Copper-catalyzed regio- and stereoselective conjugate allylation of electron-deficient alkynes with allylboronates under mild conditions

Article abstract of DOI:10.1002/chem.201103697

A good all-rounder: The copper-catalyzed conjugate allylation of electron-deficient alkynes with allylboronates produced hydroallylation products in high yields with perfect regio- and stereoselectivity. This method can be applied to alkynes with activating groups such as ester, nitrile, amide, and sulfone substituents (see scheme). Copyright

Full text of DOI:10.1002/chem.201103697

COMMUNICATION
DOI: 10.1002/chem.201103697
Copper-Catalyzed Regio- and Stereoselective Conjugate Allylation of
Electron-Deficient Alkynes with Allylboronates under Mild Conditions
Yoshihiko Yamamoto,* Satoshi Yamada, and Hisao Nishiyama[a]
Conjugate allylation of alkenes activated by an electron-
withdrawing group has been an important research subject
in organic synthesis because carbon–carbon bonds formation
occurs at the b-position to the activating group and the in-
stalled allyl moiety can be a versatile handle for further syn-
thetic manipulations.[1] Therefore, various allylic metal re-
agents, with or without promoters, have been investigated to
accomplish high 1,4 versus 1,2 selectivity,[2] and catalytic
enantioselective conjugate allylations have been recently de-
veloped.[3,4]
In striking contrast, conjugate allylations of alkynic conge-
ners have hardly been developed,[5] although they provide
a powerful entry to functionalized skipped dienes.[6] Conju-
gate allylation of alkynoates with allyl and methallyl copper
reagents was accomplished for the first time by Corey and
co-workers.[5e] Later, the scope of allylic groups was careful-
Scheme 1. Conjugate allylation of electron-deficient alkynes.
ly examined using both organocuprates and organocopper
reagents.[5d] These investigations revealed that syn stereose-
lectivity can be achieved by performing the reaction at low
temperature, typically at À908C (Scheme 1a). However, the
scope of alkyne substrates has not been established yet.
Nevertheless, the synthetic utility of this traditional method
has been well demonstrated; it has been applied to the ste-
reoselective synthesis of a functionalized allylboronate[7] and
a dienoic acid building block for the total synthesis of natu-
ral products such as (+)-amphidinolide A and pectenotoxin
2.[8]
Apart from the copper chemistry, catalyzed or non-cata-
lyzed allylmetalation of electron-deficient alkynes have
been investigated. Shirakawa, Hiyama, and co-workers re-
ported that the nickel- or palladium-catalyzed allylstanna-
tion of various alkynes activated by ester, cyano, or sulfonyl
groups afforded 1,4-dienylstannanes (Scheme 1b),[5b,c] where-
as Xie, Wang, and co-workers described the allylzincation of
alkynyl sulfones.[5a] Although these methods have an advant-
age in that the 1,4-dienylmetal products can be used for sub-
sequent cross-coupling reactions, successful results are limit-
ed to alkynyl sulfones. In fact, although palladium-catalyzed
allylstannation of a phenylethynyl sulfone proceeded at
508C for 1 h to give the corresponding product in 73% yield
with a high regioselectivity of 92:8, that of ethyl 3-phenyl-
propiolate was sluggish and the regioselectivity diminished
to 79:21 (Scheme 1b).
Therefore, there is an unmet need for a practical synthesis
method that has wide substrate scope and high regio- and
stereoselectivity. It is also important for the newly devel-
oped protocol to proceed by using a bench-top stable, readi-
ly available, and less toxic allylating agent. Because it is
highly important to develop a method for synthesizing mul-
tiply substituted alkenes, we have developed relevant
copper-catalyzed syn hydroarylations of alkynoates and al-
kynic nitriles with arylboronic acids and applied these hy-
droarylations to the synthesis of biologically significant mol-
ecules.[9] As a continuation of these studies, we herein de-
scribe preliminary results obtained from the investigation of
the copper-catalyzed conjugate allylation of electron-defi-
cient alkynes with allylboronic acid pinacol (pin) esters
(Scheme 1c). The newly established method has the follow-
ing notable advantages:
[a] Prof. Dr. Y. Yamamoto, S. Yamada, Prof. Dr. H. Nishiyama
Department of Applied Chemistry
Graduate School of Engineering, Nagoya University
Chikusa-ku, Nagoya 464-8063 (Japan)
Fax : (+81)52-789-3209
1) A wide range of electron-deficient alkyne substrates are
applicable.
