Stereoselective synthesis of α-ylidene-β-dicarbonyl compounds: A mild PhI(OAc)2-mediated dehydrogenation process

Article abstract of DOI:10.1246/cl.2012.940

PhI(OAc)2-mediated dehydrogenation of α-alkyl-β-dicarbonyl compound has been developed to afford α-ylidene-β- dicarbonyl compounds with high stereoselectivity under mild conditions. This process provides a complementary entry to stereoselectivity for the Knoevenagel reaction.

Full text of DOI:10.1246/cl.2012.940

doi:10.1246/cl.2012.940
940
Published on the web September 1, 2012
Stereoselective Synthesis of ¡-Ylidene-¢-dicarbonyl Compounds:
A Mild PhI(OAc)2-mediated Dehydrogenation Process
Liyan Fan,* Wen Chen, Kunshan Tang, and Dongbei Wu
Department of Chemistry, Tongji University, 1239 Siping Road, Shanghai, P. R. China
(Received May 7, 2012; CL-120394; E-mail: fanly@tongji.edu.cn)
PhI(OAc)2-mediated dehydrogenation of ¡-alkyl-¢-dicar-
using IBD as oxidant9 (Table 1, Entry 1).10 To our surprise, 2a
was isolated in 15% yield as the major by-product. The
elimination of H-atom in 1a would result in the formation of
compound 2a. If it was true, additional base would be necessary
to capture H-atom. Actually, the yield of 2a was promoted in
the presence of K2CO3 (Table 1, Entry 2). And after several
attempts, we found that Pd(OAc)2 was not involved into this
transformation at all (Table 1. Entries 3-6). Without PhI(OAc)2
bonyl compound has been developed to afford ¡-ylidene-¢-
dicarbonyl compounds with high stereoselectivity under mild
conditions. This process provides a complementary entry to
stereoselectivity for the Knoevenagel reaction.
In recent years, hypervalent iodine reagents have played an
increasingly important role in organic synthesis due to their low
toxicity, high stability, and unique reactivities.1 One of the
important applications is to efficiently oxidize substrates with
diverse functional groups.2 Among these oxidations, ¡-func-
tionalization of carbonyl compounds mediated by hypervalent
aryl--3-iodanes has been extensively investigated and has broad
synthetic utility (Scheme 1).3 PhI(OAc)2 (IBD) can be employed
as an oxidant to introduce an OR group (R = Ac, Me) into an
¡-position of carbonyl carbon from simple ketone compounds
(eq 1).3f,4 For instance, with ¢-dicarbonyl compounds, iodonium
ylide is formed under similar conditions (eq 2).5
¡-Ylidene-¢-dicarbonyl compounds are versatile synthetic
intermediates, and can be prepared through the Knoevenagel
condensation of aldehydes/ketones and ¢-dicarbonyl com-
pounds in general.6 And the stereochemistry of newly formed
double bond is mainly controlled by steric effects to yield
thermodynamically stable E-isomer as major product.7 Methods
to obtain thermodynamically unstable Z-isomers have been
rarely reported.8 Herein we report a mild IBD-mediated
dehydrogenation reaction of ¡-alkyl-¢-dicarbonyl compounds,
which could produce corresponding ¡-ylidene-¢-dicarbonyl
compounds (Scheme 2). The new process presented in this
paper would afford different stereoselectivity.
Table 1. Discovery journey of IBD-mediated dehydrogenation
of 1a
O
O
O
O
Ph
Ph
1a
2a
Pd(OAc)2
/equiv
PhI(OAc)2
/equiv
K2CO3
/equiv
Yield
/%
Entry
1
2
3
4
5
6
7
0.1
0.1
0.1
®
®
0.1
®
2.0
2.0
®
2.0
®
15
44
0
20
0
2.2
®
®
2.2
2.2
2.2
®
2.0
0
50
Table 2. Optimizing reaction conditions for PhI(OAc)2-medi-
ated dehydrogenationa
O
O
O
O
The reaction was found when we tested the Pd-catalyzed
dehydrogenation of ¡-ylidene-¢-dicarbonyl compound 1a by
PhI(OAc)2 / Base
MeCN/r.t.
Ph
n-Pr
Ph
n-Pr
1b
2b
O
PhI(OAc)2
/equiv
Time
/h
Yieldb
/%
O
IBD, base
R2
R1
R2
Equation
1
Entry
Base (equiv)
MeOH
R1
OR
1
2
3
4
5
6
7
8
9
0
K2CO3 (2.2)
K2CO3 (2.2)
K2CO3 (2.2)
K2CO3 (1.1)
Na2CO3 (2.2)
NaHCO3 (2.2)
NaH (2.2)
72
72
8
0
29
58
70
58
69
56
<5
<5
74
8c
1.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
O
O
O
O
IBD, base
MeOH
R1
R2
Equation
2
R1
R2
72
48
48
24
48
48
24
72
IPh
Scheme 1. ¡-Functionalization of ketone and ¢-dicarbonyl
compounds using IBD as oxidant.
Et3N (2.2)
O
O
O
O
DIPEA (2.2)
KHCO3 (2.2)
®
IBD
R1
R2
10
11
R1
R2
R
R
aReaction conditions: 1b (0.3 mmol), MeCN (3 mL), r.t. Iso-
lated yield. 76% of 1b was recovered.
b
c
Scheme 2. IBD-mediated dehydrogenation reaction.
Chem. Lett. 2012, 41, 940-942
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

941
O
O
R
Table 3. Optimizing reaction conditions for PhI(OAc)2-medi-
ated dehydrogenationa
OH
O
R
R1
R2
R1
R2
O
O
O
O
2 equiv PhI(OAc)2
R1
R2
R1
R2
2.2 equiv KHCO3
MeCN/r.t.
1
A
R
R
PhI(OAc)
1
2
2
Product 2
Time/yielda; (Z):(E)b
Product 2
Time/yielda; (Z):(E)b
Entry
1
Entry
6
O
R
O
R1OC
COR2
O
O
R1
R2
-HOAc
-PhI
O
O
R
H
I
Ph
Ph
O
Ph
O
EtO2C
2a
20 h/53%; (Z):(E) = 99:1
2f
5 h/66%; (Z):(E) = 17:1
CH3
2
B
O
O
O
O
Scheme 3. Plausible reaction mechanism for dehydrogenation
process.
Ph
OEt
2
3
4
5
7
8
nPr
Ph
2b
2g
24 h/74%; (Z):(E) = 99:1
6 h/4%; (Z):(E) = 3:2
moderate yield. Other substituted group such as benzoyl and
ester group were also combined into products (Entries 5 and 6).
Whereas the substrate with two substituents at ¢-position failed
(Entry 10). In general, the R group in product 2 was arrayed
on the (Z)-position to more bulky carbonyl group,12 which
is different from the product which was obtained by the
Knoevenagel condensation.
O
O
O
O
OEt
Ph
CO Et 2h
24 h/70%; (Z):(E) = 99:1
Ph
2
2c
6 h/74%; (Z):(E) = 10:1
O
O
O
O
In other hypervalent aryl--3-iodanes-mediated oxidation
procedures, the heteroatom ligands on iodine(III) serve as
leaving groups in both the ligand-exchange step and the
reductive elimination process of -3-iodanyl groups.1-5 Follow-
ing these general considerations, one plausible reaction mech-
anism was proposed and outlined in Scheme 3.
In conclusion, a new synthetic reaction of ¡-ylidene-¢-
dicarbonyl compounds with high stereoselectivity from corre-
sponding ¡-alkyl-¢-dicarbonyl ones has been developed by
using low toxic PhI(OAc)2 under mild conditions, which could
be complementary for the Knoevenagel condensation.
Ph
9
2d
24 h/61%; (Z):(E) = 25:1
PhOC
2i
6 h/69%; (Z):(E) = ⎯
O
O
O
O
Ph
PhOC
OEt
10
Ph
2e
2j
5 h/51%; (Z):(E) = 6:1
48 h/<5%
aIsolated yield. Estimated by H NMR.
b
1
We gratefully acknowledge the National Natural Science
Foundation of China (No. 20802052 and No. 20706045) for
financial support.
the reaction does not work (Table 1. Entries 3, 5, and 6). The
results of PhI(OAc)2-mediated transformation of a readily
available substrate into ¡-ylidene-¢-dicarbonyl compounds
prompted us for further investigations (Table 1, Entry 7).
Initially, PhI(OAc)2 dehydrogenation reaction was screened
by using various bases, and the results were showed in Table 2.
It was interesting to find that 1b could be transferred to 2b in
good yield (74% isolated yield) by using KHCO3 as the base
together with PhI(OAc)2. Other inorganic bases, such as K2CO3,
Na2CO3, NaHCO3, and NaH also could promote this reation,
while organic bases, such as Et3N and DIPEA gave lower yields.
The yield is lower with the decrease of IBD (Table 2, Entries 1
and 2). The traces of products were detected without using any
base (Table 2, Entry 11).
References and Notes
1
a) P. J. Stang, V. V. Zhdankin, Chem. Rev. 1996, 96, 1123. b)
V. V. Zhdankin, P. J. Stang, Chem. Rev. 2002, 102, 2523.
c) V. V. Grushin, Chem. Soc. Rev. 2000, 29, 315. d) T.
Okuyama, Acc. Chem. Res. 2002, 35, 12.
2
a) Hypervalent Iodine Chemistry: Modern Developments in
Organic Synthesis in Topics in Current Chemistry, ed. by T.
Wirth, Springer, Berlin, 2003. Vol. 224. doi:10.1007/3-540-
46114-0. b) V. V. Zhdankin, P. J. Stang, in Chemistry
of Hypervalent Compounds, ed. by K.-y. Akiba, VCH
Publishers, New York, 1999, Chap. 11, pp. 327-358.
a) F. Mizukami, M. Ando, T. Tanaka, J. Imamura, Bull.
Chem. Soc. Jpn. 1978, 51, 335. b) R. M. Moriarty, S. C.
Gupta, H. Hu, D. R. Berenschot, K. B. White, J. Am. Chem.
Soc. 1981, 103, 686. c) R. M. Moriarty, B. A. Berglund, R.
Penmasta, Tetrahedron Lett. 1992, 33, 6065. d) G. F. Koser,
We applied these optimized conditions to other substrates,
and the results are summarized in Table 3.11 It was found that the
reaction works well with different substituents. Various R groups
at the ¢¤-position, such as vinyl (Entries 1 and 8), alkyl (Entries
2 and 4), and phenyl (Entry 3), gave high stereoselective with
3
Chem. Lett. 2012, 41, 940-942
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

942
A. G. Relenyi, A. N. Kalos, L. Rebrovic, R. H. Wettach,
Chem. 2006, 71, 947.
J. Org. Chem. 1982, 47, 2487. e) G. F. Koser, J. S. Lodaya,
D. G. Ray, III, P. B. Kokil, J. Am. Chem. Soc. 1988, 110,
2987. f) R. M. Moriarty, R. K. Vaid, G. F. Koser, Synlett
1990, 365.
a) R. M. Moriarty, O. Prakash, Organic Reactions, John
Wiley & Sons, New York, 1999, Vol. 54, p. 273. b) T.
Fuchigami, T. Fujita, J. Org. Chem. 1994, 59, 7190. c) T.
Fujita, T. Fuchigami, Tetrahedron Lett. 1996, 37, 4725. d)
R. M. Moriarty, J. Org. Chem. 2005, 70, 2893.
a) A. Varvoglis, The Organic Chemistry of Polycoordinated
Iodine, VCH, New York, 1992. b) N. W. Alcock, A. P.
Bozopoulos, E. Hatzigrigoriou, A. Varvoglis, Acta Crystal-
logr., Sect. C: Cryst. Struct. Commun. 1990, 46, 1300.
c) R. M. Moriarty, O. Prakash, R. K. Vaid, L. Zhao, J. Am.
Chem. Soc. 1989, 111, 6443. d) R. M. Moriarty, E. J. May, O.
Prakash, Tetrahedron Lett. 1997, 38, 4333.
For reviews, see: a) G. Jones, Organic Reactions, John
Wiley & Sons, New York, 1967, Vol. 15, pp. 204-599. b)
L. F. Tietze, U. Beifuss, in Additions to CX ³-Bonds, Part 2
in Comprehensive Organic Synthesis, ed. by B. M. Trost, I.
Fleming, Pergamon Press, Oxford, 1991, Vol. 2, pp. 341-
394. doi:10.1016/B978-0-08-052349-1.00033-0.
9
a) X. Tong, M. Beller, M. K. Tse, J. Am. Chem. Soc. 2007,
129, 4906. b) H. Liu, J. Yu, L. Wang, X. Tong, Tetrahedron
Lett. 2008, 49, 6924.
10 X. Han, R. A. Widenhoefer, J. Org. Chem. 2004, 69, 1738.
11 General procedure for ¡-ylidene-¢-dicarbonyl compounds:
A typical procedure is given for the synthesis of 2a. A
mixture of ¡-alkyl-¢-dicarbonyl 1a (0.2023 g, 1 mmol),
PhI(OAc)2 (0.6442 g, 2 mmol), and KHCO3 (0.2200 g,
2.2 mmol) was dissolved in MeCN (10 mL) at room temper-
ature, and stirred at this temperature for 1 h. The TLC
showed the reaction was completed. The solvent was
removed in vacuo, and purified by chromatography
(PE:EtOAc = 5/1) to give the title compound 2a
(0.1062 g, 53%). For details, refer to the Supporting
Information which is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
html.
12 The configuration of compounds 2a-2j was assigned by
comparing 1H and 13C NMR data of known compounds. For
2a: A. V. Kazymov, E. P. Shchelkina, Chem. Heterocycl.
Compd. 1971, 7, 1287; 2b, 2c, and 2f: S. Wang, L. Zhang,
J. Am. Chem. Soc. 2006, 128, 8414; 2e: S. Sayama, Y.
Inamura, Bull. Chem. Soc. Jpn. 1991, 64, 306; 2g and 2h: J.
Barluenga, L. Riesgo, R. Vicente, L. A. López, M. Tomás,
J. Am. Chem. Soc. 2007, 129, 7772; 2f: H. Stetter, F. Jonas,
Synthesis 1981, 626.
4
5
6
7
8
R. Tanikaga, N. Konya, K. Hamamura, A. Kaji, Bull. Chem.
Soc. Jpn. 1988, 61, 3211.
a) Z. Li, H. Li, W. Guo, L. Cao, R. Yu, H. Li, S. Pan, Org.
Lett. 2008, 10, 803. b) T. Inokuchi, H. Kawafuchi, J. Org.
Chem. Lett. 2012, 41, 940-942
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www.csj.jp/journals/chem-lett/