Photoinduced Copper-Catalyzed Coupling of Terminal Alkynes and Alkyl Iodides

Article abstract of DOI:10.1002/anie.201801085

We have developed a photoinduced copper-catalyzed alkylation of terminal alkynes with primary, secondary, or tertiary alkyl iodides as electrophiles. The reaction has a broad substrate scope and can be successfully performed in the presence of ester, nitr

Full text of DOI:10.1002/anie.201801085

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Title: Photoinduced, Copper-Catalyzed Coupling of Terminal Alkynes
and Alkyl Iodides
Authors: Avijit Hazra, Mitchell T Lee, Justin F Chiu, and Gojko Lalic
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Photoinduced, Copper-Catalyzed Coupling of Terminal
Alkynes and Alkyl Iodides
Avijit Hazra, Mitchell T. Lee, Justin F. Chiu, and Gojko Lalic*
Abstract: We have developed a photoinduced, copper-catalyzed
alkylation of terminal alkynes, using primary, secondary, or tertiary
alkyl iodides as electrophiles. The reaction has a broad substrate
scope and can be successfully performed in the presence of esters,
nitriles, aryl halides, ketones, sulfonamides, epoxides, alcohols, and
amides. The alkylation is promoted by blue light (~450 nm) and
proceeds at room temperature in the absence of any additional metal
catalysts. The use of a terpyridine ligand is essential for the success
of the reaction and is shown to prevent photoinduced copper-
catalyzed polymerization of the starting materials
nickel catalyst.[13] More recently, two reports described the
extension to reactions of secondary alkyl halides.[14] Overall, the
Sonogashira reaction still provides the most general method for
the alkylation of terminal alkynes.
Alkylation of terminal alkynes and their derivatives is an
important approach to the synthesis of internal alkynes.
Numerous methods are available for the alkylation of pre-
functionalized alkyne substrates, such as haloalkynes,[1] metal
acetylides,[2] alkynylbenziodoxolones,[3] and alkynyl sulfones.[4] In
comparison, there are significantly fewer methods for the
alkylation of terminal alkynes.
Most catalytic methods[5] for the alkylation of terminal
alkynes rely on in situ formation of copper acetylides, which serve
as key catalytic intermediates (Scheme 1). They are easily formed
from terminal alkynes in the presence of a weak base and a
copper salt.[6] However, the low nucleophilicity of copper
acetylides makes their alkylation challenging.[6] Direct alkylation
can only be achieved using strong electrophiles, such as primary
alkyl triflates,[7] activated α- and β-haloamides,[8] oxocarbenium
ions,[9] and iminium ions (Scheme 1a).[10] Alternatively, the
alkylation of copper acetylides can be accomplished using
Sonogashira reaction,[11], which requires an additional transition
metal catalyst (Scheme 1b). Although examples of Sonogashira
alkylation reaction are relatively rare, the reaction can be
accomplished using primary alkyl halides and a palladium[12] or
Scheme 1. Copper-catalyzed alkylation of terminal alkynes
We were interested in developing a light-promoted, copper-
catalyzed coupling of terminal alkynes and alkyl halides that
would obviate the need for palladium or nickel catalysts (Scheme
1c). Both metals are significantly more toxic than copper,[15] and
are often difficult to remove from the alkylation product.
Our approach to the alkylation of terminal alkynes was
inspired by photoinduced, copper-catalyzed reactions developed
independantly by Fu and Peters[16] and by Hwang.[17],[18] The key
sequence in transformations reported by Fu and Peters is the
photoexcitation of the copper-nucleophile complex followed by
electron-transfer to an alkyl halide. This approach has been
applied to alkylation of a range of nitrogen-based nucleophiles.[19]
Applications to carbon-based nucleophiles have, so far, been
limited to the alkylation of cyanide[20] and specific types of
heteroarenes.[21] Numerous investigations of the photophysical
properties of copper acetylides suggest that the same approach
can be used to accomplish photoinduced, copper-catalyzed
alkylation of terminal alkynes according to the mechanism
outlined in Scheme 2.
[*]
A. Hazra, M. T. Lee, J.F. Chiu, Prof. G. Lalic
Department of Chemistry
University of Washington,
Seattle WA 98195, USA
E-mail: lalic@che.washington.edu
[b]
Supporting information for this article is given via a link at the end of
the document.
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tert-butyl-2,2’:6’,2’’-terpyridine (L1) as the ligand, K2CO3 as the
base and an acetonitrile-methanol (3:1) solvent system (entry 1).
Throughout the optimization of this reaction, several observations
were made and have been summarized in Table 1
Table 1. Reaction development
Scheme 2. Plausible mechanism of photoinduced alkylation
In 2012, simultaneously with the initial report by Fu and
Peters,[16a] Hwang reported a photoinduced, copper-catalyzed
arylation of terminal alkynes, which involves photoexcitation of the
[22]
copper acetylide intermediate.[17],
Prior to Hwang’s seminal
work, it was known that the photoexcitation of copper acetylide
complexes (acetylide  Cu transition) can be achieved by
relatively low energy photons (>350nm) ).[23] The resulting excited
states are long lived (on the order of µs), and highly reducing (E1/2
= -1.77 V vs SCE).[23c] Redox potentials of alkyl iodides (for EtI
E1/2= -0.92 V vs SCE) suggest that they can be reduced by
electron transfer from excited complex 2.[24] Finally, organocopper
complexes with similar photophysical properties to copper
acetylides have been shown to undergo fast quenching of their
excited states by electron transfer to a range of organohalides.[23b]
19a, 19b]
Using the conditions established by Fu[16,
and
Hwang[17] as a starting point for our experiments, we explored the
photochemical reaction of phenyl acetylene with n-BuI using CuCl
as a catalyst and an acetonitrile/methanol mixture as the solvent.
The reaction resulted in the formation of only 12% of the desired
product and 16% of the alkyne dimer. Together, these products
accounted for only 28% of the consumed alkyne. The rest of the
starting alkyne was incorporated into low molecular weight
polymers, which were identified by gel permeation
chromatography (GPC) of the crude reaction mixture.[25],[26]
Blue light and the copper catalyst were both necessary for the
alkylation (entries 2 and 3). L1 was determined to be essential to
the success of the reaction (entry 4). In the absence of the ligand,
we obtained only 20% of the desired product, with the major
product being polymerization of the starting material. Changing to
unsubstituted terpyridine (L2) or closely related PyBox (L3)
compromised the yield (entries 5 and 6). Additionally, structurally
similar bidentate ligands, like dtbpy (L4), were found to be
ineffective (entry 7). Solvent was also important, with pure
acetonitrile or pure methanol both giving significantly lower yields
of the alkylation product (entries 8 to 10). Potassium carbonate
was uniquely effective as the base, and even the closely related
cesium carbonate provided no alkylation product (entry 11).
Decreasing the amount of ligand to 12% did not lead to a
considerable loss in yield (entry 12).[27] Finally, we found that alkyl
bromides and chlorides are not viable substrates.
The standard reaction conditions were effective for a diverse
set of electrophiles (Table 2). Primary iodides as well as cyclic
and acyclic secondary alkyl iodides were viable substrates and
provided the desired alkylation products in high yields. The
reaction was compatible with a wide range of functional groups,
and could be successfully accomplished in the presence of aryl
bromides (11), aryl chlorides (12), alcohols (17), silyl ethers (18),
nitriles (14), esters, sulfonamides (26), and ethers (22).
Control experiments confirmed that polymerization occurs
only in the presence of both light and copper catalyst and suggest
that the polymerization involves the photoactivated copper
acetylide as a key intermediate. We surmised that with the proper
choice of ligand for the copper catalyst, we could modulate the
reactivity of the excited copper acetylide complex to suppress the
polymer formation, and enable the desired alkylation. This
approach was particularly attractive considering that ligand
effects on reactivity in related photoexcited copper complexes
have been rarely documented.
Exploration of a wide range of ligands and other reaction
parameters led to the development of the alkylation reaction
shown in Table 1. The best results were obtained using 4,4’,4”-tri-
Reactions with tertiary iodides proved to be more difficult.
Under standard reaction conditions, simple tert-butyl iodide
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underwent solvolysis faster than the coupling reaction. Changing
to tert-butyl bromide slowed down the solvolysis, but no coupling
product was obtained.
We also explored the reaction with a range of terminal
alkynes. A broad variety of alkyne coupling partners underwent
photoinduced coupling to furnish products in very good yields
(Table 3). Esters (34), nitriles (37), epoxides (41), ketones (35),
aryl fluorides (36), and alkenes (32) were all compatible with the
alkylation reaction. Similarly, excellent yield of the desired product
was obtained in the presence of a primary amide (40), which is
known to undergo N-alkylation under similar reaction
conditions.[19b] Finally, aryl (42 and 43) and heteroaryl (38)
alkynes also furnished the desired product in good yields.
Table 2. Scope of alkyl iodide[a]
Table 3. Scope of alkyne[a]
Based on the mechanism of the related photoinduced,
copper-catalyzed alkylation, we propose that the alkylation of
terminal alkynes proceeds according to the mechanism shown in
Scheme 2. In an effort to probe the mechanism of the reaction,
we performed the experiments shown in Scheme 3. The presence
of one or more equivalents of TEMPO completely shut down the
reaction, whereas 20 mol% of TEMPO partially hampered it.
Additionally, a cyclohexyl- TEMPO adduct was isolated from the
reaction mixture, indicating the presence of alkyl radical
intermediates. The results of these experiments suggest the
involvement of free-radical intermediates.[30] The competition
experiment between a primary and a secondary alkyl iodide
resulted in the formation of the similar quantities of the two
products (Scheme 3b). Considering the relatively small difference
in the redox potentials of primary and secondary alkyl halides,[24]
this result is consistent with electron-transfer as the product- and
rate-determining step of the reaction
We reasoned that destabilizing the tertiary carbocation
intermediate would prevent solvolysis and allow coupling to
proceed. This strategy proved effective and bridgehead tertiary
iodides were found to be viable coupling partners. 1-Adamantyl
(29), bicyclopentyl (28), and bicyclooctyl (30) iodides all provided
the expected alkylation product is useful yields. These results are
worth noting in light of the difficulties commonly encountered in
alkynylation[28] and other cross-coupling reactions of tertiary
bridgehead iodides.[29]
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Lett. 2017, 19, 1744-1747; (c) T. Thaler, L.-N. Guo, P. Mayer, P. Knochel,
Angew. Chem., Int. Ed. 2011, 50, 2174-2177; (d) J. He, M. Wasa, K. S.
L. Chan, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 3387-3390; (e) L.
Huang, A. M. Olivares, D. J. Weix, Angew. Chem., Int. Ed. 2017, 56,
11901-11905.
[2]
(a) T. Hatakeyama, Y. Okada, Y. Yoshimoto, M. Nakamura, Angew.
Chem., Int. Ed. 2011, 50, 10973-10976; (b) H. Ohmiya, H. Yorimitsu, K.
Oshima, Org. Lett. 2006, 8, 3093-3096; (c) O. Vechorkin, A. Godinat, R.
Scopelliti, X. Hu, Angew. Chem., Int. Ed. 2011, 50, 11777-11781; (d) C.
W. Cheung, P. Ren, X. Hu, Org. Lett. 2014, 16, 2566-2569; (e) J. Caeiro,
J. Pérez Sestelo, L. A. Sarandeses, Chem. Eur. J. 2008, 14, 741-746; (f)
J. M. Smith, T. Qin, R. R. Merchant, J. T. Edwards, L. R. Malins, Z. Liu,
G. Che, Z. Shen, S. A. Shaw, M. D. Eastgate, P. S. Baran, Angew. Chem.,
Int. Ed. 2017, 56, 11906-11910.
[3]
(a) F. Le Vaillant, T. Courant, J. Waser, Angew. Chem., Int. Ed. 2015, 54,
11200-11204; (b) X. Liu, Z. Wang, X. Cheng, C. Li, J. Am. Chem. Soc.
2012, 134, 14330-14333; (c) H. Huang, G. Zhang, L. Gong, S. Zhang, Y.
Chen, J. Am. Chem. Soc. 2014, 136, 2280-2283; (d) C. Yang, J.-D. Yang,
Y.-H. Li, X. Li, J.-P. Cheng, J. Org. Chem. 2016, 81, 12357-12363.
J. Yang, J. Zhang, L. Qi, C. Hu, Y. Chen, Chem. Commun. 2015, 51,
5275-5278.
[4]
[5]
Scheme 3. Mechanistic experiments
For an example of light-promoted alkylation of aryl acetylenes in the
absence of a copper catalyst, see: W. Liu, L. Li, C.-J. Li, Nature
Communications 2015, 6, 6526.
