On the Superior Activity of In(I) versus In(III) Cations Toward ortho-C-Alkylation of Anilines and Intramolecular Hydroamination of Alkenes

Article abstract of DOI:10.1021/acs.joc.0c01585

An efficient ortho-C-alkylation of unprotected anilines with a variety of styrenes and alkenes using a univalent cationic indium(I) catalyst is reported. Mechanistic studies revealed that the reaction likely proceeds via a tandem hydroamination/Hofmann-Martius rearrangement. The high compatibility between the cationic indium(I) complex and primary anilines led us to develop an In(I)+-catalyzed hydroamination of alkenes using unprotected primary and secondary alkenylamines. Computations support the catalytic activity of naked In(I)+ ions, with an outer sphere mechanism for the C-N bond formation and a potentially inner sphere protodemetallation.

Full text of DOI:10.1021/acs.joc.0c01585

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Article
On the Superior Activity of In(I) versus In(III) Cations Towards ortho-
C-Alkylation of Anilines and Intramolecular Hydroamination of Alkenes
Zhilong Li, Shengwen Yang, Guillaume Thiery, Vincent Gandon, and Christophe Bour
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01585 • Publication Date (Web): 22 Sep 2020
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On the Superior Activity of In(I) versus In(III)
Cations Towards ortho-C-Alkylation of Anilines and
Intramolecular Hydroamination of Alkenes
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Zhilong Li,† Shengwen Yang,†,‡ Guillaume Thiery,† Vincent Gandon,*,†,‡ and Christophe Bour*,†
†Institut de Chimie Moléculaire et des Matériaux d’Orsay (ICMMO), CNRS UMR 8182, Université
Paris-Saclay, Bâtiment 420, 91405 Orsay cedex, France. Tel: (+)33169157651 E-mail:
christophe.bour@universite-paris-saclay.fr; vincent.gandon@universite-paris-saclay.fr.
‡Laboratoire de Chimie Moléculaire (LCM), CNRS UMR 9168, Ecole Polytechnique, Institut
Polytechnique de Paris, route de Saclay, 91128 Palaiseau cedex, France.
KEYWORDS. Indium, Hydroarylation, Hydroamination, Low-valent main group metals.
ABSTRACT. An efficient ortho-C-alkylation of unprotected anilines with a variety of styrenes
and alkenes using an univalent cationic indium(I) catalyst is reported. Mechanistic studies revealed
that the reaction likely proceeds via a tandem hydroamination/Hofmann-Martius rearrangement.
The high compatibility between cationic indium(I) complex and primary anilines led us to develop
a In(I)+-catalyzed hydroamination of alkenes using unprotected primary and secondary
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alkenylamines. Computations support the catalytic activity of naked In(I)+ ions, with an outer
sphere mechanism for the C-N bond formation and a potentially inner sphere protodemetallation.
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F
CF3
CF3
CF3
CF3
CF3
O
NH
CF3
CF3
CF3
CF3
O
Al
O
O
In
n
+
CF3
CF3
CF3
NH
F
p
p
H
NH
sp
R
N
In+
sp
n
H
N
weak
INTRODUCTION. Tuning the activity of a catalyst playing on its ligands, oxidation state,
charge, and counterions is a common strategy in transition-metal catalyzed reactions. For main
group Lewis-acid catalyzed transformations on the other hand, examination of different oxidation
states becomes much more difficult due to the low availability of stable low- vs high valent species.
One notable exception is indium, for which stable species of the +I and +III oxidation states have
been described and exploited in catalysis.1,2 In(I) complexes remain underexploited in catalytic
reactions, even though their weaker Lewis acidity compared to In(III) derivatives could be a great
advantage in some reactions.3 A typical issue is the incompatibility of substrates bearing NH2
groups, such as anilines, which tend to capture the catalyst and prevent its turnover. Alkyl-
substituted anilines play a pivotal role in crop protection and pharmaceutical industries.4 In recent
decades, major efforts have been devoted to find new, efficient and selective protocols for their
synthesis. Among the most atom- and step-economical methods, the hydroarylation and
hydroamination of alkenes using anilines occupy a prominent place (Scheme 1A).5 A wide variety
of transition metal-based catalysts,6 Lewis7 and Brønsted acids,8 and organocatalysts have been
developed for this purpose.9 Despite improvements in this field, a number of challenges remains
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to be tackled. For instance, most of these methods do not allow the same functional group tolerance
on nitrogen. Some metallo- and proto-catalyzed hydrofunctionalization of styrenes (R2 = Ar) with
primary or secondary anilines eventually produce a mixture of hydroamination (N-alkylation) and
hydroarylation products (ortho- and para-C-alkylation). Selective ortho-alkylation of anilines was
only accomplished in a few cases, mainly using N- or N,N-alkylated7e,8f,9b anilines, or with 4-
substituted primary anilines.8a,b Other disadvantages of these processes include the difficulty of
using primary anilines as they tend to have a too strong binding affinity for electrophilic metal
centers.8
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One way to overcome this challenge would be to modulate the Lewis acidity by playing on the
oxidation state of the metal. Following up on our interest to develop gallium(III)-catalyzed
reactions,10 we recently disclosed that the use of a Ga(I) univalent cationic species as homogeneous
π-Lewis acid catalyst could be more advantageous in some cases than the corresponding Ga(III)
complexes.11 While Group 13 metal-based Lewis acids in their +III oxidation state are commonly
employed in catalysis, their +I oxidation state has been clearly underexplored.12 The main reasons
are their insolubility in non-polar solvents and/or their ability to readily disproportionate.13 Yet,
we revealed the potential of the Ga(I) complex [Ga(PhF)2][Al(OC(CF3)3)4]14 to catalyze transfer
hydrogenation of alkenes, hydrogenative cyclization of enynes and hydroarylation of alkynes.11
However, in our precedent investigations, we noticed a major incompatibility between
[Ga(PhF)2][Al(OC(CF3)3)4] and aniline in hydroarylation reactions (Scheme 1B), which limited
the range of applications of such catalysts. The strong binding affinity between Ga(I)+ ions and
primary anilines or unprotected amines is a likely explanation for this lack of reactivity.15 In fact,
despite some precedents in the literature featuring alkyl-aluminum catalysts,16 the use of amine
nucleophiles bearing electron-withdrawing groups such as sulfonyl was often required in Group
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13 metal-catalyzed alkene functionalization.17,18 We hypothesized that this inhibition due to the
high azaphilicity of the metal should decrease when moving down the Group 13 column, as the
atomic radius increases and the low +I state oxidation becomes more stable.1 For instance, In(I)
derivatives are softer acids compared to their In(III) analogs1 and other Group 13 M(I) or M(III)
complexes, making them more adequate for the activation of N-nucleophiles.3,19 They are Lewis
acidic by their three vacant p orbitals, but also Lewis basic by their lone electron pair. This dual
property makes such catalysts truly appealing as they could enable both the alkylation of anilines
with styrenes (typical for Lewis acids) and the hydroamination of unactivated alkenes with
alkylamines (typical for basic complexes). Apart from these possible applications, In(I)X
complexes have been scarcely used in homogeneous catalysis, including allylboration of ketones,3
asymmetric C-C bond formation,3 and C-N bond formation.19 Recent progress in the coordination
chemistry of cationic In(I) complexes bearing weakly coordinating anions (WCAs) such as
[CHB11Cl11]19 or [Al(OC(CF3)3)4]20 has made these relatively stable and soluble species more
appealing for catalytic applications. We report herein that the Lewis acidity of a univalent cationic
In(I) complex bearing a WCA might be harnessed in the hydroarylation of primary anilines by
styrenes (Scheme 1C). Mechanistic studies involving a series of control experiments and reaction
monitoring revealed that the reaction likely occurs via a tandem hydroamination/Hofmann-Martius
rearrangement to give an ortho-C-alkylation product. The compatibility between In(I) and primary
amines also led us to investigate the intramolecular hydroamination of unactivated alkenes by
primary and secondary unprotected amines.21 The proposed mechanism is supported by DFT
computations.
