Radical OfC transposition: A metal-free process for conversion of phenols into benzoates and benzamides

Article abstract of DOI:10.1021/jo102467j

We report a metal-free procedure for transformation of phenols into esters and amides of benzoic acids via a new radical cascade. Diaryl thiocarbonates and thiocarbamates, available in a single high-yielding step from phenols, selectively add silyl radicals at the sulfur atom of the CdS moiety. This addition step, analogous to the first step of the Barton-McCombie reaction, produces a carbon radical which undergoes 1,2 OfC transposition through an O-neophyl rearrangement. The usually unfavorable equilibrium in the reversible rearrangement step is shifted forward via a highly exothermic C-S bond scission in the O-centered radical, which furnishes the final benzoic ester or benzamide product. The metal-free preparation of benzoic acid derivatives from phenols provides a potentially useful alternative to metal-catalyzed carbonylation of aryl triflates.

Full text of DOI:10.1021/jo102467j

FEATURED ARTICLE
pubs.acs.org/joc
Radical OfC Transposition: A Metal-Free Process for Conversion of
Phenols into Benzoates and Benzamides
Abdulkader Baroudi, Jeremiah Alicea, Phillip Flack, Jason Kirincich, and Igor V. Alabugin*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
S Supporting Information
b
ABSTRACT: We report a metal-free procedure for transformation of phenols into
esters and amides of benzoic acids via a new radical cascade. Diaryl thiocarbonates and
thiocarbamates, available in a single high-yielding step from phenols, selectively add
silyl radicals at the sulfur atom of the CdS moiety. This addition step, analogous to the
first step of the Barton-McCombie reaction, produces a carbon radical which
undergoes 1,2 OfC transposition through an O-neophyl rearrangement. The usually
unfavorable equilibrium in the reversible rearrangement step is shifted forward via a
highly exothermic C-S bond scission in the O-centered radical, which furnishes the
final benzoic ester or benzamide product. The metal-free preparation of benzoic acid derivatives from phenols provides a potentially
useful alternative to metal-catalyzed carbonylation of aryl triflates.
’ INTRODUCTION
Direct connections between functional groups simplify che-
mical landscape and allow more efficient execution of multistep
synthetic routes. While phenols and benzoic acid derivatives are
among the most common organic functionalities, the ways for
transforming a phenol into an aryl carboxylic acid derivative are still
limited. A metal-free reaction which converts phenols into benzoic
acid derivatives would become a useful alternative to the commonly
used Pd-catalyzed carbonylation of aromatic triflates1 (Figure 1),
Figure 1. Metal-catalyzed transformation of phenols into benzoic acid
derivatives.
especially because Pd is classified as a Class I metal (significant safety
through an O-neophyl rearrangement.6,7 Consequently, substit-
uents X and Z should neither deactivate the carbon radical center
concern) in pharmaceuticals with permitted daily exposure <10 μg/
day.2 Herein, we report the design of an efficient metal-free OfC
transposition, accomplished via a new radical cascade transforma-
tion of diaryl thiocarbonates and thiocarbamates into carboxylic
esters and amides. In this process, the classic Barton-McCombie
reaction is diverted into the O-neophyl pathway driven by a
strategically introduced radical fragmentation.
nor participate in a premature β-scission step (Figure 3). Finally,
since the O-neophyl rearrangement is reversible, a fast and
selective fragmentation route via efficient β-scission of a weak
C-X bond should be available in order to trap the transposed
radical. This fragmentation should not only complete the re-
arrangement via formation of the CdO double bond in the final
product but also generate a new S-centered radical for propagat-
ing the radical chain process.8
The crucial role of the final fragmentation step in driving the
rearrangement from a more stable C-radical to a less stable
O-radical is illustrated by the fact that most literature examples of
radical O-neophyl rearrangements proceed in the opposite
direction, from alkoxy radicals to the more stable carbon
radicals.9,10 To the best of our knowledge, before our preliminary
disclosure of this work,11 there was only one example where the
reaction followed the same rearrangement pathway as enediyne
2. Ohno et al. reported the formation of methylphenylketone in
about 50% yield from the thermal decomposition of azobis-
(2-phenoxy)-2-propane (Figure 4).12 Interestingly, in analogy
The key components of our proposed synthetic design came
from our work on unraveling the mechanism of esperamycin A1
fragmentation,3 which follows Bergman cyclization4 of this natural
enediyne antibiotic. When we equipped model enediynes with
acetal rings mimicking the carbohydrate moiety of the natural
enediyne antibiotics, we found that several interesting radical
rearrangements triggered by the Bergman cyclization (Figure 2)
including the OfC transposition of enediyne 2 (Figure 2b).5
Although the yield for the rearranged benzoic ester 3 was low, this
result suggested that this process, which could serve as a synthetic
shortcut between phenols and benzoates, is possible, prompting us
to search for a more efficient version of this transformation.
Several factors are important for a successful design of the
more efficient OfC transposition (Figure 3). First, phenols
should be converted readily to a functional precursor of a
phenoxy-substituted carbon radical. Second, this radical should
initiate the key transposition step which we envisioned to proceed
Received: December 31, 2010
Published: February 23, 2011
r
2011 American Chemical Society
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Figure 2. (a) Fragmentation of natural enediynes. (b) Fragmentation of esperamycine mimics through intramolecular H-abstraction/fragmentation
cascade. (c) OfC radical transposition triggered by the Bergman cyclization of enediyne 2.
Figure 4. Example of O-neophyl rearrangement which proceeds from a
C-centered radical to an O-centered radical.
ketone shown in Figure 4, the final cleavage leads to the loss of a
methyl radical.
When this work has been already in progress, a report by
Jones and co-workers revealed a conceptually elegant alternative
Figure 3. Suggested design of an efficient radical 1,2 OfC transposi-
approach to a radical OfC transposition.13 In this approach,
tion cascade.
photochemical excitation of 1-benzyloxy-9,10-anthraquinone
leads to the formation of 1-benzoyl-9,10-anthraquinone (44%).
with the reaction observed for 2, these authors found that the
O-neophyl rearrangement of 2-phenoxyprop-2-yl radical into
2-phenylisopropoxy radical is also terminated by a homolytic
C-C bond cleavage. In our case, the bond cleavage leads to the
ring-opening of the THP moiety, whereas for the formation of
In contrast to the usual O-neophyl rearrangements, the energy
cost for the formation of strained dearomatized three-membered
intermediate is partially compensated by the coupling of the two
radical centers and return to the ground state hypersurface.
Unlike the terminating radical fragmentations described above,
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Figure 5. Rerouting Barton-McCombie reaction to the O-neophyl rearrangement pathway for the conversion of phenols into benzoate esters.
the rearranged carbonyl compound is furnished via a sequential
epoxide ring-opening and alcohol oxidation. Thus far, the scope
of this interesting transformation is limited to anthraquinones.
rearrangements of substituted thiocarbonates agree with the pro-
posed mechanism. For example, the observed similarity of the
results for the radical stabilizing p-OMe and p-CN substituents
(Table 1, entries 2-4) indicates the development of radical
character in the migrating aryl group in the rate-limiting step.16
Not only higher yields (g80%) of rearranged benzoate esters were
obtained for the p-OMe- and p-CN-substituted thiocarbonates, but
we also observed 2-4:1 selectivity toward the formation of para-
substituted benzoates (7b). Conversely, the rearrangement of
fluoro- (entry 5) and pyridinyl-substituted (entry 8) thiocarbonates
proceeded in lower yields and with lower selectivity. The correlation
between reactivity and selectivity is consistent with the proposed
mechanism (see Computational Analysis, vide infra). In a control
experiment, alkyl aryl thiocarbonates were found to undergo
complete fragmentation along the Barton-McCombie pathway
under the same reaction conditions (entries 9 and 10, Table 1).
We also explored whether the diaryl thiocarbonates equipped with
functional groups that are known to react under radical conditions can
participate in more extended cascade transformations. Although
nitro-substituted thiocarbonate (entry 7) gave a complicated reaction
mixture, the reaction of the bromo derivative (entry 6) resulted in the
formation of two compounds besides the rearranged esters 7a,b(H,
Br) (Figure 6). The new products were found to be the biphenyl
derivatives of the rearranged products 11a (12%) and 11b (25%).
The formation of these biphenyl compounds should proceed via the
abstraction of bromine atom by the triethylsilyl radical (Et3Si•)
followed by radical aromatic substitution (RAS17) of the correspond-
ing phenyl radical with benzene (solvent).
This transformation can occur either before or after O-neophyl
rearrangement via path A or B, respectively (Figure 6). Although the
two paths produce the same products, their yields and distributions
would depend on the relative rate of the two alternative cascades,
thus providing information on the rate of the cascade relative to the
rate of Br atom abstraction from an aromatic molecule.
As is shown in Table 1, 3 equiv of Et3SiH and 1.5 equiv of
TOOT fully convert the Br-Ph thiocarbonate (entry 6) to
products 7a,b(H,Br) and 11a,b in 4 h. When the relative amount
of silane and initiator was decreased by 50%, the reaction initially
produced only the rearranged aryl bromides 7a(H,Br) (5%) and
7b(H,Br) (8%) (15% conversion, 2 h, Table 2). Only upon
additional heating was a small amount (6%) of biphenyls 11a and
11b formed (4 h, 50% conversion, 38% of 7b(H,Br)/7a(H,Br)).
These two experiments suggest that, at this concentration, addi-
tion to the thiocarbonyl moiety which initiates the O-neophyl
’ RESULTS AND DISCUSSION
In order to test the experimental feasibility of the proposed
O-neophyl/fragmentation cascade, we decided to generate the
aryloxy-substituted carbon radical 4 using the initial step of the
Barton-McCombie deoxygenation reaction.14 This step in-
volves selective addition of thiophilic Si- or Sn-centered radicals
to the sulfur atom of thiocarbonyl (CdS) moiety. This choice
not only assures that the appropriate carbon-centered radical is
formed but also provides a weak C-S bond suitable for the
equilibrium-shifting β-scission final step. Remarkably, the
Barton-McCombie reaction has not been reported to provide
such rearrangement products. Instead, this process is terminated
by a fast C-O bond fragmentation forming an alkyl radical (path
4f8, Figure 5) and providing a synthetic connection between
alcohols and alkanes. We hoped to divert the Barton-McCom-
bie pathway and prevent the premature fragmentation step by
replacing the alkyl group R with an aromatic substituent. Such
a replacement provides a stronger C(sp2)-O bond and
renders the putative sp2-radical product relatively unstable. We
expected that if the fragmentation is sufficiently decelerated, the
O-neophyl rearrangement of the aryl-substituted carbon radical 4
will become the major pathway.
Rearrangement of Thiocarbonates. The first test for our
design was performed by treating diphenyl thiocarbonate with
Bu3SnH and AIBN in refluxing benzene. In this experiment,
conversion was very low, and only a trace amount of the desired
1
rearranged product (phenyl benzoate, 7) was detected by H
NMR and GC. No improvement was observed when AIBN was
replaced with other radical initiators such as benzoyl peroxide,
V-40, and di-tert-butyl peroxide (TOOT) even upon heating
with Bu3SnH at 135 °C in a sealed tube. However, when
triethylsilane (Et3SiH)15 was used instead of Bu3SnH, the
proposed 1,2 OfC transposition cascade did occur in the
presence of TOOT at 135 °C in benzene with the formation
of 59% of the phenyl benzoate product (path 4 f 7, Figure 5).
With the aim of expanding the scope of this process and gain-
ing further insight into the mechanism, we examined substituent
effects on the efficiency and selectivity of the new reaction. Diaryl
thiocarbonates were synthesized in 75-90% yield from thiophos-
gene and the corresponding phenols. The results for the
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Table 1. Results of O-Neophyl Rearrangement/Fragmentation Reaction of Diaryl Thiocarbonates
a 3 equiv of Et3SiH and 1.5 equiv of TOOT were used for full conversion of starting material. b Two additional products were formed besides 7a and 7b.
c A complicated mixture was obtained. d TTMSS was used since no reaction was observed with Et3SiH. e 100% alkyl fragmentation (Barton-
McCombie).
rearrangement, cascade is >6 times faster than bromine abstraction and
that path B is the major mechanism for the formation of 11a and 11b.
Since neither the intermediate product 10 nor the reduced
products 12, 13 were detected, we tested whether 11a and 11b can be
formed from 7a(H,Br) and 7b(H,Br) under the conditions of O-
neophyl rearrangement (entry 5, Table 2). Indeed, 11a and 11b were
the only new products observed in this experiment. This result
provides further support for path B as the major pathway for the
formation of these biphenyl compounds. The cascade can be driven
completely toward the biphenyl products by greater excess of Et3SiH
and TOOT (69% of 11aþ11b from thiocarbonate 9(H,Br)).
Hence, these conditions can be used for carrying out the
extended O-neophyl rearrangement/RAS cascade for the pre-
paration of modified biphenyl compounds from the thiocarbo-
nates of respective bromophenols.
The highest energy penalty for traveling along the O-neophyl
potential energy surface is associated with the transient loss of
aromaticity in the ipso-attack of the carbon radical 5 (Figure 3). It
is reasonable to expect such an energy penalty to be significantly
lower in polyaromatic compounds. For example, Schleyer and
P€uhlhofer reported that aromatic stabilization energy calculated
via isomerization approach (isomerization stabilization energy, ISE)
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Figure 6. Coupled radical cascades in the reaction of bromo-substituted thiocarbonate 9(H,Br) (entry 6, Table 1).
Table 2. Reaction of Bromothiocarbonate 9(H,Br) with Varying Equivalents of Radical Reagents
yield (%)
7a(H,Br)
entry
Et3SiH (TOOT)
time (h)
7a(H,Br)
11a
11b
1, 9(H,Br)
2, 9(H,Br)
3, 9(H,Br)
4, 9(H,Br)
1.5 (0.75)
1.5 (0.75)
3 (1.5)
4 (2)
2a
4b
4
∼5
14
19
0
∼8
24
27
0
0
2
0
4
12
21
14
25
48
28
10c
5, (7a(H,Br) þ 7b(H,Br)) (1:1.4)
6 (3)
3
18
17
a 15% conversion of starting material. b 50% conversion of starting material. c Traces of phenyl benzoate were detected by NMR.
due to the formation of the second ring in naphthalene is ∼14-15
kcal lower than ISE of benzene (B3LYP/6-311þG**).18
We have compared the energy cost for radical addition to
benzene and polyclic aromatics with B3LYP/6-31G** calculations.
The differences are significant (Figure 7). Radical addition of a
hydrogen atom to benzene is less exothermic than the addition to
naphthalene (8 kcal/mol for the R-attack and 3 kcal/mol for the
β-attack) and to phenanthrene (7-8 kcal/mol for the central ring
attack). If the ipso-addition of stabilized carbon radicals follows the
same trend and if O-neophyl rearrangement is a reversible process,
one can expect the analogous rearrangement of phenyl polyaromatic
thiocarbonates to be more selective.
Encouraged by these computational data, we investigated the
reaction of polyaromatic thiocarbonates (entries 9-12). The
reaction of 1-naphthylphenyl thiocarbonate (entry 1, Table 3)
provides an ideal example of a completely selective and efficient
O-neophyl rearrangement/fragmentation proceeding in ∼90%
yield. In a similar way, phenanthryl phenyl thiocarbonate under-
goes the rearrangement exclusively at the phenanthryl moiety in
65% yield19 (entry 4, Table 3).
Figure 7. Difference between energy cost for dearomatization in
benzene, naphthalene, and phenanthrene through H-radical addition
(energies in kcal/mol, B3LYP/6-31G**).
On the other hand, the reactions of β-substituted naphthyl and
quinolyl thiocarbonates proceeded in lower yields and displayed
only modest ∼4:1 regioselectivity. This observation is consistent
with ∼5 kcal/mol lower energy for the R-attack in Figure 7 and with
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Table 3. Results of O-Neophyl Rearrangement/Fragmentation Reaction of Polyaromatic Thiocarbonates
a 4 equiv of Et3SiH and 2 equiv of TOOT were used for full conversion of starting material. b Several minor unidentified products were detected by NMR.
the well-known preference for the R-attack in naphthalene which is
reproduced even at the H€uckel level of theory.20 Hence, it is clear
that the position of the substituent in the polyaromatic system has a
significant effect on the rearrangement efficiency and selectivity.
Rearrangement of Thiocarbamates. Thus far, we presented a
method for the transformation of phenols into esters of the respec-
tive aromatic carboxylic acids. However, this process has one
significant disadvantage. With the exception of several polyaromatic
substrates, the unsymmetrical diaryl thiocarbonates show only
modest selectivity. Thus, despite the high overall yields obtained
for the benzoate esters, the synthetic value of this method is limited
for unsymmetric thiocarbonates. Because the use of 2 equiv of a
starting phenol can be impractical for expensive phenols, we
continued to search for a more selective transformation which
would increase the utility of the new reaction.
In contrast to the well-known fragmentation reaction of O-alkyl-
substituted thiocarbonates (the Barton-McCombie reaction), the
radical fragmentation of an N-alkyl group through the same process
has not been reported in the literature (Figure 8a). Moreover, it has
been shown that radical fragmentation of C-N bonds is
inefficient. For instance, no scission of C-N bonds is observed
in the radical racemization of chiral amines which occurs through
a reversible abstraction of the R-hydrogen atom (Figure 8c).21
This observation is consistent with our computational analysis of
the C-N bond radical fragmentation in a model thiocarbamate
(Figure 8d). The calculated activation barrier of ∼29 kcal/mol is
much higher than the literature barriers for O-neophyl rearrange-
ments (vide infra).5a,11a,22,23 Encouraged by these results, we
decided to change the O-alkyl substituent into an N-alkyl moiety
and test whether the radical rearrangement of respective thio-
carbamates is feasible (Figure 8b).
As the first step, we examined the reaction of N,N-diethyl-O-
phenyl thiocarbamate (Figure 9a). To our disappointment, this
compound remained unreactive even after 4 h at 135 °C in benzene
in the presence of Et3SiH (2equiv) and TOOT (1equiv) (Table 4,
entry 1). We suggested that the lack of reactivity is due to the excessive
stabilization of the anomeric radical by the hyperconjugative interac-
tion with the adjacent nitrogen lone pair.24 Thus, we have decided to
moderate the nitrogen donor ability by attaching it to an aromatic
group. By making this choice, we also intended to test whether N-aryl
thiocarbamates could also react via a new N-neophyl rearrangement
pathway (Figure 9b) analogous to the O-neophyl rearrangement.
Gratifyingly, the reaction of N-methyl-N-phenyl-O-(1-naphthyl)
thiocarbamate afforded the corresponding amide as the only
detectable product (Table 4, entry 2). Since low conversion was
observed under the initial reaction conditions, we varied tem-
perature, concentration, equivalents of reagents, and the nature
of radical initiator. When the number of equivalents of Et3SiH
was increased to 4, the product yield improved to 68% (entries
2-4). A further small improvement of the amide yield (72%)
was observed with 5 equiv of Et3SiH (entry 5). Even better
results were obtained when the TOOT was replaced with
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Table 4. Reaction Optimizations for the Rearrangement of
Thiocarbamatesa
entry
Et3SiH (equiv)
radical initiator
yield (%)
conv
1
2
2
3
4
5
3
2
3
3
2
2
3
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
2
3
78
4
100
100
19
5
6b
7
67
8
100
48
9c
10d
11e
12f
80
71
0
a All entries are for N-methyl-N-phenyl-O-(1-naphthyl) thiocarba-
mate except for entry 1 which is for N,N-diethyl-O-phenyl thiocarba-
mate. Unless otherwise specified, all reactions were carried out at 11 mM
of thiocarbamate, with a 1:2 molar ratio of radical initiator to Et3SiH, at
135 °C for 4 h. b At 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 22 mM
concentration of substrate. f Reaction was run for 8 h at 100 °C.
the silicon radical addition to thiocarbonyl is not a rate-limiting step.
The above results also suggest the presence of irreversible bimole-
cular termination reactions (Figure 10) which compete with the
O-neophyl rearrangement pathway more efficiently at higher con-
centrations. Reaction with only 2 equiv of Et3SiH (entry 10) or at a
lower temperature (100 °C, entry 12) resulted in low or zero
conversions even for the longer reaction times (8 h).
Figure 8. (a) Hypothetical C-N radical fragmentation through a
Barton-McCombie-like mechanism. (b) Possible O-neophyl rearran-
gement of thiocarbamates. (c) Absence of C-N fragmentation during
racemization of chiral amines through reversible H-abstraction by thiyl
radicals. (d) Model study of radical N-alkyl fragmentation in thiocarba-
mates at the UB3LYP/6-31þG** level (energies in kcal/mol).
The proposed reaction sequence involves a formal transfor-
mation of the nucleophilic Et3Si radical into an electrophilic
(S-centered) Et3SiS radical (Figure 10). Because the initiating
and propagating radicals are different in nature, there is a
possibility of polarity mismatch which could potentially render
the overall cascade less efficient. We noticed the first indications
that such effects may be important in our early experiments when
initiation with a different source of Si radicals, tris-trimethylsi-
lylsilane (TTMSS,15 Chatgilialoglu’s reagent), was tested.
Although, in a few early attempts, we observed excellent yields
and conversions, the process suffered from poor reproducibility,
and in most of the cases, the reaction was extremely sluggish.25
Polarity reversal catalysis has been used to facilitate chain pro-
pagation in radical processes, rendering them more efficient.26
To test whether we can use this approach for the new cascade, we
carried out TTMSS-promoted reactions in the presence of thiols.
As shown in Table 5, the use of thiols (BuSH or PhSH) with
TTMSS enables the formation of rearranged products. On
the other hand, similar reactions with Et3SiH were slower in
the presence of thiols (not shown). These data suggest that a
more detailed study of kinetic factors and their effect on the
overall reaction efficiency is necessary in the future.
Figure 9. (a) Reaction of triethylsilyl radical with N,N-diethyl-O-phenyl
thiocarbamate. (b) O-Neophyl vs N-neophyl rearrangement pathways in
the reaction of thiocarbamates.
We applied the optimized rearrangement conditions (Table 4,
entry 8) to a variety of thiocarbamates, readily available from
thiophosgene, N-methyl aniline and the corresponding phenols in
75-97% isolated yields (Table 6). Since rearrangements of all
thiocarbamates into amides proceeded in good to excellent yields,
we have not attempted to optimize the reaction conditions for
individual substrates.
2,2-bis(tert-butylperoxy)butane (DTBPB). With this radical in-
itiator, only 3 equiv of Et3SiH was sufficient for obtaining 98%
yield of the rearranged amide (entry 8).
Analogous to the results given in entry 6, both yield and
conversion decreased at a higher concentration (entry 11). Clearly,
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In general, thiocarbamates with extended conjugation (entries
7-9) display higher reaction efficiency due to the greater
stabilization of the radical character developed in the O-neophyl
rearrangement step. Although, in contrast to the substituted
thiocarbonates, the presence of radical-stabilizing CN and
MeO groups (entries 2 and 3) does not further increase the
yields of rearranged products (75-80%), most yields still
compare favorably with the reactions of carbonates. Even
though in a few cases the reaction yields are slightly lower,
it is clear that the rearrangement of thiocarbamates provides a
general solution to the problem of selectivity in radical OfC
transposition. Since esters are compatible with the reaction
conditions, this transformation provides a convenient approach
to differentially substituted dicarboxylic acid derivatives (such as
the ester amide in entry 8).
To test whether N-neophyl rearrangement is possible in the
absence of O-neophyl pathway, we tested N,N0-dimethyl-N,N0-
diphenylthiourea prepared from thiophosgene and N-methyl-N-
phenylaniline and found it to be completely unreactive under the
above optimized conditions. This result suggests that N-neophyl
rearrangement should have a considerably higher activation
barrier than the O-analogue.
The observed lack of 1,2 NfC transposition is noteworthy
because a conceptually related 1,3 NfC transposition has been
reported by Zard et al. in the radical Smiles rearrangement27 of
acetylaminopyridines.28 In the latter case, the carbon-centered
radical attacks the ipso-position via the formation of a four-
membered spiro intermediate (Figure 11).29
Computational Analysis. Computational Procedures. DFT
calculations for the proposed reaction pathways utilized
Gaussian 03 software.30 All structures were fully optimized
at the UB3LYP/6-31þG** level of theory, which is reported to
provide an acceptable description of a number of radical
reactions.31 All reactants, products, and intermediates were
confirmed to be true minima by frequency calculations (zero
negative frequencies). Each transition state had one imaginary
frequency. Hyperconjugative radical stabilization energies
were estimated using the natural bond orbital (NBO) method
integrated in the Gaussian program.32
Computational Results. The potential energy surfaces for
possible O-neophyl rearrangements and fragmentation pathways
as well as the computational analysis for selected substrates are
summarized in Figures 12-14 and Table 7.
The calculations agree that the C-O bond scission (Barton-
McCombie fragmentation) for alkyl substituted substrates (blue
path) should be significantly faster than the O-neophyl rearrange-
ment. The ∼11 kcal/mol barrier difference explains why the
O-neophyl cascade does not occur in those systems where the
Barton-McCombie fragmentation pathway is available (entries 13
and 14, Table 1). On the other hand, the C-N bond scission (the
hypothetical aza- Barton-McCombie fragmentation) is predicted to
be much slower than the O-neophyl cascade. These results sug-
gested that radical rearrangements of thiocarbamates may be more
general and tolerate a greater variety of substituents at nitrogen.
More detailed hypersurfaces for the rearrangements are pre-
sented in Figure 13. For both thiocarbonates and thiocarbamates,
the first addition step of the silyl radical to the thiocarbonyl moiety is
highly exothermic (18-24 kcal/mol) and has a low barrier of ∼3
kcal/mol. However, the barrier for the subsequent O-neophyl
rearrangement step is relatively high (21-25 kcal/mol). As the
result, the O-neophyl pathway for the initially formed C-centered
radical is kinetically competitive to the fragmentation back to the
Figure 10. Possible propagation and termination steps of the radical
cascade.
Table 5. Testing the Effect of Thiols as Polarity Reversal Agents in the Rearrangement of Thiocarbonates and Thiocarbamates
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Table 6. Results of O-Neophyl Rearrangement/Fragmentation Cascade of Thiocarbamates
Figure 11. NfC transposition proceeding via a four-membered radical intermediate.
‡
starting materials (E-1 ∼ 20-27 kcal/mol, Figure 13 and
Table 7). This competition lowers efficiency of the rearrangement
step and may account for the relatively high reaction temperature
and excess of reagents needed for achieving complete conversions.
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The barrier height for the O-neophyl rearrangement is consistent
with previously calculated barriers for similar rearrangements of
carbon radicals with different degrees of stabilization.5a,22 The
relatively high value for the barrier stems from two factors: loss of
aromatic stabilization in the TS/spiro-intermediate and effective
stabilization of the carbon radical center in the reactant via interac-
tion with the lone pairs of the three adjacent heteroatoms.33 In our
systems, steric repulsion exerted by the bulky OAr and SY groups
can raise the energy of the three-membered transition state (TS)
as well.
Our calculations also provide the reason for the observed
O-neophyl . N-neophyl selectivity in thiocarbamates. The calculated
energy profile for the latter reaction is shown in Figure 13. The
N-neophyl rearrangement pathway has an ∼8 kcal/mol higher
activation barrier, and the imidate product formation is 14 kcal/mol
more endothermic than amide formation. Comparison with the
calculated parameters for the N-C fragmentation (red path in
Figure 12) illustrates that the O-neophyl rearrangement/C-S scis-
sion cascade represents the most kinetically and thermodynamically
favored process among all three analyzed pathways in thiocarbamates.
Substituent Effects. The activation barriers of O-neophyl
rearrangement are in good agreement with the experimental
substituent effects for para-substituted thiocarbonates. As ex-
pected, radical-stabilizing groups (OMe and CN) lower the
rearrangement barriers (Table 7, entries 2 and 3, respectively;
Figure 14) at the substituted aromatic rings of phenyl aryl thiocar-
bonates, whereas the rearrangements at the phenyl groups in these
compounds have the same activation barrier as in the parent
diphenyl thiocarbonate (entry 1). Lower rearrangement barriers
were also found for polyaromatic thiocarbonates (entries 7 and 8)
where the penalty for the transient aromaticity loss is lower and
resonance stabilization is higher. Encouragingly, the computational
analysis predicts, in full agreement with the experimental data, that
the rearrangements of phenyl thiocarbonates with 4-fluorophenyl,
4-bromophenyl, and 3-pyridinyl groups should have low selectivity.
In a similar way, calculations also predict that thiocarbamates with
radical-stabilizing groups should also have lower activation barriers
for O-neophyl rearrangement (entries 11-14, Table 7). In thio-
carbamates, however, the correlation between experimental yields
of rearranged amides and the radical-stabilizing effect of substituents
is less pronounced, suggesting that other factors and possible side
reactions contribute to the overall reaction yield as well.
Figure 12. Comparison of potential energy surfaces for O-neophyl
rearrangement in thiocarbonates and thiocarbamates with the C-O
and C-N fragmentations at the UB3LYP/6-31þG** level (black path,
O-neophyl rearrangement; blue path, Barton-McCombie fragmenta-
tion; red path, nitrogen analogue of Barton-McCombie fragmenta-
tion). (XR = OAr, NMePh; see Table 7 for different functional groups
(FG)). Energies are in kcal/mol.
Figure 13. Potential energy surfaces for O-neophyl rearrangement (black) and the hypothetical N-neophyl rearrangement (blue) in thiocarbamates at
the UB3LYP/6-31þG** level. Energies (kcal/mol) are summarized in Table 7.
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Table 7. Summary of the Computational Results of the Rearrangement for Selected Diaryl-Substituted Thiocarbonates and
Thiocarbamates at the UB3LYP/6-31þG** Levela
q
E1
q
q
E2
q
entry
Ar
XR
E-1
ΔE1
ΔE2
E3
ΔE3
1
2
Ph
Ph
OPh
O-(p-MeOPh)
OPh
3.2
3.1
26.3
25.4
-23.1
-22.3
24.8
24.4
23.9
24.9
23.2
24.5
24.4
24.4
24.1
24.9
24.5
22.7
21.0
22.7
21.4
22.0
23.1
22.3
20.9
21.4
21.2
-26.7
-27.3
-29.3
-25.9
-23.7
-27.0
-27.8
-26.5
-27.0
-26.8
-26.6
-28.3
-25.7
-29.0
-29.1
-30.0
-19.4
-21.2
-17.7
-17.9
-18.5
p-MeOPh
Ph
3
4
5
6
7
8
O-(p-CNPh)
OPh
3.0
3.3
3.3
3.2
2.6
3.1
27.5
26.2
27.0
25.7
24.1
24.7
-24.5
-22.9
-23.7
-23.5
-21.5
-21.6
p-CNPh
Ph
17.2
O-(p-FPh)
OPh
p-FPh
Ph
O-(p-BrPh)
OPh
p-BrPh
Ph
O-(3-pyridinyl)
OPh
3-pyridinyl
Ph
O-(1-naphthyl)
OPh
1-naphthyl
Ph
13.4
0.6
O-(2-naphthyl)
OPh
2-naphthyl
Ph
9
OEt
4.5
2.8
3.0
2.4
2.4
2.6
23.2
20.9
20.5
21.6
21.5
21.2
-18.7
-18.1
-17.5
-19.2
-19.1
-18.6
10
11
12
13
14
Ph
NMePh
NMePh
NMePh
NMePh
NMePh
p-MeOPh
p-CNPh
p-MeO2CPh
1-naphthyl
19.9
20.2
17.2
0.3
0.1
0.9
a Energies are given in kcal/mol.
Figure 14. Comparison between reaction energies of O-neophyl rearrangement and retroradical fragmentation in substituted thiocarbonates and
thiocarbamates (energies in kcal/mol).
Several considerable differences between O-neophyl rearran-
gement of thiocarbonates and thiocarbamates are demonstrated
in Figure 14. First, the rearrangement of thiocarbonates includes
more exothermic addition and fragmentation steps than the
rearrangement of thiocarbamates. Second, lower activation bar-
riers (E-1q) were found for the retro-fragmentation of carbon
radicals produced from thiocarbamates. Although the rearrangement
barriers for thiocarbonates are generally higher than those for
thiocarbamates, they are always lower than the barriers for the
retro step (E-1q). Together, the computational data suggest a
less efficient O-neophyl rearrangement in the case of thiocarba-
mates, which explains why longer reaction time and higher
equivalents of radical reagents were needed for complete con-
version of these substrates. This trade-off in the efficiency of the
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thermodynamically favorable direction. In addition, the calculated
activation barrier for N-neophyl rearrangement is relatively high,
which explains the absence of this reaction in the literature. Overall,
in accord with our initial design, the reaction cascade is driven by the
high exothermicity (37-50 kcal/mol below the initial reactants) of
the last equilibrium shifting fragmentation step.
’ EXPERIMENTAL SECTION
General Information. All NMR spectra were collected at 400
MHz for 1H NMR and 100 MHz for 13C NMR using CDCl3 as solvent.
Infrared (IR) spectroscopy was performed using a nitrogen-purged
FTIR spectrometer.
Figure 15. Concerted (P1) and shallow nonconcerted (P2 and P3)
potential energy surfaces for O-neophyl rearrangement.
rearrangement step is, however, compensated by the high
selectivity of the O-neophyl rearrangement in thiocarbamates.
Earlier computational5a,22 and experimental34 studies sug-
gested that O-neophyl rearrangement usually proceeds via a
three-membered dearomatized radical intermediate. Interest-
ingly, in our systems where the rearrangement is coupled with
fragmentation, the DFT calculations suggest a concerted path-
way for the O-neophyl rearrangement. The three-membered
intermediate could not be located for most of the substrates at
the UB3LYP/6-31þG** energy surface. Instead, all attempts for
their structural optimizations led to the final rearranged/frag-
mented products (ester or amide þ YS•, P1, Figure 15). Only in
the case of systems where higher radical stability is provided
through extended conjugation (entries 3, 7, 12-14; Table 7)
could minima for the three-membered radical intermediates be
General Procedure for the Synthesis of Symmetrical
Thiocarbonates. Phenol (2.4 mmol) was dissolved in 8 mL of
aqueous 0.3 M NaOH and added to a solution of CSCl2 (1.2 mmol)
in 10 mL of CH2Cl2. The reaction solution (two layers) was stirred
vigorously for 2 h and then diluted with CH2Cl2, washed with brine, and
dried with Na2SO4. Solvent was removed under reduced pressure, and
the crude mixture was purified by column chromatography to afford the
corresponding thiocarbonate.
