C O M M U N I C A T I O N S
Table 2. Evaluation of Substrate Scope
Figure 1. Model to explain enantioselectivity and absolute stereochemistry.
yield
(%)a
ee
with the sense of induction in other reactions catalyzed by
magnesium Lewis acids and ligand 6.13
In conclusion, we have developed a versatile strategy to access
dihydropyrazoles in highly enantioenriched form. Application of
the cycloaddition methodology in the synthesis of biologically active
targets and post modification of the dihydropyrazoles14 is underway.
entry
dipole
R1
R2
R3
R4
product
(%)b
1
2
3
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2e
2e
2c
2d
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
7a
7b
7c
7d
7e
7f
91
93
95
94
97
92
90
82
95
98
92
97
95
96
99
99
97
99
96
91
93
79
84
99
95
97
95
96
Br
Br
Br
Br
Br
Br
Br
Br
Br
H
4
2-furyl
OBz
CO2t-Bu Ph
CO2t-Bu Ph
5c
6
7d
8
7f
Acknowledgment. We thank Merck Pharmaceuticals for fi-
nancial support.
H
H
Me
Me
Ph
Ph
iPr
Ph
7g
7g
7h
7i
7j
7k
7l
9d
10
11e
12e
13
14
Supporting Information Available: Experimental procedures and
characterization data including NMR spectra for selected compounds
(PDF). Crystal information files (CIF) for compound 4k. This material
3-Br-Ph Ph
H
Me
Me
4-Br-Ph Br
Ph
OMe Br
a Isolated yield. b Determined by chiral HPLC. c Upon treatment with
NaBH4, the benzoate is cleaved to yield the corresponding diol. d Performed
with 20 mol % Mg(NTf2)2-6. e Et3N as the base, 30 mol % Mg(NTf2)2-6,
-20 °C, 48 h.
References
(1) Reviews: (a) ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991; Vol. 5, Chapter 3. (b) Gothelf, K. V.;
Jorgensen, K. A. Chem. ReV. 1998, 98, 863.
(2) Selected examples: (a) Kanemasa, S.; Kanai, K. J. Am. Chem. Soc. 2000,
122, 10710. (b) Shintani, R.; Fu, G. C. J. Am. Chem. Soc. 2003, 125,
10778. (c) Yamashita Y.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126,
11279. (d) Sibi, M. P.; Itoh, K.; Jasperse, C. P. J. Am. Chem. Soc. 2004,
126, 5366. (e) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc.
2004, 126, 718. (f) Mish, M. R.; Guerra-Martinez, F.; Carreira, E. M. J.
Am. Chem. Soc. 1997, 119, 8379.
(3) (a) Camacho, M. E.; Leo´n, J.; Entrena, A.; Velasco, G.; Carrio´n, M. D.;
Escames, G.; Vivo´, A.; Acun˜a-Castroviejo, D.; Gallo, M. A.; Espinosa,
A. J. Med. Chem. 2004, 47, 5641. (b) Upadhyay, J.; Dave, U.; Parekh, H.
J. Indian Chem. Soc. 1991, 68, 413.
(4) For intramolecular examples, see (a) Broggini, G.; Garanti, L.; Molteni,
G.; Zecchi, G. Tetrahedron: Asymmetry 1999, 10, 487. (b) Broggini, G.;
Garanti, L.; Molteni, G.; Pilati, T.; Ponti, A.; Zecchi, G. Tetrahedron:
Asymmetry 1999, 10, 2203. For intermolecular examples, see (c) Bar-
luenga, J.; Ferna´ndez-Mar´ı, F.; Gonza´lez, R.; Aguilar, E.; Revelli, G. A.;
Viado, A. L.; Fan˜ana´s, F. J.; Olano, B. Eur. J. Org. Chem. 2000, 1773.
(d) Molteni, G. Tetrahedron: Asymmetry 2004, 15, 1077. (e) Garanti, L.;
Molteni, G.; Pilati, T. Tetrahedron: Asymmetry 2002, 13, 1285.
(5) For discussion of transient nitrile imine generation, see: (a) 1,3-Dipolar
Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984;
Chapter 7. For leading examples, see: (b) Wamhoff, H.; Zahran, M.
Synthesis 1984, 876. (c) Broggini, G.; Granati, L.; Moleteni, G.; Zecchi,
G. Tetrahedron 1998, 54, 2843. (d) Kanemasa, S.; Kobayashi, S. Bull.
Chem. Soc. Jpn. 1993, 66, 2685. (e) Rai, K. M. L.; Hassner, A. Synth.
Commun. 1989, 19, 2799.
with 20 mol % catalyst loading, the enantioselectivity improved
only marginally (entry 9).
Entries 10-14 show results using different hydrazonyl halides.
The bromide 2b derived from an enolizable aliphatic aldehyde
performs well (99% ee, entry 10), providing a product with an alkyl
R2 group. Entries 11 and 12 demonstrate the suitability of a
hydrazonyl chloride 2e as the nitrile imine precursor. However,
dehydrochlorination of 2e to form the nitrile imine was more
difficult.10 Et3N proved to be more reactive than iPr2NEt and, under
optimized reaction conditions (30 mol % CLA, Et3N, -20 °C, 48
h), gave cycloadducts 7i and 7j in good yields and very high
enantioselectivity (>90% yields, >95% ee; entries 11, 12). The
use of the strong but nonnucleophilic (tert-butylimino)tris(di-
methylamino) phosphorane as the base gave product 7i in 93% yield
and 94% ee under the normal -78 °C, 6 h, 10% catalyst conditions.
Entry 14 shows that a p-methoxybenzene substituent can be used
on nitrogen, which provides a potential handle for nitrogen
deprotection. Entries 1-10 and 12-14 demonstrate that Br can be
selectively located in the R1, R2, or nitrogen aryl groups. We thus
have a versatile scaffold for potential elaboration via cross-coupling.
Dehydrobromination of N-benzyl bromide 8 did not proceed
under standard conditions (iPr2NEt, -78 °C).11 Use of DBU did
enable dipole formation, giving cycloaddition product 9 in reason-
able yield and 94% ee (eqn 1).9,11 The N-benzyl group provides
another useful handle for nitrogen deprotection.
(6) Reduction of acyl oxazolidinone 4a to the corresponding alcohol 7a was
not necessary, but the alcohol was more conducive to rapid chiral HPLC
analysis.
(7) Use of molecular sieves was not essential with Mg(NTf2)2. With
hygroscopic Lewis acids, however, the use of MS was beneficial for
optimal and reproducible results, particularly at temperatures where water
is more soluble in CH2Cl2. The sensitivity to water is probably acute
because the basic conditions facilitate formation of Lewis acid hydroxide
complexes.
(8) (a) Houk, K. N.; Sims, J.; Watts, C. R.; Luskus, L. J. J. Am. Chem. Soc.
1973, 95, 7301. (b) Caramella, P.; Houk, K. N. J. Am. Chem. Soc. 1976,
98, 6397.
(9) We believe that addition to the hydrazonyl halide may compete with nitrile
imine formation when nucleophilic amines are used and that interaction
with the Lewis acid (or the dipole itself) may also interfere.
(10) Use of DBU accelerated consumption of chloride 2e but gave lower yield
of the cycloadduct.
(11) Starting material 8 was recovered. Use of (tert-butylimino)tris(dimethyl-
amino)phosphorane gave product 9 in 68% yield and 88% ee. Conditions
were not optimized for any of the bases.
(12) See Supporting Information.
(13) (a) Sibi, M. P.; Petrovic, G.; Zimmerman, J. J. Am. Chem. Soc. 2005,
127, 2390. (b) Ref 2d.
A crystal structure was obtained for cycloadduct 4k (see Table
2, entry 13). The absolute stereochemistry was found to be (4S,5R)-
(Figure 1).12 This is consistent with a cis-octahedral model and also
(14) Guerra, F. M.; Mish, M. R.; Carreira, E. M. Org. Lett. 2000, 2, 4265.
JA051650B
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