Overall, we have developed a photoinduced, copper-
catalyzed coupling of terminal alkynes with unactivated primary,
secondary, and tertiary alkyl iodides. The reaction has a broad
substrate scope and is compatible with esters, nitriles, alcohols,
amides, epoxides, aryl halides, and ethers. The key for the
success of the reaction is the tri tert-butyl terpyridine ligand which
favors the productive alkylation at the expense of the
photoinduced copper-catalyzed polymerization of the starting
materials. The alkylation reaction proceeds through a direct
coupling between copper acetylide and an unactivated alkyl
iodide, most likely with the involvement of free-radical
intermediates
[6]
G. Evano, K. Jouvin, C. Theunissen, C. Guissart, A. Laouiti, C. Tresse,
J. Heimburger, Y. Bouhoute, R. Veillard, M. Lecomte, A. Nitelet, S.
Schweizer, N. Blanchard, C. Alayrac, A. C. Gaumont, Chem. Commun.
2014, 50, 10008-10018.
[7]
[8]
L. Jin, W. Hao, J. Xu, N. Sun, B. Hu, Z. Shen, W. Mo, X. Hu, Chem.
Commun. 2017, 53, 4124-4127.
(a) F.-X. Luo, X. Xu, D. Wang, Z.-C. Cao, Y.-F. Zhang, Z.-J. Shi, Org.
Lett. 2016, 18, 2040-2043; (b) Y. Yamane, N. Miwa, T. Nishikata, ACS
Catalysis 2017, 7, 6872-6876.
[9]
(a) P. Maity, H. D. Srinivas, M. P. Watson, J. Am. Chem. Soc. 2011, 133,
17142-17145; (b) H. D. Srinivas, P. Maity, G. P. A. Yap, M. P. Watson,
J. Org. Chem. 2015, 80, 4003-4016; (c) S. Dasgupta, T. Rivas, M. P.
Watson, Angew. Chem., Int. Ed. 2015, 54, 14154-14158.
[10] (a) H.-P. Bi, L. Zhao, Y.-M. Liang, C.-J. Li, Angew. Chem., Int. Ed. 2009,
48, 792-795; (b) C. Zhang, D. Seidel, J. Am. Chem. Soc. 2010, 132,
1798-1799; (c) H. Zhang, P. Zhang, M. Jiang, H. Yang, H. Fu, Org. Lett.
2017, 19, 1016-1019.
Experimental Section
In a nitrogen-filled glovebox, a 1.5-dram vial was charged with a Teflon
coated stir bar, CuCl (5.0 mg, 0.05 mmol, 0.10 equiv.), 4,4',4''-tri-tert-butyl-
2,2':6',2''-terpyridine (40.0 mg, 0.10 mmol, 0.20 equiv.) and K2CO3 (207.3
mg, 1.50 mmol, 3.0 equiv.). A mixture of 1:3 methanol in acetonitrile (5 mL,
0.1 M) and alkyne (0.50 mmol, 1.0 equiv.) were then added. Alkyl iodide
(1.00 mmol, 2 equiv.) was added to the reaction vessel, which was then
capped and the reaction mixture was stirred vigorously under the
irradiation of blue light in the reaction chamber (Fig. S1). After the indicated
time, the reaction was stopped. The reaction mixture was filtered through
a pad of silica gel and washed with EtOAc and DCM. The filtrate was
concentrated under reduced pressure and purified by silica gel
chromatography.
[11] (a) R. Chinchilla, C. Nájera, Chem. Rev. 2007, 107, 874-922; (b) R.
Chinchilla, C. Najera, Chem. Soc. Rev. 2011, 40, 5084-5121.
[12] M. Eckhardt, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 13642-13643.
[13] (a) P. M. Pérez García, P. Ren, R. Scopelliti, X. Hu, ACS Catalysis 2015,
5, 1164-1171; (b) O. Vechorkin, D. Barmaz, V. Proust, X. Hu, J. Am.
Chem. Soc. 2009, 131, 12078-12079.
[14] (a) G. Altenhoff, S. Würtz, F. Glorius, Tetrahedron Lett. 2006, 47, 2925-
2928; (b) J. Yi, X. Lu, Y.-Y. Sun, B. Xiao, L. Liu, Angew. Chem., Int. Ed.
2013, 52, 12409-12413.
[15] (a) Oral permitted daily exposure values recommended by Food and
Drug Administration are 200 µg/day for Ni, 100 µg/day for Pd, and 3000
µg/day for Cu. See: "Q3D Elemental Impurities Guidance for Industry",
U.S. Department of Health and Human Services, Food and Drug
Administration, September 2015; For European standards, see: (b)
European Medicines Agency, Committee for medicinal products for
human use, "Guideline on the specification limits for residues of metal
catalysts of metal reagents", London, 2008
Acknowledgements
Financial support by NSF is acknowledged (NSF CAREER Award
1254636).
[16] (a) S. E. Creutz, K. J. Lotito, G. C. Fu, J. C. Peters, Science 2012, 338,
647-651; (b) C. Uyeda, Y. Tan, G. C. Fu, J. C. Peters, J. Am. Chem. Soc.
2013, 135, 9548-9552; (c) Y. Tan, J. M. Munoz-Molina, G. C. Fu, J. C.
Peters, Chem. Sci. 2014, 5, 2831-2835.
Keywords: keyword 1 • keyword 2 • keyword 3 • keyword 4 •
keyword 5
[17] A. Sagadevan, K. C. Hwang, Adv. Synth. Catal. 2012, 354, 3421-3427.
[18] For recent overview of photocatalysis involving copper complexes, see:
(a) O. Reiser, Acc. Chem. Res. 2016, 49, 1990-1996; (b) S. Paria, O.
Reiser, ChemCatChem 2014, 6, 2477-2483.
[1]
(a) G. Cahiez, O. Gager, J. Buendia, Angew. Chem., Int. Ed. 2010, 49,
1278-1281; (b) Y. Shen, B. Huang, J. Zheng, C. Lin, Y. Liu, S. Cui, Org.
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[19] (a) Q. M. Kainz, C. D. Matier, A. Bartoszewicz, S. L. Zultanski, J. C.
Peters, G. C. Fu, Science 2016, 351, 681-684; (b) H.-Q. Do, S. Bachman,
A. C. Bissember, J. C. Peters, G. C. Fu, J. Am. Chem. Soc. 2014, 136,
2162-2167; (c) C. D. Matier, J. Schwaben, J. C. Peters, G. C. Fu, J. Am.
Chem. Soc. 2017, 139, 17707-17710; (d) A. C. Bissember, R. J.
Lundgren, S. E. Creutz, J. C. Peters, G. C. Fu, Angew. Chem., Int. Ed.
2013, 52, 5129-5133; (e) J. M. Ahn, T. S. Ratani, K. I. Hannoun, G. C.
Fu, J. C. Peters, J. Am. Chem. Soc. 2017, 139, 12716-12723.
[20] T. S. Ratani, S. Bachman, G. C. Fu, J. C. Peters, J. Am. Chem. Soc.
2015, 137, 13902-13907.
[24] A. A. Isse, C. Y. Lin, M. L. Coote, A. Gennaro, The Journal of Physical
Chemistry B 2011, 115, 678-684.
[25] Similar results were obtained in other reactions of alkyl- and aryl-
substituted alkynes with both primary and secondary alkyl iodides. See
SI for details.
[26] For a detailed discussion of these results in light of experiments
presented in reference 21, see SI.
[27] Lowering the catalyst loading to 5 mol% led to small decrease in the yield
of the product. See Table S4. in the SI.
[28] M. Messner, S. I. Kozhushkov, A. De Meijere, Eur. J. Org. Chem. 2000,
1137-1155.
[21] (a) F. Yang, J. Koeller, L. Ackermann, Angew. Chem., Int. Ed. 2016, 55,
4759-4762; (b) P. Gandeepan, J. Mo, L. Ackermann, Chem. Commun.
2017, 53, 5906-5909.
[29] F. Toriyama, J. Cornella, L. Wimmer, T.-G. Chen, D. D. Dixon, G. Creech,
P. S. Baran, J. Am. Chem. Soc. 2016, 138, 11132-11135.
[30] During the preparation of this manuscript, Fu et al. reported similar study
in the context of the alkylation of amines. See reference 19c.
[22] A. Tlahuext-Aca, M. N. Hopkinson, B. Sahoo, F. Glorius, Chem. Sci.
2016, 7, 89-93.
[23] (a) V. W. W. Yam, W. K. Lee, T. F. Lai, Organometallics 1993, 12, 2383-
2387; (b) V. W.-W. Yam, W.-K. Lee, K. K. Cheung, H.-K. Lee, W.-P.
Leung, J. Chem. Soc., Dalton Trans. 1996, 2889-2891; (c) V. W.-W. Yam,
K. Kam-Wing Lo, K. Man-Chung Wong, J. Organomet. Chem. 1999, 578,
3-30.
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