Ligand acceleration in ZnI2-catalyzed intramolecular hydroamination of unfunctionalized olefins

Article abstract of DOI:10.1016/j.tetlet.2012.06.033

Zinc halide-promoted hydroamination of 4-penten-1-amine compounds was studied. Preliminary results indicated that both steric and electronic factors are crucial for this Lewis acid-promoted reaction. ZnI₂ gave the most promising results and the reactivity could be further increased upon addition of a suitable ligand. Up to 95% isolated yields were obtained when the reactions were carried out in 1,4-dioxane in the presence of 10 mol % of ZnI₂ and 8-hydroxyquinoline.

Full text of DOI:10.1016/j.tetlet.2012.06.033

Tetrahedron Letters 53 (2012) 4393–4396
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ligand acceleration in ZnI2-catalyzed intramolecular hydroamination
of unfunctionalized olefins
⇑
Gong-Qing Liu, Wei Li, Yu-Mei Wang, Zhen-Ying Ding, Yue-Ming Li
College of Pharmacy, State Key Laboratory of Medicinal Chemical Biology and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, 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:
Zinc halide-promoted hydroamination of 4-penten-1-amine compounds was studied. Preliminary results
indicated that both steric and electronic factors are crucial for this Lewis acid-promoted reaction. ZnI2
gave the most promising results and the reactivity could be further increased upon addition of a suitable
ligand. Up to 95% isolated yields were obtained when the reactions were carried out in 1,4-dioxane in the
presence of 10 mol % of ZnI2 and 8-hydroxyquinoline.
Received 21 February 2012
Revised 31 May 2012
Accepted 8 June 2012
Available online 15 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Ligand acceleration
Zinc iodide
Hydroamination
Unfunctionalized olefins
4-Penten-1-amine
Nitrogen-containing organic compounds are the most important
components of biologically active compounds. They constitute the
most important part of privileged structures and have played vital
roles in drug discovery.1 To this end, significant efforts have been
made toward the formation of C–N bonds as well as the construction
of nitrogen-containing skeletons.2 Among all the methods studied,
hydroaminationrepresentsoneofthemoststraightforwardand effi-
cient methods for the formation of carbon–nitrogen bonds. In the
past decades, both transition metal complex-catalyzed and organo-
catalytic hydroamination have been reported for this purpose.3
Comparing to the widespread applications of organozinc re-
agents as nucleophiles in different organic reactions, the Lewis acid
property of zinc compounds is far less pursued.4 It is our purpose
to develop a facile and easily accessible reaction system for cata-
lytic hydroamination of unfunctionalized olefins, and to use this
as a starting point for catalytic asymmetric hydroamination of
unfunctionalized olefins. In this communication we wish to report
our preliminary results on ligand-accelerated hydroamination of
N-substituted 4-penten-1-amines catalyzed by zinc iodide.
triflate was able to promote intermolecular hydroamination of sty-
renes with aromatic amines.9 However, there is still a need to fully
understand the steric and electronic factors governing the activity
of a catalyst, so that easily accessible catalyst system could be
developed for hydroamination of unfunctionalized olefins.
4-Penten-1-amine (1), which was used as a model substrate in
many publications, was first tested in zinc salt-promoted hydro-
amination reactions. However, our first efforts did not give any po-
sitive result.
R
R
1 R = H
2 R = Ph
NH2
The Thorpe–Ingold or gem-dimethyl (more generally dialkyl) ef-
fect has been observed in several cyclization reactions including
hydroamination reactions.10 To see if the introduction of substitu-
ents in the mainchain of the substrate would increase the reactivity
of the substrate, 2,2-diphenyl-4-penten-1-amine (2), in which two
phenyl groups were introduced at the 2-position of substrate 1, was
then used as another model substrate. Additional advantage of
compound 2 was its UV absorption property which made us easy
to monitor the reaction with TLC. However, no product could be de-
tected after the reaction mixtures were refluxed in toluene for 48 h.
