Palladium-catalyzed cross-coupling reaction of sulfoxonium ylides and benzyl bromides by carbene migratory insertion

Article abstract of DOI:10.1039/d0cc06236g

A palladium-catalyzed cross-coupling reaction of sulfoxonium ylides and benzyl bromides has been developed, which has potential safety advantages over previous carbene coupling reactions using either diazo compounds or their in situ precursors. This reaction affords polysubstituted olefins, and features good substrate tolerance and is suitable for late-stage modification of biologically active molecules. Pd-carbene migratory insertion is supposed to be involved in this coupling reaction.

Full text of DOI:10.1039/d0cc06236g

ChemComm
View Article Online
View Journal
COMMUNICATION
Palladium-catalyzed cross-coupling reaction
of sulfoxonium ylides and benzyl bromides
Cite this:DOI: 10.1039/d0cc06236g
by carbene migratory insertion†
Received 15th September 2020,
Accepted 22nd October 2020
Kaichuan Yan, Maoyao He, Jianglian Li, Hua He, Ruizhi Lai, Yi Luo, Li Guo* and
Yong Wu
*
DOI: 10.1039/d0cc06236g
rsc.li/chemcomm
A palladium-catalyzed cross-coupling reaction of sulfoxonium ylides heterocycles have been employed as nucleophilic partners in
and benzyl bromides has been developed, which has potential safety the carbene coupling reactions.10,11 However, less progress has
advantages over previous carbene coupling reactions using either been achieved in cross coupling of sulfoxonium ylides despite
diazo compounds or their in situ precursors. This reaction affords the fact that they have become popular carbene surrogates
polysubstituted olefins, and features good substrate tolerance and is of diazo compounds.12 Compared with diazo compounds,
suitable for late-stage modification of biologically active molecules. sulfoxonium ylides are safer and more stable, and have been
Pd–carbene migratory insertion is supposed to be involved in this demonstrated to have found wide utility in carbene-related
coupling reaction.
transformations, such as C–H activation, X–H insertion and
cycloaddition.13 During recent years we have been studying
Transition-metal-catalyzed cross-coupling reactions have evolved different types of reactions involving sulfoxonium ylides as the
into one of the most indispensable tools for the formation of carbene precursor.13i–o In this regard, we reasoned the possi-
C–C and C–X bonds in the past few decades.1 Generally, a cross- bility that sulfoxonium ylides could behave as nucleophilic
coupling reaction employs an electrophile and a nucleophile to components in carbene-related coupling reactions.
provide the corresponding coupling product (Scheme 1a). In the
On the other hand, the synthesis of alkenes has attracted
past few decades, the reactions in which C–C multiple bonds or much attention because of their fascinating properties. Olefin
organometallic reagents serve as nucleophiles have been widely metathesis, Wittig reaction and its variants have always been
used throughout chemical research, such as Heck coupling,2 the most important and general approaches.14 Alternatively,
Negishi coupling,3 Suzuki–Miyaura coupling,4 Kumada coupling,5 carbene coupling reactions have also received much attention
Stille coupling6 and Hiyama coupling,7 etc. Among cross-coupling in CQC bond construction.11d,e,15 In this context, we report our
reactions, although electrophiles are still mainly halides or pseudo-
halides, exploration of nucleophilic partners has always been one of
the major tasks in the field of coupling reactions.8
The metal carbene complexes synthesized for the first time
in the early 20th century have been widely used in organic
synthesis as reactive intermediates.9 It is not surprising that
metal carbene species have been involved in cross-couplings
with a different migratory insertion mechanism10 (Scheme 1b).
