Inverse neighboring group participation: Explanation of an unusual S→N alkyl migration of isothiuronium salts containing a lactone group

Article abstract of DOI:10.1021/jo400460x

A detailed experimental and DFT study of the S to N alkyl migration of substituted S-(1(3H)-isobenzofuranon-3-yl)isothiuronium bromide to N,N′-dimethyl-N-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thiourea provided evidence for the existence of an unusual double displacement mechanism involving two consecutive back-side S_N2 reactions where a carboxylate anion has a crucial role both as a leaving group as well as an internal nucleophile. The thiazetidine zwitterionic species that is involved in this mechanism as an intermediate was characterized by infrared multiphoton dissociation spectroscopy and was trapped with methyl iodide. It was found that the intermediate has a structure of a free ion pair. The double-displacement mechanism can be considered as a new type of inverse lactone neighboring group participation.

Full text of DOI:10.1021/jo400460x

Article
pubs.acs.org/joc
Inverse Neighboring Group Participation: Explanation of an Unusual
S→N Alkyl Migration of Isothiuronium Salts Containing a Lactone
Group
†
†
†
‡
‡
‡
̌
Jirí Vana, Milos Sedlak, Richard Kammel, Jana Roithova, Anton Skríba, Juraj Jasík,
̌
́
̌
̌
́
́
̌
and Jirí Hanusek*,†
̌
†Faculty of Chemical Technology, Institute of Organic Chemistry and Technology, University of Pardubice, Studentska
10 Pardubice, The Czech Republic
́
573, CZ-532
‡Faculty of Science, Department of Organic Chemistry, Charles University in Prague, Hlavova 2030/8, CZ-128 43 Prague 2, The
Czech Republic
S
* Supporting Information
ABSTRACT: A detailed experimental and DFT study of the S
to N alkyl migration of substituted S-(1(3H)-isobenzofuranon-
3-yl)isothiuronium bromide to N,N′-dimethyl-N-(3-oxo-1,3-
dihydro-2-benzofuran-1-yl)thiourea provided evidence for the
existence of an unusual double displacement mechanism
involving two consecutive back-side SN2 reactions where a
carboxylate anion has a crucial role both as a leaving group as well as an internal nucleophile. The thiazetidine zwitterionic species
that is involved in this mechanism as an intermediate was characterized by infrared multiphoton dissociation spectroscopy and
was trapped with methyl iodide. It was found that the intermediate has a structure of a free ion pair. The double-displacement
mechanism can be considered as a new type of inverse lactone neighboring group participation.
isobenzofuranon-3-yl)isothiuronium bromides giving either
2H-isoindol-2-carbothioamides or N,N′-dimethyl-N-(3-oxo-
1,3-dihydro-2-benzofuran-1-yl)thioureas (Scheme 1) depend-
INTRODUCTION
■
The presence of sulfur atoms in biomolecules is crucial for
many biological processes. One of the most important
properties of sulfur-containing groups is their nucleophilicity.
In particular, the phenomenon of the proximity of sulfur
nucleophiles next to nitrogen nucleophiles attracts great
attention. It is mainly due to the S→N acyl migration, which
is one step of native chemical ligation (NCL) reactions.1 These
reactions enable chemoselective synthesis of large peptides
using a concept of the capture/rearrangement of the N-terminal
cysteine peptides. A similar S→N transfer was also observed
during the rearrangement of the glycosyl moiety in
glycosylsulfanyloxadiazoles.2 These reactions are practically
important yet very interesting from a mechanistic point of
view. Although both reactions can be formally considered as an
S→N migration, the proposed reaction mechanisms are
completely different.2,3 The rearrangement of glycosylsulfanyl-
oxadiazoles is not fully understood and seems to resemble the
extensively discussed mechanism of retaining glycosyltrans-
ferases.4
Scheme 1. Rearrangement of Substituted S-(1(3H)-
Isobenzofuranon-3-yl)isothiuronium Bromides
ing on substitution at the isothiuronium moiety.7 The latter
reaction represents unusual S→N alkyl migration for which we
present a detailed mechanistic study based on a variety of
experiments and theoretical calculations including a trapping
and spectroscopic characterization of the key reaction
intermediate.
In our work, we are constantly dealing with transformation
reactions of isothiuronium salts containing either a lactam or a
lactone moiety which represent versatile starting materials for
synthesis of many important heterocycles including thiazoles,
thiazolidines, thiazines, isoindoles, etc.5,6 Many of these
syntheses involve acid−base-catalyzed ring transformations
(rearrangements) proceeding under very mild conditions,
even at physiological pH.6 Recently, we have studied an
unexpected course of rearrangement of substituted S-(1(3H)-
RESULTS AND DISCUSSION
■
The ring transformation of N,N′-dimethyl S-(1(3H)-isobenzo-
furanon-3-yl)isothiuronium bromide (1) to N,N′-dimethyl-N-
(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thiourea (2) can be
formally considered as alkyl migration from sulfur to nitrogen.
Received: March 4, 2013
Published: April 5, 2013
© 2013 American Chemical Society
4456
dx.doi.org/10.1021/jo400460x | J. Org. Chem. 2013, 78, 4456−4462

The Journal of Organic Chemistry
Article
In contrast to the well-known S→N acyl migration3 in S-
acylthioureas which takes place via a four-membered ring under
mild reaction conditions, a similar S→N alkyl migration has not
been observed at all. According to the classical Winstein
scheme for nucleophilic substitution reactions, the following
four limiting reaction mechanisms (Scheme 2) can be
allowed due to the presence of a sulfur atom and hence an
easier torsional deformation. In fact four-membered rings
containing sulfur atom with bonding angle smaller than 90°
have been observed.15 The double displacement mechanism
closely resembles the addition−elimination mechanism occur-
ring during S→N acyl migration3 in S-acylthioureas.
It is well-known that the inversion of absolute configuration
is an inherent and consistent characteristic of the bimolecular
nucleophilic substitution SN2. In order to prove or disprove the
retention of configuration at carbon C-3 during the rearrange-
ment 1 to 2 we tried to prepare optically pure starting salt 1
using bromide interchange with silver L-tartrate, L-lactate, or
camphor sulfonate and crystallization. Unfortunately, we always
recovered either the starting racemate of 1 or the product of
rearrangement 2.
Scheme 2. Possible Mechanisms of Rearrangement of S-
(1(3H)-Isobenzofuranon-3-yl)isothiuronium Bromide (1)
Therefore, we have chosen another useful tool which is able
to distinguish between the SN1 and SN2 reaction mechanisms,
i.e., α-secondary kinetic isotope effect (α-SKIE). Typical
values16 of α-SKIE for SN1 mechanism are around 1.15−1.25
and for SN2 around unity or even slightly less. In our case, the
measured α-SKIE for 1 and its 3-deuterio analogue is 0.95,
which shows that there is probably no carbenium ion on the
reaction coordinate and the SN1 mechanism (paths b and b′) is
not involved.
The oxygen atom can, beside its weak stabilizing effect, play
another role in the reaction mechanism; it can act as a relatively
good leaving group. To get better insight into the reaction
mechanism and in order to prove the role of lactone oxygen we
studied under same conditions reactions of similar isothiouro-
nium salts 3 and 4 where the double displacement mechanism
(analogous to path c) is impossible. For both salts, we found
that no product of S→N alkyl migration was formed and only
free isothiourea 5 or elimination product 6 (1H-isochromen-1-
one) were isolated (Scheme 3).
proposed. First, three possibilities involve intramolecular
front-side SN2 reaction through a four-membered transition
state (path a) or an intramolecular SN1 reaction involving
rearrangement of the ion pair formed after dissociation of the
thiourea moiety (path b) or carboxylate (path b′). The fourth
possibility (path c) involves a double-displacement mechanism
i.e. two consecutive back-side SN2 reactions where the
carboxylate anion acts as both leaving group as well as internal
nucleophile. This reaction pathway involves the formation of a
four-membered thiazetidine intermediate.
Scheme 3. Base-Catalyzed Reaction of S-[2-
(Methoxycarbonyl)benzyl]-N,N′-dimethylisothiuronium
Bromide (4) and S-(1-Oxo-3,4-dihydro-1H-isochromen-4-
yl)-N,N′-dimethylisothiuronium Bromide
The front-side SN2 reaction pathway (a) belongs to a
relatively rarely suggested mechanisms for reactions associated
with a retention of the configuration. It was proposed for
intramolecular decomposition of alkyl chlorosulfites,8 for the
reaction of cumylarenesulfonates and anilino thioethers with
anilines9 and especially for some glycosyltranferase-catalyzed
reactions.10 On the other hand, an SN1 reaction proceeding
through an intimate ion pair can also explain the retention of
configuration.11 Moreover, most quantum chemical calcula-
tions12 give energy barriers of 170−200 kJ·mol−1 higher for
front-side attack as compared to the classical back-side SN2
reaction pathway although the difference steeply decreases for
protonated alcohols and amines containing bulky alkyl group.13
During the transformation following path b the oxygen atom
can stabilize (by its +M effect) the positive charge at the
benzylic carbon of an ion pair. However such stabilization is
weak due to cross-conjugation of the lone electron pair on the
oxygen atom with the adjacent carbonyl group (as seen from
comparison14 of σR(OCH3) = −0.43 and σR(OCOCH3) =
−0.19). The forth possibility (path c) avoids energetically
demanding front-side attack as well as cleavage of a relatively
poor leaving group (N,N′-dimethylthiourea). The formation of
a four-membered thiazetidine intermediate can be energetically
From both observations, one can conclude that the presence
of the oxygen atom adjacent to the benzylic carbon is an
essential feature for the S→N alkyl migration which supports
the double-displacement mechanism (path c).
Important evidence for the suggested double-displacement
mechanism in Scheme 2 (path c) would be the trapping of the
thiazetidine intermediate. Therefore, we added 10-fold excess of
methyl iodide into the reaction mixture containing isothiuro-
nium salt 1 along with sodium carbonate in acetone in order to
convert the carboxylate anion of the thiazetidine intermediate
4457
dx.doi.org/10.1021/jo400460x | J. Org. Chem. 2013, 78, 4456−4462

The Journal of Organic Chemistry
Article
1
to its methyl ester. The H and 13C NMR spectra showed a
be generated by addition of a base. Hence, all suggested
structures of possible intermediates are neutral; therefore, they
can be observed only in their protonated forms. The ions
generated from 1 do not readily undergo the rearrangement;
therefore, we have also tested a possible reverse transformation
from the side of the product 2.
The electrospray ionization of a methanolic solution of 2 did
not lead to the generation of the corresponding ions. However,
upon addition of a drop of hydrochloric acid, the protonated
ions with the corresponding mass represented the most
abundant ions. The IRMPD spectrum of the generated ions
(Figure 2) is completely different from that of 2, which suggests
complicated mixture of products including signals at 3.79 ppm
in the H and 166.9 ppm in the 13C NMR spectrum whose
1
long-range correlation was confirmed using HMBC NMR
technique (see Experimental Section and the Supporting
Information). The chemical shifts of these two signals are in
a very good agreement with those measured for the analogue
compound 3 (3.86 and 167.0 ppm). In addition, the mass
spectrum of the reaction mixture contains peak at m/z 250
which corresponds to the O-methylated thiazetidine inter-
mediate. Moreover, the increasing concentration of methyl
iodide leads to the linear increase of the methyl ester amount
(Table 1), which confirms competition between backward
Table 1. Dependence of the Methyl Ester Content (%) in the
Reaction Mixture on the Concentration of Added Methyl
Iodide
c(CH3I)
methyl ester
content (%)
c(CH3I)
methyl ester
content (%)
(mol·L−1
)
(mol·L−1
)
0.39
0.76
4.2
8.4
1.45
2.08
14.6
23.7
intramolecular attack of carboxylate group on the thiazetidine
carbon and intermolecular carboxylate attack of the methyl
iodide. Unfortunately, all attempts to isolate O-methylated
thiazetidine intermediate have failed due to its instability.
Further evidence for the existence of the thiazetidine
intermediate was obtained in the gas phase using infrared
multiphoton dissociation spectroscopy (IRMPD).17 Com-
pounds 1 and 2 were first analyzed by mass spectrometry
and their structures were probed by IRMPD spectrometry,
which provides action infrared spectra for the mass selected
ions (see the Experimental Section). Prerequisite for the direct
observation and investigation of reactive intermediates using
mass spectrometry is that the species have to be charged, which
is fulfilled for the starting salt 1.18 The IRMPD spectrum of the
isothiuronium cation 1 in the gas phase agrees well with its
theoretical IR spectrum (Figure 1), thereby confirming that the
ion is transferred to the gas phase in an identical form as
observed in the solid state and in the solution.
Figure 2. IRMPD spectrum of ions generated from 2 upon addition of
HCl (black line) and its comparison with the theoretical IR spectra
(red bars, red lines represent the theoretical spectra folded with the
Gaussian function with full width at half-maximum of 16 cm−1) of (a)
protonated 2 and (b) a possible thiazetidine intermediate (see Scheme
2, path c).
Transformation of 1 to the product 2 does not proceed in
the form of the salt because of the positively charged
isothiuronium moiety, but instead a neutral form (1′) has to
that we have generated different isomeric ions. Comparison of
the IRMPD spectrum with the theoretical IR spectrum of the
most stable isomer found for protonated 2 (Figure 2a) clearly
shows that the protonated ions do not retain this structure.
Hence, we have searched for possible structures of
intermediates. The IR spectrum of the protonated form of
the intermediate suggested in the double-displacement
mechanism almost perfectly fits the experimental IRMPD
spectrum (Figure 2b). Namely, the intense peaks at about 1670
and 1710 cm−1 correspond to the stretching vibration of the
exocyclic C−N bond and to the CO vibration of the free
carboxylic group. These two bands were found only for this
type of intermediate; IR spectra of all the other structures did
not reproduce the experimental results. It is to be noted that a
weak band at about 1830 cm−1 corresponds to the CO
Figure 1. IRMPD spectrum of 1 (black line) and theoretical IR
spectrum (red bars, red line represents the theoretical spectrum folded
with Gaussian with full width at half-maximum of 16 cm−1).
4458
dx.doi.org/10.1021/jo400460x | J. Org. Chem. 2013, 78, 4456−4462

The Journal of Organic Chemistry
Article
stretching mode of the cyclic lactone (the same band can be
also observed in the spectrum of 1 in Figure 1), and hence, we
most probably sample a minor population of protonated
product 2.
From the above-mentioned experiments, it can be concluded
that the whole lactone group can serve as a relatively good
leaving group which is cleaved simultaneously with back-side
attack at the benzylic carbon by the isothiourea nitrogen. The
intermediate thus formed containing a four-membered
thiazetidine ring then undergoes rotation around the C−C
single bond which enables the second back-side SN2 attack at
the benzylic carbon atom by the carboxylate anion with sulfur
acting as a better leaving group. Such mechanism necessitates
substantial rotational freedom of the thiazetidine ring around
the C−C single bond as well as rotational freedom of the
carboxylate anion. In other words, the zwitterionic thiazetidine
intermediate would have the structure of a relatively loose ion
pair. The “tightness” of the zwitterionic thiazetidine inter-
mediate was therefore the subject of our further investigation.
In order to evaluate the tightness of the ion pair of
thiazetidine intermediate, we prepared19 the isothiuronium salt
1 labeled at the carbonyl oxygen by the 18O isotope (25%
enrichment). If the zwitterionic thiazetidine intermediate
formed from this salt would have a relatively rigid structure
(tight ion pair) then no scrambling of 18O isotope would occur
18
in the product 2 (i.e., 100% in C O) On the other hand, if
this intermediate adopts the form of a loose or even free ion
pair then statistical scrambling of 18O isotope would be
18
observed (i.e., 50% in C O and 50% in C−18O) in product
2. The last possibility involves synchronous rotation of both
thiazetidine and carboxylate groups like two cogwheels which
would lead to 100% occurrence of 18O isotope “inside” the
lactone ring of product 2 (i.e., 100% in C−18O). The position
Figure 3. Selected signals in 13C NMR spectra of 18O-enriched
compound 1 and 2.
18
of 18O isotope in C O or C−18O can be easily determined
from 13C NMR and IR spectra.
18
The 13C NMR spectrum of the C O enriched
isothiuronium salt 1 shows two signals of carbonyl carbon
atom (Figure 3) whose 18O-isotope upfield shift is 0.036 ppm,20
whereas only a single signal is observable for the benzylic
carbon atom. Similar information can be gained from the IR
spectrum which shows two bands for carbonyl vibrations at
1782 and 1750 cm−1 (see the Supporting Information).
Completely different results were obtained for the rearranged
product 2 where three signals for the carbonyl carbon atom at
168.716 ppm (OC−O−), 168.704 ppm (OC−18O−) and
168.681 ppm (18OC−O−) and two signals for the benzylic
carbon atom at 89.957 ppm and 89.928 ppm were observed in
the 13C NMR spectrum (Figure 3).
From the same integral intensity of the two latter signals for
carbonyl group it can be concluded that the total scrambling
has occurred and the structure of thiazetidine intermediate
closely resembles that of a free ion pair. This result is also
consistent with above-mentioned trapping experiment because
only a loose or a free ion pair with a sufficiently long lifetime
can effectively attack methyl iodide. The existence of 18O
scrambling definitely rules out both pathways a and b in
Scheme 2.
Finally, we also modeled two possible reaction pathways
involving the thiazetidine intermediate and the front-side SN2
attack in the gas phase and in water using Gaussian B3LYP/6-
311+G(2d,p) (Figure 4).21
Figure 4. Potential energy surfaces (B3LYP/6-311+G(2d,p) for the
transformation of 1 to 2. (a) Double displacement mechanism (black);
(b) front-side SN2 reaction (red). The relative energies are given in
kJ·mol−1 at 298 K in water and at 0 K in the gas phase (numbers in
parentheses).
mechanism involving thiazetidine species is clearly preferred in
water. The situation in the gas phase is in good agreement with
calculations by Uggerud and co-workers,13 who showed the
While the front-side SN2 reaction pathway involves a smaller
energy barrier in the gas phase, the double displacement
4459
dx.doi.org/10.1021/jo400460x | J. Org. Chem. 2013, 78, 4456−4462

The Journal of Organic Chemistry
Article
activation energies for front-side and classical back-side SN2
reactions in the gas phase approaches. The results in water
reveal the first reaction step (i.e., the nucleophilic attack of
nitrogen to the benzylic carbon atom accompanied by leaving
of the carboxylate group) to be rate limiting with an activation
barrier of 129 kJ·mol−1. The second stage of the mechanism
involving rotation of the thiazetidine/carboxylate groups has
very small activation energy which explains the 18O scrambling
in the product 2. The relatively high activation energies of the
forward and backward reaction (57 kJ·mol−1 and 111 kJ·mol−1,
respectively) indicate sufficient thiazetidine intermediate
stability enabling its trapping with methyl iodide.
The rearrangement of 1 to 2 represents a very unusual type
of reaction. At first sight it can resemble two well-known
phenomena in organic chemistry, i.e., neighboring group
participation22 or degenerate ring transformation reaction.23
However, the classical neighboring group participation always
involves direct interaction of the reaction center with a lone
pair of electrons of an atom or with the electrons of a σ- or π-
bond contained within the parent molecule but not conjugated
with the reaction center to give temporary cyclic intermediate
which subsequently decomposes to the noncyclic product. In
our case, the reaction sequence proceeds in the reverse
direction; i.e., the lactone group behaves as neighboring leaving
group first and then as an internal nucleophile in a second step.
A ring is temporarily opened and not closed as during classical
neighboring group participation. Therefore, we called this
process as inverse neighboring group participation. To the best
of our knowledge, such an inverse neighboring group
participation has not yet been published. The reaction also
does not fulfill criteria for degenerate ring transformation
reaction because such reactions always involve ring-opening
and closing caused by the attack of an external nucleophile
whose heteroatom is incorporated into the final product but the
size of the ring, the kind and number of individual heteroatoms
remains unchanged. In our case the internal nucleophile (side
chain) undergoes the rearrangement but none of its
heteroatoms is incorporated into a heterocyclic ring.
carboxylic groups which acts as a nucleophilic catalysts
retaining and inverting glycosyltransferases.4
EXPERIMENTAL SECTION
■
Compounds. Preparation and characterization of S-(1(3H)-
isobenzofuranone-3-yl)isothiuronium bromide (1), its 3-deuterio
analogue, 18O-labeled analogue, and N,N′-dimethyl-N-(3-oxo-1,3-
dihydro-2-benzofuran-1-yl)thiourea (2) was described elsewhere.7,19
Starting 4-bromo-3,4-dihydro-1H-isochromen-1-one was synthe-
sized from isochromanone22 according to the procedure described in
1
ref 23: yield 52%; mp 201−203 °C; H NMR (400 MHz, CDCl3) δ
8.14−8.12 (m, 1H), 7.64 (dt, 1H, J = 7.6, 1.6 Hz), 7.54−7.47 (m, 2H),
5.36 (t, 1H, J = 3.2 Hz), 4.75 (dq, 2H, J = 12.4, 2.8 Hz); 13C NMR
(100 MHz, CDCl3) δ 163.2, 139.4, 134.4, 130.7, 129.9, 127.3, 123.8,
71.9, 41.0; EI-MS m/z 228 [M + (81Br)], 226 [M + (79Br)], 170, 168,
147 [M+ − Br] (100), 141, 130, 119, 102, 91, 85, 77, 63, 51, 39. Anal.
Calcd for C9H7BrO2 C, 47.61; H, 3.11; Br, 35.19. Found: C, 47.82; H,
3.17; Br, 35.26.
Methyl 2-(bromomethyl)benzoate27 was synthesized by radical
bromination of the corresponding commercially available methyl 2-
methylbenzoate and was used without further purification for synthesis
of corresponding isothiuronium salt.
Procedure for the Preparation of Isothiuronium Salts 3 and
4. To a hot solution containing 2.5 mmol of 4-bromo-3,4-dihydro-1H-
isochromen-1-one or methyl 2-(bromomethyl)benzoate in acetone
(10 mL) was added a saturated solution of N,N′-dimethylthiourea (2.5
mmol) in acetone (ca. 15 mL). The mixture was refluxed for 5 min
and left to stand overnight. Precipitated crystals were collected by
filtration.
Transformation of Isothiuronium Salts 3 and 4. Aqueous
solution of sodium carbonate (15 mL; c = 1 mol·L−1) was added to the
0.5g of the salt and left to stand for 1 h. After this time, the mixture
was extracted by 2 × 20 mL of dichloromethane. Combined extracts
were washed with water and brine, dried over anhydrous Na2SO4,
filtered, and evaporated.
S-[2-(Methoxycarbonyl)benzyl]-N,N′-dimethylisothiuronium bro-
1
mide (3): yield 0.68 g (84%); mp 103−104 °C; H NMR (400 MHz,
DMSO) δ 9.58 (bs, 1H), 9.35 (bs, 1H), 7.96 (dd, 1H, J = 7.6, 1.2 Hz),
7.71 (d, 1H, J = 7.2 Hz), 7.66 (dt, 1H, J = 7.6, 1.2 Hz), 7.54 (dt, 1H, J
= 7.6, 1.2 Hz), 4.95 (s, 2H), 3.91 (s, 3H), 3.03 (s, 3H), 2.92 (s, 3H);
13C NMR (100 MHz, DMSO) δ 166.4, 165.7, 135.8, 132.8, 131.5,
130.9, 128.8, 52.4, 34.3, 31.2, 30.9; HRMS calcd for C12H17N2O2S
253.1005, found 253.0993. Anal. Calcd for C12H17BrN2O2S: C, 43.25;
H, 5.14; Br, 23.98; N, 8.41; S, 9.62. Found: C, 43.20; H, 4.92; Br,
23.83; N, 8.63; S, 9.37.
CONCLUSIONS
■
Treatment of the N,N′-dimethylisothiuronium salts derived
from 3-bromo-1(3H)-isobenzofuranone with bases gives an
unexpected product of S→N S-(1(3H)-isobenzofuranon-3-yl)
migration, i.e., N,N′-dimethyl-N-(3-oxo-1,3-dihydro-2-benzo-
furan-1-yl)thiourea. A detailed study of this S→N alkyl
migration provided an evidence for an unusual double
displacement mechanism involving two consecutive back-side
SN2 reactions where a carboxylate anion has a crucial role both
as a leaving group as well as an internal nucleophile. The
thiazetidine zwitterionic species which is involved in this
mechanism as an intermediate was characterized by infrared
multiphoton dissociation spectroscopy and was trapped with
methyl iodide. It was found that the intermediate has a
structure of a free ion pair. The double displacement
mechanism can be considered as a new type of inverse lactone
neighboring group participation which has not yet been
reported in the literature.
S-(1-Oxo-3,4-dihydro-1H-isochromen-4-yl)-N,N′-dimethyliso-
1
thiuronium bromide (4): yield 0.47 g (57%); mp 200−202 °C; H
NMR (400 MHz, DMSO) δ 9.88 (bs, 1H), 9.44 (bs, 1H), 8.02 (dd,
1H, J = 8.0, 1.2 Hz), 7.80 (dt, 1H, J = 7.6, 1.2 Hz), 7.63−7.71 (m, 2H),
5.65 (s, 1H), 4.95 (dd, 1H, J = 12.8, 2.4 Hz), 4.66 (dd, 1H, J = 12.8,
1.6 Hz), 3.00 (2 × s, 6H); 13C NMR (100 MHz, DMSO) δ 163.1,
162.9, 136.0, 134.7, 130.2, 130.0, 128.2, 124.7, 68.9, 42.5, 31,5, 31.0;
HRMS calcd for C12H15N2O2S 251.0849, found 251.0841. Anal. Calcd
for C12H15BrN2O2S: C, 43.51; H, 4.56; Br, 24.12; N, 8.46; S, 9.68.
Found: C, 43.38; H, 4.67; Br, 24.15; N, 8.26; S, 9.84.
Methyl 2-[[(dimethylcarbamimidoyl)sulfanyl]methyl]benzoate
1
(5): yield 0.35 g (93%); oil; H NMR (400 MHz, DMSO) δ 7.82
(dd, 1H, J = 12.4, 1.2 Hz), 7.54−7.47 (m, 2H), (dt, 1H, J = 7.6, 1.6
Hz), 4.51 (s, 2H), 3.85 (s, 3H), 2,75 (s, 6H); 13C NMR (100 MHz,
DMSO) δ 167.6, 152.8, 139.7, 132.6, 131.7, 130.8, 129.8, 127.9, 52.6,
33.0, 32.6. Anal. Calcd for C12H16N2O2S: C, 57.12; H, 6.39; N, 11.10;
S, 12.71. Found: C, 56.81; H, 6.25; N, 10.92; S, 12.45.
1H-Isochromen-1-one (6). Compound 6 has the same mp and
NMR spectra as reported in ref 28.
Our reaction involving carboxylate group assistance can be
also considered as model for understanding the nature of
preorganizational effects and their relative contributions to the
enhanced rates observed in enzymatic reactions24 because it is
well-known that active sites of enzymes very often contain
Trapping Experiment. To the 25 mL flask were added 0.1 mmol
of isothiouronium salt, 200 mg of sodium carbonate, 5 mL of acetone,
and 8 mmol (0.5 mL) of methyl iodide. The reaction mixture was
refluxed for 4 h, filtered, and evaporated. The resulting oil was
analyzed using NMR and MS.
4460
dx.doi.org/10.1021/jo400460x | J. Org. Chem. 2013, 78, 4456−4462

The Journal of Organic Chemistry
Article
NMR Experiments. 1H and 13C NMR spectra were recorded on a
400 or 600 MHz Bruker Avance instruments. Chemical shifts δ are
referenced to TMS (δ = 0) or solvent residual peaks δ(DMSO-d6) =
2.50 (1H) and 39.6 ppm (13C), and δ(CDCl3) = 7.27 (1H) and 77.0
REFERENCES
■
(1) (a) Hackenberger, C. P. R.; Schwarzer, D. Angew. Chem., Int. Ed.
2008, 47, 10030−10074. (b) Yuan, L.; Lin, W.; Xie, Y.; Zhu, S.; Zhao,
S. Chem.Eur. J. 2012, 18, 14520−14526. (c) Fang, G.-M.; Wang, J.-
X.; Liu, L. Angew. Chem., Int. Ed. 2012, 51, 10347−10350. (d) Ha, K.;
Chahar, M.; Monbaliu, J.-C. M.; Todadze, E.; Hansen, F. K.;
Oliferenko, A. A.; Ocampo, Ch. E.; Leino, D.; Lillicotch, A.; Stevens,
C. V.; Katritzky, A. R. J. Org. Chem. 2012, 77, 2637−2648. (e) Ficht,
S.; Payne, J. R.; Brik, A.; Wong, C.-H. Angew. Chem., Int. Ed. 2007, 46,
5975−5979.
1
(13C). H−13C HMBC NMR experiment was carried out using the
manufacturer’s settings at 400 MHz with coupling constant 10 Hz.
Mass Spectrometric Experiments. The gas-phase infrared (IR)
spectra of mass-selected ions were recorded using an quadrupole ion
trap mounted to a free electron laser at CLIO (Centre Laser
Infrarouge Orsay, France).29 The free electron laser (FEL) was
operated in the 43.5 MeV electron-energy range, and it provided light
in a 900−1900 cm−1 range. The relative spectral line width of the FEL
is of about 1% and the precision of the measurement of the
wavenumbers with a monochromator is about 1 cm−1. Each point in a
raw spectrum is an average of 20 measurements. The ions were
generated by electrospray ionization from methanolic solution of
compounds 1 and 2. The ions were mass-selected and stored in the
ion trap. The fragmentation was induced by 4 to 5 laser macropulses of
8 μs admitted to the ion trap and the dependence of the fragmentation
intensities on the wavelength of the IR light gives the infrared
multiphoton dissociation (IRMPD) spectra. The reported IRMPD
spectra are averages of 2 raw spectra and are not corrected for the
power of the free-electron laser, which slightly changes in dependence
of the wavenumbers. The positive ions for HRMS spectra were
generated by electrospray ionization (ESI) from methanolic solutions
and detected in microTOF-Q detector.
Computational details. The calculations were performed using
the density functional method B3LYP30 in conjunction with 6-
311+G(2d,p) basis set as implemented in the Gaussian 09 suite.21 For
all optimized structures, frequency analyses at the same level of theory
were used in order to assign them as genuine minima on the potential-
energy surface. The solvent effect was included using IEFPCM model.
The calculated frequencies in the IR spectra were scaled by a factor of
0.98.31 All geometries, energies, as well as IR spectra can be found in
the Supporting Information.
(2) El Ashry, E. S. H.; El Tamany, E. S. H.; Fattah, M. E. D. A.; Aly,
M. R. E.; Boraei, A. T. A.; Duerkop, A. Beilstein J. Org. Chem. 2013, 9,
135−146.
(3) (a) Pratt, R. F.; Bruice, T. C. Biochemistry 1971, 10, 3178−3185.
(b) Pratt, R. F.; Bruice, T. C. J. Am. Chem. Soc. 1972, 94, 2823−2837.
̌
́ ́ ̌
ek, J.; Novak, J.; Sterba, V. Collect. Czech. Chem. Commun.
(c) Kaval
1982, 47, 2702−2710. (d) Kaval
̌
̌
ek, J.; Jirman, J.; Sterba, V. Collect.
́
Czech. Chem. Commun. 1985, 50, 766−778.
(4) Kirby, J.; Hollenfelder, F. From Enzyme Models to Model Enzyme;
RSC: London, 2009.
(5) (a) Tedenborg, L.; Barf, T.; Nordin, S.; Vallgarda, J.; Williams, M.
̊
(Biovitrum AB). WO 2005/075471. (b) Shimo, T.; Matsuda, Y.;
Iwanaga, T.; Shinmyozu, T.; Somekawa, K. Heterocycles 2007, 71,
1053−1058. (c) Saiz, C.; Pizzo, C.; Manta, E.; Wipf, P.; Mahler, S. G.
Tetrahedron Lett. 2009, 50, 901−904. (d) Rudenko, R. V.; Komykhov,
S. A.; Desenko, S. M. Chem. Heterocycl. Compd. 2009, 45, 1017−1018.
(6) (a) Sedlak
Heterocycl. Chem. 2002, 39, 1105−1107. (b) Sedlak
Hejtmankova, L.; Kasparova, P. Org. Biomol. Chem. 2003, 1, 1204−
1209. (c) Hanusek, J.; Hejtman
Biomol. Chem. 2004, 2, 1756−1763. (d) Van
A.; Sedlak, M. J. Heterocycl. Chem. 2009, 46, 635−639. (e) Van
Sedlak, M.; Hanusek, J. J. Org. Chem. 2010, 75, 3729−3736. (f) Van
J.; Sedlak, M.; Hanusek, J. Int. J. Chem. Kinetics 2013, 45, 248−255.
(7) Vana, J.; Sedlak, M.; Padelkova, Z.; Hanusek, J. Tetrahedron 2012,
68, 9808−9817.
́
, M.; Hejtman
́
kova,
́
L.; Hanusek, J.; Machac
́ ̌
ek, V. J.
́
, M.; Hanusek, J.;
́
́
̌
́
̌
́
kova,
́
L.; Ster
̌
ba, V.; Sedlak
́
, M. Org.
a,
a, J.;
a,
́
̌
a, J.; Hanusek, J.; Ruzick
̌
̌
̊
́
́
̌
́
́
̌
́
́
̌
́
̌
́
ASSOCIATED CONTENT
■
S
(8) (a) Schreiner, P. R.; Schleyer, P. v. R.; Hill, R. K. J. Org. Chem.
1993, 58, 2822−2829. (b) Schreiner, P. R.; Schleyer, P. v. R.; Hill, R.
K. J. Org. Chem. 1994, 59, 1849−1854.
(9) (a) Koch, H. J.; Lee, H. W.; Lee, I. J. Chem. Soc., Perkin Trans. 2
1994, 125−129. (b) Oh, H. K.; Yang, J. H.; Lee, H. W.; Lee, I. New J.
Chem. 2000, 24, 213−219.
(10) (a) Persson, K.; Ly, H. D.; Dieckelmann, M.; Wakarchuk, W.
W.; Whiters, S. G.; Strynadka, N. C. J. Nat. Struct. Biol. 2001, 8, 166−
175. (b) Negishi, M. C.; Dong, J.; Darden, T. A.; Pedersen, L. G.;
Pedersen, L. C. Biochem. Biophys. Res. Commun. 2003, 303, 393−398.
(c) Lee, S. S; Hong, S. Y.; Errey, J. C.; Izumi, A.; Davies, G. J.; Davis,
B. G. Nat. Chem. Biol. 2011, 7, 631−638. (d) Jakeman, D. L. Chem.
Biochem. 2011, 12, 2540−2542.
* Supporting Information
All NMR and IR spectra and computational details. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jiri.hanusek@upce.cz.
Notes
The authors declare no competing financial interest.
(11) (a) Kice, J. L.; Hanson, G. C. J. Org. Chem. 1973, 38, 1410−
1415. (b) Monegal, A.; Planas, A. J. Am. Chem. Soc. 2006, 128, 16030−
16031. (c) Lairson, L. L.; Henrissat, B.; Davies, G. J.; Withers, S. G.
Annu. Rev. Biochem. 2008, 77, 521−555. (d) Kubota, Y.; Kunikata, M.;
Kazuhiro, H.; Tanaka, H. J. Org. Chem. 2009, 74, 3402−3405.
(12) (a) Glukhovtsev, M. N.; Pross, A.; Radom, L. J. Am. Chem. Soc.
1996, 118, 6273−6284. (b) Glukhovtsev, M. N.; Pross, A.; Schlegel, H.
B.; Bach, R. D.; Radom, L. J. Am. Chem. Soc. 1996, 118, 11258−11264.
(c) Parthiban, S.; Oliveira, G.; Martin, J. M. L. J. Phys. Chem. A 2001,
105, 895−904. (d) Uggerud, E. J. Phys. Org. Chem. 2006, 19, 461−466.
(e) Uggerud, E. Chem.Eur. J. 2006, 12, 1127−1136. (f) Bento, A. P.;
Bickelhaupt, F. M. J. Org. Chem. 2008, 7290−7299.
ACKNOWLEDGMENTS
■
Financial support by the Ministry of Education, Youth and
Sports of the Czech Republic and European Social Fund
(Project No. CZ.1.07./2.3.00/30.0021, “Enhancement of R&D
Pools of Excellence at the University of Pardubice“), the Grant
agency of the Czech Republic (207/11/0338), the European
Research Council (StG ISORI), and the European Union’s
Seventh Framework Program (FP7/2007−2013) under grant
agreement no. 226716 are gratefully acknowledged. The CLIO
staff, and particularly Vincent Steinmetz, is gratefully acknowl-
edged for their assistance. The access to computing and storage
facilities owned by parties and projects contributing to the
National Grid Infrastructure MetaCentrum, provided under the
programme “Projects of Large Infrastructure for Research,
Development, and Innovations” (LM2010005) is highly
appreciated.
(13) (a) Laerdahl, J. K.; Uggerud, E. Org. Biomol. Chem. 2003, 1,
2935−2942. (b) Laerdahl, J. K.; Bache-Andreassen, L.; Uggerud, E.
Org. Biomol. Chem. 2003, 1, 2943−2950. (c) Laerdahl, J. K.; Civcir, P.
U.; Bache-Andreassen, L.; Uggerud, E. Org. Biomol. Chem. 2006, 4,
135−141.
(14) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165−195.
4461
dx.doi.org/10.1021/jo400460x | J. Org. Chem. 2013, 78, 4456−4462

The Journal of Organic Chemistry
Article
(15) (a) Gattow, G.; Klaeser, J. Z. Anorg. Allg. Chem. 1977, 434, 110−
114. (b) Dabholkar, V. V.; Parab, S. D. Indian J. Chem. B. 2007, 46,
195−200.
(16) (a) Harris, J. M.; Hall, R. E.; Schleyer, P. v. R. J. Am. Chem. Soc.
1971, 93, 2551−2553. (b) Bron, J. Can. J. Chem. 1973, 52, 903−909.
(17) (a) MacAleese, L.; Maitre, P. Mass Spectrom. Rev. 2007, 26,
583−605. (b) Polfer, N. C.; Oomens, J. Mass. Spectrom. Rev. 2009, 28,
468−494. (c) Roithova,
́
J. J. Chem. Soc. Rev. 2012, 41, 547−559 and
references cited therein.
(18) (a) Chen, P. Angew. Chem., Int. Ed. 2003, 42, 2832−2847.
(b) Eberlin, M. N. Eur. J. Mass Spectrom. 2007, 13, 19−28.
(19) Van
Tetrahedron Lett. submitted.
́ ̌ ́
a, J.; Panov, I.; Erben, M.; Sedlak, M.; Hanusek, J.
(20) Risley, J. M.; Van Etten, R. L. J. Am. Chem. Soc. 1980, 102,
4609−4614.
(21) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci,
B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H.
P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega,
N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.;
Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.;
̈
Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.;
Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision A.02, Gaussian, Inc., Wallingford, CT, 2009.
(22) (a) Capon, B.; McManus, S. P. In Neighboring Group
Participation; Plenum Press: New York, 1976. (b) Nic,
Kosata B. IUPAC Compendium of Chemical Terminology − Gold Book,
Version 2.3.2, 2012.
̌ ́
M.; Jirat, J.;
̌
(23) (a) van der Plas, H. C. Adv. Heterocycl. Chem. 1999, 74, 1−8.
(b) van der Plas, H. C. J. Heterocycl. Chem. 2000, 37, 427−438.
(c) Hajos
3414.
́
, G.; Riedl, Z.; Kollenz, G. Eur. J. Org. Chem. 2001, 3405−
(24) (a) Page, M.; Williams, A. Organic & Bio-organic Mechanisms;
Addison Wesley Longman Ltd.: Singapore, 1997. (b) Jencks, W. P.
Catalysis in Chemistry and Enzymology; General Publishing Comp. Ltd.:
Toronto, 1987. (c) Bruice, T. C. Enzymes; Boyer, P. D., Ed.; Academic
Press: New York, 1970; Vol. 2, pp 217−279. (d) Anslyn, E. V.;
Dougherty, D. A. Modern Physical Organic Chemistry, University
Science Books: Sausalito, 2006. (d) Lightstone, F. C.; Bruice, T. C. J.
Am. Chem. Soc. 1996, 118, 2595−2605. (e) Bruice, T. C.; Lightstone,
F. C. Acc. Chem. Res. 1999, 32, 127−136. (f) Schultz, P. G. Acc. Chem.
Res. 1989, 22, 287−294.
(25) Shaabani, A.; Mirzaei, P.; Naderia, S.; Lee, D. G. Tetrahedron
2004, 60, 11415−11420.
(26) Kotten, I. A.; Sauer R. J. Organic Syntheses; Wiley: New York,
1973; Collect. Vol. 5, 145−146. Kotten, I. A.; Sauer, R. J. Org. Synth.
1962, 42, 26.
(27) Shinkai, H.; Ito, T.; Iida, T.; Kitao, Y.; Yamada, H.; Uchida, I. J.
Med. Chem. 2000, 43, 4667−4677.
(28) Duddeck, H.; Kaiser, M. Spectrochim. Acta, Part A 1985, 41,
913−924.
(29) (a) Ortega, J. M.; Glotin, F.; Prazeres, R. Infrared Phys. Technol.
2006, 49, 133−138. (b) Mac Aleese, L.; Simon, A.; McMahon, T. B.;
Ortega, J. M.; Scuderi, D.; Lemaire, J.; Maitre, P. Int. J. Mass Spectrom.
2006, 249, 14−20.
(30) (a) Vosko, S. H.; Wilk, L.; Nusair, M. Can. J. Phys. 1980, 58,
1200−1211. (b) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37,
785−789. (c) Miehlich, B.; Savin, A.; Stoll, H.; Preuss, H. Chem. Phys.
Lett. 1989, 157, 200−206. (d) Becke, A. D. J. Chem. Phys. 1993, 98,
5648−5652.
(31) Merrick, J. P.; Moran, D.; Radom, L. J. Phys. Chem. A 2007, 111,
11683−11700.
4462
dx.doi.org/10.1021/jo400460x | J. Org. Chem. 2013, 78, 4456−4462