CaII-Catalyzed Alkenylation of Alcohols with Vinylboronic Acids

Article abstract of DOI:10.1002/chem.201501677

Direct alkenylation of a variety of alcohols with vinylboronic acids has been accomplished using the air-stable calcium(II) complex Ca(NTf₂)₂ under mild conditions with short reaction times. For reluctant transformations, an ammonium salt was used as an additive to circumvent the reactivity issue. Cross-coupling: Direct alkenylation of a variety of alcohols with vinylboronic acids has been accomplished using the air-stable calcium(II) complex Ca(NTf₂)₂ under mild conditions with short reaction times (see scheme)

Full text of DOI:10.1002/chem.201501677

DOI: 10.1002/chem.201501677
Communication
&
Homogeneous Catalysis
CaII-Catalyzed Alkenylation of Alcohols with Vinylboronic Acids
David Lebœuf, Marc Presset, Bastien Michelet, Christophe Bour, Sophie Bezzenine-LafollØe,
and Vincent Gandon*[a]
to generate carbocation intermediates,[10] so they could be rel-
evant catalysts for new CÀC bond-forming reactions. They are
Abstract: Direct alkenylation of a variety of alcohols with
air- and moisture-stable and also weakly toxic. Herein, we de-
vinylboronic acids has been accomplished using the air-
scribe our preliminary investigations towards a calcium(II)-cata-
stable calcium(II) complex Ca(NTf2)2 under mild conditions
lyzed alkenylation of a wide range of allyl, propargyl, and
with short reaction times. For reluctant transformations,
benzyl alcohols, with a series of vinylboronic acids and related
an ammonium salt was used as an additive to circumvent
reactants (Scheme 1).
the reactivity issue.
Cross-coupling reactions are of paramount importance to pro-
vide access to highly diverse molecules.[1] Among the different
cross-coupling partners, boronic acids are very popular re-
Scheme 1. Alkenylation of alcohols with vinylboron derivatives.
agents because they are readily available, easy-to-handle
solids, weakly toxic, and compatible with a broad range of
functional groups.[2] On the other hand, the synthesis of the
We first investigated the reactivity of vinylbenzyl alcohol 1a
second coupling partner (an organohalide for instance) often
requires several tedious steps. The cross-coupling bears also its
own limitations due to the use of a transition-metal complex
as the catalyst, which can be expensive, toxic, difficult to pre-
pare, and sensitive to oxygen and moisture. Regarding the
substrates, it would be especially appealing to use readily
available alcohols for CÀC bond-forming transformations with
boronic acids. However, the poor leaving ability of the hydrox-
yl group remains a major impediment. Over the last decade,
several groups have reported a few transition-metal-catalyzed
cross-couplings of allyl alcohols with arylboronic acids.[3,4] The
transition-metal-catalyzed cross-coupling of alcohols with vinyl-
boronic acids has also been sporadically reported.[5,6,7] Most of
these approaches involve the formation of p-allyl metal com-
plexes, yet, the versatility of this process remains to be demon-
strated. Currently, there are only a few methods reported for
the direct alkenylation of alcohols using simple styrene deriva-
tives or vinyl silanes by the formation of a carbocation inter-
mediate; however, these methods require either harsh condi-
tions, long reaction times, or suffer from a limited substrate
scope.[8,9] For these reasons, a general and mild reaction be-
tween alcohols and vinylboronic acids that avoids the use of
noble transition-metals would be even more elegant. In this
regard, calcium(II) salts display a high affinity towards alcohols
with (E)-styrylboronic acid 2a (Table 1). While the use of
Ca(OTf)2 did not lead to any reaction (Table 1, entry 1), we
were pleased to find that, with Ca(NTf2)2,[11] the linear product
3a was formed selectively in 73% yield after 30 min at room
temperature in CH2Cl2 (entry 2). It is noteworthy that the same
result was obtained under argon or in air using distilled CH2Cl2.
In addition, the branched cross-coupled product 3’’a was not
detected, which can be explained by the steric hindrance at
the benzylic position. The use of nitromethane, 1,4-dioxane, or
acetone as a solvent significantly decreased the reactivity lead-
ing to lower yields or no reaction (entries 3–5). Other Group 2
metal salts such as Mg(NTf2)2 and Ba(NTf2)2 were also tested,
but the reaction proceeded at a slower rate and 3a was isolat-
ed in 55 and 30% yield, respectively (entries 6 and 7). We,
then, examined the influence of additives (entries 8–10). Sever-
al reports have recently shown that the use of ammonium or
potassium salts, such as nBu4NBF4, nBu4NPF6, or KPF6,[12] could
be beneficial to reactions involving Ca(NTf2)2 as a catalyst.
Indeed, the ammonium or potassium salts of weakly coordinat-
ing anions can promote an anion metathesis to generate the
heteroleptic complex Ca(NTf2)(X) (X=BF4, PF6), which is more
Lewis acidic than Ca(NTf2)2.[11f] Surprisingly, the reaction was
less efficient and proceeded at a slower rate (entries 8–10).
Moreover, 3a was obtained admixed with the conjugated
diene 3’a, which was not detected in our previous experi-
ments. On the other hand, the use of the Brønsted acid HNTf2
as the catalyst led to a significant decrease of the yield
(entry 11). A control experiment, carried out in the absence of
Ca(NTf2)2, led to the recovery of the starting materials
(entry 12). The coupling was also tested with other boron re-
agents, which promoted either the decomposition of the alco-
hol (BPin, entry 13), led to a complex mixture (BF3K, entry 14),
[a] Dr. D. Lebœuf, Dr. M. Presset, B. Michelet, Dr. C. Bour,
Dr. S. Bezzenine-LafollØe, Prof. Dr. V. Gandon
ICMMO (UMR CNRS 8182)
UniversitØ Paris-Sud
Bâtiment 420, 91405 Orsay cedex (France)
E-mail: vincent.gandon@u-psud.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501677.
Chem. Eur. J. 2015, 21, 11001 – 11005
11001
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
boronic acids would be more reactive than vinylsilanes, boron
being more oxophilic than silicon.
Table 1. Alkenylation of vinylbenzyl alcohol 1a with the (E)-styrylboron
and -styrylsilicon derivatives 2a–e: optimizations of reaction conditions.
With these optimized conditions, we turned our attention to
the reactivity of various secondary and tertiary allyl alcohols
with 2a (Scheme 3). The alkenylation gave rise to linear prod-
Entry Catalyst
Additive
2
Solvent
t [min] Yield of 3a [%]
1
2
3
4
5
6
7
8
Ca(OTf)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Mg(NTf2)2
Ba(NTf2)2
Ca(NTf2)2 nBu4NBF4 2a CH2Cl2
Ca(NTf2)2 KPF6 2a CH2Cl2
Ca(NTf2)2 nBu4NPF6 2a CH2Cl2
HNTf2
–
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
Ca(NTf2)2
–
–
–
–
–
–
–
2a CH2Cl2
2a CH2Cl2
2a MeNO2
120
30
30
NR
73
35
NR
NR
55
2a 1,4-dioxane 120
2a acetone
2a CH2Cl2
2a CH2Cl2
60
60
120
50
30
85
15
60
50
60
30
55[b]
58[b]
57[b]
15
9
10
11
12
13
14
15
16
17
–
–
–
–
–
–
2a CH2Cl2
2a CH2Cl2
2b CH2Cl2
2c CH2Cl2
2d CH2Cl2
2e CH2Cl2
NR
–
–
NR
NR
65
120
60
60
Scheme 3. Alkenylation of allyl alcohols 1b–i with (E)-styrylboronic acid 2a.
Reaction conditions: 1b–i (1 equiv) and 2a (2 equiv) in CH2Cl2 (0.1m) in the
presence of Ca(NTf2)2 (5 mol%). [a] The reaction was carried out at 308C for
4 h.
Ca(NTf2)2 nBu4NBF4 2e CH2Cl2
[a] Reaction conditions: 1a (1 equiv) and organoboron (or organosilicon)
derivative 2 (2 equiv) in the indicated solvent (0.1m) in the presence of
the catalyst (5 mol%) with/or without additive (5 mol%). [b] The com-
pound 3a is admixed with 3’a (ratio 3:1 to 4:1).
ucts in good yields within 10–20 min at room temperature.
The only exception concerned compound 1d (R1 =Ph, R2 =Me,
R3 =H), which required heating at a more elevated tempera-
ture (308C) for a longer reaction time (4 h), presumably for
steric reasons. Remarkably, even 2-cyclohexen-1-ol (1h) and
(E)-pent-3-en-2-ol (1i), which are not activated by a phenyl
group, proved to be compatible substrates.
or did not react (BF3NnBu4, entry 15).[12] Finally, the reaction
was attempted with (E)-styrylsilane 2e, a substrate that has al-
ready been used by Niggemann et al. for a few calcium-cata-
lyzed alkenylation of alcohols.[8d] In the absence of additive, no
reaction was observed (entry 16). In this case, the use of an
ammonium salt was necessary to achieve the reaction
(entry 17).
The 1,4-diene 3a could also be obtained from the less reac-
tive cinnamyl alcohol 1j and 2a, yet in this case reinforcement
of the Lewis acidity of the calcium complex was necessary.
However, even by adding nBu4NPF6, the yield did not exceed
32% [Eq. (1)]. On the other hand, in the case of substrate 1k,
which displays an additional methyl group, the use of
nBu4NPF6 was not required [Eq. (2)], and the 1,4-diene 3b was
generated in 63% yield, similar to that of allyl alcohol 1b (see
Scheme 3).
Despite their low intrinsic nucleophilicity, organoboronic
acids have recently emerged as promising nucleophiles in tran-
sition-metal-free CÀC bond-forming reactions.[13] In our case,
the efficiency of the reaction might be explained by a synergis-
tic activation of the hydroxyl group by calcium and the boron-
ic acid to form a more reactive boron-tethered nucleophile by
a six-membered transition state (Scheme 2). As a result, vinyl-
Scheme 2. Proposed transition state in the CaII-catalyzed alkenylation of vi-
nylbenzyl alcohol 1a with (E)-styrylboronic acid 2a.
Chem. Eur. J. 2015, 21, 11001 – 11005
www.chemeurj.org
11002
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Then, we examined the reactivity of propargyl alcohols with
styrylboronic acids (Scheme 4). Gratifyingly, the transformation
was compatible with a broad substrate scope and led to the
corresponding products in good yields within 5 to 30 min. In-
terestingly, with phenylpropargyl alcohols bearing electron-
withdrawing Cl and CO2Me substituents at the para position
(5ba and 5ca), the reaction proved to be faster than with an
electron-donating OMe group (5aa). The reaction was also effi-
cient in the absence of substitution at this position (5da), and
can be applied to 2-thienyl- and alkylpropargyl alcohols to
give compounds 5ea and 5 fa in 60 and 50% yields. However,
in the latter case, it was necessary to introduce nBu4NPF6 in
the reaction mixture. We, then, explored the influence of the
substitution at the alkyne moiety and noticed that the reaction
is not only compatible with a phenyl, but also with alkyl
(5ga—ia), ester (5ja), or trimethylsilyl groups (5ka). In the
latter two cases, the reaction did not take place below 508C.
Various styrylboronic acids were also tested with phenylpro-
pargyl alcohol 4a (Scheme 5). While the presence of the elec-
tron-rich OMe and Me groups did not affect the reactivity (5ae
and 5af), no reaction occurred at room temperature with mod-
Scheme 5. Cross-Coupling of phenylpropargyl alcohol 4a with styrylboronic
acids 2e–k. [a] Reaction conditions: 4a (1 equiv) and 2e–k (2 equiv) in
CH2Cl2 (0.1m) in the presence of Ca(NTf2)2 (5 mol%) at the indicated temper-
ature.
erately electron-withdrawing F and Cl substituents. Neverthe-
less, the desired compounds could be obtained at 508C in
good yields (5ag and 5ah). In the case of substrate 2i, con-
taining a strong electron-withdrawing CF3 substituent at the
para position of the phenyl group, the product 5ai was ob-
tained in a moderate yield of 25%.[14] The more hindered sub-
strate 2-indenylboronic acid 2j or the heteroaromatic vinylbor-
onic acid 2k could also be employed to prepare the coupling
products 5aj and 5ak in 92 and 65% yields.
Next, we sought to investigate the reactivity of simple
benzyl alcohols (Scheme 6). In general, the desired products
were obtained in good yields. However, it is important to note
that no reaction occurred at room temperature, when
nBu4NPF6 was omitted, with the exception of 6b and 6h. At
elevated temperature (508C), the reaction could be conducted
without nBu4NPF6 to furnish the corresponding products in
high yields (7c and 7e). A strong electron-withdrawing CF3
substituent at the para position was also used to generate 7d
in a moderate 33% yield. The reaction was compatible with
the cyclic benzyl alcohol 6g to give the desired product in
59% yield within 10 min. To illustrate the synthetic utility of
this method, we prepared a key precursor of the anti-inflam-
matory drug (Æ)-naproxen. The cross-coupling reaction of 1-(6-
methoxynaphthalen-2-yl)ethanol 10 with (E)-styrylboronic acid
2a generated compound 11 in 65% yield, which could lead to
(Æ)-naproxen after a simple oxidation.[15]
Of particular interest, the reaction of benzyl alcohols was
also possible with less reactive vinylboronic acids, that is, those
substituted by an alkyl or a trifluoromethyl group [Eq. (3)]. For
example, the reaction of the benzhydrol 6e with 2l and 2i
provided the corresponding products in 75 and 71% yields, re-
spectively, but had to be carried out at 508C. A para-methoxy-
Scheme 4. Alkenylation of propargyl alcohols 4a–k with (E)-styrylboronic
acid 2a. [a] Reaction conditions: 4a–k (1 equiv) and 2a (2 equiv) in CH2Cl2
(0.1m) in the presence of Ca(NTf2)2 (5 mol%) at the indicated temperature.
[b] The reaction was carried out in the presence of 5 mol% of nBu4NPF6, oth-
erwise, no reaction was observed.
Chem. Eur. J. 2015, 21, 11001 – 11005
www.chemeurj.org
11003
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
ward access to a great diversity of alkenes, dienes, and enynes
under mild conditions without taking special precautions.
Experimental Section
General procedure for the calcium-catalyzed alkenylation of
alcohols with vinylboronic acids
Alcohol (0.25 mmol, 1 equiv), vinylboronic acid (0.5 mmol, 2 equiv),
Ca(NTf2)2 (5 mol%), and nBu4NPF6 (5 mol%) (when indicated) were
charged (in air) in a 10 mL screw-cap vial equipped with a stir bar.
Distilled dichloromethane (2.5 mL, 0.1m) was added and the tube
was sealed. The reaction mixture was stirred at the indicated tem-
perature until TLC analysis showed full conversion. Then, the crude
product was purified by flash column chromatography using differ-
ent gradients of pentane and ethyl acetate.
Acknowledgements
We are grateful to the CNRS, Minist›re de l’Enseignement Su-
pØrieur et de la Recherche, UniversitØ Paris-Sud, Institut Univer-
sitaire de France, and ANR JCJC HAONA.
Keywords: alcohol · calcium · cross-coupling · homogeneous
catalysis · vinylboronic acid
Scheme 6. Alkenylation of benzyl alcohols 6a–h with (E)-styrylboronic acid
2a. [a] Reaction conditions: 6a–h (1 equiv) and 2a (2 equiv) in CH2Cl2 (0.1m)
in the presence of Ca(NTf2)2 (5 mol%) with/or without nBu4NPF6 (5 mol%) at
the indicated temperature.
[1] Metal-Catalyzed Cross-Coupling Reactions and More (Eds.: A. de Meijere,
S. Bräse, M. Oestreich), Wiley-VCH, Weinheim, 2008.
[2] Boronic Acids: Preparation and Applications in Organic Synthesis Medi-
cine and Materials (Ed.: D. G. Hall), Wiley-VCH, Weinheim, 2011.
[3] a) G. W. Kabalka, G. Dong, B. Venkataiah, Org. Lett. 2003, 5, 893; b) H.
Tsukamoto, M. Sato, Y. Kondo, Chem. Commun. 2004, 1200; c) Y. Kayaki,
T. Koda, T. Ikariya, Eur. J. Org. Chem. 2004, 4989; d) K. Manabe, K.
Nakada, N. Aoyama, S. Kobayashi, Adv. Synth. Catal. 2005, 347, 1499;
e) H. Tsukamoto, T. Uchiyama, T. Suzuki, Y. Kondo, Org. Biomol. Chem.
2008, 6, 3005; f) T. Gendrineau, J.-P. Genet, S. Darses, Org. Lett. 2010, 12,
308; g) Y. Wang, X. Feng, H. Du, Org. Lett. 2011, 13, 4954; h) J. Ye, J.
Zhao, J. Xu, Y. Mao, Y. J. Zhang, Chem. Commun. 2013, 49, 9761; i) H.-B.
Wu, X.-T. Ma, S.-K. Tian, Chem. Commun. 2014, 50, 219.
phenyl, however, allowed the reaction to proceed at room
temperature to generate compound 7ee in 87% yield.
[4] For the cross-coupling of allyl alcohols with boroxines and boronates,
see respectively: a) T. Miura, Y. Takahashi, M. Murakami, Chem. Commun.
2007, 595; b) A. JimØnez-Aquino, E. F. Flegeau, U. Schneider, S. Kobaya-
shi, Chem. Commun. 2011, 47, 9456.
[5] A few examples were reported in references [3a], [3b], [3e], and [3i].
[6] For an allyl substitution of benzylvinyl alcohols with potassium vinyltri-
fluoroborates, see: J. Y. Hamilton, D. Sarlah, E. M. Carreira, J. Am. Chem.
Soc. 2013, 135, 994.
Finally, we noticed that 1-adamantanol could also be used
as a coupling partner to deliver product 9 in 79% yield at
508C [Eq. (4)].
[7] For an allyl substitution of cinnamyl hydroxides with vinylboron diha-
lides, see: G. W. Kabalka, M.-L. Yao, S. Borella, Z. Wu, Chem. Commun.
2005, 2492.
[8] For alkenylation of alcohols using simple styrene derivatives or vinyl si-
lanes, see: a) Y. Nishimoto, M. Kajioka, T. Saito, M. Yasuda, A. Baba,
Chem. Commun. 2008, 6396; b) H.-L. Yue, W. Wei, M.-M. Li, Y.-R. Yang, J.-
X. Ji, Adv. Synth. Catal. 2011, 353, 3139; c) Z.-Q. Liu, Y. Zhang, L. Zhao, Z.
Li, J. Wang, H. Li, L.-M. Wu, Org. Lett. 2011, 13, 2208; d) V. J. Meyer, M.
Niggemann, Eur. J. Org. Chem. 2011, 3671; e) S. Peng, L. Wang, J. Wang,
Org. Biomol. Chem. 2012, 10, 225; f) G.-B. Huang, X. Wang, Y.-M. Pan, H.-
S. Wang, G.-Y. Yao, Y. Zhang, J. Org. Chem. 2013, 78, 2742.
We have developed a highly efficient method for CÀC bond-
forming reactions based on a calcium-catalyzed direct coupling
of alcohols with vinylboronic acids. In addition, the reagents
and the catalytic system have the advantage of being stable
easy-to-handle compounds and commercially available. This
new protocol has a broad applicability and allows a straightfor-
[9] For CÀH alkylation of alkenes with alcohols, see also: D.-H. Lee, K.-H.
Kwon, C. S. Yi, Science 2011, 333, 1613.
[10] For reviews, see: a) S. Harder, Chem. Rev. 2010, 110, 3852; b) J.-M. Be-
gouin, M. Niggemann, Chem. Eur. J. 2013, 19, 8030; c) Topics in Organo-
metallic Chemistry, Vol. 45 (Ed.: S. Harder), Springer, Berlin, 2013.
[11] For recent examples of Ca(NTf2)2-catalyzed reactions, see: a) J.-M. Be-
gouin, F. Capitta, X. Wu, M. Niggemann, Org. Lett. 2013, 15, 1370; b) S.
Chem. Eur. J. 2015, 21, 11001 – 11005
www.chemeurj.org
11004
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Haubenreisser, P. Hensenne, S. Schçder, M. Niggemann, Org. Lett. 2013,
15, 2262; c) T. Haven, G. Kubik, S. Haubenreisser, M. Niggemann, Angew.
Chem. Int. Ed. 2013, 52, 4016; Angew. Chem. 2013, 125, 4108; d) V. J.
Meyer, L. Fu, F. Marquardt, M. Niggemann, Adv. Synth. Catal. 2013, 355,
1943; e) C. C. Dulin, K. L. Murphy, K. A. Nolin, Tetrahedron Lett. 2014, 55,
5280; f) J. Davies, D. Leonori, Chem. Commun. 2014, 50, 15171; g) D.
Lebœuf, E. Schulz, V. Gandon, Org. Lett. 2014, 16, 6464; h) M. Presset, B.
Michelet, R. Guillot, C. Bour, S. Bezzenine-LafollØe, V. Gandon, Chem.
Commun. 2015, 51, 5318; i) V. J. Meyer, C. Ascheberg, M. Niggemann,
Chem. Eur. J. 2015, 21, 6371; j) L. Fu, M. Niggemann, Chem. Eur. J. 2015,
21, 6367; k) T. Stopka, M. Niggemann, Org. Lett. 2015, 17, 1437.
[12] Besides, we evaluated the reactivity of styrene with vinylbenzyl alcohol
1a under our standard conditions, but no reaction was observed. Thus,
the presence of boron is needed for the reaction.
[13] S. Roscales, A. G. Csµky¨, Chem. Soc. Rev. 2014, 43, 8215 and references
cited therein.
[14] The yield was determined by NMR spectroscopy using 1,4-diacetylben-
zene as an internal standard.
[15] C. Li, J. Xing, J. Zhao, P. Huynh, W. Zhang, P. Jiang, Y. J. Zhang, Org. Lett.
2012, 14, 390.
Received: April 29, 2015
Published online on July 1, 2015
Chem. Eur. J. 2015, 21, 11001 – 11005
www.chemeurj.org
11005
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim