Nickel-catalyzed chemo- and stereoselective alkenylative cyclization of 1,6-enynes with alkenyl boronic acids

Article abstract of DOI:10.1002/chem.201302180

Discover nickel! A nickel-catalyzed alkenylative cyclization of 1,6-enynes and alkenyl boronic acids affording substituted pyrrolidines and dihydrofurans is described (see scheme; cod=1,5-cyclooctadiene, Ts = p-toluene sulfonate). The reaction is highly chemo- and stereoselective. A possible reaction mechanism involving a nickelacyclopentene intermediate is proposed. Copyright

Full text of DOI:10.1002/chem.201302180

DOI: 10.1002/chem.201302180
Nickel-Catalyzed Chemo- and Stereoselective Alkenylative Cyclization of
1,6-Enynes with Alkenyl Boronic Acids
Chun-Ming Yang, Subramaniyan Mannathan, and Chien-Hong Cheng*[a]
12212
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Chem. Eur. J. 2013, 19, 12212 – 12216

COMMUNICATION
Transition-metal-catalyzed cyclization of 1,6-enynes is a
powerful method for constructing carbo- and heterocyclic
molecules.[1,2] Among such reactions, the cyclization of 1,6-
enynes with the main-group organometallics or metal hy-
drides is particularly attractive because they offer new ap-
proaches for the highly stereoselective formation of ring sys-
tems with exocyclic tri- or tetrasubstituted C=C bonds.[3–8]
Important examples include rhodium- and palladium-cata-
lyzed cyclization reactions of 1,6-enynes with organoboronic
acids,[3,5,6] and nickel-catalyzed cyclization reactions of acti-
vated 1,6-enynes with organozinc, -aluminum, -boron,
-silane, and -zirconium (Scheme 1a).[4,10b] In these cycliza-
tion has not yet been studied.[3e,g] Moreover, the use of less
expensive metal catalysts in such enyne cyclization reactions
has not been extensively investigated and remains in
demand.
Organoborons are one of the versatile organometallics
that have been widely used in transition-metal-catalyzed C–
C (multiple) bond-formation reactions due to their multifar-
ious advantages, comprising safe handling, availability, and
stability to air and moisture.[9] Recently, we investigated
nickel-catalyzed intermolecular three-component coupling
reactions involving organoboronic acids, alkynes (or ben-
zynes), and alkenes,[10a–c] and a borylative coupling of al-
kynes with enones to synthesize alkenylboronates.[10d] As
part of our continuing efforts to extend the metal-catalyzed
enyne coupling[11] and multicomponent reactions,[10] we ob-
served a new nickel-catalyzed chemoselective tandem cycli-
zation of electronically unactivated 1,6-enynes with alkenyl
boronic acids in which the organic group of the boronic acid
added selectively to the ene carbon atom of 1,6-enyne in-
stead of the well-known alkyne carbon atom as shown in
Scheme 1c. This reaction offers a new approach to substitut-
ed pyrrolidines and dihydrofurans, which are found in a va-
riety of natural products and biologically active mole-
cules.[12]
An example of optimized reaction conditions for the
nickel-catalyzed cyclization–addition reaction (Table 1,
entry 7) includes 1,6-enyne 1a (0.40 mmol) and trans-2-phe-
Table 1. Optimization studies.[a]
Scheme 1. Metal-catalyzed tandem cyclization of 1,6-enynes with organo-
metallics and bimetals. Bpin=B-pinacol.
Entry
Ligand (mol%)
PPh3 (10)
CsF [equiv]
Yield [%][b]
tion–coupling reactions, a highly chemoselective addition of
an organometallic reagent to an alkyne moiety was ob-
served. In contrast, Kibayashi and co-workers reported a
PdII-catalyzed alkenylative cyclization of 1,6-enyne with vi-
nyltributyltin in which the vinyl group from the tin reagent
added selectively to the alkene moiety instead of the alkynyl
group in a rare chemoselective manner (Scheme 1b).[7a] Re-
cently, similar chemoselective cyclization reactions involving
1,6-enynes with metal hydrides[7b] or bimetallic reagents[8] in
the presence of palladium catalyst were also demonstrated
(Scheme 1b). Despite these developments, the cyclization–
coupling of 1,6-enyne by using organoboronic acid as the
coupling reagent in the rare chemoselective addition reac-
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
–
trace
–
P
P
P
ACHTUNGTRENNUNG
A
88
30
44
55
93
52
AHCTUNGTRENNUNG
PMe3 (10)
PPh2Me (10)
P
P
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
[a] Unless otherwise mentioned, all reactions were carried out using
enyne 1a (0.40 mmol) and trans-2-phenylvinylboronic acid (2a)
(0.80 mmol) in the presence of [NiACHTNUGTRENUNG(cod)2] (10 mol%), ligand (10–
15 mol%), and CsF (0.80 mmol) in MeOH (2.00 mL) at 808C for 18 h.
[b] Yields were measured from the crude mixture by the 1H NMR spec-
troscopic integration method by using mesitylene as an internal standard.
nylvinylboronic acid (2a, 0.60 mmol) in the presence of [Ni-
AHCTUNGTRENNUNG
[a] Dr. C.-M. Yang, Dr. S. Mannathan, Prof. Dr. C.-H. Cheng
Department of Chemistry
AHCTUNGTRENNUNG
National Tsing Hua University
Hsinchu, 30013 (Taiwan)
for 18 h. The reaction gave the cyclized product 3aa in 88%
isolated yield (Table 2, entry 1). The reaction is highly
chemo- and stereoselective; the alkenyl group from the or-
ganoboronic acid adds exclusively to the alkene moiety of
1a and the exocyclic double bond of product 3aa is in a Z
Fax : (+886)3572-4698
E-mail: chcheng@mx.nthu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302180.
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www.chemeurj.org
12213

C.-H. Cheng et al.
Table 2. Nickel-catalyzed alkenylative cyclization of enynes 1a–o with E-
styrylboronic acid 2a.[a]
method (entry 7). The reaction also proceeded in the ab-
sence of CsF but afforded 3aa only in 52% yield (entry 8).
Under similar catalytic reaction conditions for 3aa, we ex-
amined the cyclization–coupling reaction of various N-teth-
ered enynes 1a–y with 2a (Tables 2 and 3). Generally, 1,6-
enynes bearing an aryl substituent at the alkyne terminus
were compatible for the present cyclization reaction. How-
ever, the nature of the substituent on the aromatic ring af-
fects the yield of product 3. For example, substrates 1b–d
with a methyl substituent on the phenyl ring at ortho, meta,
and para positions, respectively, gave the corresponding cy-
clized products 3ba–da in good yields (entries 2–4), whereas
1e–g containing a methoxy group at a different position fur-
nished 3ea–ga in 60–65% yield (entries 5–7). Similarly, 1h
with an acetyl group at the para position also gave 3ha in
68% yield (entry 8). Substrates 1i–j with electron-withdraw-
ing substituents 4-CN and 4-CF3 afforded products 3ia and
3ja in high yields (entries 9 and 10). 1-Naphthyl (1k) and 2-
thienyl (1l)-substituted enynes also participated to furnish
the corresponding products in 90 and 50% yields, respec-
tively (entries 11 and 12). Notably, enyne 1m containing a
terminal alkyne also underwent tandem cyclization at 408C
to give 3ma in moderate yield (entry 13). Substrates con-
taining an alkyl substituent at the alkyne terminus also pro-
ceeded smoothly. Thus, 1n and 1o reacted with boronic acid
2a to afford pyrrolidine derivatives 3na and 3oa in good
yields (entries 14 and 15).
Entry
1
3
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
3aa: R=H
88 (93)
80
75
81
60
65
63
68
94
3ba: R=2-Me
3ca: R=3-Me
3da: R=4-Me
3ea: R=2-MeO
3 fa: R=3-MeO
3ga: R=4-MeO
3ha: R=4-CH3CO
3ia: R=4-CN
3ja: R=4-CF3
9
10
1j
85
11
1k
3ka
90
50
12
1l
3la
13
14
15
1m
1n
1o
3ma: R=H
3na: R=Me
3oa: R=nBu
44[c]
83
77
In addition to 1,6-enynes, N-tethered 1,7-enynes 1p and
1q also participated effectively to deliver the products 3pa
and 3qa in 69 and 59% yields, respectively (Table 3, en-
tries 1 and 2). Similarly, enynes containing 1,1- (1r) and 1,2-
disubstituted alkenes (1s) furnished the relative products in
good yields (entries 3 and 4). It is important to mention that
enynes bearing an alkyl group at the alkene terminus led to
the formation of Alder-ene[1] product 4 instead of 3. For in-
stance, 1t afforded diene 4ta in 50% yield, whereas 1u gave
3ua and 4ua in 59 and 32% yields, respectively (Scheme 2).
To explore the scope of the reaction, a variety of tethered
enynes 1v–y were evaluated (Table 3, entries 5–8). Thus, N-
tethered enynes containing a N-benzyl substituent 1v gave
3va in 83% yield (entry 5), whereas O-tethered enynes 1w
furnished the respective product in only 67% yield
(entry 6). Malonate-tethered enynes, 1x and 1y also under-
[a] Unless otherwise mentioned, all reactions were carried out by using
enynes (0.40 mmol) and trans-2-phenylvinylboronic acid (2a)
(0.80 mmol) in the presence of [Ni(cod)2] (10 mol%), (tBu)3
1
G
PACHTUNGTRENNUNG
(15 mol%), and CsF (0.80 mmol) in MeOH (2.00 mL) at 808C for 18 h.
1
[b] Isolated yields; the yield in parentheses were determined by H NMR
spectroscopic methods by using mesitylene as an internal standard.
[c] The reaction was carried out at 408C.
configuration, as supported by the results of single-crystal
X-ray analysis of compound 3ad (see the Supporting Infor-
mation).[14]
The present nickel-catalyzed tandem reaction was initiat-
ed by treating N-tether 1,6-enyne 1a with trans-2-phenylvi-
nylboronic acid (2a) in the presence of a [NiACTHUNGTRNEUNG(cod)2/PPh3]
system.[10b] Unfortunately, the tandem cyclized product 3aa
was obtained only in a trace amount (Table 1, entry 1). To
improve the product yield of 3aa, we examined the reaction
of 1a and 2a in the presence of various phosphine ligands
(10 mol%; see Table 1). After extensive screening, we found
that P
ACHTUNGTRENNUNG
yield (entry 3), whereas PAHCTNUGTRENNNUG
the cyclization–coupling product 3aa only in 30–55% yields
(entries 4–6). The presence of CsF and MeOH are also es-
sential for promoting the transmetalation of boronic acid,
and offering a protic and soluble system. Finally, upon
tuning the amount of PACTHNUTRGNE(NUG tBu)3 to 15 mol%, the catalyst
system gave 3aa in 93% yield, which was measured from
1
the crude product by the H NMR spectroscopic integration
Scheme 2. Cyclization of 1t and 1u with 2a.
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Alkenylative Cyclization of 1,6-Enynes
COMMUNICATION
Table 3. Nickel-catalyzed alkenylative cyclization of enynes 1p–y with
2a.[a]
Table 4. Scope of functionalized alkenyl boronic acids.[a]
Entry
1
1
3
Yield [%][b]
75
Entry
1
3
Yield
[%][b]
2b
3ab
1
2
1p
1q
3pa
3qa
69
59
2
2c
3ac
70
3
4
5
2d
2e
2 f
3ad: R=nPr
3ae: R=Cy[c]
3af: R=Bn[c]
71
70
77
3
4
1r
1s
3ra
3sa
83
77
6
7
8
9
2g
2h
2i
2j
2k
3ag: R=4-Ph
3ah: R=4-Me
3ai: R=4-OMe
3aj: R=4-Cl
88
82
85
72
68
10
3ak: R=4-CF3
5[c]
1v
1w
1x
1y
3va
3wa
3xa
3ya
83
67
81
90
11
12
2l
3al
0
0
6
2m
3am
[a] Unless otherwise mentioned, all the reactions were carried out by
using 1a (0.40 mmol) and alkenyl boronic acid 2 (0.80 mmol) in the pres-
ence of [NiACHTNUTRGENN(UG cod)2] (10 mol%), PHCATUNGTRENN(UGN tBu)3 (15 mol%), and CsF (0.80 mmol)
in MeOH (2.0 mL) at 808C for 18 h. [b] Isolated yields. [c] Cy=cyclohex-
yl, Bn=benzyl.
7
8
substituted alkenyl- 2l and alkylboronic acid 2m with 1a did
not give any cyclization–coupling product 3 (entries 11 and
12). It is important to mention that the reaction of arylbor-
onic acids with 1,6-enynes under the standard reaction con-
ditions afforded only a trace amount of tandem cyclized
product.
To understand the role of methanol and to elucidate the
mechanism of the present catalytic reaction, an isotope-
labeling experiment by using CD3OD for the tandem cycli-
zation of enyne 1a and 2a was studied (Scheme 3). The re-
action afforded the deuterated product [D1]3aa in 70%
yield with 87% deuterium incorporation at the exocyclic
alkene position in a Z configuration. This result supported
the hypothesis that the reaction proceeds via a nickelacyclo-
pentene intermediate 5 (Scheme 4) and methanol acts as the
proton source.
Based on the observation in Scheme 3, and from the re-
ported enyne coupling reactions,[1,4] a possible catalytic reac-
tion mechanism for the present reaction using 1a and 2a as
the substrates is shown in Scheme 4. First, enyne 1a is
bonded to Ni0 via the alkene and alkyne groups to form in-
termediate 4. Then oxidative cyclometallation of 4 yields
nickelacyclopentene intermediate 5.[4,13,10a–c] Selective proto-
[a] Similar reaction conditions as in Table 2. [b] Isolated yields. [c] Bn=
benzyl.
went tandem cyclization to provide the substituted pyrroli-
dines 3xa and 3ya in good to excellent yields (entries 7 and
8).
The reactivity of various alkenyl boronic acids 2b–k in
the present catalytic reaction was also examined (Table 4).
In all cases, the retention of stereochemistry of the alkenyl
group from 2 in the products was observed. Thus, alkyl-
(2b–e) and benzyl (2 f)-substituted alkenyl boronic acids ef-
ficiently coupled with 1a to give the respective products
3ab–af in 70–77% yields (entries 1–5). Substituted (E)-styr-
ylboronic acids also participated well in the tandem cycliza-
tion reaction (entries 6–10). Thus, biphenyl (2g) and elec-
tron-donating-substituted alkenyl boronic acids 2h and 2i
gave 3ag–ai in good to excellent yields (entries 6–8). Simi-
larly, p-chlorostyrylboronic acid (2j) is compatible with the
reaction conditions to furnish 3aj in 72% yield (entry 9).
Electron-withdrawing 4-CF3-substituted alkenyl boronic acid
2k also reacted smoothly with 1a to provide 3ak albeit in
slightly lower yield (entry 10). Notably, the reaction of a-
Chem. Eur. J. 2013, 19, 12212 – 12216
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C.-H. Cheng et al.
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Scheme 4. Proposed mechanism for the nickel-catalyzed alkenylative cyc-
lization reaction.
nation of 5 by MeOH affords an alkylACHTUNTRGNEUNG(methoxy)nickel inter-
mediate 6.[8,10c] Transmetallation of 6 with alkenyl boronic
acid 2a gives nickel–alkenyl intermediate 7. Reductive elim-
ination affords the final product 3aa and regenerates the Ni0
species for the following catalytic cycles.
In summary, we have demonstrated a new nickel-cata-
lyzed tandem cyclization–coupling of electronically unacti-
vated 1,6-enynes with alkenyl boronic acids to provide vari-
ous substituted pyrrolidines and dihydrofurans. The reaction
is highly chemo- and stereoselective. A variety of alkenyl
boronic acids have been successfully employed in the reac-
tion. The chemoselective protonation of the nickelacyclo-
pentene intermediate leads unusually to the addition of the
alkenyl group of boronic acid at the alkene terminus of 1,6-
enyne in the final product. Further studies to expand the
scope of the tandem cyclization are currently underway.
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Acknowledgements
We thank the National Science Council of the Republic of China (NSC-
101-2628M-007-004) for support of this research.
Keywords: cyclization
·
enynes
·
nickel
·
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Received: June 7, 2013
Published online: August 21, 2013
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Chem. Eur. J. 2013, 19, 12212 – 12216