Preparation of conjugated 1,3-enynes by Rh(III)-catalysed alkynylation of alkenes via C-H activation

Article abstract of DOI:10.1039/c4cc01141d

An experimentally simple additive-free Rh(III)-catalysed direct alkynylation of alkenes has been developed. This protocol employs commercially available TIPS-EBX as the alkyne source, giving access to conjugated terminal enynes following a simple silyl-de

Full text of DOI:10.1039/c4cc01141d

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Preparation of conjugated 1,3-enynes
by Rh(III)-catalysed alkynylation of
alkenes via C–H activation†
Cite this: Chem. Commun., 2014,
50, 4459
Received 12th February 2014,
Accepted 4th March 2014
Karl D. Collins, Fabian Lied and Frank Glorius*
DOI: 10.1039/c4cc01141d
www.rsc.org/chemcomm
An experimentally simple additive-free Rh(III)-catalysed direct alkynyla-
tion of alkenes has been developed. This protocol employs commercially
available TIPS-EBX as the alkyne source, giving access to conjugated
terminal enynes following a simple silyl-deprotection. This method
has also been applied to arenes.
Alkynes are arguably one of the most versatile functionalities in
synthetic chemistry, transformable into a multitude of functional
groups, or readily incorporated into the structural backbone of
organic molecules.1 The privileged nature of alkynes in click chemistry
further highlights their value.2 Furthermore, conjugated and non-
conjugated enynes have been widely exploited in organic synthesis.3
Over the past decade, the impact of transition metal-
Scheme 1 Initial results of Rh(III) alkynylation. Conditions:
(0.200 mmol), 1 (2.0 eq.), RhCp*(MeCN)3(SbF6)2 (10 mol%), CH2Cl2 (1.5 mL),
80 1C, 16 h.
2 or 4
We initially investigated the direct alkynylation of arene 2 using
mediated C–H activation on the preparation of organic mole- a diisopropylbenzamide directing group, and were pleased to
cules has developed considerably.4 The direct functionalisation find that following a short optimisation, the reaction proceeded
of C–H bonds, obviating the need for pre-functionalisation is of in the absence of any additives to give 3 in a moderate 54%
particular interest when considering the increasing demands yield, using 10 mol% of the cationic RhCp*(MeCN)3(SbF6)2
for efficiency in chemical synthesis. Whilst C–H activation complex (Scheme 1).11 Catalyst loading, reaction temperature,
strategies have been employed to mediate the alkynylation of reaction stoichiometry and concentration were all shown to be
(hetero)arenes and sp3-carbon atoms by Pd5 or Ru6 catalysis, critical (see ESI†). Upon changing the substrate to investigate
methods employing Rh catalysis are yet to be developed.7
the preparation of enynes, we were startled to find that using
The hypervalent iodine reagent 1-[(triisopropylsilyl)ethynyl]- the same directing group, substrate 4a gave 5a in an excellent
1,2-benziodoxol-3(1H)-one (TIPS-EBX, 1) introduced by Zhdankin8 94% isolated yield.
has recently risen to prominence as an efficient alkynylating
The reaction proceeded in the absence of any additives, and
reagent. The Waser research group has reported several beautiful under an atmosphere of air, with no special precautions taken
examples9 of the direct alkynylation of heterocycles, enolates and, to exclude moisture. Control reactions excluded the role of
most recently thiols using 1 and either by gold or palladium atmospheric oxygen as an oxidant, and confirmed the require-
catalysis, under typically very mild conditions. Encouraged by the ment of the catalyst. The reaction was also shown to proceed in
recent use of hypervalent iodonium reagents in combination with 91% yield using 5 mol% [RhCp*Cl2]2 and 20 mol% AgSbF6.
Rh(III) as demonstrated in elegant work by Li,10 we proposed to Whilst we were able to reduce the reaction temperature and
develop a Rh(III) alkynylation protocol employing 1 as the alkyne catalyst loading for the preparation of 5a, we found that these
source, and in particular to develop a novel approach to obtain conditions were unsuitable for alternate substrates (see ESI†).
synthetically valuable 1,3-enynes3 via C–H activation.
We subsequently explored the scope with regard to substitutions
on the aryl ring (Fig. 1), and were pleased to find that substitution
at the o-, m-, and p-positions with a range of electron-withdrawing
and electron-rich groups was tolerated. The preparation of 5a on
a 2 mmol scale with excellent yield demonstrated the scalability
of this reaction.
¨
¨
¨
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster,
¨
Corrensstrasse 40, 48149 Munster, Germany. E-mail: glorius@uni-muenster.de
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc01141d
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Fig. 3 Alkynylation of benzamides. For reaction conditions see Fig. 1.
