Synthesis of 1,2-disubstituted cyclopentenes by palladium-catalyzed reaction of homopropargyl-substituted dicarbonyl compounds with organic halides via 5- endo-dig cyclization

Article abstract of DOI:10.1021/ol301257m

Palladium catalysts with bulky biaryl phosphine ligands allow homopropargyl-substituted dicarbonyl compounds to undergo intramolecular addition via a rare 5-endo-dig pathway. C-C bond forming reductive elimination follows the addition to introduce alkenyl and alkynyl as well as aryl groups by using the corresponding organic halides. The cyclization is versatile enough to be applicable to the synthesis of highly substituted dihydropyrrole and a fused tricyclic compound.

Full text of DOI:10.1021/ol301257m

ORGANIC
LETTERS
2012
Vol. 14, No. 11
2914–2917
Synthesis of 1,2-Disubstituted
Cyclopentenes by Palladium-Catalyzed
Reaction of Homopropargyl-Substituted
Dicarbonyl Compounds with Organic
Halides via 5-Endo-Dig Cyclization
Daishi Fujino, Hideki Yorimitsu,* and Atsuhiro Osuka
Department of Chemistry, Graduate School of Science, Kyoto University,
Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan
yori@kuchem.kyoto-u.ac.jp
Received May 8, 2012
ABSTRACT
Palladium catalysts with bulky biaryl phosphine ligands allow homopropargyl-substituted dicarbonyl compounds to undergo intramolecular
addition via a rare 5-endo-dig pathway. CÀC bond forming reductive elimination follows the addition to introduce alkenyl and alkynyl as well as
aryl groups by using the corresponding organic halides. The cyclization is versatile enough to be applicable to the synthesis of highly substituted
dihydropyrrole and a fused tricyclic compound.
The intramolecular addition of enolates to alkynes is a
powerful tool to construct five-membered cyclic com-
pounds bearing an olefinic moiety.1 A number of metal-
catalyzed reactions have been developed to improve reac-
tion conditions and expand the scope of substrates.2 The
cyclizations usually proceedin a 5-exo-dig mode to provide
methylenecyclopentanes starting from ε,ζ-alkynyl carbo-
nyl compounds. However, synthesis of cyclopentene deri-
vatives via 5-endo-dig cyclization of δ,ε-alkynyl carbonyl
compounds has been relatively unexplored despite their
synthetic utility.3 Indeed, detailed theoretical investigations4
recently revealed an unfavorable stereoelectronic effect
operating in 5-endo-dig cyclization while the original
Baldwin rules assigned 5-endo-dig as a favorable process.5
Molybdenum and tungsten catalysts first achieved the
challenging 5-endo-dig cyclizations of enolates yet for-
mally via metal vinylidene intermediates, thus inherently
limiting the reaction scope to substrates having a terminal
alkyne moiety.6 Subsequently, gold catalysts have been
allowed to employ enolates bearing an internal alkyne
owing to their high affinity to alkynes, expanding the scope
of substrates.7À11 While these reactions overcome the
hindrances of the 5-endo-dig cyclization of enolates, they
(5) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
(6) (a) McDonald, F. E.; Olson, T. C. Tetrahedron Lett. 1997, 38,
7691–7692. (b) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120,
1928–1929. (c) Iwasawa, N.; Miura, T.; Kiyota, K.; Kusama, H.; Lee,
K.; Lee, P. H. Org. Lett. 2002, 4, 4463–4466. (d) Iwasawa, N.; Maeyama,
K.; Kusama, H. Org. Lett. 2001, 3, 3871–3873. (e) Miura, T.; Iwasawa,
N. J. Am. Chem. Soc. 2001, 124, 518–519. (f) Kusama, H.; Yamabe, H.;
Iwasawa, N. Org. Lett. 2002, 4, 2569–2571.
(7) (a) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2004, 43, 5350–5352. (b) Brazeau, J.-F.; Zhang, S.; Colomer, I.;
Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc. 2012, 134, 2742–2749.
(8) During the preparation of this manuscript, Shibata’s group
reported enantioselective 5-endo-dig cyclization using a Zn- and
Yb-cocatalyst system: Suzuki, S.; Tokunaga, E.; Reddy, D. S.; Matsumoto,
T.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2012, 51, 4131–4135.
(1) Conia, J. M.; Le Perchec, P. Synthesis 1975, 1–19.
ꢀ ꢁ
ꢀ
(2) Denes, F.; Perez-Lina, A.; Chemla, F. Chem. Rev. 2010, 110,
2366–2447.
(3) Selected examples: (a) Noyori, R.; Suzuki, M. Science 1993, 259,
44–45. (b) Nangia, A.; Prasuna, G.; Rao, P. B. Tetrahedron 1997, 53,
14507–14545. (c) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.;
Northcote, P. T.; Prinsep, M. R. Nat. Prod. Rep. 2006, 23, 26–78.
(d) Seepersaud, M.; Al-Abed, Y. Tetrahedron Lett. 2000, 41, 4291–
4293. (e) Linghu, X.; Kennedy-Smith, J. J.; Toste, F. D. Angew. Chem.,
Int. Ed. 2007, 46, 7671–7673.
(4) (a) Alabugin, I. V.; Gilmore, K.; Manoharan, M. J. Am. Chem.
Soc. 2011, 133, 12608–12623. (b) Gilmore, K.; Alabugin, I. V. Chem.
Rev. 2011, 111, 6513–6556.
r
10.1021/ol301257m
Published on Web 05/21/2012
2012 American Chemical Society

resulted in the formation of only one CÀC bond, finalized
by in situ protonation of vinylmetal intermediates (Scheme 1,
eq 1). Therefore, we envisioned that utilization of the vinyl-
metal intermediates for further bond forming events should
enhance the synthetic potential of the 5-endo-dig cycliza-
tion for preparing densely substituted complex cyclo-
pentenes. To this end, the most promising design can be
the use of π-acidic organopalladium species for alkyne
activation, which should terminate the cyclization by CÀC
bond forming reductive elimination (Scheme 1, eq 2).12
Although palladium-catalyzed arylative cyclization of
enolates was extensively investigated so far,12a,b the cycli-
zation mode was again severely restricted to exo with the
exception of highly activated substrates.9g,13
CÀC bonds in a single operation. The reaction is versatile
and offers an efficient route to various cyclopentene
derivatives containing a fully substituted endo-alkene unit,
which are otherwise difficult to synthesize.
We initially investigated the effect of a ligand on the
phenylative cyclization reaction of 1a (Table 1, Figure 1).
The use of Xantphos, which is effective in our previous
work,14c gave the desired product in only 6% yield (entry 1).
Other ligands such as dppb, tri-tert-butylphosphine, and
triphenylphosphine were also ineffective for this reaction
(entries 2, 3, and 4). Only biaryl-based bulky phosphines
served as suitable ligands for this cyclization, and the best
yield was obtained with XPhos (entry 7).15 Interestingly,
the employment of the bulky electron-richbiaryl liganddid
not retard the 5-endo-dig cyclization, which usually re-
quired highly electrophilic Lewis acids in the previous
works.6,7 It is noteworthy that the catalytic amount could
be reduced to 0.50 mol % on a large scale, which demon-
strates the high efficiency of the catalytic system (entry 8).
In addition, we could employ readily available and eco-
nomical LDA as an alternative base.
Scheme 1. Fate of Vinylmetal Intermediate Generated by
5-Endo-Dig Cyclization
The scope of aryl halides proved to be broad (Table 2).
Chlorobenzene instead of bromobenzene could be used for
the arylative cyclization at an elevated temperature (entry 1).
Electron-deficient and -rich aryl halides gave the corre-
sponding products in good to excellent yields without any
decomposition of their functional groups (entries 2À6).
Notably, sterically demanding aryl as well as heteroaryl
bromides were also converted smoothly (entries 7 and 8).
