, J.; Kambe, N. Acc. Chem. Res.
The extreme electronegativity of the fluorine atom
results in the electron-withdrawing character of a
€
2008, 41, 1545. (e) Sherry, B. D.; Furstner, A. Acc. Chem. Res. 2008, 41,
1500. (f) Doucet, H. Eur. J. Org. Chem. 2008, 2013. (g) Jun Terao, N. K.
Bull. Chem. Soc. Jpn. 2006, 79, 663. (h) Frisch, A. C.; Beller, M. Angew.
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Catal. 2004, 346, 1525. (j) Cardenas, D. J. Angew. Chem., Int. Ed. 2003,
(7) DeLuca, R. J.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 11454.
(8) DeLuca, R. J.; Sigman, M. S. Org. Lett. 2013, 15, 92.
42, 384. (k) Luh, T.-Y.; Leung, M.-k.; Wong, K.-T. Chem. Rev. 2000,
100, 3187. (l) Cardenas, D. J. Angew. Chem., Int. Ed. 1999, 38, 3018.
ꢀ
r
10.1021/ol402032a
Published on Web 08/19/2013
2013 American Chemical Society

Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Hydroalkylation of Homoallylic Alcohols and β,β-
Difluorinated Homoallylic Alcohols
entry
catalyst
x
gasb
solvent
yield of 3a (%)c
1
Pd(IiPr)(OTs)2
Pd(MeCN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
4
4
4
0
4
4
6
8
6
6
6
6
6
6
6
6
6
Ar
Ar
Ar
O2
O2
air
air
air
air
air
air
air
air
air
air
air
air
DMA
8
2
DMA
5
3
DMA
23
0e
4d
5
DMA
DMA
37
39
50
48
31
51
52
60
29
75
63
78
0e
6
DMA
7
DMA
8
DMA
9
DMF
10
11
12
13
14f
15g
16f,h
17f
DCM
gem-difluoromethylene group (CF2).9 The incorporation of a
CF2 group into organic molecules has a profound influ-
ence on their chemical and physical properties.10 There-
fore, the transposition of CH2 to CF2 at the allylic position
of the homoallylic alcohol can modify the electronic and
steric environment of the alkene of interest. Recently, the
efforts of our group have focused on the development
of the carbonꢀcarbon bond formation by using gem-
difluorinated compounds as coupling partners.11 Herein,
we report the palladium-catalyzed cross-coupling reac-
tions of β,β-difluorinated homoallylic alcohols with
alkylzinc reagents to afford the anti-Markovnikov gem-
difluoromethylene-containing hydroalkylated products in
high yields (Scheme 1c).
THF
dioxane
xylene
dioxane
dioxane
dioxane
dioxane
a Reactions were carried out on a 0.2 mmol scale. Unless stated
otherwise, nBuZnBr was added dropwise to the reaction mixture within
10 min. BQ = benzoquinone. b Gas balloon was used. c Yield relative to
benzotrifluoride as an internal standard was determined by 19F NMR.
d Without BQ. e 1a was recovered completely. f nBuZnBr was added
dropwise to the reaction mixture over 45 min. g nBuZnBr was added
dropwise to the reaction mixture over 60 min. h 5 mol % of Pd(OAc)2 was
used.
We initiated our studies by testing the reactions of
(2-(benzyloxy)-3,3-difluoropent-4-enyl)benzene 1a and
nBuZnBr 2a catalyzed by palladium complexes (Table 1).
Sigman and co-workers6ꢀ8 reported that Pd(IiPr)(OTs)2
and Pd(MeCN)2Cl2 showed excellent activities for the
anti-Markovnikov hydroalkylation of organozinc re-
agents with alkenes. Unfortunately, when we attempted
the coupling reactions of 1a and 2a using Pd(IiPr)(OTs)2
and Pd(MeCN)2Cl2 as catalysts and benzoquinnone (BQ)
as oxidant, only a small amount of hydroalkylation
product 3a was detected (entries 1, 2). When Pd(OAc)2
was employed as catalyst, a 23% yield of 3a was obtained
(entry 3). It has been reported that O2 can be used as a
terminal oxidant.12 Therefore, the reaction of 1a and 2a
was carried out under aerobic oxidation conditions.
However, no desired product was observed, and the
starting material 1a was recovered completely (entry 4).