Yields are reported for isolated materials. a Reaction repeated twice giving
identical yields.
The failure to identify any reaction product when employing
acetanilide 17 further supports this conclusion.
To facilitate the application of this method, we were keen to
establish a fuller picture of the functional group tolerance of this
reaction and consequently we undertook a robustness screen as
recently reported by Collins and Glorius.12 The screen demon-
strated that the reaction was tolerant of aromatic chlorides, nitriles,
esters and tertiary amides, with these functionalities showing high
stability under reaction conditions. Alkyl chlorides and a terminal
olefin were amenable to the reaction conditions. Aliphatic and
aromatic amines, a primary alcohol and a terminal alkyne were all
shown to inhibit the reaction. Of the heterocycles screened, aza-
cycles were typically detrimental to the reaction or unstable under
the reaction conditions with the exception of 2-chloroquinoline.
Pleasingly though, biologically relevant thiophenes and benzo-
furans were well tolerated, and proved to be stable under the
reaction conditions. The full data are reported in the ESI.†
We have demonstrated TBAF mediated-deprotection of catalysis
products to give terminal enynes and have also demonstrated a one-
pot desilylation-Sonogashira coupling reaction to give 20 in 50%
yield. The alkynylation of the natural product piperine 21 has also
been demonstrated (Fig. 4).
Fig. 1 Initial substrate scope. Conditions: 4 (0.200 mmol), 1 (2.0 eq.),
RhCp*(MeCN)3(SbF6)2 (10 mol%), CH2Cl2 (1.5 mL), 80 1C, 16 h. Yields are
reported for isolated materials. 2.00 mmol scale.
a
Fig. 2 Additional substrate scope for enyne formation. For reaction con-
ditions see Fig. 1. Yields are reported for isolated materials.
Further exploration of the scope (Fig. 2) of this reaction
determined that both alkyl and alkenyl substitutions were also
tolerated. Unfortunately, geminal substitution of the a-carbon
to the amide precluded product formation. Substitution of the
phenyl ring for thiophene resulted in product formation in an
excellent 82% yield. A number of alternative directing groups
were also explored, with diethyl and piperidene tertiary amides
giving 11 and 12 in 76% and 62% yields, respectively.
The use of different tertiary amide directing groups in the
direct alkynylation of arenes has also been investigated. As
discussed, the diisopropylamide directing group gave 3 in 54%
yield under the reported reaction conditions. We consequently
explored a number of additional tertiary amide directing
groups, and were pleased to find that all reactions proceeded
to give the mono-alkynylated products in high yields with the
exception of the diethylamide directing group (Fig. 3). Detailed
NMR analysis confirmed that the phenyl isopropyl amide
directing group results in alkynylation of the benzamide aro-
matic ring A, rather than that of the acetanilide aromatic ring B.
Fig. 4 Derivatisation of reaction products and application to a natural
product. a 21 (0.200 mmol), 1 (2.0 eq.), RhCp*(MeCN)3(SbF6)2 (10 mol%),
CH2Cl2 (1.5 mL), 80 1C, 16 h. Yields are reported for isolated materials.
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S. A. Kozmin, Adv. Synth. Catal., 2006, 348, 2271; (h) A. Lumbroso,
M. L. Cooke and B. Breit, Angew. Chem., Int. Ed., 2013, 52, 1890;
(i) X. Zeng, Chem. Rev., 2013, 113, 6864; ( j) J.-R. Kong, M.-Y. Ngai and
M. J. Krische, J. Am. Chem. Soc., 2006, 128, 718; (k) K. M. Miller,
T. Luanphaisarnnont, C. Molinaro and T. K. Jamison, J. Am. Chem. Soc.,
2004, 126, 4130; (l) H. Li and P. J. Walsh, J. Am. Chem. Soc., 2005, 127, 8355.
¨
4 For recent reviews on C–H activation, see: (a) J. Wencel-Delord, T. Droge,
F. Liu and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740; (b) S. H. Cho,
J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev., 2011, 40, 5068; (c) J. L. Bras
and J. Muzart, Chem. Rev., 2011, 111, 1170; (d) L. Ackermann, Chem. Rev.,
2011, 111, 1315; (e) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc.
Rev., 2011, 40, 1885; ( f) C. S. Yeung and V. M. Dong, Chem. Rev., 2011,
111, 1215; (g) J. Yamaguchi, A. D. Yamaguchi and K. Itami, Angew. Chem.,
Int. Ed., 2012, 51, 8960; (h) M. C. White, Science, 2012, 335, 807;
(i) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012,
45, 788; ( j) S. R. Neufeldt and M. S. Sanford, Acc. Chem. Res., 2012, 45, 936;
(k) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord and F. Glorius, Angew.