The past two decades have witnessed the development of
nucleophiles for coupling reactions involving metal carbene;
various carbene precursors including diazo compounds, hydra-
zones, allenes, alkyne, cyclopropenes and nitrogen-containing
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education
Ministry and Department of Medicinal Chemistry, West China School of Pharmacy,
Sichuan University, No. 17 Southern Renmin Road, Chengdu, Sichuan 610041,
People’s Republic of China. E-mail: wyong@scu.edu.cn
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
Scheme 1 Transition-metal-catalyzed cross-coupling reactions.
d0cc06236g
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Communication
ChemComm
Table 2 Scope of the reaction of sulfoxonium ylides with various benzyl
bromidesa
investigation on the palladium-catalyzed cross-coupling reac-
tion of sulfoxonium ylides and benzyl bromides to generate tri-
and tetra-substituted alkenes (Scheme 1c).
Initially, we chose donor/acceptor sulfoxonium ylide 1a and
benzyl bromide 2a as the model substrates. As shown in
Table 1, the reaction in the presence of Pd2(dba)3, P(2-furyl)3,
LiOtBu (2.0 equiv.) and Et3N (0.5 equiv.) at 80 1C for 24 h under
Ar gave tri-substituted alkene 3a in 76% yield (entry 1). Alter-
native Pd(0)-catalysts such as Pd(PPh3)4 or Pd(dba)2 did not
improve the yield significantly, while Pd(OAc)2 was the most
efficient palladium source (entries 2–4). Subsequent screening
of the phosphine ligands indicated that they had a great
influence in the process and gave 32–88% yields, respectively
(entries 4–7). It was noted that the absence of LiOtBu or Et3N
led to a decrease in the formation of 3a (entries 8–10). Subse-
quently, other solvents, such as MeCN, THF, and DCE, proved
to be less effective than toluene (entries 11–13). Furthermore,
we found that the reduction in the amount of 2a from 1.5 equiv.
(entry 4) to 1.2 equiv. (entry 14) led to a similar yield of the
desired product 3a.
After the optimized reaction conditions were established, we
next investigated the substrate scope of the carbene coupling
reaction (Table 2). Generally, various mono-substituted benzyl
bromides could deliver the desired alkenes in good yields and
with moderate to high Z/E selectivity (3a–3l). Among them,
electron-rich benzyl bromides exhibited higher reactivity than
their electron-deficient analogues (3b–3c), and para-substituted
benzyl bromides afforded higher yields than their ortho-/meta-
substituted analogues probably owing to the steric hindrance
(3d–3i). Notably, when benzyl chloride and 1,1,1-trifluoro-
methanesulfonic acid phenylmethyl ester were used, the
a
1a (0.1 mmol), 2a (1.2 equiv.), Pd(OAc)2 (2.5 mol%), P(2-furyl)3
Table 1 Optimization of the reaction conditionsa
(0.1 equiv.) and LiOtBu (2.0 equiv.)/Et3N (0.5 equiv.) in 1 mL of toluene
for 24 h at 80 1C under Ar. Isolated yield. The ratio of Z/E selectivity was
b
determined using the crude 1H NMR or HPLC. 2a was replaced by
c
benzyl chloride. 2a was replaced by 1,1,1-trifluoro-methanesulfonic
acid phenylmethyl ester.
corresponding product 3a was obtained in low to moderate
yields (45% and 32%, respectively).
Entry Catalyst Ligand
Solvent Base (equiv.)
Yieldb (%)
Furthermore, benzyl bromides which possess two substitu-
ents were also tolerated and produced the corresponding
products 3m–3q in 42%–86% yields with moderate to high
Z/E selectivity. Moreover, the aryl framework could be extended
to a naphthalene-derived system, such as 3r and 3s. When a
substrate with greater steric hindrance 1t was subjected to the
reaction, only low yield was offered (3t). To our delight,
the reaction with allyl bromide proceeded smoothly, providing
1,3-diene product 3u in 24% yield with high E/Z selectivity.
