Copper hydride catalyzed reductive aldol addition/lactonization domino reactions of α,β-unsaturated diesters

Article abstract of DOI:10.1055/s-0033-1340673

The first copper-catalyzed reductive aldol addition/lactonization domino reactions of α,β-unsaturated dicarboxylate esters with ketones were achieved in high yields. The method, which involves easily available reagents, a flexible combination of reactants, and mild conditions, provides a simple route to functionalized lactones bearing an ester group. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340673

724▌
LETTER
lCettoerpper Hydride Catalyzed Reductive Aldol Addition/Lactonization Domino
Reactions of α,β-Unsaturated Diesters
Copper Hydride Catalyzed Domino Reactions
Zengchang Li,a Zhenlei Zhang,a Lu Yuan,a Lan Jiang,a Zhansheng Li,b Zhengning Li*a
a
College of Environmental and Chemical Engineering, Dalian University, Dalian 116622, P. R. of China
Fax +86(411)87402449; E-mail: znli@dl.cn
b
College of Chemical Engineering, Dalian University of Technology, Dalian 116023, P. R. of China
Received: 25.11.2013; Accepted after revision: 05.01.2014
to enolates with high selectivity under mild conditions.
Abstract: The first copper-catalyzed reductive aldol addition/lac-
Utilization of the nucleophilic reactivity of the enolate re-
tonization domino reactions of α,β-unsaturated dicarboxylate esters
sults in a reductive aldol domino reaction or a reductive
with ketones were achieved in high yields. The method, which in-
volves easily available reagents, a flexible combination of reactants,
Michael addition domino reaction.8 Chiu and co-workers
and mild conditions, provides a simple route to functionalized lac- have reported that copper enolates formed in situ by con-
tones bearing an ester group.
jugate reduction of α,β-unsaturated ketones or esters with
(triphenylphosphine)copper
hydride
hexamer
Key words: reductions, aldol reactions, lactones, domino reac-
tions, copper, catalysis
[(CuHPPh3)6; Stryker’s reagent] can participate in intra-
molecular aldol cyclization reactions to give five- or six-
membered carbocyclic alcohols in an efficient one-pot
process.9,10 More-practical reactions have been performed
by using a copper hydride as a catalyst and a silane or oth-
er reagent as the reducing reagent.1,11,12
The chemistry of copper(I) hydride has received much at-
tention in recent years.1–4 Copper(I) hydride exhibits high
chemoselectivity in the reduction of C=C double bonds
conjugated to an electron-withdrawing group.5–7 The re-
duction involves conjugate addition of copper(I) hydride
to α,β-unsaturated ketones or to α,β-unsaturated esters,
and the production of copper enolates that are converted
into the reduced products by hydrolysis during the workup
procedure. The reaction also provides an alternative route
The reduction has also been extended to α,β-unsaturated
thioesters13 and to an asymmetric version that uses chiral
ligands.14,15 Lam and Joensuu have shown that α,β-unsat-
urated esters bearing an intramolecular carbonyl group in
the alkoxy moiety react in the presence of chiral bisphos-
phine copper catalysts to give five- or six-membered
CO2Me
CO2Me
1
CuH
R2
O
R1
silyl-O
OMe
CO2Me
OCu
OMe
O-silyl
OMe
D
–OMe
CO2Me
E
silane
CO2Me
A
B
R1 R2
CO2Me
O
O
silane
R2
O
R1
P
R2
O
R1
CuO
CuO
OMe
OMe
CO2Me
MeO2C
C
Scheme 1 Possible reactions in the multicomponent reaction system
SYNLETT 2014, 25, 0724–0728
Advanced online publication: 27.01.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340673; Art ID: ST-2013-W1086-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper Hydride Catalyzed Domino Reactions
725
β-hydroxy lactones with high stereoselectivities.16 Other a silane should then give the silyl ether D and regenerate
reductive intermolecular aldol addition domino reactions the copper hydride. Alternatively, alkoxide C might react
were reported in 2006 by Shibasaki’s group, who used a with an intramolecular ester group to give a lactone P to-
catalyst derived from CuF(PPh3)3·2MeOH–(R)-tol- gether with copper(I) methoxide E, which should react