Chem., Int. Ed., 2012, 51, 10236; (l) J. Wencel-Delord and F. Glorius, Nat.
Chem., 2013, 5, 369; (m) L. Ackermann, Acc. Chem. Res., 2014, 47, 281.
5 (a) J. He, M. Wasa, K. S. L. Chan and J.-Q. Yu, J. Am. Chem. Soc., 2013,
135, 3387; (b) S. H. Kim and S. Chang, Org. Lett., 2010, 12, 1868;
(c) I. V. Seregin, V. Ryabova and V. Gevorgyan, J. Am. Chem. Soc.,
2007, 129, 7742; (d) S. H. Kim, J. Yoon and S. Chang, Org. Lett., 2011,
13, 1474; (e) F. Shibahara, Y. Dohke and T. Murai, J. Org. Chem.,
2012, 77, 5381; ( f ) M. Tobisu, Y. Ano and N. Chatani, Org. Lett.,
2009, 11, 3250; (g) L. Yang, L. Zhao and C.-J. Li, Chem. Commun.,
2010, 46, 4184; (h) Y. Gu and X. Wang, Tetrahedron Lett., 2009,
50, 763; (i) S. H. Kim, S. H. Park and S. Chang, Tetrahedron, 2012,
68, 5162.
Fig. 5 Proposed mechanistic pathways.
We present two feasible mechanistic scenarios following
amide-directed C–H activation of 5 to give rhodacycle 23 (Fig. 5):
(1) Following coordination of the alkyne, addition of rho-
dium, expelling 2-iodobenzoic acid would give rise to carbene
25.8g,13,14 Carbene rearrangement to give Rh(V) species 26 would
enable formation of 5 following reductive elimination. Direct
oxidative-addition of 1 to give 26 could also be considered.
(2) In accord with the strongly polarised nature of 1, regio-selective
carborhodation generating alkenyl-rhodacycle 27, followed by
a-elimination of 2-iodobenzoic acid would give rise to rhodium
vinylidene species 28. A concerted or stepwise vinyl-migration8a and
elimination sequence would subsequently give rise to target 5 and
regenerate a catalytically active Rh(III) species: the proposed migration is
supported by labelling studies undertaken by Loh.7 Carborhodation of
the alkyne with the reverse selectivity seems to be unlikely due to
potential steric clashes between the Cp* ligand and the triisopropylsilyl
group, as well as the electronic polarisation of 1.
6 Y. Ano, M. Tobisu and N. Chatani, Synlett, 2012, 2763.
7 Immediately prior to submission of this manuscript, the following was
published: C. Feng and T.-P. Loh, Angew. Chem., Int. Ed., 2014, 53, 2722;
Whilst this manuscript was under revision the following was published:
F. Xie, Z. Qi, S. Yu and X. Li, J. Am. Chem. Soc., 2014, DOI: 10.1021/
ja501910e. For reviews on Rh(III) catalysed C–H activation see: (a) T. Satoh
and M. Miura, Chem. – Eur. J., 2010, 16, 11212; (b) D. A. Colby, A. S. Tsai,
R. G. Bergman and J. A. Ellman, Acc. Chem. Res., 2011, 45, 814; (c) G. Song,
F. Wang and X. Li, Chem. Soc. Rev., 2012, 41, 3651; (d) F. W. Patureau,
J. Wencel-Delord and F. Glorius, Aldrichimica Acta, 2012, 45, 31;
(e) S. Chiba, Chem. Lett., 2012, 41, 1554.
In summary we have presented for the first time the preparation
of enynes via a C–H activation protocol. This process introduces an
electronically inverted retrosynthetic disconnection of enynes when
compared to the classical Sonogashira coupling. This protocol has also
been applied to the alkynylation of benzamides and further validates
the potential applications of TIPS-EBX 1 by use of rhodium catalysis.
We are most grateful to Prof. Dr Zhuangzhi Shi for experimental
support and Dr Klaus Bergander for NMR analysis. Generous
financial support by the European Research Council (ERC) under
the European Community’s Seventh Framework Program (FP7 2007-
2013)/ERC grant agreement no. 25936, and the DFG (Leibniz award)
is gratefully acknowledged.
8 V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, J. T. Bolz and
A. J. Simonsen, J. Org. Chem., 1996, 61, 6547.
9 (a) J. P. Brand, J. Charpentier and J. Waser, Angew. Chem., Int. Ed., 2009,
48, 9346; (b) J. P. Brand, C. Chevalley and J. Waser, Beilstein J. Org. Chem.,
´
´
2011, 7, 565; (c) J. P. Brand, D. Fernandez Gonzalez, S. Nicolai and
J. Waser, Chem. Commun., 2011, 47, 102; (d) J. P. Brand and J. Waser,
Angew. Chem., Int. Ed., 2010, 49, 7304; (e) J. P. Brand and J. Waser, Org.
´
´
´
Lett., 2012, 14, 744; ( f ) D. Fernandez Gonzalez, J. P. Brand and J. Waser,
´
Chem. – Eur. J., 2010, 16, 9457; (g) D. Fernandez Gonzalez, J. P. Brand,
`
R. Mondiere and J. Waser, Adv. Synth. Catal., 2013, 355, 1631; (h) R. Frei
and J. Waser, J. Am. Chem. Soc., 2013, 135, 9620; (i) Y. Li, J. P. Brand and
J. Waser, Angew. Chem., Int. Ed., 2013, 52, 6743; ( j) Y. Li and J. Waser,
´
Beilstein J. Org. Chem., 2013, 9, 1763; (k) S. Nicolai, S. Erard, D. Fernandez
´
Gonzalez and J. Waser, Org. Lett., 2010, 12, 384; (l) G. L. Tolnai, S. Ganss,
J. P. Brand and J. Waser, Org. Lett., 2013, 15, 112.
10 F. Xie, Z. Qi and X. Li, Angew. Chem., Int. Ed., 2014, 52, 11862.
11 Extensive further optimisation under an atmosphere of air using
substrate 2 was unsuccessful.
12 (a) K. D. Collins and F. Glorius, Nat. Chem., 2013, 5, 597;
(b) K. D. Collins and F. Glorius, Tetrahedron, 2013, 69, 7817;
(c) K. D. Collins, A. Ru¨hling, F. Lied and F. Glorius, Chem. – Eur.
J., 2014, DOI: 10.1002/chem.201304508; (d) K. D. Collins, A. Ru¨hling
and F. Glorius, Nat. Protoc., 2014, DOI: 10.1038/nprot.2014.076;
(e) I. Churcher, Nat. Chem., 2013, 5, 554. For applications see:
Notes and references
1 (a) F. Diederich, P. J. Stang and R. R. Tykwinski, Acetylene Chemistry:
Chemistry, Biology and Material Science, Wiley-VCH, Weinheim, 2005;
(b) J. P. Brand and J. Waser, Chem. Soc. Rev., 2012, 41, 4165; (c) E. Negishi
and L. Anastasia, Chem. Rev., 2003, 103, 1979; (d) R. R. Tykwinski, Angew.
´
Chem., Int. Ed., 2003, 42, 1566; (e) R. Chinchilla and C. Najera, Chem. Rev.,
¨
2014, 114, 1783; ( f) I. A. Meretina, B. I. Ionin and J. C. Tebby, Alkynes in
Cycloadditions, Wiley-Blackwell, New Jersey, 2013.
2 H. C. Kolb, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed.,
2001, 40, 2004–2021.
3 (a) I. J. S. Fairlamb, Angew. Chem., Int. Ed., 2004, 43, 1048; (b) C. Aubert,
O. Buisine and M. Malacria, Chem. Rev., 2002, 102, 813; (c) V. Mamane,
P. Hannen and A. Fu¨rstner, Chem. – Eur. J., 2004, 10, 4556; (d) G. C. Lloyd-
( f ) N. Kuhl, N. Schroder and F. Glorius, Org. Lett., 2013, 15, 3860;
(g) H. Wang, B. Beiring, D.-G. Yu, K. D. Collins and F. Glorius,
Angew. Chem., Int. Ed., 2013, 52, 12430; (h) D.-T. D. Tang,
K. D. Collins, J. B. Ernst and F. Glorius, Angew. Chem., Int. Ed.,
2014, 53, 1809; (i) H. G. Lee, P. J. Milner and S. L. Buchwald, Org.
Lett., 2013, 15, 5602; ( j) S. C. Cullen, S. Shekhar and N. K. Nere,
J. Org. Chem., 2013, 78, 12194.
Jones, Org. Biomol. Chem., 2003, 1, 215; (e) B. M. Trost, F. D. Toste and 13 P. J. Stang, Chem. Rev., 1996, 96, 1123.
A. B. Pinkerton, Chem. Rev., 2001, 101, 2067; ( f ) S. T. Diver and 14 M. Ochiai, M. Kunishima, Y. Nagao, K. Fuji, M. Shiro and E. Fujita,
A. J. Giessert, Chem. Rev., 2004, 104, 1317; (g) L. Zhang, J. Sun and
J. Am. Chem. Soc., 1986, 108, 8281.
This journal is ©The Royal Society of Chemistry 2014
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