Direct Access to Primary Amines from Alkenes by Selective Metal-Free Hydroamination

Article abstract of DOI:10.1002/anie.202016679

Direct and selective synthesis of primary amines from easily available precursors is attractive yet challenging. Herein, we report the rapid synthesis of primary amines from alkenes via metal-free regioselective hydroamination at room temperature. Ammonium carbonate was used as ammonia surrogate for the first time, allowing for efficient conversion of terminal and internal alkenes into linear, α-branched, and α-tertiary primary amines under mild conditions. This method provides a straightforward and powerful approach to a wide spectrum of advanced, highly functionalized primary amines which are of particular interest in pharmaceutical chemistry and other areas.

Full text of DOI:10.1002/anie.202016679

Angewandte
Communications
Chemie
How to cite: Angew. Chem. Int. Ed. 2021, 60, 9875–9880
International Edition: doi.org/10.1002/anie.202016679
German Edition: doi.org/10.1002/ange.202016679
Synthetic Methods
Hot Paper
Direct Access to Primary Amines from Alkenes by Selective Metal-
Free Hydroamination
Yi-Dan Du, Bi-Hong Chen, and Wei Shu*
Dedicated to the 100th anniversary of Chemistry at Nankai University
Abstract: Direct and selective synthesis of primary amines
from easily available precursors is attractive yet challenging.
Herein, we report the rapid synthesis of primary amines from
alkenes via metal-free regioselective hydroamination at room
temperature. Ammonium carbonate was used as ammonia
surrogate for the first time, allowing for efficient conversion of
terminal and internal alkenes into linear, a-branched, and a-
tertiary primary amines under mild conditions. This method
provides a straightforward and powerful approach to a wide
spectrum of advanced, highly functionalized primary amines
which are of particular interest in pharmaceutical chemistry
and other areas.
alkenes over other polar functional groups provides oppor-
tunities for accessing molecular complexity and late-stage
functionalization.[12] In light of these benefits, metal-catalyzed
alkene hydroamination has been extensively studied for
decades with tremendous advances.[13,14] Methods for the
intermolecular coupling of unactivated alkenes with amine
source to generate aliphatic primary amines are currently
unknown.[15]
In 2018, Buchwaldꢀs group reported an elegant example of
a two-step procedure via copper-catalyzed hydroamination of
olefins to primary amines, using isoxazole electrophiles as
latent amine equivalent.[16] This reaction led to benzylic
primary amines from styrenes and linear primary amines from
aliphatic olefins.[17] Due to the steric hindrance and low
bonding affinity of tri- and tetra-substituted alkenes to the
metal center, sterically demanding a-tertiary primary amines
are inaccessible.[18] Recently, Knowlesꢀ group reported a semi-
nal work on photocatalytic coupling of primary or secondary
amine with alkenes, providing a facile approach to secondary
or tertiary aliphatic amines, respectively (Figure 1c).[19] These
protocols produce an aminium radical cation intermediate
through single electron oxidation of primary or secondary
amines, and are thus not applicable to the direct synthesis of
primary amines. A general and straightforward method for
the direct synthesis of primary amines from alkenes with
a nontoxic and cost-effective ammonia source, in particular,
for more challenging a-branched and a-tertiary primary
amines remains an unmet challenge. Several factors have
Aliphatic primary amines serve as substructure in a wide
variety of drug molecules, textiles, agrochemicals, and mate-
rials as well as precursors for secondary, tertiary amines, and
other functional groups.[1–3] Significant numbers of molecules
among the top-200 best-selling drugs are aliphatic amine
derivatives (Figure 1a).[2c] Thus, primary amines are
extremely important in chemistry and material sciences, but
the selective synthesis is challenging due to their high
reactivity.[1,4] Classical means to access aliphatic primary
amines include SN2 substitution of alkyl (pseudo)halides with
excess ammonia,[5] Gabriel reaction,[6,7] Staudinger reaction,[8]
and reduction of alkyl nitro groups,[9] nitriles,[10] oximes or
imines[11] (Figure 1b). While these methods are well-estab-
lished, they suffer from some of the following limitations:
1) Selectivity over primary, secondary, and tertiary amines is
difficult to control. 2) Limited to linear and a-branched
primary amines, more sterically demanding a-tertiary pri-
mary amines are inaccessible. 3) Tedious multistep process is
employed. 4) Harsh reaction condition is needed.
5) Advanced and/or toxic precursors are required. To date,
general and modular assembly of aliphatic amines from easily
available and abundant functional groups in a selective and
step-economic fashion is highly desirable. Alkenes are easily
available and manufactured on very large scale during
petroleum refining. In addition, the orthogonal reactivity of
[*] Dr. Y.-D. Du, B.-H. Chen, Prof. Dr. W. Shu
Shenzhen Grubbs Institute, Department of Chemistry, and
Guangdong Provincial Key Laboratory of Catalysis
Southern University of Science and Technology
Shenzhen 518055, Guangdong (P. R. China)
E-mail: shuw@sustech.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016679.
Figure 1. Significance of primary amines and reaction development.
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Table 1: Optimization of the reaction conditions.[a]
impeded the development of primary amine synthesis from
alkenes via photocatalysis: 1) Identification of a proper
ammonia source. 2) A primary amine is more electron-rich
than the parent ammonia source, and thus prone to be
oxidized prior to the ammonia surrogate. 3) A primary amine
is more nucleophilic than the parent ammonia source and
prone to undergo multifold alkylation reactions to give
a mixture of secondary and tertiary amines. A seminal work
by Nicewicz postulated that alkenes could undergo single
electron oxidation to radical cation intermediates, leaving
massive chemical space to further elaborate alkenes with
weak nucleophiles.[20] Unfortunately, this strategy is not
applicable to aliphatic amine synthesis due to the high
reductive potential of aliphatic amines compared to alkenes.
Herein, we developed the direct synthesis of primary amines
from alkenes under mild conditions using readily available
and cost-effective precursors (Figure 1d). The identification
of a latent ammonia surrogate as well as the catalytic
conditions is the key to the success of this process. This
metal-free protocol tolerates tetra-, tri-, di-, and mono-
substituted alkenes with various electronic and steric patterns,
allowing for the primary amine synthesis to proceed at room
temperature with exclusive regioselectivity.
To test our hypothesis for the regioselective synthesis of
primary amines from alkenes, 4-methylstyrene was used as
the model substrate to evaluate the reaction conditions. After
extensive optimization of reaction parameters,[21] we identi-
fied the use of 5 mol% of Mes-Acr-Ph+ (E*red =+ 2.20 V) and
30 mol% of 2-aminothiophenol as catalyst, ammonium
carbonate as ammonia source in DCM/PhCl = 10:1 under
blue LED irradiation at room temperature as the optimal
reaction conditions, affording the desired primary amine 1a
as single regioisomer in 75% isolated yield (Table 1, entry 1).
We found the use of ammonium carbonate as the ammonia
surrogate was the key to the success of this transformation,
probably due to the proper release rate of ammonia during
the reaction course. The use of other ammonium salts as
ammonia surrogate could also form 1a, albeit with inferior
efficiency (see Tables S1 and S7). The choice of hydrogen
atom donor had a substantial impact on the efficiency of this
transformation (Table 1, entries 2–14). After evaluation of
a wide variety of thiophenol derivatives (S1–S14), we found
that 2-aminothiophenol (S1) provided the optimal result.
Other thiophenol derivatives delivered primary amine 1a
with diminished yields (Table 1, entries 3–11). Phenyl disul-
fide derivatives could also catalyze the desired transformation
to give 1a, albeit in lower yields (Table 1, entries 12 and 13).
Dithiophenol could also mediate the reaction, furnishing 1a
in 67% yield (Table 1, entry 14). A 2-amino group may
interact with thiol to facilitate the hydrogen atom transfer. No
desired primary amine 1a was observed in the absence of thiol
(Table 1, entry 15). The use of chlorobenzene as co-solvent
significantly enhanced the outcome of the hydroamination
reaction. Other tested solvents, such as hexanes, acetonitrile,
tetrahydrofuran, ether, or trifluorotoluene also afforded
hydroamination product 1a in good yields (Table 1,
entries 16–21). Control experiments revealed that both pho-
tocatalyst and light irradiation are required for the reaction
(Table 1, entry 22).[21]
Entry
Variation from
“standard conditions”
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
none
79 (75)
22
15
traces
40
18
42
19
34
16
18
8
32
67
0
57
64
53
74
65
73
0
S2 instead of S1
S3 instead of S1
S4 instead of S1
S5 instead of S1
S6 instead of S1
S7 instead of S1
S8 instead of S1
S9 instead of S1
S10 instead of S1
S11 instead of S1
S12 instead of S1
S13 instead of S1
S14 instead of S1
no thiol
hexanes instead of PhCl
EtOAc instead of PhCl
CH3CN instead of PhCl
THF instead of PhCl
Et2O instead of PhCl
PhCF3 instead of PhCl
no photocatalyst/light
[a] The reaction was performed with 0.11 mmol of para-methylstyrene
with 1.65 mmol of (NH4)2CO3 in DCM (20 mL) and chlorobenzene
(2.0 mL) under irradiation with a 30 W blue LED at ambient temperature
for 12 h; DCM=dichloromethane, THF=tetrahydrofuran. [b] Yield was
determined by H NMR analysis of the crude mixture using PhTMS as
internal standard. Isolated yield in parentheses.
1
With the optimized reaction conditions in hand, we set out
to explore the scope of this transformation. The reaction
conditions could be applied to a wide variety of alkenes with
diverse substitution patterns and varied electronic properties,
delivering a broad spectrum of primary amines with sophis-
ticated and advanced functional groups (Figures 2–4). Due to
purification issues, some primary amines were isolated in
a protected form. This method could be employed to
synthesize linear primary amines (Figure 2a). Terminal
styrenes with different substitution patterns on the aromatic
ring were all good substrates for this reaction, giving the
corresponding b-aryl ethyl amines in good yields (1a–1g). 1-
Alkyl-substituted styrenes could be applied to this reaction,
furnishing various b-aryl long-chain aliphatic primary amines
in good yields (1h–1l). 1,1-Cycle-substituted alkenes could be
efficiently transformed into corresponding primary amines in
good yields (1m–1o). The b-thiazole-substituted ethyl amine
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diphenylethene could be both transformed to 2i under the
reaction conditions in 93% and 98% yield, respectively.
Methyl trans-cinnamyl ether could be converted to 2-amino-
ether 2j in 86% yield. 1,1-Diphenyl propene could undergo
hydroamination to give corresponding a-branched amine 2k
in 86% yield. Thiophene- and quinoline-substituted propenes
were compatible under the reaction conditions, furnishing the
heteroaryl-containing a-branched primary amines 2l and 2m
in 88% and 80% yield, respectively. The 2-aminoether-
bearing a-quaternary carbon center 2n was obtained in 99%
yield. Cyclic internal styrenes and aliphatic alkenes with di- or
tri-substitutions could be converted to the corresponding
aliphatic a-branched primary amines (2o–2r) in 81–99%
yield. Notably, alkenes tethered with sulfide, cyanide, nitro,
unsaturated ester, vinylbromide, or conjugated diene were all
good substrates under the reaction conditions, affording
corresponding primary amines in synthetically useful yields
(2s–2x). a-Tertiary primary amines which are challenging to
synthesize could be obtained using this mild method (Fig-
ure 2c). b,b-Dimethyl styrenes with para-, meta-, ortho-
substituents on the aromatic ring could be successfully
converted to corresponding a,a-dimethyl primary amines in
moderate to excellent yields (3a–3j). Cyclohexyl-substituted
styrene could be used to synthesize the bulky primary amine
3k in 65% yield. Tetrasubstituted alkenes were also good
substrates for this transformation, giving sterically congested
primary amines 3l–3n in synthetically useful yields.
Next, alkenes adjacent to heteroatoms were tested under
the reaction conditions (Figure 3a). 2-Aminoalcohols and 1,2-
diamines are common substructures in bioactive molecules
and organic synthesis. Vinyl ether and enamine derivatives
are well-tolerated under these reaction conditions, leading to
diverse 2-aminoalcohol and 1,2-diamine structural motifs. 3,4-
Dihydro-2H-pyran could undergo regioselective hydroami-
nation to give 3-aminotetrahydropyran 4a in 70% yield.
Seven- and eight-membered cyclic silyl enol ethers could be
tolerated in this reaction, giving medium-sized 2-aminosilyl-
ethers (4b and 4c) in synthetic useful yields. Acyclic vinyl
ethers are also good substrates in the reaction, delivering
corresponding chain 2-aminoethers (4d and 4e) in 76% and
72% yield, respectively. Free aminoalcohol 4 f could be
obtained from trans-cinnamyl alcohol in 81% yield. Enamide
derivatives could be applied to furnish 1,2-diamines contain-
ing one primary amine motif (4g and 4h) in 72% and 98%
yield, respectively.
To further demonstrate the robustness and utility of this
protocol, we applied the reaction conditions to a series of
natural product derivatives (Figure 3b). Estrone derivatives
could undergo regioselective hydroamination to afford ami-
noether-bearing free phenol 5a containing a primary amine
and ketone 5b bearing an a-linear primary amine in 65% and
80% yield, respectively. 3,4,6-Tri-O-benzyl-d-glucal could be
successfully subjected to the reaction conditions and gave 2-
amino-1,5-anhydro-2-deoxy-d-glucitol derivative 5c in 70%
yield. (S)-(À)-Terpineol was compatible with the reaction,
giving the 3-amino-a,a,4-trimethyl-cyclohexanemethanol 5d
in 51% yield. Menthol-tethered vinyl ether could be incorpo-
rated into the reaction, giving menthol-containing 2-amino-
ether 5e in 58% yield. 7-Methoxy-2,2-dimethylchromene
Figure 2. Scope of primary amine synthesis from selective hydroamina-
tion of alkene. [a] The reaction was conducted on 0.11 mmol scale
under standard conditions. Isolated yield of free amine is shown
unless otherwise noted. Yield in parentheses is based on the recovery
of alkenes. Boc=t-butoxycarbonyl, Bz=benzoyl, Cbz=benzyloxycar-
bonyl. [b] Conditions B were used. [c] Isolated yield of NHBoc. [d] Con-
ditions A were used. [e] Isolated yield of NHBz. [f] Isolated yield of
NHCbz.
derivative 1p was obtained in 86% yield. 1,1-Diaryl-substi-
tuted ethylenes with electron-rich or electron-poor substitu-
ents delivered b,b-bisaryl ethyl amines in excellent yields (1q–
1w). 4-Isopropyl styrene delivered the primary amine 1x in
85% yield, leaving the isopropyl group intact. This protocol
was applicable to the synthesis of a-branched primary amines
(Figure 2b). Internal alkenes, such as b-methyl styrenes with
para-, meta-, ortho-substituents on the aromatic ring, could be
converted to corresponding a-methyl primary amines in 73–
99% yield (2a–2h). cis-1,2-Diphenylethene and trans-1,2-
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To gain further insights into the reaction mechanism, we
carried out a set of reactions to shed light on the reaction
pathways (Figure 4). First, we conducted the radical clock
reaction using 8 under standard conditions. Allylic primary
amine product 9 was obtained in 82% yield as a mixture of
Z/E isomers, which could undergo the regioselective hydro-
amination followed by ring opening via radical intermediates
8-1 and 8-2. Interestingly, a,b-dimethylstyrene 10 with differ-
ent Z/E ratios gave the desired hydroamination product 11 in
the same diastereomeric ratio (dr= 2:1), suggesting the
reaction proceeded via the same radical intermediate 10-1.
The formation of 10-1 erases the Z/E information from 10,
followed by stereoselective hydrogen transfer to afford 11 in
81–83% yield with identical diastereoselectivity. When ger-
aniol derivative 12 was exposed to the standard conditions,
aminocyclization product 13 was obtained in 32% yield with
44% conversion. The reaction may undergo a radical cascade
cyclization mechanism via radical intermediates 12-1 and 12-
2. These two reactions both suggested the incorporation of
radical intermediates in this reaction. To further confirm the
pathway of this reaction, an alkene with an intramolecular
alcohol 14, which is difficult to be oxidized under the reaction
conditions, was tested.[20a] When 5,5-diphenyl-4-penten-1-ol
14 was submitted to the reaction conditions, the intramolec-
ular oxygen-trapped product 15 was exclusively detected in
88% yield with or without ammonium carbonate. No
intermolecular hydroamination product was detected. The
result indicated the reaction went through single electron
oxidation of an alkene moiety to give radical cation inter-
mediate 14-1, which was intramolecularly trapped by the
alcohol moiety to give 14-2. 14-2 further extracted a hydrogen
atom to deliver 15. To further prove the existence of a radical
cation intermediate, b-methyl 4-fluorostyrene 16 was sub-
jected to the reaction conditions in the presence of TEMPO
(2 equiv) under otherwise standard conditions. Hydroamina-
tion product 2d was not observed. Instead, the TEMPO
adduct with alkene 17 was obtained in 51% yield with 53%
Figure 3. Synthetic application of the hydroamination reaction of
alkenes. [a] The reaction was conducted on 0.11 mmol scale under
Conditions B. Free primary amine was isolated unless otherwise noted.
Yield based on the recovery of alkenes is shown in the parentheses.
TBS=t-butyldimethylsilyl, Bn=benzyl. [b] Isolated yield of NHBz.
[c] See Table 1, entry 1 for reaction conditions. [d] Isolated yield of
NHBoc. [e] Isolated yield of NHCbz. [f] Conditions A were used.
delivered chromene-derived primary amine 5 f in quantitative
yield. a-Cedrene underwent regioselective hydroamination to
furnish corresponding primary amine 5g in 95% yield. (R)-
Limonene and dehydroepiandrosterone are also tolerated in
this reaction, furnishing corresponding primary amines 5h
and 5i in 80% and 85% yield, respectively. It is noteworthy
that the hydroamination selectively occurred on the internal
alkene, and the terminal alkene remained intact, indicating
complete chemoselectivity of this method over different
alkenes. Inspired by this encouraging result, we further
applied this protocol to chemoselective hydroamination
over two different alkenes (Figure 3c), giving homoallylic
primary amines in moderate to good yields (6a–6 f). Vinyl
phenylacetylene was a good substrate for the reaction to
undergo selective hydroamination on alkenes, giving homo-
propargyl primary amine 6g in 92% yield. 1-Substituted
aliphatic alkenes are not reactive under the reaction con-
ditions due to their high oxidative potentials (Ep/2 > 2.2 V).
Moreover, bioactive molecules phentermine (7a) and
amphetamine (7b) could be synthesized from b-methyl
styrene and b,b-dimethyl styrene in 87% and 65% yield
(Figure 3d), which required multiple steps in traditional
syntheses.[22,23]
Figure 4. Mechanistic investigations of the reaction. [a] See Table 1,
entry 1 for reaction conditions. [b] Isolated yield of NHBoc. [c] Isolated
yield of free amine under conditions B.
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conversion via the trapping of TEMPO with radical inter-
patterns into highly functionalized primary amines. Notably,
mediate 16-2, formed by amine attack via the radical cation
intermediate 16-1.
the reaction demonstrates excellent selectivity over alkynes
and different alkenes, leading to linear, a-branched, and a-
tertiary primary amines selectively. The synthetic utility of
this methodology is successfully demonstrated by the efficient
synthesis of aminoalcohol derivatives, diamines, bioactive
molecules, late-stage functionalization of natural products, as
well as the rapid access to molecular complexity. Mechanistic
investigations revealed the process underwent a radical cation
intermediate. We anticipate this work will open a new avenue
of employing alkenes as a general chemical handle for the
practical synthesis of aliphatic primary amines in the context
of both pharmaceuticals and natural product synthesis.
Next, we set up a series of kinetic experiments to probe
the kinetic behavior of this reaction (Figure 5).[21] The time
course for the consumption of b,b-dimethylstyrene and the
generation of corresponding primary amine 7b is presented in
Figure 5a. Hammett plot studies showed that the hydro-
amination reaction is sensitive to the substituent effects
(Figure 5b). The Hammett slope (1 = À0.82) shows positive
charge buildup in the selectivity-determining transition state
of the reaction and is more negative than typically observed
for the generation of benzylic radicals. This is consistent with
the mechanistic observations, suggesting the presence of the
radical cation intermediates 14-1 or 16-1.[24] Based on the
experimental results and literature,[25] we propose the reac-
tion mechanism depicted in Figure 5c. First, PC is activated to
generate excited PC* by visible light irradiation. PC*
interacts with the alkene via single electron oxidation to
give radical cation intermediate M1 in conjunction with
reduced photocatalyst species PC-1. M1 is trapped by
ammonia released from ammonium carbonate to deliver
intermediate M2. The stability of M2 dominates the regiose-
lectivity of the amine attack. M2 can undergo HAT (hydrogen
atom transfer) with 2-aminothiophenol to furnish protonated
primary amine M3 along with intermediate M4. PC-1 can
reduce M4 to regenerate PC and 2-aminothiophenoxide M5,
which can be protonated by M3 to generate 2-aminothiophe-
nol and primary amine product.
Acknowledgements
We sincerely acknowledge NSFC (21971101 and 21801126),
Guangdong Basic and Applied Basic Research Foundation
(2019A1515011976), The Pearl River Talent Recruitment
Program (2019QN01Y261), Guangdong Provincial Key Lab-
oratory of Catalysis (No. 2020B121201002), Thousand Talents
Program for Young Scholars for financial support. We
acknowledge the assistance of SUSTech Core Research
Facilities. The authors would like to thank Prof. Wei Lu
(SUSTech) for accessing to analytic instruments. We thank
Dr. Ming-Shang Liu (SUSTech) for reproducing the results of
1j, 3a, 4h, and 5b.
In summary, a straightforward and modular route to
a wide variety of aliphatic primary amines from alkenes is
presented here based on a metal-free hydroamination at room
temperature. The use of cost-effective and easily available
ammonium carbonate allows for the efficient conversion of
terminal and internal alkenes with diverse substitution
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkene · ammonium carbonate · hydroamination ·
metal-free · primary amines
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Manuscript received: December 16, 2020
Revised manuscript received: January 28, 2021
Accepted manuscript online: February 4, 2021
Version of record online: March 18, 2021
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