General Procedures for the Synthesis of Nonsymmetrical
Thiocarbonates. Procedure A. The first phenol (1.2 mmol) was
dissolved in 4 mL of aqueous 0.3 M NaOH and added to a 10 mL of a
CH2Cl2 solution of CSCl2 (1.8 mmol). The two layers were stirred
vigorously for 1 h. The reaction mixture was diluted with CH2Cl2 and
washed with brine. The organic layers were combined and dried with
Na2SO4, and solvent and excess CSCl2 were removed under reduced
pressure. The reaction mixture was then redissolved in 10 mL of
CH2Cl2. The second phenol (1.2 mmol) was then dissolved in 4 mL
of 0.3 M NaOHaq, added to the above CH2Cl2 solution of the reaction
mixture, and stirred for 2 h. The reaction was then worked up in the same
way as before and purified by column chromatography to afford the
corresponding thiocarbonate.
Procedure B. The first phenol (1.2 mmol) and CSCl2 (1.8 mmol)
were dissolved in 10 mL of CH2Cl2 and stirred at 0 °C. Neat pyridine
(1.5 mmol) was then added dropwise at 0 °C. The reaction mixture was
allowed to warm to room temperature for 15 min upon stirring, diluted
with CH2Cl2, and washed with brine. The organic layers were combined
and dried with Na2SO4. Solvent and excess CSCl2 were removed under
reduced pressure. The reaction mixture and the second phenol (1.2
mmol) were dissolved in 10 mL of CH2Cl2 and stirred at room
temperature. Neat pyridine (1.5 mmol) was added dropwise to the
reaction mixture at room temperature. The reaction mixture was stirred
for 30 min, worked up in the same way as above, and purified by column
chromatography to afford the corresponding thiocarbonate.
q
located. However, even in those cases the calculated barrier (E3
< 1 kcal/mol) for the following ring-opening is extremely low.
No other intermediates are located because the ring-opening is
accompanied by the final C-S bond scission, directly affording
the CdO bond in the final product. Therefore, the barrier of the
ring-opening/fragmentation step is insignificant, and even when
a minimum for the three-membered radical intermediate is
located (entries 3, 7 and 14; P3), the reaction path still follows
a very shallow potential energy surface (entries 12 and 13,
Table 7; P2, Figure 15). A similar situation has been observed
for the N-neophyl rearrangement pathway where the difference
between the three-membered intermediate and earlier TS is less
than 1 kcal/mol (Figure 13, Table 7). No 3-membered radical
intermediate was located for the 2-naphthyl thiocarbonate moiety,
suggesting that it is less stable than the corresponding 1-naphthyl
thiocarbonate 3-membered intermediate.
’ CONCLUSION
We have designed an efficient 1,2 OfC radical transposition/
fragmentation cascade for the transformation of phenols into
benzoates and benzamides. This process can be used as an alter-
native to metal catalyzed carbonylation of aromatic triflates. Our
computational studies fully rationalize the moderate rearrangement
selectivity for diaryl thiocarbonates and high selectivity for diaryl
thiocarbamates. We have shown that, out of many possible path-
ways, O-neophyl rearrangement is the most kinetically and
Procedure C. The aryl alcohol (1.2 mmol) and PhOCSCl (1.8 mmol)
were dissolved in 10 mL of CH2Cl2 or MeCN. CsF-Celite (2.4 mmol)
was then added to form a heterogeneous mixture. The reaction mixture
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was stirred at room temperature for 2-6 h and monitored by TLC.
Then reaction mixture was diluted with CH2Cl2 and washed with brine.
The organic layers were combined and dried with Na2SO4, and solvent
was removed under reduced pressure. The crude mixture was purified by
column chromatography to afford the corresponding thiocarbonate.
General Procedures for the Synthesis of Thiocarbamates.
The solution was then purged with N2 for 15 min, sealed in an Ace
Glass pressure tube or thick-walled Pyrex tube, and heated at 135 °C
in an oil bath. Solvent was evaporated, and product was purified by
chromatography.
General Procedure for the Synthesis of Aryl Benzoates.
Phenol (0.214 mmol) and benzoyl chloride (0.221 mmol) were
dissolved in 6 mL of DCM/Et3N (5:1) mixture and stirred for 1 h.
The reaction solution was diluted with DCM, washed with brine, dried
with Na2SO4, and then dried under reduced pressure. The crude
reaction mixture was purified by column chromatography.
O,O-Bis(4-methoxyphenyl) thiocarbonate (2): white solid; mp
1
161-163 °C; 76%; H NMR (400 MHz, CDCl3) δ 7.07 (4H, d, J =
9.1 Hz), 6.89 (4H, d, J = 9.1 Hz), 3.77 (6H, s); 13C NMR (100 MHz,
CDCl3) δ 196.1, 158.0, 147.4, 122.7, 114.7, 55.7; IR (KBr) 3051, 2960,
2837, 1883, 1780, 1646, 1601, 1512, 1501, 1456, 1301, 1270, 1244, 1184,
1100, 1035 cm-1; HRMS (EIþ) calcd for C15H14O4S 290.06128, found
290.06040.
O-(4-Methoxyphenyl)-O-phenyl thiocarbonate (3): procedure A;
1
white solid; mp 109-111 °C; 81%; H NMR (400 MHz, CDCl3) δ
7.47 (2H, t, J = 7.5 Hz), 7.33 (1H, m), 7.23 (2H, m), 7.15 (2H, d, J = 9.1
Hz), 6.96 (2H, d, J = 9.1 Hz), 3.83 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 195.6, 158.1, 153.8, 147.4, 129.8, 127.0, 122.7, 122.0, 114.7,
55.7; IR (KBr) 3051, 2958, 2837, 1882, 1591, 1507, 1489, 1455, 1300,
1282, 1259, 1241, 1181, 1099, 1068, 1035, 1001 cm-1; HRMS (EIþ)
calcd for C14H12O3S 260.05072, found 260.05061.
Procedure D. The phenol (1.2 mmol) was dissolved in 4 mL of
aqueous 0.3 M NaOH and added to a 10 mL CH2Cl2 solution of CSCl2
(1.8 mmol). The two layers were stirred vigorously for 1 h. The reaction
mixture was diluted with CH2Cl2 and washed with brine. The organic
layer was dried with Na2SO4, and solvent and excess CSCl2 were
removed under reduced pressure. The reaction mixture was then
redissolved in 10 mL of CH2Cl2. Neat N-methylaniline (2.4 mmol)
was then added to the above CH2Cl2 solution of the reaction mixture
and stirred for 10 min. The reaction was then diluted with CH2Cl2 and
washed with brine followed by 10 mL of 0.1 N HClaq. The organic layer
was dried with Na2SO4. Solvent was removed under reduced pressure,
and the crude mixture was purified by column chromatography to afford
the corresponding thiocarbamate.
Procedure E. The phenol (1.2 mmol) and CSCl2 (1.8 mmol) were
dissolved in 10 mL of CH2Cl2 andstirredat0°C. Neat pyridine (1.5 mmol)
was then added dropwise at 0 °C. The reaction mixture was allowed to
warm to room temperature for 15 min upon stirring, diluted with CH2Cl2,
and washed with brine. The organic layer was dried with Na2SO4. Solvent
and excess CSCl2 were removed under reduced pressure. The reaction
mixture was dissolved in 10 mL of CH2Cl2 and stirred at room temperature.
Neat N-methylaniline (2.4 mmol) was then added to the above CH2Cl2
solution of the reaction mixture and stirred for 10 min. The reaction was
then diluted with CH2Cl2, washed with brine followed by 20 mL of 0.1 N
HClaq, and dried with Na2SO4. Solvent was removed under reduced
pressure, and the obtained crude mixture was purified by column chroma-
tography to afford the corresponding thiocarbamate.
Procedure F. The aryl alcohol (1.2 mmol) and Ph(Me)NCSCl (1.8
mmol) were dissolved in 10 mL of CH2Cl2 or EtOAC. Et3N (2.4 mmol)
was then added, and reaction mixture was stirred at room temperature
(or at reflux) for 12 h and monitored by TLC. Then reaction mixture was
diluted with CH2Cl2 or EtOAC and washed with brine. The organic
layers were combined and dried with Na2SO4, and solvent was removed
under reduced pressure. The crude mixture was purified by column
chromatography to afford the corresponding thiocarbonate.
Ph(Me)NCSCl. N-Methylaniline (3 mmol) was dissolved in 10 mL of
CH2Cl2 and added dropwise to a 5 mL CH2Cl2 solution of CSCl2 (1.5
mmol) at 0 °C. Then reaction mixture was diluted with CH2Cl2 and
washed with brine. The organic layers were combined and dried with
Na2SO4, and solvent was removed under reduced pressure. The crude
mixture was directly used in the preceding synthesis step.
O-(4-Cyanophenyl)-O-phenyl thiocarbonate (4): procedure A;
1
white solid; mp 157-159 °C; 75%; H NMR (400 MHz, CDCl3) δ
7.77 (2H, d, J = 8.8 Hz), 7.48 (2H, t, J = 7.6 Hz), 7.35 (3H, m), 7.22 (2H,
m); 13C NMR (100 MHz, CDCl3) δ 193.7, 156.3, 153.5, 134.1, 130.0,
127.3, 123.6, 121.8, 118.1, 111.2; IR (KBr) 3096, 3056, 2923, 2234,
1598, 1504, 1491, 1455, 1409, 1284, 1264, 1234, 1209, 1196, 1156, 1103,
1067 cm-1; HRMS (EIþ) calcd for C14H9O2NS 255.03540, found
255.03449.
O-(4-Fluorophenyl)-O-phenyl thiocarbonate (5): procedure A;
1
white solid; mp 108-112 °C; 78%; H NMR (400 MHz, CDCl3) δ
7.48 (2H, t, J = 7.5 Hz), 7.34 (1H, m), 7.3-7.1 (6H, m); 13C NMR (100
MHz, CDCl3) δ 194.8, 160.8 (d, J = 244.6 Hz), 153.5, 149.3, 129.7,
126.9, 123.3 (d, J = 8.6 Hz), 121.7, 116.3 (d, J = 23.7 Hz); IR (KBr) 3072,
3050, 1888, 1653, 1614, 1598, 1506, 1491, 156, 1415, 1290, 1278, 1243,
1176, 1147, 1088, 1068, 1002, 931, 911, 845, 827, 810, 776, 757, 738,
709, 695, 626, 603, 506, 492 cm-1; HRMS (EIþ) calcd for C13H9O2SF
248.03073, found 248.03009.
O-(4-Bromophenyl)-O-phenyl thiocarbonate (6): procedure A;
1
white solid; mp 134-136 °C; 81%; H NMR (400 MHz, CDCl3) δ
7.58 (2H, d, J = 8.9 Hz), 7.47 (2H, t, J = 7.4 Hz), 7.34 (1H, m), 7.22 (2H,
m), 7.12 (2H, d, J = 8.9 Hz); 13C NMR (100 MHz, CDCl3) δ 194.5,
153.7, 152.6, 132.9, 129.9, 127.1, 123.9, 121.9, 120.3; IR (KBr) 3071,
3050, 2919, 2850, 1948, 1899, 1878, 1746, 1661, 1598, 1485, 1456, 1397,
1376, 1309, 1283, 1244, 1231, 1209, 1191, 1164, 1093, 1067, 1014, 1002,
931, 913, 938, 795, 775, 722, 704, 691, 633, 611, 540, 494, 411, 403 cm-1
;
HRMS (EIþ) calcd for C13H9O2SBr 307.95066, found 307.95011.
O-(4-Nitrophenyl)-O-phenyl thiocarbonate (7): procedure A; white
solid; mp 158-162 °C; 74%; 1H NMR (400 MHz, CDCl3) δ 8.35 (2H,
d, J = 9.1 Hz), 7.48 (2H, m), 7.41 (2H, d, J = 9.1 Hz), 7.36 (1H, m), 7.23
(2H, m); 13C NMR (100 MHz, CDCl3) δ 193.6, 157.7, 153.5, 146.3,
130.0, 127.3, 125.6, 123.4, 121.8; IR (KBr) 3076, 1614, 1592, 1529,
1487, 1456, 1353, 1288, 1269, 1245, 1155, 1098, 1066, 1013, 1002 cm-1
;
HRMS (EIþ) calcd for C13H9O4NS 275.02523, found 275.02455.
O-Phenyl-O-3-pyridinyl thiocarbonate (8): procedure B; white solid;
mp 94-97 °C; 75%; 1H NMR (400 MHz, CDCl3) δ 8.58 (1H, dd, J =
1.2, 4.8 Hz), 8.56 (1H, d, J = 2.6 Hz), 7.59 (1H, ddd, J = 1.4, 2.8, 8.3 Hz),
7.48 (2H, m), 7.42 (1H, ddd, J = 0.3, 4.8, 8.3 Hz), 7.35 (1H, m), 7.23
(2H, m); 13C NMR (100 MHz, CDCl3) δ 194.4, 153.6, 150.3, 147.9,
144.0, 130.0, 129.9, 127.2, 124.2 121.8; IR (KBr) 3053, 1875, 1590,
General Procedure for the O-Neophyl Rearrangement/
Fragmentation Reaction. Et3SiH and TOOT were added to a
benzene solution of the starting thiocarbonate or thiocarbamate.
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1492, 1478, 1457, 1428, 1371, 1321, 1310, 1282, 1267, 1249, 1193, 1160,
1097, 1071, 1038, 1023, 1002 cm-1; HRMS (EIþ) calcd for
C12H9O2NS 232.04322 [M þ H]þ, found 232.04126 [M þ H]þ.
O-Ethyl-O-phenyl thiocarbonate (9): procedure A; colorless oil,
(100 MHz, CDCl3) δ 165.0, 151.0, 146.3, 139.8, 130.7, 129.5, 128.9,
128.3, 128.2, 127.3, 127.2, 125.8, 121.7; IR (KBr) 2919, 1730, 1456,
1404, 1264, 1196, 1083 cm-1; HRMS (EIþ) calcd for C19H14O2
274.09938, found 274.09877.
6-Quinolinyl benzoate (17): (synthesized from benzoyl chloride)
white solid; mp 77-79 °C; 69%; 1H NMR (400 MHz, CDCl3) δ 8.92
(1H, d, J = 2.92 Hz), 8.24 (2H, d, J = 7.12 Hz), 8.18 (1H, d, J = 9.12 Hz),
8.14 (1H, dd, J = 0.96, 8.36 Hz), 7.70 (1H, d, J=2.52 Hz), 7.66 (1H, m),
7.59 (1H, dd, J = 2.56, 9.08 Hz), 7.53 (2H, m), 7.42 (1H, dd, J = 4.24,
8.32 Hz); 13C NMR (100 MHz, CDCl3) δ 165.16, 150.26, 148.78,
146.33, 135.86, 133.87, 131.08, 130.25, 129.23, 128.69, 128.61, 124.88,
121.63, 118.62.
Phenyl 9-phenanthroate (18): white solid; mp 105-107 °C; 65%;
1H NMR (400 MHz, CDCl3) δ 9.07 (1H, m), 8.76 (3H, m), 8.04 (1H, d,
J = 7.72 Hz), 7.80 (1H, m), 7.72 (3H, m), 7.50 (2H, m), 7.33 (3H, m);
13C NMR (100 MHz, CDCl3) δ 165.8, 151.0, 133.6, 132.5 130.7, 130.2,
129.9, 129.5, 129.3, 129.1, 127.6, 127.1, 127.0, 126.5, 125.9, 124.9, 122.8,
122.7, 121.9; HRMS (EIþ) calcd for C21H14O2 298.09938, found
298.09928.
1
89%; H NMR (400 MHz, CDCl3) δ 7.42 (2H, t, J = 7.6 Hz), 7.29
(1H, t, J = 7.3 Hz), 7.11 (2H, d, J = 7.7 Hz), 4.60 (2H, q, J = 7.1 Hz), 1.47
(3H, t, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3) δ ; IR (KBr) 3058,
3043, 2984, 2937, 2904, 2870, 2491, 2410, 1942, 1864, 1762, 1733, 1675,
1593, 1490, 1464, 1457, 1398, 1372, 1282, 1191, 1155, 1095, 1061, 1044,
1023, 1004 cm-1; HRMS (EIþ) calcd for C9H10O2S 182.04015, found
182.03956.
O-[3-(4-Methoxyphenyl)propyl]-O-phenyl thiocarbonate (10): pro-
cedure A; colorless oil, 58%p 1H NMR (400 MHz, CDCl3) δ 7.43 (2H,
t, J = 7.5 Hz), 7.30 (1H, t, J = 7.4 Hz), 7.13 (4H, m), 6.86 (2H, d, J = 8.6
Hz), 4.54 (2H, t, J = 6.4 Hz), 3.80 (3H, s), 2.73 (2H, t, J = 7.3 Hz), 2.12
(2H, m); 13C NMR (100 MHz, CDCl3) δ 195.2, 158.0, 153.4, 132.8,
129.5, 129.3, 126.5, 121.9 113.9, 73.6, 55.3, 31.1, 30.0; IR (KBr) 3060,
3031, 2996, 2953, 2834, 2488, 1881, 1781, 1612, 1590, 1513, 1490, 1456,
1389, 1359, 1291, 1246, 1201, 1112, 1070, 1037, 1021, 1004 cm-1
;
HRMS (EIþ) calcd for C17H18O3S 302.09767, found 302.09717.
O-(4-Methoxyphenyl)-N-methyl-N-phenyl thiocarbamate (20):
procedure D; white solid; mp 109-111 °C; 91%; 1H NMR (400
MHz, CDCl3) δ 7.44 (2H, m), 7.33 (3H, m), 6.90 (4H, m), 3.78
(3H, s), 3.74 (3H, s); 13C NMR (100 MHz, CDCl3) δ 188.5, 157.3,
147.6, 143.5, 129.4, 127.7, 125.6, 123.2, 114.1, 55.5, 44.8; IR (KBr) 3059,
3003, 2930, 2835, 1596, 1505, 1495, 1477, 1380, 1295, 1277, 1250, 1207,
1171, 1121, 1103, 1073, 1033, 1007 cm-1; HRMS (EIþ) calcd for
C15H15O2NS 273.08235, found 27308181.
O-(1-Naphthyl)-O-phenyl thiocarbonate (11): procedure A; white
solid; mp 59-61 °C; 1HNMR (400 MHz, CDCl3) δ 8.03 (1H, d, J = 8.2
Hz), 7.94 (1H, d, J = 7.7 Hz), 7.85 (1H, d, J = 8.2 Hz), 7.6-7.5 (5H, m
Hz), 7.41 (1H, d, J = 7.5 Hz), 7.36 (1H, t, J = 7.4 Hz), 7.31 (2H, d, J = 7.9
Hz); 13CNMR (100 MHz, CDCl3) δ 194.7, 153.8, 149.5, 134.9, 129.9,
128.4, 127.2, 127.1, 127.0, 126.9, 126.5, 122.0, 121.3, 118.8; IR (KBr) IR
(KBr) 3062, 2921, 2850, 2459, 1936, 1600, 1591, 1509, 1490, 1457,
1392, 1277, 1194, 1153, 1079, 1042, 1014, 1003, 921, 860, 844, 799, 770,
737, 688, 658, 604, 555, 482, 433, 410 cm-1; HRMS (EIþ) calcd for
C17H12O2S 280.05580, found 280.05450.
O-(4-Cyanophenyl)-N-methyl-N-phenyl thiocarbamate (21): pro-
cedure D; white solid; mp 93-95 °C, 93%; 1H NMR (400 MHz,
CDCl3) δ 7.63 (2H, d, J = 8.5 Hz), 7.45 (2H, t, J = 7.4 Hz), 7.33 (3H, m),
7.12 (2H, d, J = 8.6 Hz), 3.73 (3H, s); 13C NMR (100 MHz, CDCl3) δ
186.4, 157.0, 143.1, 133.3, 129.6, 128.1, 125.4, 123.9, 118.3, 109.7, 44.9;
IR (KBr) 3099, 3062, 2930, 2854, 2228, 1953, 1903, 1776, 1731, 1669,
O-(2-Naphthyl)-O-phenyl thiocarbonate (12): procedure A; white
solid; mp 134-136 °C; 84%; 1H NMR (400 MHz, CDCl3) δ 7.91 (1H,
d, J = 8.92 Hz), 7.86 (2H, m), 7.66 (1H, d, J = 2.28 Hz), 7.48 (4H, m),
7.37 (1H, dd, J = 2.36, 8.88 Hz), 7.32 (1H, m), 7.26 (2H, m); 13C NMR
(100 MHz, CDCl3) δ 194.89, 153.58, 151.04, 133.66, 131.85, 129.68,
127.92, 127.86, 126.84, 126.82, 126.26, 121.82, 121.02, 118.95; HRMS
(EIþ) calcd for C17H12O2S 280.05580, found 280.05526.
1599, 1479, 1384, 1292, 1218, 1159, 1122, 1085, 1017, 1024, 1003 cm-1
;
HRMS (EIþ) calcd for C15H12ON2S 268.06704, found 268.06694.
O-(4-Methylphenyl)-N-methyl-N-phenyl thiocarbamate (22): pro-
cedure D; white solid; mp 75-77 °C, 90%; 1H NMR (400 MHz,
CDCl3) δ 7.44 (2H, m), 7.33 (3H, t, J = 6.4 Hz), 7.15 (2H, d, J = 7.6 Hz),
6.94 (2H, d, 7.6 Hz), 3.74 (3H, s), 2.33 (3H, s); 13C NMR (100 MHz,
CDCl3) δ 188.3, 151.8, 143.5, 135.5, 129.7, 129.4, 127.6, 125.6, 122.1,
44.7, 20.9; IR (KBr) 3061, 3034, 2923, 1884, 1749, 1595, 1506, 1500,
1477, 1448, 1379, 1291, 1276, 1217, 1180, 1121, 1089, 1073, 1018, 1003
cm-1; HRMS (ESIþ) calcd for C15H15ONS 280.07720 [M þ Na]þ,
found 280.07765 [M þ Na]þ.
O-(6-Quinolinyl)-O-phenyl thiocarbonate (13): procedure C; white
solid; mp 139-141 °C; 54%; 1H NMR (400 MHz, CDCl3) δ8.94 (1H, dd,
J = 1.6, 4.2 Hz), 8.19 (2H, m), 7.66 (1H, d, J = 2.56 Hz), 7.62 (1H, dd, J =
2.64, 9.08 Hz), 7.45 (3H, m), 7.33 (1H, m), 7.25 (2H, m); 13C NMR (100
MHz, CDCl3) δ 194.6, 153.5, 151.0, 150.6, 146.5, 136.0, 131.3, 129.7,
128.5, 126.9, 124.8, 121.8, 121.7, 118.9; HRMS (ESIþ) calcd for
C16H11O2NS 282.05887 [M þ H]þ, found 28205879 [M þ H]þ.
O-(1-Phenanthryl)-O-phenyl thiocarbonate (14): procedure C;
O-(3-Mmethylphenyl)-N-methyl-N-phenyl thiocarbamate (23):
1
1
procedure D; white solid; mp 82-84 °C; 87%; H NMR (400 MHz,
yellow solid; mp 96-98 °C; 79%; H NMR (400 MHz, CDCl3) δ
CDCl3) δ 7.44 (2H, m), 7.33 (3H, m), 7.24 (2H, m), 7.04-6.83 (3H,
m), 3.75 (3H, s), 2.34 (3H, s); 13C NMR (100 MHz, CDCl3) δ 187.9,
153.9, 143.4, 139.2, 129.3, 128.7, 127.5, 126.6, 125.5, 122.9, 119.4, 44.6,
21.2; IR (KBr) 3037, 2919, 1587, 1493, 1478, 1379, 1243, 1157, 1119,
1002 cm-1; HRMS (EIþ) calcd for C15H15ONS 280.07720 [M þ
Na]þ, found 280.07971 [M þ Na]þ.
8.70 (1H, dd, J = 1.92, 6.76 Hz), 8.65 (1H, d, J = 8.04 Hz), 8.06 (1H, m),
7.88 (1H, d, J = 7.68 Hz), 7.72-7.57 (4H, m), 7.44 (2H, m), 7.30 (3H,
m), 7.21 (1H, m); 13C NMR (100 MHz, CDCl3) δ 194.4, 153.7, 147.8,
131.7, 131.3, 129.8, 129.7, 128.7, 127.5, 127.3, 127.2, 127.0, 126.9, 125.9,
123.2, 122.8, 121.9, 121.8, 118.5; HRMS (EIþ) calcd for C21H14O2S
330.07145, found 330.07140.
O-(4-Chlorophenyl)-N-methyl-N-phenyl thiocarbamate (24): pro-
p-Fluorophenyl benzoate (15): (synthesized from benzoyl chloride)
white solid; mp 48-50 °C; 97%;1H NMR (400 MHz, CDCl3) δ 8.20 (2H,
d, J= 7.1 Hz), 7.65 (1H, t, J= 7.4 Hz), 7.52 (2H, t, J=7.8Hz), 7.15(2H, m),
7.12 (2H, t, J = 8.1 Hz); 13C NMR (100 MHz, CDCl3) δ 165.1, 160.2 (d, J
= 242.7 Hz), 146.7, 133.6, 130.1, 129.2, 128.5, 123.0 (d, J = 8.5 Hz), 116.1
(d, J = 23.3 Hz); IR (KBr) 3454, 3065, 2926, 2854, 1886, 1733, 1599, 1584,
1504, 1450, 1416, 1316, 1266, 1186, 1088, 1064, 1024, 1013 cm-1; HRMS
(EIþ) calcd for C13H9O2F 216.05866, found 216.05698.
1
cedure D; white solid; mp 105-107 °C; 97%; H NMR (400 MHz,
CDCl3) δ 7.46 (2H, t, J = 7.4 Hz), 7.35 (5H, m), 6.95 (2H, d, J = 8.5 Hz),
3.73 (3H, s); 13C NMR (100 MHz, CDCl3) δ 187.5, 152.4, 143.3, 131.3,
129.5, 129.2, 127.8, 125.5, 123.9, 44.8; IR (KBr) 3090, 3074, 3061, 2976,
2932, 2771, 2561, 2422, 2334, 2258, 2172, 2087, 2015, 1976, 1949, 1909,
1885, 1870, 1819, 1791, 1739, 1676, 1645, 1595, 1485, 1453, 1429, 1391,
1313, 1284, 1214, 1162, 1128, 1086, 1072, 1029, 1015, 1002 cm-1
;
HRMS (ESIþ) calcd for C14H12ONSCl 300.02258 [M þ Na]þ, found
300.02547 [M þ Na]þ.
Phenyl p-phenylbenzoate (16): white solid; mp 146-149 °C; 29%;
1H NMR (400 MHz, CDCl3) δ; 13C NMR (100 MHz, CDCl3) δ ; 8.27
(2H, d, J = 8.4 Hz), 7.74 (2H, d, J = 8.4 Hz), 7.66 (2H, d, J = 7.2 Hz), 7.49
(2H, m), 7.42 (2H, m), 7.29 (2H, d, J = 7.4 Hz), 7.24 (2H, m); 13C NMR
O-(4-Methoxycarbonylphenyl)-N-methyl-N-phenyl thiocarbamate (25):
procedure E; white solid; mp 108-110 °C; 71%; 1H NMR (400 MHz,
1534
dx.doi.org/10.1021/jo102467j |J. Org. Chem. 2011, 76, 1521–1537

The Journal of Organic Chemistry
FEATURED ARTICLE
CDCl3) δ8.03 (2H, d, J = 8.4 Hz), 7.44 (2H, m), 7.33 (3H, m), 7.07 (2H,
d, J = 8.48 Hz), 3.89 (3H, s), 3.73 (3H, s); 13C NMR (100 MHz, CDCl3)
δ 186.9, 166.1, 157.3, 143.2, 130.7, 129.4, 127.7, 127.6, 125.4, 122.6,
52.0, 44.7; IR (KBr) IR (KBr) 2925, 1723, 1599, 1495, 1386, 1277, 1175,
1109, 1010 cm-1; HRMS (EIþ) calcd for C16H15O3NS 324.06703
[M þ Na]þ, found 324.06975 [M þ Na]þ.
126.9, 52.2, 38.2; IR (KBr)) 2952, 1723, 1645, 1595, 1496, 1436, 1370,
1278, 1178, 1108, 1020 cm-1; HRMS (EIþ) calcd for C16H15O3N
269.10520, found 269.10487.
4-Phenyl-N-methyl-N-phenylbenzamide (34): white solid; mp 99-
1
102 °C; >99%; H NMR (400 MHz, CDCl3) δ 7.51 (2H, m), 7.36
(7H, m), 7.24 (2H, m), 7.15 (1H, m), 7.06 (2H, m), 3.52 (3H, s); 13C
NMR (100 MHz, CDCl3) δ 170.3, 144.9, 142.2, 140.1, 134.6, 129.3,
129.2, 128.7, 127.7, 127.0, 126.9, 126.5, 126.3, 38.5; IR (KBr)
3031, 2923, 1644, 1595, 1495, 1419, 1364, 1301, 1281, 1106, 1008
cm-1; HRMS (EIþ) calcd for C20H17ON 287.13102, found 287.
13032.
O-(4-Phenylphenyl)-N-methyl-N-phenyl thiocarbamate (26): pro-
1
cedure E; white solid; mp 128-130 °C; 82%; H NMR (400 MHz,
CDCl3) δ 7.57 (4H, m), 7.44 (4H, m), 7.35 (4H, m), 7.10 (2H, d, J =
8.08 Hz), 3.77 (3H, s); 13C NMR (100 MHz, CDCl3) δ 187.8, 153.3,
143.4, 140.2, 138.9, 129.3, 128.6, 127.8, 127.6, 127.2, 127.0, 125.5, 122.6,
44.7; IR (KBr) 2920, 1595, 1595, 1381, 1225, 1180, 1118, 1006 cm-1
;
N-Methyl-N-phenyl-2-naphthamide (35): white solid, mp 84 °C.;
79%; 1H NMR (400 MHz, CDCl3) δ 7.89 (1H, s), 7.71 (2H, m), 7.58
(1H, d, J = 8.56), 7.45 (2H, pd, J = 1.4, 6.84 Hz), 7.31 (1H, dd, J = 1.64,
8.56 Hz), 7.19 (2H, m), 7.09 (3H, m); 13C NMR (100 MHz, CDCl3) δ
187.66, 151.70, 150.25, 146.40, 143.45, 135.84, 130.61, 129.57, 128.43,
127.93, 125.93, 125.64, 121.52, 119.24, 44.90; HRMS (CIþ) calcd for
C18H16ON 262.12319, found 262.12351.
HRMS (EIþ) calcd for C20H17ONS 342.09285 [M þ Na]þ, found
342.09564 [M þ Na]þ.
O-(1-Naphthyl)-N-methyl-N-phenyl thiocarbamate (27): Proce-
dure D; white solid; mp 99-101 °C,78%; 1H NMR (400 MHz, CDCl3)
δ 7.85 (1H, m), 7.71 (2H, m), 7.47 (7H, m), 7.36 (1H, m), 7.19 (1H, d, J
= 7.4), 3.81 (3H, s); 13C NMR (100 MHz, CDCl3) δ 186.9, 148.9, 142.6,
133.5, 128.5, 127.0, 126.8, 126.3, 125.3, 125.2, 125.0, 124.6, 124.1, 120.4,
118.2, 43.8; IR (Kbr) 3059, 2929, 1597, 1493, 1477, 1448, 1379, 1291,
’ ASSOCIATED CONTENT
1276, 1256, 1227, 1180, 1166, 1153, 1125, 1073, 1024, 1012 cm-1
;
Supporting Information. 1Hand13C NMR spectra. Total
HRMS (ESIþ) calcd for C18H15ONS 316.07720 [M þ Na]þ, found
S
b
316.07901 [M þ Na]þ.
energy and Cartesian coordinates for each optimized stationary
point at the reaction hyper surfaces. This material is available free of
charge via the Internet at http://pubs.acs.org.
O-(2-Naphthyl)-N-methyl-N-phenyl thiocarbamate (28): proce-
1
dure D; white solid; mp 129-131 °C; 88%; H NMR (400 MHz,
CDCl3) δ 7.78 (3H, m), 7.41 (5H, m), 7.31 (3H, m), 7.19 (1H, m), 3.74
(3H, s); 13C NMR (100 MHz, CDCl3) δ 188.06, 151.63, 143.58, 133.68,
131.55, 129.53, 129.04, 127.90, 127.81, 127.74, 126.54, 125.79, 125.71,
122.26, 119.35; HRMS (ESIþ) calcd for C18H15ONS 294.09526 [M þ
H]þ, found 294.09548 [M þ H]þ.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: alabugin@chem.fsu.edu.
O-(6-Quinolinyl)-N-methyl-N-phenyl thiocarbamate (29): proce-
dure F; white solid; mp 124-126 °C; 35%; 1H NMR (400 MHz,
CDCl3) δ 8.88 (1H, m), 8.09 (2H, m), 7.42 (7H, m), 3.77 (3H, s); 13
C
’ ACKNOWLEDGMENT
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 providing
computational resources for the DFT calculations.
NMR (100 MHz, CDCl3) δ 187.6, 151.7, 150.2, 146.4, 143.4, 135.8,
130.6, 129.5, 128.4, 127.9, 125.9, 125.6, 121.5, 119.2, 44.9; HRMS
(ESIþ) calcd for C17H14ON2S 295.09051 [M þ H]þ, found 295.09110
[M þ H]þ.
O-Phenyl-N,N-diethyl thiocarbamate. Procedure D was followed
with the only exception that Et3N (dealkylating procedure of Millan and
Prager)35 has been used instead of N-methylaniline.
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1
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MHz, CDCl3) δ 169.6, 166.3, 144.2, 140.2, 130.7, 129.2, 129.0, 128.5,
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The Journal of Organic Chemistry
FEATURED ARTICLE
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