Protonation switching to the least-basic heteroatom of carbamate through cationic hydrogen bonding promotes the formation of isocyanate cations

Article abstract of DOI:10.1002/chem.201402447

We found that phenethylcarbamates that bear ortho-salicylate as an ether group (carbamoyl salicylates) dramatically accelerate O-C bond dissociation in strong acid to facilitate generation of isocyanate cation (N-protonated isocyanates), which undergo subsequent intramolecular aromatic electrophilic cyclization to give dihydroisoquinolones. To generate isocyanate cations from carbamates in acidic media as electrophiles for aromatic substitution, protonation at the ether oxygen, the least basic heteroatom, is essential to promote C-O bond cleavage. However, the carbonyl oxygen of carbamates, the most basic site, is protonated exclusively in strong acids. We found that the protonation site can be shifted to an alternative basic atom by linking methyl salicylate to the ether oxygen of carbamate. The methyl ester oxygen ortho to the phenolic (ether) oxygen of salicylate is as basic as the carbamate carbonyl oxygen, and we found that monoprotonation at the methyl ester oxygen in strong acid resulted in the formation of an intramolecular cationic hydrogen bond (>C=O⁺-H...O<) with the phenolic ether oxygen. This facilitates O-C bond dissociation of phenethylcarbamates, thereby promoting isocyanate cation formation. In contrast, superacid-mediated diprotonation at the methyl ester oxygen of the salicylate and the carbonyl oxygen of the carbamate afforded a rather stable dication, which did not readily undergo C-O bond dissociation. This is an unprecedented and unknown case in which the monocation has greater reactivity than the dication.

Full text of DOI:10.1002/chem.201402447

DOI: 10.1002/chem.201402447
Full Paper
&
Hydrogen Bonding
Protonation Switching to the Least-Basic Heteroatom of
Carbamate through Cationic Hydrogen Bonding Promotes the
Formation of Isocyanate Cations
[
a]
Hiroaki Kurouchi, Akinari Sumita, Yuko Otani, and Tomohiko Ohwada*
Abstract: We found that phenethylcarbamates that bear
ortho-salicylate as an ether group (carbamoyl salicylates) dra-
matically accelerate OꢀC bond dissociation in strong acid to
facilitate generation of isocyanate cation (N-protonated iso-
cyanates), which undergo subsequent intramolecular aro-
matic electrophilic cyclization to give dihydroisoquinolones.
To generate isocyanate cations from carbamates in acidic
media as electrophiles for aromatic substitution, protonation
at the ether oxygen, the least basic heteroatom, is essential
to promote CꢀO bond cleavage. However, the carbonyl
oxygen of carbamates, the most basic site, is protonated ex-
clusively in strong acids. We found that the protonation site
can be shifted to an alternative basic atom by linking methyl
salicylate to the ether oxygen of carbamate. The methyl
ester oxygen ortho to the phenolic (ether) oxygen of salicy-
late is as basic as the carbamate carbonyl oxygen, and we
found that monoprotonation at the methyl ester oxygen in
strong acid resulted in the formation of an intramolecular
+
cationic hydrogen bond (>C=O ꢀH···O<) with the phenolic
ether oxygen. This facilitates OꢀC bond dissociation of phe-
nethylcarbamates, thereby promoting isocyanate cation for-
mation. In contrast, superacid-mediated diprotonation at the
methyl ester oxygen of the salicylate and the carbonyl
oxygen of the carbamate afforded a rather stable dication,
which did not readily undergo CꢀO bond dissociation. This
is an unprecedented and unknown case in which the mono-
cation has greater reactivity than the dication.
Introduction
Hydrogen bonding in molecular complexes can be a more ef-
fective means of electrophilic activation than the use of exter-
nal inorganic/organic acid catalysis, as has been widely recog-
[
1]
[2–6]
nized in enzymatic catalysis, organocatalysis,
and general
Figure 1. Typical examples of acceleration of acid-catalyzed bond dissocia-
tion through intramolecular hydrogen bonding.
[
7–10]
acid catalysis.
The reason for this is that the hydrogen-
bonding-mediated process is entropically favored when the
hydrogen-bonding donor (an acid) and the acceptor (the basic
[
10]
and aminolysis
of esters. However, the role of hydrogen
[11]
site to be activated) are appropriately spatially located.
bonding in strongly acid media has been little studied so far,
particularly in relation to the generation of strong electrophiles
such as those used in aromatic substitution reactions.
Long-standing studies of general acid catalysis have shown
that even weak acids, such as carboxylic acids and phenols,
can catalyze reactions by proton transfer and efficiently pro-
mote cationic bond dissociation, such as in hydrolysis of ace-
Protonation of an appropriate atom is often essential for ac-
tivating particular reactions. It is well known that acylium ions
in aromatic acylation reactions are generated from ester or
equivalent functionalities in strong acidic media through disso-
ciation of the CꢀO bond between carbonyl carbon and ether
[
7]
[2]
tals (Figure 1a). Weak acids such as carboxylic acids, thiour-
[
3]
[4]
[5]
eas, phosphoric acids, and phenols have also been utilized
as organocatalysts to activate electrophiles and control confor-
mations in transition states by means of hydrogen bonding
[12]
oxygen. In this case, protonation at the most basic carbonyl
oxygen atom does not enhance the leaving-group ability of
the alcohol group, but protonation at the less-basic ether
oxygen atom promotes the CꢀO bond dissociation, even
though the concentration of the ether-protonated reactive in-
termediates is always very low, with the species being present
in biased equilibrium with the O-protonated carbonyl species.
Carbamates are considered to generate electrophiles, N-pro-
(
Figure 1b). Similar activation mechanisms have been reported
[9]
in models of enzyme-catalyzed reactions, such as hydrolysis
[
a] H. Kurouchi, A. Sumita, Prof. Dr. Y. Otani, Prof. Dr. T. Ohwada
Graduate School of Pharmaceutical Sciences
The University of Tokyo, 7-3-1 Hongo
Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5841-4735
E-mail: ohwada@mol.f.u-tokyo.ac.jp
[13–15]
tonated isocyanates,
through similar CꢀO bond cleavage.
In this case, protonation at the less-basic ether oxygen atom is
also necessary to activate the carbamate, although the carbon-
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402447.
Chem. Eur. J. 2014, 20, 8682 – 8690
8682
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
yl oxygen atom is more basic than the ether oxygen atom.
Based on the idea that selective hydrogen-bonding activation
of the least basic site, as seen in enzyme catalysis, organocatal-
ysis, and general acid catalysis, might also occur in rather
strong acids, we considered that it would be possible to in-
crease the activation efficiency of carbamates to promote aro-
matic substitution reactions by introduction of an appropriate
hydrogen-bonding substituent.
erate active intermediates. In practice, the introduction of
ortho-salicylate facilitates the cyclization reaction of the carba-
mates that proceeds even at room temperature for a short re-
action time. These conditions can suppress the side reactions
caused by heating in acidic media for a long time that are en-
countered in the case of methyl carbamates in which the leav-
[14]
ing group is a methoxy group. Thus, the present activation
method can expand the applicability of carbamates as a versa-
tile precursor of isocyanate cations.
In this paper, we show that release of strong electrophiles,
isocyanate cations, from phenylethyl carbamate derivatives is
facilitated by intramolecular cationic hydrogen bonding in
strong acids. Specifically, we found that introduction of an al- Results and Discussion
ternative basic site near the ether oxygen atom, for example,
Synergistic acceleration of reactions by ortho-methyl
salicylate as an ether moiety
ortho-methyl salicylate as an ether moiety of carbamates, facili-
tates OꢀC bond dissociation, dramatically promoting isocya-
nate cation generation, followed by aromatic cyclization reac-
tions to give dihydroisoquinolones (see Table 1). This is attrib-
To weaken the bond between the carbonyl carbon and the
ether oxygen atom of carbamates, two factors—large electro-
negativity of the leaving group and efficiency of ether O-proto-
nation—are crucial. The importance of the electronegativity of
the leaving group has been demonstrated in many previous
Table 1. Optimization of alcohol moiety in acid-catalyzed cyclization of
carbamates.
[17]
studies. As a result of our screening studies for intramolecu-
lar electrophilic aromatic substitution reaction (Table 1), ortho-
methyl salicylate was found to meet both requirements: When
the ortho-methyl salicylate moiety in carbamates is protonated,
the reaction rate is dramatically increased, more significantly
than para-methyl salicylate (Table 1, entries 3 and 4).
5
ꢀ1
Entry
R
10 k [s
]
Relative rate
[
[
[
a]
b]
b]
1
2
ꢀCH
3
(1a)
ꢀPh (1b)
0.41
4.0
1
9.8
We compared the reaction rates of dissociation of various
leaving groups (CꢀO bond cleavage) in the presence of tri-
fluoromethanesulfonic acid (TfOH) (Table 1; for other leaving
groups, see the Supporting Information). Phenethyl carbamate
derivatives were used as representative compounds to exam-
ine reaction rates. A phenoxy group (Table 1, entry 2) reacted
2
3
1.3ꢁ10
320
3
4
2.9ꢁ10
7100
[
a] The reaction rate is extrapolated from data shown in Ref. [14]. [b] The
reaction rates are extrapolated from data obtained at lower tempera-
tures.
10 times faster than the methoxy group (Table 1, entry 1). In-
troduction of a methyl ester onto the benzene ring at the para
position (1c) increased the reaction rate by approximately 33-
[18]
fold (Table 1, entry 3). An ester group at the ortho position
(1d) caused a further 22-fold rate increase (7100 times as fast
as the methoxy derivative) (Table 1, entry 4). Carbamates that
bear salicylate as an ether group (carbamoyl salicylates) were
concluded to be suitable substrates for further studies.
uted to the formation of an intramolecular cationic hydrogen
+
bond (>C=O ꢀH···O<) between the O-protonated methyl
ester of the salicylate and the phenolic ether oxygen atom in
strong acids, as well as the electron-withdrawing nature of the
aromatic functionality (Figure 2). In superacids, diprotonation
of the methyl ester of the ortho/para-methyl salicylate (methyl
Exploring the scope of aromatic cyclization of carbamates
2-/4-hydroxybenzoate) and the carbonyl group of the carba-
mate occurs to generate dications. Surprisingly, we found that
these diprotonated substrates are stable and do not readily
undergo CꢀO bond dissociation, because dications and more
protonated cations generally show higher reactivity than
The introduction of ortho-salicylate facilitated the cyclization
reaction of the carbamates, which enabled the reactions to
take place even at room temperature for a short reaction time.
These reaction conditions suppress side reactions encountered
in the case of methyl carbamates (Scheme 1). In the case of
a methoxy leaving group instead of ortho-salicylate, heating at
[
16]
monocations. Indeed, entropy-driven deprotonation of the
dications to the monocations appears to be necessary to gen-
708C for a long time (1–3 days) was necessary to complete the
cyclization reaction of the corresponding methyl carbamates
[14]
[
Scheme 1; Eqs. (1), (3), (5), (7), and (9)], which caused side
reactions: demethylation of the aromatic methoxy group
[
14,19]
[
Eq. (5)],
scrambling of the phenyl group [Eq. (7)], and bro-
[20]
mine [Eq. (9)] on the aromatic ring. By using the ortho-salicy-
late leaving group, activation of carbamates was accelerated
[Eqs. (2) and (4)] and finished within one hour. Also, the reac-
Figure 2. Cationic hydrogen bonding promotes CꢀO bond dissociation.
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8683
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Scheme 1. The ortho-salicylate leaving group expands the scope of the reactions.
tions did not cause side reactions and afforded single products
in high yields [Eqs. (6), (8), (10)].
low yield (Table 2, entry 3). The cyclization reaction is applica-
ble to a carbamate that has tertiary amine (Table 2, entry 4).
Carbamates derived from amino acids such as phenylalanine
and tyrosine also afforded cyclized product in high yield with-
out suffering loss of their enantiopurities (Table 2, entries 5, 6).
Even when another carbamate group was present in the phe-
nylalaninol derivative, the activation of the carbamoyl salicylate
preceded activation of another carbamate (Table 2, entry 7).
This new method of activation of carbamates can expand
the applicability of the reactions. We will therefore focus on
the mechanistic studies to understand why ortho-salicylate fa-
cilitates the carbamate activation significantly.
The generality of the facile reactions can be tested in other
substrates (Table 2). Similarly to the bromo group, the iodo
group did not rearrange (Table 2, entry 1). The trifluoromethyl
group did not decompose and the cyclization product was ob-
tained in moderate yield, even though a trifluoromethyl group
is a strong deactivating group and is fragile under acidic condi-
[
21]
tions whereby it transforms into a carboxylic acid (Table 2,
entry 2). Even if a substrate had a strong electron-withdrawing
nitro group, the relevant cyclization proceeded and the corre-
sponding dihydroisoquinolone derivative was obtained even in
Table 2. Generality of activation of carbamates to facilitate cyclization reactions.
[
a]
[b]
[a]
[b]
Entry
1
Starting material
Product
Yield [%]
Entry
Starting material
Product
Yield [%] ([%ee])
86 (>99)
[
[
d]
d]
81
66
5
6
2
86 (>99)
92 (>99)
[c]
[d]
3
24
93
7
4
[
[
a] Typical reaction conditions: A solution of the substrate (0.7 mmol) and TfOH (10 equiv) in dichloromethane (3.5 mL) was stirred at 208C for 1–2 h.
b] Isolated yield. [c] The products are mixture of the cyclized product and 1,3-bis(4-nitrophenethyl)urea. The yield was determined by H NMR spectrosco-
1
py. [d] The enantiopurity was determined by HPLC.
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8684
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Acidity rate relationship and protonation degree of
carbamoyl salicylates
The relationships between acidity and reaction rates of 1c,
1d, and 1e are shown in Figure 3. Initially we had anticipated
that the stronger the acid, the faster the reaction would
become, as is generally the case in superacid-catalyzed reac-
tions that involve the generation of dications or superelectro-
Rate constants of isocyanate cation release from carbamoyl sal-
icylates (para: 1c; ortho: 1d; and N-methylated ortho: 1e)
evaluated as the rate of consumption of the carbamates were
measured in moderate to strong acids of defined acidity
[
22]
(
Table 3). The reaction type depended upon the cosolvent
and the conjugate base of the acids (i.e., cyclization (2a, 2b,
type A), amine formation (3a, 3b, type B), or addition of 2,2,2-
trifluoroethanol (TFE)) to afford the carbamate (4a, type C).
The reactions were carried out in the presence of 200 equiva-
[
23]
lents of the acid in NMR spectroscopic tubes, with cooling
to maintain the required temperature. The concentration of
the starting material was monitored in terms of the integration
1
values in the H NMR spectra. All the reactions followed
pseudo-first-order kinetics (R>0.99 between lnkobs and time).
The reaction rate at ꢀH =2.7 (TFA=trifluoroacetic acid) was
0
Figure 3. Relationships between acidity and reaction rate at 37 (1c), 6 (1d),
and 258C (1e).
very slow, and the rates at 378C for 1c and 68C for 1d were
extrapolated from the rate constants obtained at higher tem-
peratures (Table 3, entry 8). In the TFA/TfOH system, only cycli-
zation (reaction type A) was observed in the high acidity
philes. Indeed, the reaction rate increased as the acidity in-
region (ꢀH =9.6–14.1; Table 3, entries 1–5) for all of the three
creased from ꢀH =2.7 to 4.9, thus indicating that protonation
0
0
reactions. As the acidity was decreased, the cyclization was ac-
accelerates the reaction. But in the acidity range between
companied by formation of the amine (reaction type B) (ꢀH =
ꢀH =8.1 and 10.8, the reaction rate reached a maximum and
0
0
8
.3, 9.1; Table 3, entries 6, 7). In TFA, amine formation was pre-
then plateaued. Then, contrary to our expectation, the reaction
dominant (ꢀH =2.7; Table 3, entry 8). In the TFE/TfOH system,
rate decreased in all of the cases for 1c, 1d, and 1e as the
0
the cyclization reaction did not proceed, and instead the nu-
cleophilic addition reaction of TFE dominated (reaction type C)
acidity was increased from ꢀH =12.2 to 14.1. This bell-shaped
0
relationship is similar to the well-known dependence of rate
on pH for the reaction of hydroxylamine and acetone, which is
promoted by protonation of the
(Table 3, entries 9, 10) for both 1c and 1d.
tetrahedral intermediate but re-
Table 3. Reaction rates of 1c, 1d, and 1e in acids of various acidities.
tarded by protonation of hy-
[24]
droxylamine.