Recently, our group reported palladium-catalyzed ary-
lative cyclization reactions of allylic alcohols, allylic
amines, and propargyl-substituted malonate esters to yield
highly strained cyclic compounds.14 To achieve these un-
precedented cyclizations, the careful choice of ligands was
crucial. Along this line, we disclose herein that the
appropriate choice of ligand realized palladium-catalyzed
5-endo-dig cyclization of homopropargyl-substituted di-
carbonyl compounds with concomitant formation of two
Table 1. Effect of Ligand on Palladium-Catalyzed 5-Endo-Dig
Arylative Cyclizationa
(9) For examples of metal-catalyzed endo-dig cyclization of enolates
having an alkyne moiety that are electronically activated and/or struc-
turally constrained, see: (a) Ito, H.; Makida, Y.; Ochida, A.; Ohmiya,
entry
ligand
x (mol %) 1a yield (%) 2aa yield (%)
ꢀ
H.; Sawamura, M. Org. Lett. 2008, 10, 5051–5054. (b) Barabe, F.;
1
Xantphos
dppb
2.5
2.5
5.0
10
88
99
74
85
14
0
6
Levesque, P.; Korobkov, I.; Barriault, L. Org. Lett. 2011, 13, 5580–
5583. (c) Kozak, J. A.; Patrick, B. O.; Dake, G. R. J. Org. Chem. 2010,
75, 8585–8590. (d) Hessa, W.; Burton, J. W. Adv. Synth. Catal. 2011, 353,
2966–2970. (e) Fei, N.; Yin, H.; Wang, S.; Wang, H.; Yao, Z.-J. Org.
Lett. 2011, 13, 4208–4211. (f) Deng, C.-L.; Zou, T.; Wang, Z.-Q.; Song,
R.-J.; Li, J.-H. J. Org. Chem. 2009, 74, 412–414. With a stoichiometric
base: (g) Hu, J.; Wu, L.-Y.; Wang, X.-C.; Hu, Y.-Y.; Niu, Y.-N.; Liu,
X.-Y.; Yang, S.; Liang, Y.-M. Adv. Synth. Catal. 2010, 352, 351–356.
2
0
3c
4
Pt-Bu3•HBF4
PPh3
8
0
5
SPhos
2.5
2.5
2.5
0.50
84
85
95b
77b
6
RuPhos
XPhos
7
8d
0
ꢀ
(h) Lavallee, J. F.; Berthiaume, G.; Deslongchamps, P. Tetrahedron
XPhos
0
Lett. 1986, 27, 5455–5458.
a A mixture of Pd2(dba)3 (1.25 mol %, 0.0038 mmol), ligand (x mol %,
0.0075 mmol), NaHMDS (1.3 equiv, 0.39 mmol), 1a (0.30 mmol),
and PhBr (0.36 mmol) was stirred at 60 °C in DMF (0.75 mL) for 6 h.
Yields were determined by 1H NMR using tetrabromoethane as an
internal standard. b Isolated yield. c 13% of protonated product 3 was
obtained. d A mixture of Pd2(dba)3 (0.25 mol %, 0.0075 mmol), XPhos
(0.50 mol %, 0.015 mmol), LDA (1.1 equiv, 3.3 mmol), 1a (3.0 mmol), and
PhBr (1.05 equiv, 3.15 mmol) was stirred at 60 °C in DMF (3.0 mL) for 12 h.
(10) For selected examples of metal-catalyzed 5-endo-dig cyclization
accompanying an attack by carbon nucleophiles other than enolates
such as allylic silane, see: (a) Buzas, A. K.; Istrate, F. M.; Gagosz, F.
Angew. Chem., Int. Ed. 2007, 46, 1141–1144. (b) Gorin, D. J.; Watson,
I. D. G.; Toste, F. D. J. Am. Chem. Soc. 2008, 130, 3736–3737. (c) Zhang,
L.; Kozmin, S. A. J. Am. Chem. Soc. 2005, 127, 6962–6963. (d) Ajamian,
A.; Gleason, J. L. Org. Lett. 2003, 5, 2409–2411. (e) Imamura, K.;
Yoshikawa, E.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem. Soc. 1998,
120, 5339–5340.
(11) For an example of metal-catalyzed 4-exo-dig cyclization of
enolate: Deng, C.-L.; Song, R.-J.; Liu, Y.-L.; Li, J.-H. Adv. Synth.
Catal. 2009, 351, 3096–3100. See also ref 9d. It should be noted that
simple ring strain does not lead to the formation of endocyclic products:
(a) Bailey, W. F.; Ovaska, T. V. Tetrahedron Lett. 1990, 31, 627–630.
(b) Bailey, W. F.; Ovaska, T. V. J. Am. Chem. Soc. 1993, 115, 3080–3090.
Org. Lett., Vol. 14, No. 11, 2012
2915

Table 3. Scope of Homopropargyl-Substituted Dicarbonyl
Compoundsa
Figure 1. Phosphine ligands examined. Cy = cyclohexyl.
Table 2. Scope of Aryl Halidesa
a Reaction conditions are identical to those in Table 2. Yields are
isolated yields. b Reaction was carried out at 100 °C.
entry
ArX
2
yield (%)
Scheme 2. Alkenylative and Alkynylative Cyclization
1b
2
3
4
5
6
7
8
C6H5Cl
2aa
2ab
2ac
2ad
2ae
2af
81
98
82
77
85
76
87
72
4-CF3C6H4Br
4-MeOC(dO)C6H4Br
4-PhC(dO)C6H4Br
4-MeOC6H4Br
4-Me2NC6H4Br
2-MeC6H4Br
2ag
2ah
3-pyridinyl-Br
a AmixtureofPd2(dba)3 (1.25 mol %, 0.0038 mmol), XPhos (2.5 mol %,
0.0075 mmol), NaHMDS (1.3 equiv, 0.39 mmol), 1a (0.30 mmol),
and ArX (0.36 mmol) was stirred at 60 °C in DMF (0.75 mL) for 8 h.
Yields are isolated yields. b Reaction was carried out at 100 °C.
a Reaction was carried out at 100 °C.
The cyclization strategy is also applicable to the synth-
esis of 3-pyrroline 5 from aminomalonate 4 despite the
high Lewis basicity of a tertiary amine (Scheme 3). Aza-
cycle 5 has an unsaturated proline skeleton, which will find
application in organic synthesis.9d,17 In this case, RuPhos
was the better ligand and the Pd-XPhos system gave a low
yield of 5 due to the competitive protonation of the
vinylpalladium intermediate.18
Starting from 6, intramolecular arylative cyclization
afforded tricyclic compound 7 in good yield (Scheme 4).
This achievement highlights the robustness of our 5-endo-
dig cyclization since the intramolecular coordination of the
alkyne moiety to the palladium center (vide infra) might be
unfavorable due to the resulting strain on the tethering chain.
A wide range of homopropargyl-substituted dicarbonyl
compounds underwent the arylative 5-endo-dig cyclization
(Table 3).16 Bulky tert-butyl malonate ester derivative 1a
participated in the cyclization reaction (entry 1). Aside
from diesters, a β-diketone and ketoester were also viable
nucleophiles (entries 2 and 3). 1,2-Diarylcyclopentene 2ea
was synthesized in high yield (entry 4). It is worth noting
that substrate 1f bearing an alkene moiety neither suffered
from direct MizorokiÀHeck reaction of the double bond nor
underwent tandem 5-endo-dig cyclization/intramolecular
5-exo-trig cyclization to form a bicyclic skeleton (entry 5).
The optimized conditions are so robust and versatile that
we could introduce alkenyl and alkynyl halides, besides aryl
halides (Scheme 2). The resulting conjugated diene and
enyne motifs can be platforms for further functionalizations
to construct complex cyclic frameworks.
Scheme 3. Synthesis of 3-Pyrroline
(12) (a) Balme, G.; Bouyssi, D.; Lomberget, T.; Monterio, N. Synth-
esis 2003, 2115–2134. (b) Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Acc.
Chem. Res. 2011, 44, 111–122. (c) Wolfe, J. P. Synlett 2008, 2913–2937.
(d) Schultz, D. M.; Wolfe, J. P. Synthesis 2012, 44, 351–361. Pd-
catalyzed Conia-ene reaction: (e) Corkey, B. K.; Toste, F. D. J. Am.
Chem. Soc. 2005, 127, 17168–2053.
(13) 5-Endo-dig arylative cyclizations of structurally limited sub-
strates, which were activated by the conjugation of the aromatic ring
and structural rigidity: (a) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu,
X.-Y.; Liang, Y.-M. J. Org. Chem. 2006, 71, 3325–3327. (b) Zhang, D.;
Liu, Z.; Yum, E. K.; Larock, R. C. J. Org. Chem. 2007, 72, 251–262.
(c) Duan, X.-H.; Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org.
Lett. 2006, 8, 3053–3056.
(14) (a) Hayashi, S.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2009, 131, 2052–2053. (b) Hayashi, S.; Yorimitsu, H.; Oshima, K.
Angew. Chem., Int. Ed. 2009, 48, 7224–7226. (c) Fujino, D.; Yorimitsu,
H.; Oshima, K. J. Am. Chem. Soc. 2011, 133, 9682–9685.
2916
Org. Lett., Vol. 14, No. 11, 2012

Scheme 4. Intramolecular Arylative Cyclizationa
Scheme 5. Plausible Mechanism
a AmixtureofPd2(dba)3 (2.5mol%, 0.0075 mmol), XPhos (5.0 mol %,
0.015 mmol), NaHMDS (1.3 equiv, 0.39 mmol), and 6 (0.30 mmol)
was stirred at 100 °C in DMF (0.75 mL) for 8 h.
tions of byproduct 3 (Table 1, entry 3) and 8 (Scheme 3)18
indicate the intermediacy of C in our system.21 The suc-
cessful intramolecular cyclization (Scheme 4) also elimi-
nates the possibility of the intermediacy of D.
In conclusion, we have demonstrated that palladium
catalysts with bulky biaryl phosphine ligands allow
homopropargyl-substituted dicarbonyl compounds to
undergo intramolecular addition via a rare 5-endo-
dig pathway. The addition is followed by CÀC bond
forming reductive elimination, resulting in the efficient
synthesis of 1,2-disubstituted cyclopentenes of syn-
thetic difficulty. Syntheses of other heterocycles by this
methodology are currently under investigation in our
laboratory.
Figure 2. ORTEP drawing of compound 2af.
A plausible mechanism is shown in Scheme 5, based on
the unambiguously determined structure of one of the
products (Figure 2)19 and Toste’s and our reports.7,14c
After oxidative addition, arylpalladium intermediate A
would activate the alkyne moiety of 2a through π-coordi-
nation. Deprotonation of the acidic methine proton by
NaHMDS would induce 5-endo-dig cyclization to form
vinylpalladium C. The following reductive elimination
yields phenyl-substituted cyclopentene 2aa and regener-
ates the initial palladium complex. One would conceive
another mechanism that involves sequential syn-arylpalla-
dation/isomerization,13a,20 or less likely a direct anti-aryl-
palladation, toaffordpalladacycleD. However, the forma-
Acknowledgment. This work was partly supported by
Grants-in-Aid for Scientific Research (No. 22106523,
“Reaction Integration”) from MEXT. D.F. acknowl-
edges a JSPS Fellowship for Young Scientists. H.Y. is
thankful for financial support from The Uehara Mem-
orial Foundation, NOVARTIS Foundation (Japan)
for the Promotion of Science, and Takeda Science
Foundation.
Supporting Information Available. General procedure,
1
spectroscopic data, and the H/13C NMR spectra of all
(15) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–
1473.
the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
(16) We examined the reaction of bishomopropargyl-substituted
malonate ester, instead of homopropargyl malonate, which resulted in the
formation of a cyclopentane derivative via a 5-exo cyclization. See ref 12a.
(17) (a) Takahashi, K.; Midori, M.; Kawano, K.; Ishihara, J.;
Hatakeyama, S. Angew. Chem., Int. Ed. 2011, 50, 2342–2345. (b) Hess,
W.; Burton, J. W. Chem.;Eur. J. 2010, 16, 12303–12306.
(18) The reaction led to the concomitant formation of a protonated
byproduct 8.
(20) Chernyak, N.; Gorelsky, S. I.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2011, 50, 2342–2345 and references therein.
(21) It was unlikely that a Heck reaction of 3 that might be first
generated in situ led to product 2 via intermediate E because none
of double bond isomers 9 were observed. The formation of 2ea also
supports our mechanism since the plausible cyclopentylpalladium
intermediate that can be formed by the arylpalladation of 3 can-
not undergo syn-β-hydride elimination due to the anti H/Pd stereo-
chemistry.
(19) Crystal data for compound 2af: C19H25NO4, Mw = 331.40,
monoclinic, space group Cc, final R indices [I > 2σ(I)], R1 = 0.0462,
wR2 = 0.1068, R indices (all data) R1 = 0.0563, wR2 = 0.1154, a =
˚
˚
˚
7.9128(2) A, b = 13.2027(3) A, c = 17.3219(4) A, β = 105.2565(15)°,
V = 1745.85(7) A , T = 123 K, Z = 4, reflections collected/unique:
3
˚
2807/2373. GOF = 1.055 [I > 2σ(I)]. CCDC No.: 868309.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 11, 2012
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