Rhodium-catalyzed domino conjugate addition-cyclization reactions for the synthesis of a variety of N- and O-heterocycles: Arylboroxines as effective carbon nucleophiles

Article abstract of DOI:10.1021/ol100610v

Facile and efficient Rh(I)-catalyzed domino conjugate addition-cyclization reactions of olefins bearing two electrophilic sites and a pendant nucleophile with organoboroxines have been developed to afford a variety of N- and O-heterocycles, such as 3,4-dihydroquinolin-2(1H)-ones, 3,4-dihydrocoumarins, and pyrrolidin-2-ones, which constitute important motifs in biologically active natural and synthetic organic compounds.

Full text of DOI:10.1021/ol100610v

ORGANIC
LETTERS
2010
Vol. 12, No. 10
2258-2261
Rhodium-Catalyzed Domino Conjugate
Addition-Cyclization Reactions for the
Synthesis of a Variety of N- and
O-Heterocycles: Arylboroxines as
Effective Carbon Nucleophiles†
Ja Ock Park‡ and So Won Youn*,§
Department of Chemistry, Hanyang UniVersity, Seoul 133-791, Korea, and Department
of Chemistry, Pukyong National UniVersity, Busan 608-737, Korea
sowony73@hanyang.ac.kr
Received March 15, 2010
ABSTRACT
Facile and efficient Rh(I)-catalyzed domino conjugate addition-cyclization reactions of olefins bearing two electrophilic sites and a pendant
nucleophile with organoboroxines have been developed to afford a variety of N- and O-heterocycles, such as 3,4-dihydroquinolin-2(1H)-ones,
3,4-dihydrocoumarins, and pyrrolidin-2-ones, which constitute important motifs in biologically active natural and synthetic organic compounds.
The conjugate addition of organometallic reagents to electron-
deficient olefins is one of the most useful processes for
carbon-carbon bond formation. Among many different
procedures, the Rh(I)-catalyzed conjugate addition of orga-
noboron reagents to R,ꢀ-unsaturated carbonyl compounds,
known as the Hayashi-Miyaura reaction,1 has attracted
considerable attention as an important synthetic method for
a variety of organic transformations.2 This type of reaction
is usually carried out in aqueous solvents and tolerates
various functional groups. In recent years, there has been
considerable research interest in Rh(I)-catalyzed tandem
annulations in which the tandem cyclization was triggered
by conjugate addition of organoborons to activated alkenes
for the construction of carbocycles and heterocycles.3
Recently, we reported the Rh(I)-catalyzed tandem conju-
gate addition-Mannich cyclization reaction of imine-
substituted electron-deficient alkenes with arylboronic acids
to afford 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines.4
Our continued interest in Rh(I)-catalyzed tandem reactions
prompted us to investigate the possibility of a domino
conjugate addition-cyclization reaction of R,ꢀ-unsaturated
esters bearing a nucleophile in the molecule. Since the
Hayashi-Miyaura reaction is compatible with the presence
of unprotected hydroxyl and amino groups,2 we envisaged
the Rh(I)-catalyzed domino conjugate addition-cyclization
reaction of R,ꢀ-unsaturated esters bearing unprotected amino
and hydroxyl moieties placed at an appropriate position for
subsequent nucleophilic cyclization to afford N- and O-
heterocycles, respectively (Scheme 1). In parallel with our
efforts to develop efficient synthetic methods for heterocyclic
† Dedicated to the late Professor Chi Sun Hahn in admiration of his
contributions to organic chemistry of Korea.
‡ Pukyong National University.
§ Hanyang University.
(1) Hayashi, H.; Miyaura, N. Organometallics 1997, 16, 4229.
(2) For reviews, see: (a) Hayashi, T. Synlett 2001, 879. (b) Fagnou, K.;
Lautens, M. Chem. ReV. 2003, 103, 169. (c) Hayashi, T.; Yamasaki, K.
Chem. ReV. 2003, 103, 2829. (d) Hayashi, T. Pure Appl. Chem. 2004, 76,
465. (e) Hayashi, T. Bull. Chem. Soc. Jpn. 2004, 77, 13. (f) Yoshida, K.;
Hayashi, T. In Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A.,
Ed.; Wiley-VCH: Weinheim, 2005; Chapter 3, p 55.
(3) For reviews, see: (a) Youn, S. W. Eur. J. Org. Chem. 2009, 2597.
(b) Miura, T.; Murakami, M. Chem. Commun. 2007, 217. (c) Guo, H.-C.;
Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354.
10.1021/ol100610v  2010 American Chemical Society
Published on Web 04/29/2010

Scheme 1
.
Domino Conjugate Addition-Cyclization Reaction
Table 1. Optimization Studies for the Domino Conjugate
Addition-Cyclization Reaction of 1a
for the Synthesis of Heterocyclic Skeletons
entry
conditions
2a (%)a 2a′ (%)a
1
2
PhB(OH)2 with baseb in dioxane
0-5
0
PhB(OH)2 with baseb in dioxane/H2O 0-10
0-40
(10:1)
synthesis,4,5 we were interested in developing a one-pot
synthesis of various heterocycles, involving sequential C-C
and C-heteroatom bond formations in an efficient manner.
Herein we disclose the realization of this propasal, together
with an in depth investigation of reaction parameters and
optimization of reaction conditions,6,7 which ultimately led
to the construction of a diverse range of 3,4-dihydroquinolin-
2(1H)-ones,8 3,4-dihydrocoumarins,9 and pyrrolidin-2-ones.10
In view of the prevalence of these structural motifs in a
number of natural and designed bioactive compounds or
precursors thereof, such a synthetic methodology is particu-
larly valuable. It also has been found that arylboroxines act
as effective nucleophiles in this reaction system.
3
4
5
6
7
8
9
PhB(OH)2 with baseb in THF
0-10
0-20
35
0-50
0-70
0
PhB(OH)2 in solventc
PhB(OH)2 in THF
PhB(OH)2 with ligandd in THF
(PhBO)3 in THF
0
0
40
0
NaBPh4 or PhBF3K in THF
(PhBO)3 with baseb (except NEt3) or
ligandd in THF
0-10
5-70
0-10
0-50
10 (PhBO)3 with NEt3 in THF
11 (PhBO)3 with NEt3 in solventc
12 (PhBO)3 with NEt3 and ligandd in
THF
90 (95)e trace
0-80
50-80
0-70
0-10
13 (PhBO)3 with other metal catalystf
and NEt3 in THF
0
0
a Yields were determined by 1H NMR using trichloroethylene as an
internal standard. b Base: Na2CO3, K2CO3, Cs2CO3, K3PO4, KOH, NaOH,
NEt3. c Solvent: THF/H2O (10:1), dioxane/H2O (10:1), dioxane, MeOH,
toluene, MeCN, DMF. d Ligand: PPh3, P(o-Tol)3, P(C6F5)3, dppp, BIPHEP,
BINAP. e Performed at 100 °C for 1 h. f For other Rh, Pd, Ir, Cu catalysts,
see Supporting Information.
In light of our recent success in Rh(I)-catalyzed tandem
conjugate addition-Mannich cyclization reactions,4 we
began our studies on the proposed domino conjugate
addition-cyclization reaction using o-benzylamino methyl
cinnamate (1a)11 as the test substrate. The results of our
reaction optimizations are summarized in Table 1. In the
presence of base (Table 1, entries 1-3), [Rh(OH)(cod)]2-
catalyzed reaction of 1a with PhB(OH)2 in dioxane, dioxane/
H2O (10/1) or THF afforded predominantly the 1,4-addition
product (2a′, 0-50%) with only trace amounts of desired
product (2a, 0-10%). In the absence of base, reactions
proceeded with an appreciable increase in the formation of
2a (Table 1, entry 4), in particular, with THF as solvent
giving 2a as the sole product (35% yield, Table 1, entry 5).
The use of phosphine ligands (Table 1, entry 6) proved
counterproductive for the reaction, where only the recovery
of starting material (1a) was observed. The source of
organoboron reagent was also investigated (Table 1, entries
7 and 8), where the use of (PhBO)3 gave a yield comparable
to that of PhB(OH)2 (Table 1, entry 7 vs entry 5).12 The
combination of base or phosphine additives with (PhBO)3
led to a notable increase in the formation of 2a, but still
accompanied with significant amounts of 1,4-addition product
(4) Youn, S. W.; Song, J.-H.; Jung, D.-I. J. Org. Chem. 2008, 73, 5658
.
(5) (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055.
(b) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, 59, 8859. (c)
Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6, 581. (d) Youn,
S. W.; Eom, J. I. Org. Lett. 2005, 7, 3355. (e) Youn, S. W. J. Org. Chem.
2006, 71, 2521. (f) Youn, S. W. Org. Prep. Proced. Int. 2006, 38, 505. (g)
Youn, S. W.; Eom, J. I. J. Org. Chem. 2006, 71, 6705. (h) Youn, S. W.
Synlett 2007, 3050. (i) Youn, S. W.; Bihn, J. H. Tetrahedron Lett. 2009,
50, 4598. (j) Ock, S. K.; Youn, S. W. Bull. Korean Chem. Soc. 2010, 31,
704
.
(6) For related examples of Rh(I)-catalyzed conjugate addition of
organoboronic acids to R,ꢀ-unsaturated carbonyl compounds, however,
requiring a discrete extra step such as deprotection, hydrogenation, oxidation,
etc. for the following cyclization reaction to afford heterocyclic compounds,
see the following. Deprotection: (a) Becht, J.-M.; Meyer, O.; Helmchen,
G. Synthesis 2003, 2805. (b) Zoute, L.; Kociok-Ko¨hn, G.; Frost, C. G. Org.
Lett. 2009, 11, 2491. Hydrogenation: (c) Paquin, J.-F.; Stephenson, C. R. J.;
Defieber, C.; Carreira, E. M. Org. Lett. 2005, 7, 3821. For related Pd-
catalyzed reactions followed by oxidation, see: (d) Kobayashi, K.; Nishikata,
T.; Yamamoto, Y.; Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1019. (e)
Nishikata, T.; Yamamoto, Y.; Miyaura, N. AdV. Synth. Catal. 2007, 349,
1759. For examples of similar reactions for the synthesis of γ-lactones,
see: (f) Segura, A.; Csa´ky¨, A. G. Org. Lett. 2007, 9, 3667. (g) Cacchi, S.;
(11) Various protecting groups such as Bn, Ts, Ac, and Boc for amine
moieties and free amines have been examined, and benzyl appeared
preferable as an effective protecting group among them for this reaction.
For further details, see Supporting Information.
Fabrizi, G.; Goggiamani, A.; Sferrazza, A. Synlett 2009, 1277
(7) For Rh(I)-catalyzed conjugate addition of arylboronic acids to coumarins,
see: Chen, G.; Tokunaga, N.; Hayashi, T. Org. Lett. 2005, 7, 2285
.
(12) Selected examples of successful Rh(I)-catalyzed reactions involving
other organoborons in place of organoboronic acids. Arylboroxines: (a)
Miura, T.; Takahashi, Y.; Murakami, M. Chem. Commun. 2007, 595. (b)
Chen, F.-X.; Kina, A.; Hayashi, T. Org. Lett. 2006, 8, 341. (c) Goossen,
L. J.; Paetzold, J. AdV. Synth. Catal. 2004, 346, 1665. (d) Hayashi, T.; Senda,
T.; Takaya, Y.; Ogasawara, M. J. Am. Chem. Soc. 1999, 121, 11591.
NaBPh4: (e) Shintani, R.; Tsutsumi, Y.; Nagaosa, M.; Nishimura, T.;
Hayashi, T. J. Am. Chem. Soc. 2009, 131, 13588. Examples of successful
use of arylboroxines in other transition metal-catalyzed reactions. Pd
catalysis: (f) Perkins, J. R.; Carter, R. G. J. Am. Chem. Soc. 2008, 130,
3290. Ni catalysis: (g) Antoft-Finch, A.; Blackburn, T.; Snieckus, V. J. Am.
Chem. Soc. 2009, 131, 17750.
.
(8) (a) Jones, G. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon: Oxford, U.K., 1996; p
167. (b) Zhou, W.; Zhang, L.; Jiao, N. Tetrahedron 2009, 65, 1982, and
references therein.
(9) (a) Donnelly, D. M. X.; Boland, G. M. In The FlaVonoids. AdVances
in Research Since 1986; Harborne, J. B., Ed.; Chapman and Hall: London,
1993; p 239. (b) Semeniuchenko, V.; Groth, U.; Khilya, V. Synthesis 2009,
3533, and references therein.
(10) For a review, see: Shorvon, S. Lancet 2001, 358, 1885.
Org. Lett., Vol. 12, No. 10, 2010
2259

Table 2. Rh(I)-Catalyzed Domino Conjugate Addition-Cyclization Reaction for the Synthesis of 3,4-Dihydroquinolin-2(1H)-ones
entry
substrate
Ar
catalyst (mol %)
time (h)
product
yield (%)a
1
2
3
4
5
6
7
8
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) R2 ) R3 ) H (1a)
R1 ) Me, R2 ) R3 ) H (1b)
R1 ) R3 ) Me, R2 ) H (1c)
R2 ) MeO, R1 ) R3 ) H (1d)
R1 ) CF3, R2 ) R3 ) H (1e)
R2 ) NO2, R1 ) R3 ) H (1f)
Ph
2.5
2.5
2
2
2
2
5
5
5
5
7
5
3
3
3
2.5
2.5
1
1
1
1
7
1
1
1
3
3
5
24
1
20
3
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
88
84
81
80
49
83
80
88
77
54
53
37
82
67
73
61
76
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
4-HOC6H4
2-naphthyl
3-O2NC6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
4-CH3COC6H4
ꢀ-styryl
Ph
9
10
11
12
13
14
15
16
17
Ph
Ph
Ph
Ph
7
7
a Isolated yields.
2a′ (Table 1, entry 9). Ultimately, we were delighted to find
that the use of NEt3 as a base in THF gave full conversion
of 1a, furnishing 2a in 90% yield with only trace amounts
of 1,4-addition product 2a′ (Table 1, entry 10). Performing
the reaction at elevated temperature (100 °C) further
improved the reaction yield to 95% (Table 1, entry 10).
Having identified NEt3 as the crucial ingredient, the beneficial
effect by varying the solvent or the use of phosphine ligand
as additive was reinvestigated but proved insignificant (Table
1, entries 11 and 12). Finally, [Rh(OH)(cod)]2 proved unique
for the success of this reaction, where a variety of other Rh-,
Pd-, Ir-, and Cu-based catalysts were found to be totally
ineffective (Table 1, entry 13). It is noteworthy that, in
contrast to the conventional reaction conditions employed
in the Rh(I)-catalyzed conjugate additions and related domino
processes (e.g., entries 1-3, Table 1), the reagent system
and reaction conditions developed herein proved uniquely
successful for substrate 1a leading to domino product 2a.
Having established the optimal reaction conditions, we set
out to explore the scope of this domino process. As shown
in Table 2, reaction of o-benzylamino methyl cinnamate
(represented by generic structure 1) with arylboroxines
[(ArBO)3] gave 3,4-dihydroquinolin-2(1H)-one 2 in moderate
to good yields. Arylboroxines bearing electron-donating
(Table 2, entries 2-5) or electron-withdrawing (Table 2,
entries 7-11) groups were well tolerated, and the reaction
conditions were compatible with a variety of functional
groups. In some cases, more catalysts were required to drive
the reactions to completion in acceptable time periods, giving
products in good yields. Generally, electron-rich arylborox-
ines required lower catalyst loadings than their electron-
deficient counterparts (Table 2, entries 2-5 vs 7-11).
2-Naphthylboroxine also reacted with 1a to give the corre-
sponding dihydroquinolinone 2f (Table 2, entry 6). Alkenyl-
boroxine (Table 2, entry 12) and hydroxyl- or acetyl-
substituted phenylboroxine (Table 2, entries 5 and 11)
afforded the corresponding products in moderate yields. In
stark contrast, this domino cyclization reaction failed with
sterically hindered aryl- (2-MeOC6H4), heteroaryl- (2-thienyl,
2-furanyl), and formyl-substituted aryl- (3-CHOC6H4) borox-
ines to give the desired products in significantly lower yields
(0-30%). On the other hand, the size of the ester group also
appeared to influence the reactivity. Reactions of substrates
with large ester groups such as cyclohexyl or tert-butyl gave
13
1
low (30% by H NMR) or no conversions, respectively.
Subsequently, we explored the effects of substituents at the
aryl moiety of 1. The yields remained equally good with
both electron-donating and electron-withdrawing substituents
on the phenyl ring (Table 2, entries 13-17).
We proceeded to extend the application of this reaction
system to the formation of pyrrolidin-2-ones 4 from (E)-
ethyl 4-benzylamino-2-butenoate 3 (Scheme 2). Linear
aliphatic R,ꢀ-unsaturated esters bearing an amino group also
proved to be good substrates, giving the corresponding five-
membered N-heterocyles, pyrrolidin-2-ones in good yields,
irrespective of the arylboroxines used.
Encouraged by the successful synthesis of N-heterocycles,
we then turned our attention to the synthesis of O-hetero-
cycles. R,ꢀ-Unsaturated carbonyl compounds with an OH
(13) (a) Takaya, Y.; Senda, T.; Kurushima, H.; Ogasawara, M.; Hayashi,
T. Tetrahedron: Asymmetry 1999, 10, 4047. (b) Sukuma, S.; Sakai, M.;
Itooka, R.; Miyaura, N. J. Org. Chem. 2000, 65, 5951.
2260
Org. Lett., Vol. 12, No. 10, 2010

Scheme 2
.
Rh(I)-Catalyzed Domino Conjugate
Scheme 4. Proposed Mechanism for the Rh(I)-Catalyzed
Addition-Cyclization Reaction for the Synthesis of
Domino Conjugate Addition-Cyclization Reaction
Pyrrolidin-2-ones
group are interesting bifunctional substrates with regard to
the possibility of this domino process to afford O-heterocy-
cles such as 3,4-dihydrocoumarins. To our delight, reaction
of 5 with various arylboroxines proceeded smoothly as well
to form the corresponding 3,4-dihydrocoumarins in good
yields (Scheme 3). Compared to the amino-substituted
Subsequently, either direct cyclization of C or cyclization
of X-boryl species (D) via transmetalation of C with
arylboroxine produces the cyclized product along with A to
promote the next catalytic cycle. The reluctance of uncyclized
1,4-addition product 2a′ to undergo cyclization under the
same or similar related reaction conditions is suggesting an
activated species C or D (see Supporting Information).
Furthermore, conducting the reaction in protic solvents also
led to predominant formation of 1,4-addition product 2a′ (see
Supporting Information), suggesting the competing proton-
ation of activated species C or D in favor of the desired
cyclization.
Scheme 3. Rh(I)-Catalyzed Domino Conjugate
Addition-Cyclization Reaction for the Synthesis of
3,4-Dihydrocoumarins
In summary, we have developed a Rh(I)-catalyzed domino
conjugate addition-cyclization reaction to construct a wide
range of N- and O-heterocycles, including but not limited to
3,4-dihydroquinolin-2(1H)-ones, 3,4-dihydrocoumarins, and
pyrrolidin-2-ones. Furthermore, a variety of functional groups
could be tolerated under the reaction conditions, and
circumvent the use of protecting groups in contrast to related
processes. This method should find wide scope applications
in chemical and biological investigations, and the studies in
these areas are currently underway in our laboratory.
substrates, hydroxyl-containing substrates required rather
longer reaction times to complete the second cyclization step
of the conjugate addition intermediate, which could be
observed on TLC during the reaction progress and isolated
if the reaction was stopped midway, probably due to the
lower nucleophilicity of the OH group.
A plausible mechanism for the Rh-catalyzed domino
conjugate addition-cyclization presented herein is outlined
in Scheme 4.2,3,14 Initially, an organorhodium(I) species (A)
is generated by transmetalation of hydroxorhodium(I) with
arylboroxine. Then, conjugate addition of the arylrhodium(I)
species (A) to R,ꢀ-unsaturated ester occurs to afford the (oxa-
π-allyl)rhodium(I) intermediate (B),15 which undergoes in-
tramolecular proton exchange between RhI-enolate and the
XH (X ) N, O) group, forming X-rhodium(I) species (C).
Acknowledgment. This work was supported by National
Research Foundation of Korea Grant funded by the Korean
Government (Nos. R01-2008-000-20332-0 and 2009-0063856).
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL100610V
(15) It cannot be excluded that conjugate addition of A to R,ꢀ-
unsaturated ester may take place by chelation of A with XH group or X-
under the basic conditions. For an example of a Rh(I)-catalyzed conjugate
addition under chelation or nonchelation conditions by OH group, see: de
la Herra´n, G.; Mba, M.; Murcia, M. C.; Plumet, J.; Csa´ky¨, A. G. Org. Lett.
2005, 7, 1669.
(14) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052
.
Org. Lett., Vol. 12, No. 10, 2010
2261