Palladium-catalyzed condensation of N -aryl imines and alkynylbenziodoxolones to form multisubstituted furans

Article abstract of DOI:10.1021/ja5059795

A palladium(II) catalyst promotes condensation of an N-aryl imine and an alkynylbenziodoxolone derivative to afford a multisubstituted furan, whose substituents are derived from the alkynyl moiety (2-position), the imine (3- and 4-positions), and the 2-iodobenzoate moiety (5-position), along with an N-arylformamide under mild conditions. The 2-iodophenyl group of the furan product serves as a versatile handle for further transformations. A series of isotope-labeling experiments shed light on the bond reorganization process in this unusual condensation reaction, which includes cleavage of the C-C triple bond and fragmentation of the carboxylate moiety.

Full text of DOI:10.1021/ja5059795

Communication
pubs.acs.org/JACS
Palladium-Catalyzed Condensation of N‑Aryl Imines and
Alkynylbenziodoxolones To Form Multisubstituted Furans
Beili Lu,† Junliang Wu,† and Naohiko Yoshikai*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
S
* Supporting Information
Scheme 1. Pd(II)-Catalyzed Coupling of Imine and
Alkynylbenziodoxolone (PMP = p-MeOC6H4)
ABSTRACT: A palladium(II) catalyst promotes con-
densation of an N-aryl imine and an alkynylbenziodox-
olone derivative to afford a multisubstituted furan, whose
substituents are derived from the alkynyl moiety (2-
position), the imine (3- and 4-positions), and the 2-
iodobenzoate moiety (5-position), along with an N-
arylformamide under mild conditions. The 2-iodophenyl
group of the furan product serves as a versatile handle for
further transformations. A series of isotope-labeling
experiments shed light on the bond reorganization process
in this unusual condensation reaction, which includes
cleavage of the C−C triple bond and fragmentation of the
carboxylate moiety.
ypervalent iodine compounds have found increasing
Happlications as oxidants and electrophilic reagents for
organic synthesis.1 Among them, those having a benziodoxolone
skeleton have emerged as unique and effective reagents for the
delivery of electrophiles such as trifluoromethyl and alkynyl
groups to nucleophilic reaction partners.1c,d In these iodine(III)
reagents, the 2-iodobenzoate moiety serves to modulate their
stability and reactivity and upon transfer of the electrophile leaves
as 2-iodobenzoic acid, which usually behaves as an innocent
byproduct. Here we report on a coupling reaction of N-aryl imine
1 and ethynylbenziodoxolone (EBX) reagent 22,3 under
palladium(II) catalysis to afford multisubstituted furan 3 bearing
substituents derived from the alkynyl moiety of 2 (2-position), 1
(3- and 4-positions), and the 2-iodobenzoate moiety of 2 (5-
position), accompanied by the concomitant formation of N-
arylformamide 4 (Scheme 1a). This reaction is unusual as a
transformation of EBX in a few aspects such as cleavage of the
C−C triple bond4 and participation/fragmentation of the 2-
iodobenzoate moiety.
also undergo Pd(II)-catalyzed cycloisomerization leading to
furan 6′.11
Contrary to the initial expectation, imine 1a (0.2 mmol)
derived from 4-acetylbiphenyl and p-anisidine reacted with
phenyl-EBX 2a (2 equiv) in the presence of Pd(OAc)2 (10 mol
%) in toluene under a nitrogen atmosphere at room temperature
to afford 2,3,5-trisubstituted furan 3aa in 72% yield (as
1
determined by H NMR; isolated in 64% yield) along with N-
(4-methoxyphenyl)formamide (4) (71% NMR yield, 60%
isolated yield) (eq 1). The structure of 3aa was unambiguously
We recently reported on palladium(II)-catalyzed dehydrogen-
ative synthesis of indoles,5 pyrroles,6 and aryl amines7 through α-
palladation of an imine as a key elementary step (1 to A; Scheme
1b). The present finding originated from our attempt to expand
the synthetic versatility of α-palladated imine A. Thus, we
envisioned that interception of species A with EBX 2 would give a
palladium(IV) intermediate,3b,e,f which would then undergo
reductive elimination to afford α-alkynylated imine 5 along with
2-iodobenzoic acid.3i,8 With the aid of the Pd(II) catalyst, imine 5
might be cycloisomerized to pyrrole 6.9,10 Alternatively,
hydrolysis of 5 would give α-alkynyl ketone 5′, which might
determined by X-ray crystallographic analysis [see the
Supporting Information (SI)]. The phenyl, 4-phenylphenyl,
and 2-iodophenyl groups of 3aa appear to originate from the
alkynyl moiety of 2a, 1a, and the 2-iodobenzoate moiety of 2a,
Received: June 14, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ja5059795 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
respectively. Also, the formyl group of 4 appears to come from
2a. While the bond reorganization process in this reaction seems
puzzling (vide infra), it is important to note that the combined
molecular formula of 3aa and 4 (C36H28INO3) is identical to that
of 1a and 2a. Thus, despite the moderate yields due to formation
of other intractable byproducts, the major products 3aa and 4
appear to be formed through 1:1 coupling of 1a and 2a.
Scheme 2. Coupling of Various Imines with 2a
Screening of the reaction conditions was performed using 4′-
methylacetophenone imine and 2a (see Table S1 in the SI).
Essential observations include the following: (1) Besides
Pd(OAc)2, Pd2(dba)3 and [1,2-bis(phenylsulfinyl)ethane]-
palladium(II) acetate (White’s catalyst) promoted the coupling
reaction, albeit in lower yields, while PdCl2, PdCl2(PPh3)2, and
Pd(PPh3)4 did not give the desired product at all. (2) The
reaction did not take place with other metal catalysts such as
AuCl and CuI or without a catalyst. (3) Additives such as AcOH
and PivOH did not improve the product yield, while Bu4NBr,
LiCl, and K2CO3 completely shut down the reaction. (4) The
reaction took place in CH2Cl2 as efficiently as in toluene, while
coordinating solvents such as DMSO and DMF inhibited the
reaction. It should also be noted that the use of 4′-
methylacetophenone instead of the imine did not give the
furan at all. The imines derived from parent aniline afforded the
desired product in a comparable yield, while the reaction became
sluggish with those derived from 4-dimethylaminoaniline and
benzylamine (see Table S2).
Scheme 2 shows the scope of imines as explored by the
coupling reaction with 2a. A wide variety of imines derived from
substituted acetophenones participated in the reaction to afford
the corresponding furans 3aa−3oa in moderate to good yields.
The reaction tolerated both electron-donating and electron-
withdrawing substituents on the imine, including bromine and
iodine atoms as well as cyano and trifluoromethyl groups. Methyl
imines bearing 2-thienyl, 2-furyl, and styryl groups also afforded
the corresponding furan derivatives 3pa, 3qa, and 3ra, albeit in
modest yields. Unlike our indole/pyrrole synthesis,5,6 imines
bearing β-hydrogen atoms are tolerated. Thus, propiophenone-
and 6-methoxy-1-tetralone-derived imines furnished the desired
tetrasubstituted furans 3sa and 3ta, respectively. Likewise,
tetraarylfuran 3ua was obtained, albeit in a modest yield. The
reaction of 4-pyridyl imine 1v and 2a did not afford the desired
furan derivative, while 2-iodobenzoate ester 7 was obtained in
22% yield, presumably through ring-opening rearrangement and
hydration of 2a (eq 2).12 Imines derived from aliphatic ketones
such as pinacolone failed to participate in the present reaction.
a
b
The reaction was performed on a 0.2 mmol scale. The reaction time
c
d
was 48 h. The reaction was performed at 40 °C for 20 h. The
reaction was performed at 70 °C for 24 h.
triisopropylsilyl-EBXs (see 3cm). Phenyl-EBXs derived from
substituted 2-iodobenzoic acids also reacted with 1c or 1d to
afford the corresponding furan derivatives 3cn, 3co, and 3dp in
moderate yields.
The 2-iodophenyl moiety of the furan product serves as a
versatile handle for further synthetic transformations (Scheme
4). Pd(0)-catalyzed cyclocarbonylation13 of 3ca proceeded
smoothly to give indenone-embedded furan 8. Domino
Suzuki−Miyaura coupling/intramolecular direct arylation14
using 2-bromophenylboronic acid afforded phenanthro[9,10-
b]furan derivative 9. A sequence of iodine−lithium exchange,
electrophilic trapping with PhPCl2, intramolecular phospha-
Friedel−Crafts reaction,15 and oxidation with H2O2 furnished
phosphole derivative 10 in good yield.
