Storable and air-stable zirconium complex-catalyzed highly enantioselective darzens reaction of diazoacetamide with aldehydes

Article abstract of DOI:10.1002/adsc.200900845

An asymmetric Darzens reaction of aldehydes with diazo-N,N- dimethylacetamide (3) catalyzd by an air-stable and storable chiral zirconium Lewis acid catalyst, which is formed from 3,3′-diiodobinaphthol and tetrabutoxyzirconium, gives solely the cis-glycid

Full text of DOI:10.1002/adsc.200900845

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DOI: 10.1002/adsc.200900845
Storable and Air-Stable Zirconium Complex-Catalyzed Highly
Enantioselective Darzens Reaction of Diazoacetamide with
Aldehydes
Long He,a Wei-Jun Liu,a Lei Ren,a Tao Lei,a and Liu-Zhu Gonga,*
a
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of Science
and Technology of China, Hefei 230026, Peopleꢀs Republic of China
Fax : (+86)-551-360-6266; e-mail: gonglz@ustc.edu.cn
Received: December 6, 2009; Revised: March 24, 2010; Published online: April 22, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900845.
Abstract: An asymmetric Darzens reaction of alde-
hydes with diazo-N,N-dimethylacetamide (3) cata-
lyzd by an air-stable and storable chiral zirconium
Lewis acid catalyst, which is formed from 3,3’-di-
iants have been reported with synthetically useful ste-
reoselectivity.[6] Very recently, we found a chiral tita-
nium(IV) Lewis acid-catalyzed Darzens reaction of
diazo-N,N-dimethylacetamide (3) with a wide range
of aldehydes, providing cis-epoxides in high yields
with excellent enantioselectivity.[7] Although promis-
ing, titanium-based chiral Lewis acids are usually sen-
sitive to air and moisture and thus have to be pre-
pared in situ under strictly anhydrous and inert condi-
tions. Consequently, a more storable and air-stable
catalyst system for the asymmetric Darzens reaction
would provide promise for the practical organic syn-
thesis of epoxy carbonyls and amides in high enantio-
meric purity.
ACHTUNGTRENNUNGiodobinaphthol and tetrabutoxyzirconium, gives
solely the cis-glycidic amides in high yields with ex-
cellent enantioselectivity (up to 97% yield, >99%
ee).
Keywords: asymmetric catalysis; Darzens reaction;
epoxides; cis-glycidic amides; zirconium Lewis
acids
Kobayashi and co-workers have continuously docu-
mented that the chiral zirconium complex of binaph-
Optically pure epoxides represent one of the most im- thol combined with molecular sieves has been an ef-
portant types of chiral intermediates with a broad fective catalyst for many transformations[8] including
array of applications in organic synthesis.[1] In particu- Mannich-type reaction,[9] aldol reaction,[10] Strecker
lar, glycidic esters and amides have attracted much in- reaction,[11] cycloaddition reaction,[12] aza Diels–Alder
terest as chiral building blocks in the synthesis of reaction,[13] allylation of imines,[14] and epoxidation re-
some key chiral intermediates to construct pharma- action.[15] These successes and the storable and air-
ceutically relevant molecules because they contain the stable features of zirconium complexes prompted us
additional ester and amide functional groups to there- to develop a highly enantioselective Darzens reaction
by facilitate transformations with a great degree of by using them as chiral catalysts.
regio- and stereocontrol.[2] The most common ap-
Initially, we explored the Darzens reaction of
proach to access these molecules in enantiomerically diazo-N,N-dimethylacetamide (3) with 4-nitrobenzal-
enriched form is the asymmetric epoxidation of the dehyde (2a) in CHCl3 at room temperature by using
corresponding a,b-unsaturated carbonyl compound 10 mol% of the zirconium complex of (R)-binol com-
with the diastereochemistry essentially being depen- bined with 3ꢁ molecular sieves, which was prepared
dent on the configuration of the carbon-carbon following the procedure reported by Kobayashi and
double bond.[3,4] The Darzens reaction has been co-workers.[8,9] Encouragingly, the reaction proceeded
known for over 100 years and has been recognized as smoothly to generate cis-glycidic amide (4a) in 57%
one of the most powerful methods to produce a,b- yield with 71% ee (Table 1, entry 1). It is worth noting
epoxy carbonyl and related compounds.[5] Although that this reaction exhibited excellent diastereoselec-
numerous efforts have been dedicated to the discov- tivity and the trans-diastereomer was not detectable
ery of an enantioselective Darzens reaction, very few by 1H NMR analysis of the crude product. Interesting-
successful examples of the catalytic asymmetric var- ly, studies on the correlation between the binaphthol-
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Long He et al.
Table 1. Effect of chiral ligand on Darzens reaction of 4-nitrobenzaldehyde with diazo-N,N-dimethylacetamide.[a]
COMMUNICATIONS
Entry
Ligand
Ligand/Zr
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
1a
1b
1c
1c
1d
1c
1c
2:1
2:1
2:1
2:1
2:1
1:1
1:2
3
3
1
1
1
1
1
57
50
94
88
92
95
95
71 (S,S)
59 (S,S)
97 (R,R)
96 (R,R)[d]
95 (R,R)
94 (R,R)
91 (R,R)
[a]
The reaction was carried out on a 0.1 mmol scale in chloroform (1 mL) and the ratio of 2/3 was 1.2/1.
Isolated yield.
[b]
[c]
The ee was determined by chiral HPLC and the absolute configuration of the product was assigned by comparison of the
optical rotation with that reported in the literature.[7]
[d]
The reaction was conducted in the absence of 3ꢁ MS.
derived ligands 1b–1d and the reaction performance
Screening of different solvents indicated that the
revealed that 3,3’-substituents have considerable yield and enantioselectivity are both dependent on
impact on the stereochemistry. In comparison with re- the solvent (Table 2). Thus, halogenated solvents such
actions using binaphthol and its 6,6’-substituted deriv- as chloroform, dichloromethane, and 1,2-dichloro-
atives that preferred the (S,S)-epoxide, the introduc- ethane gave comparably higher yields and enantiose-
tion of 3,3’-substituents to the BINOL not only fa- lectivity than oxygenated solvents such as diethyl
vored the generation of the opposite enantiomer but ether and tetrahydrofuran and non-polar solvents as
also provided an even faster reaction and higher exemplified by toluene (entries 1–6). A much slower
enantiomeric excesses (Table 1, entries 2–5). The most reaction was observed in a protic solvent although the
optimal ligand turned out to be 3,3’-diiodobinaphthol enantioselectivity remained moderate (entry 7). Inter-
(1c) in terms of the stereochemical outcome, which in estingly, a polar solvent, acetonitrile, provided the
combination with tetrabutoxyzirconium, delivered highest yield and enantioselectivity (entry 8). Conse-
94% yield and 97% ee to (R,R)-glycidic amide (4a) quently, the investigation of the temperature effect on
(Table 1, entry 3). Notably, we reported previously the reaction performance was carried out in acetoni-
that the titanium complex of (R)-binaphthol also gave trile and we found that conducting the reaction at
high yields and excellent enantioselectivity, but fa- room temperature resulted in the highest levels of
vored the formation of (S,S)-4a.[7] Thus the current enantioselectivity (entries 8–11).
protocol provided an important alternative comple-
We then explored the generality of the protocol for
mentary to the chiral titanium-catalyzed variant in ad- the aldehyde component under the optimal conditions
dition to the advantages associated with the storable (Table 3). Benzaldehyde derivatives bearing electron-
and air-stable characteristics. The absence of 3ꢁ mo- withdrawing substituents at either the ortho or para
lecular sieves led to a lower yield but with maintained positions provided cis-epoxides in high yields and
ee (entry 4). Additional studies on the stoichiometry with excellent enantioselectivity (96 to >99% ee, en-
of 1c and tetrabutoxyzirconium found that tuning the tries 1–7 and 17–19). It is worth noting that the cur-
ratio of 1c/tetrabutoxyzirconium from 2/1 to 1/2 led to rent Darzens reaction offered higher yields and enan-
a slightly decreased enantioselectivity (entries 3, 6 tioselectivity for meta-substituted benzaldehdyes than
and 7).
the previous variant by using a titanium complex cata-
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Storable and Air-Stable Zirconium Complex-Catalyzed Highly Enantioselective Darzens Reaction
Table 2. Effect of solvent and temperature on the Darzens reaction.[a]
Entry
Solvent
Time [h]
Temperature [oC]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
CHCl3
CH2Cl2
DCE
PhCH3
Et2O
1
1
1
10
10
10
24
1
25
25
25
25
25
25
25
25
40
10
0
94
76
97
77
70
74
45
96
98
96
96
97
97
98
81
87
89
79
>99
97
98
98
THF
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
9
10
11
1
2
3
[a]
The reaction was carried out on a 0.1 mmol scale in solvent (1 mL) and the ratio of 2/3 was 1.2/1.
Isolated yield based on 3.
Determined by chiral HPLC.
[b]
[c]
lyst (entries 8 and 10–12).[7] Electronically rich benzal- hyde 2a proceeded smoothly to give cis-epoxide 4a in
dehdyes also engaged in a clean Darzens reaction 88% yield and 98% ee (Scheme 1).
with higher enantioselectivity than the titanium com-
plex-catalyzed similar reaction (entries 13–15). Inter- zens reaction of aldehydes with diazo-N,N-dimethyl-
estingly, the heteroaromatic aldehydes could also be acetamide by using air-stable and storable chiral zir-
In summary, we have disclosed an asymmetric Dar-
AHCTUNGTRENNUNG
tolerated with high stereoselectivity, as exemplified by conium Lewis acid catalyst formed from 3,3’-diiodobi-
picolinaldehyde (entry 16). The extension of the reac- naphthol and tetrabutoxyzirconium, solely giving cis-
tion conditions to aliphatic aldehydes including linear glycidic amides with excellent enantioselectivity. The
and branched aliphatic aldehydes was highly success- current protocol is easier to operate than the titani-
ful, giving rise to glycidic amides with 96–98% ee (en- um-catalyzed variant and thus provides an important
tries 20–24). Benzyloxyacetaldehyde was able to par- alternative to prepare epoxy amides with high enan-
ticipate in the Darzens reaction in 64% yield and with tiomeric purity. Further theoretical studies on transi-
91% ee, both values being lower than those obtained tion states of reactions either by titanium[7] or zirconi-
by using the titanium complex of binaphthol um complexes by DFT calculations to understand the
(entry 25). Interestingly, a substrate with an unpro- stereochemistry are now underway and the related re-
tected OH group in the aldehyde was also able to par- sults will be reported in due course.
ticipate in Darzens reaction, as exemplified by 3-hy-
droxybenzaldehyde, providing a cis-epoxide in 76%
yield and with 97% ee (entry 26).
Experimental Section
The current Darzens reaction could be scaled up to
the gram-scale with maintained efficiency, albeit with
a very subtle erosion of the stereoselectivity. For ex-
Preparation of (R)-3-I-ZrMs
The catalyst was prepared according to a literature proce-
ample, the reaction of 3 (1.1 g) with 4-nitrobenzalde-
dure.[8] To a suspension of (R)-3,3’-diiodo-BINOL (107.5 mg,
0.2 mmol) in toluene (4 mL) was added ZrACTHNURTGNENG(U O-n-Bu)4
Scheme 1. Gram-scale synthesis of cis-epoxide 4a.
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Long He et al.
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Table 3. Enantioselective Darzens reaction of various aldehydes.[a]
Entry
R
Product
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4-NO2C6H4
Ph
4-FC6H4
4-MeO2CC6H4
4-ClC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
96
94
96
92
81
82
89
95
87
93
95
94
91
97
95
76
89
78
88
83
97
82
73
93
64
76
>99
99
99
97
96
>99
99
99
94
98
99
>99
99
>99
>99
98
99
99
99
97
4-BrC6H4
4-CNC6H4
3-CNC6H4
2-NO2C6H4
3-BrC6H4
3-ClC6H4
3-CH3OC6H4
4-CH3C6H4
a-naphthyl
b-naphthyl
2-pyridinyl
2-BrC6H4
2-ClC6H4
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2-FC6H4
CH3CH2
CH3CH2CH2
C6H5CH2CH2
4s
4t
4u
4v
4w
4x
4y
4z
97
98
95
98
A
c-C6H11
C6H5CH2OCH2
3-OHC6H4
91
97d
[a]
The reaction was carried out on a 0.1 mmol scale in CH3CN (1 mL) at room temperature, and the ratio of 2/3 was 1.2/1.
Isolated yields based on the 3.
[b]
[c]
The ee was determined by chiral HPLC and the absolute configuration of the product was assigned by comparison of the
optical rotation with that reported in the literature.[7]
[d]
The reaction was carried out at 408C.
(38.4 mg, 0.1 mmol) at room temperature, and the solution
was stirred for 3 h at the same temperature. 3ꢁ MS (1.0 g)
was added, and the mixture was stirred for 10 min. After re-
moval of the solvents under reduced pressure, the resulting
solid was dried at room temperature under the vacuum for
1 h, giving (R)-3-I-ZrMs, which was used directly.
Supporting Information
Experimental details and characterization data of new com-
pounds are given in the Supporting Information.
Acknowledgements
General Procedure for the Asymmetric Darzens
Reactions
We are grateful for financial support from MOST (973 pro-
gram 2009CB825300), the Ministry of Education, and CAS.
We thank Miss Rui Guo in our group for reproducing the re-
sults presented in entry 1 of Table 1 and entries 1, 5, 6 and 15
of Table 3.
To
a suspension of (R)-3-I-ZrMs catalyst (0.01 mmol,
10 mol%) in CH3CN was added an aldehyde (0.12 mmol)
and diazo-N,N-dimethylacetamide (3) (0.1 mmol). The reac-
tion mixture was stirred at 258C until the reaction was com-
plete (monitored by TLC). Then the reaction mixture was
filtered to remove molecular sieves, and the solid powder
was washed with ethyl acetate (5.0 mL). After evaporation
under reduced pressure, the residue was purified through References
flash column chromatography on silica gel (eluent: petrole-
um ether: ethyl acetate=15:1–1:1) to yield pure products
(4a–4z).
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