Rh(I)-catalyzed decarbonylation of diynones via C-C activation: Orthogonal synthesis of conjugated diynes

Article abstract of DOI:10.1021/ol400815y

Utilization of C-C bond activation as a unique mode of reactivity for constructing C-C bonds provides new strategies for preparing important organic molecules. Development of a Rh(I)-catalyzed C-C activation of diynones to synthesize symmetrical and unsymmetrical conjugated diynes through decarbonylation is reported. This C-C cleavage strategy takes advantage of the innate reactivity of conjugated ynones without relying on any ring strain or auxiliary directing group. This alkynation method also has orthogonal properties compared to typical cross-coupling reactions.

Full text of DOI:10.1021/ol400815y

ORGANIC
LETTERS
2013
Vol. 15, No. 9
2242–2245
Rh(I)-Catalyzed Decarbonylation of
Diynones via CꢀC Activation: Orthogonal
Synthesis of Conjugated Diynes
Alpay Dermenci, Rachel E. Whittaker, and Guangbin Dong*
Department of Chemistry and Biochemistry, The University of Texas at Austin, Austin,
Texas 78712, United States
gbdong@cm.utexas.edu
Received March 25, 2013
ABSTRACT
Utilization of CꢀC bond activation as a unique mode of reactivity for constructing CꢀC bonds provides new strategies for preparing important
organic molecules. Development of a Rh(I)-catalyzed CꢀC activation of diynones to synthesize symmetrical and unsymmetrical conjugated
diynes through decarbonylation is reported. This CꢀC cleavage strategy takes advantage of the innate reactivity of conjugated ynones without
relying on any ring strain or auxiliary directing group. This alkynation method also has orthogonal properties compared to typical cross-coupling
reactions.
Nonmetathesis-based transition-metal-catalyzed CꢀC
bond activation has recently emerged as a unique platform
for developing new catalytic transformations.1 Among
Scheme 1
various activation modes, CꢀC cleavage assisted by an
adjacent carbonyl group has become an increasingly re-
cognized strategy due to the high occurrence of ketones in
organic molecules.1b,d,j In particular, oxidative insertion
The elegant work by Murakami/Ito,3 Kondo,4 and
of metals into the ketone R CꢀC bond followed by CO
Yamamoto5 has demonstrated catalytic pathways for
decarbonylation of four-membered ketones leading to ring
extrusion and reductive elimination (namely decarbonyla-
tive CꢀC cleavage/coupling, as shown in Scheme 1) re-
contraction or expansion (Figure 1A). More recently, Shi
et al.6 disclosed a Rh-catalyzed biaryl synthesis through
CꢀC decarbonylation/coupling using a pyridyl group as
anauxiliary directing group(ADG, Figure 1B). Incontrast
to these two strategies, catalytic decarbonylative CꢀC
cleavage/coupling with linear ketones lacking ring strain
or ADGs remains largely underdeveloped.7 Conjugated
diynes, namely 1,3-diynes, are an important structural
presents an underutilized but attractive method to form
CꢀC bonds.2
(1) For recent reviews on CꢀC activation, see: (a) Rybtchiski, B.;
Milstein, D. Angew. Chem., Int. Ed. 1999, 38, 870. (b) Murakami, M.;
Ito, Y. Top. Organomet. Chem. 1999, 3, 97. (c) M. E. van der Boom,
M. E.; Milstein, D. Chem. Rev. 2003, 103, 1759. (d) Jun, C. H. Chem. Soc.
Rev. 2004, 33, 610. (e) Satoh, T.; Miura, M. Top. Organomet. Chem.
2005, 14, 1. (f) Jun, C. H.; Park, J. W. Top. Organomet. Chem. 2007, 24,
117. (g) Necas, D.; Kotora, M. Curr. Org. Chem. 2007, 11, 1566. (h)
Crabtree, R. H. Chem. Rev. 1985, 85, 245. (i) W. D. Jones, W. D. Nature
1993, 364, 676. (j) Kondo, T.; Mitsudo, T. A. Chem. Lett. 2005, 34, 1462.
