Synthesis of tetrahydropyridazines by a metal-carbene-directed enantioselective vinylogous N-H insertion/Lewis acid-catalyzed diastereoselective Mannich addition

Article abstract of DOI:10.1002/anie.201203962

A versatile cascade of reactions, triggered by Rh^II-catalyzed diazo decomposition followed by a vinylogous N-H insertion/Lewis acid catalyzed Mannich addition, that produces highly substituted 1,2,3,6-tetrahydropyridazines in up to 97% ee with high yield and diastereocontrol has been developed. Copyright

Full text of DOI:10.1002/anie.201203962

Angewandte
Chemie
DOI: 10.1002/anie.201203962
Cascade Catalysis
Synthesis of Tetrahydropyridazines by a Metal–Carbene-Directed
ꢀ
Enantioselective Vinylogous N H Insertion/Lewis Acid-Catalyzed
Diastereoselective Mannich Addition**
Xinfang Xu, Peter Y. Zavalij, and Michael P. Doyle*
Although rare, formal [3+3]-cycloaddition reactions are
known to occur through sequential reactions of an activated
substrate, first with the nucleophilic site of a dipole and then
with its electrophilic site to form the cycloaddition product.[1]
Systems that follow this pathway include reactions of catalyti-
cally-generated substrates with nitrones[2,3] and azomethine
imines;[2b,4] enantiocontrol, examples of which have only
recently been published, occurs through the intervention of
a chiral catalyst.[5] We envisioned that readily accessible
hydrazones could be employed in place of azomethine imines
to form tetrahydropyridazines[6] with enoldiazoacetates
1 (Scheme 1). Nucleophilic addition of hydrazone 3 to metal
carbene intermediate 2 could occur either at the metal
carbene center (2!TS I) or at the vinylogous position
(2!TS II) to give 6 or 7, respectively, after 1,2-hydrogen
transfer between the two nitrogen atoms and Mannich
addition (Path A and Path B). The 1,2-hydrogen transfer is
ꢀ
formally a N H insertion reaction but, in contrast to the
direct process (TS I!4),[7] the 1,4-hydrogen transfer (TS II!
5) from nitrogen to carbon is a vinylogous variant for which
there has been no previous example of stereocontrol,
ꢀ
although non-asymmetric vinylogous O H insertion reac-
ꢀ
tions and the asymmetric vinylogous C H functionalization
of several vinyldiazoacetates have recently been reported.[8]
Herein, we report a highly selective catalytic process involv-
ing enoldiazoacetates in combination with aldehyde-derived
hydrazones that occurs with high enantioselectivity and
catalyst-controlled diastereoselectivity.
To determine the feasibility of the formal [3+3]-cyclo-
addition with hydrazones we treated 3-(tert-butyldimethylsi-
loxy)-2-diazo-3-butenoate 1a and the phenylhydrazone of
4-chlorobenzaldehyde (3a) with a catalytic amount of dirho-
dium tetraacetate at room temperature in dichloromethane.
Complete conversion occurred within one hour, but, instead
of forming tetrahydropyridazines, the product from vinyl-
ꢀ
ogous N H insertion (8a) was formed exclusively as the
terminal product (Scheme 2). The Z geometry of the newly
=
formed trisubstituted C C bond in 8a was confirmed by
single crystal X-ray diffraction.[9] That the reaction process
Scheme 2. Test reaction for a formal [3+3]-cycloaddition with hydra-
zones. Yield shown is of isolated product. MS=molecular sieves,
TBS=tert-butyldimethylsilyl, OAc=acetate.
Scheme 1. Competitive pathways for [3+3]-cycloaddition reactions of
arylhydrazones.
ꢀ
was indeed a vinylogous N H insertion was established by
ꢀ
performing the reaction with deuterium-labeled 3a (N H
proton exchange) from which deuterium was found to reside
exclusively on the vinylic carbon atom alpha to the carbox-
ylate ester.[10] Instead of undergoing the 1,2-proton transfer
envisioned in Scheme 1, the hydrogen on nitrogen replaced
the dirhodium catalyst at the original metal carbene center.
