Palladium(0)-catalyzed cis-selective alkylative and arylative cyclization of alkynyl enones with organoboron reagents

Article abstract of DOI:10.1016/j.tetlet.2008.04.111

A palladium(0)-tricyclohexylphosphine catalyzes cis-selective alkylative and arylative cyclization of alkyne-containing electron-deficient alkenes with organoboron reagents to provide five- or six-membered rings with exo tri- or tetra-substituted alkenes. The opposite stereoselectivity to that for the alkyne-aldehyde cyclization using the same reagents would result from palladacycle-forming oxidative addition of the substrates to the Pd⁰ catalyst followed by transmetalation with the boron reagents, protonation, and reductive elimination. The functional group compatibility, availability, stability, and non-toxicity of the reagents, and the fact that no additives are needed make the process more practical than the Ni⁰-catalyzed cyclization with organozinc reagents.

Full text of DOI:10.1016/j.tetlet.2008.04.111

Tetrahedron Letters 49 (2008) 4174–4177
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Tetrahedron Letters
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Palladium(0)-catalyzed cis-selective alkylative and arylative cyclization
of alkynyl enones with organoboron reagents
*
Hirokazu Tsukamoto , Takamichi Suzuki, Tomomi Uchiyama, Yoshinori Kondo
Graduate School of Pharmaceutical Sciences, Tohoku University, Aramai-aza aoba 6-3, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium(0)-tricyclohexylphosphine catalyzes cis-selective alkylative and arylative cyclization of
alkyne-containing electron-deficient alkenes with organoboron reagents to provide five- or six-mem-
bered rings with exo tri- or tetra-substituted alkenes. The opposite stereoselectivity to that for the
alkyne–aldehyde cyclization using the same reagents would result from palladacycle-forming oxidative
addition of the substrates to the Pd0 catalyst followed by transmetalation with the boron reagents, pro-
tonation, and reductive elimination. The functional group compatibility, availability, stability, and non-
toxicity of the reagents, and the fact that no additives are needed make the process more practical than
the Ni0-catalyzed cyclization with organozinc reagents.
Received 7 March 2008
Revised 16 April 2008
Accepted 18 April 2008
Available online 23 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Organoboron reagents are generally non-toxic, commercially
available, stable, and compatible with various functional groups,
and often employed for a wide variety of Pd0-catalyzed carbon–
carbon bond formations such as cross-coupling reactions,1 aryla-
tions of unsaturated carbon–carbon bonds,2–4 and alkylative cycli-
zation reaction of functionalized unsaturated carbon–carbon
bonds.5–7 Our recent interest has been focused on base-free trans-
formations of substrates containing no halogens because they are
atom-economical and does not form inorganic salts.4a,5
Recently, we discovered the palladium(0)/monophosphine-
catalyzed trans-selective alkylative cyclization of alkyne–aldehyde
1 with organoboron reagents to provide structurally complex cyc-
lic allylic alcohols 2a and 2b (Scheme 1).5a,b The trans selectivity is
in striking contrast to for the Ni0-catalyzed cis-selective one with
organozinc reagents.8 The opposite selectivity in these cyclization
reactions would originate from the different oxidative addition
mode of alkynal 1 to these catalysts. Whereas ‘anti-Wacker’-type
oxidative addition to the Pd0 catalyst and concomitant transmeta-
lation with the boron reagents would occur in the former cycliza-
tion, metallacycle-forming one to the Ni0 catalyst and subsequent
transmetalation with the zinc reagents would occur in the latter
