Rhodium-catalyzed highly regioselective hydroaminomethylation of styrenes with tetraphosphorus ligands

Article abstract of DOI:10.1021/ol4012635

The highly linear-selective hydroaminomethylation of styrenes is very challenging. Herein, an efficient, highly chemoselective, and linear-selective hydroaminomethylation (l/b up to >99:1) of styrenes using Rh(nbd) ₂SbF₆ with a pyrrole-based 3,3′,5,5′- substituted tetraphosphorus ligand is documented. This is in sharp contrast to other available processes leading to branched amines and provides a novel atom economic approach to 3-arylpropylamines.

Full text of DOI:10.1021/ol4012635

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium-Catalyzed Highly Regioselective
Hydroaminomethylation of Styrenes with
Tetraphosphorus Ligands
Shengkun Li,†,‡ Kexuan Huang,‡ Jiwen Zhang,† Wenjun Wu,*,† and Xumu Zhang*,‡
College of Science, Northwest A&F University, Yangling, Shaanxi 712100, P. R. China,
and, Department of Chemistry and Chemical Biology, Rutgers, the State University of
New Jersey, Piscataway, New Jersey 08854, United States
wuwenjun@nwsuaf.edu.cn; xumu@rci.rutgers.edu
Received May 6, 2013
ABSTRACT
The highly linear-selective hydroaminomethylation of styrenes is very challenging. Herein, an efficient, highly chemoselective, and linear-
selective hydroaminomethylation (l/b up to >99:1) of styrenes using Rh(nbd)2SbF6 with a pyrrole-based 3,30,5,50-substituted tetraphosphorus
ligand is documented. This is in sharp contrast to other available processes leading to branched amines and provides a novel atom economic
approach to 3-arylpropylamines.
Amines are an important class of molecules in bulk as
well as fine chemicals. Many amines can serve as versatile
building blocks in the synthesis of pharmaceuticals, agro-
chemicals, natural products, and dyes.1 Various methods
for preparing amines have been developed, including
alkylation of ammonia and amines, reduction of imines,
and hydrocyanation of alkenes followed by reduction.
Making amines directly from inexpensive and readily
available alkenes is an attractive approach due to the atom
economy. While hydroamination of olefins2 and reductive
hydroamination of alkynes3 can lead to certain amines,
those methods still remain to be developed. Hydroamino-
methylation of alkenes, originally discovered by W. Reppe
at BASF,4 is a powerful method and holds great potential
for commercial applications.
The hydroaminomethylation consists of a tandem reac-
tion of hydroformylation of an alkene to aldehyde and
† Northwest A&F University.
‡ Rutgers, the State University of New Jersey.
(1) (a) March, J. Advanced Organic Chemistry: Reactions, Mechan-
isms, and Structure, 4th ed.; Wiley: New York, 1992 (b) McMurry, J. E.
Organic Chemistry, 3rd ed.; Wadsworth: Belmont, 1992 (c) Eller, K.;
€
Henkes, E.; Rossbacher, R.; Hoke, H. Ullmann’s Encyclopedia of Industrial
Chemistry; Wiley-VCH: Weinheim, 2005.
€
(2) (a) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (b)
Yamamoto, Y.; Radhakrishnan, U. Chem. Soc. Rev. 1999, 28, 199. (c)
^
€
Nobis, M.; Drieuen-Holscher, B. Angew. Chem. 2001, 113, 4105–4108.
Angew. Chem., Int. Ed. 2001, 40, 3983–3985. (d) Hartwig, J. F. Pure
Appl. Chem. 2004, 76, 507–516.
Figure 1. Regioselective hydroaminomethylation of styrenes.
(3) (a) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123,
2923. (b) Pohlki, F.; Doye, S. Angew. Chem., Int. Ed. 2001, 40, 2305. (c)
Tillack, A.; Castro, I. G.; Hartung, C. G.; Beller, M. Angew. Chem., Int.
Ed. 2002, 41, 2541. (d) Severin, R.; Doye, S. Chem. Soc. Rev. 2007, 36,
1407.
subsequent condensation with an amine to form enamine
or imine, followed by hydrogenation. It is an atom economic
and environment benign approach to amines.5 The challenge
r
10.1021/ol4012635
XXXX American Chemical Society

of this reaction is to combine the highest chemo- and regios-
electivity together to efficiently obtain the expected amine.
Linear-selective hydroaminomethylation of styrenes is very
challenging among the different alkenes due to the intrinsic
trend to form branched amines (the highest l/b = 82/186). To
the best of our knowledge, there is no general report on the
highly linearꢀselective hydroaminomethylation of styrenes to
produce 3-arylpropylamines. Herein, a rhodium catalytic
system is presented with a tetraphosphorus ligand, which
allows for an efficient and unprecedented linear-selective (l/b
up to >99:1) hydroaminomethylation of styrenes (Figure 1).
We envision that the highly linear-selective hydroami-
nomethylation of styrene and its derivatives is an elegant
and powerful tool to synthesize many small molecular
phamarceuticals,7 such as Sensipar, NPS 467, NPS 568,
and Strattera (Figure 2). Many catalytic systems have been
developed to achieve highly branched-selective hydroami-
nomethylation of styrenes (the ratio of b/l varies from
59:41 to 96:4), such as the zwitterionic Rh complex devel-
oped by Alper (b/l up to 15),8 Rh/P,N-ligands reported by
Kostas group (b/l up to 6.6),9 Rh/carbene catalyst docu-
mented by Beller (b/l = 79:21),10 and catalytic system of
Rh/bidentate phosphine ligands promoted by a Lewis acid
disclosed by Beller and Thiel (b/l up to 96:4).11 Without
any phosphine ligand, Rh can catalyze the hydroamino-
methylation of styrenes to offer branched products with
good selectivity (b/l up to 16).12 The linear selective
hydroaminomethylation of styrenes can be easily achieved
with R-substituted styrenes, with the l/b ratio up to >99:1,
in either intra-13 or intermolecular reactions.10,11a This
high regioselectivity can be attributed to the steric hin-
drance of the substituents. Selective hydroaminomethyla-
tion of styrene to linear amine (l/b = 82/18) in the presence
of Xantphos as a ligand was first reported by Beller’s
group.6 We believe that the development of new ligands
is the key to implementing the highly linear selective
hydroaminomethylation of styrenes.
Figure 2. Sensipar, NPS 467, NPS 568, and Strattera.
chelating Tetrabi ligands (Tetrabi = 2,20,6,60-tetrakis-
((diphenylphosphino)methyl)-1,10-biphenyl)14 and BTPP
ligands (BTPP = biphenyl-2,206,60-tetrakis(dipyrrolyl
phosphoramidite))15 were reported in hydroformylation.
Those two kinds of ligands have found many applications
in the highly regioselective hydroformylation of simple term-
inal alkenes and functionalized alkenes, as well as internal
alkenes. The good performance was envisioned to result from
the multiple chelating ability and improved local ligand
concentration. Among the studied alkenes, styrene has been
hydroformylated to the linear aldehyde with surprisingly high
linear selectivity (l/b = 22 for styrene, l/b up to >99:1 for its
derivatives).16 The high linear regioselectivity prompted us to
assess our ligands further in the hydroaminomethylation of
styrenes, since the selectivity in hydroaminomethylation is
provided by the initial hydroformylation step.
Figure 3. Structures of the tested ligands.
