Mechanism of Boron-Catalyzed N-Alkylation of Amines with Carboxylic Acids

Article abstract of DOI:10.1021/acs.joc.6b00778

Mechanistic study has been carried out on the B(C₆F₅)₃-catalyzed amine alkylation with carboxylic acid. The reaction includes acid-amine condensation and amide reduction steps. In condensation step, the catalyst-free mechanism is found to be more favorable than the B(C₆F₅)₃-catalyzed mechanism, because the automatic formation of the stable B(C₆F₅)₃-amine complex deactivates the catalyst in the latter case. Meanwhile, the catalyst-free condensation is constituted by nucleophilic attack and the indirect H₂O-elimination (with acid acting as proton shuttle) steps. After that, the amide reduction undergoes a Lewis acid (B(C₆F₅)₃)-catalyzed mechanism rather than a Br?nsted acid (B(C₆F₅)₃-coordinated HCOOH)-catalyzed one. The B(C₆F₅)₃)-catalyzed reduction includes twice silyl-hydride transfer steps, while the first silyl transfer is the rate-determining step of the overall alkylation catalytic cycle. The above condensation-reduction mechanism is supported by control experiments (on both temperature and substrates). Meanwhile, the predicted chemoselectivity is consistent with the predominant formation of the alkylation product (over disilyl acetal product).

Full text of DOI:10.1021/acs.joc.6b00778

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Article
Mechanism of Boron-Catalyzed N-Alkylation of Amines with Carboxylic Acids
Qi Zhang, Ming-Chen Fu, Hai-Zhu Yu, and Yao Fu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00778 • Publication Date (Web): 21 Jul 2016
Downloaded from http://pubs.acs.org on July 24, 2016
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Mechanism of BoronꢀCatalyzed NꢀAlkylation of Amines with
Carboxylic Acids
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Qi Zhang,a MingꢀChen Fu,a HaiꢀZhu Yu,*b Yao Fu *a
a Collaborative Innovation Center of Chemistry for Energy Materials, CAS Key Laboratory of
Urban Pollutant Conversion, Department of Chemistry, University of Science and Technology of
China, Hefei 230026
b Department of Chemistry and Centre for Atomic Engineering of Advanced Materials, Anhui
University, Hefei, 230601
Emails: fuyao@ustc.edu.cn; yuhaizhu@ahu.edu.cn
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Abstract
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Mechanistic study has been carried out on the B(C6F5)3ꢀcatalyzed amine alkylation
with carboxylic acid. The reaction includes acidꢀamine condensation and amide
reduction steps. In condensation step, the catalystꢀfree mechanism is found to be more
favorable than the B(C6F5)3ꢀcatalyzed mechanism, because the automatic formation of
the stable B(C6F5)3ꢀamine complex deactivates the catalyst in the latter case.
Meanwhile, the catalystꢀfree condensation is constituted by nucleophilic attack and
the indirect H2Oꢀelimination (with acid acting as proton shuttle) steps. After that, the
amide reduction undergoes Lewis acid (B(C6F5)3)ꢀcatalyzed mechanism rather than
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Brønsted
acid
(B(C6F5)3ꢀcoordinated
HCOOH)ꢀcatalyzed
one.
The
B(C6F5)3)ꢀcatalyzed reduction includes twice silylꢀhydride transfer steps, while the
first silyl transfer is the rateꢀdetermining step of the overall alkylation catalytic cycle.
The above condensationꢀreduction mechanism is supported by control experiments
(on both temperature and substrates). Meanwhile, the predicted chemoselectivity is
consistent with the predominant formation of the alkylation product (over disilyl
acetal product).
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1. Introduction
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Nꢀalkylated amines are ubiquitous structures in organic synthesis,
pharmaceuticals and biological systems.1 Given the significance of these structures,
developing straightforward and economic synthetic methods has become an important
research topic.2 Compared with the traditional substitution reactions of amines with
hazardous alkyl halides,3 transition metalꢀcatalyzed amine alkylation has recently
attracted extensive interest.4 In recent years, Rh,5 Ir,6 Ru,7 Pd8 etc. catalyzed
hydrogenative reduction of imines and enamines has become powerful strategy to
prepare Nꢀalkylated amines (Scheme 1A). However, the substrates (imine and
enamine) always require additional preparation from carbonyl compounds. With H2,
CO or silane as reductants, Rh,9 Ir,10 Ru,11 Re,12 Fe,13 etc. catalyzed reductive
amination of carbonyl compounds14 (aldehydes, ketones, formic acid and CO2)
provides a more straightforward method (Scheme 1B). For example, Beller group15
successfully achieved the Ptꢀcatalyzed alkylation of the more stable and available
carboxylic acid substrates (Scheme 1C). In this context, our group recently reported a
metalꢀfree amine alkylation reaction using B(C6F5)3 as catalyst and silane as reductant
(Scheme 1D).16 The alkylation of various aromatic and aliphatic amines with formic
acid and general carboxylic acid was achieved. In addition, three important
commercialized drug molecules, Butenafine, Cinacalcet and Piribedil were easily
synthesized through this method.16
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Scheme 1. The synthetic methods of Nꢀalkylated amines
In studying the mechanism of the B(C6F5)3ꢀcatalyzed amine alkylation, the
control experiments indicate that amide is the possible intermediate, rather than
aldehyde or alcohol.16 Accordingly, we proposed that carboxylic acid 1 and amine 2
first undergo condensation to generate amide 3. Reduction of 3 then occurs to give the
alkylation product 4 (Scheme 2A). Nonetheless, there are still some unsolved
mechanistic problems. First, the detailed mechanism of the condensation is unclear.
According to Whiting’s recent study on the condensation reaction between benzoic
acid and phenylethylamine,17 the mechanism mainly undergoes the acid dimerization,
nucleophilic attack (with one carboxylic acid acting as proton acceptor) and
H2Oꢀelimination steps (catalystꢀfree mechanism, Scheme 2B). On the other hand,
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Yamamoto18a and Brookhart18b et al. suggest that B(C6F5)3 catalyzed condensation
between carboxylic acid and amine might start with a rapid silaneꢀcarboxylic acid
interaction, and the formed silyl ester then react with amine to generate the amide
(B(C6F5)3ꢀcatalyzed system, Scheme 2B).19 Both of these two mechanisms are
plausible for the condensation step in our reaction system. Second, the mechanism of
amide reduction is uncertain. According to the recent studies,20ꢀ24 either Lewis acid or
the Brønsted acid (B(C6F5)3ꢀcoordinated acid) might catalyze the reduction of the
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carbonyl group (Scheme 2C). Third, the acid was found to be easily reduced to disilyl
A. The proposed alkylation mechanism
O
O
H
N
condensation
R3
OSiR3
OSiR3
acid
amide
R3
R1
N
R1
N
R2
R3
R1
OH
R2
R1
reduction
reduction
R2
4
5
2
1
3
B. Possible condensation mechanisms
catalyst-free condensation
Ph
Ph
Ph
Ph
H
H
H
H
Ph
O
H
H
O
O
N
N
N
Ph
O
HO
HO
Ph
HO
O
O
O
Ph
Ph
H
O
A
B
C
D
B(C6F5)3 -catalyzed condensation
O
O
HOSiR'3
OSiR'3
H
O
1 equiv HNR2R3
1.0 mol% B(C6F5)3
O
H
R3
SiR'3
R1
N
N
H
R
O
4 equiv HSiR'3
R2
R1
O
R2
R3
3
E
F
1
C. Possible reduction mechanisms
Lewis acid-catalyzed reduction
H
H Si
Ph
B(C6F5)3
O
SiH2Ph
R3
1.0 mol% B(C6F5)3
R3
R3
O
B(C6F5)3
HSiR'3
R3
R2
R1
N
O
N
N
R1
N
R2
3
R2
4 equiv HSiR'3
R2
R1
H
H
R1
B(C6F5)3
G
H
4
Br nsted acid-catalyzed reduction
H
O
R3
R2
Ar3B
R1
Ar3B
R1
R1
R2
N
HSiR'3
O
O
BAr3
3
R3
R1
N
H
H
N
O
O
R1
O
R2
HSiR'3
R3
I
6
J
4
Scheme 2. (A) The possible mechanisms of the boronꢀcatalyzed amine alkylation and
acid reduction; (B) The possible condensation mechanisms; (C) The possible
reduction mechanisms.
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acetal 5 under the B(C6F5)3ꢀcatalyzed system (Scheme 2A),18 whereas no disilyl acetal
product was observed in our system. The origin for the interesting chemoselectivity is
worth clarification. To solve these problems, we carried out combined theoretical and
experimental mechanistic studies on the reaction shown in Scheme 1D.
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2. Computational methods
The Gaussian09 suite of program25 was used for calculations in this study. The
B3LYP26ꢀ28 method combined with the 6ꢀ31G* basis set and SMD model29 was used
for geometry optimization in dibutylether solvent (consistent with our experiments16).
To get the thermodynamic corrections of Gibbs free energy and verify the stationary
points to be local minima or saddle points, we conducted frequency analysis at the
same level with optimization. For all transition states, we performed the intrinsic
reaction coordinate (IRC) analysis to confirm that they connect the correct reactants
and products on the potential energy surfaces.30 M06ꢀ2X31/6ꢀ311++G** method with
the SMD29 model was used for the solution phase singleꢀpoint energy calculations of
all these stationary points (with dibutylether solvent). All energetics involved in this
study are calculated by adding the Gibbs free energy correction calculated at
B3LYP/6ꢀ31G* and the singleꢀpoint energy calculated at the M06ꢀ2X/6ꢀ311++G**
method.32
3. Results and Discussions
3.1 Model reaction
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In accordance with our experimental work,16 the generation of dimethylaniline 3a
by the reaction of formic acid 1a with methylaniline 2a (eq 1) is chosen as the model
reaction. B(C6F5)3, PhSiH3 and nBu2O are used as catalyst, reductant and solvent,
respectively.
3.2 The mechanism of the amine alkylation
Efforts were first put into examining the energy demands of the mechanism of the
amine alkylation. In this mechanism, 1a and 2a first undergo condensation to generate
amide (section 3.2.1), from which reduction occurs to yield the alkylation product 3a
(Section 3.2.2).
3.2.1 The acidꢀamine condensation
The detailed catalyst-free mechanism. As mentioned in introduction, catalystꢀfree
mechanism includes nucleophilic attack and H2Oꢀelimination steps.17 The
nucleophilic attack step (Figure 1) starts with the dimerization of carboxylic acid 1a.
The calculation results indicate that the formation of the dimer Int1 is slightly
exergonic by 0.1 kcal/mol, and the two monomers ligate with each other via the
hydrogen bonds (Figure 1). After that, the amine substrate 2a nucleophilically attacks
Int1 via the transition state TS1 to generate the intermediate Int2. In TS1, CꢀN bond
formation, and the two proton transfer processes (H transfers from O2 to O, H1
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transfers from N to O3, Figure 2) occur simultaneously, and the free energy barrier is
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18.2 kcal/mol (Int1→TS1).
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Figure 1. The energy profiles of catalystꢀfree condensation mechanism (in kcal/mol).
N
N
H1
O3
C
O1
O
O1
C
H
H
O
O2
C-N =1.452
O-H =0.974
C-O1=1.411
TS1 C-N=1.791
Int2
O1
H
O3
H1
O1
C
O2
N
O
H
C
O
O-H =1.130
C-O1=1.936
O-H =1.028
C-O1=1.783
TS3
TS2
Figure 2. Optimized structures for selected species of Catalystꢀfree mechanism. Bond
lengths are given in Å.
For the H2Oꢀelimination from Int2, we first investigated the direct elimination
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mechanism via the transition state TS2. In this transition state, the eliminating H, OH
group and the forming carbonyl constitute a fourꢀmembered ring. The breaking OꢀH
and CꢀOH bonds stretch to 1.130 and 1.936 Å in TS2 from 0.974 and 1.411 Å in Int2
(Figure 2), respectively. The energy barrier for this step is as high as 46.6 kcal/mol
(Int1→TS2), and thus the possibility for the direct H2Oꢀelimination can be excluded.
Considering that formic acid could possibly act as the proton shuttle,33 we also
examined the energy demand of the indirect H2Oꢀelimination process. As shown in
Figure 1, the two proton transfer processes (H transfers from O to O2, H1 transfers
from O3 to O1, Figure 2) and CꢀO1 cleavage might occur simultaneously via the
transition state TS3. The breaking OꢀH bond and CꢀO1 bond stretch to 1.028 and
1.783 Å respectively. The free energy barrier of the indirect elimination process is
25.6 kcal/mol (Int1 → TS3), which is much lower than that of the direct elimination
(46.6 kcal/mol). The reason may be attributed to the higher acidity of HCOOH than
OH group in Int2. After the indirect H2Oꢀelimination, the amide 4a was generated.
According to the aforementioned discussions, the dimerizationꢀnucleophilic
attackꢀindirect H2Oꢀelimination represents the feasible catalystꢀfree condensation
mechanism, and the energy demand is 25.6 kcal/mol.
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The detailed B(C6F5)3-catalyzed mechanism. As mentioned in the introduction, the
condensation might also occur via the silyl ester formation, nucleophilic attack and
HOSiR'3ꢀelimination steps (B(C6F5)3ꢀcatalyzed mechanism). According to the
calculation results, the coordination of either substrate 1a or 2a to the catalyst
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B(C6F5)3 can stabilize the boron center (Figure 3A), and the coordination is exergonic
by 0.9 or 12.3 kcal/mol, respectively. In addition, the generation of protonꢀtransferred
intermediate 12aꢀB is exergonic by 11.5 kcal/mol. Therefore, 2aꢀB is the main
existing form of the catalyst, and was chosen as the starting point of the catalyst
B(C6F5)3.
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A
Ar3B
O
1a
Ar3B
1a,2a
O
BAr3
H
OH
H
O
H2N
G = -0.9 kcal/mol
cat
G = -11.5 kcal/mol
1a-B
12a-B
2a
HN
BAr3
2a-B
G = -12.3 kcal/mol
O
B
B(C6F5)3
H
H
Ar = C6F5
O
H
H
O
H
SiH2
Ph
H
O
H
SiH2
Ph
TS5 68.1
H
Ar
TS4
O
H
Si
Ar
H
B
O
H
44.6
Ar
H
Ph
Ar
H
H
Si
Ph
TS6
O
Ar
B
OH
Ar
TS7
H
29.6
TS6
Int3
23.3
23.3
1a, PhSiH3
2a
Ar
H
Si
H
H2,2a-B
Ar
B
H
O
2a
1a, PhSiH3
OH
cat
Ar
Ph
H
12.3
H
H
Si
O
O
Ph
Int4
-12.3
0.0
H
2a-B
hydride transfer
silyl transfer
Figure 3. (A) The equilibrium between cat, 1aꢀB, 2aꢀB and 12aꢀB; (B) The energy
profiles of the silyl ester formation process (in kcal/mol).
Figure 3B shows the detailed energy profiles of the silyl ester formation process.
The dissociation of 2a from 2aꢀB occurs first to generate the free catalyst cat. PhSiH3
and acid substrate 1a then participate the silyl transfer step, and the metathesisꢀtype
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silyl ester formation was first investigated. In the related transtion state TS4, the
catalyst B(C6F5)3 is coordinated on the carbonyl group of acid, and the breaking OꢀH
of hydroxy and SiꢀH of PhSiH3 constitute a fourꢀmembered ring. The free energy of
TS4 is 44.6 kcal/mol. For comparison, we also located the similar fourꢀmembered
cyclic transition state TS5 without the coordination of B(C6F5)3. The free energy of
TS5 (68.1 kcal/mol) is significantly higher than TS4, indicating that the Lewis acidity
of B(C6F5)3 benefits the cleavage of OꢀH bond. Nonetheless, both activation barriers
are too high to overcome under the experimental conditions (100oC), and we have to
consider the other possibilities.
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Inspired by Sakata’s recent DFT study34a on B(C6F5)3ꢀcatalyzed ketone
hydrosilylation, we took into account the possibility of the B(C6F5)3 promoted SiꢀH
cleavage. The energy barrier of the step is 23.3 kcal/mol (2aꢀB→TS6). In the
optimized strucutre of TS6 (Figure 4), the SiꢀH bond stretches from 1.49 Å (in free
PhSiH3) to 1.58 Å, the SiꢀO and BꢀH bonds shorten to 2.83 and 1.51 Å, respectively.
Therefore, we concluded that the breaking of SiꢀH bond, formation of SiꢀO and BꢀH
bonds occur simultaneously. In the generated intermediate Int3, the SiꢀO and BꢀH
bonds further shorten to 2.19 and 1.34 Å, and the SiꢀH distance stretches to 1.69 Å.
ꢀ
From Int3, hydride transfer34 from HB(C6F5)3 group to the hydroxyl group occurs via
the synergistic transition state TS7, and the formation of HꢀH bond, cleavage of OꢀH
and BꢀH bonds occur simultaneously. This step gives silyl ester intermediate Int4 and
H2 as the products, and the energy barrier is 29.6 kcal/mol (2aꢀB→TS7). The
regenerated catalyst B(C6F5)3 then easily coordinates another 2a to generate the more
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stable 2aꢀB.
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B
1.58
H
B
1.34
H
O
O
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Si
Si
1.51
1.69
Int3
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Si
H-
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H+
H1
O
N
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H
TS10
TS7
Figure 4. Optimized structures for selected species of B(C6F5)3ꢀcatalyzed
condensation. Bond lengths are given in Å.
Figure 5. The energy profile of the transformation from silyl ester to amide (in
kcal/mol).
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From Int 4, the energy profiles for the subseqeunt nucleophilic attack and
HOSiH2Phꢀelimination processes are given in Figure 5. It’s found that the B(C6F5)3
exchange between Int4 and 2aꢀB in generating B(C6F5)3ꢀcoordinated silyl ester Int5
is endergonic by 7.7 kcal/mol. After that, nucleophilic attack of 2a to Int5 occurs via
the transition state TS8 with energy barrier of 19.7 kcal/mol (Int4→TS8). This step
generates the CꢀN bond formed intermediate Int6. For the following
HOSiH2Phꢀelimination, both the direct elimination and the indirect elimination (with
the formic acid as proton shuttle33) were investigated. For the direct
HOSiH2Phꢀelimination process, the free energy of the related fourꢀmembered cyclic
transition state (i.e. TS9 in Figures 5) is 33.5 kcal/mol. By contrast, with formic acid
acting as proton shuttle, the free energy of the indirect elimination transition state
TS10 is much lower (i.e. 11.7 kcal/mol, Figures 4 & 5). After TS10, HOSiH2Ph is
released and the amide Int7 is formed. The energy barrier of this step is 24.0 kcal/mol
(Int4→TS10) and the system energy decreases to ꢀ18.1 kcal/mol. According to
Figures 3 and 5, the energy demand for the B(C6F5)3ꢀcatalyzed mechanism is 29.6
kcal/mol (2aꢀB→TS7).
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Comparison between the catalyst-free and B(C6F5)3-catalyzed condensation
pathways. Figure 6 shows the comparison between the two possible condensation
pathways. For the catalystꢀfree condensation, nucleophilic attack and H2Oꢀelimination
occur successively to obtain amide 4a (Figure 1). The indirect H2Oꢀelimination
transition state TS3 is the highest energyꢀlying species with free energy of 25.5
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kcal/mol (Figure 6). For the B(C6F5)3ꢀcatalyzed condensation, silyl transferꢀhydride
transfer process first occurs from 2aꢀB to give silyl ester Int4 (Figure 3), from which
nucleophilic attack and HOSiH2Phꢀelimination occur to obtain Int7 (Figure 5).
During these processes, the hydride transfer transition state TS7 is the highest
energyꢀlying species, and its free energy is 29.6 kcal/mol. Therefore, catalystꢀfree
condensation is more favorable than the B(C6F5)3ꢀcatalyzed one.
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Figure 6. The comparison between the catalystꢀfree and the B(C6F5)3ꢀcatalyzed
condensation mechanism.
Analyzing the reason for facility of catalystꢀfree condensation than the
B(C6F5)3ꢀcatalyzed one, we found that the formation of the stable complex 2aꢀB is
mainly responsible. Without 2aꢀB, the energy barrier of B(C6F5)3 catalyzed
mechanism is only 17.3 kcal/mol (2a→TS7). However, the formation of 2aꢀB is
automatic, as long as the boron catalyst is exposed to the amine substrate 2a.
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Therefore, the coordination passivates the catalyst, and results in the more feasible
catalystꢀfree condensation mechanism.
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3.2.2 The reduction of amide
Lewis acid-catalyzed reduction
The detailed energy profiles for the Lewis acidꢀcatalyzed reduction has been shown in
Figure 7. B(C6F5)3 exchange first occurs between 4a and 2aꢀB to give
B(C6F5)3ꢀcoordinated amide Int7 and 2a. From Int7, the first silyl transfer occurs via
the transition state TS11 to transfer ꢀSiPhH2 group from silane to carbonyl group of
the amide. The energy barrier is 28.4 kcal/mol (Int7→TS11). The generated
intermediate Int8 then undergoes hydride transfer transition state TS12 to transfer Hꢀ
ꢀ
from HB(C6F5)3 group to carbonyl C atom, and the energy barrier is 20.5 kcal/mol
(Int7 → TS12). After that, the siloxane intermediate Int9 is generated, and the
released catalyst is capped by the amine substrate 2a. Int9 then undergoes ꢀSiPhH2
transfer from silane to the O atom of siloxane via the second silyl transfer transition
state TS13. The generated intermediate Int10 then easily dissociates SiOSi
(PhH2SiOSiPhH2) to generate the imine cation Int11 and the anion intermediate Int12.
Finally, a facile hydride transfer occurs between these two intermediates to generate
alkylation product 3a with the regeneration of 2aꢀB. According to Figure 7, the first
silyl transfer transition state TS11 determines the overall energy demand of the amide
reduction process (28.4 kcal/mol, Int7→ TS11).
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Figure 7. The energy profile of Lewis acid catalyzed amide reduction (in kcal/mol).
Figure 8. The energy profile of Brønsted acid catalyzed amide reduction (in
kcal/mol).
Brønsted acid-catalyzed reduction
Figure 8 shows the detailed energy profiles for the Brønsted acidꢀcatalyzed amide
reduction. B(C6F5)3 first transfers from Int7 to 1a, giving B(C6F5)3ꢀcoordinated acid
1aꢀB as the product. The process is endergonic by 11.9 kcal/mol, because amide is
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more nucleophilic than acid. Then, the proton in 1aꢀB transfers to the O atom in 4a to
generate Int13. The process is barrierless with energy decrease of 8.2 kcal/mol.
Subsquently, with the participation of silane, hydride transfer occurs via the transition
states TS14. In TS14, the COOꢀ group nucleophilicly attacks the Si atom of silane and
the hydride of silane transfers to the carbon cation. The energy barrier of the
elementary hydride transfer step is 37.0 kcal/mol (Int13→TS14). After this step,
B(C6F5)3ꢀcoordinated silyl ester Int5 and Int14 are generated with energy decrease of
38.8 kcal/mol. Thereafter, two mechanisms might be responsible for the reduction of
Int14 to the product 3a (Figure 8). In the Brønsted acid catalyzed reduction (in blue),
the proton transfer in intermediate Int15 first occurs to generate Int16. With the
release of H2O, Int17 is generated with energy decrease of 6.1 kcal/mol. The silane
mediated hydride transfer then occurs via the transition state TS15. The energy barrier
of this step is 23.9 kcal/mol. The product 3a is finally yielded with Int5. In the Lewis
acid (i.e. B(C6F5)3) catalyzed reduction (in red), Int14 first goes through silyl transfer
transition state TS16 to generate the intermediate Int18. The Int18 dissociates SiOSi
to give cation Int11. The facile hydride transfer occurs between Int11 and Int12 to
obtain 3a and regenerate 2aꢀB. The energy barrier of this mechanism is 23.7 kcal/mol
(Int17→TS16). Therefore, for the reduction of Int14, both of these mechanisms are
possible (23.9 vs 23.7 kcal/mol). For the overall Brønsted acidꢀcatalyzed amide
reduction, the first hydride transfer transition state TS14 determines the overall
energy barrier (40.7 kcal/mol, Int7→TS14). It is unfavorable compared with the
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Lewis acidꢀcatalyzed one (28.4 kcal/mol, Figure 7).
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3.3 The overall mechanism of amine alkylation
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For clarity reasons, the overall mechanism of the B(C6F5)3ꢀcatalyzed amine alkylation
is shown in Figure 9. The acid 1a and amine 2a first undergo the catalystꢀfree
condensation (including nucleophilic attack and H2Oꢀelimination) to generate amide
4a. The H2Oꢀelimination step determines the energy demand of the condensation
(25.6 kcal/mol). The following amide reduction undergoes twice silyl transferꢀhydride
transfer processes to generate alkylation product 3a. The first silyl transfer determines
the energy demand of the amide reduction (28.4 kcal/mol). According to these results,
the first silyl transfer in amide reduction is the rate determining step of the amine
alkylation reaction, and the overall activation barrier is 28.4 kcal/mol.
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Figure 9. The overall mechanism of the amine alkylation (in kcal/mol).
To verify the above calculation results, some experiments were carried out. First,
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condensation product amide were mainly obtained under lowered temperature (eq 2),
and this observation is consistent with the calculation results that acidꢀamine
condensation is easier than the amide reduction. Second, without the catalyst B(C6F5)3
and reductant PhSiH3, the reaction of 1a and 2a gives amide 4a as the product (eq 3),
and this is consistent with the catalystꢀfree condensation mechanism.35
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3.4 Discussions on acid reduction mechanism
According to the previous studies by Yamamoto18a and Brookhart 18b, the carboxylic
acid could be reduced to disilyl acetal under the B(C6F5)3ꢀsilane system.18 Note that
our reaction system is highly similar to Yamamoto’s, whereas no disilyl acetal was
obtained. To explore the origin of the interesting chemoselectivity, we carried out the
following calculations and discussions.
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Figure 10. The energy profile of acid reduction process (in kcal/mol).
In our system, the carboxylic acid could be first reduced to the silyl ester (2aꢀB +
1a + PhSiH3→Int4, as shown in Figure 3B), and then the second reduction can occur
to obtain the disilyl acetal. The energy barrier for the transformation of 1a to silyl
ester Int4 is 29.6 kcal/mol. From Int4, silyl transfer occurs via transition state TS17,
transferring the silyl group from silane to the carbonyl in Int4 to generate
intermediate Int19. The free energy barrier of this step is 26.8 kcal/mol (Int4→TS17).
Next, Int19 undergoes the hydride transfer step to give the disilyl acetal Int20 via the
transition state TS18. The free energy barrier of this step is 23.6 kcal/mol
(Int4→TS18). Accordingly, the transformation from 1a to Int20 undergoes twice
silyl transferꢀhydride transfer processes. The first hydride transfer transition state TS7
determines the overall energy barrier (29.6 kcal/mol).
Comparing the acid reduction (Figure 10) with amine alkylation (Figure 7), we
found that the amide 4a would be facilely generated, because the acidꢀamine
condensation is stoichiometric and has lower energy barrier than the acid reduction
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(25.6 vs 29.6 kcal/mol). From 4a, the energy barrier of amide reduction is still lower
than that of acid reduction (28.4 vs 29.6 kcal/mol). Therefore, the amine alkylation is
kinetically more favorable than acid reduction, which is consistent with our previous
experiments that alkylation product was obtained predominantly. In addition, the
origin of the chemoselectivity is the same as the selectivity origin of the catalystꢀfree
condensation mechanism (over the B(C6F5)3ꢀcatalyzed one). That is, the formation of
the stable amineꢀB(C6F5)3 complex (2aꢀB) passivates the catalyst and results in the
unfavorable B(C6F5)3ꢀcatalyzed acid reduction.
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4. Conclusions
Our group recently reported the B(C6F5)3ꢀcatalyzed carboxylic acidꢀparticipated
alkylation of various aromatic and aliphatic amines with silane as reductant. In the
present study, DFT calculations were carried out to investigate the detailed
mechanism. The calculation results show that the condensation of amine and acid
undergoes catalystꢀfree mechanism rather than B(C6F5)3ꢀcatalyzed mechanism. For
the catalystꢀfree condensation, nucleophilic attack of amine to acid occurs prior to the
H2Oꢀelimination, and indirect elimination process with acid as proton shuttle is the
favorable H2Oꢀelimination mechanism. The following amide reduction undergoes
Lewis acid (B(C6F5)3)ꢀcatalyzed mechanism rather than the Brønsted acid
(B(C6F5)3ꢀcoordinated HCOOH)ꢀcatalyzed one. The favorable reduction process
includes twice silyl transferꢀhydride transfer processes to obtain the alkylation product,
with the first silyl transfer acting as the rateꢀdetermining step of the overall alkylation
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process. The alkylation mechanism is supported by the control experiments of
temperature and substrates. Finally, the catalyst passivation caused by the automatic
coordination of amine with B(C6F5)3 catalyst are determininant to the
chemoselectivity, because it results in the unfavorable acid reduction step and the
associated B(C6F5)3ꢀcatalyzed acid reduction mechanisms.
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EXPERIMENTAL SECTION
General Procedure. In a Schlenk tube under argon atmosphere, B(C6F5)3 (1.0
n
mol%,1.1 mg) was dissolved in dry Bu2O (1.0 mL), and PhSiH3 (4.0 equiv) was
added. Then, NꢀMethylaniline (1.0 equiv, 0.2 mmol) and HCO2H (2.3 equiv, 4.6
o
mmol) were added via a syringe. The reaction mixture was stirred for 8 h at 100 C.
After completion, the mixture was diluted with ethyl acetate (5 mL), quenched with
aqueous NaOH (3 M solution; 3 mL) carefully, and stirred for 3 h at room temperature.
The yields were analyzed by GC using nꢀDodecane as an internal standard.
N,NꢀDimethylaniline (3a): The compound data was in agreement with the literature
1
(Ref. Adv. Synth. Catal. 2015, 357, 714). H NMR (400 MHz, CDCl3) δ 7.29 – 7.19
(m, 2H), 7.02 – 6.34 (m, 3H), 2.94 (s, 6H).
NꢀMethylformanilide (4a)：The compound data was in agreement with the literature
1
(Ref. Chem. Commun., 2014, 50, 189). H NMR (400 MHz, CDCl3) δ 8.48 (s, 1H),
7.42 (t, J = 7.9 Hz, 1H), 7.35 – 7.26 (m, 1H), 7.22 – 7.15 (m, 1H), 3.33 (s, 1H).
ASSOCIATED CONTENT
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Supporting Information
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Details of the control experiments, and Cartesian coordinates, free energies, and
thermal corrections. The Supporting Information is available free of charge on the
ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
fuyao@ustc.edu.cn; yuhaizhu@ahu.edu.cn
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NSFC (21325208, 21172209, 21361140372), the 973 Program
(2012CB215306), Scientific research funds of Anhui University (J10117700074),
FRFCU (WK2060190025, WK2060190040), CAS (KJCX2ꢀEWꢀJ02), PCSIRT and
National Supercomputing Center in Shenzhen and USTC for providing the
computational resources.
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