Synthesis of biologically active amines via rhodium-bisphosphite-catalyzed hydroaminomethylation

Article abstract of DOI:10.1021/ol050848y

(Chemical Equation Presented) We report the use of a highly regioselective rhodium-bisphosphite catalyst for olefin hydroaminomethylation. This catalyst system was successfully applied in the synthesis of two biologically active tertiary amines, ibutilide and aripiprazole.

Full text of DOI:10.1021/ol050848y

ORGANIC
LETTERS
2005
Vol. 7, No. 22
4795-4798
Synthesis of Biologically Active Amines
via Rhodium Bisphosphite-Catalyzed
−
Hydroaminomethylation
John R. Briggs, Jerzy Klosin, and Gregory T. Whiteker*,†
Chemical Sciences, The Dow Chemical Company, 1776 Building,
Midland, Michigan 48674
whitekgt2@dow.com
Received April 18, 2005 (Revised Manuscript Received July 8, 2005)
ABSTRACT
We report the use of a highly regioselective rhodium−bisphosphite catalyst for olefin hydroaminomethylation. This catalyst system was
successfully applied in the synthesis of two biologically active tertiary amines, ibutilide and aripiprazole.
Rhodium-catalyzed olefin hydroformylation is an industrially
practiced transformation for the synthesis of aldehydes and
their derivatives.1 A number of tandem reactions, which
employ hydroformylation, have been developed that further
extend the synthetic utility of the hydroformylation reaction.2
In particular, hydroaminomethylation (tandem olefin hydro-
formylation followed by reductive amination) is an attractive
transformation that allows for the synthesis of secondary and
tertiary amines from readily available olefins (Scheme 1).2,3
phosphite ligands are unsuitable for this reaction and lead
to low yields of amine products.4,5 The inability of rhodium-
phosphite catalysts to promote hydroaminomethylation was
attributed to hydrolytic instability of the ligand under the
reaction conditions. However, a few reports describing
successful application of bisphosphite ligands in hydroami-
nomethylation have also appeared.6 Bisphosphite ligands
such as 1a form highly regio-7 and chemoselective8 rhodium-
based hydroformylation catalysts. Additionally, these bis-
phosphites are very active and lead to hydroformylation rates
which are significantly higher than those observed with
Scheme 1. Hydroaminomethylation Reaction
(2) Eilbracht, P.; Ba¨rfacker, L.; Buss, C.; Hollmann, C.; Kitsos-Rzychon,
B. E.; Kranemann, C. L.; Rishe, T.; Roggenbuck, R.; Schmidt, A. Chem.
ReV. 1999, 99, 3329-3365.
(3) (a) Rische, T.; Eilbracht, P. Tetrahedron 1999, 55, 1915-1920. (b)
Rische, T.; Eilbracht, Muller, K.-S. Tetrahedron 1999, 55, 9801-9816.
(4) (a) Seayad, A.; Ahmed, M.; Klein, H.; Jackstell, R.; Gross; T.; Beller,
M. Science 2002, 297, 1676-1678. (b) Ahmed, M.; Seayad, A. M.; Jackstell,
R.; Beller, M. J. Am. Chem. Soc. 2003, 125, 10311-19318.
(5) Angelovski, G.; Eilbracht, P. Tetrahedron 2003, 59, 8265-8274.
(6) Only intramolecular examples of hydroaminomethylation with rhod-
ium-bisphosphite catalysts have been reported: (a) Bergmann, D. J.; Campi,
E. M.; Jackson, W. R.; Patti, A. F.; Saylik, D. Tetrahedron Lett. 1999, 40,
5597-5600. (b) Ojima, I.; Tzamarioudaki, M.; Eguchi, M. J. Org. Chem.
1995, 60, 7078-7079.
Recent applications of rhodium-catalyzed hydroamino-
methylation have predominantly employed phosphine
ligands.2-4 Several of these studies have concluded that
† Current address: Dow Agrosciences, 9330 Zionsville Rd, Indianapolis,
IN 46268
(1) Rhodium Catalyzed Hydroformylation; Claver, C., van Leeuwen, P.
W. N. M., Eds.; Kluwer Academic Publishers: Dordrecht, 2000.
(7) Billig, E.; Abatjoglou, A. G.; Bryant, D. R. US Pat. 4,769,498, 1988.
(8) Cuny, G. D.; Buchwald, S. L. J. Am. Chem. Soc. 1993, 115, 2066-
2068.
10.1021/ol050848y CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/27/2005

bisphosphine ligands. These attributes make pursuit of
hydroaminomethylation reactions with bisphosphite ligands
attractive. Herein, we report our initial results on the nature
of rhodium-phosphite catalyst systems along with their
application in the synthesis of two pharmacologically active
amines using olefin hydroaminomethylation.
phite 1b led to clean formation of amine products with
marginal regioselectivity for the linear isomer (l/b ) 1.5:1).
Neither aldehyde nor enamine intermediates were detectable.
The regioselectivity of the amine products was identical to
that of the aldehydes produced by 1-pentene hydroformy-
lation in the absence of piperidine.
To evaluate the utility of rhodium-phosphite catalysts in
hydroaminomethylation reactions, we first attempted the
reaction of 1-pentene and piperidine in the presence of 1:2
CO/H2 (Table 1). Reactions were performed in THF using
Hydroaminomethylation of 1-pentene with piperidine using
bisphosphite 1a gave amine products, but the selectivity of
this reaction was initially irreproducible. A detailed study
of the effect of reaction conditions was performed. The rate
of amine formation was reduced at lower H2/CO pressures
where hydroformylation readily occurs. These studies also
revealed a strong effect of 1a/Rh ratio on the selectivity of
this reaction. When the reaction was performed using
equimolar amounts of 1a and Rh(CO)2(acac), N-hexylpip-
eridine was formed with high selectivity toward the linear
isomer (l/b ) 40:1), consistent with the high linear regiose-
lectivity observed for this catalyst in hydroformylation.
Enamine and aldol impurities were observable by GC, and
the yield of this reaction was lower than that obtained using
the monodentate phosphite. As the ratio of 1a to rhodium
was decreased below the stoichiometric level, the yield of
amine increased but was accompanied by a concurrent
decrease in the linear:branched ratio. These results suggest
that enamine hydrogenation using the catalyst system formed
by reaction of 1a with Rh(CO)2(acac) occurs predominantly
by a catalyst which does not contain phosphite ligand. At
sub-stoichiometric ratios of 1a relative to rhodium, enamine
hydrogenation becomes faster, but hydroformylation by a
phosphite-free species derived from excess Rh(CO)2(acac)
reduces the regioselectivity of the reaction.
Table 1. Hydroaminomethylation of 1-Pentene with Piperidinea
ligand
L/Rh
% conv
% amine
l/bb
1a
1a
1a
1b
1.0
0.9
0.8
2.4
96.6
97.0
97.3
100
8
92
100
100
40.0
12.1
6.4
1.5
a Conditions: 90 °C, 400 psi 1:2 CO/H2, 0.2 mol % Rh, 18 h, decane
internal standard. bl/b ) linear/branched ratio of amines (1-hexylpiperidine/
1-(2-methylpentyl)piperidine).
0.2 mol % Rh(CO)2(acac) and either bisphosphite 1a or
phosphite 1b (Figure 1).9 GC and NMR analysis of reaction
Rhodium complexes of bulky monodentate phosphite
ligands such as 1b are in equilibrium with unligated Rh-
carbonyl complexes and require very large concentrations
of phosphite to bind all available Rh centers.10 Under the
conditions used in our hydroaminomethylation reactions with
1b, a sufficient concentration of unligated rhodium is present
to efficiently hydrogenate the enamine intermediate. Garland
has reported that Rh(CO)4H is a highly active, unselective
hydroformylation catalyst which is also capable of hydro-
genating olefins.11 This species is presumably responsible
Figure 1. Phosphite ligands used in this study.
mixtures revealed that these catalysts are very effective in
promoting hydroaminomethylation. The monodentate phos-
Scheme 2. Synthesis of Olefin Precursor to Ibutilide
4796
Org. Lett., Vol. 7, No. 22, 2005

Scheme 3. Synthesis of Ibutilide and Aripiprazole via Hydroaminomethylation
for the enamine hydrogenation observed with phosphite
ligands 1a and 1b.
regioselectivity in favor of the desired linear isomer (Scheme
3).18 A slight excess of bisphosphite 1a was utilized in this
reaction to maximize the regioselectivity at the expense of
product yield.
Given the successful use of rhodium-phosphite catalysts,
we next applied hydroaminomethylation to the synthesis of
the anti-arrhythmia drug ibutilide.12 The required allylic
alcohol 3 was synthesized from N-(4-formylphenyl)-meth-
anesulfonamide 2, which was prepared via two different
routes (Scheme 2).13 The 1,3-dioxolane of 4-nitrobenzalde-
hyde was reduced with hydrogen using PtO2 catalyst.14 It
was found that the presence of MgSO4 was required to
remove water formed during reduction of the nitro functional
group. Reductions performed without efficient removal of
water led to formation of a bright orange insoluble material,
presumably resulting from condensation polymerization of
4-aminobenzaldehyde formed by hydrolysis of the acetal
protecting group. Introduction of the sulfonamide group
followed by deprotection of the acetal gave N-(4-formylphe-
nyl)-methanesulfonamide, 2. An alternate one-step synthesis
of 2 was also developed and employed Pd/Xantphos-
catalyzedcouplingof4-bromobenzaldehydewithMeSO2NH2.15
Addition of 2 equivalents16 of vinyl Grignard reagent led to
the allylic alcohol precursor (3) of Ibutilide. The amine
coupling partner, N-ethyl-1-heptanamine, was synthesized by
LiAlH4 reduction of n-heptylacetamide.17 Reaction of 3 with
N-ethylheptylamine using 1 mol% Rh(CO)2(acac) and bis-
phosphite 1a (Rh:1a ) 1:1.1) in THF at 75 °C under 400
psi 1:1 CO/H2 gave Ibutilide in 55% yield with 48:1
1
The H NMR spectrum of Ibutilide prepared via hy-
droaminomethylation (Scheme 3) was identical to that
previously reported.19 Notably, protection of the alcohol
moiety in 3 was found to be unnecessary. Although the
intermediate hydroxy aldehyde produced from hydroformy-
lation of 3 could cyclize to form a lactol,20 this potential
side reaction did not impact the reductive amination step of
the hydroaminomethylation reaction.
The second target studied for application of hydroami-
nomethylation was the antidepressant aripiprazole.21 The
amine and olefin coupling partners required for synthesis of
aripiprazole were prepared following published procedures.
The olefinic substrate, 7-(allyloxy)-3,4-dihydro-2(1H)-quino-
line, 4, was synthesized by reaction of 3-aminophenol with
3-chloropropionyl chloride followed by O-allylation with
allyl bromide.22 The arylpiperazine 5 was prepared by
palladium-catalyzed amination using excess piperazine to
minimize formation of diarylated product.23 Hydroamino-
methylation of allyl ether 4 with 5 led to aripiprazole in 67%
yield with high regioselectivity (l/b ) 37:1) using a 1:1.3
ratio of Rh(CO)2(acac) and bisphosphite 1a (Scheme 3). The
1H NMR spectrum of the product, after acidic workup, was
identical to NMR data of aripiprazole reported by Oshiro et
(9) van Leeuwen, P. W. N. M.; Roobeek, C. F. J. Organomet. Chem.
1983, 258, 343-360.
(17) Fitch, W. L.; Baer, T. A.; Chen, W.; Holden, F.; Holmes, C. P.;
Maclean, D.; Shah, N.; Sullivan, E.; Tang, M.; Waybourn, P.; Fischer, S.
M.; Miller, C. A.; Snyder, L. R. J. Comb. Chem. 1999, 1, 188-194.
(18) Identical selectivities were observed using 2:1 and 1:1 H2/CO at
400 psi.
(19) (a) Hester, J. B.; Gibson, J. K.; Cimini, M. G.; Emmert, D. E.;
Locker, P. K.; Perricone, S. C.; Skaletsky, L. L.; Sykes, J. K.; West, B. E.
J. Med. Chem. 1991, 34, 308-315. (b) Perricone, S. C.; Chidester, C. G.;
Hester, J. B. Tetrahedron: Asymmetry 1996, 7, 677-690.
(20) Trzeciak, A. M.; Wolszczak, E.; Ziolkowski, J. J. New J. Chem.
1996, 20, 365-370.
(21) Inoue A.; Miki S.; Seto M.; Kikuchi T.; Morita S.; Ueda H.; Misu
Y.; Nakata Y. Eur. J. Pharm. 1997, 321, 105-111.
(22) Oshiro, Y.; Tanaka, T.; Nishi, T.; Kuwahara, K.; Fujisawa, S.;
Takasu, K.; Wada, Y. WO 9602508(A1), 1996.
(23) Morita, S.; Kitano, K.; Matsubara, J.; Ohtani, T.; Kawano, Y.;
Otsubo, K.; Uchida, M. Tetrahedron 1998, 54, 4811-4818.
(10) Jongsma, T.; Challa, G.; van Leeuwen, P. W. N. M. J. Organomet.
Chem. 1991, 421, 121-128.
(11) (a) Feng, J.; Garland, M. Organometallics 1999, 18, 417-427. (b)
Reference 1, Chapter 2.
(12) Lee, K. S. J. Pharm. Exp. Ther. 1992, 262, 99-108.
(13) New compounds were characterized by 1H and 13C{1H} NMR,
HRMS and combustion analysis. See Supporting Information.
(14) (a) Walton, R.; Lahti, P. M. Synth. Commun. 1998, 28, 1087-1092.
(b) Folkes, A.; Roe, M. B.; Sohal, S.; Golec, J.; Faint, R.; Brooks, T.;
Charlton, P. Bioorg. Med. Chem. Lett. 2001, 11, 2589-2592.
(15) (a) Steinhuebel, D.; Palucki, M.; Askin, D.; Dolling, U. Tetrahedron
Lett. 2004, 45, 3305-3307. (b) Yin, J.; Buchwald, S. L. Org. Lett. 2000,
2, 1101-1104.
(16) The presence of the acidic sulfonamide group necessitated the use
of an additional equivalent of Grignard reagent.
Org. Lett., Vol. 7, No. 22, 2005
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al.24 Notably, the rhodium-bisphosphite catalyst was tolerant
of aryl chloride functionality and exhibited chemoselective
reaction of the arylpiperazine N-H bond25 in the presence
of the secondary amide moiety.
The bisphosphite 1a leads to highly regioselective rhodium-
catalyzed intermolecular hydroaminomethylation. Catalyst
studies indicate that hydrogenation of the intermediate
enamine occurs by a rhodium species which is not coordi-
nated by phosphite ligands. Hydroaminomethylation using
ligand 1a requires significantly lower reaction temperature
(70-90 °C) than bisphosphine ligands4b (>110 °C). Ligand
1a leads to high linear regioselectivity and tolerates a variety
of functional groups in both the amine and olefin, making
this a useful catalyst for synthesis of complex amines via
intermolecular hydroaminomethylation reaction. Experiments
aimed at further optimization of rhodium-bisphosphite
catalysts for hydroaminomethylation reactions are underway.
The use of alternative heterogeneous enamine hydrogenation
catalysts with these highly selective homogeneous hydro-
formylation catalysts is currently under investigation.
Acknowledgment. Cynthia Rand of Dowpharma is
gratefully acknowledged for her encouragement and support
of this work. Tia Jackson is thanked for performing
preliminary experiments.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) Oshiro, Y.; Sato, S.; Kurahashi, N.; Tanaka, T.; Kikuchi, T.; Tottori,
K.; Uwahodo, Y.; Nishi, T., J. Med. Chem. 1998, 41, 658-667.
(25) It is known that amides can undergo analogous reactions with olefins.
(a) Ojima, I.; Korda, A.; Shay, W. R. J. Org. Chem. 1991, 56, 2024-2030.
(b) Ojima, I.; Korda, A. Tetrahedron Lett. 1989, 30, 6283-6286.
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