To gain insight into the bond reorganization process in the
present reaction, we performed a series of experiments using 13C-
or 18O-labeled imine 1c* and EBX 2a* (Scheme 5a; see the SI for
the details of each experiment). As summarized in Scheme 5a, a
one-to-one correspondence between the starting materials and
the products was established for each of the color-coded carbon
and oxygen atoms. Notably, the acetylenic carbon atoms of 2a*
underwent bond cleavage, and the one originally bonded to the
iodine atom ended up as the formyl carbon of 4*. The benzoate
moiety of 2a* was also dissected to constitute the furan C5−O
moiety of 3ca* and the formyl oxygen of 4*. We also performed a
crossover experiment using imine 1d, EBX 2a, and 2-iodo-6-
methylbenzoic acid under the standard conditions, which
Next, we explored the scope of EBXs (Scheme 3). Aryl-EBXs
derived from a series of arylacetylenes participated in the
coupling reaction with imine 1c or 1d to afford the
corresponding furans 3cb−3cf, 3dg, and 3ch−3ck in moderate
to good yields with tolerance of substituents such as
trifluoromethyl, cyano, nitro, bromo, and thienyl groups. By
contrast, n-butyl-EBX reacted rather sluggishly, affording the
desired furan 3dl in only 8% isolated yield along with
unidentified byproducts as well as unreacted imine (26%). No
desired product could be obtained with trimethylsilyl- and
B
dx.doi.org/10.1021/ja5059795 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a
Scheme 3. Coupling of 1c or 1d with Various EBXs
Scheme 5. (a) Summary of Isotope Labeling Experiments and
(b) Crossover Experiment
mechanism. Nevertheless, on the basis of the isotope-labeling
and crossover experiments (Scheme 5) and the accepted wisdom
in alkynyliodonium chemistry,2a we have attempted to draw a
possible reaction pathway (Scheme 6).16 The reaction may be
Scheme 6. Possible Reaction Pathway (IBz = 2-Iodobenzoyl;
IPh = 2-Iodophenyl)
a
b
The reaction was performed on a 0.2 mmol scale. The reaction was
c
d
performed at 40 °C for 20 h. The reaction time was 48 h. CH2Cl2
was used as the solvent instead of toluene.
Scheme 4. Transformations of Furan 3ca (p-An = 4-
a
MeOC6H4)
a
Reaction conditions: (a) Pd2(dba)3, PCy3, CsOPiv, CO (1 atm),
DMF, 110 °C, 12 h. (b) Pd2(dba)3, PCy3, 2-bromophenylboronic acid,
DBU, DMF, 155 °C, 48 h. (c) (1) nBuLi, −78 °C, THF, 30 min; (2)
PhPCl2, −78 to 60 °C, 4 h; (3) AlCl3, iPr2NEt, −78 to 90 °C, 12 h;
(4) H2O2, 30 min.
initiated by the addition of a palladium(II) 2-iodobenzoate
species to the electrophilic C−C triple bond of EBX. Cleavage of
the resulting vinyl−I(III) bond and reduction of I(III) to I(I)
would then lead to palladium−vinylidene species B. Addition of
an enamine form of the imine to B and subsequent
protodepalladation would afford enamine intermediate D with
elimination of the palladium(II) 2-iodobenzoate species.
Although highly speculative, a sequence of skeletal rearrange-
ments from D initiated by intramolecular attack of the enamine
to the ester would eventually lead to oxaazabicyclic intemediate J.
afforded a 1:1.6 mixture of the expected furan 3da and another
furan 3dp bearing a 2-iodo-6-methylphenyl group at the 5-
position (Scheme 5b). The formation of 3dp indicates that the
C2-aryl and C5-aryl moieties of the furan product do not
necessarily come from the same EBX molecule.
Unfortunately, we have not been able to observe any
intermediates that may shed further light on the reaction
C
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Journal of the American Chemical Society
Communication
Chen, P.; Liu, G. ACS Catal. 2013, 3, 178. (c) Wang, A.; Jiang, H. J. Am.
