Investigation of alkyne regioselectivity in the Ni-catalyzed benzannulation of cyclobutenones

Article abstract of DOI:10.1002/chem.201405863

A Ni-catalyzed benzannulation reaction of cyclobutenones and alkynes provides a rapid synthesis of heavily substituted phenols. The regioselectivity of this reaction can be modulated by variation of substituents on the alkyne. Though the incorporation of

Full text of DOI:10.1002/chem.201405863

DOI: 10.1002/chem.201405863
Full Paper
&
Cycloaddition
Investigation of Alkyne Regioselectivity in the Ni-Catalyzed
Benzannulation of Cyclobutenones
Timo Stalling, Wesley R. R. Harker, Anne-Laure Auvinet, Erik J. Cornel, and Joseph
[a]
P. A. Harrity*
Abstract: A Ni-catalyzed benzannulation reaction of cyclobu-
tenones and alkynes provides a rapid synthesis of heavily
substituted phenols. The regioselectivity of this reaction can
be modulated by variation of substituents on the alkyne.
Though the incorporation of Lewis basic donors provides
modest selectivities, the use of aryl substituents can provide
high levels of regiocontrol. Finally, alkynylboronates derived
from alkyl-substituted acetylenes provide both high yields
and regioselectivities. This study suggests that alkynes bear-
2
3
ing one sp - and one sp -based substituent can undergo
benzannulation with high levels of regiocontrol whereby the
3
sp -based group is incorporated ortho-to the phenolic OH.
Introduction
Transition-metal-catalyzed annulation reactions offer an effec-
tive strategy for the synthesis of aromatic and heteroaromatic
[
1]
compounds. This approach complements the stepwise intro-
duction of substituents by electrophilic aromatic substitution
and directed ortho-metalation reactions, and represents
a more convergent way of generating polysubstituted prod-
ucts. Among the many examples of metal-catalyzed annula-
tions, the transition-metal-catalyzed activation of four-mem-
bered ring compounds is an interesting subset that has attract-
ed significant attention. Specifically, cyclobutanones, 3-oxeta-
nones and 3-azetidonones are efficiently transformed into the
corresponding carbo- and heterocycles when reacted with al-
Scheme 1. Liebeskind’s investigations in the Ni-catalyzed benzannulation of
cyclobutenones.
[
4]
Scheme 1 outlines some general trends relating to alkyne re-
gioselectivity in the Ni-catalyzed benzannulation of cyclobute-
[4]
nones developed by the Liebeskind group. The reaction ap-
pears to be relatively insensitive to the steric volume of alkyl
substituents but the inclusion of a homopropargylic ether can
lead to enhanced regiocontrol. Liebeskind suggested that this
selectivity could be rationalized by invoking a Lewis acid-base
[
2]
kynes. In addition, Rh-catalysis has been shown to offer
routes to a range of carbocycles from both inter- and intramo-
[
3]
lecular cyclization reactions of alkenes.
With respect to the synthesis of aromatic products, Liebe-
skind reported that the Ni-catalyzed reaction of cyclobute-
nones and alkynes generated densely substituted phenols via
II
interaction between the ether moiety and Ni center during
the cyclometalation step.
[
4,5]
an intermediate vinylketene complex.
The reaction was
found to proceed at room temperature but unsymmetrical al-
kynes were found to be incorporated with only modest levels
of regiocontrol. In an effort to explore the potential of this re-
action to generate products with higher regioselectivities, we
decided to undertake a study of the scope of the reaction with
a particular focus on the nature of the alkyne, and we report
our findings herein.
Results and Discussion
As the reactivity of arylacetylenes had not been disclosed in
the original report, we began our studies by investigating ben-
zannulation reactions of alkynes bearing a combination of
phenyl and alkyl groups, with examples of the latter bearing
Lewis basic heteroatoms (Table 1). The reactions were conduct-
ed in the presence of a Ni catalyst (30 mol%) in each case to
minimize the effect of catalyst quality on reaction conversion.
Under these conditions, we found that the reaction of 1-phe-
nylhex-1-yne 3 proceeded in low conversion, affording the cor-
responding products in low yield but with high levels of regio-
selectivity. Analysis of these products confirmed that the major
regioisomer had incorporated the nBu group in the ortho-posi-
tion (entries 1 and 2). We were able to enhance selectivity fur-
[a] Dr. T. Stalling, Dr. W. R. R. Harker, Dr. A.-L. Auvinet, E. J. Cornel,
Prof. J. P. A. Harrity
Department of Chemistry
University of Sheffield
Brook Hill, Sheffield, S3 7HF (UK)
E-mail: j.harrity@sheffield.ac.uk
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405863.
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Table 1. Preliminary investigations.
Table 2. Benzannulation optimization.
[
a]
1
2
3
[a]
Entry
R
R
R
Yield [%]
Entry
Solvent
Promoter
Yield [%]
(a:b)
[
b,c]
[b,c]
(
a:b)
1
2
3
4
5
6
7
nBu; 1
Ph; 2
nBu; 1
nBu; 1
Ph; 2
nBu
nBu
Ph; 3
Ph; 3
Ph;4
nBu; 5
nBu; 5
nBu; 6
nBu; 6
33 (93:7); 7
38 (94:6); 8
1
2
3
4
THF
Toluene
THF
–
–
29 (85:15)
30 (93:7)
35 (89:11)
45 (95:5)
(CH
(CH
(CH
Bn
2
)
)
)
2
OMe
2
OMe
2
OMe
30 (>98:2); 9
42 (60:40); 10
61 (52:48); 11
Norbornadiene (0.5 equiv)
Norbornadiene (0.5 equiv)
2
2
Toluene
[
d]
[a] The reaction was performed with cyclobutenone 1,
0.40 mmol) and alkyne (1.1 equiv, 0.44 mmol) in the presence of Ni(COD)
10%, 0.04 mmol) under an argon atmosphere. [b] Isolated yield after
2 (1 equiv,
nBu; 1
Ph; 2
60 (65:35); 12
[
e]
2
Bn
52 (64:36); 13
(
[
0
a] The reaction was performed with cyclobutenone 1,
.40 mmol) and alkyne (1.1 equiv, 0.44 mmol) in the presence of Ni(COD)
2
(1 equiv,
column chromatography. [c] The ratio of isomers was determined by
H NMR spectroscopy of crude material.
1
2
(30%, 0.12 mmol) under an argon atmosphere. [b] Isolated yield after
column chromatography. [c] The ratio of isomers was determined by
1
H NMR spectroscopy of crude material. [d] The ratio was determined by
LC-MS. [e] The ratio was determined by GC-MS.
ther by the incorporation of a homopropargylic methyl ether,
but again the product yield was disappointingly low (entry 3).
In order to explore the chelation effect proposed by Liebe-
skind, we prepared the pseudo-symmetrical alkyne 4 and
found that this provided the phenol in higher yield, but with
only a marginal preference for incorporation of the propargyl
ether at C-2 (entries 4 and 5). Finally, the effect of adding
a methylene spacer group between the alkyne and Ph-group
on reaction efficiency and selectivity was explored. It was
found that the products were generated in relatively good
yield but with modest selectivity (entries 6 and 7).
These preliminary studies highlighted a significant problem
with low reaction conversions, even at high catalyst loading.
Attempts to enhance catalyst lifetime by addition of phos-
phine ligands resulted in further diminished reaction conver-
sion; however, the inclusion of norbornadiene had the effect
of promoting benzannulation. Indeed, improved yields could
be obtained in the case of 1-phenylhex-1-yne 3 when the reac-
tion was conducted in toluene in the presence of this ligand
and Ni catalyst (10 mol%; see Table 2).
Scheme 2. Ni-catalyzed benzannulation using unsymmetrical alkynes. The re-
action was performed with cyclobutenone 1, 2 (1 equiv, 0.40 mmol) and
alkyne (1.1 equiv, 0.44 mmol) in the presence of Ni(COD) (10%, 0.04 mmol)
2
We next set out to employ these optimized conditions in re-
actions involving a selection of unsymmetrical alkynes. Our re-
sults are shown in Scheme 2. It was found that the correspond-
ing products were generated in comparable or better yields to
those obtained at higher catalyst loading in the absence of
promoter. However, the addition of norbornadiene did not
serve to affect the regioselectivity of the reaction and broadly
similar regiochemical outcomes were observed.
and norbornadiene (0.5 equiv, 0.20 mmol) under an argon atmosphere.
