Pummerer fragmentation vs. Pummerer rearrangement: A mechanistic analysis

Article abstract of DOI:10.1039/b605187a

Depending upon the nature of the substituent at the β-position of the sulfoxide moiety, a Pummerer reaction can be oriented "at will" towards C_α-H (rearrangement) or C_α-C _β (fragmentation) bond cleavage. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b605187a

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
Pummerer fragmentation vs. Pummerer rearrangement: a mechanistic
analysis{
Benoˆıt Laleu, Marco Santarem Machado and Je´roˆme Lacour*
Received (in Cambridge) 11th April 2006, Accepted 5th May 2006
First published as an Advance Article on the web 25th May 2006
DOI: 10.1039/b605187a
Depending upon the nature of the substituent at the b-position
of the sulfoxide moiety, a Pummerer reaction can be oriented
‘‘at will’’ towards Ca–H (rearrangement) or Ca–Cb (fragmenta-
tion) bond cleavage.
The Pummerer reaction, which is the reaction of alkylsulfoxides
with electrophilic reagents, has been extensively studied since its
discovery in 1909.1 Numerous synthetic applications have been
developed as in situ-generated thionium ion intermediates can be
trapped by a variety of nucleophiles2 either intramolecularly
(cyclization reactions) or intermolecularly.3,4 Stereoselective reac-
tions,5 cascade processes,6 as well as additive, vinylogous or
aromatic Pummerer reactions,7 have extended further the scope of
its applications. Unusual Pummerer rearrangements, including
‘‘interrupted’’ Pummerer reactions, have also been reported,8 as
Scheme 1 Mechanistic rationalization of the Pummerer (a) rearrange-
well as novel experimental conditions (fluorous or solid phase)9 in
ment and (b) fragmentation pathways. (E–X: reactive electrophile).
their implementation.
highly positive pKR+ value (¢19)12—is the driving force for the
unusual fragmentation. Herein, we report that this is indeed the
Technically, the Pummerer reaction is most often realized by the
addition of a stoichiometric amount of strong acid or anhydride to
case; the Pummerer reaction being oriented ‘‘at will’’ towards Ca–
an alkylsulfoxide. The reaction is then thought to proceed by
H or Ca–Cb bond cleavage through careful selection of the
protonation or esterification of the oxygen atom of the sulfoxide to
b-carbon substituent.
generate a sulfonium intermediate. Subsequent cleavage of the
In the literature, there are relatively few examples of elimination
S–O and Ca–H bonds results in the release of a proton and
reactions using isolable carbenium ions as electrofugal groups;13,14
the formation of a thionium moiety,10 which is trapped by the
the nature of these carbenium ions being relatively stable
counterpart of the electrophilic reagent or by any other (better)
carbocations of, for instance, tropylium nature (pKR+ = 4.75).15,16
nucleophile present in the reaction medium. This Pummerer
As mentioned, cation 1+ is more stable than the tropylium ion by
rearrangement affords a-substituted sulfides in generally good
several orders of magnitude. As such, 1+ should depart readily
yields (Scheme 1, route a).
without the two electrons of the Ca–Cb bond as soon as a positive
Recently, we reported a mechanistic alternative to this usual
Pummerer rearrangement in the context of the resolution of chiral
cationic dyes of type 1+ (Fig. 1, P-enantiomer).11 The single
enantiomers of this [4]helicenium ion were isolated through a
Pummerer fragmentation of diastereomerically pure sulfoxides
that released the enantiopure cation 1+ by Ca–Cb bond rupture
instead of the usual Ca–H bond cleavage (Scheme 1, route b over
route a, R+ = 1+).
To our knowledge, this was the first example of such a
Pummerer fragmentation pathway, and hence came the question
of the origin of this mechanistic ‘‘switch’’; the driving force
possibly being the stronger electrofugal character of carbenium 1+
vs. H+. In other words, we wondered whether the high chemical
stability of cation 1+—translated in quantitative terms into a
Department of Organic Chemistry, University of Geneva, Quai E.
Ansermet 30, CH-1211 Geneva 4, Switzerland.
E-mail: jerome.lacour@chiorg.unige.ch
Fig. 1 Carbenium ions 1+ (pKR+ y 19, P-enantiomer depicted), 2+
{ Electronic supplementary information (ESI) available: Spectral data for
(pKR+ y 23.7), 3+ (pKR+ y 14.5) and crystal violet 4+ (pKR+ y 9.4).
5, 6, 7, 8 and 10. See DOI: 10.1039/b605187a
2786 | Chem. Commun., 2006, 2786–2788
This journal is ß The Royal Society of Chemistry 2006

View Article Online
With this result in-hand, the reaction of 6 was considered. As
expected, the treatment of 6 with TFAA under analogous
conditions yielded salt [2+][CF3CO22] (98% isolated yield) and 9
exclusively; this confirming our mechanistic supposition that a
highly stable carbenium ion is indeed a more electrofugal group
than H+.
However, definite validation of our hypothesis was achieved
only when the Pummerer reactions of compounds 7 and 8 were
studied. In the case of 8, after treatment with TFAA, no trace of
1
crystal violet 4+ was observed in the UV or H NMR spectra of
the crude mixture. Purification by chromatography (basic Al2O3,
CH2Cl2/MeOH = 97 : 3) afforded trifluoroacetate-sulfide deriva-
tive 10 (Fig. 3) as the major product.20 The formation of this
adduct is consistent with the Pummerer rearrangement pathway
(Scheme 1, route a); the lower chemical stability of crystal violet 4+
(pKR+ 9.4) rendering this moiety an unlikely leaving group for a
fragmentation.
Fig. 2 Sulfoxides 5, 6, 7 and 8 derived from cations 1+, 2+, 3+ and 4+,
Finally, compound 7 was treated under Pummerer reaction
conditions. An immediate red color was observed upon the
addition of TFAA. 1H NMR analysis of the crude products
revealed a rather complex mixture containing, along with minor
unidentified derivatives,21 both cation 3+ and a-trifluoroacetoxy-
methyl sulfide 11 (Fig. 3) as products. This observation indicates
that both fragmentation and rearrangement pathways are
operative for the Pummerer reaction of 7.
respectively.
charge develops on the neighboring sulfur atom. Any reduction in
carbenium ion stability ought to reduce the electrofugality of the
moiety17 and favor the classical rearrangement pathway. On the
contrary, sulfoxides made from carbenium ions more stable than
1+ should also cleave exclusively by Ca–Cb bond fragmentation.
To validate this hypothesis, carbenium ions of both lower and
Compound 11 was prone to decomposition and, unlike 10, the
isolation of this moiety was not feasible by chromatography. If one
considers that the amount (%) of cation 3+ recovered at the end of
the reaction is indicative of the percentage of fragmentation,22 then
the isolation of salt [3+][CF3CO22] by chromatography (basic
Al2O3, CH2Cl2/MeOH = 97 : 3) in 48% yield indicates that the
Pummerer rearrangement and fragmentation reactions occur with
essentially equal probability. The reaction of sulfoxide 7 is thus
indicative of the ‘‘turning point’’ between the two elimination
routes—a pKR+ value of 14.5 being the requisite for a ‘‘fair’’
competition between H+ (rearrangement) and R+ (fragmentation)
electrofugal groups.
higher chemical stability than 1+ were selected (9.4 ¡ pKR+
¡
23.7) and treated with the carbanion of racemic methyl-para-
tolylsulfoxide. The resulting sulfoxides 5, 6, 7 and 8, derived from
1+ (pKR+ y 19), 2+ (pKR+ y 23.7), 3+ (pKR+ y 14.5) and crystal
violet 4+ (pKR+ 9.4), respectively, are reported in Fig. 2.
Traditional reaction conditions (TFAA,18 CH2Cl2) were then
chosen to promote the Pummerer rearrangement of these
derivatives. Care was first taken to reproduce the chemistry
reported previously for the enantio- and diastereomerically pure
analogues with racemic 5 (rac-5, 1.5 : 1 mixture of diastereo-
mers).11 Treatment of rac-5 with TFAA (1.1 equiv., 20 uC) resulted
in the immediate appearance of a dark green color, indicative of
the presence of 1+. After 20 min, the crude mixture was
concentrated in vacuo and analyzed by 1H and 19F NMR
spectroscopy, revealing only two products: salt [1+][CF3CO22],
isolated almost quantitatively after chromatography (SiO2,
CH2Cl2/MeOH = 97 : 3, 96%), and para-tolylthiomethyl 2,2,2-
trifluoroacetate (9) (Fig. 3).19 This compound resulted from a
reaction of the thionium ion with the trifluoroacetate anion.
In conclusion, experimental data indicate that the Pummerer
reaction can be oriented ‘‘at will’’ towards two different chemical
pathways through the careful selection of the b-carbon substitu-
ent—moeties leading to carbocations of pKR+ values higher than
14.5 promote Pummerer fragmentation reactions (Ca–Cb bond
rupture), whereas the others (pKR+ , 14.5) lead to the usual
Pummerer rearrangement.
We are grateful for the financial support of this work by the
Swiss National Science Foundation, the State Secretariat for
Education and Research and the ERASMUS program.
Notes and references
1 R. Pummerer, Chem. Ber., 1909, 42, 2282; R. Pummerer, Chem. Ber.,
1910, 43, 1401; L. Horner and P. Kaiser, Liebigs Ann. Chem., 1959, 626,
19; L. Horner, Liebigs Ann. Chem., 1960, 631, 198.
2 G. A. Russell and G. J. Mikol, in Acid-Catalyzed Rearrangements of
Sulfoxides and Amine Oxides. The Pummerer and Polonovski Reactions,
ed. B. S. Thyagaragan, Wiley Interscience, New York, 1968;
J. P. Marino, in Topics in Sulfur Chemistry, ed. A. Senning, George
Thieme, Stuttgart, 1976; S. Oae and T. Numata, in Isotopes in Organic
Chemistry, ed. E. Buncel and C. E. Lee, Elsevier, New York, 1980;
S. Oae, T. Numata and T. Yoshimura, in The Chemistry of the
Sulfonium Group, ed. C. J. M. Stirling and S. Patai, John Wiley, New
York, 1981; P. Welzel, Nachr. Chem., Tech. Lab., 1983, 31, 892;
Fig. 3 Trifluoroacetate sulfide derivatives from the Pummerer reactions.
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 2786–2788 | 2787

View Article Online
A. M. Moiseenkov, V. A. Dragan and V. V. Veselovsky, Russ. Chem.
Rev., 1991, 60, 643; M. Kennedy and M. A. McKervey, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, Oxford, 1991; D. S. Grierson and H. P. Husson, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, Oxford, 1991; O. De Lucchi, U. Miotti and G. Modena, in
The Pummerer Reaction of Sulfinyl Compounds, ed. L. A. Paquette, John
Wiley, New York, 1991; Y. Kita, Phosphorus, Sulfur Silicon Relat.
Elem., 1997, 120–121, 145; A. Padwa and A. G. Waterson, Curr. Org.
Chem., 2000, 4, 175; T. Sano, Trends Heterocycl. Chem., 2001, 7, 117;
S. K. Bur and A. Padwa, Chem. Rev., 2004, 104, 2401; K. S. Feldman,
Tetrahedron, 2006, 62, 5003.
3 Y. Oikawa and O. Yonemitsu, J. Org. Chem., 1976, 41, 1118;
M. Harmata, V. R. Fletcher and R. J. Claassen, II, J. Am. Chem.
Soc., 1991, 113, 9861; H. Abe, J. Itani, C. Masunari, S. Kashino and
T. Harayama, J. Chem. Soc., Chem. Commun., 1995, 1197; A. Padwa,
T. M. Heidelbaugh and J. T. Kuethe, J. Org. Chem., 2000, 65, 2368;
R. Ga´mez Montan˜o and J. Zhu, Chem. Commun., 2002, 2448;
P. Magnus, T. Rainey and V. Lynch, Tetrahedron Lett., 2003, 44,
2459; S. Akai, T. Tsujino, N. Fukuda, K. Iio, Y. Takeda,
K.-i. Kawaguchi, T. Naka, K. Higuchi, E. Akiyama, H. Fujioka and
Y. Kita, Chem.–Eur. J., 2005, 11, 6286.
4 D. K. Bates, J. Org. Chem., 1977, 42, 3452; O. Itoh, T. Numata,
T. Yoshimura and S. Oae, Bull. Chem. Soc. Jpn., 1983, 56, 343;
H. Kosugi, Y. Watanabe and H. Uda, Chem. Lett., 1989, 1865;
C. G. Gourdoupis and I. K. Stamos, J. Heterocycl. Chem., 1996, 33,
987; K. Kobayashi, E. Koyama, C. Kono, K. Namatame, K. Nakamura
and N. Furukawa, J. Org. Chem., 2001, 66, 2085.
5 B. Stridsberg and S. Allenmark, Acta Chem. Scand. Ser. B, 1976, 30,
219; T. Numata, O. Ito and S. Oae, Tetrahedron Lett., 1979, 1869;
Y. Kita and N. Shibata, Synlett, 1996, 289; N. Shibata, M. Matsugi,
N. Kawano, S. Fukui, C. Fujimori, K. Gotanda, K. Murata and
Y. Kita, Tetrahedron: Asymmetry, 1997, 8, 303; J. L. Garcia Ruano,
J. Aleman, M. T. Aranda, M. J. Arevalo and A. Padwa, Org. Lett.,
2005, 7, 19.
I. Sakata, H. Nakanishi and M. Sakamoto, Tetrahedron Lett., 1997, 38,
3251; Y. Kita, Yakugaku Zasshi, 1997, 117, 282; R. A. Aitken, L. Hill,
P. Lightfoot and N. J. Wilson, Chem. Commun., 1999, 1673;
Y. Horiguchi, A. Sonobe, T. Saitoh, J. Toda and T. Sano, Chem.
Pharm. Bull., 2001, 49, 1132; H.-M. Wang, H.-Y. Huang, I.-J. Kang
and L.-C. Chen, Heterocycles, 2001, 55, 1231; A. Volonterio, P. Bravo,
W. Panzeri, C. Pesenti and M. Zanda, Eur. J. Org. Chem., 2002, 3336.
9 L. A. McAllister, S. Brand, R. de Gentile and D. J. Procter, Chem.
Commun., 2003, 2380; L. A. McAllister, R. A. McCormick, S. Brand
and D. J. Procter, Angew. Chem., Int. Ed., 2005, 44, 452 and references
therein.
10 The cleavage of the S–O and Ca–H bonds can be synchronous—or
not—and it is still a topic of discussion, see: N. Veerapen, S. A. Taylor,
C. J. Walsby and B. M. Pinto, J. Am. Chem. Soc., 2006, 128, 227 and
references therein; although of importance, this issue does not have a
direct influence on our analysis.
11 B. Laleu, P. Mobian, C. Herse, B. W. Laursen, G. Hopfgartner,
G. Bernardinelli and J. Lacour, Angew. Chem., Int. Ed., 2005, 44, 1879.
12 B. W. Laursen and F. C. Krebs, Angew. Chem., Int. Ed., 2000, 39, 3432;
B. W. Laursen and F. C. Krebs, Chem.–Eur. J., 2001, 7, 1773.
13 I. M. Gordon and H. Maskill, J. Chem. Soc., Perkin Trans. 2, 2001,
2059; K. Vyakaranam, S. Koerbe, H. Divisova and J. Michl, J. Am.
Chem. Soc., 2004, 126, 15795; R. W. Darbeau, G. A. Trahan and
L. M. Siso, Org. Biomol. Chem., 2004, 2, 695.
14 There is a strong analogy between the described chemistry of this article
and the known Beckmann rearrangement/fragmentation chemistry,
although, in this latter case, most carbenium ions cannot be isolated:
C. A. Grob, H. P. Fischer, W. Raudenbusch and J. Zergenyi, Helv.
Chim. Acta, 1964, 47, 1003; C. A. Grob, Angew. Chem., Int. Ed. Engl.,
1969, 8, 535; H. P. Fischer, Tetrahedron Lett., 1968, 285; R. T. Conley
and S. Ghosh, in Mechanisms of Molecular Migrations, ed. B. S.
Thyagarajan, Wiley Interscience, New York, 1971; J. Kehler and
E. Breuer, Chem. Commun., 1997, 1751; M. S. Laxmisha and
G. S. R. S. Rao, Tetrahedron Lett., 2000, 41, 3759; K. Blaszczyk,
H. Koenig, K. Mel and Z. Paryzek, Tetrahedron, 2006, 62, 1069 and
references therein.
6 A. Padwa, Pure Appl. Chem., 2003, 75, 47; A. Padwa, Pure Appl. Chem.,
2004, 76, 1933.
15 I. Erden, J. R. Keeffe, F. P. Xu and J. B. Zheng, J. Am. Chem. Soc.,
1993, 115, 9834; W. Cao, I. Erden, R. H. Grow, J. R. Keeffe, J. Song,
M. B. Trudell, T. L. Wadsworth, F.-P. Xu and J.-B. Zheng, Can. J.
Chem., 1999, 77, 1009 and references therein.
16 W. v. E. Doering and L. H. Knox, J. Am. Chem. Soc., 1954, 76, 3203;
C. D. Ritchie and H. Fleischauer, J. Am. Chem. Soc., 1972, 94, 3481.
17 B. Denegri, A. Streiter, S. Juric, A. R. Ofial, O. Kronja and H. Mayr,
Chem.–Eur. J., 2006, 12, 1648; B. Denegri, A. R. Ofial, S. Juric,
A. Streiter, O. Kronja and H. Mayr, Chem.–Eur. J., 2006, 12, 1657;
C. Denekamp and Y. Sandlers, Angew. Chem., Int. Ed., 2006, 45, 2093.
18 TFAA: Trifluoroacetic anhydride.
7 J. P. Marino, S. Bogdan and K. Kimura, J. Am. Chem. Soc., 1992, 114,
5566; D. Craig, K. Daniels and A. R. MacKenzie, Tetrahedron, 1993,
49, 11263; Y. Kita, Y. Takeda, M. Matsugi, K. Iio, K. Gotanda,
K. Murata and S. Akai, Angew. Chem., Int. Ed. Engl., 1997, 36, 1529;
A. Padwa and J. T. Kuethe, J. Org. Chem., 1998, 63, 4256;
K. S. Feldman and D. B. Vidulova, Org. Lett., 2004, 6, 1869;
K. S. Feldman, D. B. Vidulova and A. G. Karatjas, J. Org. Chem.,
2005, 70, 6429; A. Padwa, S. Nara and Q. Wang, Tetrahedron Lett.,
2006, 47, 595; S. Akai, N. Kawashita, Y. Wada, H. Satoh,
A. H. Alinejad, K. Kakiguchi, I. Kuriwaki and Y. Kita, Tetrahedron
Lett., 2006, 47, 1881.
19 Y. D. Vankar and C. T. Rao, Tetrahedron, 1985, 41, 3405;
K. Kobayashi, Y. Kubota and N. Furukawa, Chem. Lett., 2000, 29,
400.
20 This compound is prone to decomposition and could be isolated only in
59% yield.
21 The use of trapping agents for cationic intermediates such as hydride
transfer reagents (e.g. Et3SiH) or electron-rich aromatic moieties (e.g.
mesitylene or indole) did not allow ‘‘cleaner’’ crude mixtures.
22 This is essentially the case with compounds 5 and 6, from which salts
[1+][CF3CO22] and [2+][CF3CO22] were isolated with 96 and 98% yield,
respectively.
8 J. Kitchin and R. J. Stoodley, J. Chem. Soc., Chem. Commun., 1972,
959; T. Terasawa and T. Okada, Heterocycles, 1978, 11, 181; T. P. Ahern,
R. F. Langler and R. L. McNeil, Can. J. Chem., 1980, 58, 1996;
Y. Uchida and S. Oae, Gazz. Chim. Ital., 1987, 117, 649; D. K. Bates,
R. T. Winters and J. A. Picard, J. Org. Chem., 1992, 57, 3094; S. G. Pyne
and A. R. Hajipour, Tetrahedron, 1994, 50, 13501; A. Arnone, P. Bravo,
L. Bruche, M. Crucianelli, L. Vichi and M. Zanda, Tetrahedron Lett.,
1995, 36, 7301; K. Shimada, A. Otaki, M. Yanakawa, S. Mabuchi,
N. Yamakado, T. Shimoguchi, K. Inoue, T. Kagawa, K. Shoji and
Y. Takikawa, Bull. Chem. Soc. Jpn., 1996, 69, 1043; M. Xia, S. Chen
and D. K. Bates, J. Org. Chem., 1996, 61, 9289; T. Kawasaki, H. Suzuki,
2788 | Chem. Commun., 2006, 2786–2788
This journal is ß The Royal Society of Chemistry 2006