Gallium trichloride catalyzed hydroamination of alkynes: Scope, limitation, and mechanistic studies by dft

Article abstract of DOI:10.1002/ejoc.201200829

The successful application of gallium trichloride as a catalyst for the intermolecular hydroamination of alkynes with aromatic amines is reported. The reaction is effective with many aniline derivatives and shows exclusive selectivity for the Markovnikov

Full text of DOI:10.1002/ejoc.201200829

Job/Unit: O20829
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FULL PAPER
DOI: 10.1002/ejoc.201200829
Gallium Trichloride Catalyzed Hydroamination of Alkynes: Scope, Limitation,
and Mechanistic Studies by DFT
Lei Li,[a] Genping Huang,[b] Zhou Chen,[b] Wei Liu,[a] Xiufang Wang,[b] Yanmei Chen,[a]
Lijuan Yang,[a] Wu Li,[b] and Yahong Li*[a,c]
Keywords: Synthetic methods / Hydroamination / Gallium / Alkynes / Reaction mechanisms / Density functional calculations
The successful application of gallium trichloride as a catalyst
for the intermolecular hydroamination of alkynes with aro-
matic amines is reported. The reaction is effective with many
aniline derivatives and shows exclusive selectivity for the
Markovnikov products. The mechanism of the transformation
was investigated by DFT calculations and a plausible path-
way is proposed.
Two different mechanisms have been proposed for the
hydroamination of alkenes and alkynes: 1) The activation
of amines and 2) the activation of alkenes or alkynes. The
amine activation mechanism has been well established for
alkali and alkaline-earth metals, lanthanides, and group 4
and 5 metals. Depending on the catalyst used, both mecha-
nisms have been suggested for the hydroamination reaction
catalyzed by late-transition-metal complexes.
Introduction
The hydroamination of alkenes, alkynes, and related un-
saturated substrates is an attractive strategy for the prepara-
tion of amines, enamines, and imines, which are valuable
and industrially important bulk chemicals, specialty chemi-
cals, and pharmaceuticals.[1] Because of the high activation
barrier of the hydroamination reaction,[2] the development
of catalytic transformations is necessary and has been the
focus of numerous studies during the last two decades.[3]
A plethora of catalytic systems are known to effect such
transformations, including those based on alkali and alk-
aline-earth metals,[4] rare-earth metals and actinides,[5]
group 4 and 5 metals,[3a,6] late-transition metals of groups
8–12,[7] bases,[8] Brønsted acids,[9] and various types of
heterogeneous catalysts.[10] However, the potential of
group 13–15 metal-based hydroamination catalysts has re-
ceived less attention. For example, there are only a very
limited number of reports available on the use of group 13–
15 metal-based catalysts, for example, InBr3,[11] GaCl3,[12]
Bi(OTf)3,[13] aluminium compounds,[14] and BiCl3,[15] for
the hydroamination of alkenes and little attention has been
paid to the use of these catalysts for the hydroamination of
alkynes.[16]
The accepted hydroamination pathway mediated by al-
kali and alkaline-earth metals and lanthanides involves C–
C multiple bond insertion into a M–N bond followed by
rapid protonolysis by other amine substrates.[4,5] The hy-
droamination reaction catalyzed by group 4 and 5 metals
occurs by the formation of an imido species, which reacts
further with the C–C multiple bond through a [2+2] cyclo-
addition to form an azametallacyclobutene species, which
is protonolyzed by other amine substrates to release the
product.[17] For late-transition-metal-catalyzed hydroamin-
ation reactions, the activation of alkenes or alkynes occurs
by coordination of the alkene or alkyne to the metal to give
a coordination complex, which is subsequently subjected to
nucleophilic attack by the amine;[18] the activation of
amines can be achieved by oxidative addition of an amine
to the metal center, then a C–C unsaturated bond is inserted
into the M–N bond, and the subsequent reductive elimi-
nation of the metal complex generates the hydroamination
product.[19] The Lewis acid–base interaction between BiCl3
and amine substrates has been proposed as the key initia-
tion step for the BiCl3-catalyzed hydroamination reaction
of norbornene with aromatic amines,[15] whereas C=C
double-bond activation by the interaction between
Bi(OTf)3 and the diene to generate an allyl cationic species,
which is subsequently trapped with an amide, has been pos-
tulated as the mechanism for Bi(OTf)3-catalyzed hydro-
amination of 1,3-dienes with carbamates, sulfonamides, and
carboxamides.[13]
[a] Key Laboratory of Organic Synthesis of Jiangsu Province,
College of Chemistry, Chemical Engineering and Materials
Science, Soochow University,
Suzhou 215006, China
Fax: +86-512-6588-0089
E-mail: liyahong@suda.edu.cn
Homepage: http://chemistry.suda.edu.cn/
index.aspx?lanmuid=69&sublanmuid=603&id=66
[b] Key Laboratory of Salt Lake Resources and Chemistry of the
Chinese Academy of Sciences, Qinghai Institute of Salt Lakes,
Xining 810008, China
[c] State Key Laboratory of Applied Organic Chemistry, Lanzhou
University,
Lanzhou 730000, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200829.
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None of the above-described mechanisms has been ex- Table 1. Hydroamination reaction between phenylacetylene (1) and
2,4-dichloroaniline (2a) catalyzed by group 13–15 metal complex-
plored for the GaCl3- or InBr3-catalyzed hydroamination of
alkenes with sulfonamides, neither have mechanisms for the
es.[a]
hydroamination of alkynes catalyzed by group 13–15 metal
complexes been reported. Our previous studies indicated
that BiCl3 and AlCl3 are efficient catalysts for the hydro-
amination of alkenes with aromatic amines.[14a,15] As a con-
tinuation of our ongoing efforts on the hydroamination of
alkenes catalyzed by group 13–15 metal complexes, and also
driven by an impetus for exploring the mechanisms of the
hydroamination of alkenes and alkynes catalyzed by
group 13–15 metal complexes, we have investigated the hy-
droamination of alkynes catalyzed by several group 13–15
metal complexes. Gratifyingly, GaCl3 was found to be an
efficient catalyst. Herein we report the first successful use
of GaCl3 as a catalyst for the intermolecular hydroamin-
ation of alkynes. Mechanistic studies were performed by
DFT calculations and a plausible mechanism for the reac-
tion is proposed based on the results of the calculations,
which support the C–C activation pathway. The regioselec-
tivities of the reactions as well as the reactivities of the dif-
ferent amine substrates can be well explained by the pro-
posed mechanism.
Entry
Catalyst
Yield of 3a [%][b]
1
2
3
4
5
6
7
8
AlCl3
GaCl3
InCl3
SnCl2
SnCl4
PbCl2
SbCl3
BiCl3
trace
70
51
0
0
0
0
0
[a] Reaction conditions: 1 (3 mmol), 2a (4.5 mmol), catalyst
(10 mol-%), toluene (4 mL). [b] Isolated yield after reduction by
LiAlH4.
catalyst loading, and temperature on the yields of the hy-
droamination reactions were examined and the results are
presented in Table 2.
Results and Discussion
Table 2. Reactions of 2,4-dichloroaniline (2a) with alkynes 1Ј cata-
lyzed by GaCl3 under different conditions.[a]
Optimization of the Conditions for the Gallium Trichloride
Catalyzed Hydroamination Reaction
An initial catalyst screening was performed for the reac-
tion between phenylacetylene (1) and 2,4-dichloroaniline
(2a) in toluene as solvent by using a variety of group 13–
15 metal catalysts (Table 1). Typically, a reaction mixture
consisting of 10 mol-% of catalyst, 1, 2a, and toluene was
sealed in a pressure tube and heated in an oil bath at 60 °C.
Because the resulting imines were not stable to column
chromatography, the hydroamination products were directly
reduced to amines with LiAlH4 in toluene for 3 h. The
product 3a was isolated by flash chromatography. The re-
sults are summarized in Table 1.
As we can see from Table 1, GaCl3 stands out as an ex-
cellent catalyst for this reaction, generating 70% of 3a
(Table 1, entry 2). The other group 13 metal compounds
either gave a trace amount (Table 1, entry 1) or a decreased
yield of 3a (Table 1, entry 3). The group 14 metal com-
plexes, SnCl2 (Table 1, entry 4), SnCl4 (Table 1, entry 5),
and PbCl2 (Table 1, entry 6), did not give the expected
products. Likewise, the group 15 metal compounds SbCl3
and BiCl3 were not catalytically active (Table 1, entries 7
and 8), which contrasts with the BiCl3-catalyzed hydro-
Entry
Alkyne
Catalyst Solvent T [°C] Prod- Yield [%][b]
loading
[mol-%]
uct
1
2
3
4
5
6
7
8
PhCϵCH
PhCϵCH
PhCϵCH
PhCϵCH
PhCϵCPh
EtCϵCEt
10
10
10
10
10
10
THF
60
60
60
60
60
60
60
60
60
50
70
80
3a
3a
3a
3a
3b
3c
3d
3a
3a
3a
3a
3a
66
trace
0
87
43
44
48
trace
Ͻ10
66
CH3CN
CH2Cl2
[c]
–
–
–
–
–
–
–
–
–
HCϵCC6H13 10
PhCϵCH
PhCϵCH
PhCϵCH
PhCϵCH
PhCϵCH
1
5
10
10
10
9
10
11
12
69
65
[a] Reaction conditions: 1Ј (3 mmol), 2a (4.5 mmol), solvent
(4 mL). [b] Isolated yield after reduction by LiAlH4. [c] Under sol-
vent-free conditions.
As shown in Table 2, the yield of the reaction depends
amination of norbornene, in which BiCl3 effectively cata- on the solvent used. THF (Table 2, entry 1) and toluene
lyzed the hydroamination reaction.[15]
(Table 1, entry 2) are feasible solvents, whereas little or no
Pleasingly, the hydroamination of 1 with 2a proceeded 3a was obtained with CH3CN or CH2Cl2 (Table 2, entries 2
with very good regioselectivity, and 100% Markovnikov and 3). However, solvent-free conditions are most suitable
selectivity was observed for all group 13 metal catalysts.
for the reaction (Table 2, entry 4) as the yield of 3a was
Following the catalyst screening, we were interested in 87%. Next, the reactivities of a variety of alkynes (diphenyl-
optimizing the reaction conditions of the hydroamination acetylene, 3-hexyne, 1-octyne) catalyzed by 10 mol-% GaCl3
reactions catalyzed by GaCl3. The effects of solvent, alkyne, at 60 °C under solvent-free conditions were investigated. We
2
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Gallium Trichloride Catalyzed Hydroamination of Alkynes
found that aliphatic alkynes are not as reactive as aryl- Table 3. Hydroamination of phenylacetylene (1) with various
amines 2 under the optimized conditions.[a]
alkynes; this is evident from the reactions of 3-hexyne
(Table 2, entry 6) and 1-octyne (Table 2, entry 7) with 2,4-
dichloroaniline (2a), which gave yields of 44 and 48% of
2,4-dichloro-N-(3-hexyl)aniline (3c) and 2,4-dichloro-N-(2-
octyl)aniline (3d), respectively, as compared with an 87%
yield for the reaction of phenylacetylene (1) with 2a under
the same conditions. Diphenylacetylene gave a 43% yield,
presumably due to the steric hindrance of the bulky phenyl
group (Table 2, entry 5). Thus, phenylacetylene (1) is a suit-
able substrate for the hydroamination reaction. Catalyst
loading is very important to the yield of the reaction. A
5 mol-% catalyst loading at 60 °C gave a yield of less than
10% of 3a after 12 h (Table 2, entry 9); on further reducing
the catalyst loading to 1 mol-% (Table 2, entry 8), only a
trace amount of the product was observed, as determined
by GC–MS, and could not be isolated. The temperature of
the reaction did not dramatically influence the yield of 3a.
As the temperature was reduced to 50 °C, the product 3a
was obtained in 66% yield under solvent-free conditions
with a catalyst loading of 10 mol-% (Table 2, entry 10);
yields of 69 and 65% were obtained at 70 (Table 2, entry 11)
and 80 °C (Table 2, entry 12), respectively.
Gallium Trichloride Catalyzed Hydroamination of
Phenylacetylene (1) with Aromatic Amines
[a] Reaction conditions: 1 (3 mmol), 2 (4.5 mmol), GaCl3 (10 mol-
%). Yields of the isolated products are reported. [b] The products
were isolated as imines. [c] Trace amounts of anti-Markovnikov
products were detected for 2o, 2q, and 2s by GC–MS [Markovni-
kov/anti-Markovnikov = 98:2 (2o), 91:9 (2q), 86:14 (2s)]. [d] A quin-
oline derivative was isolated as the main product (see the Support-
ing Information).
With the optimized reaction conditions in hand, we fur-
ther investigated the scope of the reaction by screening a
larger selection of amines. The results are given in Table 3.
As we can see in Table 3, the GaCl3-catalyzed hydro-
amination of phenylacetylene (1) has been achieved with
both primary and secondary aromatic amines. For the pri-
mary aromatic amines, hydroamination products containing
different functionalities, including halogens (3e–3l), meth-
oxy (3m), isopropyl (3o), and nitrile (3p), were formed in 4.85 gave a yield of 18%, and still lower pKa(H2O) values,
moderate-to-excellent yields. In most cases, the Markovni- 3.52 (3-chloroaniline), 3.58 (4-fluoroaniline), and 3.53 (4-
kov products were obtained exclusively (3e–3n, 3p, 3r). The bromoaniline), gave higher yields of 65, 64, and 80%,
anti-Markovnikov products were occasionally formed, but respectively.
the Markovnikov product was favored, often in an excess
Encouraged by the successful demonstration that 4-
of 91:9, over the anti-Markovnikov product (2o, 2q, and 2s). bromoaniline (2j) is a highly effective nitrogen source and
Steric effects in the primary aromatic amines tested did not hydroaminates phenylacetylene (1) with excellent yield and
have any significant impact on the reaction. For example, high regioselectivity, we sought to expand the scope of the
2,6-diisopropylamine (2o) and naphthalen-1-amine (2q) hy- reaction by using functionalized phenylacetylenes and
droaminated phenylacetylene in high yields. Secondary aro- heteroarylalkynes. Accordingly, (4-methoxyphenyl)acetyl-
matic amines gave lower yields than the primary aromatic ene (1ЈЈt), 2-chlorophenylacetylene (1ЈЈu), 2-ethynylthio-
amines. The hydroamination of phenylacetylene (1) with N- phene (1ЈЈv), and 2-ethynylpyridine (1ЈЈw) were subjected
methylaniline (2r) proceeded in 18% yield, whereas only a to the hydroamination reaction with 2j (Table 4). With an
trace amount of the hydroamination product was observed electron-donating OMe substituent at the para position,
with diphenylamine (2s). The GaCl3-catalyzed hydroamin- alkyne 1ЈЈt gave an excellent yield of 3t with exclusive
ation reactions of phenylacetylene (1) with tertiary bu- Markovnikov regioselectivity. The electron-deficient alkyne
tylamine, benzylamine, and p-toluenesulfonamide were also 1ЈЈu with a chloro group at the ortho position was not a
examined but no hydroamination products were detected. satisfactory substrate for this transformation, affording the
It is evident that the acidities of the amines affect their reac- corresponding hydroamination product 3u in moderate
tivities. Amines with high pKa values [tBuNH2, pKa(H2O) yield. Heteroarylalkyne 1ЈЈv was found to be efficiently hy-
= 10.69; BnNH2, pKa(H2O) = 9.34; TsNH2, pKa(H2O) = droaminated by 2j, affording the desired product 3v in good
10.17] do not react, N-methylaniline with a pKa(H2O) of yield. However, heteroarylalkyne 1ЈЈw was not a good sub-
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strate for the reaction; the expected hydroamination prod- Mechanistic Considerations
uct 3w was not detected.
To gain a better understanding of this hydroamination
process, the detailed mechanism[20] was studied computa-
tionally by DFT.[21,22] The calculated potential energy sur-
face of the GaCl3-catalyzed hydroamination reaction of
phenylacetylene (1) by 4-chloroaniline (2g) is shown in Fig-
ure 1. The geometric structures of selected transition states
and intermediates are presented in Figure 2.
Table 4. Hydroamination of arylacetylenes 1ЈЈ with 4-bromoaniline
(2j) under the optimized conditions.[a]
As shown in Figure 1, the reaction starts with the coordi-
nation of phenylacetylene (1) to the GaCl3 catalyst to give
the π complex IN-1 with a free energy lower than the start-
ing substrates by 1.2 kcal/mol. In complex IN-1, the CϵC
triple bond is highly asymmetrically bonded to the Ga cen-
ter with Ga–C distances of 2.248 and 2.788 Å (Figure 2).