2) Readily available allylboronic acid pinacol esters and in-
expensive copper(II) acetate as a catalyst are used.
E-mail: yamamoto@apchem.nagoya-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103697.
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Table 2. Scope of alkyne substrates.[a]
3) The reaction proceeds at room temperature to deliver
1,4-diene products with perfect regio- and stereoselectiv-
ity.
To the best of our knowledge, there is no example of
a copper-catalyzed conjugate addition of alkylboron re-
agents to electron-deficient alkynes, although that to a,b-un-
saturated imidazolyl ketones was recently reported by Sawa-
mura and co-workers.[10]
1
Cu
[mol%]
t
Yield
[%]
G
[h]
1
2
1b
1c
3
3
2
3
3ba 93
3ca 91
At the outset, copper salts were screened using alkynoate
1a and allylboronate 2a, as outlined in Table 1. In a similar
3
4
1d
1e
3
3
3
3
3da 88
3ea 99
Table 1. Optimization of reaction conditions.
5
6
1 f
1g
3
3
3
3
3 fa 92
3ga 99 (96)[b]
7
1h
56
6
3ha 89
Cu salt
[mol%]
2a
[equiv]
t
Yield
3aa [%]
29[a]
trace
G
N
[h]
8
9
1i
1j
3
24
3
3ia trace[c]
3ja 94
1
2
3
4
5
6
CuCl (5)
CuBr (5)
CuI (5)
2
2
2
2
24
24
24
1
33
no reaction
Cu
Cu
Cu
Cu
N
91[b]
2
1
3
4
93[b]
10
1k
1l
82
3
2
3
3ka quant
1.5
1.2
1.5
92[b]
7
84[a]
8[c]
none
24
no reaction
11
3la 84
1
[a] Crude yields determined by H NMR spectroscopy. [b] Isolated yields.
[c] Reflux.
[a] Conditions:
1
(0.5 mmol or 0.3 mmol for entries
7
and 8), 2a
(1.5 equiv), MeOH solvent, 258C. [b] Yields of 10 mmol-scale reaction.
[c] 1,2-adduct 4ia was obtained in 61% yield.
manner to our previous copper-catalyzed hydroarylation, 1a
and 2a were treated with a copper salt in MeOH at 258C.
Among the copper(I) halides examined, only CuCl exhibit-
ed catalytic activity (entries 1–3). The crude yield of 3aa
was, however, as low as 30% with a 5 mol% catalyst loading
after 24 h, as determined by H NMR spectroscopy. In con-
trast, the reaction reached completion within 1 h when Cu-
ACHTUNGTRENNUNG
tably, all these examples gave high isolated yields ranging
from 88 to 99% and excellent stereoselectivity, exclusively
producing syn adducts. The reaction of 1g was also per-
formed on a 10 mmol (ca. 1.7 g) scale without erosion of the
yield and selectivity. On the other hand, a bulky TBS-substi-
tuted propiolate failed to undergo conjugate allylation
(Figure 1).
1
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
cessfully reduced to 3 mol% and 1.5 equivalents, respective-
ly (entry 6). A further reduced loading of 2a diminished the
yield of 3aa (entry 7). The copper catalyst is essential as no
reaction occurred even in refluxing MeOH in the absence of
the catalyst (entry 8). On the basis of these results, further
Figure 1. Inefficient alkynes and by-product.
explorations were carried out using Cu
mal copper source.
(OAc)2 as the opti-
The influence of activating groups was next examined.
One limitation of the present method is its failure to obtain
conjugate allylation product 3ia from alkynyl ketone 1i
(Table 2, entry 8). In this case, 1,2-allylation product 4ia was
formed as the major product in 61% yield (Figure 1).[11] In
contrast, cyanoalkyne 1j and propiolylamide 1k underwent
conjugate allylation to deliver 3ja and 3ka, respectively, in
excellent yields (Table 2, entries 9 and 10). In the latter case,
a catalyst loading of 8 mol% was necessary to ensure the
complete conversion of 1k, because the amide group has in-
The substrate scope was investigated by performing allyla-
tions with various alkynes under optimized conditions
(Table 2). Chloroalkyl, non-protected hydroxy, N-allyl tosyl-
amide, and cyclopropyl groups were well tolerated (en-
tries 1–4), and only a 1,4-addition was observed for the con-
jugated enyne substrate 1 f (entry 5). Aromatic and hetero-
aromatic alkynes 1g and 1h participated in the present con-
jugate allylation without any difficulty (entries 6 and 7). No-
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Chem. Eur. J. 2012, 18, 3153 – 3156

Hydroallylation
COMMUNICATION
ferior electron-withdrawing ability, rendering the reaction
sluggish. Hydroallylation of alkynyl sulfone 1l proceeded
with a 3 mol% catalyst loading for 3 h to exclusively deliver
syn adduct 3la in 84% yield (entry 10). The syn selectivity
of the present hydroallylation was supported by X-ray crys-
tallographic analysis of 3la (Supporting Information).
The effective electron-withdrawing group is imperative
because diphenylacetylene and 2-(phenylethynyl)pyridine
proved completely ineffective toward the present protocol
(Figure 1). This is in contrast to the observation that the
rhodium-catalyzed hydroarylation proceeded regio- and ste-
reoselectively with 2-alkynylpyridines in water at 808C.[12]
With an efficient hydroallylation method having been es-
tablished with allylboronate 2a, the scope of other allylboro-
nate reagents was briefly examined (Scheme 2). The reac-
tion of 1g with methallylboronate 2b (2.0 equiv) was carried
Scheme 3. Derivatization of conjugate allylation product 3ga by hydro-
boration.
1) It is desirable that the metathesis reaction occurs at the
terminal alkene moiety rather than at the electron-defi-
cient tri-substituted alkene moiety.
2) Skipped dienes might undergo isomerization, giving rise
to conjugated 1,3-dienes under metathesis conditions.[15]
In fact, CM of 3ga with methyl acrylate was carried out in
refluxing CH2Cl2 for 24 h using the Hoveyda–Grubbs cata-
lyst[16] to deliver the expected product with several insepara-
ble minor by-products, which were presumably formed by
alkene isomerization. The same reaction was performed
with sulfone 3la; in this reaction, the complete isomeriza-
tion of the tri-substituted alkene moiety occurred to afford
conjugated diene 8 as a mixture of E and Z isomers
(Scheme 4). This result shows that the selective functionali-
Scheme 2. Reactions of 1g with substituted allylboronates 2b–d.
out using 5 mol% CuACHTNUGTRNEUNG(OAc)2 in MeOH at 258C. In contrast
to the case of parent 2a, this reaction proceeded sluggishly
and 1g was not completely consumed within 24 h. To in-
crease the reaction rate, a 10 mol% loading of CuACTHNUTRGNEUNG(OAc)2
1
was used. Nevertheless, the H NMR analysis of the crude
products revealed that small amounts of 1g remained intact,
although 2b completely disappeared. Thus, the loading of
2b was increased to 2.4 equivalents to observe the full con-
version of 1g. Ultimately, the desired 3gb was isolated in
a high yield of 96%. Similarly, the use of 2-phenylallylboro-
nate 2c yielded 3gc (94% yield) with a shorter reaction
time. In contrast, further erosion of reactivity was observed
for crotylboronate 2d; the reaction was very sluggish under
the same conditions and an inseparable mixture of several
products was formed in a poor yield.
Although the installation of g-substituted allyl groups is
problematic at this stage, the parent allyl moiety can be
easily functionalized in various ways. To demonstrate the
synthetic utility of the developed method, we performed the
derivatization of the conjugate allylation products. After hy-
Scheme 4. Derivatization of conjugate allylation products through meta-
thesis.
droboration with 9-borabicyclo
[3.3.1]nonane (9-BBN), sub-
zation of the introduced allyl group is possible using olefin
metathesis. Olefin ring-closing metathesis (RCM) has been
used for the construction of heterocyclic compounds.[17] In
our study, RCM of 3da proceeded effectively in a similar
manner to obtain seven-membered nitrogen heterocycle 9 in
87% yield without isomerization of the exo-cyclic alkene
(Scheme 4).
In summary, we successfully developed a copper-catalyzed
conjugate allylation of electron-deficient alkynes with com-
mercially available allylboronic acid pinacol esters and cop-
per(II) acetate. This method can be applied to a variety of
sequent oxidation with NaBO3 or Suzuki–Miyaura coupling
with p-acetylphenyl bromide transformed 3ga into alcohol 5
and arylation product 6 in 85 and 77% yields, respectively
(Scheme 3).[13]
Olefin cross metathesis (CM) is also a powerful method
for homologating terminal alkenes.[14] However, CM of skip-
ped dienes such as 3ga poses some selectivity issues.
Chem. Eur. J. 2012, 18, 3153 – 3156
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3155

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regio- and stereoselectivity. On the other hand, an alkynyl
ketone underwent 1,2-addition to deliver a propargylic alco-
hol. It was demonstrated that the obtained products can be
transformed into synthetically useful compounds using hy-
droboration or olefin metathesis of the introduced allyl
moiety. Further studies of a superior catalytic system as well
as synthetic applications of the present protocol are actively
underway in our laboratory.
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Experimental Section
Representative procedure—synthesis of 3aa: A solution of CuACTHNUTRGNEUNG(OAc)2
(2.83 mg, 0.015 mmol), alkynoate 1a (83 mL, 0.50 mmol) and allylboro-
nate 2a (142 mL, 0.75 mmol) in MeOH (1 mL) was degassed at À788C
and then was stirred at 258C under Ar atmosphere for 3 h. The reaction
mixture was diluted with Et2O (3 mL) and was filtered through a plug of
alumina. The residue was washed with Et2O (20 mL), and the filtrate was
concentrated in vacuo. The residue was purified by silica gel flash
column chromatography (hexane-AcOEt 100:1) to give dienoate 3aa
(90.6 mg, 92%) as colorless oil: 1H NMR (300 MHz, CDCl3): d=0.90 (t,
J=7.2 Hz, 3H), 1.26–1.52 (m, 6H), 2.61 (t, J=7.8 Hz, 2H), 2.89 (dq, J=
6.6, 1.4 Hz, 2H), 3.69 (s, 3H), 5.07–5.15 (m, 2H), 5.65 (s, 1H), 5.77 ppm
(ddt, J=16.8, 10.5, 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=14.1,
22.6, 28.2, 32.0, 32.1, 42.5, 50.7, 115.4, 117.5, 134.1, 162.4, 166.3 ppm; IR
(CHCl3): n˜ =1712 cmÀ1 (C=O); HRMS (FAB): m/z calcd for C12H20O2·H:
197.1542; found: 197.1549 [M+H]+.
[10] H. Ohmiya, M. Yoshida, M. Sawamura, Org. Lett. 2011, 13, 482–
485.
[11] For examples of Cu-catalyzed allylation of ketones and imines with
allylboronates, see: a) R. Wada, K. Oisaki, M. Kanai, M. Shibasaki,
J. Am. Chem. Soc. 2004, 126, 8910–8911; b) R. Wada, T. Shibuguchi,
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[12] M. Lautens, M. Yoshida, Org. Lett. 2002, 4, 123–125.
[13] For reviews of B-alkyl Suzuki–Miyaura coupling, see: a) H. Doucet,
Eur. J. Org. Chem. 2008, 2013–2030; b) S. R. Chemler, D. Trauner,
S. J. Danishefsky, Angew. Chem. 2001, 113, 4676–4701; Angew.
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Acknowledgements
This research was partially supported by the MEXT, Grant-in-Aid for
Scientific Research (B) (20350045). We thank Dr. K. Oyama (NU) for
mass measurements, and Mr. N. Kirai (TIT) for preliminary experiments.
Keywords: alkynes
· copper · dienes · homogeneous
catalysis · hydroallylation · organoboron
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Received: November 24, 2011
Published online: February 16, 2012
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Chem. Eur. J. 2012, 18, 3153 – 3156