Catalytic asymmetric three-component 1,3-dipolar cycloaddition of aldehydes, hydrazides, and alkynes

Article abstract of DOI:10.1021/ja405444c

Catalytic asymmetric 1,3-dipolar cycloadditions offer expeditious ways to afford synthetically important chiral heterocycles. Although a variety of 1,3-dipoles can be employed in this context, the use of acyclic azomethine imines as a facile means to give chiral pyrazolines and pyrazolidines remains completely unexplored. We report herein the first catalytic asymmetric 1,3-dipolar cycloaddition of terminal alkynes with acyclic azomethine imines generated in situ from the corresponding aldehydes and hydrazides, which was realized using Cu(I)/pybox and axially chiral dicarboxylic acid cocatalysts.

Full text of DOI:10.1021/ja405444c

Communication
pubs.acs.org/JACS
Catalytic Asymmetric Three-Component 1,3-Dipolar Cycloaddition of
Aldehydes, Hydrazides, and Alkynes
Takuya Hashimoto, Yuka Takiguchi, and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
S
* Supporting Information
purpose.8,9 At present, the catalytic asymmetric [3 + 2]
ABSTRACT: Catalytic asymmetric 1,3-dipolar cycloaddi-
tions offer expeditious ways to afford synthetically
important chiral heterocycles. Although a variety of 1,3-
dipoles can be employed in this context, the use of acyclic
azomethine imines as a facile means to give chiral
pyrazolines and pyrazolidines remains completely unex-
plored. We report herein the first catalytic asymmetric 1,3-
dipolar cycloaddition of terminal alkynes with acyclic
azomethine imines generated in situ from the correspond-
ing aldehydes and hydrazides, which was realized using
Cu(I)/pybox and axially chiral dicarboxylic acid cocata-
lysts.
cycloaddition of hydrazones and reactive alkenes is the only
method that offers an alternative.10
As a synthetically attractive and challenging dipolarophile that
would be compatible with in situ generation of acyclic
azomethine imines, we selected catalytically generated copper
acetylide (Figure 2) to afford chiral pyrazolines, a strategy
atalytic asymmetric multicomponent reactions (MCRs)
Chave been widely investigated as an attractive strategy for
constructing complex chiral molecules in a single operation.1
Apart from minimizing the overall number of manipulations, the
implementation of MCRs is advantageous in terms of exploiting
labile chemical species that are not suitable for isolation. In this
context, we recently developed chiral Brønsted acid-catalyzed
three-component asymmetric reactions using aldehydes, hydra-
zides, and nucleophiles such as diazoacetate and isocyanide,2
wherein the in situ generation of acyclic azomethine imines as
unstable electrophiles plays a pivotal role (Figure 1).
Figure 2. 1,3-Dipolar cycloaddition of acyclic azomethine imines and
copper acetylide.
initially introduced in catalytic asymmetric 1,3-DC of N,N′-cyclic
azomethine imines by Fu.8a,b The major concern in implement-
ing this three-component 1,3-DC is the possible formation of
three different compounds: two regioisomeric cycloadducts
stemming from 1,3-DC (path a) and a propargyl hydrazide via
alkynylation (path b).11,12 Understandably, one of the two
regioisomers from path a can also be generated by sequential
alkynylation/cyclization (paths b and c), as evidenced by recent
studies by Fujii and Ohno13 and Kobayashi.14
Figure 1. In situ generation of acyclic azomethine imines.
Our optimal catalyst system was composed of Cu(I)/pybox
and axially chiral dicarboxylic acid cocatalysts,15,16 which gave
rise to 3,4-disubstituted pyrazolines in high yields with excellent
enantioselectivities and also exhibited broad substrate scope with
respect to the aldehyde, the alkyne, and even the hydrazide.
While the reaction generally proceeded in a regiospecific manner,
the reaction pathway had to be controlled by the judicious choice
of a catalyst system to favor 1,3-DC over alkynylation. In
addition, it was also necessary to suppress the dimerization of the
acyclic azomethine imine when a linear aliphatic aldehyde was
used as the substrate (Figure 2, path d).
Our next step was to use these labile species in catalytic
asymmetric three-component 1,3-dipolar cycloadditions (1,3-
DCs),3 exploiting their innate 1,3-dipolar nature. The reaction
would provide a novel and rapid process for synthesizing chiral
pyrazolines and pyrazolidines, an important class of heterocycles
that appear in biologically active compounds4,5 and also serve as
synthetic intermediates for chiral 1,3-diamines. In sharp contrast
to the extensive utility of 1,3-DCs in every aspect of organic
synthesis,6 this catalytic asymmetric transformation has yet to be
realized.7 Previously, only preformed, isolable N,N′-cyclic and
C,N-cyclic azomethine imines, which have intrinsic limitations in
terms of structural flexibility and diversity, have been used for this
Received: May 31, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja405444c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
At the beginning of this study, the reaction of cyclo-
hexanecarbaldehyde, N′-benzylbenzohydrazide, and phenyl-
acetylene was carried out in the presence of CuOAc/(R,R)-Ph-
pybox (L) in CH2Cl2 at room temperature (rt) (Table 1). Use of
turned our attention to the use of axially chiral dicarboxylic acid
(R)-3 as a cocatalyst,11 expecting that it would interact with the
azomethine imine via hydrogen bonding (entries 8−11).2 This
strategy was found to be effective in increasing not only the
enantioselectivity but also the product ratio, especially when (R)-
3d with 3,3′-disilyl groups was used (entry 11).18 The
mismatched chiral pair using (S,S)-Ph-pybox (ent-L) and (R)-
3d gave the pyrazoline with 55% ee (entry 12).
a
Table 1. Optimization of the Reaction Conditions
Even though this cocatalysis was also successfully applied to
cyclohexanecarbaldehyde (compare entries 6 and 13), we faced
another problem in a further attempt to use hydrocinnamalde-
hyde as a typical linear aliphatic aldehyde (entry 14). In this case,
only a dimer of the azomethine imine was obtained (see Figure 2,
path d). As this dimerization is known to proceed under acidic
conditions,2a we planned to attenuate it by returning to a less
acidic copper source, CuOAc, while using the cocatalyst system.
This finally led us to the optimized conditions, which have very
broad generality. When CuOAc/L and (R)-3d were used as
cocatalysts, hydrocinnamaldehyde was transformed to the
desired product 1c in high yield with excellent enantioselectivity
at rt (entry 15). Gratifyingly, this cocatalysis uniformly provided
excellent results when other aldehydes were used at 40 °C
(entries 16 and 17).
b
c
d
entry
R1
Cu(I)
3
yield (%)
1:2
ee (%)
e
1
Cy
Cy
Cy
Cy
Cy
Cy
Ph
Ph
Ph
Ph
Ph
Ph
Cy
CuOAc
CuCl
−
−
−
−
−
−
−
3a
3b
3c
3d
3d
3d
3d
3d
3d
3d
16
71
68
71
45
81
74
50
80
68
91
91
89
60:40
58:42
37:63
64:36
79:21
87:13
93:7
82
83
68
63
97
97
78
78
89
84
92
55
99
−
e
2
e
3
CuBr
With the optimized conditions in hand, we examined the
substrate scope using a variety of aldehydes with phenylacetylene
as a fixed reaction partner at a catalyst loading of 5 mol % on a 0.2
mmol scale (Chart 1). Although the catalyst loading was reduced
to half compared with the optimization study in Table 1, the
representative aldehydes (cyclohexanecarbaldehyde, benzalde-
hyde, and hydrocinnamaldehyde) all were converted to the
corresponding pyrazolines 1a−c in high yields and selectivities. A
series of aromatic aldehydes could be utilized to give pyrazolines
1d−f in high yields, enantioselectivities, and product ratios,
irrespective of the electronic property and position of the
functionality. The use of 2-furfural led to a slight decrease in the
enantioselectivity (1g). As for aliphatic aldehydes, the
enantioselectivities of the products 1h−l were no less than
98% ee, and the exclusive formation of pyrazolines was observed
in all of the reactions using linear aliphatic aldehydes. In some
cases, it was preferable to reduce the loading of (R)-3d to 2.5 mol
% to minimize the formation of the azomethine imine dimer.
Next, the alkyne scope was evaluated (Chart 2). The reactions
of aromatic and aliphatic alkynes using cyclohexanecarbaldehyde
as a reaction partner gave rise to pyrazolines 1m−p with
exceptionally high enantioselectivities and minimal erosion of the
product ratio. Ethyl propiolate was also a good substrate,
exclusively giving pyrazoline 1q having ester functionality. As
shown by the reaction of hydrocinnamaldehyde and 1-hexyne to
give pyrazoline 1r, the reaction using other aldehydes also
proceeded without difficulty. The absolute configuration of 1m
was determined by X-ray crystallography to be R (see the
Supporting Information). The only limitation of this reaction
system was the combination of sterically demanding substrates
such as cyclohexanecarbaldehyde and 2-tolylacetylene, for which
alkynylation became a competing pathway (data not shown).
This three-component 1,3-DC was also compatible with
various substituents on the hydrazide moiety. The reactions
using N′-butyl hydrazide and N-Cbz hydrazide gave rise to the
corresponding pyrazolines 4 and 5 in good yields with over 90%
ee (Scheme 1). Accordingly, the method developed herein can be
used as a general way to form at will pyrazolines having four
different functionalities.
e
4
CuI
e
5
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOTf
CuOAc
CuOAc
CuOAc
6
7
8
85:15
>95:5
>95:5
93:7
9
10
11
f
12
93:7
13
93:7
g
h
14
g
Ph(CH2)2
Ph(CH2)2
Cy
n.d.
−
15
87
92
89
>95:5
>95:5
>95:5
>99
>99
96
16
17
Ph
a
Performed with N′-benzylbenzohydrazide (0.10 mmol), aldehyde
(0.12 mmol), phenylacetylene (0.12 mmol), copper catalyst (0.01
b
mol), L (0.012 mmol), and (R)-3 (0.01 mmol). Combined yield of 1
c
and 2. Determined by 1H NMR analysis of the crude material.
d
e
f
Determined by chiral HPLC analysis. Performed at rt. Performed
with (S,S)-Ph-pybox (ent-L). Performed at rt for 1 day. n.d. = not
g
h
detected.
4 Å molecular sieves (MS4A) was necessary to scavenge water
generated by the condensation of the aldehyde and the
hydrazide. This 1,3-DC gave 3,4-disubstituted pyrazoline 1a
regiospecifically with 82% ee, although the conversion was still
low after 3 days (entry 1). Furthermore, a nearly equal amount of
the alkynylation product 2a was observed, thereby urging us to
identify conditions that selectively provide the cycloadduct. In
the first optimization, the effect of the Cu source was examined
(entries 2−5). Among those, the use of CuOTf led to the
preferential formation of 1a with modest conversion and high
enantioselectivity (entry 5). Full conversion without deterio-
ration of the enantioselectivity was attained by running the
reaction at 40 °C (entry 6).
Benzaldehyde was then used as substrate to clarify the
generality of the reaction conditions. Whereas pyrazoline 1b was
obtained with a good product ratio, the enantioselectivity was
only modest (entry 7). As a facile means to improve it,17 we
B
dx.doi.org/10.1021/ja405444c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
a
Chart 1. Substrate Scope Using Various Aldehydes
Chart 2. Substrate Scope Using Various Alkynes
a
Performed with N′-benzylbenzohydrazide (0.20 mmol), aldehyde
(0.24 mmol), alkyne (0.20 mmol), CuOAc (0.01 mol), L (0.012
b
mmol), and (R)-3d (0.01 mmol). Combined yield of 1 and 2.
c
d
Determined by 1H NMR analysis of the crude material. Determined
e
by chiral HPLC analysis. Performed with 2.5 mol % (R)-3d (0.05
mmol).
Scheme 1. Use of Other Hydrazides
a
Performed with N′-benzylbenzohydrazide (0.20 mmol), aldehyde
(0.24 mmol), phenylacetylene (0.20 mmol), CuOAc (0.01 mol), L
b
(0.012 mmol), and (R)-3d (0.01 mmol). Combined yield of 1 and 2.
c
d
Determined by 1H NMR analysis of the crude material. Determined
e
by chiral HPLC analysis. Performed with 2.5 mol % (R)-3d (0.05
mmol).
To demonstrate the utility of 3,4-disubstituted pyrazolines, we
conducted two transformations generating an additional stereo-
center (Scheme 2). In one reaction, the benzoyl moiety of 1b was
removed under basic conditions to give pyrazoline 6 having two
phenyl groups oriented in a trans fashion. Formation of the trans
isomer is assumed to be thermodynamically controlled, as some
amount of the cis isomer was observed in the early stage of the
reaction. On the other hand, hydrogenation of 1b furnished
pyrazolidine 7 bearing two phenyl groups in a cis fashion.
Furthermore, acyclic 1,3-diamine 8 could be synthesized by
SmI2-mediated cleavage of the N−N bond in 7.
Scheme 2. Synthetic Applications
In conclusion, we have developed the first catalytic asymmetric
three-component 1,3-DC of aldehydes, hydrazides, and terminal
alkynes, exploiting acyclic azomethine imines as key species.19
Two major obstacles to attaining this goal were control of the
reaction pathway toward 1,3-DC while suppressing undesired
alkynylation and identification of general reaction conditions
applicable to both aromatic and aliphatic aldehydes. As a
solution, we opted for the use of CuOAc/Ph-pybox and axially
chiral dicarboxylic acid cocatalysts, with which a variety of 3,4-
C
dx.doi.org/10.1021/ja405444c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
(7) 1,3-DC of acyclic azomethine imines has already been utilized in
total synthesis. See: (a) Jacobi, P. A.; Brownstein, A.; Martinelli, M.;
Grozinger, K. J. Am. Chem. Soc. 1981, 103, 239. (b) Jacobi, P. A.;
Martinelli, M. J.; Polanc, S. J. Am. Chem. Soc. 1984, 106, 5594.
(c) Nilsson, B. L.; Overman, L. E.; Read de Alaniz, J.; Rohde, J. M. J. Am.
Chem. Soc. 2008, 130, 11297.
disubstiuted pyrazolines could be obtained with high enantio-
selectivities. This asymmetric transformation also has a tolerance
with regard to the hydrazide functionality, opening up a new
direct way to construct a diverse array of chiral pyrazolines.
ASSOCIATED CONTENT
(8) For N,N′-cyclic azomethine imines, see: (a) Shintani, R.; Fu, G. C.
J. Am. Chem. Soc. 2003, 125, 10778. (b) Suarez, A.; Downey, C. W.; Fu,
́
■
S
* Supporting Information
G. C. J. Am. Chem. Soc. 2005, 127, 11244. (c) Chen, W.; Yuan, X.-H.; Li,
R.; Du, W.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Adv. Synth. Catal. 2006, 348,
1818. (d) Chen, W.; Du, W.; Duan, Y.-Z.; Wu, Y.; Yang, S.-Y.; Chen, Y.-
C. Angew. Chem., Int. Ed. 2007, 46, 7667. (e) Suga, H.; Funyu, A.;
Kakehi, A. Org. Lett. 2007, 9, 97. (f) Sibi, M.; Rane, D.; Stanley, L. M.;
Soeta, T. Org. Lett. 2008, 10, 2971. (g) Kato, T.; Fujinami, S.; Ukaji, Y.;
Inomata, K. Chem. Lett. 2008, 37, 342. (h) Tanaka, K.; Kato, T.;
Fujinami, S.; Ukaji, Y.; Inomata, K. Chem. Lett. 2010, 39, 1036. (i) Suga,
H.; Arikawa, T.; Itoh, K.; Okumura, Y.; Kakehi, A.; Shiro, M. Heterocycles
2010, 81, 1669.
Experimental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
maruoka@kuchem.kyoto-u.ac.jp
Notes
The authors declare no competing financial interest.
(9) For C,N-cyclic azomethine imines, see: (a) Hashimoto, T.; Maeda,
Y.; Omote, M.; Nakatsu, H.; Maruoka, K. J. Am. Chem. Soc. 2010, 132,
3489. (b) Hashimoto, T.; Omote, M.; Maruoka, K. Angew. Chem., Int.
Ed. 2011, 50, 3489.
(10) (a) Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.;
Kobayashi, J. J. Am. Chem. Soc. 2002, 124, 13678. (b) Yamashita, Y.;
Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 11279. (c) Shirakawa, S.;
Lombardi, P. J.; Leighton, J. L. J. Am. Chem. Soc. 2005, 127, 9974.
(d) Tran, K.; Lombardi, P. J.; Leighton, J. L. Org. Lett. 2008, 10, 3165.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for Scientific
Research from the MEXT, Japan.
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dx.doi.org/10.1021/ja405444c | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX