Cooperative effect in organocatalytic intramolecular hydroamination of unfunctionalized olefins

Article abstract of DOI:10.1039/c3ra47060a

The cooperative effect in organocatalytic hydroamination of unfunctionalized olefins was reported. In the presence of 3-hydroxy-2-naphthoic acid, N-benzyl 4-penten-1-amines and 5-hexen-1-amines produced the intramolecular cyclization products in good isol

Full text of DOI:10.1039/c3ra47060a

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Cooperative effect in organocatalytic
intramolecular hydroamination of unfunctionalized
Cite this: RSC Adv., 2014, 4, 9517
olefins†
Received 26th November 2013
Accepted 21st January 2014
Yu-Mei Wang, Ting-Ting Li, Gong-Qing Liu, Li Zhang, Lili Duan, Lin Li
*
and Yue-Ming Li
DOI: 10.1039/c3ra47060a
www.rsc.org/advances
The cooperative effect in organocatalytic hydroamination of unfunc- unfunctionalized C]C bonds as well.20 The rate determining
tionalized olefins was reported. In the presence of 3-hydroxy-2- step was the formation of a carbocation intermediate via proton
naphthoic acid, N-benzyl 4-penten-1-amines and 5-hexen-1-amines transfer to the C]C double bond, and the hydroamination
produced the intramolecular cyclization products in good isolated product was produced by trapping the intermediate with
yields.
sulfonamide nitrogen. Based on this rationale, peruorous
sulfonic acid21 or heteropoly acids22 were also used to promote
hydroamination of unfunctionalized olens bearing electron
decient nitrogen atoms. In contrast, Brønsted acid-promoted
electron rich nitrogen sources-involved intramolecular hydro-
amination of unfunctionalized olens were rare.23 In this
communication, we wish to report the effect of cooperative
catalysis on organocatalytic hydroamination of N-alkyl amino
alkenes.
Benzoic acid in combination with palladium compounds has
been reported to promote hydroamination of alkynes.24 In our
course of searching for new catalyst systems for intramolecular
hydroamination of unfunctionalized olens bearing electron-
rich amino groups, we found that aromatic acids alone could
also promote the hydroamination of electron-rich amine
substrate N-benzyl-2,2-diphenyl-4-penten-1-amine (1a). In the
presence of 20 mol% of salicylic acid, 58% of 1a was converted
to hydroamination product N-benzyl 2-methyl-4,4-diphe-
nylpyrrolidine (2a) aer 24 hours (Scheme 1).
Nitrogen-containing heterocyclic compounds are paramount in
medicinal chemistry,1 and different methods have been devel-
oped for the preparation of nitrogen-containing heterocycles.2
These methods include electrophile-induced cyclization of N-
protected pent-4-en-1-amines or pent-4-en-1-imines with
bromine3 or PhSeBr.4 The thus obtained functionalized
heterocycles could be converted to 2-methylpyrrolidines upon
LiAlH4 (ref. 3) or tributylstannane5 reduction. Similarly, ring
expansion of substituted aziridines6 or azetidines7 furnished a
variety of substituted pyrrolidines and piperidines in good to
excellent yields.
Among the variety of methods developed, intramolecular
hydroamination of C]C double bonds should be one of the
most straightforward ones for the formation of C–N bonds and
N-containing heterocycles.8 This has been realized by using
organolanthanides or other rare earth metal,9 group-IV metal,10
noble metal such as palladium,11 platinum,12 silver,13 gold,14
rhodium,15 iridium16 and ruthenium17 compounds as well as
some rst row transition metal compounds18 as catalysts. In
addition, Brønsted acids were also used to promote the intra-
molecular hydroamination of several unfunctionalized olens
bearing amide functional groups. Using triic or sulphuric acid
as catalyst, intramolecular hydroamination of N-tosylamides
proceeded readily, giving the corresponding N-tosyl pyrroli-
dines and piperidines in high yields,19 and triic acid was
Encouraged by this result, the reaction was further studied to
get detailed understanding of the reaction. Table 1 summarised
the results from different solvents. These results indicated that
high temperature was generally needed for an efficient hydro-
amination reaction, and polar solvents such as THF, DMSO or
1,4-dioxane would interact efficiently with the catalyst which
would in turn affect its interaction with the substrates (entries 2,
effective
for
intermolecular
hydroamination
of
College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai
University, 94 Weijin Road, Tianjin 300071, People's Republic of China. E-mail: ymli@
nankai.edu.cn; Fax: +86 22 23507760; Tel: +86 22 23504028
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47060a
Scheme 1 Salicylic acid promoted hydroamination.
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Table 1 Solvent effect in salicylic acid-promoted hydroaminationa
the reaction (entries 4, and 8–12) and 20 mol% of catalyst was
enough to promote the reaction (entry 11).
Entry
Solvent
T (ꢀC)
Conversionb (%)
As a bifunctional molecule, salicylic acid could work differ-
ently to promote the reaction. While the carboxyl group would
act as a Brønsted acid, the hydroxyl group could act either as a
hydrogen bond donor (H atom) or as a hydrogen bond acceptor
(O atom). To study the role of hydroxyl group in the reaction and
to nd a suitable organocatalyst for the intramolecular hydro-
amination of 1a, Brønsted acids with different functional
groups were tested, and the results were summarised in Table 2.
As indicated in Table 2, a signicant cooperative effect was
observed in the reaction, i. e., both the hydroxyl group and the
carboxyl group were important, and they acted cooperatively to
promote the intramolecular hydroamination of 1a. Carboxyl
group or hydroxyl group alone was not powerful enough to
promote the reaction as indicated by the results from benzoic
acid (entry 5) and phenol (entry 8). Results from o-, m- and p-
hydroxybenzoic acids (entries 1, 6 and 7) indicated that the
distance between hydroxyl group and carboxyl group was also a
very important factor governing the reaction. Further, the acidity
1
2
3
4
5
6
7
EDC
THF
90
70
90
19
NRc
Trace
91
Benzene
Xylene
Toluene
DMSO
1,4-Dioxane
Xylene
Xylene
Xylene
Xylene
Xylene
130
120
130
100
130
130
130
130
130
58
19
14
26
63
86
90
91
8d
9e
10f
11g
12h
a
b
Reaction time: 24 hours. Based on crude NMR analysis of the
c
d
reaction mixture. NR ¼ no reaction. Amount of salicylic acid: 5
e
f
mol%. Amount of salicylic acid: 10 mol%. Amount of salicylic acid:
g
h
15 mol%. Amount of salicylic acid: 40 mol%. Amount of salicylic
acid: 60 mol%.
6, and 7), and these solvents were generally unsuitable for the of the Brønsted acid seemed also to be a crucial factor for the
reaction. Xylene was found to be a suitable solvent (entry 4) for reaction, and sulfonic acids (entries 9–12) didn't show any
the reaction possibly due to the high boiling point of the solvent benecial effects on the reaction. The use of weaker Brønsted
which could ensure a high temperature required for the reac- acid allows the presence of an acid base equilibrium that
tion. The amount of salicylic acid also showed some impact on preserves some free acid as well as free amino group in the
Table 2 Intramolecular hydroamination of 1a with different acidsa
a
Reaction conditions: solvent ¼ xylene (reux), reaction time ¼ 24 hours, catalyst loading ¼ 20 mol%.
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Table 3 Intramolecular hydroamination of unfunctionalized olefins
reaction system, and the use of a strong Brønsted acid would
force the equilibrium completely towards the deprotonated
species and the ammonium would not be able to undergo any
hydroamination reaction. This is also the reason why previous
reports mainly focused on amide substrates. Results from sali-
cylic acid (entry 1) and o-anisic acid (entry 2) indicated that the
hydroxyl group acted as a hydrogen bond donor in the reaction,
and changing the hydrogen bond donor (OH in salicylic acid,
entry 1) to hydrogen bond acceptor (OMe in o-anisic acid, entry 2)
led to a sharp drop of the reactivity. Aer a thorough survey of the
available acids, 3-hydroxy-2-naphthoic acid (entry 14) was found
to be an ideal catalyst for intramolecular hydroamination of 1a.
Reactions of different naphthoic acid isomers (Table 2,
entries 13 and 14) also showed a stereo demanding feature of
the reaction. While 3-hydroxy-2-naphthoic acid (3) led to
complete conversion of the substrate 1a, 1-hydroxy-2-naphthoic
acid (4) gave only 17% conversion of the substrate under
otherwise identical conditions. We reasoned that during the
reaction, carboxyl group would act as an acid to activate the C]
C double bond, and hydroxyl group will bring the amino group
to the reaction centre through hydrogen bond. Due to the 1,8-
repulsion of 1-hydroxy-2-naphthoic acid (4), the hydrogen bond
between N-substituted amino groups and 4 may not be strong
enough to initiate a reaction. In the case of compound 3, the 3-
hydroxy group was open to the substrates, and the access of N-
substituted amino groups was not affected (Fig. 1).
catalysed by 3-hydroxy-2-naphthoic acida
Entry
Substrate
R1
n
R2
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
–(CH2)5–
Ph
H
1
1
1
1
1
1
1
1
2
2
2
2
2
1
2
1
1
1
1
Bn
92
90
83
92
87
58
70
65
63
60
61
58
58
46
46
67
NRd
NR
NR
4-MeBn
4-MeOBn
4-FBn
4-ClBn
4-O2NBn
iBu
nBu
Bn
9c
10c
11c
12c
13c
14
15c
16
17
18
19
4-MeBn
4-MeOBn
4-FBn
4-ClBn
Bn
Bn
Bn
Ts
nBu
1s
H
Bn
Aer establishing a general procedure for intramolecular
hydroamination of 1a, the scope of the substrates was studied.
The reactions were carried out in xylene at reuxing tempera-
ture, 20 mol% of 3-hydroxy-2-naphthoic acid (3) was used as
catalyst, and the results were summarised in Table 3.
a
b
c
Catalyst loading ¼ 20 mol%. Isolated yields. Reaction time ¼ 72
hours. d NR ¼ no reaction.
As indicated in Table 3, both 2-methylpyrrolidines and 2-
methylpiperdines could be prepared via intramolecular hydro-
amination of the open chain aminoolens. Thorpe–Ingold
effect was observed in the reaction,25 and substrates without
substituents on the main chain failed to react (entries 19 and
20). N-substituted 5-hexen-1-amines (entries 9–13, and entry 15)
generally showed low reactivity comparing to their 4-penten-1-
amine counterparts (entries 1–8), possibly due to the unfav-
ourable entropy nature of the reaction.
On the basis of the current results, a tentative reaction
mechanism was drawn in Scheme 2. At room temperature,
carboxyl group and amino group would interact with each
other through electrostatic interaction,19 and no reaction
would occur at this stage. This also accounts for the high
temperature needed for Brønsted acid-catalysed hydro-
amination reactions. At high temperature, interaction of free
Scheme 2 A tentative mechanism of the reaction.
carboxyl group with C]C double bond leads to the activation of
the latter, and nucleophilic attack of amino group on the acti-
vated C]C double bond produced the hydroamination product.
N-tosyl amide (entry 18 of Table 3) failed to react, possibly due to
the weak hydrogen bond between the catalyst hydroxyl group
and the substrate amide as well as the low nucleophilicity of the
nitrogen atom.
Fig. 1 Low catalytic activity of 1-hydroxy-2-naphthoic acid caused by
1,8-repulsion.
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In summary, cooperative effect played an important role in 3- 12 (a) J. J. Brunet, M. Cadena, N. C. Chu, O. Diallo, K. Jacob and
hydroxy-2-naphthoic
acid-catalysed
hydroamination
of
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We acknowledge the nancial support from National Natural
Science Foundation of China (NSFC 20972072, NSFC 21272121).
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