This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 8709–8711 8709

Cite this: Chem. Commun., 2012, 48, 8709–8711

Triflimide-catalyzed allyl–allyl cross-coupling: a metal-free allylic

alkylationw

Feiqing Ding, Ronny William, Fei Wang and Xue-Wei Liu*

Received 21st May 2012, Accepted 9th July 2012

DOI: 10.1039/c2cc33641c

A highly efficient metal-free intermolecular C(sp3)–C(sp3) allyl–

allyl cross-coupling protocol between allyl acetates and allyltri-

methylsilanes, which proceeded smoothly in the presence of

catalytic triflimide to form 1,5-dienes with good to excellent

regioselectivity, has been developed.

Allylic alkylation reactions are among the most versatile

and efficient carbon–carbon and carbon–heteroatom bond

formation methods in organic synthesis because allyl moieties

can serve as a powerful handle for further transformation to

access a wide array of functional groups.1 Early work reported

by Trost and Tsuji on the metal-catalyzed allylic alkylation of

a variety of soft and hard nucleophiles with allylic compounds

has attracted a great deal of attention (Scheme 1, eqn (1)).2 Of

particular significance, the metal-mediated allyl–allyl cross-

coupling between allyl metal compounds and allylic electro-

philes possessing functional groups that exhibit good leaving

group ability such as halides, carboxylates, carbonates,

triflates or phosphates provides a reliable method for the

synthesis of valuable 1.5-dienes. These dienes are not only

ubiquitous in naturally occurring terpenes but also serve as

highly versatile intermediates and building blocks in organic

synthesis.3,4 Despite rapid advances in the transition metal-

catalyzed allylic alkylation, the intermolecular C(sp3)–C(sp3)

allyl–allyl coupling remains a challenging task.5 To date,

several transition-metal catalysts such as copper, nickel and

palladium have been developed to enable allylation of organo-

metallic compounds, including magnesium, aluminum, boron,

and zinc reagents (eqn (2)).6 The use of palladium catalysts, in

particular, has seen considerable success in the past due to a high

and predictable level of regio- and stereoselectivity. Although it

represents a highly valuable synthetic tool, the presence of heavy

transition-metal impurities complicates the purification step, and

thus results in an increase in the cost involved throughout the

process. In addition, most reactions employ an excess of toxic or

harmful reagents and require harsh conditions.

The development of metal-free allylic alkylation, on the

other hand, constitutes a significant challenge in organic

synthesis, and in spite of the exciting developments in the field

of Brønsted acid catalysis, metal-free allylic alkylations invol-

ving allylic p ion pairs have remained elusive.7,8 Inspired by

our previous work in carbohydrate chemistry, whereby

Brønsted acids were used to catalyze the Ferrier rearrange-

ment reaction through generation of a carbocation inter-

mediate (eqn (3)), we are encouraged to pursue a different

highly challenging strategy for the Brønsted acid-catalyzed

allyl–allyl cross-coupling.9 To the best of our knowledge, this

is the first report concerning such direct intermolecular allylic

coupling reaction of cinnamyl acetate with allyltrimethylsilane

using Brønsted acid (eqn (4)).

We began our investigation using readily available cinnamyl

acetate (1a) and allyltrimethylsilane (2a) for reaction develop-

ment (Table 1). Unexpectedly, however, the results demon-

strated that the reaction between 1a and 2a was not successful

in the presence of common Brønsted acids such as TsOH, HCl,

AcOH, H3PO4, MeSO3H (Table 1, entry 1). After a series of

trials, we found that triflimide10 (Tf2NH) afforded the desired

allyl–allyl coupling products 1,5-hexadienes 3a and 4a in 39%

total yield with a linear to branched diene ratio of 69/31

(Table 1, entry 2).11 Encouraged by these results, both solvents

and reaction temperatures were evaluated to identify the

optimal conditions (Table 1, entries 2–4, for details see ESIw).Subsequently, slight increase or decrease in Tf2NH catalyst

Scheme 1 Earlier studies and the concept of the present work.

Division of Chemistry and Biological Chemistry, School of Physicaland Mathematical Sciences, Nanyang Technological University,637371, Singapore. E-mail: xuewei@ntu.edu.sg; Fax: +65 6791 1961w Electronic supplementary information (ESI) available: Experimentalprocedures, characterization, 1H and 13C NMR spectra of all newcompounds. See DOI: 10.1039/c2cc33641c

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8710 Chem. Commun., 2012, 48, 8709–8711 This journal is c The Royal Society of Chemistry 2012

loading has no significant detrimental effect on the reaction

yield and regioselectivity (Table 1, entry 5). Finally, under the

optimized conditions, the total yield of coupling reaction was

enhanced to 89% and the ratio of the linear product to the

branched product improved to 91/9 when 3 equiv. of 2a was

used. Moreover, when the reaction was performed on a

5.0 mmol scale, a similar result was obtained (Table 1, entry 6).

In the absence of the triflimide catalyst, however, formation of

desired 1,5-diene was not observed at all. Moreover, examina-

tion of a set of simple allylic electrophiles bearing a potential

leaving group revealed that the reaction is well tolerated with

various leaving groups (see ESIw).Having established the optimal reaction conditions (Table 1,

entry 6), we next explored the scope and limitation of the

reaction with a variety of allylic acetates and allyltrimethyl-

silanes (Table 2). The reaction occurred smoothly with ortho-,

para-, and meta-substituted aromatic cinnamyl acetates afford-

ing the desired 1,5-dienes in moderate to good yields and

regioselectivities (Table 2, products 3a–3f). Notably, reaction

of the cinnamyl acetate bearing substituents at both ortho

positions with allyltrimethylsilane also furnished dienes in good

yields with excellent regioselectivities, suggesting that substitu-

tion leading to a branched product is sterically disfavored

(Table 2, products 3g–3i). The naphthylallylic acetate and

biphenyl allylic acetate were also suitable substrates for this

reaction (Table 2, products 3j–3k).12a Substitution at the double

bond of cinnamyl acetate was well-tolerated as demonstrated

by the facile stereoselective formation of methyl-substituted

1,5-diene 3n and 3o when treated with the allylsilane reagent

under the present reaction conditions (Table 2).12 Weak electron-

withdrawing groups such as Br were tolerated on the aromatic

ring of cinnamyl acetate (Table 2, product 3m), the resulting

bromide group in the corresponding product is synthetically

useful for further transformation.13 Interestingly, we found that

analogous reaction of phenyldienyl acetate14 also proceeded in

the same manner to afford the corresponding 1,5,7-triene in

65% yield with high regioselectivity (Table 2, product 3p).15

Unfortunately, strong electron-withdrawing groups such as

–NO2, ketone, and �CF3 groups on the aromatic ring did not

lead to the formation of a coupling product but instead starting

materials were recovered at the end of the reaction. Next, we

examined the substrate generality of the cross-coupling reaction

with respect to allyltrimethylsilane derivatives as coupling

partners. We found that b-methallyltrimethylsilane is also a

viable coupling partner giving good yield of the product, albeit

with low selectivity of linear over branched diene 3q.10b,11b,16

Under the same reaction conditions, cinnamyl-trimethylsilane

reacted smoothly to give the corresponding diene 3r in 70%

yield with moderate regioselectivity. Interestingly, a highly

sterically hindered vinylcyclohexyl trimethylsilane also reacted

with cinnamyl acetate albeit with low conversion. Finally, cyclic

allylsilane compounds such as trimethylsilyl-cyclopentadiene

efficiently coupled to provide cinnamyl-substituted cyclopenta-

diene 3t.

Although detailed studies are required, we would like to

propose a plausible mechanism for the allyl–allyl cross-

coupling reaction as depicted in Scheme 2.17 Activation of

the acetate moiety of the allylic acetate derivative by the

triflimide leads to the formation of ion pairs between the

benzylic p carbocation intermediate and the triflimide anion.

