An unexpected two-group migration involving a sulfonynamide to nitrile rearrangement. Mechanistic studies of a thermal N → C tosyl rearrangement

Article abstract of DOI:10.1021/ol0477327

(Chemical Equation Presented) We report the discovery of the first double-barreled thermal rearrangement of a sulfonynamide and a methoxybenzyl to a nitrite and the first rearrangement of an SO₂ group from sulfonamide to ketoimine. The rearrang

Full text of DOI:10.1021/ol0477327

ORGANIC
LETTERS
2005
Vol. 7, No. 5
783-786
An Unexpected Two-Group Migration
Involving a Sulfonynamide to Nitrile
Rearrangement. Mechanistic Studies of
a Thermal N
f C Tosyl Rearrangement
Michael Bendikov, Hieu M. Duong, Eduardo Bolanos, and Fred Wudl*
Exotic Materials Institute, Department of Chemistry and Biochemistry,
UniVersity of California, Los Angeles, Los Angeles, California 90095
wudl@chem.ucla.edu
Received November 4, 2004 (Revised Manuscript Received January 21, 2005)
ABSTRACT
We report the discovery of the first double-barreled thermal rearrangement of a sulfonynamide and a methoxybenzyl to a nitrile and the first
rearrangement of an SO2 group from sulfonamide to ketoimine. The rearrangement occurs under surprisingly mild conditions (onset at 100
in the melt).
°C
Sulfonamides have been studied for at least 100 years.1 They
are robust compounds that are known to be one of the most
stable nitrogen protecting groups.2 Cleavage of the S(O2)-N
bond requires extremely harsh conditions such as strong acid
or base, as well as dissolving metal reduction.3,4 To the best
of our knowledge, there is no reported example of an ArS-
(O2)-N bond breakage under mild, thermal, and neutral
conditions.5
toluene, 1 underwent a clean, truly deep-seated rearrangement
to furnish sulfone 2 (Scheme 1 and Figure 1).8 To the best
of our knowledge this rearrangement is unprecedented in
organic chemistry since both the p-toluenesulfonyl (Ts) and
p-methoxybenzyl (PMB) groups have migrated from the
nitrogen atom onto a neighboring carbon at the â-position.9
We sought to elucidate the mechanism of this novel
rearrangement in detail, and here we report our preliminary
results.10
In our effort to develop a novel benzyne precursor,6 we
have synthesized the ynamide 1.7,8 Unexpectedly, in refluxing
The rearrangement proceeds cleanly (isolated yield, 92%)
in both neat (melt) and solutions (toluene, 1,2-dichloroben-
zene, o-xylene, decalin) at 100-120 °C.11 The rearrangement
(1) (a) Sulfur in Organic and Inorganic Chemistry; Senning, A., Ed.;
Marcel Dekker: New York, 1971-1982; Vols. 1 and 4. (b) The Chemistry
of Sulfonic Acids, Esters and their DeriVatiVes; Patai, S., Rappoport, Z.,
Eds.; John Wiley & Sons: Chichester, 1991.
(2) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd Ed.; John Wiley & Sons: New York 1999.
(3) Iley, J. In The Chemistry of Sulfonic Acids, Esters and their
DeriVatiVes; Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: Chichester,
1991; Chapter 12, pp 447-485.
Scheme 1
(4) Searles, S., Jr.; Nukina, S. Chem. ReV. 1959, 59, 1077-1103.
(5) For base-catalized 1,3-shift of the Ts group, see ref 3. For
photochemical rearangment, see: Elghamry, I.; Do¨pp, D.; Henkel, G.
Synthesis 2001, 1223-1227.
10.1021/ol0477327 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/05/2005

Scheme 2
Figure 1. ORTEP drawing of product 2.
was confirmed by X-ray analysis (Figure 3).13 The tosyl
group is the first to migrate onto the former alkynyl carbon
(labeled in red in Scheme 2) while the p-methoxybenzyl
group remains attached to the nitrogen atom. From the crystal
structure of amide 4, a keteneimine structure was inferred
as intermediate 3. The observed 1H and 13C NMR signals of
the reaction mixture are consistent with that inference for 3.
This rearrangement required the breaking of an ArS(O2)-N
bond under neutral conditions, which is unprecedented in
organic chemistry. Thus, we discovered the first thermal
uncatalyzed tosyl rearrangement from sulfonamide to
sulfone.
was conveniently followed by variable temperature 1H
NMR.8 In the nonpolar nonaromatic solvent12 decalin, the
rearrangement occurred via a detectable intermediate (3),
Scheme 2. Rearrangement from the reactant 1 to an
intermediate 3 was found to be first-order in reactant (k1-
(1f3) ) 5.69 × 10-5 s-1. The concentration of this
intermediate accumulated up to about 29%, followed by a
decrease as the reaction progressed (Figure 2). The reaction
Figure 2. Rearrangement in decalin-d18 at 394 K: (2) reactant 1,
(b) intermediate 3, (9) product 2.
leading from the intermediate 3 to product 2 was again a
first-order process. The intermediate was found to be stable
at room temperature under inert atmosphere; however, it
reacts readily with water during purification on a preparative
TLC plate to afford amide 4 (Scheme 2). The structure of 4
Figure 3. X-ray structure of 4 resulting from hydration of the
intermediate 3.
(6) Duong, H. M.; Bendikov, M.; Steiger, D.; Zhang, Q.; Sonmez, G.;
Yamada, J.; Wudl, F. Org. Lett. 2003, 5, 4433-4436.
(7) Our original idea was to synthesize compound 5 by following
reaction:
Interestingly, in 1,2-dichlorobenzene (ODCB-d4) and o-
xylene, the reaction was found to be second-order in reactant
with a nearly perfect straight fit in the Arrhenius plot (R2 )
(10) Preliminary results with several related sulfonynamides are presented
in Supporting Information.
(11) In other high boiling solvents (hexachlorobutadiene and nitroben-
zene) that were investigated, the rearranged product was also detected but
in a less pure conversion.
(12) No dependence could be found between reaction rate and solvent
polarity, suggesting no ionic species as intermediate or rate-determining
transition state.
(13) An intermediate was detected (although in a smaller amount, the
concentration accumulated up to about 5%) when the reaction was performed
in hexachlorobutadiene and as neat.
(8) For details see Supporting Information.
(9) We note that a relatively strained tertiary nitrile is produced. For
hydrogen and silyl group rearrangement, see: Chiang, Y.; Grant, A. S.;
Guo, H.-X.; Kresge, A. J.; Paine, S. W. J. Org. Chem. 1997, 62, 5363.
Gornowicz, G. A.; West, R. J. Am. Chem. Soc. 1971, 93, 1571. Ketenimine
to nitrile rearrangement: Lee, K.-W.; Horowitz, N.; Ware, J.; Singer, L.
A. J. Am. Chem. Soc. 1977, 99, 2622. Neuman, R. C., Jr.; Sylwester, A. P.
J. Org. Chem. 1983, 48, 2285.
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Org. Lett., Vol. 7, No. 5, 2005

Figure 4. Arrhenius plot of the rearrangement of 1 established by
1H NMR (ODCB-d4), R2 ) 0.999.
Figure 5. Dynamic DSC of 1. Scan rate is 10 °C/min.
(where R ) alkyl or aryl). Compared to high level ab initio
theory, density functional theory is known to overestimate
electron-electron repulsions in the S-N bond,15 which led
to significant overestimation of the SO2-N bond length. The
calculated S-N bond energy of Me2N-SO2Me is 71.8 kcal/
mol at the G2 level, whereas it is only 47.4 kcal/mol at
B3LYP/6-31G*+ZPVE.16,17 Apparently the tosyl group
rearrangement is facilitated by strong resonance stabilization
of the transition state, i.e., scission of the S-N bond in 1
requires 16.5 kcal/mol less energy than in Me2N-SO2Me (at
B3LYP/6-31G*+ZPVE). Since a G2 level calculation pre-
dicts an S-N bond energy of 71.8 kcal/mol for Me2N-SO2-
Me, we believe that the dissociation of the same bond in 1
in the gas phase requires only ca. 55 kcal/mol.17 At the
B3LYP/6-31G*+ZPVE level, the intermediate 3 and product
2 are more stable than the reactant 1 by 24.2 and 35.3 kcal/
mol, respectively, while G2 corrected8,18 energies are 16.8
and 34.4 kcal/mol, respectively. The latter value is in good
agreement with the DSC experiment. Thus, both steps of
the rearrangement are thermodynamically favored.
0.999, T ) 375-415 K), Figure 4. The second-order rate
constant was determined to be 1.41 × 10-3 M-1 s-1 at 394
K, with an activation energy of 32.4 kcal/mol. Despite data
acquisition at multiple temperatures, no intermediate was
detected during the course of the rearrangement. In aromatic
solvents the reaction is second-order, indicating that the
mechanism is different from the nonaromatic solvent studied
(decalin), where the rearrangement is first-order in reactant.14
The rearrangement occurred much faster when 1 was
heated neat, compared to solution. According to differential
scanning calorimetry (DSC), 1 melts around 89 °C, followed
by a very exothermic process (ca. 34 kcal/mol, Figure 5).
Undoubtedly the exothermic process is due to the energy
released as a result of the rearrangement.
To further understand this unusual transmogrification, we
have used quantum mechanical calculations.8 Since this
rearrangement involves the breaking of an S-N bond without
the assistance of acid or base, the question that arises is what
is the S-N bond energy? Unfortunately, to the best of our
knowledge, there are no experimental or theoretical data on
the value of the SO2-N bond energy in RSO2-NR2 systems
To conclude, we have discovered the first uncatalyzed
thermal sulfonynamide to sulfone rearrangement and the first
rearrangement of an arylsulfonyl group from a sulfonamide
to keteneimine.
(14) Surprisingly, the activation energy was positive (+8 eu) in this
bimolecular rearrangement. A possible speculation might be a rearrangement
that gives an intermediate 3, which is reversibly trapped in more polar
solvents by a second molecule of starting material (zwiterionic [2 + 2]
reaction), giving a second intermediate that falls apart to product plus
reactant. Thus, the PMB group might either rearrange directly from linear
ketoimine in nonpolar solvents and lead to ketoimine intermediate, or the
PMB rearrangement might be assisted by [2 + 2] reaction in more polar
solvent (which may not necessarily lead to a cyclobutene but might just
begin to form a new C-C bond, by coordination, that leads to bending of
the ketoimine, concomitantly assisting the PMB rearrangement). Hence,
the activation barrier for the latter case is lowered and no ketoimine
intermediate is observed. We note that this suggestion will require further
investigation.
Acknowledgment. We are grateful to Dr. S. I. Khan for
X-ray crystallographic analysis, Prof. Ohyun Kwon (UCLA)
and Prof. William J. Leigh (McMaster University) for helpful
discussions, and Dr. R. E. Taylor for help with NMR
measurements (Department of Chemistry and Biochemistry,
(15) Bharatam, P. V.; Gupta, A.; Kaur, D. Tetrahedron 2002, 58, 1759-
1764.
(16) Similarly, B3LYP/6-31G*+ZPVE predicts the S-N bond energy
of Me2N-SMe to be 47.0 kcal/mol, whereas G2 theory predicts 61.1 kcal/
mol.
(17) We note that our calculations are for heterolytic bond cleavage in
gas phase. In contrast, in solution, we expect the dissociation energy to be
lower as a result of solvation of the intermediate. We do not suggest that
the reaction proceeds via complete S-N bond cleavage in the TS. However,
we believe that reduced S-N bond energy in 1 or in Me2N-SO2Me
contributes to the low temperature of the rearrangement in Scheme 1.
(18) The large size of these molecules forbids studying them at the ab
initio level of theory, so we used B3LYP/6-31G*+ZPVE for 1, 2, and 3
with corrections from examination of model compounds 1M, 2M, and 3M
at both G2 and B3LYP/6-31G*+ZPVE levels of theory.
Org. Lett., Vol. 7, No. 5, 2005
785

UCLA). We are grateful to the National Science Foundation
for support through grant DGE-0114443 and grant DMR-
0209651, as well as to the National Computational Science
Alliance support under CHE300048N.
IR, MS, elemental analysis); a kinetic study of 1; X-ray data
and CIF files for 1, 2, and 4; and DFT calculations. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: Experimental details
for the synthesis of 1-4 and their characterization (NMR,
OL0477327
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Org. Lett., Vol. 7, No. 5, 2005