Zinc triflate-catalyzed intermolecular hydroamination of vinylarenes and anilines: Scopes and limitations

Article abstract of DOI:10.1016/j.tetlet.2011.10.124

Intermolecular hydroamination of vinylarenes and anilines was studied using zinc triflate as catalyst. NMR experiments supported a Lewis acid activation of the CC double bond. Electronic/steric effect study indicated that Lewis acidity of the catalyst as well as the coordination property of the amine were the governing factors for successful hydroamination of the substrates. More nucleophilic amine would bind more tightly to the central metal, leading to an unproductive coordination. Approach of bulky amine to CC bond would be hindered, and an alternative electrophilic substitution on benzene ring of the amine would become the major reaction. Electrophilic substitution would become predominant when strong electron-donating group is presented on aniline benzene ring.

Full text of DOI:10.1016/j.tetlet.2011.10.124

Tetrahedron Letters 52 (2011) 7168–7170
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Zinc triflate-catalyzed intermolecular hydroamination of vinylarenes and
anilines: scopes and limitations
⇑
Gong-Qing Liu, Yue-Ming Li
College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, 94 Weijin Road, Tianjin 300071, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Intermolecular hydroamination of vinylarenes and anilines was studied using zinc triflate as catalyst.
NMR experiments supported a Lewis acid activation of the C@C double bond. Electronic/steric effect
study indicated that Lewis acidity of the catalyst as well as the coordination property of the amine were
the governing factors for successful hydroamination of the substrates. More nucleophilic amine would
bind more tightly to the central metal, leading to an unproductive coordination. Approach of bulky amine
to C@C bond would be hindered, and an alternative electrophilic substitution on benzene ring of the
amine would become the major reaction. Electrophilic substitution would become predominant when
strong electron-donating group is presented on aniline benzene ring.
Received 21 August 2011
Revised 12 October 2011
Accepted 21 October 2011
Available online 28 October 2011
Keywords:
Zinc triflate
Styrene
Ó 2011 Elsevier Ltd. All rights reserved.
Aniline
Hydroamination
Hydroarylation
Nitrogen-containing compounds have been found extensive
application in medicinal chemistry, and significant efforts have
been made toward the synthesis of these types of important com-
pounds.1 Traditional synthesis of nitrogen-containing compounds
would involve multistep functional group transformations, and in
many cases are proved to be problematic due to the normally harsh
reaction conditions involved. Many state-of-the-art methods have
been developed for C–N bond formations, and hydroamination of
C–C multiple bonds is among the most straightforward and atom
economical methods for the construction of C–N bonds and related
heterocyclic skeletons.2
Due to the electron-rich property of both the substrates and the
nucleophiles, hydroamination of unfunctionalized olefins is gener-
ally difficult in the absence of a catalyst. An ideal catalyst should
bear balanced steric and electronic effects to ensure an effective
activation of C@C bond, and also a free amino group which is
nucleophilic enough for a meaningful hydroamination reaction.
In addition to their successful application in nucleophilic addi-
tion reactions,3 some zinc related materials such as zinc triflate,4
zinc-exchanged montmorillonite clay,5 or aminotroponiminate
methyl/ethyl zinc complexes6,7 were also found effective in hydro-
amination of different aminoalkenes and aminoalkynes. However,
to the best of our knowledge, there is no report on zinc salt-cata-
lyzed homogeneous intermolecular hydroamination of unactivated
alkenes with amines. Detailed study is therefore required to fully
understand the electronic/steric factors governing the performance
of the catalysts.
We are interested in developing efficient and practical method
for both intra- and intermolecular hydroamination of unfunction-
alized olefins, and it is our first purpose to fully understand the
electronic/steric factors which are important for successful hydro-
amination reactions. In this communication, we wish to report our
preliminary results on zinc salts-catalyzed intermolecular hydro-
amination of vinylalkenes with anilines.
