Highly active rhodium catalyst with electron-poor diphosphine enables efficient synthesis of chiral 4-aryl-δ-lactones

Article abstract of DOI:10.3987/COM-09-S(S)40

Chiral 4-aryl-δ-lactones could be synthesized efficiently with high enantioselectivity through asymmetric 1,4-addition of arylboronic acid to α,β-unsaturated lactones using Rh catalyst including electron-poor diphosphine (MeO-F₁₂-BIPHEP) at room temperature for 1 h. In particular, our catalytic system proved to be applicable to relatively large coumarin analogues, giving optically pure 4-phenylchroman-2-one analogues in a short time.

Full text of DOI:10.3987/COM-09-S(S)40

HETEROCYCLES, Vol. 80, No. 1, 2010
157
HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 157 - 162. © The Japan Institute of Heterocyclic Chemistry
Received, 25th June, 2009, Accepted, 18th August, 2009, Published online, 18th August, 2009
DOI: 10.3987/COM-09-S(S)40
HIGHLY ACTIVE RHODIUM CATALYST WITH ELECTRON-POOR
DIPHOSPHINE ENABLES EFFICIENT SYNTHESIS OF CHIRAL
4-ARYL--LACTONES†
Toshinobu Korenaga,* Ryota Maenishi, Kazutaka Osaki, and Takashi
Sakai*
Division of Chemistry and Biochemistry, Graduate School of Natural Science
and Technology, Okayama University, 3-1-1 Tsushima-naka, Okayama 700-8530,
Japan
E-mail: korenaga@cc.okayama-u.ac.jp
Abstract – Chiral 4-aryl--lactones could be synthesized efficiently with high
enantioselectivity through asymmetric 1,4-addition of arylboronic acid to
α,β-unsaturated lactones using Rh catalyst including electron-poor diphosphine
(MeO-F12-BIPHEP) at room temperature for 1 h. In particular, our catalytic
system proved to be applicable to relatively large coumarin analogues, giving
optically pure 4-phenylchroman-2-one analogues in a short time.
Since Akira Suzuki and Norio Miyaura reported on the Suzuki-Miyaura coupling reaction in 1979,1
researchers have utilized arylboronic acids for metal catalyzed cross-coupling reactions.2 Furthermore,
the utility of arylboronic acids has been further enhanced by the development of the rhodium catalyzed
asymmetric 1,4-addition of arylboronic acid to an α,β-unsaturated ketone.3 Using these reactions, chiral
4-substituted--lactones such as 4-phenyltetrahydro-2H-pyran-2-one (2) can also be synthesized from the
α,β-unsaturated lactone, 5,6-dihydro-2H-pyran-2-one (1). The reactivity of 1 was equal to or less than
that of 2-cyclohexenone (Scheme 1).4 The reaction usually requires 3 – 5 mol% Rh catalyst and a
relatively higher reaction temperature (30 – 100 °C). In addition, the reaction at room temperature or
with less catalyst loading required a longer reaction time. In contrast, highly active rhodium catalysts for
the reaction of 1 even at room temperature were developed in 2008.5 Here, 1 or 2 mol% Rh catalysts with
chiral diene ligand obtained (R)-2a in a high yield with high enantioselectivity at room temperature for 3
or 1 h, respectively. Recently, we have developed a new type of electron-poor MeO-F12-BIPHEP ligand,
which highly accelerates the rhodium-catalyzed 1,4-addition (Scheme 1).6 The catalytic system enabled
†
This paper is dedicated to Professor Emeritus Akira Suzuki on the occasion of his 80th birthday.

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HETEROCYCLES, Vol. 80, No. 1, 2010
highly efficient reaction of 1 even at room temperature. Thus, the reaction of 1 with 4-CF3-C6H4-B(OH)2
at 20 °C for 1 h gave 90% optically pure (R)-4-(4-trifluorophenyl)-tetrahydro- 2H-pyran-2-one (2b),
using only 0.5 mol% Rh catalyst. This paper reports that our previously developed catalytic system with
electron-poor diphosphine ligand is successfully applied to the asymmetric 1,4-addition of arylboronic
acid to yield α,β-unsaturated lactone under mild conditions, yielding highly optically active
4-aryl--lactones.
F
0.25 mol% [RhCl(C2H4)2]2
O
O
MeO
MeO
PAr2
PAr2
0.5 mol% (R)-MeO-F12-BIPHEP
Ar =
F
+
Ar-B(OH)2
X
X
20% KOH
Toluene / H2O
*
F
Ar
20C, 0.5 - 1 h
(R)-MeO-F12-BIPHEP
X = CH2: 2-cyclohexenone
X = CH2: (R)-3-aryl-cyclohexanone
X = O: 5,6-dihydro-2H-pyran-2-one (1)
(,-unsaturated lactone)
X = O: (R)-4-aryl-tetrahydro-2H-pyran-2-one (2)
((R)-4-aryl--lactones)
Scheme 1. Rh catalyzed asymmetric 1,4-addition of Ar-B(OH)2 to α,β-unsaturated carbonyl compounds.
First, the reactions of 1 with arylboronic acids were performed using 0.5 mol% Rh catalyst with
(R)-MeO-F12-BIPHEP, based on the procedure reported in our previous paper6 (Table 1). Although the
reaction of 1 with phenylboronic acid in the presence of the catalyst with KOH in toluene/H2O (10/1) at
20 °C for 1 h gave (R)-2a in an excellent yield, the enantioselectivity was less than 90% ee (85% ee,
Entry 1). However, the use of substituted
Table 1. Synthesis of chiral 4-aryl--lactones through
rhodium-catalyzed 1,4-addition.
arylboronic
acid
gave
excellent
0.25 mol% [RhCl(C2H4)2]2
O
O
enantioselectivity with a high yield (Entry
2 – 7). Irrespective of the position of the
substituent on the phenyl group and the
electronic nature of the substituent, the
enantioselectivity of (R)-2 reached at
least 97% ee. In contrast to the reaction of
2-cyclohexenone,6 the enantioselectivity
was susceptible to the steric effect of
arylboronic acid.
0.5 mol% (R)-MeO-F12-BIPHEP
+
Ar-B(OH)2
O
O
20% KOH
Toluene / H2O
20C, 1 h
*
1.05 equiv.
Ar
1
(R)-2
Entry
Ar
Ph (a)
% yield of 2c % ee of 2d
1
96
90
81
83
81
90
87
85
>99
98
98
97
2a
3b
4
4-CF3-C6H4 (b)
4-F-C6H4 (c)
4-MeO-C6H4 (d)
3-MeO-C6H4 (e)
3-Me-C6H4 (f)
2-MeO-C6H4 (g)
5
6
7
97
>99
(a) Ref. 6. (b) 1.3 equiv. of Ar-B(OH)2. (c) Isolated yield. (d)
Determined by chiral HPLC analysis.
Next, the reaction of coumarin analogues 3, which are bulkier substrates than 1, was focused upon
because the resulting products are useful for biologically active compounds7 or their synthetic
intermediates.8 The reaction of coumarin (3a) using the rhodium catalyzed asymmetric 1,4-addition has
been reported only twice in the past. In the first report, the reaction in the presence of 3 mol% Rh catalyst

HETEROCYCLES, Vol. 80, No. 1, 2010
159
with a chiral diene ligand at 50 °C gave (R)-4-phenylchroman-2-one (4a) in a 43% yield with 98% ee.9 In
the second, researchers obtained almost optically pure (R)-4a (99.6% ee) in an 88% yield using 3 mol%
Rh catalyst with (R)-Segphos and 10 equivalents of Ph-B(OH)2 in dioxane/H2O (10/1) at 60 °C for 8 h.8
In contrast to these reports, our catalytic system achieved the reaction smoothly under significantly milder
conditions (Table 2). Thus, the reaction of 3a with 10 equivalents of Ph-B(OH)2 in the presence of 1
mol% Rh catalyst in toluene / sat. NaHCO3 aq. (1/1) at 30 °C for 1 h gave (R)-4a in a 94% yield with
>99% ee (Entry 1),10 and HPLC analysis detected no (S)-enantiomer. In our catalytic system, a higher
yield with sufficient enantioselectivity was obtained in a shorter reaction time (1 h) despite using a
reduced amount of the catalyst under a lower temperature (30 °C). The result is attributed to the electronic
effect of MeO-F12-BIPHEP, because the reaction using MeO-BIPHEP did not proceed at all (Entry 2).6
The catalyst loading could be reduced to 0.5 mol% to give (R)-4a still in a 90% yield without any loss of
enantioselectivity (Entry 3). When 1.5 mol% Rh catalyst was used at 20 °C, (R)-4a was obtained in a
94% yield (Entry 4). Our highly reactive catalyst system enabled the reduction in the amount of
Ph-B(OH)2, which is hydrolyzed at high temperatures. The use of 3 equivalents of Ph-B(OH)2 gave
optically pure (R)-4a in a 90% yield, but 3 mol% Rh catalyst was necessary in this case (Entry 5). The
optimized conditions in Entry 4 was then successfully applied to 6-methylcoumarin (3b) to obtain
(R)-6-methyl-4-phenylchroman-2-one (4b),11 which can be converted into (R)-tolterodine used as a
urological drug,8 in a 94% yield (>99% ee, Entry 6). Interestingly, 7-methoxycoumarin (3c) also
smoothly reacted with Ph-B(OH)2 to obtain (R)-7-methoxy-4-phenylchroman-2-one (4c)12,13 in an 85%
yield with >99% ee (Entry 7), even though 3c was inactive to the Rh-Segphos catalyst.8 These results
show that the Rh / MeO-F12-BIPHEP complex acts as an extremely highly active catalyst for the
asymmetric 1,4-addition to synthesize α,β-unsaturated lactones even when using less reactive substrates.
Table 2. Synthesis of (R)-4-phenylchroman-2-one analogues through rhodium-catalyzed 1,4-addition.
Ph
[RhCl(C2H4)2]2 / (R)-MeO-F12-BIPHEP
(Rh : Ligand = 1 : 1)
R
+
Ph-B(OH)2
R
Toluene / sat. NaHCO3 aq.
1 h
O
O
O
O
(R)-4
3
Entry
substrate (3)
coumarin (a)
coumarin (a)
coumarin (a)
coumarin (a)
% Rh Ph-B(OH)2 temp. % yield of 4a % ee of 4b,c
1
2d
3
4
5
6
7
1.0
1.0
0.5
1.5
3.0
1.5
10 equiv.
10 equiv.
10 equiv.
10 equiv.
3 equiv.
30
30
30
20
20
20
20
94
0
>99
-
90
94
90
94
85
>99
>99
>99
>99
>99e
coumarin (a)
6-Me-coumarin (b)
7-MeO-coumarin (c) 1.5
10 equiv.
10 equiv.
(a) Isolated yield. (b) Determined by chiral HPLC analysis. (c) All cases in Table 2, the (S)-enantiomers were
not detected by HPLC analysis. (d) (R)-MeO-BIPHEP was used. (e)Absolute configuration could not be
determined exactly {[α]D31.3 = -43.0° (c 1.0, CHCl3)}. See ref. 13.

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HETEROCYCLES, Vol. 80, No. 1, 2010
The optically pure 4-aryl--lactones were synthesized efficiently using our catalytic system under mild
conditions. In particular, the facts that both high reactivity and complete enantioselectivity were attained
with relatively large substrates such as coumarin are promising indicators that our catalytic system could
be widely utilized for the synthesis of natural and/or biologically active compounds in the future.
ACKNOWLEDGEMENTS
This work was supported by Mitsui Chemicals Award in Synthetic Organic Chemistry, Japan and a
Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and
Technology, Japan, and JGC-S SCHOLARSHIP FOUNDATION. We thank the SC-NMR Laboratory of
Okayama University for 1H, 13C, and 19F NMR measurements.
REFERENCES AND NOTES
1. N. Miyaura, K. Yamada, and A. Suzuki, Tetrahedron Lett., 1979, 3437.
2. N. Miyaura, Bull. Chem. Soc. Jpn, 2008, 81, 1535.
3. Y. Takaya, M. Ogasawara, T. Hayashi, M. Sakai, and N. Miyaura, J. Am. Chem. Soc., 1998, 120,
5579.
4. Rh-catalyzed asymmetric 1,4-addition of Ar-B(OH)2 to 1a: J. L. Nôtre, J. C. Allen, and C. G. Frost,
Chem. Commun., 2008, 3795; R. Mariz, X. Luan, M. Gatti, A. Linden, and R. Dorta, J. Am. Chem.
Soc., 2008, 130, 2172; C. Monti, C. Gennari, and U. Piarulli, Chem. Euro. J., 2007, 13, 1547; W.-L.
Duan, H. Iwamura, R. Shintani, and T. Hayashi, J. Am. Chem. Soc., 2007, 129, 2130; K. Kurihara, N.
Sugishita, K. Oshita, D. Piao, Y. Yamamoto, and N. Miyaura, J. Organomet. Chem., 2007, 692,
428; P. Kasak, V. B. Arion, and M. Widhalm, Tetrahedron: Asymmetry, 2006, 17, 3084; S. L. X.
Martina, A. J. Minnaard, B. Hessen, and B. L. Feringa, Tetrahedron Lett., 2005, 46, 7159; R.
Shintani, W.-L. Duan, T. Nagano, A. Okada, and T. Hayashi, Angew. Chem. Int. Ed., 2005, 44,
4611; Y. Otomaru, K. Okamoto, R. Shintani, and T. Hayashi, J. Org. Chem., 2005, 70, 2503; K.
Yoshida and T. Hayashi, Heterocycles, 2003, 59, 605; T. Hayashi, M. Takahashi, and Y. Takaya, J.
Am. Chem. Soc., 2002, 124, 5052; M. T. Reetz, D. Moulin, and A. Gosberg, Org. Lett., 2001, 3,
4083; Y. Takaya, T. Senda, H. Kurushima, M. Ogasawara, and T. Hayashi, Tetrahedron: Asymmetry,
1999, 10, 4047.
5. T. Gendrineau, O. Chuzel, H. Eijsberg, J.-P. Genet, and S. Darses, Angew. Chem. Int. Ed., 2008, 47,
7669; C.-G. Feng, Z.-Q. Wang, C. Shao, M.-H. Xu, and G.-Q. Lin, Org. Lett., 2008, 10, 4101.
6. T. Korenaga, K. Osaki, R. Maenishi, and T. Sakai, Org. Lett., 2009, 11, 2325.
7. I. Singh, A. K. Prasad, A. K. Sharma, R. K. Saxena, C. E. Olsen, A. L. Cholli, L. A. Samuelson, J.
Kumar, A. C. Watterson, and V. S. Parmar, Bioorg. Med. Chem., 2003, 11, 529.

HETEROCYCLES, Vol. 80, No. 1, 2010
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8. G. Chen, N. Tokunaga, and T. Hayashi, Org. Lett., 2005, 7, 2285.
9. C. Defieber, J.-F. Paquin, S. Serna, and E. M. Carreira, Org. Lett., 2004, 6, 3873.
10. General procedure for the reactions of coumarin analogues: A 20 mL Schlenk flask was charged
with (R)-MeO-F12-BIPHEP (12.4 mg, 15.5 μmol), μ-dichlorotetraethylene dirhodium(I) (3.0 mg, 7.7
μmol) and 0.5 mL of deoxygenated toluene under argon atmosphere. The mixture was stirred at
room temperature for 5 min for complexation. To the mixture was added 2.5 mL of deoxygenated
toluene, phenylboronic acid (1.89 g, 15.5 mmol), 2.0 mL of deoxygenated sat. NaHCO3 aq, and
coumarin (3a, 227 mg, 1.55 mmol). After being stirred at 30 °C for 1 h, to the solution was added
saturated aqueous NaHCO3 solution. The resulting mixture was extracted with EtOAc (three times).
The organic layer was dried over MgSO4, filtrated with suction, and then concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (Hexane / EtOAc = 3/1) to
give (R)-4-phenylchroman-2-one (4a) as a white solid (327 mg, 94% yield, >99% ee).
m.p. 114 – 115 °C; 1H NMR (300 MHz, CDCl3): δ 3.01 (dd, J = 14.7, 7.8 Hz, 1H), 3.08 (dd, J = 14.7,
7.8 Hz, 1H), 4.32 – 4.36 (m, 1H), 6.96 – 6.99 (m, 1H), 7.08 (dt, J = 7.2, 1.2 Hz, 1H), 7.12 – 7.17 (m,
3H), 7.25 – 7.38 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 36.9, 40.6, 117.1, 124.6, 125.7, 127.5,
127.6, 128.3, 128.8, 129.1, 140.2, 151.7, 167.6; IR (KBr): 1767, 1497, 1454, 1418, 1335, 1277, 1202,
30.2
1188, 1134, 966, 895, 816, 760, and 708 cm-1; [α]D
–41.1° (c 1.0, CHCl3); HPLC (Daicel
Chiralcel OD-H, Hexane/i-PrOH = 95/5, flow rate = 1.0 mL/min) tR of (S)-4a: 13.8 min (0%); tR of
(R)-4a: 15.2 min (>99%).
11. (R)-6-Methyl-4-phenylchroman-2-one (4b): m.p. 112 – 113 °C; 1H NMR (300 MHz, CDCl3): δ 2.25
(s, 3H), 2.98 (dd, J = 15.6, 6.3 Hz, 1H), 3.06 (dd, J = 15.6, 6.3 Hz, 1H), 4.27 – 4.31 (m, 1H), 6.78 (m,
1H), 7.02 (d, J = 8.4 Hz, 1H), 7.07 – 7.17 (m, 3H), 7.25 – 7.38 (m, 3H); 13C NMR (75 MHz, CDCl3):
δ 20.7, 37.1, 40.7, 116.8, 125.3, 127.5, 127.6, 128.6, 129.1, 129.3, 134.3, 140.5, 149.6, 167.8; IR
(KBr): 1760, 1610, 1587, 1487, 1450, 1339, 1337, 1221, 1205, 1136, 1111, 966, 908, 874, 767, 756,
and 700 cm-1; [α]D30.7 –3.6° (c 1.0, CHCl3); HPLC (Daicel Chiralcel OD-H, Hexane/i-PrOH = 90/10,
flow rate = 1.0 mL/min) tR of (S)-4b: 12.2 min (0%); tR of (R)-4b: 14.0 min (>99%).
1
12. 7-Methoxy-4-phenylchroman-2-one (4c): m.p. 133 – 134 °C; H NMR (300 MHz, CDCl3): δ 2.98
(dd, J = 15.9, 7.8 Hz, 1H), 3.07 (dd, J = 15.9, 7.8 Hz, 1H), 3.80 (s, 3H), 4.26 – 4.31 (m, 1H), 6.63
(dd, J = 8.4, 2.7 Hz, 1H), 6.69 (d, J = 2.7 Hz, 1H), 6.85 – 6.88 (m, 1H), 7.13 – 7.17 (m, 2H), 7.25 –
13
7.37 (m, 3H); C NMR (75 MHz, CDCl3): δ 37.3, 40.1, 55.5, 102.5, 110.7, 117.6, 127.5, 127.6,
128.9, 129.1, 140.7, 152.4, 160.0, 167.6; IR (KBr): 1755, 1629, 1585, 1508, 1456, 1325, 1267, 1221,
31.3
1134, 1109, 1030, 972, 880, 833, 752, and 700 cm-1; [α]D –43.0° (c 1.0, CHCl3); HPLC (Daicel
Chiralcel OD-H, Hexane/i-PrOH = 95/5, flow rate = 1.0 mL/min) tR of minor enantiomer of 4c: 17.3
min (0%); tR of major enantiomer of 4c: 21.5 min (>99%).

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HETEROCYCLES, Vol. 80, No. 1, 2010
13. In ref. 8, plus sign of optical rotation of 4c had been assigned to be (R)-enantiomer. However, the
determination had been performed by analogy with (R)-4b (in addition, the optical rotation of (R)-4b
had shown minus sign in ref. 8 as well as our result). If absolute configuration of 4c is determined by
analogy with (R)-4a or 4b, 4c in table 2 is (R)-enantiomer.