BINAP [tol-BINAP = 2,2′-bis(di-4-tolylphosphino)-1,1′- with a silane to regenerate copper(I) hydride. Experiments
binaphthyl],17 and by Riant’s group, who used catalysts have shown that copper alkoxides react with silanes faster
derived from CuF(PPh3)3·2MeOH–Taniaphos18,19 or Cu– than do copper enolates. Accordingly, if the reaction of
N-heterocyclic carbene complexes.20 We found that the enolate A with the carbonyl compound proceeds, the pres-
copper complex of bis[(2-diphenylphosphino)phenyl] ence of the carbonyl compound in the reaction system
ether (DPEphos) is efficient in catalyzing the reduction of should accelerate the reaction of dimethyl maleate. If the
electron-deficient polar C=C double bonds conjugated to rate of lactonization of C is faster than that of the reaction
electron-withdrawing groups,21 and that this complex can between C and the silane, a three-step domino reaction
also catalyze reductive intramolecular aldol reactions in should occur.
high yields and high diastereoselectivities.22 Recently, we
We were pleased to find that lactones were obtained as the
reported that high diastereoselectivities can be achieved in
major products in the presence of acetophenone and a cat-
reductive intermolecular aldol reactions of unsaturated es-
alytic amount of CuH–DPEphos (Table 1, entry 1), as this
ters with ketones in the presence of a copper–4,5-bis(di-
confirmed that the rate of lactonization is much higher
phenylphosphino)-9,9-dimethylxanthene complex (Cu–
than the rate of the reaction of aldol alkoxide C with
Xantphos) catalyst.23
In continuing our interest in copper hydride chemistry, we
explored some novel copper(I) hydride-catalyzed multi-
Table 1 Domino Reactions of Acetophenone
CO2Me
step domino reactions.24,25 We hypothesized that the cop-
per alkoxylate intermediate formed in a reductive aldol
addition reaction might react further with another electro-
phile in a three-step domino reaction. To test this hypoth-
esis, we chose dialkyl maleates to act as both copper
hydride acceptors and as intramolecular electrophiles for
the alkoxide.
O
O
[CuF(PPh3)3]⋅2MeOH
Ph
+
PMHS
+
O
Ph
ligand
CO2Me
MeO2C
anti-4a
1
2
3a
+
O
Ph
O
MeO2C
Recognizing that conjugate addition and regeneration of
the copper(I) hydride would be critical to the success of
the catalytic domino reaction, we began our studies with
the conjugated reduction of dimethyl maleate with po-
ly(methylhydrosiloxane) (PMHS) in the presence of a
copper hydride catalyst formed in situ, a reaction that had
not previously been explored. Only 39% of the dimethyl
syn-4a
Entrya
Ligand
PMHS Time
(equiv) (h)
Yieldb (%) syn/anti
of 4a
1
2
DPEphos
DPE
2
2.6
1.3
3.5
1.1
3.3
3.3
1.0
4.0
2.0
1.6
1.0
1.0
86.0
52.6
33.0
35.2
15.2
93.1
68.9
24.1
99.2
80.9
83.8
94.3
60.4:39.6
54.1:45.9
38.4:61.6
53.9:46.1
49.1:50.9
66.9:33.1
68.9:31.1
76.8:23.2
68.0:32.0
41.1:58.9
68.6:31.4
71.5:28.5
2
maleate was reduced in one hour by using
a
3
DPP
2
CuF(PPh3)3·2MeOH–DPEphos-derived catalyst, even
though this catalyst is efficient in the reduction of acry-
lates and crotonates. Similarly, partial reduction of the
maleate was observed when we used copper-1,2-bis(di-
phenylphosphino)benzene (DPBen) complex catalyst that
is efficient in catalyzing the reduction of relatively inert
unsaturated compounds, including bulky enones11 and
thioesters.13 The inertness of maleates was further demon-
strated by competitive reduction of one equivalent of t-bu-
tyl acrylate and one equivalent of dimethyl maleate; little
of the maleate was reduced, whereas the acrylate was al-
most completely reduced. We reasoned that the low con-
version of maleate might be due to its low reactivity and
to slow regeneration of copper hydride from enolate A
(Scheme 1). The ease with which copper hydride is
formed from a silane and a copper alkoxide,26 coupled
with the successful reductive intermolecular aldol addi-
tion reaction of unsaturated esters to carbonyls,22 led us to
introduce a carbonyl compound into the reaction system.
If we assume that this carbonyl compound reacts with the
copper enolate A, it should give the copper alkoxide C
through an aldol reaction. The reaction of alkoxide C with
4
DPB
2
5
DPBen
2
6
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
2
7c
8d
9e
10f
11
12g
2
2
2
2
4
1.5
a Reaction conditions: 3a (0.6 mmol),
3a/1/ligand/CuF(PPh3)3·2MeOH = 1:1.3:0.015:0.01 (molar), THF,
r.t., unless otherwise stated.
b By GC.
c At 0 °C.
d At –30 °C.
e In toluene.
f Cu(OAc)2·H2O was used as the copper source.
g Ph2SiH2 was used.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 724–728

726
Z. Li et al.
LETTER
tion was very slow at this temperature. Replacing the
dimethyl ester with the diethyl ester had little effect on the
selectivity. Whereas dimethyl maleate was active, diethyl
fumarate was almost inert to the reaction. When diethyl
fumarate was used as the substrate, more than 80% was
recovered after 22 hours of reaction. In comparison, 93%
of the maleate was consumed in 3.3 hours. Therefore, the
addition reaction of copper hydride is sensitive to the po-
larity of the C=C double bond in the α,β-unsaturated ester.
Shono and co-workers reported that lactones bearing an
ester group can be obtained as a mixture of diastereomers
by a reaction involving a maleate, a ketone, zinc, and an
alkyl iodide,29 whereas fumarate is inert. In comparison
with Shono’s method for the synthesis of lactones, our
copper-catalyzed domino reaction has advantages in
terms of higher yields, cheaper reagents, and shorter reac-
tion times. Lactones have also been prepared by deproton-
ation of substituted succinates and subsequent aldol
addition to aldehydes;30,31 however, the method is limited
to aldehydes, and the yields were low even though long
reaction times were used.
Table 2 Conjugate Addition/Aldol Addition/Lactonization Domino
Reaction of Dimethyl Maleate with a Silane and Substituted Acetophe-
nones
O
CO2Me
CO2Me
1
O
[CuF(PPh3)3]⋅2MeOH
ligand, 2
R
O
+
MeO2C
R
3a–e
4a–e
Entrya
3 (R)
Yieldb (%) of 4
syn/anti
1
2
3
4
5
3a (H)
quant (99)
98.4 (96)
quant (97)
88.6 (76)
84.1 (80)
69.0:31.0
60.6:39.4
59.1:40.9
72.3:27.7
68.5:31.5
3b (Cl)
3c (Br)
3d (Me)
3e (OMe)
a Reaction conditions: 3 (0.6 mmol),
3/1/Xantphos/CuF(PPh3)3·2MeOH/PMHS = 1:1.3:0.015:0.01:3 (mo-
lar), THF, r.t., 1 h.
b GC yield; the isolated yield is given in parentheses.
Our previous studies on the reductive aldol reaction
showed that substituents on the acetophenone affect the
diastereoselectivity.23 Accordingly, we used substituted
acetophenones to explore the generality of the current re-
action and its selectivity. As shown in Table 2, good to ex-
cellent yields were obtained in all the cases. The
introduction of a chloro or bromo substituent on the phe-
nyl group decreased the selectivity toward the syn-lac-
tone, whereas the presence of a methyl substituent on the
phenyl group favored the formation of the syn-isomer.
Surprisingly, methoxyl group did not affect the syn/anti
ratio.
PMHS.27 This can be attributed to the ease with which in-
tramolecular reaction occurs in comparison with intermo-
lecular reaction. There was little difference in the amounts
of syn- and anti-lactones formed in this domino reaction.28
Attempts to improve the diastereoselectivity by changing
the ligand or the copper source were not unsuccessful (en-
tries 2–12). Among the ligands that we tested, Xantphos,
which has shown high diastereoselectivities in other cop-
per-catalyzed reductive aldol reactions, gave the best re-
sults in terms of the diastereomeric ratio and the yield. By
using this ligand, we obtained a 93.1% yield of the cy-
clized products with a 66.9:33.1 isomeric ratio in favor of
the syn-isomer in 3.3 hours at room temperature (entry 6).
The isomeric ratio could be increased to 76.8:23.2 by de-
creasing the temperature to –30 °C (entry 8), but the reac-
Dimethyl itaconate (5) was also used as a copper hydride
acceptor to test the domino reaction. This ester was more
reactive than maleate. As shown in Table 3, the domino
reactions were completed in one hour with acetophenone
Table 3 Conjugate Addition/Aldol Addition/Lactonization Domino Reactions of Dimethyl Itaconate
O
CO2Me
O
R
[CuF(PPh3)3]⋅2MeOH
ligand, 2
O
+
CO2Me
MeO2C
6a–e
R
5
3a–e
Entrya
3 (R)
Time (h)
Yieldc (%)
syn/antib
d
1
2
3
4
5
3a (H)
0.75
97
96
98
92
98
–
3b (Cl)
3c (Br)
3d (Me)
3e (OMe)
1
1
1
1
45.5:54.5
47.4:52.6
35.4:64.6
35.6:64.4
a Reaction conditions: 3 (0.6 mmol), 3/5/Xantphos/CuF(PPh3)3·2MeOH/PMHS = 1:1.3:0.015:0.01:2 (molar), THF, r.t.
b By GC.
c Isolated yield.
d Not determined (inseparable products).
Synlett 2014, 25, 724–728
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper Hydride Catalyzed Domino Reactions
727
or substituted acetophenones, giving separable lactones
containing two adjacent tertiary carbon atoms.32 The reac-
tion was also relatively clean, and little or none of the
phenylethanol-type product was observed. Once again,
the importance of the polarity of the C=C double bond in
unsaturated esters is demonstrated by the ease with which
itaconate 5 reacts. Although the diastereoselectivity to-
ward the product is poor, the excellent yields obtained
from this domino reaction make it particularly useful for
preparing lactones with an exo-ester moiety.
References and Notes
(1) Chiu, P. Synthesis 2004, 2210.
(2) Deutsch, C.; Lipshutz, B. H.; Krause, N. Angew. Chem. Int.
Ed. Engl. 2007, 46, 1650.
(3) Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008,
108, 2916.
(4) Li, Z.; Liu, G.; Chiu, P. Huaxue Jinzhan 2008, 20, 1909;
Chem. Abstr. 2009, 151, 100615.
(5) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am.
Chem. Soc. 1988, 110, 291.
(6) Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett. 1989,
30, 5677.
(7) Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J.
M. Tetrahedron Lett. 1990, 31, 3237.
(8) Kamenecka, T. M.; Overman, L. E.; Ly Sakata, S. K.
Org. Lett. 2002, 4, 79.
(9) Chiu, P.; Chen, B.; Cheng, K. F. Tetrahedron Lett. 1998, 39,
9229.
(10) Chiu, P.; Szeto, C. P.; Geng, Z.; Cheng, K.-F. Org. Lett.
2001, 3, 1901.
(11) Baker, B. A.; Bošković, Z. V.; Lipshutz, B. H. Org. Lett.
2008, 10, 289.
(12) Welle, A.; Cirriez, V.; Riant, O. Tetrahedron 2012, 68,
3435.
The use of symmetric ketones produces a single stereo-
center in the products and therefore eliminates the prob-
lem of a low anti/syn ratio. The reaction of benzophenone
with dimethyl maleate and PMHS gave the expected lac-
tone in 84% yield (Table 4, entry 1). Replacement of ma-
leate with itaconate and the use of the aliphatic carbonyl
compounds acetone and pentan-3-one gave the corre-
sponding lactones in reasonable yields (entries 2 and 3). A
spiro compound was obtained in 88% yield when cyclo-
pentanone was used as the carbonyl compound (entry 4).
Table 4 Conjugate Addition/Aldol Addition/Lactonization Domino
Reactions of Symmetric Ketones
(13) Li, N.; Ou, J.; Miesch, M.; Chiu, P. Org. Biomol. Chem.
2011, 9, 6143.
(14) Ou, J.; Wong, W.-T.; Chiu, P. Org. Biomol. Chem. 2012, 10,
5971.
(15) Ou, J.; Wong, W.-T.; Chiu, P. Tetrahedron 2012, 68, 3450.
(16) Lam, H. W.; Joensuu, P. M. Org. Lett. 2005, 7, 4225.
(17) Zhao, D.; Oisaki, K.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2006, 47, 1403.
R
O
O
R
[CuF(PPh3)3]⋅2MeOH
+
2
+
1 or 5
O
R'
MeO2C
ligand
R
R
7a–d
Entrya
Diester 7 (R, R, R)
Time (h) Yieldb (%)
(18) Chuzel, O.; Deschamp, J.; Chausteur, C.; Riant, O. Org. Lett.
2006, 8, 5943.
1c
2d
3d
4d
1
5
5
5
7a (Ph, Ph, H)
7b (Me, Me, Me)
7c (Et, Et, Me)
2
1
3
84
92
62
88
(19) Deschamp, J.; Chuzel, O.; Hannedouche, J.; Riant, O.
Angew. Chem. Int. Ed. 2006, 45, 1292.
(20) Welle, A.; Díez-González, S.; Tinant, B.; Nolan, S. P.; Riant,
O. Org. Lett. 2006, 8, 6059.
(21) Zheng, A.-J.; Shan, F.-J.; Li, Z.-N.; Li, Z.-C.; Jiang, L.
Chem. Pap. 2013, 67, 1271.
7d [–(CH2)4–, Me] 2
(22) Zheng, A.; Jiang, L.; Li, Z. Chin. J. Chem. 2012, 30, 2587.
(23) Li, Z.; Jiang, L.; Li, Z.; Chen, H. Chin. J. Chem. 2013, 31,
539.
(24) Du, Y.; Xu, L.-W.; Shimizu, Y.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 16146.
(25) For a report on a cobalt-catalyzed aldol
addition/lactonization from a maleate monoester monamide,
see: Lumby, R. J. R.; Joensuu, P. M.; Lam, H. W. Org. Lett.
2007, 9, 4367.
a Reaction conditions: ketone (0.6 mmol),
ketone/diester/ligand/CuF(PPh3)3·2MeOH/PMHS = 1:1.3:0.015:
0.01:3 (molar), THF, r.t.
b Isolated yield.
c Xantphos was used as the ligand.
d BINAP was used as the ligand.
In conclusion, we have developed the first three-step cop-
per hydride catalyzed domino reactions of unsaturated di-
esters, ketones, and silanes, which proceed in high yields.
The ready availability and flexible combination of the re-
actants, the mild reaction conditions, and the conciseness
of the procedure make this reaction useful in the synthesis
of functionalized lactones. Efforts to improve the diaste-
reoselectivity are underway in this laboratory.
(26) Chiu, P.; Li, Z. N.; Fung, K. C. M. Tetrahedron Lett. 2003,
44, 455.
(27) Methyl 2-Methyl-5-oxo-2-phenyltetrahydrofuran-3-
carboxylate: Typical Procedure
A dried Schlenk tube was charged with CuF(PPh3)3·2MeOH
(5.9 mg, 0.0063 mmol), Xantphos (5.6 mg, 0.0097 mmol),
and THF (2.0 mL) under N2. The mixture was stirred for 30
min and then PMHS (0.15 mL, 2.5 mmol) was added, and
the mixture was stirred for a further 15 min. A soln of ketone
3a (84 mg, 0.70 mmol) and dimethyl maleate (137 mg, 0.951
mmol) in THF (2 × 0.5 mL) was added, and the mixture was
stirred until 3a was almost consumed (GC). The reaction
was quenched by addition of a 0.3 M soln of NH4F in 3:1
MeOH–H2O (10 mL). The syn/anti ratio of 4a (66.9:33.1)
was then determined by GC. Column chromatography [silica
gel, PE–EA (100:0 to 85:15)] gave a diastereomeric mixture
of the products as a colorless liquid; yield: 153 mg (93%).
Further chromatographic separation gave pure anti-4a and
syn-4a.
Acknowledgment
This work was supported by NSFC (No. 20972020), LNET
(LR2012041), National Training Programs of Innovation and
Entrepreneurship for Undergraduates (201311258006), and the
Liaoning Innovative Program for Undergraduate Students
(201311258006).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 724–728

728
Z. Li et al.
LETTER
anti-4a: colorless oil. Rf = 0.50 (EA–PE, 30:70). 1H NMR
(400 MHz, CDCl3):  = 7.46–7.31 (m, 5 H), 3.82 (s, 3 H),
3.60–3.49 (m, 1 H), 2.98 (dd, J = 17.8, 5.1 Hz, 1 H), 2.63
(ddd, J = 17.7, 8.7, 0.9 Hz, 1 H), 1.67 (d, J = 0.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3):  = 174.42, 171.11, 143.74,
128.84, 128.22, 124.29, 86.96, 52.60, 51.60, 32.04, 25.38.
LRMS (EI, 70 ev): m/z (%) = 234 (10, M+), 219 (4), 175 (4),
131 (9), 114 (100), 77 (24), 55 (27), 27 (3).
(28) The relative configurations of the 4a diastereoisomers were
deduced by base-catalyzed isomerization of the product
mixture and by NOSEY spectroscopy. DBU-catalyzed
isomerization of mixtures of 4a with syn/anti ratios of 68:32
or 54:46 in refluxing toluene each gave a mixture with a
37:63 syn/anti ratio.
(29) Shono, T.; Hamaguchi, H.; Nishiguchi, I.; Sasaki, M.;
Miyamoto, T.; Miyamoto, M.; Fujita, S. Chem. Lett. 1981,
1217.
(30) Pohmakotr, M.; Sampaongoen, L.; Issaree, A.; Tuchinda, P.;
Reutrakul, V. Tetrahedron Lett. 2003, 44, 6717.
(31) Pohmakotr, M.; Komutkul, T.; Tuchinda, P.; Prabpai, S.;
Kongsaeree, P.; Reutrakul, V. Tetrahedron 2005, 61, 5311.
(32) The stereochemistries of the 6a isomers were deduced from
their NOESY spectra.
syn-4a: colorless oil. Rf = 0.43 (EA–PE, 30:70). 1H NMR
(400 MHz, CDCl3): d = 7.40–7.24 (m, 5 H), 3.46 (t, J = 7.8
Hz, 1 H), 3.33 (s, 3 H), 3.02 (dd, J = 17.9, 7.0 Hz, 1 H), 2.82
(dd, J = 17.9, 8.7 Hz, 1 H), 1.93 (s, 3 H). 13C NMR (101
MHz, CDCl3):  = 174.52, 169.99, 139.83, 128.46, 128.40,
124.91, 87.23, 52.72, 52.08, 32.01, 28.72. LRMS (EI, 70
ev): m/z (%) = 219 (13), 191 (8), 160 (3), 114 (100), 77 (27),
55 (28), 27 (3).
Synlett 2014, 25, 724–728
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