Nucleophilic attack of the allyltrimethyl silane moiety followed

by desilylation of the b-silyl carbocation intermediate by the

triflimide anion affords the corresponding coupling products.

Depending on the position attacked by allyltrimethylsilane,

either the linear or branched product is obtained. Coupling at

the terminal end of the allylic acetate derivative affords the

Table 1 Optimization studies

Entry Catalysts (mol%) Solvent Temp. (1C) 3a/4aa Yieldb (%)

1 BA (1)c DCMd rt — nrf

2 Tf2NH (1) DCMd rt 69/31 393 Tf2NH (1) CH3NO2

d rt — Trace4 Tf2NH (1) DCMe 0 76/24 455 Tf2NH (0.5) DCMe rt 78/22 576g Tf2NH (0.5) DCMe �20 91/9 89h (85)i

a The ratio determined by crude NMR. b Isolated yield after purifica-

tion. c BA = Brønsted acid (TsOH, H3PO4, HCl, AcOH, MeSO3H).d [M] = 0.5 M. e [M] = 0.1 M. f nr = no reaction. g Using 3.0 equiv.

of 2a. h Reaction was performed on a 0.2 mmol scale. i Performed on

a 5.0 mmol scale.

Table 2 Scope for allyl acetates and allyltrimethylsilanesa

a All reactions are performed as described in Table 1 (entry 6) on a

0.2 mmol scale, unless otherwise noted. Yields are given for isolated

products after column chromatography. New C–C bonds are shown in

bold. The ratio of the linear product and the branched product (L/B) is

determined by crude 1H NMR.Dow

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 8709–8711 8711

corresponding linear product via path a. On the other hand, an

alternative attack via path b affords the corresponding branched

product as a minor product because of steric hindrance.

In conclusion, we have uncovered a new protocol for direct

catalytic allylic alkylation of acetates using a Brønsted acid

catalyst. Traditionally, allylic alkylation was promoted by

transition metal catalysts that are associated with limitations

like the presence of heavy metal impurities in the final product

and harsh reaction conditions. In contrast, this new method

is operationally simple and proceeds under remarkably mild

reaction conditions. It is noteworthy that use of just 0.5 mol%

of a simple, cheap, and easily accessible organic substance is

sufficient to catalyze intermolecular allyl–allyl cross-coupling.

The only waste produced in this new protocol for allylic

coupling reaction is acetic acid which is not harmful and

environmentally benign. The transformations occur with

excellent regioselectivity and yield. Further studies of asym-

metric ally–allyl cross coupling are ongoing in our lab and

would be reported in due course.

We thank Prof. Narasaka Koichi for invaluable suggestion

on reaction mechanisms. We gratefully acknowledge Nanyang

Technological University (RG50/08) and the Ministry of

Education, Singapore (MOE 2009-T2-1-030) for the financial

support of this research.

Notes and references

1 For recent reviews, see: (a) D. J. Cardenas, Angew. Chem., Int. Ed.,2003, 42, 384; (b) B. M. Trost, Acc. Chem. Res., 2002, 35, 695;(c) J. Tsuji, Transition Metal Reagents and Catalysts, Wiley,New York, 2000; (d) B. M. Trost, Science, 1991, 254, 1471.

2 (a) J. Tsuji, H. Takahashi and M. Morikawa, Tetrahedron Lett.,1965, 6, 4387; (b) J. Tsuji, Acc. Chem. Res., 1969, 2, 144;(c) B. M. Trost, Tetrahedron, 1977, 33, 2615; (d) B. M. Trost, Acc.Chem. Res., 1980, 13, 385; (e) B. M. Trost and T. R. Verhoeven,Comprehensive Organometallic Chemistry, Pergamon, Oxford, 1982;(f) B. M. Trost, J. Organomet. Chem., 1986, 300, 263; (g) For recentreviews, see: D. J. Cardenas, Angew. Chem., Int. Ed., 2003,42, 384(h) D. J. Cardenas and A. M. Echavarren, New J. Chem.,2004, 28, 338; (i) C. A. Falciola and A. Alexakis, J. Org. Chem.,2008, 73, 3765; (j) S. Norsikian and C. W. Chang, Curr. Org. Synth.,2009, 6, 264; (k) I. G. Rios, A. R. Hernandez and E. Martin,Molecules, 2011, 16, 970.

3 (a) E. Breitmaier, Terpenes, Flavors, Fragrances, Pharmaca, Phero-mones, Wiley-VCH, Weinheim, 2006; (b) K. C. Nicolaou andT. Montagnon, Molecules that Changed the World, Wiley-VCH,Weinheim, 2008.

4 For selected examples of organic synthesis by using 1,5-dienes, see:(a) R. C. D. Brown and J. F. Keily, Angew. Chem., Int. Ed., 2001,40, 4496; (b) H. Nakamura and Y. Yamamoto, in Handbook ofOrganopalladium Chemistry for Organic Synthesis, Wiley-Inter-science, West Lafayette, 2002, vol. 2; (c) T. J. Donohoe and

S. Butterworth, Angew. Chem., Int. Ed., 2003, 42, 948;(d) Y. J. Zhao, S. S. Chng and T. P. Loh, J. Am. Chem. Soc.,2007, 129, 492; (e) A. J. Feducia and M. R. Gagne, J. Am. Chem.Soc., 2008, 130, 592.

5 E.-i. Negishi and B. Liao, in Hand book of OrganopalladiumChemistry for Organic Synthesis, Wiley-Interscience, WestLafayette, 2002, vol. 1.

6 Examples of allyl–allyl cross-coupling reactions: (a) P. Zhang,L. A. Brozek and J. P. Morken, J. Am. Chem. Soc., 2010,132, 10686; (b) R. Matsubara and T. F. Jamison, J. Am. Chem.Soc., 2010, 132, 6880; (c) E. F. Flegeau, U. Schneider andS. Kobayashi, Chem.–Eur. J., 2009, 15, 12247; (d) Y. Sumida,S. Hayashi, K. Hirano, H. Yorimitsu and K. Oshima, Org. Lett.,2008, 10, 1629; (e) H. Yoshino, N. Toda, M. Kobata, K. Ukai,K. Oshima, K. Utimoto and S. Matsubara, Chem.–Eur. J., 2006,12, 721; (f) P. H. Lee, S. Sung, K. Lee and S. Chang, Synlett, 2002,146; (g) H. Nakamura, M. Bao and Y. Yamamoto, Angew. Chem.,Int. Ed., 2001, 40, 3208.

7 (a) J. M. O’Bren and A. H. Hoveyda, J. Am. Chem. Soc., 2011,133, 7712; (b) M. Rueping, U. Uria, M. Y. Lin and I. Atodiresei,J. Am. Chem. Soc., 2011, 133, 3732; (c) V. Bizet, V. Lefebvre,J. Baudoux, M. C. Lasne, A. Boulange, S. Leleu, X. Franck andJ. Rouden, Eur. J. Org. Chem., 2011, 4170; (d) D. Cheng andW. Bao, Adv. Synth. Catal., 2008, 350, 1263; (e) G. W. Kabalka,M. L. Yao, S. Borella and Z. Wu, Chem. Commun., 2005, 2492.

8 For reviews on Brønsted acid catalysis, see: (a) T. Akiyama, Chem.Rev., 2007, 107, 5744; (b) T. Akiyama, J. Itoh and K. Fuchibe,Adv.Synth. Catal., 2006, 348, 999; (c) M. S. Taylor and E. N. Jacobsen,Angew. Chem., Int. Ed., 2006, 45, 1520; (d) A. G. Doyle andE. N. Jacobsen, Chem. Rev., 2007, 107, 5713; (e) H. Yamamotoand N. Payette, in Hydrogen Bonding in Organic Synthesis, Wiley-VCH, Weinheim, 2009; (f) D. Kampen, C. M. Reisinger andB. List, Top. Curr. Chem., 2010, 291, 395.

9 (a) R. J. Ferrier and N. J. Prasad, J. Chem. Soc. C, 1969, 570;(b) R. J. Ferrier and O. A. Zubkov, Org. React., 2003, 62, 569 andreferences therein; (c) R. J. Ferrier, Top. Curr. Chem., 2001, 215, 153;(d) B. K. Gorityala, R. Lorpitthaya, Y. Bai and X.-W. Liu, Tetra-hedron, 2009, 65, 5844; (e) F. Q. Ding, R. William, S. M. Wang,B. K. Gorityala and X.-W. Liu, Org. Biomol. Chem., 2011, 9, 3929;(f) F. Q. Ding, R. William, F. Wang, J. M. Ma, L. Ji and X.-W. Liu,Org. Lett., 2011, 13, 652; (g) F. Q. Ding, S. T. Cai, J. M. Ma andX.-W. Liu, J. Org. Chem., 2012, 77, 5245.

10 Examples of triflimide-catalyzed reactions: (a) D. A. Mundal,C. Avetta and R. J. Thomson, Nat. Chem., 2010, 2, 294;(b) M. B. Boxer and Y. Yamamoto, Nat. Protocols, 2006,1, 2434; (c) T. Antonsson, C. Moberg, L. Tottie andA. Heumann, J. Org. Chem., 1989, 54, 4914; (d) Y. Yamamoto,H. Yatagai and K. Maruyama, J. Am. Chem. Soc., 1981, 103, 1969.

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12 (a) T. Azemi, M. Kitamura and K. Narasaka, Tetrahedron, 2004,60, 1339; (b) E. F. Flegeau, U. Schneider and S. Kobayashi,Chem.–Eur. J., 2009, 15, 12247.

13 (a) M. Ono, M. Hori, M. Haratake, T. Tomiyama, H. Mori andM. Nakayama, Bioorg. Med. Chem., 2007, 15, 6388;(b) P. Ayyappan, O. Evans, Y. Cui, K. A. Wheeler and W. Lin,Inorg. Chem., 2002, 41, 4978; (c) T. Bosanac and C. Wilcox, J. Am.Chem. Soc., 2002, 124, 4194; (d) I. Cade, N. J. Long, A. J. Whiteand D. J. Williams, J. Organomet. Chem., 2006, 691, 1389.

14 (a) N. Winssinger, S. Barluenga and M. Karplus, WO/2008/021213, 2008; (b) R. Chen, A. Rubenstein, J. C. Yu,N. Winssinger and S. Barluenga, US 2010292218, 2010;(c) G. Onodera, K. Watabe, M. Matsubara, K. Oda, S. Kezukaand R. Takeuchi, Adv. Synth. Catal., 2008, 350, 2725;(d) G. Lipowsky and G. Helmchen, Chem. Commun., 2004, 116.

15 (a) J. E. H. Day, S. Y. Sharp, M. G. Rowlands, W. Aherne,W. Lewis, S. M. Roe, C. Prodromou, L. H. Pearl, P. Workman andC. J. Moody, Chem.–Eur. J., 2010, 16, 10366; (b) P. Maurin,M. Ibrahim-Ouali and M. Santelli, Tetrahedron Lett., 2001,42, 8147; (c) T. Miyashi, A. Hazato and T. Mukai, J. Am. Chem.Soc., 1978, 100, 1008.

16 W. E. Crowe and Z. J. Zhang, J. Am. Chem. Soc., 1993, 115, 10998.17 T. Jin, M. Himuro and Y. Yamamoto, J. Am. Chem. Soc., 2010,

132, 5590.

Scheme 2 Proposed reaction mechanism.

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