Radical 1,2-o→c transposition for conversion of phenols into benzoates by o-neophyl rearrangement/fragmentation cascade

Article abstract of DOI:10.1002/chem.201001056

Figure Presented Radical merry-go-round! Diaryl thiocarbonates, available in a single step from phenols, can be directly transformed into benzoates by a new radical cascade that transposes O and C atoms at the aromatic core. The cascade bypasses the common Barton McCombie fragmentation in favor of the usually unfavorable O-neophyl rearrangement, which is rendered irreversible and efficient by a highly exothermic C-S bond scission in the O-centered radical (see scheme; FG = functional group).

Full text of DOI:10.1002/chem.201001056

COMMUNICATION
DOI: 10.1002/chem.201001056
Radical 1,2-O!C Transposition for Conversion of Phenols into Benzoates by
O-Neophyl Rearrangement/Fragmentation Cascade
Abdulkader Baroudi, Jeremiah Alicea, and Igor V. Alabugin*[a]
Both phenols and benzoic acid derivatives are among the
most common organic functional groups in organic chemis-
try. The transformation of an aryl alcohol into an aryl car-
boxylic acid derivative requires substitution of the phenol
oxygen with a carbon atom, which is usually accomplished
by metal-catalyzed carbonylation.[1] A metal-free O!C
transposition reaction designed to convert phenols or their
derivatives into benzoate esters would be a useful alterna-
tive to this important class of organic molecules.
This work has been inspired by our attempts to unravel
the mechanisms of fragmentation of the natural enediyne
antibiotic esperamycin A1 as the result of its activation to
the Bergman cyclization.[2] In our studies, we have discov-
ered a variety of radical rearrangements that follow Berg-
man cyclization in enediynes equipped with acetal rings,
mimicking the carbohydrate moiety of natural enediyne an-
tibiotics. A particularly interesting finding was that of a radi-
cal cascade proceeding by an O-neophyl rearrangement,
which transposes the O and C atoms of the substituent
(Scheme 1).[3] Although the observed yield of the rearranged
benzoic ester 2 from enediyne 1 was low, this product for-
mation suggested the possibility of the rational design of a
radical process that would allow a useful transformation of
phenols into benzoate esters.
Scheme 1. O!C Radical transposition triggered by the Bergman cycliza-
tion of enediynes.
pared from phenols. Second, the design should incorporate
an efficient step that selectively creates a radical at the cor-
rect carbon atom from the above functional group in either
an intra- or intermolecular manner. Third, the radical
should be sufficiently reactive to initiate the key 1,2 O!C
transposition through an ipso attack at the aromatic ring,
ꢀ
Intrigued by these observations, we decided to develop a
more efficient radical cascade that improves on the transfor-
mation illustrated in Scheme 1. Several elements were im-
portant for the structural design. First, the ideal sequence
should start from a functional group that can be readily pre-
followed by C O bond cleavage (O-neophyl rearrange-
ment).[4,5] For this purpose, substituents X and Z should not
deactivate the radical center through excessive stabilization
and should not participate in a premature b-scission step
(Scheme 2). Finally, the transposed radical should possess a
ꢀ
weak C X bond which can undergo an efficient terminating
b-scission step that renders the overall process irreversible,
[a] A. Baroudi, J. Alicea, Prof. Dr. I. V. Alabugin
Department of Chemistry and Biochemistry
Florida State University
as shown in Scheme 2.[6]
The final fragmentation step is important because most
O-neophyl rearrangement examples in the literature pro-
ceed in the opposite direction in which alkoxy radicals rear-
range to more stable carbon radicals.[7,8] To the best of our
knowledge, there is only one literature example in which the
rearrangement occurs in the direction we observed in the re-
action of enediyne 1—from a carbon-centered radical to an
oxygen-centered radical.[9]
Tallahassee, FL 32306-4390 (USA)
Fax : (+1)850644-8281
E-mail: alabugin@chem.fsu.edu
Supporting information for this article is available on the WWW
1
under http://dx.doi.org/10.1002/chem.2001001056. It contains H and
13C NMR data, MS and FTIR analyses for new compounds as well as
total energy and Cartesian coordinates for each optimized stationary
point at the reaction hyper surfaces.
