Palladium(0)-catalyzed alkylative cyclization of alkynals and alkynones: Remarkable trans-addition of organoboronic reagents

Article abstract of DOI:10.1021/ja056458o

Palladium/monophosphine complexes catalyze trans-selective arylative, alkenylative, and alkylative cyclization reactions of alkynals and alkynones with organoboronic reagents. These reactions afford six-membered allylic alcohols with endo-tri- or tetrasub

Full text of DOI:10.1021/ja056458o

Published on Web 01/11/2006
Palladium(0)-Catalyzed Alkylative Cyclization of Alkynals and Alkynones:
Remarkable trans-Addition of Organoboronic Reagents
Hirokazu Tsukamoto,* Tatsuhiko Ueno, and Yoshinori Kondo
Graduate School of Pharmaceutical Sciences, Tohoku UniVersity, Aobayama, Aoba-ku, Sendai 980-8578, Japan
Received September 20, 2005; E-mail: hirokazu@mail.pharm.tohoku.ac.jp
Scheme 1. Transition Metal-Catalyzed Alkylative Alkynal
Cyclizations
Transition metal-catalyzed, cis-addition specific coupling reac-
tions between alkynes, carbonyls, and organometallic reagents1-4
serve as a powerful one-step method to prepare synthetically useful
allylic alcohols.5 Particularly interesting are intramolecular versions
of this process using less nucleophilic organometallics 5 containing
B, Zn, and Zr, which transforms simple precursors 1 into complex,
cyclic allylic alcohols 2 that contain exo-tetrasubstituted olefin
groups (Scheme 1).1,2,6 Despite their desirability in terms of
diversity-oriented synthesis,7 catalysts that promote the correspond-
ing trans-addition8 process leading to geometrically related cyclic
allylic alcohols 4 or cycloalkenols 3 have not been reported. Below,
we describe newly discovered palladium/monophosphine9-catalyzed
trans-selective alkylative, arylative, and alkenylative cyclization
reactions of alkynals 1 with organoboron reagents 6, in which
alkyne substituents and phosphine ligands govern the ratios of the
endo- and exo-cyclic allylic alcohol products (3 and 4).
Table 1. Pd(PPh3)4-Catalyzed Aryl-, Alkenyl-, and Alkylative
Cyclizations of 1a-h
This effort began by developing reaction conditions for the
arylative cyclization reaction of terminal alkyne-aldehyde 1a. Upon
heating at 65 °C in the presence of an excess of phenylboronic
acid (6A) and a catalytic amount of Pd(PPh3)4, 1a undergoes
phenylative cyclization to afford a single cyclized product 3aA10
along with 7, the product of hydroarylation.11 The yield of 3aA is
dramatically affected by solvent, with reaction in MeOH leading
to exclusive formation of 3aA (Table 1, entries 1-3 vs 4).
Importantly, no reaction takes place in the absence of the palladium
catalyst.
Arylboronic acids with electron-donating (entries 5-8) or
-withdrawing (entries 9-12) groups serve as nucleophiles in this
process, which leads to formation of cyclized products 3aB-I in
high yields. Generally, electron-rich boronic acids require shorter
reaction times and give higher yields than their electron-deficient
counterparts. These cyclization reactions also occur with heteroaryl-
boronic acids 6J-K (entries 13 and 14). Retention of stereochem-
istry attends reactions of 1a with alkenylboronic acids 6L-M that
afford 2,4-dien-1-ols 3aL-M (entries 15 and 16). Trialkylboranes
possessing â-hydrogens participate in this process without undergo-
ing competitive â-hydride elimination (entries 17 and 18).12
Arylative cyclization reactions of alkynones 1b-c require higher
temperatures and longer times but provide tertiary allylic alcohols
3b-cA in excellent yields (Table 1, entries 19 and 20). While
alkynals 1d-f and 1h, containing Boc-protected nitrogen, tertiary
carbon, and aryl tethers, also undergo efficient cyclization reactions
(entries 21-23, 25), the conformationally more flexible methylene-
tethered substrate 1g does not cyclize under these conditions (entry
24).