Surprisingly, when benzoquinone (BQ) was used as oxi-
dant with O2 as co-oxidant, a 37% yield of the hydroalk-
ylation product was formed (entry 5). It indicated that
BQ is essential to this reaction. Recently, Lei and co-
workers13 described that dry air can also be used as the
terminal oxidant for the Pd-catalyzed aerobic oxidative
cross-coupling between terminal alkynes and alkylzinc
reagents. Accordingly, when 1a and 2a were treated with
BQ under a dry air atmosphere, the yield of 3a was slightly
improved to 39% (entry 6). In consideration of the fact
that nBuZnBr 2a served not only as a coupling partner but
also as a hydride source, the increasing amount of
nBuZnBr 2a would result in better performance of the
coupling reaction. As expected, the desired product 3a
was formed in 50% yield in the presence of 6 equiv of
nBuZnBr 2a (entry 7). However, when the amount of
nBuZnBr 2a was further increased, there was no improve-
ment of this reaction (entry 8). The exploration of sol-
vents then demonstrated that dioxane was the most
efficient solvent (entries 9ꢀ13). To our delight, when
nBuZnBr 2a was added dropwise to the reaction mixture
over 45 min, the yield of 3a was further improved to 75%
yield (entry 14). Nevertheless, the addition of nBuZnBr 2a
to the reaction mixture over 60 min led to the lower yield
of 3a (entry 15). Interestingly, the reaction of 1a and 2a
(9) (a) O’Hagan, D. Chem. Soc. Rev. 2008, 37, 308. (b) Schlosser, M.;
Michel, D. Tetrahedron 1996, 52, 99. (c) Bondi, A. J. Phys. Chem. 1966,
70, 3006. (d) Bondi, A. J. Phys. Chem. 1964, 68, 441.
(10) (a) O’Hagan, D.; Wang, Y.; Skibinski, M.; Slawin, A. M. Z. Pure
Appl. Chem. 2012, 84, 1587. (b) Qing, F.-L.; Zheng, F. Synlett 2011,
1052. (c) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(11) (a) Lin, X.; Zheng, F.; Qing, F.-L. Organometallics 2012, 31,
1578. (b) Lin, X.; Zheng, F.; Qing, F.-L. J. Org. Chem. 2012, 77, 8696.
(12) Selected papers: (a) Podhajsky, S. M.; Iwai, Y.; Cook-Sneathen,
A.; Sigman, M. S. Tetrahedron 2011, 67, 4435. (b) Liao, L.; Sigman,
M. S. J. Am. Chem. Soc. 2010, 132, 10209. (c) Gligorich, K. M.; Iwai, Y.;
Cummings, S. A.; Sigman, M. S. Tetrahedron 2009, 65, 5074. (d)
Gligorich, K. M.; Cummings, S. A.; Sigman, M. S. J. Am. Chem. Soc.
2007, 129, 14193.
(13) Chen, M.; Zheng, X.; Li, W.; He, J.; Lei, A. J. Am. Chem. Soc.
2010, 132, 4101.
Org. Lett., Vol. 15, No. 17, 2013
4479

proceeded smoothly and provided a slightly higher yield
of 3a when the amount of Pd(OAc)2 was decreaed from 20
to 5 mol % (entry 16). No product formation was
observed without palladium catalyst (entry 17).
Table 2. Substrate Scope of the Pd-Catalyzed Hydroalkylatio-
na,b,c
With the optimized conditions in hand (Table 1, entry
16), the substrate scope (β,β-difluorinated homoallylic
alcohols and alkylzinc reagents) of the hydroalkylation
reaction was investigated. As shown in Table 2, benzyl-
protected β,β-difluorinated homoallylic alcohol 1a reacted
with nBuZnBr 2a smoothly to give the linear hydroalkyla-
tion product 3a in 78% yield (entry 1). A free homoallylic
alcohol 1a0 also gave the coupling product 3a0 in 73% yield
(entry 2). Additionally, the homoallylic alcohols bearing
an alkyl-substitution on R1 underwent efficient hydroalk-
ylation with2ato givethe couplingproducts (3b0, 3c, 3c0) in
good yields (entries 3ꢀ5). The doubly protected homo-
allylic amine 1e was found to be compatible with the
reaction conditions, furnishing compound 3e in 59% yield
(entry 8). In addition, substrates with electron-donating
(1fꢀ1g0) or electron-withdrawing (1hꢀ1i0) substituents as
well as ortho substituents (1g, 1g0) on the arene were
efficient coupling partners to afford the coupled products
in moderate to good yields (entries 9ꢀ17). In comparison,
the products (3fꢀ3g0) with electron-donating groups were
obtained in slightly higher yields than the products
(3hꢀ3i0) with electron-withdrawing groups. It was note-
worthy that aryl chloride (3j, 3j0) could be retained; no
product arising from the Negishi-type coupling was ob-
served, providing opportunities for further transforma-
tion. Further investigation revealed that a heteroaromatic
thiophene group was also well tolerated to give the product
(3k, 3k0) in good yields (entries 18, 19). Interestingly, when
the substrate (1l0) containing both internal and terminal
double bonds was subjected to the coupling reaction
conditions, the linear product (3l0) was formed exclusively
in 73% yield, in which the internal double bond remained
intact (entry 20). Finally, our attention was turned to the
compatibility of alkyl organozinc reagents. It was found
that the hydroalkylation of 1f with octylzinc(II) bro-
mide and (cyclohexylmethyl)zinc(II) bromide gave the
products 3m and 3n, respectively, in good yields
(entries 21, 22). It should be noted that the anti-Markoni-
kov product (linear product) was exclusively formed in the
palladium-catalyzed hydroalkylation of β,β-difluorinated
homoallylic alcohol derivatives with alkylzinc reagents
(Tables 1 and 2).
