Cleavage of C–C and C–O Bonds to Form C–C Bonds: Direct Cross-Coupling between Acetylenic Alcohols and Benzylic Carbonates

Article abstract of DOI:10.1002/ejoc.201800861

A palladium-catalyzed cross-coupling reaction between C(sp) and C(sp³) centers was achieved in excellent yields via C–C bond cleavage and C–O bond cleavage. This procedure uses relatively stable acetylenic alcohols as reactants instead of unsta

Full text of DOI:10.1002/ejoc.201800861

A Journal of
Accepted Article
Title: Cleavage of C-C and C-O Bonds to Form C-C Bonds: Direct
Cross-coupling Between Acetylenic Alcohols and Benzylic
Carbonates
Authors: Zhiyuan Mi, Jiahao Tang, Zhipeng Guan, Wei Shi, and Hao
Chen
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10.1002/ejoc.201800861
European Journal of Organic Chemistry
Cleavage of C-C and C-O Bonds to Form C-C Bonds: Direct
Cross-coupling Between Acetylenic Alcohols and Benzylic
Carbonates
Zhiyuan Mia, Jiahao Tangb, Zhipeng Guanb, Wei Shi*b and Hao Chenb
a School of Food and Biological Engineering, Hubei University of Technology
b College of Science, Huazhong Agricultural University
Corresponding author: Dr. Wei Shi, shiwei@mail.hzau.edu.cn https://orcid.org/0000-0002-7065-4654
Dedicated to Prof. Xiyan Lu on the occasion of his 90th birthday.
Abstract:
A Palladium catalyzed cross-coupling reaction between C(sp) and C(sp3) centers was achieved via
the C-C bond cleavage in acetone protected terminal alkynes and C-O bond cleavage in benzylic
carbonates. Good to excellent yields are observed for 24 examples. This procedure uses the
relatively stable acetylenic alcohols, a widely used alkynyl reagent in laboratory synthesis, instead
of the unstable and volatile terminal alkynes as the reactant. The employment of benzylic
carbonates has also avoided the involvement of lachrymatory benzyl halides, making this method
more practical in synthesis. Ligands play an important role in the procedure. K2CO3 is proved to
be able to accelerate the reaction.
Key words:
Acetylenic alcohols, benzylic carbonates, C-C bond forming, cleavage of C-C bonds.
Introduction:
Acetylene moieties are one of the most important structures in organic synthesis1-3.
Cross-coupling of terminal alkynes with other structures represent one of the most useful and
efficient method to introduce the acetylene moieties into the target molecules4-6. Over the past
several decades, the coupling reactions involving terminal alkynes have been well studied7, 8, as
known as the Sonogashira type coupling reactions, and also have been widely applied in organic
synthesis from laboratory preparation to industrial scaled-up production. However, only simple
terminal alkynes are commercially available. For more complex structures containing terminal
alkyne moieties in laboratory synthesis, they are often prepared from the cross-coupling between
electrophiles with acetylenic alcohols9 or silanes, as shown in Scheme 1. For acetylenic silanes,
the high cost has restricted their applications in scaled-up preparation. Although the acetylenic
alcohols are usually of much lower cost, the generation and isolation of terminal alkynes may
cause extra effort and waste. Thus it would be much more efficient if the relative cheap acetylenic
alcohols (1 in Scheme 1) could be directly used as the alkynyl sources in cross-coupling reactions
with other substrates, as shown in Scheme 1.
Scheme 1. Methods to introduce the acetylenic moieties into benzylic structures
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10.1002/ejoc.201800861
European Journal of Organic Chemistry
There have already a few reports that employed acetylenic alcohols as the alkyne source in
coupling reactions. Chow et al. reported an early example of Pd/Cu catalyzed coupling between
aryl halides with acetylenic alcohols under phase transfer conditions10. Similar work using
acetylenic alcohols as the source of alkynes were reported respectively by several team, include
Tsai11, Wu12, 13, Chang14, Wen15, Uemura16, Endo17 and Gu18. It is noted that most of these reports
have employed aryl halides or alkenes as the other coupling reagents, forming a Csp-Csp2 bond.
There are also several reports that focus on the coupling reactions between terminal alkynes and
benzyl halides to form the Csp-Csp3 bond. Pérez et al. have described the cross-coupling reaction
of indium acetylides as nucleophiles with benzyl bromine.19 Deepak and co-workers reported an
nickel catalyzed coupling reaction between benzyl bromine and aluminum acetylides.20
Meanwhile, researchers also obtained benzylic alkynes through breakage of C-H bond in terminal
alkynes instead breakage of C-M(In, Zn, Al).21-24 Zhang has also disclosed an example of
decarboxylative cross-coupling between alkynyl carboxylic acids and benzyl halides for the
synthesis of benzylic alkynes25. Considering about the lachrymatory property of benzyl halides,
using the easy-handling benzylic carbonates instead may represent a better choice. Hirano et al.
have reported that diaryl methyl carbonates could undergo cross-coupling with terminal alkynes
smoothly, with moderate to good yields26. However, simple diphenylmethyl carbonate did not
perform well, and another limitation was that arylacetylenes, like phenylacetylene, did not react
under this condition. A very recent report by Chatani et al. reveals a Rh-catalyzed C-O bond
alkynylation using aryl carbamates with propargyl alcohols27, indicating the importance of the
acetylenic alcohols in organic synthesis. However, to our best knowledge, there is no report that
realized the cross-coupling between benzylic carbonates and acetylenic alcohols directly till now.
Based on these discoveries and our earlier study on the preparation of terminal alkynes from
acetylenic alcohols9, we wish to report our latest discoveries on the formation of C(sp)-C(sp3)
bonds through the cleavage of C(sp)-C(sp3) bonds in aryl propargyl alcohols and C(sp3)-O in
benzylic carbonates.
Results and Discussion:
We initiate our model reaction exploration utilizing benzylic carbonate 2a as the electrophile in
the presence of Pd catalyst, as shown in Table 1. By employing 5 mol% of Pd(OAc)2 and 5 mol%
phosphine ligand, the reaction did merely occur (entries 1-7). Screening of the bases (entries 8-12)
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10.1002/ejoc.201800861
European Journal of Organic Chemistry
or increasing the catalyst loading (entry 13) did not improve the yield either. To our delight, excess
of ligand over the Pd catalyst have reversed the reaction, and satisfactory results were achieved
when 10 mol% Pd(OAc)2 with 20 mol% of dppb (1,4-Bis(diphenylphosphino)butane) as the
ligand (99%, entry 15) was employed. Stoichiometric amount of base was required, while
decreasing the amount of base may lead to lower yields (entries 17-19). It is also noteworthy that
this reaction could occur effectively in air atmosphere (entry 16).
Table 1. Condition optimization for the cross-coupling of acetylenic alcohols with benzylic
carbonates
With the optimized conditions in hand (Table 1, entry 16, 99%), we then examined the
cross-coupling reaction of acetylenic alcohol 1a with a variety of benzylic carbonates for the
synthesis of benzylic alkynes, as shown in Table 2. Satisfactory results were obtained using this
method. The model reaction initiate from 1a and 2a gave 99% isolated yield of the product 3aa.
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10.1002/ejoc.201800861
European Journal of Organic Chemistry
The electronic properties of the substitute group on aryl moiety of the benzylic carbonates did not
affect the reaction, with the exception of trifluoromethyl group, of which only 41% product (3ah)
was obtained. NMR analysis showed the tautomeric transformation of the product 3ah between
alkyne form and allene form21. Furthermore, the secondary benzyl carbonates also worked well
under this condition (3aj and 3ak).
Table 2. Substrate scope of benzylic carbonates a
We have also examined the substrates scope of different acetylenic alcohols and the results were
shown in Table 3. A series of aryl propargylic alcohols were proved to be compatible, generating
the products in good to excellent yields. Ortho-, meta- and para-substituents on the phenyl ring of
the aryl propargylic alcohols were tolerated and all gave good yields (3ba~3da). Aryl propargylic
alcohols bearing electron-donating or electron-withdrawing substituents also gave acceptable
yields of the corresponding products. Naphthalene and heterocyclic aromatic substituents were
also tolerated in this reaction (3ja, 3ma and 3na).
Table 3. Substrate scope of acetylenic alcohols a
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10.1002/ejoc.201800861
European Journal of Organic Chemistry
A scaled up experiment under similar condition has also been taken, employing 5 mmol of the
acetylenic alcohol 1a and equal amount of benzylic carbonate 2a to yield the product 3aa in 86%
isolated yield. It is notable that in this gram scale reaction the catalyst loading of Pd(OAc)2 could
be halved into 5 mol%, as shown in Scheme 2.
Scheme 2. Gram scale synthesis of 3aa
A proposed mechanism of this transformation is shown in Scheme 3. Firstly, Pd(Ⅱ) is reduced to
form an active species Pd(0) , which then goes through the oxidative addition step by 2a to
generate B. B could easily undergo the decarboxylation step to form the intermediate C, which
could interconvert with its tautomer, (η1-benzyl)(alkoxo)-palladium (D), and further reacts with 1a
in the presence of K2CO3 to form the Pd(II) intermediate E via a deacetonative step28-30. Finally,
the desired product 3a together with the active catalyst center Pd(0) is generated through reductive
elimination of E to fulfill the catalytic cycle.
Scheme 3. Proposed mechanism
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10.1002/ejoc.201800861
European Journal of Organic Chemistry
Conclusions:
In summary, we have developed a palladium-catalyzed deacetonative cross-coupling reaction
between aryl propargyl alcohols with benzylic carbonates, which involves the breakage of
C(sp)-C(sp3) bonds in aryl propargyl alcohols and C(sp3)-O bonds in benzylic carbonates for the
formation of C(sp)-C(sp3) bonds in benzylic alkynes. This reaction avoids the employment of
more expensive terminal alkynes and lachrymatory benzyl halides, and could proceed smoothly in
moderate to good yields in air atmosphere with a broad substrate scope in both propargyl alcohols
and benzylic carbonates.
Experimental Section
General procedure for preparation of benzylic alkynes
To a solution of 1,4-dioxane (3 mL) in a flame dried flask were sequentially added propargyl
alcohol 1 (0.25 mmol), benzyl carbonate 2 (0.375 mmol), Pd(OAc)2 (0.025 mmol), dppb (0.05
mmol) and K2CO3 (0.25 mmol). After stirring under 120℃ for 12 h, the reaction mixture was
carefully quenched with 20 mL of brine and extracted by EtOAc (6 mL × 2), dried over anhydrous
Na2SO4 and concentrated. Finally, the residue was purified by a flash chromatograph on silica gel
to give the desired product.
Acknowledgement:
This work was supported by the Fundamental Research Funds for the Central Universities
(Program No. 2662018PY051) and the National Natural Science Foundation of China (NSFC)
(51572101, 21202050).
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10.1002/ejoc.201800861
European Journal of Organic Chemistry
References:
1.
2.
3.
W. Shi, Curr. Organocatal., 2015, 2, 2-13.
W. Shi and A. Lei, Tetrahedron Lett., 2014, 55, 2763-2772.
P. Siemsen, R. C. Livingston and F. Diederich, Angew. Chem., Int. Ed., 2000, 39,
2632-2657.
4.
A. Lei, W. Shi, C. Liu, W. Liu, H. Zhang and C. He, Oxidative Cross-Coupling Reactions,
Wiley-VCH Verlag GmbH & Co., Weinheim, Germany, 2017.
5.
6.
7.
8.
W. Shi, C. Liu and A. Lei, Chem. Soc. Rev., 2011, 40, 2761-2776.
C. Liu, H. Zhang, W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780-1824.
E.-I. Negishi and L. Anastasia, Chem. Rev., 2003, 103, 1979-2017.
W. Shi, Y. Luo, X. Luo, L. Chao, H. Zhang, J. Wang and A. Lei, J. Am. Chem. Soc., 2008, 130,
14713-14720.
9.
Z. Guan, Y. Shi, W. Shi and H. Chen, Chin. J. Org. Chem., 2017, 37, 418-422.
H. F. Chow, C. W. Wan, K. H. Low and Y. Y. Yeung, J. Org. Chem., 2001, 66, 1910-1913.
T. T. Hung, C. M. Huang and F. Y. Tsai, Chemcatchem, 2012, 4, 540-545.
X. Li, S. Y. Sun, F. Yang, J. X. Kang, Y. S. Wu and Y. J. Wu, Org. Biomol. Chem., 2015, 13,
2432-2436.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
H. Hu, F. Yang and Y. J. Wu, J. Org. Chem., 2013, 78, 10506-10511.
F. Chang and Y. P. Liu, Synth. Commun., 2017, 47, 961-967.
T. Li, Z. Wang, W. B. Qin and T. B. Wen, Chemcatchem, 2016, 8, 2146-2154.
T. Nishimura, H. Araki, Y. Maeda and S. Uemura, Org. Lett., 2003, 5, 2997-2999.
C. K. Choi, I. Tomita and T. Endo, Chem. Lett., 1999, 1253-1254.
F. G. Sun, M. Li and Z. H. Gu, Org. Chem. Front., 2016, 3, 309-313.
I. Pérez, J. P. Sestelo and L. A. Sarandeses, J. Am. Chem. Soc., 2001, 123, 4155-4160.
D. B. Biradar and H.-M. Gau, Chem. Commun., 2011, 47, 10467-10469.
C. H. Larsen, K. W. Anderson, R. E. Tundel and S. L. Buchwald, Synlett, 2006, 2006,
2941-2946.
22.
23.
24.
25.
26.
27.
28.
29.
30.
K. A. Davies, R. C. Abel and J. E. Wulff, J. Org. Chem., 2009, 74, 3997-4000.
T. Nakane, Y. Tanioka and N. Tsukada, Organometallics, 2015, 34, 1191-1196.
M. Qian and E.-i. Negishi, Tetrahedron Lett., 2005, 46, 2927-2930.
W.-W. Zhang, X.-G. Zhang and J.-H. Li, J. Org. Chem., 2010, 75, 5259-5264.
S. Tabuchi, K. Hirano and M. Miura, Chem.-Eur. J., 2015, 21, 16823-16827.
K. Yasui, N. Chatani and M. Tobisu, Org. Lett., 2018, 20, 2108-2111.
Z. Novák, P. Nemes and A. Kotschy, Org. Lett., 2004, 6, 4917-4920.
H. Hu, F. Yang and Y. Wu, J. Org. Chem., 2013, 78, 10506-10511.
C. Yi, R. Hua, H. Zeng and Q. Huang, Adv. Synth. Catal., 2007, 349, 1738-1742.
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