Similar plots
have been also reported for sev-
eral dissociation reactions such
as in benzaldehyde disalicyl
acetal, an acetal that bears two
carboxylic acids, with the reac-
tion being activated by mono-
anion formation but deactivated
[25,26]
1
c (378C)
ꢀH
1d (68C)
ꢀH
1e (258C)
ꢀH
by dianion formation.
In previous studies, the inde-
pendent pKBH values of carba-
5
5
5
Entry Reaction Reaction
TfOH
[%]
0
10 k
TfOH
[%]
(w/w)
0
10 k
TfOH
[%]
(w/w)
0
10 k
ꢀ
1
ꢀ1
ꢀ1
system
type
[s
]
[s
]
[s
]
+
(
w/w)
mates and esters were both esti-
1
TFA/
A
100
14.1 21.8
13 37.5
12.2 59.9
10.6 121
100
14.1 2.83
13 5.38
12.2 27.8
10.8 109
100
14.1 9.07
[27]
mated to be around ꢀ4–6.
TfOH
Thus, esters and carbamates in
2
3
4
5
6
A
A
A
A
A, B
trace)
A, B
B
91
62
25
10
–
91
62
25
11
6
–
—
–
62
27
11
–
12.2 55.5
10.9 134
TFA (ꢀH =2.7) are protonated
0
to only a very small extent.
9.6
–
93.6
–
9.7
9.1
120
106
9.7
–
140
–
13
Indeed, the C NMR spectro-
scopic chemical shifts of carba-
moyl ortho-salicylate 1 f in TFA
are similar to those measured in
CDCl3 (Table 4, entries 1, 2). As
the acidity was further in-
(
7
8
2
0
8.1
2.7
74.1
0.0721
3
0
8.3
2.7
93.7
0.212
3
–
8.4
–
112
–
[
a]
9
1
TFE/TfOH
C
C
1
–
4.9
–
15.4
–
1
0.5
4.9
4.6
17.0
3.87
–
–
–
–
–
–
0
13
creased, the C chemical shifts
of the two carbonyl carbon
[a] The reaction rate is extrapolated from data obtained at higher temperatures.
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8685
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
tween these two carbonyl oxygen atoms (see SM1 in Figure 7
below). Considering the similar kinetic behaviors of para-
methyl salicylate (1c) and ortho-methyl salicylate (1d) shown
above, the reason for the stability of the carbamate dication
might be the intrinsic unfavorability of CꢀO bond dissociation
to form the isocyanate dication and electronically neutral
ortho- or para-methyl salicylate, because the putative isocya-
1
3
Table 4. C NMR spectroscopic chemical shifts of carbamoyl ortho-salicy-
late 1 f in media at various levels of acidity.
[28]
1
3
C NMR spectroscopic chemical
nate dication would be highly unstable.
[
a]
shift [ppm]
C2 C3
Entry Solvent
ꢀH
0
C1
165.4
C4
27.8
27.7
26.8
28.8
Presence of intramolecular hydrogen bonding in
monocations
1
2
CDCl
TFA
3
–
155.1
159.8
52.1
53.2
2.7 168.8
1
58.8
[
b]
To examine whether or not protonated ortho-salicylic acid de-
rivatives form an intramolecular cationic hydrogen bond in
strong acidic media, direct observation of protonated salicylic
acid derivatives was conducted using 2-methoxybenzoic acid
3
4
5
TfOH/TFA=1:3 (w/w)
10.9 170.5
69.2
14.1 179.8
79.1
179.9
79.6
160.6
55.3
55.0
63.4
63.3
64.3
63.9
1
TfOH
160.1
159.6
159.7
159.1
29.5
1
TfOH/SbF
5
=4:1 (w/w) >17
29.6
29.5
5
a and methyl-2-methoxybenzoate 5b as model compounds.
1
These compounds were dissolved in TfOH/SbF solution (4:1
5
[
a] The spectra were measured at ꢀ168C. [b] The spectrum was measured
1
(
w/w)), and the H NMR spectra were measured at ꢀ168C. In
at ꢀ278C to suppress the decomposition reaction.
the case of the carboxylic acid compound 5a, two OH proton
signals were observed at d=14.2 and 11.2 ppm (Figure 5a).
The strongly low-field-shifted proton signal at d=14.2 ppm is
atoms were deshielded (Table 4, entry 3), and finally diprotona-
tion seems to be complete in acids stronger than TfOH (ꢀH =
0
14.1) (Table 4, entries 4, 5). Formation of the O,O-diprotonated
species (1 f’) is consistent with the presence of two OH protons
1
in the H NMR spectra observed in TfOH/SbF =4:1 (w/w)
5
(Figure 4). These results are consistent with the idea that the
Figure 5. a,b) Direct observation of cationic hydrogen bonding, and c) dicat-
ion formation.
strong evidence for the presence of intramolecular hydrogen
bonding. A similarly deshielded proton signal was observed at
d=14.6 ppm when the ester compound 5b was dissolved in
the same superacid medium (Figure 5b). This also supports the
formation of intramolecular hydrogen bonding. When carba-
moyl salicylate mimics were dissolved in TfOH/SbF (4:1 (w/w)),
5
1
the H NMR spectrum of dication 1g was observed (Figure 5c),
which showed a deshielded signal equivalent to two protons
(
(
d=12.7 ppm), which remained inseparable even at ꢀ168C
Figure 5). This signal is attributed to the O-protonated carbox-
ylic acid group. Another low-field proton signal was seen at
d=10.5 ppm. In the case of ester 1 f described above, two de-
shielded protons were observed at d=12.8 and 10.3 ppm.
These results indicate that O,O-diprotonated dicationic species
are generated but do not form intramolecular hydrogen bond-
ing, probably because the hydrogen-bond acceptor ability of
Figure 4. NMR spectroscopic signals of diprotonated carbamate.
carbamates are monoprotonated in the acidity range of ꢀ7 to
[29]
ꢀ
11. Protonation at a carbonyl group of the ester or the carba-
the carbamate ether oxygen was diminished by protonation.
mate is consistent with the observed low-field shifts in the sig-
nals of the ester carbonyl carbon (d=168.8 ppm at ꢀH =2.7,
0
Thermodynamic parameters of the reactions
d=170.5 and 169.2 ppm at ꢀH =10.9) and the methyl group
0
adjacent to the nitrogen atom of the carbamate (d=27.7 and
We measured the activation parameters for the cyclization re-
2
6.8 ppm at ꢀH =2.7, d=28.8 ppm at ꢀH =10.9). On the
actions in the moderately acidic region (ꢀH =9.7–10.8) and
0
0
0
basis of these results, it is reasonable to conclude that proto-
nation at these carbonyl oxygen atoms is in equilibrium, or
that an intramolecular cationic hydrogen bond is formed be-
highly acidic region (ꢀH =14.1–17.0) for the two substrates,
0
NꢀH 1d and NꢀMe 1e (Table 5). The activation entropy was
found to be positive in all acidity regions. This is consistent
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8686
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
cation also supported the pres-
ence of hydrogen bonding (Fig-
ure 6b): the second-order per-
turbation energies were found
Table 5. Activation parameters for the cyclization reactions.
ꢀ
1
to be 13.5 kcalmol
(n (1)–
O
sOH* interaction) and 7.9 kcal
5
°
°
°
ꢀ1
Entry Substrate Acid
ꢀH
0
T
10 k
DG (258C) DH
DS
[calmol K ]
mol
(n (2)–sOH* interaction).
O
ꢀ
1
[a]
ꢀ1
ꢀ1
ꢀ1 ꢀ1
[
8C]
[s
]
[kcalmol
]
[kcalmol
]
The structures of the dication
1
2
3
4
5
6
R=H
1d)
TFA/TfOH
=8:1 (w/w)
9.7
10.8
14.1
17
6.2 120 (ꢁ2)
20.0 (ꢁ1.9) 20.3 (ꢁ0.9)
20.0 (ꢁ1.6) 21.1 (ꢁ0.8)
0.7 (ꢁ3.3)
3.7 (ꢁ2.8)
(1 f’) were also optimized. The
(
0.0
6.3
47.3 (ꢁ1.1)
21.0 (ꢁ1.3)
carbonyl-separated
structure
ꢀ
ꢀ
(
1 f’-1) was found to be the
R=H
1d)
TFA/TfOH
=3:1 (w/w)
6.2 109 (ꢁ4)
most stable structure, and the
ester-rotated structure (1 f’-2)
was less stable than 1 f’-1 by
(
0.0
6.3
18.6
12.4
42.9 (ꢁ1.7)
17.7 (ꢁ0.9)
25.6 (ꢁ0.6)
9.18 (ꢁ0.58)
2.83 (ꢁ0.04)
29.9 (ꢁ0.2)
8.53 (ꢁ0.20)
3.37 (ꢁ0.11)
R=H
1d)
TfOH
21.7 (ꢁ1.7) 28.2 (ꢁ0.8) 21.7 (ꢁ2.9)
22.3 (ꢁ2.7) 29.1 (ꢁ1.3) 23.0 (ꢁ4.6)
21.3 (ꢁ0.4) 24.6 (ꢁ0.2) 10.9 (ꢁ0.7)
23.0 (ꢁ2.0) 30.0 (ꢁ1.0) 23.4 (ꢁ3.3)
(
ꢀ
1
0
.4 kcalmol (Figure 6a). In the
6
.2
dication, the O-protonated ester
group did not form similar intra-
molecular hydrogen bonding,
presumably because hydrogen-
bonding acceptor strength of
the protonated carbamate is
much weaker than neutral car-
bamate. And charge–charge re-
pulsion between the O-proton-
ated carbamate and the O-pro-
tonated ester group separated
them as far as possible. NBO
analysis of the dication 1 f’-2
did not detect any hydrogen-
bonding interaction.
R=H
1d)
TfOH/SbF
=99:1 (w/w)
5
24.8
18.6
(
1
2.4
R=Me
1e)
TFA/TfOH
=8:1 (w/w)
9.7
24.8 140 (ꢁ3)
18.6
2.4
(
55.6 (ꢁ0.5)
1
22.1 (ꢁ0.3)
71.6 (ꢁ1.2)
23.7 (ꢁ0.7)
9.07 (ꢁ0.40)
R=Me
1e)
TfOH
14.1
37.2
31.0
(
2
4.8
[
b]
ꢀ4
7
1a
TfOH
14.1
0.0
1.04ꢁ10
27.0
29.1
6.9
[a] Listed values are average of three runs. Standard errors are shown in parentheses. [b] The reaction constant
at 08C is extrapolated from data shown in Ref. [14].
with a mechanism in which the CꢀO bond dissociation step of
methyl salicylate is rate-determining. As the acidity was in-
creased, activation enthalpy and entropy increased for both
compounds (Table 5, entries 1, 2, 5 versus entries 3, 4, 6).
In superacid media, the substrate–acid bulk system is ther-
modynamically stable when the substrate is diprotonated. The
increase in activation enthalpy for the cyclization reflects de-
stabilization of the bulk reaction system owing to transforma-
tion of the stable dication into the monocation. It is reasonable
to assume that this transformation leads to an increase in en-
tropy of the bulk reaction system, and therefore this deproto-
nation step is entropy-driven. The results for methyl carba-
mate, wherein methanol is the leaving group, are also shown
in Table 5 (entry 7). On the basis of these data, the reaction of
5
the methyl salicylate carbamate is 4.5ꢁ10 times faster than
that of methyl carbamate in moderately acidic medium, a mix-
ture of TFA/TfOH=8:1 (w/w) at 08C.
Computational studies
Intramolecular hydrogen bonding
We also characterized the intramolecular hydrogen bonding in
the ester-protonated monocationic species by means of DFT
calculations (Figure 6a). Calculations were carried out using the
[
30]
Gaussian 09 suite of programs. The distance between ortho-
+
phenolic oxygen and proton (>OꢀH O(=)) was calculated to
Figure 6. a) DFT-optimized structures of monocation and dication, and
b) bonding nature of the monocation.
[
31]
be 1.66 ꢂ. Natural bond orbital (NBO) analysis of the mono-
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8687
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Energy profiles of reactions
increasing acidity in the moderate acidity region, in which one
of the carbonyl oxygen atoms of salicylate methyl ester and
the carbamate is partially protonated. In the superacid region,
in which diprotonation occurred, the reaction was hampered.
These observations can be interpreted in terms of two factors
that influence the dissociation reaction: the electron-withdraw-
ing nature of the ortho-/para-salicylic ester group and the for-
mation of intramolecular six-membered cationic hydrogen
bonding between the ester carbonyl and the phenolic ether
oxygen atoms of the ortho-methyl salicylate. This intramolecu-
lar cationic hydrogen bonding was observed spectroscopically
in the monoprotonated ortho-salicylic acid derivative. The cal-
culated transition-state structures also supported the forma-
tion of intramolecular cationic hydrogen bonding within the
monoprotonated carbamoyl ortho-salicylate. And calculations
also suggested that the bond dissociation reaction is more
energy-demanding than with electrophilic aromatic cyclization
reaction, so the former is the rate-determining step. This disso-
ciation mechanism is an unprecedented and unknown exam-
ple of a reaction in which the monocation is more reactive
than the dication, and this is probably general in CꢀO bond
dissociation-type electrophile generation. From a practical
standpoint, the introduction of ortho-salicylate is valuable. It
accelerates the cyclization reaction of the carbamates that ena-
bles the reactions to take place even at room temperature for
a short reaction time. These conditions can suppress side reac-
tions and provide high-yield reactions. Thus, the present acti-
vation method can expand the applicability of carbamates as
a versatile precursor of isocyanate cations.
Energy profiles for dissociation of ortho-methyl salicylate and
cyclization of the resultant isocyanate cation of phenethylcar-
bamate were also calculated (Figure 7). For monoprotonated
substrates, the most stable structure is that in which the two
carbonyl oxygen atoms shared one proton between them
(SM1; Figure 7a). When SM1 is rearranged to dissociation pre-
cursor SM2 by scrambling the hydrogen-bonding protonation
ꢀ
1
network, SM2 is destabilized by 5.9 kcalmol . However, the
carbamate-protonated structure SM3 was as stable as SM1.
The CꢀO bond dissociation was the most energy-demanding
ꢀ
1
step (SM2!TS1, 15.7 kcalmol ). At this step, proton transfer
and CꢀO bond dissociation occur in a concerted manner, but
asynchronously, that is, proton transfer occurs first, followed
by dissociation (Figure 7). The magnitude of the calculated ac-
tivation enthalpy is consistent with that obtained experimen-
tally (Table 3, entry 2).
The activation energy of the cyclization was calculated to be
ꢀ
1
7
.4 kcalmol (Figure 7b). This value is much lower than that of
the dissociation step, so this is expected to be a very fast reac-
tion. This result is in accord with the observations that the
rate-determining step is the CꢀO bond dissociation process
and that the isocyanate intermediate was not observed during
in situ NMR spectroscopic analysis of the reaction mixture.
Conclusion
The leaving-group efficiency of ortho-/para-methyl salicylate
from embedded carbamates is highly dependent on the acidity
of the reaction medium. The dissociation was accelerated with
Figure 7. Calculated reaction profile of bond dissociation and cyclization processes.
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8688
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[
7] a) A. J. Kirby, A. Parkinson, J. Chem. Soc. Chem. Commun. 1994, 707–
Experimental Section
708; b) A. J. Kirby, Acc. Chem. Res. 1997, 30, 290–296; c) C. Buffet, G.
General procedure for the synthesis of carbamoyl salicylates
Lamaty, Recl. Trav. Chim. Pats-Bas 1976, 95, 1–6; d) T. H. Fife, E. Ander-
son, J. Am. Chem. Soc. 1971, 93, 6610–6614; e) S. E. Barber, K. E. S.
Dean, A. J. Kirby, Can. J. Chem. 1999, 77, 792–801.
(starting materials shown in Table 2)
A solution of a phenethylamine derivative (3.3 mmol, 1.1 equiv), di-
methyl 2,2’-[carbonylbis(oxy)]dibenzoate (3.0 mmol), and tetrahy-
drofuran (10.0 mL) was stirred at 208C for the appropriate time (3–
[8] a) I. R. Greig, A. J. Kirby, J. Phys. Org. Chem. 2004, 17, 498–506; b) T. H.
Fife, L. H. Brod, J. Am. Chem. Soc. 1970, 92, 1681–1684; c) B. Capon,
M. I. Page, J. Chem. Soc. Perkin Trans. 2 1972, 522–529.
[
9] A. Arcelli, C. Coneilio, J. Chem. Soc. Perkin Trans. 2 1977, 1563–1568.
4
8 h). The solvent of the reaction mixture was evaporated under
[
[
10] E. Ciuffarin, A. Loi, M. Isola, A. Lupetti, L. Sagramora, L. Senatore, J. Org.
Chem. 1983, 48, 1047–1051.
11] a) A. Sievers, M. Beringer, M. V. Rodnina, R. Wolfenden, Proc. Natl. Acad.
Sci. USA 2004, 101, 7897–7901; b) W. M. Kati, R. Wolfenden, Biochemistry
reduced pressure to give a crude compound (oil). The crude prod-
uct was purified by column chromatography (eluent: diethyl ether/
hexane=1:5–1:1) to afford carbamoyl salicylate in high yield.
1
989, 28, 7919–7927.
[
12] a) G. A. Olah, D. H. O’Brien, A. M. White, J. Am. Chem. Soc. 1967, 89,
General procedure for the cyclization reaction of carbamoyl
salicylates (Table 2)
5
2
694–5700; b) K. Yates, R. A. McClelland, J. Am. Chem. Soc. 1967, 89,
686–2692.
[
[
13] V. C. Armstrong, R. B. Moodie, J. Chem. Soc. B 1969, 934–938.
14] H. Kurouchi, K. Kawamoto, H. Sugimoto, S. Nakamura, Y. Otani, T.
Ohwada, J. Org. Chem. 2012, 77, 9313–9328.
Trifluoromethanesulfonic acid (0.53 mL, 10 equiv) was added to
a solution of carbamoyl salicylate (0.60 mmol) in dichloromethane
(
3.0 mL, 0.2m) at 08C. The whole was stirred at 208C under argon
[
15] E. K. Raja, S. O. N. Lill, D. A. Klumpp, Chem. Commun. 2012, 48, 8141–
atmosphere for the appropriate time (0.5–2 h). Then the mixture
was quenched with ice water (30 mL), and the whole was extract-
ed with dichloromethane (30 mLꢁ3). The organic layer was dried
over sodium sulfate, and the solvent was evaporated to give
a crude solid mixture. The crude product was purified by column
chromatography (eluent: ethyl acetate/dichloromethane=1:4–1:1)
to afford cyclized products.
8143.
[
16] For generation of strong electrophiles: a) G. A. Olah, D. A. Klumpp, Su-
perelectrophiles and Their Chemistry, Wiley, New York, 2008 and referen-
ces cited therein; b) H. Kurouchi, H. Sugimoto, Y. Otani, T. Ohwada, J.
Am. Chem. Soc. 2010, 132, 807–815; c) R. R. Naredla, C. Zheng, S. O. N.
Lill, D. A. Klumpp, J. Am. Chem. Soc. 2011, 133, 13169–13175. For elec-
trophilicity scale: d) C. D. Ritchie, Acc. Chem. Res. 1972, 5, 348–354;
e) H. Mayr, B. Kempf, A. R. Ofial, Acc. Chem. Res. 2003, 36, 66–77.
[
[
17] a) A. F. Hegarty, L. N. Frost, J. Chem. Soc. Perkin Trans. 2 1973, 1719–
1
5
728; b) T. Vontor, M. Ve cˇ e rˇ a, Collect. Czech. Chem. Commun. 1973, 38,
16–522.
Acknowledgements
18] Generally, the electronegativity of the leaving group plays an important
role in accelerating reactions as exemplified in Ref. [16]. For the present
reactions of the substrates in which 4-substituted phenol derivatives
are used as the leaving group, the 1 value of the Hammett plot be-
tween s values of 4-substituents and the reaction rates was found to
be positive (1= +0.65), thus indicating that electron-withdrawing sub-
stituents can accelerate the reactions. For more information, see the
Supporting Information.
Hiroaki Kurouchi is a research fellow of Japan Society for the
Promotion of Science (JSPS) and thanks the Research Fellow-
ship for Young Scientists from JSPS. We gratefully acknowledge
financial support from The University of Tokyo. The computa-
tions were performed at the Research Center for Computation-
al Science, Okazaki, Japan. We thank the computational facility
for generous allotments of computer time.
[19] M. Ko zˇ elj, A. Petri cˇ , Synlett 2007, 11, 1699–1702.
[
20] A. Ajaz, E. C. McLaughlin, S. L. Skraba, R. Thamatam, R. P. Johnson, J.
Org. Chem. 2012, 77, 9487–9495.
Keywords: aromatic substitution
carbamates · cations · hydrogen bonds
·
bond dissociation
·
[21] a) S. Saito, Y. Sato, T. Ohwada, K. Shudo, J. Am. Chem. Soc. 1994, 116,
2312–2317; b) A. Kethe, A. F. Tracy, D. A. Klumpp, Org. Biomol. Chem.
2
011, 9, 4545–4549.
22] S. Saito, S. Saito, T. Ohwada, K. Shudo, Chem. Pharm. Bull. 1991, 39,
718–2720.
[
[
[
1] a) R. F. Atkinson, T. C. Bruice, J. Am. Chem. Soc. 1974, 96, 819–825;
b) T. C. Bruice, S. J. Benkovic, Biochemistry 2000, 39, 6267–6274; c) S.
Nakano, D. M. Chadalavada, P. C. Bevilacqua, Science 2000, 287, 1493–
2
23] A large excess amount of acids was employed to minimize the decrease
in acidity of the media, which is caused by protonation of the sub-
strate. We have already checked the effect of addition of the base on
lowering the acidity of the media. Lowering the acidity occurred upon
addition of a base substrate such as water, but the magnitude of the
change was constant. Therefore, the relationship between the relative
acidity strength and the rate of reactions does not change significantly.
See a) T. Ohwada, T. Suzuki, K. Shudo, J. Am. Chem. Soc. 1998, 120,
1497; d) S. R. Das, J. A. Piccirilli, Nat. Chem. Biol. 2005, 1, 45–52.
[
[
2] a) F. R. Clemente, K. N. Houk, Angew. Chem. 2004, 116, 5890–5892;
Angew. Chem. Int. Ed. 2004, 43, 5766–5768; b) B. List, R. A. Lerner, C. F.
Barbas III, J. Am. Chem. Soc. 2000, 122, 2395–2396.
3] For urea: a) D. P. Curran, L. H. Kuo, J. Org. Chem. 1994, 59, 3259–3261.
For thiourea: b) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003,
1
25, 12672–12673; c) M. S. Taylor, E. N. Jacobsen, Angew. Chem. 2006,
18, 1550–1573; Angew. Chem. Int. Ed. 2006, 45, 1520–1543; d) R. P.
Herrera, V. Sgarzani, L. Bernardi, A. Ricci, Angew. Chem. 2005, 117, 6734–
737; Angew. Chem. Int. Ed. 2005, 44, 6576–6579.
4629–4637; b) A. Yokoyama, T. Ohwada, K. Shudo, J. Org. Chem. 1999,
1
6
4, 611–617.
[
[
24] W. P. Jencks, J. Am. Chem. Soc. 1959, 81, 475–481.
25] a) B. E. Anderson, T. H. Fife, J. Chem. Soc. D. 1971, 1470–1471; b) B.
Capon, M. I. Page, J. Chem. Soc. Perkin Trans. 2 1972, 2057–2062.
6
[
4] a) T. Akiyama, Chem. Rev. 2007, 107, 5744–5758 and references cited
therein; b) M. Terada, Synthesis 2010, 12, 1929–1982 and references
cited therein; c) Q. Kang, Z. A. Zhao, S. L. You, J. Am. Chem. Soc. 2007,
[26] For example, Anderson et al. proposed a mechanism of base-catalyzed
hydrolysis of benzaldehyde disalicyl acetal shown below (see
Ref. [24a]).
[27] a) V. C. Armstrong, R. B. Moodie, J. Chem. Soc. B 1968, 275–277; b) C. C.
Greig, C. D. Johnson, J. Am. Chem. Soc. 1968, 90, 6453–6457.
[28] On the basis of this result, methyl carbamates do not release isocyanate
dication in superacid media (see Ref. 14). As cited in Ref. 14, the dissoci-
ation reaction of methanol from methyl carbamate functionality to gen-
erate isocyanate cation can proceed by means of a dicationic dissocia-
1
29, 1484–1485; d) J. Seayad, A. M. Seayad, B. List, J. Am. Chem. Soc.
006, 128, 1086–1087.
5] a) N. T. McDougal, S. E. Schaus, J. Am. Chem. Soc. 2003, 125, 12094–
2095; b) A. Hasegawa, Y. Naganawa, M. Fushimi, K. Ishihara, H. Yama-
2
[
[
1
moto, Org. Lett. 2006, 8, 3175–3178.
6] H. Sardon, A. C. Engler, J. M. W. Chan, J. M. Garcꢃa, D. J. Coady, A. Pascu-
al, D. Mecerreyes, G. O. Jones, J. E. Rice, H. W. Horn, J. L. Hedrick, J. Am.
Chem. Soc. 2013, 135, 16235–16241.
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8689
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E.
Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers,
K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand,
K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J.
Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E.
Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Mo-
rokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J.
Dannenberg, S. Dapprich, A. D. Daniels, ꢄ. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian,
Inc. Wallingford CT, 2009..
tion mechanism, which has been proposed in Scheme 7 by Cox: R. A.
Cox, Can. J. Chem. 2005, 83, 1391–1399.
[
31] NBO Version 3.1, E. D. Glendening, A. E. Reed, J. E. Carpenter, and F.
Weinhold.
[
[
29] G. A. Olah, P. W. Westerman, J. Org. Chem. 1974, 39, 1307–1308.
30] Gaussian 09, Revision A.02, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E.
Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Men-
nucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian,
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O.
Received: March 3, 2014
Published online on June 11, 2014
Chem. Eur. J. 2014, 20, 8682 – 8690
www.chemeurj.org
8690
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim