One-pot cross-coupling of N-acyl N,O-acetals with α,β- unsaturated compounds

Article abstract of DOI:10.1039/b915488d

The synergistic action of BF₃·OEt₂ and SmI₂ allowed a series of intermolecular cross-couplings of readily available N-acyl N,O-acetals with α,β-unsaturated compounds to be performed in high yields, which was applied to the

Full text of DOI:10.1039/b915488d

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One-pot cross-coupling of N-acyl N,O-acetals with a,b-unsaturated
compoundsw
a
a
Yong-Gang Xiang,z Xiang-Wu Wang,z Xiao Zheng,*bc Yuan-Ping Ruana and
Pei-Qiang Huang*a
Received (in Cambridge, UK) 29th July 2009, Accepted 23rd September 2009
First published as an Advance Article on the web 13th October 2009
DOI: 10.1039/b915488d
The synergistic action of BF3ꢀOEt2 and SmI2 allowed a series
of intermolecular cross-couplings of readily available N-acyl
N,O-acetals with a,b-unsaturated compounds to be performed
in high yields, which was applied to the stereoselective synthesis
of pyrrolizidine alkaloid (+)-xenovenine.
Table 1 SmI2-mediated reductive coupling of N,O-acetal TMS ether
5 with a,b-unsaturated compounds
After the Mannich reaction,1 the N-acyliminium ion (A)-based
a-amidoalkylation reaction2 is probably the most powerful
methodology for carbon–carbon bond formation at the
N-a-carbon3,4 (Scheme 1, A to 2). The versatility of this
methodology is due to both the high reactivity and ready
availability of a variety of N-acyliminium ions from N-acyl
N,O-acetal precursors 1. The latter are, in turn, readily available
by a number of methods,2 such as the partial reduction
of imides 3,5 condensation of carbonyl compounds with
carbamates/amides 4,6a,b and so on.6c One of the most recent
developments in these areas is the one-pot C–C bond formation
starting from amines7 or carbamates.8 In the light of these
developments, we assumed that N-acyl N,O-acetals 1 could
serve as versatile precursors of acylaminoalkyl radicals9 B,
via N-acyliminium ions A, for one-pot C–C bond formation
(Scheme 1). In connection with our research on the development
of synthetic methodologies based on the use of N-acyliminium
ions,10 N-a-carbanions,11 and SmI2,12 we have undertaken
a,b-Unsaturated
compound
Product
(% yield)a
Entry
1
2
6a (72)
6b (78)
6c (73)
3
a
Isolated yield.
a study on the one-pot Lewis acid and SmI2-mediated
cross-coupling of N-acyl N,O-acetals with a,b-unsaturated
compounds, and wish to report the results herein.
Our initial efforts were focused on exploring BF3ꢀOEt2 and
samarium(II) diiodide-mediated13 reductive coupling of the
known and readily-available N-carbamoyl N,O-acetal TMS
ether 5,5a with ethyl acrylate (Table 1). After extensive
investigations, we found that treatment of a mixture of ethyl
acrylate (2 equiv.), N,O-acetal TMS ether 5 (1 equiv.) and
BF3ꢀOEt2 (2 equiv.) with a freshly prepared t-BuOH-containing
(4 equiv.) SmI2 solution (4 molar equiv.) in THF at ꢁ40 1C,
followed by stirring at ꢁ40 1C for 5 min, afforded the desired
coupling product 6a in 72% yield (Table 1, entry 1).14 No
reduced product 7 was observed. The reaction with a,b-
unsaturated compounds such as t-butyl acrylate and acrylonitrile
also produced the corresponding coupled products 6b and 6c
in similar yield (Table 1, entries 2 and 3).
Encouraged by these results, the cross-coupling reaction
of N-benzyloxycarbonyl-2-hydroxypyrrolidine 8 was investi-
gated. Under the above mentioned optimized conditions,
the reaction of ethyl acrylate (2 equiv.) with 8 afforded the
desired coupling product 9a in 76% yield (Table 2, entry 1).
The reaction was extended to a variety of a,b-unsaturated
compounds and similar results were obtained, displayed in
Table 2.
Scheme 1 N-Acyl N,O-acetal initiated C–C formation methods.
a Department of Chemistry and The Key Laboratory for Chemical
Biology of Fujian Province, College of Chemistry and Chemical
Engineering, Xiamen University, Xiamen, Fujian 361005,
P. R. China. E-mail: pqhuang@xmu.edu.cn; Fax: +86-592-2186400
b Department of Pharmaceutical Sciences, Medical College,
Xiamen University, Xiamen, Fujian 361005, P. R. China
c Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences. E-mail: zxiao@xmu.edu.cn
To confirm the formation of the a-acylaminoalkyl radical
intermediate,8 the reaction of N-carbamoyl N,O-acetal 8 was
performed in the absence of an a,b-unsaturated compound. As
anticipated, the homo-coupling product 11 (Fig. 1) was
obtained as a mixture of diastereomers in 24% yield, along
with 74% of the reduction product 10 (Table 2, entry 7).
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. See DOI: 10.1039/b915488d
z Y.-G. X. and Y.-W. W. contributed equally to this project.
ꢂc
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Table
2
SmI2-mediated cross-coupling of N,O-acetal
8
with
Table 3 SmI2-mediated cross-coupling of N,O-acetals 12a–c with
a,b-unsaturated compounds
a,b-unsaturated compounds
a,b-Unsaturated
compound
Product 9 (% yield) (d.r.)
and 10 (% yield)a
Entry
Substrate and
a,b-unsaturated
compound
Product (% yield)
(trans : cis ratio and/or d.r.)
and 14 (% yield)
1
2
3
4
9a (76)
Entry
9b (67)
9c (79)
9d (84) (70:30)b
1
2
3
4
13 (67) (69 : 31):a14a (5)
15 (62) (90 : 10)b
16a (73) (91 : 9)b
5
6
9e (52) (51:49);b10 (19)
16b (74) (91 : 9)ab
9f (88) (Z:E = 58:42)
11 (24) (50:50); 10 (74)
7
none
5
6
16c (74) (91 : 6 : 3)b
a
b
Isolated yield. Determined by HPLC.
16d (48) (67 : 33);c14c (20)
7
8
a
16e (73)d
16f (53) (92 : 8)b; 14c (12)
b
Ratio determined on the desilylated product. Ratio determined by
HPLC. Ratio determined by 1H NMR at variant temperatures.
c
d
Only one isomer was detected by HPLC and 1H NMR at variant
temperatures.
Fig. 1 Homo-coupling product 11.
Subsequently, we examined the cross-coupling of N-carbamoyl
N,O-acetals 12a–c, derived from (S)-pyroglutamic acid, with
a,b-unsaturated compounds, with results summarized in
Table 3. As can be seen, the coupling reactions proceeded
smoothly, with both the N- and O-protecting groups showing
an effect on the diastereoselectivity of the reaction. The use of
more sterically hindered TBDPS as the O-protecting group
gave excellent trans-diastereoselectivities (Table 3, entries, 3–8).
With the dual aim of confirming the stereoselectivity of
the reaction and demonstrating the synthetic value of the
method, we undertook the synthesis of pyrrolizidine alkaloid
(+)-xenovenine15 (22) (Scheme 2). The diastereomeric mixture
16b was treated with TBAF to give the desilylated product 17
and its diastereomer. To our delight, the two diastereomeric
products were separable by flash chromatography. Iodination
of the major diastereomer 17 (I2, Ph3P, imidazole) gave the
desired iodide 18, which was reduced (H2, 10% Pd/C) to afford
the pyrrolidine 19. Conversion of ester 19 into the Weinreb
amide 20 (Me3Al, HN(OMe)MeꢀHCl)16 followed by treatment
with n-heptyl magnesium bromide led to the formation of
(2S,5R)-21. Finally successive N-deprotection and intramolecular
reductive amination yielded (+)-xenovenine (22).15 These
results confirmed that the cross-coupling reaction (Table 3)
is 2,5-trans-diastereoselective.
Scheme 2 Reagents and conditions: i. TBAF, THF, 77%; ii. I2, Ph3P,
imidazole, THF, 86%; iii. 10% Pd/C, H2, Et3N, MeOH, 97%;
iv. AlMe3, NH(OMe)MeꢀHCl, CH2Cl2, 0 1C, 3 h, 81%; v. n-C7H15MgBr,
THF, 50 1C, 80%; vi. (1) 2 N HCl, AcOEt; (2) MeONa, MeOH;
(3) 10% Pd/C, H2, MeOH, 42% for three steps.
efficient and versatile for the synthesis of a variety of cyclic and
alicyclic N-containing compounds in either a racemic or
enantioselective manner. The reaction of the pyroglutamic
acid derived N-carbamoyl N,O-acetal 12c exhibited excellent
2,5-trans-diastereoselectivity, which was applied to the total
synthesis of the ant venom alkaloid (+)-xenovenine. Extension
of this method to one-pot coupling of N-acyl N,O-acetals with
other electrophiles such as aldehydes is in progress in our
laboratory, and will be reported in due course.
In summary, we have demonstrated that the one-pot
reductive cross coupling of N-carbamoyl N,O-acetals 5, 8,
and 12 with a,b-unsaturated compounds can be conveniently
and efficiently achieved by synergistic action of both Lewis
acid BF3ꢀOEt2 and SmI2viaN-acyliminium ion and a-acylamino-
alkyl radical intermediates. The ready availability of the N-acyl
N,O-acetals renders this C–C bond formation method both
The authors are grateful to the NSF of China (20402012;
20832005), the National Basic Research Program (973 Program)
of China (Grant No. 2010CB833206), and the Program for
New Century Excellent Talents in Xiamen University for
financial support.
ꢂc
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cooled THF solution of an N,O-acetal (1.0 equiv.), a,b-unsatu-
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ꢂc
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Chem. Commun., 2009, 7045–7047 | 7047