It is generally acceptable that the choice of an amino group is
crucial for successful hydroamination of a substrate. Strongly
nucleophilic amines would coordinate tightly to the metal center,
leading to the blockage of an essential site for C@C binding and
Studies on zinc-exchanged zeolite-catalyzed hydroamination of
alkynes5 and the interaction between C@C double bond and zinc6
can be traced back to 1970s. Later, Penzien and Müller reported
the hydroamination of several unfunctionalized olefins using zinc
ion exchanged b-zeolites as catalysts.7 Roesky et al. showed that
aminotroponate zinc compounds were effective in hydroamination
of a variety of substrates.8 Very recently we showed that zinc
⇑
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 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.06.033

4394
G.-Q. Liu et al. / Tetrahedron Letters 53 (2012) 4393–4396
the decrease of reactivity of the amino group, and finally resulting
in an unproductive substrate binding.11 It is reasonable to assume
that the reactivity of an amino group would be resumed if its coor-
dination to zinc could be weakened. Introducing a bulky group to
the nitrogen atom would in some extent increase the steric hin-
drance of the amino group and therefore weaken the coordination
of the amino group to the central metal. Introduction of an alkyl
group to nitrogen atom could also compensate the loss of nucleo-
philicity caused by metal coordination. In this context, another
substrate 3a, in which the nitrogen atom was benzylated, was used
for a further study. Reported conditions were adopted for the ini-
tial study. The substrate and catalyst were mixed in toluene, and
the mixture was heated in an oil bath at 130 °C. To our delight,
intramolecular hydroamination products were detected for most
cases. Some results were listed in Table 1. A sealed tube could be
used to avoid the escape of the solvent, but this was not a requisite.
Preliminary studies showed that counter anions and the
amount of zinc salts had significant effects on the course of the
reaction. Metal zinc was not able to promote the reaction due to
the lack of Lewis acidity, zinc hydroxide was also not able to pro-
mote the reaction due to the lack of sufficient Lewis acidity, and
zinc iodide gave the best results. Balanced Lewis acidity was cru-
cial for successful hydroamination of the substrate. Strong Lewis
acid such as zinc triflate failed to give high yield (entry 2) possibly
due to the strong coordination of the amino group to the central
metal. Reducing the catalyst loading resulted in a drop of yield,
and the yield could be regained through prolongation of reaction
time.
Results in Table 1 indicated that in order for hydroamination to
proceed in a reasonable rate, the promoter must have enough Le-
wis acidity. However, Lewis acidity alone was not the governing
factor for successful hydroamination of the substrates. Zinc chlo-
ride was more acidic than zinc iodide but sterically less hindered,
and gave lower yield under identical conditions. An ideal promoter
should bear balanced Lewis acidity and steric hindrance to ensure
enough C@C double bond activation whereas the coordination of
amine could be reduced to the minimum extent.
After getting general information about the key factors govern-
ing the reactions, efforts were made to find an optimal reaction
condition for this easy-to-operate reaction. ZnCl2 was used as the
reaction promoter in order to observe big differences among differ-
ent conditions, and ZnI2-promoted reactions were carried out for
comparison. Some results are shown in Table 2.
As these results indicated, toluene or 1,4-dioxane was more
suitable for the reaction, and ZnI2 was superior to ZnCl2 in most
cases. ZnI2 was then used as a reaction promoter for further opti-
mization of the reaction conditions.
One of the important properties for zinc-catalyzed (or -pro-
moted) reaction is its ligand acceleration feature, that is, the reac-
tion rate of an organozinc reagent can be accelerated upon addition
of suitable ligands. To see if ligands would have some positive ef-
fects on ZnI2-promoted hydroamination reactions, commercially
available mono- and bidentate ligands were tested. We assumed
that the ligands should bear balanced bulkiness to ensure the effi-
cient coordination and activation of substrate C@C double bonds,
while the strong binding of substrate amino group to the central
metal should be avoided so that the nucleophilicity of the amino
group would be preserved. Such system would ensure the nucleo-
philic attack of the amino group on the activated C@C bond, lead-
ing to a meaningful hydroamination of the substrate. Figure 1
listed some of the ligands which would accelerate the ZnI2-pro-
moted hydroamination of substrate 3a.
Results in Figure 1 indicated that 8-hydroxyquinoline was one
of the ligands able to accelerate the hydroamination reaction.
While reaction carried out in the presence of 50 mol % of ZnI2 alone
under otherwise identical conditions gave 14% hydroaminated
product, 78% yield was observed when 8-hydroxyquinoline was
presented in the reaction mixture. Other ligands bearing a similar
planar structure could also accelerate the reaction. Monodentate
triphenylphosphine gave 70% yield, and bidentate DPPE gave the
product in less than 5% yield, possibly due to the lack of enough
space for C@C double bond binding, and thus indicating a stereo-
demanding feature of the reaction. 8-Hydroxyquinoline was finally
chosen as the ligand due to its easy availability.
To see if similar ligand acceleration could be observed for other
zinc salts, ZnCl2, ZnBr2, and Zn(OTf)2 in combination with 8-
hydroxyquinoline were also tested for hydroamination of 3a, and
the results are summarized in Table 3. As these results indicated,
zinc iodide in combination with 8-hydroxyquinoline was the most
effective catalyst system in hydroamination of substrate 3a. Reduc-
ing the catalyst loading resulted in a drop of reaction rate, and
longer reaction time resulted in a complete conversion of the
substrate.
Other substrates were then tested to study the scope of the
reaction, and the results are shown in Table 4.12 The reactions were
carried out in 1,4-dioxane at 110 °C for 36 h, 10 mol % of zinc io-
dide and 10 mol % of 8-hydroxyquinoline were used as catalyst.
Both toluene and 1,4-dioxane were suitable for the reaction. The
latter was finally chosen as the solvent due to its less toxicity
and its ease of removal. Longer reaction time and higher tempera-
ture were used to ensure a complete conversion of all the
Table 1
Hydroamination of 3a using different zinc saltsa
Ph
Table 2
Ph
Hydroamination of N-benzyl 2,2-diphenyl-4-pentenamine in different solventsa
Ph Ph H
Toluene
N
Ph
Entry
Solvent
Reaction temperature (°C)
3a:4ab
Me
130 °C
N
3a
Bn
4a
1
2
3
4
5
6
7
8
Hexane
DCE
CH3CN
Benzene
Toluene
1,4-Dioxane
Toluene
1,4-Dioxane
Toluene
Toluene
80
80
80
80
80
83:17
80:20
76:24 (71:29)
89:11 (87:13)
75:25 (80:20)
70:30 (67:33)
40:60
39:61 (16:84)
14:86
39:61
Entry
Zinc salt
Reaction time (h)
3a:4ab
1
2
3
4
5
6
7
8
9
ZnSO4Á7H2O
Zn(OTf)2
Zn(OAc)2
ZnCl2
24
24
24
24
24
24
24
48
48
87
60
95
40
81
22
19
14
<5
13
40
5
60
19
78
81
86
95
80
130
120
130
130
9c
10d
Zn(ClO4)Á6H2O
ZnBr2
ZnI2
ZnCl2
ZnI2
a
Reaction conditions: 100 mol % ZnCl2, 24 h.
Based on crude NMR analysis of the reaction mixtures. Data in parentheses are
results from 100 mol % ZnI2 under identical conditions.
b
c
a
Reaction time: 48 h.
200 mol % ZnCl2, 48 h.
Amount of zinc salt = 1 equiv.
Ratios were calculated based on crude NMR analysis of the reaction mixtures.
d
b

G.-Q. Liu et al. / Tetrahedron Letters 53 (2012) 4393–4396
4395
Table 4
ZnI2 (no ligand): 20mol%: <5%, 50 mol%: 14%
ZnI2–8-hydroxyquinoline-catalyzed hydroamination of unfunctionalized olefins
DBU: 20 mol%, 13%, 50 mol%, 64%
DABCO: 20 mol% 9%, 50 mol%, 55%
R1
PPh3: 20 mol%, 62%
50 mol%, 70%
R1
1,4-dioxane, catalyst
R1 R1
H
CH3
N
R2
N
R2
4
N
N
PPh2
110 °C, 36 h
3
OH HO
PPh2
Entry
Substrate
R1
R2
Yielda (%)
20 mol%, 8%
50 mol%, 20%
20 mol%, < 5%
50 mol%, < 5%
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
H
Bn
95
86
86
84
93
91
95
82
4-MeBn
4-i-PrBn
4-MeOBn
3-MeOBn
4-FBn
4-BrBn
4-O2NBn
Ac
Ts
Boc
i-Pr
Cy
N
N
OMe N
OMe
Ph
OH
20 mol%, 32%
50 mol%, 39%
20 mol%, 74%
50 mol%, 78%
20 mol%, 46%
50 mol%, 73%
9
N.R.b
N.R.
N.R.
84
58
92
92
N.R.
94
10
11
12
13
14
15
16
17
N
N
i-Bu
Bn
Bn
Bn
N
N
20 mol%, 9%
50 mol%, 29%
20 mol%, 21%
50 mol%, 20%
–(CH2)5–
H
N
18
19
3r
3s
N.R.
N.R.
Bn
R = H
20 mol%, 61%
50 mol%, 73%
CH3
N
H
N
R
N
OH
NHBn
R = OCH3
20 mol%, 64%
50 mol%, 62%
OH
a
Isolated yields.
N.R. = no reaction.
20 mol%, 14%
50 mol%, 23%
b
Reaction conditions: benzene, 80 °C, 48 h, ZnI2:Ligand = 1 : 1
8-hydroxyquinoline) (Scheme 1). This compound contains two
different 4-pentenyl groups, one of which was substituted with
two phenyl groups.
Figure 1. Ligand acceleration in ZnI2-promoted hydroamination of 3a in the
presence of different ligands.
Results showed that compound 6 was obtained in 93% isolated
yield, and the sterically less hindered product 7 was not observed,
indicating the positive effect of gem-disubstituents on the activity
of the substrate.
Table 3
8-Hydroxyquinoline-accelerated hydroamination of 3a with different zinc saltsa
Entry Catalyst
Catalyst loading (mol %) Reaction time (h)
3a:4ab
1
2
3
4
5
6
7
8
9
ZnI2
ZnCl2
ZnBr2
20
20
20
24
24
24
24
48
48
48
24
36
7
93
80 20
86 14
87 13
<1 >99
<1 >99
12 88
10 90
<1 >99
H3C
Zn(OTf)2 20
N
Ph
Ph
ZnI2
ZnI2
ZnI2
ZnI2
ZnI2
20
10
5
10
10
7
In summary, we have shown that both steric and electronic fac-
tors played important roles in Zn(II)-catalyzed hydroamination of
unfunctionalized olefins. The catalyst should bear balanced Lewis
acidity as well as steric hindrance to ensure an efficient C@C bond
activation and to avoid an over-strong interaction between the
central metal and the amino group. Zinc iodide showed highest
activity among all zinc salts studied, and its catalytic activity could
a
Reaction conditions: solvent = 1,4-dioxane, ligand = 8-hydroxyquinoline, tem-
perature = 110 °C (oil bath temperature).
b
Based on crude NMR analysis of the reaction mixtures.
substrates. The reactions proceeded readily, giving the pyrrolidine
product 4 in good to excellent isolated yields. Amides (3i–3k) or
aromatic amine (3s) failed to react, possibly due to the low reactiv-
ity of the nitrogen atoms (entries 9–11, and entry 19). Sterically
less hindered substrates (3p and 3r) also failed to react (entries
16 and 18), possibly due to a tighter coordination between the
amino group to central metal and the lack of Thorpe–Ingold effect.
To further test the influenceof Thorpe–Ingold effect onthe course
of the reaction, substrate 5 was also subjected to hydroamination
reaction under the same conditions (10 mol % ZnI2 + 10 mol %
H3C
1,4-dixoane
Ph Ph
H
N
N
110 °C, 36 h
5
Ph
6
Ph
Scheme 1. Thorpe–Ingold effect in ZnI2-catalyzed hydroamination reaction.

4396
G.-Q. Liu et al. / Tetrahedron Letters 53 (2012) 4393–4396
4. (a) Coates, G. W.; Moore, D. R. Angew. Chem., Int. Ed. 2004, 43, 6618–6639; (b)
Cokoja, M.; Bruckmeier, C.; Rieger, B.; Herrmann, W. A.; Kuhn, F. E. Angew.
Chem., Int. Ed. 2011, 50, 8510–8537.
be further increased upon addition of suitable ligands. 8-Hydroxy-
quinoline and other similar ligands showed prominent results in
rate acceleration. Another most important advantage of the current
catalyst system is its ease of operation. Both the catalyst and the
ligand were easily accessible, and all the operations could be car-
ried out in the open air without any loss of yields. Ligand acceler-
ation and steric demanding features of the current catalyst system
may shed light on the design of chiral ligands for stereoselective
hydroamination of unfunctionalized olefins.
5. Neale, R. S.; Elek, L.; Malz, R. E. J. Catal. 1972, 27, 432–441.
6. (a) Denis, J. S.; Smart, J. B.; Oliver, J. P. J. Organomet. Chem. 1972, 44, C32–C36;
(b) Denis, J. S.; Oliver, J. P.; Dolzine, T. W.; Smart, J. B. J. Organomet. Chem. 1974,
71, 315–323.
7. Penzien, J.; Su, R. Q.; Müller, T. E. J. Mol. Catal. A: Chem. 2002, 182, 489–498.
8. (a) Zulys, A.; Dochnahl, M.; Hollmann, D.; Lohnwitz, K.; Herrmann, J. S.; Roesky,
P. W.; Blechert, S. Angew. Chem., Int. Ed. 2005, 44, 7794–7798; (b) Dochnahl, M.;
Pissarek, J. W.; Blechert, S.; Lohnwitz, K.; Roesky, P. W. Chem. Commun. 2006,
3405–3407; (c) Meyer, N.; Lohnwitz, K.; Zulys, A.; Roesky, P. W.; Dochnahl, M.;
Blechert, S. Organometallics 2006, 25, 3730–3734; (d) Dochnahl, M.; Lohnwitz,
K.; Pissarek, J. W.; Biyikal, M.; Schulz, S. R.; Schon, S.; Meyer, N.; Roesky, P. W.;
Blechert, S. Chem. Eur. J. 2007, 13, 6654–6666; (e) Dochnahl, M.; Lohnwitz, K.;
Pissarek, J. W.; Roesky, P. W.; Blechert, S. Dalton Trans. 2008, 2844–2848; (f)
Dochnahl, M.; Lohnwitz, K.; Luhl, A.; Pissarek, J. W.; Biyikal, M.; Roesky, P. W.;
Blechert, S. Organometallics 2010, 29, 2637–2645.
Acknowledgment
We acknowledge the financial support from National Natural
Science Foundation of China (NSFC 20972072).
9. Liu, G.-Q.; Li, Y.-M. Terahedron Lett. 2011, 52, 7168–7170.
10. (a) Kaneti, J.; Kirby, A. J.; Koedjikov, A. H.; Pojarlieff, I. G. Org. Biomol. Chem.
2004, 2, 1098–1103; (b) Crimmin, M. R.; Arrowsmith, M.; Barrett, A. G. M.;
Casely, I. J.; Hill, M. S.; Procopiou, P. A. J. Am. Chem. Soc. 2009, 131, 9670–9685;
(c) Kostal, J.; Jorgensen, W. L. J. J. Am. Chem. Soc. 2010, 132, 8766–8773; (d)
Duncan, C.; Biradar, A. V.; Asefa, T. ACS Catal. 2011, 1, 736–750.
11. (a) Akermark, B.; Backvall, J. E.; Hegedus, L. S.; Zetterbe, K.; Siiralah, K.; Sjoberg,
K. J. Organomet. Chem. 1974, 72, 127–138; (b) Schaffrath, H.; Keim, W. J. Mol.
Catal. A: Chem. 2001, 168, 9–14; (c) Li, X. W.; Chianese, A. R.; Vogel, T.; Crabtree,
R. H. Org. Lett. 2005, 7, 5437–5440.
Supplementary data
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.06.033.
References and notes
12.
A general procedure for intramolecular hydroamination reaction: All
commercially available starting materials were purchased from Aladdin
Reagents (Beijing) and J&K Chemicals (Shanghai) and were used as received.
1. (a) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.; Pippin, D. A.
Comb. Chem. High Throughput Screen. 2004, 7, 473–494; (b) Costantino, L.;
Barlocco, D. Curr. Med. Chem. 2006, 13, 65–85.
2. Trost, B. M.; Fleming, I.; Winterfeldt, E. Comprehensive Organic Synthesis:
Selectivity, Strategy and Efficiency in Modern Organic Chemistry. Heteroatom
Manipulation; Pergamon Press, 1991.
3. For a leading review, see: Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.;
Tada, M. Chem. Rev. 2008, 108, 3795–3892; For recent examples on
organocatalytic hydroamination, see: (a) Schlummer, B.; Hartwig, J. F. Org.
Lett. 2002, 4, 1471–1474; (b) Ackermann, L.; Kaspar, L. T.; Althammer, A. Org.
Biomol. Chem. 2007, 5, 1975–1978; (c) Ackermann, L.; Althammer, A. Synlett
2008, 995–998.
A
sealed tube was charged with dry 1,4-dixoane (1 mL), aminoalkene
(1.00 mmol). To this tube were added ZnI2 (0.1 mmol, 10 mol %) and 8-
hydroxyquinoline (0.1 mmol, 10 mol %). The tube was then sealed and was
heated in an oil bath (110 °C). The reaction mixture was stirred at this
temperature for 36 h and was then cooled to room temperature. The mixture
was transferred to separating funnel with the aid of CH2Cl2 (20 mL) (Caution:
care must be taken when opening the sealed tube.). The reaction mixture was
washed with saturated Na2CO3 solution, dried (MgSO4), and concentrated to
give an oil which was purified by flash chromatography to give the
corresponding product.