Palladium-catalyzed Intramolecular Coupling Reactions between Vinyl Bromides, Aryl and Vinyl Halides, and Aryl Iodides Mediated by Indium: Preparation of Five- to Eight-membered Carbocycles and Heterocycles

Full text of DOI:10.1002/bkcs.10106

Note
DOI: 10.1002/bkcs.10106
BULLETIN OF THE
W. H. Jeon et al.
KOREAN CHEMICAL SOCIETY
Palladium-catalyzed Intramolecular Coupling Reactions between Vinyl
Bromides, Aryl and Vinyl Halides, and Aryl Iodides Mediated by Indium:
Preparation of Five- to Eight-membered Carbocycles and Heterocycles
†,
Woo Hyung Jeon,†,§ Hyunseok Kim,†,§ Jang-Sik Choi,† Kooyeon Lee,‡, and Phil Ho Lee
*
*
†Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea.
*E-mail: phlee@kangwon.ac.kr
‡Department of Bio-Health Technology, Kangwon National University, Chuncheon 200-701,
Republic of Korea. *E-mail: lky@kangwon.ac.kr
Received October 23, 2014, Accepted October 31, 2014, Published online January 20, 2015
Keywords: Palladium, Indium, Homo-coupling Reaction, Carbocycle, Heterocycle
Vinyl–vinyl, aryl–vinyl, and aryl–aryl bond-forming reactions
are one of the most significant methods in synthetic organic
chemistry, because the structures produced by the reaction
are the general moieties found in natural products, biologically
active compounds, and electronic organic materials.1 To date,
transition metal-catalyzed coupling reactions have been widely
used for the formation of these bonds. Thus, the synthetic
approaches for the homo- and cross-coupling reactions using
an array of transition metals have so far been reported.2 Among
them,theoriginalandmostbroadlyusedmethodistheUllmann
reaction, which is homo-coupling reaction between aryl halides
mediated by copper.1f,3 However, the stoichiometric amounts
of copper reagent, high temperature, and poor substrate scope
are the limitations of the reaction. Moreover, although a variety
of aryl–aryl bond-forming reactions via intermolecular cou-
pling reaction have been developed, the intramolecular cou-
pling reaction for vinyl–vinyl, aryl–vinyl, and aryl–aryl bond
formation is still rare.4 These results prompted us to investigate
the intramolecular coupling reaction.
Since the beginning of the past decade, we have engaged in
the development of efficient transition metal-catalyzed cross-
coupling reactions using organoindium reagents.5 In the
course of our continuing interest in this area, we have recently
described Pd-catalyzed intermolecular homo-coupling reac-
tions between aryl and heteroaryl halides.6 Based on these
results, we report herein Pd-catalyzed intramolecular coupling
reactions between vinyl bromides, aryl and vinyl halides, and
aryl iodides mediated by indium, producing medium-sized
carbocycles and heterocycles, particularly seven- and eight-
membered ring compounds that have received significant
attention due to the ubiquity of their skeletons in many natural
products (Scheme 1).
Pd2dba3CHCl3, and (π-allyl)2PdCl2]. DMF (0.5 M) proved to
be the solvent of choice among THF, THF–H2O, DMF,
DMF–H2O, PhCH3, and CH3CN. The best results were
obtained with Pd/C (10 mol%), indium (2.0 equiv), and LiCl
(3.0 equiv) in DMF (0.5 M) at 100 ꢀC for 3 h under nitrogen
atmosphere, producing the cyclized product 2a in 61% yield.
Moreover, high dilution conditions were not required despite
of intramolecular reaction. Additives such as LiBr, LiI, KBr,
and KI failed to afford the coupling product in good yield. Con-
trol experiments revealed that no coupling product was
observed without indium and Pd/C. The use of stoichiometric
amounts of indium accelerated the coupling reaction, and
indium (10 mol%) resulted in sluggish reaction. Bis(vinyl bro-
mide) 1a pretreated with indium and lithium chloride in DMF
wassubjectedtoPd/Ctoproduce2ainlowyield, indicatingthat
arylindium reagent was not involved in this reaction.
To demonstrate the efficiency and scope of the present
method, we studied the reactions of a wide range of
bis(vinyl bromides) 1 obtained from active methylene com-
pounds and 2,3-dibromo-1-propene (Table 1). Bis(vinyl
bromides) 1b derived from bis(phenylsulfonyl)methane
was converted to the desired 1,3-diene 2b in 55% yield
(entry 2). When 2,2-bis(2-bromoallyl)malononitrile (1c)
was treated with Pd/C (10 mol%), indium (2.0 equiv), and
LiCl (3.0 equiv) in DMF, 3,4-dimethylenecyclopentane-
1,1-dicarbonitrile (2c) wasproduced in48%yield viaintramo-
lecular coupling reaction between two vinyl carbons (entry 3).
Bis(vinyl bromide) 1d having N-tosylamino group as a linker
was cyclized to produce 2d in 45% yield (entry 4). Likewise,
six-membered carbocyclic and heterocyclic compounds bear-
ing two exo-methylene groups were obtained in moderate
yields ranging from 45 to 57%, starting from bis(vinyl bro-
mides) including diethyl malonate moiety, ether group, and
N O bond (entries 5–9). Medium-sized carbocycles and het-
erocycles, particularly seven- and eight-membered ring com-
pounds, turned outtobecompatible withtheoptimumreaction
conditions. 4,5-Dimethylene-2-phenyloxepane (2j) was pro-
duced in 48% yield (entry 10). Moreover, bis(vinyl bromide)
An initial attempt to achieve the intramolecular coupling
reaction is conducted with bis(vinyl bromide) 1a obtained from
ethyl phenylsulfonylacetate and 2,3-dibromo-1-propene. Pd on
charcoal isthe bestcatalystamong several catalysts [Pd(PPh3)4,
§ These authors contributed equally to this work.
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Table 1. Pd-catalyzed intramolecular coupling reactions between
vinyl bromides mediated by indium.a
Yield
Entry
1
Vinyl bromide
Diene
(%)
1a
2a
61
Scheme 1. Pd-catalyzed intramolecular coupling reactions between
vinyl bromides, aryl and vinyl halides, and aryl iodides mediated
by indium.
2
3
4
5
1b
1c
1d
1e
2b
2c
2d
2e
55
48
45
55
1k having an ester group as linker was cyclized to afford the
desired product 2k in 61% yield (entry 11). The present pro-
tocol would be highly useful in Diels–Alder reaction due to the
fact that 1,3-dienyl groups can easily be introduced.
Encouraged by these results, we next investigated Pd-
catalyzed intramolecular coupling reaction between aryl
iodide and vinyl bromide moieties mediated by indium
(Table 2). Coupling reaction between aryl iodide and vinyl
bromide tethered by diethyl malonate selectively afforded
dihydroindene 4a in 69% yield without the production of
indene via isomerization (entry 1). Exposure of substrates
3b to PdCl2 (10 mol%) produced the cyclized products
4b/4b0 (75%, 3.5:1) (entry2). Also, substrates bearing dimethyl
malonate, ethyl phenylsulfonylacetate, bis(phenylsulfonyl)-
methane, and malononitrile moieties on alkyl chain between
aryl iodide and vinyl bromide were smoothly cyclized to afford
4d, 4e, 4f, and 4g in good yields ranging from 61 to 73%
(entries 4–7). Likewise, the Pd-catalyzed intramolecular cou-
pling reaction occurred efficiently with substrate 3h tethered
by N-tosylamino group to deliver tetrahydroisoqinoline 4h
in 75% yield (entry 8).
6
7
8
1f (R = Ph)
1g (R = n-Bu)
1h (R = C6H11)
2f
2g
2h
57
53
49
9
1i
2i
45
10
1j
2j
48
11
1k
2k
61
As an extension of this work, a wide range of bis(aryl
iodides) were used for the Pd-catalyzed intramolecular cou-
plingreaction mediated by indium(Table3). Diethyl malonate
derivative 5a possessing 2-iodophenyl and 2-iodobenzyl
group at active methylene carbon was treated with Pd/C,
indium, and lithium chloride, producing dihydrophenanthrene
6a in 61% yield (entry 1). Bis(aryl iodides) 5b and 5c having
N-tosylamino and ether group as linker was converted to 6b
and 6c in 58 and 49% yields, respectively (entries 2 and 3).
Symmetric seven-membered-ring biaryls were also obtained
via intramolecular coupling reactions (entries 4, 6, and 7).
We were pleased to obtain biaryl 6e in 57% yield from sub-
strate 5e under the optimum reaction conditions (entry 5).
Intramolecular coupling reaction between two aryl sp2 car-
bons took place, leading to the formation of biaryl 6h in
55% yield (entry 8).
a Reactions were carried out with 1 (0.2 mmol), Pd/C (10 mol%), In (2.0
equiv), and LiCl (3.0 equiv) in DMF (0.5 M) at 100 ꢀC for 3 h.
A plausible mechanism for our Pd-catalyzed intramolecular
coupling reaction is shown in Scheme 2. First, Pd catalyst is
oxidatively added to aryl iodide, providing palladium com-
plex A, which undergoes another oxidative addition to give
intermediate B. After that, reductive elimination of B affords
the cyclized products 2, 4, and 6 with regeneration of the pal-
ladium catalyst. Also, the resulting Pd(II) is reduced to Pd(0)
by indium.
Bull. Korean Chem. Soc. 2015, Vol. 36, 711–714
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Table 2. Pd-catalyzed intramolecular coupling reactions between
Table 3. Pd-catalyzed intramolecular coupling reactions between
aryl and vinyl halides mediated by indium.a
aryl iodides mediated by indium.a
Yield
(%)
Entry Aryl vinyl bromide
1
Product
Yield (%)
69
Entry
1
Aryl iodide
Diene
61
4a
3a
5a
6a
6b
6c
2
75b (3.5:1)
2
3
58
49
4b, 4b0
3b
3
65
5b
5c
3c
4c
4d
4e
4f
4
61
73
70
69
3d
5
4
5
5d (E1, E2 = CO2Et)
5e (E1 = CO2Et, E2 =
6d
6e
58
57
SO2Ph)
3e
6
7
8
5f (E1, E2 = SO2Ph)
5g (E1, E2 = CN)
6f
63
67
55
6
6g
3f
7
5h
6h
a Reactions were carried out with 5 (0.2 mmol), Pd/C (10 mol%), In (2.0
4g
4h
3g
equiv), and LiCl (3.0 equiv) in DMF (0.5 M) at 100 ꢀC for 3 h.
8
75
3h
a Reactions were carried out with 3 (0.2 mmol), Pd/C (10 mol%), In (2.0
equiv), and LiCl (3.0 equiv) in DMF (0.5 M) at 100 ꢀC for 3 h.
b PdCl2 (10 mol%) was used.
In conclusion, we have developed a Pd-catalyzed intramo-
lecular coupling reaction between vinyl bromide, aryl and
vinyl halide, and aryl iodide, which can afford a wide variety
of carbocycles and heterocycles mediated by indium in the
presence of lithium chloride in DMF at 100 ꢀC. Further related
investigations for the synthesis of natural products using the
present method are currently underway in our laboratory.
Scheme 2. A plausible mechanism.
Bull. Korean Chem. Soc. 2015, Vol. 36, 711–714
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
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Note
KOREAN CHEMICAL SOCIETY
Chem. Soc. 1994, 116, 4832; (l) E. Schulz, K. Fahmi, M. Lemaire,
Acros Org. Acta 1995, 1, 10; (m) S. S. Zhu, T. M. Swager,
Adv. Mater. 1996, 8, 497; (n) J. Papillon, E. Schulz, S. Gelinas,
J. Lessard, M. Lemaire, Synth. Met. 1998, 96, 155; (o)J. T. Manka,
F. Guo, J. Huang, H. Yin, J. M. Farrar, M. Sienkowska, V. Benin,
P. Kaszynski, J. Org. Chem. 2003, 68, 9574; (p) J. M. Lehn
Ed., Supramolecular Chemistry, 1st ed., Wiley-VCH,
Weinheim, 1995; (q) R. Noyori, Angew. Chem. Int. Ed. 2002,
41, 2008.
Experimental
Typical Experimental Procedure. A mixture of dihalides
(0.2 mmol), Pd/C (10 wt%, 10 mol%), indium (0.4 mmol),
and LiCl (0.6 mmol) in dry DMF (0.4 mL) was stirred at
100 ꢀC for 3 h under a nitrogen atmosphere. The reaction mix-
ture was quenched with NaHCO3 (sat aq.). The aqueous layer
was extracted with ether (3 × 20 mL), and the combined
organic phase was washed with water and brine, dried with
MgSO4, filtered, and concentrated under a reduced pressure.
The residue was purified by silica gel column chromatography
to give desired product.
2. (a)B. O. Achburn, R. G. Carter, L. N. Zakharov, J. Am. Chem.Soc.
2007, 129, 9109; (b) K. Yoshida, T. Imamoto, J. Am. Chem. Soc.
2005, 127, 10470; (c) G. Nishida, K. Noguchi, M. Hirano,
K. Tanaka, Angew. Chem. Int. Ed. 2007, 46, 3951;(d)D. Alberico,
M. E. Scott, M. Lautens, Chem. Rev. 2007, 107, 174; (e) G. P.
McGlacken, L. M. Bateman, Chem. Soc. Rev. 2009, 38,
2447; (f ) L. Ackermann, R. Vicene, A. R. Kapdi, Angew. Chem.
Int. Ed. 2009, 48, 9792; (g) A. Jutand, A. Mosleh, J. Org.
Chem. 1997, 62, 261; (h) S. Mukhopadhyay, G. Rothenberg, N.
Qafisheh, Y. Sasson, Tetrahedron Lett. 2001, 42, 6117; (i) M.
Brenda, A. Knebelkamp, A. Greiner, W. Heitz, Synlett 1991,
809; (j) J.-H. Li, Y.-X. Xie, D.-L. Yin, J. Org. Chem. 2003,
68, 9867.
3. (a)P.E. Fanta, Chem. Rev. 1946, 46, 139;(b)P.E. Fanta, Synthesis
1974, 9; (c) T. Cohon, I. Cristea, J. Org. Chem. 1975, 40, 3649;
(d) G. Bringmann, R. Walter, R. Weirich, Angew. Chem. Int.
Ed. 1990, 29, 977; (e) T. D. Nelson, A. I. Meyers, J. Org. Chem.
1994, 59, 2655; (f ) A. I. Meyers, J. Heterocycl. Chem. 1998,
35, 991.
Dimethyl 4-methylene-3,4-dihydronaphthalene-2,2(1H)-
dicarboxylate (4d): white solid; yield 61%; H NMR (400
1
MHz, CDCl3) δ 7.58 (d, J = 8.0 Hz, 1H), 7.10–7.20 (m,
3H), 5.55 (d, J = 0.6 Hz, 1H), 5.05 (d, J = 0.6 Hz, 1H), 3.70
(s, 6H), 3.33 (s, 2H), 3.05 (s, 2H); 13C NMR (100 MHz,
CDCl3) δ 171.1, 138.9, 133.5, 133.1, 129.0, 128.3, 126.5,
123.9, 111.1, 54.4, 52.8, 37.9, 35.5.
Acknowledgment. This work was supported by a National
Research Foundation of Korea (NRF) grant funded by the
Korea government (MSIP) (No. 2014001403).
References
4. (a) D. D. Hennings, T. Iwama, V. H. Rawal, Org. Lett. 1999, 1,
1205; (b) E. Piers, J. G. K. Yee, P. L. Gladsrone, Org. Lett.
2000, 2, 481; (c) G. Cahiez, C. Chaboche, F. Mahuteau-Betzer,
M. Ahr, Org. Lett. 2005, 7, 1943.
1. (a) J. Hassan, M. Sevignon, C. Gozzi, E. Schulz, M. Lemaire,
Chem. Rev. 2002, 102, 1359;(b) H. Shimizu, I. Nagasaki, T. Saito,
Tetrahedron 2005, 61, 5405; (c) G. Bringmann, A. J. Price Mor-
timer, P. A. Keller, M. J. Gresser, J. Garner, M. Breuning, Angew.
Chem. Int. Ed. 2005, 44, 5384; (d) R. Noyori, H. Takaya, Acc.
Chem. Res. 1990, 23, 345; (e) C. Rosini, L. Franzini, A. Raffaelli,
P. Salvadori, Synthesis 1992, 503; (f ) M. Sainsbury, Tetrahedron
1980, 36, 3327; (g) G. Bringmann, R. Walter, R. Weirich, In Ster-
eoselective Synthesis, 4th ed., Vol. E21a, G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann Eds., Georg Thieme Verlag,
Stuttgart, 1995, p. 567; (h) G. Bringmann, M. Ochse, O. Schupp,
S. Tasler, Progress in the Chemistry of Organic Natural Products,
Vol. 82, Springer, Wien, 2001; (i) D. A. Horton, G. T. Bourne, M.
L. Smythe, Chem. Rev. 2003, 103, 893; (j) G. T. Wang, S. Wang,
R. Gentles, T. Sowin, S. Leitza, E. B. Reilly, T. W. von Geldern,
Bioorg. Med. Chem. Lett. 2005, 15, 195; (k) T. Yamamoto, T.
Maruyama, Z. Zhou, T. Ito, T. Fukada, Y. Yoneda, F. Begum,
T. Ikeda, S. Sasaki, H. Takezoe, A. Fukada, K. Kubota, J. Am.
5. (a) P. H. Lee, S.-Y. Sung, K. Lee, Org. Lett. 2001, 3, 3201; (b) K.
Lee, D. Seomoon, P. H. Lee, Angew. Chem. Int. Ed. 2002, 41,
3901; (c) P. H. Lee, D. Seomoon, K. Lee, S. Kim, H. Kim, H.
Kim, E. Shim, M. Lee, S. Lee, M. Kim, M. Sridhar, Adv. Synth.
Catal. 2004, 346, 1641; (d) D. Seomoon, K. Lee, H. Kim, P. H.
Lee, Chem. Eur. J. 2007, 13, 5197; (e) H. Kim, K. Lee, S. Kim,
P. H. Lee, Chem. Commun. 2010, 46, 6341; (f ) J. Mo, S. H.
Kim, P. H. Lee, Org. Lett. 2010, 12, 424; (g) D. Kang, D. Eom,
D. H. Kim, P. H. Lee, Eur. J. Org. Chem. 2010, 2330; (h) P. H.
Lee, J. Mo, D. Kang, D. Eom, C. Park, C.-H. Lee, Y. M. Jung,
H. Hwang, J. Org. Chem. 2011, 76, 312; (i) K. Lee, H. Kim, J.
Mo, P. H. Lee, Chem. Asian J. 2011, 6, 2147.
6. (a) P. H. Lee, D. Seomoon, K. Lee, Org. Lett. 2005, 7, 343; (b) K.
Lee, P. H. Lee, Tetrahedron Lett. 2008, 49, 4302.
Bull. Korean Chem. Soc. 2015, Vol. 36, 711–714
© 2015 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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