Cu(I)-catalyzed macrocyclic Sonogashira-type cross-coupling

Article abstract of DOI:10.1021/ol501898b

A macrocyclic Cu-catalyzed Sonogashira-type cross-coupling reaction has been developed that employs an operationally simple CuCl/phen/Cs ₂CO₃ catalyst system. Macrocyclizations can be performed at relatively high concentrations witho

Full text of DOI:10.1021/ol501898b

Letter
pubs.acs.org/OrgLett
Cu(I)-Catalyzed Macrocyclic Sonogashira-Type Cross-Coupling
Jeffrey Santandrea, Anne-Catherine Bedard, and Shawn K. Collins*
́
́ ́
Department of Chemistry and Centre for Green Chemistry and Catalysis, Universite de Montreal, CP 6128 Station Downtown,
Montreal, Quebec, Canada, H3C 3J7
́ ́
S
* Supporting Information
ABSTRACT: A macrocyclic Cu-catalyzed Sonogashira-type cross-
coupling reaction has been developed that employs an operation-
ally simple CuCl/phen/Cs2CO3 catalyst system. Macrocyclizations
can be performed at relatively high concentrations without the
need for slow addition techniques and form macrocycles with
various ring sizes and functional groups. The optimized protocol
was employed in the synthesis of (S)-zearalane, demonstrating
applicability toward the synthesis of a macrocycle with known
biological activity.
s applications of macrocycles continue to emerge in
cyclization reactions. One avenue for an improved macrocyclic
process would involve developing a Cu-catalyzed variant that
would include lower costs, lower toxicity, and greater
availability relative to Pd-based strategies.5 Current Cu-
catalyzed reactions6 inspired by the original Castro−Stephens
cross-coupling7 (CuI/PPh3, Cu(neo)(PPh3), and [Cu-
(DMEDA)2]Cl2) focus on couplings of aryl alkynes, with little
emphasis placed on aliphatic alkynes and no reports of
intramolecular variants. Herein we report the development of
an efficient macrocyclic Cu(I)-catalyzed macrocyclic Sonoga-
shira-type cross-coupling process, with high functional group
tolerance and demonstrate its applicability to the synthesis of
biologically active natural products.
To investigate the development of a macrocyclic Sonogashira
cross-coupling, the cyclization of the iodoarene 1 to afford the
15-membered macrolactone 2 was selected as a model
macrocyclization. The acyclic precursor 1 possesses a long,
flexible alkyl chain with little conformational bias toward
cyclization. As such, it is not surprising that Bracher et al.
reported that the cyclization of alkyne 1 to form benzolactone 2
was challenging, requiring high catalyst loadings (Pd(PPh3)2Cl2
(35 mol %), CuI (1.5 equiv)) and providing low yields (15%).3f
Attempts at improving the process through modification of the
ligand or the Pd source did not improve the yield of
benzolactone 2.8 Consequently, the use of Cu-based catalysis
for the intramolecular Sonogashira-type cross-coupling of alkyl
alkynes and aryl iodides was investigated for the first time.
Optimization of the macrocyclic Cu-catalyzed Sonogashira
cross-coupling involved the macrocyclization of alkyne 1 using
CuCl as a Cu source with various other amine-based ligands
(Table 1). Furthermore, Cs2CO3 was selected as base and
toluene at 135 °C (oil bath temperature) as solvent. When
CuCl was investigated for the macrocyclization of iodide 1
using 2,2′-bipyridine 3a or the more electron-donating ligand
A
diverse fields,1 the development of strategies for the
synthesis of macrocycles has attracted increased interest. While
the design of conformational control techniques and solutions
for the control of dilution effects have emerged, the discovery
of catalysts and/or catalytic transformations remains a
challenging aspect in macrocyclization chemistry. The develop-
ment of catalysis is particularly critical for macrocyclization via
the formation of carbon−carbon bonds. In a recent account of
the synthesis of the drug candidate vaniprevir,2 various Pd-
catalyzed cross-coupling strategies were investigated for macro-
cyclization via carbon−carbon bond formation; an intra-
molecular Sonogashira cross-coupling3 was plagued by various
difficulties that made it unappealing in the context of drug
discovery efforts (Figure 1).4 The Sonogashira cross-coupling
Figure 1. Macrocyclic Sonogashira cross-coupling processes.
traditionally employs a Pd-based catalyst and a Cu-based
additive (catalytic or stoichiometric), and high catalyst loadings
are often used to improve macrocyclizations. Consequently, the
high cost and toxicity of Pd combined with the high dilution
often necessary can render macrocyclic Sonogashira reactions
problematic. In addition, the coupling of terminal alkynes and
aryl/alkenyl electrophiles can be complicated by competing
alkyne dimerization resulting in low yields in many macro-
Received: May 30, 2014
Published: July 23, 2014
© 2014 American Chemical Society
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Table 1. Optimization of a Cu(I)-Catalyzed Macrocyclic
Sonogashira-Type Cross-Coupling
Table 2. Scope of the Cu(I)-Catalyzed Macrocyclic
Sonogashira-Type Cross-Coupling
a
a
entry
ligand
base
yield 2 (%)
recovered 1 (%)
1
3a
3b
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
25
25
30
58
30
32
58
73
78
78
38
<5
19
<5
19
48
19
<5
<5
<5
<5
32
46
2
b
3
3c
c
4
3c
5
3d
3f
6
7
3g
3e
3h
3i
8
9
10
11
12
13
d
3i
81
3i
70
63
3i
K3PO4
a
Yields following chromatography. Reactions run on 0.12 mmol scale.
b
Temperature refers to the temperature of the oil bath. In place of
CuCl, the preformed catalyst [Cu(DMEDA)2]Cl2 (5 mol %) was used
c
without any other added ligand. In place of CuCl, the preformed
d
catalyst [Cu(DMEDA)2]Cl2 (5 mol %) was used. Using 20 mol % of
3i.
3b, a 25% yield of the desired macrocycle 2 was obtained, along
with significant amounts of starting material 1 (38%). Using the
preformed catalyst [Cu(DMEDA)2]Cl2 (5 mol %) developed
by Bolm et al. afforded a low yield of 2 as well (30%); however,
employing [Cu(DMEDA)2]Cl2 with 30 mol % added 3c
provided an increased yield of 58%. Similarly higher yields of
the macrocycle resulted when employing the neocuproine 3g or
bipyrazine ligand 3e (58% and 73% of 2 respectively); however,
the most efficient ligands surveyed were bathophenanthroline
3h and 1,10-phenanthroline (phen) 3i, which afforded the
macrocycle 2 in an identical 78% yield. The ligand loading of
phen (3i) was subsequently investigated, and catalyst loadings
of 20 → 30 mol % afforded the best yields.8 Conducting the
macrocyclization in the absence of phen resulted in only 19% of
the desired macrocycle 2. When the reaction was repeated in
the absence of CuCl or Cs2CO3, no reaction was observed.9
Exchanging the Cs2CO3 base for other bases (K2CO3, K3PO4)
did not afford improvements in the yield of macrocycle 2.
Decreasing the concentration led to very slow reactions and
low yields of desired macrocycle 2.8 As CuCl/phen/Cs2CO3
was identified as a promising catalyst system, the synthesis of
various macrocycles with varying ring sizes and functionality
was explored (Table 2).
a
Yields following chromatography. Reactions typically performed on
0.12 mmol scale. Ring size of the macrocycles are indicated in red.
Using 20 mol % of phen. Reaction time was 48 h. Starting material
b
c
d
was the corresponding aryl bromide.
(entries 3 → 5): the benzolactone 6 was cyclized in 78%
yield. Replacing the ester functionality of 6 with an ether
afforded the macrocycle 7 in 71% yield. A pyridine-containing
analogue 8 was also prepared in good yield (58%). The 15-
membered macrocycle 2 was prepared in 81% yield, and the
macrocyclization could easily be scaled up to gram scale (∼2.5
mmol, 75%, 48 h). The macrocycle 2 could also be prepared
from the corresponding aryl bromide. Although the yield was
A 10-membered macrolactone 4 could be prepared in
modest yield (46%) demonstrating the viability of the method
for forming strained macrocycles. An analogous 13-membered
macrocycle 5 could be formed in higher yield (83%, entry 2). A
variety of 14-membered macrocycles were also prepared
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slightly lower (54%), the Cu-catalyzed macrocyclic Sonoga-
shira-type coupling represents a rare example of such a
transformation from a corresponding aryl bromide.10 The aryl
iodide moiety could be extended to naphthalene-derived motifs,
and the corresponding macrocycle 9 was isolated in good yield
(71%). The macrocycle 10 was formed from a corresponding
aryl diiodide. Interestingly, macrocyclization was observed with
complete selectivity to afford the 15-membered 10 in 77%
yield. The macrocyclization was also tolerant to varying the
position of the ester unit, as in the 15-membered macrocycle 11
(59% yield). Macrocyclization to form the enyne containing 15-
membered macrolactone 12 was hampered by the stability of
the corresponding starting material. While the macrocycle 12
could be isolated in 38% yield (entry 11), the β-iodo alkenyl
ester was sensitive to the basic conditions employed. Macro-
cyclization to form meta-substituted benzolactones occurred in
good yields; the 16- and 18-membered macrocycles 13 and 15
were obtained in 72% and 62% yields respectively (entries 12
and 14). Finally, the synthesis of larger rings was explored
(entries 13, 15, and 16). The 17-membered macrocycle 14 was
prepared in 66% yield, while the analogous 23- and 25-
membered benzolactones 16 and 17 were obtained in 65% and
61% yield, respectively.