In our continuing efforts to develop novel catalysts for
organic synthesis, synthesis and application of novel multiple
Initially, combinations of [Rh(nbd)2BF4] with different
tetraphosphorus ligands (Figure 3) were tested in the
model reaction of styrene with piperidine. Some represen-
tative results are shown in Table 1, regarding the influence
of ligands and solvents. Except for L11 (Table 1, entry 11),
most Rh complexes give high conversions. It should be
noted that, compared with pyrrole-based tetraphosphorus
ligands (L1ꢀ9), Tetrabi ligands produced more ethyl-
benzene as a byproduct through direct hydrogenation
(Table 1, entries 10 and 11). However, the linear selectivity
of Tetrabi ligands is very poor with the branched amines as
major products. Although the amines selectivity is not
(4) (a) Reppe, W.; Vetter, H. Liebigs Ann. Chem. 1953, 582, 133. (b)
Reppe, W. Experientia 1949, 5, 93. (c) Crozet, D.; Urrutigoity, M.;
Kalck, P. ChemCatChem 2011, 3, 1102.
(5) (a) Seayad, A.; Ahmed, M.; Klein, H.; Jackstell, R.; Gross, T.;
Beller, M. Science 2002, 297, 1676. (b) Hartwig, J. F. Science 2002, 297,
1653. (c) Crozet, D.; Gual, A.; MaKay, D.; Dinoi, C.; Godard, C.;
Urrutigoity, M.; Daran, J.; Maron, L.; Claver, C.; Kalck, P. Chem.;
Eur. J. 2012, 18, 7128.
(6) Ahmed, M.; Seayad, A. M.; Jackstell, R.; Beller, M. J. Am. Chem.
Soc. 2003, 125, 10311.
(7) (a) McGrath, N.; Brichacek, M.; Njardarson, J. J. Chem. Educ.
2010, 87, 1348. (b) Nemeth, E. F.; Steffey, M. E.; Hammerland, L. G.;
Hung, B. C. P.; Wagenen, B. C. V.; DelMar, E. G.; Balandrin, M. F.
Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 4040.
(8) Lin, Y.-S.; Ali, B. E.; Alper, H. Tetrahedron Lett. 2001, 42, 2423.
(9) (a) Kostas, I. D. J. Chem. Res. (S) 1999, 630. (b) Kostas, I. D.;
Screttas, C. G. J. Organomet. Chem. 1999, 585, 1.
(10) Seayad, A. M.; Selvakumar, K.; Ahmed, M.; Beller, M. Tetra-
hedron Lett. 2003, 44, 1679.
(11) (a) Routaboul, L.; Buch, C.; Klein, H.; Jackstell, R.; Beller, M.
Tetrahedron Lett. 2005, 46, 7401. (b) Sun, Y.; Ahmed, M.; Jackstell, R.;
Beller, M.; Thiel, W. R. Organometallics 2004, 23, 5260.
(12) Rische, T.; Eilbracht, P. Synthesis 1997, 11, 1331.
(13) (a) Vieira, T. O.; Alper, H. Chem. Commun. 2007, 2710. (b)
Vieira, T. O.; Alper, H. Org. Lett. 2008, 10, 485. (c) Okuro, K.; Alper, H.
Tetrahedron Lett. 2010, 51, 4959.
(14) (a) Yan, Y.; Zhang, X.; Zhang, X. Adv. Synth. Catal. 2007, 349,
1582. (b) Yu, S.; Zhang, X.; Yan, Y.; Cai, C.; Da, L.; Zhang, X. Chem.;
Eur. J. 2010, 16, 4938. (c) Cai, C.; Yu, S.; Liu, G.; Zhang, X.; Zhang, X.
Adv. Synth. Catal. 2011, 353, 2665.
(15) (a) Yan, Y.; Zhang, X.; Zhang, X. J. Am. Chem. Soc. 2006, 128,
16058. (b) Yu, S.; Chie, Y.; Guan, Z.; Zhang, X. Org. Lett. 2008, 10,
3469. (c) Yu, S.; Chie, Y.; Zhang, X. Adv. Synth. Catal. 2009, 351, 537.
(d) Cai, C.; Yu, S.; Cao, B.; Zhang, X. Chem.;Eur. J. 2012, 18, 9992.
(16) Yu, S.; Chie, Y.; Guan, Z.; Zou, Y.; Li, W.; Zhang, X. Org. Lett.
2009, 11, 241.
B
Org. Lett., Vol. XX, No. XX, XXXX

satisfactory, the linear selectivity is promising with the
pyrrole-based ligands, with which the production of ethyl-
benzene is also surpressed (Table 1, entries 1ꢀ9).
In the survey of solvent effects on the regioselectivity,
aromatic solvent xylene was tested first, in which both the
yield and linear selectivity were brought down to some
extent, although full conversion was achieved (Table 1,
entry 12). The reaction proceeds smoothly in more polar
solvents (Table 1, entries 13ꢀ15), and the yields of amines
are excellent; however, the regioselectivity of this reaction
was converted to a branched amine. The linear selectivity
increased following the trend MeOH < EtOH < iPrOH.
It motivated us to test alcohol with more bulky groups and
higher pKa values. Though hydrogenation of the in situ
produced enamine is the rate-determining step,4c the re-
gioselectivity improved dramatically in tert-amyl alcohol
with l/b = 9.5.
The chemo- and regioselectivity of hydroaminomethy-
lation is significantly influenced by ligand structure.
Compared with ligand L1, the attachment of electron-
donating methyl and ethyl groups at the 3,30,5,50-posi-
tions of the biphenyl backbone results in higher amines
selectivity with yields of 56.3% and 55.2% and linear
selectivity with an l/b ratio of 4.6 and 4.1, respectively
(Table 1, entries 3 and 4). The reverse effect was detected
with an electron-withdrawing group (Table 1, entry 2).
The linear selectivity is somewhat improved when re-
placed by a phenyl group (Table 1, entry 5). The effect of
the substituents of the phenyl moiety on selectivity is also
remarkable (Table 1, entries 5ꢀ9). Among the tested
ligands, L3 appeared to be the optimal ligand giving good
regioselectivity (l/b = 4.52), which is a little different
from our previous report on the corresponding hydro-
formylation where the L6 is the best ligand.16 It is
expected that the presence of amines will influence the
l/b selectivity of the initial hydroformylation.
To improve the l/b ratio, other Rh sources with different
counterions were screened with L3 in tert-amyl alcohol; all
the reactions proceeded with almost full conversion, and
the formation of N-formylpiperidine is also suppressed.
Interestingly, a positive impact on regioselectivity was
ꢀ
observed when the BF4 counterion was replaced by
SbF6ꢀ (Table 2, entry 5, l/b = 15.5). Further optimizations
demonstrated that increasing the partial pressure of CO
and doubling the reaction time raised the proportion of
amines up to 92.4% and suppressed the formation of
enamine thoroughly when one more equivalent of styrene
was added (Table 2, entry 10). The ligand/Rh ratio can be
reduced from 4 to 1, without an obvious decline in
conversion and the yield of amines (Table 2, entry 11).
The consumption of ligands decreased compared with the
available bisphosphorus and monophosphorus ligands in
the hydroaminomethylation. This can be explained by the
enhanced chelating ability of the ligand through multiple
Table 1. Hydroaminomethylation of Styrene with Piperidine
with Different Ligands and Solventsa
product distribution (%)b
conv
entry
L
(%)
6
7
8
3þ4
3c
l/bd
Table 2. Hydroaminomethylation of Styrene with Piperidine
with Different Metal Sources and Pressuresa
1
L1
L2
L3
L4
L5
L6
L7
L8
L9
L10
L11
L3
L3
L3
L3
L3
L3
97
4.8
7.8
1.5
3.1
3.9
3.9
5.1
6.1
8.5
5.1
1.7
5.8
0.7
0.2
0.5
1.9
0.4
3.1
5.6
1.9
1.9
16.0
13.5
24.1
9.4
10.7
4.5
6.7
2.2
2.3
1.4
1.2
0.3
2.4
59.9
56.1
40.2
39.8
41.6
42.7
32.7
57.7
57.4
52.3
21.2
41.4
0
32.2
30.4
56.3
55.2
38.1
39.8
38.0
26.8
23.4
34.8
66.3
50.6
97
60.0
58.3
82.1
80.4
62.9
64.3
54.5
50.0
47.4
47.4
23.1
77.8
11.5
14.5
16.0
90.5
52.4
1.5
1.4
4.6
4.1
1.7
1.8
1.2
1.0
0.9
0.9
0.3
3.5
0.13
0.17
0.19
9.5
1.1
2
92
distribution(%)b
3
100
100
100
100
98
4
CO/H2
entry
L/Rh
(bar)
8
3þ4
3c
l/bd
5
6
1
4
4
4
4
4
4
4
4
4
2
1
2
30/10
30/10
30/10
30/10
30/10
20/10
20/20
10/30
40/10
40/10
40/10
40/10
33.6
44.8
32.9
34.4
50.3
53.7
44.2
42.1
ꢀ
62.4
48.9
61.1
60.3
44.2
42.3
46.3
50.6
92.2
92.4
91.1
54.4
87.2
91.1
91.9
92.8
93.9
93.4
93.2
91.8
93.5
93.8
92.8
91.4
6.8
7
2
10.2
11.4
12.8
15.5
14.1
13.6
11.2
14.4
15.1
12.9
10.6
8
100
100
98
3
9
4
10
11
12
13
14
15
16
17
5e
6e
7e
8e
9f
82
100
100
100
100
98
0
98.4
98.3
46.5
79.2
0
10f
11f
12f,g
ꢀ
51.3
18.0
7.1
99
45.4
a Unless otherwise mentioned, all reactions were carried out with a
[Rh(nbd)2]BF4/ligand/substrate ratio of 1:4:500, under syngas of CO/H2
(30 bar/10 bar) at 125 °C for 8 h. Ethylbenzene accounts for the product
balance. Solvents used: entries 1ꢀ11 (toluene), 12 (xylene), 13 (methanol),
14 (ethanol), 15 (isopropanol), 16 (tert-amylalcohol), 17 (tert-amyl alcohol/
methanol = 1:1). b Determined by GC analysis using bis(methoxyethyl) ether
as an internal standard. c Percentage of linear amine in all amines. d The linear/
branched ratio was determined on the basis of GC analysis and repeated three
times; error is estimated to be <0.2. nbd = 2,5-norbornadiene.
a Rh/substrate = 1:500, styrene/piperidine = 1:1, tert-amyl alcohol,
125 °C, 8 h. Full conversion was achieved based on piperidine. Ethyl-
benzene and aldehydes account for the product balance. Entry 1
([Rh(cod)Cl]2), 2 (Rh(cod)2BF4), 3 (Rh(acac)(CO)2), 4(Rh(acac)(C2H4)2),
entries 5ꢀ12 (Rh(nbd)2SbF6). b See Table 1 footnote b. c See Table 1
footnote c. d See Table 1 footnote d. e Trace of N-formylpiperidine was
detected. f Styrene/piperidine = 2, 16 h. g Rh/substrate = 1:1000. cod = 1,
5-cyclooctadiene, acac = acetyl acetonate, nbd = 2,5-norbornadiene.
Org. Lett., Vol. XX, No. XX, XXXX
C

of pyrrolidine (yield of 80%, l/b = 85.3/14.7, 3b), in which
trace aldol product was also detected. The hydroamino-
methylation of styrene with morpholine proceeded with
excellent regioselectivity (l/b = 98.6/1.4) to give 94% of
the desired amines (3c). The primary amines were also
investigated in this reaction (3i and 3j). Although the yield
and selectivity were not satisfactory (bishydroaminomethyl-
ation and carbonylation of amines were detected), it demon-
strated the feasibility of using primary amines. Ammonia was
also tested, but no promising result was achieved. Hydro-
aminomethylation of para-substituted styrenes with piperi-
dine gave higher linear selectivities, regardless of the electronic
effects of the substituents (3k and 3l). Both the high yield of
amines and good linear selectivity were obtained from the
reaction of substituted styrenes with morpholine (3mꢀ3s),
among which p-chloro, p-fluoro, and m-methyl styrenes furn-
ished excellent linear selectivity with l/b up to 99/1 (3pꢀ3r).
In conclusion, a highly chemo- and regioselective hydro-
aminomethylation of styrene and its derivatives to linear
amines using Rh(nbd)2SbF6 with pyrrole-based 3,30,5,50-
substituted tetraphosphorus ligands was disclosed. Those
ligands are highly stable at rt and can be easily handled in
air. The highest linear selectivity was reported for the
hydroaminomethylation of styrene and its derivatives.
Based on ealier reports on the effect of bite angle and the
electronic property of the ligand on the regioselectivity of
hydroformylation,17 the performance of the present sys-
tem can be accounted for by the electron-withdrawing
property of the pyrrole moiety and the steric interactions
between the more bulky tetraphosphorus ligands and the
substrates. This creates an obstacle for the formation of an
η3-Rh-complex that favors the branched product in the
initial step. This protocol is in sharp contrast to other
available processes leading to branched amines and pro-
vides a novel atom economic approach to 3-arylpropyla-
mines. Further studies are in progress with the aim of
exploring the mechanism and optimizing the ligands to
develop more efficient, selective catalytic systems.
Scheme 1. Hydroaminomethylation of Styrenes and Aminesa
a Conditions: Rh(nbd)2SbF6/L3/styrenes/amine = 0.2:0.4:200:100,
CO/H2 (40 bar/10 bar), 125 °C,16 h. Full conversion was achieved based
on the amines. Yields (data in parentheses) of the total amines were
determined by GC analysis using bis(methoxyethyl) ether as an internal
standard. l/b = linear amine (%)/branched amine (%), determined
on the basis of GC analysis and repeated three times; error is estimated to
be <0.2.
chelating modes.15,16 Both the conversion and amines selec-
tivity decreased when the catalyst loading was <0.2%
(Table 2, entry 12). The optimized conditions were set
as styrene/amine = 2:1, 0.2% Rh (L/Rh = 2), CO/H2
(40 bar/10 bar), at 125 °C for 16 h.
The compatibility of our protocol in the hydroamino-
methylation of styrenes with various amines was tested. As
shown in Scheme 1, styrene was hydroaminomethylated
smoothly with a series of aliphatic secondary amines in full
conversion, including both cyclic amines (3aꢀ3d) and chain
amines (3eꢀ3h). Compared with cyclic amines without a
heteroatom, the chain amines produced better regioselec-
tivity with l/b > 95:5, and the linear selectivity followed the
trend Ethyl < n-Propyl < n-Butyl (3e, 3g, 3h). Compared
with piperidine (3a), azepane afforded a higher yield of
amine (95%, 3d), although the linear selectivity is some-
what decreased. The erosion of both total amines and
regioselectivity was detected in the hydroaminomethylation
Acknowledgment. This research was supported by the
National Institutes of Health (GM58832), China Scholar-
ship Council, and The National Key S&T Research Foun-
dation of China (2010CB126105). Scholarship Award for
Excellent Doctoral Student granted by Ministry of Educa-
tion for S.L.
Supporting Information Available. Experimental pro-
cedures and analytic data (NMR, GC traces). This ma-
terial is available free of charge via the Internet at http://
pubs.acs.org.
(17) (a) Klein, H.; Jackstell, R.; Wiese, K.; Borgmann, C.; Beller, M.
Angew. Chem., Int. Ed. 2001, 40, 3408. (b) Veen, L. A.; Boele, M. D. K.;
Bregman, F. R.; Kamer, P. C. J.; Van Leeuwen, P.W. N. M.; Goubitz,
K.; Fraanje, J.; Schenk, H.; Bo, C. J. Am. Chem. Soc. 1998, 120, 11616.
(c) Peng, W.; Bryant, D. R. (UCC) PCT Int. Patent WO/2003/078444,
2003.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX