Steering reaction pathways: From benzyl Claisen rearrangements to powerful ionic shifts

Article abstract of DOI:10.1002/chem.201003591

Take a walk on the wild side: A novel benzyl Claisen cascade rearrangement of keteniminium salts is described. The reaction leads to α-arylated lactones under metal-free conditions (top scheme; Tf=trifluoromethanesulfonyl). It is further demonstrated that the cationic intermediates involved can be steered away from pericyclic reaction manifolds into powerful ionic shifts through reaction design (bottom scheme). Copyright

Full text of DOI:10.1002/chem.201003591

DOI: 10.1002/chem.201003591
Steering Reaction Pathways: From Benzyl Claisen Rearrangements to
Powerful Ionic Shifts
Viviana Valerio, Claire Madelaine, and Nuno Maulide*[a]
The aromatic Claisen rearrangement is originally the skel-
etal rearrangement of allylphenyl ethers 1 into o- (or p-) al-
lylated phenols 2 (Scheme 1).[1] This transformation, as-
Scheme 2. Aliphatic Claisen rearrangement and proposed mechanism;
Tf=trifluoromethanesulfonyl.
ates, thus triggering an unusual cascade of nucleophilic
attack and sigmatropic rearrangement events that lead to
the final products. We were eager to address the challenge
of developing a “benzyl variant” of this reaction because it
could potentially lead to synthetically useful a-arylated lac-
tones.[8,9] We describe, herein, our preliminary results in this
endeavor, as well as the mechanistic exploitation of a side
result that permits us to advance our method beyond strictly
pericyclic reaction pathways.
Scheme 1. Aromatic Claisen rearrangement and proposed benzyl Claisen
variant.
sumed to proceed through a dearomatized cyclohexadi-
ACHTUNGTRENNUNGenone A, was originally reported by Claisen nearly 100
years ago and is arguably a “textbook reaction” in organic
chemistry.[2] Intriguingly, the analogous rearrangement of
benzylvinyl ethers 3 is much less developed. Presumably, the
energetic barrier associated with generation of the consider-
ably less-stabilized triene intermediate B is too high, and
various literature reports actually document the unfeasibility
of this process as a general transformation, particularly if
R=H (3a).[3] This is a remarkable fact, given that the poten-
tial products arising from rearrangement of 3 would be the
valuable a-(ortho-alkyl)arylated carbonyl derivatives 4.[4,5,6]
Our group has recently reported a novel “Claisen-like”
rearrangement of keteniminium salts that allows direct and
stereoselective access to challenging substituted lactones.[7]
As depicted in Scheme 2, this process initially converts
simple w-allyloxyamides into keteniminium ion intermedi-
We initially explored the rearrangement of the readily
available benzyloxyamide 5a (Scheme 3). Unsurprisingly
(see above), this proved a difficult transformation although
the desired product could be detected from the very first at-
tempts. After reaction optimization (not shown), we were
pleased to obtain the a-arylated lactone 6a, with an ortho-
methyl substituent, in moderate yield. We then proceeded
to examine the scope of the reaction (Scheme 3). Since the
starting benzyloxyamides are easily accessible by simple
benzylation of the corresponding hydroxyl derivatives,[10]
a
broad range of substrates could be prepared. The rearrange-
ment proved to be tolerant to the presence of varied sub-
stituents on the aromatic ring, affording the desired a-ary-
lated lactones 6a–6e in moderate yields. Indeed, the trans-
formations in Scheme 3 conceptually represent rare metal-
free a-arylation reactions of lactones,[11] delivering com-
pounds with peculiar aromatic substitution patterns that
would not be straightforward to prepare by other routes.
Interestingly, the methyl mandelate derivatives 5 f–5i
(R2 =CO2Me, Scheme 3) smoothly rearranged to a-arylated
lactones 6 f–6i in very good to excellent yields.[4d] We pre-
sume that the introduction of an electron-withdrawing sub-
stituent at the benzylic position (R in compounds 3,
[a] V. Valerio, Dr. C. Madelaine, Dr. N. Maulide
Max-Planck-Institut fꢀr Kohlenforschung
Kaiser-Wilhelm-Platz 1
45470 Mꢀlheim an der Ruhr (Germany)
Fax : (+49)2083062999
E-mail: maulide@mpi-muelheim.mpg.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003591.
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Chem. Eur. J. 2011, 17, 4742 – 4745

COMMUNICATION
Scheme 4. Formation of a-benzylated lactone products.
vinyl oxonium intermediate C takes place. Intermediate C
can undergo a charge-accelerated “Claisen-like” [3,3] sigma-
tropic rearrangement,[7] delivering the a-arylated lactone
products via the putative dearomatized species
D
(Scheme 5, pathway a). On the other hand, the observed for-
mation of “benzyl-transfer” products suggests the dissocia-
tion of the benzylic moiety from the oxonium intermediate
C, generating two fragments E, the recombination of which
could account for product 7j (Scheme 5, pathway b). An al-
ternative mechanistic scenario might explain the formation
of such products from electron-poor benzyl moieties 7k–7l
as proceeding through an uncharged electrophile of the type
depicted in F (Scheme 5, pathway c).
The formation of such benzyl-transfer products 7j–7l was
particularly informative. Since our mechanistic rationale
(Scheme 5) assumes that they are formed through non-peri-
cyclic, ionic manifolds, it was tempting to speculate whether
this could be further explored by designing substrates with
even stronger positive charge stabilization ability (see
Scheme 5, pathway b). Analogous cationic transfers were re-
ported by the groups of Fꢀrstner and Yamamoto during
their elegant independent studies of metal-catalyzed rear-
rangements of enynes.[12,13]
Scheme 3. Scope of the benzyl Claisen rearrangement.
Scheme 1) renders the energetics of the rearrangement
more favorable through conjugative stabilization of inter-
mediate B (see Scheme 1). Importantly, not only is the ester
function well tolerated by the rearrangement conditions, but
the products thus obtained contain two chemo-differentiated
carboxylate moieties for further elaboration.
In addition to the a-arylated
Aiming to influence the reaction pathway in a similar
manner, we chose the simple THF- and THP-protected hy-
lactones, most of the crude re-
action mixtures always dis-
played the presence of the cor-
responding a-benzylated lac-
tones as side products. In par-
ticular,
substrates
5j–5l
(Scheme 4) afforded the benzyl-
ic transfer adducts 7j–7l as the
only rearranged products of the
reaction. Although this was
somewhat anticipated in the
case of the electron-rich para-
methoxy benzyl moiety of 5j,
we were surprised to observe a
similar phenomenon for the
electron poor 5k and 5l. Our
working mechanistic hypothesis
to accommodate these observa-
tions
is
summarized
in
Scheme 5. After keteniminium
formation, intramolecular nu-
Scheme 5. Working mechanistic hypothesis; EDG=electron-donating group, EWG=electron-withdrawing
cleophilic attack to the benzyl- group.
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N. Maulide et al.
droxylamides 8a and 8b as challenging probes. Pleasingly,
upon submission to our reaction conditions, these substrates
smoothly rearranged to the corresponding adducts 9a–9b in
moderate to very good yields (Scheme 6).
a solvent cage. If that is indeed the case, then opportunities
for observing “chiral memory” phenomena may be within
reach.[14] In an encouraging preliminary experiment, when
enantiomerically enriched (99.8% enantiomeric excess (ee))
8a* was employed as a substrate (Scheme 7), the major dia-
stereoisomer of 9a* was formed upon rearrangement with
30% ee.[15]
Scheme 7. Preliminary results for chirality transfer in the O–C shift.
In summary, we have developed a benzyl-Claisen variant
of our keteniminium rearrangement. The efficiency of this
reaction draws decisively from the compelling ability of ke-
teniminium intermediates to undergo cascade rearrange-
ments and delivers a-arylated lactone products under metal-
free conditions. In addition, we have used mechanistic in-
sight collected during later studies to design unprecedented
O–C shifts that proceed in high yields, are amenable to
“chiral memory” phenomena, and further highlight the
unique features of our system. The ability, documented
herein, to completely steer the rearrangement pathway from
pericyclic to cationic purely by design raises exciting pros-
pects for future developments. These, including more de-
tailed mechanistic studies and exploration of additional re-
action modes, are underway and will be reported in due
course.
Scheme 6. Ionic O–C shift of THF and THP substrates.
As depicted in Scheme 6, the introduction of a methyl
substituent a to the carbonyl (8d) did not affect the efficien-
cy of the reaction, leading to the generation of the corre-
sponding lactone 9d with a quaternary centre in 60% yield,
albeit with low diastereocontrol. Additionally, both an in-
crease of the length of the tethered chain (9e) and introduc-
tion of substituents on the migrating moiety (9c) are well
tolerated.
Acknowledgements
This interesting reaction effectively converts what might
be seen as trivial THF- and THP-protected alcohols into
otherwise powerful cationic oxacycle donors through an es-
This work was supported financially by the Deutsche Forschungsgemein-
schaft (Grant MA4861/1-1) and the Alexander von Humboldt-Founda-
tion (Scholarship to C.M.). We are grateful to the Max-Planck Society
and the Max-Planck Institut fꢀr Kohlenforschung for generous funding of
our research programs. Invaluable assistance from our excellent NMR
spectroscopy and HPLC departments is acknowledged. We further ac-
knowledge M. Winzen for the preparation of starting materials and Prof.
L. Veiros (IST, Lisbon) for preliminary theoretical calculations and
useful discussions.
À
sentially irreversible C C bond-formation step. The efficien-
cy of the THP shift is even more noteworthy, considering
that the rearrangement of THP derivatives was shown not
to proceed at all in the systems previously reported by
Fꢀrstner/Yamamoto, which are analogous to the reactions
reported herein.[12] Presumably, in those cases facile elimina-
tion to dihydropyran (or dihydrofuran, in the case of THF)
takes place before rearrangement can occur. In contrast to
such a scenario, we have seldom observed minute amounts
of cyclic enol ethers in the reaction mixtures, indicating that
in our system the O–C shift uniquely outperforms elimina-
tion of the migrating moiety.
Keywords: chirality · Claisen rearrangement · ionic shift ·
lactones · rearrangement
[1] The transformation of 1 into 2 indeed forms much of the seminal,
landmark report by Claisen: a) L. Claisen, Chem. Ber. 1912, 45,
3157. For reviews, see: b) U. Nubbemeyer, Synthesis 2003, 961;
c) A. M. Martin Castro, Chem. Rev. 2004, 104, 2939. See also: d) The
Claisen Rearrangement: Methods and Applications (Eds.: M. Hierse-
mann, U. Nubbemeyer), Wiley-VCH, Weinheim, 2007, and referen-
ces therein. For recent examples of aromatic Claisen rearrangement,
The facility with which these rearrangements take place
raises additional mechanistic questions. In particular, it sug-
gests that the dissociation–recombination events occur at a
very high rate or that at least the recombining fragments
merge at a rate that is competitive with diffusion away from
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Steering Reaction Pathways
COMMUNICATION
see: e) P.-Y. Chiang, Y.-C. Lin, Y. Wang, Y.-H. Liu, Organometallics
2010, 29, 5776; f) T. R. Ramadhar, J.-I. Kawakami, A. J. Lough,
R. A. Batey, Org. Lett. 2010, 12 , 4446; g) N. Voꢂte, D. Philp,
A. M. Z. Slawin, Ni. J. Westwood, Org. Biomol. Chem. 2010, 8, 442;
h) K. C. Majumdar, B. Chattopadhyay, S. Samanta, Tetrahedron Lett.
2009, 50, 3178; i) N. Duguet, A. M. Z. Slawin, A. D. Smith, Org.
Lett. 2009, 11, 3858; j) K. C. Majumdar, Synlett 2008, 2400.
[8] For a review, see: a) F. Bellina, R. Rossi, Chem. Rev. 2010, 110,
1082.
[9] a) D. J. Spielvogel, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124,
3500; b) S. C. Malcolm, S. Ribe, F. Wang, M. C. Hewitt, N. Bhongle,
R. P. Bakale, L. Shao, Tetrahedron Lett. 2005, 46, 6871.
[10] See the Supporting Information for details.
[11] For a review on metal-catalyzed a-arylation of carbonyl compounds,
see: a) C. C. C. Johansson, T. J. Colacot, Angew. Chem. 2010, 122,
686; Angew. Chem. Int. Ed. 2010, 49, 676; for selected reviews on or-
ganobismuth reagents for arylation reactions, see: b) D. H. R.
Barton, J.-P. Finet, Pure Appl. Chem. 1987, 59, 937; c) R. A. Abra-
movitch, D. H. R. Barton, J.-P. Finet, Tetrahedron 1988, 44, 3039;
d) J.-P. Finet, Chem. Rev. 1989, 89, 1487; e) G. Elliott, J. P. Konopel-
ski, Tetrahedron 2001, 57, 5683; for recent applications, see: f) T.
Ooi, R. Goto, K. Maruoka, J. Am. Chem. Soc. 2003, 125, 10494;
g) P. K. Koech, M. J. Krische, J. Am. Chem. Soc. 2004, 126, 5350; for
selected examples on the use of aryl organolead reagents, see: h) K.
Orito, T. Sasaki, H. Suginome, J. Org. Chem. 1995, 60, 6208; i) J.
Morgan, J. T. Pinhey, B. R. Rowe, J. Chem. Soc. Perkin Trans. 1
1997, 1005; j) G. I. Elliott, J. P. Konopelski, M. M. Olmstead, Org.
Lett. 1999, 1, 1867; for recent reviews on polyvalent iodine in aryla-
tions, see: k) V. V. Zhdankin, P. J. Stang, Chem. Rev. 2008, 108, 5299;
l) B. Olofsson, E. A. Merritt, Angew. Chem. 2009, 121, 9214; Angew.
Chem. Int. Ed. 2009, 48, 9052.
[2] a) M. B. Smith, J. March, Advanced Organic Chemistry, Wiley, New
York, 2001; b) J. Clayden, N. Geeves, S. Warren, Organic Chemistry,
Oxford University Press, Oxford, 2000.
[3] For a discussion of the [3,3] sigmatropic rearrangement of benzyl
vinyl ethers, see a) G. B. Gill, Quart. Rev. 1968, 22, 338; b) A. Jeffer-
son, F. Schneinmann, Quart. Rev. 1968, 22, 391; thermal rearrange-
ments of benzyl vinyl ethers generally occur by radical processes,
see: c) K. B. Wiberg, R. R. Kintner, E. L. Motell, J. Am. Chem. Soc.
1963, 85, 450; d) A. W. Burgstahler, L. K. Gibbons, I. C. Nordin, J.
Chem. Soc. 1963, 4986; free-radical processes also occur in heterocy-
clic systems, see: e) A. F. Thomas, Helv. Chim. Acta 1970, 53, 605.
[4] a) W. J. Le Noble, P. J. Crean, B. Gabrielson, J. Am. Chem. Soc.
1964, 86, 1649; for successful examples, see: b) A. E. Wick, D. Felix,
K. Steen, A. Eschenmoser, Helv. Chim. Acta 1964, 47, 2425; c) D.
Felix, K. Gschwend-Stehen, A. E. Wick, A. Eschenmoser, Helv.
Chim. Acta 1969, 52, 1030; d) S. Raucher, A. S.-T. Lui, J. Am. Chem.
Soc. 1978, 100, 4902.
[5] For a related transformation, see: a) D. M. DꢃSouza, W.-W. Liao, F.
Rominger, T. J. J. Mꢀller, Org. Biomol. Chem. 2008, 6, 532.
[12] a) A. Fꢀrstner, H. Szillat, F. Stelzer, J. Am. Chem. Soc. 2000, 122,
6785; b) A. Fꢀrstner, P. W. Davies, J. Am. Chem. Soc. 2005, 127,
15024; c) I. Nakamura, Y. Mizushima, Y. Yamamoto, J. Am. Chem.
Soc. 2005, 127, 15022; for classical Lewis acid mediated THP- and
THF-alkylation of silylenol ethers with THP and THF acetates, see:
d) R. Noyori, S. Murata, M. Suzuki, Tetrahedron 1981, 37, 3899.
[13] This reaction can be considered akin to an indirect C-glycosylation:
R. M. Williams, A. O. Stewart, Tetrahedron Lett. 1983, 24, 2715.
[14] For a general review, see: a) H. Zhao, D. C. Hsu, P. R. Carlier, Syn-
thesis 2005, 1; for an example of memory of chirality in carbenium
ion chemistry, see: b) Y. Matsumura, Y. Shirakawa, Y. Satoh, M.
Umino, T. Tanaka, T. Maki, O. Onomura, Org. Lett. 2000, 2, 1689.
[15] This result does not rule out possible alternative mechanistic scenar-
ios including bimolecular direct transfer and/or stereospecific nucle-
ophilic displacement. Further mechanistic investigations may allow
a more clear distinction between pathways.
[6] However, such reactions occur more readily when the benzyl frag-
ment is part of a heteroaromatic ring or when the reactants are elec-
tronically biased, see: a) X. Xiong, M. C. Pirrung, Org. Lett. 2008,
10, 1151; b) J. Ficini, J. C. Pouliquen, C.R. Acad. Sci. Ser. C 1969,
268, 1446; c) C. R. Costin, C. J. Morrow, H. Rapoport, J. Org. Chem.
1976, 41, 535; d) S. Raucher, A. S-T. Lui, J. E. Macdonald, J. Org.
Chem. 1979, 44, 1885; e) T. Lee, Tetrahedron Lett. 1979, 20, 2297;
f) G. Bꢀchi, D. E. Vogel, J. Org. Chem. 1983, 48, 5406; g) H.
Nemeto, E. Shitara, K. Fukumoto, T. Kametani, Heterocycles 1985,
23, 549; h) O. Reinaud, P. Capdevielle, M. Maumy, Synthesis 1988,
293.
[7] a) C. Madelaine, V. Valerio, N. Maulide, Angew. Chem. 2010, 122,
1628; Angew. Chem. Int. Ed. 2010, 49, 1583. For leading references
on the keteniminium chemistry, see: b) L. Ghosez, Angew. Chem.
1972, 84, 901; Angew. Chem. Int. Ed. Engl. 1972, 11, 852; c) L.
Ghosez, J. Marchand-Brynaert, Adv. Org. Chem. 1976, 9, 21; d) C.
Schmit, J. B. Falmagne, J. Escudero, H. Vanlierde, L. Ghosez, Org.
Synth. 1990, 69, 199; e) C. Genicot, B. Gobeaux, L. Ghosez, Tetrahe-
dron Lett. 1991, 32, 3827; f) L. Ghosez, F. Mahuteau-Betzer, C. Gen-
icot, A. Vallribera, J.-F. Cordier, Chem. Eur. J. 2002, 8, 3411.
Received: December 13, 2010
Revised: February 2, 2011
Published online: March 22, 2011
Chem. Eur. J. 2011, 17, 4742 – 4745
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