Enantioselective Synthesis of N-Alkylamines through β-Amino C-H Functionalization Promoted by Cooperative Actions of B(C6F5)3and a Chiral Lewis Acid Co-Catalyst

Article abstract of DOI:10.1021/jacs.0c13200

We disclose a catalytic method for β-C(sp3)-H functionalization of N-alkylamines for the synthesis of enantiomerically enriched β-substituted amines, entities prevalent in pharmaceutical compounds and used to generate different families of chiral catalysts. We demonstrate that a catalyst system comprising of seemingly competitive Lewis acids, B(C6F5)3, and a chiral Mg- or Sc-based complex, promotes the highly enantioselective union of N-alkylamines and α,β-unsaturated compounds. An array of δ-amino carbonyl compounds was synthesized under redox-neutral conditions by enantioselective reaction of a N-alkylamine-derived enamine and an electrophile activated by the chiral Lewis acid co-catalyst. The utility of the approach is highlighted by late-stage β-C-H functionalization of bioactive amines. Investigations in regard to the mechanistic nuances of the catalytic processes are described.

Full text of DOI:10.1021/jacs.0c13200

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Article
Enantioselective Synthesis of N‑Alkylamines through β‑Amino C−H
Functionalization Promoted by Cooperative Actions of B(C F ) and
6
5 3
a Chiral Lewis Acid Co-Catalyst
†
†
Yejin Chang, Min Cao, Jessica Z. Chan, Cunyuan Zhao, Yuankai Wang, Rose Yang,
and Masayuki Wasa*
Cite This: J. Am. Chem. Soc. 2021, 143, 2441−2455
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*
sı Supporting Information
3
ABSTRACT: We disclose a catalytic method for β-C(sp )−H functional-
ization of N-alkylamines for the synthesis of enantiomerically enriched β-
substituted amines, entities prevalent in pharmaceutical compounds and
used to generate different families of chiral catalysts. We demonstrate that a
catalyst system comprising of seemingly competitive Lewis acids, B(C F ) ,
6
5 3
and a chiral Mg- or Sc-based complex, promotes the highly enantioselective
union of N-alkylamines and α,β-unsaturated compounds. An array of δ-
amino carbonyl compounds was synthesized under redox-neutral conditions
by enantioselective reaction of a N-alkylamine-derived enamine and an
electrophile activated by the chiral Lewis acid co-catalyst. The utility of the
approach is highlighted by late-stage β-C−H functionalization of bioactive
amines. Investigations in regard to the mechanistic nuances of the catalytic
processes are described.
1
. INTRODUCTION
none 1a to give organometallic intermediate I en route to
aziridine 2a (Figure 1a). Equally noteworthy is Pd/PR3-
catalyzed stereospecific cross-coupling of 1,3-oxazinane 1c
52
Enantioselective synthesis of N-alkylamines through the
3
transformations of amino C(sp )−H bonds has emerged as a
powerful strategy to access key building blocks of N-based
natural products, drugs and catalysts for stereoselective
(
prepared by s-BuLi/(+)-sparteine-mediated α-lithiation of 1b
and Li/Zn exchange with ZnCl ) and Ph−Br to give 2c via
2
1
−18
54
synthesis.
A plethora of organometallic catalysts have
LnPd−enamine II (Figure 1b). Still, key shortcomings
remain unaddressed. For instance, acid−base complexation
often occurs in a mixture that contains a Lewis acidic catalyst
been introduced that can promote reaction at an α-amino C−
H bond by conversion of an amine substrate to appropriately
reactive intermediate (e.g., α-amino radical, iminium ion),
19−31
(
e.g., Pd(OAc) ) and a Lewis basic N-alkylamine substrate
32,33
2
metal−carbenoid insertion,
or heteroatom-directed metal-
More remote γ-amino C−H bonds may be
activated by L Pd-catalyzed and N-directed cyclometala-
and/or product which may also contain other Lewis acid-
3
4−36
ation.
55−62
sensitive functional groups.
Additionally, because these
n
3
7−41
methods require IOAc or s-BuLi, moieties that readily react
with oxidants and Lewis bases can be problematic. As a result,
substrate scope is confined to highly sterically encumbered
and/or Boc-protected amines (1a, 1b, and analogues) with
minimal electronic and steric affinity toward Lewis acids, Lewis
bases or oxidants. A compelling research objective is thus
development of a sustainable element-based and enantiose-
lective catalyst system, highly tolerant of functional groups,
tion.
However, development of methods for synthesis of
enantiomerically enriched amines by β-amino C−H function-
alization is a major challenge that remains to be
addressed.
or hydride transfer is facilitated by stabilization of the resulting
species through hyperconjugation with the nitrogen lone pair.
Nonetheless, such processes do not readily occur at the β
position of amines. Furthermore, L Pd-catalyzed β-amino C−
H activation requires the presence of a strained 4-membered
palladacycle (vs a more favorable 5-membered metallacycle
4
2−50
α-Amino C−H activation by hydrogen atom
n
42−44
Received: December 21, 2020
Published: January 29, 2021
formed by γ-amino C−H activation).
There are only a limited number of protocols for preparing
enantiomerically enriched β-substituted amines through
5
1−54
activation of a β-amino C−H bond.
A notable strategy
is Pd/phosphoric acid-catalyzed and IOAc-mediated desym-
metrization of gem-dimethyl groups in tetramethyl-morpholi-
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2021 American Chemical Society
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2
441

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Figure 1. Enantioselective transformations of β-amino C−H bonds.
which allows access to β-substituted N-alkylamines via β-amino
C−H functionalization under redox-neutral conditions.
Conversion of β-amino C−H bonds can be achieved
nonstereoselectively through in situ generation of enamines
catalyzed dehydrogenation of N-alkylamines has not been
utilized in an enantioselective transformation.
In contemplating ways to develop a protocol that involves β-
C−H alkylation of N-alkylamines (1) through an enantiose-
lective union with α,β-unsaturated compounds (3), we
63−85
from N-alkylamines,
but enamine precursors are largely
envisioned using a set of B(C F ) , a Brønsted base catalyst,
limited to N,N-dialkylanilines. In the case of more Lewis basic
trialkylamines and substrates containing acid- and/or base-
sensitive moieties, catalyst deactivation can become problem-
6 5 3
and a chiral Lewis acid co-catalyst (M−L*) that might be
63−76,93−102
induced to function cooperatively (Figure 1c).
We
5
5−62
imagined B(C F ) as the recipient of a hydride from an amine
6
5 3
atic.
One strategy to overcome mutual quenching would
(
1), leading to the formation of a borohydride and an iminium
be to use strongly Lewis acidic and sterically hindered
8
6−88
63−76
ion (III). A Brønsted base catalyst would subsequently
deprotonate III to furnish enamine IV. The ensuing enantio-
and diastereo-selective C−C bond formation between enamine
IV and α,β-unsaturated compound, activated by the chiral
Lewis acid co-catalyst (V), would deliver zwitterionic VI. This
would be followed by protonation and reduction to give β-
alkylation product 4. A key advantage of using untethered and
independently operational catalysts is that efficiency and
stereoselectivity may be easily optimized by evaluation of
readily accessible Lewis acids, Lewis bases, and chiral ligands
(vs bifunctional catalysts that require tethering of different
catalytic sites). However, B(C F ) and the chiral Lewis acid
B(C F )
to convert trialkylamines into enamines;
6
5 3
this would involve (F C ) B-mediated hydride abstraction
5
6 3
6
3−76
from the amine to give a borohydride/iminium complex,
which would in turn be deprotonated to yield an enamine
Figure 1c, 1 → III → IV).
89−92
(
Chang and co-workers have
shown that B(C F ) is capable of promoting β-silylation of N-
6
5 3
64
arylpiperidines to generate rac-bridged sila-N-heterocycles.
We have introduced a method for (F C ) B-catalyzed
5
6 3
hydrogen isotope exchange involving β-amino C−H bonds
65
of various bioactive molecules. Still, engagement of the
enamine intermediates formed by (F C ) B/Brønsted base-
5
6 3
6 5 3
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Table 1. Evaluation of Various Reaction Parameters , ,
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Article
a b
c
entry
Lewis acid
B(C F )
Brønsted base
time (h)
yield of 4d (%)
yield of 5d (%)
1
2
3
4
5
6
Et N
3
3
3
3
3
12
12
12
12
50
25
<5
73
54
91
0
23
29
<5
25
5
7
0
0
0
6
5
3
3
3
3
3
3
3
B(C F )
TMP
DBU
none
none
none
none
none
none
6
5
B(C F )
6
5
B(C F )
6
5
d
B(C F )
6
5
d
B(C F )
6
5
7
8
9
BCl3
BPh3
none
0
0
a
Conditions: N,N-dibenzylethanamine (1d, 0.20 mmol), diisopropyl fumarate (3d, 0.30 mmol), Lewis acid, Brønsted base, C H (0.20 mL), under
6
6
b
1
c
N , 50 °C. Yield was determined by the H NMR analysis of unpurified reaction mixtures with m-xylene as the internal standard. The structure
and relative configuration of 5d were established by the nuclear Overhauser effect spectroscopy (NOESY) studies. Using 0.80 mL of C H .
2
d
6
6
a
Figure 2. β-Alkylation of different N-alkylamines. The values correspond to yields of isolated and purified products. Conditions: N-alkylamine (1,
b
0
.20 mmol), diisopropyl fumarate (3d, 0.30−0.40 mmol), B(C F ) (10 mol %), C H , under N , 50 °C. Yield of isolated and purified product.
6
5
3
6
6
2
1
c
The dr values were determined by the H NMR analysis of the unpurified reaction mixtures. The structure and relative configurations of 4f, 4j, 4l,
and 4m were assigned in analogy. The stereochemistries of 4n and 4o were assigned in analogy and by the NOESY studies. The absolute
configuration of 4g was determined based on the specific rotation of the derivative. The structure and absolute configuration of 4i was established
d
e
by the X-ray crystallographic analysis. The stereochemistry of 4h was assigned in analogy and also by the NOESY studies. See the Supporting
Information for details.
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Figure 3. Stereoselective β-functionalizations of N-alkylamines. The values correspond to yields of isolated and purified products. See the
Supporting Information for details.
1
Figure 4. Evaluation of chiral ligands. Yield and diastreomeric ratio (dr) values were determined by the H NMR analysis of unpurified reaction
mixtures with mesitylene as the internal standard. Enantiomeric ratio (er) values were determined by the HPLC analysis of isolated and purified
product. Conditions: N-arylpyrrolidine (1p, 0.20 mmol), α,β-unsaturated compound (6c, 0.30 mmol), B(C F ) (10 mol %), Sc(OTf) (5.0 mol
6
5
3
3
%
), ligand (6.0 mol %), CH Cl (2.0 mL), under N , 60 °C, 1 h. See the Supporting Information for details.
2 2 2
co-catalyst must be able to perform their independent roles
2. RESULTS AND DISCUSSION
without overlapping functions; otherwise, B(C F5)3 could
6
2.1. Method Development. 2.1.1. Identification of
Optimal Conditions. To begin, we set out to investigate if
B(C F ) might activate both N,N-dibenzylethanamine (1d)
promote the racemic reaction through activation of both
substrates, most likely resulting in diminished enantioselectiv-
6
5 3
ity. Here, we report that functionally similar B(C F ) and a
6
5 3
and diisopropyl fumarate (3d), generating 4d (Table 1).
Treatment of 1d and 3d with 10 mol % B(C F ) and 10 mol
chiral Lewis acid co-catalyst can operate in concert to engender
enantioselective coupling of N-alkylamines and α,β-unsatu-
rated compounds.
6
5 3
% Et N, 2,2,6,6-tetramethylpiperidine (TMP) or 1,8-
3
diazabicyclo[5.4.0]undec-7-ene (DBU) afforded 4d in 50, 25,
2
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Figure 5. Stereochemical rationale for enamine addition to α,β-unsaturated compounds catalyzed by [L10−Sc(OTf)3].
Figure 6. Stereoselective processes. Cooperative functions of B(C F ) and L−Sc(OTf) promote stereoselective β-alkylation of N-alkylamines.
6
5
3
3
a
Conditions: N-alkylamine (1, 0.10 mmol), α,β-unsaturated compound (6, 0.15−0.20 mmol), B(C F ) (10 mol %), L10−Sc(OTf) (10 mol %),
6
5
3
3
b
c
d
CH Cl (1.0 mL), under N , 60 °C, 1−36 h. 10 mol % of L6−Sc(OTf) was used. Using 20 mol % of B(C F ) . Using 20 mol % of L10−
2
2
2
3
6 5 3
e
f
Sc(OTf) . The reaction was performed at 80 °C. Using 10 mol % of L8−Sc(OTf) . See the Supporting Information for details.
3
3
and <5% yield, respectively (entries 1−3). Other than 4d,
over-alkylation product 5d was also formed (entries 1−6),
probably through in situ conjugate addition of an enolate (VI,
Figure 1c) to 3d. When the transformation was carried out
without a Brønsted base, 4d (73% yield) and 5d (25% yield)
were formed more efficiently (entry 4), suggesting that 1d, 4d,
and/or 5d can deprotonate an iminium to form an enamine
1−4), we were able to obtain 4d (91% yield) within 12 h
103
(entry 6). Moreover, no 4d was formed when less hindered
BCl or less acidic BPh were involved (entries 7−8). Without
3
3
B(C F ) , 4d was not generated (entry 9). These findings
6
5 3
support the notion that strongly Lewis acidic B(C F ) in
6
5 3
combination with sterically demanding and electron-rich N-
alkylamines constitute the most effective catalyst−substrate
combination.
(III → IV, Figure 1c). To suppress formation of 5d, the
mixture was diluted (entries 5−6); by using 10 mol % of
2.1.2. Scope. Many acyclic and cyclic N-alkylamines may be
used in the reaction with diisopropyl fumarate 3d to generate
B(C F ) and 0.80 mL of benzene (vs 0.20 mL used in entries
6
5 3
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+
Figure 7. Additional data interpretation. (a) Sequential β-alkylation and Mannich-type reaction gave piperidine derivative 7g. (b) D derived from
j-d was incorporated into enolizable positions of 7h-d and 8h-d.
1
Figure 8. Modification of products and scalability. (a) The enantioselective reaction is amenable to gram-scale operations. (b) Transformation of
pyrazolidinone auxiliary into thioester, alcohol, and then to carbamate was achieved. The absolute configuration of 9b was obtained through X-ray
crystallographic analysis. (c) The versatility of enamine 7h was demonstrated through catalytic hydrogenation and fluorocyanation reactions. See
the Supporting Information for details.
the corresponding β-substituted amines (4d−4o, Figure 2).
Reaction with N,N-dibenzylethanamines 1d and 3d afforded
the amino ester in enantiomerically pure form. As indicated by
synthesis of 4h and 4i, chiral pyrrolidines may be used as
starting materials. Whereas the reaction with the less hindered
1-(4-methoxy-2,6-dimethylphenyl)piperidine furnished 4j as
the only product in 89% yield, with the bulkier 4,4-dimethyl-
substituted piperidine substrate, enamine 4k was obtained in
4
1
d in 88% yield. N-Benzhydryl-substituted secondary amines
e and 1f were suitable substrates, furnishing 4e (93% yield)
and 4f (87% yield, 2.1:1 dr), respectively. None of the 1,4-
addition product was observed in the case of a secondary
amine bearing a more hindered trityl group (e.g., N-
tritylethanamine); this may be attributed to rapid substrate
decomposition. With less hindered N-benzylethanamine, the
formation of (F C ) B−amine adduct may compete with
104
93% yield.
The method is applicable to late-stage modification of N-
containing bioactive molecules that possess an array of Lewis
acid-sensitive functional groups (1l−1n; Figure 2). In addition
to the N-alkylamine moieties of 1l−1n, a ketone (1l), a
benzothiophene (1l), an ether (1l, 1n), a pyrimidinone (1m),
and a benzoisoxazole (1m) were tolerated. Thus, structures of
piperidine-based compounds, such as raloxifene (osteoporosis
treatment), risperidone (antipsychotic), and paroxetine (anti-
5
6 3
Lewis acid catalyzed hydride abstraction, resulting in minimal
formation of the desired product. We then investigated
reactions with different chiral N-alkylamines (1g−1i, Figure
2
). Accordingly, 4g was produced in 90% yield as a 1.4:1
mixture of easily separable diastereomers, allowing us to secure
2
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Figure 9. Determination of reaction orders. Log(rate) vs log(concentration) plot is employed to determine the reaction order for (a) B(C F ) , (b)
6
5 3
L6−Sc(OTf) , (c) amine 1p, and (d) α,β-unsaturated compound 6g. See the Supporting Information for details.
3
depressant) could be readily altered. Silyl-protected raloxifene
l reacted efficiently with 3d to afford 4l in 80% yield and 2.5:1
dr. Risperidone 1m, possessing more sterically hindered β-
amino C−H bonds (vs 1l), was merged with 3d, furnishing
enamine 4m (32% yield); minimal amounts (<5%) of the
<5% yield. These findings suggest that B(C F ) facilitates the
6 5 3
1
conversion of 1i into an enamine but does not sufficiently
activate 6a. We therefore decided to evaluate a blend of
B(C F ) and various Lewis acid co-catalysts, the latter of
6
5 3
which may activate 6a, to establish that, with 10 mol %
B(C F ) and ZnI , the reaction can give product 7a-(R,R,R,S)
product derived from alkylation of acyclic β-amino C−H bond
6
5 3
2
1
(
H labeled in red) could be observed ( H NMR analysis). The
in 82% yield as a single diastereomer (>20:1 dr; see the
Supporting Information for details). The presence of HBPin
led to enhanced dr, as 7a was isolated in 67% yield and 10:1 dr
in its absence (see the Supporting Information for details). We
also explored the suitability of developing an enantioselective
β-amino C−H alkylation reaction between achiral substrates
process involving N-benzyl paroxetine 1n and 3d afforded 4n
and 4o in 39 and 14% yield, respectively.
2
.1.3. Diastereo- and Enantioselective Processes. To
develop a highly diastereoselective and catalytic β-amino C−
H alkylation variant, we chose to utilize prolinol derivative
1
05−108
1
i
and (S,E)-4-phenyl-3-(4,4,4-trifluorobut-2-enoyl)-
oxazolidin-2-one 6a as model substrates (Figure 3a). The
F C ) B-catalyzed reaction of 1i and diisopropyl fumarate 3d
1
o and 6b, promoted by a combination of B(C F ) and an
6 5 3
enantiomerically pure organometallic co-catalyst (Figure 3b).
We discovered that with a complex of PyBOX L1−Mg(ClO4)2,
(
5
6 3
gave β-alkylation product 4i in only 56% yield and 2.5:1 dr
Figure 2). To probe whether the use of enantiomerically pure
(
the β-amino C−H alkylation of 1o proceeds to afford 7b in
67% yield (1.6:1 dr, up to 90:10 er). However, neither
efficiency nor enantioselectivity could be improved by further
electrophile leads to improved dr, we reacted 1i and 6a in the
presence of B(C F ) to find that product 7a was formed in
6
5 3
2
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Figure 10. Catalytic cycle consistent with the results of mechanistic investigations. Kinetic and NMR studies indicate that the turnover-limiting step
is intramolecular proton transfer step.
catalyst optimization (with 6b as electrophile; see the
Supporting Information for details).
high level of enantioselectivity observed in the formation of 7c-
(R,S) can be explained by selective 1,4-addition of the enamine
To improve enantioselectivity, we probed the trans-
formations involving a number of chiral Lewis acid co-catalysts
and α,β-unsaturated compounds bearing different auxilia-
to the re-face of [L10−Sc(OTf) ]-bound 6c; as depicted in
3
model VIII, the si-face is effectively shielded by a sec-butyl
group of the PyBOX ligand.
1
09−112
ries.
p reacts efficiently with 2-acryloylpyrazolidinone derivative 6c
in the presence of 10 mol % of B(C F ) together with
We found that 1-(4-methoxyphenyl)pyrrolidine
Enantioselective reactions with an array of N-alkylamines
were carried out in the presence of B(C F ) , a L−Sc(OTf)
1
6
5 3
3
complex, and 6c−6f (Figure 6). β-Alkyl derivatives of 1-(4-
6
5 3
Sc(OTf) and various chiral bisoxazoline ligands (Figure 4).
methoxyphenyl)pyrrolidine (1p) bearing γ-ester, ketone, or
3
We then found that reactions with Ph−BOX, Ph−DBFOX,
and Ph−PyBOX ligands (e.g., L2−L4) are hardly enantiose-
lective (58:42−50:50 er). The situation improved considerably
with alkyl-substituted PyBOX ligands (e.g., L5−L8), and in the
presence of (S)-i-Bu−PyBOX (L8), 7c was formed in 72%
yield, 2.7:1 dr, and up to 98:2 er. Reaction efficiency improved
CF groups (7c−7f) were thus synthesized in 62−83% yield,
3
2.0:1−6.7:1 dr, and 95:5−98:2 er. The reaction of 1p with 6c
5
5
(R = Et) and 6d (R = Bn) gave 7c (2.0:1 dr, up to 98:2 er)
and 7d (3.0:1, up to 95:5 er), respectively, indicating that N-
substituents of the pyrazolidinone unit have an influence over
both diastereo- and enantioselectivity. When acyclic N-ethyl-4-
(
85% yield) when L9 and its diastereomer L10 were used. The
methoxy-N,2,6-trimethylaniline 1q was reacted with F C-
3
stereochemical course of 1p-derived enamine addition to
substituted 6f (Figure 7a), N-arylpiperidine derivative 7g was
produced in 67% yield (>20:1 dr, 95:5 er); generation of 7g
probably entails β-amino C−H alkylation of 1q by 6f to afford
a zwitterionic intermediate containing an iminium and an
enolate (IX), followed by isomerization of the iminium to give
[
L10−Sc(OTf) ]-activated 6c can be rationalized by the
113−115
3
models presented in Figure 5.
Models VII and VIII
represent the energetically minimized structures of [L10−
113−115
Sc(OTf) ] docked with 6c.
As shown in model VII, the
3
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Figure 11. Origin of enamine and N-alkylamine products. (a, b) Reaction progress analysis of the coupling of 1j and 3d. (c) 5j and/or 1j-d can
+
+
serve as H or D and hydride sources in (F C ) B-catalyzed transfer hydrogenation of 5j. See the Supporting Information for details.
5
6 3
1
18
X. The ensuing intramolecular Mannich-type reaction gives 7g.
The unions of N-arylpiperidines (1j−1k) or N-arylazapene
nuances of the catalytic process.
These studies included
determining reaction orders, kinetic isotope effects, and
Hammett ρ values (Figures 9, 12, and 13, respectively).
Additionally, these investigations led to revised pathways for
the catalytic β-C−H alkylation reaction (Figures 10 and 11).
2.2.1. Determination of Reaction Orders and a Consistent
Mechanistic Pathway. We found that the reaction of N-
arylpyrrolidine 1p with α,β-unsaturated compound 6g has a
second-order dependence on B(C F ) concentration (Figure
(
1r) with 6f afforded enamines 7h−7j in 74−95% yield and
9
4:6−96:4 er. The reaction of N-arylpiperidine-3,3,5,5-d 1j-d
4
(
0.10 mmol) and 6f (0.20 mmol) gave 7h-d (84% yield, 95:5
er) and 8h-d (0.08 mmol; Figure 7b). Spectroscopic analysis of
h-d and 8h-d revealed that there is deuterium incorporation
at their enolizable α-carbonyl units and that there is D/H
7
65
exchange at C5 of 7h-d (>95% in 1j-d → 81% in 7h-d).
These results imply that in situ generated [(F C ) B−H]
6
5 3
−
9a) but is not at all impacted by the concentration of L6−
Sc(OTf) complex (Figure 9b). Furthermore, we found a first-
order dependence on amine concentration of 1p (Figure 9c)
but a reverse first-order dependence on the concentration of
electrophile 6g (Figure 9d). The independence of the reaction
5
6 3
+
[
base−D] reacts with 6f to produce 8h-d to regenerate
3
B(C F ) (vs by releasing H−D). We were able to function-
6
5 3
alize the β-amino C−H bonds of bioactive trialkylamines,
including cloperastine (cough suppressant) 1s and raloxifene
1
l, to generate enamines 7k (53% yield, 90:10 er) and 7l (57%
yield, 95:5 er), respectively.
.1.4. Scalability and Modifications of β-Functionalized
rate on the initial concentration of L6−Sc(OTf) suggests that
3
enantioselective C−C bond forming event between in situ
2
generated enamine and [L6−Sc(OTf) ]-activated 6g (Figure
3
Amines. The catalytic method is scalable. For example,
treatment of 4.0 mmol of N-arylpiperidine 1j and 6f with 10
mol % B(C F ) and 10 mol % L10−Sc(OTf) , (CH Cl , 12 h,
10, XV → XVI) occurs after the turnover-limiting step.
Furthermore, the negative first-order dependence on the
concentration of 6g implies that the resting state consists of
6g and the Lewis acid. Spectroscopic analysis of the reaction
6
5 3
3
2
2
6
0 °C) afforded 7h in 95% yield (1.9 g; Figure 8a). Treatment
1
9
of 7f-(R,S) with LiSEt followed by reduction of the resulting
thioester with LiAlH4 furnished alcohol 9a-(R,S) in 95%
overall yield (Figure 8b). Compound 9a-(R,S) was sub-
sequently converted to its derived carbamate 9b-(R,S) which
was subjected to the X-ray crystallographic analysis for
determination of absolute configuration (see the Supporting
Information for details). Enamines obtained by enantioselec-
tive β-alkylation were found to be versatile intermediates
mixture ( F NMR) supports the proposal in regard to
119
formation of [6g−B(C F ) ] (XI).
6
5 3
Thus, it is likely that β-C−H alkylation proceeds by the
release of B(C F ) from XI, which then abstracts a hydride
6
5 3
from 1 to form an iminium/borohydride complex (XII).
Borohydride reduction of (F C ) B-activated 6 delivers a
5
6 3
−
+
28,120
[(F C ) B−enolate] [iminium] complex (XII → XIII).
5
6 3
Subsequent irreversible isomerization of the iminium into an
enammonium (XIII → XIV) is likely the turnover-limiting step
(see the following kinetic isotope effect and Hammett studies,
(
Figure 8c). Hydrogenation of enamine 7h by a chiral Ir-based
116
catalyst afforded 9c in 83% yield and 5.0:1 dr, and treatment
of 7h with NFSI and TMSCN gave fluorocyanation product
1
21−124
as well as the Supporting Information for details).
117
−
9
d in 88% yield and 4.0:1 dr.
.2. Mechanistic Investigations. We designed and
performed studies to gain insight regarding the mechanistic
Protonolysis of [(F C ) B−enolate] in XIV releases B-
(C F ) , 8, and an enamine (XV). Then, enantioselective
5
6 3
2
6 5 3
C−C bond forming reaction between the enamine and [L−
2
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Figure 12. Kinetic isotope effect studies. The independent rate measurement studies indicate that intramolecular proton transfer is the turnover-
limiting step. See the Supporting Information for details.
Sc(OTf) ]-activated electrophile 6 leads to a zwitterionic
intermediate that bears an iminium and an enolate moiety (XV
transfer hydrogenation of XVI without the intermediacy of 7-
enamine. Nonetheless, the source of proton and hydride
remained to be identified.
3
→
XVI). Finally, proton transfer within XVI produces 7-
enamine and regenerates L−Sc(OTf) , thus closing the cycle.
To probe further if, and under precisely what conditions, 5j
3
Alternatively, the borohydride reduction of the iminium and
protonation of the resulting enolate in XVI produces an N-
alkylamine product (7-alkylamine), as illustrated by the
studies described below.
can be converted to 4j, we investigated the transformation of
5
j (isolated and purified by flash silica gel chromatography) in
the presence of 20 mol % B(C F ) (C H , 12 h; Figure 11c).
6
5 3
6
6
This led us to observe that there was 30% conversion to 4j; in
2
.2.2. Origins of Enamine and N-Alkylamine Products. β-
+
−
addition, [pyridinium] [C F ] (9j, 15%) was also produced.
6
5
Amino C−H alkylation products (Figures 2 and 6) were
obtained either as an enamine, an N-alkylamine, or a mixture
of the two (e.g., 4n and 4o, Figure 2). We wondered if the N-
alkylamine products were formed by transfer hydrogenation of
XVI (XVI → 7-alkylamine, Figure 10) or they were generated
through reduction of enamines (7-enamine → 7-alkylamine).
To identify each product’s origins, we studied the progress of
Treatment of 5j with N-arylpiperidine-3,3,5,5-d 1j-d furnished
4
4
j-d in 50% yield. We found not only that was there significant
deuterium incorporation at C3 and C5 positions of 4j-d (71%
and 67%, respectively) but also that the recovered 1j-d had also
undergone D/H exchange. These data suggest that B(C F )
6
5 3
can catalyze transfer hydrogenation of 5j in the presence of
+
another molecule of 5j and/or 1j-d serving as sources of H (or
(
F C ) B-catalyzed reaction between N-arylpiperidine 1j and
5 6 3
+
D ) and hydride (Figure 11c). Nevertheless, under the
3d (Figure 11a) which gives a mixture of N-alkylamine 4j
standard conditions for (F C ) B-catalyzed β-C−H alkylation
(
57% yield) and enamine 5j (29% yield) using 0.4 mL of C D
5
6 3
6
6
reaction (Figures 10 and 11a), in situ generated [(F C ) B−
(
vs the process involving 1.6 mL of C H which selectively
5
6 3
6
6
−
+
H] [Base−H] (derived from the reaction of B(C F ) and N-
gives 4j; Figure 2). We found that there is minimal
transformation of 5j into 4j as evidenced by the mostly
unchanged concentration of 5j once the β-alkylation reaction
was completed (2 h; Figure 11b). These results are consistent
with the scenario that 7-alkylamine (Figure 10a) is formed by
6 5 3
alkylamine 1) appears to react with either a highly reactive
zwitterionic intermediate (XVI → 7-alkylamine) or (F B-
C )
6 3
5
activated α,β-unsaturated compounds (XII → XIII→ XIV →
8). As a consequence, hydrogenation of relatively unreactive
2
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Figure 13. Hammett studies. Hammett plots of rates for the reaction of N-aryl-substituted pyrrolidines 1 and aryl-substituted α,β-unsaturated
compounds 6. (a, c) N-Arylpyrrolidine derivatives 1 that contain electron-donating substituents reacted more rapidly. (b, d) α,β-Unsaturated
compounds 6 that contain electron-withdrawing substituents reacted more rapidly. See the Supporting Information for details.
enamine 5j to give 4j may be outcompeted by these more
facile processes.
(ρ = −4.9, Figures 13a,c). The large negative ρ value obtained
supports the proposed mechanism (Figure 10) in which
B(C F ) abstracts a hydride from N-arylpyrrolidine 1 into a
2
.2.3. Kinetic Isotope Effect Studies. To shed light on the
6
5 3
hydride abstraction (Figure 10, 1 → XII), and deprotonation
steps (XIII → XIV → XV), deuterium-labeled N-arylpyrroli-
dines 1t-d and 1u-d were prepared, and their reactions with 6g
were probed (Figure 12). On the basis of the aforementioned
rate studies (Figure 9) hinting that the turnover-limiting is
prior to the stereoselective C−C bond forming process (Figure
N-aryl iminium cation (1 → XII), and its isomerization into an
enammonium species (XII → XIII → XIV); these processes
take place at or prior to the turnover-limiting step. While the
reaction rate was found to be less dependent on the electronic
properties of α,β-unsaturated compounds 6, those involving
more electron-withdrawing groups reacted with higher
efficiency (ρ = 0.92, Figure 13b,d). This latter outcome is
1
0, XV → XVI), the overall rate of the reaction can be affected
congruent with the hypothesis that 6 reacts with in situ
for reactions involving both α-deuterated 1t-d and β-
1
25,126
−
generated [(F C ) B−H] to afford a boron−enolate inter-
deuterated 1u-d.
However, independent rate measure-
5
6 3
mediate (Figure 10b; XII → XIII) and that this hydride
ments involving 1p and 1t-d (Figure 12a) were found to have
1
27
transfer also occurs at or prior to the turnover-limiting step.
k /k = 1.28 ± 0.07.
Comparison of the reaction rate
H
D
between 1p and 1u-d (Figure 12b) revealed that 1p reacts 2.5
times faster than 1u-d (k /k = 2.50 ± 0.13). These KIE
127
3. CONCLUSIONS
H
D
experiments support the notion that the turnover-limiting step
is the conversion of iminium into enammonium (Figure 10,
XIII → XIV) which entails the cleavage of α-imino C−H or
C−D bonds; furthermore, (F C ) B-catalyzed hydride abstrac-
In brief, we have developed an efficient catalytic method for
functionalization of β-amino C−H bonds to generate
enantioenriched δ-amino carbonyl compounds. We find that
by using a blend of B(C F ) and a chiral Sc-based complex, it
is possible to convert an N-alkylamine into an enamine and
then promote its enantio- and diastereoselective reaction with
an α,β-unsaturated compound. The catalyst system is tolerant
of a wide variety of Lewis acid sensitive functional units and
therefore applicable to late-stage modification of relatively
complex (and bioactive) trialkylamine molecules. Mechanistic
investigations reveal that the turnover-limiting step is probably
5
6 3
6 5 3
tion (1 → XII) and the following borohydride reduction (XII
XIII) steps are reversible, thus leading to the equilibrium
KIE of 1.28.
→
2
.2.4. Hammett Studies. Hammett studies revealed a strong
dependence of the reaction rate on the electronic properties of
the N-alkylamines, with N-arylpyrrolidine derivatives (1)
bearing electron-donating substituents reacting more rapidly
2
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isomerization of N-alkylamine-derived iminium ion into an
enammonium intermediate.
ACKNOWLEDGMENTS
■
Financial support was provided by the NIH (GM-128695),
Sloan Foundation, and Boston College. Y.C. was supported by
Boston College Chemistry Department Graduate Fellowship.
We thank Professor Amir H. Hoveyda for helpful discussions
and Professor Shih-Yuan Liu for assistance with mechanistic
investigations. Dr. Juan del Pozo del Valle and Dr. Filippo
Romitti are thanked for their assistance with this project. We
are grateful to Dr. Bo Li for the X-ray crystallographic analysis.
The principles outlined above demonstrate that proper
combination of an achiral organoborane and an enantiomeri-
cally pure organometallic catalyst may be used for chemo- and
enantioselective C−H bond functionalization, providing a
rational basis for future development of processes for late-stage
stereoselective β-functionalization of multifunctional bioactive
amines. Studies aimed at achieving these objectives are
underway.
REFERENCES
ASSOCIATED CONTENT
■
■
(
1) Vardanyan, R. Piperidine-Based Drug Discovery; Elsevier, 2017; p
*
sı Supporting Information
147.
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13200.
(2) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A graphical
journey of innovative organic architectures that have improved our
lives. J. Chem. Educ. 2010, 87, 1348−1349.
Experimental procedures and spectral data for all new
compounds (PDF)
(3) Campos, K. R.; Coleman, P. J.; Alvarez, J. C.; Dreher, S. D.;
Garbaccio, R. M.; Terrett, N. K.; Tillyer, R. D.; Truppo, M. D.;
Parmee, E. R. The importance of synthetic chemistry in the
pharmaceutical industry. Science 2019, 363, No. eaat0805.
Accession Codes
(
4) Nugent, T. C., Ed. Chiral Amine Synthesis: Methods, Developments
and Applications; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim,
010; p 15−457.
5) Weiner, B.; Szymans
CCDC 1902810−1902813, 2056852, and 2056853 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
2
(
́
ki, W.; Janssen, D. B.; Minnaard, A. J.;
Feringa, B. L. Recent advances in the catalytic asymmetric synthesis of
β-amino acids. Chem. Soc. Rev. 2010, 39, 1656−1691.
(6) Dick, A. R.; Sanford, M. S. Transition metal catalyzed oxidative
1
223 336033.
functionalization of carbon−hydrogen bonds. Tetrahedron 2006, 62,
2
(
439−2463.
7) Davies, H. M.; Manning, J. R. Catalytic C−H functionalization
AUTHOR INFORMATION
■
by metal carbenoid and nitrenoid insertion. Nature 2008, 451, 417−
424.
Corresponding Author
Masayuki Wasa − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States; orcid.org/0000-
(8) Baudoin, O. Transition metal-catalyzed arylation of unactivated
3
C(sp )−H bonds. Chem. Soc. Rev. 2011, 40, 4902−4911.
(
9) Haibach, M. C.; Seidel, D. C−H Bond functionalization through
intramolecular hydride transfer. Angew. Chem., Int. Ed. 2014, 53,
010−5036.
10) Girard, S. A.; Knauber, T.; Li, C.-J. The cross-dehydrogenative
0
002-3309-9129; Email: wasa@bc.edu
5
(
Authors
coupling of Csp3−H bonds: A versatile strategy for C−C bond
Yejin Chang − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Min Cao − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
Jessica Z. Chan − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States
Cunyuan Zhao − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States
Yuankai Wang − Department of Chemistry, Merkert
Chemistry Center, Boston College, Chestnut Hill,
Massachusetts 02467, United States
Rose Yang − Department of Chemistry, Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
formations. Angew. Chem., Int. Ed. 2014, 53, 74−100.
(11) Daugulis, O.; Roane, J.; Tran, L. D. Bidentate, monoanionic
auxiliary-directed functionalization of carbon−hydrogen bonds. Acc.
Chem. Res. 2015, 48, 1053−1064.
(12) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-
catalyzed transformations of alkyl C−H bonds. Chem. Rev. 2017, 117,
8
(
754−8786.
13) Chu, J. C. K.; Rovis, T. Complementary strategies for directed
3
C(sp )−H functionalization: A comparison of transition-metal-
catalyzed activation, hydrogen atom transfer, and carbine/nitrene
transfer. Angew. Chem., Int. Ed. 2018, 57, 62−101.
(
14) Davies, H. M.; Liao, K. Dirhodium tetracarboxylates as catalysts
for selective intermolecular C−H functionalization. Nat. Rev. Chem.
019, 3, 347−360.
15) Campos, K. R. Direct sp C−H bond activation adjacent to
2
(
3
nitrogen in heterocycles. Chem. Soc. Rev. 2007, 36, 1069−1084.
(16) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes,
B. U. W. Direct α-functionalization of saturated cyclic amines. Chem. -
Eur. J. 2012, 18, 10092−10142.
(
17) He, C.; Whitehurst, W. G.; Gaunt, M. J. Palladium-catalyzed
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13200
3
C(sp )−H bond functionalization of aliphatic amines. Chem. 2019, 5,
031−1058.
18) Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New strategies for
1
(
Author Contributions
Y.C. and M.C. contributed equally to this work.
the transition-metal catalyzed synthesis of aliphatic amines. Chem. Rev.
2020, 120, 2613−2692.
†
(
19) Noble, A.; MacMillan, D. W. Photoredox α-vinylation of α-
Notes
amino acids and N-aryl amines. J. Am. Chem. Soc. 2014, 136, 11602−
11605.
The authors declare no competing financial interest.
2
452
https://dx.doi.org/10.1021/jacs.0c13200
J. Am. Chem. Soc. 2021, 143, 2441−2455

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(
20) Osberger, T. J.; Rogness, D. C.; Kohrt, J. T.; Stepan, A. F.;
(39) Chan, K. S.; Fu, H. Y.; Yu, J. Q. Palladium(II)-catalyzed highly
enantioselective C−H arylation of cyclopropylmethylamines. J. Am.
Chem. Soc. 2015, 137, 2042−2046.
White, M. C. Oxidative diversification of amino acids and peptides by
small-molecule iron catalysis. Nature 2016, 537, 214−219.
(
21) Le, C.; Liang, Y.; Evans, R. W.; Li, X.; MacMillan, D. W. C.
(40) Rodrigalvarez, J.; Nappi, M.; Azuma, H.; Floden, N. J.; Burns,
3
3
Selective sp C−H alkylation via polarity-match-based cross-coupling.
M. E.; Gaunt, M. J. Catalytic C(sp )−H bond activation in tertiary
Nature 2017, 547, 79−83.
alkylamines. Nat. Chem. 2020, 12, 76−81.
(22) McManus, J. B.; Onuska, N. P. R.; Nicewicz, D. A. Generation
(41) Zhuang, Z.; Yu, J. Q. Pd (II)-catalyzed enantioselective
3
and alkylation of α-carbamyl radicals via organic photoredox catalysis.
J. Am. Chem. Soc. 2018, 140, 9056−9060.
C(sp )−H functionalizations of free cyclopropylmethylamines. J. Am.
Chem. Soc. 2020, 142, 12015−12019.
(23) Ye, J.; Kalvet, I.; Schoenebeck, F.; Rovis, T. Direct α-alkylation
(42) McNally, A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J.
Palladium-catalysed C−H activation of aliphatic amines to give
strained nitrogen heterocycles. Nature 2014, 510, 129−133.
(43) Smalley, A. P.; Gaunt, M. J. Mechanistic insights into the
palladium-catalyzed aziridination of aliphatic amines by C−H
activation. J. Am. Chem. Soc. 2015, 137, 10632−10641.
(44) Willcox, D.; Chappell, B. G. N.; Hogg, K. F.; Calleja, J.;
Smalley, A. P.; Gaunt, M. J. A general catalytic β-C−H carbonylation
of aliphatic amines to β-lactams. Science 2016, 354, 851−857.
(45) Huang, Z.; Wang, C.; Dong, G. A hydrazone-based exo-
directing-group strategy for β C−H oxidation of aliphatic amines.
Angew. Chem., Int. Ed. 2016, 55, 5299−5303.
of primary aliphatic amines enabled by CO and electrostatics. Nat.
Chem. 2018, 10, 1037−1041.
(
2
24) Li, Z.; Li, C.-J. Catalytic enantioselective alkynylation of
3
prochiral sp C−H bonds adjacent to a nitrogen atom. Org. Lett.
004, 6, 4997−4999.
25) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. Catalytic
2
(
enantioselective intramolecular redox reactions: Ring-fused tetrahy-
droquinolines. J. Am. Chem. Soc. 2009, 131, 13226−13227.
(26) Mori, K.; Ehara, K.; Kurihara, K.; Akiyama, T. Selective
3
activation of enantiotopic C(sp )−hydrogen by means of chiral
phosphoric acid: Asymmetric synthesis of tetrahydroquinoline
derivatives. J. Am. Chem. Soc. 2011, 133, 6166−6169.
(46) Cabrera-Pardo, J. R.; Trowbridge, A.; Nappi, M.; Ozaki, K.;
Gaunt, M. J. Selective palladium(II)-catalyzed carbonylation of
methylene β-C−H bonds in aliphatic amines. Angew. Chem., Int. Ed.
2017, 56, 11958−11962.
(27) DiRocco, D. A.; Rovis, T. Catalytic asymmetric α-acylation of
tertiary amines mediated by a dual catalysis mode: N-heterocyclic
carbene and photoredox catalysis. J. Am. Chem. Soc. 2012, 134, 8094−
8
(
097.
(47) Hogg, K. F.; Trowbridge, A.; Alvarez-Pérez, A.; Gaunt, M. J.
The α-tertiary amine motif drives remarkable selectivity for Pd-
catalyzed carbonylation of β-methylene C−H bonds. Chem. Sci. 2017,
8, 8198−8203.
28) Shang, M.; Chan, J. Z.; Cao, M.; Chang, Y.; Wang, Q.; Cook,
B.; Torker, S.; Wasa, M. C−H Functionalization of amines via alkene-
derived nucleophiles through cooperative action of chiral and achiral
Lewis acid catalysts: Applications in enantioselective synthesis. J. Am.
Chem. Soc. 2018, 140, 10593−10601.
(48) Nappi, M.; He, C.; Whitehurst, W. G.; Chappell, B. G. N.;
Gaunt, M. J. Selective reductive elimination at alkyl palladium(IV) by
3
(29) Chan, J. Z.; Yesilcimen, A.; Cao, M.; Zhang, Y.; Zhang, B.;
dissociative ligand ionization: Catalytic C(sp )−H amination to
Wasa, M. Direct conversion of N-alkylamines to N-propargylamines
through C−H activation promoted by Lewis acid/organocopper
catalysis: Application to late-stage functionalization of bioactive
molecules. J. Am. Chem. Soc. 2020, 142, 16493−16505.
azetidines. Angew. Chem., Int. Ed. 2018, 57, 3178−3182.
(49) Millet, A.; Dailler, D.; Larini, P.; Baudoin, O. Ligand-controlled
α- and β-arylation of acyclic N-Boc amines. Angew. Chem., Int. Ed.
2014, 53, 2678−2682.
3
(
30) Chen, W.; Ma, L.; Paul, A.; Seidel, D. Direct α-C−H bond
functionalization of unprotected cyclic amines. Nat. Chem. 2018, 10,
65−169.
31) Paul, A.; Seidel, D. α-Functionalization of cyclic secondary
(50) He, Y.; Wang, F.; Zhang, X.; Fan, X. C(sp )−H Dehydrogen-
2
ation and C(sp )−H alkoxy carbonylation of inactivated cyclic amines
1
(
towards functionalized N-heterocycles. Chem. Commun. 2017, 53,
4002−4005.
amines: Lewis acid promoted addition of organometallics to transient
(51) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.;
3
imines. J. Am. Chem. Soc. 2019, 141, 8778−8782.
Homs, A.; Yu, J.-Q. Ligand-controlled C(sp )−H arylation and
(32) Davies, H. M.; Venkataramani, C.; Hansen, T.; Hopper, D. W.
olefination in synthesis of unnatural chiral α-amino acids. Science
2014, 343, 1216−1220.
New strategic reactions for organic synthesis: catalytic asymmetric C-
H activation α to nitrogen as a surrogate for the Mannich reaction. J.
Am. Chem. Soc. 2003, 125, 6462−6468.
(52) Smalley, A. P.; Cuthbertson, J. D.; Gaunt, M. J. Palladium-
catalyzed enantioselective C−H activation of aliphatic amines using
chiral anionic BINOL-phosphoric acid ligands. J. Am. Chem. Soc.
2017, 139, 1412−1415.
(33) Liu, W.; Babl, T.; Rother, A.; Reiser, O.; Davies, H. M.
̈
Functionalization of piperidine derivatives for the site-selective and
stereoselective synthesis of positional analogues of methylphenidate.
Chem. - Eur. J. 2020, 26, 4236−4241.
(53) Su, B.; Lee, T.; Hartwig, J. F. Iridium-catalyzed, β-selective
3
C(sp )−H silylation of aliphatic amines to form silapyrrolidines and
(34) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
1,2-amino alcohols. J. Am. Chem. Soc. 2018, 140, 18032−18038.
(54) Lin, W.; Zhang, K.-F.; Baudoin, O. Regiodivergent
enantioselective C−H functionalization of Boc-1,3-oxazinanes for
Chen, C. Y. Enantioselective, palladium-catalyzed α-arylation of N-
Boc-pyrrolidine. J. Am. Chem. Soc. 2006, 128, 3538−3539.
2
3
(35) Cordier, C. J.; Lundgren, R. J.; Fu, G. C. Enantioconvergent
the synthesis of β - and β -amino acids. Nat. Catal. 2019, 2, 882−888.
(55) Yamamoto, H.; Futatsugi, K. Designer Acids”: Combined acid
catalysis for asymmetric synthesis. Angew. Chem., Int. Ed. 2005, 44,
1924−1942.
cross-couplings of racemic alkylmetal reagents with unactivated
secondary alkylelectrophiles: Catalytic asymmetric Negishi α-
alkylations of N-Boc-pyrrolidine. J. Am. Chem. Soc. 2013, 135,
1
(
0946−10949.
(56) Paull, D. H.; Abraham, C. J.; Scerba, M. T.; Alden-Danforth, E.;
Lectka, T. Bifunctional asymmetric catalysis: Cooperative Lewis acid/
base systems. Acc. Chem. Res. 2008, 41, 655−663.
36) Jain, P.; Verma, P.; Xia, G.; Yu, J. Q. Enantioselective amine α-
functionalization via palladium-catalysed C−H arylation of thio-
amides. Nat. Chem. 2017, 9, 140−144.
(57) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Catalytic
enantioselective formation of C−C bonds by addition to imines and
hydrazones: A ten-year update. Chem. Rev. 2011, 111, 2626−2704.
(58) Trost, B. M.; Bartlett, M. J. ProPhenol-catalyzed asymmetric
additions by spontaneously assembled dinuclear main group metal
complexes. Acc. Chem. Res. 2015, 48, 688−701.
(37) Topczewski, J. J.; Cabrera, P. J.; Saper, N. I.; Sanford, M. S.
Palladium-catalysed transannular C−H functionalization of alicyclic
amines. Nature 2016, 531, 220−224.
(
38) Xu, Y.; Young, M. C.; Wang, C.; Magness, D. M.; Dong, G.
3
Catalytic C (sp )−H arylation of free primary amines with an exo
directing group generated in situ. Angew. Chem., Int. Ed. 2016, 55,
(59) Shibasaki, M.; Kumagai, N.; Peters, R. Lewis Acid−Brønsted
Base Catalysis. Coop. Catal. 2015, 1−34.
9084−9087.
2
453
https://dx.doi.org/10.1021/jacs.0c13200
J. Am. Chem. Soc. 2021, 143, 2441−2455

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(
60) Lu, X.; Deng, L.; Peters, R. Hydrogen Bonding-Mediated
(78) Ma, L.; Paul, A.; Breugst, M.; Seidel, D. Redox-neutral
aromatization of cyclic amines: Mechanistic insights and harnessing of
reactive intermediates for amine α- and β-C−H functionalization.
Chem. - Eur. J. 2016, 22, 18179−18189.
Cooperative Organocatalysis by Modified Cinchona Alkaloids. Coop.
Catal. 2015, 145−167.
(
61) Wang, M. H.; Scheidt, K. A. Cooperative catalysis and
activation with N-heterocyclic carbenes. Angew. Chem., Int. Ed. 2016,
5, 14912−14922.
62) Romiti, F.; del Pozo, J.; Paioti, P. H. S.; Gonsales, S. A.; Li, X.;
(79) Xia, X.-F.; Shu, X.-Z.; Ji, K.-G.; Yang, Y.-F.; Shaukat, A.; Liu, X.-
Y.; Liang, Y.-M. Platinum-catalyzed Michael addition and cyclization
of tertiary amines with nitroolefins by dehydrogenation of oooo,β,β-
5
(
3
Hartrampf, F. W. W.; Hoveyda, A. H. Different strategies for
designing dual-catalytic enantioselective processes: From fully
cooperative to non-cooperative systems. J. Am. Chem. Soc. 2019,
sp C-H bonds. J. Org. Chem. 2010, 75, 2893−2902.
(80) Sundararaju, B.; Tang, Z.; Achard, M.; Sharma, G. V. M.;
Toupet, L.; Bruneau, C. Ruthenium-catalyzed cascade N- and C(3)-
dialkylation of cyclic amines with alcohols involving hydrogen
autotransfer processes. Adv. Synth. Catal. 2010, 352, 3141−3146.
1
41, 17952−17961.
63) Millot, N.; Santini, C. C.; Fenet, B.; Basset, J. M. Formation and
characterization of zwitterionic stereoisomers from the reaction of
(
3
(81) Sundararaju, B.; Achard, M.; Sharma, G. V. M.; Bruneau, C. sp
+
B(C F ) and NEt Ph: (E)- and (Z)-[EtPhN =CHCH >
C−H Bond activation with ruthenium(II) catalysts and C(3)-
alkylation of cyclic amines. J. Am. Chem. Soc. 2011, 133, 10340−
10343.
(82) Yuan, K.; Jiang, F.; Sahli, Z.; Achard, M.; Roisnel, T.; Bruneau,
C. Iridium-catalyzed oxidant-free dehydrogenative C−H bond
functionalization: Selective preparation of N-arylpiperidines through
tandem hydrogen transfers. Angew. Chem., Int. Ed. 2012, 51, 8876−
8880.
(83) Takasu, N.; Oisaki, K.; Kanai, M. Iron-catalyzed oxidative
C(3)IH functionalization of amines. Org. Lett. 2013, 15, 1918−1921.
(84) Zhou, M.-J.; Zhu, S.-F.; Zhou, Q.-L. Copper-catalyzed
Mannich-type oxidative β-functionalization of tertiary amines. Chem.
Commun. 2017, 53, 8770−8773.
(85) Shi, X.; Chen, X.; Wang, M.; Zhang, X.; Fan, X. Regioselective
synthesis of acylated N-heterocycles via the cascade reactions of
saturated cyclic amines with 2-oxo-2-arylacetic acids. J. Org. Chem.
2018, 83, 6524−6533.
(86) Ishihara, K.; Hananki, N.; Yamamoto, H. Tris-
(pentafluorophenyl) boron as a new efficient, air stable, and water
tolerant catalyst in the aldol-type and Michael reactions. Synlett 1993,
1993, 577−579.
(87) Ishihara, K.; Funahashi, M.; Hanaki, N.; Miyata, M.;
Yamamoto, H. Tris(pentafluorophenyl) boron as an efficient catalyst
in the aldol-type reaction of ketene silyl acetals with imines. Synlett
1994, 1994, 963−964.
(88) Ishihara, K.; Hanaki, N.; Yamamoto, H. Tris-
(pentafluorophenyl)boron as an efficient catalyst in the stereoselective
rearrangement of epoxides. Synlett 1995, 1995, 721−722.
(89) Wagner, J.; Lerner, R. A.; Barbas, C. F. Efficient aldolase
catalytic antibodies that use the enamine mechanism of natural
enzymes. Science 1995, 270, 1797−1800.
(90) Bock, D. A.; Lehmann, C. W.; List, B. Crystal structures of
proline-derived enamines. Proc. Natl. Acad. Sci. U. S. A. 2010, 107,
20636−20641.
(91) Nielsen, M.; Worgull, D.; Zweifel, T.; Gschwend, B.; Bertelsen,
S.; Jørgensen, K. A. Mechanisms in aminocatalysis. Chem. Commun.
2011, 47, 632−649.
(92) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Asymmetric
enamine catalysis. Chem. Rev. 2007, 107, 5471−5569.
(93) Phipps, R. J.; Hamilton, G. L.; Toste, F. D. The progression of
chiral anions from concepts to application in asymmetric catalysis.
Nat. Chem. 2012, 4, 603−614.
(94) Brak, K.; Jacobsen, E. N. Asymmetric ion-paring catalysis.
Angew. Chem., Int. Ed. 2013, 52, 534−561.
(95) Stephan, D. W., Erker, G., Eds. Frustrated Lewis Pairs I:
Uncovering and Understanding; Topics in Current Chemistry Series
Vol. 332; Springer: Berlin, 2013.
6
5
3
2
2
−
B (C F ) ]. Eur. J. Inorg. Chem. 2002, 2002, 3328−3335.
6
5 3
(
64) Zhang, J.; Park, S.; Chang, S. Catalytic access to bridged sila-N-
3
2
heterocycles from piperidines via cascade sp and sp C−Si bond
formation. J. Am. Chem. Soc. 2018, 140, 13209−13213.
(65) Chang, Y.; Yesilcimen, A.; Cao, M.; Zhang, Y.; Zhang, B.; Chan,
J. Z.; Wasa, M. Catalytic deuterium incorporation within metabol-
ically stable β-amino C−H bonds of drug molecules. J. Am. Chem. Soc.
2
(
019, 141, 14570−14575.
66) Focante, F.; Mercandelli, P.; Sironi, A.; Resconi, L. Complexes
of tris(pentafluorophenyl)boron with nitrogen-containing com-
pounds: Synthesis, reactivity and metallocene activation. Coord.
Chem. Rev. 2006, 250, 170−188.
(67) Dureen, M. A.; Brown, C. C.; Stephan, D. W. Addition of
enamines or pyrroles and B(C F ) “Frustrated Lewis Pairs” to
alkynes. Organometallics 2010, 29, 6422−6432.
(
Intramolecular frustrated N/B Lewis pairs by enamine hydroboration.
Chem. Sci. 2011, 2, 1842−1849.
(
6
5 3
68) Schwendemann, S.; Frohlich, R.; Kehr, G.; Erker, G.
̈
69) Maier, A. F. G.; Tussing, S.; Schneider, T.; Florke, U.; Qu, Z.-
̈
W.; Grimme, S.; Paradies, J. Frustrated Lewis pair catalyzed
dehydrogenative oxidation of indolines and other heterocycles.
Angew. Chem., Int. Ed. 2016, 55, 12219−12223.
(
70) Kojima, M.; Kanai, M. Tris(pentafluorophenyl)borane-
catalyzed acceptorless dehydrogenation of N-heterocycles. Angew.
Chem., Int. Ed. 2016, 55, 12224−12227.
(
̈
Florke, U.; Daniliuc, C. G.; Grimme, S.; Paradies, J. Borane-catalyzed
synthesis of quinolines bearing tetrasubstituted stereocenters by
71) Maier, A. F. G.; Tussing, S.; Zhu, H.; Wicker, G.; Tzvetkova, P.;
hydride abstraction-induced electrocyclization. Chem. - Eur. J. 2018,
2
(
4, 16287−16291.
72) Tian, J.-J.; Zeng, N.-N.; Liu, N.; Tu, X.-S.; Wang, X.-C.
Intramolecular cyclizations of vinyl-substituted N,N-dialkyl arylamines
enabled by borane-assisted hydride transfer. ACS Catal. 2019, 9, 295−
300.
(
73) Li, R.; Chen, Y.; Jiang, K.; Wang, F.; Lu, C.; Nie, J.; Chen, Z.;
Yang, G.; Chen, Y.-C.; Zhao, Y.; Ma, C. B(C F ) -Catalyzed redox-
neutral β-alkylation of tertiary amines using p-quinone methides via
borrowing hydrogen. Chem. Commun. 2019, 55, 1217−1220.
6
5 3
(
74) Chan, J. Z.; Chang, Y.; Wasa, M. B(C F ) -Catalyzed C−H
6
5 3
alkylation of N-alkylamines using silicon enolates without external
oxidant. Org. Lett. 2019, 21, 984−988.
(
75) Zhang, J.; Chang, S. cine-Silylative ring-opening of α-methyl
azacycles enabled by the silylium-induced C−N bond cleavage. J. Am.
Chem. Soc. 2020, 142, 12585−12590.
(76) Chen, Y.; Wan, H. L.; Huang, Y.; Liu, S.; Wang, F.; Lu, C.; Nie,
J.; Chen, Z.; Yang, G.; Ma, C. B(C F ) -Catalyzed β-functionalization
6
5 3
of pyrrolidines using isatins via borrowing hydrogen: Divergent access
(96) Erker, G., Stephan, D. W., Eds. Frustrated Lewis Pairs II:
Expanding the Scope; Topics in Current Chemistry Series Vol. 334;
Springer: Berlin, 2013.
to substituted pyrrolidines and pyrroles. Org. Lett. 2020, 22, 7797−
7803.
(77) Yu, P.; Zheng, S.-C.; Yang, N.-Y.; Tan, B.; Liu, X.-Y. Phosphine-
(97) Ashley, A. E.; O’Hare, D. FLP-mediated activations and
catalyzed remote β-C−H functionalization of amines triggered by
trifluoromethylation of alkenes: One-pot synthesis of bistrifluorome-
thylated enamides and oxazoles. Angew. Chem., Int. Ed. 2015, 54,
reductions of CO and CO. Top. Curr. Chem. 2012, 334, 191−218.
2
(98) Feng, X.; Du, H. Metal-free asymmetric hydrogenation and
hydrosilylation catalyzed by frustrated Lewis pairs. Tetrahedron Lett.
2014, 55, 6959−6964.
4041−4045.
2
454
https://dx.doi.org/10.1021/jacs.0c13200
J. Am. Chem. Soc. 2021, 143, 2441−2455

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
(
99) Stephan, D. W.; Erker, G. Frustrated Lewis pair chemistry:
Development and perspectives. Angew. Chem., Int. Ed. 2015, 54,
400−6441.
100) Stephan, D. W. Frustrated Lewis pairs. J. Am. Chem. Soc. 2015,
37, 10018−10032.
101) Stephan, D. W. The broadening reach of frustrated Lewis pair
chemistry. Science 2016, 354, No. aaf7229.
102) Stephan, D. W. Catalysis, FLPs, and beyond. Chem. 2020, 6,
520−1526.
103) β-Alkylated amine 4d may undergo (F C ) B/base-catalyzed
series of studies with ester-substituted 6c. See the Supporting
Information for details.
(119) Parks, D. J.; Piers, W. E. Tris(pentafluorophenyl)boron-
catalyzed hydrosilation of aromatic aldehydes, ketones, and esters. J.
Am. Chem. Soc. 1996, 118, 9440−9441.
(120) Chen, G. Q.; Kehr, G.; Daniliuc, C. G.; Bursch, M.; Grimme,
S.; Erker, G. Intermolecular redox-neutral amine CoH functionaliza-
6
(
1
(
(
1
(
tion induced by the strong boron Lewis acid B(C F ) in the
6 5 3
frustrated Lewis pair regime. Chem. - Eur. J. 2017, 23, 4723−4729.
(121) Sorgi, K. L.; Maryanoff, C. A.; McComsey, D. F.; Graden, D.
W.; Maryanoff, B. E. Asymmetric induction in an enammonium-
iminium rearrangement. Mechanistic insight via NMR, deuterium
labeling, and reaction rate studies. Application to the stereoselective
synthesis of pyrroloisoquinoline antidepressants. J. Am. Chem. Soc.
1990, 112, 3567−3579.
(122) Han, J.; Lu, Z.; Flach, A. L.; Paton, R. S.; Hammond, G. B.;
Xu, B. Role of hydrogen-bonding acceptors in organo-enamine
catalysis. Chem. - Eur. J. 2015, 21, 11687−11691.
(123) Ashley, M. A.; Hirschi, J. S.; Izzo, J. A.; Vetticatt, M. J. Isotope
effects reveal the mechanism of enamine formation in L-proline-
catalyzed α-amination of aldehydes. J. Am. Chem. Soc. 2016, 138,
5
6 3
dehydrogenation to afford a disubstituted enamine; however, no such
product was obtained. This could be because the disubstituted
enamine readily undergoes sequential protonation and borohydride
reduction to afford 4d (vs processes involving N-alkylamine substrates
that afford more stable trisubstituted enamines; see Figures 2 and 6
for details).
(
104) To synthesize 4j and 4k more selectively, different reaction
conditions were used. See the Supporting Information for details.
105) Gotoh, H.; Masui, R.; Ogino, H.; Shoji, M.; Hayashi, Y.
(
Enantioselective ene reaction of cyclopentadiene and α,β-enals
catalyzed by a diphenylprolinol silyl ether. Angew. Chem., Int. Ed.
1
(
756−1759.
2
(
006, 45, 6853−6856.
124) The proton transfer process involving the conversion of the
106) Hayashi, Y.; Gotoh, H.; Masui, R.; Ishikawa, H.
iminium to enammonium intermediates (XIII−XIV, Figure 10) may
occur through deprotonation of XIII by an appropriate Brønsted base
Diphenylprolinol silyl ether as a catalyst in an enantioselective,
catalytic, formal aza [3 + 3] cycloaddition reaction for the formation
of enantioenriched piperidines. Angew. Chem., Int. Ed. 2008, 47,
(
e.g., H O), followed by protonation of the resulting enamine species.
2
(125) Simmons, E. M.; Hartwig, J. F. On the interpretation of
4
(
012−4015.
107) Dell’Amico, L.; Albrecht, Ł.; Naicker, T.; Poulsen, P. H.;
Jørgensen, K. A. Beyond classical reactivity patterns: Shifting from
,4- to 1,6- additions in regio- and enantioselective organocatalyzed
deuterium kinetic isotope effects in C−H bond functionalizations by
transition-metal complexes. Angew. Chem., Int. Ed. 2012, 51, 3066−
3
072.
1
(
126) Blackmond, D. G. Kinetic profiling of catalytic organic
reactions as a mechanistic tool. J. Am. Chem. Soc. 2015, 137, 10852−
0866.
127) Intermolecular competition KIE experiments were also
vinylogous reactions of olefinic lactones with enals and 2,4-dienals. J.
Am. Chem. Soc. 2013, 135, 8063−8070.
(
1
(
108) McLeod, D.; Izzo, J. A.; Jørgensen, D. K. B.; Lauridsen, R. F.;
Jørgensen, K. A. Development and investigation of an organocatalytic
conducted, providing the results that are consistent with those of
the independent KIE experiments. See the Supporting Information for
details.
enantioselective [10 + 2] cycloaddition. ACS Catal. 2020, 10, 10784−
10793.
(
109) Evans, D. A.; Chapman, K. T.; Bisaha, J. Asymmetric Diels-
Alder cycloaddition reactions with chiral β,β-unsaturated N-
acyloxazolidinones. J. Am. Chem. Soc. 1988, 110, 1238−1256.
(110) Sibi, M. P.; Ji, J. Practical and efficient enantioselective
conjugate radical additions. J. Org. Chem. 1997, 62, 3800−3801.
(111) Adachi, S.; Takeda, N.; Sibi, M. P. Evaluation of achiral
templates with fluxional Brønsted basic substituents in enantiose-
lective conjugate additions. Org. Lett. 2014, 16, 6440−6443.
(112) Ruiz Espelt, L.; McPherson, I. S.; Wiensch, E. M.; Yoon, T. P.
Enantioselective conjugate additions of α-amino radicals via
cooperative photoredox and Lewis acid catalysis. J. Am. Chem. Soc.
2
(
015, 137, 2452−2455.
113) Evans, D. A.; Masse, C. E.; Wu, J. C -Symmetric Sc(III)-
2
Complexes as Chiral Lewis Acids. Catalytic Enantioselective Aldol
Additions to Glyoxylate Esters. Org. Lett. 2002, 4, 3375−3378.
(114) Evans, D. A.; Fandrick, K. R.; Song, H.-J.; Scheidt, K. A.; Xu,
R. Enantioselective Friedel- Crafts Alkylations Catalyzed by Bis-
oxazolinyl)pyridine-Scandium(III) triflate complexes. J. Am. Chem.
Soc. 2007, 129, 10029−10041.
115) Sibi, M. P.; Itoh, K.; Jasperse, C. P. Chiral Lewis Acid
Catalysis in Nitrile Oxide Cycloadditions. J. Am. Chem. Soc. 2004,
26, 5366−5367.
116) Hou, G. H.; Xie, J. H.; Yan, P. C.; Zhou, Q. L. Iridium-
(
(
1
(
catalyzed asymmetric hydrogenation of cyclic enamines. J. Am. Chem.
Soc. 2009, 131, 1366−1367.
(117) Dilman, A. D.; Belyakov, P. A.; Struchkova, M. I.; Arkhipov,
D. E.; Korlyukov, A. A.; Tartakovsky, V. A. Fluorocyanation of
enamines. J. Org. Chem. 2010, 75, 5367−5370.
(118) For the purpose of investigating the rate order, KIE, and
Hammett values, aryl-substituted α,β-unsaturated compounds were
used as electrophiles (e.g., 6g and their related compounds). To probe
whether the β-alkylation may proceed through different reaction
mechanism when a different electrophile is used, we carried out a
2
455
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J. Am. Chem. Soc. 2021, 143, 2441−2455