For the following C–N bond-formation process, both
inner-[23] and outer-sphere pathways[24] have been sug-
gested. Our computational results indicate that the energy
barrier of the outer-sphere C–N bond-formation process
via TS1b is higher by about 2.4 kcal/mol than that of the
inner-sphere C–N bond-formation process via TS1a. Com-
parison of the geometric structures of TS1a and TS1b
shows that the greater rearrangement of the alkyne moiety
in TS1b (Є C1–C2–C3 149.2°) than in TS1a (Є C1–C2–C3
167.5°) may account for the preference for the inner-sphere
C–N bond-forming pathway (Figure 2). The zwitterionic in-
[a] Reaction conditions: 1ЈЈ (3 mmol), 2j (4.5 mmol), GaCl3
(10 mol-%). Yields are reported for the isolated products. [b] A
trace amount of the anti-Markovnikov product was determined by
GC–MS (Markovnikov/anti-Markovnikov = 90:10).
The high regioselectivity of the hydroamination reaction termediate 6 generated from IN-1 and 2g via TS1a is
and low reactivities of the secondary aromatic amines and slightly endergonic by 1.4 kcal/mol. The subsequent intra-
alkylamines prompted us to study the mechanism of the molecular proton-transfer step from 6 is kinetically unfa-
reactions.
vorable with an activation energy barrier of 37.9 kcal/mol
Figure 1. Potential energy surface for the GaCl3-catalyzed hydroamination reaction of phenylacetylene (1) by 4-chloroaniline (2g) (R =
vinyl).
4
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Gallium Trichloride Catalyzed Hydroamination of Alkynes
Figure 2. Geometric structures of the selected intermediates and transition states of the GaCl3-catalyzed hydroamination reaction of
phenylacetylene (1) by aniline 2g. Selected distances and angles are given in angstroms and degrees.
via transition state TS2 (Figure 1). Several recent studies ene (1), the yield was found to increase in the order alk-
have revealed that ligand and solvent could act as proton ylamine Ͻ secondary aromatic amine Ͻ primary aromatic
shuttle to facilitate the hydrogen-migration process.[25] We amine. As mentioned above, the crucial step that affects the
hypothesize that the Cl ligand of the GaCl3 catalyst or 4- efficiency is expected to be the C–N bond-forming process.
chloroaniline may serve as the proton shuttle in these reac- Therefore we studied this step for these substrates in detail
tions. According to Figure 1, the proton-transfer step can to gain an understanding of the factors that affect the effi-
be realized easily with the assistance of 4-chloroaniline in a ciency of the reaction.
stepwise fashion.[26] Here, to save computational cost, a sec-
As shown in Scheme 1, for the secondary aromatic amine
ond molecule of 4-chloroaniline (2g) was modeled by the 2gЈ and alkylamine 2gЈЈ, the free energies of the C–N bond-
amine 2t. The formation of the hydrogen-bonding interme- formation process via transition states TS1Ј and TS1ЈЈ are
diate 7 from 6 and 2t is slightly exergonic by 1.2 kcal/mol. 16.6 and 9.9 kcal/mol, that is, equal to or smaller than that
The transition state TS3 corresponding to the hydrogen- of TS1a, which indicates that this step is little influenced by
abstraction process from the N1 atom to the N2 atom is steric factors. The main reason for the trend in the experi-
3.7 kcal/mol above the intermediate 7. The reaction via this mental observations is that the initial amine/phenylacetyl-
transition state leads to the formation of the zwitterionic ene substitution step is more accessible for the less electron-
intermediate 8, which is only 0.5 kcal/mol less stable than donating amine.
7. The subsequent hydrogen-donation process from 8 via
For the alkylamine 2gЈЈ, the coordination of 2gЈЈ to
TS4 is quite facile with an activation barrier of 0.1 kcal/ GaCl3 to give the σ complex 11ЈЈ is exergonic by 27.6 kcal/
mol. Finally, the hydroamination product 10 can be gener- mol, and thus the energy barrier for the C–N bond-forming
ated from 9 with the loss of a molecule of 2t. Other possible process is 37.5 kcal/mol. For the primary aromatic amine
mechanisms starting with amine activation by the catalyst 2g and secondary aromatic amine 2gЈ, the formation of the
have recently been proposed for the Lewis acid catalyzed σ complexes 11 and 11Ј is exergonic by 13.0 and 15.2 kcal/
intermolecular olefin hydroamination.[14] We also consid- mol, and thus the energy barriers for the C–N bond-form-
ered these mechanisms for the title reaction, but the energy ing process are 29.3 and 31.8 kcal/mol, respectively. Thus,
barriers were found to be high, ruling out these possibi- the low reactivities of the alkylamines are well explained by
lities.[22]
the higher energy barriers of the C–N bond-forming pro-
The potential energy surface for the formation of anti- cess of these amines.
Markovnikov products was also calculated. The free energy
On the basis of previous work[14,18] and our computa-
of the transition state TSЈ-anti leading to the formation of tional results, we propose the reaction mechanism for the
the anti-Markovnikov products is 22.6 kcal/mol (Figure 1), GaCl3-catalyzed hydroamination of alkynes shown in
which is 6.3 kcal/mol higher than that of TS1a, which ac- Scheme 2. Coordination of phenylacetylene (1) to the
counts for the exclusive Markovnikov selectivities of the re- GaCl3 catalyst produces the intermediate IN-1. The subse-
actions.
quent nucleophilic addition of aniline 2 to the intermediate
The efficiency of the hydroamination reaction is highly IN-1 by an inner-sphere pathway gives the zwitterionic in-
amine-dependent. For the hydroamination of phenylacetyl- termediate 6, which can lead to the enamine intermediate
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Scheme 1. Energies for the C–N bond-formation processes of the amines 2g, 2gЈ, and 2gЈЈ.
12 and regenerate the active catalyst GaCl3 through aniline-
Experimental Section
assisted proton-transfer processes. Finally, the enamine in-
General: All reactions were carried out in pressure tubes (35 mL,
150 psi) equipped with a magnetic stirring bar and capped with a
solid PTFE plug. GaCl3 was purchased from commercial suppliers
and used without further purification. Amines were distilled from
CaH2. Alkynes were stored over molecular sieves (4 Å). A Varian
Unity Plus 400 MHz (or 300 MHz) spectrometer was used to re-
cord 1H and 13C NMR spectra. GC–MS was performed with a
GC–MS-QP2010 instrument using dodecane as internal standard
and MS spectra were obtained by TOF-MS.
termediate 12 isomerizes to the final product ketimine 13.
General Procedure for the Hydroamination Reaction: GaCl3
(0.0528 g, 0.3 mmol), aniline (4.5 mmol), and phenylacetylene
(0.306 g, 3 mmol) were added to a 35 mL pressure tube in a drybox.
A stirring bar was added to the pressure tube, which was then fitted
with a Teflon™ stopper and removed from the drybox. The tube
was heated with stirring at 60 °C for 12 h. Then at 0 °C, the reac-
tion solution was carefully added to a suspension of LiAlH4
(0.171 g, 4.5 mmol) in toluene (2 mL) and the mixture was heated
with stirring at 60 °C for 3 h. After cooling the solution to 0 °C,
the excess LiAlH4 was hydrolyzed with iced water and the precipi-
tate was dissolved by the dropwise addition of an aqueous NaOH
solution (2.0 molL–1). The mixture was then extracted with CH2Cl2
(3ϫ 20 mL) and the combined organic layers were dried with
MgSO4 and concentrated under vacuum. Column chromatography
of the residue on silica gel gave a pure product.
Scheme 2. Proposed mechanism for the GaCl3-catalyzed hydro-
amination reaction of phenylacetylene (1).
Conclusions
GaCl3 has been identified as an effective catalyst for the
hydroamination of phenylacetylene with aromatic amines,
predominantly giving the Markovnikov hydroamination
products. A plausible mechanism has been proposed based
on DFT studies. This mechanism involves the coordination
of alkynes to GaCl3, the subsequent nucleophilic attack of
2,4-Dichloro-N-(1-phenylethyl)aniline (3a): Product 3a (87%) was
obtained as a colorless oil by column chromatography with petro-
1
leum ether as eluent. H NMR (400 MHz, CDCl3): δ = 7.45–7.22
(m, 6 H), 6.94 (dd, J = 8.8, 1.9 Hz, 1 H), 6.34 (d, J = 8.8 Hz, 1 H),
4.70 (s, 1 H), 4.51 (m, J = 6.3 Hz, 1 H), 1.59 (d, J = 10.4 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.4, 144.1, 131.2,
amines to the coordination π complex to generate zwitter- 130.9, 130.0, 129.6, 128.0, 123.5, 121.5, 115.5, 55.8, 27.5 ppm.
HRMS: calcd. for C14H13Cl2N 265.0425; found 265.0430.
ionic intermediates, and the final aniline-assisted proton-
transfer process to produce the Markovnikov products. The
proposed mechanism accounts for the Markovnikov selectiv-
2,4-Dichloro-N-(1,2-diphenylethyl)aniline (3b): Product 3b (43%)
was obtained as a light-green oil by column chromatography with
1
ity of the reactions and the different reactivities of the amine. petroleum ether as eluent. H NMR (400 MHz, CDCl3): δ = 7.31–
6
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Gallium Trichloride Catalyzed Hydroamination of Alkynes
7.27 (m, 3 H), 7.24 (d, J = 6.2 Hz, 5 H), 7.17 (d, J = 2.3 Hz, 1 H),
7.11 (d, J = 6.6 Hz, 2 H), 6.85 (dd, J = 8.8, 2.4 Hz, 1 H), 6.23 (d,
J = 8.7 Hz, 1 H), 4.81 (s, 1 H), 4.54 (m, 1 H), 3.17 (dd, J = 13.9,
2,5-Dichloro-N-(1-phenylethyl)aniline (3i): Product 3i (60%) was
obtained as a pale-yellow oil after column chromatography with
petroleum ether/ethyl acetate (60:1) as eluent. 1H NMR (400 MHz,
5.8 Hz, 1 H), 3.05 (dd, J = 13.8, 8.0 Hz, 1 H) ppm. 13C NMR CDCl3): δ = 7.37–7.28 (m, 4 H), 7.26–7.19 (m, 1 H), 7.12 (d, J =
(100 MHz, CDCl3): δ = 142.7, 142.2, 137.5, 129.8, 129.2, 129.0, 8.4 Hz, 1 H), 6.57–6.48 (m, 1 H), 6.38 (s, 1 H), 4.72 (s, 1 H), 4.46
128.9, 127.9, 127.4, 126.7, 121.8, 120.1, 113.7, 59.8, 45.7 ppm.
HRMS: calcd. for C20H17Cl2N 341.0738; found 341.0735.
(m, J = 6.5 Hz, 1 H), 1.54 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 143.8, 143.8, 133.4, 129.6, 128.9, 127.3,
125.7, 117.1, 117.0, 112.2, 53.3, 24.9 ppm. HRMS: calcd. for
C14H13Cl2N 265.0425; found 265.0419.
2,4-Dichloro-N-(3-hexyl)aniline (3c): Product 3c (44%) was ob-
tained as a colorless oil by column chromatography with petroleum
ether as eluent. 1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J =
2.3 Hz, 1 H), 7.06 (dd, J = 8.8, 2.3 Hz, 1 H), 6.54 (d, J = 8.8 Hz,
1 H), 4.07 (s, 1 H), 3.30 (d, J = 7.3 Hz, 1 H), 1.67–1.24 (m, 5 H),
0.92 (t, J = 7.3 Hz, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
143.1, 129.1, 128.0, 120.4, 119.4, 112.3, 54.5, 36.9, 27.6, 19.5, 14.6,
10.4 ppm. HRMS: calcd. for C12H17Cl2N 245.0738; found
245.0737.
4-Bromo-N-(1-phenylethyl)aniline (3j): Product 3j (80%) was ob-
tained as a yellow oil after column chromatography with petroleum
ether/ethyl acetate (60:1) as eluent. 1H NMR (400 MHz, CDCl3):
δ = 7.32 (d, J = 4.8 Hz, 4 H), 7.24–7.19 (m, 1 H), 7.15 (d, J =
8.8 Hz, 2 H), 6.37 (d, J = 8.8 Hz, 2 H), 4.43 (m, J = 6.7 Hz, 1 H),
4.07 (s, 1 H), 1.51 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 146.1, 144.6, 131.8, 128.7, 127.0, 125.7, 114.9, 108.8,
53.5, 25.0 ppm. HRMS: calcd. for C14H14BrN 275.0310; found
275.0298.
2,4-Dichloro-N-(2-octyl)aniline (3d): Product 3d (48%) was ob-
tained as a colorless oil by column chromatography with petroleum
ether as eluent. 1H NMR (400 MHz, CDCl3): δ = 7.23 (d, J =
2.4 Hz, 1 H), 7.07 (dd, J = 8.8, 2.3 Hz, 1 H), 6.54 (d, J = 8.8 Hz,
1 H), 4.08 (d, J = 7.8 Hz, 1 H), 3.50–3.36 (m, 1 H), 1.64–1.23 (m,
10 H), 1.19 (d, J = 6.3 Hz, 3 H), 0.88 (t, J = 6.5 Hz, 3 H) ppm.
13C NMR (100 MHz, CDCl3): δ = 142.6, 129.2, 128.0, 120.6, 119.6,
112.4, 49.0, 37.3, 32.2, 29.7, 26.4, 23.0, 21.0, 14.5 ppm. HRMS:
calcd. for C14H21Cl2N 273.1051; found 273.1052.
2-Fluoro-N-(1-phenylethyl)aniline (3k): Product 3k (52%) was ob-
tained as a colorless oil after column chromatography with petro-
leum ether/ethyl acetate (30:1) as eluent. 1H NMR (400 MHz,
CDCl3): δ = 7.37 (dt, J = 13.9, 6.8 Hz, 4 H), 7.31–7.20 (m, 1 H),
6.99 (dd, J = 11.8, 8.1 Hz, 1 H), 6.85 (t, J = 7.7 Hz, 1 H), 6.67–
6.54 (m, 1 H), 6.47 (t, J = 8.4 Hz, 1 H), 4.61–4.48 (m, 1 H), 4.34
(s, 1 H), 1.58 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 152.7, 150.4, 145.0, 135.9, 128.9, 127.2, 125.9, 124.6,
116.7, 114.4, 113.4, 53.5, 25.3 ppm. HRMS: calcd. for C14H14FN
215.1110; found 215.1110.
2-Chloro-N-(1-phenylethyl)aniline (3e): Product 3e (49%) was ob-
tained as a colorless oil after column chromatography with petro-
leum ether/ethyl acetate (30:1) as eluent. 1H NMR (400 MHz,
CDCl3): δ = 7.37–7.28 (m, 4 H), 7.23 (s, 1 H), 6.95 (t, J = 7.8 Hz,
1 H), 6.56 (t, J = 7.6 Hz, 1 H), 6.39 (d, J = 8.1 Hz, 1 H), 4.68 (s,
1 H), 4.52 (dd, J = 12.4, 6.3 Hz, 1 H), 1.57 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.6, 143.0, 129.0,
128.7, 127.6, 127.0, 125.7, 118.9, 117.2, 112.5, 53.4, 25.2 ppm.
HRMS: calcd. for C14H14ClN 231.0815; found 231.0815.
4-Fluoro-N-(1-phenylethyl)aniline (3l): Product 3l (64%) was ob-
tained as a yellow oil after column chromatography with petroleum
ether/ethyl acetate (30:1) as eluent. 1H NMR (400 MHz, CDCl3):
δ = 7.37–7.27 (m, 4 H), 7.23–7.15 (m, 1 H), 6.78 (t, J = 8.7 Hz, 2
H), 6.42 (dd, J = 8.7, 4.4 Hz, 2 H), 4.40 (m, J = 6.7 Hz, 1 H), 3.91
(s, 1 H), 1.49 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 145.2, 143.8, 128.8, 127.2, 126.0, 115.8, 115.6, 114.2,
54.3, 25.3 ppm. HRMS: calcd. for C14H14FN 215.1110; found
215.1112.
3-Chloro-N-(1-phenylethyl)aniline (3f): Product 3f (65%) was ob-
tained as a yellow oil after column chromatography with petroleum
ether/ethyl acetate (60:1) as eluent. 1H NMR (400 MHz, CDCl3):
δ = 7.35–7.27 (m, 4 H), 7.22 (dd, J = 7.1, 5.1 Hz, 1 H), 6.96 (t, J
= 8.1 Hz, 1 H), 6.59 (d, J = 7.9 Hz, 1 H), 6.48 (s, 1 H), 6.34 (d, J
= 8.2 Hz, 1 H), 4.44 (d, J = 6.1 Hz, 1 H), 4.09 (s, 1 H), 1.48 (d, J
= 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 148.2,
144.4, 134.8, 130.1, 128.7, 127.1, 125.8, 117.2, 113.1, 111.5, 53.4,
24.8 ppm. HRMS: calcd. for C14H14ClN 231.0815; found 231.0809.
4-Methoxy-N-(1-phenylethyl)aniline (3m): Product 3m (21%) was
obtained as a colorless oil after column chromatography with pe-
troleum ether/ethyl acetate (8:1) as eluent. 1H NMR (400 MHz,
CDCl3): δ = 7.39–7.27 (m, 4 H), 7.22 (dd, J = 12.3, 5.1 Hz, 1 H),
6.68 (d, J = 8.7 Hz, 2 H), 6.46 (d, J = 8.8 Hz, 2 H), 4.40 (m, J =
6.5 Hz, 1 H), 3.80 (s, 1 H), 3.68 (s, 3 H), 1.49 (d, J = 6.7 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 152.0, 145.6, 141.7,
128.8, 127.0, 126.0, 114.9, 114.7, 55.9, 54.4, 25.3 ppm. HRMS:
calcd. for C15H17NO 227.1310; found 227.1313.
4-Chloro-N-(1-phenylethyl)aniline (3g): Product 3g (61%) was ob-
tained as a colorless oil after column chromatography with petro-
leum ether/ethyl acetate (60:1) as eluent. 1H NMR (400 MHz,
CDCl3): δ = 7.31 (d, J = 3.1 Hz, 4 H), 7.24 (s, 1 H), 7.01 (d, J =
8.8 Hz, 2 H), 6.40 (d, J = 8.8 Hz, 2 H), 4.47–4.37 (m, 1 H), 4.04
(s, 1 H), 1.50 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 146.0, 145.0, 129.2, 129.0, 127.3, 126.0, 122.0, 114.7,
53.8, 25.3 ppm. HRMS: calcd. for C14H14ClN 231.0815; found
231.0816.
N-(1-Phenylethyl)aniline (3n): Product 3n (25%) was obtained as a
colorless oil after column chromatography with petroleum ether/
ethyl acetate (60:1) as eluent. 1H NMR (300 MHz, CDCl3): δ =
7.32 (dt, J = 14.9, 7.4 Hz, 4 H), 7.19 (dd, J = 11.8, 4.8 Hz, 1 H),
7.07 (t, J = 7.8 Hz, 2 H), 6.63 (t, J = 7.3 Hz, 1 H), 6.49 (d, J =
8.1 Hz, 2 H), 4.46 (q, J = 6.7 Hz, 1 H), 4.06 (d, J = 21.8 Hz, 1 H),
1.49 (d, J = 6.7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
147.21, 145.17, 129.08, 128.61, 126.84, 125.81, 117.21, 113.27,
53.42, 24.96 ppm. HRMS: calcd. for C14H15N 197.1204; found
197.1205.
3,4-Dichloro-N-(1-phenylethyl)aniline (3h): Product 3h (66%) was
obtained as a colorless oil after column chromatography with pe-
troleum ether/ethyl acetate (60:1) as eluent. 1H NMR (400 MHz,
CDCl3): δ = 7.31 (d, J = 6.0 Hz, 4 H), 7.24 (d, J = 5.5 Hz, 1 H),
7.07 (d, J = 8.7 Hz, 1 H), 6.57 (d, J = 2.7 Hz, 1 H), 6.31 (dd, J =
8.8, 2.6 Hz, 1 H), 4.41 (m, J = 6.7 Hz, 1 H), 4.12 (s, 1 H), 1.50 (d, 2,6-Diisopropyl-N-(1-phenylethylidene)aniline (3o): Product 3o
J = 6.7 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 146.8,
144.2, 132.7, 130.6, 129.0, 127.4, 125.8, 119.8, 114.6, 113.0, 53.6,
25.0 ppm. HRMS: calcd. for C14H13Cl2N 265.0425; found
265.0433.
(82%) was obtained as a yellow crystal by recrystallization (meth-
anol). H NMR (300 MHz, CDCl3): δ = 8.12–7.96 (m, 2 H), 7.47
(d, J = 3.5 Hz, 3 H), 7.15 (d, J = 6.9 Hz, 2 H), 7.07 (dd, J = 8.5,
6.5 Hz, 1 H), 2.75 (dt, J = 13.7, 6.8 Hz, 2 H), 2.10 (s, 3 H), 1.22–
1
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

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/KAP1
Date: 20-08-12 16:03:15
Pages: 10
Y. Li et al.
FULL PAPER
1.07 (m, 12 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.88,
146.86, 139.23, 136.21, 130.52, 128.54, 127.26, 123.42, 123.06,
28.33, 23.26, 18.25 ppm. HRMS: calcd. for C20H25N 279.1987;
found 279.1985.
Acknowledgments
The authors appreciate the financial support of the Hundreds of
Talents Program of the Chinese Academy of Sciences (grant
4-[(1-Phenylethylidene)amino]benzonitrile (3p): Product 3p (64%) number 2005012), the National Natural Science Foundation of
was obtained as a yellow crystal by recrystallization (methanol).
1H NMR (300 MHz, CDCl3): δ = 7.97 (d, J = 7.4 Hz, 2 H), 7.63
(d, J = 8.3 Hz, 2 H), 7.47 (q, J = 6.2 Hz, 3 H), 6.86 (d, J = 8.3 Hz,
2 H), 2.23 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.45,
156.04, 138.65, 133.52, 131.40, 128.76, 127.56, 120.26, 119.61,
106.70, 18.02 ppm. HRMS: calcd. for C15H22N2 220.1000; found
220.1001.
China (NSFC) (grant number 20872105), the “Qinglan Project” of
Jiangsu Province (grant number Bu109805), and a project funded
by the Priority Academic Program Development of Jiangsu Higher
Education Institutions.
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troleum ether/ethyl acetate (40:1) as eluent. 1H NMR (300 MHz,
CDCl3): δ = 7.91 (d, J = 4.8 Hz, 1 H), 7.75 (dt, J = 16.3, 7.6 Hz,
1 H), 7.53–7.35 (m, 4 H), 7.29 (t, J = 7.2 Hz, 2 H), 7.24–7.12 (m,
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1.64 (d, J = 6.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
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125.72, 124.77, 123.32, 119.87, 117.31, 106.10, 53.62, 25.34 ppm.
HRMS: calcd. for C18H17N 247.1361; found 247.1362.
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N-Methyl-N-(1-phenylethyl)aniline (3r): Product 3r (18%) was ob-
tained as a colorless liquid after column chromatography with pe-
troleum ether as eluent. 1H NMR (300 MHz, CDCl3): δ = 7.49–
7.17 (m, 7 H), 6.88 (d, J = 8.2 Hz, 2 H), 6.77 (t, J = 7.2 Hz, 1 H),
5.17 (q, J = 6.8 Hz, 1 H), 2.71 (s, 3 H), 1.59 (d, J = 6.9 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.49, 143.09, 129.50,
128.67, 127.19, 127.11, 116.93, 113.33, 56.78, 32.14, 16.61 ppm.
HRMS: calcd. for C15H17N 211.1361; found 211.1363.
4-Bromo-N-[1-(4-methoxyphenyl)ethyl]aniline (3t): Product 3t
(93%) was obtained as a yellow oil after column chromatography
with petroleum ether/ethyl acetate (10:1) as eluent. 1H NMR
(300 MHz, CDCl3): δ = 7.40–7.10 (m, 4 H), 6.89 (dd, J = 6.3,
2.2 Hz, 2 H), 6.41 (dd, J = 6.6, 2.1 Hz, 2 H), 4.42 (s, 1 H), 4.07 (s,
1 H), 3.81 (s, 3 H), 1.52 (d, J = 6.5 Hz, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 153.84, 141.52, 131.89, 127.02, 122.09,
110.18, 109.35, 104.03, 50.53, 48.13, 20.27 ppm. HRMS: calcd. for
C15H16BrNO 305.0415; found 306.0476(M + 1).
4-Bromo-N-[1-(2-chlorophenyl)ethyl]aniline (3u): Product 3u (44%)
was obtained as a light-yellow oil after column chromatography
with petroleum ether/ethyl acetate (15:1) as eluent. 1H NMR
(300 MHz, CDCl3): δ = 7.34 (d, J = 2.7 Hz, 2 H), 7.26–7.07 (m, 4
H), 6.29 (dd, J = 6.5, 2.0 Hz, 2 H), 4.90–4.74 (m, 1 H), 4.11 (d, J
= 6.6 Hz, 1 H), 1.47 (d, J = 6.3 Hz, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 140.92, 136.67, 127.75, 127.11, 125.07, 123.48, 122.69,
121.84, 110.03, 104.38, 45.57, 18.17 ppm. HRMS: calcd. for
C14H13BrClN 308.9920; found 309.9987 [M + 1]+.
4-Bromo-N-[1-(2-thienyl)ethyl]aniline (3v): Product 3v (75%) was
obtained as a light-yellow oil after column chromatography with
petroleum ether/ethyl acetate (25:1) as eluent. 1H NMR (300 MHz,
CDCl3): δ = 7.28–7.08 (m, 3 H), 6.91 (d, J = 4.2 Hz, 2 H), 6.45
(dd, J = 6.3, 2.3 Hz, 2 H), 4.85–4.64 (m, 1 H), 3.98 (s, 1 H), 1.57
(d, J = 6.2 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.87,
141.19, 127.18, 122.14, 119.11, 118.50, 110.42, 104.73, 44.83,
20.05 ppm. HRMS: calcd. for C12H12BrNS 280.9874; found
281.9928, (M + 1).
Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures for the hydroamination re-
action, spectroscopic data and computational details.
8
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Gallium Trichloride Catalyzed Hydroamination of Alkynes
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Received: June 21, 2012
Published Online: ᭿
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9

Job/Unit: O20829
/KAP1
Date: 20-08-12 16:03:15
Pages: 10
Y. Li et al.
FULL PAPER
Hydroamination of Alkynes
L. Li, G. Huang, Z. Chen, W. Liu,
X. Wang, Y. Chen, L. Yang, W. Li,
Y. Li* .............................................. 1–10
Gallium Trichloride Catalyzed Hydroamin-
ation of Alkynes: Scope, Limitation, and
Mechanistic Studies by DFT
Keywords: Synthetic methods / Hydroamin-
ation / Gallium / Alkynes / Reaction mech-
anisms / Density functional calculations
The hydroamination of alkynes with aro-
matic amines catalyzed by gallium tri-
chloride is presented. Markovnikov prod-
ucts were exclusively obtained with most of
the aniline derivatives. The reaction mech-
anism was investigated by DFT calcu-
lations. The regioselectivities of the reac-
tions as well as the reactivities of the differ-
ent amine substrates are well explained by
the proposed mechanism.
10
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Eur. J. Org. Chem. 0000, 0–0