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Ring opening of the azetidine moiety of J would then afford furan
3 and formamide 4.
Regardless of the mechanistic ambiguity, the result of the
crossover experiment (Scheme 5b) implies the possibility of a
three-component furan synthesis using imine, alkynyliodonium-
(III) reagent, and carboxylic acid. Indeed, a preliminary
experiment using imine 1c, phenyl(2-phenylethynyl)iodonium
tosylate, and benzoic acid afforded the desired trisubstituted
furan 11 in 31% yield (eq 3).
(7) (a) Hajra, A.; Wei, Y.; Yoshikai, N. Org. Lett. 2012, 14, 5488.
(b) Girard, S. A.; Hu, X.; Knauber, T.; Zhou, F.; Simon, M.-O.; Deng,
G.-J.; Li, C.-J. Org. Lett. 2012, 14, 5606.
(8) For transition-metal-free α-alkynylation of carbonyl compounds
with EBXs, see: (a) Gonzal
2010, 16, 9457. (b) Gonzal
Adv. Synth. Catal. 2013, 355, 1631.
(9) For a review of transition-metal-mediated synthesis of pyrroles and
furans, see: Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V.
Chem. Rev. 2013, 113, 3084.
(10) While no example of cycloisomerization of propargyl imine to
pyrrole has been reported, its isomers (e.g., alkynyl imine, allenyl imine)
are known to participate in such a reaction.
(11) (a) Utimoto, K. Pure Appl. Chem. 1983, 55, 1845. (b) Fukuda, Y.;
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(12) The mechanism of the formation of 7 is not clear at this moment.
(13) Campo, M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
(14) Wegner, H. A.; Scott, L. T.; de Meijere, A. J. Org. Chem. 2003, 68,
883.
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13, 2130.
(16) The reaction of 1c and 2a in the presence of TEMPO (2 equiv)
afforded 3ca without a significant decrease in the yield (70%), suggesting
that a free radical is not involved.
́
ez, D. F.; Brand, J. P.; Waser, J. Chem.Eur. J.
́
ez, D. F.; Brand, J. P.; Mondiere, R.; Waser, J.
̀
In summary, we have found a palladium(II)-catalyzed coupling
reaction of imines and EBXs to afford multisubstituted furans17
that involves unique condensation and fragmentation processes.
Our current studies are focused on the synthetic potential and
mechanistic aspects of the three-component coupling of imine,
alkynyliodonium reagent, and carboxylic acid.
ASSOCIATED CONTENT
* Supporting Information
Detailed experimental procedures, compound characterization,
and crystallographic data (CIF). This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
nyoshikai@ntu.edu.sg
■
Author Contributions
†B.L. and J.W. contributed equally.
(17) For transition-metal-mediated furan synthesis through cross-
coupling of two reactants, see ref 9 and the following recent examples:
(a) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.; Chen, H.; Lei, A. J. Am. Chem.
Soc. 2012, 134, 5766. (b) Kramer, S.; Skrydstrup, T. Angew. Chem., Int.
Ed. 2012, 51, 4681. (c) Huang, X.; Peng, B.; Luparia, M.; Gomes, L. F.
R.; Veiros, L. F.; Maulide, N. Angew. Chem., Int. Ed. 2012, 51, 8886.
(d) Cui, X.; Xu, X.; Wojtas, L.; Kim, M. M.; Zhang, X. P. J. Am. Chem.
Soc. 2012, 134, 19981. (e) Lian, Y.; Huber, T.; Hesp, K. D.; Bergman, R.
G.; Ellman, J. A. Angew. Chem., Int. Ed. 2013, 52, 629. (f) Zheng, M.;
Huang, L.; Wu, W.; Jiang, H. Org. Lett. 2013, 15, 1838. (g) Yang, Y.; Yao,
J.; Zhang, Y. Org. Lett. 2013, 15, 3206.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Research Foundation
Singapore (NRF-RF-2009-05) and Nanyang Technological
University. We thank Dr. Yongxin Li (Nanyang Technological
University) for assistance with X-ray crystallographic analysis.
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D
dx.doi.org/10.1021/ja5059795 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX