Phosphoric acid diesters as efficient catalysts for hydroaminations of nonactivated alkenes and an application to asymmetric hydroaminations

Article abstract of DOI:10.1055/s-2008-1072505

Catalytic amounts of phosphoric acid diesters enabled highly efficient intramolecular hydroaminations of nonactivated alkenes. With an enantiomerically enriched Br?nsted acid catalyst an unprecedented metal-free asymmetric hydroamination of a non-activate

Full text of DOI:10.1055/s-2008-1072505

LETTER
995
Phosphoric Acid Diesters as Efficient Catalysts for Hydroaminations of
Nonactivated Alkenes and an Application to Asymmetric Hydroaminations
Brønsted
Acid
C
u
atalyzed H
y
t
droam
z
inations of
Nonac
A
tivated Alkenes ckermann,* Andreas Althammer
Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstr. 2, 37077 Göttingen, Germany
Fax +49(551)396777; E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Received 24 December 2007
R
Abstract: Catalytic amounts of phosphoric acid diesters enabled
highly efficient intramolecular hydroaminations of nonactivated
alkenes. With an enantiomerically enriched Brønsted acid catalyst
an unprecedented metal-free asymmetric hydroamination of a non-
activated alkene was accomplished.
O
O
cat.
P
OH
O
R
Bn
NH
Key words: alkenes, amines, asymmetric catalysis, Brønsted acids,
phosphates
Bn
3
Ph
Ph
Ph
Ph
N
solvent
Me
1a
2a
Intramolecular additions of amines to unsaturated C–C
multiple bonds are among the most direct strategies for
the synthesis of N-heterocycles, which are important sub-
structures of numerous biologically active compounds. A
variety of methodologies for intramolecular hydroamina-
tions of alkynes and allenes were reported.1–4 On the con-
trary, cycloisomerization of more easily accessible
aminoalkenes, particularly displaying electronically non-
activated alkenyl moieties, proved significantly more
challenging.1–4 Notably, asymmetric hydroaminations of
nonactivated5 alkenes relied thus far entirely on metal-
based catalysts, in expressis verbis, main-group-metal
bases or transition-metal complexes.6–8
Scheme 1 Phosphoric acid diesters 3 as catalysts for intramolecular
hydroaminations of unactivated alkene 1a
RO
O
cat.
P
Bn
NH
RO
OH
Bn
4
Ph
Ph
Ph
Ph
N
solvent
Me
1a
2a
Scheme 2 Catalytic hydroamination with acyclic phosphoric acid
diesters 4
Recently, we9 found that intramolecular hydroaminations
of nonactivated alkenes with basic amines10,11 can be ac-
complished with catalytic amounts of Brønsted acids.
During these studies we focused on the use of simple, eco-
nomically attractive NH4O2CCF3 as catalyst.12 We also
found that cyclization of aminoalkene 1a was viable with
substituted diesters 4a and 4b provided unsatisfactory
yields of desired product 2a (entries 2, and 3), more effi-
cient catalysis was accomplished with aryl-substituted de-
rivative 4c (entry 4). A further increase in catalytic
performance was accomplished with 1,1,2,2-tetrachloro-
ethane as solvent (entry 6),15 which allowed for a signifi-
cant reduction in catalyst loading (entry 7).
substoichiometric
amounts
of
BINOLP(O)OH
(Scheme 1, 3a, R = H). However, despite a relatively high
catalyst loading (20 mol%) of 3a, only 33% of pyrrolidine
2a could be obtained even at 130 °C.12
As aromatic phosphoric acid diester 4c proved most effi-
cient, we extended our studies to cyclic aromatic phos-
phoric acid diesters
3
(Table 2). Compared to
Given the recently proved practical relevance of phospho-
ric acid diesters as Brønsted acids for synthetic organic
chemistry,13,14 we set out to identify a more effective
phosphoric acid diester as organocatalyst for hydroamina-
tions of nonactivated alkenes (Scheme 1), on which we re-
port herein. Importantly, our studies include, to the best of
our knowledge, a first asymmetric hydroamination of a
nonactivated alkene with a metal-free catalyst.
BINOLP(O)OH (3a, entry 1), 3,3¢-disubstituted deriva-
tives 3b–e14 displayed significantly improved catalytic ac-
tivities (entries 2–10), with sterically hindered acid 3e
being most effective (entries 8–10). Further, 1,1,2,2-tetra-
chloroethane as solvent was found superior (entries 5–7,
9, and 10). Importantly, these optimized reaction condi-
tions allowed for cyclization of substrate 1a at lower reac-
tion temperature with reduced catalyst loading (entry 10).
At the outset of our studies, we tested representative acy-
clic phosphoric acid diesters 4 in the intramolecular hy-
droamination reaction of 1a (Table 1). While alkyl-
With highly active phosphoric acid diester 3e in hand, we
probed its scope in intramolecular hydroaminations of
representative nonactivated alkenes 1 (Table 3).16 The
mild reaction conditions allowed for the use of substrates
bearing various valuable functional groups, such as an
ether- (entry 2), a nitro- (entry 3), an ester- (entry 4), or a
SYNLETT 2008, No. 7, pp 0995–0998
x
x.
x
x.
2
0
0
8
Advanced online publication: 17.03.2008
DOI: 10.1055/s-2008-1072505; Art ID: G41907ST
© Georg Thieme Verlag Stuttgart · New York