on Murakami’s Ni-catalyzed alkyne insertion into cyclobutano-
[2a]
nes, and Kurosawa’s work on the mechanism of Ni-catalyzed
addition of carbonyl compounds to alkenes and alkynes. In
this case, a cyclopentannulation provides spirocycle II that pro-
[7]
With regard to the mechanism of the benzannulation, Liebe-
skind proposed that the Ni-catalyst first inserts into the cyclo-
butenone to provide a metal ketene complex I, before under-
gresses to product via IV (Scheme 3). In this context, and
during our initial investigations into the reaction of 1 and 3,
we observed a small amount of byproduct 17, which was iso-
lated as a mixture of alkene isomers, making clear characteriza-
tion of this compound rather challenging. However, saponifica-
tion of the crude material from the benzannulation reaction
successfully hydrolyzed these esters and provided a slightly en-
[4]
going a cyclization and reductive elimination sequence. A re-
lated mechanism has recently been suggested by Lin in the cy-
[
6]
cloaddition of alkynes and 3-azetidinones. However, an alter-
native proposal that can conceivably be put forward is based
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Scheme 4. Ni-catalyzed benzannulation using alkynylboronates. The reaction
was performed with cyclobutenone 1, 2 (1 equiv, 0.40 mmol) and alkyne
(
2 equiv, 0.80 mmol) in the presence of Ni(COD)
argon atmosphere. [a] Reaction conducted in the presence of Ni(COD)
20 mol%). [b] Alkyne (1.1 equiv) was used. Pin=pinacol.
2
(10%, 0.04 mmol) under an
2
(
Scheme 3. Mechanism of the benzannulation reaction.
nylboronates bearing alkyl substituents are very selective. The
inclusion of ether substituents only appears to have a marginal
effect on selectivity but does not offer a means for controlling
the predominant regiochemical pathway. Studies towards for-
mulating an explanation for these intriguing regiochemical in-
sertion patterns are underway and will be reported in due
course.
hanced yield of phenols 7a,b (cf. Scheme 2). Moreover, sub-
jecting phenol to benzannulation in the presence of 2 allowed
18 to be isolated cleanly, albeit in modest yield. Taken togeth-
er, these results are consistent with the formation of ketene in-
termediates, suggesting that the Liebeskind mechanism pro-
vides the more accurate description of the reaction pathway.
Recent studies in our labs have exploited alkynylboronates
as substrates for the rapid construction of highly functionalized
Although the present study has been restricted to the em-
ployment of 3-substituted cyclobutenones, cycloadditions of
3,4-disubstituted cyclobutenones with unsymmetrical dialkyl-
[4]
[10]
acetylenes, and alkynylboronates, have been reported and
follow the same regiochemical trends as in the 3-substituted
systems. In contrast, our studies on the cycloaddition of 2,3-
disubstituted cyclobutenones suggest these substrates are
[
8,9]
aromatic boronic acid derivatives.
These alkynes often pro-
vide much higher levels of regiocontrol in cycloadditions as
compared to similar reactions of unsymmetrical hydrocarbon-
substituted alkynes. Accordingly, we decided to undertake
a study of Ni-catalyzed benzannulations of alkynylboronates
and cyclobutenones and our results are presented in
[11]
inert to Ni-catalyzed benzannulation.
Finally, as well as representing a regiochemical controlling
unit, the boronate offers the opportunity for late-stage incor-
poration of aryl groups. This appears to be particularly impor-
tant in the Ni-catalyzed benzannulation as arylacetylenes are
generally less reactive than their alkyl-counterparts. In order to
verify the potential of these substrates for the incorporation of
aryl groups, we carried out a Pd-catalyzed cross-coupling of
borylated phenol 20 with bromobenzene and obtained phenol
8 in high yield (Scheme 5).
[
10]
Scheme 4. As shown, the alkynylboronate derived from 1-
hexyne underwent a highly regioselective cycloaddition to pro-
vide the corresponding products in excellent yield. In contrast,
the boronic esters derived from phenylacetylene were much
less selective and favored formation of the other regioisomer.
We next turned our attention to the reaction of alkynylboro-
nates bearing Lewis basic substituents. These reactions were
found to undergo efficient benzannulation to provide a single
regioisomer with the boronate at C-3.
Conclusion
Overall, these studies suggested that the regioselectivity of
the Ni-catalyzed benzannulation of the cyclobutenones pro-
ceeds in favor of incorporating alkyl groups ortho to the newly
formed phenol, whereas aryl groups are incorporated at C-3. A
BPin-substituent (Pin=pinacol) also appears to prefer incorpo-
ration at C-3, hence arylacetylene derived alkynylboronates un-
dergo benzannulation with low regiocontrol. In contrast, alky-
In conclusion, the Ni-catalyzed benzannulation of cyclobute-
nones and unsymmetrical alkyl-substituted alkynes generally
proceeds with low levels of regioselectivity, in line with the ob-
servations made in Liebeskind’s original report. Alkynes bear-
ing aryl groups offer greater regiocontrol, but at the expense
of alkyne reactivity. We have found that the inclusion of nor-
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Keywords: catalysis · cycloadditions · nickel · phenols ·
regioselectivity
[
[
[
1] a) D. M. D’Souza, T. J. J. Mꢁller, Chem. Soc. Rev. 2007, 36, 1095–1108;
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932–6933; b) K. Y. T. Ho, C. A ¨ı ssa, Chem. Eur. J. 2012, 18, 3486–3489;
Scheme 5. Pd-catalyzed cross-coupling. The reaction was performed with
phenol 20 (1 equiv, 0.23 mmol), bromobenzene (1.1 equiv, 0.25 mmol) and
6
K
2
CO
3 3 4
(4 equiv, 0.92 mmol) in the presence of Pd(PPh ) ) (10%, 0.023 mmol)
c) P. Kumar, J. Louie, Org. Lett. 2012, 14, 2026–2029.
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2
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Xu, G. Dong, Angew. Chem. 2012, 124, 7685–7689; Angew. Chem. Int.
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[4] M. A. Huffman, L. Liebeskind, J. Am. Chem. Soc. 1991, 113, 2771–2772.
bornadiene as a promoter can provide improved yields of
products in these cases. However, alkynylboronates appear to
be particularly well-suited to the Ni-catalyzed reaction with cy-
clobutenones, providing superior yields and regioselectivities
in many cases. The isolation of aryl esters as byproducts in
some cases is suggestive of the formation of ketene intermedi-
ates in this process and may help to guide further work in elu-
cidating the reaction mechanism. Nonetheless, this study sug-
[
5] For studies on the synthesis and reactions of vinylketene complexes,
see: a) M. A. Huffman, L. S. Liebeskind, W. T. Pennington, Organometal-
lics 1990, 9, 2194–2196; b) M. A. Huffman, L. S. Liebeskind, W. T. Pen-
nington, Organometallics 1992, 11, 255–266; c) M. A. Huffman, L. S. Lie-
beskind, J. Am. Chem. Soc. 1990, 112, 8617–8618; For a related ap-
proach that does not require the use of a transition metal catalyst,
see:d) R. L. Danheiser, S. K. Gee, J. Org. Chem. 1984, 49, 1672–1674.
6] Y. Li, Z. Lin, Organometallics 2013, 32, 3003–3011.
[7] a) S. Ogoshi, M.-a. Oka, H. Kurosawa, J. Am. Chem. Soc. 2004, 126,
11802; b) S. Ogoshi, M. Ueta, T. Arai, H. Kurosawa, J. Am. Chem. Soc.
2005, 127, 12810; c) M. Ohashi, H. Saijo, T. Arai, S. Ogoshi, Organometal-
lics 2010, 29, 6534.
8] a) J. E. Moore, M. W. Davies, K. M. Goodenough, R. A. J. Wybrow, M. York,
C. N. Johnson, J. P. A. Harrity, Tetrahedron 2005, 61, 6707–6714; b) M. D.
Helm, J. E. Moore, A. Plant, J. P. A. Harrity, Angew. Chem. 2005, 117,
3957–3960; Angew. Chem. Int. Ed. 2005, 44, 3889–3892; c) J. E. Moore,
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J. E. Moore, J. P. A. Harrity, Chem. Commun. 2006, 3323–3325; e) D. L.
Browne, J. F. Vivat, A. Plant, E. Gomez-Bengoa, J. P. A. Harrity, J. Am.
Chem. Soc. 2009, 131, 7762–7769; f) J. Huang, S. J. F. Macdonald, J. P. A.
Harrity, Chem. Commun. 2009, 436–438.
[
2
3
gests that alkynes bearing one sp - and one sp -based sub-
stituent can undergo benzannulation with high levels of regio-
3
control whereby the sp -based group is incorporated ortho-to
the phenolic OH.
[
Experimental Section
General procedure for the Ni-catalyzed benzannulation, ex-
emplified by the synthesis of 8
A flame-dried Schlenk tube was charged with 3-phenylcyclobut-2-
enone (2) (57.7 mg, 0.40 mmol), 1-phenyl-1-hexyne 3 (69.6 mg,
[9] For metal catalyzed variants, see: a) V. Gandon, D. Leboeuf, S. Amsling-
0
.44 mmol) and norbornadiene (18.4 mg, 0.02 mmol) in anhydrous
er, K. P. C. Vollhardt, M. Malacria, C. Aubert, Angew. Chem. 2005, 117,
7
276–7280; Angew. Chem. Int. Ed. 2005, 44, 7114–7118; b) G. Hilt, K. I.
Smolko, Angew. Chem. 2003, 115, 2901–2903; Angew. Chem. Int. Ed.
003, 42, 2795–2797; c) Y. Yamamoto, J.-i. Ishii, H. Nishiyama, K. Itoh, J.
Am. Chem. Soc. 2004, 126, 3712–3713; d) A.-L. Auvinet, J. P. A. Harrity,
G. Hilt, J. Org. Chem. 2010, 75, 3893–3896.
and degassed toluene (1 mL) under an argon atmosphere. The
mixture was cooled to 08C before Ni(COD)2 (5.5 mg, 0.02 mmol,
2
5
mol%) was added. The mixture was stirred at 08C for 1.5 h and
another portion of Ni(COD)2 (5.5 mg, 0.02 mmol, 5 mol%) was
added. The solution was allowed to reach room temperature and
stirred for 16 h. All volatiles were removed in vacuo to obtain the
crude product (ratio 92:8). Purification by flash chromatography
[
10] For a preliminary account of this work, see: A.-L. Auvinet, J. P. A. Harrity,
Angew. Chem. 2011, 123, 2821–2824; Angew. Chem. Int. Ed. 2011, 50,
2769–2772.
over silica gel eluting with n-hexane/EtOAc (95:5) provided phenol
[11] For example, the benzannulation of a mixture of 2,3-di-nPr cyclobute-
none and the corresponding 3,4-isomer shows that only the latter sub-
strate reacts:.
1
8
as a colorless oil (74.4 mg, 62%). H NMR (400.1 MHz, CDCl ): d=
3
0
.82 (3H, t, J=7.4 Hz, CH ), 1.22–1.31 (2H, m, CH ), 1.47–1.53 (2H,
3 2
m, CH ), 2.57–2.61 (2H, m, CH ), 4.94 (1H, s, OH), 7.05 (1H, d, J=
2
2
1
7
2
1
3
1
.8 Hz, Ar-H), 7.09 (1H, d, J=1.8 Hz, Ar-H), 7.31–7.45 (8H, m, Ar-H),
13
.58–7.60 ppm (2H, m, Ar-H); C NMR (100.6 MHz, CDCl ): d=13.9,
3
3.0, 26.7, 32.2, 113.0, 121.7, 126.2, 127.1, 127.1, 127.4, 128.1, 128.9,
29.3, 139.5, 140.6, 142.0, 144.2, 154.3 ppm; FTIR (film): 3413 (m),
083 (w), 3058 (w), 3028 (w), 2956 (s), 2925 (s), 2856 (s), 1599 (w),
566 (m), 1463 (m), 1442 (w), 1402 (m), 1263 (m), 1187 (m), 1130
À1
+
(
m), 757 (s), 697 (s) cm ; HRMS (ESI): m/z calcd for C H O :
22 23
+
3
03.1749 [M+H] ; found: 303.1747.
Acknowledgements
Received: October 29, 2014
We are grateful to the EPSRC and the Deutsche Forschungs-
meinschaft (DFG) for financial support. We also thank the Por-
tius group for providing glovebox assistance.
Published online on && &&, 0000
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FULL PAPER
&
Cycloaddition
T. Stalling, W. R. R. Harker, A.-L. Auvinet,
E. J. Cornel, J. P. A. Harrity*
&& – &&
Investigation of Alkyne
Regioselectivity in the Ni-Catalyzed
Benzannulation of Cyclobutenones
The Ni-catalyzed benzannulation of cy-
clobutenones and a series of alkynes
highlight a preference for the incorpora-
tion of alkyl substituents at C-2 of the
phenol products. In contrast, aryl and
pinacol borane esters show a preference
for incorporation at C-3. Accordingly, al-
2
kynes bearing a combination of sp -
3
and sp -based substituents undergo
benzannulation with high levels of
regiocontrol.
Chem. Eur. J. 2014, 20, 1 – 5
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