cyclization. The different oxidative addition mode to the same
group VIII metals would imply that the Pd0 catalyst has lower ten-
dency to form p-complex with the carbonyl group than the Ni0
catalyst. Herein, we have investigated whether a,b-unsaturated
carbonyls in 4 as an electrophile change the oxidative addition
mode to the Pd0 catalyst.9 The alkyne–enones 4 were reported to
undergo cis-selective alkylative cyclization under the Ni0
catalysis.10
The arylative cyclization of (2E)-1-phenyl-2-octen-7-yn-1-one
(4a) with a slight excess of phenylboronic acid and its anhydride
mixture in a ratio of 2 to 111 proceeds in the presence of 5 mol %
of PdCp(g3–C3H5)12 and 15 mol % of PCy3, and provides cis-addition
product 5aA in good yield (Scheme 2, Table 1, entry 1).13 In con-
trast to the cyclization of alkynal 1, methanol is not an essential
solvent for the cyclization of 4a and 1,4-dioxane turns out to be
better. The yield of 5aA is dramatically decreased as the ratio of
phenylboronic anhydride in the mixture increases (entry 1 vs
entries 2 and 3). These results indicate that Brønsted acidity of
the boronic acid is important for the cyclization. Importantly, a
Pd0 catalyst ligated with less r-donating PPh3 is less effective for
the cyclization than the one with more r-donating PCy3 (entry 2
vs entry 4).14
Arylboronic acids with electron-donating (Table 1, entries 5 and
6) or -withdrawing (entries 7 and 8) groups serve as nucleophiles
in this process, which leads to formation of cyclized products 5aB–
E in moderate to good yields. Generally, electron-rich boronic acids
give higher yields than their electron-deficient counterparts. Trial-
kylborane possessing b-hydrogens participates in this process
without undergoing competitive b-hydride elimination only when
reaction is conducted in methanol (entries 9 and 10).
Enones 4b–d containing aryl, alkyl, and methoxycarbonyl
group-substituted internal alkynes also undergo the cis-selective
cyclization with reaction in methanol (Scheme 3, Table 2, entries
1–3). Tertiary carbon, oxygen, and nitrogen-tethered alkynyl enon-
es 4e–g also cyclize and provide five-membered carbo- and hetero-
cycles 5e–gB (entries 4–6). Alkynyl enone 4h as a homologue of 4g
is successfully converted to six-membered cyclized compound 5hB
(entry 7).
Next, cyclization reactions of terminal alkynes 4i–m containing
various electron-deficient alkenes were explored (Scheme 4, Table
* Corresponding author. Tel./fax: +81 22 795 3906.
E-mail address: hirokazu@mail.pharm.tohoku.ac.jp (H. Tsukamoto).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.111

H. Tsukamoto et al. / Tetrahedron Letters 49 (2008) 4174–4177
4175
Pd0
Ni2+
X
via A
O
X
via B
O
R
R
cis addition
trans addition
by Tsukamoto
R
+
X
X
X
X
by Montgomery
OH
3
OH
O
OH
1
2a
2b
cat. Ni0
cat. Pd0
R
-ZnX
R-BX2
cis or trans
addition
cis addition
R
?
X
X
COR'
COR'
this work
Pd0
by Montgomery
5
4
Ni2+
O
Pd2+
O
or
X
X
X
COR'
R'
R'
via B
via A
via B
A: 'anti-Wacker'-type oxidative addition. B: metallacycle-forming oxidative addition.
Scheme 1. Ni0- and Pd0-catalyzed alkylative cyclization reactions of alkyne–aldehyde 1 and –enone 4.
Table 2
a
R
Effects of alkyne substituents and tethers on the arylative cyclizationa
cis addition !
COPh
COPh
Entry
4
R1
X
n
5
Yield (%)
4a
5aA-F
1
2
3
4
5
6
7
4b
4c
4d
4e
4f
Ph
Me
CO2Me
H
H
H
H
CH2
CH2
CH2
CMe2
O
1
1
1
1
1
1
2
5bB
5cB
5dB
5eB
5fB
92
73
82
84
38
69
71
Scheme 2. Pd-catalyzed arylative and alkylative cyclization of 4a. Reagents and
conditions: (a) 1.2 equiv [R-B] 6A–F, 5 mol % PdCp(g3-C3H5), 15 mol % PCy3, 1,4-
dioxane, 80 °C, 30 min.
4g
4h
NTs
NTs
5gB
5hB
Table 1
Effects of boron reagents on the arylative and alkylative cyclization of 4a
a
Reaction in MeOH (entries 1–3, 5 and 7) and 1,4-dioxane (entries 4 and 6).
Entry
[R-B] 6
5a
Yield (%)
1
2
PhB(OH)2/(PhBO)3 (2:1) 6A
PhB(OH)2/(PhBO)3 (1:1)
PhB(OH)2/(PhBO)3 (2:3)
PhB(OH)2/(PhBO)3 (1:1)
p-MeO–C6H4B(OH)2 6Bb
p-Me–C6H4B(OH)2 6Cb
p-Ac–C6H4B(OH)2 6Db
m-NO2–C6H4B(OH)2 6Eb
Et3B 6F
5aA
5aA
5aA
5aA
5aB
5aC
5aD
5aE
5aF
5aF
77
65
23
5
70
69
56
43
ndd
85
a
C6H4-p-OMe
R2
3
R2
4a
5
R3
4i-m
R3
5i-mB
6
7
8
9c
10c,e
Scheme 4. Effect of electron-deficient alkenes on the arylative cyclization. Reagents
and conditions: (a) 1.2 equiv 6B, 5 mol % PdCp(g3-C3H5), 15 mol % PCy3, 1,4-dioxane
or MeOH, 80 °C, 30 min.
Et3B 6F
a
Reaction with 5 mol % of Pd(PPh3)4 as a catalyst.
Boronic anhydride is also contained.
1.6 equiv of nucleophile is used.
Formation of 5aF was not observed by TLC.
Reaction in MeOH in place of 1,4-dioxane.
b
c
d
e
Table 3
Effect of electron-deficient alkenes on the arylative cyclizationa
Entry
4
R2
R3
5
Yield (%)
1
2
3
4
5
6
7
4i
4j
4j
4k
4k
4l
CHO
H
H
H
H
H
CO2Et
H
5iB
5jB
5jB
5kB
5kB
5lB
64
39
57
ndb
36
49
40
R1
R1
COMe
COMe
CO2Et
CO2Et
CO2Et
NO2
a
C6H4-p-OMe
COPh
X
X
COPh
( )n
( )n
4b-h
5b-hB
4m
5mB
Scheme 3. Effects of alkyne substituents and tethers on the arylative cyclization.
Reagents and conditions: (a) 1.2 equiv 6B, 5 mol % PdCp(g3-C3H5), 15 mol % PCy3,
1,4-dioxane or MeOH, 80 °C, 30 min.
a
Reaction in 1,4-dioxane (entries 1, 2, 4, 6 and 7) and MeOH (entries 3 and 5).
Hydroarylation of the alkyne instead of cyclization occurred.
b
3). More electron-deficient alkenes such as enal, alkylidene malon-
ate, and nitroalkene make the cyclization in 1,4-dioxane smoother
than less electron-deficient ones such as methyl vinyl ketone and
enoate (entries 1, 6 and 7 vs entries 2 and 4). Methanol as a solvent
increases the yield of the cyclization reaction of the substrates con-
taining the latter alkenes, again (entries 2 vs 3 and 4 vs 5).

4176
H. Tsukamoto et al. / Tetrahedron Letters 49 (2008) 4174–4177
R1
Acknowledgments
R1
R2
Ar-B(OH)2, cat. Pd(PCy3)n
1,4-dioxane or MeOH
Ar
X
This work was partly supported by a Grant-in-Aid from the
Japan Society for Promotion of Sciences (No.18790003) and Banyu
Pharmaceutical Co. Ltd Award in Synthetic Organic Chemistry,
Japan.
X
H+
COR2
O
4
5
H
palladacycle-forming
oxidative addition
reductive
elimination
References and notes
R1
R1
Ar
1. Suzuki–Miyaura cross-coupling: Miyaura, N. In Top. Curr. Chem.; Miyaura, N.,
Ed.; Springer: New York, 2002; Vol. 219, pp 11–59.
2. Diarylation of allenes and alkynes: (a) Huang, T.-H.; Chang, H.-M.; Wu, M.-Y.;
Cheng, C.-H. J. Org. Chem. 2002, 67, 99–105; (b) Zhou, C.; Emrich, D. E.; Larock,
R. C. Org. Lett. 2003, 5, 1579–1582; (c) Zhou, C.; Larock, R. C. J. Org. Chem. 2005,
70, 3765–3777.
Pd2+
O
Pd
transmetalation with Ar-B(OH)2
followed by protonation
X
X
COR2
R2
H
7
8
3. Hydroarylation of alkynes and allenes: (a) Oh, C. H.; Jung, H. H.; Kim, K. S.; Kim,
N. Angew. Chem., Int. Ed. 2003, 42, 805–808; (b) Kim, N.; Kim, K.-S.; Gupta, A. K.;
Oh, C. H. Chem. Commun. 2004, 618–619; (c) Oh, C. H.; Park, S. J.; Ryu, J. H.;
Gupta, A. K. Tetrahedron Lett. 2004, 45, 7039–7042; (d) Oh, C. H.; Ahn, T. W.;
Reddy, V. R. Chem. Commun. 2003, 2622–2623; (e) Ma, S.; Jiao, N.; Ye, L. Chem.
Eur. J. 2003, 9, 6049–6056; (f) Qian, R.; Guo, H.; Liao, Y.; Guo, Y.; Ma, S. Angew.
Chem., Int. Ed. 2005, 42, 4771–4774; (g) Ma, S.; Guo, H.; Yu, F. J. Org. Chem. 2006,
71, 6634–6636; (h) Guo, H.; Ma, S. Synthesis 2007, 2731–2745.
4. Arylation of allylic and propargylic alcohols: (a) Tsukamoto, H.; Sato, M.;
Kondo, Y. Chem. Commun. 2004, 1200–1201; (b) Kayaki, Y.; Koda, T.; Ikariya, T.
Eur. J. Org. Chem. 2004, 4989–4993; (c) Manabe, K.; Nakada, K.; Aoyama, N.;
Kobayashi, S. Adv. Synth. Catal. 2005, 347, 1499–1503; (d) Yoshida, M.; Gotou,
T.; Ihara, M. Chem. Commun. 2004, 1124–1125; (e) Yoshida, M.; Gotou, T.; Ihara,
M. Tetrahedron Lett. 2004, 45, 5573–5575.
Scheme 5. Possible mechanism of the arylative cyclization of 4.
Me
Me
COPh
a
C6H4-p-OMe
COPh
5cB-d
81% (dr=7:3)
4c
D
5. Alkylative cyclization of alkyne– and allene–aldehydes: (a) Tsukamoto, H.;
Ueno, T.; Kondo, Y. J. Am. Chem. Soc. 2006, 128, 1406–1407; (b) Tsukamoto, H.;
Ueno, T.; Kondo, Y. Org. Lett. 2007, 9, 3033–3036; (c) Tsukamoto, H.;
Matsumoto, T.; Kondo, Y. J. Am. Chem. Soc. 2008, 130, 388–389.
Scheme 6. Arylative cyclization of 4c in methanol-d4. Reagents and conditions: (a)
1.2 equiv 6B, 5 mol % PdCp(g3-C3H5), 15 mol % PCy3, CD3OD, 80 °C, 30 min.
6. Arylative cyclization of allene–aldehydes using reducing metals: (a) Ha, Y.-H.;
Kang, S.-K. Org. Lett. 2002, 4, 1143–1146; (b) Kang, S.-K.; Lee, S.-W.; Jung, J.;
Lim, Y. J. Org. Chem. 2002, 67, 4376–4379.
7. Arylative cyclization of other functionalized alkynes and allenes: (a) Zhu, G.;
Zhang, Z. Org. Lett. 2003, 5, 3645–3648; (b) Zhu, G.; Zhang, Z. Org. Lett. 2004, 6,
4041–4047; (c) Wang, F.; Tong, X.; Cheng, J.; Zhang, Z. Chem. Eur. J. 2004, 10,
5338–5344; (d) Gupta, A. K.; Rhim, C. Y.; Oh, C. H. Tetrahedron Lett. 2005, 46,
2247–2250; (e) Oh, C. H.; Park, D. I.; Jung, S. H.; Reddy, V. R.; Gupta, A. K.; Kim,
Y. M. Synlett 2005, 2092–2094.
8. (a) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065–9066; (b) Ni,
Y.; Amarasinghe, K. K. D.; Montgomery, J. Org. Lett. 2002, 4, 1743–1745; (c)
Ogoshi, S.; Arai, T.; Ohashi, M.; Kurosawa, H. Chem. Commun. 2008, 1347–1349.
9. There is one example of the Pd-catalyzed cis-selective acylative cyclization of
alkynyl enones and subsequent intramolecular aldol reaction with
acylzirconocene chloride: Hanzawa, Y.; Yabe, M.; Oka, Y.; Taguchi, T. Org.
Lett. 2002, 4, 4061.
10. (a) Montgomery, J.; Savchenko, A. V. J. Am. Chem. Soc. 1996, 118, 2099–2100;
(b) Montgomery, J.; Seo, J.; Chui, H. M. P. Tetrahedron Lett. 1996, 37, 6839–
6842; (c) Montgomery, J.; Oblinger, E.; Savchenko, A. V. J. Am. Chem. Soc. 1997,
119, 4911–4920; (d) Montgomery, J.; Chevliakov, M. V.; Brielmann, H. L.
Tetrahedron 1997, 53, 16449–16462; (e) Amarasinghe, K. K. D.; Chowdhury, S.
K.; Heeg, M. J.; Montgomery, J. Organometallics 2001, 20, 370–372; (f)
Hratchian, H. P.; Chowdhury, S. K.; Gutiérrez-García, V. M.; Amarasinghe, K.
K. D.; Heeg, M. J.; Schlegel, H. B.; Montgomery, J. Organometallics 2004, 23,
4636–4646; (g) Herath, A.; Thompson, B. B.; Montgomery, J. J. Am. Chem. Soc.
2007, 129, 8712–8713.
The plausible mechanism for the arylative cyclization is out-
lined in Scheme 5. The catalytic cycle would be initiated by oxida-
tive addition of alkynyl enones
4
to Pd0 with metallacycle
formation.15–17 Transmetalation and protonation with the boronic
acid or its reverse sequence followed by reductive elimination
reproduces the Pd0 catalyst along with cis-addition product 5.
The oxidative addition mode is quite different from that of the
Pd0-catalyzed alkylative cyclization of alkynyl aldehydes and
would result from much higher tendency for carbon–carbon dou-
ble bond to form p-complex with the Pd0 catalyst than that for car-
bon–heteroatom double bond. The oxidative addition step could be
accelerated by use of hydrogen donors such as boronic acids and
methanol solvent for the activation of the carbonyl group in 4 as
well as the Pd catalyst ligated with more r-donating PCy3. Incorpo-
ration of a deuterium atom into the a-position of phenyl ketone in
5cB with reaction in methanol-d4 was observed (Scheme 6) and
would support the formation of palladacycle 7.
In summary, we have developed the Pd0-catalyzed arylative and
alkylative cyclization reaction of alkynyl enones with organoboron
reagents. The functional group compatibility, availability, stability,
and non-toxicity of the reagents and the fact that no additives are
needed make the process more practical than the Ni0-catalyzed
cyclization with organozinc reagents. RhI catalyst is also reported
to promote the same type of cyclization via transmetalation with
arylboronic acid and sequential carborhodations of alkyne and
enones,18 but it has some limitations including unlikely alkyl group
introduction and chemo- and regioselectivity in the cyclization of
alkyne–enals and phenyl-substituted alkyne–enones such as 4i
and 4b. Although the five- and six-membered ring systems con-
taining both exo-alkylidene and (carbonyl)methyl groups can also
be produced by other Pd0-catalyzed cyclization of alkyne–allylic
alcohols19 and -allylic geminal diacetate,20 these require a base
additive leading to stoichiometric salt formation, and troublesome
substrate preparation and methanolysis of the enolacetate formed
by the cyclization, respectively. Further studies on transformation
of the functionalized cyclic compounds generated in these
reactions are underway.
11. Commercially available arylboronic acids contain its boronic anhydrides.
12. PdCp(g3-C3H5) generates phosphine-ligated Pd0 and CpC3H5 in the presence of
an excess of phosphines: Otsuka, S.; Yoshida, T.; Matsumoto, M.; Nakatsu, K. J.
Am. Chem. Soc. 1976, 98, 5850–5858.
13. General procedure: To
a test tube containing 4a (20.1 mg, 0.101 mmol),
PhB(OH)2 (15.4 mg, 0.126 mmol), PdCp(g3-C3H5) (1.1 mg, 5.2 lmol), and PCy3
(4.8 mg, 17.1 lmol) was added anhydrous 1,4-dioxane (0.5 mL) under argon.
The resulting mixture was sealed with a screw cap and agitated at 80 °C for
30 min. The mixture was cooled down to room temperature, and then PS-
DEAMTM (1.58 mmol/g, 0.15 g, 0.24 mmol) and THF (2 mL) were added to the
mixture. The mixture was agitated at room temperature for 2 h. The mixture
was filtered and thoroughly washed with CHCl3. The filtrate was concentrated
in vacuo and the residue was purified by preparative TLC eluting with toluene–
EtOAc (40:1) to yield 5aA (21.5 mg, 0.0778 mmol, 77%). Cis-selectivity was
determined by NOESY experiments and the spectral data of 5aA agreed with
those of the reported one.10a
14. However, Pd(PPh3)4 turned out to be effective for the cyclization of more
reactive alkyne–enones such as 4g.
15. At this time, it is not possible to rule out a mechanism involving formation of p-
allylpalladium via oxidative addition of enone moiety in 4 to the Pd0 catalyst
followed by insertion of the intramolecular alkyne to generate the common
intermediates 7 and 8. However, the cyclization reaction of 9, which cannot
form palladacycle owing to its short tether, did not afford alkyne insertion
products 11 or 12. It is reported that the oxidative addition of enone to the Pd0

H. Tsukamoto et al. / Tetrahedron Letters 49 (2008) 4174–4177
4177
occurs in the presence of strong Brønsted or Lewis acid: (a) Ogoshi, S.; Yoshida,
T.; Nishida, T.; Morita, M.; Kurosawa, H. J. Am. Chem. Soc. 2001, 123, 1944–
16. So far, Pd0-catalyzed reactions of alkynyl enone 4a as well as alkynyl aldehydes
in the absence of nucleophiles gave no cyclized products.
1950; (b) Ogoshi, S.; Morita, M.; Kurosawa, H. J. Am. Chem. Soc. 2003, 125,
9020–9021.
17. Ruthenium and cobalt catalysts were also reported to form metallacycle with
alkynyl enones. (a) Trost, B. M.; Brown, R. E.; Toste, F. D. J. Am. Chem. Soc. 2000,
122, 5877; (b) Chang, H.-T.; Jayanth, T. T.; Wang, C.-C.; Cheng, C.-H. J. Am. Chem.
Soc. 2007, 129, 12032–12041.
18. Shintani, R.; Tsurusaki, A.; Okamoto, K.; Hayashi, T. Angew. Chem., Int. Ed. 2005,
44, 3909–3912.
O
O
O-
Pd+
Ar
HO
Ph
a
Ph
Ph
Ph
or
19. Kressierer, C. J.; Müller, T. J. J. Angew. Chem., Int. Ed. 2004, 43, 5997–6000.
20. Holzapfel, C. W.; Marais, L. Tetrahedron Lett. 1998, 39, 2179–2182.
Ar
a 1.2 equiv 6B, 5 mol % PdCp( 3-C3H5), 15 mol % PCy3,
9
10
11
12
η
1,4-dioxane or MeOH, 80 ˚C, 30 min. Ar = C6H4-p-OMe.
.