Copper/iron-cocatalyzed highly selective tandem reactions: Efficient approaches to Z-γ-alkylidene lactones

Article abstract of DOI:10.1002/adsc.200800695

Inexpensive copper/iron-cocatalyzed, efficient, highly regioselective and stereoselective onepot tandem conjugate addition-cyclization-hydrolysis- decarboxylation reactions have been developed, which provide efficient tandem reactions for C-C and C-O bond

Full text of DOI:10.1002/adsc.200800695

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DOI: 10.1002/adsc.200800695
Copper/Iron-Cocatalyzed Highly Selective Tandem Reactions:
Efficient Approaches to Z-g-Alkylidene Lactones
Si Li,a Wei Jia,a and Ning Jiaoa,b,*
a
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of Pharmaceutical Sciences, Peking
University, Xue Yuan Rd. 38, Beijing 100191, Peopleꢀs Republic of China
Fax : (+86)-010-8280-5297; e-mail: jiaoning@bjmu.edu.cn
State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, Peopleꢀs Republic
b
of China
Received: November 11, 2008; Revised: February 9, 2009; Published online: March 12, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800695.
Abstract: Inexpensive copper/iron-cocatalyzed, effi-
cient, highly regioselective and stereoselective one-
pot tandem conjugate addition–cyclization–hydroly-
sis–decarboxylation reactions have been developed,
be addressed: 1) The acetylenic acids as starting ma-
terials require several steps from their corresponding
propargylmalonic esters[4] via hydrolysis and decar-
boxylation generating waste from solvents and purifi-
cations (Scheme 1). 2) Generally, toxic and noble late
transition metals such as Hg, Pd, Rh, Au, and Ag
were employed.[3] 3) 4-Substituted g-alkylidenebutyro-
lactones (R2 ¼H, Scheme 1) could not be easily ap-
proached through the reported methods.[5] Herein, we
wish to report a novel and reliable method to con-
struct substituted g-alkylidenebutyrolactones via inex-
pensive Cu/Fe cocatalysis starting from readily avail-
able aryl-substituted alkynes and 5-alkylidene-Mel-
drumꢀs acids (Scheme 1) which can be easily precipi-
ꢀ
which provide efficient tandem reactions for C C
ꢀ
and C O bond formation, and the novel synthetic
methods of g-alkylidenebutyrolactones.
Keywords: copper; cyclization; hydrolysis; iron; lac-
tones
g-Alkylidene lactones have attracted considerable at- tated in water via their relative condensation reac-
tention due to their diverse biological activities and tions.[6]
ubiquitous structural units in natural products,[1,2] such
Transition metal-catalyzed reactions have long been
as atranone[2a] and growth regulating reagent.[2b] In used for organic synthesis.[7] Recently, the develop-
the past several decades, transition metal-catalyzed ment of inexpensive, practical and environmentally
intramolecular hydroacyloxylation reactions of acety- benign catalytic system constitutes a challenging re-
lenic acids have been demonstrated to construct this search area. In this concept, iron has been extensively
unique structural unit (Scheme 1).[3] Among those investigated.[8,9] Furthermore, inexpensive copper and
previous studies, there remain several challenges to iron-cocatalyzed reactions presented an attractive
Scheme 1. Synthesis of substituted g-alkylidenebutyrolactones via transition metal-catalyzed reactions.
Adv. Synth. Catal. 2009, 351, 569 – 575
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Si Li et al.
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strategy in cooperative catalysis.[10,11] However, copper
and iron-cocatalyzed hydroacyloxylations of alkynes
have never been documented. In the presented novel
system, the first copper and iron-cocatalyzed highly
selective tandem conjugate addition–cyclization–hy-
drolysis–decarboxylation reactions of alkynes and 5-
alkylidene-Meldrumꢀs acids were achieved leading to
substituted Z-g-alkylidenebutyrolactones, which rep-
resents one of the rare examples of efficient coopera-
tive catalysis.
Table 1. One-pot tandem conjugate addition–cyclization–hy-
drolysis–decarboxylation reaction of 1a and 2a.[a]
Entry
Cocatalyst
FeCl3
t [min]
Yield of Z-3a [%]
Our initial efforts focused on the metal-catalyzed
tandem reaction of phenylacetylene 1a with Mel-
drumꢀs acid-derived Michael acceptors 2a. Although
the reactions of 1a and 2a catalyzed by metal cata-
1
2
3
4
40
55
60
50
120
120
65
65
70
70
60
60
12
77
41
55
24
30
40
36
31
33
54
40
Fe
Fe
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
lysts, such as Au, Al, Ir, Cu and Fe in water gave Z-3a 5[b]
Cu
Cu
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
6
7
8
9
10
11
12
in low yields (Table S1, Supporting Information),
FeCl3 showed positive characteristics for the forma-
tion of Z-3a (Table S1, Supporting Information). We
next examined the bimetallic catalysis: combining
copper with iron catalysts in one step produced the
expected product Z-3a in very low yield (7%) [Eq.
(1)].
After further screening of different parameters, we
were pleased to find that Z-3a was formed highly re-
gioselectively and stereoselectively in 77% yield when
the reaction was simply divided into two steps in one-
pot (entry 2, Table 1). This one-pot operation is
simple and practical. When the Cu(I)-catalyzed conju-
gate addition[4b,12] as the first step was finished as
monitored by TLC, FeCl3 and DMF (1/2 volume of
H2O) were directly added, followed by heating at
1008C for 55 min. However, only 12% of Z-3a was
observed when the reaction was carried out in the ab-
sence of FeCl3 (entry 1, Table 1). FeCl3 was more ef-
PtCl2
AuCl3
IrCl3
MnO2
AgNO3
PdACTHNUTRGNE(UNG PhCN)2Cl2
[a]
1a (1.0 mmol), 2a (0.5 mmol), CuACTHNUTRGNEUNG(OAc)2 (0.1 mmol),
sodium ascorbate (0.2 mmol), and aqueous solvent (H2O/
t-BuOH=10:1, 2.2 mL) were allowed to react at room
temperature under N2. Then 1 mL DMF and cocatalyst
(0.1 mmol) were added to the reaction mixture and
heated at 1008C under air.
[b]
Sodium ascorbate (40%) was added.
fective than other iron catalysts, such as Fe
Fe2A(SO4)3 (cf. entries 2–4, Table 1). It was noted that
the yield decreased greatly to 24% when additional
Cu(OAc)2 (20 mol%) was added at the second step
ACHTUGNRTNE(NUNG NO3)3 and
CHTUNGTRENNUNG
ACHTUNGTRENNUNG
instead of FeCl3 (entry 5). Lower yields were obtained
by other metal cocatalysts (31–54%, entries 7–12). All
the observed results indicate that the cooperative cat-
alysis of copper and iron plays a key role for the high
yield in these reactions. Lower yields were observed Figure 1. Crystal structure of Z-3a.
respectively when DMF was added in other ratios or
in the absence of the additive (t-BuOH) (see Support-
ing Information). The structure of Z-3a was deter- drumꢀs acid-derived alkylidenes 2 containing alkyl,
mined by X-ray diffraction (Figure 1).
aryl and heteroaryl groups, leading to Z-3 in moder-
Under these optimized one-pot conditions, aryl- ate yields (Table 2, 37–77%). Since the Z-3 products
substituted alkynes 1 reacted successfully with Mel- were produced from 1 and 2 via 4 steps (addition, cy-
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Copper/Iron-Cocatalyzed Highly Selective Tandem Reactions
Table 2. One-pot tandem conjugate addition–cyclization–hydrolysis–decarboxylation reaction of 1 and 2.[a]
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Entry
R1 (1)
R2 (2)
t [min]
Yield of Z-3 [%]
1
2
3
4
5
6
7
8
9
Ph (1a)
i-Pr (2a)
i-Pr (2a)
i-Pr (2a)
i-Pr (2a)
i-Pr (2a)
i-Pr (2a)
4-OMe-C6H4 (2b)
Furan (2c)
4-Me-C6H4 (2d)
55
30
75
45
60
60
60
70
60
77 (Z-3a)
66 (Z-3b)
68 (Z-3c)
57 (Z-3d)
48 (Z-3e)
65 (Z-3f)
51 (Z-3g)
37 (Z-3h)
53 (Z-3i)
4-OMe-C6H4 (1b)
3-Cl-C6H4 (1c)
4-F-C6H4 (1d)
4-Br-C6H4 (1e)
2-F-4-F-C6H4 (1f)
Ph (1a)
Ph (1a)
Ph (1a)
[a]
1 (1.0 mmol), 2 (0.5 mmol), CuACTHNUTRGEN(UNG OAc)2 (0.1 mmol), sodium ascorbate (0.2 mmol), and aqueous solvent (H2O/t-BuOH=
10:1, 2.2 mL) were allowed to react at room temperatute under N2. Then 1 mL DMF and FeCl3 (0.1 mmol) were added to
the reaction mixture and heated at 1008C under air.
ACHTUNGTRENNUNG
These observed results inspired us to complete under Cu(I)-catalyzed conjugate addition conditions
these Cu/Fe-cocatalyzed tandem methodologies. We even for 4 days (entry 1, Table 3). It is noteworthy
then investigated the Cu/Fe-cocatalyzed tandem reac- that the yields were low (20% and 26%, respectively)
tions of propargyl-Meldrumꢀs acid 4 which can extend when copper or iron was used alone, even when 40%
the substrate scope, such as with R3 groups (Table 4). Cu catalyst was used instead of a mixture of Cu (20
Gratifyingly, Z-3a was highly regioselectively and ste- mol%) and Fe (20 mol%) (cf. entries 2 and 3, 4 and 6,
reoselectively formed in 81% yield cocatalyzed by Table 3). These results indicate that the presence of
CuACHTUNGTRENNUNG(OAc)2 and FeCl3 under our optimized one-pot re- both copper and iron catalysts is essential for the high
action conditions in 1 h (entry 3, Table 3). Further in- yield. The reactions did not work in the presence of
vestigation indicated that the reaction achieved the base or acid (Table S3, Supporting Information).
highest yield (92%) when H2O/DMF (4:1) was used
Table 3. Transtion metal-catalyzed decarboxylation–cyclization reaction of propargyl-Meldrumꢀs acids 4a.[a]
Entry
Catalyst (%)
Cu(OAc)2 (20)
Cocatalyst (%)
Additive (%)
H2O:DMF
Yield of Z-3a [%]
1[b]
2
3
4
5
G
Na-ascorbate (40)
1:0
2:1
2:1
4:1
4:1
4:1
0
FeCl3 (20)
Cu(OAc)2 (20)
Cu(OAc)2 (20)
26
81
92
0[c]
20[d]
E
ACHTUNGTRENNUNG
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
Na-ascorbate (40)
Na-ascorbate (40)
Na-ascorbate (40)
Na-ascorbate (80)
6
CuACHTUNGTRENNUNG(OAc)2 (40)
[a]
To 4a (0.25 mmol) and catalyst, H2O (1 mL) and DMF were added in the appropriate volume ratio and the mixture was
allowed to react at 1008C under air.
The reaction was carried out at room tempertaure for 4 days.
80% of 4a was recovered.
The reaction needed 8 h to finish completely.
[b]
[c]
[d]
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Si Li et al.
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Table 4. Cu/Fe-cocatalyzed decarboxylation–cyclization reac-
tion of propargyl-Meldrumꢀs acids 4.[a]
butyrolactone Z-3p can also be synthesized under
these conditions with an acceptable yield (37%,
entry 15, Table 4).
It is interesting to find that dipropargyl-Meldrumꢀs
acid 4q did not afford the spiro-bis-g-methylenebutyr-
olactone 5, but gave a hydroxylation product 3q in
39% yield. We were pleased to find that the yield in-
creased to 62% when 4q’ was used as substrate [Eq.
(2)]. The respective acids with different substitution
at the R3 position, such as 4r and 4s, led to 3-substitut-
ed g-alkylidenebutyrolactones in good yields (70%
and 72%, respectively) [Eq. (3)]. Therefore, g-alkyli-
denebutyrolactones with different R3 substituents can
be successfully prepared under these conditions from
the respective acids.
Entry
4
R1
Ph
R2
R3
Yield of
Z-3 [%]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4j
4h
4i
4k
4l
4m Ph
i-Pr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
92 (Z-3a)
67 (Z-3b)
69 (Z-3c)
80 (Z-3d)
83 (Z-3e)
68 (Z-3f)
68 (Z-3j)
43 (Z-3h)
48 (Z-3i)
51 (Z-3k)
46 (Z-3l)
63 (Z-3m)
52 (Z-3n)
60 (Z-3o)
4-OMe-C6H4 i-Pr
3-Cl-C6H4
4-F-C6H4
4-Br-C6H4
2,4-di-F-C6H3 i-Pr
4-Me-C6H4
Ph
Ph
Ph
Ph
i-Pr
i-Pr
i-Pr
i-Pr
Furan
4-Me-C6H4
Ph
9
10
11
12
13
14
15
Et
c-Hex
n-Hex
i-Bu
4n
4o
4p
Ph
Ph
Ph
i-Pr
Me 37 (Z-3p)
[a]
1a
(0.25 mmol),
CuACTHNGURETNNU(G OAc)2
(0.05 mmol), FeCl3
As we mentioned above, although acetylenic acids
can be catalyzed by noble transition metal leading to
corresponding lactones,[3] b-substituted acetylenic
acids, such as 6, were rarely reported in these meth-
ods.[5] It is of importance to note that acetylenic acid
(0.05 mmol), sodium ascorbate (0.1 mmol), and aqueous
solvent (H2O/DMF=4:1, 1.25 mL) were allowed to react
at 1008C under air.
The scope of this tandem cyclization–hydrolysis–de- 6, which was prepared from 4a via hydrolysis and de-
carboxylation reaction was expanded to a variety of carboxylation, successfully transformed to Z-3a in
substituted propargyl-Meldrumꢀs acids (Table 4). 68% yield under the optimized conditions (entry 1,
These results show that the reaction is tolerant of a Table 5). Compared with Cu/Fe cooperative catalysis,
wide range of substituent groups on the propargyl- the yields decreased greatly when copper or iron was
Meldrumꢀs acids. Substrates with mostly aryl substitu- used as the sole catalyst (4% and trace, respectively)
ents at the R1 position reacted efficiently (68–92%, (cf. entries 1–3, Table 5).
see entries 1–7, Table 4). Particularly, the 4-bromoar-
Based on the above observed results, we have con-
yl-substituted product Z-3e (R1 =4-Br-C6H4) was ob- sidered two pathways for the tandem reactions
tained in 83% yield, which is amenable to further (Scheme 2). It is clear that the first conjugate addition
transformation (entry 5). In contrast with limited re- step is catalyzed by Cu(I).[4b,12]Although the collabora-
ports on 4-substituted g-alkylidenebutyrolactones, tion of Cu and Fe was not clear yet, the compatibility
substrates bearing various demanding R2 substituents, of Cu and Fe is high. We believe that both of them
alkyl, aryl and heteroaryl groups, successfully afford- act as Lewis acids to promote the cyclization. In the
ed the expected 4-substituted g-alkylidenebutyrolac- sense of hard-soft acid-base (HSAB) concept,[13a] Fe-
tones with moderate yields under these conditions
ACHTUNGTREN(NGNU III) which is a harder Lewis acid than Cu(I) prefers
(entries 8–14, Table 4). Poly-substituted g-alkylidene- to interact with the oxygen atom of the intermediate
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Copper/Iron-Cocatalyzed Highly Selective Tandem Reactions
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Table 5. Cu/Fe-cocatalyzed cyclization reaction of acetylenic
acid 6.
intermediate A and B to the metal activated alky-
ne.[3g,16]
The transformation from 4a to 3a has been tracked
by HPLC. The product growth and substrate con-
sumption were clear. However, acetylenic acid 6 was
not observed during the process. On the other hand,
compared to the 92% yield of the reaction using 4a as
substrate (entry 1, Table 4), the yield in cyclization of
acetylenic acid 6 was very low (68%, entry 1, Table 5)
under the same conditions. Moreover, the transforma-
tion from 6 took a much longer reaction time (3 h)
than that from 4a (1 h). To further understand this
transformation, we carried out some preliminary
mechanistic studies. Deuterated product [D]-Z-3a was
isolated in 61% yield when D2O was used instead of
H2O [Eq. (4)]. However, the hydrogen-deuterium ex-
Entry Catalyst
Cocatalyst t [h] Yield of Z-3a [%]
[a]
1
2
Cu
G
3
68
Cu(OAc)2
E
37
3
24
12
4
3
FeCl3
trace[b]
8
4
CuBr
CuBr
5[c]
0[d]
[a]
[b]
[c]
Sodium ascorbate (40% mol) was used.
78% of 6 was recovered.
The reaction was carried at room tempertaure in the sol-
vent (H2O/t-BuOH=1:1).
61% of 6 was recovered.
[d]
change was not observed at the 5-position when Z-3a
was treated with D2O under the reaction conditions
[Eq. (5)]. Based on these results, although both paths
a and b are reasonable, we consider that the reactions
prefer to occur through path b. A detailed mechanis-
tic study is ongoing in our laboratory.
Scheme 2. The proposed pathways for the tandem reaction.
A or B.[13,14] Simultaneously, Cu(I) binds and activates
In conclusion, for the first time, we have developed
the p-system of the alkyne rending it susceptible to Cu/Fe-cocatalyzed efficient and highly selective one-
be attacked by the O-nucleophile.[13] In path a, inter- pot tandem reactions leading to poly-substituted g-al-
mediate A would be produced through hydrolysis and kylidenebutyrolactones. This method has the follow-
decarboxylation reactions, then the intramolecular hy- ing advantages: 1) the catalysts are cheap, less toxic
droacyloxylation would proceed to give intermediate and stable to air and moisture; 2) 4-substituted g-al-
D. In path b, Fe as Lewis acid-promoted enolization kylidenebutyrolactones can be successfully produced
of 3a leads to intermediate B, which would undergo in this catalytic system; 3) the reactions are readily
intramolecular cyclization giving intermediate C, fol- handled and carried out in aqueous solvent under air;
lowed by concurrent rearrangement[15] and liberation 4) this method presents a rare example of efficient co-
of acetone and CO2 to form intermediate D. A subse- operative catalysis. The use of alkyl-substituted al-
quent proton-transfer step from intermediate D af- kynes for the transformation remains a challenging
fords the final product and regenerates metal cata- task. Further studies on the reaction scope, mecha-
lysts. The high Z stereoselectivity can be explained nism and synthetic applications are ongoing in our
reasonably on the anti intramolecular addition of the laboratory.
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Si Li et al.
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Experimental Section
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General Procedure A
A tube was charged with CuACHTNUGRTENUNG(OAc)2 (20 mg, 0.1 mmol),
sodium ascorbate (40 mg, 0.2 mmol), and 2 mL H2O, the
mixture was stirred until the color turned orange. Subse-
quently, 102 mg of 1a were added. The resulting mixture
was stirring at room temperature for about 5 min, then
100 mg (0.5 mmol) of 2a and 0.2 mL of t-BuOH were added.
The reaction was stirred at room temperature under N2 for
10 h as monitored by TLC. After the starting material had
completely diminished, 1 mL of DMF and 16 mg (0.1 mmol)
of FeCl3 were subsequently added, then the reaction mixture
was stirred at 1008C for 55 min as monitored by TLC. Upon
completion, the reaction was quenched with 10 mL saturat-
ed NH4Cl solution and extracted three times with dichloro-
methane (10 mL each). The organic layers were combined,
and dried with Na2SO4. After evaporation. The crude mix-
ture was purified by silica gel chromatography (eluent: pe-
troleum ether/ethyl acetate=20:1) to afford Z-3a; yield:
84 mg (77%).
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General Procedure B
A mixture of CuACHTUNGTRENNUNG(OAc)2 (10 mg, 0.05 mmol), sodium ascor-
bate (20 mg, 0.1 mmol), and 1 mL H2O was stirred until the
color turned orange, then 4a (75 mg, 0.25 mmol), FeCl3
(8 mg, 0.05 mmol), and DMF (0.25 mL) were added. The re-
sulting mixture was stirred at 1008C for 1 h as monitored by
TLC. Work-up of the mixture was the same as for procedure
A and afforded Z-3a as a solid; yield: 50 mg (92%);
1H NMR (300 MHz, CDCl3): d=7.58 (d, J=1.2 Hz, 2H),
7.36–7.31 (m, 2H), 7.26–7.18 (m, 1H), 5.53 (s, 1H), 3.16–
3.09 (m, 1H), 2.73 (dd, J=18.2, 9.9 Hz, 1H), 2.47 (dd, J=
18.2, 3.9 Hz, 1H), 2.07–1.96 (m, 1H), 0.99 (d, J=6.8 Hz,
3H), 0.95 (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=174.59, 151.65, 133.88, 128.41, 126.72, 105.38, 44.80,
31.94, 29.56, 19.54, 17.20; MS (70 eV): m/z (%)=216.3 (75)
[M+], 118.2 (100).
Acknowledgements
Financial support from Peking University, National Science
Foundation of China (Nos. 20702002, 20872003) and Nation-
al Basic Research Program of China (973 Program
2009CB825300) are greatly appreciated.
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