Synthesis of α-Tertiary Amine Derivatives by Intermolecular Hydroamination of Unfunctionalized Alkenes with Sulfamates under Trifluoromethanesulfonic Acid Catalysis

Article abstract of DOI:10.1002/adsc.201500646

An efficient and mild trifluoromethanesulfonic acid-catalyzed hydroamination of unfunctionalized alkenes to afford α-tertiary amine derivatives at temperatures as low as room temperature is reported. 2,2,2-Trifluoroethyl sulfamate was found to be the optimal nitrogen source because its good solubility in both organic solvents and water facilitated both conversion and purification. The reaction conditions were compatible with a variety of substrate functional groups and afforded moderate to good yields. The desired amine compounds could be obtained easily by means of a mild, one-pot, redox-neutral deprotection procedure. Caryolane amine was synthesized with excellent chemo- and regioselectivities by means of a cascade hydroamination reaction of β-caryophyllene.

Full text of DOI:10.1002/adsc.201500646

UPDATES
DOI: 10.1002/adsc.201500646
Synthesis of a-Tertiary Amine Derivatives by Intermolecular
Hydroamination of Unfunctionalized Alkenes with Sulfamates
under Trifluoromethanesulfonic Acid Catalysis
Jun Fei,a Zhen Wang,a Zheren Cai,a Hao Sun,a and Xu Chenga,*
a
Institute of Chemistry and Biomedical Sciences, School of Chemistry and Chemical Engineering, Nanjing University,
Xianlin Road 163, Nanjing 210023, Peopleꢀs Republic of China
Fax: (86)-25-8468-7372; e-mail: chengxu@nju.edu.cn
Received: July 22, 2015; Revised: September 17, 2015; Published online: December 4, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500646.
Abstract: An efficient and mild trifluoromethane-
sulfonic acid-catalyzed hydroamination of unfunc-
tionalized alkenes to afford a-tertiary amine deriva-
tives at temperatures as low as room temperature is
reported. 2,2,2-Trifluoroethyl sulfamate was found
to be the optimal nitrogen source because its good
solubility in both organic solvents and water facili-
tated both conversion and purification. The reaction
conditions were compatible with a variety of sub-
strate functional groups and afforded moderate to
good yields. The desired amine compounds could
be obtained easily by means of a mild, one-pot,
redox-neutral deprotection procedure. Caryolane
amine was synthesized with excellent chemo- and
regioselectivities by means of a cascade hydroami-
nation reaction of b-caryophyllene.
proceeds via a nitrene intermediate.[3g] With this
method, a variety of compounds with tertiary C H
centers can be transformed into the corresponding
À
À
compounds with quaternary C N centers in good
yields. When both benzylic and tertiary C H groups
À
are present, reaction of the former is favored, and
benzylic sulfamides are the predominant products. In
2014, Schomaker reported an intramolecular tertiary
À
C H amination reaction with up to 8:1 tertiary/ben-
zylic selectivity.[4]
Intermolecular hydroamination[5] of alkenes is an-
other strategy for incorporating a nitrogen atom. Sig-
nificant progress has been made using organometallic
catalysts[6] and organocatalysts[7] with various alkene
substrates.[8] Although ammonia is the ideal nitrogen
Keywords: alkenes; amines; hydroamination; sulfa-
mates
a-Tertiary amines, which are more resistant to degra-
dation than amines bearing an a-hydrogen,[1] are
found in natural products, pharmaceuticals, and vari-
ous molecules with potent biological activity
(Figure 1) and have therefore attracted the attention
of synthetic chemists. There is a well-established pro-
tocol for incorporating a nitrogen atom into a tertiary
carbon center by addition of organometallic carbon
nucleophiles to ketimines, and this strategy is espe-
cially advantageous for preparing benzylic a-tertiary
amines.[2] Recently, direct C H amination has been
À
extensively used for the efficient construction of a-
tertiary amine derivatives.[3] In 2013, Du Bois et al. re-
À
ported the rhodium-catalyzed intermolecular C H
amination of tertiary carbon centers using 2,2,2-tri-
chloroethyl sulfamate and an oxidant; this reaction Figure 1. Molecules containing an a-tertiary amine moiety.
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Jun Fei et al.
source, harsh conditions are frequently required for TsNH2 (entry 1). No trace of the desired product was
its use.[9] TsNH2 is another widely used nitrogen detected with NsNH2, again as a result of its poor sol-
source for Markovnikov hydroamination reactions.[10] ubility (entry 2). When a soluble phenyl sulfamate
However, intermolecular hydroamination with TsNH2 ester was used instead, we were delighted to find that
to afford a-tertiary amine derivatives has not been ex- the desired product could be isolated in 55% yield
tensively studied, for several reasons. First, hydroami- (entry 3). Both butyl sulfamate and 2,2,2-trifluoroeth-
nation consumes the alkene and nitrogen source com- yl sulfamate (3), which is partially soluble in toluene,
pletely without the formation of any side products, gave 2a as the only hydroamination product, but the
leading to a decrease in entropy; and a low reaction latter gave a higher yield (80% after reaction for 1 h;
temperature is preferred for this type of process.[11] entries 4 and 5). Decreasing the catalyst loading was
However, the marginal solubility of TsNH2 in solvents detrimental (entries 6 and 7), as was using an excess
typically employed for hydroamination, for example, of sulfamate 3 (entry 8). Subsequently, we evaluated
DCM and toluene, requires a relatively high reaction the effects of temperature (entries 9 and 10). An ex-
temperature.
cellent yield (96%) was achieved at 508C, but a com-
Second, the Ts group is inert to a variety of depro- plex mixture was obtained when the temperature was
tection protocols. Herein, we report that we were able elevated to 1008C, and the yield of the target mole-
to circumvent these problems and synthesize a-terti- cule was only 20%. Switching the solvent to DCE de-
ary amine derivatives by TfOH-catalyzed intermolec- creased the yield to 84% (entry 11). When we used
ular hydroamination of unfunctionalized alkenes with PdCl2/AgOTf (2.5 mol% each) as a Lewis acid cata-
sulfamate esters as nitrogen sources.
lyst, an almost quantitative yield of the hydroamina-
We began by investigating reactions of (3-methyl- tion product was obtained (entry 12). The excess
but-3-en-1-yl)benzene (1a) with a variety of nitrogen alkene was recovered and identified to be (3-methyl-
sources and catalysts in toluene at room temperature but-2-en-1-yl)benzene, produced by isomerization of
(Table 1). In the presence of TsNH2 and 5 mol% 1a. When this trisubstituted alkene was resubjected to
TfOH, the reaction yielded only trace amounts of the hydroamination reaction under the same condi-
target molecule 2, owing to the poor solubility of tions, 2a was obtained in 71% yield (entry 12).[12] We
Table 1. Optimization of the hydroamination conditions.[a]
Entry
N source
Catalyst
T
Yield[b]
1
2
3
4
TsNH2
NsNH2
phenyl sulfamate
butyl sulfamate
5 mol% TfOH
5 mol% TfOH
5 mol% TfOH
5 mol% TfOH
r.t.
r.t.
r.t.
r.t.
trace[c]
N.D.[c]
55%
68%
5
5 mol% TfOH
r.t.
80%
6
7
8
9
10
11
12
13
3
3
3
3
3
3
3
3
2 mol% TfOH
1 mol% TfOH
5 mol% TfOH
5 mol% TfOH
5 mol% TfOH
5 mol% TfOH
PdCl2/AgOTf
5 mol% TfOH
r.t.
r.t.
r.t.
508C
1008C
508C
508C
r.t.
40%[d]
trace
64%[e]
96%
20%
84%[f]
99%, 71%[g]
82%[h]
[a]
Conditions (unless otherwise stated): 1a (0.15 mmol), N source (0.10 mmol), TfOH, toluene (0.7 mL), 1 h. Pg=protecting
group.
Isolated yield after silica gel chromatography. N.D.=not detected.
The sulfonamide was poorly soluble in toluene.
The yield did not improve with prolonged reaction time.
1a (0.10 mmol), 3 (0.15 mmol).
DCE was used as the solvent.
Yield obtained from recovered alkene.
The reaction was carried out on a 5.0 mmol scale.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
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Synthesis of a-Tertiary Amine Derivatives by Intermolecular Hydroamination
Table 2. Substrate scope of hydroamination reaction.[a]
Table 2. (Continued)
[a]
Conditions
(unless
otherwise
stated):
alkene
1 (0.15 mmol), 3 (0.10 mmol), 5 mol% TfOH, room tem-
perature, in toluene, 1 h.
508C, 1 h.
508C, 48 h.
Room temperature, 12 h.
[b]
[c]
[d]
[e]
[f]
E/Z=3:2.
The yield in parentheses was obtained by washing with
cold water; no chromatography was required.
508C, 12 h.
[g]
[h]
BF3·etherate (7.0 equiv.) was added, 508C, 12 h.
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Jun Fei et al.
obtained an 82% yield of 2a when the reaction was vated the acidic catalyst, owing to binding between
carried out on a gram scale with TfOH as the catalyst the TfOH and the carbonyl oxygen or the nitrogen
(5 mmol, entry 13).
atom of the imide group; this problem could be ad-
Because TfOH is a widely used, inexpensive cata- dressed by introducing another Lewis acid,
lyst, we used it to explore the substrate scope of the BF3·etherate, which resulted in a moderate yield of
reaction with sulfamate 3 as a nitrogen source desired diamide 2r (entry 17). A substrate bearing
(Table 2). To achieve a broad substrate scope, we car- a reactive cyclopropane ester moiety (2s), which can
ried out the reaction at room temperature (Table 1, readily undergo ring opening under acidic conditions,
entry 5) unless elevated temperature was required to yielded desired product 2s in 74% yield with an intact
ensure complete conversion of the starting material cyclopropyl ring (entry 18).
(Table 1, entry 9). First, we evaluated the effects of
With the products of reactions between the alkenes
[13]
functional groups on the phenyl ring (entries 1–4). As and TsNH2 or 3 in hand, we investigated deprotec-
expected, substrate 1b, which has an electron-donat- tion of the amine by means of a redox-neutral strat-
ing methoxy group, showed reactivity comparable to egy, which is more compatible with various functional
that of 1a. A substrate with a trifluoromethyl group groups than single-electron transfer procedures using
(1c) also gave the desired product (2c, 79% yield). metal species (Scheme 1). We found that a compound
Moderate yields were achieved with bromo- and
ester-substituted substrates (1d and 1e, respectively).
Even when the steric bulk of the substrate was in-
creased (1f), a good yield of 2f was still obtained
(entry 5). Substrate 1g, which contains a trisubstituted
alkene, also underwent the reaction, affording 2f as
the only hydroamination product (entry 6) and dem-
onstrating regioselectivity for the tertiary carbon
center. Next we determined whether the protocol was
compatible with acid-labile groups. We found that the
alkyne group in 1h was tolerated; product 2h was ob-
tained in 75% yield after an extended reaction time
Scheme 1. Removal of protecting groups.
at room temperature (entry 7). To investigate the re-
gioselectivity of the reaction, we designed substrate
1i, which has two similar vinyl groups, and found that bearing the Ts group decomposed completely in the
the two C=C bonds could be differentiated; monohy- presence of hydrobromic acid, a typical reagent used
droamination product 2i was obtained in 66% yield as for removing the Ts group. In contrast, with the pro-
an E/Z (3:2) mixture, owing to a double bond shift tocol reported by Du Bois et al.,[3g] the sulfamate pro-
(entry 8). Heterocycles were also tested under the tecting group was cleaved smoothly in a one-pot pro-
standard conditions. A substrate bearing a thiophenyl cedure to give a-tertiary amine 4 in an overall yield
group (1j) was converted to a-tertiary amine deriva- of 92%.