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Scheme 1. Hydroamination or Hydroarylation of Alkenes using Anilines
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A. Representative catalytic systems for the hydroamination/hydroarylation of alkenes using anilines
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R2
HN
metal-based catalysts:
NH2
Rh,6b-d Ru,6e Ti,6f Ir,6h Co,6i
Zn,7b Au,7c-d Y,7e Sc,7g
previous work
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+
R2
R1
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R1
Brønsted acid-based catalysts:
PhNH3B(C6F5)4,8a CF3SO3H,8b-c
H3PW12O40,8d HI,8e HBF4,8f
N-alkylation
NH2
NH2
+
Common drawbacks
R2
- poor selectivity control
- few examples with primary anilines
- side-reactions
R1
R1
R2
ortho-C-alkylation para-C-alkylation
B. Incompatible aniline substrates in Ga(I)-catalyzed Friedel-Crafts reaction
[Ga(PhF)2][Al(OC(CF3)3)4
]
NH2
Me
F
CF3
O
CF3
CF3
Me
NH2
CF3
[Ga(PhFH)2][Al(OC(CF3)3)4]
CF3
E
E
CF3
CF3
CF3
CF3 O Al O
+
Ga
E
E
O
no reaction
CF3
CF3
CF3
F
(E = CO2Me)
(3 equiv)
NH2
C. This work
[In(PhF)2][Al(OC(CF3)3)4
]
Ph Ph
NHR2
+
F
CF3
CF3
CF3
CF3
CF3
CF3
Ph
CF3
R1
CF3
O
CF3 O Al O
In
O
CF3
NH2
Ph
HN
Ph
Ph
CF3
CF3
F
Ph
NR2
Hofmann-Martius
rearrangement
R1
R1
R2 = H, alkyl
intramolecular
hydroamination of primary
and secondary
intermolecular ortho-
hydroarylation of primary
and secondary anilines
Extension to
aliphatic alkenylamines
RESULTS AND DISCUSSION. We started our investigation using the In(I) complex
[In(PhF)2][Al(OC(CF3)3)4] reported by Scheer20a and Krossing,20b and tested by us as catalyst for
cycloisomerizations.10e Initial experiments showed that the use of a catalytic amount (5 mol%) of
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this complex converted efficiently aniline 1a in the presence of one equivalent of styrene 2a in
fluorobenzene at 110 °C into the Markovnikov-type ortho-C-alkylation product 3a in 61% isolated
yield (Table 1, entry 1). It is worth mentioning that no N-alkylation or para-C-alkylation products
could be detected. In comparison, the corresponding univalent gallium salt was far less efficient
under the same reaction conditions (entry 2), which might be explained, by both a stronger
interaction between aniline and the metal center, hampering the catalyst turn-over, and the
occurrence of styrene polymerization under these stronger acidic conditions.15,22 A change in the
relative stoichiometry between 1a/2a led to 3a, albeit in lower yields (entry 3). An excess of
styrene afforded a mixture of mono- and dialkylated products with ortho-selectivity (entry 4).
Lowering the temperature to 80 °C or performing the reaction in toluene resulted in slower rates
and lower yields (entries 5-6). In addition, polar solvents were not compatible with the reaction
(entries 7-10). As we11,23 and other groups6i,8a,24 have already noticed in related reactions, the WCA
has an important effect on the efficiency of the hydroarylation. Indeed, no reaction was observed
in the presence of In(I)X halides (X = Cl, Br) (entries 11-12). The same observation was made
with the soluble In(III) salts InBr3 and InI3 (entries 13-14) or the in situ generated In(III) complex
[InBr2][SbF6] (entry 15). In contrast, switching the SbF6- counterion with [Al(OC(CF3)3)4]-
provided 3a in 53% yield with both In(III) salts precatalysts (entries 16-17). Similar results were
obtained with the in situ generated cationic complex of InI2+ stabilized by another WCA known to
be very efficient in cyclisation processes,24 i.e. [B(C6F5)4]- (entry 18). Even though the counterion
effect is not as pronounced as with the In(I) complex (entry 1), the use of this WCA clearly has
also a positive effect on the reaction outcome.
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Table 1. Catalyst Screening in the Intermolecular Hydroarylation of Styrene by Anilinea
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NH2
NH2
cat. 5 mol%
solvent (0.4 M), T °C, 12 h
+
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1a
2a
3a
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Entry Catalyst
Ratio
1a:2a
Solvent
T (oC)
Yield 3ab,c
1
[In(PhF)2][Al(OC(CF3)3)4] 1:1
[Ga(PhF)2][Al(OC(CF3)3)4] 1:1
[In(PhF)2][Al(OC(CF3)3)4] 3:1
[In(PhF)2][Al(OC(CF3)3)4] 1:3
[In(PhF)2][Al(OC(CF3)3)4] 1:1
[In(PhF)2][Al(OC(CF3)3)4] 1:1
[In(PhF)2][Al(OC(CF3)3)4] 1:1
[In(PhF)2][Al(OC(CF3)3)4] 1:1
[In(PhF)2][Al(OC(CF3)3)4] 1:1
[In(PhF)2][Al(OC(CF3)3)4] 1:1
PhF
PhF
110
110
110
110
80
61
2
34d
56
3
PhF
4
PhF
22e
15
5
PhF
6
Toluene
DCE
THF
MeOH
DMF
PhF
110
80
59
7
27
8
70
NR
NR
31
9
70
10
11
12
13
14
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18
150
110
110
110
110
110
110
110
110
InCl
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
NR
NR
NR
NR
7
InI
PhF
InBr3
PhF
InI3
PhF
[InBr2][SbF6]f
[InBr2][Al(OC(CF3)3)4]f
[InI2][Al(OC(CF3)3)4]f
[InI2][B(C6F5)4]f
PhF
PhF
53
PhF
53
PhF
49
a Reaction conditions: aniline (0.2 mmol) and styrene (0.2 mmol) in solvent (1 mL), 12 h.
b
c
Hydroamination product detected in less than 10% yield. Isolated yields, NR = no reaction.
e
d According TLC, full conversion of styrene was observed. Mixture of mono- and dialkylated
f
products was observed. Generated in situ by using InBr3 or InI3 and [Ag(DCM)3][Al(OC(CF3)3)],
AgSbF6 or [Ag][B(C6F5)4].
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Encouraged by these results, we explored the generality of this protocol with a wide range of
styrene, alkene, and aniline derivatives, including both cyclic and acyclic ones (Scheme 2). While
anilines displaying an electron-donating group or a halide at the para-position were found
compatible under the optimized reaction conditions (3b-f), an important decrease of catalytic
activity was observed with the CF3 electron-withdrawing groups (3g). Anilines bearing an ortho-
halide substituent were also successfully converted into the ortho-C-alkylated products when
reacted with styrene (3h-i, 52-63% yields). Remarkably, a variety of moderately deactivated
halide-substituted styrenes were tolerated in this reaction (3j-l, 3p-q). This was achieved in a very
selective manner, without detecting the presence of N-alkylation products, which differs from the
methodologies described above reporting a 1/1 ratio of C/N-alkylation products.7b,8d However,
para-cyano, -nitro and -trifluoromethyl styrene, derivatives were found to be unreactive substrates
(3m-o). With such electron-poor styrenes, the hydroamination reaction prevails in most previously
reported cases.29 Unlike unreactive monosubstituted aliphatic alkenes (3r-t), cyclic 1,3-
cyclohexadiene and norbornene were successfully used, affording products 3u and 3v in 62% and
44% yield respectively. We noted complete selectivity for the C-alkylation product, a trend that
was not found in previous studies.6i Substrates exhibiting more basic secondary N-alkyl anilines
were also well-tolerated (3w-y). Notably, hydroarylation of 1,2,3,4-tetrahydroquilonine and
indoline gave rise to addition products 3u and 3v in 89 and 99% yield respectively. By contrast, a
tertiary aniline such as the N,N-dimethylaniline reacted sluggishly under the same reaction
conditions (3z, 13% yield), suggesting a more complex activation mode than a simple Friedel-
Crafts reaction.
