Chiral Phosphine–Phosphite Ligands in Asymmetric Gold Catalysis: Highly Enantioselective Synthesis of Furo[3,4-d]-Tetrahydropyridazine Derivatives through [3+3]-Cycloaddition

Article abstract of DOI:10.1002/chem.201800042

The Au^I-catalyzed reaction of 2-(1-alkynyl)-2-alken-1-ones with azomethine imines regio- and diastereoselectively affords furo[3,4-d]tetrahydropyridazines in a tandem cyclization/intermolecular [3+3]-cycloaddition process under mild conditions.

Full text of DOI:10.1002/chem.201800042

A Journal of
Accepted Article
Title: Chiral Phosphine-Phosphite Ligands in Asymmetric Gold
Catalysis: Highly Enantioselective Synthesis of Furo[3,4-d]-
Tetrahydropyridazine Derivatives through [3+3]-Cycloaddition
Authors: Qingwei Du, Jörg-Martin Neudörfl, and Hans-Günther
Schmalz
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201800042
Link to VoR: http://dx.doi.org/10.1002/chem.201800042
Supported by

10.1002/chem.201800042
Chemistry - A European Journal
COMMUNICATION
Chiral Phosphine-Phosphite Ligands in Asymmetric Gold
Catalysis: Highly Enantioselective Synthesis of Furo[3,4-d]-
Tetrahydropyridazine Derivatives through [3+3]-Cycloaddition
Qingwei Du, Jörg-Martin Neudörfl, Hans-Günther Schmalz*[
Dedicated to Prof. Stefan Toma on the occasion of his 80th birthday
Abstract: The Au(I)-catalyzed reaction of 2-(1-alkynyl)-2-alken-1-
ones with azomethine imines regio- and diastereoselectively affords
furo[3,4-d]tetrahydropyridazines in a tandem cyclization/intermole-
cular [3+3]-cycloaddition process under mild conditions. By
employing a chiral gold catalyst (prepared in-situ from a Taddol-
derived phosphine-phosphite ligand, Me2SAuCl, and AgOTf) high
yields and enantioselectivities (up to 94% yield, up to 96% ee) are
obtained. The method provides an efficient modular route to
substituted heterotricyclic furan derivatives and can be easily scaled
up (using catalyst loads of only 0.15 mol%).
ones to give 3,4-fused bicyclic furans were extensively
investigated by Zhang[9a-f] and others.[9g-i] In this context several
new reaction types were realized, however, only few examples
of enantioselective Au-catalyzed transformations of 2-(1-
alkynyl)-2-alken-1-ones have been reported (Scheme 1a).[9a,9d,11]
Inspired by these seminal works and being aware of the
importance of pyridazine derivatives in drug design, we asked
ourselves whether the Au-catalyzed reaction of 2-(1-alkynyl)-2-
alken-1-ones with azomethine imines[12] would open an entry to
substituted furo[3,4-d]pyridazines derivatives through tandem
cyclization/[3+3]-cycloaddition (Scheme 1b). We here report the
successful realization of this concept and the development of a
practical protocol for the atom- and step-economic synthesis of
furo[3,4-d]tetrahydropyridazines in high yields and with excellent
enantioselectivity (up to 96% ee). To the best of our knowledge,
this is also the first example of a simultaneous construction of a
furan and a hydropyridazine ring in a single synthetic operation.
Due to the unique capability of gold(I) complexes to activate C-C
multiple bonds Au-catalyzed organic transformations have
emerged as efficient and powerful tools for the synthesis of
complex and highly functionalized organic molecules during the
past decade.[1] Noteworthy are methods for the synthesis of
polysubstituted furans, which have attracted considerable
attention due to the fact that the furan skeleton is found in
bioactive natural products and important pharmaceuticals, and
furans also represent versatile building blocks for the synthesis
of more complex heterocyclic compounds.[2] However, the
potential of gold catalysis in the context of heterocycle synthesis,
especially with respect to the modular assembly of novel ring
systems (in a diastereo- and enantioselective fashion) through
intermolecular cycloaddition/annulation processes, remains an
interesting challenge.
Pyridazines and their hydrogenated derivatives represent a
class of heterocycles known to exhibit various kinds of biological
activities including anti-tumor,[3] anti-tuberculosis,[4] analgesic,[5]
and antimicrobial activities.[6] Some pyridazine-based drugs are
used in the treatment of Alzheimer’s, Parkinson’s, and other
diseases.[6b,7] Moreover, pyridazine derivatives belong to the
most developable heterocyclic structures for small-molecule-
based drug design.[8]
a) Previous work (ref. 9a):
R5
R3
R4
O
N
O
N
R1
R4
R1
∗
R1
R3
O
[Au]
R2
R5
∗
[L*Au]
[3+3]
L* = tunephos
or segphos
R2
R3
O
O
R2
up to 98% ee
b) This work:
R3
O
• new class of heterocycles
• up to 96% ee (≤94% yield)
• new chiral ligands for Au
• operationally simple
O
N
R1
N
N
O
[L*Au]
R4
R1
R3
∗
∗
N
R4
• gram-scale synthesis
R2
R2
O
Scheme 1. Au-catalyzed enantioselective tandem cyclization [3+3]-cyclo-
addition reactions of 2-(1-alkynyl)-2-alken-1-ones with 1,3-dipoles.
Due to their unique reactivity and easy availability 2-(1-
alkynyl)-2-alken-1-ones have been used as versatile precursors
in the synthesis of important heterocyclic scaffolds.[9] The first
example of an Au(III)-catalyzed heterocyclization of such
substrates to give polysubstituted furans was reported by Larock
et al. in 2004.[10] Subsequently, Au-catalyzed heterocyclization/
[3+n]-cycloaddition cascade reactions of 2-(1-alkynyl)-2-alken-1-
We started our investigation by probing the reaction of 2-(1-
alkynyl)-2-alken-1-one 3a[9b,10] with azomethine imine 4a[13] in the
presence of a catalyst generated in situ from Ph3PAuCl and
AgOTf. To our delight, the reaction proceeded smoothly to give
the desired product rac-5a in 69% yield with a diastereo-
selectivity of ≥95:5 in favor of the trans isomer (see the
Supporting Information). Encouraged by this result, we next
focused on the asymmetric version of this reaction by employing
chiral ligands.[14] However, several established ligands, such as
DIOP, the Trost ligand, BINAP, Josiphos, DTBM-SEGPHOS,
and phosphoramidites derived from 3,3’-disubstituted BINOLs,[15]
only gave low enantioselectivities. In the best case, the product
5a was obtained with 34% ee (41% yield) using a phosphor-
amidite ligand (for details see the Supporting Information).
Dr. Q. Du, Dr. J.-M. Neudörfl, Prof. Dr. H.-G. Schmalz
Department of Chemistry
University of Cologne
Greinstr. 4, D-50939 Koeln, Germany
E-mail: schmalz@uni-koeln.de
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800042
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COMMUNICATION
We next tested phosphine-phosphites of type 2, a class of
readily accessible modular chiral ligands, which were developed
in our laboratory[16] and had shown to perform particularly well in
various asymmetric transition-metal-catalyzed reactions.[17]
substituents instead of the common phenyl units (Figure 2 and
Supporting Information).
2k, R1 = i-Pr, R2 = H
R1
O
O
O
O
2l, R1 = Ph, R2 = H
Ph
Ph
O
P
2m, R1 = t-Bu, R2 = t-Bu
2n, R1 = t-pentyl, R2 = H
2o, R1 = t-pentyl, R2 = t-pentyl
R1
O
O
O
R2
PPh2
O
P
O
R2
PPh2
Ph
Ph
Figure 2. A second set of phosphine-phosphite ligands tested.
2
Figure 1. Chiral phosphine-phosphite ligands initially used in this study.
The examination of these new ligands (2k-2o) in the Au-
catalyzed reaction of 3a with 4a under the improved conditions
(Table 2, entries 7-11) revealed that the structural modification
of the Taddol unit led indeed to significant changes in the
reaction outcome. The substitution pattern of the ligand back-
bone again had a pronounced effect on the ligand performance.
In this case ligand 2k with an iso-propyl group in R1 position
gave better results (entry 7) than the ligands 2m-2o with a
bulkier tertiary R1 substituent (entries 9-11). Using ligand 2k the
product 5a was formed in 85% yield with a greatly improved
enantioselectivity of 83% ee.
Remarkably, ligands of type 2 indeed performed quite well in
the Au-catalyzed reaction of 3a and 4a under standard
conditions (Table 1). Most notably, the sterically most hindered
ligands 2f and 2h afforded the cycloadduct 5a with encouraging
yield (65-71%) and selectivity (49% and 54% ee, respectively)
(entries 6 and 8) while ligand 2a with a small methyl substituent
in R1 position only gave 18% ee (entry 1).
Table 1. Screening of chiral phosphine-phosphite ligands of type 2 in the Au-
catalyzed reaction of 2-(1-alkynyl)-2-alken-1-one 3a and azomethine imine 4a.
Table 2. Screening of different solvents and further ligands of type 2 in the Au-
catalyzed reaction of 3a with 4a.
5 mol% Me2SAuCl
2.5 mol % 2
5 mol% AgOTf
O
O
5 mol% Me2SAuCl
2.5 mol % 2
5 mol% AgOTf
O
O
O
O
N
N
Ph
Me
N
N
N N
Ph
Me
Ph
Me
N
N
Ph
Me
2.0 mL CH2Cl2
24 h at r.t.
2.0 mL solvent
24 h at r.t.
Ph
Ph
3a (0.2 mmol)
O
Ph
Ph
3a (0.2 mmol)
O
4a (0.22 mmol)
5a
4a (0.22 mmol)
5a
Entry
Ligand
R1
R2
5a [%]a
ee [%]b
18
Entry
Ligand (L*)
Solvent
CH2Cl2
5a [%]a
65
ee [%]b
49
1
2a
2b
2c
2d
2e
2f
Me
H
32
35
48
43
49
65
39
71
52
49
1
2f
2
Et
H
23
2
2f
CH2ClCH2Cl
CH3CN
53
46
3
i-Pr
H
32
3
2f
68
61
4
Ph
H
21
4
2h
2h
2h
2k
2l
CH2Cl2
71
54
5
t-Bu
t-Bu
t-pentyl
t-pentyl
t-Bu
Pr
H
42
5
CH2ClCH2Cl
CH3CN
61
50
6
t-Bu
H
49
6
79
67
7
2g
2h
2i
19
7
CH3CN
85
83
8
t-pentyl
OMe
H
54
8
CH3CN
76
59
9
47
9
2m
2n
2o
CH3CN
71
69
10
2j
51
10
11
CH3CN
69
58
a Isolated yield based on 3a. b Determined by chiral-phase HPLC.
CH3CN
70
72
Employing ligands 2f and 2h we next investigated the effect
of the solvent on the reaction outcome (Table 2, entries 1-6).
While improved yields (up to 79%) and enantioselectivities (up to
67% ee) were observed in CH3CN as a solvent (entries 3 and 6),
the results were still not satisfying. Therefore, following our
established scheme,[16] we synthesized a set of five additional
and even bulkier phosphine-phosphite ligands (2k-2o) which are
a Isolated yield based on 3a. b Determined by chiral-phase HPLC.
Having identified 2k as the most suitable ligand for the
enantioselective synthesis of 5a, we further optimized the
reaction by varying the temperature and the amount of catalyst.
As the results shown in Table 3 indicate, a significant decrease
of the enantioselectivity was observed upon raising the reaction
temperature from r.t. to 40 °C. In contrast, decreasing the
all derived from
a
Taddol carrying 3,5-dimethylphenyl
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10.1002/chem.201800042
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reaction temperature had no major effect on the enantio-
selectivity, only the yield dropped slightly (Table 3, entries 1-4).
Therefore, all following reactions were run at r.t. Not surprisingly,
the amount of catalyst was found to mainly influence the yield
(conversion) while the enantioselectivity was little affected
(Table 3, entries 2 and 5-7). The best result was obtained with 5
mol% of the catalyst generated in situ from equimolar amounts
of 2k, Me2AuCl, and AgOTf.
assume all products of type 5 prepared using 2k as a chiral
ligand belong to the same series of absolute configuration. This
is additionally supported by the fact that all products showed a
related chiroptical behavior (with usually positive [α] values at
436 nm which decrease or even become negative at larger
wavelengths).
R1
O
Table 3. Effects of temperature and amount of catalyst on the Au-catalyzed
reaction of 3a with 4a.
O
O
5 mol%
2k[AuCl]2/AgOTf
Ph
Me
N
N
N
N
O
O
R1
Ar
Ph
Ar
O
2.0 mL CH3CN,
r.t., 24 h
2k, Me2SAuCl
N
N
Ph
Me
N
N
AgOTf
Ph
Ph
Me
Ph
Me
O
CH3CN
3a (0.3 mmol)
4 (0.36 mmol)
5
Ph
Ph
3a (0.2 mmol)
O
4a (0.22 mmol)
5a
O
O
O
Ph
Me
MeO
OMe
5a [%]a
L*[AuCl]2
(mol%)
AgOTf
(mol%)
ee
Entry
Temp. (°C)
N
N
N
N
N
N
[%]b
73
83
84
82
80
85
83
79
69
80
R2
Ph
Ph
Me
5k 86%, 65% ee
1
40
r.t.
-10
-20
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
2.5
2.5
2.5
2.5
1.25
5
2.5
2.5
2.5
2.5
1.25
5
87
85
72
59
43
89
86
81
82
87
Ph
Me
Ph
Ph
O
O
O
2
5a: R2 = H, 89%, 85% ee
5b: R2 = OMe, 87%, 90% ee
5c: R2 = F, 94%, 87% ee
5d: R2 = Cl, 92%, 93% ee
5e: R2 = Br, 93%, 95% ee
5f: R2 = NO2, 92%, 83% ee
5g: R2 = Me, 83%, 85% ee
5h: R2 = t-Bu, 94%, 87% ee
5i: R2 = CN, 95%, 77% ee
5j 91%, 81% ee
3
O
O
NO2
O2N
4c
5
N
N
N
N
Ph
Ph
Me
Ph
Me
Ph
5l 93%, 80% ee
O
O
6
5m 90%, 86% ee
7
7.5
5
7.5
7.5
10
O
O
O
Cl
MeO
MeO
8
N
N
N
N
N N
Ph
Me
Ph
Ph
9
5
10 d
5
5
Ph
Me
Ph
Ph
Me
O
O
O
Conditions: x mol % of in situ formed catalyst (2k/Me2SAuCl = 1:2), CH3CN 2.0
5n 86%, 75% ee
5o 93%, 65% ee
5p no reaction
b
c
mL, 24 h. a Determined by GC-FID. Determined by chiral-phase HPLC.
Reaction was run for 32 hours. d 2k/Me2SAuCl = 1.1:2.
O
O
N
N
O
N
N
O
Recent reports suggested that gold complexes of type
L2Au2ClX with a weakly bound anion X, generated in situ from a
1:1 mixture of [L2Au2Cl2] and an AgX activator, may give better
enantioselectivities than bicationic [LAu2X2] species.[9a,18] How-
ever, changing the 2k[AuCl]2/AgOTf ratio from 1:1 to 1:2 only
resulted in a slight decrease of the enantiomeric excess of the
product 5a (Table 3, entry 10).
Taking the optimized conditions (Table 3, entry 6) as a
standard, we now explored the substrate scope of this novel
cycloaddition by reacting 3a with various azomethine imines 4
(Scheme 2). Much to our delight, the products of type 5 were
obtained in most cases in high yield (83%-95%) and with good
to excellent enantioselectivity (65-96% ee). As the results shown
in Scheme 2 indicate, the reaction worked reliably with a broad
range of substrates of type 4 independent of the nature of the
aryl (or heteroaryl) substitutent. Only an α-methylated substrate
(4p) failed to give the expected product 5p. The relative (trans)
configuration of the products was initially proven by X-ray crystal
structure analysis of rac-5a and rac-5f (see the Supporting
Information), and in the case of 5e and 5r the absolute
configuration could also be determined this way (Figure 3). We
Ph
Ph
Me
Ph
Me
Ph
5r 91%, 96% ee
O
O
5q 93%, 86% ee
Scheme 2. Au-catalyzed reaction of 3a with various azomethine imines 4.
Yields refer to isolated products. Enantiomeric purities (ee) were determined
by chiral-phase HPLC.
Figure 3. Structures of 5e (left) and 5r (right) in the crystalline state.[19]
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COMMUNICATION
The scope of the developed method was further investigated
by employing differently substituted 2-(1-alkynyl)-2-alken-1-ones
(Scheme 3). While the 4-para-methoxyphenyl substituted
product 5s was formed even with improved ee (as compared to
the parent product 5a), replacement of the phenyl group by
aliphatic R1 substituents at the alkyne resulted in a dramatic
decrease of the enantioselectivity and the cycloaddition products
5t and 5u were obtained only in ≤12% ee and ≤20% ee,
respectively, as major components of inseparable mixtures.
Here some limitations of the method become apparent.
In conclusion, we have discovered and developed a novel
gold-catalyzed transformation of 2-(1-alkynyl)-2-alken-1-ones
with azomethine imines furnishing highly substituted furo[3,4-
d]tetrahydropyridazines as a new type of heterocyclic system.
The tandem cyclization/[3+3]cycloaddition process was shown to
proceed with virtually complete regio- and diastereoselectivity to
give the products in good to excellent yields and with up to 96%
enantiomeric excess. The key for this success was the identi-
fication of the new chiral phosphine-phosphite ligand 2k as a
most suitable catalyst precursor, which performed superior in
comparison to other established ligands in asymmetric gold
catalysis. Other salient features of the developed method
include operational simplicity and mild conditions, easy
accessibility of substrates, functional group tolerance, and
scalability (with a catalyst loading of only 0.15 mol% of catalyst
on a gram scale). Thus, the developed method might find future
application in the stereoselective synthesis of furo[3,4-d]-
pyridazines as potentially bioactive compounds. In addition, the
demonstrated potential of our phosphine-phosphite ligands
(such as 2k) might be of interest to other researchers working in
the active field of asymmetric gold catalysis.
O
5 mol%
O
O
2k[AuCl]2/
Me
N
N
N
N
AgOTf
Ph
R1
R
R
Ph
CH3CN,
r.t., 24 h
R1
Me
O
3 (0.3 mmol)
4a (0.36 mmol)
5
O
O
N
N
N
N
Ph
OMe
Ph
Me
Me
O
O
Acknowledgements
5a 89%, 85% ee
5s 92%, 89% ee
This work was supported (doctoral fellowships to Q. Du) by the
China Scholarship Council and the Deutscher Akademischer
Austausch Dienst (DAAD). We gratefully thank Dipl. Ing.
Andreas Adler for performing the HPLC measurements.
O
O
N
N
N
N
Ph
Ph
Me
5tb , <12% ee
Me
5ub , <20% ee
O
O
Keywords: Gold • Enantioselective Catalysis • Chiral
Phosphorous Ligands • Heterocyclic Compounds • 1,3-Dipoles
Scheme 3. Au-catalyzed reaction of different 2-(1-alkynyl)-2-alken-1-ones (3)
a
[1]
For selected recent general reviews on gold catalysis, see: a) S. M. Abu
Sohel, R. S. Liu, Chem. Soc. Rev. 2009, 38, 2269-2281; b) A. Corma, A.
Leyva-Perez, M. J. Sabater, Chem. Rev. 2011, 111, 1657-1712; c) R.
Dorel, A. M. Echavarren, Chem. Rev. 2015, 115, 9028-9072; d) D. J.
Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008, 108, 3351-3378; e)
A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180-3211; f) M. Joost, A.
Amgoune, D. Bourissou, Angew. Chem. Int. Ed. 2015, 54, 15022-
15045; g) Z. G. Li, C. Brouwer, C. He, Chem. Rev. 2008, 108, 3239-
3265; h) B. L. Lu, L. Dai, M. Shi, Chem. Soc. Rev. 2012, 41, 3318-
3339; i) D. Qian, J. Zhang, Chem. Soc. Rev. 2015, 44, 677-698; j) D. Y.
Qian, J. L. Zhang, Chem. Rec. 2014, 14, 280-302.
with azomethine imine 4a. Yields refer to isolated products. Enantiomeric
purities (ee) were determined by chiral-phase HPLC. b Main component of an
inseparable product mixture.
Finally, to demonstrate the preparative usefulness of the
developed methodology we applied it in a gram-scale synthesis
of the furo[3,4-d]tetrahydropyridazine 5s (Scheme 4). In this
transformation the catalyst loading could be reduced to 0.15
mol% on a 5 mmol scale without any loss of selectivity and
efficiency providing 5s in 91% yield with an enantiomeric excess
of 88% ee.
[2]
For selected accounts and general reviews, see: a) D. A. Barancelli, A.
C. Mantovani, C. Jesse, C. W. Nogueira, G. Zeni, J. Nat. Prod. 2009,
72, 857-860; b) U. Erdenebileg, I. Hostmark, K. Polden, L. K. Sydnes, J.
Org. Chem. 2014, 79, 1213-1221; c) A. Gandini, T. M. Lacerda, A. J.
Carvalho, E. Trovatti, Chem. Rev. 2016, 116, 1637-1669; d) B. A. Keay,
Chem. Soc. Rev. 1999, 28, 209-215; e) T. Montagnon, M. Tofi, G.
Vassilikogiannakis, Acc. Chem. Res. 2008, 41, 1001-1011; f) C. Raji
Reddy, M. Damoder Reddy, J. Org. Chem. 2014, 79, 106-116; g) Y.
Wang, Y. C. Luo, X. Q. Hu, P. F. Xu, Org. Lett. 2011, 13, 5346-5349.
a) V. A. Nikolaev, D. Cantillo, C. O. Kappe, J. J. Medvedev, G. K.
Prakash, M. B. Supurgibekov, Chem. Eur. J. 2016, 22, 174-184; b) S.
Demirayak, A. C. Karaburun, R. Beis, Eur. J. Med. Chem. 2004, 39,
1089-1095; c) R. M. Butnariu, I. I. Mangalagiu, Bioorg. Med. Chem.
2009, 17, 2823-2829.
O
Me
MeO
O
0.15 mol% 2k[AuCl]2
0.15 mol% AgOTf
Ph
3b (5 mmol)
N
N
OMe
[3]
[4]
CH3CN, r.t.
O
Ph
Me
O
N
N
5s, 91%, 88% ee
4a (6 mmol)
a) M. D. Varney, C. L. Palmer, J. G. Deal, S. Webber, K. M. Welsh, C.
A. Bartlett, C. A. Morse, W. W. Smith, C. A. Janson, J. Med. Chem.
Scheme 4. Gram-scale synthesis of the furo[3,4-d]pyridazine 5s.
1995, 38, 1892-1903; b) M. Rodrıguez-Ciria, A. M. Sanz, M. J. R. Yunta,
́
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F. Gomez-Contreras, P. Navarro, I. Fernandez, M. Pardo, C. Cano,
Bioorg. Med. Chem. 2003, 11, 2143-2148; c) E. Isabel, D. A. Powell, W.
C. Black, C. C. Chan, S. Crane, R. Gordon, J. Guay, S. Guiral, Z.
Huang, J. Robichaud, K. Skorey, P. Tawa, L. Xu, L. Zhang, R. Oballa,
Bioorg. Med. Chem. Lett. 2011, 21, 479-483.
[13] a) M. Keller, A. S. S. Sido, P. Pale, J. Sommer, Chem. Eur. J. 2009, 15,
2810-2817; b) Y. Xin, J. W. Zhao, J. W. Gu, S. Z. Zhu, J. Fluorine
Chem. 2011, 132, 402-408.
[14] For recent reviews of enantioselective gold catalysis, see: a) W. Zi, F. D.
Toste, Chem. Soc. Rev. 2016, 45, 4567-4589; b) R. A. Widenhoefer,
Chem. Eur. J. 2008, 14, 5382-5391; c) Y. M. Wang, A. D. Lackner, F. D.
Toste, Acc. Chem. Res. 2014, 47, 889-901; d) S. Sengupta, X. Shi,
ChemCatChem 2010, 2, 609-619; e) V. Michelet, A. Pradal, P. Toullec,
Synthesis 2011, 1501-1514; f) N. Bongers, N. Krause, Angew. Chem.
Int. Ed. 2008, 47, 2178-2181.
[5]
[6]
F. Rohet, C. Rubat, P. Coudert, J. Couquelet, Bioorg. Med. Chem. 1997,
5, 655-659.
a) M. D. Caprosu, R. M. Butnariu, I. I. Mangalagiu, Heterocycles 2005,
65, 1871; b) R. M. Butnariu, M. D. Caprosu, V. Bejan, M. Ungureanu, A.
Poiata, C. Tuchilus, M. Florescu, I. I. Mangalagiu, J. Heterocyclic Chem.
2007, 44, 1149-1152.
[15] For selected recent applications of phosphoramidite ligands in
enantioselective gold catalysis, see: a) D. Qian, H. Hu, F. Liu, B. Tang,
W. Ye, Y. Wang, J. Zhang, Angew. Chem. Int. Ed. 2014, 53, 13751-
13755; b) Y. Wang, P. Zhang, Y. Liu, F. Xia, J. Zhang, Chem. Sci. 2015,
6, 5564-5570; c) H. Teller, S. Flugge, R. Goddard, A. Fürstner, Angew.
Chem. Int. Ed. 2010, 49, 1949-1953; d) H. Teller, M. Corbet, L. Mantilli,
G. Gopakumar, R. Goddard, W. Thiel, A. Fürstner, J. Am. Chem. Soc.
2012, 134, 15331-15342; e) S. Klimczyk, A. Misale, X. Huang, N.
Maulide, Angew. Chem. Int. Ed. 2015, 54, 10365-10369; f) I. Alonso, B.
Trillo, F. Lopez, S. Montserrat, G. Ujaque, L. Castedo, A. Lledos, J. L.
Mascarenas, J. Am. Chem. Soc. 2009, 131, 13020-13030.
[7]
a) Z. Wan, A. Hall, Y. Jin, J. N. Xiang, E. Yang, A. Eatherton, B. Smith,
G. Yang, H. Yu, J. Wang, L. Ye, L. F. Lau, T. Yang, W. Mitchell, W. Cai,
X. Zhang, Y. Sang, Y. Wang, Z. Tong, Z. Cheng, I. Hussain, J. D. Elliott,
Y. Matsuoka, Bioorg. Med. Chem. Lett. 2011, 21, 4016-4019; b) P.
Sridhar, M. Alagumuthu, B. Ram, S. Arumugam, S. R. Reddy,
ChemistrySelect 2017, 2, 842-847.
[8]
[9]
a) A. M. Shelke, G. Suryavanshi, Org. Lett. 2016, 18, 3968-3971; b) T.
J. Ritchie, S. J. F. Macdonald, S. Peace, S. D. Pickett, C. N. Luscombe,
Med. Chem. Comm. 2012, 3, 1062; c) H. Bel Abed, O. Mammoliti, O.
Bande, G. Van Lommen, P. Herdewijn, J. Org. Chem. 2013, 78, 7845-
7858.
[16] a) J. Velder, T. Robert, I. Weidner, J.-M. Neudörfl, J. Lex, H.-G.
Schmalz, Adv. Syn. Catal. 2008, 350, 1309-1315; b) M. Dindaroğlu, A.
Falk, H.-G. Schmalz, Synthesis 2013, 45, 527-535.
a) F. Liu, D. Qian, L. Li, X. Zhao, J. Zhang, Angew. Chem. Int. Ed. 2010,
49, 6669-6672; b) F. Liu, Y. Yu, J. Zhang, Angew. Chem. Int. Ed. 2009,
48, 5505-5508; c) H. Gao, X. Zhao, Y. Yu, J. Zhang, Chem. Eur. J.
2010, 16, 456-459; d) Y. Wang, P. Zhang, D. Qian, J. Zhang, Angew.
Chem. Int. Ed. 2015, 54, 14849-14852; e) H. Gao, X. Wu, J. Zhang,
Chem. Eur. J. 2011, 17, 2838-2841; f) L. Zhou, M. Zhang, W. Li, J.
Zhang, Angew. Chem. Int. Ed. 2014, 53, 6542-6545; g) T. He, P. Gao,
Y.-F. Qiu, X.-B. Yan, X.-Y. Liu, Y.-M. Liang, RSC Adv. 2013, 3, 19913;
h) Y. Zheng, Y. Chi, M. Bao, L. Qiu, X. Xu, J. Org. Chem. 2017, 82,
2129-2135; i) A. L. Siva Kumari, K. C. Kumara Swamy, J. Org. Chem.
2016, 81, 1425-1433.
[17] a) S. Werle, T. Fey, J. M. Neudorfl, H. G. Schmalz, Org. Lett. 2007, 9,
4085-4085; b) T. Robert, J. Velder, H. G. Schmalz, Angew. Chem. Int.
Ed. 2008, 47, 7718-7721; c) T. Robert, Z. Abiri, J. Wassenaar, A. J.
Sandee, S. Romanski, J. M. Neudörfl, H. G. Schmalz, J. N. H. Reek,
Organometallics 2010, 29, 478-483; d) T. Robert, Z. Abiri, A. J. Sandee,
H.-G. Schmalz, J. N. H. Reek, Tetrahedron: Asymmetry 2010, 21,
2671-2674; e) Q. Naeemi, T. Robert, D. P. Kranz, J. Velder, H.-G.
Schmalz, Tetrahedron: Asymmetry 2011, 22, 887-892; f) S. Movahhed,
J. Westphal, M. Dindaroğlu, A. Falk, H. G. Schmalz, Chem. Eur. J.
2016, 22, 7381-7384; g) W. Lölsberg, S. Ye, H.-G. Schmalz, Adv. Syn.
Catal. 2010, 352, 2023-2031; h) A. Falk, A. L. Göderz, H. G. Schmalz,
Angew. Chem. Int. Ed. 2013, 52, 1576-1580; i) A. Falk, L. Fiebig, J. M.
Neudörfl, A. Adler, H. G. Schmalz, Adv. Syn. Catal. 2011, 353, 3357-
3362; k) A.Falk, A. Cavalieri, G. S. Nichol, D. Vogt, H.-G. Schmalz, Adv.
Syn. Catal. 2015, 357, 3317-3320.
[10] T. L. Yao, X. X. Zhang, R. C. Larock, J. Am. Chem. Soc. 2004, 126,
11164-11165.
[11] M. Chen, Z.-M. Zhang, Z. Yu, H. Qiu, B. Ma, H.-H. Wu, J. Zhang, ACS
Catal. 2015, 5, 7488-7492.
[12] For the use of azomethine imines in gold-catalysis, see: a) W. Zhou,
X.-X. Li, G.-H. Li, Y. Wu, Z. Chen, Chem. Commun. 2013, 49, 3552-
3554; b) N. D. Shapiro, Y. Shi, F. D. Toste, J. Am. Chem. Soc. 2009,
131, 11654–11655; c) S. Sugita, N. Takeda, N. Tohnai, M. Miyata, O.
Miyata, M. Ueda, Angew. Chem. Int. Ed. 2017, 56, 2469 – 2472; for a
review on 1,3-diploar cycloadditions of azomethine imines, see also: d)
C. Nájera, J. M. Sansano, M. Yus, Org. Biomol. Chem., 2015, 13,
8596–8636.
[18] G. Zhou, F. Liu, J. Zhang, Chem. Eur. J. 2011, 17, 3101-3104.
[19] CCDC 1586501 (rac-5a), 1586502 (5s), 1586503 (rac-5f), and 1586504
(5e) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
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10.1002/chem.201800042
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Q. Du, J.-M. Neudörfl, H.-G. Schmalz*
Page No. – Page No.
Chiral Phosphine-Phosphite Ligands
in Asymmetric Gold Catalysis: Highly
Enantioselective Synthesis of
Furo[3,4-d]-Tetrahydropyridazine
Derivatives through [3+3]-
Cycloaddition
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