Asymmetric Rh-catalyzed intermolecular hydroacylation of 1,5-hexadiene with salicylaldehyde

Article abstract of DOI:10.1248/cpb.57.1158

Asymmetric intermolecular hydroacylation between salicylaldehyde (1) and 1,5-hexadiene (2) using a combination of [RhCl(C₈H₁₄) ₂]₂ (0.10 eq), (S)-BINAP (0.10 eq), and ZnBr₂ (0.20 eq) afforded an enant

Full text of DOI:10.1248/cpb.57.1158

1158
Notes
Chem. Pharm. Bull. 57(10) 1158—1160 (2009)
Vol. 57, No. 10
Asymmetric Rh-Catalyzed Intermolecular Hydroacylation of
1,5-Hexadiene with Salicylaldehyde
a
Yasuhiro INUI, Masakazu TANAKA, ,a,b Masanori IMAI,c Keitaro TANAKA,a and Hiroshi SUEMUNE*,a
*
a Graduate School of Pharmaceutical Sciences, Kyushu University; 3–1–1 Maidashi, Higashi-ku, Fukuoka 812–8582,
Japan: b Graduate School of Biomedical Sciences, Nagasaki University; 1–14 Bunkyo-machi, Nagasaki 852–8521, Japan:
and c Hokkaido College of Pharmacy; Hokkaido 047–0264, Japan.
Received June 19, 2009; accepted July 10, 2009; published online July 13, 2009
Asymmetric intermolecular hydroacylation between salicylaldehyde (1) and 1,5-hexadiene (2) using a com-
bination of [RhCl(C8H14)2]2 (0.10 eq), (S)-BINAP (0.10 eq), and ZnBr2 (0.20 eq) afforded an enantiomerically
enriched hydroacylated product iso-3 of 84% ee, along with an achiral product normal-3.
Key words rhodium; intermolecular hydroacylation; chelation; enantioselective reaction
Rh-catalyzed intramolecular1—7) and intermolecular hy- aldehyde and promote hydroacylation. In contrast, the addi-
droacylations8—19) have recently been the focus of synthetic tion of silver salt would change the property of Rh-complex
organic and organometallic chemists. Although Rh-catalyzed to a cationic species to accelerate the reaction. Unfortunately,
asymmetric intramolecular hydroacylation (asymmetric cy- the addition of bases, such as K2CO3, KOAc, and NaOAc,
clization) has been extensively studied by us,20—24) and other did not improve the yield (entries 3—5), and the addition of
groups,25—28) Rh-catalyzed asymmetric intermolecular hy- silver salts, such as AgClO4 and CF3CO2Ag, improved the
droacylation has attracted only limited attention,29—31) except yield of products but their specific rotations were zero, mean-
for asymmetric hydroformylation.32,33) This may be because ing that the products were racemic (entries 6—8). Finally, it
Rh-catalyzed intermolecular hydroacylation did not proceed was found that the addition of Lewis acid improved the yield
under mild reaction conditions, but required vigorous reac- of products (entries 9—12); in particular, the addition of
tion conditions. Recently, we have found that Rh-catalyzed Zn(OTf)2 (0.20 eq) improved the yield of product and its spe-
intermolecular hydroacylations proceed under mild reaction cific rotation showed ꢁ26° (entry 11). However, the addition
conditions based on the “double chelation” of aldehyde and of Zn(OTf)2 and elevated temperature (50 °C) induced the
diene (Eq. 1).34—37) Here we report enantioselective Rh-cat- migration of olefin function to produce inseparable olefin
alyzed intermolecular hydroacylation between salicylalde- mixtures of iso-3, along with normal-3 as a by-product.
hyde (1) and 1,5-hexadiene (2).
Therefore, the enantiomeric excess of iso-3 could not be di-
rectly determined by HPLC using a chiral column. Thus, the
mixture of products was hydrogenated by H2/5% Pd–C to
produce saturated hydroacylated products iso-4 and normal-4
(1)
Table 1. Effect of Additive on Asymmetric Intermolecular Hydroacylation
The hydroacylation between salicylaldehyde (1) and 1,5-
hexadiene (2, 6 eq) using RhCl(PPh3)3 (0.20 eq) at room tem-
perature afforded a mixture of iso-hydroacylated product 3
and normal-hydroacylated product 3 in the ratio of 4 to 1 in
quantitative yield (Eq. 1). The iso-hydroacylated product 3
has a chiral carbon at the a-position. Thus, we envisaged that
the asymmetric induction from prochiral 1,5-hexadiene
would be possible, if Rh-complex with chiral phosphine lig-
and were used instead of achiral RhCl(PPh3)3.