To illustrate the synthetic application of this palladium-
catalyzed hydroalkylation reaction, we undertook the
preparation of 10 (Scheme 2). Compound 10 is an impor-
tant precursor in the synthesis of target molecular 4-deoxy-
4,4-difluoro-KRN7000,14which is a potent stimulator of
Natural Killer T-cells (NKT-cells). The preparation of 10
(14) (a) Hunault, J.; Diswall, M.; Frison, J.-C.; Blot, V.; Rocher, J.;
Marionneau-Lambot, S.; Oullier, T.; Douillard, J.-Y.; Guillarme, S.;
Saluzzo, C.; Dujardin, G.; Jacquemin, D.; Graton, J.; Le Questel, J.-Y.;
Evain, M.; Lebreton, J.; Dubreuil, D.; Le Pendu, J.; Pipelier, M. J. Med.
Chem. 2012, 55, 1227. (b) Leung, L.; Tomassi, C.; Van Beneden, K.;
Decruy, T.; Elewaut, D.; Elliott, T.; Al-Shamkhani, A.; Ottensmeier, C.;
Van Calenbergh, S.; Werner, J.; Williams, T.; Linclau, B. Org. Lett.
2008, 10, 4433.
a Unless stated otherwise, reactions were performed using
(0.4 mmol), nBuZnBr (6 equiv), Pd(OAc)2 (5 mol %), BQ (4 equiv),
and Zn(OTf)2 (1 equiv) in dioxane/DMA at room temperature for 5 h
under a dry air atomosphere. Isolated yield. b C8H17ZnBr was used.
c CyCH2ZnBr was used.
1
4480
Org. Lett., Vol. 15, No. 17, 2013

started from commercially available Garner’s aldehyde 5
(Scheme 2). The allylation of aldehyde 5 with 3-bromo-3,3-
difluoroprop-1-ene 6 provided the β,β-difluorinated
homoallylic alcohol 7 in 90% yield (dr = 1.5:1). The two
diastereomers of 7 could not be separated by chromato-
graphy. Treatment of alcohol 7 with dodecylzinc(II) bro-
mide under the optimized Pd-catalyzed hydroalkylation
reaction conditions provided the linear product 8 in 58%
yield. Subsequently, deprotection of compound 8 gave the
ammonium salt9 in 57% yield. Finally, the transformation
of the amino group of compound 9 to the azide group gave
the important precursor 10 in 64% yield.
the formed intermediate C would easily undergo β-fluoro
elimination to afford compound D.15 The 19F NMR of the
reaction mixture showed that compound D was not
formed. Therefore, the insertion of Pd-hydride A to the
double bond of difluorinated homoallylic alcohol deriva-
tive 1 proceeded exclusively via 1,2-insertion. Finally, the
primary Pdꢀalkyl intermediate B underwent transmetala-
tion, followed by reductive elimination, to give the anti-
Markonikov product 3.
Scheme 3. Proposed Mechanism
Scheme 2. Synthesis of the Precursor of 4-Deoxy-4,4-difluoro-
KRN7000
In summary, we have developed a complementary pro-
tocol for the synthesis of gem-difluorinated compounds
through a palladium-catalyzed hydroalkylation of β,β-
difluorinated homoallylic alcohols with alkyl organozinc
reagents. This result further showed that the transposition
of CH2 to CF2 at the allylic position of the homoallylic
alcohols can modify the electronic and steric environment
of alkenes, and the β,β-difluorinated homoallylic alcohols
successfully afforded the anti-Markovnikov product
selectively.
On the basis of Sigman0s works on palladium-catalyzed
hydroalkylation of olefins withorganozinc reagents,6ꢀ8 we
proposed the reaction mechanism outlined in Scheme 3.
The transmetalation of the Pd(II) complex with organo-
zinc reagent 2, followed by β-hydride elimination, gave Pd-
hydride A. The coordination and insertion of A with β,β-
difluorinated homoallylic alcohol derivative 1 would pro-
ceed via either a 1,2-insertion or a 2,1-insertion to give
intermediates B and C, respectively. As the gem-difluor-
omethylene (CF2) group is the electron-withdrawing
group, the 1,2-insertion would proceed preferentially to
give intermediate B. Further, in the case of a 2,1-insertion,
Acknowledgment. The National Natural Science Foun-
dation of China (21072028, 21272036) and the National
Basic Research Program of China (2012CB21600) are
gratefully acknowledged for funding this work.
Supporting Information Available. Detailed experimen-
tal procedures and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
(15) Ichkawa, J.; Nadano, R.; Ito, N. Chem. Commun. 2006, 4425.
Org. Lett., Vol. 15, No. 17, 2013
4481