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Copper-mediated SN2’ Allyl-Alkyl and Allyl-Boryl Couplings of
nyl Cyclic Carbonates

Vi-

Núria Miralles,† José Enrique Gómez, § Arjan W. Kleij,*,§,‡ Elena Fernández*†
†

Department Química Física i Inorgànica, University Rovira i Virgili, C/Marcel·lí Domingo s/n, 43007 Tarragona, Spain.
Institute of Chemical Research of Catalonia (ICIQ), the Barcelona Institute of Science and Technology, Av. Països Catalans
16, 43007 Tarragona, Spain.
‡
Catalan Institute of Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain.
§

ABSTRACT: A method for the copper-catalyzed borylmethylation and borylation of vinyl cyclic carbonates through an SN2’ mechanism is reported. These singular reactions involve selective S N2’ allylic substitutions with concomitant ring opening of the cyclic
carbonate, and with extrusion of CO2 and formation of a useful hydroxyl functionality in a single step. The stereoselectivity of the
homoallylic borylation and allylic borylation processes can be controlled, and synthetically useful unsaturated (E)-pent-2-ene-1,5diols and (E)-but-2-ene-1,4-diols accessed.

Molecular diversity through organoboron chemistry provides
easy-to-handle and shelf-stable materials that can be utilized in
diverse transformations. The great potential of boron-selective
reactions in simplifying experimental operations is due to the
direct generation of CB bonds formed from diboron reagents.1
Alternatively, the use of 1,1-diborylalkane reagents to conduct
nucleophilic borylmethylation has been less studied, despite the
tremendous interest that homologated organoboron products offer as scaffolds in organic synthesis. Gem-diborylated compounds have shown to be useful reagents with alkyl-2 and arylbased electrophiles,3 as well as with carbonyl compounds4
mainly via base-induced deborylation. Diborylmethane reacts
with allylic electrophiles to promote selective substitution reactions via SN2 pathways under Pd/Cu catalysis or metal-free conditions (Scheme 1, top left).5 However, to the best of our
knowledge, there has only been one example related to the nucleophilic borylmethylation through an SN2’ mechanism, based
on a copper-catalyzed selective allylic substitution of primary
and secondary allylic chlorides with 1,1-diborylalkanes
(Scheme 1, top right).6a Despite the usefulness of this approach,
for substrates such as alkyl cinnamyl carbamates, the SN2’ allylalkyl coupling reaction proved to be unproductive.
Inspired by this limitation and in order to be able to extend the
nucleophilic borylmethylation reaction through an SN2’ mechanism, we have explored copper (I)-catalyzed SN2’ allylic alkylation of vinyl cyclic carbonates with diborylmethane (1)
(Scheme 1). This new approach would allow additional functionality to be retained in the homoallylic borylated product
since a hydroxyl group is generated with the concomitant loss
of CO2, providing access to scaffolds that are not easily prepared through other routes. For the sake of comparison, the copper(I)-catalyzed SN2’ allylic borylation of the same allylic cyclic carbonates with B2pin2 2 has also been studied and control
over the stereoselectivity of the allylic borylated product was

explored since both E to Z isomers can be formed. Stereoselective synthesis of allylboronates with a hydroxyl terminus would
potentially provide an unprecedented route towards functionalized allylboronates.7
Scheme 1. Allyl-Alkyl Couplings using Allylic Electrophiles
and Gem-Diborylated Compounds (eq 1), and New Allyl-Alkyl or Allyl-Boryl Couplings using Vinyl Cyclic Carbonates
and Diborylmethane or B2pin2 (eq 2)

Initially we carried out the reaction between the vinyl cyclic
carbonate 3 and diborylmethane 1 in the presence of MeOH as
solvent and base to in situ generate the Cu-OMe derivative from
CuCl (Table 1). The estimated copper salt loading and ligand
(where required) was 9 and 13 mol %, respectively. At rt, substrate 3 (0.2 mmol scale) reacted with reagent 1 (1.2 equiv)
providing moderate conversions of the desired homoallylic
borylated
product
(E)-(5-hydroxy-4-phenylpent-3-en-1yl)boronate ester 4 mediated by CuCl/SIPr or CuCl/PPh3 (Table
1, entries 1 and 2). The exclusive formation of the new CC
bond at the terminal position exemplifies the regiocontrol of the
allyl-alkyl cross-coupling reaction, but of particular note is that
the SN2’ process allows for simple extrusion of CO2 from the

cyclic carbonate precursor, keeping a synthetically useful OH
functionality. In the absence of any ligand, the unmodified copper species generated product (E)-4 in up to 58% yield (Table
1, entry 3). Neither the use of a double amount of diborylmethane nor the presence of alternative bases such as LiOtBu improved the reaction outcome (Table 1, entries 4 and 5). A higher
Cs2CO3 loading (50 mol %) was optimal to achieve quantitative
conversion and 4 was obtained in a yield of 75% (E/Z = 4:1)
(Table 1, entry 6). Interestingly, the ratio of E/Z stereoisomers
is higher than the E/Z ratios observed in the cross-coupling of
vinyl cyclic carbonates with arylboronic acids catalyzed by Pd
nanoparticles.6b
Table 1. Allyl-Alkyl Couplings between Diborylmethane
and the Vinyl Cyclic Carbonate 3.a

Cu/ligand

base (mol %)

E/Z

yield (E)b

1

CuCl/SIPr

Cs2CO3, 15

3.9:1

35

2

CuCl/PPh3

Cs2CO3, 15

4:1

13

3

CuCl

Cs2CO3, 15

4:1

58

4c

CuCl

Cs2CO3, 15

4:1

40

5

CuCl

t-OBuLi, 15

4:1

24

6

CuCl

Cs2CO3, 50

4:1

75

entry

a

Conditions: carbonate (0.2 mmol), CH2(Bpin)2 (1.2 equiv), CuCl (9 mol
%), ligand (13 mol %), Cs2CO3 (50 mol %), MeOH (0.10 mL), rt, 16 h.
b
NMR yield using naphthalene as internal standard. cCH2(Bpin)2 (2 equiv).

Since the only examples known for copper-catalyzed SN2’selective allylic substitution reaction between 1,1-diborylalkanes and allylic chlorides6a were unproductive for allylic
acylic carbonates, the newly developed protocol (Table 1) provides complementary reactivity. In addition, no sign of SN2substitution could be detected and the proposed copper-catalyzed SN2’-selective allylic substitution thus represents a carbonate ring opening reaction under relatively high stereocontrol.
We next explored the allyl-alkyl coupling of a series of substituted vinyl cyclic carbonates and diborylmethane to further
expand this Cu-catalyzed process (Scheme 2) (conditions: Table 1, entry 6). A general trend is observed in the formation of
the borylated products 511 with the E isomer being the favored
stereoisomer. In all crude reaction products, the E/Z ratios were
close to 4:1 independent from the substituent present in the vinyl cyclic carbonates. Both stereoisomers could be isolated
from the reaction media; the corresponding isolated yields of
the E isomer are shown in Scheme 2 (Supporting Information,
SI, for details on the Z-isomers). Electron-donating or -withdrawing substituents in the aryl group (as well as their relative
position) did not interfere in the formation of the homoallyl
boronates (E)-5, (E)-6, (E)-7, (E)-8 and (E)-10, with yields of
up to 70%. The reaction is also tolerant towards other functionalities present in the vinyl cyclic carbonate substrate, including
thiophenyl groups (cf (E)-9), and an interesting butadiene derivative (E)-11, which was isolated in high yield (82%).
Scheme 2. Substrate Scope for the Allyl-Alkyl Couplings between Diborylmethane and Vinyl Cyclic Carbonates.

To further test the viability of the CB bond formation from
vinyl cyclic carbonates, we carried out the reaction between
substrate 3 and B2pin2 2 in the presence of MeOH as solvent
and base (Table 2). When CuCl (9 mol %) was used (Table 2,
entry 1), the conversion of 3 was quantitative with the principal
formation of the allyl boronate (E)-12 (isolated yield 60%) together with a minor amount of a secondary product. Interestingly, the latter was isolated as a result of an in situ intramolecular cyclization process from the Z stereoisomer. The nucleophilic attack of the boryl moiety onto the vinyl cyclic carbonate
3 readily takes place at rt through a “Cu-Bpin” intermediate that
is formed in situ from a CuCl/MeOH/base/B2pin2 combination.8
Notably, the transition-metal free version does not allow for the
allylic borylation of vinyl cyclic carbonates. 9
The copper catalyzed reaction proceeds regioselectively as
the CB bond was exclusively formed at the terminal position
of the allylic intermediate confirming the SN2’ mechanism.10 In
the absence of any ligand, the formation of some degraded substrate could be observed (Table 2, entry 1), and the use of alternative bases such as t-OBuK in the allylic borylation of 3 reduced both the overall conversion and stereoselectivity (entry
2). We also carried out a reaction with a preformed CuOt-Bu
catalyst (entry 3)11 and found that it worked comparably to the
in situ formed catalyst derived from CuCl/t-OBuK in MeOH.
Therefore, we continued with the in situ prepared catalyst in the
presence of B2pin2. The amount of base was optimized to 15
mol %, which is significantly less than the amount of base used
in similar copper-catalyzed allylic borylations requiring typically 13 equiv. The use of an N-heterocyclic carbene ligand
slightly modified the reaction outcome in the allylic borylation
of 3 since the process was more efficient in terms of total conversion towards the borylated products (entry 4). In the presence of SIPr, the formation of the allylboronate (E)-12 also gave
an improved yield of 69%. A CuCl/PPh3 based catalyst gave a
mixture of borylated compounds 12 with an E/Z ratio of 57:35
(Table 2, entry 5). The use of bidentate phosphine ligands, however, favors the formation of boracycle (Z)-13. An improved selectivity towards (Z)-13 was achieved when the diphosphine
1,2-bis(diphenylphosphino)ethane (dppe) was used, giving an
E/Z ratio of 36:52 (Table 2, entry 6). Interestingly, when the
diphosphine
1,2-bis(di-tert-butylphosphinomethyl)benzene
(PP) was added, exclusive formation of boracycle (Z)-13 could
be achieved (Table 2, entry 7).
Table 2. Allyl-Boryl Couplings between B2pin2 and the Vinyl Cyclic Carbonate 3.a

entry

Cu/ligand

base

convb (%)
c

(E)-13 (%)b

(Z)-13 (%)b

1

CuCl/

Cs2CO3

95

62 (60)

17

2

CuCl/

KOtBu

61

41 (40)

19

3

CuOtBu/

Cs2CO3

64

47 (37)

15

4

CuCl/SIPr

Cs2CO3

99

69 (65)

31 (30)

5

CuCl/PPh3

Cs2CO3

99

57

35

6

CuCl/dppe

Cs2CO3

91

36 (24)

52 (39)

7

CuCl/PP

Cs2CO3

99



(Z)-Boracycles are important in the context of diversity-oriented organic synthesis,16 as well as in organoboron based drug
discovery.17 Other boracycles have exclusively been obtained
through our copper-catalyzed borylation to allylic cyclic carbonates, but the isolated yields were relatively low (see SI for
details). The molecular structure of (Z)-13 was also confirmed
by X-ray diffraction (Scheme 4, inset).

72 (45)

Scheme 4. (Z)-Selective Allyl-Boryl Couplings between
B2pin2 and Vinyl Cyclic Carbonates.

a

Conditions: carbonate (0.2 mmol), B2pin2 (1.2 equiv), Cu salt (9 mol %),
ligand (13 mol %), Cs2CO3 (15 mol %), MeOH (0.10 mL), rt, 16 h. A high
throughput screening of ligands can be found in the SI. bCalculated by 1H
NMR (CDCl3) using mesitylene as internal standard. Values in brackets
represent isolated yields. c <5% degraded substrate was observed.

While copper-mediated decarboxylative allylic borylation reactions of acyclic carbonates have been used to obtain allenylboronates,12,13 vinylboronates14 and allylboronates,15 those
methods lose the whole OCO2R functional group during the
CB bond formation. Our method permits additional functionality to be retained in the final product. Taking advantage of this
new methodology, we explored the borylation of a series of vinyl cyclic carbonates using CuCl/SIPr as the catalyst system
(conditions: Table 2, entry 4) to give the (E)-allylboronates 12
and 1419 as the main product (Scheme 3). The conversion of
different carbonate precursors into their borylated products was
almost quantitative in most cases, with some minor amount of
the (Z)-isomers being formed (<10%) together with some degraded substrate. In general, rather similar isolated yields were
obtained (5265%) independent from the type of substrate. The
borylation of 3 could also be carried out on gram scale in a
slightly lower yield (56%, Scheme 3), but the use of vinyl carbonates with alkyl groups (R = Me, Cy) was unproductive.

A proposed reaction mechanism for the SN2’ allyl-alkyl coupling (Figure 1 and SI for further details) and SN2’ allyl-boryl
coupling reactions may involve first activation of the diborylmethane reagent or B2pin2 to form Cu-CH2Bpin or CuBpin, respectively. Figure 1 shows that Cu-CH2Bpin intermediate A coordinates the terminal alkene of substrate to generate B
followed by regioselective addition producing a new alkyl-Cu
intermediate C. Hereafter, elimination of the product from D in
a formal anti-SN2’ pathway releases CO2 and regenerates the
copper complex.

Scheme 3. (E)-Selective Allyl-Boryl Couplings between
B2pin2 and Vinyl Cyclic Carbonates.

Figure 1. Proposed Mechanism for SN2’ Allyl-Alkyl Coupling

When 1,2-bis(di-tert-butylphosphinomethyl)benzene (PP)
was used as ligand, the allylic borylation of alkyl/aryl-substituted vinyl cyclic carbonates advanced towards the (Z)-stereoisomer following intramolecular cyclization to afford the boracycles 13 and 2022 (Scheme 4) (conditions: Table 2, entry 7).

To demonstrate the synthetic use of the homoallylic and allylic borylated products, we conducted an in situ copper-catalyzed SN2’ allyl-alkyl and SN2’ allyl-boryl coupling followed by
oxidative work up (H2O2, NaOH). The corresponding (E)-configured pent-2-ene-1,5-diols and but-2-ene-1,4-diols were isolated as the main products (Figure 2). The corresponding (Z)isomers of the pent-2-ene-1,5-diols could also be isolated in low
yield (see the SI). Interestingly, the (E)-isomers of such but-2ene-1,4-diols are valuable compounds, being about 190 times
more expensive than their corresponding (Z)-isomers.18 Therefore, our versatile one-pot approach opens a new straightforward route towards these scaffolds19 which are useful in organic
synthesis.20

Figure 2. One-Pot Preparation of But-2-ene-1,4-Diols and
Pent-2-Ene-1,5-Diols

In conclusion, we present a stereoselective copper-catalyzed
selective SN2’ allylic substitutions of vinyl cyclic carbonate to
form allylboranes and homoallylboranes. The stereoselectivity
is catalyst-controlled and in situ copper-catalyzed CCH2B and
CB bond formation followed by oxidative workup provides
direct access to valuable (E)-configured pent-2-ene-1,5-diols
and but-2-ene-1,4-diols.

ASSOCIATED CONTENT
Supporting Information
The Supporting Information contains experimental procedures and
characterization of all allyl-alkyl couplings using vinyl cyclic carbonates and diborylmethane or B2pin2. It is available free of charge
on the ACS Publications website at DOI: 10.1021/XXX

AUTHOR INFORMATION
Corresponding Author
*mariaelena.fernandez@urv.cat, akleij@iciq.es.

Author Contributions
The manuscript was written through contributions of all authors.

ACKNOWLEDGMENT
This research was supported by MINECO through projects
CTQ2016-80328-P, CTQ-2014–60419-R and the Severo Ochoa
Excellence Accreditation 2014–2018 through project SEV-2013–
0319.

REFERENCES
(1) (a) Xu, L.; Zhang, S.; Li, P. Chem. Soc. Rev. 2015, 44, 8848. (b)
Neeve, E.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.; Marder, T. B.
Chem. Rev. 2016, 116, 9091. (c) Cuenca, A. B.; Shishido, R. I.; Ito, H.;
Fernandez, E. Chem. Soc. Rev. 2017, 46, 415.
(2) Latest contributions: (a) Kim, J.; Park, S.; Park, J.; Cho, S. H.
Angew. Chem., Int. Ed. 2016, 55, 1498. (b) Shi, Y.; Hoveyda, A. H.
Angew. Chem., Int. Ed. 2016, 55, 3455. (c) Zhang, Z.-Q.; Zhang, B.;
Lu, X.; Liu, J.-H.; Lu, X.-Y.; Xiao, B.; Fu, Y. Org. Lett. 2016, 18, 952.
(d) Zhan, M. Li, R.-Z.; Mou, Z.-D.; Cao, C.-G.; Liu, J.; Chen, Y.-W.;
Niu, D. ACS Catal. 2016, 6, 3381. (e) Ahmed, E.-A.; Zhang, Z.-Q.;
Gong, T.-J.; Su, W.; Lu, X.-Y.; Xiao B.; Fu, Y.; Chem. Commun. 2016,
52, 4891. (f) Lu, X.; Xiao, B.; Zhang, Z.-Q.; Gong, T.-J.; Su, W.; Fu
Y.; Liu, L. Nat. Commun. 2016, 7, 11129. (g) Li, F.; Zhang, Z.-Q.; Lu,
X.; Xiao, B.; Fu, Y. Chem. Commun. 2017, 53, 3551.
(3) (a) Endo, K.; Ohkubo, T.; Hirokami, M.; Shibata, T. J. Am. Chem.
Soc. 2010, 132, 11033. (b) Endo, K.; Ohkubo, T.; Shibata, T. Org. Lett.
2011, 13, 3368. (c) Sun, C.; Potter, B.; Morken, J. P. J. Am. Chem. Soc.

2014, 136, 6534. (d) Potter, B.; Szymaniak, A. A.; Edelstein, E. K.;
Morken, J. P. J. Am. Chem. Soc. 2014, 136, 17918. (e) Potter, B.; Edelstein, E. K. Morken, J. P. Org. Lett. 2016, 18, 3286.
(4) (a) Endo, K.; Hirokami, M.; Shibata, T. J. Org. Chem. 2010, 75,
3469. (b) Coombs, J. R.; Zhang, L.; Morken, J. P. Org. Lett. 2015, 17,
1708. (c) Joannou, M. V.; Moyer, B. S.; Goldfogel, M. J.; Meek, S. J.
Angew. Chem., Int. Ed. 2015, 54, 14141. (d) Joannou, M. V.; Moyer,
B. S.; Meek, S. J. J. Am. Chem. Soc. 2015, 137, 6176. (e) Murray, S.
A.; Green, J. C.; Tailor, S. B.; Meek, S. J. Angew. Chem. Int. Ed. 2016,
55, 9065.
(5) (a) Endo, K.; Ohkubo, T.; Ishioka, T.; Shibata, T. J. Org. Chem.
2012, 77, 4826. (b) Hong, K.; Liu, X.; Morken, J. P. J. Am. Chem. Soc.
2014, 136, 10581. (c) Zhang, Z.-Q.; Yang, C.-T.; Liang, L.-J.; Xiao,
B.; Lu, X.; Liu, J.-H.; Sun, Y.-Y.; Marder, T. B. Fu, Y. Org. Lett. 2014,
16, 6342.
(6) (a) Kim, J.; Park, S.; Park, J.; Cho, S. H. Angew. Chem., Int. Ed.
2016, 55, 1498. (b) Mao, Y, Zhai, X.; Khan, A.; Cheng, J.; Wu, X.;
Zhang, Y. J. Tetrahedron Lett. 2016, 57, 3268.
(7) (a) Diner, C.; Szabó, K. J. J. Am. Chem. Soc. 2017, 139, 2. (b)
Ramachandran, P. V.; Gagare, P. D.; Nicponski, D. R. Allylborons,
Comprehensive Organic Synthesis (2nd Edition), Knochel, P.; Molander G. A. 2014, pp 1-71.
(8) (a) Makoto, Y. Bull. Chem. Soc. Japan, 2011, 84, 984. (b) Cid, J.
Gulyás, H.; Carbó, J. J.; Fernández, E. Chem. Soc. Rev. 2012, 41, 3558.
(c) Dewhurst, R. D.; Neeve, E. C.; Braunschweig, H.; Marder, T. B.
Chem. Commun. 2015, 51, 9594.
(9) For alkoxide-catalyzed borylation of allylic and propargylic alcohols: (a) Miralles, N.; Alam, R.; Szabó, K. J.; Fernández, E. Angew.
Chem. Int. Ed. 2016, 55, 4303. (b) Harada, K.; Nogami, M.; Hirano,
K.; Kurauchi, D.; Kato, H.; Miyamoto, K.; Saito, T.; Uchiyama, M.
Org. Chem. Front. 2016, 3, 565.
(10) For opposite regioselectivity in decaboxylative borylation, see:
Ito, H.; Kosaka, Y.; Nonoyama, N.; Sasaki, Y.; Sawamura, M. Angew.
Chem. Int. Ed. 2008, 47, 7424.
(11) Bonet, A.; Lillo, V.; Ramírez, J.; Díaz-Requejo, M. M.; Fernández, E. Org. Biomol. Chem. 2009, 7, 1533.
(12) Ito, H.; Sasaki, Y.; Sawamura, M. J. Am. Chem. Soc. 2008, 130,
15774.
(13) (a) Zhao, T. S. N.; Yang, Y.; Lessing, T.; Szabó, K. J. J. Am.
Chem. Soc. 2014, 136, 7563. (b) Yang, Y.; Szabó, K. J. J. Org Chem.
2016, 81, 250.
(14) For carboxylic acids: (a) Feng, Q.; Yanga, K.; Song, Q. Chem.
Commun. 2015, 51, 15394. (b) Zhao, Y.-W.; Feng, Q.; Song, Q.-L.
Chin. Chem. Lett. 2016, 27, 571.
(15) (a) Ito, H.; Kawakami, C.; Sawamura, M. J. Am. Chem. Soc.
2005, 127, 16034. (b) Ito, H.; Ito, S., Sasaki, Y.; Matsuura, K.;
Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856. (c) Guzman-Martínez, A.; Hoveyda, A. H. J. Am. Chem. Soc., 2010, 132, 10634.
(16) Micalizio, G. C.; Schreiber, S. Angew. Chem. Int. Ed. 2002, 41,
152.
(17) (a) Ramachandran, P. V. Future Med. Chem. 2013, 5, 611. (b)
Baker, S. J.; Ding, C. Z.; Akama, T.; Zhang, Y.-K.; Hernandez, V.; Xia,
Y. Future Med. Chem. 2013, 1, 1275.
(18) (a) Ezawa, T.; Kawashima, Y.; Noguchi, T.; Jung, S.; Imai, N.
Tetrahedron Asymm. 2017, 28, 266. (b) Guo, W.; Martínez-Rodriguez,
L.; Martin, E.; Escudero-Adán, E. C.; Kleij, A. W. Angew. Chem. Int.
Ed. 2016, 55, 11037.
(19) (a) Ishino, I.; Wakamoto, K.; Hirashima, T. Chem. Lett. 1984,
765. (b) Klimovica, K.; Grigorjeva, L.; Maleckis, A.; Popelis, J.;
Jirgensons, A. Synlett. 2011, 2849. (c) De Silva, A. N.; Francis, C. L.;
Ward, A. D. Aust. J. Chem. 1993, 46, 1657.
(20) (a) Emayavaramban, B.; Sen, M.; Sundararaju, B. Org. Lett.
2017, 19, 6. (b) Tortosa, M. Angew. Chem. Int. Ed. 2011, 50, 3950.