First, we examined the hydroacylation between salicyl-
aldehyde (1) and 1,5-hexadiene (2) using Rh[(R)-BINAP]Cl
(0.40 eq) at room temperature. Fortunately, the reaction af-
forded the mixture of iso-3 and normal-3 in the ratio of 3 to
1, and the specific rotation [a]D of the mixture showed ꢀ9.6.
This result means that the iso-product is not racemic but op-
tically active, even though the chemical yield was merely 4%
(entry 1 in Table 1). This result prompted us to further im-
prove the chemical yield of the product and increase its spe-
cific rotation. We increased the amount of Rh-catalyst to
1.0 eq, but the yield of products was not improved. Several
additives, such as bases, silver salts, and Lewis acids, were
then examined, as shown in Table 1. We thought that the ad-
dition of base would deprotonate phenolic protons of salicyl-
Additive
(eq)
Temp.
(°C)
Time
(h)
3: Yield %
(i : n)
Entry
[a]Da)
ꢀ9.6
1
—
—
rtb)
rt
rt
40
40
40
50
120
120
120
120
120
120
14
4 (3 : 1)
5 (3 : 1)
2 (2 : 1)
13 (2 : 1)
16 (3 : 1)
23 (3 : 1)
90 (2 : 1)
2c)
3
—
—
—
—
d)
K2CO3 (0.4)e)
K2CO3 (0.4)f)
KOAc (0.4)f)
AgClO4 (0.4)
AgClO4 (0.4),
NaOAc (0.4)f)
CF3CO2Ag (0.4),
NaOAc (0.4)f)
Mg(OTf)2 (0.2)f)
MgCl2 (0.2)f)
Zn(OTf)2 (0.2)f)
Cu(OTf)2 (0.2)f)
d)
d)
4
5
6
7
d)
0
0
8
50
72
88 (4 : 1)
0
9
10
11
12
50
50
50
50
72
72
48
72
22 (2 : 1)
Trace
ꢁ1.8
d)
—
85 (3 : 1) ꢁ26.8g)
17 (1 : 1)
ꢁ1.8
a) Specific rotation of the mixture of products. b) Reaction at 50 °C afforded a
mixture of products in 15% yield. c) 1.0 eq of Rh-complex was used. d) Not meas-
ured. e) NaOAc was also examined. f) 5% EtOH in ClCH2CH2Cl was used as a
solvent. g) Enantiomeric excess of iso-3 was 68% ee.
© 2009 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: matanaka@nagasaki-u.ac.jp

October 2009
1159
Table 2. Effect of Phosphine Ligand on Asymmetric Hydroacylation
in quantitative yield, and the enantiomeric excess of iso-4
was determined by HPLC using a chiral column. The
enantiomeric excess of iso-4 in entry 11 was determined
to be 68% ee.
Next, we studied the effect of chiral bidentate phosphine
ligand on the enantiomeric excess of product. The results are
summarized in Table 2. We examined hydroacylation using
Rh(ligand)Cl (0.20 eq) and Zn(OTf)2 (0.10 eq) at 50 °C. In
these conditions, where a reduced amount of Rh-catalyst was
used, the yield of products generally decreased, except for the
(R,R)-Me-BPE ligand, and enantiomeric excesses fell. Even
using Rh[(S)-BINAP]Cl (0.20 eq), the enantiomeric excess of
iso-3 decreased to 53% ee (entry 1). Thus, we have not found
a phosphine ligand which showed better enantiomeric excess
than the (S)-BINAP ligand.
We optimized the reaction conditions of Rh-catalyzed hy-
droacylation in the presence of zinc salts (Table 3). Hydro-
acylation by Rh[(S)-BINAP]Cl (0.20 eq) in the presence of
Zn(OTf)2 and K2CO3 did not efficiently proceed at room tem-
perature (entry 1). The equivalence of Zn(OTf)2 was tested
(entries 2—4), and when 0.10—0.20 eq Zn(OTf)2 was added,
the reaction afforded iso-3 of 53—54% ee (entries 3, 4), but
the decrease of Zn(OTf)2 to 0.05 eq was disadvantageous for
the enantiomeric excess of the product. Furthermore, addi-
tion of a base was detrimental to the enantiomeric excess
(entry 5). When ZnBr2 (0.10 or 0.20 eq) was added as a zinc
salt, the best enantiomeric excess (78% ee) of iso-3 was at-
tained (entries 6—9), although the ratio of iso/normal (2 : 1)
was not good.
In the aforementioned reactions, the neutral Rh-com-
plex Rh[(R)-BINAP]Cl was prepared in situ by mixing
[RhCl(C8H14)2]2 (0.10 eq, 0.20 eq as Rh-metal) with bidentate
phosphine ligand (S)-BINAP (0.2 eq) in 5% EtOH of ClCH2–
CH2Cl solution,38) and then the ratio of [RhCl(C8H14)2]2 and
BINAP ligand was checked. The results are summarized in
Table 4. A reduced amount of (S)-BINAP ligand to 0.10 eq,
that is to say, the ratio of Rh-metal/ligand is 2/1, enhanced
the enantiomeric excess of iso-(ꢁ)-3 to 84% ee, although the
ratio of iso/normal decreased (entry 2). However, the use of
further reduced (S)-BINAP ligand (0.05 eq) was detrimental
to the reaction and the enantiomeric excess (entry 3). Enan-
tiomeric (R)-BINAP ligand afforded the enantiomeric (ꢀ)-
product (entry 4). To improve the enantiomeric excess, the
reaction was performed at 40 °C, but a lower temperature
was disadvantageous, and the enantiomeric excess of iso-3
decreased to 71% ee (entry 5). The best enantiomeric excess
(84% ee) of iso-3 was attained in entries 2 and 4 of Table 4,
although under these reaction conditions a mixture of iso-
and normal-3 in the ratio of 1 to 1 was obtained, and the mi-
gration of olefin in the products was observed.
Time
(h)
Yield %
(i : n)
Entry
Liganda)
(S)-BINAP
(S)-Tol-BINAP
(R,R)-Me-BPE
(R,R)-Me-DUPHOS
(R,R)-DIOP
iso-3 % ee
1
2
3
4
5
6
72
72
48
72
72
72
68 (2 : 1)
65 (1 : 1)
85 (1 : 2)
18 (1 : 2)
50 (4 : 1)
45 (2 : 1)
53
53
6
17
0
(S)-(R)-PPFA
0
a) Abbreviations: (S)-BINAP: (S)-2,2ꢂ-bis(diphenylphosphino)-1,1ꢂ-binaphthyl; (S)-
Tol-BINAP: (S)-2,2ꢂ-bis(di-p-tolylphosphino)-1,1ꢂ-binaphthyl; (R,R)-Me-BPE: 1,2-bis-
((2R,5R)-2,5-dimethylphospholano)ethane; (R,R)-Me-DUPHOS: 1,2-bis((2R,5R)-2,5-
dimethylphospholano)benzene; (R,R)-DIOP: (4R,5R)-4,5-bis(diphenylphosphinometh-
yl)-2,2-dimethyl-1,3-dioxolane; (S)-(R)-PPFA: (R)-N,N-dimethyl-1-[(S)-2-(diphenyl-
phosphino)ferrocenyl]ethylamine.
Table 3. Effect of Zinc Salts and Reaction Conditions on Intermolecular
Hydroacylation
Entry
Zinc salt (eq)
Yield % (i : n) iso-3 % ee
b)
1
Zn(OTf)2 (0.2), K2CO3 (0.2)a)
Zn(OTf)2 (0.05)
Zn(OTf)2 (0.1)
5 (2 : 1)
84 (2 : 1)
68 (2 : 1)
78 (2 : 1)
82 (2 : 1)
96 (2 : 1)
81 (1 : 1)
83 (2 : 1)
75 (2 : 1)
—
2
44
3c)
4
53
54
8
62
77
78
60
Zn(OTf)2 (0.2)
Zn(OTf)2 (0.1), K3PO4 (0.1)
ZnCl2 (0.1)
ZnBr2 (0.1)
ZnBr2 (0.2)
5
6
7
8
9
ZnI2 (0.1)
a) Reaction was carried out at room temperature. b) Not measured. c) Entry 3
is same as entry 1 in Table 2.
Table 4. Effect of Ratio of RhCl[(C8H14)2]2 and Phosphine Ligand BINAP
c)
Entry
BINAP (eq)
Yield % (i : n) iso-3 % ee
[a]D
1d)
2
3
(S)-BINAP (0.2)
(S)-BINAP (0.1)
(S)-BINAP (0.05)
(R)-BINAP (0.1)
(S)-BINAP (0.1)
83 (2 : 1)
86 (1 : 1)
68 (1 : 2)
81 (1 : 1)
89 (1 : 1)
78
84
61
84
71
ꢁ30.8
ꢁ26.7
ꢁ15.8
ꢀ24.8
ꢁ21.2
4
5e)
a) 0.2 eq as Rh-metal. b) 5% EtOH in ClCH2CH2Cl was used as a solvent, and the
reaction was performed at 50 °C. c) Specific rotation of mixture of iso- and normal-
3. d) Entry 1 is the same as entry 8 in Table 3. e) Reaction was performed at 40 °C.
The reaction mechanisms, such as the role of zinc salt, and
the enantio-face selection are unclear. We considered that
zinc salt as Lewis acid may coordinate the carbonyl function
of aldehyde and promote the reaction. The best enantiomeric
excess of iso-3 (84% ee as a hydrogenated iso-4) was at- using a combination of [RhCl(C8H14)2]2, (S)-BINAP, and
tained when the reaction was performed using the ratio of 2 ZnBr2. The reaction afforded an enantiomerically enriched
to 1 of Rh-metal and BINAP ligand; thus, the real Rh-cata- hydroacylated iso-3 of 84% ee (as a hydrogenated iso-4),
lyst may be dimeric Rh-complexes, such as h6-Ph-bi-Rh- along with an achiral normal-3 in 86% yield.39)
complexes and m2-ligand-Rh-complexes.
Typical Procedure A solution of [RhCl(C8H14)2]2 (72 mg, 0.10 mmol,
droacylation between salicylaldehyde 1 and 1,5-hexadiene 2 0.20 mmol as Rh-metal) and (S)-BINAP (62.3 mg, 0.10 mmol) in 5% EtOH
Experimental
In summary, we developed asymmetric intermolecular hy-

1160
Vol. 57, No. 10
of ClCH2CH2Cl (4 ml) was stirred at room temperature for 1 h under Ar
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of the solvent, the residue was purified by column chromatography on silica
gel (10% EtOAc in hexane) to give a 1 : 1 mixture of iso-3 and normal-3
(176 mg, 86%) as a colorless oil. [a]D ꢁ26.7 (cꢃ1.0, CHCl3).
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phenyl)heptan-1-one (normal-4)
A
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(2007).
(50 mg, 0.245 mmol) and 5% Pd–C (50 mg) in MeOH (5 ml) was rigorously
stirred under H2 atmosphere at room temperature for 4 h. Then, the Pd-cata-
lyst was filtered off, and the filtrate was evaporated in vacuo. The residue
was purified by column chromatography on silica gel (10% EtOAc in hexane)
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mers could be separated by preparative TLC. iso-4: a colorless oil; IR (neat)
cmꢁ1: 3045, 2959, 2932, 1638; 1H-NMR (400 MHz, CDCl3) d: 12.6 (1H , s),
7.76 (1H, br d, Jꢃ8 Hz), 7.43 (1H, br t, Jꢃ8 Hz), 6.97 (1H, br d, Jꢃ8 Hz),
6.87 (1H, br t, Jꢃ8 Hz), 3.48 (1H, sestet, Jꢃ6.5 Hz), 1.80 (1H, m), 1.39 (1H,
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1
br d, Jꢃ8 Hz), 7.43 (1H, br t, Jꢃ8 Hz), 6.95 (1H, br d, Jꢃ8 Hz), 6.87 (1H,
br t, Jꢃ8 Hz), 2.96 (2H, t, Jꢃ7.4 Hz), 1.72 (2H, quintet, Jꢃ7.4 Hz), 1.19—
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Acknowledgements This work was supported in part by a Grant-in-Aid 29) While we were studying an asymmetric intermolecular hydroacylation
for Young Scientists (B) from the Japan Society for the Promotion of Sci-
ence.
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unprecedented Rh-catalyzed asymmetric intermolecular hydroacyla-
tion of norbornadiene and norbornene. Also, Willis et al., reported the
Rh-catalyzed asymmetric intermolecular hydroacylation of allenes.
See refs. 30 and 31.
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