Hydroaminations of unactivated alkenes with basic alkylamines: Group 4 metal halide catalysts and Bronsted-acid organocatalysts

Article abstract of DOI:10.1039/b706301f

Two distinct economical catalysts for intramolecular hydroaminations of electronically unactivated alkenes with basic amines are described, which are based on (a) group 4 metal halides under basic reaction conditions or (b) Bronsted-acid organocatalysts.

Full text of DOI:10.1039/b706301f

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Hydroaminations of unactivated alkenes with basic alkylamines: group 4
metal halide catalysts and Brønsted-acid organocatalysts†
Lutz Ackermann,*a,b Ludwig T. Kasparb and Andreas Althammera,b
Received 25th April 2007, Accepted 8th May 2007
First published as an Advance Article on the web 17th May 2007
DOI: 10.1039/b706301f
Two distinct economical catalysts for intramolecular hydroaminations of electronically unactivated
alkenes with basic amines are described, which are based on (a) group 4 metal halides under basic
reaction conditions or (b) Brønsted-acid organocatalysts.
Table 1 MCl4-catalyzed hydroamination of an unactivated alkene
Introduction
Saturated N-heterocycles are ubiquitous in natural products as
well as biologically active compounds.1 Their synthesis through
direct intramolecular additions of basic amines to alkenes are
attractive, because of their atom-economical nature.2 Recently,
significant progress has been achieved through the use of group
Entrya
MCl4
Additive (equiv.)b
Yield (%)
4 metal complexes, previously developed for elegant hydroam-
inations of alkynes and allenes.3 Thus, cyclizations of both
secondary4,5 and primary6 aminoalkenes were reported, and for
the latter transformations strong evidence was provided for
a mechanism involving group 4 metal imido complexes.7 We
proposed comparable imido species as intermediates for the use
of the inexpensive Lewis-acid TiCl4 (99.9%, Acros 2006, 0.01
EUR mmol−1)8 (and HfCl4) in hydroamination reactions.9 Given
the importance of economical heterocycle syntheses, we became
interested in probing preparatively useful group 4 metal halide-
based catalysts for intramolecular addition reactions of basic
alkylamines to unactivated olefins. Additionally, as Brønsted-acids
have thus far only been employed as catalysts for addition reactions
of significantly less basic amides10,11 or anilines,12 we explored
their use in organocatalytic additions of basic alkylamines to
unactivated alkenes.
1
2
3
4
5
6
7
TiCl4
TiCl4
TiCl4
TiCl4
HfCl4
ZrCl4
—
t-BuNH2 (1.2)
t-BuNH2 (1.2), 2,6-(t-Bu)2C5H3N
TMP (1.2)
LDA (0.8)
LDA (0.8)
LDA (0.8)
LDA (0.8)
11c
29
26
37c
59
87
6
a Reagents and conditions: 1a (1.0 mmol), MCl4 (20 mol%), PhMe (2.0 mL),
18 h, 120 ◦C; (CF3CO)2O (2.0 mmol), 20 ◦C, 15 min. b TMP: 2,2,6,6-
tetramethylpiperidine; LDA: lithium diisopropylamide. c GC conversion.
(entries 5 and 6, respectively). Importantly, these transformations
proceeded in the presence of an excess of either a sterically
hindered pyridine (entry 2)13 or a basic amide (entries 4–6),
rendering Brønsted-acid catalysis less likely. Based on a control
experiment a base-catalyzed14 hydroamination is also unlikely
(entry 7).
Further, the catalysts were probed using secondary amine 1b.
Interestingly, formation of heterocycle 2b was not observed using
catalytic amounts of either TiCl4, HfCl4 or ZrCl4 in combination
with LDA (Scheme 1). This lack of reactivity suggests that alkene
hydroamination is catalyzed by in situ-generated group 4 metal
imido complexes, which subsequently undergo an intramolecular
[2 + 2] cycloaddition reaction with the alkene.
Results and discussion
Group 4 metal halide catalysts
At the outset of our studies, we probed various additives for
TiCl4-catalyzed intramolecular hydroamination reactions using
8,9
aminoalkene 1a (Table 1). Previously employed t-BuNH2 pro-
vided unsatisfactory results (entry 1). In contrast, excess of a basic
pyridine or amine gave rise to more efficient conversion of amine 1a
(entries 2 and 3, respectively). A significantly increased reactivity
was achieved with catalysts comprising a group 4 metal halide
9d
and LDA as additive, particularly when using HfCl4 or ZrCl4
aInstitut fuer Organische und Biomolekulare Chemie, Georg-August-
Universitaet, Tammannstr. 2, 37077, Goettingen, Germany. E-mail: Lutz.
Ackermann@chemie.uni-goettingen.de; Fax: +49 551 396777
Scheme 1 Test reaction using secondary amine 1b.
bDepartment Chemie und Biochemie, Ludwig-Maximilians-Universitaet
Muenchen, Butenandtstrasse 5–13, Haus F, 81377, Muenchen, Germany
This Bergman mechanism is well established for alkyne
hydroaminations3 and has been postulated for alkene hydroami-
nations.6,7
† Electronic supplementary information (ESI) available: Full experimental
procedures and analytical data for hydroamination products. See DOI:
10.1039/b706301f
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Table 3 Hydroamination of unactivated alkenes with basic amines
Brønsted-acids as organocatalysts
Intramolecular hydroamination reactions of unactivated alkenes
with basic alkylamines are often employed to evaluate the
performance of metal-based catalysts. As studies on the use of
Brønsted-acids as catalysts in these important transformations
have not previously been reported, we probed the efficacy of
such reagents in the challenging conversion of basic primary and
secondary aminoalkenes.15 We observed unprecedented Brønsted-
acid-catalyzed hydroamination reactions with basic alkylamines
(Table 2). Particularly, salts of weakly coordinating anions16
enabled efficient catalysis. While PhMe2NH+ −B(C6F5)4 (98%,
Strem, 120.16 EUR mmol−1) proved highly active (entries 13 and
14), the use of NH4+ −O2CCF3 (98%, Aldrich, 0.12 EUR mmol−1)17
constitutes an economically attractive, preparatively simple, yet
efficient alternative (entries 15 and 16).
With two highly promising catalysts in hand, we studied the
scope of the methodology (Table 3). The mild reaction conditions
allowed for the use of substrates bearing a variety of valuable
functional groups, such as a chloro- (entry 2), an ester- (entry 3),
a nitro- (entry 4) or a cyano-substituent (entry 5). Further,
a hydroxy-substituted substrate was chemoselectively converted
to pyrrolidine 2h in high yield (entry 6). Importantly, gem-
disubstitution18 is not a stringent requirement for the success of
the protocol, and more challenging substrates were converted with
high efficacy (entries 9 and 10). Finally, it is noteworthy that this
methodology is not limited to secondary aminoalkenes, but also
proved applicable to primary alkylamines (entry 11).
Entry Substrate
Product
Yield (%)
1a
2a
3a
4a
5a
6b
7b
R = OMe
R = Cl
2c 63
2d 84
2e 93
2f 80
2g 82
2h 84
2i 75
R = CO2Me
R = NO2
R = CN
R = OH
8b
2j 84
9b
2k 82 (2.6 : 1)c
Conclusions
In summary, we have presented herein two distinct economical
catalysts for intramolecular addition reactions of basic amines to
10b,d
2l 74
2a 83
Table 2 Brønsted-acid-catalyzed hydroamination with a basic amine
11e
+
a Reagents and conditions: 1 (1.0 mmol), NH4 −O2CCF3 (20 mol%), 1,4-
Entrya
Catalyst
T/◦C
Yield (%)
◦
dioxane (2.0 mL), 24 h, 130 C. b Reagents and conditions: 1 (0.5 mmol),
PhMe2NH+ −B(C6F5)4 (10 m◦ol%), 24 h, 120 ◦C. c Diastereomeric ratio.
d Reaction conducted at 130 C. e Reagents and conditions: 1 (0.5 mmol),
PhMe2NH+ −B(C6F5)4 (20 mol%), 18 h, 120 ◦C; (CF3CO)2O (2.0 mmol),
20 ◦C, 15 min.
1
2
3
4
5
6
7
8
9
10
11
12
13c
14
15
16
—
130
120
120
120
120
120
120
130
120
130
120
130
120
80
—
—
7b
(NH4)2SO4
+
NH4 −O2CCH3
NH4F
NH4Cl
NH4Br
NH4I
<5b
5b
5b
10b
20b
25b
33
39
44
83
76
56
74
unactivated olefins. Under basic reaction conditions, group 4
metal halides were employed for efficient hydroamination reac-
tions of primary aminoalkenes, which likely proceed through
in situ generation of group 4 metal imido complexes. Further,
we have described the unprecedented use of Brønsted-acids
for generally applicable and efficient catalytic hydroamination
reactions of unactivated alkenes with basic alkyl-substituted
amines. Generally, these findings are of fundamental significance
for the evaluation of metal-based hydroamination catalysts.
Form a preparative viewpoint, NH4+ −O2CCF3 represents an
economically attractive catalyst with a broad functional group
tolerance.
+
NH4 −O3SCF3
(NH4)BF4
BINOLP(O)OH
NH4PF6
PhMe2NH+ −B(C6F5)4
+
NH4 −O2CCF3
120
130
a Reagents and conditions (unless otherwise indicated): 1b (1.0 mmol),
catalyst (20 mol%), 1,4-dioxane (2.0 mL), 24 h. b GC conversion. c Reagents
and conditions: 1b (0.5 mmol), catalyst (10 mol%), 1,4-dioxane (1.0 mL).
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(18) [M+], 312 (75), 147 (100), 91 (64), 56 (98). HR-MS (EI) m/z
calcd for C24H25N 327.1987, found 327.2002.
Experimental†
Representative procedure for MCl4-catalyzed intramolecular
hydroaminations of unactivated olefins
Acknowledgements
1-Trifluoroacetyl-2-methyl-4,4-diphenylpyrrolidine (2a, Table 1,
entry 6). An oven-dried sealed tube was charged under a positive
pressure of nitrogen with ZrCl4 (47 mg, 0.20 mmol, 20 mol%),
toluene (2 mL) and LDA (2.0 M in THF–n-heptane–ethylbenzene,
0.40 mL, 0.80 mmol). The resulting solution was stirred for
30 min at ambient temperature, followed by the addition of
1a (237 mg, 1.00 mmol). The reaction mixture was stirred at
120 ◦C for 18 h. The cold solution was subsequently treated
with trifluoroacetic anhydride (420 mg, 2.00 mmol). After stirring
for 15 min at ambient temperature, Et2O (50 mL) and saturated
aqueous (NH4)2CO3 (30 mL) were added. The separated aqueous
phase was extracted with Et2O (2 × 50 mL). The combined organic
layers were washed with brine (50 mL), dried over MgSO4 and
concentrated in vacuo. The remaining residue was purified by
column chromatography on silica gel (n-pentane–Et2O = 60 : 1 →
30 : 1) to yield 2a (290 mg, 0.87 mmol, 87%) as a light yellow solid
(mp 78.8–79.6 ◦C).
1H-NMR (300 MHz, CDCl3): d = 7.34–7.37 (m, 10H), 4.61 (dt,
J = 11.5, 1.8 Hz, 1H), 4.12–4.02 (m, 1H), 3.98 (d, J = 11.5 Hz, 1H),
3.06–2.97 (m, 1H), 2.32–2.25 (m, 1H), 1.40 (d, J = 6.2 Hz, 3H).
13C-NMR (75 MHz, DEPT, CDCl3): d = 155.3 (q, J = 36.1 Hz,
CO), 144.7 (Cq), 143.6 (Cq), 128.8 (CH), 128.7 (CH), 126.9 (CH),
126.8 (CH), 126.5 (CH), 126.3 (CH), 116.1 (q, J = 288.0 Hz, CF3),
56.2 (q, J = 2.6 Hz, CH2), 54.6 (CH), 53.3 (Cq), 44.4 (CH2), 18.9
(CH3). 19F-NMR (275 MHz, CDCl3): d = −72.37 (s). IR (ATR):
3060, 2932, 1685, 1496, 1446, 1253, 1205, 1180, 1136, 1033, 753,
696 cm−1. MS (EI), m/z (relative intensity) 334 (18) [M + H+], 333
(90) [M+], 220 (19), 207 (46), 193 (66), 179 (100), 115 (40), 91 (31),
69 (35). HR-MS (EI) m/z calcd for C19H18F3NO 333.1340, found
333.1322.
We thank the DFG (Emmy Noether-Program) and Sanofi-Aventis
for substantial financial support. Further support by the Fonds
der Chemischen Industrie, DuPont and BASF AG is gratefully
acknowledged.
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A solution of 1b (328 mg, 1.00 mmol) and NH4+ −O2CCF3
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J = 13.3 Hz, 1H), 3.70 (d, J = 10.0 Hz, 1H), 3.30 (d, J = 13.3 Hz,
1H), 2.99–2.83 (m, 3H), 2.25 (dd, J = 12.2, 7.2 Hz, 1H), 1.21 (d,
J = 6.1 Hz, 3H). 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
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1978 | Org. Biomol. Chem., 2007, 5, 1975–1978
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©