entrya
1
6
3
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19c
20c
21
22
23
24c
25
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
C6H5 6A
3aA
3aA
3aA
3aA
3aB
3aC
3aD
3aE
3aF
3aG
3aH
3aI
6
6
6
17 (8)b
23 (25)b
53 (15)b
92
85
86
79
85
88
80
73
75
89
96
90
83
100
67
85
6A
6A
6A
6
p-MeO-C6H4 6B
p-Me-C6H4 6C
o-Me-C6H4 6D
m-Me-C6H4 6E
p-Cl-C6H4 6F
p-F3C-C6H4 6G
p-OHC-C6H4 6H
p-NC-C6H4 6I
3-thiophene 6J
2-thiophene 6K
trans-propenyl 6L
cis-propenyl 6M
Et3B 6N
3.5
3.5
3.5
3.5
6
6
12
18
12
24
6
6
9
9
30
18
12
6
12
24
24
3aJ
3aK
3aL
3aM
3aN
3aO
3bA
3cA
3dA
3eA
3fA
3gA
3hC
octyl-9-BBN 6O
6A
6A
6A
6A
6A
6A
6C
97
81
68
80
0
46
1g
1h
a Reactions in CH2Cl2 (entry 1), toluene (entry 2), THF (entry 3), and
MeOH (entries 4-25). b Hydrophenylated product 7 is also obtained in the
yields shown in parentheses. c Reaction at 80 °C.
The 3:4 ratios depend on both steric and electronic requirements
of substituents R1 on the alkyne carbon. Large primary alkyl groups
lower the reaction rate and lead to preferences for formation of 3
(entries 1, 2, and 4), while electron-withdrawing aryl substituents
at this position facilitate cyclization and again favor formation of
3 (entry 3). These results contrast to those coming from the Pd-
(PPh3)4-catalyzed reactions of alkynals 1a and 1h with terminal
Arylative cyclization reactions of the internal alkyne containing
aldehydes 1i-k were also explored (Table 2, entries 1-3). Pd-
(PPh3)4 does not promote these processes. A ligand screening effort
revealed that palladium ligated with the more σ-donating tricyclo-
hexylphosphine effectively catalyzes cyclization reactions of these
substrates to yield mixtures of trans-addition products 3 and 4.10
9
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J. AM. CHEM. SOC. 2006, 128, 1406-1407
10.1021/ja056458o CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Pd2dba3/PCy3-Catalyzed Arylative Alkynal Cyclizations
This study has uncovered the first examples of trans-selective,
alkylative, arylative, and alkenylative cyclization reactions of
alkynals and alkynones. The functional group compatibility, avail-
ability, stability, and nontoxicity of the organoboronic reagents and
the fact that no additives are needed make the process highly
practical. The proposed mechanism, involving oxidative addition
without oxametallacycle formation, is different from that for the
corresponding nickel-catalyzed reaction. Finally, cyclic allylic
alcohol products generated in these reactions should be useful
intermediates in carbo- and heterocycle synthesis since they contain
a rich array of preparatively important functional groups. Studies
probing the detailed mechanism and expanding the scope of the
cyclization process are underway.
entry
1
R1
product
time (h)
yield (%)
3:4
1a
2a
3b
4a
5c
1i
1j
1k
1a
1h
Me
Bu
iA
2
8
1
0.2
0.5
90
66
97
78
41
61:39d
83:17d
93:7d
jA
kB
aA
hC
p-Me-C6H4
H
H
32:68e
4 onlye
a 6A is the nucleophile. b 6B is the nucleophile. c 6C is the nucleophile.
d The ratio is determined from isolated yields. e The ratio is determined by
1H NMR analysis.
Scheme 2. Possible Mechanism for the Arylative Alkynal
Cyclization Process
Supporting Information Available: Experimental procedures and
compound characterization data (PDF). This material is available free
of charge via the Internet at http://pubs.acs.org.
References
(1) Ni-catalyzed reaction: (a) Oblinger, E.; Montgomery, J. J. Am. Chem.
Soc. 1997, 119, 9065. (b) Ni, Y.; Amarasinghe, K. K. D.; Montgomery,
J. Org. Lett. 2002, 4, 1743. (c) Montgomery, J. Angew. Chem., Int. Ed.
2004, 43, 3890 and references therein. For the synthesis of allylamines,
see: (d) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2003, 42,
1364. (e) Patel, S. J.; Jamison, T. F. Angew. Chem., Int. Ed. 2004, 43,
3941.
(2) Rh-catalyzed reaction: (a) Shintani, R.; Okamoto, K.; Otomaru, Y.;
Ueyama, K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54. (b) Miura, T.;
Shimada, M.; Murakami, M. Synlett 2005, 667.
(3) Fe-catalyzed reaction: Hojo, M.; Murakami, Y.; Aihara, H.; Sakuragi,
R.; Baba, Y.; Hosomi, A. Angew. Chem., Int. Ed. 2001, 40, 621.
(4) Mn-catalyzed reaction: (a) Rang, J.; Okada, K.; Shinokubo, H.; Oshima,
K. Tetrahedron 1997, 53, 5061. (b) Yorimitsu, H.; Tang, J.; Okada, K.;
Shinokubo, H.; Oshima, K. Chem. Lett. 1998, 11.
(5) We recently reported the palladium(0)-catalyzed direct cross-coupling
reaction of allyl alcohols with arylboronic acids. Tsukamoto, H.; Sato,
M.; Kondo, Y. Chem. Commun. 2004, 1200.
(6) Intramolecular hydroacylation of 5-alkynals followed by reduction would
also provide 2 (R2 ) H). Takeishi, K.; Sugishima, K.; Sasaki, K.; Tanaka,
K. Chem.sEur. J. 2004, 10, 5681 and references therein.
(7) Burke, M. D.; Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46 and
reference therein.
(8) Some examples of trans-selective carbometalation of functionalized
alkynes are reported. (a) Normant, J. F.; Alexakis, A. Synthesis 1981,
841. (b) Fallis, A. G.; Forgoine, P. Tetrahedron 2001, 57, 5899 and
references therein.
(9) Palladium catalysts have not been employed previously because they are
less suitable for insertion into carbonyl groups. The limited number of
palladium-catalyzed carbonyl alkenylations are based on carbonyl inser-
tions into organopalladium(II) formed in situ. (a) Vicente, J.; Abad, J.-
A.; Gil-Rubio, J. J. Organomet. Chem. 1992, 436, C9. (b) Vicente, J.;
Abad, J.-A.; Gil-Rubio, J. Organometallics 1996, 15, 3509. (c) Vicente,
J.; Abad, J.-A.; Lopez-Pelaez, B.; Martinez-Viviente, E. Organometallics
2002, 21, 58. (d) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem.
Soc. 1999, 121, 3545. (e) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 4089. (f) Zhao, L.; Lu, X. Angew. Chem.,
Int. Ed. 2002, 41, 4343.
alkyne groups, which yield 4aA and 4hC predominantly (Table 2,
entries 4 and 5).
A plausible mechanism for the alkylative cyclization reactions
of alkynals (Scheme 2) starts with a novel intramolecular electro-
philic addition of the carbonyl group to the alkyne, promoted by
nucleophilic addition of the electron-rich palladium/phosphine
complex to the adjacent alkyne carbon (i.e., anti-Wacker-type
oxidative addition).13 The cyclic cationic alkenylpalladium(II)
intermediates 8a or 8b, generated in this manner, then undergo
solvolysis to form (methoxo)palladium(II) complexes 9a or 9b,
which upon transmetalation with organoboronic acids produce
dioorganopalladium complexes 10a or 10b.14 Reductive elimination
then gives 3 or 4 and the Pd(0) complex.
This mechanism can be used to explain the regiochemical
preferences (3:4 ratio) associated with the cyclization reactions. For
example, the σ-donating character of the ligand coordinated to Pd-
(0) should control whether oxidative addition occurs at the terminal
or internal alkyne carbon. Addition of the lower σ-donating PPh3
coordinated, less nucleophilic Pd(0) to the internal alkyne carbon
of 1 (Path A) would require activation of the alkyne by overlap of
its π-system with the carbonyl π*-orbital (transition state 11). This
corresponds to Markovnikov-type selectivity. It is expected that
electron-donating alkyl substituents at the terminal alkyne position
would hinder nucleophilic addition of this Pd(0) complex. In
contrast, the more σ-donating PCy3 ligated Pd(0) should be
sufficiently nucleophilic to undergo unassisted addition to the less
hindered alkyne carbon (Paths A and B). Here, electron-withdrawing
aryl groups at the terminal carbon or within the tether would guide
nucleophilic attack of the Pd(0) complex to the opposite alkyne
position.
(10) Structure determinations were performed by using NOESY techniques,
transformations into the known compounds, and preparations of authentic
samples; see Supporting Information.
(11) Oh, C. H.; Jung, H. H.; Kim, K. S.; Kim, N. Angew. Chem., Int. Ed.
2003, 42, 805.
(12) Alkylboronic acids are not suitable as nucleophiles.
(13) An “anti-Wacker”-type mechanism was proposed for hydroalkoxylation
of electron-deficient alkenes and alkynes. See: (a) Camacho, D. H.; Saito,
S.; Yamamoto, Y. Tetrahedron Lett. 2002, 43, 1085. (b) Matsukawa, Y.;
Mizukado, J.; Quan, H.; Tamura, M.; Sekiya, A. Angew. Chem., Int. Ed.
2005, 44, 1128.
The existence of alkenylpalladium(II) intermediates 8-10a in
this pathway is evidenced by the domino cyclization reaction of
diynal 12 (eq 1). Treatment of 12 with triethylborane in the presence
of Pd(0)/PCy3 for 16 h leads to formation of tricyclic 2,4-dien-1-
ol 14 (63%) as a single isomer in an anti-Wacker-type oxidative
addition-carbopalladation process.
(14) Miyaura, N.; Yamada, K.; Suginome H.; Suzuki, A. J. Am. Chem. Soc.
1985, 107, 972.
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