Hydrogen-bond-assisted controlled C-H functionalization via adaptive recognition of a purine directing group

Article abstract of DOI:10.1021/ja4118472

We have developed the Rh-catalyzed selective C-H functionalization of 6-arylpurines, in which the purine moiety directs the C-H bond activation of the aryl pendant. While the first C-H amination proceeds via the N1-chelation assistance, the subsequent second C-H bond activation takes advantage of an intramolecular hydrogen-bonding interaction between the initially formed amino group and one nitrogen atom, either N1 or N7, of the purinyl part. Isolation of a rhodacycle intermediate and the substrate variation studies suggest that N1 is the main active site for the C-H functionalization of both the first and second amination in 6-arylpurines, while N7 plays an essential role in controlling the degree of functionalization serving as an intramolecular hydrogen-bonding site in the second amination process. This pseudo-Curtin-Hammett situation was supported by density functional calculations, which suggest that the intramolecular hydrogen-bonding capability helps second amination by reducing the steric repulsion between the first installed ArNH and the directing group.

Full text of DOI:10.1021/ja4118472

Article
pubs.acs.org/JACS
Hydrogen-Bond-Assisted Controlled C−H Functionalization via
Adaptive Recognition of a Purine Directing Group
Hyun Jin Kim,†,‡ Manjaly J. Ajitha,§ Yongjae Lee,‡ Jaeyune Ryu,‡ Jin Kim,‡ Yunho Lee,‡ Yousung Jung,*,§
and Sukbok Chang*,†,‡
†Center for Catalytic Hydrocarbon Functionalizations, Institute of Basic Science (IBS), Daejeon 305-701, Republic of Korea
‡Department of Chemistry and §Graduate School of EEWS, Korea Advanced Institute of Science and Technology (KAIST), Daejeon
305-701, Republic of Korea
S
* Supporting Information
ABSTRACT: We have developed the Rh-catalyzed selective
C−H functionalization of 6-arylpurines, in which the purine
moiety directs the C−H bond activation of the aryl pendant.
While the first C−H amination proceeds via the N1-chelation
assistance, the subsequent second C−H bond activation takes
advantage of an intramolecular hydrogen-bonding interaction
between the initially formed amino group and one nitrogen
atom, either N1 or N7, of the purinyl part. Isolation of a
rhodacycle intermediate and the substrate variation studies
suggest that N1 is the main active site for the C−H functionalization of both the first and second amination in 6-arylpurines,
while N7 plays an essential role in controlling the degree of functionalization serving as an intramolecular hydrogen-bonding site
in the second amination process. This pseudo-Curtin−Hammett situation was supported by density functional calculations,
which suggest that the intramolecular hydrogen-bonding capability helps second amination by reducing the steric repulsion
between the first installed ArNH and the directing group.
Scheme 1
INTRODUCTION
■
Transition-metal-catalyzed C−H bond activation and subse-
quent functionalizations are of great synthetic utility in various
research areas since it enables the direct introduction of
functional groups without relying on the conventional
prefunctionalization approaches.1 With an appropriate combi-
nation of metal catalysts and chelate groups, a range of direct
C−H functionalizations has been successfully developed
including alkenylation,2 arylation,3 amination,4 hydroxylation,5
and halogenation.6 In spite of these remarkable recent
advances, the degree of functionalization (mono vs di) is
often difficult to control (Scheme 1a). This selectivity issue
becomes more critical when two different groups need to be
introduced.
Recently, we have developed the transition-metal-catalyzed
direct intermolecular C−H amination of arenes and alkenes
using organic azides as the nitrogen source (Scheme 1b).7 The
reaction is characterized to have broad substrate scope and high
functional group tolerance. Reaction conditions are mild,
releasing molecular nitrogen as the single byproduct. A wide
range of azides could efficiently be employed to include variants
of sulfonyl, aryl, alkyl, and acyl azides.8 In addition, we have
optimized three catalytic systems based on rhodium,7a−c
ruthenium,7d and iridium,7e,f each of which displays a unique
reactivity pattern depending on the combination of substrates
and azides.
substrates and catalysts employed. For example, most substrates
bearing conventional chelation groups are exclusively mono-
aminated even when excessive equivalents of azides are used
without formation of diaminated products. In sharp contrast,
the degree of amination with 6-arylpurines was found to be
During the course of these studies, we observed an
interesting aspect that the degree of amination depends on
Received: November 23, 2013
Published: December 30, 2013
© 2013 American Chemical Society
1132
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
controlled to deliver either mono- or diaminated products
depending on the stoichiometry of azides. We initially
hypothesized that the unique structural feature of a purinyl
group is responsible for this outcome. Described herein are our
detailed experimental and theoretical studies to validate the
working hypothesis in the direct functionalization of 6-
arylpurines, especially focusing on the selectivity issue in the
amination (Scheme 1c).
An additional motivation for the current work is the high
synthetic utility of purine building blocks in medicinal
chemistry.9−12 Compounds containing purine skeleton are
widely present in nature with interesting biological activities
which are originated presumably through the hydrogen-
bonding-based molecular interactions.9 In addition, 6-arylpur-
ine derivatives are of particular importance since they exhibit
high potency of antimycobacterial, cytostatic, and anti-HCV
activities (Scheme 2).10 In this study, the propensity of purine
place in an opposite manner; a diaminated product (6) was
exclusively generated, while a monoaminated compound (7)
was not observed under otherwise identical conditions (Scheme
3b).
A main difference between two chelates, 2-pyridyl and
purinyl group, is the presence of additional nitrogen atoms in
the purine moiety. In particular, in addition to N1, N7 in purine
may work as an additional coordinating site to the rhodium
metal center during the course of the C−H activation process.
Since N3 and N9 are remote from the reacting site of a
phenyl pendant, it is reasonable to assume that these two
nitrogen atoms are not involved in the amination pathway. As a
result, two paths can be presupposed in the C−H bond
activation process to generate the corresponding cyclometalates
(Scheme 4). A rhodacycle intermediate I will be formed from
Scheme 4. Two Modes in the First C−H Amination
Scheme 2. Medicinal Applications of Purine Derivatives
the N1-chelation-assisted C−H bond activation. Alternatively, a
rhodacycle II generated via N7-chelation assistance is another
possibility. It should be addressed that the C−H amination
product will be the same irrespective of the chelation mode.
To gain insights into the mechanistic details, a series of
experiments were carried out (Scheme 5). First, we obtained a
rhodacycle (8) in 65% yield upon treatment of 6-aryl-(N-
isopropyl)purine (5) with 0.5 equiv of [RhCp*Cl2]2 and 2.7
equiv of NaOAc.14 A solid structure of 8 was determined by an
X-ray crystallographic analysis, in which the formation of a
to have H-bonding interaction was used as a key component in
controlling the degree of catalytic mono- versus difunctional-
ization reactions. DFT calculations were carried out to validate
the proposed hypothesis and interpret the data.
RESULTS AND DISCUSSION
■
Control of the Degree in the Amination of 6-
Arylpurines. When the previously developed conditions of
the Rh-catalyzed direct C−H amination were applied to 2-
phenylpyridine (1),7a a monoaminated product (3) was
exclusively obtained after 24 h without forming a diaminated
compound (4) even when excess amounts (3 equiv) of aryl
azide (2) were used (Scheme 3a).13 In contrast, it was
surprising to see that the amination of 6-phenylpurine (5) took
Scheme 5. Preparation and Reactivity of a Rhodacycle (8)
Derived from 6-Arylpurine (5)
Scheme 3. C−H Amination of Arenes with Different DGs
1133
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
rhodacycle derived from the N1 atom was clearly shown
(Scheme 5a). When the isolated rhodacycle was reacted with 3-
nitrophenyl azide, a monoaminated product (9) could be
obtained after protonolysis (Scheme 5b). The fact that
chemical shift of amino NH in 9 appeared at 11 ppm, being
shifted by 3−5 ppm relative to a typical diarylamino peak,15
strongly indicates the presence of H-bonding. Indeed, a solid
structural analysis of 9 confirmed an intramolecular hydrogen
bonding; 2.02 Å of the NH···N bond length with 121.9° bond
angle between those three atoms. In addition, the direct C−H
amination of 5 was efficiently catalyzed by 8 (4 mol %) in the
presence of a silver additive, suggesting that a cationic
rhodacycle is indeed involved in the catalytic amination process.
In the second amination stage, as in the first amination, two
nitrogen atoms (N1 or N7) might be involved in the chelation-
assisted C−H bond activation (Scheme 6). In this process, we
Scheme 7. Detection of a Rhodacycle in the Second
Amination
diaminated product (11) in a quantitative yield (Scheme 7b).
A solid structure of 11 revealed an interesting aspect: while a
purinyl nitrogen atom N7 participates in an intramolecular H-
bonding with one of the produced amino NH atoms, N1
exhibits an intermolecular interaction with another NH bond of
a neighboring molecule 11.26
Scheme 6. Plausible Pathways of the Second Amination
In order to examine which nitrogen atom of N1 and N7 is
more responsible for the second amination (paths A and B in
Scheme 6), we designed two model substrates, in which either
N1 or N7 of the purine skeleton was removed. A substrate (12)
devoid of the N1 atom was completely unreactive to the
amination conditions (Scheme 8a), indicating that N1 in the
Scheme 8. Tests of Two Model Substrates 12 and 13
postulated that an intramolecular H-bonding between an
initially formed arylamino NH group and a purinyl nitrogen
(either N1 or N7) would play an important role in facilitating
the rhodacycle formation leading to III or IV, respectively.16 In
fact, there are a number of examples to utilize hydrogen
bonding as a key motif to control reactivity and/or selectivity in
Michael addition,17 epoxidation,18 hydrogenation,19 cyclo-
addition,20 Diels−Alder,21 and aldol reaction.22 We also
reported hydrogen-bond-directed stereoselective synthesis of
Z-enamides via Pd-catalyzed oxidative amidation of conjugated
olefins,23 in which an intramolecular H-bonding between an
amido proton and carbonyl oxygen was proposed as a key
driving force to obtain an excellent level of stereoselectivity.
However, only a few reports of utilizing an in situ formed H-
bonding are known in the C−H bond activation process. For
example, Lassaletta et al. elegantly demonstrated that an iridium
complex can catalyze diborylation and sequential functionaliza-
tion of arenes bearing hydrazone as a directing group.24 They
proposed that an intramolecular H-bonding makes the reaction
more facile. In addition, one recent example has been revealed
by Glorius and co-workers in the chelation-assisted direct
amidation of arenes using aroyloxycarbamates as the nitrogen
source under a rhodium catalytic system.25 In this study, the
observation that diamidated products were sometimes obtained
for certain substrates was explained by assuming a H-bonding
interaction between a directing group and the first-formed
amide NH. However, detailed experimental or theoretical
studies were not presented in their communication.
purine moiety is essential for the C−H bond activation process
mediated by a rhodium metal species. On the other hand, a
substrate 13 that does not bear the N7 atom in the purine
skeleton underwent the reaction, but giving rise to only
monoaminated product 14 (Scheme 8b). It was intriguing that,
even when excessive amounts of aryl azide (3 equiv) were
employed, diamination of 13 did not proceed.27 This result
strongly suggests that N7 displays a role in the second
amination process presumably through an intramolecualr H-
bonding with the first-formed amino NH hydrogen atom
(Scheme 6, path A).
Computational Insights. To gain additional insights into
the role played by N1 and N7 in the C−H amination process,
density functional theory calculations were carried out using
B3LYP functional28,29 as implemented in the Q-CHEM
quantum chemistry package.30 Stuttgart relativistic small core
(SRSC)31 effective core potential basis set was used for
rhodium and for all other atoms, and 6-31G* basis set was
employed in geometry optimization and 6-311G** in single-
Although we could not obtain a single crystal of a postulated
rhodacycle (III or IV in Scheme 6) suitable for the X-ray
crystallographic analysis, its in situ generation was confirmed by
a mass spectroscopic analysis (ESI-HRMS, Scheme 7a). On the
other hand, the second amination of 10 was found to be facile
under the present rhodium catalytic system to give a
1134
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
point energy calculations. The -R, -R′, and -R″ groups of model
substrates in the calculations were CH3, C6H5, and C6H5,
respectively (Schemes 4 and 6) to reduce the computational
cost. Stationary points were confirmed by frequency calcu-
lations, showing all positive vibrations for minima and one
imaginary vibration for transition states.
interactions between N1 and Rh versus N7 and Rh. The
remaining difference between the net energy difference (6.9
kcal/mol) and the electrostatic component (4.8 kcal/mol)
would be due to the dispersion interactions, the steric
repulsion, and orbital interactions associated with metal
chelation. V and VI are expected to be generated by the C−
H activation process (via TS1 and TS2, respectively) and their
relative activation energies (ΔΔG⧧ = 7.4 kcal/mol) favor 99.9%
of V in excess according to eq 2, where ΔΔG⧧ is the difference
in the activation energies to form the rhodacycles (Figure 1).
This result as well as the thermodynamic energy difference (6.9
kcal/mol) between V versus VI are consistent with the
experimental data of a rhodacycle (8) shown in Scheme 5a.
The wave function generated from the gas-phase-optimized
geometry of purines was used for the molecular electrostatic
potential (MESP) analysis. The MESP of a molecule at a point
is formally defined as the work done in bringing a unit positive
test charge from infinity to that point; the more negative value
meaning the higher electron density. It is a real physical
property that can be determined experimentally by X-ray
diffraction techniques or rigorously calculated using eq 1, where
ZA is the charge on nucleus A located at RA, ρ(r′) is the electron
density of the molecule, and r′ is the dummy integration
variable.32,33 The first and second terms on the right-hand side
of the equation represent the bare nuclear and electronic
contributions, respectively, and the sign of V(r) depends on
whether the nuclear or electronic effects are dominant in a
particular region. All reported free energies involve zero-point
vibrational corrections and thermal corrections to the Gibbs
free energy on the gas-phase-optimized geometries at 298.15 K.
ΔΔG⧧/RT
[N1‐rhodacycle]
[N7‐rhodacycle]
= e
(2)
As described above (Scheme 6), it can be assumed that either
N1 or N7 site is available for the chelation-assisted second C−
H amination process by a rotation of the monoaminated
product (via TSrot in Figure 2; ΔG⧧ = 9.9 kcal/mol). It was
calculated that two conformers of a monoaminated molecule
(B and C in Figure 2) differ in energy by only 3.1 kcal/mol.
The H-bonding between the introduced ArNH and nitrogen
atom of N1 or N7 (B and C, respectively) is expected to assist
the second amination by reducing steric repulsion between
ArNH and the directing group. During the course of generating
the corresponding rhodacycle, the N1-assisted metal chelate
(VII) was calculated to be more stable than the N7 counterpart
(VIII) by 4.7 kcal/mol. The higher stability of VII is expected
to arise from the stronger electrostatic interaction of the metal
center to the electron-rich N1 site in C compared to the N7 site
in B by −7.3 kcal/mol (Vmin = −55.0 versus −47.7 kcal/mol),
which is then offset by the less favorable intramolecular H-
bonding energy of C (NH-N7) compared to B (NH-N1) by
3.1 kcal/mol ΔG0 in Figure 2. This simple decomposition of
the relative stability of rhodacycles into electrostatic metal−
nitrogen interaction (−7.3 kcal/mol) and intramolecular H-
bonding interaction (3.1 kcal/mol) yields VII more stable than
VIII by 4.2 kcal/mol, in good agreement with the actual
difference in free energy, 4.7 kcal/mol.
N
ρ(r′)d3r′
|r − r′|
ZA
|r − RA|
V(r) =
−
∑
∫
(1)
A
We denote Vmin as the lowest MESP value (the highest
electron density) in space (A) in Figure 1, which indicates that
It is interesting to note that the presence of the first aminated
group increases the electron density at N1 in C, whereas it
slightly decreases that at the N7 site in B when compared to the
initial substrate (Figure 1). Even though the relative population
of B seems to be higher than that of C, it is actually the relative
activation energy in a process leading to the rhodacycles that
determine their actual proportion (Curtin−Hammett principle).
VII and VIII are expected to be given by the second C−H
activation process (via TS3 and TS4, respectively), and their
relative activation energies (ΔΔG⧧ = 3.6 kcal/mol) favor 99.5%
of VII in excess according to eq 2, where ΔΔG⧧ = ΔGC⧧ + ΔG0
− G⧧B (Figure 2). This indicates that VII (second N1-chelated
rhodacycle) will be a major intermediate to initiate the second
amination. In other words, it is clear that the N1 site is more
favored over N7 for both the first and second amination as this
is proved by experiment (no product in the case of substrate
12) and theory (explained more clearly on the basis of Curtin−
Hammett principle). Although both VII and VIII have
intramolecular H-bonding interactions shown as the dotted
line in Figure 2, lower activation barrier and hence preferred
reaction path for VII relative to VIII is perhaps due to the
higher stability of a planar five-membered rhodacycle for VII
Figure 1. Relative energies of metal chelates expected to be formed in
the first amination. Values in the parentheses are the relative free
energies (kcal/mol). The MESP minimum Vmin values are also given in
kcal/mol. Distances are given in Å. Color code: gray, C; blue, N; and
red, Rh. Hydrogen atoms are omitted for clarity.
N1 moiety (Vmin = −52.8 kcal/mol) has a higher electron
density compared to that of N7 moiety (Vmin = −48.0 kcal/
mol). A simpler Mulliken charge analysis (−0.36 e− for N1
versus −0.35 e− for N7) was qualitatively consistent with the
more physical MESP analysis. It was also observed that the
metal chelate formed after the first C−H activation is stabilized
more when the metal chelation occurs at N1 (V in Figure 1)
than at N7 (VI in Figure 1) by an amount of 6.9 kcal/mol of
energy, similar to the electrostatic potential energy difference
between the two nitrogen sites (4.8 kcal/mol). This similarity
suggests that the relative stability of N1-chelated complex and
N7 counterpart arises mainly from the difference in electrostatic
1135
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
Figure 2. Relative energies of metal chelates expected to be formed in the second amination. Values in the parentheses are the relative free energies
(kcal/mol). Vmin values are also given in kcal/mol. Distances are given in Å. Color code: gray, C; blue, N; ivory, H; and red, Rh. Less important
hydrogen atoms are omitted for clarity.
compared to a less stable puckered six-membered rhodacycle
for VIII.
above to form a diaminated product. Indeed, it is observed that
when the reaction time was extended to 48 h, diamination of 1
also occurred albeit in low yield (6%), supporting the active
role of H-bonding in the product selectivity.13 Similarly, for
13a, the equilibrium population ratio of rotated versus
unrotated monoamino product is 1:1300, suggesting that the
diaminated product will hardly be obtained under optimized or
even extended reaction time conditions.27
Detailed additional analyses of the reaction mechanism for
various substrates, currently under investigation, would
undoubtedly be helpful to offer further insights, but all of the
present experimental and computational results point quite
conclusively to the fact that the H-bonding is actively assisting
the second amination by lowering the steric repulsion and
facilitating the regeneration of the N1 site by rotation.
Substrate Scope. On the basis of the above mechanistic
studies and computational calculations, we envisioned that an
orthogonal strategy can be designed to afford various types of
direct C−H functionalization products starting from 6-
arylpurines (Scheme 9). As hinted from the result of Scheme
3, optimal procedures to deliver mono- or symmetric
diaminated products were predicted to be plausible by tuning
the stoichiometry of azide reactants. Sequential diamination at
the arene pendant by employing two different azides will
provide unsymmetrical diamination products. In addition, we
The C−H bond activation barrier for the second amination
seems to be comparable to the first amination for both
substrates 2-phenylpyridine (1) and 9-methyl-6-phenylpurine
(A, Figure 1). In fact, for 1, the activation barrier for the second
amination reaction (20.8 kcal/mol) is even slightly lower than
the first amination reaction (21.2 kcal/mol), implying that as
long as there is enough rhodacycle formation after the first
amination, we would observe the second amination eventually
for 2-phenylpyridine also. It is expected that a rotation of the
directing group around the central C−C bond should occur
prior to the second amination to form a more stable rhodacycle
at the N1 site, and this may bring steric repulsion between the
directing group and the initially installed ArNH group for
certain substrates such as 2-phenylpyridine (1). In this case, the
rotated isomer is less stable than its unrotated isomer by 3.8
kcal/mol (Table 1) due to the loss of intramolecular H-
Table 1. Free Energy Difference and Population Ratio of
Rotational Isomers for Monoaminated Compounds at 358
a
K
substrate
ΔG (kcal/mol)
[rotated]/[unrotated]
1
3.8
3.1
5.1
1:200
1:80
A
13a
1:1300
Scheme 9. Orthogonal C−H Functionalization Approaches
a
13a is an analogue of 13 in which the N-iPr group is replaced by N-
CH3 for the computational simplicity.
bonding and the creation of the steric repulsion accordingly. In
case of 9-methyl-6-phenylpurine (A), however, the rotated
form still retains the stability by newly formed H-bonding
between the N7 and ArNH group, and thus the energy
difference between rotated versus unrotated isomers is reduced
to 3.1 kcal/mol. These free energy differences correspond to
the equilibrium population ratio of rotated (active) versus
unrotated (inactive) conformations to be 1:200 and 1:80 for 1
and A, respectively, at 358 K. It is assumed that a longer
reaction time would be required for 1 than that of A in order to
have sufficient population of the rotated isomers mentioned
1136
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
also envisaged to develop an unsymmetric difunctionalization
procedure by applying an initial amination followed by a
reaction with different organic electrophiles. It should be
addressed that the diversity attainable through the present C−
H functionalization strategy can be attributed to the unique
structural property of the purinyl group.
Table 3. Scope of Aryl Azides
As the proof of concept, we examined the substrate scope of
6-arylpurines in the mono- versus symmetric diamination
reaction (Table 2). Two procedures differ only in the
c
c
18 (yield, %)
R
19 (yield, %)
90 (18a)
85 (18b)
66 (18c)
64 (18d)
99 (9)
4-CF3
92 (19a)
95 (19b)
3-CF3
Table 2. Substrate Scope of Arenes in 6-Arylpurines
d
4-CO2Me
3-CO2Me
3-NO2
98 (19c)
96 (19d)
90 (19e)
de
,
82 (18f)
74 (18g)
95 (7)
4-SO2Me
4-C(O)CH3
3,5-(CF3)2
99 (19f)
75 (19g)
95 (6)
de
,
a
Conditions A: 5 (2 equiv), aryl azide (0.2 mmol), [RhCp*Cl2]2 (2
b
c
c
16 (yield, %)
R1/R2
17 (yield, %)
mol %), and AgSbF6 (8 mol %) for 12 h. Conditions B: 5 (0.2
mmol), aryl azide (3 equiv), [RhCp*Cl2]2 (4 mol %), and AgSbF6 (16
99 (16a)
99 (16b)
99 (16c)
93 (16d)
88 (16e)
99 (16f)
82 (16g)
52 (16h)
45 (16i)
91 (16j)
99 (16k)
87 (16l)
96 (10)
R1 = iPr, R2 = 4-Me
R1 = iPr, R2 = 4-CF3
R1 = iPr, R2 = 4-Cl
R1 = iPr, R2 = 4-CO2Me
R1 = iPr, R2 = 4-Ac
R1 = iPr, R2 = 4-OMe
R1 = iPr, R2 = 4-OBn
R1 = iPr, R2 = 4-OH
R1 = iPr, R2 = 4-CHO
R1 = iPr, R2 = 4-NO2
R1 = iPr, R2 = 3-Me
R1 = Bn, R2 = H
86 (17a)
72 (17b)
95 (17c)
90 (17d)
93 (17e)
94 (17f)
76 (17g)
58 (17h)
63 (17i)
98 (17j)
c
d
mol %) for 24 h. Isolated yield. With 5 equiv of aryl azide.
e
Cl2CHCHCl2 was used as a solvent.
excellent, and 5 was aminated in high efficiency with a wide
range of aryl azides.
After successful exploration of the substrate scope with 6-
arylpurines and aryl azides, we turned our attention to a
different type of directing groups to examine our working
hypothesis on the H-bonding-assisted C−H functionalizations
(Table 4). A phenyl group substituted at the 2-position of
90 (17l)
84 (11)
Table 4. Direct Amination of Various Phenylheterocycles
R1 = Et, R2 = H
83 (16m)
R1 = n-Bu, R2 = H
92 (17m)
a
Conditions A: 6-arylpurine (2 equiv), aryl azide (0.2 mmol),
b
[RhCp*Cl2]2 (2 mol %), and AgSbF6 (8 mol %) for 12 h. Conditions
B: substrate (0.2 mmol), aryl azide (3 equiv), [RhCp*Cl2]2 (4 mol %),
c
and AgSbF6 (16 mol %) for 24 h. Isolated yield.
stoichiometry of two reactants and reaction time: while azide
was used as a limiting reagent for the monoamination
(conditions A), excessive azides were employed with longer
reaction time to obtain doubly aminated products (conditions
B).
Product yields were good to excellent in general, and the
functional group tolerance was also found to be satisfactory.
Electronic variation on substrates did not much influence the
reactivity and selectivity: all examined substrates bearing
electron-donating or electron-withdrawing groups underwent
the selective amination with high efficiency. Variation of N9
substituents in the purine moiety was flexible, thus allowing a
range of different amino groups. Interestingly, a substrate
bearing a meta-substituent underwent the first amination at the
sterically more accessible position in quantitative yield (16k),
but the second amination did not proceed mainly due to the
steric congestion.
The scope of aryl azides was subsequently explored again to
validate our orthogonal approach (Table 3). As shown in our
previous study,7b aryl azides bearing electron-withdrawing
substituents such as trifluoromethyl, ester, nitro, sulfonyl, or
acetyl groups at the para- or meta-position underwent the
desired mono- and diamination in good to excellent yields. As
proved in Table 2, the functional group compatibility was also
a
Conditions A: substrate (3 equiv), aryl azide (0.2 mmol),
[RhCp*Cl2]2 (4 mol %), and AgSbF6 (16 mol %) for 12 h.
b
Conditions B: substrate (0.2 mmol), aryl azide (3 equiv),
c
[RhCp*Cl2]2 (4 mol %), and AgSbF6 (16 mol %) for 24 h. Isolated
yield. With 2 equiv of substrate.
d
pyrimidine and quinazoline underwent the catalytic C−H
amination in excellent yields, leading to the corresponding
diaminated products (21a and 21b, respectively) under
conditions B. However, the monoamination was not selective
unlike the above 6-arylpurine derivatives, and a mixture of
mono- and diaminated products was obtained under conditions
A using azide as a limiting reagent. For example, a reaction of 2-
phenylpyrimidine afforded a mixture of 20a and 21a (2.7:1)
under these conditions (entry 1). A similar pattern was also
observed with 2-phenylquinazoline to give a mixture of mono-
and diaminated products (3.7:1, entry 2) under the conditions
1137
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
a
A. Based on our above experimental results and theoretical
interpretations, the formation of diaminated compounds albeit
in minor under conditions A may be ascribed to the presence of
an additional nitrogen atom in the directing groups that can
form favorable rhodacycle. It is assumed that this nitrogen
readily allows the formation of a rhodacycle for the second
amination since a presumed H-bonding between an initially
formed amino NH and one of two “equivalent” nitrogen atoms
in these directing groups does not need to be broken, nor the
rotation required as in 6-arylpurines. Indeed, a solid structure of
a monoaminated compound (20a) reveals a H-bonding while a
free nitrogen atom is also available in the pyrimidinyl group for
the formation of a rhodacycle eventually leading to the second
amination (Figure 3a). The molecular skeleton of aminated 2-
Scheme 10. Unsymmetric Diamination
a
b
Isolated yield. At 110 °C.
all participated in the second amination reaction with high
efficiency.
Sequential C−H functionalization was also briefly tested
either with different types of organic electrophiles or using a
different metal catalytic system to extend the applicability of the
present approach (Scheme 11). We observed that a direct
Scheme 11. Unsymmetric Difunctionalization
Figure 3. X-ray structure of 20a (a) and 20c (b).
phenylpyrimidine (20c) is revealed to be almost planar
(dihedral angle of 6°) in the X-ray structure, implying that
the formation of a rhodacycle for the second amination would
be facile, maintaining the intramolecular hydrogen bond. We
believe that this would be an origin being responsible for the
different selectivity between 6-arylpurines which requires
rotation for second amination and arylpyrimidines (and
arylquinazolines) which does not require such a rotation.
When 3-(N,N-dimethylamino)-2-phenylpyridine was allowed
to react under conditions A, a monoaminated product (20c)
was obtained exclusively without diamination (entry 3).
Surprisingly, the same result was also observed even under
conditions B by using excess amounts of aryl azide. A crystal
structure of 20c showed that a H-bonding is present between
the introduced amino NH and NMe2 substituent while the 2-
phenylpyridine skeleton is significantly distorted with a dihedral
angle of 57° (Figure 3b). It is thus anticipated that the
formation of a rhodacycle for the second amination from the
first aminated compound (20c) would be difficult since the
required coplanarity of the 2-phenylpyridine skeleton is not
accessible due to the severe steric congestion between the
dimethylamino (-NMe2) substituent and installed amino group.
Sequential Arene Functionalization of Arylpurines. In
the chelation-assisted direct C−H functionalization, the
introduction of two different groups at the ortho-position relative
to the directing groups has been challenging. The key to
success in dealing with this issue will be the minimal inhibitory
effects of the first installed groups toward the second
introduction of functional groups. In this regard, we envisioned
to take advantage of the unique controlling property of the
purinyl directing group for the formation of unsymmetric
diaminated compounds. Indeed, we were pleased to observe
that the second amination of monoaminated compound (7)
was highly facile over a range of azides (Scheme 10). Not only
aryl azides (22a−22e) bearing various substituents at the para-
or meta-position but also sulfonyl (22f) and benzyl azide (22g)
imine addition took place with a monoaminated phenylpurine
(7) under the slightly modified Ellman’s conditions.34 Although
the product yield was moderate, this result is noteworthy in that
two different functional groups could be introduced in
sequence at our will. We also successfully carried out the Ir-
catalyzed amidation of 7 using acyl azide as the coupling
partner at room temperature according to our recent
protocol.7e
CONCLUSION
■
We have described herein the unique structural utility of purine
in the metal-catalyzed direct C−H functionalization of an aryl
pendant with an emphasis on the selectivity control. Highly
selective mono- or double C−H amination was achieved with
the assistance of an intramolecular hydrogen-bonding inter-
action. For the first amination of 6-arylpurines, a rhodacycle
was found to form through the chelation assistance of a purinyl
N1 atom. Experimental data including the isolation of the
rhodacycle and the demonstration of its catalytic activity
supported this postulate. The presence of N7, however, was
observed to be essential for the second functionalization
through an intramolecular H-bonding with the first introduced
amino NH moiety. It was also shown that the steric repulsion
between the first installed amino group and the directing group
is reduced by the H-bond assistance in order to perform the
second functionalization. This interpretation was validated by
1138
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
(3) (a) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem., Int. Ed. 2013, 52,
4453. (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,
11904. (c) Wencel-Delord, J.; Nimphius, C.; Wang, H.; Glorius, F.
Angew. Chem., Int. Ed. 2012, 51, 13001. (d) Stuart, D. R.; Fagnou, K.
Science 2007, 316, 1172. (e) Wei, W.; Su, W. J. Am. Chem. Soc. 2010,
132, 16377. (f) Potavathri, S.; Pereira, K. C.; Gorelsky, S. I.; Pike, A.;
LeBris, A. P.; DeBoef, B. J. Am. Chem. Soc. 2010, 132, 14676. (g) Zhao,
X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132, 5837.
(h) Yeung, C. S.; Zhao, X.; Borduas, N.; Dong, V. M. Chem. Sci. 2010,
1, 331. (i) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am.
Chem. Soc. 2013, 135, 6030. (j) Wang, X.; Leow, D.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 13864. (k) Wencel-Delord, J.; Nimphius, C.;
Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 2247.
(l) Morimoto, K.; Itoh, M.; Hirano, K.; Satoh, T.; Shibata, Y.; Tanaka,
K.; Miura, M. Angew. Chem., Int. Ed. 2012, 51, 5359. (m) Qin, X.; Liu,
H.; Qin, D.; Wu, Q.; You, J.; Zhao, D.; Guo, Q.; Huang, X.; Lan, J.
Chem. Sci. 2013, 4, 1964.
DFT calculations and well rationalized by taking the Curtin−
Hammett principle into account. On the basis of the unique
chelation property of a purine moiety, we have developed
orthogonal approaches to the selective functionalization of 6-
arylpurines either symmetrically or unsymmetrically. The
present strategy is anticipated to have a high utility in such
areas as catalysis and synthetic chemistry.
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedure and characterization of new
compounds, including 1H, 13C NMR spectra, Cartesian
coordinates of computed structures, and CIF files of 8, 9, 11,
20a, and 20c. This material is available free of charge via the
Internet at http://pubs.acs.org.
(4) (a) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068. (b) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11,
5178. (c) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900. (d) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L.
J. Am. Chem. Soc. 2011, 133, 1466. (e) Tsang, W. C. P.; Zheng, N.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. (f) Jordan-Hore, J.
A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am.
Chem. Soc. 2008, 130, 16184. (g) Cho, S. H.; Yoon, J.; Chang, S. J. Am.
Chem. Soc. 2011, 133, 5996. (h) Yu, D.-G.; Suri, M.; Glorius, F. J. Am.
Chem. Soc. 2013, 135, 8802. (i) Lian, Y.; Hummel, J. R.; Bergman, R.
G.; Ellman, J. A. J. Am. Chem. Soc. 2013, 135, 12584.
AUTHOR INFORMATION
Corresponding Authors
ysjn@kaist.ac.kr
sbchang@kaist.ac.kr
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by the Institute of Basic Science
(IBS) in Korea.
■
(5) (a) Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912.
(b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126,
2300. (c) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yun, F.; Wang, J.-Y.; Sheng,
J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135,
1236. (d) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 12203. (e) Mo, F.; Trzepkowski, L. J.; Dong, G. Angew.
Chem., Int. Ed. 2012, 51, 13075. (f) Shan, G.; Yang, X.; Ma, L.; Rao, Y.
Angew. Chem., Int. Ed. 2012, 51, 13070. (g) Thirunavukkarasu, V. S.;
Ackermann, L. Org. Lett. 2012, 14, 6206. (h) Yan, Y.; Feng, P.; Zheng,
Q.-Z.; Liang, Y.-F.; Lu, J.-F.; Cui, Y.; Jiao, N. Angew. Chem., Int. Ed.
2013, 52, 5827. (i) Gulevich, A. V.; Melkonyan, F. S.; Sarkar, D.;
Gevorgyan, V. J. Am. Chem. Soc. 2012, 134, 5528. (j) Huang, C.;
Ghavtadze, N.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc.
2011, 133, 17630.
(6) (a) Hull, K. L.; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 7134. (b) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford,
M. S. Org. Lett. 2006, 8, 2523. (c) Wan, X.; Ma, Z.; Li, B.; Zhang, K.;
Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006, 128, 7416. (d) Giri,
R.; Chen, X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2005, 44, 2112.
(e) Bedford, R. B.; Haddow, M. F.; Mitchell, C. J.; Webster, R. L.
Angew. Chem., Int. Ed. 2011, 50, 5524. (f) Mei, T.-S.; Giri, R.; Maugel,
N.; Yu, J.-Q. Angew. Chem., Int. Ed. 2008, 47, 5215.
(7) (a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang,
S. J. Am. Chem. Soc. 2012, 134, 9110. (b) Ryu, J.; Shin, K.; Park, S. H.;
Kim, J. Y.; Chang, S. Angew. Chem., Int. Ed. 2012, 51, 9904. (c) Shin,
K.; Baek, Y.; Chang, S. Angew. Chem., Int. Ed. 2013, 52, 8013. (d) Kim,
J.; Kim, J.; Chang, S. Chem.Eur. J. 2013, 19, 7328. (e) Ryu, J.; Kwak,
J.; Shin, K.; Lee, D.; Chang, S. J. Am. Chem. Soc. 2013, 135, 12861.
(f) Lee, D.; Kim, Y.; Chang, S. J. Org. Chem. 2013, 78, 11102.
(8) For recent reports on the metal-mediated C−N bond formation
using azides as the nitrogen source, see: (a) Nguyen, Q.; Sun, K.;
Driver, T. G. J. Am. Chem. Soc. 2012, 134, 7262. (b) Shi, J.; Zhou, B.;
Yang, Y.; Li, Y. Org. Biomol. Chem. 2012, 10, 8953. (c) Nguyen, Q.;
Nguyen, T.; Driver, T. G. J. Am. Chem. Soc. 2013, 135, 620. (d) Yadav,
M. R.; Rit, R. K.; Sahoo, A. K. Org. Lett. 2013, 15, 1638.
(e) Bhanuchandra, M.; Yadav, M. R.; Rit, R. K.; Kuram, M. R.;
Sahoo, A. K. Chem. Commun. 2013, 49, 5225. (f) Zheng, Q.-Z.; Liang,
Y.-F.; Qin, C.; Jiao, N. Chem. Commun. 2013, 49, 5654. (g) Nishioka,
Y.; Uchida, T.; Katsuki, T. Angew. Chem., Int. Ed. 2013, 52, 1739.
(h) Hennessy, E. T.; Betley, T. A. Science 2013, 340, 591.
REFERENCES
■
(1) (a) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc.
Rev. 2011, 40, 4740. (b) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (c) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215. (d) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew.
Chem., Int. Ed. 2009, 48, 9792. (e) Li, C.-J. Acc. Chem. Res. 2009, 42,
335. (f) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107,
174. (g) Lui, C.; Zhang, H.; Sui, W.; Lei, A. Chem. Rev. 2011, 111,
1780. (h) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(i) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42,
1074. (j) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res. 2008, 41,
222. (k) Lewis, L. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res.
2008, 41, 1013. (l) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew.
Chem., Int. Ed. 2012, 51, 8960. (m) Chen, X.; Engle, K. M.; Wang, D.-
H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (n) Seregin, I. V.;
Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (o) Dudnik, A. S.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49, 2096. (p) Campeau, L.
C.; Stuart, D. R.; Fagnou, L. Aldrichimica Acta 2007, 40, 35.
(q) Hirano, L.; Miura, M. Synlett 2011, 294. (r) Sun, C.-L.; Li, B.-J.;
Shi, Z.-J. Chem. Commun. 2010, 46, 677. (s) Kulkarni, A. A.; Daugulis,
O. Synthesis 2009, 4087. (t) Satoh, T.; Miura, M. Chem.Eur. J. 2010,
16, 11212.
(2) (a) Baxter, R. D.; Sale, D.; Engle, K. M.; Yu, J.-Q.; Blackmond, D.
G. J. Am. Chem. Soc. 2012, 134, 4600. (b) Engle, K. M.; Mei, T.-S.;
Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (c) Song, G.; Wang,
F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (d) Ryu, J.; Cho, S. H.;
Chang, S. Angew. Chem., Int. Ed. 2012, 51, 3677. (e) Park, S. H.; Kim,
J. Y.; Chang, S. Org. Lett. 2011, 13, 2372. (f) Cho, S. H.; Hwang, S. J.;
Chang, S. J. Am. Chem. Soc. 2008, 130, 9254. (g) Dams, M.; De Vos,
D. E.; Celen, S.; Jacobs, P. A. Angew. Chem., Int. Ed. 2003, 42, 3512.
(h) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc.
2011, 133, 12406. (i) Wu, J.; Cui, X.; Chen, L.; Jiang, G.; Wu, Y. J. Am.
Chem. Soc. 2009, 131, 13888. (j) Patureau, F. W.; Glorius, F. J. Am.
Chem. Soc. 2010, 132, 9982. (k) Ryu, T.; Kim, J.; Park, Y.; Kim, S.; Lee,
P. H. Org. Lett. 2013, 15, 3986. (l) Itoh, M.; Hashimoto, Y.; Hirano,
K.; Satoh, T.; Miura, M. J. Org. Chem. 2013, 78, 8098. (m) Umeda, N.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7094.
(n) Zhao, D.; Nimphius, C.; Lindale, M.; Glorius, F. Org. Lett. 2013,
15, 4504.
1139
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140

Journal of the American Chemical Society
Article
(9) (a) Hermann, T.; Patel, D. J. Science 2000, 287, 820. (b) Johnson,
R. E.; Haracska, L.; Prakash, L.; Prakash, S. Mol. Cell. Biol. 2006, 26,
6435. (c) Pullman, B.; Claverie, P.; Caillet, J. Proc. Natl. Acad. Sci.
U.S.A. 1967, 57, 1663.
(10) (a) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med.
Chem. 2000, 43, 1817. (b) Hocek, M.; Naus, P.; Pohl, R.; Votruba, I.;
Furman, P. A.; Tharnish, P. M.; Otto, M. J. J. Med. Chem. 2005, 48,
5869. (c) Bakkestuen, A. K.; Gundersen, L.-L.; Utenova, B. T. J. Med.
Chem. 2005, 48, 2710. (d) Gundersen, L.-L.; Nissen-Meyer, J.;
Spilsberg, B. J. Med. Chem. 2002, 45, 1383.
(11) For recent reports on the metal-catalyzed C−H activation using
purine as a directing group, see: (a) Guo, H.-M.; Jiang, L.-L.; Niu, H.-
Y.; Rao, W.-H.; Liang, L.; Mao, R.-Z.; Li, D.-Y.; Qu, G.-R. Org. Lett.
2011, 13, 2008. (b) Lakshman, M. K.; Deb, A. C.; Chamala, R. R.;
Pradhan, P.; Pratap, R. Angew. Chem., Int. Ed. 2011, 50, 11400.
(c) Guo, H.-M.; Rao, W.-H.; Niu, H.-Y.; Jiang, L.-L.; Meng, G.; Jin, J.-
J.; Yang, X.-N.; Qu, G.-R. Chem. Commun. 2011, 47, 5608.
(d) Chamala, R. R.; Parrish, D.; Pradhan, P.; Lakshman, M. K. J.
Org. Chem. 2013, 78, 7423.
(12) For instance, see: Xiao, D.; Li, J.; Hu, Y.; Wang, H.; Wang, Z.;
Wang, Z.; Wei, Y.; Sun, U.; Wu, Q.; Zhang, H.; Peng, Y.; Kong, F.;
Sung, U.; Luo, H.; Han, Y. Kinase Modulating Compounds,
Compositions Containing the Same and Use Thereof. WO
2013071865, 2013.
(13) After extending the reaction time to 48 h, an isolable amount of
a diaminated product (4) was obtained albeit in low yield (6%).
(14) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008,
130, 12414.
(15) Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrometric
Identification of Organic Compounds; John Wiley & Sons: New York,
2005.
(16) (a) Steiner, T. Angew. Chem., Int. Ed. 2002, 41, 78. (b) Pihko, P.
M. Hydrogen Bondings in Organic Synthesis; Wiley-VCH: Weinheim,
Germany, 2009.
(27) Unlike a substrate 1 that afforded a diaminated compound (4)
in 6% after 48 h (ref 13), diaminated product 15 was not detected
even after 72 h from the reaction of 13.
(28) Becke, A. D. J. Chem. Phys. 1993, 98, 5648.
(29) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(30) Shao, Y.; Molnar, L. F.; Jung, Y.; Kussmann, J.; Ochsenfeld, C.;
Brown, S. T.; Gilbert, A. T. B.; Slipchenko, L. V.; Levchenko, S. V.;
O’Neill, D. P.; DiStasio, R. A., Jr.; Lochan, R. C.; Wang, T.; Beran, G. J.
O.; Besley, N. A.; Herbert, J. M.; Lin, C. Y.; Van Voorhis, T.; Chien, S.
H.; Ryan, A. S.; Steele, P.; Rassolov, V. A.; Maslen, P. E.; Korambath,
P. P.; Adamson, R. D.; Austin, B.; Baker, J.; Byrd, E. F. C.; Dachsel, H.;
Doerksen, R. J.; Dreuw, A.; Dunietz, B. D.; Dutoi, A. D.; Furlani, T. R.;
Gwaltney, S. R.; Heyden, A.; Hirata, S.; Hsu, C.-P.; Kedziora, G.;
Khalliulin, R. Z.; Klunzinger, P.; Lee, A. M.; Lee, M. S.; Liang, W. Z.;
Lotan, I.; Nair, N.; Peters, B.; Proynov, E. I.; Pieniazek, P. A.; Rhee, Y.
M.; Ritchie, J.; Rosta, E.; Sherrill, C. D.; Simmonett, A. C.; Subotnik, J.
E.; Woodcock, H. L., III; Zhang, W.; Bell, A. T.; Chakraborty, A. K.;
Chipman, D. M.; Keil, F. J.; Warshel, A.; Hehre, W. J.; Schaefer, H. F.,
III; Kong, J.; Krylov, A. I.; Gill, P. M. W.; Head-Gordon, M. Phys.
Chem. Chem. Phys. 2006, 8, 3172.
(31) Andrae, D.; Haeussermann, U.; Dolg, M.; Stoll, H.; Preuss, H.
Theor. Chim. Acta 1990, 77, 123.
(32) Politzer, P.; Truhlar, D. G. Chemical Applications of Atomic and
Molecular Electrostatic Potentials: Reactivity, Structure, Scattering, And
Energetics of Organic, Inorganic, And Biological Systems; Plenum Press:
New York, 1981.
(33) Gadre, S. R.; Shirsat, R. N. Electrostatics of Atoms and Molecules;
Universities Press: Hyderabad, India, 2000.
(34) (a) Tauchert, M. E.; Incarvito, C. D.; Rheingold, A. L.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2012, 134, 1482.
(b) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2011, 133, 1248. (c) Li, Y.; Li, B.-J.; Wang, W.-H.; Huang,
W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew. Chem., Int. Ed. 2011,
50, 2115.
(17) (a) Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2006, 128, 9413. (b) Wang, Y.-F.; Chen, R.-X.; Wang, K.; Zhang, B.-
B.; Li, Z.-B.; Xu, D.-Q. Green Chem. 2012, 14, 893.
(18) (a) Freccero, M.; Gandolfi, R.; Sarzi-Amade, M.; Rastelli, A.
Tetrahedron 1998, 54, 12323. (b) Wahlen, J.; De Vos, D. E.; Jacobs, P.
A. Org. Lett. 2003, 5, 1777. (c) Kamata, K.; Hirano, T.; Kuzuya, S.;
Mizuno, N. J. Am. Chem. Soc. 2009, 131, 6997. (d) Fackler, P.;
Berthold, C.; Voss, F.; Bach, T. J. Am. Chem. Soc. 2010, 132, 15911.
(19) (a) Schneider, J. F.; Lauber, M. B.; Muhr, V.; Kratzer, D.;
Paradies, J. Org. Biomol. Chem. 2011, 9, 4323. (b) Meemken, F.;
Maeda, N.; Hungerbuhler, K.; Baiker, A. Angew. Chem., Int. Ed. 2012,
51, 8212.
(20) (a) Corsaro, A.; Buemi, G.; Chiacchio, U.; Perrini, G.; Pistara,
V.; Romeo, R. Tetrahedron 1996, 52, 7885. (b) Quadrelli, P.; Fassardi,
V.; Cardarelli, A.; Caramella, P. Eur. J. Org. Chem. 2002, 2058.
(c) Talavera, G.; Reyes, E.; Vicario, J. L.; Carrillo, L. Angew. Chem., Int.
Ed. 2012, 51, 4104.
(21) (a) Aggarwal, A.; Lancaster, N. L.; Sethi, A. R.; Welton, T. Green
Chem. 2002, 4, 517. (b) Thadani, A. N.; Stankovic, A. R.; Rawal, V. H.
Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5846. (c) Tan, B.; Hernandez-
Torres, G.; Barbas, C. F., III. J. Am. Chem. Soc. 2011, 133, 12354.
(22) (a) Gondi, V. B.; Gravel, M.; Rawal, V. H. Org. Lett. 2005, 7,
5657. (b) McGilvra, J. D.; Unni, A. K.; Modi, K.; Rawal, V. H. Angew.
Chem., Int. Ed. 2006, 45, 6130. (c) Gondi, V. B.; Hagihara, K.; Rawal,
V. H. Chem. Commun. 2010, 46, 904. (d) Chen, X.-H.; Yu, J.; Gong,
L.-Z. Chem. Commun. 2010, 46, 6437.
(23) Lee, J. M.; Ahn, D.-S.; Jung, D. Y.; Lee, J.; Do, Y.; Kim, S. K.;
Chang, S. J. Am. Chem. Soc. 2006, 128, 12954.
(24) Ros, A.; Lopez-Rodriguez, R.; Estepa, B.; Alvarez, E.; Fernandez,
R.; Lassaletta, J. M. J. Am. Chem. Soc. 2012, 134, 4573.
(25) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2013, 15, 3014.
(26) (a) Roitzsch, M.; Lippert, B. Inorg. Chem. 2004, 43, 5483.
(b) Cetina, M.; Dzolic, Z.; Mrvos-Sermek, D.; Hergold-Brundic, A.;
Nagl, A.; Mintas, M. J. Peptide Res. 2004, 63, 391.
1140
dx.doi.org/10.1021/ja4118472 | J. Am. Chem. Soc. 2014, 136, 1132−1140