Catalytic four-component assembly based on allenylboronate platform: New access to privileged allylic amine structures

Article abstract of DOI:10.1021/ja057778a

We developed a novel palladium-catalyzed four-component assembly based on allenylboronate platform, by which privileged allylic amine structures can be constructed in a regioselective, stereoselective, and diversity-oriented manner. The boryl group acts not only as a useful group that can be transformed to various functional groups afterward but also as a stereochemical controller in the generation of key (π-allyl)palladium intermediates. A short synthesis of rolipram (selective phosphodiesterase-4 inhibitor) is also demonstrated. Copyright

Full text of DOI:10.1021/ja057778a

Published on Web 01/12/2006
Catalytic Four-Component Assembly Based on Allenylboronate Platform:
New Access to Privileged Allylic Amine Structures
Keisuke Tonogaki,† Kenichiro Itami,*,‡,§ and Jun-ichi Yoshida*,†
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto 615-8510, Japan, and Research Center for Materials Science, Nagoya UniVersity, Nagoya 464-8602, Japan
Received November 16, 2005; E-mail: itami@chem.nagoya-u.ac.jp; yoshida@sbchem.kyoto-u.ac.jp
The multicomponent assembly reaction has emerged as a
powerful means for rapid generation of molecular complexity and
diversity, thereby being particularly well-adapted for combinatorial
chemistry and diversity-oriented synthesis.1 In particular, multi-
component assembly based on a simple molecule bearing multiple
reaction sites (platform) serves as a powerful synthetic strategy.2
In such synthesis, it is extremely important to consider what kind
of platform, assembling components, and reactions to use and what
kind of privileged target structures to aim for.
coordinates to an arylpalladium complex, formed by 3c and Pd(0),
at the face opposite to the pinacolatoboryl group to avoid steric
congestion. The subsequent arylpalladation across CdC bond leads
to a π-allyl complex 7 with the boryl group anti to the aryl group.
The stoichiometric reaction also furnished 7 in high yield. Then,
amine 2a attacks 7, presumably at unsubstituted terminal carbon
of allyl ligand, to give 4ac with the regeneration of the Pd(0)
catalyst. The anti stereochemistry of π-allyl intermediate 7 accounts
for the Z stereochemistry of 4ac. The stoichiometric reaction also
furnished 4ac quantitatively with virtually complete regio- and
stereoselectivity as in the catalytic reaction.
On the basis of such consideration, we recently developed
vinylboronate ester as a useful platform for triarylethene-based
functional π-systems.3 The synthesis began with Pd-catalyzed
double C-H arylation (Mizoroki-Heck coupling) of vinylboronate,
followed by Suzuki-Miyaura coupling at the remaining C-B bond.
Such orthogonal and sequential assembly using an organoboron
platform (reaction at the organic part followed by C-B function-
alization) has attracted much interest in the context of diversity-
oriented synthesis.4 Herein we describe a novel catalytic four-
component assembly based on the allenylboronate platform, by
which privileged allylic amine structures5 can be constructed in a
regioselective, stereoselective, and diversity-oriented manner.
Allenylboronate pinacol ester (1: 1.2 equiv) was treated with
benzylamine (2a: 1.2 equiv) and 4-iodotoluene (3c: 1.0 equiv) in
the presence of Pd2(dba)3 (2.5 mol %), P(2-furyl)3 (10 mol %),
and i-Pr2NEt (3.0 equiv) in toluene at 80 °C for 24 h. A three-
component assembling reaction took place to afford alkenylboronate
4ac quantitatively with virtually complete regio- and stereoselec-
tivity (eq 1).6,7 As for supporting ligands on Pd, π-acidic ligands
such as P(2-furyl)3, P(OPh)3, and P(C6H4CF3-4)3 were found to be
superior (see Supporting Information). It should be mentioned that
neither the possible Suzuki-Miyaura coupling product 5 nor the
Buchwald-Hartwig-type amination product 6 was formed in this
reaction.
The virtually complete stereoselectivity observed is notable. Tsuji
reported in his pioneering work that the Pd-catalyzed three-
component assembly of substituted allenes, organic halides, and
secondary amines proceeds with low stereoselectivity (1/3 ∼ 1/9).6a
Elsevier also reported that the stereoselectivity is highly dependent
on substrates employed.6b To assess the effect of the boryl group
in this reaction, phenylallene, cyclohexylallene, and triisopropyl-
silylallene were subjected to the conditions shown in eq 1.
Surprisingly none of these substrates are comparable to 1 in terms
of productivity and selectivity (see Supporting Information).
Although the origin of high reactivity and selectivity is still under
investigation, the boryl group clearly acts not only as a useful group
that can be transformed into various functional groups afterward
(vide infra) but also as a stereochemical controller in this three-
component assembly.
With this extremely selective tandem three-component assembly
reaction in hand, we subsequently examined catalytic four-
component assembly through post C-B arylation (Suzuki-Miyaura
coupling)8 of alkenylboronates 4 formed in situ (Table 1). Thus,
by simply adding second aryl iodides 8 (1.5 equiv), Cs2CO3 (5
equiv), and H2O (4 equiv) into the reaction mixture of the three-
component assembling reaction (1 + 2 + 3), multisubstituted allylic
amines 9 were obtained in good to excellent yields with virtually
complete isomeric purity. The reaction proceeded efficiently with
electronically and structurally diverse aryl and heteroaryl iodides.
Various functional groups on the aromatic ring of 3 and 8 remained
unchanged in this reaction. As for amines in this coupling,
secondary amines generally gave good results. Although primary
amines such as 2a can afford the three-component product 4 very
The selective production of 4ac can be explained by assuming
the following mechanism (eq 2).6 The terminal CdC bond of 1
† Kyoto University.
‡ Nagoya University.
§ PRESTO, Japan Science and Technology Agency (JST).
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10.1021/ja057778a CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Synthesis of Multisubstituted Allylic Amines 9 through
Scheme 2. Synthesis of Roliprama
Catalytic Four-Component Assemblya
run
2b
Ar1
Ar2
9 (yield, %)c
1
2b
2b
2b
2b
2b
2c
2c
2c
2d
2d
2d
2d
C6H5 (a)
4-MeC6H4 (c)
3-thienyl (e)
4-CF3C6H4 (f)
1-naphthyl (g)
4-MeC6H4 (c)
4-MeOC6H4 (d)
4-EtOCOC6H4 (i)
4-MeC6H4 (c)
C6H5 (a)
4-MeCOC6H4 (b)
4-MeOC6H4 (d)
4-MeC6H4 (c)
C6H5 (a)
3-MeOC6H4 (h)
C6H5 (a)
3-thienyl (e)
2-MeC6H4 (j)
4-MeOC6H4 (d)
3-pyridyl (k)
4-EtOCOC6H4 (i)
4-ClC6H4 (m)
9bab (73)
9bcd (74)
9bec (90)
9bfa (80)
9bgh (59)
9cca (66)
9cde (69)
9cij (66)
9dcd (52)
9dak (67)
9dei (82)
9dlm (74)
2
3
4
5
6
a Conditions: (a) Pd2(dba)3, P(2-furyl)3, i-Pr2NEt, toluene, 80 °C; (b)
Pd(OAc)2, PPh3, p-benzoquinone, CO (1 atm), MeOH, 50 °C; (c) Pd/C, H2
(60 atm), EtOH, 60 °C; (d) Li, liq. NH3, -40 °C.
7
8
9
10
11
12
3-thienyl (e)
4-NCC6H4 (l)
allylic amines are ubiquitous structural constituents in pharmaco-
logically important molecules with many interesting actions,5 the
present diversity-oriented synthesis should find many uses in the
development of new biofunctional small molecules. Investigations
along this line as well as the elucidation of reaction mechanism
are currently ongoing.
a Reaction conditions: (i) 1 (0.36 mmol), 2 (0.36 mmol), Ar1-I (3: 0.30
mmol), Pd2(dba)3 (0.0075 mmol), P(2-furyl)3 (0.03 mmol), i-Pr2NEt (0.90
mmol), toluene (1.5 mL), 80 °C; (ii) Ar2-X (8: 0.45 mmol), Cs2CO3 (1.5
mmol), H2O (1.2 mmol), toluene (0.5 mL), 90 °C (one-pot). b Morpholine
(2b), pyrrolidine (2c), N-benzylmethylamine (2d). c Isolated yields.
Scheme 1. Synthesis of Various Allylic Amines through C-B
Functionalization of 4a
Acknowledgment. This work was financially supported in part
by a Grant-in-Aid for Scientific Research from the Japan Society
for the Promotion of Science (JSPS). K.T. is a recipient of the JSPS
Predoctoral Fellowships for Young Scientists.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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a Conditions: (a) see eq 1 (Ar ) p-tolyl); (b) Pd(OAc)2, PPh3, Cs2CO3,
H2O, toluene, 90 °C, under air; (c) ethyl cis-3-iodoacrylate, Cs2CO3, H2O,
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efficiently as shown in eq 1, the remaining N-H functionality seems
to interfere with the last C-B arylation step.
In addition to the rapid synthesis of 2,3-diarylated allylic amines
9 through post C-B arylation, other transformations of boryl groups
of three-component products 4 are feasible. As demonstrated in
Scheme 1, Pd-catalyzed homocoupling,9 Suzuki-Miyaura coupling
using alkenyl halide,8 esterification,10 and carbonylative cyclization10
are possible to afford various potentially useful allylic amines 10-
13 in good yields.
Finally, we applied our four-component assembly strategy to a
short synthesis of rolipram, which is a selective inhibitor of
phosphodiesterase-4 (PDE-4), an antiinflammatory agent and
antidepressant (Scheme 2).11 Thus, catalytic three-component
assembly of 1, benzylamine (2a), and aryl iodide 3n, followed by
carbonylative cyclization afforded unsaturated lactam 14 in 59%
yield (two steps). Hydrogenation of CdC bond and deprotection
of N-benzyl group with Li/NH3 gave rolipram in 81% yield.
In summary, we have developed a novel catalytic four-component
assembly based on an allenylboronate platform, by which a range
of functionalized allylic amine structures can be constructed in a
regioselective, stereoselective, and diversity-oriented manner. Since
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127, 9625 and references therein.
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A. G.; Santana, C. C.; Correia, C. R. D. J. Org. Chem. 2005, 70, 1050
and references therein.
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