Nucleophilicities and Lewis basicities of isothiourea derivatives

Article abstract of DOI:10.1021/jo200803x

Rate and equilibrium constants for the reactions of a series of isothioureas with benzhydrylium ions have been measured photometrically. The data were employed to determine the nucleophilicities and nucleofugalities of isothioureas and compare them with t

Full text of DOI:10.1021/jo200803x

ARTICLE
pubs.acs.org/joc
Nucleophilicities and Lewis Basicities of Isothiourea Derivatives
Biplab Maji,† Caroline Joannesse,‡ Tobias A. Nigst,† Andrew D. Smith,‡ and Herbert Mayr*,†
†Department Chemie, Ludwig-Maximilians-Universit€at M€unchen, Butenandtstr. 5ꢀ13 (Haus F), 81377 M€unchen, Germany.
‡EaStCHEM, School of Chemistry, University of St. Andrews, North Haugh, St. Andrews, Fife KY16 9ST, United Kingdom
S Supporting Information
b
ABSTRACT: Rate and equilibrium constants for the reactions of a series of
isothioureas with benzhydrylium ions have been measured photometrically.
The data were employed to determine the nucleophilicities and nucleofugal-
ities of isothioureas and compare them with those of other organocatalysts.
’ INTRODUCTION
Lewis bases (e.g., 1ꢀ17, Figure 1) have the ability to promote
the acylation of alcohols and amines.1 4-(Dimethylamino)pyridine2
(DMAP, 1) and N-methylimidazole3 (NMI, 2) as well as the
amidines 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 3)4 or 1,
5-diazabicyclo[4.3.0]non-5-ene (DBN, 4)4 are among the most
common achiral catalysts used for these reactions. Birman has
shown that chiral amidines act as enantioselective catalysts for
the kinetic resolution of alcohols.5 Recent independent work by
the Okamoto and Birman groups has demonstrated that iso-
thioureas are highly active O-acylation catalysts.6,7 Okamoto found
3,4-dihydro-2H-pyrimido[2,1-b]benzothiazole (DHPB, 10) to
be remarkably active for catalyzing the acylation of 1-phenyl-
ethanol, even more active than the “benchmark” catalyst DMAP
(1).6 Birman’s concurrent investigations of the acylations of
primary and secondary alcohols with a series of amidines and
isothioureas revealed a significant variation in catalytic activity
with ring size. Notably, tetrahydropyrimidine-based isothioureas
THTP (9) and DHPB (10) showed catalytic activity in chloro-
form similar to or slightly higher than that of DMAP, depending
on their concentrations.7 Subsequent related studies probed the
ability of a variety of amidines and isothioureas to catalyze the O-
to C-carboxyl transfer rearrangement of oxazolyl and related
heterocyclic carbonates and the C-acylation of silyl ketene acetals
and showed that tetrahydropyrimidine-based DHPB (10) was
also the optimal achiral catalyst in Figure 1.8
Given their promising reactivity profiles, a series of chiral iso-
thioureas have been prepared and utilized in asymmetric cata-
lysis. Pioneering studies by Birman and Li showed that tetra-
misole 11 and its benzannulated analogue BTM 12 can catalyze
Figure 1. Selected nitrogen-containing heterocycles commonly used as
acyl transfer catalysts.
the kinetic resolution of alcohols with exquisite selectivity.9 Since
the demonstration of this methodology, a range of chiral
isothioureas (of which 12ꢀ17 are representative) have been
tetramisole 11 and the ease of synthesis of chiral isothioureas
such as 12ꢀ17 from enantiopure amino alcohols arguably make
successfully utilized in a variety of asymmetric processes includ-
ing kinetic resolutions,10 desymmetrizations,11,12 dynamic ki-
these derivatives more readily accessible than many common
netic resolutions,13 and the generation of ammonium enolates
from carboxylic acids,14 as well as enantioselective carboxy and
acyl group transfer reactions.15 The commercial availability of
Received: April 19, 2011
Published: May 13, 2011
r
2011 American Chemical Society
5104
dx.doi.org/10.1021/jo200803x J. Org. Chem. 2011, 76, 5104–5112
|

The Journal of Organic Chemistry
ARTICLE
Table 1. Abbreviations and Electrophilicity Parameters for
the Benzhydrylium Ions Used for this Work
Scheme 1. Products from Reactions of Isothioureas with
ꢀ
(dma)2CHþBF4
a Electrophilicity parameters E for benzhydrylium ions from ref 19a.
chiral DMAP derivatives.16 Notably, in many of these processes
the catalytic activity and enantioselectivity vary significantly with
ring size and stereodirecting unit. For example, Birman has
shown that the incorporation of an additional syn-C(3)-methyl
group within the HBTM-skeleton (14, Me instead of iPr) has a
dramatic effect upon both catalytic activity and stereoselectivity
in kinetic resolutions of aryl-cycloalkanols,17 and a similar effect
has been noted on the kinetic resolution of aryl alkyl alcohols
when introducing a syn-C(3)-isopropyl unit (14).18
While it may be expected that the organocatalytic activities of
these heterocycles will depend on their relative nucleophilicities
and Lewis basicities, to date a quantitative comparison of these
properties has not been reported. To gain insight into some of
the factors that may affect their catalytic activities, we have
determined rate and equilibrium constants of the reactions of
the isothiourea derivatives 5ꢀ10 and 13ꢀ17 with stabilized
benzhydrylium ions (Table 1) and compared these data with
those of other nucleophilic organocatalysts such as DMAP (1),
NMI (2), DBU (3) and DBN (4).19,20
Figure 2. Exponential decay of the absorbance at 613 nm during the
reaction of 6 (2.11 ꢁ 10ꢀ4 M) with (dma)2CHþBF4ꢀ (1.41 ꢁ 10ꢀ5 M)
at 20 °C in CH2Cl2 (kobs = 13.0 sꢀ1). Insert: Determination of the
second-order rate constant k = 6.56 ꢁ 104 Mꢀ1 sꢀ1 from the
dependence of kobs on the concentration of 6.
adducts 7P-BF4 and 10P-BF4 were not isolated but identified by
NMR after mixing the isothioureas 7 and 10 with equimolar
ꢀ
amounts of (dma)2CHþBF4 in deuterated dimethyl sulfoxide;
details are specified in the Supporting Information.
Kinetics. Using this information, the rates of the reactions of
the isothioureas 5ꢀ10 and 13ꢀ17 with the benzhydrylium ions
shown in Table 1 were measured photometrically by monitor-
ing the decay of the absorbances of the benzhydrylium ions;
conventional or stopped-flow techniques were used as pre-
viously described.19 By employing the isothioureas in high
excess over the benzhydrylium ions, first-order conditions were
achieved. The first-order rate constants kobs (sꢀ1), obtained by
fitting the decay of the absorbances of the benzhydrylium ions
obst
to the monoexponential function A = A0 eꢀk þ C correlated
’ RESULTS AND DISCUSSIONS
linearly with the nucleophile concentrations (Figure 2). The
slopes of these correlation lines yielded the second-order rate
Product Studies. When CH2Cl2 solutions of the isothioureas
6 or 9 were added to CH2Cl2 solutions of (dma)2CHþBF4ꢀ at
room temperature, the thiouronium tetrafluoroborates 6P-BF4
and 9P-BF4 formed, which were isolated and characterized
(Scheme 1). The 13C NMR spectra show that the benzhydryl
carbon, which absorbs at δ ≈ 160 ppm in (dma)2CHþ, is shifted
to δ ≈ 70 ppm due to the change in hybridization from sp2 to sp3.
Since the reactions of the benzannulated isothioureas 7 and 10
with (dma)2CHþBF4ꢀ are highly reversible, the corresponding
constants k (Mꢀ1 ꢀ1), which are collected in Table 2. The
s
kinetic profiles of the reactions of (ind)2CHþ with 7, 9 and 10
were also studied at variable temperature to determine the
Eyring activation parameters, which are collected in the foot-
notes of Table 2. The negative activation entropies (ꢀ57 to
ꢀ68 J molꢀ1
CH2Cl2.20
K
ꢀ1) are similar to those reported for the
reactions of other n-nucleophiles with benzhydrylium ions in
5105
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112

The Journal of Organic Chemistry
ARTICLE
Table 2. Second-Order Rate Constants k for the Reactions of the Isothiourea Derivatives 5ꢀ10 and 13ꢀ17 with Benzhydrylium
Ions (Ar2CHþ, Table 1) in CH2Cl2 at 20 °C
c
a Parameters as defined by eq 1. b Eyring activation parameters: ΔHq = 32.6 ( 1.3 kJ molꢀ1, ΔSq = ꢀ68.0 ( 4.7 J molꢀ1
K
ꢀ1. Eyring activation
parameters: ΔHq = 29.3 ( 0.7 kJ molꢀ1, ΔSq = ꢀ57.3 ( 2.5 J molꢀ1 Kꢀ1. d Eyring activation parameters: ΔHq = 30.6 ( 1.8 kJ molꢀ1, ΔSq = ꢀ63.0 ( 6.3
J molꢀ1 Kꢀ1
.
Correlation Analysis. In previous publications, we have
shown that the rates of the reactions of carbocations and Michael
acceptors with n-, π-, and σ-nucleophiles can be described by the
linear-free-energy relationship (eq 1), where electrophiles are
characterized by the electrophilicity parameter E, nucleo-
philes are characterized by the nucleophilicity parameter
N and the nucleophile-dependent sensitivity parameter sN
(previously termed s). On the basis of eq 1 it was possible to
develop the most comprehensive nucleophilicity scale pre-
sently available.19
that their relative nucleophilicities are almost independent of the
reactivity of the electrophilic reaction partner. In contrast, the
chiral derivatives 13ꢀ17 have somewhat lower, variable, sN
parameters reflecting the dependence of their relative nucleo-
philicities on the reaction partner.
Lewis Basicities and Intrinsic Reactivities of Isothioureas.
Brønsted basicities, which have often been used for a first
screening of potential nucleophilic organocatalysts, have been
reported for only a few isothioureas.21 As Lewis basicities are
more relevant for their reactions with carbon electrophiles, we
have now studied the equilibrium constants of the reactions of
several isothioureas with benzhydrylium ions.
The reactions of 7, 9, and 10 and of the C(2)-substituted chiral
isothioureas 13ꢀ17 with several colored amino-substituted
benzhydrylium ions proceed incompletely, allowing the mea-
surement of the equilibrium constants for these reactions by
UVꢀvis spectroscopy. Assuming proportionality between the
absorbances and the concentrations of the benzhydrylium ions
(as for the evaluation of the kinetic experiments), the equilibrium
constants for the reactions (eq 2) can be determined from the
initial absorbances (A0) of the benzhydrylium ions and the
log k20 °C ¼ sNðN þ EÞ
ð1Þ
Figure 3 shows linear correlations between the second-order
rate constants k and the previously published electrophilicity
parameters E, as required by eq 1. The slopes of the correlation
lines yield the nucleophile-specific sensitivity parameters sN, and
the intercepts on the abscissa give the nucleophilicity parameters
N, which are tabulated in Table 2.
The almost equal slopes (0.73 < sN < 0.83) of the correlation
lines for the isothioureas 5ꢀ10 (unsubstituted at C-2) indicate
5106
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112

The Journal of Organic Chemistry
ARTICLE
Figure 3. Plots of log k for the reactions of some isothioureas with benzhydrylium ions versus their electrophilicity parameters E in CH2Cl2 at 20 °C.
Rate constants for DMAP were taken from ref 20a.
absorbances at equilibrium (A) according to eq 3, and results are
listed in Table 3.
ion used as the reaction partner, we will first consider the rate and
equilibrium constants for the reactions with (ind)2CHþ, for
which directly measured rate and equilibrium constants are
available for most isothioureas (Figure 4).
Comparison of the imidazoline derivatives 5ꢀ7 shows that
their nucleophilic reactivities are only slightly affected by the
nature of the annelated sulfur-containing heterocycle. The
benzannulation in compound 7 accelerates the reverse reaction
kr, however, with the consequence that the equilibrium constant
for adduct formation becomes measurable for the reaction of
(ind)2CHþ with 7.
A comparable trend was observed for the tetrahydropyrimi-
dine series 8ꢀ10 (line 2 of Figure 4), which are approximately 1
order of magnitude more nucleophilic than their lower homo-
logues 5ꢀ7 (k(8)/k(5) ≈ 8; k(9)/k(6) ≈ 13; k(10)/k(7) ≈ 4).
Also in this series, variation of the annelated sulfur heterocycle
had a relatively small effect (k(9)/k(10) ≈ 3) on the nucleophilic
reactivity but a large effect on Lewis basicity (K(9)/K(10) ≈
102). Thus lines 1 and 2 of Figure 4 show the same trend that
benzannulation has a much larger effect on Lewis basicity than on
nucleophilicity.
Introduction of the phenyl group in the 2-position of 10
(f 13) reduces the nucleophilic reactivity by a factor of 4.5 but
the Lewis basicity by a factor of 100. Remarkably, an additional
syn-C(3)-isopropyl group in 14 (relative to HBTM 13) increases
its Lewis basicity (by a factor of 6) and nucleophilicity (by a
factor of 3.6). Though there is no direct correlation between
these data, it is notable that this trend corresponds with the
experimentally observed beneficial effect of an additional syn-3-
substituent to 13 (f 14) in kinetic resolution reactions in terms
of catalytic activity and enantioselectivity.17,18 The last entry of
Figure 4 shows that both nucleophilicities and Lewis basicities of
the tetrahydropyrimidine derivatives 9 and 10 are comparable to
those of DMAP (1).
K
Ar2CHþ þ Nu
Ar CH-Nuþ
ð2Þ
ð3Þ
F
R
2
CH2Cl2
½Ar2CH-Nuþꢂ
½Ar2CHþꢂ½Nuꢂ
A0 ꢀ A
¼
K ¼
A½Nuꢂ
Substitution of the activation free energies ΔGq and Gibbs free
energies ΔG0 into the Marcus equation (eq 4)22 yields the
q
intrinsic barriers ΔG0 (i.e., the barriers of the corresponding
reactions with ΔG0 = 0), which are also listed in Table 3.
2
ΔGq ¼ ΔG0 þ 0:5ΔG° þ ððΔG°Þ =16ΔG0 Þ
ð4Þ
q
q
With ΔG0q between 54 and 65 kJ molꢀ1, the intrinsic barriers
are of similar magnitude as previously reported for the reactions
of benzhydrylium ions with pyridines20a,b and azoles.20c Table 3
shows also that the dependence of the intrinsic barriers ΔG0q on
the structures of the benzhydrylium ions mirrors previously
observed patterns. In particular, the intrinsic barriers for the
reactions of the five-membered ring compounds (ind)2CHþ and
(lil)2CHþ are always 1ꢀ2 kJ molꢀ1 higher than those of the
corresponding six-membered ring analogues (thq)2CHþ and
(jul)2CHþ, respectively, resulting in a breakdown of rate-equi-
librium relationships.23,24
Structure Reactivity Relationships. From the observation
that the isothioureas 5, 6, and 8 (like the amidines DBU 3 and
DBN 4) react quantitatively with all benzhydrylium tetrafluoro-
borates investigated, it can be derived that they have Lewis
basicities higher than those of the isothioureas listed in Table 3.
As Figure 3 shows that the relative reactivities of isothioureas
are somewhat dependent on the reactivity of the benzhydrylium
5107
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112

The Journal of Organic Chemistry
ARTICLE
Table 3. Equilibrium Constants K, Activation Free Energies ΔGq, Reaction Free Energies ΔG0, Intrinsic Barriers ΔG0 , and the
Reverse Rate Constants (kr) for the Reactions of Isothioureas with Benzhydrylium Ions (Ar2CHþ) in CH2Cl2 at 20 °C
q
a From rate constants in Table 2 using the Eyring equation. b From equilibrium constants K in this table (ꢀRT ln K). c From eq 4. d kr = k/K. e From
eq 5 assuming sf = 1. f ΔH° = ꢀ49.8 kJ molꢀ1, ΔS° = ꢀ87.7 J molꢀ1 Kꢀ1. g ΔH° = ꢀ63.9 kJ molꢀ1, ΔS° = ꢀ97.9 J molꢀ1 Kꢀ1. h ΔH° = ꢀ50.2 kJ molꢀ1
,
ΔS° = ꢀ88.7 J molꢀ1 Kꢀ1. i Equilibrium constant extrapolated from a van’t Hoff plot from measurements at lower temperatures (see the Supporting
Information). ΔH° = ꢀ44.2 kJ molꢀ1, ΔS° = ꢀ106.9 J molꢀ1 Kꢀ1. j Calculated using eq 1 and reactivity parameters from Table 1 and Table 3. k Data for
DMAP was taken from ref 20a. l From ref 24.
5108
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112

The Journal of Organic Chemistry
ARTICLE
Table 4. Second-Order Rate Constants k, Reverse Rate Con-
stants kr, and Equilibrium Constants K for the Reactions of
the Isothiourea Derivatives 13 and 15ꢀ17 with
(dma)2CHþBF4ꢀ in CH2Cl2
R
k (Mꢀ1 sꢀ1
)
kr (sꢀ1
)
K (Mꢀ1
)
Ph (13)
5.15 ꢁ 104
3.38 ꢁ 104
3.73 ꢁ 104
2.8 ꢁ 103a
4.81
1.07 ꢁ 104
9.95 ꢁ 102
2.70 ꢁ 103
≈ 6 ꢁ 101b
CHPh2 (15)
iPr (16)
3.40 ꢁ 101
1.38 ꢁ 101
≈ 5 ꢁ 101
tBu (17)
a Rate constant calculated by using eq 1, the E value of (dma)2CHþ,
(Table 1), and the N/sN values of 17(Table 2). b Estimated by dividing
K[(mpa)2CHþ] by 40, the ratio derived from equilibrium constants of
15 and 16 with (mpa)2CHþ and (dma)2CHþ.
plots of log kr (25 °C) vs the previously reported24 electro-
fugality parameters Ef of the benzhydrylium ions, analogously to
the procedure used in Figure 3 for determining the nucleophile-
specific parameters N and sN. It has been suggested, however, to
assume sf = 1.0 if only heterolysis rate constants of low precision
and/or referring to benzhydrylium ions of similar electrofugality
are known. This is the case for the kr values given in Table 3,
which are obtained indirectly as the ratios of k/K and further-
more refer to 20 °C. Neglecting the small difference in tempera-
ture, we have therefore calculated the Nf parameters of
isothioureas (listed in Table 3) from eq 5 setting the sf parameter
to 1.0 (see also Tables S39 in the Supporting Information).
Due to the high Lewis basicities of DBU 3, DBN 4, and the
isothioureas 5, 6, and 8 equilibrium constants could not be
measured, indicating that they are poor nucleofuges. The trends
in Nf shown in Table 3 are equivalent to the trends in kr
discussed for Figure 4 and Table 4.
It is the benefit of the Nf values in Table 3 that they allow a
comparison of the leaving group abilities in CH2Cl2 of isothiour-
eas with those of other nucleofuges. Thus, comparison with Nf
values listed in ref 24 shows that the nucleofugalities of 7, 9, and
10 are comparable to those of DMAP (1) (Nf = ꢀ5.32), N-
methyl-imidazole (2) (Nf = ꢀ6.29 in CH3CN) and N-phenyl-
imidazole (Nf = ꢀ5.59 in CH3CN), or tris(p-tolyl)phosphane
(Nf = ꢀ5.20) and tris(p-anisyl)phosphane (Nf = ꢀ5.91).
The nucleofugalities of 13 and 14 are comparable to that of
triphenylphosphane (Nf = ꢀ4.44), and Nf of the tert-butyl
substituted compound 17 is similar to that of 4-methoxypyridine
(Nf = ꢀ2.80) and isoquinoline (Nf = ꢀ3.04 in CH3CN).
Figure 4. Second-order rate constants k, reverse rate constants kr,
and equilibrium constants K for the reactions of the isothiourea
derivatives 5ꢀ10 with (ind)2CHþBF4ꢀ in CH2Cl2 at 20 °C. Rate
a
constant calculated by using eq 1, the E value of (ind)2CHþ (Table 1)
b
and the N and sN values of 13 from Table 2. Data for 1 was taken
from ref 20a.
The influence of the substituent at C-2 can be derived from the
rate and equilibrium constants of its reactions with (dma)2CHþ
(Table 4). As in the comparisons of Figure 4, variation of the
substituents affects the equilibrium constants much more than
the rate constants. While the change from phenyl to tert-butyl
reduces nucleophilicity by approximately 1 order of magnitude,
the equilibrium constant decreases by more than 2 orders of
magnitude.
Nucleofugalities of Isothioureas. In analogy to eq 1,19 which
has been used to construct a comprehensive nucleophilicity scale,
eq 524 has recently been suggested as the basis for a comprehen-
sive nucleofugality scale. Benzhydrylium ions of variable electro-
fugality (characterized by Ef) have been employed as reference
electrofuges for characterizing the nucleofugalities of leaving
groups in different solvents.
’ CONCLUSION
In a systematic study Birman et at. observed that the relative
catalytic activities of DMAP (1) and THTP (9) in the acylation
of alcohols with Ac2O/iPr2NEt in chloroform vary dramatically
and can be reversed when the concentration of the catalyst and/
or the nature of the alcohols are altered.7 One must, therefore,
conclude that there is not a single, best acylation catalyst. Thus
the nucleophilicities and Lewis basicities of isothioureas reported
in this work are two important but not the only factors control-
ling catalytic activities.
log krð25 °CÞ ¼ sf ðEf þ Nf Þ
ð5Þ
In general, the nucleofugality parameters Nf and the nucleo-
fuge-specific sensitivity parameters sf are obtained from the linear
5109
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112

The Journal of Organic Chemistry
ARTICLE
Figure 5. Comparison of the nucleophilicities N of isothioureas with
other nucleophilic organocatalysts (solvent is CH2Cl2 unless otherwise
stated, N from ref 20).
As the reactions of isothioureas with benzhydrylium ions have
been found to follow the linear-free energy relationship (eq 1), it
was possible to determine the nucleophilicity parameters for the
isothioureas 5ꢀ10 and 13ꢀ17 and to include these compounds
into our comprehensive nucleophilicity scale. Figure 5 shows that
the nucleophilicities N of the investigated isothioureas are in
between those of the classical organocatalysts DMAP (1) and
NMI (2).
The availability of rate and equilibrium constants for the
reactions of these nucleophiles with the benzhydrylium ion
(ind)2CHþ furthermore allows us to construct the quantitative
energy profile diagrams as depicted for some reactions in
Figure 6. It is thus found that imidazoles are less nucleophilic
as well as less Lewis basic than isothioureas. Although the kinetic
and thermodynamic properties of most isothioureas investigated
are comparable to those of DMAP, DABCO is a stronger
nucleophile than all isothioureas investigated, while its Lewis
basicity is comparable to those of the least basic isothioureas.
In future work we will examine the relevance of these kinetic and
thermodynamic data for various organocatalytic transformations.
Figure 6. Gibbs energy profiles for the reactions of various nucleophilic
organocatalysts with the benzhydrylium ion (ind)2CHþ in CH2Cl2 at 20
a
°C (ΔGq and ΔG° values from Table 3 or from ref 20). ΔG° was
estimated in ref 20e.
of the solutions was kept constant at 20.0 ( 0.1 °C during all kinetic
studies by using a circulating bath thermostat. The pseudo-first-order
rate constants kobs (sꢀ1) were obtained by least-squares fitting of the
absorbances to the monoexponential function At = A0 exp(ꢀkobst) þ C.
The second-order rate constants k (Mꢀ1 sꢀ1) were obtained from the
slopes of the linear plots of kobs against the nucleophile concentrations.
Tables with concentrations of reactants and individual rate constants are
collected in the Supporting Information.
’ EXPERIMENTAL SECTION
Determination of Equilibrium Constants. Equilibrium con-
stants were determined by UVꢀvis spectroscopy as follows. To solutions
of benzhydrylium tetrafluoroborates in CH2Cl2 were added small
amounts of stock solutions of isothioureas, and the absorbances of the
benzhydrylium tetrafluoroborates were monitored at their corresponding
λmax before (A0) and immediately after (A) the addition of isothioureas.
This procedure was carried out with different concentrations of the
isothioureas. The temperature was kept constant at 20.0 ( 0.1 °C using
a circulating bath thermostat. For details see the Supporting Information.
Product Studies. Formation of 6P-BF4. To a blue solution of
(dma)2CHþBF4ꢀ (21 mg, 0.062 mmol) in CH2Cl2 (1 mL) was added
drop by drop a solution of 6 (7.9 mg, 0.062 mmol) in dry CH2Cl2
(1 mL) under nitrogen at room temperature. After the disappearance of
the blue color of the solution the solvent was evaporated, and the residue
was washed with i-hexane to afford 6P-BF4: 27 mg (0.058 mmol,
General. CH2Cl2 was freshly distilled over CaH2. Isothioureas were
synthesized according to literature procedures.7,15,18 Benzhydrylium
tetrafluoroborates were prepared as described before.19a All other
chemicals were purchased from commercial sources and (if necessary)
purified by recrystallization or distillation prior to use. 1H and 13C NMR
spectra were recorded on NMR-systems (400 MHz) in d6-DMSO or
CD3CN, and the chemical shifts in ppm refer to the solvent residual
signal as internal standard (δH(CD3CN) = 1.94, δC(CD3CN) = 1.4
ppm; δH(d6-DMSO) = 2.50, δC(d6-DMSO) = 39.5 ppm).
Kinetics. The reactions of isothioureas with the colored benzhy-
drylium ions (Ar2CHþ) were followed photometrically at or close to the
absorption maxima of (Ar2CHþ) by UVꢀvis spectroscopy as described
previously.19 Slow reactions (τ1/2 > 10 s) were determined by using
conventional UVꢀvis spectrophotometers. Stopped-flow techniques were
used for the investigation of rapid reactions (τ1/2 < 10 s). The temperature
1
93%, viscous liquid). 6P-BF4: H NMR (CD3CN, 400 MHz): δ 2.93
5110
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112

The Journal of Organic Chemistry
ARTICLE
(s, 12 H), 3.59ꢀ3.66 (m, 4 H), 3.72ꢀ3.77 (m, 2 H), 4.03ꢀ4.08 (m, 2 H),
5.67 (s, 1 H), 6.74 (d, J = 8.9 Hz, 4 H), 7.11 ppm (d, J = 8.9 Hz, 4 H). 13C
NMR (CD3CN, 100 MHz): δ 38.0 (t), 40.6 (q), 47.4 (t), 48.1 (t), 56.6 (t),
66.9 (d), 113.2 (d), 124.0 (s), 130.7 (d), 152.1 (s), 177.5 ppm (s). HRMS
(ESI) calculated for C22H29N432S [Mþ] 381.2107, found 381.2112.
(2) (a) H€ofle, G.; Steglich, W.; Vorbr€uggen, A. Angew. Chem., Int. Ed.
1978, 17, 569–583. (b) Murugan, R.; Scriven, E. F. V. Aldrichimica Acta
2003, 36, 21–27. (c) Spivey, A. C.; Arseniyadis, S. Angew. Chem., Int. Ed.
2004, 43, 5436–5441. (d) For mechanistic interpretations, see: Xu, S.;
Held, I.; Kempf, B.; Mayr, H.; Steglich, W.; Zipse, H. Chem.—Eur. J.
2005, 11, 4751–4757. (e) Lutz, V.; Glatthaar, J.; W€urtele, C.; Serafin,
M.; Hausmann, H.; Schreiner, P. R. Chem.—Eur. J. 2009, 15, 8548–
8557.
ꢀ
Formation of 7P-BF4. Equimolar amounts of (dma)2CHþBF4
(16 mg, 0.047 mmol) and 7 (8.3 mg, 0.047 mmol) were mixed in d6-
DMSO (0.6 mL) in an NMR tube under nitrogen and the NMR was
taken after few minutes of shaking. 7P-BF4: 1H NMR (d6-DMSO, 400
MHz): δ 2.93 (s, 12 H), 4.27ꢀ4.32 (m, 2 H), 4.53ꢀ4.58 (m, 2 H), 5.91
(s, 1 H), 6.77 (d, J = 8.8 Hz, 4 H), 7.25 (d, J = 8.8 Hz, 4 H), 7.30ꢀ7.35
(m, 1 H), 7.55 (d, J = 3.9 Hz, 2 H), 7.93 ppm (d, J = 8.1 Hz, 1 H). 13C
NMR (d6-DMSO, 100 MHz): δ 39.9 (q), 44.8 (t), 55.1 (t), 65.2 (d),
112.0 (d), 112.2 (d), 123.0 (s), 124.3 (d), 124.4 (d), 127.5 (s), 128.1 (d),
129.5 (d), 134.0 (s), 150.4 (s), 168.8 ppm (s).
(3) For a select example, see: Connors, K. A.; Pandit, N. K. Anal.
Chem. 1978, 50, 1542–1545.
(4) For select examples, see: (a) Lohmeijer, B. G. G.; Pratt, R. C.;
Leibfarth, F.; Logan, J. W.; Long, D. A.; Dove, A. P.; Nederberg, F.; Choi,
J.; Wade, C.; Waymouth, R. M.; Hedrick, J. L. Macromolecules 2006,
39, 8574–8583. (b) Shieh, W.-C.; Dell, S.; Repic, O. J. Org. Chem. 2002,
67, 2188–2191. (c) Zhang, W.; Shi, M. Org. Biomol. Chem. 2006,
4, 1671–1674. (d) Price, K. E.; Larrivꢀee-Aboussafy, C.; Lillie, B. M.;
McLaughlin, R. W.; Mustakis, J.; Hettenbach, K. W.; Hawkins, J. M.;
Vaidyanathan, R. Org. Lett. 2009, 11, 2003–2006. (e) Larrivꢀee-Aboussafy, C.;
Jones, B. P.; Price, K. E.; Hardink, M. A.; McLaughlin, R. W.; Lillie, B. M.;
Hawkins, J. M.; Vaidyanathan, R. Org. Lett. 2010, 12, 324–327. (f)
Taylor, J. E.; Jones, M. D.; Williams, J. M. J.; Bull, S. D. Org. Lett. 2010,
12, 5740–5743.
(5) (a) Birman, V. B.; Uffman, E. W.; Jiang, H.; Li, X.; Kilbane, C. J. J.
Am. Chem. Soc. 2004, 126, 12226–12227. (b) Birman, V. B.; Jiang, H.
Org. Lett. 2005, 7, 3445–3447. (c) Birman, V. B.; Li, X.; Jiang, H.;
Uffman, E. W. Tetrahedron 2006, 62, 285–294.
(6) Kobayashi, M.; Okamoto, S. Tetrahedron Lett. 2006, 47, 4347–
4350.
Formation of 9P-BF4. To a blue solution of (dma)2CHþBF4ꢀ (22
mg, 0.065 mmol) in CH2Cl2 (1 mL) was added drop by drop a solution
of 9 (9.2 mg, 0.062 mmol) in dry CH2Cl2 (1 mL) under nitrogen at
room temperature. After the disappearance of the blue color of the
solution the solvent was evaporated, and the residue was washed with i-
hexane to get 9P-BF4: 27 mg (0.058 mmol, 89%, viscous liquid). 9P-
BF4: 1H NMR (CD3CN, 400 MHz): δ 2.02ꢀ2.07 (m, 2 H), 2.94 (s, 12
H), 3.17ꢀ3.20 (m, 2 H), 3.41ꢀ3.47 (m, 4 H), 4.00 (t, J = 7.7 Hz, 2 H),
5.98 (s, 1 H), 6.75 (d, J = 8.9 Hz, 2 H), 7.03 ppm (d, J = 8.4 Hz, 4 H). 13C
NMR (CD3CN, 100 MHz): δ 20.2 (t), 29.2 (t), 40.6 (q), 44.5 (t), 45.6
(t), 57.0 (t), 72.9 (d), 113.3 (d), 124.3 (s), 130.4 (d), 151.8 (s), 168.3
ppm (s). HRMS (ESI) calculated for C23H31N432S [Mþ] 395.2264,
found 395.2265.
(7) Birman, V. B.; Li, X.; Han, Z. Org. Lett. 2007, 9, 37–40.
(8) (a) Joannesse, C.; Simal, C.; Concellꢀon, C.; Thomson, J. E.;
Campbell, C. D.; Slawin, A. M. Z.; Smith, A. D. Org. Biomol. Chem. 2008,
6, 2900–2907. (b) Woods, P. A.; Morrill, L. C.; Lebl, T.; Slawin, A. M. Z.;
Bragg, R. A.; Smith, A. D. Org. Lett. 2010, 12, 2660–2663.
ꢀ
Formation of 10P-BF4. Equimolar amounts of (dma)2CHþBF4
(13 mg, 0.038 mmol) and DHPB 10 (7.3 mg, 0.038 mmol) were mixed
in d6-DMSO (0.6 mL) in an NMR tube under nitrogen, and the NMR
was taken after few minutes of shaking. 10P-BF4: 1H NMR (d6-DMSO,
400 MHz): δ 2.28ꢀ2.31 (m, 2 H), 2.92 (s, 12 H), 3.43ꢀ3.45 (m, 2 H),
4.23 (t, J = 5.9 Hz, 2 H), 6.12 (s, 1 H), 6.76 (d, J = 8.9 Hz, 4 H), 7.15 (d,
J = 8.7 Hz, 4 H), 7.41ꢀ7.45 (m, 1 H), 7.59ꢀ7.63 (m, 1 H), 7.69 (d, J =
7.8 Hz, 1 H), 8.04 ppm (d, J = 8.0 Hz, 1 H). 13C NMR (d6-DMSO, 100
MHz): δ 18.4 (t), 39.9 (q), 43.0 (t), 45.0 (t), 70.9 (d), 112.2 (d), 112.9
(d), 121.9 (s), 122.4 (s), 123.3 (d), 125.0 (d), 128.0 (d), 129.4 (d), 138.8
(s), 150.3 (s), 164.3 ppm (s).
(9) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351–1354.
(10) For kinetic resolutions using anhydrides as acylating
agents, see: (a) Birman, V. B.; Jiang, H.; Li, X.; Geo, V.; Uffman,
E. W. J. Am. Chem. Soc. 2006, 128, 6536–6537. (b) Reference 9. (c)
Birman, V. B.; Geo, L. Org. Lett. 2006, 8, 4859–4861. (d) Birman, V. B.;
Li, X. Org. Lett. 2008, 10, 1115–1118. (e) Yang, X.; Birman, V. B. Adv.
Synth. Catal. 2009, 351, 2301–2304. (f) Xu, Q.; Zhou, H.; Geng, X.;
Chen, P. Tetrahedron 2009, 65, 2232–2238. For kinetic resolutions
using carboxylic acids as acylating agents utilizing in situ formation of a
reactive mixed anhydride, see: (g) Shiina, I.; Nakata, K. Tetrahedron. Lett.
2007, 48, 8314–8317. (h) Shiina, I.; Nakata, K.; Sugimoto, M.; Onda, Y.;
Iizumi, T.; Ono, K. Heterocycles 2009, 77, 801–810. (i) Yang, X.; Birman,
V. B. Adv. Synth. Catal. 2009, 351, 2301–2304. (j) Shiina, I.; Nakata, K.
Heterocycles 2010, 80, 169–175. (k) Shiina, I.; Nakata, K.; Onda, Y. Eur. J.
Org. Chem. 2008, 5887–5890. (l) Shiina, I.; Nakata, K.; Ono, K.;
Sugimoto, M.; Sekiguchi, A. Chem.—Eur. J. 2010, 16, 167–172. (m)
Nakata, K.; Onda, Y.; Ono, K.; Shiina, I. Tetrahedron. Lett. 2010,
51, 5666–5669. (n) Shiina, I.; Ono, K.; Nakata, K. Chem. Lett. 2011,
40, 147–149.
’ ASSOCIATED CONTENT
S
Supporting Information. Copies of NMR spectra of the
b
products, details of the equilibrium and rate measurements.
This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
(11) Birman, V. B.; Jiang, H.; Li, X. Org. Lett. 2007, 9, 3237–3240.
(12) Kalow, J. A.; Doyle, A. G. J. Am. Chem. Soc. 2010, 132, 3268–3269.
(13) Yang, X.; Lu, G.; Birman, V. B. Org. Lett. 2010, 12, 892–895.
(14) (a) Purohit, V. C.; Matla, A. S.; Romo, D. J. Am. Chem. Soc.
2008, 130, 10478–10479. (b) Leverett, C. A.; Purohit, V. C.; Romo, D.