tive 2j in good yield (entry 9). Ts-protected indole 1k
We speculated that the hydroamination reaction
was also reactive enough to give target compound 2k proceeds via a carbocation and that therefore a cas-
in 73% yield (entry 10). When alkene 1l was subject- cade reaction with the sulfamate ester as the terminal
ed to the reaction, the advantage of the 2,2,2-tri- nucleophile might be possible. To investigate this pos-
fluoroethyl sulfamate nitrogen source over TsNH2 sibility, we applied our catalytic protocol to b-caryo-
was further demonstrated. After 1 h of reaction under phyllene. With 5 mol% TfOH, the reaction of b-car-
the standard conditions, the solvent and excess alkene yophyllene with 3 proceeded at room temperature
were removed under reduced pressure, the residue with good selectivity to generate sulfamate 5, which
was washed with water to remove traces of sulfamate, has a caryolane skeleton, as the major product in
and product 2l was obtained in 76% yield and was as 82% yield. The free amine compound (6) was formed
pure as that obtained by chromatography (entry 11). under the standard deprotection conditions, and its
Another fully aliphatic product, 2m, was obtained in structure was confirmed by X-ray analysis of its Ts
excellent yield from 1m (entry 12). The TBDPS pro- derivative (Scheme 2).[14]
tecting group of substrate 1n remained intact, and 2n
In summary, we have developed a protocol for
was obtained in moderate yield (entry 13). Hydroami- TfOH-catalyzed intermolecular hydroamination of
nations of alkenes 1o and 1p gave the corresponding unfunctionalized alkenes to afford a-tertiary amine
amino esters (entries 14 and 15). Product 2q was ob- derivatives with water-soluble 2,2,2-trifluoroethyl sul-
tained in 68% yield; this substrate showed the prefer- famate as the nitrogen source. The mild reaction con-
ence for hydroamination over Michael addition ditions were compatible with a variety of substrate
(entry 16). We found that imide substrate 1r deacti- functional groups. The deprotection procedure was
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Synthesis of a-Tertiary Amine Derivatives by Intermolecular Hydroamination
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Scheme 2. Cascade hydroamination of b-caryophyllene.
À
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convenient and redox-neutral. The protocol was used
to carry out a cascade reaction with a sulfamate ester
as the terminal nucleophile.
Experimental Section
General Procedure for Hydroamination Reactions
A flask equipped with a rubber septum and a magnetic stir
bar was charged with 3 (0.1 mmol), alkene (0.15 mmol), and
toluene (0.7 mL) under a nitrogen atmosphere. Then TfOH
(5 mol%, 0.44 mL) was added slowly, and the resulting mix-
ture was stirred at room temperature for 1 h. The reaction
mixture was concentrated and purified by column chroma-
tography (silica gel, petroleum ether/AcOEt) to give the
product.
[4] J. M. Alderson, A. M. Phelps, R. J. Scamp, N. S. Dolan,
J. M. Schomaker, J. Am. Chem. Soc. 2014, 136, 16720–
16723.
[5] For a recent review of hydroamination using late tran-
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Gooben, H. Heydt, L. J. Gooben, Chem. Rev. 2015,
115, 2596–2697.
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Acknowledgements
This work was supported by the NSFC program (21572099,
21332005), the Natural Science Foundation of Jiangsu Prov-
ince (BK20151379), and the Qinglan project. Dr. Hao Sun
appreciates support from the NSFC program (21402087). We
thank Dr. Suresh Kumar for some early-stage work.
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Adv. Synth. Catal. 2015, 357, 4063 – 4068