Copper-catalyzed borylation reactions of alkynes and arynes

Article abstract of DOI:10.1002/anie.201106706

One, two, three, four: A copper(I)-phosphine complex catalyzes the diborylation of alkynes and arynes, and the tri- or tetraborylation of propargyl ethers (see scheme; pin=pinacolato). In the latter cases, the C-O bond(s) as well as the C≡C bond are borylated in one pot. Furthermore, a diborylation product serves as an intermediate in the efficient synthesis of ortho-terphenyls with pharmacological activity.

Full text of DOI:10.1002/anie.201106706

Angewandte
Chemie
DOI: 10.1002/anie.201106706
Borylation
Copper-Catalyzed Borylation Reactions of Alkynes and Arynes**
Hiroto Yoshida,* Shota Kawashima, Yuki Takemoto, Kengo Okada, Joji Ohshita, and
Ken Takaki
Table 1: Cu-catalyzed diborylation of alkynes.[a]
Much attention has recently been given to the formation of
À
C B bonds by borylation reactions of unsaturated carbon
linkages under copper catalysis. In this method, nucleophilic
borylcopper species, which are formed by s-bond metathesis
between copper(I) complexes and diboron compounds, serve
as key intermediates.[1,2] While various organoboron com-
Entry
1
R
R’
Ligand
t
[h]
2
Yield
[%][b]
pounds that are of great synthetic value are readily accessible
by the above-mentioned method, efforts have been devoted
largely to the development of monoborylation reactions, in
which one boryl moiety of a diboron compound is incorpo-
rated into the final product. On the other hand, installation of
both boryl moieties of a diboron compound into the product,
that is, diborylation,[3,4] is also of high synthetic significance,
1
1a nPr
1a nPr
1a nPr
1a nPr
1b Me
nPr
nPr
nPr
nPr
nPen
nBu
iPr
PCy3
P(tBu)3
P(nOc)3 42
PPh3
PCy3
PCy3
PCy3
3
4
2a 82
2a 83
2a 81
2a 58
2b 76
2[c]
3[c]
4[c]
5
16
3
6
7
8
9
10
11
12[d]
13[e]
14
15
16
1c
1d Me
nBu
6
2c
72
À
since the resulting two C B bonds can both be utilized for the
4.5 2d 78
synthesis of complex molecules by Suzuki–Miyaura coupling
and other methods.[5] However, potential copper catalysis for
diborylation reactions remains to be exploited.[6] Herein, we
report the first diborylation of unsaturated carbon linkages by
copper catalysis; the broad substrate scope makes this a
universal method for the synthesis of vic-diborylalkenes
(from alkynes) and vic-diborylarenes (from arynes), further-
more, this method is more practical and economical than that
with the well-known catalytic system based on platinum.[4]
We first carried out the reaction of 4-octyne (1a) with
1e
nHex
Ph
(CH2)2OMe PCy3
Ph PCy3
4-MeOC6H4 PCy3
1h 4-MeOC6H4 4-MeOC6H4 PCy3
6
2e
73
78
1 f
11.5 2 f
13.5 2g 82
16
77
43.5 2j
8.5 2k
1g Ph
2h 76
2i
1i
1j
1k
1l
Ph
Ph
Ph
Ph
4-BrC6H4
4-NCC6H4
Me
Et
tBu
PCy3
PCy3
PCy3
PCy3
PCy3
48
43
78
78
24
46
2l
1m Ph
2m 64
À
[a] General procedure: alkyne (0.30 mmol), (pin)B B(pin) (0.39 mmol),
Cu(OAc)2 (6.0 mmol), ligand (0.021 mmol), toluene (0.1 mL). [b] Yields
of isolated products. [c] Alkyne (1 equiv), (pin)B B(pin) (2 equiv),
Cu(OAc)2 (10 mol%), ligand (35 mol%), no solvent. [d] Toluene
(0.2 mL). [e] Toluene (0.3 mL). Cy=cyclohexyl, nHex=n-hexyl, nPen=n-
pentyl, nOc=n-octyl.
À
bis(pinacolato)diboron ((pin)B B(pin)) in the presence of
À
PCy3 and Cu(OAc)2,[7,8] and observed that the B B bond was
À
ꢀ
smoothly added to the C C bond in a cis fashion to afford
diborylated product 2a in 82% yield (Table 1, entry 1).
Trialkylphosphine ligands P(tBu)3 and P(nOc)3 also promoted
the diborylation, but a prolonged reaction time was required
in the latter case (Table 1, entries 2 and 3, respectively); the
reaction with PPh3 resulted in a moderate yield (entry 4).
With PCy3 as the optimum ligand, other aliphatic alkynes,
including 2-octyne (1b), 5-decyne (1c), and 4-methyl-2-
pentyne (1d), could be diborylated and afforded the respec-
tive vic-diborylalkenes in high yields (2b–2d; Table 1,
entries 5–7). The reaction of homopropargyl ether 1e resulted
À
in the formation of 2e, the C OMe bond of which remained
intact throughout the reaction (Table 1, entry 8). The broad
substrate scope of alkynes was further demonstrated by the
successful reaction of diarylalkynes (1 f–1j) and aryl-
(alkyl)alkynes (1k and 1l) to products 2 f–2l (Table 1,
entries 9–15), and also by the reaction of (tert-butyl)pheny-
lacetylene (1m), which is sterically hindered around the triple
bond (entry 16).
[*] Prof. H. Yoshida, S. Kawashima, Y. Takemoto, K. Okada,
Prof. J. Ohshita, Prof. K. Takaki
Department of Applied Chemistry
Graduate School of Engineering, Hiroshima University
Higashi-Hiroshima 739-8527 (Japan)
E-mail: yhiroto@hiroshima-u.ac.jp
[**] This work was financially supported by Research for Promoting
Technological Seeds from the Japan Science and Technology Agency
(JST), the Electric Technology Research Foundation of Chugoku, The
Mazda Foundation, and the Furukawa Technology Promotion
Foundation. We thank Central Glass Co., Ltd. for a generous gift of
trifluoromethanesulfonic anhydride, and Prof. Masahiro Sadakane,
Dr. Hiroshi Fukuoka, and Masaya Itakura (Hiroshima University) for
EDX measurements.
The copper-catalyzed diborylation was also applicable to
transient arynes.[9] The vic-diborylbenzene 4a was produced
in 68% yield by treatment of an in situ generated benzyne
(obtained from 3a[10] and KF/[18]crown-6) with (pin)B
À
B(pin) in the presence of [(PPh3)3CuOAc] (Table 2,
entry 1). In addition, a variety of monosubstituted (from
3b–3d) and disubstituted (from 3e–3h) arynes reacted
smoothly with the diboron reagent to afford the respective
vic-diborylarenes 4b–4h in good yields (Table 2, entries 2–8).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201106706.
Angew. Chem. Int. Ed. 2012, 51, 235 –238
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
235

.
Angewandte
Communications
Table 2: Cu-catalyzed diborylation of arynes.[a]
Scheme 2. Cu-catalyzed reaction of methyl propargyl ether with
Entry
3
R
t [h]
4
Yield [%][b]
À
À
(pin)B B(pin). a) Methyl propargyl ether (1 equiv), (pin)B B(pin)
(2.5 equiv), Cu(OAc)2 (2 mol%), PCy3 (7 mol%), toluene, 808C, 1o
(21 h), 1p (22 h), 1q (29 h).
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3 f
3g
3h
3i
H
7
4a
4b
4c
4d
4e
4 f
4g
4h
4i
68
79
61
55
73
73
69
62
69
4-Me
4-tBu
4-Ph
4,5- (CH2)3
4,5- (CH2)4
4,5-Me2
4,5-(nHex)2
4-TMS
14
20
20
24
18
12
60
22
À
À
À
À
8
9[c]
À
[a] General procedure: aryne precursor (0.45 mmol), (pin)B B(pin)
(0.30 mmol), KF (0.90 mmol), [18]crown-6 (0.45 mmol), [(PPh3)3CuOAc]
(6.0 mmol), 1,2-diethoxyethane (1 mL). [b] Yields of isolated products.
[c] [(PPh3)3CuOAc] (5 mol%). TMS=trimethylsilyl.
Scheme 3. Proposed catalytic cycle for the diborylation.
À
bond of an alkyne or an aryne into the Cu B bond gives
organocopper species 6, subsequent s-bond metathesis with a
diboron compound provides a diborylation product and
regenerates 5.[12] The validity of the proposed second step of
the catalytic cycle was confirmed by the stoichiometric
It should be noted that the silyl moiety of 4-(trimethylsilyl)-
benzyne (from 3i) was stable in the presence of the fluoride
ion, and diborylated product 4i was formed selectively
(Table 2, entry 9).
The most striking feature of the copper catalysis was
observed in the reactions of propargyl ethers (Scheme 1).
With the aid of the copper catalyst, 1,4-dimethoxy-2-butyne
(1n) was converted exclusively into a tetraborylated product,
1,2,3,4-tetraboryl-2-butene (2n),[11] in which the MeO groups
À
reaction of mesityl copper(I) with (pin)B B(pin) that led to
2
2
À
À
the transformation of the C(sp ) Cu bond into the C(sp ) B
bond (Scheme 4).
À
Scheme 4. Reaction of mesityl copper(I) with (pin)B B(pin).
Formation of borylallene 7n by b-oxygen elimination
from alkenyl copper species 6n should trigger the tetrabor-
ylation of 1n (Scheme 5).[13,14] The resulting borylallene is
À
then inserted into the Cu B bond of 5 to furnish p-allyl
À
Scheme 1. Cu- or Pt-catalyzed reaction of 1n with (pin)B B(pin).
DMF=N,N-dimethylformamide.
À
are replaced by boryl groups, and all four C B bonds were
formed in one pot. This result was completely different from
that obtained by using the established platinum catalyst
[Pt(PPh3)4], which furnished the expected diborylation prod-
uct 2’n. In addition, propargyl ethers 1o and 1p likewise
underwent triborylation under the copper catalysis to give 2o
and 2p as major products (Scheme 2), thus demonstrating
that the borylation of propargyl ethers offers direct and
unique access to multifunctionalized organoboron com-
pounds that bear two alkenyl boryl and two (or one) allyl
boryl moieties. In contrast, phenyl-substituted propargyl
ether 1q provided exclusively diborylation product 2’q.
A key intermediate of the diborylation might be boryl-
copper species 5, which is generated from copper acetate and
ꢀ
a diboron reagent (Scheme 3). Insertion of the C C triple
Scheme 5. Proposed catalytic cycle for the tetraborylation.
Angew. Chem. Int. Ed. 2012, 51, 235 –238
236
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angewandte
Chemie
copper species 8n, which is transformed into 2,3-diborylbu-
tadiene (10) by a second b-oxygen elimination from s-allyl
copper species 9n. Finally, 1,4-diborylation of 10 occurs in a
similar manner as mentioned above (Scheme 3) to provide
2n.[15,16] In the reaction of 1o or 1p, the triborylation product
(2o or 2p) would arise from the s-bond metathesis of the p-
allyl copper species (8o-Bsyn or 8p-Bsyn), generated via the
alkenyl copper species (6o or 6p), with the diboron com-
pound attacking at the sterically less-hindered carbon center;
the regioisomeric alkenyl copper species (6’o or 6’p) gives the
diborylation product (2’o or 2’p) according to the simple
diborylation process (Scheme 6). Although p-allyl species 8-
Scheme 8. Synthesis of F050 and F1070. a) 4i (1 equiv), iodobenzene
(2.5 equiv), Cs2CO3 (2.5 equiv), H2O (20 equiv), [Pd(PtBu3)2] (5 mol%),
DME, 808C, 40.5 h; b) 11 (1 equiv), ICl (1.5 equiv), 1,2-dichloroethane,
08C, 5.5 h; c) 12 (1 equiv), propargyl alcohol (2 equiv), CuI (6 mol%),
[(PPh3)2PdCl2] (6 mol%), THF/NEt3 (2.5:1), RT, 21 h; d) 13 (1 equiv),
H2 (4 atm), Pd/C (10 mol%), EtOH, 308C, 21 h; e) 12 (1 equiv), (3-
benzyloxyphenyl)acetylene (2 equiv), CuI (6 mol%), [(PPh3)2PdCl2]
(6 mol%), THF/NEt3 (2.5:1), RT, 18 h; f) 15 (1 equiv), H2 (4 atm), Pd/
C (10 mol%), EtOH, 308C, 22 h; g) 16 (1 equiv), methyl bromoacetate
(1.3 equiv), K2CO3 (1.3 equiv), DMF, RT, 24 h; h) 17 (1 equiv), 1n
NaOH (10 equiv), MeOH, RT, 6.5 h. Bn=benzyl, DME=1,2-dime-
thoxyethane, THF=tetrahydrofuran.
Scheme 6. Proposed catalytic cycle for the triborylation.
treatment of thrombotic diseases (Scheme 8). Suzuki–
Miyaura coupling of 4i with iodobenzene afforded ortho-
terphenyl 11, which was then converted into 12 by iodode-
silylation using iodine monochloride. Sonogashira coupling of
12 with propargyl alcohol gave 13, the alkynyl moiety of
which was hydrogenated to give F050 (14, 81% overall yield
based on 4i). Similarly, 12 was coupled with 3-(benzyloxy)-
phenylacetylene to produce diarylacetylene 15, which was
transformed into 16 by hydrogenation and deprotection of the
benzyl moiety in one step. Subsequent alkylation of the
hydroxy group with methyl bromoacetate afforded 17, and
subsequent hydrolysis gave F1070 (18, 44% overall yield
based on 4i).
Banti would also be produced in the borylcupration of
borylallene 7, owing to sterically disfavored Banti configura-
tion, isomerization to 8-Bsyn proceeds readily through p–s–p
rearrangement, which leads to the exclusive formation of
Z triborylation products. In addition, the selective diboryla-
tion of 1q can be ascribed to the regioselective generation of
intermediate 6’q, which is induced by the directing electronic
effect of the phenyl moiety.[1l,17]
We also showed that diborylated products 2’ are not
intermediates of the tetra- and triborylation. The reaction of
À
2’p with (pin)B B(pin) under copper catalysis gave no trace
of 2p, thus verifying that SN2-type reactions at the allyl carbon
do not occur in the process (Scheme 7).[1b]
In conclusion, we have demonstrated that an easily
accessible copper–phosphine complex served as a potent
catalyst for the direct formation of diverse cis-vic-diborylal-
kenes (or vic-diborylarenes) by diborylation of alkynes (or
arynes). With this catalyst, propargyl ethers smoothly under-
Finally, the synthetic utility of diborylation products was
demonstrated by the total synthesis of F050[18] and F1070,[19]
which are new candidates and lead compounds for the
À
went tetra- and triborylation by formal C O bond borylation
accompanied by diborylation of the alkyne moieties. More-
over, the resulting diborylation product has been demon-
strated to serve as an intermediate in the synthesis of the
pharmacologically significant compounds F050 and F1070.
Further studies on insertion reactions of unsaturated hydro-
À
Scheme 7. Reaction of 2’p with (pin)B B(pin) under copper catalysis.
Angew. Chem. Int. Ed. 2012, 51, 235 –238
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
237

.
Angewandte
Communications
Hiyama, Proc. Jpn. Acad. Ser. B 2008, 84, 75; For the Suzuki –
Miyaura coupling with vic-diborylalkenes, see: c) S. D. Brown,
R. W. Armstrong, J. Am. Chem. Soc. 1996, 118, 6331; d) M.
Shimizu, I. Nagao, Y. Tomioka, T. Hiyama, Angew. Chem. 2008,
120, 8216; Angew. Chem. Int. Ed. 2008, 47, 8096.
carbons into boron-containing s bonds under copper catal-
ysis, and on synthetic applications of the borylation products
are in progress.
Received: September 21, 2011
Published online: November 14, 2011
À
[6] Although the only example on diborylation of unsaturated C C
bonds under copper catalysis was reported by Fernꢂndez et al.,
this reaction required the use of reactive bis(catecholato)di-
boron, and was unsuccessful with bis(pinacolato)diboron, see: V.
Lillo, M. R. Fructos, J. Ramꢀrez, A. A. C. Braga, F. Maseras,
M. M. Dꢀaz-Requejo, P. J. Pꢁrez, E. Fernꢂndez, Chem. Eur. J.
2007, 13, 2614.
Keywords: alkynes · arynes · boron · copper · total synthesis
.
[1] For examples, see: a) K. Takahashi, T. Ishiyama, N. Miyaura,
J. Organomet. Chem. 2001, 625, 47; b) H. Ito, S. Ito, Y. Sasaki, K.
Matsuura, M. Sawamura, J. Am. Chem. Soc. 2007, 129, 14856;
c) H. Ito, Y. Sasaki, M. Sawamura, J. Am. Chem. Soc. 2008, 130,
15774; d) J.-E. Lee, J. Yun, Angew. Chem. 2008, 120, 151; Angew.
Chem. Int. Ed. 2008, 47, 145; e) H. Ito, Y. Kosaka, K. Nonoyama,
Y. Sasaki, M. Sawamura, Angew. Chem. 2008, 120, 7534; Angew.
Chem. Int. Ed. 2008, 47, 7424; f) J.-E. Lee, J. Kwon, J. Yun,
Chem. Commun. 2008, 733; g) Y. Lee, A. H. Hoveyda, J. Am.
Chem. Soc. 2009, 131, 3160; h) Y. Lee, H. Jang, A. H. Hoveyda,
J. Am. Chem. Soc. 2009, 131, 18234; i) V. Lillo, A. Prieto, A.
Bonet, M. M. Dꢀaz-Requejo, J. Ramꢀrez, P. J. Pꢁrez, E. Fernꢂn-
dez, Organometallics 2009, 28, 659; j) H.-R. Kim, I.-G. Jung, K.
Yoo, K. Jang, E.-S. Lee, J. Yun, S.-U. Son, Chem. Commun. 2010,
46, 758; k) Y. Sasaki, C. Zhong, M. Sawamura, H. Ito, J. Am.
Chem. Soc. 2010, 132, 1226; l) H. Ito, T. Toyoda, M. Sawamura, J.
Am. Chem. Soc. 2010, 132, 5990; m) C. Zhong, S. Kunii, Y.
Kosaka, M. Sawamura, H. Ito, J. Am. Chem. Soc. 2010, 132,
11440; n) H.-R. Kim, J. Yun, Chem. Commun. 2011, 47, 2943.
[2] For studies on borylcopper species, see: a) D. S. Laitar, P. Mꢃller,
J. P. Sadighi, J. Am. Chem. Soc. 2005, 127, 17196; b) Y. Segawa,
M. Yamashita, K. Nozaki, Angew. Chem. 2007, 119, 6830;
Angew. Chem. Int. Ed. 2007, 46, 6710; c) Y. Okuno, M.
Yamashita, K. Nozaki, Angew. Chem. 2011, 123, 950; Angew.
Chem. Int. Ed. 2011, 50, 920.
[7] B. Hammond, F. H. Jardine, A. G. Vohra, J. Inorg. Nucl. Chem.
1971, 33, 1017.
[8] Platinum was not observed in the EDX spectrum of Cu(OAc)2
used in this study, thus supporting the hypothesis that the present
borylations are catalyzed by copper. See the Supporting
Information for details.
[9] We have already reported the Pt-catalyzed diborylation of
arynes, see: H. Yoshida, K. Okada, S. Kawashima, K. Tanino, J.
Ohshita, Chem. Commun. 2010, 46, 1763.
[10] Y. Himeshima, T. Sonoda, H. Kobayashi, Chem. Lett. 1983, 1211.
[11] For studies on cascade triple-aldehyde addition of 2n, see: a) M.
Shimizu, K. Shimono, T. Hiyama, Chem. Lett. 2006, 35, 838;
b) M. Shimizu, K. Shimono, T. Hiyama, Chem. Asian J. 2007, 2,
1142.
[12] For a computational study on a catalytic cycle of this type, see: L.
Dang, H. Zhao, Z. Lin, T. B. Marder, Organometallics 2008, 27,
1178.
[13] For synthesis of borylallenes by the Cu-catalyzed reaction of
propargyl carbonates with diboron compounds, see Ref. [1c].
[14] b-Oxygen elimination was proposed to be a key step in the Cu-
catalyzed reaction of allyl carbonates with diboron compounds,
see Ref. [1b].
[15] The Z stereochemistry of 2n would result from s-cis conforma-
tion of 10 in the borylcupration step.
À
[3] For reviews on diborylation of unsaturated C C bonds, see:
[16] The validity of the cycle was confirmed by the formation of 2n in
À
a) T. B. Marder, N. C. Norman, Top. Catal. 1998, 5, 63; b) T.
Ishiyama, N. Miyaura, J. Organomet. Chem. 2000, 611, 392.
the Cu-catalyzed reaction of 10 with (pin)B B(pin). See the
Supporting Information for details.
À
[4] For Pt-catalyzed diborylation of unsaturated C C bonds, see:
[17] L. Dang, H. Zhao, Z. Lin, T. B. Marder, Organometallics 2007,
26, 2824.
[18] K. Hongou, T. Miyamae, H. Hashizume, K. Oshima, T. Ogawa,
T. Hongou, T. Morikawa, M. Hagiwara, Arzneim.-Forsch. 1997,
47(II), 1104.
[19] T. Miyamae, H. Hashizume, T. Ogawa, T. Okayama, E. Nukui,
K. Oshima, T. Morikawa, M. Hagiwara, Arzneim.-Forsch. 1997,
47(I), 13.
a) T. Ishiyama, N. Matsuda, N. Miyaura, A. Suzuki, J. Am. Chem.
Soc. 1993, 115, 11018; b) T. Ishiyama, N. Matsuda, M. Murata, F.
Ozawa, A. Suzuki, N. Miyaura, Organometallics 1996, 15, 713;
c) G. Lesley, P. Nguyen, N. J. Taylor, T. B. Marder, A. J. Scott, W.
Clegg, N. C. Norman, Organometallics 1996, 15, 5137; d) R. L.
Thomas, F. E. S. Souza, T. B. Marder, J. Chem. Soc. Dalton Trans.
2001, 1650; e) H. E. Burks, L. T. Kliman, J. P. Morken, J. Am.
Chem. Soc. 2009, 131, 9134.
[5] For reviews, see: a) V. M. Dembitsky, H. A. Ali, M. Srebnik,
Appl. Organomet. Chem. 2003, 17, 327; b) M. Shimizu, T.
238
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 235 –238