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

Article abstract of DOI:10.1021/jacs.0c08599

An efficient catalytic method to convert an α-C-H bond of N-alkylamines into an α-C-alkynyl bond was developed. In the past, such transformations were carried out under oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline derivatives. Here, we disclose a method for the union of N-alkylamines and trimethylsilyl alkynes, without the presence of an external oxidant and promoted through cooperative actions of two Lewis acids, B(C6F5)3 and a Cu-based complex. A variety of propargylamines can be synthesized in high diastereo-and enantioselectivity. The utility of the approach is demonstrated by the late-stage site-selective modification of bioactive amines. Kinetic investigations that shed light on various mechanistic nuances of the catalytic process are presented.

Full text of DOI:10.1021/jacs.0c08599

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Article
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
Jessica Zee Chan, Ahmet Yesilcimen, Min Cao, Yuyang Zhang, Bochao Zhang, and Masayuki Wasa
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 24 Aug 2020
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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
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Jessica Z. Chan,‡ Ahmet Yesilcimen,‡ Min Cao, Yuyang Zhang, Bochao Zhang, and
Masayuki Wasa1*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467,
United States
ABSTRACT: An efficient catalytic method to convert an -C–H bond of N-alkylamines into an
-C–alkynyl bond was developed. In the past, such transformations were carried out under
oxidative conditions, and the enantioselective variants were confined to tetrahydroisoquinoline
derivatives. Here, we disclose a method for union of N-alkylamines and trimethylsilyl alkynes,
without the presence of an external oxidant, and promoted through cooperative actions of two
Lewis acids, B(C6F5)3 and a Cu-based complex. A variety of propargylamines can be synthesized
in high diastereo- and enantioselectivity. The utility of the approach is demonstrated by late-stage
site-selective modification of bioactive amines. Kinetic investigations that shed light on various
mechanistic nuances of the catalytic process are presented.
1. INTRODUCTION
Propargylamines are prevalent in pharmaceuticals and are commonly used intermediates
in synthesis of bioactive amines (Figure 1a).1 Enantiomerically enriched propargylamines have
been prepared by addition of an alkynylmetal compound to an imine.2-4 An attractive alternative
would entail the conversion of an -amino C(sp3)–H bond into a -C–alkynyl bond. One way to
accomplish this would be through in situ generation of an iminium ion intermediate formed from
the corresponding amine under oxidative conditions.5-6 An illustrative case is enantioselective Cu–
PyBOX-catalyzed coupling of a benzylic -amino C–H bond of N-phenyl tetrahydroisoquinoline
1a with ethynylbenzene 2a to afford propargylamine 3a (Figure 1b).6 Still, development of a
precious transition metal- and oxidant-free catalytic C–H functionalization process represents a
compelling research objective.5-7 Particularly noteworthy would be the direct conversion of -C–
H bonds contained in bioactive N-alkylamines into -C–alkynyl bonds because these entities
constitute over 50% of the top-selling drugs; the resulting derivatives of these pharmaceuticals
possessing the alkyne unit can serve as modifiable intermediates for late-stage structural
diversification that could lead to new leads and/or more effective therapeutics.8
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(a)
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Me
N
H
F3C
N
Cl
NH
Me
9
N
O
H
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Rasagiline
(Parkinson's disease)
Selegiline
(antidepressant,
Parkinson's disease)
DPC 961
(reverse transcriptase
inhibitor)
(b)
10 mol % CuOTf
N
N
+
H
Ph
O
O
N
H
N
N
Ph
Ph
Ph
15 mol %
1a, 0.4 mmol
2a
3a, 67% yield
82:18 er
, 0.2 mmol
1.0 equiv t-BuOOH
THF, 50 °C, 48 h
(c) Union of N-alkylamines and trimethylsilyl alkynes by cooperative Lewis acid/Lewis acid catalysts
(this work)
B(C6F5)3
cat.
R2
G
R2
G
cat.
L
Cu PF6
N
N
R3
+
Me3Si
R1
R1
H
R
OH
R3
2
3
1
Cooperative Lewis acid catalysts
Proposed catalytic cycle:
G
R2
G
R2
N
N
PF6
R3
R1
H
B(C6F5)3
R1
Cu
R3
R
H
3
R
IV
L
5
C C bond
formation
III
B(C6F5)3
L
Cu PF6
hydride
abstraction
Me3Si
R3
transmetalation
G
R2
R2
2
+
G
R
PF6
N
N
L
Cu
R3
R
OH
R1
R1
H
H
B(C6F5)3
II
Me3Si OH
1
4
I
Figure 1. Representative bioactive compounds containing N-propargylamines and the synthesis strategy
to be pursued. (a) Examples of pharmaceutical agents that contain a propargylamine unit. (b) Enantioselective
organocopper-catalyzed transformation of an -amino C–H bond of tetrahydroisoquinolines into C–alkyne bond
under oxidative conditions. (c) Coupling of N-alkylamines with trimethylsilylacetylenes by cooperative Lewis
acid/Lewis acid catalysis. A possible mechanism might involve enantioselective C–C bond formation between
an iminium ion and a chiral alkynylcopper complex via reactive intermediates that are generated in situ by
cooperative functions of a chiral and an achiral Lewis acid co-catalyst.
In contemplating ways to design a possible method for the reaction of an N-alkylamine 1
with trimethylsilylacetylene 2,9-10 which can be easily prepared, we envisioned utilizing the
combination of two Lewis acid catalysts, an organoborane and a Cu-based complex, so that they
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might function cooperatively (Figure 1c).11-14 Specifically, we surmised that B(C6F5)3 might
receive a hydride from an amine (1), generating a borohydride and an iminium ion (I).15-21
Subsequently, Cu-based catalyst might undergo transmetalation with alkynyl silane 2 with the aid
of an alcohol additive (R–OH) to afford a LnCu–alkynyl complex (II) and trimethylsilanol 4.22 An
ensuing C–C bond formation (III) between in situ generated LnCu–alkynyl complex and iminium
ion would afford the desired propargylamine 3. Hydride transfer from borohydride to R–OH-
derived cationic species (IV 5) would then regenerate B(C6F5)3, thereby closing the cycle. Here,
we report the development of a cooperative Lewis acid/Lewis acid catalyst system for the
transformation of -amino C–H bonds of N-alkylamines into C–alkyne bonds and its utility in
synthesis, including late-stage incorporation of alkynyl units into bioactive amines.
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2. RESULTS AND DISCUSSION
2.1. Method Development
2.1.1. Identification of optimal conditions. To begin, we set out to identify a suitable
combination of catalysts (Table 1). We probed the ability of B(C6F5)3 and various Cu-based
complexes to catalyze the reaction between 1b and 2b, generating -alkynyl amines 3b and 6b.
Treatment of 1b (0.10 mmol) and 2b (0.15 mmol) with B(C6F5)3, (MeCN)4CuPF6, Xantphos (10
mol % of each) afforded 3b in 7% yield (C2H4Cl2, 60 °C, 24 h; entry 1, Table 1).23 Use of an
alcohol as an additive improved efficiency (entries 37), likely by accelerating the transmetalation
between 2b and (MeCN)4CuPF6/Xantphos complex, releasing trimethylsilanol 4 as byproduct.
Whereas the use of i-PrOH was ineffective (entry 2), addition of the more hindered t-BuOH
resulted in the formation of 3b in 17% yield (entry 3). With Ph3COH as the hydroxyl source, a
mixture of 3b (52% yield) and 6b (34% yield) was formed (entry 4) and Ph3CH was obtained as
a byproduct (i.e., 5, R = Ph3C; Figure 1c). When less Ph3COH was used (1.0 equiv.), 3b (83%
yield) was formed more selectively (vs 6b in 15% yield; entry 5), and the desired product 3b was
isolated in 90% yield when the reaction time was shortened to 12 h (vs 24 h; entry 6). The
transformation was efficient with less B(C6F5)3 (5.0 mol %), affording 3b in 81% yield (entry 7).
There was no transformation in the absence of B(C6F5)3 or when the less hindered BF3 or less
Lewis acidic BPh3 were used (entries 8–10, Table 1).
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Table 1. Evaluation of Various Reaction Parametersa,b
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a
Conditions: Reactions were performed under N2 atmosphere. N-arylpyrrolidine (1b, 0.10 mmol), 3-
(trimethylsilyl)propiolate (2b, 0.15 mmol), B-based Lewis acid, (MeCN)4CuPF6 (10 mol %), Xantphos (10
mol %), alcohol additive, C2H4Cl2 (0.4 mL), 60 °C, 24 h. b Yield values were determined by analysis of the 1H
NMR spectra of unpurified mixtures with mesitylene as the internal standard. c Reaction mixture was allowed to
stir for 12 h. See the Supporting Information for details.
2.1.2. Scope. An assortment of cyclic and acyclic N-alkylanilines (1b–1g) may be used
in reaction with 3-(trimethylsilyl)propiolate 2b to generate the corresponding propargylamines
(3b–3g, Figure 2). With B(C6F5)3 and LnCu–Xantphos complex as catalysts, N-aryl pyrrolidines
(1b, 1c), and N-aryl azepane (1d) were converted to 3b–3d in 77–90% yield. In a number of
instances there was efficient hydride abstraction at the N-methyl site (cf. 1e–1j). 4-Methoxy-
N,N,2,6-tetramethylaniline 1e reacted with 2b to afford 3e (90% yield) along with minimal
amounts of the byproduct containing two propargyl amine moieties (<5%). With 1f and 1g, C–C
bond formation occurred predominantly at the N-methyl site to furnish 3f (42% yield) and 3g (70%
yield), respectively; there was <10% reaction at the -amino C–H bonds of N-ethyl and N-benzyl
groups. Tertiary amines 1h–1j, which lack the fused N-aryl group, readily underwent
transformation to afford 3h–3j in 76%–97% yield. For synthesis of propargylamines 3h–3j the use
of the less hindered and conformationally more flexible 1,2-bis(diphenylphosphino)ethane (dppe)
ligand was optimal (vs <30% conv. with Xantphos).23 Furthermore, the more sizeable benzhydryl
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moiety was identified as a superior N-substituent as benzhydryl-substituted 3j was obtained in
higher yield than benzyl-substituted 3i (97% vs 86% yield).
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Figure 2. Incorporation of an alkyne unit into various N-alkylamines with 3-(triemthylsilyl)propiolate.
The values correspond to yields of isolated and purified products. Conditions: N-alkylamine (1, 0.20 mmol),
a
3-(trimethylsilyl)propiolate (2b, 0.30 mmol), B(C6F5)3 (10 mol %), (MeCN)4CuPF6 (10 mol %), Xantphos (10
b
mol %), triphenylmethanol (0.20 mmol), C2H4Cl2 (0.4 mL), under N2 atmosphere, 60 °C, 12 h. 1,2-
Bis(diphenylphosphino)ethane (10 mol %) was used as a ligand, 0.40 mmol of triphenylmethanol was used, and
c
the reaction mixture was allowed to stir at 80 °C for 24 h. Blue color indicates protecting groups. See the
Supporting Information for details.
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The method is applicable to late-stage modification of N-containing bioactive molecules
that possess an array of Lewis acid-sensitive functional groups (1k–1p; Figure 2). In addition to
the N-alkylamine moieties of 1k–1p, an ester (1l), an ether (1l, 1m, 1o), a thienyl (1o) and an aryl
chloride (1p) were tolerated, affording 3k–3p in 56–76% yield. The structures of antifungal
compounds bearing a tertiary amine, such as butenafine 1k and trimebutine 1l, were readily altered
(3k, 3l). For secondary amines, such as atomoxetine (used for treatment of ADHD), as well as
antidepressants nortriptyline, duloxetine, and sertraline, incorporation of N-benzhydryl group was
necessary for efficient generation of 3m–3p.
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The catalytic protocol may involve the use of trimethylsilylacetylenes containing different
alkynyl substituents (2b–2i, Figure 3). The reactions of fluoxetine derivative 1q with
trimethylsilylacetylenyl esters (2b, 2c) and amide (2d) afforded 7b–7d in 76–82% yield. A series
of phenyl-, para-(trifluoromethyl)phenyl-, para-chlorophenyl- or 3-thiophenyl-substituted
trimethylsilylacetylenes were coupled with 1q to furnish 7e–7h in 74–82% yield. Whereas the
transformation involving 1q and trimethylsilylacetylene (X = H) was inefficient (<10% yield),23
1,2-bis(trimethylsilyl)ethyne 2i proved to be a suitable reaction partner, affording 7i in 87% yield.
Figure 3. Reactions of N-Bzh fluoxetine with triemthylsilylacetylenes. The values correspond to yields of
isolated and purified products. The reaction conditions are identical to those in Figure 2, aside from the ligands
used. Blue color indicates protecting groups. a 1,2-bis(diphenylphosphino)ethane was used as a ligand. b (S)-Ph–
PyBOX was used as ligand. See the Supporting Information for details.
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2.1.3. Diastereo- and Enantio-selective Processes. To develop a stereoselective
version of the catalytic C–alkynyl bond forming process, we chose to use B(C6F5)3 in combination
with an appropriate chiral organocopper complex, with N-arylpyrrolidine 1b and 3-
(trimethylsilyl)propiolate 2b as model substrates. Accordingly, we performed systematic
evaluation of catalyst systems comprised of (MeCN)4CuPF6 and a chiral ligand (Figure 4). The
effectiveness of various bis-phosphine ligands (e.g., L1–L2) were evaluated in the presence of 10
mol % of B(C6F5)3.23 These transformations afforded 8b with minimal enantiomeric purity. We
then explored the suitability of bis-oxazoline ligands (e.g., L3–L7), leading us to establish that
with (S)-Ph–PyBOX (L3), 8b can be obtained in 84% yield and 82:18 er. Enantioselectivity
improved when more sizeable 2,6-bis((S)-4-(m-tolyl)-4,5-dihydrooxazol-2-yl)pyridine (L4) and
2,6-bis((S)-4-(3,5-dimethylphenyl)-4,5-dihydrooxazol-2-yl)pyridine (L5) were used: 8b was
isolated in 53% yield and 90:10 er, and 75% yield and 95:5 er, respectively. Neither efficiency nor
enantioselectivity improved when L6 and L7 were used.
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Figure 4. Evaluation of chiral ligands. Yield values were determined by the 1H 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 (1b, 0.10 mmol), 3-
(trimethylsilyl)propiolate (2b, 0.15 mmol), B(C6F5)3 (10 mol %), (MeCN)4CuPF6 (10 mol %), ligand (10 mol %),
triphenylmethanol (0.20 mmol), C2H4Cl2 (0.4 mL), under N2 atmosphere, 60 °C, 12 h. See the Supporting
Information for details.
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2.1.4. Stereoselective Synthesis and Functionalization of Propargylamines.
Reactions with an array of N-alkylamines were carried out in the presence of B(C6F5)3 and
(MeCN)4CuPF6, L5 and 2b (Figure 5). N-Arylpyrrolidines ((S)-8b, 8c, 8d) as well as N-
arylazepane (8e) bearing -alkynyl group were thus synthesized in 64–75% yield and 83:17–95:5
er; there was minimal double-alkynyl byproduct formed (<5% yield). When rac-2-methyl-1-
arylpyrrolidine was reacted with 2b, trans-8c was produced preferentially in 83:17 er. The reaction
with 3,3-dimethyl-1-arylpyrrolidine and 2b furnished 8d as the sole regioisomer (vs the isomer
formed through the formation of more sterically hindered iminium ion). An -benzylic C–H bond
of (E)-N,N-dibenzyl-4,4,4-trifluorobut-2-en-1-amine was functionalized to give propargylamine
8f in 45% yield and 84:16 er. Additionally, a range of enantiomerically enriched pyrrolidine
substrates underwent transformation in the presence of B(C6F5)3 and (MeCN)4CuPF6/L5 to afford
8g–8i. With (S)-3-methyl- or (S)-3-phenyl-substituted pyrrolidine as substrate, reaction occurred
at the less hindered -amino C–H bond, affording 8g and 8h in 64% yield (11.8:1 trans:cis) and
68% yield (10.1:1 trans:cis), respectively. The union of a -amino carbonyl compound19 and 2b
resulted in the formation of 8i in 93% yield and 7.7:1 trans:cis ratio. The use of L5 was crucial in
these latter processes, as 8g–8i were obtained in notably lower dr with an achiral ligand (e.g., Xantphos).23
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B(C6F5)3
10 mol %
10 mol %
G
R2
N
G
R2
(MeCN)4Cu PF6
O
N
+
Me3Si
R1
O
R1
H
OEt
L5
10 mol %
0.20 mmol Ph3COH
OEt
1, 0.20 mmol
2b, 0.30 mmol
8
t-BuOMe, 60 °C, 12 h
Me
Me
Me
N
Ar
N
Ar
H
N
Ar
N
Ar
O
O
O
O
OEt
OEt
OEt
OEt
(S)-8b, 75% yield
8c, 66% yield
6.3:1 trans:cis
8d, 69% yield
8e, 64% yield
95:5 er
93:7 er
95:5 er
83:17 er (trans isomer)
O
Me
Ph
O
Ph
O
N
F3C
N
N
Ar
N
Ar
O
N
Ar
Me
O
O
Ph
O
Ph
OEt
OEt
OEt
OEt
8f, 45% yield
84:16 er
8g, 64% yield
11.8:1 trans:cis
8h, 68% yield
10.1:1 trans:cis
8i, 93% yield
7.7:1 trans:cis
97:3 er (trans isomer)
88:12 er (trans isomer)
Figure 5. Diastereo- and enantio-selective processes. Cooperative functions of B(C6F5)3 and
(MeCN)4CuPF6/L5 catalysts promote stereoselective conversion of N-alkylamines to the corresponding dialkyl
propargylamines. Conditions: N-alkylamine (1, 0.20 mmol), 3-(trimethylsilyl)propiolate (2b, 0.30 mmol),
B(C6F5)3 (10 mol %), (MeCN)4CuPF6 (10 mol %), L5 (10 mol %), triphenylmethanol (0.20 mmol), C2H4Cl2
(0.4 mL), under N2 atmosphere, 60 °C, 12 h. See the Supporting Information for details.
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Figure 6. Modification of propargyl amine products and scalability. (a) Sequential conversion of CH bond
into C–alkynyl bond and removal of N-benzhydryl and O-TBS protecting groups can be achieved to afford
propargylamine 9. (b) The fluoxetine derivative 10 can undergo organocopper-catalyzed Click reaction with
biotin-PEG3-azide to give 11. (c) The method is amenable to gram-scale operations. (d) Enantioselective
reactions may be carried out on 1.0 mmol scale. (e) The versatility of (S)-8b was demonstrated by its
transformation to a -alkene 12a and a propargyl alcohol 12b. See the Supporting Information for details.
A benzhydryl group can be removed, as illustrated by the reaction of 1j and 2e with Et3SiH
and trifluoroacetic acid, which afforded 9 in 64% yield (Figure 6a). The silyl moiety of fluoxetine
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derivative 7i (Figure 3) was excised by its treatment with (n-Bu)4NF, furnishing terminal alkyne
10 in >95% yield.23 Subjection of 10 with biotin-PEG3-azide to CuSO4/L-ascorbic acid and K2CO3
afforded heterocyclic derivative 11 in 70% yield (Figure 6b).24
1.4. Scalability. The catalytic method is scalable. For example, treatment of 1.0 g (2.1
mmol) of N-benzhydryl fluoxetine 1q and 2b with 10 mol % B(C6F5)3, 10 mol %
(MeCN)4CuPF6/dppe, 2.0 equivalents of Ph3COH (C2H4Cl2, 48 h, 80 °C) afforded 7b in 93% yield
(1.12 g; Figure 6c). Furthermore, enantioselective coupling of N-arylpyrrolidine 1b (0.21 g, 1.0
mmol) with 2b in the presence of 5.0 mol % B(C6F5)3, 5.0 mol % (MeCN)4CuPF6/L5, and 1.0
equivalent of Ph3COH (t-BuOMe, 72 h, 60 °C) gave (S)-8b in 85% yield (0.26 g) and 95:5 er
(Figure 6d). Hydrogenation of (S)-8b delivered Z-alkene 12a in 96% yield and reduction of (S)-
8b furnished propargyl alcohol 12b in >99% yield.
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2.2. Mechanistic Investigations
We designed and performed studies aimed at shedding light on the mechanism of the
catalytic process (a revised catalytic cycle, based on the investigations described below, is
illustrated in Figure 7).
2.2.1. Kinetic studies. These investigations revealed that the rate of the reaction of 4-
methoxy-N,N,2,6-tetramethylaniline 1e with ethyl 3-(trimethylsilyl)propiolate 2b is independent
of the concentration of 1e, (MeCN)4CuPF6/Xantphos complex, and Ph3COH (Figure 8).23 However,
there were 0.5-order dependence on the B(C6F5)3 concentration (Figure 8a),25 and 1.0-order
dependence on the concentration of 2b (Figure 8b). These data imply that C–H bond cleavage
through (F5C6)3B-catalyzed hydride abstraction (Figure 7, 1  IX) occurs after the turnover-
limiting step (kinetic span).26,27 They further suggest that the transformation has a resting state that
consists of two B(C6F5)3 units, such as an ionic complex containing a borate anion [(F5C6)3B(-
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OH)B(C6F5)3]– (VI, [X]+ = H+ and/or Ph3C+).28 The B NMR spectra acquired for the reaction
mixture under the standard catalytic conditions (Figure 8) are in agreement with the formation of
the borate anion VI.23, 28 In the presence of Ph3COH and/or H2O, two molecules of [(F5C6)3B–
OH]–[X]+ (V) may be produced from VI.28 Ensuing reaction of V and trimethylsilylacetylene 2 to
afford [(F5C6)3B–alkyne]– [X]+ (VII) is turnover-limiting. Treatment of preformed [(F5C6)3B–
CC–CO2Et]–[H–NR3]+ (NR3 = 1e)29 with 100 mol % of (MeCN)4CuPF6/Xantphos complex was
found to give propargylamine product 3e in 24% yield, thereby demonstrating the competency of
intermediate VII in the alkyne incorporation process.23 Subsequent to the turn-over limiting step
(V  VII), [(F5C6)3B–alkynyl]– [X]+ undergoes transmetalation with (MeCN)4CuPF6/Xantphos
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complex to afford a LnCu–alkynyl complex and B(C6F5)3, latter of which converts amine 1 into
iminium ion through hydride abstraction (VII  VIII  IX). C–C bond formation between in
situ generated LnCu–alkynyl complex and iminium ion would afford the desired propargylamine
(IX  3). The reaction between borohydride and Ph3COH would then produce Ph3C–H 5 and
regenerate V, thereby closing the cycle.
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Figure 7. A catalytic cycle consistent with the results of mechanistic investigations. Kinetic and NMR studies
indicate that the turnover-limiting step occurs prior to the (F5C6)3B-catalyzed hydride abstraction, and that the
C–H bond cleavage step is irreversible.
2.2.2. Kinetic Isotope Effect Studies. To shed light on the hydride abstraction step
(Figure 7, 1  IX), deuterium-labeled methylaniline 1g-d was prepared, and its reaction with 2b
was studied (Figure 9). Based on the aforementioned rate studies (Figure 8), which suggested that
C–H bond cleavage might not be turnover-limiting, the overall rate of the reaction should be
unaffected for a reaction involving 1g-d, and, indeed, there was no significant kinetic isotope effect
with independent rate measurements (Figure 9a).26 On the other hand, with competition rate
measurements, there could be an observable KIE if (F5C6)3B-catalyzed C–H bond cleavage step
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were irreversible (Figure 9b), as these experiments measure a change in product distribution that
results from a difference in the rate of an irreversible C–H bond cleavage event.26 That is, these
experiments should provide a product ratio that reflects a primary KIE, despite the C–H bond
cleavage not being turnover-limiting.26 In the event, independent rate measurements (Figure 9a)
involving 1g and 1g-d was found to have kH/kD = 1.02 ± 0.02 (average of 2 measurements;).23
What is more, intermolecular competition rate measurements (Figure 9b) showed that 1g reacts
4.4 times faster than 1g-d (kH/kD = 4.4). These isotope effect experiments support the notion that
the turnover-limiting step is before the (F5C6)3B-catalyzed hydride abstraction, and that C–H bond
cleavage step is irreversible.
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Figure 8. Kinetic studies. The reaction of 1e and 2b to afford propargylamine 3e was found to be 0.5-order in
B(C6F5)3 and 1.0-order in alkyne, suggesting that the resting state of B(C6F5)3 contains two B(C6F5)3 units and
that the turnover-limiting involves the reaction of 2b with in situ generated [(F5C6)3B–OH]– to give [(F5C6)3B–
alkynyl] – and TMS–OH. (a) Log(rate) vs Log[B(C6F5)3] plot is employed to determine the reaction order for
B(C6F5)3. (b) Log(rate) vs Log[2b] plot is employed to determine the reaction order for 2b. See the Supporting
Information for details.
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Figure 9. Kinetic isotope effect studies. These studies indicate that hydride abstraction is not the turnover-
limiting step, and yet the deuterium-labeling caused an amine to react 4.4 times slower in the competition rate
measurement studies. See the Supporting Information for details.
2.2.3. Origin of Regioselectivity. Next, we chose to investigate why an N-methyl C–
H bond of an N-methyl-N-benzylamine moiety is preferentially activated (e.g., Figure 9b, 1g)
while N-benzyl and N-benzhydryl groups remain intact (c.f., Figures 2, 3). We considered two
possible scenarios. In one, B(C6F5)3 activation cannot convert an N-benzyl or an N-benzyhydryl
group to the corresponding iminium intermediate ([ArMeN=CHPh]+ (e.g., Figure 10a, XI and XII),
and in the other, the C-phenyl iminium intermediates are formed but are too hindered and/or not
sufficiently electrophilic to react with a LnCu–alkynyl complex. To establish whether a C-phenyl
iminium intermediate can be formed, we prepared 1g-d and subjected it to 10 mol % B(C6F5)3 at
60 ℃ for 16 hours (in C2H4Cl2; Figure 10a). The 1H NMR spectrum of purified 13g-d (>95% yield)
indicated that 63% of benzylic C–H bonds were converted to C–D bonds, while 37% of N-methyl
C–D bonds were transformed to C–H bonds. The finding that deuterium incorporation takes
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Figure 10. B(C6F5)3 promotes intramolecular and intermolecular H/D exchange. (a) (F5C6)3B-catalyzed
H/D exchange occurs within N-benzyl-4-methoxy-2,6-dimethyl-N-(methyl-d3)aniline. (b) Intermolecular H/D
exchange was shown to take place between 1e and 1g-d. See the Supporting Information for details.
place at the benzylic site indicates that B(C6F5)3 is capable of generating a C-phenyl iminium ion
(XI), which might occur through (F5C6)3B-catalyzed deuteride abstraction at the N–CD3 moiety
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of 1g-d to afford iminium ion X followed by isomerization to the lower energy intermediate XI.30
Subsequent reduction of C-phenyl iminium then furnishes a benzylic C–D bond (13g-d).
Nonetheless, direct formation of C-phenyl iminium intermediate by (F5C6)3B-catalyzed benzylic
C–H abstraction cannot be ruled out (1g-d  XII; Figure 10a).31
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Alternatively, intermolecular H/D exchange between two 1g-d molecules, promoted by
B(C6F5)3, might generate 13g-d. That is, iminium/borohydride complexes X and XII (Figure 10a)
could exchange their anionic and cationic components, after which hydride or deuteride iminium
reduction might produce 13g-d. To probe whether H/D exchange is intermolecular, we treated a
mixture of 1e and 1g-d in the presence of 10 mol % B(C6F5)3 (Figure 10b). Analysis of the
corresponding 1H NMR spectrum and HRMS data of the resulting products 13e-d and 13g-d (both
were obtained in >95% yield) revealed that 28% of N-methyl C–H bonds in 1e was converted to
C–D bonds and 27% of N-benzylic C–H bonds in 1g-d was transformed to C–D bonds. This
intermolecular H/D exchange reaction might proceed through formation of iminium complexes
XIV and XV, generated by (F5C6)3B-catalyzed hydride or deuteride abstraction from 1e and 1g-d,
respectively. The iminium/borohydride complexes XIV and XV could then exchange their anionic
and cationic components followed by hydride or deuteride reduction of XVI to furnish 13e-d and
13g-d. These results (Figure 10) imply that in the absence of (MeCN)4CuPF6/Xantphos and 2b,
the iminium/borohydride complexes are sufficiently long-lived to undergo isomerization and/or
intermolecular anion/cation exchange.
To determine whether the H/D exchange reaction is possible under the standard reaction
conditions, we performed the reaction involving 0.10 mmol 1g-d, 0.15 mmol of 3-
(trimethylsilyl)propiolate 2b and 0.10 mmol Ph3COH (Figure 11a); this allowed us to isolate
propargylamine product 3g-d in 31% yield. However, <5% of the benzylic C–H bonds in 3g-d
were converted to C–D bonds, whereas the propargylic position of 3g-d retained >98% of C–D
bonds from 1g-d. Additionally, there was no detectable H/D exchange in the recovered 1g-d (0.067
mmol of 1g-d was isolated); namely, there was no H/D exchange under the catalytic conditions
(vs H/D exchange processes shown in Figure 10). The above findings indicate that the in situ
generated [ArBnN=CD2]+[D–B(C6F5)3]– is short-lived and rapidly consumed by its reaction with
LnCu–alkynyl complex and Ph3COH to afford propargylamine 3g-d and Ph3C–D 5-d (1  IX 
3, Figure 7); thus, it neither undergoes intra- and/or intermolecular H/D exchange (vs the pathway
in Figure 10) nor does borodeuteride reduction generate B(C6F5)3 and 1g-d.
We examined the structure of byproducts to determine the fate of deuteride from amines
1g-d and 1e-d as well as trimethylsilyl group from 2b (Figure 11ab). Based on our proposed
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mechanism (Figure 7), the expected byproducts generated by the reaction between 1g-d and 2b (to
give 3g-d in 31% yield; Figure 11a) would be Ph3C–D (5-d) and Me3Si–OH (4). Although the
formation of Ph3C–D (5-d) could be confirmed by 2H NMR spectroscopy of the unpurified mixture
(24% yield), we were unable to detect any Me3Si–OH (4). To confirm that 4 is formed, we reacted
1e-d and 2b, which led to the formation of 3e-d (together with other byproducts; Figure 11b).
Spectroscopic analysis indicated that when the latter mixture was heated at 60 ℃ for 7 hours, 3e-
d (37% yield), Ph3C–D (5-d, 39% yield) and Me3SiO–SiMe3 (14, 14% yield) are generated;
Me3Si–O–SiMe3 is likely produced by (F5C6)3B-catalyzed condensation between two molecules
of Me3Si–OH (4) to afford 14 and H2O.32
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Figure 11. Structure Determination of Products. (a) Under the standard reaction conditions for installation of
the alkyne unit, no intra- and/or intermolecular H/D exchange was observed between N–CD3 and N–CH2Ph
groups, indicating that in situ generated iminium salt is rapidly consumed through C–alkynyl bond forming
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reaction vs H/D scrambling. (b) Spectroscopic studies (1H and H NMR) involving pure compounds revealed
that Ph3C–D and Me3Si–O–SiMe3 are the stable byproducts. See the Supporting Information for details.
3. CONCLUSIONS
In summary, we have developed an efficient and diastereo- and enantio-selective method
for activation of -amino C–H bonds to generate propargyl amines. We find that by using a blend
of B(C6F5)3 and an organocopper complex, it is possible to generate an iminium from an N-
alkylamine and a LnCu–alkynyl complex from an alkynylsilane. The catalyst system tolerates a
wide variety of Lewis acid-sensitive functional groups and is therefore applicable to late-stage
transformation of a complex (and bioactive) trialkyl amine molecule to its derived propargylamine.
Mechanistic investigations indicate that the turnover-limiting step occurs prior to (F5C6)3B-
catalyzed C–H abstraction, and that (F5C6)3B-catalyzed C–H abstraction is an irreversible process
under the reaction conditions for alkyne incorporation. The principles outlined here demonstrate
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that proper combination of an achiral organoborane and a chiral organometallic catalyst can be
used for chemo- and enantioselective C–H bond activation, providing a rational framework for
further development of processes involving the late-stage stereoselective -functionalization of
bioactive amines. Studies aimed at achieving these objectives are currently underway.
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ASSOCIATED CONTENT
Supporting Information Available: Experimental procedures and spectral data for all new compounds
(PDF). This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*wasa@bc.edu
Notes
The authors declare no competing financial interest.
Author Contributions
‡J. Z. C. and A. Y. contributed equally to this paper.
ACKNOWLEDGEMENTS
Financial support was provided by the NIH (GM-128695), the Sloan Foundation, and Boston College. J.Z.C.
and A. Y. were supported as John LaMattina Graduate Fellows in Chemical Synthesis. We thank Professor
Amir H. Hoveyda for helpful discussions, and Professor Shih-Yuan Liu for assistance with mechanistic
investigations. We are grateful to Professor Abhishek Chatterjee for a loan of biotin-PEG3-azide. Dr. Juan
del Pozo del Valle, Dr. Yuebiao Zhou, Dr. Ryan Morrison, Ms. Katherine Grasso, and Ms. Eleni Kisty
(Boston College) are also thanked for their assistance on this project. We are grateful to Dr. Bo Li (Boston
College) for the X-ray crystallographic analysis.
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