Chem. Eur. J. 2010, 16, 7683 – 7687
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7683

mentation step can be avoided by replacing the alkyl group
R with an aromatic substituent. Not only does an aryloxy
2
ꢀ
group have a stronger C
G
tion would also result in a relatively unstable sp2 radical.
Initially, we tested our design by treating diphenyl thiocar-
bonate with Bu3SnH and AIBN in benzene at reflux. Only
traces of the desired product (D) were detected by H NMR
spectroscopy and GC, even after heating at 1358C in a
sealed tube, with very low conversion of starting material.
However, when the reaction was performed using triethylsi-
lane (TES)[11] and di-tert-butyl peroxide (TOOT) at 1358C
in benzene, the proposed O!C transposition cascade
indeed proceeded to afford 59% of phenyl benzoate.
To expand the scope of this process and to gain a deeper
insight into its mechanism, we investigated substituent ef-
fects on the efficiency and selectivity of the new reaction.
Thus, several diaryl thiocarbonates were synthesized from
thiophosgene and the corresponding phenols in 75–90%
yield. In full agreement with the proposed mechanism, both
OMe and CN substituents facilitate the rearrangement
(Table 1, entries 2, 3, and 4), indicating the development of
radical character at the para position of the migrating aryl
group in the rate-limiting step.[12] High yields (ꢁ80%) of re-
arranged products were obtained when at least one of the
aryl groups was equipped with a radical-stabilizing substitu-
ent. On the other hand, lower yields and selectivities were
observed for fluoro-substituted aryl thiocarbonate (Table 1,
entry 5) and pyridinyl substituted thiocarbonate (Table 1,
entry 8). We will show (see below) that this correlation of
reactivity and selectivity is not surprising. For comparison,
we also included alkyl-substituted thiocarbonates and ob-
served fragmentation along the Barton–McCombie pathway
under the same reaction conditions (Table 1, entries 9 and
10).
Scheme 2. Suggested design of an efficient radical 1,2 O!C transposition
cascade.
A plausible approach to the selective generation of an ar-
yloxy radical precursor A for the rearrangement step is pro-
vided by the initial steps of the Barton–McCombie deoxyge-
nation of alcohols (Scheme 3).[10] This method involves the
reaction of thiocarbonates with Si- or Sn-centered radicals.
Due to thiophilicity of these radicals, they regioselectively
attack the sulfur atom of the C=S moiety. Not only does this
attack provide the appropriate carbon-centered radical, but
ꢀ
it also forms a weak C S bond positioned for b-scission at
the final, equilibrium-shifting fragmentation.
We also investigated whether other functional groups in
thiocarbonates could react under these conditions, opening
the possibility for further cascade transformations. Unlike
nitro-substituted thiocarbonate (Table 1, entry 7), which pro-
vided a complex reaction mixture, the p-bromo-substituted
reactant (Table 1, entry 6) was
However, in order for the carbon radical to undergo O-
neophyl rearrangement, the Barton–McCombie pathway has
to be rerouted away from the fast fragmentation step A!E
(Scheme 3). We decided to test whether the premature frag-
converted into biphenyl deriva-
tives of the rearranged prod-
ucts, D3 (12%) and D4 (25%)
(Scheme 4).
The
biphenyl
moiety formation can be readily
explained by abstraction of the
p-bromine atom by the TES
radical followed by the reaction
of the resulting aryl radical with
benzene solvent (radical aro-
matic substitution, RAS[13]). To
investigate the two possible
pathways for the formation of
D3 and D4 (Scheme 4), we stud-
ied the reaction of the bromo-
thiocarbonate at lower conver-
sions and obtained 13% of D1
Scheme 3. Rerouting the Barton–McCombie reaction to the O-neophyl rearrangement pathway for the conver-
sion of aryl alcohols into benzoate esters.
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Chem. Eur. J. 2010, 16, 7683 – 7687

Radical 1,2-O!C Transposition
COMMUNICATION
Table 1. Results of O-neophyl rearrangement/fragmentation reaction of
diaryl thiocarbonates.
Table 2. Reaction of bromothiocarbonate with different equivalents of
radical reagents.
Et3SiH
(equiv TOOT)
t
Yield [%]
[h]
D1
D2
D3
D4
6 (p-BrPh)
1.5 (0.75)
1.5 (0.75)
3 (1.5)
4 (2)
2[a]
ꢂ5
14
19
0
ꢂ8
24
27
0
0
2
12
21
14
0
4
25
48
28
4[b]
4
Entry
R
R’
t [h]
(1358C)
Yield
Yield
10[c]
3
G
D1 [%]
D2 [%]
11 (D1 +D2) (1:1.4)
6 (3)
18
17
1
2
3
4
5
6
7
8
9
Ph
p-MeOPh
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2
2
2
1.5
2
4
2–5
4
2
2
59
93
30
16
31
NA
NA
61
63
31
27
–
34
NA
NA
[a] 15% Conversion of starting material. [b] 50% Conversion of starting
material. [c] Traces of phenyl benzoate were detected by NMR.
p-MeOPh
p-MeOPh
p-CNPh
p-FPh
p-BrPh[a,b]
p-NO2Ph
3-Pyridinyl[a]
Et[d]
19
[c]
only products obtained in the same ratio. It is noteworthy
that the total yield of the two products in this one-pot se-
quence approaches 70%. Hence, this one-pot radical se-
quence reaction of rearrangement can be expanded to the
synthesis of modified biphenyl esters from thiocarbonates of
simple and commercially available bromophenols.
To gain further insight into the observed experimental
trends, we carried out DFT calculations of the proposed re-
action pathway for selected substrates. All structures were
30
[e]
[e,g]
10
Ph
p-MeOPh-Pr[d,f]
[a] 3 equiv of Et3SiH and 1.5 equiv of TOOT were used for full conver-
sion of starting material. [b] Two additional products were formed be-
sides D1 and D2. [c] A complicated mixture was obtained. [d] TTMSS
was used since no reaction was observed with TES. [e] 100% alkyl frag-
mentation (Barton–McCombie). [f] 1-(p-Methoxyphenyl)propyl group.
[g] p-Propyl anisole was formed in 60% yield.
fully
optimized
at
the
UB3LYP/6-31+G** level by
using Gaussian 03 software.[14]
Figure 1 shows the calculated
potential energy surface of the
possible O-neophyl rearrange-
ments and fragmentation path-
ways of thiocarbonates. As
shown in Table 3, the radical
addition step for diaryl thiocar-
bonates is highly exothermic
(22-24 kcalmolꢀ1) with a barrier
as low as ꢂ3 kcalmolꢀ1. How-
ever, the activation barrier for
the subsequent O-neophyl rear-
rangement step is relatively
high (23–25 kcalmolꢀ1), making
the rearrangement kinetically
competitive with the backward
fragmentation step. The rela-
tive inefficiency of the rear-
rangement step is the likely
reason for the high tempera-
tures and excess of reagents
needed for achieving high con-
versions. The significant barrier
magnitude stems from efficient
Scheme 4. Coupled radical cascades in the reaction of bromo-substituted thiocarbonate (Table 1, entry 6) with
the TES radical.
and D2 as the only products (Table 2). Upon additional heat-
ing, 38% of D1 and D2 were formed in addition to 6% of
D3 and D4. These experiments suggest that the O-neophyl
rearrangement pathway is more than six times faster than
bromine abstraction and that path B (Scheme 4) serves as
the major route to the formation of the biphenyl products
D3 and D4. When a mixture of isolated bromoesters D1 and
D2 was subjected to the same conditions, biphenyls were the
anomeric radical stabilization of the carbon radical inter-
mediate through two n(O)!n(C) and one n(S)!n(C) inter-
actions. This result agrees well with the relative values for
previously calculated barriers for similar rearrangements of
carbon radicals with varying degrees of stabilization.[3a,15] In
addition to the electronic factors, steric repulsion exerted by
the bulky OAr and SY groups can contribute to raising the
energy of the three-membered transition state.
Chem. Eur. J. 2010, 16, 7683 – 7687
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
7685

I. V. Alabugin et al.
designed, the reaction is effi-
ciently driven by the high exo-
thermicity of the final step
(ꢂ50 kcalmolꢀ1 below the reac-
tants thiocarbonate and the
silyl radical).
Our experimental substituent
effects agree with the lower
values for the computed activa-
tion barriers for the rearrange-
ment of substituted aryl groups
(Figure 1, blue path). In partic-
ular, lower barriers were ob-
tained for aryl rings with radical
stabilizing groups (OMe and
CN) at the para position. On
the other hand, the rearrange-
ment at the phenyl group of
monosubstituted diaryl thiocar-
bonates (Figure 1, black path)
has essentially the same activa-
tion barrier as the parent di-
phenyl thiocarbonate (Table 3,
entry 1). The sufficient accuracy
of the computational methods
is illustrated by the observed
lack of differences for the com-
peting rearrangement directions
Figure 1. Calculated potential energy diagrams for O-neophyl rearrangement and fragmentation pathways
(black: O-neophyl rearrangement of diaryl thiocarbonate at the phenyl group; blue: O-neophyl rearrangement
of diaryl thiocarbonate at the p-substituted aryl group; red: Barton–McCombie fragmentation). See Table 3
for the calculated energy values.
Table 3. Computational analysis of the rearrangements of diaryl thiocar-
bonates at the UB3LYP/6-31+G** level.[a]
of those thiocarbonates (with 4-fluorophenyl, 4-bromophen-
yl, and 3-pyridinyl groups) that do not show significant ex-
perimental selectivity. It is noteworthy that the rearrange-
ment barrier is considerably higher than the barrier of
Barton–McCombie fragmentation for alkyl substituted sub-
strates (Figure 1, red path). This difference would kinetically
favor the Barton–McCombie fragmentation pathway when
this path is available (Table 1, entries 9 and 10).
In summary, we found that this radical cascade can be
used as a convenient procedure for the transformation of
phenols into esters of the respective aromatic carboxylic
acids. O-Neophyl rearrangement from a C-centered radical
to an O-centered radical is rendered irreversible when it is
coupled to a subsequent highly exothermic fragmentation.
Ea1
E1
Ea2 (Eaf)
E2 (Ef)
Ea2’
E2’
[kcalmolꢀ1
]
[kcalmolꢀ1
]
[kcalmolꢀ1
]
[kcalmolꢀ1
]
1
3
4
5
6
8
9
3.2
3.1
3.0
–
–
–
ꢀ23.1
ꢀ22.3
ꢀ24.5
ꢀ22.9
ꢀ23.7
ꢀ23.5
ꢀ18.7
24.8
24.4
24.9
24.5
24.4
24.9
ꢀ26.7
ꢀ27.3
ꢀ25.9
ꢀ27.0
ꢀ26.5
ꢀ26.8
NA[b] NA[b]
23.9
23.2
24.4
24.1
24.5
ꢀ29.3
ꢀ23.7
ꢀ27.8
ꢀ27.0
ꢀ26.6
4.5
22.0 (13.1) ꢀ30.0 (ꢀ9.1) NA[b] NA[b]
[a] Entries are relative to Table 1. Energies are given in kcalmolꢀ1 rela-
tive to the previous intermediate in the reaction path. See the Supporting
Information for computational details. [b] NA=not applicable.
In a number of earlier computational[3a,15] and experimen-
tal[16] studies, O-neophyl rearrangements have been found to
proceed via a three-membered radical intermediate B. How-
ever, our calculations suggest that the O-neophyl rearrange-
ment/fragmentation pathway is a concerted process for the
systems presented herein on the UB3LYP/6-31+G** energy
surface. Excluding p-CN substituted thiocarbonate (entry 4),
neither of the radical intermediates B or C (Scheme 2) was
located for any of the above diaryl thiocarbonates. Instead,
all attempts for their structural optimizations lead to the
Experimental Section
General procedures for the synthesis of symmetrical thiocarbonates:
Phenol (2.4 mmol) was dissolved in 0.3m aqueous NaOH (8 mL) and
added to a solution of CSCl2 (1.2 mmol) in CH2Cl2 (10 mL). The reaction
solution (two layers) was stirred vigorously for 2 h and then diluted with
CH2Cl2, washed with brine, and dried with Na2SO4. The solvent was re-
moved under reduced pressure and the crude mixture was purified by
column chromatography to afford the corresponding thiocarbonate.
C
final rearranged/fragmented products (D+YS ). On the
General procedures for the synthesis of nonsymmetrical thiocarbonates
other hand, a three-membered dearomatized radical inter-
mediate (B) was located for the p-CN thiocarbonate proba-
bly due to additional radical stabilization provided by the
extended conjugation of the cyano group. Overall, as it was
Procedure A: The first phenol (1.2 mmol) was dissolved in 0.3m aqueous
NaOH (4 mL) and added to a solution of CSCl2 (1.8 mmol) in CH2Cl2
(10 mL). The two layers were stirred vigorously for 1 h. The reaction
mixture was diluted with CH2Cl2 and washed with brine. The organic
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Radical 1,2-O!C Transposition
COMMUNICATION
ꢀ
layer was dried with Na2SO4. The solvent and excess CSCl2 were re-
moved under reduced pressure. The reaction mixture was then redis-
solved in CH2Cl2 (10 mL). The second phenol (1.2 mmol) was then dis-
solved in 0.3m aqueous NaOH (4 mL) and added to the above solution
of the reaction mixture in CH2Cl2 and stirred for 2 h. The reaction was
then worked up in the same way as before and purified by column chro-
matography to afford the corresponding thiocarbonate.
[5] For another example of the use of oxygen in the C C bond forma-
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Mamatyuk, Y. V. Gatilov, I. V. Alabugin, J. Org. Chem. 2009, 74,
6143.
[6] A similar approach, which occurs through a five-membered transi-
tion state (1,4 O!C transposition), was used in the total synthesis
of the aromatic series of podophyllotoxin, see: A. J. Reynold, A. J.
Scott, C. I. Turner, M. S. Sherburn, Am. Chem. Soc. 2003, 125,
12108; J. Fischer, A. J. Reynold, L. A. Sharp, M. S. Sherburn, Org.
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[7] a) J. T. Banks, J. C. Scaiano, J. Phys. Chem. 1995, 99, 3527; b) R. L.
Donkers, J. Tse, M. S. Workentin, Chem. Commun. 1999, 135; c) K.
Wietzerbin, J. Bernadou, B. Meunier, Eur. J. Inorg. Chem. 1999,
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[8] a) M. Kamata, K. Komatsu, Tetrahedron Lett. 2001, 42, 9027;
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Procedure B: The first phenol (1.2 mmol) and CSCl2 (1.8 mmol) were dis-
solved in CH2Cl2 (10 mL) and stirred at 08C. Neat pyridine (1.5 mmol)
was then added dropwise at 08C. The reaction mixture was left to warm
to room temperature for 15 min with stirring, before it was diluted with
CH2Cl2 and washed with brine. The organic layer was dried with Na2SO4.
The solvent and excess CSCl2 were removed under reduced pressure. The
reaction mixture and the second phenol (1.2 mmol) were dissolved in
CH2Cl2 (10 mL) and stirred at room temperature. Neat pyridine
(1.5 mmol) was then added dropwise to the reaction mixture at room
temperature. The reaction mixture was stirred for 30 min, worked up in
the same way as described above, and purified by column chromatogra-
phy to afford the corresponding thiocarbonate.
General procedure for the O-neophyl rearrangement/fragmentation reac-
tion: Et3SiH (0.052 mmol) and TOOT (0.026 mmol) were added to a so-
lution of the starting thiocarbonate (0.035 mmol) in benzene. The solu-
tion was then purged with N2 for 15 min, sealed in an Ace Glass pressure
tube or thick-walled Pyrex tube, and heated at 1358C in an oil bath. The
solvent was evaporated and the product was purified by chromatography.
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radicals. However, in our hands, the rearrangement has poor repro-
ducibility with this silane.
[12] a) H. E. Zimmerman, R. D. Rieke, J. R. Scheffer, J. Am. Chem. Soc.
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Acknowledgements
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 for allowing us to use their fast computing sys-
tems.
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Keywords: alkynes
rearrangement · thiocarbonates
· phenols · radical fragmentation ·
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Received: April 21, 2010
Published online: June 2, 2010
Chem. Eur. J. 2010, 16, 7683 – 7687
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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