Pd-catalyzed branching cyclizations of enediyne-imides toward furo[2,3-b ]pyridines

Article abstract of DOI:10.1021/ol500574b

The convergent synthesis of a class of enediyne-imides as well as their palladium-catalyzed branching cyclizations, which can be accomplished in two ways leading to a set of polysubstituted furo[2,3-b]pyridines upon using the N-tosyl carboxamide moiety as an N,O-bisnucleophile, are presented.

Full text of DOI:10.1021/ol500574b

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed Branching Cyclizations of Enediyne-Imides toward
Furo[2,3‑b]pyridines
Zexiang Li,† Fei Ling,† Dong Cheng, and Cheng Ma*
Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027, P. R. China
S
* Supporting Information
ABSTRACT: The convergent synthesis of a class of enediyne-
imides as well as their palladium-catalyzed branching cyclizations,
which can be accomplished in two ways leading to a set of
polysubstituted furo[2,3-b]pyridines upon using the N-tosyl
carboxamide moiety as an N,O-bisnucleophile, are presented.
ince the discovery of natural enediyne antibiotics, the
cycloaromatization of (Z)-hexa-1,5-diyn-3-enes has at-
of ynals 1 with monoalkynes and sulfonyl azides via in situ
S
generated metallo-ynamides.9 Subsequent studies disclosed that
this protocol could afford N-tosyl enediyne-carboxamides 3,
which are difficult to synthesize according to known methods,10
by using diynes 2 as the substrate instead of monoalkynes
(Scheme 2). Specifically, exposure of substituted ynals 1 to aryl-
tracted tremendous attention and has emerged as a reliable
method for the generation of aromatic compounds.1 In this
regard, the thermal and photoinduced benzannulation of
enediynes has been studied extensively over the past decades.2
Remarkably, there have recently been some fascinating
examples of transition-metal-catalyzed cascade reactions,3
which have also been developed for the construction of
benzene- and fulvene-fused heterocyclic frameworks from
readily available enediyne substrates bearing heteroatom
nucleophiles in a substituent attached to the triple bonds via
C1−C6 or C1−C5 ring-closure routes, respectively (Scheme
1a).4 Inspired by this progress, we speculated that embedding a
a
Scheme 2. Convergent Synthesis of Enediynes 3
Scheme 1. Annulations of Eneynes Tethered to Heteroatom
Nucleophiles
a
Yields shown are of isolated products.
or alkyl-substituted diynes 2 and tosyl azide in the presence of
CuI (10 mol %) and LiOH (1.5 equiv) in a mixture of THF/
tBuOH (10:1) at 10 °C provided enediyne-imides 3a−o in 41−
81% isolated yields with excellent geometric selectivity at the
nucleophilic functional group at the double bond of enediynes
might result in other cyclization modes of enediyne motifs
treated by transition-metal catalysts.5 Herein we present a
convergent synthesis of cross-conjugated6 enediyne-imides and
a study of their sequential palladium-catalyzed cyclization
through in situ generated imidate intermediates,7 which gives
rise to a class of polysubstituted furanopyridine with high
chemo- and regioselectivity (Scheme 1 b).8
1
newly formed double bond (E/Z > 95:5) according to the H
NMR spectra of the crude reaction products.11
The cyclization of 3a was initially explored in the presence of
3-bromoprop-1-ene (4a) and palladium catalysts in air at 60 °C
(Table 1). Whereas almost no conversion of 3a was observed
without any catalysts, Pd(OAc)2 (3 mol %) yielded a mixture of
We recently developed an approach to conjugated enynes
that involved the CuI-catalyzed formal (E)-selective olefination
Received: February 21, 2014
Published: March 6, 2014
© 2014 American Chemical Society
1822
dx.doi.org/10.1021/ol500574b | Org. Lett. 2014, 16, 1822−1825

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Synthesis of 3,5-Diallylfuro[2,3-b]pyridine 5
b
b
b
entry
3
R1
R2
R3
5
(%)
entry
Pd cat.
none
condition
t (h)
5aa (%)
6aa (%)
1
3a
3b
3c
3d
3e
3f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
5aa
5ba
5ca
5da
5ea
5fa
81
81
76
73
61
58
75
77
75
71
67
87
72
83
61
67
1
DMF, air
DMF, air
DMF, air
DMF, air
DMA, air
MeCN, air
THF, air
12
24
8
−
41
−
8
2
2-CH3C6H4
4-CH3C6H4
4-BrC6H4
4-FC6H4
4-NO2C6H4
4-MeOC6H4
2-thienyl
cyclopropyl
n-C5H11
Ph
H
2
Pd(OAc)2
Pd(acac)2
PdCl2
3
H
3
71
trace
trace
trace
28
4
H
4
4
76
5
H
5
PdCl2
3
73
6
H
6
PdCl2
10
21
20
21
4
42
7
3g
3h
3i
H
5ga
5ha
5ia
7
PdCl2
18
45
8
H
8
PdCl2
toluene, air
toluene, air
DMF, N2
DMF, N2
trace
trace
81
73
9
H
9
Pd(OAc)2
PdCl2
76
10
11
12
13
14
15
16
3j
H
5ja
10
11
trace
−
3l
4-FC6H4
4-MeOC6H4
n-C5H11
n-C5H11
Ph
H
5la
Pd(PPh3)4
12
−
a
3m
3n
3o
3a
3a
Ph
H
5ma
5na
5oa
5ab
5ac
Imide 3a (0.2 mmol), and Pd catalyst (3 mol %) in solvent (2 mL),
then 4a (2.0 mmol) at 60 °C. Yields of isolated products.
b
Ph
H
n-C4H9
Ph
H
Ph
CH3
3,5-diallyl-furo[2,3-b]pyridine 5aa (41%) and bromide 6aa
(8%) in DMF after 24 h (entries 1 and 2). After exploring a set
of palladium(II) salts, PdCl2 was identified as the optimal
catalyst for the synthesis of 5aa (entries 2−4). In the presence
of PdCl2, it was found that solvents significantly influenced the
reaction outcomes (entries 4−8). While the tandem reaction
proceeded quickly in DMF or DMA to form 5aa as the
predominating product, the conversion of 3a occurred
sluggishly in either MeCN or THF, affording mixtures of 5aa
and 6aa in varying ratios, respectively (entries 6 and 7). In
contrast, switching the solvent to toluene almost only gave the
regioselective HBr adduct 6aa as a mixture of geometric
isomers relating to the newly formed bromo-alkene unit (Z/E =
3:1) in 73% combined yield (entry 8).12 These results indicated
that the current reaction initially proceeds via a 5-endo-dig
oxypalladation/carbodepalladation process to provide an oxy-
cyclization intermediate, which then undergoes competitive N-
nucleophilic palladation and HBr addition reactions to furnish
furopyridine 5aa or bromide 6aa, respectively. The distinct
ability of DMF and DMA to accelerate the conversion of 3a
could be partially explained by their Brønsted basicity to trap
the eliminated HBr.13 Dipolar solvents with strong Lewis
basicity should facilitate the N-nucleophilic palladation of
alkyne by prompting the cleavage of the N−S bond between
the imidate nitrogen atom and tosyl group to form a nitrogen
nucleophilic partner,14d although these solvents might simulta-
neously coordinate with the Pd(II) species and thereby weaken
the Lewis acidity of palladium catalysts.14,15 On the other hand,
for the reaction in nonpolar solvents such as toluene, the
cleavage of the N−S bond was inhibited, resulting in HBr
adduct 6aa as the major product (entries 8 and 9).16 Under a
nitrogen atmosphere, a cleaner conversion of 3a was achieved
with PdCl2 as the catalyst, whereas Pd(PPh3)4 was totally
ineffective (entries 10 and 11).
Ph
Ph
a
Imides 3 (0.2 mmol), PdCl2 (3 mol %), 4 (2.0 mmol), DMF (2 mL),
b
60 °C, N2. Yields of isolated products.
5ca from ortho- and para-substituted arenes in similar yields,
respectively (entries 2 and 3). An aryl bromide substrate also
produced the targeted 5da in 73% yield (entry 4), providing the
possibility of further manipulation. Nevertheless, the reaction of
substrates with an electron-donating substituent on the
aromatic ring (entries 7 and 12) proceeded in better yield
than those of the electron-withdrawing counterparts (entries 5,
6, and 11). In addition, a thienyl group was tolerated in this
reaction (entry 8). On the other hand, 2-substituted propenes
4b and 4c, no matter whether they contained aryl or alkyl
substituents, underwent the reaction with 3a smoothly to yield
the targeted 5ab and 5ac (entries 15 and 16). Unfortunately,
cinnamyl bromide could not afford the desired product
presumably due to the steric issue encountered in the coupling
step.
The palladium-catalyzed branching annulation protocol was
further exploited in the absence of allylic bromide 4 for the
synthesis of furopyridines 7 (Scheme 3).17 Under the optimal
a
Scheme 3. Synthesis of 2,6-Disubstituted Furopyridines 7
Under the optimal conditions (Table 1, entry 10), a set of
enediyne-imides 3 participated in the reaction with 4a
smoothly, giving the desired products 5 in good yields (Table
2, entries 1−14). Both alkyl and aryl substituents on the termini
of enediyne units were well tolerated. The substitution patterns
of aryl moieties had little effect on this reaction, forming 5ba or
a
Yields shown are of isolated products. Yield in parentheses is
obtained in AcOH.
1823
dx.doi.org/10.1021/ol500574b | Org. Lett. 2014, 16, 1822−1825

Organic Letters
Letter
conditions for obtention of 5aa, only a traceless cyclization
product was formed from imide 3a. Gratifyingly, this reaction
proceeded smoothly in acetic acid under N2 at 60 °C, giving the
desired product 7a in 39% yield after 12 h. When using
Pd(acac)2 as the catalyst, it was observed that substrate 3a
quickly converted into furan 8a, which slowly gave 7a in 46%
yield along with some decomposition compounds. A stronger
acid such as TFA instead of AcOH enabled a cleaner
conversion of 3a to 7a (85%) in the presence of Pd(acac)2
within 3 h. A blank experiment in the absence of palladium
catalysts in TFA afforded no products except the recovered 3a
(91%), revealing that the palladium catalyst was necessary for
this cascade sequence. Illustrative examples of the reaction
scope were also shown in Scheme 3. Accordingly, both aryl-
and heteroaryl-substituted substrates as well as alkyl-substituted
compounds readily participated in this transformation, forming
the corresponding products 7 in 41−88% yield, respectively.
To gain deeper insight into the reaction mechanism, the
light-labile (E)-alkenyl furan 8a was successfully isolated in 54%
yield by terminating the reaction of 3a in acetic acid after 0.75 h
for subsequent studies (Scheme 4). While the treatment of 8a
Scheme 5. Proposed Mechanism
Scheme 4. Two-Step Synthesis of Furo[2,3-b]pyridines
In summary, we have presented the single-step construction
of cross-conjugated enediyne-imides as well as their palladium-
catalyzed branching cyclizations through imidate intermediates.
It was found that, upon using the N-tosyl carboxamide moiety
as an N,O-bisnucleophile, the cyclization of this type of
enediynes could be accomplished in two ways leading to a set
of polysubstituted furo[2,3-b]pyridines. Additional studies on
reaction mechanism details and the synthetic potential of 3-
substituted enediyne scaffolds for the creation of facile
strategies toward valuable fused ring systems are now in
progress.
with Pd(acac)2 in TFA gave 7a in 90% yield, 8a could not
convert into 7a and decomposed completely in the absence of
Pd(II) catalysts or an external acid at 60 °C after 6 h. These
results suggested that both palladium catalysts and external
acids are critical for this annulation reaction, although the
mechanism details were not very clear.18 Moreover, exposure of
8a to 4a and PdCl2 in DMF should furnish 2,5,6-substituted
furopyridine 9a in 92% yield, offering a flexible method for the
synthesis of a class of substituted furanopyridines.
ASSOCIATED CONTENT
* Supporting Information
■
S
X-ray crystallographic data of 3e, 5ab, and (Z,Z)-6aa;
experimental procedures and characterization data of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
A possible mechanism for the Pd-catalyzed branching
cyclizations of enediyne-imides 3 toward furopyridines is
depicted in Scheme 5. Initial coordination of alkyne units of
3a to the Pd(II) catalyst would induce a trans-oxypalladation19b
via a 5-endo-dig pathway to generate the vinyl-palladium species
I, which would be partially stabilized by coordination with the
tethered alkyne moiety. In acidic media, protonolysis of I
furnishes imidate 8a, which then undergoes cycloisomerization
to yield the product 7a with the elimination of the tosyl groups.
On the other hand, the species I undergoes a coupling reaction
with the allylic bromide 4a leading to intermediate II via olefin
insertion and β-bromide elimination.19 Subsequent olefin E/Z
isomerization20 and N-nucleophilc cyclopalladation of the
intermediate II, with the assistance of dipolar Lewis basic
solvents to break the N−S bond, gives access to another
palladium species III. The latter intermediate couples with 4a
to form 5aa, while releasing the Pd(II) catalyst.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mcorg@zju.edu.cn.
Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Zhejiang Provincial Natural Science Foundation
of China (R4110055), the National Natural Science Founda-
tion of China (21372196), and the Program for New Century
Excellent Talents in University for financial support of this
project.
1824
dx.doi.org/10.1021/ol500574b | Org. Lett. 2014, 16, 1822−1825

Organic Letters
Letter
Cambridge Crystallographic Data Center and also available in the
Supporting Information.
(12) Isolated (Z,Z)-6a can convert to a mixture of (Z,Z)-6a and
(E,Z)-6a at 25 °C.
(13) Addition of either an external base or oxiranes results in the N-
allylation of 3a.
(14) The N-cyclization was proposed to occur upon Pd(II)/Lewis
base cocatalysis. For reviews of synergistic catalysis, see: (a) Shao, Z.;
Zhang, H. Chem. Soc. Rev. 2009, 38, 2745. (b) Allen, A. E.; MacMillan,
D. W. C. Chem. Sci. 2012, 3, 633. For a palladium/amine cocatalyzed
REFERENCES
■
(1) For reviews, see: (a) Nicolaou, K. C.; Dai, W.-M. Angew. Chem.,
Int. Ed. 1991, 30, 1387. (b) Kar, M.; Basak, A. Chem. Rev. 2007, 107,
2861. (c) Joshi, M. C.; Rawat, D. S. Chem. Biodiversity 2012, 9, 459.
(2) For recent reviews, see: (a) Peterson, P. W.; Mohamed, R. K.;
Alabugin, I. V. Eur. J. Org. Chem. 2013, 2505. (b) Mohamed, R. K.;
Peterson, P. W.; Alabugin, I. V. Chem. Rev. 2013, 113, 7089.
(3) For examples, see: (a) Odedra, A.; Wu, C.-J.; Pratap, T. B.;
Huang, C.-W.; Ran, Y.-F.; Liu, R.-S. J. Am. Chem. Soc. 2005, 127, 3406.
(b) Cheong, P. H.; Morganelli, P.; Luzung, M. R.; Houk, K. N.; Toste,
F. D. J. Am. Chem. Soc. 2008, 130, 4517. (c) Ye, L.; Wang, Y.; Aue, D.
H.; Zhang, L. J. Am. Chem. Soc. 2012, 134, 31. (d) Hashmi, A. S. K.;
́
α-allylic alkylation of aldehydes, see: (c) Ibrahem, I.; Cordova, A.
Angew. Chem., Int. Ed. 2006, 45, 1952. For a supposed procedure of
DBU-prompted sulfonyl dissociation, see: (d) Yu, X.; Xin, X.; Wan, B.;
Li, X. J. Org. Chem. 2013, 78, 4895.
Braun, I.; Nosel, P.; Schadlich, J.; Wieteck, M.; Rudolph, M.;
̈
̈
(15) For PdII acting as a Lewis acid and transition-metal catalyst, see:
(a) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem.
Soc. 2002, 124, 764. (b) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817.
(16) A halopalladation and protonolysis cascade might be involved.
For a recent example, see: Li, J.; Yang, S.; Huang, L.; Chen, H.; Jiang,
H. RSC Adv. 2013, 3, 11529.
Rominger, F. Angew. Chem., Int. Ed. 2012, 51, 4456.
(4) For examples: (a) Lee, C. Y.; Wu, M. J. Eur. J. Org. Chem. 2007,
3463. (b) Hirano, K.; Inaba, Y.; Takahashi, N.; Shimano, M.; Oishi, S.;
Fujii, N.; Ohno, H. J. Org. Chem. 2011, 76, 1212. (c) Byers, P. M.;
Rashid, J. I.; Mohamed, R. K.; Alabugin, I. V. Org. Lett. 2012, 14, 6032.
(d) Hou, Q.; Zhang, Z.; Kong, F.; Wang, S.; Wang, H.; Yao, Z.-J.
Chem. Commun. 2013, 49, 695. For a review on electrophilic
cyclizations of enediyne, see: (e) Gulevskaya, A. V.; Lazarevich, R. Yu.
Chem. Heterocycl. Compd. 2013, 49, 116.
(17) See Supporting Information for experimental details.
(18) For alkyne activation with Brønsted acids, see: (a) Yamamoto,
Y.; Ilya, G.; Patil, N. T.; Jin, T. Chem. Commun. 2009, 5075. For
noncatalyzed [4 + 2] cyclization of in situ generated imidate
intermediates, see: (b) Fortunak, J. M. D.; Mastrocola, A. R.;
Mellinger, M.; Sisti, N. J.; Wood, J. L.; Zhuang, Z.-P. Tetrahedron
Lett. 1996, 37, 5679. (c) Zhou, H.-B.; Liu, G.-S.; Yao, Z.-J. Org. Lett.
2007, 9, 2003. (d) Liang, Y.; Jiang, X.; Yu, Z.-X. Org. Lett. 2009, 11,
5302.
(19) (a) Wakabayashi, Y.; Fukuda, Y.; Shiragami, H.; Utimoto, K.;
Nozaki, H. Tetrahedron 1985, 41, 3655. (b) Fukuda, Y.; Shiragami, H.;
Utimota, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816. (c) Trost, B. M.;
Lumb, J.-P.; Azzarelli, J. M. J. Am. Chem. Soc. 2011, 133, 740. For an
elegant example of a Pd-catalyzed heteroallylation of alkenes, see:
(d) Hewitt, J. F. M.; Williams, L.; Aggarwal, P.; Smith, C. D.; France,
D. J. Chem. Sci. 2013, 4, 3538.
(5) For 3-substituted enediynes, see: Dai, W.-M. Curr. Med. Chem.
2003, 10, 2265.
(6) For cross-conjugated systems, see: (a) Phelan, N. F.; Orchin, M.
J. Chem. Educ. 1968, 45, 633. (b) Gholami, M.; Tykwinski, R. R. Chem.
Rev. 2006, 106, 4997. For examples, see: (c) Yao, T.; Zhang, X.;
Larock, R. C. J. Am. Chem. Soc. 2004, 126, 11164. (d) Xiao, Y.; Zhang,
J. Angew. Chem., Int. Ed. 2008, 47, 1903. (e) Zhao, L.; Xie, F.; Cheng,
G.; Hu, Y. Angew. Chem., Int. Ed. 2009, 48, 6520. (f) He, T.; Gao, P.;
Zhao, S.-C.; Shi, Y.-D.; Liu, X.-Y.; Liang, Y.-M. Adv. Synth. Catal. 2013,
355, 365.
(7) For reviews on palladium-catalyzed cascade cyclization, see:
(a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (b) Zeni,
G.; Larock, R. C. Chem. Rev. 2004, 104, 2285. (c) Wasilke, J.-C.;
Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005, 105, 1001.
(20) For an example, see: Rubina, M.; Conley, M.; Gevorgyan, V. J.
Am. Chem. Soc. 2006, 128, 5818.
(d) De Meijere, A.; Zezschwitz, P. V.; Brase, S. Acc. Chem. Res. 2005,
38, 413. (e) Balme, G.; Bouyssi, D.; Monteiro, N. Pure Appl. Chem.
2006, 78, 231. (f) Vlaar, T.; Ruijter, E.; Orru, R. V. A. Adv. Synth.
̈
Catal. 2011, 353, 809. (g) Deng, Y.; Persson, A. K. Å.; Backvall, J.-E.
̈
Chem.Eur. J. 2012, 18, 11498. (h) Gulevich, A. V.; Dudnik, A. S.;
Chernyak, N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084. (i) Ohno,
H. Asian J. Org. Chem. 2013, 2, 18. For N-sulfonyl amides as a
nitrogen nucleophile in Pd-catalyzed cyclization, see: (j) Lei, A.; Lu, X.
Org. Lett. 2000, 2, 2699. (k) Wu, L.; Qiu, S. F.; Liu, G. S. Org. Lett.
2009, 11, 2707. (l) Bajracharya, G. B.; Koranne, P. S.; Nadaf, R. N.;
Gabr, R. K. M.; Takenaka, K.; Takizawa, S.; Sasai, H. Chem. Commun.
2010, 46, 9064.
(8) (a) Robinson, R.; Watt, J. S. J. Chem. Soc. 1934, 1536.
(b) Shiotani, S. Heterocycles 1997, 45, 975. (c) Michael, J. P. Nat. Prod.
Rep. 2005, 22, 627. (d) Wishka, D. G.; Walker, D. P.; Yates, S. C. K.;
Jia, S.; Myers, J. K.; Olson, K. L.; Jacobsen, E. J.; Wolfe, M. L.; Groppi,
V. E. J. Med. Chem. 2006, 49, 4425.
(9) (a) Yao, W.; Pan, L.; Zhang, Y.; Wang, G.; Wang, X.; Ma, C.
Angew. Chem., Int. Ed. 2010, 49, 9210. (b) Cheng, D.; Ling, F.; Li, Z.;
Yao, W.; Ma, C. Org. Lett. 2012, 14, 3146. For the pioneering CuI-
catalyzed synthesis of N-tosyl carboxamides, see: (c) Cho, S. H.; Yoo,
E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005, 127, 16046.
(d) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed.
2006, 45, 3154.
(10) For a recent review on enediyne synthesis through a coupling
reaction, see: (a) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.
Tetrahedron 2013, 69, 7869. For enediyne-ester synthesis via the aldol
condensation of allenic esters with ynals, see: (b) Tsuboi, S.; Kuroda,
H.; Takatsuka, S.; Fukawa, T.; Sakai, T.; Utaka, M. J. Org. Chem. 1993,
58, 5952.
(11) Crystallographic data of 3e (CCDC 965933), 5ab (CCDC
965934), and (Z,Z)-6aa (CCDC 973098) are deposited in the
1825
dx.doi.org/10.1021/ol500574b | Org. Lett. 2014, 16, 1822−1825