and subsequent analysis13 confirmed the macrocyclic structure
of 22 (Scheme 1).
The mechanisms of existing Cu-catalyzed Sonogashira-type
cross-couplings have not all been studied in detail, and many
imply similar mechanistic proposals that have been described
for related Cu-catalyzed C−O, C−N, and C−X bond
formations.14 Recently, Bolm et al. have put forth some
mechanistic evidence for intermolecular Cu-catalyzed cou-
plings.15 A likely first step would involve in situ formation of
copper acetylide A (Scheme 2). Bolm reported experimental
Scheme 2. (Top) Possible Mechanism for the Cu-Catalyzed
Macrocyclic Sonogashira-Type Cross-Coupling; (Bottom)
Preliminary Mechanistic Investigations
To further demonstrate the utility of the Cu-catalyzed
macrocyclic Sonogashira-type strategy, the polyketide-derived
product (S)-zearalane was prepared, which has been reported
to have interesting anabolic, estrogenic, anthelminthic, and
immunomodulating properties (Scheme 1).11 The enantioen-
Scheme 1. Total Synthesis of (S)-Zearalane Using a Cu-
Catalyzed Macrocyclic Sonogashira-Type Coupling
evidence for the importance of excess ligand to promote the
formation of species such as copper acetylide A versus other
polymeric Cu acetylide complexes.15 Bolm also reported
computational studies suggesting against the formation of a
high energy Cu(III)-intermediate C via direct oxidative
addition. Alternatively, single electron transfer (SET) could
generate the radical anion B or B′. The formation of a radical
ion pair may help to induce a conformational preference which
is conducive to the formation of Cu(III)-intermediate C.
Preliminary investigations reveal a strong solvent dependence
for the macrocyclization. When the cyclization (1 → 2, CuCl (5
mol %), phen (30 mol %), Cs2CO3 (2 equiv), 135 °C) was
carried out in nonpolar solvents the yields were typically higher
(PhMe: 78%; PhCl: 74%; xylenes: 72%) than in polar solvents
(DMF: <5%; dioxane: 57%) which favor disassociation in the
proposed radical ion pair. As radical ion pairs are not
commonly invoked in mechanisms of the Pd-catalyzed
Sonogashira, it is possible that these mechanistic differences
are partially responsible for the efficiency of the Cu-catalyzed
strategy. Similar SET pathways for Cu-intermediates have been
proposed for photocatalytic Sonogashira cross-couplings.16
Formation of a carbon centered radical from B was
investigated: macrocyclization of alkyne 1 in the presence of
TEMPO as a radical trap still proceeded in high yield (72% vs
78% in the absence of TEMPO) (Scheme 2). In addition,
riched secondary alcohol 18, prepared via known procedures,12a
underwent Mitsunobu-type coupling with known acid 1912b to
provide the ester 20 (98% yield). Attempts at conducting the
macrocyclization of ester 20 using known Pd-based cross-
coupling conditions (Pd(PPh3)2Cl2 (5 mol %), CuI (10 mol
%), THF, 18 h) were unsuccessful. When using slow addition
and high dilution ([24 or 2.4 mM]), Sonogashira cross-
coupling of alkyne 20 did not afford any of the desired product
21, despite 100% consumption of the starting material 20. In
contrast, treating ester 20 with the catalytic system afforded the
14-membered macrolactone 21 in 56% yield. Hydrogenation of
the aryl alkyne (96% yield) and subsequent BBr3-mediated
cleavage of the methyl ethers afforded (S)-zearalane 22 in 36%
yield over two steps. X-ray quality crystals of (S)-zearalane were
obtained from slow diffusion of a CH2Cl2 solution into hexanes,
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Bruck, A.; Irran, E.; Meier, F.; Kaupp, M.; Driess, M.; Hartwig, J. F. J.
Am. Chem. Soc. 2013, 135, 15617.
submitting the allylated iodophenol 23 to the optimized
conditions for cross-coupling did not afford any of the cyclized
26.17 This is in contrast to recently reported Cu-catalyzed
photoinduced C−N bond formation in which C−I bond
cleavage was observed.18 The final step would involve reductive
elimination from C and regeneration of the active catalyst.19
In summary, a Cu-catalyzed macrocyclic Sonogashira-type
cross-coupling reaction has been developed that outperforms
other Pd-catalyzed protocols. Utilization of an operationally
simple CuCl/phen/Cs2CO3 catalyst system promotes macro-
cyclization at relatively high concentrations without the need
for slow addition techniques and does not afford homodime-
rization side products. The macrocyclizations are efficient even
when employing alkyl alkyne coupling partners which have
rarely been reported.6 Macrocycles with various ring sizes (10-
to 25-membered rings), functional groups, and arene
substituents (poly- and heteroaromatic) are accessible using
the optimized conditions. The protocol described herein
demonstrates that copper can replace the conventional,
expensive, and toxic Pd-catalyzed macrocyclic Sonogashira
cross-coupling reactions. The synthesis of biologically active
(S)-zearalane has been demonstrated and suggests that further
application in the synthesis of other natural products and
compounds of medicinal interest is possible.
(4) Marsault, E.; Peterson, M. L. J. Med. Chem. 2011, 54, 1961.
(5) (a) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. Tetrahedron
Lett. 1992, 16, 5363. (b) Sonogashira, K.; Tohda, Y.; Hagihara, N.
Tetrahedron Lett. 1975, 4467. (c) Sonogashira, K. In Metal-Catalyzed
Cross Coupling Reactions; Wiley-VCH: Weinheim, 2007; p 203.
(d) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084.
(e) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(6) For examples of Cu-catalyzed Sonogashira couplings, see:
(a) Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J.
Org. Chem. 1993, 58, 4716. (b) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-
F.; Xie, Y.-X.; Zhang, M.-B.; Hu, X. C. J. Org. Chem. 2007, 72, 2053.
(c) Monnier, F.; Turtaut, F. O.; Duroure, L.; Taillefer, M. Org. Lett.
2008, 10, 3203. (d) Saejueng, P.; Bates, C. G.; Venkataraman, D.
Synthesis 2005, 10, 1706. (e) Carril, M.; Correa, A.; Bolm, C. Angew.
Chem., Int. Ed. 2008, 47, 4862. (f) Zuidema, E.; Bolm, C. Chem.Eur.
J. 2010, 16, 4181. (g) Thathagar, M. B.; Beckers, J.; Rothenberg, G.
Green Chem. 2004, 6, 215. (h) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315.
(7) Stephens, R. D.; Castro, C. E. J. Org. Chem. 1963, 28, 3313.
(8) For a full description of the attempts to catalyze 1→2 using Pd-
catalysis, as well as more details concerning optimization of catalyst
loadings and concentrations, see the Supporting Information.
(9) The Pd-content of the starting materials was not measured. Note
that it has been shown that various chemicals can have trace amounts
of Pd that can promote Sonogashira couplings; see: Gonda, Z.; Tolnai,
G. L.; Novak
́
, Z. Chem.Eur. J. 2010, 16, 11822.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
(10) Cu-catalyzed Sonogashira of aryl bromides are rare, see:
(a) Thakur, K. G.; Jaseer, E. A.; Naidu, A. B.; Sekar, G. Tetrahedron
Lett. 2009, 50, 2865 (three examples, yields 35%−51%). (b) Mao, J.;
Guo, J.; Ji, S.-j.; Mao, J. J. Mol. Catal. A: Chem. 2008, 284, 85 (two
examples, yields 23%). (c) Yang, D.; Li, B.; Yang, H.; Fu, H.; Hu, L.
Synlett 2011, 5, 702 (four examples, yields 48%−72%).
(11) (a) Stob, M.; Baldwin, R.; Tuite, J.; Andrews, F. N.; Gillette, K.
G. Nature 1962, 196, 1318. (b) Furstner, A.; Thiel, O. R.; Kindler, N.;
Bartkowska, B. J. Org. Chem. 2000, 65, 7990. (c) Bracher, F.; Krauß, J.
Eur. J. Org. Chem. 2001, 4701.
(12) (a) Marshall, J. A.; Wang, X.-J. J. Org. Chem. 1991, 56, 4913.
(b) Mikula, H.; Skrinjar, P.; Sohr, B.; Ellmer, D.; Hametner, C.;
Frohlich, J. Tetrahedron 2013, 69, 10322.
(13) CCDC 999557 (22) contains the supplementary crystallo-
graphic data. These data can be obtained free of charge from The
Cambridge Crystallographic DataCentre via www.ccdc.cam.ac.uk/
data_request/cif.
(14) (a) Jones, G. O.; Liu, P.; Houk, K. N.; Buchwald, S. L. J. Am.
Chem. Soc. 2010, 132, 6205. (b) Casitas, A.; Ribas, X. Chem. Sci. 2013,
4, 2301.
S
AUTHOR INFORMATION
Corresponding Author
■
̈
*E-mail: shawn.collins@umontreal.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
The authors acknowledge the Natural Sciences and Engineering
Research Council of Canada (NSERC), Universite
Montreal, and the Centre for Green Chemistry and Catalysis
for generous funding. A.-C.B. thanks NSERC for a Vanier
graduate scholarship.
■
́
de
(15) Liang-Hua Zou, L.-H.; Johansson, A. J.; Zuidema, E.; Bolm, C.
Chem.Eur. J. 2013, 19, 8144.
(16) Sagadevana, A.; Hwanga, K. C. Adv. Synth. Catal. 2012, 354,
3421.
REFERENCES
■
(1) (a) Vendeville, S.; Cummings, M. D. Annu. Rep. Med. Chem.
2013, 48, 371. (b) Yu, X.; Sun, D. Molecules 2013, 18, 6230.
(c) Wolfson, W. Chem. Biol. 2012, 19, 1356. (d) White, C. J.; Yudin, A.
K. Nat. Chem. 2011, 3, 509. (e) Gross, D. E.; Zang, L.; Moore, J. S.
Pure Appl. Chem. 2012, 84, 869.
(2) Kong, J.; Chen, C.-y.; Balsells-Padros, J.; Cao, Y.; Dunn, R. F.;
Dolman, S. J.; Janey, J.; Hongmei Li, H.; Zacuto, M. J. J. Org. Chem.
2012, 77, 3820.
(3) Pd-catalyzed macrocyclic Sonogashira couplings: (a) Hussain, A.;
Khalid, S.; Kumar, D. Y.; Lambu, M.; Singh, B.; Maity, S.; Mukherjeea,
D. Adv. Synth. Catal. 2012, 354, 1933. (b) Hussain, A.; Rao, M.;
Sharma, D. K.; Tripathi, A. K.; Singhb, B.; Mukherjee, D. RSC Adv.
2013, 3, 19899. (c) Spivey, A. C.; McKendrick, J.; Srikaran, R. J. Org.
Chem. 2003, 68, 1843. (d) Balraju, V.; Reddy, D. S.; Periasamy, M.;
Iqbal, J. J. Org. Chem. 2005, 70, 9626. (e) Yamasaki, R.; Shigeto, A.;
Saito, S. J. Org. Chem. 2011, 76, 10299. (f) Krauss, J.; Unterreitmeier,
D.; Neudert, C.; Bracher, F. Arch. Pharm. Chem. Life Sci. 2005, 338,
605. For a Ni-catalyzed Sonogashira cross-coupling: (g) Gallego, D.;
(17) (a) Tye, J. W.; Weng, Z.; Johns, A. M.; Incarvito, C. D.; Hartwig,
J. F. J. Am. Chem. Soc. 2008, 130, 9971. There is some debate about
the validity of using 23 as a mechanistic probe. See: (b) Sperotto, E.;
van Klink, G. P. M.; Koten, G.; de Vries, J. G. Dalton Trans. 2010, 39,
10338.
(18) Creutz, S. E.; Lotito, K. J.; Fu, G. C.; Peters, J. C. Science 2012,
338, 647.
(19) Direct evidence for the involvement of aryl−Cu(III)
intermediates in copper-catalyzed C−H methoxylation reactions has
been reported: King, A. E.; Huffman, L. M.; Casitas, A.; Ribas, X.;
Stahl, S. S. J. Am. Chem. Soc. 2010, 132, 12068.
3895
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