Angew. Chem., Int. Ed. 2010, 49, 9479–9483. (c) Belmessieri, D.; Morrill,
L. C.; Simal, C.; Slawin, A. M. Z.; Smith, A. D. J. Am. Chem. Soc. 2011,
133, 2714–2720. For other Lewis base mediated reactions utilizing
carboxylic acids as ammonium enolate precursors, see: (d) Cortez, G. S.;
Tennyson, R. L.; Romo, D. J. Am. Chem. Soc. 2001, 123, 7945–7946. (e)
Cortez, G. S.; Oh, S. H.; Romo, D. Synthesis 2001, 1731–1736. (f) Oh,
S. H.; Cortez, G. S.; Romo, D. J. Org. Chem. 2005, 70, 2835–2838. (g)
Henry-Riyad, H.; Lee, C.; Purohit, V. C.; Romo, D. Org. Lett. 2006,
8, 4363–4366. (h) Ma, G.; Nguyen, H.; Romo, D. Org. Lett. 2007,
9, 2143–2146. (i) Nguyen, H.; Ma, G.; Romo, D. Chem. Commun. 2010,
46, 4803–4805. (j) Morris, K. A.; Arendt, K. M.; Oh, S. H.; Romo, D.
Corresponding Author
*E-mail: Herbert.Mayr@cup.uni-muenchen.de.
’ ACKNOWLEDGMENT
We thank the Deutsche Forschungsgemeinschaft (SFB 749),
the Royal Society (URF to A.D.S.), and the EPSRC (C.J.) for
financial support. Valuable suggestions by Dr. Armin R. Ofial and
Dr. Mahiuddin Baidya are gratefully acknowledged.
’ REFERENCES
(1) For an excellent review, see: Denmark, S. E.; Beutner, G. L.
Angew. Chem., Int. Ed. 2008, 47, 1560–1638.
5111
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112

The Journal of Organic Chemistry
ARTICLE
Org. Lett. 2010, 12, 3764–3767. (k) Nguyen, H.; Ma, G.; Gladysheva, T.;
Fremgen, T.; Romo, D. J. Org. Chem. 2011, 76, 2–12.
(15) Joannesse, C.; Johnston, C. P.; Concellꢀon, C.; Simal, C.; Philp,
D.; Smith, A. D. Angew. Chem., Int. Ed. 2009, 48, 8914–8918.
(16) (a) Fu, G. C. Acc. Chem. Res. 2000, 33, 412–420. (b) Fu, G. C.
Acc. Chem. Res. 2004, 37, 542–547. (c) Shaw, S. A.; Aleman, P.; Vedejs,
E. J. Am. Chem. Soc. 2003, 125, 13368–13369. (d) Shaw, S. A.; Aleman,
P.; Christy, J.; Kampf, J. W.; Va, P.; Vedejs, E. J. Am. Chem. Soc. 2006,
128, 925–934. (e) Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org.
Lett. 2006, 8, 769–772.
(17) Zhang, Y.; Birman, V. B. Adv. Synth. Catal. 2009, 351, 2525–
2529.
(18) Belmessieri, D.; Joannesse, C.; Woods, P. A.; MacGregor, C.;
Jones, C.; Campbell, C. D.; Johnston, C. P.; Duguet, N.; Concellꢀon, C.;
Bragg, R. A.; Smith, A. D. Org. Biomol. Chem. 2011, 9, 559–570.
(19) Reviews on nucleophilicities: (a) Mayr, H.; Bug, T.; Gotta,
M. F.; Hering, N.; Irrgang, B.; Janker, B.; Kempf, B.; Loos, R.; Ofial,
A. R.; Remennikov, G.; Schimmel, H. J. Am. Chem. Soc. 2001,
123, 9500–9512. (b) Mayr, H.; Kempf, B.; Ofial, A. R. Acc. Chem. Res.
2003, 36, 66–77. (c) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008,
21, 584–595. (d) Mayr, H.; Ofial, A. R. Pure Appl. Chem. 2005,
77, 1807–1821. (e) For a comprehensive listing of nucleophilicity
parameters N and electrophilicity parameters E, see http://www.cup.
uni-muenchen.de/oc/mayr/DBintro.html.
(20) (a) For pyridines, see: Brotzel, F.; Kempf, B.; Singer, T.; Zipse,
H.; Mayr, H. Chem.—Eur. J. 2007, 13, 336–345. (b) De Rycke, N.;
Berionni, G.; Couty, F.; Mayr, H.; Goumont, R.; David, O. R. P. Org.
Lett. 2011, 13, 530–533. (c) For azoles, see: Baidya, M.; Brotzel, F.;
Mayr, H. Org. Biomol. Chem. 2010, 8, 1929–1935. (d) For Ph3P, see:
Kempf, B.; Mayr, H. Chem.—Eur. J. 2005, 11, 917–927. (e) For DBU
and DBN, see: Baidya, M.; Mayr, H. Chem. Commun. 2008, 1792–1794.
(f) ForDABCO, see: Baidya, M.;Kobayashi, S.; Brotzel, F.; Schmidhammer,
U.; Riedle, E.; Mayr, H. Angew. Chem., Int. Ed. 2007, 46, 6176–6179.
(21) Vana, J.; Sedlak, M.; Hanusek, J. J. Org. Chem. 2010, 75,
3729–3736 and references therein.
(22) (a) Marcus, R. A. J. Phys. Chem. 1968, 72, 891–899. (b) Albery,
W. J. Annu. Rev. Phys. Chem. 1980, 31, 227–263.
(23) Schaller, H. F.; Tishkov, A. A.; Feng, X.; Mayr, H. J. Am. Chem.
Soc. 2008, 130, 3012–3022.
(24) Streidl, N.; Denegri, B.; Kronja, O.; Mayr, H. Acc. Chem. Res.
2010, 43, 1537–1549.
5112
dx.doi.org/10.1021/jo200803x |J. Org. Chem. 2011, 76, 5104–5112