Finally, we examined the scope of sulfoxonium ylides under the
optimized conditions. The sulfoxonium ylides which bear an
electron-donating substituent or electron-withdrawing substi-
tuent on the aryl ring were good substrates for this reaction,
except for 3y (3v–3y). In addition, a decrease in yield was
observed when ethyl was replaced by a more sterically hindered
1
2
3
4
Pd2(dba)3 P(2-furyl)3 Tol LiOtBu (2.0)/Et3N (0.5) 76
Pd(PPh3)4 P(2-furyl)3 Tol
Pd(dba)2 P(2-furyl)3 Tol
Pd(OAc)2 P(2-furyl)3 Tol
LiOtBu (2.0)/Et3N (0.5) 69
LiOtBu (2.0)/Et3N (0.5) 79
LiOtBu (2.0)/Et3N (0.5) 88
LiOtBu (2.0)/Et3N (0.5) 65
LiOtBu (2.0)/Et3N (0.5) 32
LiOtBu (2.0)/Et3N (0.5) 45
K2CO3 (2.0)/Et3N (0.5) 31
5
6
7
Pd(OAc)2 dppf
Pd(OAc)2 PCy3ÁHBF4 Tol
Pd(OAc)2 xphos Tol
Tol
8
9
10
11
12
13
Pd(OAc)2 P(2-furyl)3 Tol
Pd(OAc)2 P(2-furyl)3 Tol
Pd(OAc)2 P(2-furyl)3 Tol
Pd(OAc)2 P(2-furyl)3 MeCN LiOtBu (2.0)/Et3N (0.5) Trace
Pd(OAc)2 P(2-furyl)3 THF
Pd(OAc)2 P(2-furyl)3 DCE
LiOtBu (2.5)
Et3N (2.5)
52
24
LiOtBu (2.0)/Et3N (0.5) 47
LiOtBu (2.0)/Et3N (0.5) 34
LiOtBu (2.0)/Et3N (0.5) 87
14c Pd(OAc)2 P(2-furyl)3 Tol
a
1a (0.1 mmol), 2a (1.5 equiv.), catalyst (2.5 mol%), ligand (0.1 equiv.)
b
and base in 1 mL of solvent for 24 h at 80 1C under Ar. Isolated yield.
c
1.2 equiv. of 2a was used.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
ChemComm
Communication
Scheme 4 Rationalization of stereoselectivity.
behave as nucleophiles. This reaction employs various benzyl
bromides as electrophilic partners to furnish the corresponding
tri- and tetra-substituted alkenes. Additionally, this method
features feasibility for the late-stage modification of structurally
complex bioactive molecules. We believe that this work pro-
vides a novel nucleophile for the transition-metal-catalyzed
carbene cross-coupling reactions and would further expand
the application of sulfoxonium ylides in organic synthesis.
Financial support from the NSFC (grant number 81373259,
81573286, 81773577 and 81602954) is gratefully acknowledged.
Scheme 2 Applications in late-stage modifications of complex active
molecules.
isobutyl (3z). Unfortunately, we tried some other sulfoxonium
ylides under the standard conditions, but did not get the
corresponding products, such as a-carbonyl and N-aryl imidoyl
sulfoxonium ylides.
Of note, cholesterol-derived and estrone-derived sulfoxo-
nium ylides were also amenable to this cross coupling protocol,
affording 4 in 34% yield and 5 in 47% yield, illustrating that
this protocol might be applicable to the late-stage modification
of structurally complex bioactive molecules (Scheme 2).
Based on the literature of the carbene cross coupling reac-
tions,15 we performed a plausible mechanism in Scheme 3. At
the beginning of the catalytic cycle, Pd(OAc)2 is reduced to Pd(0)
species I by the phosphorus ligand, followed by the oxidative
addition of benzyl bromide to Pd(0) to generate II. Then, the
reaction of sulfoxonium ylide 1a with II would afford Pd(II)
carbene complex III by extruding DMSO. Migratory insertion of
a benzyl group produces intermediate IV, which undergoes b-H
elimination, which results in the formation of alkene 3a. The
Pd(0) catalyst regenerated by the reductive elimination of V then
participates in the next catalytic cycle.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1 (a) R. Jana, T. P. Pathak and M. S. Sigman, Chem. Rev., 2011,
111, 1417; (b) C. C. Johansson Seechurn, M. O. Kitching,
T. J. Colacot and V. Snieckus, Angew. Chem., Int. Ed., 2012,
51, 5062; (c) Handbook of Organopalladium Chemistry for Organic
Synthesis, ed. E. Negishi and A. de Meijere, Wiley, Hoboken, NJ,
2002; (d) A. de Meijere and F. Diederich, Metal-Catalyzed Cross-
Coupling Reactions, 2nd Completely Revised and Enlarged, Wiley-VCH,
Weinheim, Germany, 2004, vol. 1; (e) F. Diederich and P. J. Stang,
Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinhein,
Germany, 1998.
2 (a) M. Beller, A. Zapf and T. H. Riermeier, in Transition Metals for
Organic Synthesis, ed. M. Beller and C. Bohm, Wiley-VCH, Weinheim,
2nd edn, 2004, vol. 1, pp. 271–305; (b) S. Braese and A. de Meijere,
in Metal-Catalyzed Cross-Coupling Reactions, ed. A. de Meijere
and F. Diederich, Wiley-VCH, Weinheim, 2nd edn, 2004, vol. 1,
pp. 217–315; (c) A. M. Trzeciak and J. J. Ziolkowski, Coord. Chem.
Rev., 2005, 249, 2308; (d) N. J. Whitcombe, K. K. Hii and S. E. Gibson,
Tetrahedron, 2001, 57, 7449; (e) R. F. Heck, Acc. Chem. Res., 1979,
12, 146.
The moderate to high Z-stereoselectivity can be rationalized
as follows (Scheme 4): two bulky aryl groups prefer a trans-
arrangement in the transition state in the b-elimination for the
formation of trisubstituted alkenes.11e,16
In conclusion, we have developed a novel palladium cata-
lyzed cross-coupling reaction in which sulfoxonium ylides
3 (a) O. King, N. Okukado and E. Negishi, J. Chem. Soc., Chem.
Commun., 1977, 683; (b) E. Negishi, Acc. Chem. Res., 1982, 15, 340;
(c) V. B. Phapale and D. J. Cardenas, Chem. Soc. Rev., 2009, 38, 1598;
(d) M. M. Heravi, E. Hashemi and N. Nazari, Mol. Diversity, 2014,
18, 441.
4 (a) N. Miyaura, in Metal-Catalyzed Cross-Coupling Reactions, ed. de
Meijere, A., Diederich, F., Wiley-VCH, Weinheim, 2nd edn, 2004,
vol. 1, pp. 41–124; (b) S. Kotha, K. Lahiri and D. Kashinath, Tetrahedron,
2002, 58, 9633; (c) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95, 2457;
(d) A. Suzuki, Angew. Chem., Int. Ed., 2011, 50, 6722.
5 (a) K. Tamao, K. Sumitani and M. Kumada, J. Am. Chem. Soc., 1972,
94, 4374; (b) M. M. Heravi, V. Zadsirjan, P. Hajiabbasi and
H. Hamidi, Monatsh. Chem., 2019, 150, 535; (c) M. Kumada, Pure
Appl. Chem., 1980, 52, 669.
6 J. K. Stille, Angew. Chem., Int. Ed. Engl., 1986, 25, 508.
7 (a) T. Hiyama and Y. Hatanaka, Pure Appl. Chem., 1994, 66, 1471;
(b) S. E. Denmark and M. H. Ober, Aldrichimica Acta, 2003, 36, 75.
8 (a) C. C. C. Johansson Seechurn, M. O. Kitching, T. J. Colacot and
V. Snieckus, Angew. Chem., Int. Ed., 2012, 51, 5062; (b) C. E. I. Knappke
and A. J. von Wangelin, Chem. Soc. Rev., 2011, 40, 4948.
´
9 (a) P. de Fremont, N. Marion and S. P. Nolan, Chem. Rev., 2009,
253, 862; (b) L. Tschugajeff, M. Skanawy-Grigorjewa and A. Posnjak,
Z. Anorg. Allg. Chem., 1925, 148, 37; (c) Z. Zhang and J. Wang,
Scheme 3 Proposed mechanism.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020

View Article Online
Communication
ChemComm
Tetrahedron, 2008, 64, 6577; (d) M. P. Doyle, R. Duffy, M. Ratnikov
and L. Zhou, Chem. Rev., 2010, 110, 704; (e) A. Ford, H. Miel, A. Ring,
C. N. Slattery, A. R. Maguire and M. A. McKervey, Chem. Rev., 2015,
115, 9981.
and X. Fan, Adv. Synth. Catal., 2018, 360, 3781; (h) X. F. Cui,
Z. H. Ban, W. F. Tian, F. P. Hu, X. Q. Zhou, H. J. Ma, Z. Z. Zhan
and G. S. Huang, Org. Biomol. Chem., 2019, 17, 240; (i) R. Lai, X. Wu,
S. Lv, C. Zhang, M. He, Y. Chen, Q. Wang, L. Hai and Y. Wu, Chem.
Commun., 2019, 55, 4039; ( j) Y. Luo, L. Guo, X. Yu, H. Ding,
H. Wang and Y. Wu, Eur. J. Org. Chem., 2019, 3203; (k) R. Nie,
R. Lai, S. Lv, Y. Xu, L. Guo, Q. Wang and Y. Wu, Chem. Commun.,
2019, 55, 11418; (l) J. Li, H. He, M. Huang, Y. Chen, Yi. Luo, K. Yan,
Q. Wang and Y. Wu, Org. Lett., 2019, 21(22), 9005; (m) Y. Xu,
X. Huang, G. Lv, R. Lai, S. Lv, J. Li, L. Hai and Y. Wu, Eur. J. Org.
Chem., 2020, 4635; (n) J. Vaitla, A. Bayer and K. H. Hopmann, Angew.
Chem., Int. Ed., 2017, 56, 4277; (o) I. K. Mangion, I. K. Nwamba,
M. Shevlin and M. A. Huffman, Org. Lett., 2009, 11, 3566.
10 (a) Y. Xia, D. Qiu and J. Wang, Chem. Rev., 2017, 117, 13810;
(b) Q. Xiao, Y. Zhang and J. Wang, Acc. Chem. Res., 2013, 46, 236;
(c) K. L. Greenman, D. S. Carter and D. L. Van, Vranken, Tetrahedron,
2001, 57, 5219; (d) Y. Xia, Y. Zhang and J. Wang, ACS Catal., 2013,
3, 2586; (e) Y. Zhang and J. Wang, Eur. J. Org. Chem., 2011, 1015;
( f ) Z. Liu and J. Wang, J. Org. Chem., 2013, 78, 10024.
11 (a) J. Barluenga and C. Valdes, Angew. Chem., Int. Ed., 2011, 50, 7486;
(b) Z. Shao and H. Zhang, Chem. Soc. Rev., 2012, 41, 560; (c) Y. Gao,
G. Wu, Q. Zhou and J. Wang, Angew. Chem., Int. Ed., 2018, 57, 2716;
(d) Q. Xiao, J. Ma, Y. Yang, Y. Zhang, J. Wang, Y. Zhang and J. Wang,
Org. Lett., 2009, 11, 4732; (e) J. Barluenga, P. Moriel, C. Valdes and
F. Aznar, Angew. Chem., Int. Ed., 2007, 46, 5587; ( f ) Y. Xia, Y. Xia,
R. Ge, Z. Liu, Q. Xiao, Y. Zhang and J. Wang, Angew. Chem., Int. Ed.,
2014, 53, 3917; (g) S. Ma and J. Zhang, Chem. Commun., 2000, 117;
(h) H. Zhang, B. Wang, K. Wang, G. Xie, C. Li, Y. Zhang and J. Wang,
Chem. Commun., 2014, 50, 8050; (i) N. Selander, B. T. Worrell,
S. Chuprakov, S. Velaparthi and V. V. Fokin, J. Am. Chem. Soc.,
2012, 134, 14670; ( j) X. Zhao, G. Wu, C. Yan, K. Lu, H. Li, Y. Zhang
and J. Wang, Org. Lett., 2010, 12, 5580.
12 (a) C. Janot, P. Palamini, B. C. Dobson, J. Muir and C. Aissa, Org.
Lett., 2019, 21, 296; (b) C. Janot, J. B. Chagnoleau, N. R. Halcovitch,
J. Muir and C. Aissa, J. Org. Chem., 2020, 85, 1126; (c) B. Shu,
X.-T. Wang, Z.-X. Shen, T. Che, M. Zhong, J.-L. Song, H.-J. Kang,
H. Xie, L. Zhang and S.-S. Zhang, Org. Chem. Front., 2020, 7, 1802.
13 (a) J. Vaitla and A. Bayer, Synthesis, 2019, 612; (b) X. Wu, S. Sun,
J.-T. Yu and J. Cheng, Synlett, 2019, 21; (c) L.-Q. Lu, T.-R. Li, Q. Wang
and W.-J. Xiao, Chem. Soc. Rev., 2017, 46, 4135; (d) A. C. B. Burtoloso,
R. M. P. Dias and I. A. Leonarczyk, Eur. J. Org. Chem., 2013, 5005;
(e) M. Barday, C. Janot, N. R. Halcovitch, J. Muir and C. Aissa, Angew.
Chem., Int. Ed., 2017, 56, 13117; ( f ) X. Chen, M. Wang, X. Zhang and
X. Fan, Org. Lett., 2019, 21, 2541; (g) G. Chen, X. Zhang, R. Jia, B. Li
14 (a) B. E. Maryanoff and A. B. Reitz, Chem. Rev., 1989, 89, 863;
(b) B. P. J. Murphy and J. Brennan, Chem. Soc. Rev., 1988, 17, 1;
(c) Z. Lao and P. H. Toy, J. Org. Chem., 2016, 12, 2577;
(d) N. Mukherjee, S. Planer and K. Grela, Org. Chem. Front., 2018,
5, 494; (e) O. M. Ogba, N. C. Warner, D. J. O’Leary and R. H. Grubbs,
Chem. Soc. Rev., 2018, 47, 4510.
15 (a) Y. Zhang and J. Wang, Alkene Synthesis Through Transition Metal-
Catalyzed Cross-Coupling of N-Tosylhydrazones, in Stereoselective
Alkene Synthesis, ed. Wang, J., Springer Berlin Heidelberg, Berlin,
Heidelberg, 2012, pp. 239–269; (b) J. Barluenga, M. Escribano,
F. Aznar and C. Valdes, Angew. Chem., Int. Ed., 2010, 49,
6856; (c) T. Bzeih, K. Zhang, A. Khalaf, A. Hachem, M. Alami and
A. Hamze, J. Org. Chem., 2019, 84, 228; (d) K. L. Greenman and D. L. Van
Vranken, Tetrahedron, 2005, 61, 6438; (e) D. P. Ojha and K. R. Prabhu,
J. Org. Chem., 2012, 77, 11027; ( f ) M. Roche, A. Hamze, O. Provot,
J. D. Brion and M. Alami, J. Org. Chem., 2013, 78, 445; (g) K. Wang,
S. Chen, H. Zhang, S. Xu, F. Ye, Y. Zhang and J. Wang, Org. Biomol.
Chem., 2016, 14, 3809; (h) X. Wang, Y. Xu, Y. Deng, Y. Zhou, J. Feng,
G. Ji, Y. Zhang and J. Wang, Chem. – Eur. J., 2014, 20, 961.
16 Y.-T. Tsoi, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org. Lett., 2010,
12, 4506.
Chem. Commun.
This journal is © The Royal Society of Chemistry 2020