(k) Ruhland, K. Eur. J. Org. Chem. 2012, 2683. (l) Korotvicka, A.;
Necas, D.; Kotora, M. Curr. Org. Chem. 2012, 16, 1170. (m) Seiser, T.;
Saget, T.; Tran, D. N.; Cramer, N. Angew. Chem., Int. Ed. 2011, 50,
7740.
(3) (a) Murakami, M.; Amii, H.; Ito, Y. Nature 1994, 370, 540. (b)
Murakami, M.; Amii, H.; Shigeto, K.; Ito, Y. J. Am. Chem. Soc. 1996,
118, 8285. (c) Matsuda, T.; Shigeno, M.; Murakami, M. Chem. Lett.
2006, 35, 288.
(4) Kondo, T.; Nakamura, A.; Okada, T.; Suzuki, N.; Wada, K.;
Mitsudo, T. A. J. Am. Chem. Soc. 2000, 122, 6319.
(5) Yamamoto, Y.; Kuwabara, S.; Hayashi, H.; Nishiyama, H. Adv.
Synth. Catal. 2006, 348, 2493.
(6) Lei, Z. Q.; Li, H.; Li, Y.; Zhang, X. S.; Chen, K.; Wang, X.; Sun,
(2) For seminal reports on decarbonylation of ketones using stoi-
chiometric Wilkinson’s complex, see: (a) Rusina, A.; Vlcek, A. A.
Nature 1965, 206, 295. (b) Kaneda, K.; Azuma, H.; Wayaku, M.;
Teranishi, S. Chem. Lett. 1974, 3, 215. For a Ru-catalyzed decarbonyla-
tion of keteones without CꢀC bond formation, see: Chatani, N.; Ie, Y.;
Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 1999, 121, 8645.
J.; Shi, Z. J. Angew. Chem., Int. Ed. 2012, 51, 2690.
r
10.1021/ol400815y
Published on Web 04/15/2013
2013 American Chemical Society

Table 1. Selected Optimization of Decarbonylation of Diynone 1aa
cat.
bite
loading
angle time yieldb
(deg)c (h) (%)
entry
cat.
(mol %) ligand
1
2
3
4
5
6
7
8
9
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COE)2Cl]2
[Rh(C2H4)2Cl]2
5
5
5
5
5
5
dppe
85
8
8
8
42
73
99
dppp
91
dppf
96
98
dppb
24 32 (57)
24 36 (53)
24 41(51)
24 91
DPEphos
103
XANTphos 111
2.5 dppf
2.5 dppf
2.5 dppf
2.5 dppf
96
ꢀ
24 67
ꢀ
24 73
Figure 1. General strategies for transition metal-catalyzed CꢀC
10 [Rh(COD)
(CH3CN)2]þ BF4
11 [Ir(COD)Cl]2
12 Ru3(CO)12
ꢀ
24 47
activation involving decarbonylation.
ꢀ
2.5 dppf
2.5 dppf
ꢀ
ꢀ
24 N.R.d
24 N.R.d
motif found in a diversity of molecules ranging from
materials tonatural products.8 Their preparation generally
relies on Cu- or Pd-mediated coupling reactions,9 such as
GlaserꢀHay,10,11 CadiotꢀChodkiewicz,12 or Sonogashira
reactions.13 Although highly effective, high-loading or
stoichiometric reagents (e.g., oxidants) are often needed
(particularly for preparing unsymmetrical diynes, vide
infra). Given the importance of diynes, the development
of alternative, ideally orthogonal methods for synthesizing
these moieties is of significant value. Here, we describe our
development of a Rh(I)-catalyzed decarbonylation of
conjugated diynones to 1,3-diynes via strain and ADG-
free CꢀC activation (Figure 1C).
a Conditions: diynone 1a (0.21 mmol), [Rh]/ligand = 1:1.2, PhCl (0.1 M).
b Isolated yields; yield in parentheses is based on recovered starting material.
c See ref 18 for the bite-angle values. d N.R. = No Reaction.
be unreactive.14a Inspired by the aldehyde decarbonylation
reactions,15 we envisioned that such a challenge could be
addressed by using a bidentate phosphine ligand bearing
a wide bite angle, because, first, CO dissociation, which is
expected to be the turnover-limiting step, could be accel-
erated due to the bulkiness of the ligand15 and, second,
reductive elimination leading to the formation of the diyne
products would also be enhanced.16
€
Muller’s seminal study in 1969 on stoichiometric reac-
To test our hypothesis, we attempted the catalytic
decarbonylation using phenyl-diynone 1a as the model
substrate (Table 1). By subjecting 1a to 5 mol %
[Rh(COD)Cl]2 and 12 mol % bidentate phosphine ligand
(dppe, dppp, and dppf) in chlorobenzene (PhCl) at
135ꢀ140 °C, full conversion of the starting material was
achieved within 8 h (Table 1, entries 1ꢀ3).17 While decom-
position products were observed using dppe and dppp,
dppf proved highly selective for this transformation and a
quantitative yield was obtained (Table 1, entry 3).18 The
use of bidentate phosphine ligands was crucial for catalyst
turnover, as use of PPh3, PCy3, or no phosphine ligands
only resulted in <10% yield. Nonetheless, we discovered
that the catalyst loading can be lowered to 2.5 mol % and
the desired product was still obtained in 91% yield after
tions between conjugated diynones and Wilkinson’s com-
plex [Rh(PPh3)3Cl] shows the feasibility for decarbonyla-
tion of ynones.14 However, a catalytic transformation has
not been realized to date. We postulated that the challenge
for developing an efficient catalytic decarbonylation
of diynones is attributed to the difficulty of removing
CO from the Rh center, as the Rh(CO)(PPh3)2Cl
€
complex generated from Muller’s conditions proved to
(7) (a) For Rh-catalyzed decarbonylations of 1,2- and 1,3-diketones,
see: Reference 2a. (b) For a Rh-mediated decarbonylation of cyclode-
canone and -pentanone, see: Reference 3a. (c) For a recent Rh-mediated
decarbonylation of aryl ketones, see: Daugulis, O.; Brookhart, M.
Organometallics 2004, 23, 527.
(8) For typical reviews, see: (a) Acetylene Chemistry; Diederich, F.,
Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, Germany, 2006.
(b) Chemistry of Acetylenes; Cadiot, P., Chodkiewicz, W., Eds.; Marcel
Dekker: New York, 1969.
(9) For a recent review, see: Siemson, P.; Livingston, R. C.; Diedrich,
F. Angew. Chem., Int. Ed. 2000, 39, 2632.
(10) Glaser, C. Chem. Ber. 1869, 2, 422.
(15) For seminal work of bidentate ligand-assisted decarbonylation
of aldehydes, see: Doughty, D. H.; Pignolet, L. H. J. Am. Chem. Soc.
1978, 100, 7083.
(11) Hay, A. S. J. Org. Chem. 1960, 25, 1275.
(12) Chodkiewicz, W.; Cadiot, P. C. R. Hebd. Seances Acad. Sci.
1955, 241, 1055.
(16) For a kinetic study of the bite-angle effect on reductive elimina-
tions, see: Marcone, J. E.; Moloy, K. G. J. Am. Chem. Soc. 1998, 120,
8527.
(13) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
(17) Chlorobenzene was found to be the optimal solvent, whereas use
of toluene proved to be inefficient.
€
(14) (a) Muller, E.; Segnitz, A.; Langer, E. Tetrahedron Lett. 1969, 14,
(18) For average ligand bite angles, see: (a) Dierkes, P.; van Leeuwen,
P. W. N. M. J. Chem. Soc., Dalton Trans. 1999, 1519. (b) van Leeuwen,
P. W. N. M.; Kamer, P. D. J.; Reek, J. N. H.; Dierkes, P. Chem. Rev.
2000, 100, 2741.
€
1129. (b) Muller, E.; Segnitz, A. Liebigs Ann. Chem. 1973, 1583. (c) For a
€
related transformation involving carbonyl migration, see: Muller, E.;
Segnitz, A. Synthesis 1970, 147.
Org. Lett., Vol. 15, No. 9, 2013
2243

Scheme 2. Substrate Scope of Rh-Catalyzed Decarbonylation of
Symmetrical Diynonesa,b
Scheme 3. Substrate Scope of Rh-Catalyzed Decarbonylation of
Unsymmetrical Diynonesa,b
a Conditions: diynone (0.19ꢀ0.21 mmol), [Rh(COD)Cl]2 (2.5 mol %),
dppf (6 mol %), PhCl (0.1 M), reflux, 16ꢀ24 h. b Isolated yields.
a Conditions: diynone (0.19ꢀ0.21 mmol), [Rh(COD)Cl]2 (2.5 mol %),
dppf (6 mol %), PhCl (0.1 M), reflux, 16ꢀ24 h. b Isolated yields. c Yield in
parentheses is based on recovered starting material.
diyne products were isolated and no symmetrical products,
such as diphenyl bisacetylene, were observed. This
indicates that the catalytic process is an intramolecular
process and no intermolecular transfer of acetylenic
units takes place.
24 h (Table 1, entry 7). Furthermore, addition of a Lewis
acid (ZnCl2) did not promote the reaction tooccur at lower
temperature.19
The substrate scope was explored first with symmetrical
diynones (Scheme 2). A range of diynone substrates under-
went decarbonylation to give the corresponding diynes.
For example, aryl-substituted diynones with various elec-
tronic properties gave products in good to excellent yields
(2aꢀe). Sterically hindered substrates 1fꢀg were also ex-
amined and no major decrease in yield or reactivity was
observed, even with relatively bulky mesityl substituents.20
In addition, alkenyl- and alkyl-substituted diynones also
afforded the desired diyne products 2hꢀj. With the sub-
strate-containing homopropargylic PMB-ether 1j, we ob-
served slight decomposition and isomerization of the
starting material, thus leading to a decreased yield (see
Supporting Information).
Classical methods for the synthesis of unsymmetrical
diynes (from monoalkynes) generally rely on either using
a large excess of one coupling partner under Glaserꢀ
Hay conditions or employing alkynyl halides (prepared
from halogenation of terminal alkynes) under Cadiot-
Chodkiewicz conditions.9 Our CꢀC activation method
provides an alternative way to prepare unsymmetrical
diynes (Scheme 3).21 Of note, the substituents that led to
relatively low yields in the symmetrical substrates (e.g.,
p-Cl-phenyl 2d and PMB ether 2j) showed improved
reactivity in the unsymmetrical case 4d and 4f, respectively.
In addition, the protected indole moiety in 4g is compatible
under the decarbonylation conditions. Furthermore, when
unsymmetrical diynones were used, only unsymmetrical
A catalytic cycle is proposed for the Rh-catalyzed
decarbonylation of diynones (Figure 2). The initial step
likely involves substrate coordination to the Rh(I) through
either one or both acetylenes to give complex I (step 1).
Promoted by proximity, Rh(I) would oxidatively insert
into the CꢀC bond R to the carbonyl group to generate
acyl-Rh(III) acetylide II (step 2), despite the inertness of the
spꢀsp2 σ-bond.22 Subsequent elimination of CO (step 3)
followed by reductive eliminationoftheresultantbisacetylide
III (step 4) would provide the conjugated diyne. Note that the
first three steps in the catalytic cycle are in principle all
reversible. Finally, influenced by the bidentate phosphine
ligand, the CO would be extruded from the metal center
through ligand exchange with the diynone substrate, allowing
the resulting Rh(I) complex I to re-enter the catalytic cycle.
The syntheticvalue of theRh-catalyzeddecarbonylation
of diynones has been further demonstrated in the deriva-
tization of natural products, such as citronellal, myrtenal,
and ethinyl estradiol (Scheme 4). A number of interesting
aspects were found: (1) ynones can be prepared from the
corresponding aldehydes23,24 with no need to isolate the
alkyne intermediates (e.g., synthesis of ynone 8,
Scheme 4A); (2) the sensitive four-membered ring of
myrtenal remained intact (Scheme 4B); (3) for unsymme-
trical-diyne synthesis, this method has advantages over the
(22) For examples of activation of sp2ꢀsp alkyne CꢀC bonds, see: (a)
Baddley, W. H.; Panattonni, C.; Bandoli, G.; Clemente, D. A.; Belluco,
U. J. Am. Chem. Soc. 1971, 93, 5590. (b) Anderson, G. K.; Lumetta,
(19) We recently demonstrated that using ZnCl2 can promote cata-
lytic CꢀC activation: Xu, T.; Dong, G. Angew. Chem., Int. Ed. 2012, 51,
7567.
€
G. J.; Siria, J. W. J. Organomet. Chem. 1992, 434, 253. (c) Muller, C.;
Iverson, C. N.; Lachicotte, R. J.; Jones, W. D. J. Am. Chem. Soc. 2001,
123, 9718. For recent reviews on activation of CꢀCN bonds, see: (d)
Nakao, Y.; Hiyama, T. Pure Appl. Chem. 2008, 80, 1097. (e) Tobisu, M.;
Chatani, N. Chem. Soc. Rev. 2008, 37, 300. (f) Bonesi, S. M.; Fagnoni,
M. Chem.;Eur. J. 2010, 16, 13572.
(23) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
(24) Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815.
(20) In comparison, triisopropylsilyl-containing substrates resulted
in no reaction.
(21) (a) For a Cu-catalyzed unsymmetrical diyne synthesis via dec-
arboxylative cross-coupling, see: Yu, M.; Pan, D.; Jia, W.; Chen, W.;
Jiao, N. Tetrahedron Lett. 2010, 51, 1287. (b) For a lithium dialkynyl-
dialkylborate-mediated unsymmetrical diyne synthesis, see: Sinclair,
J. A.; Brown, H. C. J. Org. Chem. 1976, 41, 1078.
2244
Org. Lett., Vol. 15, No. 9, 2013

Figure 2. Putative catalytic cycle of Rh-catalyzed decarbonyla-
tion of diynones.
Figure 3. Orthogonal reactivity to the Pd/Cu-catalyzed couplings.
Scheme 4. Applications in Natural-Product Modification
the Rh-catalyzed decarbonylation conditions the CꢀC bond
was selectively cleaved instead of the CꢀX bonds. The diyne
products 20 and 21 containing aryl halides (Br and I) were
provided in good yields (Figure 3). Further Sonogashira
coupling with terminal alkyne 22 gave an interesting ynediyne
compound 23 that previously required eight steps to prepare.26
In summary, we have developed the first catalytic de
carbonylation of diynones to prepare conjugated diynes.
This CꢀC activation reaction takes advantage of the innate
reactivity of ynones without relying on ADG or ring-strain
release, which, to our knowledge, constitutes the only other
approachfor catalytic cleavage/functionalization ofspꢀsp2
CꢀC bonds besides the established CꢀCN activation.22dꢀf
It is noteworthy that the reaction conditions are pH/redox
neutral and highly atom-economical. Given that (1) the
reaction substrates (diynones) are readily available and
(2) the reaction conditions are orthogonal to the cross-
couplings, this catalytic transformation is expected to serve
as an important alternative means to prepare conjugated
diynes. It is alsoanticipated that the use of CꢀC cleavage as
a distinct mode of reactivity in CꢀC formation reactions,
as described in this report, would have broad implications
for the discovery of new types of transformations.
catalytic GlaserꢀHay coupling.25 For example, ethinyl
estradiol-derived unsymmetrical diyne 13 was synthesized
in 79% yield over two steps from alkyne 12 using our
approach (Scheme 4C). Although use of GlaserꢀHay
coupling would save one operation, this reaction gave
much lower yields and a complex mixture of hetero- and
homodimers that are difficult to separate.26
Furthermore, we found that this CꢀC activation-based
alkynation method also has orthogonal reactivity to typical
cross-coupling reactions. While it is well established that aryl
iodides and bromides are highly reactive under Pd- or Cu-
catalyzed coupling conditions,9 our study shows that under
Acknowledgment. We thank UT Austin and CPRIT for
a start-up fund and the Welch Foundation (F-1781) for
research grants. G.D. thanks ORAU for a new faculty
enhancement award. NMR assistance by Mrs. Spangen-
berg at UT Austin is greatly appreciated. We also thank
Prof. J. L. Sessler from UT Austin for helpful advice.
Johnson Matthey company is thanked for Rh salts.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data (1H, 13C NMR; IR;
HRMS). This material is available free of charge via the
Internet at http://pubs.acs.org.
(25) The modifiedGlaserꢀHay reactionconditionswereadopted from
a recent report, see: Balaraman, K.; Kesavan, V. Synthesis 2010, 3461.
(26) Doi, T.; Orita, A.; Matsuo, D.; Saijo, R.; Otera, J. Synlett 2008, 55.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 9, 2013
2245