Competitive reaction pathways for o-Anilide aryl radicals: 1,5-Or 1,6-hydrogen transfer versus nucleophilic coupling reactions. A novel rearrangement to afford an amidyl Radical

Article abstract of DOI:10.1021/jo801892c

The photoinduced reactions of o-iodoanilides (o-IC₆H ₄N(Me)COR, 4a-d) with sulfur nucleophiles such as thiourea anion (1, ^-SCNH(NH₂)), thioacetate anion (2, MeCOS^-), and sulfide anion (3,S^2-

Full text of DOI:10.1021/jo801892c

Competitive Reaction Pathways for o-Anilide Aryl Radicals: 1,5- or
1,6-Hydrogen Transfer versus Nucleophilic Coupling Reactions. A
Novel Rearrangement to Afford an Amidyl Radical
Valentina Rey, Adriana B. Pierini, and Alicia B. Pen˜e´n˜ory*
INFIQC, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias Qu´ımicas, UniVersidad Nacional de
Co´rdoba, Ciudad UniVersitaria, 5000 Co´rdoba, Argentina
penenory@fcq.unc.edu.ar
ReceiVed August 26, 2008
The photoinduced reactions of o-iodoanilides (o-IC6H4N(Me)COR, 4a-d) with sulfur nucleophiles such
-
as thiourea anion (1, SCNH(NH2)), thioacetate anion (2, MeCOS-), and sulfide anion (3, S2-) follow
different reaction channels, giving the sulfides by a radical nucleophilic substitution or the dehalogenated
products by hydrogen atom transfer pathways. After an initial photoinduced electron transfer (PET) from
1 to iodide 4, the o-amide aryl radicals 12 are generated. These aryl radicals 12 afford alternative reaction
pathways depending on the structure of the R-carbonyl moiety: (a) 12b (R ) Me) adds to 1 to render the
methylthio-substituted compounds by quenching the thiolate anion intermediate with MeI after irradiation;
(b) 12c (R ) -CH2Ph) follows a 1,5-hydrogen transfer to give a stabilized R-carbonyl radical (17); and
(c) 12d (R ) t-Bu) affords 1,6-hydrogen transfer, followed by a 1,4-aryl migration to render an amidyl
radical (20), which is reduced to the N-benzyl-N,2-dimethylpropanamide (10). Together with this last
rearranged product, the ipso substitution derivative was also observed. Similar results were obtained in
the PET reactions of 4d (R ) t-Bu) with anions 2 and 3 under entrainment conditions with the enolate
anion from cyclohexenone (5) or the tert-butoxide anion (6). From this novel rearrangement, and only
under reductive conditions by PET reaction with anion 5, iodide 4d (R ) t-Bu) affords quantitatively the
propanamide 10. The energetic of the intramolecular rearrangements followed by radicals 12b-d were
rationalized by B3LYP/6-31+G* calculations.
Introduction
leaving group at the ipso position by a nucleophile. This
process is considerably broad in scope in relation to substrates
and nucleophiles and to synthetic capabilities.2 Carbanions,
nitrogen nucleophiles, and anions from tin, phosphorus,
arsenic, antimony, sulfur, selenium, and tellurium are able
At present, the use of radical reactions for the synthesis
of target organic compounds is widely recognized, and many
studies describe the synthetic applications of different radical
procedures.1 The radical nucleophilic substitution involving
electron transfer (ET) steps or the SRN1 mechanism has
proven to be a versatile mechanism for replacing an adequate
(1) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, Germany, 2001. (b) Top. Curr. Chem. 2006, 263 and 264.
Rossi, R. A.; Pen˜e´n˜ory, A. B. Curr. Org. Synth. 2006, 3, 121–158.
* Fax: (+54) 351-4333030/ 4334174. Phone: (+54) 351-4334170/73.
10.1021/jo801892c CCC: $40.75
Published on Web 01/12/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1223–1230 1223

Rey et al.
CHART 1
to react with nonactivated aryl halides to yield new C-C or
C-heteroatom bonds.2
Among the sulfur-centered nucleophiles known to react under
photostimulation we can find alkane, arene, and heteroarene
thiolate anions. Recently, we have described the reactivity of
sulfur anions, such as thiourea anion (1, -SCNH(NH2)),3 and
thioacetate anion (2, MeCOS-)4 in photoinduced aromatic
radical nucleophilic substitution as a “one-pot” method for the
synthesis of several sulfur aromatic compounds in moderate to
good yields. These reactions offer a very good alternative to
introduce sulfur functionalities in aryl compounds at the position
of the halide leaving group. By using hydrogen abstraction from
DMSO as a competitive reaction, we have also determined the
absolute rate constants for the addition of ions S2- (3), 1, 2,
thiobenzoate (PhCOS-), and benzene thiolate (PhS-) anions to
1-naphthyl radicals (0.5 × 109 M-1 s-1, 1.0 × 109 M-1 s-1, 1.2
respectively, at 25 °C).5 Furthermore, for the reactions of
1-bromonaphthalene with anions 1, 2, and PhCOS-, we have
elucidated the mechanism for the photoinduced electron transfer
(PET) at the initiation step, the chain length, as well as the nature
of the chain carrier in the propagation cycle.5b
It is known that the o-iodoanilides with hydrogen atom at
the R-carbon are appropriate substrates for the synthesis of
oxindoles derivatives by intramolecular radical nucleophilic
substitution reactions.6 In addition, the o-haloanilides are also
suitable precursors of aryl radicals employed for the generation
of radicals adjacent to a carboxyl group by a 1,5-hydrogen
transfer. The so-formed radicals can follow synthetically useful
reactions, such as intramolecular cyclization,7 intermolecular
addition,7b or homolytic substitution to afford oxindoles.8
methylanilides 4a-d were chosen,9 for which the R group
comprises Ph, Me, PhCH2, and t-Bu, well suited for the
mechanistic elucidation of possible competitive reaction chan-
nels (Chart 1).
Results
o-Iodoanilides 4 were synthesized from o-iodoaniline by
standard acylation and alkylation procedures. These anilides are
found predominantly in the E conformation (CO/Ar trans
>%95).7b Table 1 summarizes the results obtained in the
photoinduced reactions of thiourea anion 1 with anilides 4a-c
and after being quenched with MeI.
Iodide 4a (R ) Ph) did not react with anion 1 after 3 h of
irradiation, and the substrate was completely recovered. Similar
results were found with other sulfur anions (2 and 3) and with
suitable electron donors, such as enolate anion of cyclohexenone
(5) or tert-butoxide anion (6) commonly used as entrainment10
reagents in radical nucleophilic substitutions. Both alkoxide
anions are able to transfer one electron to aryl iodides under
irradiation to initiate an SRN1 reaction; however, they are not
reactive toward aryl radicals in the addition step.4
× 109 M-1 s-1, 3.5 × 109 M-1 s-1, and 5.1 × 109 M-1 s-1
,
TABLE 1. Reactions of o-Iodoanilide with Thiourea Anion in
DMSOa
product yieldc
Taking into consideration our simple and effective methodol-
ogy for replacing an iodide atom by a sulfur anion, we are
concerned with finding out the scope of this reaction for the
synthesis of sulfur heterocycles. Thus, we have studied the
reactivity of o-iodoanilides with anions 1-3 in photoinduced
reactions in DMSO. Replacing the iodide by a sulfur anion and
its subsequent reaction with the carbonyl group would render
benzothiazole derivatives. Therefore, and in mechanistic terms,
it is of interest to study the effect of the nature of the R-carbonyl
alkyl moiety on the reactivity of the o-iodoanilides in photo-
induced reactions with sulfur anions. For this purpose, N-
entry 4 (ArI), R compound addedb convn ArSMe (7) ArH (8)
1
4a, Ph
4b, Me
2d
3
<4
100
58
93
43
97
5
<5
<5
4
p-DNB
5e
6d
7
100
4c, CH2Ph
65
18
20
100
67
45
23
8
p-DNB
TEMPO
9
32
10f
11h
<4g
50i
a ArI ) 4a-c, 0.05 M; anion 1, 0.5 M (ratio 4:1 ) 1:10). After 3 h
of irradiation under nitrogen atmosphere, the reaction was quenched by
MeI. b Compounds added (20%). c Determined by GC using the internal
standard method, error 5%. The conversion (convn) was determined by
quantification of the recovered substrate. d In the dark. e ArI ) 0.1 M.
f In the absence of anion 1, with an ArI/tert-butoxide ion ratio of 1:10.
g Together with oxindole 9 in 95% yield. h In the absence of anion 1,
with an ArI/enolate anion of cyclohexenone ratio of 1:1. i Together with
oxindole 9 in 23% yield.
(2) Rossi, R. A.; Pierini, A. B.; Pen˜e´n˜ory, A. B. Chem. ReV. 2003, 103, 71–
167. Rossi, R. A.; Pierini, A. B.; Santiago, A. N. In Organic Reactions; Paquette,
L. A., Bittman, R., Eds.; John Wiley & Sons, Inc.: New York, 1999; Vol. 54,
Chapter 1, pp 1-271. Rossi, R. A.; Pierini, A. B.; Pen˜e´n˜ory, A. B. Recent
Advances in the SRN1 Reaction of Organic Halides. In The Chemistry of
Functional Group; Patai, S., Rappoport, Z., Eds.; Wiley: Chichester, 1995; Suppl.
D2, Chapter 24, 1395-1485. Rossi, R. A.; Pen˜e´n˜ory, A. B. In CRC Handbook
of Organic Photochemistry and Photobiology, 2nd ed.; Horspool, W. M., Lenci,
F., Eds.; CRC Press Inc.: Boca Raton, 2003; Chapter 47, pp 47-1-47-24. Save´ant,
J. M. Acc. Chem. Res. 1993, 26, 455–461. Kornblum, N. Aldrichim. Acta 1990,
23, 71–78.
(3) Argu¨ello, J. E.; Schmidt, L. C.; Pen˜e´n˜ory, A. B. Org. Lett. 2003, 5, 4133–
4136.
(4) Schmidt, L. C.; Rey, V.; Pen˜e´n˜ory, A. B. Eur. J. Org. Chem. 2006, 2210–
02214.
(5) (a) Argu¨ello, J. E.; Schmidt, L. C.; Pen˜e´n˜ory, A. B. ARKIVOC 2003,
Part 5 (x), 411–419. (b) Schmidt, L. C.; Argu¨ello, J. E.; Pen˜e´n˜ory, A. B. J.
Org. Chem. 2007, 72, 2936–2944.
(6) (a) Wolfe, J. F.; Sleevi, M. C.; Goehring, R. R. J. Am. Chem. Soc. 1980,
102, 3646–3647. (b) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi,
M. C.; Wolfe, J. F. J. Am. Chem. Soc. 1985, 107, 435–443.
(7) (a) Jones, K.; Storey, J. M. D. J. Chem. Soc., Chem. Commun. 1992,
1766–1767. (b) Curran, D. P.; Yu, H.; Liu, H. Tetrahedron 1994, 50, 7343–
7366. (c) Xu, X.; Che, X.; Gao, S.; Wu, J.; Bai, X. Synlett 2005, 1865–1868.
(8) Beckwith, A. L. J.; Storey, J. M. D. J. Chem. Soc., Chem. Commun.
1995, 977–978.
For the methyl derivative 4b (R ) Me), there was no reaction
with anion 1 after 3 h in the dark. Under photostimulation (λmax
) 365 nm), however, it gave mainly N-methyl-N-(2-methylth-
io)phenyl)acetamide (7b) (93%) and a small amount of N-
methyl-N-phenylacetamide (8b) (5%), after quenching with MeI
(9) Preliminary results showed that when a solution of o-iodophenylacetamide
and thiourea anion in a 1:10 ratio, respectively, was irradiated for 3 h, and after
addition of MeI, the substrate was recovered methylated on the nitrogen atom.
Thus, deprotonation of the nitrogen inhibited the photoinduced initiation reaction.
In view of this result, we performed the present study with N-methyl derivatives.
(10) Braslavsky, S. E. Pure Appl. Chem. 2007, 79, 293–465.
1224 J. Org. Chem. Vol. 74, No. 3, 2009

Reaction Pathways for o-Anilide Aryl Radicals
(eq 1). This photoinduced reaction was strongly inhibited by
the addition of 20% of p-dinitrobenzene (p-DNB), a good
electron acceptor. Moreover, when the concentration of iodide
doubled, the photoinduced reaction afforded quantitatively
product 7 (Table 1, entries 1-5).
Anilide 4c (R ) CH2Ph) did not react with anion 1 in the
dark, and after 3 h, the photoinduced reaction afforded the
reduction product (8c) in 45% isolated yield without any traces
of a substitution product from the thiourea anion. Unfortunately,
when this last reaction was performed in DMSO-d6 as solvent,
product 8c was not labeled by deuterium; this was because in
the basic reaction medium the benzylic hydrogens are easily
exchanged during workup. This photostimulated reaction was
inhibited by the presence of p-DNB or TEMPO (Table 1, entries
6-9). When the photoinduced reaction was performed in the
absence of thiourea anion with a 10-fold excess of anion 6,
oxindole 9 was obtained in 95% isolated yield, together with
traces of 8c (eq 2). On the other hand, the photostimulated
reaction of aryl iodide 4c with anion 5 in a molar ratio 1:1 gave
the reduction product 8c and 9 in 50% and 23% yield,
respectively (Table 1, entries 10 and 11).
In the presence of 20 mol % of a highly efficient radical trap
like TEMPO, this photoinduced reaction was strongly inhibited
with only a 30% conversion yield. Moreover, this reaction did
not occur in the dark, and the substrate was recovered in 96%
yield. When pivalamide 4d was irradiated in the presence of
anion 5, a good electron donor, and in the absence of thiourea
anion, only the rearranged reduction product 10 was isolated
in 70% yield. In addition, when this last reaction was performed
in DMSO-d6 as solvent, the reduced rearranged product 10 was
not labeled by deuterium (Table 2, entries 2-4).
The reactivity of this pivalamide 4d toward thioacetate (2)
and sulfide (3) anions was determined under entrainment
conditions in the presence of anion 5 or 6. Although the
photoinduced reactions of these sulfur anions proceeded at low
conversion rates, the same products with a distribution similar
to that of the reaction with thiourea anion were observed (Table
2, entries 5 and 6).
Discussion
A detailed study of the photochemical reactions between
o-iodoanilides 4 with different sulfur-centered nucleophiles was
performed in DMSO. The absence of reaction in the dark, the
inhibition of the photoinduced reactions in the presence of an
electron acceptor such as p-DNB or by a radical trap like
TEMPO, the formation of the dehalogenated products 8, and
the rearranged derivatives 10 and 11 (Tables 1 and 2) evidence,
in these reactions, the participation of aryl radicals. These
intermediates are generated by a PET reaction from a suitable
electron donor to aryl iodide 4. Electron transfer to these
compounds may follow either a concerted dissociative pathway
through which the electron capture is accompanied by the
dissociation of the C-iodine bond or a stepwise mechanism
with formation of radical anions intermediates. Theoretical
inspection of the anionic surface of 4a-d with the B3LYP
functional and the LANL2DZ basis set in the presence of
DMSO, simulated as a continuum, shows the ET to 4b-d to
be dissociative; in other words, no radical anion intermediates
could be located on these surfaces; the ET to these compounds
leading to the dissociated radicals (12b-d)-halide anion
fragments (Scheme 1 and Figure 1b). On the other hand, the
ET to 4a follows a stepwise pathway with formation of a π
radical anion 4a•- in which the unpaired electron mainly
localizes at the PhCO moiety (Figure 1a).
Finally, the reactivity of tert-butyl derivative 4d was studied
under different reaction conditions; the results are summarized
in Table 2. The reaction of iodide 4d with thiourea anion (1)
gives, after 3 h of irradiation and the addition of MeI, the
expected methylthio derivative 7d from ipso substitution in only
10% yield and the dehalogenated product 8d in 2% yield. Apart
from these derivatives, two main products are observed: a
reduction (10) and a substitution (11) derivative in 38% and
25% yields, respectively, both arising from a radical rearrange-
ment (Table 2, entry 1, eq 3).
TABLE 2. Reactions of o-Haloanilide (R ) t-Bu, 4d) with
Nucleophiles in DMSOa
product yieldb
entry
Nu-
convn
7d
8d
10
11
1
1
1
1
97
70
<4
100
70
10
6
2
38
13
25
15
2c
3d
4e
5e
6e
70f
20
2
2
3
10
5
3
5
12
15
86
a ArI ) 4d, 0.05 M; nucleophiles (Nu-), 0.5 M, (ratio 4d/Nu-, )
1:10). After 3 h of irradiation under nitrogen atmosphere, the reaction
was quenched by MeI. b Determined by GC using the internal standard
method, error 5%. The conversion (convn) was determined by
quantification of the recovered substrate. c In the presence of 20 mol %
of TEMPO. d In the dark. e In the presence of the enolate anion of
cyclohexenone, 0.25 M. f Isolated.
As shown in Figure 1a, the unpaired spin density in 4a•- is
highly localized at the PhCO moiety. On the basis of this spin
density distribution, the dissociation of 4a•- by an intramolecular
ET from the π PhCO system to the σ* C-iodine bond is
expected to be a disfavored process.11 In agreement with this
finding, 4a was found to be unreactive under our experimental
J. Org. Chem. Vol. 74, No. 3, 2009 1225

Rey et al.
SCHEME 3
FIGURE 1. B3LYP/LANL2DZ unpaired spin density of (a) 4a•- and
(b) of the charge-radical complex formed by ET to 4d, both in DMSO
(density isovalue ) 0.005).
SCHEME 1
carbon radical 15 (eq 4, Scheme 2). Deprotonation of carbon
radical 15 renders cyanamide radical anion which, by ET to
the aryl iodide, may continue the SRN1 cycle (eq 5, Scheme
2).5b The reduction or dehalogenation product 8b can be ascribed
to a competitive 1,5-hydrogen atom transfer to render an
R-carbonyl methyl radical (16) followed by subsequent hydrogen
atom abstraction from the solvent (eq 6, Scheme 2). After
irradiation, thiolate ion 14 is quenched with MeI to give
methylthio derivative 7b (eq 7, Scheme 2). Due to steric
hindrance, the addition of anion 14 to the o-amidophenyl radical
12b is not a competitive reaction and Ar2S is not formed.4
The photoinduced reaction of iodide 4c with anion 1 gave
the dehalogenation product 8c, and no trace of the coupling
product was observed. In this reaction, the aryl radical inter-
mediate 12c (R ) CH2Ph, Scheme 3) yields, by 1,5-hydrogen
transfer, an R-carbonyl radical stabilized by the phenyl group
(17). This reaction is faster than the coupling of aryl radical
intermediate 12c with thiourea anion.13 As a result, radical 17
affords 8c as the only product by hydrogen atom abstraction
from the solvent (eq 8, Scheme 3). In the absence of thiourea
anion, and with an excess of potassium tert-butoxide, the
deprotonation of the R-carbonyl carbon is complete and the
resulting enolate anion affords oxindole 9 (95% yield) by an
intramolecular SRN1 reaction (eq 9, Scheme 3). A similar ring-
closure reaction with a 64% yield was reported using the strong
base lithium diisopropylamide in tetrahydrofuran at -78 °C.6
In the presence of only 1 equiv of the enolate anion of
cyclohexenone, the deprotonation equilibrium is not completely
favorable to the generation of the enolate anion, and both 8c
and 9 products were observed.
SCHEME 2
conditions. Similar results have been reported for the reaction
of o-iodohalobenzenes with enolate anions of aromatic ketones
in DMSO under ET conditions. In this system, the formation
of monosubstitution with halide retention as main reaction
product was rationalized by theoretical studies and attributed
to the intermediacy of a highly stabilized radical anion having
the unpaired spin at the π ArCO system.12
As seen from Tables 1 and 2, aryl radicals 12b-d follow
different reaction pathways as a function of the structure of the
R-carbonyl alkyl moiety (R).
Aryl iodide 4b gave methylthio derivative 7b in excellent
yields, and the observed results (Table 1, entries 2-5) can be
described by a radical nucleophilic substitution mechanism, such
as the following: aryl radical 12b (R ) Me, Scheme 2) adds
efficiently to thiourea anion to afford a new radical anion
intermediate 13, which fragments into arene thiolate ion 14 and
Finally, iodide 4d reacted by photostimulation with anion 1
to yield a mixture of unrearranged (7d and 8d) and rearranged
(10 and 11) products (Table 2). The same compounds were also
observed for the PET reactions with the sulfur-centered anions
2 and 3 under entrainment conditions. These results can be
(13) The lack of observation of coupling product indicates at least a ratio
[ArH]t/[ArNu]t ) 100 (where ArH and ArNu are the concentrations of the
reduction and substitution products at time t). Thus, the ratio between the rate
constants for the 1,5-H transfer and for the addition step shoul be k1-5-H/kc )
100[Nu-]o, where [Nu-]o is the initial concentration of the nucleophile. Taking
into consideration that the concentration of the nucleophile is 0.5 M, the rate
constant for the 1,5-hydrogen migration should be at least 1 order of magnitude
higher than the rate constant for the addition of thiourea anion to the aryl radical.
The rate constant for coupling with thiourea anion can be estimated around 5 ×
107 M-1 s-1; this considering that PhS- is 5.1 times more reactive than thiourea
anion (ref 5b) and that the rate constant determined for the coupling of o-(ω-
alkenyl)phenyl radical with PhS- anion is 2.6 × 108 M-1 s-1. Beckwith, A. L. J.;
Palacios, S. M. J. Phys. Org. Chem. 1991, 4, 404–412. For a similar 1,5 hydrogen
migration, a value higher than 108 s-1 was suggested (ref 8).
(11) The reaction of N-(1-bromonaphthalen-2-yl)-N-methylbenzamide with
thiourea anion in DMSO afforded, after 3 h of irradiation and quenching with
MeI, the substituted methylthio derivative in only 11% yield with a conversion
of 30% (from the recovered substrate). In this case, the unpaired spin distribution
in the radical anion intermediate localizes mainly at the p PhCO system with a
small but detectable density on the bromonaphthyl moiety.
(12) Baumgartner, M. T.; Jime´nez, L. B.; Pierini, A. B.; Rossi, R. A. J. Chem.
Soc., Perkin Trans. 2 2002, 1092–1097.
1226 J. Org. Chem. Vol. 74, No. 3, 2009

Reaction Pathways for o-Anilide Aryl Radicals
SCHEME 4
SCHEME 5
N-arylated sulfonamides with Bu3SnH/AIBN.17 Recently, an
unusual 1,3-aryl migration from a nitrogen to a carbon atom to
afford an amidyl radical has been reported.18 To the best of
our knowledge, we here report for first time a radical 1,4-phenyl
migration from a nitrogen to a primary carbon radical to afford
an amidyl radical 20. The yield of amide 10 increased to 70%
when the photoinduced reaction of iodide 4d was performed in
the presence of only the enolate anion of cyclohexenone as an
electron donor.
In addition, the rate constant for this novel rearrangement
from 12d to 20 (kr, pathway c, Scheme 4) can be evaluated in
DMSO using the nucleophilic addition step (pathway b, Scheme
4) as a competitive reaction. Once the yields from the substitu-
tion (ArNu ) 7d) and the rearranged reduced (Ar′H ) 10)
products were determined in the photoinduced reactions of 4d
with ion 1 in excess, in order to estimate the rate constant for
the rearrangement (kr) equation 10 can be used (Table 2).19
explained as follows: aryl radical 12d (R ) t-Bu) generated by
PET (Scheme 1) has three competitive reaction pathways, as
summarized in Scheme 4: (a) hydrogen atom abstraction from
the solvent to yield the reduction product 8d; (b) coupling
with sulfur anions (1, 2, or 3) at the ipso position to give
methylthio derivative 7d, after quenching with MeI; and (c)
1,6-hydrogen transfer to render a primary radical (18),
followed by a 1,4-aryl migration through the intermediacy
of a spiro radical 19 to afford an amidyl radical (20). This
nitrogen-centered radical can be reduced by hydrogen atom
abstraction from the medium to give the rearranged amide
10, the main product of this reaction.14 In addition, further
evidence of the intermediacy of the spiro radical 19 is also
provided by the formation of the para-substituted methylthio
derivative (11). Coupling reaction of sulfur anions 1, 2, or 3
at the para position of the spiro radical 19, followed by
fragmentation, proton transfer, and ring opening of the spiro,
affords a thiolate anion. Quenching with MeI after irradiation
finally yields the p-methylthio substituted product 11.
Radical aryl migration reactions are well-known processes,
the most extensively investigated example of 1,2-aryl migration
being the neophyl-type rearrangement.15 In the literature, there
are also many examples of 1,4 and 1,5-aryl migration reactions
from carbon to carbon. Nevertheless, few examples are known
involving aryl migration between nitrogen and carbon atoms,
for example, the 1,4-aryl migration from nitrogen to an aryl
radical to yield an amidyl radical16 and the 1,4-aryl migration
from nitrogen to primary carbon radicals in the reactions of
kr
[Ar′H]t[Nu-]o
)
(10)
kc-1
[ArNu]t
Therefore, for the reaction with thiourea anion (1, 0.5 M), kr
) 1.9 kc-1 in DMSO at 25 °C, where kc-1 is the rate constant for
the coupling reaction between 1 and the o-substituted phenyl
radical. Due to steric effects, the kc-1 for the o-(N-methylpiv-
alamide)aryl radical (12d) is expected to be slower that the rate
constant for the coupling of an o-alkenyl or the o-(N-methyl-
2-phenylacetamide)aryl radical (12c).13 Thus, considering that
the reactivity of thiourea anion toward 12d should be inferior
to 5 × 107 M-1 s-1, a superior limit of 108 s-1 (DMSO at 25
°C) can be estimated for the rate constant for rearrangement of
12d to 20. This rearrangement involves the individual contribu-
tion of the 1,6-H transfer, the formation of the spiro radical 19,
and finally, the ring opening to afford the amidyl radical 20.
The experimental findings were further investigated by a
theoretical gas-phase study of the energetic of the intramolecular
hydrogen transfer in radicals 12b-d and the barriers for rotation
of the radical center around the CPh-N bond (ꢀ dihedral, see
the Supporting Information) at the B3LYP/6-31+G* level
(Scheme 5).
The most stable conformations of radicals 12b and 12d
characterize by the proximity of the radical center to the H atoms
(14) The intramolecular 1,6-hydrogen abstraction from the ortho aromatic
carbon atom to the amidyl radical to afford an aryl radical is not a thermody-
namically favorable process. The absence of labeled product 10, when the reaction
was performed in DMSO-d6, further supports this statement.
(15) For a review on radical aryl migration reactions, see: Studer, A.; Bossart,
M. Tetrahedron 2001, 57, 9649–9667. Studer, A.; Bossart, M. In Radicals in
Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH: Weinhein,
Germany, 2001; Vol. 2, pp 62-80.
(17) Lee, E.; Whang, H. S.; Chung, C. K. Tetrahedron Lett. 1995, 36, 913–
914.
(18) Bacque´, E.; El Qacemi, M.; Zard, S. Z. Org. Lett. 2005, 7, 3817–3820.
(19) [Nu-]o is the initial concentration of the nucleophile; Ar′H and ArNu
are the concentrations of the rearranged reduction and substitution products at
time t. These equations are based on the assumption that the reactions of the
aryl radicals with the nucleophiles and the solvent are first order in the latter
species and their concentrations are constant during the experiments.
(16) Grimshaw, J.; Hamilton, R.; Trocha-Grimshaw, J. J. Chem. Soc., Perkin
Trans. 1 1982, 229–234.
J. Org. Chem. Vol. 74, No. 3, 2009 1227

Rey et al.
FIGURE 2. B3LYP/6-31+G* most stable conformations for radicals 12b-d. Shortest radical center-hydrogen distance (Å).
FIGURE 3. B3LYP/6-31+G* hydrogen-transfer TSs calculated for (a)
12b and (b) 12d. Distances of CH distinguished coordinates (Å).
of the alkyl group (Figure 2). The difference in energy between
these conformations and those in which the radical is more
available for coupling with a nucleophile is in the order of 0.1
and 0.9 kcal/mol for 12b and 12d, respectively (see the
Supporting Information). On the other hand, the most stable
conformation of 12c characterizes by an appropriate disposition
of the radical toward coupling (Figure 2). The stability of this
conformation can be ascribed to an interaction between both
FIGURE 4. B3LYP/6-31+G* potential energy surface for the reaction
12d f 18 f 19.
phenyl rings.
The activation barriers evaluated for hydrogen transfer follow
the order 12b (5.41 kcal/mol) > 12d (3.56 kcal/mol) > 12c
(1.46 kcal/mol), the exothermicity of the reaction being 12c
(-31.37 kcal/mol) > 12b (-16.06 kcal/mol) > 12d (-14.16
kcal/mol). The 1,5- and 1,6-H transfer transition states (TSs)
calculated for 12b and 12d, respectively, are presented in Figure
3, as representative.
As seen, the 1,5-H transfer in 12c is a highly exothermic
reaction accompanied by the lowest activation energy. So,
despite the most stable conformation of this radical has an
appropriate geometry for coupling, the 1,5-H transfer is the
favored pathway, and in agreement with the experimental
findings, 12c affords 8c through the intermediacy of radical
17.
Comparison of the activation energy for hydrogen transfer
of the three radicals point the 1,5-H transfer of radical 12b to
require the highest activation energy. The reaction occurs
through a cyclic 6 member TS in which a planar geometry is
retained (see Figure 3). Despite the conformers for hydrogen
transfer and nucleophile coupling have similar probability
distribution at equilibrium, substitution is the main reaction
followed by this radical. This result indicates that for 12b
coupling with anion 1 competes efficiently with the 1,5-H
transfer.
Conclusion
The 1,6-H transfer in 12d occurs through a cyclic 7-membered
TS stabilized by a distorted boat arrangement (see Figure 3).
The conformer of 12d that prevails under equilibrium has the
adequate geometric disposition for 1,6-H transfer. Moreover,
the radical center is surrounded by two proximal Me groups,
and thus, the reaction proceeds exothermically with low
activation energy to afford radical 18. In the latter intermediate,
the radical center, at 2.79 Å from the substituted CPh, has a
favorable spatial arrangement toward cyclization to render
radical 19. This addition to give the spiro-radical 19 occurs
exothermically (-13.4 kcal/mol) with an activation barrier of
3.9 kcal/mol (Figure 4).
o-Iodoanilides react by PET with thiourea anion (1), the
enolate anion from cyclohexenone (5), or tert-butoxide anion
(6) to afford o-amidoaryl radical (12) after fragmentation. The
use of the enolate anion 5 under photostimulation is a good
alternative to generate aryl radicals by PET under mild condi-
tions (room temperature, irradiation with a medium-pressure Hg
lamp, soft basic conditions, etc.).
For radical 12, different reaction channels are possible
depending on the structure of the alkyl substituent R to the
carbonyl group: for o-(N-methylacetamide)aryl radical (12b),
coupling with sulfur anions 1, 2,or 3 is the main reaction to
render, after quenching with MeI, the ipso-substituted me-
thylthio derivative in excellent yield. On the other hand, o-(N-
methyl-2-phenylacetamide)aryl radical (12c) gives only the
stabilized R-carbonyl benzyl radical by 1,5-hydrogen transfer,
This cascade of exothermic intramolecular reactions is thus
responsible of the experimental profile shown for compound
4d which mainly affords the rearranged amide 10.
1228 J. Org. Chem. Vol. 74, No. 3, 2009

Reaction Pathways for o-Anilide Aryl Radicals
N-(2-Iodophenyl)-N-methylpivalamide (4d)25: white solid; mp
132.4-133.4 °C; 1H NMR (400.16 MHz, CDCl3, 30 °C) δ ) 1.06
(s, 9H, C(Me)3), 3.16 (s, 3H, NMe), 7,04 (ddd, 1H, Ar-H, Jo )
which is reduced by hydrogen abstraction. Finally, o-(N-
methylpivalamide)aryl radical (12d) affords a novel rear-
rangement to an amidyl radical by a 1,6-hydrogen transfer,
followed by a 1,4-aryl migration through a spiro radical
intermediate. Aryl radical intermediate 12d can also give the
ipso-substituted methylthio derivative and the unrearranged
reduction compound as minor products. Taking into account
the magnitude of the rate constant for the coupling reaction
between thiourea anion and aryl radicals, a superior limit of
108 s-1 (DMSO at 25 °C) can be estimated for the rate
constant for rearrangement of 12d to 20.
The B3LYP functional succeeds to predict the intramo-
lecular rearrangements of the radicals proposed as intermedi-
ates. The calculations indicate that the kinetically and
thermodynamically preferred reaction pathway for 12c is
1,5-H transfer, while for radical 12d the formation of the
main experimental products, ascribed to a 1,6 H transfer
followed by a 1,4 phenyl migration, is possible due to a
sequence of two exothermic steps.
7.56, Jo ) 7.64, Jm ) 1.60), 7.28 (dd, 1H, Ar-H Jo ) 7.64, Jm
)
1.60), 7.38 (ddd, 1H, Ar-H, Jo ) 8.04, Jo ) 7.56, Jm ) 1.40), 7.90
(dd, 1H, Ar-H, Jo ) 8.04, Jm ) 1.40); 13C NMR (100.62 MHz,
CDCl3, 30 °C) δ 29.2, 39.8, 40.9, 129.2, 129.4, 140.1, 140.1, 147.5,
177.8; the assignments are supported by COSY 45 and HSQC
spectra; GC/MS (EI) (m/z) 57 (100), 77 (14), 104 (13), 139 (9),
166 (5), 190 (73), 233 (14), 260 (2); HRMS (electrospray) calcd
for C12H17INO 318.0349 (M + H)+, found. 318.0356.
N-Methyl-N-(2-(methylthio)phenyl)acetamide (7b). white solid;
1H NMR (200 MHz, CDCl3, 30 °C) δ 1.80 (s, 3H, COMe), 2.45
(s, 3H, SMe), 3.18 (s, 3H, NMe), 7.11-7.43 (m, 4H, Ar-H); 13C
NMR (50 MHz, CDCl3, 30 °C) δ 14.0, 21.7, 35.0, 124.9, 125.4,
128.1, 128.8, 138.4, 141.2, 170.8; the assignments are supported
by COSY 45 and HSQC spectra; GC/MS (EI) (m/z) 195 (5, M+),
148 (100), 138 (29), 122 (10), 109 (9), 94 (22), 77 (13), 51 (6);
HRMS (EI) calcd for C10H13NOS 195.07179 M+, found 195.07217.
N-Methyl-N-(2-(methylthio)phenyl)pivalamide (7d): white
1
solid; mp 80.5-81.3 °C; H NMR (200 MHz, CDCl3, 30 °C) δ
1.06 (s, 9H, t-Bu), 2.45 (s, 3H, SMe), 3.14 (s, 3H, NMe), 7.11-7.37
(m, 4H, Ar-H); 13C NMR (50 MHz, CDCl3, 30 °C) δ 14.1, 28.9,
38.9, 40.9, 124.7, 128.9, 129.1, 139.0, 141.9, 178.6; the assignments
are supported by COSY 45, HSQC and HMBC spectra; GC/MS
(EI) (m/z) 190 (100), 180 (9), 153 (9), 134 (18), 133 (14), 120 (3),
94 (4), 77 (4), 57 (60); HRMS (electrospray) calcd for C13H20NOS
238.1260 (M + H)+, found 238.1265; IR (KBr) ν (cm-1) 1633,
1354.
In view of the results herein reported, the use of o-iodoanilides
with sulfur-centered nucleophiles is not an appropriate alterna-
tive for the synthesis of benzothiazole derivatives, due to
competitive hydrogen atom transfer and radical rearrangement
reactions.
Experimental Section
2-Benzyl-N,2-dimethylpropanamide (10): white solid; mp
1
79-80 °C; H NMR (400.16 MHz, CDCl3, 30 °C) δ 1.18 (s, 6H,
Chemicals. t-BuOK, SC(NH2)2, MeCOSK, Na2S, 2-iodoaniline,
2-chloroaniline, cyclohexenone, p-dinitrobenzene, TEMPO, DTBN,
N-methyl-N-phenylacetamide (8b), N-methyl-N,2-diphenylaceta-
mide (8c), and MeI were all high purity commercial samples which
were used without further purification. DMSO was distilled under
vacuum and stored over molecular sieves (4 Å). Anion 1 and the
cyclohexenone enolate anion were generated in situ by acid-base
deprotonation using t-BuOK. N-Methylanilides 4a-d and 8 were
synthesized by standard procedures from the reaction between
commercial 2-haloanilines and the corresponding acid chloride in
CH2Cl2 in the presence of pyridine.20
C(Me)2) 2.73 (d, 3H, NMe) 2.84 (s, 2H, CH2), 5.46 (s, 1H, NH),
7.11-7.28 (m, 5H, Ar-H); 13C NMR (50 MHz, CDCl3, 30 °C) δ
24.8, 26.1, 43.1, 46.6, 126.0, 127.6, 129.8, 137.9, 177.3; the
assignments are supported by COSY 45 and HSQC spectra; GC/
MS (EI) m/z 191 (M+, 11), 176 (20), 149 (30), 132 (5), 133 (8),
117 (14), 100 (8), 92 (19), 91 (100), 58 (16); HRMS (EI) calcd for
C12H17NO 191.13101 (M+), found 191.13077; IR (KBr) ν (cm-1
3293, 1633, 1555.
)
2-(4-(Methylthio)benzyl)-N,2-dimethylpropanamide (11):
white solid; mp 95.0-95.3 °C; 1H NMR (400.16 MHz, CDCl3, 30
°C) δ 1.16 (s, 6H, C(Me)2), 2.46 (s, 3H, SMe), 2.72 (d, 3H, NMe),
2.77 (s, 2H, CH2), 5.44 (s, 1H, NH), 7.03 (d, 2H, J ) 8,42), 7.13
(d, 2H, J ) 8.42); 13C NMR (100,62 MHz, CDCl3, 30 °C) δ 15.9,
25.1, 26.4, 43.5, 46.4, 126.3, 130.6, 135.2, 136.1, 177.5; the
assignments are supported by COSY 45, HSQC and DEPT 135
spectra; CG/MS (EI) m/z 237 (M+, 29), 179 (5), 137 (100), 122
(7), 91 (5), 58 (7); HRMS (EI) calcd for C13H19NOS 237.11873
(M+), found 237.11820; IR (KBr) ν (cm-1) 3337, 1633, 1540.
Computational Procedure. All calculations were performed
with the Gaussian03 program, the B3LYP26 DFT functional, and
the LANL2DZ basis set for iodine-containing compounds. This
effective core potential (ECP) basis set27 was previously used
in the evaluation of the anionic surfaces of halobenzenes and
afforded results of acceptable quality to compare the electronic
properties of PhI with respect to PhX (X ) F, Cl, Br).28 The
6-31+G* basis set was used to study all of the remaining
systems.
All the reaction products were isolated by radial chromatography
1
from the reaction mixture and characterized by H and 13C NMR
and mass spectrometry. The known substrates 4a,21 4b,22 4c,23 8d,24
and 96b exhibited physical properties identical to those reported in
the literature.
Representative Experimental Procedure. The reactions were
carried out in a 10 mL three-necked Schlenk tube, equipped with
a nitrogen gas inlet and a magnetic stirrer. The tube was dried
under vacuum, filled with nitrogen, and then charged with dried
DMSO (10 mL). t-BuOK (280.5 mg, 2.5 mmol), potassium
thioacetate (285.5 mg, 2.5 mmol), and aryl halide (0.5 mmol)
were added to the degassed solvent under nitrogen. After 3 h of
irradiation with a medium-pressure Hg lamp emitting maximally
at 365 nm, the reaction was quenched by addition of MeI (342
µL, 5.5 mmol) and water (30 mL), and the mixture was extracted
with methylene chloride (3 × 20 mL). The organic extract was
washed twice with water and dried over anhydrous MgSO4, and
the products were quantified by GC by the internal standard
method or isolated by radial chromatography from the crude
product reaction mixture.
The characterization of stationary points was done by Hessian
matrix calculations. The effect of DMSO as polar aprotic solvent
was evaluated through Tomasi’s Polarized Continuum Model
(PCM)29 as implemented in Gaussian03. The energy informed
(20) Fersht, A. R.; Jencks, W. P. J. Am. Chem. Soc. 1970, 92, 5432–5442.
(21) Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun 2004,
2228–2229.
(22) Ryo, S.; Takafumi, Y.; Tamio, H. Org. Lett. 2006, 8, 4799–4801.
(23) Tomohiro, S.; Itaru, N.; Yoshinori, Y. J. Am. Chem. Soc. 2004, 126,
10546–10547.
(25) The bromide derivative N-(2-bromophenyl)-N-methylpivalamide is
known. Gade, T.; Streek, M.; Voss, J. Chem. Ber. 1992, 125, 127–141.
(26) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785. Becke,
A. D. Phys. ReV. A 1988, 38, 3098. Miehlich, B.; Savin, A.; Stoll, H.; Preuss,
H. Chem. Phys. Lett. 1989, 157, 200–206.
(24) Itai, A.; Toriumi, Y.; Saito, S.; Kagechita, H.; Shudo, K. J. Am. Chem.
Soc. 1992, 114, 10649–10650.
(27) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 270–71.
(28) Pierini, A. B.; Vera, D. M. A. J. Org. Chem. 2003, 68, 9191–9199.
J. Org. Chem. Vol. 74, No. 3, 2009 1229

Rey et al.
for TSs and radicals includes zero-point corrections. The
calculations related to the radicals were performed in the gas
phase.
Argentina. V.R. gratefully acknowledges the receipt of a
fellowship from CONICET.
Supporting Information Available: 1H NMR and 13C NMR
of compounds 4d, 7b,d, 10, and 11. COSY 45 and HSQC or
HMBC spectra to support the assignments. xyz coordinates
and total energies in atomic units of the species calculated.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported partly by the
Consejo Nacional de Investigaciones Cient´ıficas y Te´cnicas
(CONICET) and Fondo de Ciencia y Tecnolog´ıa (FONCYT),
(29) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117–129.
Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239. Cossi, M.; Barone, V.;
Cammi, R.; Tomasi, J. Chem. Phys. Lett. 1996, 255, 327–335.
JO801892C
1230 J. Org. Chem. Vol. 74, No. 3, 2009