Palladium-catalyzed direct functionalization of imidazolinone: Synthesis of dibromophakellstatin

Article abstract of DOI:10.1021/ja072844p

The direct C-H functionalization of imidazolinone is achieved with Pd(OAc)₂/NaOAc in DMSO. Dibromophakellstatin can be synthesized in five steps with 40% overall yield using this new C-H activation method. Copyright

Full text of DOI:10.1021/ja072844p

Published on Web 06/01/2007
Palladium-Catalyzed Direct Functionalization of Imidazolinone: Synthesis of
Dibromophakellstatin
Jianming Lu, Xianghui Tan, and Chuo Chen*
Department of Biochemistry, The UniVersity of Texas Southwestern Medical Center at Dallas,
5323 Harry Hines BouleVard, Dallas, Texas 75390-9038
Received April 23, 2007; E-mail: chuo.chen@utsouthwestern.edu
Table 1. Scope of the Direct Arylation of Imidazolinonea
The popularity of transition metal-catalyzed C-H activation
chemistry has grown rapidly in the recent years.1 Both direct2 and
entry
Ar
X
catalyst loading
time
yield
functional group-directed3 C-H insertion reactions have been
developed to form a C-X or a C-C bond using transition-metal
catalysts. This reaction is particularly useful in heterocycle deriva-
tization and several protocols have been reported.4 Despite its
potentials, the application to natural product synthesis is rare.5 The
limitation is partly due to the relatively harsh reaction conditions
and limited functional group compatibility. We describe herein a
C-H functionalization reaction of imidazolinone (1) under mild
conditions (eq 1). We also demonstrate its synthetic utility with
dibromophakellstatin synthesis.6,7
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
I
I
I
I
I
I
I
I
I
I
I
I
5 mol %
2 mol %
20 mol % Pd/C
10 mol % at 23 °C
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
5 mol %
10 mol %
10 mol %
10 mol %
10 mol %
6 h
30 h
16 h
5 d
78%
71%
63%
68%
75%
62%
61%
52%
77%
85%
62%
87%
85%
68%
62%
64%
68%
2-Me-Ph
6 h
4-F-Ph
12 h
12 h
12 h
6 h
6 h
6 h
6 h
6 h
24 h
36 h
36 h
36 h
4-Cl-Ph
4-Br-Ph
3-MeO-Ph
4-MeO-Ph
2-HOCH2-Ph
3-HOCH2-Ph
4-HO-Ph
2-NO2-Ph
I
Br
Br
Br
3-MeCO-Ph
4-CF3-Ph
Ph-CHdCHBr
a Conditions: 1.5 equiv Ar-X, catalyst Pd(OAc)2, 3.0 equiv NaOAc·3H2O,
degassed DMSO, 80 °C.
Our study started with the coupling of 1 and iodobenzene. We
systematically studied the effects of palladium source, ligand,
additive, and solvent.8 The reaction proceeds most efficiently with
5 mol % Pd(OAc)2 and 3 equiv NaOAc‚3H2O in DMSO at 80 °C
(Table 1, entry 1). A small amount of water (<5% v/v) can be
tolerated. The reaction can also be carried out with 2 mol % Pd-
(OAc)2 (entry 2), 20 mol % Pd/C (entry 3), or at room temperature
(entry 4).
Scheme 1
Scheme 2
The scope of this palladium-catalyzed imidazolinone C-arylation
reaction is shown in Table 1. Substitution at the 2-position of aryl
iodide does not affect the reaction (entry 5). Both electron-deficient
(entry 6-8) and electron-rich (entry 9-13) aryl iodides can be used.
However, electron-deficient aryl iodides are less reactive. Extending
the reaction time leads to a small amount of bisarylation product.
Notably, hydroxyl and phenol groups are tolerated (entry 11-13).
Aryl bromides are also less reactive; however, good results can be
obtained with electronic-deficient aryl bromides (entry 14-16).8
Finally, the direct vinylation of 1 can also be achieved (entry 17).
We have carried out a series of mechanistic studies and found
the C-H insertion pathway most consistent with the experimental
data. If the reaction proceeds through the Heck-type mechanism,
the migratory insertion intermediate 3 would bear no syn-â-H for
the subsequent â-hydride elimination (Scheme 1).
Although a â-H is present at the N-3 position in 3, the reaction
does not proceed through N-H â-hydride elimination, as 5 also
reacts (Scheme 2). We next carried out the linear free-energy
relationship (LFER) analysis to test if the reaction proceeds through
the anti-â-H elimination pathway.9 The anti-â-H elimination is
believed to be promoted by base via an E2 or E1cb mechanism and
a non-negative F value is expected with 3. However, we have
obtained a strongly negative F value (F ) -1.1) in the LFER
analysis.8
Scheme 3
We then considered the possibility of Pd(0)-mediated SN2-
inversion10 of the C-4 stereogenic center in 3 followed by syn-â-
hydride elimination to give 2. While a secondary kinetic isotope
effect (KIE) is expected for this sterically encumbered SN2-
inversion, we have observed a primary KIE (kH/kD ) 4.5) in the
competing experiment of 1 with 4,5-dideuterated 1 (94% D)
(Scheme 3).
The Busacca-Farina mechanism, which involves an R-H
elimination of 3 followed by a 1,2-H shift,11 would be consistent
with the experimental primary KIE; however, we did not observe
significant amounts of H/D shift with 4-deuterated 8 (91% D)
(Scheme 4).12 The absence of crossover products further suggests
9
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J. AM. CHEM. SOC. 2007, 129, 7768-7769
10.1021/ja072844p CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Scheme 4
Scheme 5
Supporting Information Available: Experimental procedures,
characterization data, and computational details. This material is
available free of charge via the Internet at http://pubs.acs.org.
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Scheme 6
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shift (C5 f C4)13 to give 2 after losing a proton.
We have also ruled out the possibility of electrophilic palladation
mechanism.14 A secondary,4f instead of the observed primary KIE
(Scheme 3) with 1 is expected for the electrophilic pathway. The
regioselectivity of 8 (Scheme 4) is also opposite to that of the
electrophilic reactions. Only the C-H insertion mechanism (Scheme
5) is consistent with all the experimental data. Our DFT calculations
(B3LYP/LACVP**++)15 support the acetate ligand-assisted C-H
insertion pathway.
The synthetic utility of this catalytic C-H activation reaction is
illustrated with the synthesis of dibromophakellstatin (Scheme 6).
The direct coupling of 1 and vinyl bromide 11 proceeded smoothly.
Imidazolinone 12, together with the resultant palladium black, was
subjected to hydrogenation, phthalimide deprotection, and acyl
pyrrole installation to give 13.8 While the bromine oxidants were
reported to promote the biomimetic oxidative cyclization7a,f of 13
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with PhI(OAc)2 gave dibromophakellstatin in nearly quantitative
yield.
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In summary, we have developed a palladium catalyst system that
allows the direct arylation and vinylation of imidazolinone under
mild conditions. This method is proved useful in natural product
synthesis. Dibromophakellstatin was synthesized with significantly
improved efficiency (40% overall yield).
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Acknowledgment. Financial supports are provided by NIH
(Grant NIGMS R01-GM079554), Welch Foundation (I-1596), and
UT Southwestern. C.C. is a Southwestern Medical Foundation
Scholar in Biomedical Research.
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