Metal-free transformation of phenols into substituted benzamides: A highly selective radical 1,2-O→C transposition in O-aryl-N-phenylthiocarbamates

Article abstract of DOI:10.1002/chem.201002303

Radical merry-go-round: A highly efficient metal-free transformation of phenols into benzamides is designed through one-step conversion of phenols to aryl thiocarbamates and a subsequent radical addition/rearrangement/ fragmentation cascade. Computational analysis fully rationalizes the experimentally observed selectivity. Despite the possible competition from N-C fragmentation and N-neophyl rearrangement, the transformation exclusively follows the most kinetically and thermodynamically favored O-neophyl rearrangement path.

Full text of DOI:10.1002/chem.201002303

DOI: 10.1002/chem.201002303
Metal-Free Transformation of Phenols into Substituted Benzamides: A
Highly Selective Radical 1,2-O!C Transposition in O-Aryl-N-
phenylthiocarbamates
Abdulkader Baroudi, Phillip Flack, and Igor V. Alabugin*[a]
There are a limited number of reactions that utilize the
cently developed a convenient procedure for the conversion
of phenols into benzoate esters.[3] This transformation was
designed through rerouting the Barton–McCombie[4] reac-
tion via an O-neophyl rearrangement[5]/fragmentation se-
ꢀ
reactivity of the O C bond in phenols for the formation of
benzoic acid derivatives. Most frequently, these transforma-
tions are based on metal(Pd)-catalyzed carbonylation of aro-
matic triflates.[1] An expedient metal-free approach for the
conversion of phenols into benzoic acid derivatives would
become a significant synthetic advance by providing a useful
alternative to these processes. Inspired by the observation of
O!C radical transposition triggered by the Bergman cycli-
zation of enediynes (Scheme 1, [Eq. (1)]),[2] our lab has re-
quence (Scheme 1,ACTHNUGTRNEUNG[Eq. (2)]).
Although the radical transformation of diaryl thiocarbon-
ates affords aryl benzoates in good to high yields [Eq. (2)],
it can be unpractical for expensive phenols because it re-
quires two equivalents of the corresponding starting materi-
al. As unsymmetrical diaryl thiocarbonates show only mod-
erate selectivity, a different approach to selective O!C
transposition has been necessary for broadening the scope
of this reaction and taking the full advantage of this poten-
tially very useful two-step transformation of phenols into
benzoic acid derivatives.
The rearrangement of O-alkyl-substituted thiocarbonates
leads to the well-known radical fragmentation (incorporated
in the Barton–McCombie deoxygenation pathway) without
the formation of rearrangement product (benzoate ester).[3]
ꢀ
In contrast, radical fragmentation of C N bonds through
the same process is inefficient. For example, although rever-
sible radical abstraction of the a-hydrogen readily occurs in
ꢀ
amines, no scission of C N bonds is observed under these
conditions.[6] Our computational study on the C N radical
ꢀ
Scheme 1. Equation (1): O!C Radical transposition triggered by the
Bergman cyclization of enediynes. Equation (2): Radical transformation
of diaryl thiocarbonates into benzoate esters.
fragmentation in a model thiocarbamate estimates a barrier
of about 29 kcalmolꢀ1 (Scheme 2a),[7] which is 5–7 kcalmolꢀ1
higher than that of the O-neophyl rearrangement in thiocar-
bonates. Encouraged by these results, we replaced the O-
alkyl substituent with an N-alkyl moiety to investigate
whether respective thiocarbamates will afford a more selec-
tive radical rearrangement (Scheme 2b).
[a] A. Baroudi, P. Flack, Prof. I. V. Alabugin
Department of Chemistry and Biochemistry
Florida State University
We initially tested the viability of the O!C transposition
in N,N-diethyl-O-phenyl thiocarbamate. Unfortunately, this
compound remained unreactive towards Et3SiH (2 equiv)
and tert-butyl peroxide (TOOT, 1 equiv) even after heating
for 4 h at 1358C in benzene (Scheme 3a; Table 1, entry 1).
To test whether the lack of reactivity is due to the excessive
stabilization of the anomeric radical by the hyperconjugative
interaction with the adjacent nitrogen lone pair, we modi-
Tallahassee, FL 32306-4390 (USA)
Fax : (+1)850-644-8281
E-mail: alabugin@chem.fsu.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201002303. It contains detailed
experimental procedures for the synthesis and the rearrangement of
1
thiocarbamates, H and 13C NMR spectroscopic data, MS, and FTIR
for new compounds, as well as total energy and Cartesian coordinates
for each optimized stationary point at the reaction hyper surfaces.
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Chem. Eur. J. 2010, 16, 12316 – 12320

COMMUNICATION
Table 1. Reaction optimizations for the rearrangement of thiocarba-
mates. All entries are for N-methyl-N-phenyl-O-(1-naphthyl) thiocarba-
mate except for entry 1 which is for N,N-diethyl-O-phenylthiocarbama-
te.[a]
Entry
Et3SiH
Radical
initiator
Yield
[%]
Conv.
[%]
1
2
3
4
2 equiv
2 equiv
3 equiv
4 equiv
5 equiv
3 equiv
2 equiv
3 equiv
3 equiv
2 equiv
2 equiv
3 equiv
TOOT
TOOT
TOOT
TOOT
TOOT
TOOT
DTBPB
DTBPB
DTBPB
DTBPB
DTBPB
DTBPB
0
17
33
68
72
~10
33
98
32
55
43
0
0
48
78
100
100
19
67
100
48
80
71
5
6[b]
7
8
9[c]
10[d]
11[e]
12[f]
Scheme 2. a) Model study of radical N-alkyl fragmentation in thiocarba-
mates at the UB3LYP/6-31+G** level (energies are in kcalmolꢀ1). b)
Proposed O-neophyl rearrangement of thiocarbamates.
0
[a] Unless otherwise specified, all reactions were carried out at 11 mm of
thiocarbamate, with the 1:2 molar ratio of radical initiator to Et3SiH, at
1358C for 4 h. [b] At 0.33 mm concentration of substrate. [c] 1:4 molar
ratio of the radical initiator to Et3SiH. [d] Reaction was run for 8 h.
[e] At 0.22 mm concentration of substrate. [f] Reaction was run for 8 h at
1008C.
entry 2), we proceeded to optimize the conditions via varia-
tions in temperature, concentration and equivalents of reac-
tants, and the nature of the radical initiator. By increasing
the equivalents of Et3SiH to four, the product yield im-
proved to 68% with complete conversion of the starting ma-
terial (Table 1, entries 2–4). With five equivalents of Et3SiH,
a further slight improvement of the amide yield was ob-
served (72%, Table 1, entry 5).[8]
Even better results were obtained when 2,2-bis(tert-butyl-
peroxy)butane (DTBPB) was used instead of TOOT as a
radical initiator. Only three equivalents of Et3SiH were suf-
ficient for obtaining an excellent yield (98%) of the amide
with 100% conversion of the starting material (Table 1,
entry 8). Similar to what was obtained in Table 1, entry 6, a
lower yield and conversion were obtained at a higher con-
centration (Table 1, entry 11). Assuming that the silicon rad-
ical addition to the S=C bond is reversible, the above results
suggest that side reactions, such as irreversible termination
steps of the silicon radical, may compete with the O-neophyl
rearrangement pathway at the higher concentrations (see
the Supporting Information). It is noteworthy that carrying
out the reaction with either only two equivalents of Et3SiH
(Table 1, entry 10) or at a lower temperature (1008C,
Table 1, entry 12) resulted in low or zero conversions, even
for the longer reaction times (8 h). The formation of S-cen-
tered radicals may be important for the chain propagation
step via polarity reversal catalysis.[9]
Scheme 3. a) Reaction of triethylsilyl radical with N,N-diethyl-O-phenyl-
thiocarbamate. b) O-Neophyl versus N-neophyl rearrangement pathways
in the reaction of thiocarbamates.
fied the donor ability of the nitrogen atom by attaching it to
an aromatic substituent. Although in N-aryl-substituted thio-
carbamates, the N-neophyl rearrangement A!C’ could, in
principle, complicate the situation via an alternative compet-
ing pathway (Scheme 3), this pathway had no literature
precedents.
In accord to these expectations, N-methyl-N-phenyl-O-(1-
naphthyl)thiocarbamate rearranged to the corresponding
amide as the only detectable product. Albeit the conversion
was low under the above reaction conditions (Table 1,
We tested the scope of this process in a variety of thiocar-
bamates, all of which can be synthesized conveniently from
thiophosgene, N-methylaniline, and the corresponding phe-
nols in 75–97% yield. As shown in Table 2, the yields of re-
arranged amides range from good to excellent. Interestingly,
unlike the rearrangement of related thiocarbonates, yields
of the amide products do not correlate perfectly with the
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12317

I. V. Alabugin et al.
Table 2. Results of O-neophyl rearrangement/fragmentation cascade of
thiocarbamates.
Entry
Ar
Yield [%]
1
2
3
4
5
6
7
8
9
1-naphthyl
Ph
p-MeOPh
p-CNPh
p-ClPh
p-MePh
m-MePh
p-PhPh
98
88
80
75
63
72
76
>99
97
p-(MeO2C)Ph
radical-stabilizing effect of the substituents. For example,
thiocarbamates with para-OMe or -CN substituents do not
show higher reaction yields. On the other hand, thiocarba-
mates with extended conjugation (Table 2, entries 1 and 8),
which provides stabilization for the developing radical char-
acter in the O-neophyl rearrangement step clearly demon-
strate higher reaction efficiency.
To understand the reasons for the selectivity observed for
the rearrangement of thiocarbamates, we performed DFT
calculations for both the O-neophyl and N-neophyl rear-
rangement, as well as the alkyl fragmentation pathways. All
structures were fully optimized at the UB3LYP/6-31+G**
level[10] using Gaussian 03 software.[11] Calculated potential
Figure 2. Calculated potential energy diagram for N-neophyl rearrange-
ment of N-methyl-N-phenyl-O-phenyl thiocarbamate at the UB3LYP/6-
31+G** level. Energies are given in kcalmolꢀ1
.
lized by the three adjacent heteroatoms (O, N, S) and does
not have a fast escape path available. Although the fastest
of the productive reaction steps is the desired O-neophyl re-
°
arrangement (E2 ~21–23 kcalmolꢀ1), the barrier for this
ꢀ
process is comparable with the barrier for the S Si bond
scission, which reforms the starting material (Eꢀ1 ~20–
°
21 kcalmolꢀ1). This unproductive kinetic competition may
be one of the reasons why the excess of the radical source
(Et3SiH) is needed to achieve complete conversion.
N-neophyl rearrangement has not been studied computa-
tionally before. The first calculated energy profile for this
process presented in Figure 2 illustrates that this reaction
should be significantly slower than the O- and N-neophyl re-
arrangement in this system.
ꢀ
energy surfaces for the O-neophyl rearrangement and C N
fragmentation pathways are shown in Figure 1, whereas the
data for the putative N-neophyl path are presented in
Figure 2. Although silicon radical addition to thiocarbonyl is
°
highly exothermic (17–19 kcalmolꢀ1) and fast (E1
~3 kcalmolꢀ1) (Table 3), the resulting radical is highly stabi-
Similar to the previous DFT
calculations performed on the
rearrangement of diaryl thiocar-
bonates,[3] our computational
analysis at the UB3LYP/6-31+
G** level on thiocarbamates
suggests
a concerted mecha-
nism for the O-neophyl rear-
rangement/fragmentation path-
way. This observation contrasts
with earlier computational[2,12]
and experimental[13] support for
a stepwise mechanism with the
formation of a three-membered
radical intermediate in systems
where the O-neophyl rear-
rangement step is not coupled
with fragmentation.[14]
Among all the three analyzed
pathways, the highly selective
Figure 1. Calculated potential energy diagrams for O-neophyl rearrangement and fragmentation pathways of
ꢀ
thiocarbamates. See Table 3 for the calculated energy values.
O-neophyl rearrangement/C S
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Chem. Eur. J. 2010, 16, 12316 – 12320

Radical 1,2-O!C Transposition
COMMUNICATION
Table 3. Summary of the computational results of the rearrangement for selected diaryl-substituted thiocarba-
mates at the UB3LYP/6-31+G** level.
ers, M. S. Workentin, J. Am.
Chem. Soc. 2004, 126, 1688;
g) C. S. Aureliano Antunes, M.
Bietti, G. Ercolani, O. Lanzalun-
ga, M. Salamone, J. Org. Chem.
2005, 70, 3884; h) M. Bietti, M.
Salamone, J. Org. Chem. 2005,
70, 10603; i) K. U. Ingold, M.
Smeu, G. A. DiLabio, J. Org.
Chem. 2006, 71, 9906.
°
°
°
Entry[a]
Ar
E1 (Eꢀ1
)
DE1
E2° (Ef°
)
DE2
E3
DE3 (DEf)
1
2
3
4
9
1-naphthyl
Ph
p-MeO-Ph
p-CN-Ph
p-MeO2-Ph
2.6 (21.2)
2.8 (20.9)
3.0 (20.5)
2.4 (21.6)
2.4 (21.5)
ꢀ18.6
ꢀ18.1
ꢀ17.5
ꢀ19.2
ꢀ19.1
21.2
23.1 (30.1)
22.3
20.9
21.4
17.2
–
–
19.9
20.2
0.9
–
–
0.3
0.1
ꢀ18.5
ꢀ19.4 (12.8)
ꢀ21.2
ꢀ17.7
ꢀ17.9
[a] Entries refer to those in Table 2. Energies are given in kcalmolꢀ1 (see Supporting Information for the com-
putational details).
[6] a) S. Escoubet, S. Gastaldi, N.
Vanthuyne, G. Gil, D. Siri, M. P.
Bertrand, Eur. J. Org. Chem.
2006, 3242; b) S. Escoubet, S.
scission cascade has the lowest barrier and the greatest ther-
Gastaldi, N. Vanthuyne, G. Gil, D. Siri, M. P. Bertrand, J. Org.
modynamic driving force. Thus, the new process represents
the most kinetically and thermodynamically favored radical
reaction of O-arylthiocarbamates. As the result, phenols can
be efficiently converted into benzoate amides through this
radical addition/O-neophyl rearrangement/fragmentation se-
quence.
Chem. 2006, 71, 7288.
ꢀ1
ꢀ
[7] The C O bond fragmentation barrier for this radical is 11 kcalmol
as it is exothermic by 14 kcalmolꢀ1 at the UB3LYP/6-31+G** level.
[8] Assuming that addition of Et3Si radical to the thiocarbonyl moiety
is reversible, one can attempt to shift the equilibrium for this step
using higher concentrations of the reagents with the same molar
excess of Et3SiH. However, lower yields and conversions of the
starting material were observed under these conditions (Table 1, en-
tries 3 and 6).
[9] Our calculations at the UB3LYP/6-31+G** level suggest that H-
Acknowledgements
transfer from Et3SiH to Et3SiS radical is exothermic by 6 kcalmolꢀ1
.
For further information about similar reactions and polarity reversal
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Chem. Soc. Perkin Trans. 1 1991, 103; b) B. P. Roberts, Chem. Soc.
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I.A. is grateful to the National Science Foundation (CHE-0848686) for
partial support of this research. We are grateful to the high-performance
computing facility at FSU.
Keywords: alkynes · amides · phenols · radical reactions ·
thiocarbamates
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the latter case, minima for three-membered dearomatized O-neo-
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on a very shallow potential energy surface. The barrier for the fol-
°
lowing ring opening step is extremely low (E3 <1 kcalmolꢀ1) and
ꢀ
this step is accompanied by the final C S bond scission and C=O
bond formation directly affording the final product.
Received: July 2, 2010
Published online: September 17, 2010
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Chem. Eur. J. 2010, 16, 12316 – 12320