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Scheme 2. Scope and Limitations of the In(I)+-Catalyzed ortho-C-alkylation of Anilinesa
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[In(PhF)2][Al(OC(CF3)4]
[In(PhF)2][Al(OC(CF3)4]
NH
NH
F
CF3
O
(5 mol%)
CF3
CF3
CF3
CF3
CF3
+
CF3
CF3 O Al O
PhF (0.4 M), 110 °C, 12 h
In
10
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O
CF3
CF3
3
1
CF3
CF3
F
Product obtained (isolated yield)b
NH2
NH2
NH2
NH2
NH2
Cl
R
R
R
3b (R = Me), 40%c
3r (R = Bn), 0%
3s (R = hexyl), 0%
3t (R = heptyl), 0%
3h (R = Br), 52%
3i (R = F), 63%
3j (R = Cl), 60%
3k (R = Br), 61%
3l (R = F), 63%
3m (R = CF3), 0%
3n (R = CN), 0%
3o (R = NO2), 0%
3p (o-Cl), 51%
3q (m-Cl), 47%
R
3c (R = OMe), 33%
3d (R = Cl), 80%
3e (R = Br), 63%
3f (R = F), 71%
3g (R = CF3), <10%
NH2
NH2
NH
NH
N
NH
3y, 89%
3u, 62%
3v, 44%
3w, 46%
3x, 99%
3z, 13%
a Reaction conditions: aniline (0.2 mmol), alkene (0.2 mmol), [In(PhF)2][Al(OC(CF3)3)4] (5 mol%),
b
PhF (0.5 mL) at 110 C for 12 h in an argon atmosphere. Isolated yields after column
c
chromatography on Al2O3 (MeOH/CH2Cl2 = 95/5).
[In(PhF)2][Al(OC(CF3)3)4] was used.
38% yield when 10 mol% of
Then, after having established the catalytic activity of univalent In(I) cations for ortho-C-
alkylation of anilines, a few control experiments were carried out to delineate its mechanism. One
option could be a Friedel-Crafts type reaction. It is well known that SEAr processes can be mediated
by Group 13 salts;25 however, regarding the hydroarylation of styrenes with primary anilines, no
examples were described. A second option could be that the C-alkylation products results from a
hydroamination process followed by a Hofmann-Martius rearrangement. 26 ,7g,8a,8f To test this
assumption, we synthesized the secondary amine 4a as a putative hydroamination intermediate27
and subjected it to the optimized reaction conditions (Scheme 3a). This compound was indeed
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converted into 3a in 43% isolated yield with complete ortho-selectivity as already described.8a,28
On the other hand, secondary amine 4b, arising from the N-alkylation of 3,5-
bis(trifluoromethyl)aniline, was isolated as the sole product under the same reaction conditions
(Scheme 3b). These results clearly suggest that the Hofmann-Martius rearrangement takes place
after a first step of In(I)-catalyzed hydroamination of styrene. This second step is hampered by the
presence of strongly electron-withdrawing groups at the aniline moiety. Moreover, with a
moderately deactivating group such as Cl, the hydroamination intermediate could be detected. We
thus performed a GC monitoring using para-chloroaniline (Scheme 3c). As it can be seen in the
graphic, styrene is fully consumed within 2 h, the N-alkylated compound 4d (ca. 70% GC yield)
and the final C-alkylated compound 3d (ca. 30% GC yield) being the only detected products. This
suggests a tandem hydroamination/ Hoffmann-Martius rearrangement reaction and shows that the
latter is the rate-limiting step. The low proportion of 3d after 2 h rules out a classical Friedel-Crafts
mechanism, and may also reveal a concerted mechanism.
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Scheme 3. Mechanistic Investigations Related of the In(I)+-Catalyzed ortho-C-alkylation of
Anilinesa,b,c
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[In(PhF)2][Al(OC(CF3)4]
NH2
(5 mol%)
HN
Ph
7
8
9
Ph
(a)
(b)
PhF (0.4 M), 110 °C, 12 h
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4a
3a (43%)
[In(PhF)2][Al(OC(CF3)4]
NH2
(5 mol%)
HN
Ph
+
PhF (0.4 M), 110 °C, 1 h
CF3
CF3
CF3
CF3
4b (78%)
[In(PhF)2][Al(OC(CF3)4]
NH2
Cl
NH2
Cl
HN
Ph
(5 mol%)
Ph
+
+
(c)
PhF (0.4 M), 110 °C, 12 h
Cl
4d
2a
3d
a Reaction conditions: aniline (0.2 mmol), alkene (0.2 mmol), catalyst (5 mol%), PhF (0.5 mL)
at 110 C for 12 h in an argon atmosphere. b Isolated yields after column chromatography on Al2O3
(MeOH/CH2Cl2 = 95/5). c GC reaction profiles of para-chloroaniline in PhF (0.4 M) at 110 °C in
the presence of catalyst (5 mol%).
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The compatibility between primary and secondary anilines with In(I) cations, as well as presence
of intermolecular hydroamination products in few cases, encouraged us to study the intramolecular
hydroamination of alkenes.29 We started this study with the hydroamination of 5a under our
optimized reaction conditions for the hydroarylation of styrenes: [In(PhF)2][Al(OC(CF3)3)4] (A) in
PhF (0.4 M) at 110 °C for 12 h (Table 2; see the Supporting Information for a detailed solvent
screening). Gratifyingly, the desired secondary amine 6a was isolated in 89% yield after a flash
column chromatography on alumina (entry 1). It is important to stress out that this reactivity is
unique for Lewis acids as they usually require the presence of an electron-withdrawing group on
the nitrogen functionality to promote the reaction. Indeed, their strong coordination to more basic
alkylamines generally precludes the transformation. The univalent indium(I) catalyst A (10 mol%)
was essential for the reaction (entries 1-11). While no reaction took place with InCl, the reaction
proceeded moderately with additional WCA silver or lithium salt (entries 2-4). The use of AgSbF6
as additive with the insoluble InCl salt did not trigger the reaction (entry 5). The utilization In(III)
complexes instead of A as catalyst resulted in a much lower efficiency when compared to the
standard reaction conditions (entries 6-10). As anticipated, InBr3, which was previously used to
promote alkene hydroamination using N-tosylamine,18 was not efficient with an unprotected amine
(entry 6). The crucial role of the [Al(OC(CF3)3)4]- counterion was once again emphasized, as low
conversions were found with other anions (e.g. OTf-, SbF6-, entries 7-9), even in the case of a
cationic In(III) complex known to be very active in other reactions (entry 10).23, 24 While the
influence of the [Al(OC(CF3)3)4]- counterion is pivotal in this process, the use of an univalent In(I)
derivative should not be overlooked. Indeed, the univalent Ga(I) catalyst was not as efficient as A
under the same reaction conditions (40%, entry 11), confirming that the cornerstone of this reaction
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is the association of a univalent In(I) cation and a WCA such as [Al(OC(CF3)3)4]-. In other words,
a naked In(I)+ ion is the most effective.
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Table 2. Catalyst Screening for the Intramolecular Hydroamination of Alkene 5aa
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Ph
Ph
NH2
cat. (10 mol%)
Ph
Ph
N
PhF (0.4 M), 110 °C, 12 h
5a
6a
H
Entry Catalysta
Yield (%)b
89c
1
[In(PhF)2][Al(OC(CF3)3)4]
2
InCl
NR
55
3
InCl + [Ag][Al(OC(CF3)3)4]
InCl + [Li][Al(OC(CF3)3)4]
InCl + AgSbF6
4
48
5
NR
NR
42
6
InBr3
7
In(OTf)3
8
IPr·InBr3 + AgSbF6
InBr3 + [Ag][Al(OC(CF3)3)4]
IPr·InBr3 + [Ag][Al(OC(CF3)3)4)4]
[Ga(PhF)2][Al(OC(CF3)3)4]
NR
47
9
10
11
44
40
a Reaction conditions: alkenylamine 5a (0.2 mmol), catalyst (5 mol%), PhF (0.5 mL) at 110° C for
b
12 h under an argon atmosphere. Isolated yields after column chromatography on Al2O3
c
1
(Cyclohexane/EtOAc = 95/5), NR = no reaction. 99% yield determined H NMR yield using
ferrocene (0.5 equiv) as internal standard.
The optimized reaction conditions for the intramolecular hydroamination of alkenes were
applicable to a broad scope of substrates (Scheme 4). As often mentioned in previous reports,29b
the cyclohydroamination forming a five-membered nitrogen heterocycle is significantly affected
by the nature of the gem-disubstituents or by the presence substituents at the alkene moiety (6b-j).
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This deleterious effect was not observed for six-membered rings where yields remained excellent
(up to 99% yield, 6k-m). Secondary alkenylamine were also suitable substrates (6n-u, 6w, 6x).
Both five- and six-membered nitrogen-heterocycles bearing benzyl or alkyl groups on the nitrogen
have been isolated in high yields while requiring a shorter reaction time and a lower catalyst
loading (1 h, with 5 mol% of A at 110 °C). It is worth mentioning that, unlike many examples
catalyzed by metal-alkyl or -amido complexes, the absence of gem-dialkyl/aryl substituents does
not affect the rate of the reaction (6w).29 The Markovnikov cyclization has also been achieved
efficiently from primary amines with more reactive functionalities such as an alkyne (6y) and an
allene (6z). Interestingly, and in contrast with In(III)-catalyzed hydroamination,18 the reaction does
not proceed with a tosylamine (6j), which raises questions about the activation mode of the
alkenylamine by our cationic univalent indium(I) catalyst.
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Scheme 4. Scope and Limitations of the In(I)-Catalyzed Intramolecular Hydroamination of
Alkenesa
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[In(PhF)2][Al(OC(CF3)4] A
n
(5-10 mol%)
n
NH
N
7
PhF (0.4 M), 110 °C, 1-12 h
8
5
6
9
Product obtained (isolated yield)
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R
Ph
Ph
Ph
Ph
.HCl
Ph
Ph
NH
6e, 0%
NH
NH
6b, 42%b
NH
NH
NH
NH
6j, 0%
6g (R = H), 23%b,d
6h (R = p-Cl), 33%b,d
6i (R = p-CF3), 35%b,d
6f, 40%b,d
6c, 37%b,c
6d, 30%b
R
Ph
Ph
Ph
Ph
NH
R
NH
N
2-Naph
Ph
N
R
N
Ph
Ph
6s, 69%e
N
6n (R = H), 81%e
6m, 99%b
N
6k (R = Me), 88%b,d
6l (R = Ph), 88%b
Ts
Ph
6t, 85%e
6o (R = p-Me), 85%e
6p (R = p-OMe), 78%e
6q (R = p-Cl), 76%e
6r (R = o-F), 77%e
6u, 72%e
6v, 0%
extension to alkyne and allene hydroamination
Ph
Ph
Ph
Ph
Ph
Ph
N
N
N
NH
6z, 78%e
6y, 91%e
6w, 86%e
6x, 75%e
a Isolated yields after column chromatography on Al2O3. b Reaction conditions: alkenylamine 5b-
m (0.2 mmol), A (10 mol%), PhF (0.5 mL) at 110 °C for 12 h under an argon atmosphere;
according TLC, full conversion of starting material was observed. Determined by H NMR
spectroscopy using ferrocene (0.5 equiv) as internal standard. C6D6 as solvent. Reaction
conditions: alkenylamine 5n-z (0.2 mmol), A (5 mol%), PhF (0.5 mL) at 110 °C for 1 h under an
argon atmosphere; according TLC full conversion of starting material was observed.
d
1
e
To elucidate how this low-valent indium(I) complex is so efficient for this Lewis acid-catalyzed
hydroamination, we decided to investigate the transformation of 5a by DFT calculations (Figure
1). For geometry optimizations, the M06-2X functional, the LANL2DZ basis set for In and the 6-
31G(d,p) basis set for the other elements were used. The discussed values are DG383 in kcal/mol
obtained after single point calculations at the M06-2X/def2-TZVP(In)-6-311+G(2d,p) (other
elements) and solvent correction (SMD model for fluorobenzene). More computational details and
less favorable mechanistic options are provided in the computational section of the Supporting
Information. Since conformational sampling of the ion-pairs is particularly challenging, the
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[Al(OC(CF3)3)4]- WCA was not taken into consideration. We have compared pathways starting
from different naked In+/aminoalkene 5a complexes after releasing the two PhF ligands (for less
favorable options with one or no PhF release, see the Supporting Information). The ammonium
complex 2zero is the most stable starting compound, located at -15.1 kcal/mol on the PES (zero
stands for no PhF). Forming the N-C bond from this complex requires the coordination of the
alkene moiety to give 3zero, which is slightly less stable than 2zero, and then insertion of the alkene
into the In-N bond through transition state 4zero-ts. The latter was located 15.0 kcal/mol above the
reference system [5a + In(PhF)2+] and leads to pyrrolidinium 5zero in an endergonic fashion (8.1
kcal/mol above the reference system). If intramolecular, the protodemetallation can be modeled
via 12zero-ts, lying at 25.2 kcal/mol, a barrier that can be spanned at 383 K. The resulting compound
is the amino indium complex 10zero, located at -29.3 kcal/mol. The final product 6a is obtained
after catalyst regeneration at the expense of 16.7 kcal/mol (-12.6 kcal/mol). The main issue with
this hypothesis (Path A) is the large energy difference between 2zero and 12zero-ts of 40.3 kcal/mol,
which rather suggests that 2zero is a resting state rather than an intermediate. We then studied Path
C in which In+ is first associated with the alkene moiety of 5a and one of its Ph group to provide
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6
the h -Ph chelate 6zero with a release of 3.8 kcal/mol. Connection to the previously described
intermediate 5zero could be achieved after anti attack of the nitrogen to the alkene ligand (7zero-ts)
and rotation of the CH2In fragment (11zero-ts). These two transition states lie lower in energy than
12zero-ts (1.9 and 11.8 kcal/mol respectively, vs 25.2 kcal/mol), which still corresponds to the RDS.
However, from the lower point 6zero to 12zero-ts, the barrier becomes 29.0 kcal/mol, which can be
overcome at 383 K. Of note, cleavage of the C-In bond from 8zero is much more energetically
demanding than from 5zero (Path B, 9zero-tslying at 34.4 kcal/mol on the PES).
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DG383 (fluorobenzene)
[kcal/mol]
Ph
Ph
path A
path B
path C
Ph
H
Ph
N
H
H
In
34.4
9zero-ts
N
9
Ph
Ph
H
In
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25.2
H
12zero-ts
N
In
H
11zero-ts
11.8
15.0
zero-ts
Ph
Ph
+
In(PhF)2
4
Ph
H
+
Ph Ph
NH2
8.1
5zero
Ph
N
H
In
3.8
In
H
N
5a
1.9
2PhF
Ph
Ph
Ph
8zero
H
0.0
1
7zero-ts
Ph
Ph
-3.8
H
N
N
H
6zero
Ph
Ph
N
In
H
In
H
Ph
Ph
In
N
H
In
H
H
rotation
-12.6
6a
N
H
-13.2
3zero
-15.1
2zero
Ph
Ph
2PhF
+
In(PhF)2
H
Ph Ph
H
H
N
-29.3
10zero
N
In
In
H
Proton Migration
Formation of Pyrrolidinium Cation
Ligand exchange
Catalyst Regeneration
Figure 1. Calculated Gibbs Free Energy Profile
Thus, in agreement with previous reports,30 the computed catalytic cycle contains four main
steps: (i) ligand exchange between the pre-catalysts and the substrate; (ii) nucleophilic attack of
the amine on the bound alkene forming a free rotating alkyl-In(I) intermediate for facilitating the
transfer of proton;30b (iii) migration of a proton from the nitrogen atom to the ß-carbon to provide
the secondary amine product; (iv) displacement of the secondary amine to complete the catalytic
cycle. These computations support the catalytic role of naked In(I)+ ions which reversibly bind to
primary amines.
CONCLUSION.
In summary, teamwork between a low oxidation state of indium and a weakly coordinating anion
allowed the catalytic selective ortho-C-alkylation of unprotected anilines with styrenes.
Mechanistic studies regarding the formation of ortho-C-alkylated anilines support an
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intermolecular hydroamination reaction followed by Hofmann-Martius rearrangement.
Remarkably, this protocol proved to be both chemo- and regioselective with respect to the widely
investigated acid-catalyzed Friedel-Crafts alkylation (direct hydroarylation of styrenes). The
unique properties of the In(I) catalysts led us to develop an efficient alkene hydroamination
protocol using unprotected primary and secondary alkenylamines under mild conditions.
Computations support the catalytic activity of naked In(I)+ ions, with an outer sphere mechanism
for the C-N bond formation and a potentially inner sphere protodemetallation. Investigations are
underway to exploit the potential of such ambivalent species in other Lewis acid-catalyzed
reactions.
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EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reactions and manipulations were performed
in an inert atmosphere (argon) in a glovebox, or using standard Schlenk and high vacuum-line
techniques. Glassware was dried overnight at 120 °C before use. Reactions in overheated solvent
were performed in 10 mL reaction tubes sealed with Teflon-coated Rodaviss and immersed in a
pre-heated oil bath. Reactions were monitored using thin-layer chromatography (TLC) on silica
gel plates (0.25 mm) precoated with a fluorescent indicator. The spots were visualized with
ultraviolet light and/or p-anisaldehyde stain with heat as developing agents. NMR characterization
data was collected at 296 K on a AM 250, AV 300, AV 360 or DRX 400 Bruker spectrometers
operating at 250, 300, 360 or 400 MHz for 1H NMR. 1H NMR chemical shifts are reported in ppm
using residual solvent peak as reference (CHCl3: δ = 7.26 ppm). Data for 1H NMR are presented
as follows: chemical shift δ (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
br = broad), coupling constant J (Hz) and integration; 13C NMR spectra were recorded at 63, 75,
91 or 100 MHz using broadband proton decoupling and chemical shifts are reported in ppm using
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residual solvent peaks as reference (CHCl3: δ = 77.16 ppm). MS were recorded on DSQ Thermo
Fisher instrument by electronic impact. HRMS was performed on a MicrOTOF Bruker
spectrometer.
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Materials. All materials purchased from commercial suppliers were used without further
purification. All solvents for catalytic reactions were distilled under argon and degassed via three
freeze-pump-thaw cycles before use. The catalysts and non-commercial substrates were
synthesized by the reported procedures: [Ga(PhF)2][Al(OC(CF3)3)4],14a primary aminoalkenes 5a-
m,31,32 secondary aminoalkenes 5n-x,33 aminoalkyne 5y,34 and aminoallene 5z.35
Synthesis of [In(PhF)2][Al(OC(CF3)3)4] adapted from Krossing’s procedure:20b In the glove
box, finely ground dry LiAlH4 (1 equiv, 0.643 g, 17 mmol) was transferred into a 100 mL three-
neck round bottom. This flask was then sealed with rubber stoppers, moved out of the glove box
and equipped on one side with an argon inlet on a vacuum line. Under argon, the middle neck of
the flask was equipped with a dry reflux condenser connected to a -20 °C cryostat. The condenser
was surmounted by an argon balloon via a rubber stopper. The other side neck of the flask was
equipped with a dropping funnel. Then perfluoro-tert-butanol (4.1 equiv, 16.4 g, 9.7 mL, 69.5
mmol) was added dropwise through this funnel at 0 °C and the mixture was stirred until the end
of the observed gas evolution. After that, a clear solution was formed. The reaction was heated to
reflux for 16 h, during which a white precipitate was formed. The equipment of the flask containing
the reaction mixture was removed and all necks tightly sealed with rubber stopper. The flask was
then transferred into a glovebox. The reaction mixture was filtered inside the glovebox, washed
with hexane, and dried under vacuum, resulting in 12.7 g of [Li][Al(OC(CF3)3)4] as a white solid
(77% yield). This crude product was sufficiently pure for the preparation of
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[In(PhF)2][Al(OC(CF3)3)4]. Li NMR (117 MHz, CDCl3 25 °C) δ 0.9. C{1H} NMR (63 MHz,
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CDCl3, 25 °C) δ 120.9 (q, J (C,F) = 292.8 Hz; CF3). 19F NMR (235 MHz, CDCl3 25 °C) δ 76.9 (s,
5
6
27
CF3). Al NMR (78 MHz, CDCl3, 25 °C) δ 33.8 (s, V1/2 = 130 Hz). Spectroscopic data for
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[Li][Al(OC(CF3)3)4] match those previously reported by Krossing et al.20b Then a solution of
[Li][Al(OC(CF3)3)4] (0.5 g, 0.51 mmol) in 10 mL fluorobenzene containing InCl (150 mg, 2 equiv,
1.03 mmol) was allowed to react under ultrasonic activation for 13 h. The resulting mixture was
then filtered in the glove box and the solvent was removed from the filtered solution under vacuum
to afford [In(PhF)2][Al(OC(CF3)3)4] as a creamy white powder (87%, 568.1 mg). However, we
also found that some batches give a light yellow powder without losing the catalytic activity.
[In(PhF)2][Al(OC(CF3)3)4] can be kept in a Schlenk tube in the glovebox for years without
decomposition. mp = 160-162 °C. 13C{1H} NMR (101 MHz, CD2Cl2) δ 79.4, 121.6. 19F NMR (282
MHz, CD2Cl2) δ –75.6. 27Al NMR (104 MHz, CD2Cl2) d 33.7. Spectroscopic data for
[In(PhF)2][Al(OC(CF3)3)4] match those previously reported in the literature.20a
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General procedure for In(I) catalyzed hydroarylation of styrene by anilines (Table 1). In a
glove box, a reaction tube was charged with the catalyst (5 mol%) and dry solvent (0.4 M). Aniline
1a (18.6 mg, 0.2 mmol) and styrene 2a (20.8 mg, 0.2 mmol) were then added in this solution in
portions. The reaction tube was sealed with a screw cap and stirred outside of the glove box at the
indicated temperature for 12 h (see entries 1-15). The reaction mixture was diluted with Et2O,
filtered through a pad of celite (thoroughly rinsed with Et2O) and concentrated under reduced
pressure by rotary evaporation. Purification by FC over neutral Al2O3 (MeOH/CH2Cl2 = 95/5)
afforded product 3a as clear oil.
General procedure for In(I) catalyzed hydroarylation of styrene by anilines (Scheme 2). In
a glove box, a reaction tube was charged with [In(PhF)2][Al(OC(CF3)3)4] (13 mg, 0.01 mmol) and
anhydrous degassed PhF (0.5 mL). Aniline 1 (0.2 mmol) and alkenes 2 (0.2 mmol) were then
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added in this solution in portions. The reaction tube was sealed with a screw cap and stirred outside
of the glove box at 110 oC for 12 h. The reaction mixture was diluted with Et2O, filtered through a
pad of celite (thoroughly rinsed with Et2O) and concentrated under reduced pressure by rotary
evaporation. Purification by FC over neutral Al2O3 (CH2Cl2/MeOH = 95/5) afforded desired
product 3a-v.
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Compound 3a. Following the general procedure, product 3a was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (61% yield, 24.1 mg). H NMR (250 MHz, CDCl3) δ
7.39 – 7.19 (m, 6H), 7.14 (td, J = 7.5, 1.6 Hz, 1H), 6.90 (td, J = 7.5, 1.3 Hz, 1H), 6.68 (dd, J = 7.8,
1.3 Hz, 1H), 4.12 (q, J = 7.2 Hz, 1H), 3.25 (s, 2H), 1.67 (d, J = 7.2 Hz, 3H).13C{1H} NMR (63
MHz, CDCl3) δ 145.8, 144.4, 129.9, 128.9, 127.6, 127.4, 126.5, 118.9, 116.4, 40.4, 21.9.
Spectroscopic data for 3a match those previously reported in the literature.6i
Compound 3b. Following the general procedure, product 3b was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (40% yield, 16.9 mg). H NMR (360 MHz, CDCl3) δ
7.34 – 7.27 (m, 2H), 7.23 (dt, J = 7.7, 1.4 Hz, 3H), 7.13 (d, J = 2.0 Hz, 1H), 6.93 (dd, J = 8.0, 2.0
Hz, 1H), 6.58 (d, J = 7.9 Hz, 1H), 4.10 (q, J = 7.2 Hz, 1H), 3.17 (s, 2H), 2.34 (s, 3H), 1.64 (d, J =
7.2 Hz, 3H). 13C{1H} (91 MHz, CDCl3) δ 145.9, 141.8, 130.1, 128.8, 128.0, 127.8, 127.6, 126.4,
116.5, 40.3, 21.9, 21.0. Spectroscopic data for 3b match those previously reported in the literature.6i
Compound 3c. Following the general procedure, product 3c was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (33% yield, 15.0 mg). H NMR (360 MHz, CDCl3) δ
7.33 – 7.25 (m, 2H), 7.24 – 7.17 (m, 3H), 6.93 (d, J = 2.8 Hz, 1H), 6.69 (dd, J = 8.5, 2.8 Hz, 1H),
6.60 (d, J = 8.5 Hz, 1H), 4.10 (q, J = 7.1 Hz, 1H), 3.80 (s, 3H), 3.11 (s, 2H), 1.62 (d, J = 7.2 Hz,
3H). C{1H} NMR (91 MHz, CDCl3) δ 153.1, 145.5, 138.0, 131.9, 128.9, 127.6, 126.5, 117.2,
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114.2, 111.7, 55.8, 40.4, 21.9. Spectroscopic data for 3c match those previously reported in the
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Compound 3d. Following the general procedure, product 3d was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (80% yield , 37.1 mg). H NMR (360 MHz, CDCl3) δ
7.35 – 7.15 (m, 6H), 7.05 (dd, J = 8.4, 2.5 Hz, 1H), 6.56 (d, J = 8.4 Hz, 1H), 4.03 (q, J = 7.1 Hz,
1H), 3.42 (s, 2H), 1.61 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (91 MHz, CDCl3) δ 144.8, 143.0, 131.4,
129.0, 127.4, 127.2, 127.1, 126.7, 123.5, 117.3, 40.3, 21.9. Spectroscopic data for 3d match those
previously reported in the literature.6f
Compound 3e. Following the general procedure, product 3e was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (63% yield, 34.8 mg). H NMR (300 MHz, CDCl3) δ
7.39 (dd, J = 2.4, 0.7 Hz, 1H), 7.36 – 7.13 (m, 6H), 4.02 (q, J = 7.2 Hz, 1H), 3.43 (s, 2H), 1.61 (d,
J = 7.2 Hz, 3H). 13C{1H} NMR (63 MHz, CDCl3) δ 144.9, 143.6, 132.0, 130.1, 129.0, 127.5, 126.8,
117.8, 110.8, 40.4, 21.9. HRMS (ESI, m/z) calcd for C14H14BrNNa [M+Na]+: 298.0207, found
298.0221
Compound 3f. Following the general procedure, product 3f was obtained by FC (CH2Cl2/MeOH
= 95/5) as a colorless oil (71% yield, , 30.6 mg). 1H NMR (300 MHz, CDCl3) δ 7.34 – 7.16 (m,
5H), 7.03 (ddd, J = 10.1, 2.9, 0.7 Hz, 1H), 6.80 (td, J = 8.5, 2.9 Hz, 1H), 6.57 (dd, J = 8.5, 5.0 Hz,
1H), 4.06 (q, J = 7.1 Hz, 1H), 3.29 (s, 2H), 1.61 (d, J = 7.1 Hz, 3H). C{1H} NMR (91 MHz,
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CDCl3) δ 156.9 (d, CF, J = 235.3 Hz), 145.0, 140.4(m1-CF), 131.7 (d, p-CF, J = 6.5 Hz), 129.0,
127.5, 126.7, 117.0 (d, m2-CF, J = 7.8 Hz),114.1 (d, o1-CF, J = 23.1 Hz), 113.55 (d, o2-CF, J = 20.7
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Hz), 40.4, 22.0. F NMR (235 MHz, CDCl3) δ -127.7. Spectroscopic data for 3f match those
previously reported in the literature.6f
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Compound 3h. Following the general procedure, product 3h was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (52% yield, 28.7 mg). H NMR (360 MHz, CDCl3) δ
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7.34 – 7.23 (m, 3H), 7.25 – 7.14 (m, 3H), 6.96 (dd, J = 8.2, 2.1 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H),
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4.11 – 3.87 (m, 3H), 1.59 (d, J = 7.2 Hz, 3H). C{1H} NMR (63 MHz, CDCl3) δ 146.5, 142.2,
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138.0, 131.5, 128.5, 127.8, 127.6, 126.2, 115.9, 109.5, 43.8, 22.1. HRMS (ESI, m/z) calcd for
C14H15BrN [M+H]+: 276.0388, found 276.0367.
Compound 3i. Following the general procedure, product 3i was obtained by FC (CH2Cl2/MeOH
= 95/5) as a colorless oil (63% yield, , 27.1 mg). 1H NMR (250 MHz, CDCl3) δ 7.36 – 7.09 (m,
5H), 6.91 – 6.65 (m, 3H), 4.06 (q, J = 7.2 Hz, 1H), 3.62 (s, 2H), 1.60 (d, J = 7.2 Hz, 3H). 13C{1H}
NMR (63 MHz, CDCl3) δ 151.79 (d, CF, J = 238.6 Hz), 146.6, 137.6 (d, m1-CF, J = 5.5 Hz),
132.40 (d, o1-CF, J = 13.2 Hz), 128.5, 127.6, 126.2, 123.5 (d, p-CF, J = 2.6 Hz), 116.9 (d, m2-CF,
J = 4.1 Hz), 114.56 (d, o2-CF, J = 18.7 Hz), 44.0, 22.1. F NMR (235 MHz, CDCl3) δ -135.0.
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Spectroscopic data for 3i match those previously reported in the literature.6f
Compound 3j. Following the general procedure, product 3j was obtained by FC (CH2Cl2/MeOH
= 95/5) as a colorless oil (60% yield, 27.8 mg). 1H NMR (360 MHz, CDCl3) δ 7.32 – 7.24 (m, 3H),
7.21 – 7.10 (m, 3H), 6.89 (td, J = 7.5, 1.3 Hz, 1H), 6.70 (dd, J = 7.8, 1.3 Hz, 1H), 4.09 (q, J = 7.2
Hz, 1H), 3.43 (s, 2H), 1.64 (d, J t’as= 7.2 Hz, 3H). 13C{1H} NMR (63 MHz, CDCl3) δ 144.3, 132.2,
129.4, 129.0, 127.6, 127.3, 119.0, 116.5, 39.7, 21.8. HRMS (ESI, m/z) calcd for C14H15ClN
[M+H]+: 232.0893, found 232.0877.
Compound 3k. Following the general procedure, product 3k was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (61% yield, 34.0 mg). H NMR (300 MHz, CDCl3) δ
7.47 – 7.38 (m, 2H), 7.32 – 7.24 (m, 1H), 7.17 – 7.04 (m, 3H), 6.88 (td, J = 7.5, 1.3 Hz, 1H), 6.68
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(dd, J = 7.9, 1.3 Hz, 1H), 4.07 (q, J = 7.2 Hz, 1H), 3.40 (s, 3H), 1.63 (d, J = 7.2 Hz, 3H). 13C{1H}
NMR (63 MHz, CDCl3) δ 144.8, 144.2, 131.9, 129.4, 127.6, 127.3, 120.3, 119.0, 116.5, 39.8, 21.8.
HRMS (ESI, m/z) calcd for C14H15BrN [M+H]+: 276.0388, found 276.0373.
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Compound 3l. Following the general procedure, product 3l was obtained by FC (CH2Cl2/MeOH
= 95/5) as a colorless oil (63% yield, 27.1 mg). 1H NMR (300 MHz, CDCl3) δ 7.34 – 7.25 (m, 1H),
7.16 (ddd, J = 17.4, 11.6, 6.4 Hz, 3H), 6.99 (t, J = 8.6 Hz, 2H), 6.88 (t, J = 7.7 Hz, 1H), 6.68 (d, J
= 7.9 Hz, 1H), 4.09 (q, J = 7.1 Hz, 1H), 3.35 (s, 2H), 1.63 (d, J = 7.1 Hz, 3H). 13C{1H} NMR (63
MHz, CDCl3) δ 161.45 (d, CF, J = 244.7 Hz), 144.3 (p-CF), 141.4, 129.7, 129.0 (d, m-CF, J = 8.0
Hz), 127.40 (d, o-CF, J = 15.9 Hz) 119.0, 116.5, 115.8, 115.5, 39.6, 22.0. Spectroscopic data for
3l match those previously reported in the literature.8e
Compound 3p. Following the general procedure, product 3p was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (51% yield, 23.6 mg). H NMR (300 MHz, CDCl3) δ
7.31 – 7.18 (m, 4H), 7.17 – 7.08 (m, 2H), 6.88 (td, J = 7.5, 1.3 Hz, 1H), 6.69 (dd, J = 7.8, 1.3 Hz,
1H), 4.09 (q, J = 7.2 Hz, 1H), 3.43 (s, 2H), 1.64 (d, J = 7.2 Hz, 3H). 13C{1H} NMR (63 MHz,
CDCl3) δ 148.0, 144.2, 134.7, 130.1, 129.1, 127.7 (2CH), 127.4, 126.8, 125.8, 119.0, 116.5, 40.1,
21.8. HRMS (ESI, m/z) calcd for C14H15ClN [M+H]+: 232.0893, found 232.0905.
Compound 3q Following the general procedure, product 3q was obtained by FC
(CH2Cl2/MeOH = 95/5) as a colorless oil (47% yield, 21.8 mg).1H NMR (360 MHz, CDCl3) δ 7.38
(dd, J = 5.8, 3.5 Hz, 1H), 7.33 – 7.28 (m, 1H), 7.18 – 7.07 (m, 3H), 7.03 (dd, J = 5.8, 3.7 Hz, 1H),
6.86 (td, J = 7.5, 1.3 Hz, 1H), 6.66 (dd, J = 7.8, 1.3 Hz, 1H), 4.53 (q, J = 7.0 Hz, 1H), 1.59 (d, J =
7.0 Hz, 3H). 13C{1H} NMR (63 MHz, CDCl3) δ 144.2, 143.1, 133.6, 129.6, 128.9, 128.6, 127.8,
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127.5, 127.2, 118.7, 116.1, 36.3, 20.3. HRMS (ESI, m/z) calcd for C14H15ClN [M+H]+: 232.0893,
found 232.0902.
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Compound 3u. Following the general procedure, product 3u was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (62% yield, 17.0 mg). H NMR (360 MHz, CDCl3) δ
7.12 – 7.02 (m, 2H), 6.75 (td, J = 7.4, 1.3 Hz, 1H), 6.68 (dd, J = 7.8, 1.3 Hz, 1H), 6.01 – 5.91 (m,
1H), 5.79 – 5.68 (m, 1H), 3.69 (s, 2H), 3.48 – 3.37 (m, 1H), 2.16 – 2.07 (m, 2H), 2.03 – 1.91 (m,
1H), 1.83 – 1.57 (m, 4H). C{1H} NMR (91 MHz, CDCl3) δ 144.1, 130.0, 129.9, 129.2, 127.2,
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118.7, 116.2, 38.1, 28.5, 25.1, 21.3. Spectroscopic data for 3u match those previously reported in
the literature.8a
Compound 3v. Following the general procedure, product 3v was obtained by FC
(CH2Cl2/MeOH = 95/5) as a red-brown oil (44% yield, 16.5 mg). 1H NMR (360 MHz, CDCl3) δ
7.15 (dd, J = 7.7, 1.4 Hz, 1H), 7.02 (td, J = 7.6, 1.4 Hz, 1H), 6.76 (td, J = 7.6, 1.3 Hz, 1H), 6.69
(dd, J = 7.7, 1.3 Hz, 1H), 3.63 (s, 2H), 2.59 (dd, J = 9.0, 5.3 Hz, 1H), 2.50 – 2.45 (m, 1H), 2.41 –
2.35 (m, 1H), 1.84 – 1.76 (m, 1H), 1.68 – 1.53 (m, 4H), 1.37 – 1.27 (m, 3H). 13C{1H} NMR (91
MHz, CDCl3) δ 131.6, 126.4, 125.5, 118.5, 42.1, 40.5, 38.0, 37.0, 36.4, 30.4, 29.4. Spectroscopic
data for 3v match those previously reported in the literature.6i
Compound 3w. Following the general procedure, product 3w was obtained by FC
(CH2Cl2/MeOH = 95/5) as a colorless oil (46% yield, 19.4 mg). 1H NMR (360 MHz, CDCl3) δ
7.31 – 7.24 (m, 4H), 7.23 – 7.16 (m, 4H), 6.82 (td, J = 7.4, 1.3 Hz, 1H), 6.63 (dd, J = 8.0, 1.3 Hz,
1H), 4.03 (q, J = 7.2 Hz, 1H), 3.48 (s, 1H), 2.71 (s, 3H), 1.62 (d, J = 7.1 Hz, 3H). 13C{1H} NMR
(91 MHz, CDCl3) δ 146.9, 145.8, 129.4, 128.9, 127.5, 126.9, 126.5, 117.1, 110.4, 40.0, 31.0, 22.4.
Spectroscopic data for 3w match those previously reported in the literature.6i
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Compound 3x. Following the general procedure, product 3x was obtained by FC
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(CH2Cl2/MeOH = 95/5) as a colorless oil (99% yield, 44.2 mg). H NMR (360 MHz, CDCl3) δ
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7.32 – 7.25 (m, 2H), 7.25 – 7.17 (m, 3H), 7.11 – 7.03 (m, 2H), 6.78 (t, J = 7.5 Hz, 1H), 4.01 (q, J
= 7.2 Hz, 1H), 3.51 – 3.30 (m, 2H), 3.06 – 2.96 (m, 2H), 1.62 (d, J = 7.2 Hz, 3H). 13C{1H} NMR
(91 MHz, CDCl3) δ 149.8, 145.7, 129.5, 128.8, 127.6, 127.1, 125.1, 122.8, 47.2, 40.9, 30.0, 21.2.
Spectroscopic data for 3x match those previously reported in the literature.9b
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Compound 3y. Following the general procedure, product 3y was obtained by FC
(CH2Cl2/MeOH = 95/5) as a colorless oil (89% yield , 42.2 mg). 1H NMR (360 MHz, CDCl3) δ
7.34 – 7.27 (m, 2H), 7.26 – 7.20 (m, 3H), 7.17 – 7.11 (m, 1H), 6.95 (dd, J = 7.5, 1.4 Hz, 1H), 6.74
(t, J = 7.5 Hz, 1H), 4.00 (q, J = 7.1 Hz, 1H), 3.29 – 3.19 (m, 1H), 3.18 – 3.09 (m, 1H), 2.80 (t, J =
6.6 Hz, 2H), 1.96 – 1.80 (m, 2H), 1.63 (d, J = 7.1 Hz, 3H). C{1H} NMR (91 MHz, CDCl3) δ
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146.0, 142.3, 128.8, 128.0, 127.6, 126.4, 124.9, 122.1, 116.7, 42.4, 39.8, 27.7, 22.5, 22.0.
Spectroscopic data for 3y match those previously reported in the literature.9b
Compound 3z. Following the general procedure, product 3z was obtained by FC (pentane/
EtOAc = 95/5) as a colorless oil (13% yield, 5.8 mg). 1H NMR (300 MHz, CDCl3) δ 7.28 (br, 2H),
7.27 (d, J = 1.4 Hz, 2H), 7.25 – 7.22 (m, 1H), 7.22 – 7.20 (m, 1H), 7.19 (s, 1H), 7.18 – 7.13 (m,
1H), 7.11 – 7.04 (m, 1H), 4.88 (q, J = 7.3 Hz, 1H), 2.64 (s, 6H), 1.61 (d, J = 7.2 Hz, 3H). 13C{1H}
NMR (75 MHz, CDCl3) δ 152.4, 147.0, 142.1, 128.4, 128.1, 127.6, 126.7, 125.5, 124.1, 120.5,
45.8, 37.4, 22.3. Spectroscopic data for 3z match those previously reported in the literature.7c
Mechanistic investigations (Scheme 3). Eq 3a. Substrate 4a was synthesized by a reported
method.27 In a glove box, a reaction tube was charged with [In(PhF)2][Al(OC(CF3)3)4] (0.05 equiv,
13 mg, 0.01 mmol) and anhydrous degassed PhF (0.5 mL, 0.4 M). Compounds 4a (1 equiv, 39.5
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mg, 0.2 mmol) was added in this solution. The reaction tube was sealed with a screw cap and
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stirred outside of the glove box at 110 C for 12 h. The reaction mixture was diluted with Et2O,
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pressure by rotary evaporation. Purification by FC over neutral Al2O3 (CH2Cl2/MeOH = 95/5)
afforded desired product 3a in 43% yield. Eq 3b. The hydroamination product 4b was obtained in
78% yield (52.0 mg) following the general catalytic procedure using 3,5-
bis(trifluoromethyl)aniline (1 equiv, 45.8 mg, 0.2 mmol) and styrene (1 equiv, 20.8 mg, 0.2 mmol).
1H NMR (360 MHz, CDCl3) δ 7.35 (s, 4H), 7.30 – 7.25 (m, 1H), 7.09 (s, 1H), 6.86 (s, 2H), 4.59 –
4.46 (m, 2H), 1.57 (d, J = 6.5 Hz, 3H). C{1H} NMR (91 MHz, CDCl3) δ 147.8, 132.5, 132.2,
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129.1, 127.7, 125.8, 125.1, 122.1, 112.6, 112.5, 110.4, 110.3, 53.6, 24.7. F NMR (235 MHz,
CDCl3) δ -63.2. Spectroscopic data for 3v match those previously reported in the literature.3f
Eq 3c. The GC monitoring experiment of the generation of 3d was achieved by taking samples
at 15 min, 30 min, 1 h, 2 h, 3 h, 4 h, 7 h, and 12 h. All calibrations were performed using 4-tert-
butylcyclohexanone as an internal standard with four points.
Procedure for In(I) catalyzed hydroarylation of styrene by aniline 1d on 2 mmol scale.
In a glove box, a 25 mL sealed reaction vessel was charged with [In(PhF)2][Al(OC(CF3)3)4] (169
mg, 0.13 mmol) and anhydrous degassed PhF (6.7 mL). Aniline 1d (340 mg, 2.67 mmol) and
styrene 2 (277.5 mg, 2.67 mmol) were then added in this solution in portions. The reaction tube
was sealed with a screw cap and stirred outside of the glove box at 110 oC for 18 h. The reaction
mixture was diluted with 30 ml of Et2O, filtered through a pad of celite (thoroughly rinsed with
Et2O) and concentrated under reduced pressure by rotary evaporation. Purification by FC over
(cyclohexane/EtOAc: 100/0 to 95/5) over silica gel afforded 4-chloro-2-(1-phenylethyl)aniline 3d
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(62%, 384 mg) as colorless oil. Spectroscopic data for 3d match those previously reported in the
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General procedure for the intramolecular hydroamination of alkenes (Table 2). In a glove
box, catalyst (0.05 equiv, 0.02 mmol) was added into anhydrous degassed fluorobenzene (0.5 mL)
in a reaction tube. Then aminoalkenes 5a (47.5mg, 0.2 mmol) were added in this solution. The
reaction tube was sealed with a screw cap and stirred outside of the glove box at 110 oC for 12 h.
After all the starting material had been consumed (TLC), the reaction mixture was diluted with
Et2O, filtered through a pad of of aluminum oxide (thoroughly rinsed with Et2O) and concentrated
under reduced pressure by rotary evaporation. Purification by FC over neutral Al2O3
(cyclohexane/EtOAc = 95/5) afforded product 6a. The optimization of solvents and temperature
are shown in Table S1 (See the Supporting Information).
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General procedures for the intramolecular hydroamination of alkenes (Scheme 4). For
substrates 5a-m: In a glove box, [In(PhF)2][Al(OC(CF3)3)4] (26mg, 0.02 mmol, 0.1 equiv) was
added into anhydrous degassed fluorobenzene (0.5 mL) in a reaction tube. Then alkenylamine 5a-
m (0.2 mmol) was added in this solution. The reaction tube was sealed with a screw cap and stirred
outside of the glove box at 110 oC for 12 h. The reaction mixture was diluted with Et2O, filtered
through a pad of of aluminum oxide (thoroughly rinsed with Et2O) and concentrated under reduced
pressure by rotary evaporation. Purification by FC over neutral Al2O3 (cyclohexane/EtOAc = 95/5)
afforded desired product 6a-m. For substrates 5n-z: In a glove box, [In(PhF)2][Al(OC(CF3)3)4]
(13 mg, 0.01 mmol, 0.05 equiv) was added into anhydrous degassed fluorobenzene (0.5 mL) in a
reaction tube. Then alkenylamine 5n–z (0.2 mmol) was added in this solution. The reaction tube
o
was sealed with a screw cap and stirred outside of the glove box at 110 C for 1 h. The reaction
mixture was diluted with Et2O, filtered through a pad of of aluminum oxide (thoroughly rinsed
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The Journal of Organic Chemistry
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with Et2O) and concentrated under reduced pressure by rotary evaporation. Purification by FC over
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silica gel (cyclohexane/EtOAc = 95/5) afforded desired product 6n-z.
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Compound 6a. Following the general procedure, product 6a was obtained by FC
(cyclohexane/EtOAc = 95/5) as a colorless oil (89% yield, 42.2 mg). 1H NMR (250 MHz, CDCl3)
δ 7.24 – 7.06 (m, 10H), 3.60 (dd, J = 11.4, 1.1 Hz, 1H), 3.39 (d, J = 11.4 Hz, 1H), 3.34 – 3.23 (m,
1H), 2.67 (dd, J = 12.7, 6.6 Hz, 1H), 2.00 (s, 1H, NH), 1.98 – 1.91 (m, 1H), 1.13 (d, J = 6.4 Hz,
3H). 13C{1H} NMR (75 MHz, CDCl3) δ 147.7, 146.9, 128.4, 127.1, 127.0, 126.1, 57.6, 57.2, 53.1,
47.0, 22.1. Spectroscopic data for 6a match those previously reported in the literature.31
Compound 6b. Following the general procedure, product 6b was obtained by FC
(cyclohexane/EtOAc = 95/5) as a colorless oil (42% yield, 12.9 mg). 1H NMR (360 MHz, CDCl3)
δ 3.21 – 3.09 (m, 1H), 2.79 (d, J = 11.0 Hz, 1H), 2.61 (d, J = 11.0 Hz, 1H), 1.95 (brs, 2H, NH),
1.75 (dd, J = 12.5, 6.6 Hz, 1H), 1.47 – 1.31 (m, 10H), 1.14 (d, J = 6.3 Hz, 3H), 1.00 (dd, J = 12.5,
9.2 Hz, 1H). 13C{1H} NMR (91 MHz, CDCl3) δ 59.3, 54.2, 47.7, 44.1, 38.8, 37.4, 26.2, 24.0, 23.8,
21.6. Spectroscopic data for 6b match those previously reported in the literature.31
Compound 6c. The product 6c was obtained as colorless crystals following with a modified
purification procedure.3 Once the reaction was over, the reaction mixture was concentrated, and
the residue was dissolved in Et2O (15 mL). The solution was acidified with aqueous HCl (2 M, 15
mL), and extracted with aqueous HCl (2 M, 5 mL × 3). The combined aqueous layers were
evaporated under reduced pressure to give the pure desired product (37% yield, 11.1 mg). 1H NMR
(360 MHz, CDCl3) δ 9.90 (s, 1H), 9.47 (s, 1H), 3.92 – 3.75 (m, 1H), 3.17 – 3.05 (m, 1H), 3.05 –
2.93 (m, 1H), 1.91 (dd, J = 12.9, 6.4 Hz, 1H), 1.62 – 1.55 (m, 1H), 1.52 (d, J = 6.4 Hz, 3H), 1.20
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