996
L. Ackermann, A. Althammer
LETTER
Table 1 Evaluation of Acyclic Phosphoric Acid Diesters in the
Hydroamination of Substrate 1a (Scheme 2)a
SiPh3
O
O
P
Entry Catalyst
(mol%)
Solvent
Yield
(%)
OH
O
R2
NH
1
2
–
1,4-Dioxane
1,4-Dioxane
–
SiPh3
3e (10 mol%)
R2
N
R1
R1
R1
R1
(BuO)2P(O)OH
(4a) (20.0)
27
Cl2HCCHCl2, 130 °C, 23 h
Me
3
4
(BnO)2P(O)OH
(4b) (20.0)
1,4-Dioxane
1,4-Dioxane
26
46
1
2
Scheme 3 Hydroamination of unactivated alkenes 1 catalyzed by
acid 3e
(PhO)2P(O)OH
(4c) (20.0)
Bn
5
6
7
4c (20.0)
4c (20.0)
4c (10.0)
MeCN
34
88
73
Bn
NH
(R)-3b (20 mol%)
Ph
Ph
Ph
Ph
N
1,1,2,2-Tetrachloroethane
1,1,2,2-Tetrachloroethane
1,4-dioxane, 130 °C, 20 h
Me
1a
(S)-2a
a Reaction conditions: 1a (0.5 mmol), 4 (10–20 mol%), solvent (1.0
mL), 20 h, 130 °C; yield of isolated product.
17% ee
Scheme 4 Chiral phosphoric acid diester (R)-3b as catalyst for
asymmetric hydroamination of nonactivated alkene 1a
Table 2 BINOL-Derived Phosphoric Acids 3 as Catalysts for
Cyclizations of Substrate 1a (Scheme 1)a
In summary, we reported on highly active phosphoric acid
diesters for intramolecular hydroaminations of nonacti-
vated alkenes. Importantly, the use of an enantiomerically
enriched Brønsted acid catalyst allowed for an unprece-
dented metal-free asymmetric hydroamination of a nonac-
tivated alkene.
Entry Catalyst
(mol%)
Solvent
Yield
(%)
1
2
R = H (3a) (20.0)
1,4-Dioxane
1,4-Dioxane
33
72
R = 3,5-(F3C)2C6H3
(3b) (20.0)
3
4
5
6
3b (20.0)
3b (20.0)
3b (20.0)
1,1,2,2-Tetrachloroethane
PhMe
93
43
71
55
Acknowledgment
Financial support by the DFG, the Fonds der Chemischen Industrie,
the Dr. Otto Röhm Gedächtnisstiftung, and the Georg-August-Uni-
versität Göttingen is gratefully acknowledged.
NMP
R = 4-FC6H4
1,1,2,2-Tetrachloroethane
(3c) (10.0)
References and Notes
7
8
R = 9-Phenanthryl
(3d) (10.0)
1,1,2,2-Tetrachloroethane
1,4-Dioxane
94
95
(1) (a) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem.
Int. Ed. 2004, 43, 3368. (b) Müller, T. E.; Beller, M. Chem.
Rev. 1998, 98, 675.
R = SiPh3
(3e) (20.0)
(2) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079.
9
3e (10.0)
3e (10.0)
1,1,2,2-Tetrachloroethane
1,1,2,2-Tetrachloroethane
97
(3) Brunet, J. J.; Neibecker, D. In Catalytic
Heterofunctionalization; Togni, A.; Grützmacher, H., Eds.;
Wiley-VCH: Weinheim, 2001, 91–132.
10
57b
a Reaction conditions: 1a (0.5 mmol), 3 (10–20 mol%), solvent (1.0
mL), 20–24 h, 130 °C; yield of isolated product.
b Temp = 100 °C.
(4) Selected additional reviews: (a) Lee, A. V.; Schafer, L. L.
Eur. J. Inorg. Chem. 2007, 2243. (b) Widenhoefer, R. A.;
Han, X. Eur. J. Org. Chem. 2006, 4555. (c) Odom, A. L.
Dalton Trans. 2005, 225. (d) Hong, S.; Marks, T. J. Acc.
Chem. Res. 2004, 37, 673. (e) Hartwig, J. F. Pure Appl.
Chem. 2004, 76, 507. (f) Duncan, A. P.; Bergman, R. G.
Chem. Rec. 2002, 2, 431; and references cited therein.
(5) For representative examples of organocatalytic conjugate
additions of N-nucleophiles to activated alkenes, see:
(a) Fustero, S.; Jimenez, D.; Moscardo, J.; Catalan, S.;
del Pozo, C. Org. Lett. 2007, 9, 4251. (b) Sibi, M. P.; Itoh,
K. J. Am. Chem. Soc. 2007, 129, 8064. (c) Diner, P.;
Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew. Chem.
Int. Ed. 2007, 46, 1983. (d) Li, H.; Wang, J.; Xie, H.; Zu, L.;
Jiang, W.; Duesler, E. N.; Wang, W. Org. Lett. 2007, 9, 965.
(e) Chen, Y. K.; Yoshida, M.; MacMillan, D. W. C. J. Am.
chloro-substituent (entry 5). Further, it is noteworthy that
this methodology is not limited to hydroaminations with
benzyl-substituted amines, but also proved applicable to
alkyl- (entry 7) as well as arylamines (entry 8).17
Importantly, further experiments showed that metal-free
asymmetric hydroaminations of non-activated alkenes are
also possible. Thus, enantiomerically enriched phosphoric
acid diester catalyst (R)-3b18 enabled an asymmetric hy-
droamination of substrate 1a, albeit with modest selectiv-
ity (Scheme 4).
Synlett 2008, No. 7, 995–998 © Thieme Stuttgart · New York

LETTER
Brønsted Acid Catalyzed Hydroaminations of Nonactivated Alkenes
997
Table 3 Intramolecular Hydroaminations with Acid 3e (Scheme 3)a
Entry
1
Substrate 1
Product 2
Yield (%)
97
Bn
NH
Bn
Ph
Ph
Ph
Ph
N
Me
1a
2a
OMe
NO2
CO2Me
Cl
Ph
Ph
N
NH
2
3
4
5
96
97
95
96
Ph
Ph
OMe
NO2
CO2Me
Cl
Me
Me
Me
1b
2b
Ph
Ph
N
N
N
NH
NH
NH
Ph
Ph
1c
2c
Ph
Ph
Ph
Ph
1d
2d
Ph
Ph
Ph
Ph
Me
1e
2e
Bn
NH
Bn
N
6
7
8
53b,c
Me
1f
2f
Oct
NH
Oct
Me
Ph
Ph
N
Ph
Ph
93
1g
2g
Mes
NH
Mes
Me
85b
Ph
Ph
Ph
Ph
N
1h
2h
a Reaction conditions: 1 (0.5 mmol), 3e (10 mol%), Cl2HCCHCl2 (1.0 mL), 130 °C, 23 h; yield of isolated product; Mes = 2,4,6-Me3C6H2.
b GC conversion.
c Compound 3e (20 mol%).
Synlett 2008, No. 7, 995–998 © Thieme Stuttgart · New York

998
L. Ackermann, A. Althammer
LETTER
Chem. Soc. 2006, 128, 9328. (f) Guerin, D. J.; Miller, S. J.
J. Am. Chem. Soc. 2002, 124, 2134; and references cited
therein.
Chennamadhavuni, S.; Wang, Y.; Antilla, J. C. J. Am. Chem.
Soc. 2005, 127, 15696. (g) Uraguchi, D.; Terada, M. J. Am.
Chem. Soc. 2004, 126, 5356. (h) Akiyama, T.; Itoh, J.;
Yokota, K.; Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43,
1566; and references cited therein. (i) For the elegant use of
3,3¢-bis(trisarylsilyl)-substituted binaphtholate rare-earth-
metal catalysts in asymmetric hydroaminations, see:
Gribkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem.
Soc. 2006, 128, 3748; and references cited therein.
(15) Acetone, benzene, MTBE, cyclohexane, and CCl4 gave only
traces of the desired product.
(6) (a) Hultzsch, K. C. Adv. Synth. Catal. 2005, 347, 367.
(b) Hultzsch, K. C. Org. Biomol. Chem. 2005, 1819.
(7) Roesky, P. W.; Mueller, T. E. Angew. Chem. Int. Ed. 2003,
42, 2708.
(8) Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. Dalton
Trans. 2007, 5105.
(9) For metal-catalyzed hydroamination reactions from our
laboratories, see: (a) Ackermann, L. Organometallics 2003,
22, 4367. (b) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J.
Chem. Commun. 2004, 2824. (c) Ackermann, L.; Kaspar, L.
T. J. Org. Chem. 2007, 72, 6149. (d) Ackermann, L. Synlett
2007, 507; and references cited therein.
(10) For acid-catalyzed hydroamidation reactions of olefins,
which were found not applicable to more basic amines, see:
Intramolecular: (a) Schlummer, B.; Hartwig, J. F. Org. Lett.
2002, 4, 1471. (b) Haskins, C. M.; Knight, D. W. Chem.
Commun. 2002, 2724. (c) Haskins, C. M.; Knight, D. W.
Chem. Commun. 2005, 3162. (d) Yin, Y.; Zhao, G.
Heterocycles 2006, 68, 23. Intermolecular: (e) Li, Z.;
Zhang, J.; Brouwer, C.; Yang, C.-G.; Reich, N. W.; He, C.
Org. Lett. 2006, 8, 4175. (f) Rosenfeld, D. C.; Shekhar, S.;
Takemiya, A.; Utsunomiya, M.; Hartwig, J. F. Org. Lett.
2006, 8, 4179.
(11) For acid-catalyzed hydroaminations with anilines as
nucleophiles, see: (a) Anderson, L. L.; Arnold, J.; Bergman,
R. G. J. Am. Chem. Soc. 2005, 127, 14542. (b) Cherian, A.
E.; Domski, G. J.; Rose, J. M.; Lobkovsky, E. B.; Coates, G.
W. Org. Lett. 2005, 7, 5135.
(12) Ackermann, L.; Kaspar, L. T.; Althammer, A. Org. Biomol.
Chem. 2007, 1975.
(13) Akiyama, T. Chem. Rev. 2007, 5744.
(16) Representative Procedure: Synthesis of 2a (Table 3,
Entry 1)
A solution of 1a (162 mg, 0.495 mmol) and 3e (42.8 mg,
0.050 mmol) in dry Cl2HCCHCl2 (1.0 mL) was stirred under
N2 for 23 h at 130 °C. At ambient temperature sat. aq
NaHCO3 (25 mL) and Et2O (50 mL) were added. The
separated aqueous phase was extracted with Et2O (2 × 50
mL). The combined organic layers were dried over Na2SO4
and concentrated in vacuo. The remaining residue was
purified by column chromatography on silica gel (n-
pentane–Et2O, 15:1) to yield 2a (158 mg, 97%) as a light
yellow solid (mp 71.2–72.4 °C). 1H NMR (300 MHz,
CDCl3): d = 7.42–7.37 (m, 15 H), 4.12 (d, J = 13.3 Hz, 1 H),
3.70 (d, J = 10.0 Hz, 1 H), 3.30 (d, J = 13.3 Hz, 1 H), 2.99–
2.83 (m, 3 H), 2.25 (dd, J = 12.2, 7.2 Hz, 1 H), 1.21 (d,
J = 6.1 Hz, 3 H). 13C NMR (75 MHz, DEPT, CDCl3):
d = 150.5 (Cq), 148.6 (Cq), 139.9 (Cq), 128.6 (CH), 128.2
(CH), 128.1 (CH), 127.8 (CH), 127.4 (CH), 127.2 (CH),
126.8 (CH), 125.8 (CH), 125.4 (CH), 66.4 (CH2), 59.7 (CH),
58.0 (CH2), 52.5 (Cq), 47.9 (CH2), 19.5 (CH3). IR (ATR):
3061, 3029, 2960, 2924, 2788, 1491, 1445, 1373, 730, 695
cm–1. MS (EI): m/z (relative intensity) = 327 (18) [M+], 312
(75), 147 (100), 91 (64), 56 (98). HRMS (EI): m/z calcd for
C24H25N 327.1987; found: 327.2002. The spectral data are in
accordance with those reported in the literature: Bender, C.
F.; Widenhoefer, R. A. J. Am. Chem. Soc. 2005, 127, 1070.
(17) Under these reaction conditions, there was no indication for
catalyst decomposition, and primary aminoalkenes reacted
less efficiently.
(14) Representative examples: (a) Hamilton, G. L.; Kang, E. J.;
Mba, M.; Toste, F. D. Science 2007, 317, 496.
(b) Nakashima, D.; Yamamoto, H. J. Am. Chem. Soc. 2006,
128, 9626. (c) Storer, R. I.; Carrera, D. E.; Ni, Y.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84.
(d) Hoffmann, S.; Seayad, A. M.; List, B. Angew. Chem. Int.
Ed. 2005, 44, 7424. (e) Rueping, M.; Sugiono, E.; Azap, C.;
Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781.
(f) Rowland, G. B.; Zhang, H.; Rowland, E. B.;
(18) Enantiomerically enriched catalyst 3a provided, under
otherwise identical reaction conditions, only racemic
product.
Synlett 2008, No. 7, 995–998 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.