Copper-catalyzed diastereoselective aerobic intramolecular dehydrogenative coupling of hydrazones via sp3 C-H functionalization

Article abstract of DOI:10.1039/c5sc01736j

Transition metal-catalyzed cross dehydrogenative coupling is an important tool for functionalization of the α Csp³-H bond of amines. Among this reaction category, copper-catalyzed selective C-C bond formation under atmospheric O₂ is

Full text of DOI:10.1039/c5sc01736j

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Copper-Catalyzed Diastereoselective Aerobic
Intramolecular Dehydrogenative Coupling of
Hydrazones via sp3 C−H Functionalization†
Cite this: DOI: 10.1039/x0xx00000x
Xuesong Wu,a Mian Wang,b Guangwu Zhang,a Yan Zhao,a Jianyi Wangb* and
Haibo Gea*
Received 00th January 2015,
Accepted 00th January 2015
DOI: 10.1039/x0xx00000x
Transition metal-catalyzed cross dehydrogenative coupling is an important tool for functionalization of
the α Csp3−H bond of amines. Among this reaction category, copper-catalyzed selective C−C bond
formation under atmospheric O2 is of considerable research interest and significant progress has been
achieved in recent years. In comparison, development of the intramolecular version of this transformation
is still in its infancy. Furthermore, diastereoselective cyclization with this transformation has not been
achieved. Here, we describe the highly diastereoselective intramolecular dehydrogenative cyclization of
N,N-disubstituted hydrazones by a copper-catalyzed sp3 C−H bond functionalization process. The
reaction protocol utilizes O2 as the oxidant and shows great functional group compatibility.
Computational studies suggest that a 5center/6-electron disrotatory cyclization mechanism is probably
involved in the process for controlling the diastereoselectivity. This work represents the first example of
www.rsc.org/
a
copper-catalyzed, direct intramolecular diastereoselective coupling reaction via an iminium ion
intermediate. Additionally, it provides an environmentally friendly and atom efficient approach to access
substituted pyrazolines, an important structural unit in many biologically active compounds.
C
−
C bond construction, and a variety of copper-catalyzed
aerobic dehydrogenative coupling reactions have been reported
via sp or sp2
H bond functionalization. Representative
Introduction
Selective carbon-carbon (C−C) bond formation is a fundamental
focus in chemical research due to its importance in organic,
medicinal, agricultural, and material chemistry.1 Conventional
C−
examples, which have expanded product diversity, include
oxidative dimerization of phenols, naphthols and electron-
deficient arenes, cross coupling of terminal alkynes with
electron-deficient arenes, and intramolecular dehydrogenative
cyclization of anilides.4e,g,6 Furthermore, copper-catalyzed
methods for the construction of C−C bonds, such as nucleophilic
addition and substitution reactions, Friedel-Crafts-type
reactions, and transition-metal-catalyzed or -mediated cross
coupling reactions, rely primarily on prefunctionalized reactants,
which somehow limits the synthetic application of these
thransformations.2 Additionally, stoichiometric amounts of toxic
metal waste are often generated in the processes, which
constitutes an environmental issue. For these reasons, transition
metal-catalyzed cross coupling reactions via direct
functionalization of relatively unreactive C−H bonds has been of
great interest in the past two decades.3 Among this reaction class,
copper-catalyzed aerobic dehydrogenative couplings via a
double C−H bond functionalization process have received
considerable attention in recent years due to the economical and
ecological advantages.4
The oxidative dimerization of terminal alkynes, the Glaser
reaction reported in 1869, is the first example of copper-
catalyzed aerobic dehydrogenative coupling.5 Since then,
considerable efforts have been devoted in this area for selective
aerobic cross dehydrogenative coupling (CDC) via an sp3 C
−H
bond functionalization process has also been established on
tertiary amines by Miura, Li, and others.4a,e,g It has been
demonstrated that a wide range of nucleophiles, such as alkynes,
nitroalkanes, malonic esters, ketones, and electron-rich
(hetero)arenes, are compatible coupling partners under aerobic
oxidative conditions. Mechanistically, an iminium ion
intermediate is generated via oxidation of the corresponding
amine. This intermediate then serves as an active electrophile for
the subsequent nucleophilic addition reaction.7 Despite its
considerable potential, this reaction suffers from a restricted
substrate scope of tertiary amines; only substituted 1,2,3,4-
tetrahydroisoquinoline and N,N-dimethylaniline derivatives
have been reported as suitable substrates. Furthermore, this
transformation is limited to the intermolecular version, in part
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the cyclization could also be effectively catalyzed by other CuI or CuII
sources under the above modified conditions (entries 13–17).
due to the non-selective oxidation of the amine over the internal
nucleophile.8
We envisaged that the use of an enamine-type motif as an
internal nucleophile could potentially overcome this drawback
and extend the reaction scope to intramolecular cyclizations.9
Based on this design, copper-catalyzed aerobic intramolecular
dehydrogenative cyclization of hydrazones was examined and
realized in our laboratory.10,11 However, it was noted that the
initial cyclized intermediate was very unstable under the reaction
conditions and was rapidly aromatized to pyrazoles.
Furthermore, only α-unsubstituted 1-benzyl-1-isopropyl-2-(1-
phenylethylidene)hydrazines were well tolerated under the
catalyst system. Additionally, aliphatic hydrazones completely
failed in this process due to competitive decomposition of the
starting materials. To overcome these drawbacks and thus to
provide a straightforward environmentally friendly and atom
efficient access to diversified pyrazoline derivatives, copper-
catalyzed diastereoselecive cyclization of aromatic and aliphatic
hydrazones was investigated. It is noteworthy that pyrazoline is
Table 1. Optimization of reaction conditionsa
a
prominent structural motif in many pharmacological
compounds, and pyrazoline derivatives display a broad spectrum
of biological activities including antibacterial, antidepressant,
antidiabetic, antiepileptic, antihypotensive, anti-inflammatory,
antimalarial,
antimicrobial,
antipyretic-analgestic,
antituberculotic, antitumor, immunosuppression, insecticidal,
muscle relaxant, psycho analeptic, and tranquilizing activities.12
Here we report detailed studies in which the copper-catalyzed
sp3 C−H functionalization strategy was thoroughly examined
and further explored to expand its scope of synthetic utility. To
provide important mechanistic insights into various factors that
control the product distribution, density functional theory (DFT)
calculations were further conducted to rationalize the
diastereoselectivity observed. The combined work of chemical
synthesis, NMR, and computation revealed how the interplay of
molecular configurations, steric effects, and the symmetry
requirement of electronic structure reactivity, can be utilized to
precisely control the diastereoselectivity in the products, thereby
providing a valuable guidance to rational designs of the related
synthetic routes.
a Reaction conditions: 1a (0.3 mmol), Cu source, base, additive, O2 (1 atm), 2
mL of solvent, 100 oC, 4 h. b Yields and conversions are based on 1a,
determined by GC/MS using diphenylketone as the internal standard. c d.r.
(anti:syn): determined by 1H NMR spectroscopy. d 2 : 3 (v/v). e 12 h. f Isolated
yields.
With the optimized conditions in hand, the scope of
hydrazone substrates was studied (Table 2). As expected,
aromatic, acyclic and cyclic aliphatic hydrazones were
compatible with the oxidative reaction conditions (2a
Interestingly, the reaction showed substrate-dependent
diastereoselectivity pattern, and the anti-isomers of 2a and 2b
were obtained as the major products while the syn-isomers of 2c
were the major forms. It is noteworthy that the current methods
-h).
a
-
g
for the synthesis of syn-4,5-pyrazolines rely primarily on the
[3+2]-cyclization of a diazo compound and an olefin, which
often suffers from poor regioselectivity.13 Furthermore, the N-
Results and discussion
benzyl group could also be replaced with another alkyl group (2i
-
Our study commenced with copper-catalyzed dehydrogenative
cyclization of 1,1-dibenzyl-2-(1-phenylpropylidene)hydrazine (1a)
under atmospheric O2 (Table 1). After an initial screening of the
catalyst, base, and solvent, it was found that the pyrazoline 2a was
obtained in 27% yield, with only trace amount of the undesired
pyrazole compound 3, by using a catalytic amount of Cu(OTf)2 and
stoichiometric KI, KOAc, and DBU in NMP with O2 as the external
oxidant (entry 5). Interestingly, this reaction showed high
diastereoselectivity, with the anti isomer as the major product. Further
optimization showed that this reaction was improved by using NMP
n
), in which the aromatic hydrazones favored the anti-isomers,
and the aliphatic substrates favored the syn-isomers.
Additionally, an N-phenyl substituted hydrazone yielded
exclusively the syn-isomer 2o, providing an important and
tunable strategy to selectively access either anti or syn
pyrazolines. Moreover, 1,2,3,4-tetrahydroquinoliine is also an
effective substrate (2p).
t
and AmOH as co-solvent (entry 8). It was then noticed that the
reaction yield was significantly increased by extending the reaction
time to 12 h from 4 h (entry 9). In addition, the replacement of DBU
with DBN significantly increased the reaction rate, and the desired
product was obtained in 86% yield within 4 h (entry 10). Moreover,
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Table 2. Scope of hydrazonesa,b,c
Furthermore, systematic electronic or steric effects of the above
reactions on 1,2,3,4-tetrahydroisoquinolines have barely been
studied.
As shown in Table 3, both electron-donating and electron-
withdrawing groups on the phenyl ring are compatible under the
current catalytic system. Interestingly, high diastereoselectivity
was observed in all cases with the syn diastereoisomers as the
major products (5b-o). Generally, electron-withdrawing group-
substituted substrates provided better yields compared with
electron-donating substituents in the same position. Considering
that an iminium ion intermediate is formed prior to cyclization,
these results are not surprising since an electron-withdrawing
group increases the electrophilicity of the iminium ion and thus
facilitates the cyclization. Additionally, an electron-withdrawing
group may retard the further oxidation of pyrazolines and thus
minimize formation of the by-product pyrazoles. Furthermore, a
steric effect was observed for this reaction: C8-substituted
hydrazones gave lower yields of desired products compared with
the C5-, C6-, or C7-substituted substrates. Finally, halogens (F,
Cl, and Br) are also well tolerated, which provides the
opportunity for further product manipulation.
Table 3. Scope of 1,2,3,4-tetrahydroisoquinolines a,b,c
a Reaction conditions: 1 (0.3 mmol), Cu(OTf)2 (10 mol%), KOAc (0.5
equiv.), DBN (0.5 equiv.), KI (1.0 equiv.), O2 (1 atm), 2 mL co-solvent NMP
and tAmOH (NMP/tAmOH = 2:3, v/v), 100 oC, 3-14 h. b Isolated yield. c d.r.
was determined by 1H NMR spectroscopy.
In
our
previous
study
of
of
dehydrogenative
cyclization/aromatization
1-benzyl-1-isopropyl-2-(1-
phenylethylidene)hydrazine, it has been demonstrated that both
electron-donating and electron-withdrawing groups on the
phenyl rings were compatible.11 It is also believed that an
oxidized iminium ion intermediate is involved in this process,
serving as the precursor for the cyclization. Therefore, in order
to simplify the complexity of configuration of the iminium ion
intermediates, and thus to better understand the outcome of
diastereoselectivity, we carried out an extensive substrate scope
study on N-cyclohexylidene-3,4-dihydroisoquinolin-2(1H)-
amine (Table 3). For each substrate, only one isomeric iminium
ion intermediate will be generated, which will undergo either 5-
center/6-electron cyclization or intramolecular nucleophilic
addition to provide the corresponding diastereoisomers. It is
worth mentioning that extensive synthetic studies have been
carried out with azomethine imines, which have resulted in a
variety of applications of the products obtained.14 However, to
our knowledge, there are only two reported examples which
involve the direct use of a dihydroisoquinoline derivative via an
oxidative sp3 C−H activation process: mercuric oxide-mediated
a Reaction conditions: 4 (0.3 mmol), Cu(OTf)2 (10 mol%), KOAc (0.5
equiv.), DBU (0.5 equiv.), KI (1.0 equiv.), O2 (1 atm), 2 mL co-solvent NMP
and tAmOH (NMP/tAmOH = 2:3, v/v), 100 oC, 3.5-4.5 h. b Isolated yield. c
d.r. (syn:anti) was determined by 1H NMR spectroscopy.
NOESY analysis was carried out to confirm the relative
configuration of the product (Figure 1). NOEs between the
dimerization
and
Rh(III)-catalyzed
cycloaddition.9,15
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Table 4. Scope of the Imine Moiety a,b,c
aromatic proton H1 of 2a and H12a, H12b were observed.
Additionally, there was no observable NOE between H1 and H13,
or H14 and H12a or H12b. These results indicate that H13 and H14
have the syn relationship.
Figure 1. NOESY and relative configuration of 2a
Next, an imine substrate scope study was carried out (Table
4). The reaction occurred with high diastereoselectivity on
substrates with a larger ring (5q and 5r). The 5-membered ring
substrate also provided a good yield of product 5p under the
modified reaction conditions. Furthermore, α,β-unsaturated
hydrazones are also compatible (5u and 5v), which allows for
further transformation of the initial products. As expected, good
to high yields of products were obtained on substrates with
substituted cyclohexylidenehydrazine moieties (5s, 5t, 5w-z and
5aa). In addition, good to excellent diastereoselectivity was
observed with α-substituted cyclohexylidenehydrazine, favoring
the anti-products (5w-y). In comparison, γ-substituents on the
cyclohexylidenehydrazine moiety did not significantly affect the
relative diastereoselectivity (5z and 5aa). Additionally, linear
hydrazones are also compatible with the oxidative conditions,
favoring the formation of the syn-isomers. However, in this case,
the ratio of diastereoselectivity was dramatically decreased.
Considering that there are two possible conformers present in the
iminium ion intermediate oxidized either from 5z or 5aa, the
above result is not surprising.
a Reaction conditions: 4 (0.3 mmol), Cu(OTf)2 (10 mol%), KOAc (0.5
equiv.), DBU (0.5 equiv.), KI (1.0 equiv.), O2 (1 atm), 2 mL co-solvent NMP
and tAmOH (NMP/tAmOH = 2:3, v/v), 100 oC, 1-20 h. b Isolated yield. c d.r.
was determined by 1H NMR spectroscopy.
On the basis of the above results and our previous report,11
plausible reaction mechanism is proposed (Scheme 1).4g,7
a
Oxidation of the amine nitrogen on
1
generates the radical cation
is then converted into
A
via an SET process. The radical cation
A
the iminium ion intermediates B1 and B2 via either an
oxidation/deprotonation or a homolytic cleavage process.
Tautomerization of the imine moiety on B1 and B2 to enamine-
type diastereoisomers C1
subsequent nucleophilic addition provides the intermediate D1
and D2, which then give pyrazoline upon deprotonation. The
, C2, C3 and C4, followed by
2
rationale of high syn over anti diastereoselectivity is also
proposed based on the previous reports by Hoffmann and
List.16,17 It is believed that the neutral nitrogen in intermediate
C
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will behave as an sp2 hybridized atom. Therefore, the lone-pair Frequency analysis was carried out to verify the optimized
of electrons on the nitrogen will participate in the π-conjugation geometry as minima or transition state, and to obtain its free
together with the four π electrons in the double bonds, resulting energy. The intrinsic reaction coordinate (IRC)21 calculation was
in a 5-center/6-electron system, similar to the situation found in applied to judge whether the transition state connects the
a pentadienyl anion. For such homoconjugated systems, the reactants and the products.
HOMO is actually a "symmetric" nonbonding orbital, which is In all systems, the symbols used to represent the related species
1,5-bonding with the preferred U planar configuration. For are: hydrazine (
thermally induced electrocyclic ring closures, the symmetric intermediate ( ), the charged pyrazoline product (
HOMO requires a disrotatory mechanism, which results in the final pyrazoline product. For 2f, 2p, 5a, and 5ab
corresponding product . It should be mentioned that α-alkyl Cu represents the enamine-type intermediates with trans/cis
species could potentially be formed from deprotonation of the conformation for the C=C double bond; D1 D2 represent the
intermediates B1 B2 under basic conditions. Intramolecular syn/anti charged pyrazoline intermediates and the syn/anti final
nucleophilic addition of these Cu species could also provide the pyrazoline products. For 2a B1 B2 is the iminium ion with
trans/cis conformation for the C=N+ double bond; D1
D2 are the
1
), the iminium ion (
B
), the enamine-type
) and the
C1 C2
C
D
,
/
2
/
/
,
/
desired products.
/
anti/syn charged pyrazoline intermediates. Given the
conformational combinations of the C=N+ and C=C double
bonds, four enamine-type intermediates are considered for this
system, which are referred to as C1(trans, cis), C2(cis, trans),
C3(trans, trans) and C4(cis, cis), respectively. The transition
state of a disrotatory/conrotatory reaction is specified by “a”/
“b”, for example, TS2a
/TS2b is the transition state of the
disrotatory/conrotatory reaction of C2
.
The proposed
mechanism, optimized geometries, some free energy profiles,
and original data are shown in Supporting Information (SI).
Computational Results for the Formation of 5a Based on the
complexity of these systems, the computational results of 5a is
first represented here. The charge of the carbon atom in the C=N+
bond is -0.769e in C1, -0.609e in TS1a, and -0.466e in TS1b
respectively. The charge of the terminal carbon atom in the C=C
bond is 0.916e in C1, 0.679e in TS1a, and 0.729e in TS1b
respectively. As shown in Figure S1, the dihedral angles
D(C=N+-N-C) and D(N+-N-C=C) of the pyrazoline ring in TS1a
are 22.1° and -19.6°, respectively. The C=N+ and C=C bonds
,
Scheme 1. Proposed reaction mechanism
,
Mechanistic Studies with Computation Toward molecular-
level understanding of diastereoselective 5-center/6-electron
cyclization mechanism displayed in these copper-based C−H
functionalization reactions, we performed density functional
theory (DFT) investigations on five representative systems (2a
2f, 2p, 5a, and 5ab).
form a pseudo-plane with the dihedral angle D(C=N+⋯C=C) to
,
be 3.1°, and the neutral nitrogen atom is a little out of that plane.
For TS1b, the values of D(C=N+-N-C), D(N+-N-C=C) and
D(C=N+
⋯C=C) are 35.0°, 7.5°, and 40.2°, respectively,
Computational Methods All the calculations were carried out
for the five systems by using Gaussian 09 program suites.18 The
Kohn−Sham density functional theory (DFT) was solved with
the B3LYP functional,19 and the 6-31G+(d,p) basis sets were
selected. The key stationary species (B, C, D) related to
diastereoselective cyclization in Scheme 1 of these five systems
implying that the pyrazoline ring in TS1b is twisted and it looks
like a helical folding conformation. Clearly, compared with the
C=N+-N-C=C in TS1b, the C=N+-N-C=
C
in TS1a is closer to a
coplanar conformation. The distance R(C=N+
C=C) between
the two terminal carbon atoms of the pyrazoline ring is 2.25 Å in
TS1a and 2.15 Å in TS1b. These show that the C D reaction is
⋯
→
a 5-center/6-electron cyclization constituted by C=N+-NH-C=C,
although this system does not completely satisfy the Hückel rule
(not typically coplanar).
were fully optimized in the gas phase. The transition states (TS
)
from C→D, which seems to be the most relevant step in
determining the diastereoselectivity of the products, were
especially emphasized, and the transition states from B→C are
outside the scope of this work and thus were excluded. The
influence of the solvent environment on the reaction was
evaluated by using the polarizable continuum models (PCM)
method20 with the gas-phase optimized geometries. The
molecular cavity was treated using the united atom Hartree-Fock
(UAHF) parameterization. Since N-methylpyrrolidone (ε=32.2)
and 2-methyl-2-butanol (ε=5.78) are not available in
Gaussian09, we chose ethanol as the solvent (ε=24.55).
In the free energy profiles (Figure 2),
tautomer by 10.9 kcal/mol. The reaction is endothermic by 1.9
kcal/mol for D1 process, and exothermic by 4.3 kcal/mol for
D2 process. Even though the conformation of the
cyclohexane is chair in D1 and twist boat in D2 D2 (anti) shows
more stability than D1 (syn) The reason may be that the two
C is less stable than its
B
C
→
C
→
,
.
bulky substituents are on the same side of the pyrazoline ring in
D1, while the two substituents are on the different side of the
pyrazoline ring in D2, causing the steric repulsion being stronger
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in D1 than in D2. However, the active free energy generating D1 same as that captured from gas-phase calculations. Such a huge
is 1.6 kcal/mol lower than that generating D2, indicating that improvement of the reaction is mainly attributed to the solvation
C
prefers to undergo disrotatory process (TS1a) to form D1, rather of ions.
than conrotatory process (TS1b) to afford D2. This may be Computational Results for the Formation of 2a The charge of
because the C=N+-N-C=C (5-center/6-electron) in TS1a is more the carbon atom in the C=N+ bond is -0.464e in C1, -0.321e in
coplanar and more satisfies the Hückel rule compared with that C2, -0.313e in C3, -0.579e in C4, -1.407e in TS1a, -0.388e in
in TS1b
.
These are in good agreement with the TS1b, -0.983e in TS2a and -0.656e in TS2b, respectively. The
diastereoselectivity observed in the copper-based C−H charge of the terminal carbon atom in the C=C bond is separately
functionalization reactions (syn-D1 is major product).
0.139, 0.337, 0.641, -0.077, 0.131, 0.297, 0.042 and -0.161e for
the corresponding species. Seen from Figure S2, the dihedral
angles D(C=N+-N-C) and D(N+-N-C=C) of the pyrazoline ring
in TS1a are 30.0° and -33.8°, respectively. The C=N+ and C=C
bonds form
a
pseudo-plane with the dihedral angle
D(C=N+ C=C) of -2.4°, and the neutral nitrogen atom is a little
⋯
out of that plane. The corresponding values are separately -44.1°,
4.3° and -37.7° in TS1b, also suggesting that the pyrazoline ring
in TS1b is a pseudo-plane. However, this pyrazoline ring in
TS1b is slightly apart from the coplanar conformation compared
with that in TS1a. In TS2a, the values of D(C=N+-N-C), D(N+-
N-C=C) and D(C=N+
⋯C=C) are separately 37.6°, 23.3° and
56.5°, implying that the pyrazoline ring is twisted and it looks
like a helical folding conformation. The corresponding values
are separately -29.2, -18.9° and -43.7° in TS2b, showing that the
pyrazoline ring in TS2b is twisted with the opposite direction,
but the twist with the opposite direction would increase the steric
hindrance between the methyl group and the benzyl group. The
Figure 2. Free energy profiles of the reaction generating 5a in the gas phase. Free
energies in the solution phase are given in parentheses.
distance R(C=N+
⋯C=C) between the two terminal carbon atoms
To better understand this point, HOMOs of TS1a and TS1b
were compared. As shown in Figure 3, the under lobe of the
orbital of the C atom in the C=N+ bond overlaps with the under
lobe of the orbital of the terminal C atom in the C=C bond, and
of the pyrazoline ring is 2.36 Å in TS1a, 2.32 Å in TS1b, 2.34
Å in TS2a, and 2.34 Å in TS2b. These also demonstrate that the
C=N+-NH-C=C constitutes a 5-center/6-electron system, but not
a typical Hückel system (not completely coplanar).
C=N+-NH constitutes a delocalized system in TS1a. In TS1b
,
As shown in Figure 4, C1 and C2 are more stable than C3 and
the under lobe of the orbital of the C atom in the C=N+ bond
overlaps with the upper lobe of the orbital of the terminal C atom
in the C=C bond. However, the delocalized orbitals of the N-NH
bond do not overlap with the C atom in the C=N+ bond,
generating an orbital nodal surface between the C atom and the
N atoms. These demonstrate that TS1b is less stable and more
C4, supporting that C1 and C2 are major intermediate compared
with C3 and C4. The anti product D1 is more stable than the syn
product D2 in the gas phase, which is also attributed to the steric
repulsion between the two bulky substituents on the same side of
the pyrazoline ring in D2 compared with D1
kcal/mol relative to TS1b, and TS2a is -3.1 kcal/mol relative to
TS2b, showing that tends to undergo disrotatory
TS1a/TS2a) process to give the product, rather than a
. TS1a is -3.3
difficult to cross than TS1a, supporting that the intermediate
tends to undergo a disrotatory process to form D1, rather than a
conrotatory process to afford D2
C
C
a
(
.
conrotatory process (TS1b/TS2b) to afford the product. The
reason may be that the C=N+-N-C=C in TS1a is closer to the
Hückel system compared with that in TS1b (5-center/6-electron
and coplanar conformation), and the steric hindrance between
the methyl group and the benzyl group in TS2a is smaller than
that in TS2b. Compared with C3 and C4, C1 and C2 overcome
less of a free energy barrier, determining the diastereoselectivity
of this reaction. Similar to 5a, the presence of a solvent can
obviously improve the reaction process (the
C → D1/D2
processes are exothermic and the active energy barriers become
easier to overcome), but the overall diastereoselective trend is the
same as that captured from gas-phase calculations. The main
reason for such a huge improvement of the reaction is also the
solvation of ions.
Figure 3. HOMOs of TS1a and TS1b generating 5a
The presence of a solvent can obviously improve the reaction
process (the
C→D1/D2 processes are exothermic and the active
free energy barriers are easier to overcome, shown in parentheses
in Figure 3), but the overall diastereoselective tendency is the
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Figure 5. HOMOs of TS1a, TS1b, TS2a and TS2b generating 2a
Furthermore, computational studies of three more
representative substrates were also carried out to account for the
diastereoselective outcome (Scheme 2). For 2f, two enamine-
type iminium ion intermediates are formed in the cyclization
process, resulting in two different diastereoisomers. Based on the
calculation (see Supporting Information), the (E)-isomer is more
stable, resulting in syn-2f as the major product via a 5-center/6-
electron disrotatory cyclization process. In the case of 2p, the
intermediate with the methyl and phenyl groups on the opposite
side is the major isomer, and thus the anti-isomer becomes the
major product. For 5ab, the intermediate with two alkyl groups
on the same side becomes the major isomers, and thus the syn-
5ab is the major product. Compared with 5ab
, the
diastereoselectivity in 5ac is lower because the ratio of the major
isomer is decreased due to the stronger steric effect by the
isopropyl group. The combined results from experimental and
computational studies suggest that the diastereoselectivity of
products is possibly determined by the relative stability of the
enamine-type iminium ion intermediates via a 5-center/6-
electron disrotatory cyclization process.
Figure 4. Free energy profiles of the reaction generating 2a in the gas phase. Free
energies in the solution phase are given in parentheses.
To better understand this point, HOMOs of TS1a, TS1b,
TS2a and TS2b were compared. Seen from Figure 5, the under
lobe of the orbital of the C atom in the C=N+ bond overlaps with
the under lobe of the orbital of the terminal C atom in the C=C
bond, and C=N+-NH-C=C and phenyl group constitute a
delocalized system in TS1a. In TS1b the under lobe of orbital of
C atom in C=N+ bond overlaps with the under lobe of the orbital
of the terminal C atom in the C=C bond, but the delocalized
system only consists of C=N+-NH and phenyl groups. The
delocalized system in TS1b is smaller than TS1a, suggesting that
Scheme 2. Interpretation of stereoselectivity of 2f, 2p, and 5ab.
Conclusions
TS1b is less stable and more difficult to overcome than TS1a
.
In summary, a highly diastereoselective aerobic intramolecular
dehydrogenative cyclization of N,N-disubstituted hydrazones
with good functional group tolerance was developed using a
copper-catalyzed double sp3 C−H bond functionalization
process. The observed diastereoselectivity was rationalized by a
5center/6-electron disrotatory cyclization mechanism, which
was supported by computational studies. As the first example of
Compared with the orbital in TS2a, the C=N+-NH-C=C in TS2b
does not constitute a complete delocalized orbital, and two
orbital nodal surfaces are found between the C and N+-NH, and
N+-NH and C=C bonds, also suggesting that TS2b is less stable
and more difficult to cross than TS2a. Therefore, C1 (C2) goes
through a disrotatory process to form D1(D2), instead of a
conrotatory process to afford D2 (D1).
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the copper-catalyzed aerobic diastereoselective intramolecular
cyclization of amines via an iminium ion intermediate, this
transformation provides a straightforward, environmentally
friendly and atom efficient access to pyrazolines with up to five
fused-ring systems. The enantioselective version of this
transformation is currently under study in our laboratory.
4
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Acknowledgements
The authors gratefully acknowledge Indiana University-Purdue
University Indianapolis and NSF CHE-1350541 for financial
support. We also would like to thank Dr. Yan Zhou and Professor
Jingzhi Pu for helpful discussions of this manuscript.
Additionally, Jianyi Wang would like to thank the National
Natural Science Foundation of China (No.21262004) for
financial support.
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Table of Contents
Diastereoselective aerobic dehydrogenative cyclization of hydrazones is
described via a copper-catalyzed sp3 C−H functionalization process.
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