Reaction between styrene and aniline was first chosen as a
model reaction to study the effects of Lewis acidity of the zinc salts
on the course of reaction, and the results are summarized in Table
1. Reported conditions such as solvent, reaction temperature, cata-
lyst loading, and reaction time were first adopted, and our preli-
minary results supported a Lewis acid-catalyzed mechanism.8
Entries 1–7 in Table 1 indicated that relatively higher yields were
observed for stronger Lewis acidic catalysts, and zinc dust or zinc
hydroxide did not promote any reaction (entries 1 and 2). Zinc tri-
flate was proved to be the most suitable catalyst in the current
reaction system, other substrates and anilines were then tested
with Zn(OTf)2 under the current conditions. Higher yield was ob-
served at higher catalyst loading (Table 1, entry 8), and coordina-
tion solvent such as dioxane was inappropriate for this type of
reaction (Table 1, entry 9). Reaction carried out in xylene at higher
temperature failed to give a good yield (Table 1, entry 10), possibly
due to the deterioration of the substrate at the refluxing tempera-
ture. Only trace amounts of product were detected when trifluoro-
sulfonic acid (HOTf) was used as the catalyst (Table 1, entry 11),
indicating that zinc triflate was responsible for the hydroamination
⇑
Corresponding author. Tel.: +86 22 23506290; fax: +86 22 23507760.
E-mail address: ymli@nankai.edu.cn (Y.-M. Li).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.124

G.-Q. Liu, Y.-M. Li / Tetrahedron Letters 52 (2011) 7168–7170
7169
Table 1
11). Substituents on vinylarenes also showed strong effect on the
course of the reaction. The reaction proceeded much faster for elec-
tron-donating group substituted olefins than for electron-with-
drawing group substituted substrates (entries 7 and 8 vs 9), the
former produced mainly para-substituted hydroarylation product,
and ortho-substituted hydroarylation products were obtained for
the latter (entry 9 vs 8). This is also in agreement with our preli-
minary calculation of the charge distributions on the benzene
ring.11
Hydroamination of styrene (1a) with aniline (2a) under different reaction conditionsa
Me
NH2 Me
NH2
Catalyst
HN
+
+
2a
1a
4a
3a
Solvent
To confirm if the hydroarylation product was formed through
an electrophilic process or through Hofmann–Martius rearrange-
ment12 of the formed hydroamination product, the reaction be-
tween styrene and aniline was carried out, and the ratio of 3a to
4a was monitored at different stage of the reaction. The result
showed that this ratio remained almost unchanged during the
course of the reaction, and was not significantly influenced by
reaction temperature. This indicated that hydroarylation product
was formed through a Friedel–Crafts reaction of the substrate in
competition with hydroamination. A control experiment demon-
strated that isolated 3a did not undergo a Hofmann–Martius rear-
rangement13 under reaction conditions (Scheme 1). This is in
Entry
Zn source
Catalyst (mol %)
T (°C)
Yield 3ab (%)
1
2
3
4
5
6
7
8
Zn
10
10
10
10
10
10
10
20
20
20
20
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
Xylene
130
130
130
130
130
130
130
130
100
160
130
—
—
6
9
15
8
32
46
12
22
<2
Zn(OH)2
ZnSO4Á7H2O
ZnCl2
ZnI2
Zn(OAc)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
Zn(OTf)2
HOTf
9
10
11
Toluene
a
Reagents and conditions: aniline (1.1 mmol), styrene (1 mmol), catalyst in
contrast to proton14 and TiCl4 catalyzed reactions where pro-
15
solvent (1.0 mL), 24 h.
b
Isolated yield.
longed reaction time favored the formation of hydroarylation
products.
NMR experiments were carried out to study the possible inter-
action between C@C bond and Zn(OTf)2. When equal equivalents of
styrene and zinc triflate were mixed in CDCl3, a down field shift of
0.1 ppm was observed for C@C proton signals (d 7.03, 6.06,
5.55 ppm in the absence of zinc triflate versus d 7.13, 6.17 and
5.65 ppm in the presence of zinc triflate, respectively), indicating
product. This is also in good agreement with the observations
made by Schlummer and Hartwig that the intramolecular addition
of amines without an electron-withdrawing group did not occur
using concentrated sulfuric acid.9
Different vinylarenes and anilines were then subjected to inter-
molecular hydroamination under the optimized conditions, and
the results were listed in Table 2.10 In addition to the expected
hydroamination products, hydroarylation (Friedel–Crafts) products
were also observed in some cases. For the reactions studied, the
selectivity between hydroamination and hydroarylation depended
on the nucleophilicity of the aniline nitrogen atom: electron-with-
drawing group substituted anilines increased the chemoselectivity
and favored the hydroamination products, and electron-donating
group substituted aniline increased the amount of hydroarylation
of the substrates (entry 1 vs 2–4, entries 2–4 vs 6, and entry 7 vs
a possible p-coordination of C@C double bond to Zn(OTf)2. Similar
down field shifts were also observed in 13C NMR experiments: the
chemical shifts for olefin bond: @CH2 113.93 and @CH–
137.04 ppm without zinc triflate moved to 114.06 and
137.30 ppm, respectively when equal equivalents of zinc triflate
were added. Though weak the interaction may be, it is strong
enough for a nitrogen atom to undergo a nucleophilic attack on
the C@C double bond of the substrate when the electron-donating
property of the substituent on aniline is not strong enough to
Table 2
Hydroamination reaction of different vinylarenes and anilinesa
NH2
NH2
Me
NH2 Me
20 mol% Zn(OTf)2
HN
+
R1
toluene 130 °C
R2
R1
+
R1
+
R2
R2
Me
R2
R1
Yield 3 + 4 + 5b (%)
1
3
4
2
R2
5
Entry
R1
Yield 3b (%)
Yield 4b (%)
Yield 5b (%)
1
2
3
4
5
6
7
8
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
H (1a)
F (1b)
Br (1c)
OMe (1d)
OMe (1d)
F (1b)
H (2a)
p-F (2b)
46 (3a)
28 (3b)
26 (3c)
45 (3d)
24 (3e)
—
27 (3g)
31 (3h)
35 (3i)
55 (3j)
20 (3k)
31 (4a)
15 (4b)
19 (4c)
16 (4d)
—
57 (4f)
—
17 (4h)
—
—
—
—
—
—
—
—
—
77
43
45
61
24
57
27
48
77
86
73
p-Cl (2c)
p-Br (2d)
p-NO2 (2e)
p-OMe (2f)
H (2a)
H (2a)
H (2a)
p-OMe (2f)
p-OMe (2f)
9c
10c
11
42 (5i)
—
—
31 (4j)
53 (4k)
a
b
c
Reaction conditions: aniline (1.1 mmol), styrene (1 mmol), 20 mol % Zn(OTf)2 in solvent (1.0 mL), 24 h.
Isolated yield.
Reaction time 12 h.

7170
G.-Q. Liu, Y.-M. Li / Tetrahedron Letters 52 (2011) 7168–7170
reaction mechanism and the improvement of the chemoselectivity
are in good progress.
Me
Ar
NH2 Me
Ar
Zn(OTf)2
HN
Toluene 130 °C 24h
Acknowledgment
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 20972072).
3a
4a
Scheme 1. Thermo-stability study of the hydroaminated product 3a.
References and notes
1. O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446.
NH2
2. For leading reviews: (a) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada,
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Pohlki, F.; Doye, S. Chem. Soc. Rev. 2003, 32, 104–114; (e) Seayad, J.; Tillack, A.;
Hartung, C. G.; Beller, M. Adv. Synth. Catal. 2002, 344, 795–813; (f) Müller, T. E.;
Beller, M. Chem. Rev. 1998, 98, 675–704; (g) Bates, R. W.; Satcharoen, V. Chem.
Soc. Rev. 2002, 31, 12–21; (h) Widenhoefer, R. A.; Han, X. Eur. J. Org. Chem. 2006,
4555–4563; (i) Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. Dalton Trans.
2007, 44, 5105–5118; (j) Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. Rev.
1999, 28, 199–207.
3. (a) Nakamura, E. In Organometallics in Synthesis - A Manual; Schlosser, M., Ed.;
John Wiley & Sons Ltd: Chichester, 2002; pp 579–664; (b)The Chemistry of
Organozinc Compounds (Patai Series: The Chemistry of Functional Groups);
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4. (a) Bódis, J.; Müller, T. E.; Lercher, J. A. Green Chem. 2003, 5, 227–231; (b) Neff,
V.; Müller, T. E.; Lercher, J. A. Chem. Commun. 2002, 906–907; (c) Müller, T. E.;
Pleier, A.-K. J. Chem. Soc. Dalton Trans. 1999, 583–588; (d) Müller, T. E.; Grosche,
M.; Herdtweck, E.; Pleier, A.-K.; Walter, E.; Yan, Y.-K. Organometallics 2000, 19,
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6. (a) Zulys, A.; Dochnahl, M.; Hollmann, D.; Löhnwitz, K.; Herrmann, J.-S.; Roesky,
P. W.; Blechert, S. Angew. Chem., Int. Ed. 2005, 44, 7794–7798; (b) M. Dochnahl,
Ph. D. Thesis, Technische Universität Berlin, Germany, 2007.; (c) Meyer, N.;
Löhnwitz, K.; Zulys, A.; Roesky, P. W.; Dochnahl, M.; Blechert, S. Organometallics
2006, 25, 3730–3734.
7. (a) Dochnahl, M.; Löhnwitz, K.; Pissarek, J.-W.; Roesky, P. W.; Blechert, S. Dalton
Trans. 2008, 2844–2848; (b) Dochnahl, M.; Pissarek, J.-W.; Blechert, S.;
Löhnwitz, K.; Roesky, P. W. Chem. Commun. 2006, 3405–3407; (c) Dochnahl,
M.; Löhnwitz, K.; Pissarek, J.-W.; Biyikal, M.; Schulz, S. R.; Schön, S.; Meyer, N.;
Roesky, P. W.; Blechert, S. Chem. Eur. J. 2007, 13, 6654–6666.
Me
Zn(OTf)2
HN
δ+
Zn(OTf)2
2
δ-
1
3
Scheme 2. A tentative reaction pathway leading to the hydroamination product.
trigger an electrophilic substitution on the aromatic ring. This also
accounts for the Friedel–Crafts products for strong electron-donat-
ing group substituted anilines.
When N-substituent was presented in aniline, the reactivity of
the nitrogen atom was decreased due to the increased bulkiness,
and an electrophilic substitution on aniline could then occur, lead-
ing to the formation of by-products 4 and 5. This process could be
strengthened when electron-donating group is presented on the
benzene ring of aniline.16 In these cases, electrophilic substitution
overrides the hydroamination and becomes the major reaction.
Aliphatic amines such as benzylamine or morpholine failed to un-
dergo hydroamination or hydroarylation reaction possibly due to
the strong coordination to the central metal, leading to an unpro-
ductive substrate binding as well as the deactivation of the ben-
zene ring for further electrophilic substitution.17 This was also
supported by NMR experiments: NMR signals for aniline were
almost unchanged when it was mixed with zinc triflate, while a
down field shift was observed when 4-chlorobenzylamine was
mixed with zinc triflate.18 The preliminary NMR experiments indi-
cated that free amino groups were presented in anilines, while
aliphatic amines such as benzylamines coordinated more tightly
to zinc triflate, rendering the nitrogen atom less nucleophilic for
further hydroamination of the C@C bond.
8. Burling, S.; Field, L. D.; Messerle, B. A.; Turner, P. Organometallics 2004, 23,
1714–1721.
9. (a) Schlummer, B.; Hartwig, J. F. Org. Lett. 2002, 4, 1471–1474; (b) Talluri, S. K.;
Sudalai, A. Org. Lett. 2005, 7, 855–857.
10. General procedure of the reaction: All commercially available products were
purchased from Aladdin and used as received. A sealed tube purged with argon
was charged dry toluene (1 mL), vinylarene (1.00 mmol) and anilines
(1.10 mmol). Zn(OTf)2 (0.20 mmol, 20 mol %) was added, the tube was sealed
and the reaction mixture was stirred at 130 °C for 24 h. The reaction mixture
was then transferred to a vial and volatile materials were removed in vacuo to
give an oil which was purified by flash chromatography to give the
corresponding product.
11. The calculation was carried out with semi-empirical AM1 method in MOAPC
provided by Chem3D.
12. (a) Hofmann, A. W.; Martius, C. A. Ber. 1871, 4, 742–748; (b) Hofmann, A. W.
Ber. 1872, 5, 720–722.
On the basis of these observations, a tentative reaction pathway
could be proposed as shown in Scheme 2. The C@C double bond
was activated upon zinc coordination, and a subsequent nucleo-
philic attack of the aniline nitrogen atom gave the expected prod-
uct 3. Hydroarylation would become predominant when the
aniline benzene ring was further activated by the additional elec-
tron-donating groups such as alkoxyl groups.
In summary, Zn(OTf)2 can be used to promote intermolecular
hydroamination of unactivated alkenes such as styrenes with ani-
lines, and some functional groups could be tolerated in both sub-
strates and nucleophiles. When strong electron-donating groups
are presented, hydroarylation would occur as a competing reac-
tion. This process could be enhanced with secondary amines and
the presence of strong electron-donating groups on the aniline
benzene ring. Preliminary NMR experiments supported the activa-
13. Reilly, J.; Hickinbottom, W. J. J. Chem. Soc. 1920, 103–137.
14. Anderson, L. L.; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005, 127, 14542–
14543.
15. Kaspar, L. T.; Fingerhut, B.; Ackermann, L. Angew. Chem., Int. Ed. 2005, 44, 5972–
5974.
16. When N-benzyl-4-ethoxyaniline was allowed to react with 4-methoxystyrene,
the corresponding hydroarylation product was isolated in 63% and only trace
amounts hydroamination product was detected.
17. (a) Schaffrath, H.; Keim, W. J. Mol. Catal. A: Chem. 2001, 168, 9–14; (b) Li, X.;
Chianese, A. R.; Vogel, T.; Crabtree, R. H. Org. Lett. 2005, 7, 5437–5740; (c)
Åkermark, B.; Bäckvall, J. E.; Hegedus, L. S.; Zetterberg, K.; Siirala-Hansén, K.;
Sjöberg, K. J. Organomet. Chem. 1974, 72, 127–138.
18. The interaction between amino groups and zinc triflate was studied by
monitoring the 1H NMR chemical shift of the phenyl group. When equal
equivalents of 4-chloroaniline and zinc triflate were mixed in CDCl3, the
chemical shift of the phenyl group was almost unchanged (d 7.12, 6.62 ppm, in
the absence of zinc triflate vs d 7.12, 6.64 ppm in the presence of zinc triflate,
respectively). When equal equivalents of 4-chlorobenzylamine and zinc triflate
were mixed in CDCl3, a down field shift was observed for phenyl group and
methylene proton signals (d 7.24, 7.19, 3.78 ppm in the absence of zinc triflate
versus d 7.30, 7.24 and 3.84 ppm in the presence of zinc triflate, respectively).
These data suggest a stronger coordination between aliphatic amines and zinc
triflate than anilines and zinc triflate.
tion of the C@C double bond by zinc triflate through
p-coordina-
tion, and a possible reaction pathway could be proposed on the
basis of these observations. Further studies on the details of the