Intramolecular Cyclizations of Vinyl-Substituted N, N-Dialkyl Arylamines Enabled by Borane-Assisted Hydride Transfer

Article abstract of DOI:10.1021/acscatal.8b04485

Catalytic amounts of B(C₆F₅)₃ have been found to be able to promote the intramolecular cyclization of vinyl-substituted N,N-dialkyl arylamines to afford nitrogen-containing heterocycles. Our mechanistic studies indicate th

Full text of DOI:10.1021/acscatal.8b04485

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Letter
Intramolecular Cyclizations of Vinyl-Substituted N,N-Dialkyl
Arylamines Enabled by Borane-Assisted Hydride Transfer
Jun-Jie Tian, Ning-Ning Zeng, Ning Liu, Xian-Shuang Tu, and Xiao-Chen Wang
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b04485 • Publication Date (Web): 07 Dec 2018
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Intramolecular Cyclizations of Vinyl-Substituted N,N-Dialkyl Aryla-
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mines Enabled by Borane-Assisted Hydride Transfer
#,
#,
,
†
Jun-Jie Tian, Ning-Ning Zeng, † Ning Liu,† Xian-Shuang Tu,† Xiao-Chen Wang* †,‡
†State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin
300071, China.
‡Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China.
ABSTRACT: Catalytic amounts of B(C6F5)3 have been found to be able to promote the intramolecular cyclization of vinyl-substi-
tuted N,N-dialkyl arylamines to afford nitrogen-containing heterocycles. Our mechanistic studies indicate the reaction is initiated by
abstraction of an α-hydride from an N-alkyl substituent by B(C6F5)3, which is followed by cyclization, and is concluded by delivery
of the hydride to the cyclic cationic intermediate. The dual roles of B(C6F5)3, first as an oxidant and then as a hydride-carrying
reductant, have enabled a rare redox-neutral cyclization process between a sp3 carbon and an electron-rich olefin without using a
transition metal or an external oxidant.
KEYWORDS: boron, hydride abstraction, cyclization, heterocycles, homogeneous catalysis
Studies of C–H functionalization reactions have attracted tre-
mendous attention due to their fast and convenient access to
new carbon-carbon and carbon-heteroatom bonds with selective
disconnection of ubiquitous carbon-hydrogen bonds.1 To acti-
vate the α-C–H bonds adjacent to a nitrogen atom in particular,
common methods include 1) lithiation followed by addition
with an electrophile,2 2) oxidation to generate an iminium ion
that is subsequently trapped by nucleophiles,3 3) transition
metal-catalyzed C–H activation reactions,4,5 and 4) carbene in-
sertions6 (Scheme 1a). These methods require the use of either
stoichiometric amounts of an organometallic reagent or an oxi-
dant, or catalytic amounts of a transition metal with a tailor-
made ligand. Alternatively, the hydride-transfer-induced intra-
molecular cyclization reactions have been found effective in
constructing various cyclic and heterocyclic scaffolds via direct
activation of α-C–H bonds (Scheme 1b).7 These reactions rely
on the use of starting materials having both a good hydride do-
nor (e.g. α-C–H bonds) and a good hydride acceptor (e.g. alde-
hydes, imines, and α,β-unsaturated carbonyls) so that a hydride
transfer from the donor to the acceptor will initiate the cycliza-
tion process. The high energy barrier for the hydride transfer is
the primary challenge for the reactivity. To improve the reac-
tivity, Lewis acids or Brønsted acids were often added to in-
crease the electrophilicity of acceptors by coordination. Despite
this, these cyclization reactions are still limited in substrate
scope, and starting materials without an acceptor group are nor-
mally unreactive.
Scheme 1. C–H functionalizations of α-C–H bonds adjacent
to a nitrogen atom.
During the past decade, the versatile reactivities of B(C6F5)3
with small molecules have been utilized to develop a myriad of
catalytic organic reactions.8 Among them, hydrogenations,9
hydrosilylations,10 transfer hydrogenations,11 and transfer
hydrosilylations12 have been extensively studied. However, a
known reactivity of B(C6F5)3, that is its capability to abstract a
hydride from α-carbons of an amine to generate an iminium ion
and a borohydride,13 has rarely been studied for a catalytic
reaction, and the existing examples have been confined to
transfer hydrogenation reactions using amines as a hydride
donor,11a dehydrogenation reactions of heterocycles14 and
intermolecular coupling reactions15 between tertiary amines and
electron-deficient olefins. Recently, we questioned whether this
reactivity could be utilized in promoting hydride-transfer-
induced cyclization reactions. Specifically, we hypothesized
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B(C6F5)3
B(C6F5)3
BF3•OEt2
Sc(OTf)3
Zn(OTf)2
FeCl3
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
1,2-Cl2C6H4
THF
34
that B(C6F5)3 could function as an transient hydride acceptor so
that the requirement of having an acceptor group in a starting
material could be obviated. Herein, we report that B(C6F5)3 is
able to function as a transient acceptor in the cyclization
reactions of vinyl-substituted N,N-dialkyl arylamines (Scheme
1c). Our mechanistic studies indicate the conventional two-step
mechanism in a hydride-transfer-induced cyclization reaction
has been broken down into three steps: borane-mediated
hydride abstraction, cyclization, and rebound of hydride from
B(C6F5)3. Notably, when our paper was under review, the
Paradies group reported a similar cyclization process using an-
other group of vinyl-substituted N,N-dialkyl arylamines.16 In
their report, the hydride abstraction occurs at a secondary N-
alkyl group so that the obtained products contain tetrasubsti-
tuted stereocenters. And, N-methyl was unreactive under their
reaction conditions.
4
toluene
toluene
toluene
toluene
n. d.
n. d.
n. d.
n. d.
a Unless otherwise specified, all reactions were performed in 0.5
mL toluene with 0.2 mmol S1 under N2. b Isolated yield; n. d. = not
detected.
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With the optimal conditions in hands, we began to investigate
the scope of this cyclization reaction (Table 2). Various aryl
groups on the olefin was first examined. Alkyl (P2), halo (P3
and P4) and Bpin (P5) at the para position of a phenyl ring were
tolerated, giving the desired products in 75–86% yields. Meta-
substituted (P6 and P7), ortho-substituted (P8) phenyls and 2-
naphthyl (P9) were also compatible. Changing the aryl group to
an alkyl group, such as methyl (P10), npropyl (P11), isopropyl
(P12), cyclohexyl (P13) and benzyl (P14), was feasible; the
desired products were obtained in 55–67% yields. We
subsequently tested sterically encumbered tri-substituted
olefins. Gratifyingly, these substrates underwent cyclization
with exclusive formation of the cis products (P15–P17) in 84–
86% yields. Interestingly, with a starting material having a
conjugated diene (S18), double bond migration occurred after
cyclization, affording P18 in 69% yield. Moreover, a starting
We commenced the study by testing styryl-substituted N,N-
dimethyl-1-naphthylamine S1 as the starting material (Table 1).
Conventionally, S1 is unreactive for cyclization due to the lack
of an acceptor group. The absence of any cyclization product
after reacting S1 in toluene at 80 °C for 48 h proved its poor
reactivity (entry 1). Encouragingly, in the presence of 10 mol%
of B(C6F5)3, the desired cyclization occurred, giving product P1
in 72% yield (entry 2). Less Lewis acidic triarylboranes,
including B(p-C6F4H)3, B(2,6-F2C6H3)3 and BPh3, were found
less active or inactive (entries 3–5). After an extensive
optimization, we discovered that the addition of a silyl triflate
as an addtive could influence the reactivity. The addition of 20
mol% of TMSOTf improved the yield to 88% (entry 6) while
the addition of bulkier Lewis acids, such as TESOTf and
TBSOTf, decreased the yields (entries 7 and 8). On the contrary,
the addition of TMSCl or TESCl as an additive had no obvious
influence on the reactivity (entries 9 and 10). Without B(C6F5)3,
TMSOTf itself was unable to promote the reaction probably
because of its relatively weak Lewis acidity (entry 11). Various
solvents were next evaluated (entries 12–16), but toluene still
gave the highest yield. We then tested several commonly used
Lewis acids as a substitute for B(C6F5)3, including BF3•OEt2,
Sc(OTf)3, Zn(OTf)2 and FeCl3, but these Lewis acids were
found to be inactive (entries 17–20).
Table 2. Investigation of vinyl-substituted N,N-dialkyl ar-
ylaminesa
R4
R1
R2
R3
R1
R1 R2
B(C6F5)3 (10 mol%)
TMSOTf (20 mol%)
N
N
R3
toluene, 80 oC, 48 h
S1-S23
P1-P23
N
N
R = H (P1), 88%
R = Et (P2), 75%
R = Cl (P3), 81%
R = Br (P4), 86%
R = Bpin (P5), 78%b
N
F
Me
R
P6, 68%
P7, 81%
N
Cl
N
N
N
2-nap
Me
nPr
Table 1. Optimization of the reaction conditionsa
P11, 66%b
P8, 41%b
P9, 74%b
P10, 67%b
N
N
N
N
Ph
entry
1
Lewis acid
none
additive
none
solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
p-xylene
PhCF3
yield (%)b
n. d.
72
P15, 86%b
P12, 60%b
P13, 66%b
P14, 55%b
Ph
N
N
N
N
2
B(C6F5)3
B(p-C6F4H)3
B(2,6-F2C6H3)3
BPh3
none
H
3
none
51
P16, 85%b
P17, 84%c
P18, 69%b
4
none
n. d.
n. d.
88
P19, 38%d
nBu
Ph
5
none
N
N
Bn
N
CH3(CH2)4
N
6
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
B(C6F5)3
none
TMSOTf
TESOTf
TBSOTf
TMSCl
TESCl
TMSOTf
TMSOTf
TMSOTf
TMSOTf
Ph
Ph
Me
7
70
8
42
P20, 94%e
P21, 97% (14:1)f
P22, 33%b
P23, 87%
9
74
a
Unless otherwise specified, all reactions were performed in 0.5
mL toluene with 0.2 mmol substrate under N2; Isolated yields were
reported. Reaction temperature, 120 °C. Reaction temperature,
100 °C. d Reaction temperature, 140 °C; reaction solvent, p-xylene.
e Reaction temperature, 25 °C. f Reaction temperature, 40 °C; 14:1
is the ratio of cis/trans.
10
11
12
13
14
75
b
c
n. d.
75
B(C6F5)3
B(C6F5)3
B(C6F5)3
31
DCE
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material having a phenyl group at the distal carbon of the olefin
We subsequently performed a similar crossover experiment us-
ing S1 and S1-[D6] with a shortened reaction time of 2 h
(Scheme 2c). At low conversions, the ratio of H to D at the ben-
zylic carbon was 77:23, giving an approximate KIE value of
3.35, which is in agreement with the hydride addition as the
rate-determining step.19
underwent a cyclization/dehydrogenation reaction to give P19
in 38% yield. Changing the N-alkyl group from methyl to
npentyl (P20) and benzyl (P21)17 was feasible. However,
changing the naphthylamine to an aniline significantly
decreased the reactivity; product P22 was obtained in only 33%
yield. On the contrary, a pyrenamine-derived substrate was
highly reactive, giving the corresponding product (P23) in 87%
yield.
Table 3. Investigation of vinyl-substituted N,N-dibenzylani-
linesa
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We reasoned that the decreased reactivity of the N,N-dime-
thylaniline (P22) compared with those N,N-dimethylnaphthyla-
mines might be due to the diminished steric hindrance around
the nitrogen atom, resulting in undesired acid/base coordination.
Therefore, in order to improve the reactivity, we changed the N
alkyl substituent from methyl to benzyl to increase steric bulk
around the nitrogen atom and simultaneously to provide more
stabilization to the iminium ion by conjugation. To our delight,
N,N-dibenzylanilines were significantly more reactive (Table 3).
Anilines with various phenyls at the proximal carbon of the ole-
fin were tolerated, providing products P24–P33 in 54–95%
yields with good stereocontrol in favor of the cis configuration.
Notably, in the reaction of S31, a separate olefin group was pre-
served (P31) without undergoing an intermolecular Friedel-
Crafts reaction; and in the reaction of S32, a coordinative MeS
group did not inhibit the reaction. Furthermore, 2-naphthyl (P34)
and heterocyclic aryls (P35 and P36) were compatible substit-
uents. Various substituents on the aniline ring were also tested.
The presence of para (P37–P39), ortho (P40, P41) and meta
(P42, P43) substituents was allowed, giving the cyclization
products in 48–81% yields. A staring material with a fused car-
bocyclic structure was reactive, giving P44 in 38% yield. More-
over, same as the reaction with P18, the double bond migration
occurred with a substrate having a conjugated diene, generating
P45 in 51% yield and 1.7:1 diastereomeric ratio. An N-benzyl-
N-methylaniline underwent cyclization selectively at the benzyl
side, giving P46 in 75% yield with the trans isomer as the major
diastereomer.18
a
Unless otherwise specified, all reactions were performed in 1.0
mL toluene with 0.2 mmol substrate under N2; Isolated yields were
reported; cis/trans ratios were given in parentheses. b 2.0 mL tolu-
ene was used. c Reaction temperature, 60 °C. d Reaction time, 24
We then investigated the reaction mechanism by several con-
trol experiments (Scheme 2). Firstly, we subjected the deuter-
ium-labelled N,N-dimethylnaphthylamine S1-[D6] to the stand-
ard reaction conditions (Scheme 2a), the corresponding product
was obtained in 46% yield with deuterium exclusively trans-
ferred to the benzylic position, which is consistent with the pro-
posed mechanism shown in Scheme 1c. The significantly di-
minished yield compared to the reaction of non-deuterated S1
is indicative of a large kinetic isotope effect, which suggests that
either the hydride abstraction from α-carbons or the hydride ad-
dition to cyclic benzylic cations is probably the rate-determin-
ing step. To look into the details, we performed two crossover
experiments. One experiment was done by subjecting a 1:1 mix-
ture of S10 and S1-[D6] to the reaction conditions (Scheme 2b).
It was observed that significant exchange of H/D occurred at α-
carbons and benzylic carbons in the obtained cyclization prod-
ucts. This result suggests that the hydride abstraction is reversi-
ble, and the resulting borohydrides are not confined to their par-
ent ion pairs and would freely react with iminium ions and cy-
clic benzylic cations produced from other molecules. Moreover,
the ratios of H to D at α-carbons of these products were close to
1, but the ratios of H to D at benzylic carbons were relatively
large. Therefore, the hydride abstraction and its reverse reaction
should be relatively facile while the hydride addition to cyclic
benzylic cations is highly possibly the rate-determining step.
h. Reaction temperature, 90 °C. f Reaction temperature, 40 °C. g
e
Solvent, p-xylene; reaction temperature, 140 °C; trans/cis = 3.0:1.
Scheme 2. Control Experiments
The role of TMSOTf was then studied. We monitored both
reactions of S1 with and without the addition of TMSOTf (20
mol%) for the first two hours using H NMR, and the yield of
P1 was plotted against the reaction time (Figure 1a). The graph
1
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indicates that the reactivity enhancement by TMSOTf is obvi-
Author Contributions
#These authors contributed equally.
ous. We hypothesized that the hydride exchange between the
borohydride anion [B(C6F5)3–H]– and TMSOTf might occur to
generate small amounts of
a
pentacoordinate anion
ACKNOWLEDGMENT
[Me3Si(OTf)H]–,20 which is a better hydride donor than
[B(C6F5)3–H]– because of the weaker Lewis acidity of TMSOTf,
so that the rate-determining hydride addition to the cyclic ben-
zylic cation would be facilitated.21 To gain experimental
evidence, we firstly prepared [B(C6F5)3–H]– by reacting Et2NPh
with B(C6F5)3,22 whose 11B NMR spectrum gave a characteristic
doublet signal at δ -23.4 (d, J = 77.5 Hz) due to B–H coupling.
After the addition of 1 equiv. of TMSOTf, this signal became a
broad singlet, indicating the hydride exchange between
[B(C6F5)3-H]– and TMSOTf might have occurred (Figure 1b).
Financial support was provided by the National Natural Science
Foundation of China (21602114 and 21871147), the Natural Sci-
ence Foundation of Tianjin (16JCYBJC42500), 1000-Talent Youth
Program and the Fundamental Research Funds for Central
Universities. We thank Professor Qi-Lin Zhou and Fang Lan for
helpful discussions. This paper is dedicated to the 100th anniver-
sary of Nankai University.
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Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-Cata-
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Ed. 2012, 51, 10236–10254; (g) Sun, C.-L.; Shi, Z.-J. Transition-
Metal-Free Coupling Reactions. Chem. Rev. 2014, 114, 9219–
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(2) For a review, see: (a) Beak, P.; Basu, A.; Gallagher, D. J.; Park,
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Enantioselective Lithiation−Substitution Sequences: Reaction
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552–560; For selected examples, see: (b) Beak, P.; Kerrick, S.
T.; Wu, S.; Chu, J. Complex Induced Proximity Effects: Enanti-
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pyrrolidine. J. Am. Chem. Soc. 2006, 128, 3538–3539.
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α-Methoxylation of Amides via Cuprous Ion-Promoted Decom-
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Am. Chem. Soc. 2004, 126, 11810–11811; (d) Li, Z.; Li, C.-J.
Highly Efficient CuBr-Catalyzed Cross-Dehydrogenative Cou-
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Methylene Compounds. Eur. J. Org. Chem. 2005, 3173–3176.
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A.; Elias, Z.; Herrebout, W.; Berthelot, D.; Meerpoel, L.; Maes,
Figure 1. (a) Yield of P1 versus reaction time for reactions with
(red) and without (blue) TMSOTf, (b) 11B NMR spectra (128 MHz,
25 ºC, C6D6) of [B(C6F5)3-H]– before (left) and after (right) the
addition of TMSOTf.
In summary, we have developed a B(C6F5)3-catalyzed
hydride-transfer-induced cyclization reaction of vinyl-
substituted N,N-dialkyl arylamines. The use of B(C6F5)3 as a
transient hydride acceptor has enabled the cyclization of
substrates without an acceptor unit. Moreover, this protocol
features broad substrate scope and provides easy acess to
various synthetically useful N-heterocyles. Further studies
aiming at extending the reaction to other hydride donors (e.g. α-
C–H bonds adjacent to an oxygen atom) as well as developing
enantioselective variant using a chiral borane catalyst are under
way in our laboratory.
ASSOCIATED CONTENT
Supporting Information. Experimental Procedures, characteriza-
tions of new compounds, and NMR spectra. This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*xcwang@nankai.edu.cn
ORCID
Xiao-Chen Wang: 0000-0001-5863-0804
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(16) Maier, A. F. G.; Tussing, S.; Zhu, H.; Wicker, G.; Tzvetkova, P.;
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(17) CCDC 1865384 contains the supplementary crystallographic
data for this paper. These data are provided free of charge by The
Cambridge Crystallographic Data Centre.
(18) The cis isomer is the kinetic product while the trans isomer is the
thermodynamic product (formed via repeated hydride abstrac-
tion/addition at the α carbon), so a high reaction temperature will
increase the percentage of the trans product. For P46, we had to
use 140 °C for a good yield, and the trans isomer became the
major product.
(19) For a very informative essay that provides guidelines for KIE
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(21) The use of a weaker Lewis acid as co-catalyst to facilitate hy-
dride delivery has been described and studied by Paradies, see
Ref 14a.
(22) We had tried to prepare [B(C6F5)3-H]– by mixing equimolar
B(C6F5)3 and S1 at various temperatures, but only trace amounts
of [B(C6F5)3-H]– can be detected by 11B NMR, probably because
the equilibrium of the reversible hydride abstraction highly fa-
vors the starting materials B(C6F5)3/S1 rather than their ion pair
form. Therefore, we used a reported reaction of Et2NPh with
B(C6F5)3 to generate reasonable amounts of [B(C6F5)3-H]– for
studying the interaction between [B(C6F5)3-H]– and TMSOTf.
For the original literature, see Ref 13a.
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