Recognizing the advantages of this method, we investigated
[*] Dr. X. Xu, Dr. P. Y. Zavalij, Prof. M. P. Doyle
Department of Chemistry and Biochemistry
University of Maryland
College Park, MD 20742 (USA)
E-mail: mdoyle3@umd.edu
[**] Support for this research to M.P.D. from the National Institutes of
Health (GM 46503) is gratefully acknowledged.
ꢀ
this transformation for enantiocontrol in the vinylogous N H
insertion reaction and, as 8 is suitable for intramolecular
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203962.
iminium ion ring closure,[11] Lewis acid catalysis was probed
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
for subsequent diastereoselective cyclization to tetrahydro-
pyridazines.
in enantioselectivity (entry 8 vs. entry 3). Using [Rh2{(R)-
pta}4] at temperatures down to ꢀ408C provided additional
improvements in the control of enantioselectivity, giving 8c in
up to 82% ee with high yield in toluene (entries 9–15).
However, the highest yield and selectivity were obtained with
[Rh2{(R)-ptl}4] (R1 = iBu), which effected 100% conversion
within 2 h to give 8c, which was isolated in 82% yield and
ꢀ
To address enantiocontrol in the vinylogous N H inser-
tion reaction, 3-(tert-butyldimethylsiloxy)-2-diazo-3-pent-
enoates 1b (R1 = Me, R2 = Me) and 1c (R1 = Me, R2 = Bn;
Bn = benzyl) were treated with hydrazone 3a in the presence
of various chiral dirhodium catalysts, and the results from this
investigation are summarized in Table 1. Except for [Rh2{(S)-
pttl}4] (entry 4; see Table 1 for ligand structures), the
phthalimide/amino acid-based chiral dirhodium carboxylate
catalysts reported by Hashimoto et al.[12] showed higher
reactivity and enantioselectivity than the [Rh2{(S)-dosp}4]
catalyst reported by Davies et al.[13] (entries 1 and 2 vs.
entry 7), and dirhodium carboxamidate catalysts[14] were
ineffective (entries 5 and 6). Adopting benzyl enoldiazoace-
tate 1c instead of methyl ester 1b resulted in an improvement
=
92% ee (entry 16). The Z geometry of the newly formed C C
bond in 8 was further confirmed by a 1D-nOe study.[9]
Having established the optimized conditions for the
ꢀ
vinylogous N H insertion, we investigated the potential of 8
to undergo Mannich addition to complete the tetrahydropyr-
idazine synthesis. Heating (1008C in toluene for 3 h) did not
provide any ring-closed product, and 8 was recovered intact.
Various achiral Lewis acids were examined for the cyclization
of 8c,[15] and 5 mol% of Sc(OTf)3 (OTf = trifluoromethane-
sulfonate) was found to be superior to other acid catalysts in
smoothly promoting the formation of 1,2,3,6-tetrahydropyr-
idazine 10a and in maintaining the high enantiomeric excess
of the reactant. However, product diastereoselectivity was
moderate (Table 2, entry 1, cis/trans = 72:28). In our efforts to
influence diastereocontrol by changing the size of the tert-
butyldimethylsilyl (TBS) group, various organosilyl protect-
ing groups were used on the enoldiazoacetate reactants.[16]
ꢀ
Table 1: Optimization for the enantioselective vinylogous N H insertion
of a phenylhydrazone.[a]
T [8C] Solvent Yield ee [%][c]
Table 2: Optimization of Lewis acid catalyzed Mannich addition for the
Entry
1
Catalyst (9)
synthesis of 1,2,3,6-tetrahydropyridazines.[a]
[%][b]
1
2
3
4
5
6
7
8
1b [Rh2{(R)-ptpa}4] (9a)
1b [Rh2{(R)-pta}4] (9b)
1b [Rh2{(R)-pta}4] (9b)
1b [Rh2{(S)-pttl}4] (9c)
1b [Rh2{(S)-mepy}4] (9 f)
1b [Rh2{(S)-mppim}4] (9g)
1b [Rh2{(S)-dosp}4] (9h)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-pta}4] (9b)
1c [Rh2{(R)-ptl}4] (9d)
1c [Rh2{(S)-ptn}4] (9e)
25 CH2Cl2
25 CH2Cl2
78
71
68
<5
<5
<5
65
91
85
78
72
75
71
77
75
82
79
38
45
51
–
–
–
ꢀ35
56
69
74
69
68
70
82
80
92
ꢀ83
0
CH2Cl2
25 CH2Cl2
25 CH2Cl2
25 CH2Cl2
0
0
0
CH2Cl2
CH2Cl2
toluene
9
10
11
12
13
14
15
16
17
ꢀ25 toluene
ꢀ25 ClC6H5
ꢀ25 FC6H5
ꢀ25 CF3C6H5
ꢀ40 toluene
ꢀ40 TBME
ꢀ40 toluene
ꢀ40 toluene
Entry
1
Solvent
T [8C] d.r. (10a)[b] Conversion ee (cis/trans)
cis/trans
8!10 [%][c]
10a [%][d]
1
2
3
1c CH2Cl2
1d CH2Cl2
1e CH2Cl2
1e toluene
1e CH2Cl2
1e CH2Cl2
1e acetonitrile 25
1e acetonitrile 50
1e acetonitrile
25
25
25
25
0
72:28
70:30
76:24
60:40
76:24
23:77
80:20
50:50
82:18
>95
>95
>95
65
>95
>95
>95
>95
>95
92/–
<5
96/–
95.5/–
95.5/–
–/93
96/93
95/93
96/93
4[e]
5
6
7
50
[a] Reactions were carried out over 2 h on a 0.10 mmol scale:
1 (0.12 mmol), 3a (0.10 mmol), 4 ꢀ MS (50 mg), in 1.0 mL solvent with
2.0 mol% catalyst at the stated temperature. [b] Yield of isolated
product. Except for entries 4–6, reactions proceeded to 100% comple-
tion. [c] Determined by HPLC analysis on a chiral stationary phase.
TBME=tert-butyl methyl ether.
8
9[f]
0
[a] Reactions were carried out on a 0.10 mol scale: 1 (0.12 mmol), 3a
(0.10 mmol), and 4 ꢀ MS (50 mg) in 1.0 mL toluene with 2.0 mol%
[Rh2{(R)-ptl}4] at ꢀ408C for 2 h. The reaction solution was then passed
through a short flash chromatography column (dimensions:
0.5 cmꢁ10 mm), the solvent was evaporated, and the solvent for the
Mannich addition was added along with Sc(OTf)3 (5.0 mol%) at the
1
indicated temperature. [b] Determined from the H NMR spectra of the
1
reaction mixtures. [c] Determined from the H NMR spectra of the
reaction mixtures based on limiting reagent 8. [d] Determined by HPLC
analysis on a chiral stationary phase; see the Supporting Information.
[e] The reaction mixture from the first step was used for the second step
without removal of the solvent. [f] The reaction was run overnight at 08C.
Bn=benzyl, TBS=tert-butyldimethylsilyl, TIPS=triisopropylsilyl,
TMS=trimethylsilyl, OTf=trifluoromethanesulfonate.
2
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
ꢀ
The labile TMS derivative 1d underwent vinylogous N H
(entries 12 and 13) gave mixtures of the corresponding
tetrahydropyridazines 10l or 10m along with hydrolyzed
insertion, but gave the hydrolyzed product derived from 8
that, although proceeding to 10a,[10] did so with complete
racemization (entry 2). However, with the triisopropylsilyl
(TIPS) derivative 1e, 10a was formed with 96% ee under
same conditions (entry 3), although the diastereoselectivity
was only modestly improved to 76:24. Further investigation of
the conditions for optimization found that solvent plays an
important role in the Mannich addition process; the reaction
performed in toluene was much slower than that which was
run in dichloromethane and occurred with much lower
diastereoselectivity, but when acetonitrile was used as the
reaction medium the diastereoselectivity improved to 82:12
(entry 9). The major cis diastereoisomer was confirmed by
single-crystal X-ray diffraction analysis.[17] Surprisingly, the
reaction performed in dichloromethane at 508C in a closed
container reversed the diastereoselectivity while retaining
high enantioselectivity (entry 6).
ꢀ
racemic ketone from the vinylogous N H insertion reac-
tion.[10] However, these sterically hindered substrates pro-
duced only one tetrahydropyridazine diastereoisomer with
enantiomeric excesses of up to 97%.
Enoldiazoacetate 1, which has a methyl group in the
vinylogous position, is optimum for enantioselective vinoyl-
ogous reactions with hydrazones. However, enoldiazoacetates
with larger substituents in the vinylogous position (R = Et,
Ph, Bn) were deleterious to the reaction. Enantioselectivity
ꢀ
decreased when R = Et (Scheme 3), and vinylogous N H
The generality of this enantioselective cascade reaction
was further investigated using these optimum conditions, and
the results of this investigation are given in Table 3. Product
yields were high, and 1,2,3,6-tetrahydropyridazines 10 were
the sole isolated reaction products. The position of the chloro
substituent on the aryl group did not affect the efficiency of
the reaction, and these substrates underwent the two-step
process with high stereoselectivity (entries 1–3). The elec-
tronic nature of the substituents had little influence on
reactivity and selectivity (entries 4–10), except in cases where
Scheme 3. Effect on enantioselective cascade sequences with enoldia-
zoacetates having bulky substituents at the vinylogous position.
insertion was effectively inhibited when R = Ph or Bn. Davies
ꢀ
reactant solubility required that the vinylogous N H insertion
reaction be conducted at higher temperature (entries 5, 6, and
11–13). Reactions with bulky mesityl and anthranyl substrates
et al. have reported that vinylogous carbenoid reactions from
ꢀ
O H insertion reactions using dirhodium(II) catalysts are
highly restricted, but can be overcome in selected cases with
the use of more electron deficient silver(I), molybdenum, or
diruthenium(I) catalysts.[8] The data in Scheme 3 suggests that
steric effects are primarily responsible for the reactivity and
selectivity that is observed for reactions with hydrazones.
In summary, we have developed a cascade transformation
that enables the efficient preparation of highly substituted
1,2,3,6-tetrahydropyridazines[18] starting from enoldiazoace-
tates and hydrazones in good overall yields, high diastereo-
selectivities, and excellent enantioselectivities that are con-
trolled by catalysts and conditions. The sequence of reactions
is triggered by RhII-catalyzed dinitrogen extrusion followed
Table 3: Enantioselective cascade sequences synthesis of 1,2,3,6- tetra-
hydropyridazines from 1e and hydrazones.[a]
Entry Ar (3)
10
d.r.[b]
Yield
[%][c]
ee (cis/trans)
[%][d]
ꢀ
1
2
4-ClC6H4 (3a)
10a
10b
10c
10d
10e
10 f
10g
10h
10i
82:18
84:16
81:19
76:24
81:19
95:5
86:14
83:17
79:21
77
82
73
91
90
72
80
85
77
96/93
95/93
97/95
92/91
92/88
90/78
91/91
90/93
78/77
91/–
by asymmetric vinylogous N H insertion into hydrazones.
3-ClC6H4 (3b)
2-ClC6H4 (3c)
4-MeOC6H4 (3d)
4-NO2C6H4 (3e)
4-BrC6H4 (3 f)
4-FC6H4 (3g)
4-MeC6H4 (3h)
2-furyl (3i)
Subsequent Lewis acid promoted Mannich addition of 8
smoothly produces 1,2,3,6-tetrahydropyridazines 10 with high
diastereocontrol (Scheme 4). To the best of our knowledge,
this is the first example of highly enantioselective vinylogous
3[e]
4
5[e,f]
6[f]
7
ꢀ
N H insertion. Further expansion of vinylogous reactivity
with enoldiazoacetates are being pursued.
8
9
10
11[f]
12[f]
13[e,f]
4-PhC6H4 (3j)
2-CF3C6H4 (3k)
2,4,6-Me3C6H2 (3l) 10l
10j
10k
>95:5 70
>95:5 67
>95:5 35 (57) 89/–
87/–
Experimental Section
Enoldiazoacetate 1e (0.12 mmol) in toluene (0.5 mL) was added over
a 1 h period by a syringe pump at the indicated temperature (either
ꢀ40 or ꢀ208C) to an oven-dried flask containing a magnetic stirring
bar, hydrazone 3 (0.1 mmol), 4 ꢀ molecular sieves (50 mg), and
[Rh2{(R)-ptl}4] (2.0 mol%) in toluene (0.5 mL). The reaction mixture
was stirred for another hour under these conditions, then passed
through a short flash column of silica gel (dimensions: 0.5 cm ꢁ 10 cm)
and, after removal of the solvent under reduced pressure, acetonitrile
9-anthryl (3m)
10m >95:5 29 (60) 97/–
1
[a] See the Experimental Section. [b] Determined from the H NMR
spectra of the reaction mixtures. [c] Yield of isolated 10 (cis+trans) based
on limiting reagent 3. Numbers in parentheses are yields of hydrolyzed
product from the vinylogous N H insertion [d] Determined by HPLC
analysis on a chiral stationary phase. [e] The second step was performed
ꢀ
at room temperature. [f] The first step was performed at ꢀ208C.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
Hlobilovꢂ, G. Zahn, H.-U. Reißig, Eur. J. Org. Chem. 2005, 1003;
e) H. K. Grover, T. P. Lebold, M. A. Kerr, Org. Lett. 2011, 13,
220; f) A. I. Gerasyuto, R. P. Hsung, N. Sydorenko, B. Slafer, J.
Org. Chem. 2005, 70, 4248.
[6] With the exception of [3+3]-cycloaddition reactions, syntheses
of 1,2,3,6-tetrahydropyridazine are rare; see: a) S. Xu, R. Chen,
Z. Qin, G. Wu, Z. He, Org. Lett. 2012, 14, 996; b) R. Na, C. Jing,
Q. Xu, H. Jiang, X. Wu, J. Shi, J. Zhong, M. Wang, D. Benitez, E.
Tkatchouk, W. A. Goddard, H. Guo, O. Kwon, J. Am. Chem.
Soc. 2011, 133, 13337; c) L. Shen, L. Sun, S. Ye, J. Am. Chem. Soc.
2011, 133, 15894; d) Q. Zhang, L. Yang, X. Tong, J. Am. Chem.
Soc. 2010, 132, 2550; e) A. J. Oelke, D. J. France, T. Hofmann, G.
Wuitschik, S. V. Ley, Angew. Chem. 2010, 122, 6275; Angew.
Chem. Int. Ed. 2010, 49, 6139; f) V. Nair, S. C. Mathew, A. T.
Biju, E. Suresh, Angew. Chem. 2007, 119, 2116; Angew. Chem.
Int. Ed. 2007, 46, 2070; g) H. H. Jensen, L. Lyngbye, A. Jensen,
M. Bols, Chem. Eur. J. 2002, 8, 1218.
[7] For enantioselective heteroatom-carbene insertion reactions,
see: a) S.-F. Zhu, B. Xu, G.-P. Wang, Q.-L. Zhou, J. Am. Chem.
Soc. 2012, 134, 346; b) B. Liu, S.-F. Zhu, W. Zhang, C. Chen, Q.-
L. Zhou, J. Am. Chem. Soc. 2007, 129, 5834; c) C. J. Moody,
Angew. Chem. 2007, 119, 9308; Angew. Chem. Int. Ed. 2007, 46,
9148; d) B. Xu, S. Zhu, X. Xie, J. Shen, Q. Zhou, Angew. Chem.
2011, 123, 11685; Angew. Chem. Int. Ed. 2011, 50, 11483; e) E. C.
Lee, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 12066.
Scheme 4. Tandem catalysis of the [3+3]-cycloaddition reaction from
ꢀ
vinylogous N H insertion/Mannich addition.
(2.0 mL) was added. This solution was transferred to a reaction tube
containing a magnetic stirring bar, and the temperature of the
solution was decreased to 08C (or to room temperature, as indicated),
followed by the addition of Sc(OTf)3 (5.0 mol%). The reaction
ꢀ
[8] For non-asymmetric vinylogous O H insertion, see: a) J. H.
Hansen, H. M. L. Davies, Chem. Sci. 2011, 2, 457; b) H. M. L.
Davies, Y. Yokota, Tetrahedron Lett. 2000, 41, 4851; c) Y.
Sevryugina, B. Weaver, J. Hansen, J. Thompson, H. M. L.
Davies, M. A. Petrukhina, Organometallics 2008, 27, 1750; for
1
mixture was stirred for another 4 h, and then subjected to H NMR
spectroscopic analysis after solvent removal to determine product
diastereoselectivity. The crude reaction mixture was purified by
column chromatography on silica gel (eluent hexanes/EtOAc = 100:0
to 90:10) to give the pure tetrahydropyridazines 10.
ꢀ
asymmetric vinylogous C H functionalization, see: d) Y. Lian,
H. M. L. Davies, Org. Lett. 2012, 14, 1934.
[9] CCDC 881732 (8a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
Received: May 22, 2012
Revised: July 3, 2012
Published online: && &&, &&&&
[10] See the Supporting Information.
[11] For selected examples of Mannich addition with silicon enolates,
see: a) T. Akiyama, J. Itoh, K. Yokota, K. Fuchibe, Angew.
Chem. 2004, 116, 1592; Angew. Chem. Int. Ed. 2004, 43, 1566;
b) M. Sugiura, S. Kobayashi, Angew. Chem. 2005, 117, 5306;
Angew. Chem. Int. Ed. 2005, 44, 5176; c) M. S. Taylor, E. N.
Jacobsen, Angew. Chem. 2006, 118, 1550; Angew. Chem. Int. Ed.
2006, 45, 1520; d) M. M. B. Marques, Angew. Chem. 2006, 118,
356; Angew. Chem. Int. Ed. 2006, 45, 348.
[12] a) S. Hashimoto, N. Watanabe, T. Sato, M. Shiro, S. Ikegami,
Tetrahedron lett. 1993, 34, 5109; b) H. Tsutsui, T. Abe, S.
Nakamura, M. Anada, S. Hashimoto, Chem. Pharm. Bull. 2005,
53, 1366; c) S. Kitagaki, M. Anada, O. Kataoka, K. Matsuno, C.
Umeda, N. Watanabe, S. Hashimoto, J. Am. Chem. Soc. 1999,
121, 1417.
[13] a) J. Wu, J. Becerril, Y. Lian, H. M. L. Davies, J. A. Porco, Jr.,
J. S. Panek, Angew. Chem. 2011, 123, 6060; Angew. Chem. Int.
Ed. 2011, 50, 5938; b) R. P. Reddy, G. H. Lee, H. M. L. Davies,
Org. Lett. 2006, 8, 3437; c) H. M. L. Davies, P. R. Bruzinski,
D. H. Lake, N. Kong, M. J. Fall, J. Am. Chem. Soc. 1996, 118,
6897; d) Y. Lian, K. I. Hardcastle, H. M. L. Davies, Angew.
Chem. 2011, 123, 9542; Angew. Chem. Int. Ed. 2011, 50, 9370.
[14] M. P. Doyle, M. A. McKervey, T. Ye, Modern Catalytic Methods
for Organic Synthesis with Diazo Compounds, Wiley, New York,
NY, 1998.
Keywords: asymmetric catalysis · cycloaddition ·
enantioselectivity · rhodium · tetrahydropyridazines
.
[1] For reviews of formal [3+3]-cycloaddition reactions, see: a) R. P.
Hsung, L.-L. Wei, H. M. Sklenicka, H. C. Shen, M. J. McLaugh-
lin, L. O. Zehnder, Org. Biomol. Chem. 2005, 3, 1349; b) G. S.
Buchanan, J. B. Feltenberger, R. P. Hsung, Curr. Org. Synth.
2010, 7, 363; for enantioselective organocatalytic formal [3+3]-
cycloadditions, see: c) H. M. Sklenicka, R. P. Hsung, M. J.
McLaughlin, L.-L. Wie, A. I. Gerasyuto, W. B. Brennessel, J.
Am. Chem. Soc. 2002, 124, 10435; d) B.-C. Hong, M.-F. Wu, H.-
C. Tseng, J.-H. Liao, Org. Lett. 2006, 8, 2217; e) A. Chan, K. A.
Scheidt, J. Am. Chem. Soc. 2007, 129, 5334.
[2] a) F. Liu, D. Qian, L. Li, X. Zhao, J. Zhang, Angew. Chem. 2010,
122, 6819; Angew. Chem. Int. Ed. 2010, 49, 6669; b) R. Shintani,
T. Hayashi, J. Am. Chem. Soc. 2006, 128, 6330.
[3] X. Wang, X. Xu, P. Y. Zavalij, M. P. Doyle, J. Am. Chem. Soc.
2011, 133, 16402.
[4] a) N. D. Shapiro, Y. Shi, F. D. Toste, J. Am. Chem. Soc. 2009, 131,
11654; b) C. Perreault, S. R. Goudreau, L. E. Zimmer, A. B.
Charette, Org. Lett. 2008, 10, 689.
[15] The use of In(OTf)3 or Cu(OTf)2 gave similar results, but
required longer reaction times.
[5] a) Y. Hayashi, H. Gotoh, R. Masui, H. Ishikawa, Angew. Chem.
2008, 120, 4076; Angew. Chem. Int. Ed. 2008, 47, 4012; b) K.
Kanao, Y. Miyake, Y. Nishibayashi, Organometallics 2010, 29,
2126; c) A. Al-Harrasi, H.-U. Reißig, Angew. Chem. 2005, 117,
6383; Angew. Chem. Int. Ed. 2005, 44, 6227; d) M. Helms, W.
Schade, R. Pulz, T. Watanabe, A. Al-Harrasi, L. Fisera, I.
[16] The Z/E ratios of 1b–1e were determined by 1H NMR
spectroscopy: 1b = 90:10, 1c = 89:11, 1d = 96:4, 1c = 82:18.
See the Supporting Information for details. a) H. M. L. Davies,
Z.-Q. Peng, J. H. Houser, Tetrahedron Lett. 1994, 35, 8939; b) Y.
4
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!

Angewandte
Chemie
Ueda, G. Roberge, V. Vinet, Can. J. Chem. 1984, 62, 2936;
c) H. M. L. Davies, G. Ahmed, M. R. Churchill, J. Am. Chem.
Soc. 1996, 118, 10774; d) K. Kundu, M. P. Doyle, Tetrahedron:
Asymmetry 2006, 17, 574; e) X. Xu, P. Y. Zavalij, W. Hu, M. P.
Doyle, Angew. Chem. 2011, 123, 11348; Angew. Chem. Int. Ed.
2011, 50, 11152.
[18] 1,2,5,6-Tetrahydropyridazines are structural components of
potent novel inhibitors of human immunodeficiency virus
(HIV) and hepatitis C virus (HCV); see: a) W. J. Watkins, A. S.
Ray, L. S. Chong, Curr. Opin. Drug Discovery Dev. 2010, 13, 441;
b) A. Manlove, M. P. Groziak in Progress in Heterocyclic
Chemistry, Vol 21 (Eds.: G. Gordon, J. John) Elsevier Ltd.,
Oxford, UK, 2009, pp. 375 – 414; c) F. Ruebsam, et al., Bioorg.
Med. Chem. Lett. 2008, 18, 3616; d) F. Stefania, A. Stefano, L. B.
Maria, D. L. Laura, C. Frauke, G. Rosaria, J. Heterocycl. Chem.
2009, 46, 1420.
[17] CCDC 881733 (10a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Cascade Catalysis
X. Xu, P. Y. Zavalij,
M. P. Doyle*
&&&& — &&&&
Synthesis of Tetrahydropyridazines by
a Metal–Carbene-Directed
A versatile cascade of reactions, triggered
that produces highly substituted 1,2,3,6-
tetrahydropyridazines in up to 97% ee
with high yield and diastereocontrol has
been developed.
Enantioselective Vinylogous N H
Insertion/Lewis Acid-Catalyzed
by RhII-catalyzed diazo decomposition
ꢀ
ꢀ
followed by a vinylogous N H insertion/
Diastereoselective Mannich Addition
Lewis acid-catalyzed Mannich addition,
6
www.angewandte.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!