Catalytic asymmetric construction of chiral hydropyridazines via conjugate addition of N-monosubstituted hydrazones to enones

Article abstract of DOI:10.1021/ol4020865

The first example of a highly enantioselective and scalable formal diaza-ene reaction between N-monosubstituted hydrazones and enones catalyzed by a simple chiral primary-second diamine salt has been developed. The catalytic process provides a highly prac

Full text of DOI:10.1021/ol4020865

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Catalytic Asymmetric Construction of
Chiral Hydropyridazines via Conjugate
Addition of N‑Monosubstituted
Hydrazones to Enones
Wenbin Wu, Xiaoqian Yuan, Juan Hu, Xinxin Wu, Yuan Wei, Zunwu Liu, Junzhu Lu,
and Jinxing Ye*
Engineering Research Centre of Pharmaceutical Process Chemistry, Ministry of
Education, School of Pharmacy, East China University of Science and Technology,
130 Meilong Road, Shanghai 200237, China
yejx@ecust.edu.cn
Received July 24, 2013
ABSTRACT
The first example of a highly enantioselective and scalable formal diazaꢀene reaction between N-monosubstituted hydrazones and
enones catalyzed by a simple chiral primary-second diamine salt has been developed. The catalytic process provides a highly practical and
stereoselective synthetic method for chiral hydropyridazines.
The chemistry of hydropyridazine derivatives has been
extensively studied reflecting their wide range of pharma-
cological activities, performing as anti-inflammatory
and cardiovascular agents, antidepressants, and GABA
antagonists.1 Tetrahydropyridazine derived molecules
levosimendan and pimobendan were used as an ionotropic
agent and cardiotonic vasodilator, respectively. 1,4-
Dihydropyridazine derivatives acted as vasodilators, cor-
onary therapeutic agents, and spasmolytic agents, parti-
cularly when the substituent at C4 was aromatic.2 Despite
this, only limited asymmetric methodologies have been
Figure 1. Design approaches for chiral hydropyridazines.
realized for the synthesis of hydropyridazines.3,4 Moti-
(1) (a) Heinisch, G.; Kopelent-Frank, H. In Progress in Medicinal
vated by the variable and significant biological activities
Chemistry, Vol 29; Ellis, G. P.; Luscombe, D. K. Elsevier: Amsterdam,
observed in tetrahydropyridazines and 1,4-dihydropyrida-
zines, we envisioned that the hydropyridazine skeleton
1992. (b) Joule, J. A.; Mills, K. Hetreocyclic Chemistry, 5th ed.; Blackwell
Science, Oxford, 2000. (c) Kolar, P.; Tiler, M. In Advances in Heterocyclic
Chemistry, Vol. 75; Katritzky, A. R. Academic Press: San Diego, 2000.
(d) Testa, R.; Leonardi, A.; Tajana, A.; Riscassi, E.; Magliocca, R.; Sartani, A.
Cardiovasc. Drug Rev. 1997, 15, 187–219.
(2) (a) Frankowiak, G.; Meyer, H.; Bossert, F.; Heise, A.; Kazda, S.;
Stoepel, K.; Towart, R.; Wehinger, E. U.S. Patent 1982, No. 4348395. (b)
Scarsdale, B. L.; Ossining, H. J.; Shroff, J. R.; Conn. R. U.S. Patent 1984, No.
4,435,395. (c) Riehen, A. V. U.S. Patent 1985, No. 4491581.
(3) For selected examples on the synthesis of achiral hydropyridazines:
(a) Nair, V.; Mathew, S. C.; Biju, A. T.; Suresh, E. Angew. Chem., Int.
Ed. 2007, 46, 2070–2073. (b) Oelke, A. J.; France, D. J.; Hofmann, T.;
Wuitschik, G.; Ley, S. V. Angew. Chem., Int. Ed. 2010, 49, 6139–6142. (c)
Zhang, Q.; Yang, L.; Tong, X. J. Am. Chem. Soc. 2010, 132, 2550–2551.
r
10.1021/ol4020865
XXXX American Chemical Society

could be constructed through sequential base-catalytic
asymmetric conjugate reactions between enones and
N-monosubstituted hydrazones using an umpolung
strategy,5 intramolecular aminal formation, and subse-
quent dehydrationinonepot(Figure1),whichcouldenrich
asymmetric access to this type of chiral diaza-heterocycle.6
Hydrazones, which show very diverse reactivity, can be
used as formyl anion equivalents in organic synthesis,
where they participate in nucleophileꢀelectrophile interac-
tions.7 Conventionally, N,N-dialkylhydrazones were ap-
plied in the total synthesis of natural products as practical
chiral auxiliary reagents8 and have been reported as useful
ligands and catalysts9 in asymmetric reactions. Besides,
differing from the reactions where they acted as electro-
philes,10 conjugate additions where N,N-dialkylhydrazones
were used as nucleophiles have been realized recently.11ꢀ13
In comparison, asymmetric conjugate addition of
N-monosubstituted hydrazones in organocatalysis still
remains problematic and challenging due to the competi-
tive aza-Michael addition14 and carbo-Michael addition15
(formal diaza-ene reaction). The site selectivity was depen-
dent on the N-monosubstituted hydrazones used in each
organocatalytic reaction.
Herein, our ongoing interest was extended to an efficient
and highly enantioselective formal diazaꢀene reaction be-
tween N-monosubstituted hydrazones with broad substrate
variables and enones, avoiding a competitive reversible16
aza-Michael reaction simultaneously, which have not been
reported to the best of our knowledge.
Table 1. Reaction Optimizationa
(4) For selected examples on asymmetric synthesis of hydropyrida-
zines: (a) Shen, L.-T.; Sun, L.-H.; Ye, S. J. Am. Chem. Soc. 2011, 133,
15894–15897. (b) Xu, X.; Zavalij, P. Y.; Doyle, M. P. Angew. Chem., Int.
Ed. 2012, 51, 9829–9833. (c) Das, A.; Volla, C. M. R.; Atodiresei, I.;
Bettray, W.; Rueping, M. Angew. Chem., Int. Ed. 2013, 52, 8008–8011.
(5) For reviews on umpolung strategies, see: (a) Grobel, B. T.;
Seebach, D. Synthesis 1977, 357–402. (b) Seebach, D. Angew. Chem.,
Int. Ed. Engl. 1979, 18, 239–258. (c) Enders, D.; Balensiefer, T. Acc.
Chem. Res. 2004, 37, 534–541. (d) Bugaut, X.; Glorius, F. Chem. Soc.
Rev. 2012, 41, 3511–3522.
(6) For selected examples on the synthesis of chiral diaza-heterocycles
catalyzed by a transition metal, see: (a) Kanemasa, S.; Kanai, T.
J. Am. Chem. Soc. 2000, 122, 10710–10711. (b) Yamashita, Y.; Kobayashi,
K. J. Am. Chem. Soc. 2004, 126, 11279–11282. (c) Sibi, M. P.; Stanley,
L. M.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127, 8276–8277. (d) Kano,
T.; Hashimoto, T.; Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2174–2175.
For selected examples on synthesis of chiral aza-heterocycles catalyzed by
T
time
(h)
yield
(%)b
ee of
entry
cat.
4a/4b (°C)
5/50
5/50(%)c
1
1aꢀ1e
2a
2b
2c
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
rt
rt
rt
rt
rt
rt
rt
rt
rt
0
24
24
24
24
3
44ꢀ58d <1/99 n.d./0
€
an organocatalyst, see: (e) Muller, S.; List, B. Angew. Chem., Int. Ed. 2009,
2
96
97
96
96
95
95
94
95
94
90
94
3/97
n.d./0
€
ꢀ
48, 9975–9978. (f) Muller, S.; List, B. Synthesis 2009, 2171–2178. (g) Mahe,
3
<1/99 n.d./0
40/60 90/0
ꢁ
O.; Dez, I.; Levacher, V.; Briere, J.-F. Angew. Chem., Int. Ed. 2010, 49,
7072–7075. (h) Campbell, N. R.; Sun, B.; Singh, R. P.; Deng, L. Adv. Synth.
4
5
2c
7/93
89/0
Catal. 2011, 353, 3123–3128.
(7) Forreviews, see:Brehme, R.;Enders, D.;Fernandez, R.;Lassaletta,
J. M. Eur. J. Org. Chem. 2007, 5629–5660.
6e
7f
8g
9
2c
24
24
48
72
72
72
72
38/62 90/0
42/58 90/0
2c
(8) For excellent reviews on hydrazones used as practical chiral
auxiliary reagents in total synthesis: (a) Job, A.; Janeck, C. F.; Bettray,
W.; Peters, R.; Enders, D. Tetrahedron2002, 58, 2253–2329. (b) Samment,
K.; Gastl, C.; Baro, A.; Laschat, S.; Fischer, P.; Fetting, I. Adv. Synth.
Catal. 2010, 352, 2281–2290.
(9) For an excellent review on hydrazones used as ligands and
catalysts: Lazny, R.; Nodzewska, A. Chem. Rev. 2010, 110, 1386–1434.
(10) For reviews, also see ref 7and: (a) Enders, D.; Bolkenius, M.;
2c
93/7
96/n.d.
2c
80/20 90/0
27/73 92/0
10
11
12h
2c
2c
ꢀ40
rt
2/98
n.d./0
2c
>99/1 90/n.d.
a Reaction conditions: 0.20 mmol of 3a, 0.30 mmol of 4a, catalyst
(10 mol %), and acid (20 mol %) were stirred in CPME (C = 0.5 M) at rt.
b Yield was determined after chromatography. c Enantiomeric excess
was determined by chiral HPLC. d Yields for catalysts 1aꢀ1e are 44%,
55%, 58%, 51%, 58% respectively. e 10 mol % acid. f 30 mol % acid.
g 160 mol % acid. h 20 mol % catalyst and 40 mol % acid. The ratio of the
two products was determined by 1H NMR of the crude reaction and
confirmed by chiral HPLC. All products’ dr were >20/1. CPME =
Cyclopentyl methyl ether.
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We initiated our studies by exploring the nucleophilic
character of N-monosubstituted hydrazones 4. Choosing
the model reaction between compounds 3a and 4a, we
focused our studies on a series of achiral amines with
(13) (a) Dixon, D.; Tillman, A. L. Synlett 2005, 2635–2638. (b)
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B
Org. Lett., Vol. XX, No. XX, XXXX

variouspKa values. Onlythe aza-Michael addition product
was detected when the reaction was catalyzed by 1aꢀ1e’s
o-fluorobenzoic acid (OFBA) salt with a 44% to 58% yield
(Table 1, entry 1). Next, we turned our attention to bifunc-
tional chiral diamine catalysts. Using 9-amino(9-deoxy)-
epi-quinine’s OFBA salt as the catalyst, the aza-Michael
product was detected with a 96% yield while 3% trace
formal diaza-ene reaction product was detected (entry 2).
To our delight, 40% of the desired product with 90% ee
was observed catalyzed by diamine 2cderived from a chiral
amino acid17 in the presence of OFBA after stirring for
24 h (entry 4), while only a racemic aza-Michael addition
product was detected catalyzed by 2b (entry 3). With these
distinct results in hand, we attempted to study the compe-
titive reaction between aza/carba-Michael additions. The
aza-Michael reaction completed in 3 h catalyzed by 2c with
7% of the formal diazaꢀene reaction product (entry 5).
After testing the amount of the acidic additives, it was
found thatthe results were basically the same(entries 6ꢀ7).
Considering the reversible aza-Michael reaction step, the
reaction time was extended to 72 h and the ratio of the two
products was raised to 80/20 (entry 9). Moreover, when
160 mol % of OFBA was added, the reaction was com-
pleted in 48 h and 93% of the formal diazaꢀene reaction
product was obtained with 96% ee (entry 8). Lowering the
reaction temperature could selectively synthesize the aza-
Michael product but with poor enantioselectivity (entries
10ꢀ11). On the other hand, only the formal diazaꢀene
reaction product was observed using monosubstituted
N-aryl hydrazone 4b with a 94% yield and 90% ee without
the aza-Michael reaction product (entry 12).
As shown in Scheme 1 (top), the ratio of aza-Michael/
carba-Michael reaction products slowly changed from
93/7 to 1/>99 along with extending the reaction time
(for details, see Supporting Information (SI)). To prove
the validity of the proposed reaction process, control ex-
periments were carried out (Scheme 1, bottom). Full
conversion of the carba-Michael reaction product with
83% ee was obtained when racemic aza-Michael product
5b0 was used as the only substrate catalyzed by 2c and
starting materials 3a and 4b were detected in the process of
the reaction. The enantioselectivity was raised to 93% by
adding 2 equiv of cyclohex-2-enone.
After the optimal conditions had been established, the
substrate scope was investigated. As summarized in Scheme 2,
electron-withdrawing aromatic aldehyde related mono-
substituted N-alkyl hydrazones were found to be tolerant
of the reaction, affording the products 5a to 5f with ex-
cellent yields and 91ꢀ96% ee. 2-Hydrazinylethanol, iso-
propylhydrazine, and benzylhydrazine related hydrazones
were also tested, leading to the products (5g to 5i) with
excellent enantioselectivities. Less than 5% of conversion
was detected when N,N-dialkylhydrazones were used as
the substrate (5j). When the reaction between monosub-
stituted N-aryl hydrazone 4b and cyclic enones was eval-
uated, the formal diazaꢀene reaction product was detected
when cyclohex-2-enone was employed with a 94% yield
and 90% ee (5k).
Scheme 2. Asymmetric Enantioselective Reaction of N-Mono-
substituted Hydrazones To Synthesize Bicycle 1,4,5,6-Tetrahy-
dropyridazinesa
Scheme 1. Competitive Aza-Michael and Carba-Michael
Reactions and Control Experiments
a Reaction conditions: 0.20 mmol of 3, 0.30 mmol of 4, catalyst 2c
(10 mol %), and o-F-PhCO2H (160 mol %) were stirred in CPME (C =
0.5 M) at rt for 48 h. b 2c (20 mol %) and o-F-PhCO2H (40 mol %). c For
72 h. Yields refer to isolated yields. The ee value was determined by
chiral HPLC analysis.
(17) (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc. 2005, 127,
10504–10505. (b) Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas,
C. F., III. J. Am. Chem. Soc. 2007, 129, 288–289. (c) Yang, Y.-Q.; Zhao,
G. Chem.;Eur. J. 2008, 14, 10888–10891. (d) Li, J.; Luo, S.; Cheng,
J.-P. J. Org. Chem. 2009, 74, 1747–1750. (e) Hong, L.; Sun, W.; Liu, C.;
Wang, L.; Wong, K.; Wang, R. Chem.;Eur. J. 2009, 15, 11105–11108.
(f) Huang, H.; Jin, Z.; Zhu, K.; Liang, X.; Ye, J. Angew. Chem., Int. Ed.
2011, 50, 3232–3235. (g) Hu, S.; Zhang, L.; Li, J.; Luo, S.; Cheng, J.-P.
Eur. J. Org. Chem. 2011, 3347–3352. (h) Yu, F.; Hu, H.; Gu, X.; Ye, J.
Org. Lett. 2012, 14, 2038–2041. (i) Wu, W.; Huang, H.; Yuan, X.; Zhu,
K.; Ye, J. Chem. Commun. 2012, 48, 9180–9182. (j) Wu, W.; Li, X.;
Huang, H.; Yuan, X.; Lu, J.; Zhu, K.; Ye, J. Angew. Chem., Int. Ed. 2013,
52, 1743–1747. (k) Huang, H.; Wu, W.; Zhu, K.; Hu, J.; Ye, J. Chem.;
Eur. J. 2013, 19, 3838–3841.
After this, we attempted to synthesize 1,4-dihydropyi-
dazines. As summarized in Scheme 3, enones with different
electron-withdrawing and -donating substituents at ortho,
meta, and para positions on the aromatic ring were found
to be tolerant of the reaction, affording a 76ꢀ99% yield
and 92ꢀ94% ee (6aꢀ6i). Interestingly, bridged-ring com-
pound 6f was synthesized through the following oxa-
Michael addition to the iminium intermediate in 90% yield
with 91% ee. Extending the length of the alkyl chain in the
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Asymmetric Enantioselective Reaction of N-Mono-
substituted Hydrazones To Synthesize 1,4-Dihydropyridazinesa
Scheme 4. Transformations of the Formal DiazaꢀEne Reaction
Products
Finally, we tried to demonstrate the synthetic transforma-
tions of these products (Scheme 4). 1,4-Dihydropyridazine
6a was successfully converted to 1,4,5,6-tetrahydropyrida-
zine 7a with >20/1 dr by reduction with NaCNBH3 at 0 °C
in the presence of AcOH. 6a was hydrolyzed to form a
carbonyl group in situ and immediately transformed into
thiosemicarbazide related hydrazone 7b by refluxing in
MeOH/AcOH overnight. 7b was obtained in 85% yield
via single-crystal X-ray analysis, and the result revealed the
configuration to be R (for details see SI). Multisubstituted
pyrroles 7c and 7d were successfully synthesized in good
yield (for X-ray analysis details see SI) utilizing carbonyl-
hydrazone compounds as starting materials. Besides,
gram-scale (0.9ꢀ2.15 g) synthesis of products 5a, 5b, and
6a were realized in high yields and 91ꢀ96% enantioselec-
tivities (see SI).
a Reaction conditions: 0.20 mmol of 3a, 0.30 mmol of 4a, catalyst 2c
(20 mol %), and o-F-PhCO2H (40 mol %) were stirred in CPME (C =
0.5 M) at rt for 72 h. b 0.60 mmol of 3, 0.20 mmol of 4a. c 50 °C for 72 h.
d CPME/DCM = 1/1 (C = 0.5 M). e 2c (30 mol %) and o-F-PhCO2H
(60 mol %), with additional 15 μL of H2O. Yields refer to isolated
yields. The ee value was determined by chiral HPLC analysis. PMP =
o-CH3OꢀC6H4.
In summary, we have disclosed the first example of a
highly enantioselective and scalable formal diazaꢀene
reaction between N-monosubstituted hydrazones and en-
ones with broad substrate variables catalyzed by a primary-
second diamine salt, affording enantioenriched products with
excellent results (up to 98% yield and 99% ee). The catalytic
process provides a highly practical synthetic method for
bicycle 1,4,5,6-tetrahydropyridazines, 1,4-dihydropyida-
zines, which would be interesting in the search for diaza-
heterocyclic compounds for novel therapeutic agents.
R0 position of ketone lowered the reactivity, and 88% ee
was obtained (6j). The reaction proceeded satisfactorily in
all cases of alkyl enones with various chain lengths,
furnishing adducts 6kꢀ6m in good yields and 90ꢀ95%
ee. In further exploration, different types of hydrazones
were tested. The ethyl ester group was changed into methyl
and isopropyl ester, with 92% and 85% ee obtained
respectively (6n and 6o). When a weaker electron-
withdrawing moiety (benzyl and Weinreb amide) was
introduced to the substrate, the reactivity decreased. After
a slight modification of the reaction parameters, including
increasing the catalyst dosage and adding a small amount
of deionized water, the yield and enantioselectivity of
products 6p and 6q reached a satisfactory level. We then
investigated the effect of the electronic properties of the N-
aryl group. Electron-donating, neutral, and electron-with-
drawing aromatic substituted hydrazones afforded the
adducts in moderate to good yields with good enantios-
electivities (6r to 6u). The reaction hardly proceeded when
N-alkyl substituted hydrazone was employed (6v). We are
committed to exploring the nature of N-monosubstituted
hydrazones in asymmetric organocatalytic reactions in the
future.
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (21272068),
the Innovation Program of Shanghai Municipal Educa-
tion Commission (11ZZ56), and the Fundamental Re-
search Funds for the Central Universities.
Supporting Information Available. Experimental pro-
cedures, structural proofs, NMR spectra, HPLC chro-
matograms of the products, and cif files for compounds
CCDC 934931 (5b), CCDC 934930 (6a), CCDC 917404
(7b), CCDC 931694 (7c). This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX