Enantioselective synthesis of chiral α-aminoalkyl-1,2,3-triazoles using a three-component reaction

Article abstract of DOI:10.1055/s-2005-918931

A range of chiral α-aminoalkyl-1,2,3-triazoles have been prepared in a modular fashion in 3 steps with up to 98% ee. The key step is a CuBr/Quinap-catalyzed enantioselective asymmetric three-component synthesis of propargylamines. Georg Thieme Verlag Stut

Full text of DOI:10.1055/s-2005-918931

2796
LETTER
Enantioselective Synthesis of Chiral a-Aminoalkyl-1,2,3-triazoles Using a
Three-Component Reaction
Enantioselective
S
i
ynthesi
n
s
of Chira
l
a
a
-
Aminoalkyl-1,2,
G
Ludwig-Maximilians-Universität München, Department Chemie und Biochemie, Butenandtstr. 5-13, Haus F, 81377 München, Germany
Fax +49(89)218077680; E-mail: paul.knochel@cup.uni-muenchen.de
Received 6 September 2005
CuBr (5 mol%)
toluene, r.t.
1–6 d
Abstract: A range of chiral a-aminoalkyl-1,2,3-triazoles have been
SiMe3
prepared in a modular fashion in 3 steps with up to 98% ee. The key
step is a CuBr/Quinap-catalyzed enantioselective asymmetric three-
component synthesis of propargylamines.
R
HNBn2
SiMe3
+
+
RCHO
(R)-Quinap
(5.5 mol%)
NBn2
1
2a
4
3a
up to 99%;
up to 98% ee
Key words: alkynes, asymmetric synthesis, C–H activation, copper
catalysis, heterocycles
N
N
N
R1N3 (7), Cu0
R1
R
Bu4NF
R
NBn2
Heterocyclic compounds have found numerous applica-
tions as pharmaceuticals and agrochemicals. Therefore,
the development of new and efficient synthesis of com-
plex heterocycles is an active field of research. The expe-
ditious and modular preparation of heterocyclic rings is of
special importance.1 The 1,3-dipolar cycloaddition reac-
tions are especially useful for the preparation of 5-mem-
bered heterocycles.2 The copper(I)-catalyzed reaction of
terminal alkynes and organic azides to give 1,4-disubsti-
tuted 1,2,3-triazoles exhibits the best click reaction3 to
date. Recently, we4 and others5 have developed a new
synthesis of chiral propargylamines of type 1 using three
components: an amine 2, a terminal alkyne 3 and an alde-
hyde 4 (Scheme 1). This reaction is efficiently catalyzed
with CuBr (5 mol%) and (R)-Quinap6 (5.5 mol%) and
produces propargylamines of type 1 with high enantio-
selectivity (up to 98% ee) and good yields (up to 98%).
NBn2
5
6
Scheme 2 Formation of chiral a-aminotriazoles of type 6
potential biological activity.7 Our approach provides a
modular synthesis of a new family of 1,2,3-triazoles 6
(Scheme 2).
The reaction of various aldehydes 4 (RCHO) with di-
benzylamine 2a and trimethylsilylacetylene 3a in the
presence of CuBr (5 mol%) and (R)-Quinap (5.5 mol%)
provided propargylamines 1a–j in 58–98% yield and 73–
98% ee. After treatment either with Bu4NF (0.3 equiv,
THF, 0 °C, 15 min) or aqueous KOH (1.2 equiv, MeOH,
r.t., 12 h), the corresponding terminal alkynes 5a–j were
obtained in 91–99% yield (Scheme 2).
These terminal alkynes of type 5 were subsequently
reacted with benzyl azide8 (7a) in the presence of copper
powder. The reaction was performed in t-BuOH–H2O
mixtures at room temperature to 60 °C. This procedure is
equally well suited for aromatic and aliphatic substituted
propargylamines (Table 1).
R3
R2
R1
CuBr (5 mol%)
N
H
R4
1
N
+
+
R CHO
R2
R3
MS 4 Å, toluene, r.t.
R4
N
2
3
4
1: up to 98% ee
PPh2
In most cases, the reaction proceeded already at room
temperature, but with sometimes longer reaction times.
For propargylamines 5a–h, derived from aliphatic alde-
hydes, the 1,3-dipolar cycloaddition reaction with benzyl
azide (7a) proceeded with general high yield (up to 98%,
entries 1–8). Propargylamines bearing cyclic substituents
like cyclopropyl, cyclopentyl or cyclohexyl groups 5f–h
afforded longer reaction times. This could be overcome
by heating the reaction mixture to 40–60 °C leading to the
corresponding triazoles 6f–h in high yield (74–96%).
Propargylamines 5i–j, derived from heteroaromatic alde-
hydes, could be reacted likewise, giving triazoles 6i–j in
moderate to good yield (76–98%, entries 9, 10). For these
propargylamines, the reaction was carried out at 40 °C.
No racemization was observed during the addition
reaction as was proven by analysis of the starting material
(R)-Quinap (5.5 mol%)
Scheme 1 Asymmetric three-component synthesis of propargyl-
amines
Herein, we wish to report the conversion of terminal
propargylamines 5 (obtained by the three-component
reaction and subsequent desilylation of 1) to chiral a-ami-
noalkyl-1,2,3-triazoles of type 6 by a 1,3-dipolar cycload-
dition with an organic azide 7 in the presence of
copper(0). Triazoles are of great interest due to their
SYNLETT 2005, No. 18, pp 2796–2798
0
3
.1
1
.2
0
0
5
Advanced online publication: 10.10.2005
DOI: 10.1055/s-2005-918931; Art ID: G27305ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Synthesis of Chiral a-Aminoalkyl-1,2,3-triazoles
2797
Table 1 Triazoles of Type 6 Prepared from Chiral Propargylamines 1
Entry Propargylamine 1
Yield (%) ee (%)
Propargylamine 5
Yield (%) Triazole 6
Conditions
r.t., 8 d
Yield (%)
98
1
82
85
94
87
95
90
94
94
96
98
92
94
94
91
98
NBn2
NBn2
NBn2
n-Bu
n-Bu
n-Bu
Bn
N
N
N
SiMe3
5a
6a
1a
2
r.t., 3 d
r.t., 4 d
r.t., 2 d
r.t., 4 d
85
97
73
89
NBn2
NBn2
NBn2
Bn
N
N
NBn2
N
SiMe3
N
5b
1b
1c
1d
1e
6b
6c
6d
3
4
5
NBn2
NBn2
Bn
N
SiMe3
N
5c
NBn2
NBn2
NBn2
Bn
N
N
SiMe3
N
5d
NBn2
NBn2
NBn2
N
Bn
N
SiMe3
N
5e
6e
6f
6
7
8
98
98
86
92
96
97
99
99
95
40 °C, 1 d
r.t., 8 d
95
74
NBn2
NBn2
NBn2
Bn
N
SiMe3
N
N
5f
1f
NBn2
NBn2
NBn2
NBn2
N
Bn
N
N
SiMe3
SiMe3
5g
1g
1h
6g
60 °C, 2.5 d 92
NBn2
N
NBn2
Bn
Bn
N
N
N
5h
6h
9
58
92
73
82
99
93
40 °C, 1 d
40 °C, 8 d
98
76
NBn2
NBn2
N
NBn2
N
N
SiMe3
O
O
O
1i
5i
6i
10
NBn2
NBn2
NBn2
N
Bn
SiMe3
S
S
S
N
1j
5j
6j
5h and the product 6h (98% ee) by chiral HPLC. In each Furthermore, this methodology was successfully applied
case, both the non-racemic and the racemic product were to the synthesis of a-alkoxy-1,2,3-triazoles. Thus, chiral
analyzed.
propargyl ether 8 was successfully reacted with benzyl
azide (7a) in the presence of copper powder leading to the
desired triazole 9 in 92% yield and 99% ee (Scheme 4).
Besides benzyl azide (7a), other functionalized azides
were used in the cycloaddition reaction. 4-Methoxy-ben-
zyloxycarbonyl azide (7b) was reacted with propargyl- In summary, we have developed a short and highly mod-
amine 5k under standard conditions, furnishing the ular synthesis of chiral a-aminotriazoles of type 6 using a
cycloaddition product 6k in 52% yield (Scheme 3). Like- copper-catalyzed asymmetric three-component reaction
wise, 2-azidocyclohexanol9 (7c) was reacted with propar- for the preparation of propargylamines and subsequent
gylamine 5l leading to product 6l in 95% yield 1,3-dipolar cycloaddition reaction with organic azides.
(Scheme 3).
The obtained products display a high synthetic potential.
Synlett 2005, No. 18, 2796–2798 © Thieme Stuttgart · New York

2798
N. Gommermann et al.
LETTER
N3
O
Acknowledgment
n-Pent
NBn2
O
We thank the Fonds der Chemischen Industrie and Merck Research
Laboratories (MSD) for financial support. We thank the DFG (SPP
1118 ‘Sekundäre Wechselwirkungen als Steuerungsprinzip zur
gerichteten Funktionalisierung reaktionsträger Substrate’) for a
fellowship for N.G. and Chemetall GmbH (Frankfurt) and BASF
AG (Ludwigshafen) for generous gift of chemicals.
Cu0
NBn2
N
N
+
N
O
n-Pent
t-BuOH/H2O
O
OMe
OMe
5k: 88% ee
7b
6k: 52%
n-Pent
NBn2
References
OH
N3
NBn2
Cu0
(1) (a) Joule, J. A.; Mills, K.; Smith, G. F. Heterocyclic
Chemistry; Stanley Thornes Publishers Ltd: Cheltenham,
1998. (b) Wang, Y.; Dong, X.; Larock, R. C. J. Org. Chem.
2003, 68, 3090. (c) Larock, R. C.; Roesch, K. R. J. Org.
Chem. 2002, 67, 86. (d) Larock, R. C.; Pace, P.; Yang, H.;
Russel, C. E. Tetrahedron 1998, 54, 9961. (e) Larock, C.
L.; Yum, E. K.; Doty, M. J.; Sham, K. K. C. J. Org. Chem.
1995, 60, 3270. (f) Larock, R. C.; Yang, H. J. Org. Chem.
1994, 59, 4172. (g) Lindsay, D. M.; Dohle, W.; Jensen, A.
E.; Kopp, F.; Knochel, P. Org. Lett. 2002, 4, 1819.
(2) (a) Huisgen, R. Angew. Chem., Int. Ed. Engl. 1963, 2, 565.
(b) Huisgen, R. In 1,3-Dipolar Cycloaddition Chemistry,
Vol. 1; Padwa, A., Ed.; Wiley: New York, 1984.
N
+
N
N
OH
n-Pr
t-BuOH/H2O
5l: 90% ee
rac-7c
6l: 95%
Scheme 3 Formation of functionalized chiral a-aminotriazoles 6k–l
OMe
OMe
Cu0
N3
+
N
t-BuOH/H2O
N
Ph
N
Br
Br
(3) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem.
Int. Ed. 2001, 40, 2004. (b) Kolb, H. C.; Sharpless, K. B.
Drug Discov. Today 2003, 8, 1128.
9: 92%, 99% ee
8: 99% ee
7a
Scheme 4 Synthesis of a-alkoxytriazole 9
(4) (a) Gommermann, N.; Koradin, C.; Polborn, K.; Knochel, P.
Angew. Chem. Int. Ed. 2003, 42, 5763. (b) Gommermann,
N.; Knochel, P. Chem. Commun. 2004, 2324. (c) Dube, H.;
Gommermann, N.; Knochel, P. Synthesis 2004, 2015.
(5) For an excellent review, see: (a) Wei, C. M.; Li, Z.; Li, C.-J.
Synlett 2004, 1472. (b) Wei, C. M.; Li, C.-J. J. Am. Chem.
Soc. 2003, 125, 9584. (c) Akullian, L. C.; Snapper, M. L.;
Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4244.
(d) Sakaguchi, S.; Kubo, T.; Ishii, Y. Angew. Chem. Int. Ed.
2001, 40, 2534. (e) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-
M.; Fan, C.-A. Org. Lett. 2004, 6, 1001. (f) Wei, C. M.; Li,
C.-J. J. Am. Chem. Soc. 2002, 124, 5638. (g) Wei, C. M.;
Li, Z. G.; Li, C.-J. Org. Lett. 2003, 5, 4473. (h) Li, Z.; Li,
C.-J. Org. Lett. 2004, 6, 4997. (i) Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. Org. Lett. 2003, 5, 3273. (j) For the
preparation of chiral propargylic alcohols see: Frantz, D. E.;
Faessler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122,
1806.
(6) (a) Valk, J. M.; Whitlock, G. A.; Layzell, T. P.; Brown, J. M.
Tetrahedron: Asymmetry 1995, 6, 2593. (b) Fernandez, E.;
Maeda, K.; Hooper, M. W.; Brown, J. M. Chem.–Eur. J.
2000, 6, 1840.
(7) (a) Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.;
Sharpless, K. B.; Wong, C.-H. J. Am. Chem. Soc. 2003, 125,
9588. (b) Mocharla, V. P.; Colasson, B.; Lee, L. V.; Röper,
S.; Sharpless, K. B.; Wong, C.-H.; Kolb, H. C. Angew.
Chem. Int. Ed. 2005, 44, 116.
Further applications of this methodology towards the
preparation of natural products and biologically active
compounds are currently underway in our laboratories.
Preparation of (–)-N,N-Dibenzyl-1-(1-benzyl-1H-1,2,3-triazol-
4-yl)-2-ethylbutan-1-amine (6e)
Propargylamine (–)-5e (306 mg, 1.0 mmol)4b was dissolved in t-
BuOH–H2O (2:1, 3 mL) at r.t. Benzyl azide 7a (200 mg, 1.5 mmol)
was added, followed by copper(0) powder (1.0 g). The reaction
mixture was stirred at r.t. for 4 d, diluted with CH2Cl2 and filtered
over a pad of Celite. The filtrate was concentrated and the crude
product was purified by column chromatography (SiO2, pentane–
Et2O 4:1) leading to triazole (–)-6e (389 mg, 0.9 mmol, 89%) as a
colorless solid.
25
1
[a]D –88 (c 0.56, CHCl3); mp 91–93 °C. H NMR (300 MHz,
CDCl3): d = 7.35–7.11 (m, 16 H), 5.31 (d, J = 2.9 Hz, 2 H), 3.81–
3.73 (m, 3 H), 3.11 (d, J = 13.8 Hz, 2 H), 2.14–2.01 (m, 1 H), 1.91–
1.76 (m, 1 H), 1.64–1.43 (m, 2 H), 1.06–0.91 (m, 1 H), 0.90–0.73
(m, 1 H), 0.63 (t, J = 7.5 Hz, 3 H), 0.51 (t, J = 7.5 Hz, 3 H). 13C
NMR (75 MHz, CDCl3): d = 145.3, 140.3, 135.6, 129.5, 129.4,
129.0, 128.6, 128.1, 127.1, 122.9, 56.8, 54.7, 54.4, 40.4, 22.1, 20.4,
10.5, 9.5. IR (KBr): 2963, 2936, 1495, 1454, 747, 727, 699 cm–1.
MS (EI, 70 eV): m/z (%) = 438 (<1) [M+], 368 (24), 367 (100), 91
(63). HRMS (EI, 70 eV): m/z calcd for C29H34N4: 438.2783; found:
438.2788.
(8) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
(9) Swift, G.; Swern, D. J. Org. Chem. 1967, 32, 511.
Synlett 2005, No. 18, 2796–2798 © Thieme Stuttgart · New York