The role of ni-carboxylate during catalytic asymmetric iodolactonization using pybidine-ni(OAc)

Article abstract of DOI:10.1055/s-0033-1339676

The combination of a PyBidine-Ni(OAc)₂ complex with a catalytic amount of iodine efficiently catalyzed asymmetric iodolactonization to generate chiral iodolactones with up to 89% enantiomeric excess. The formation of an intermediate Ni-carboxylate species from the alkenyl carboxylic acid is a key role in promoting the iodolactonization. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339676

LETTER
▌2045
letter
The Role of Ni-Carboxylate During Catalytic Asymmetric Iodolactonization
Using PyBidine-Ni(OAc)2
Ni-Carboxylate in Iodolactonization with PyBidine-Ni(OAc)2
Takayoshi Arai,* Satoshi Kajikawa, Eri Matsumura
Department of Chemistry, Graduate School of Science, Chiba University, Inage 263-8522, Japan
Fax +81(43)2902889; E-mail: tarai@faculty.chiba-u.jp
Received: 09.07.2013; Accepted after revision: 01.08.2013
Working towards the development of metal-catalyzed
Abstract: The combination of a PyBidine-Ni(OAc)2 complex with
asymmetric reactions, we have designed and synthesized
a catalytic amount of iodine efficiently catalyzed asymmetric iodo-
a bis(imidazolidine)pyridine ligand, abbreviated PyBidine
lactonization to generate chiral iodolactones with up to 89% enan-
tiomeric excess. The formation of an intermediate Ni-carboxylate
(L1), which is useful in combination with metal salts.11
species from the alkenyl carboxylic acid is a key role in promoting The PyBidine-Cu(OTf)2 complex, for example, was
the iodolactonization.
shown to be an efficient catalyst for the [3+2] cycloaddi-
tion of iminoesters with nitroalkenes. The efficiency of
PyBidine as a chiral ligand for metal-catalyzed asymmet-
ric iodolactonization is demonstrated by the data present-
ed in Table 1.
Key words: asymmetric catalysis, iodolactone, nickel, carboxylate,
ligands
Iodolactonization, a type of halocyclization, represents
one of most powerful synthetic tools for generating io-
dine-functionalized cyclic compounds in a single reac-
tion. The resulting iodolactones are both versatile and
useful, and have applications as synthetic intermediates in
the total synthesis of natural products as well as in the pro-
duction of biologically significant pharmaceutical com-
pounds and agricultural chemicals.1 Recently, the
development of a catalytic, asymmetric version of the halo-
lactonization reaction has become an important goal of the
modern synthetic chemistry community.2 In 1992, Tagu-
chi et al. reported the first reagent-controlled enantiose-
lective halolactonization, and they were able to achieve
65% ee by using a stoichiometric amount of a chiral tita-
nium complex.3 With regard to iodolactonization, Gross-
man et al. reported successful reagent-controlled
asymmetric iodolactonization in 1998,4a while, in a pio-
neering study, Jacobsen developed a catalytic version of
the asymmetric iodolactonization reaction by using a chi-
ral thiourea catalyst.5 More recently, Johnston reported an
asymmetric iodolactonization catalyzed by a bis(amidine)
(BAM)-based Brønsted acid.6 In addition to iodolactoni-
zation,5–7 chlorolactonization8 and bromolactonization9
have also been accomplished in an enantioselective man-
ner by using chiral organocatalysts. The development of
metal-catalyzed asymmetric halolactonization reactions,
however, has been rather limited. One of the few exam-
ples is a report by Gao, who examined the use of a Co-
salen complex as a Lewis acid catalyst for asymmetric io-
dolactonization.10 Since Japan produces significant quan-
tities of iodine, our group at Chiba University also has an
interest in devising metal-catalyzed asymmetric iodolac-
tonization as part of a broader program associated with the
exploration of new methods of utilizing this element.
When the original (S,S)-diphenylethylenediamine-
derived PyBidine-Cu(OTf)2 complex11a was applied to the
iodolactonization of 5-phenylhex-5-enoic acid (1a), (S)-
iodolactone 2a was obtained with only 5% ee (Table 1,
entry 1). The use of Cu(OAc)2 slightly improved the se-
lectivity to 17% ee, although the yield remained low
(25%; entry 3). The catalytic activity was drastically im-
proved by the addition of a catalytic amount of I2 (entry
4), although the selectivity was essentially unchanged.
Reducing the polarity of the solvent by increasing the ra-
tio of toluene to CH2Cl2 from 1:1 to 3:1 improved the en-
antioselectivity to 49% ee (entry 5). We next examined
the effects of the diacetates of first row transition metals,
and found that use of PyBidine-Ni(OAc)2 as catalyst gave
the S-configured product in 85% yield with the highest en-
antioselectivity (78% ee; entry 7). Among the nickel salts
tested, the catalyst prepared with Ni(OAc)2 exhibited the
best performance in terms of balancing both yield and en-
antiomeric excess (entries 7 and 9–11). Further results
regarding the optimization of this asymmetric iodo-
lactonization reaction are included in the Supporting In-
formation. It is noteworthy that performing the reaction
with pybim (L2)12 under the same conditions to those ap-
plied in Table 1, entry 7 generated the product with only
27% ee (entry 12). This clearly demonstrates the advan-
tage of the efficient asymmetric reaction sphere associat-
ed with the PyBidine ligand. Using the optimized
conditions determined in the above trials, the scope of
substrates to which this reaction is applicable was exam-
ined; the results are presented in Table 2.
Each of the 5-arylhexenoic-5-acid substrates was effi-
ciently converted by the PyBidine-Ni(OAc)2 catalyst into
the corresponding chiral gluconolactone in reasonably
good enantiomeric excess (Table 2, entries 1 and 3–8), al-
though the reaction generating γ-butyrolactone resulted in
a somewhat lower ee value (53%; entry 2). The presence
of electron-donating substituents on the benzene ring was
SYNLETT 2013, 24, 2045–2048
Advanced online publication: 28.08.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339676; Art ID: ST-2013-U0637-L
© Georg Thieme Verlag Stuttgart · New York

2046
T. Arai et al.
LETTER
Table 1 Optimization of PyBidine-Metal Catalyzed Iodolactonization
Ph
Ph
Ph
Ph
Ph
I
ligand (10.5 mol%)
O
NH
HN
N
N
Ph
O
O
metal salt (10 mol%)
Ph
Ph Ph
N
N
Ph
OH
N
N
N
N
NIS (1.1 equiv), I2 (X equiv)
toluene–CH2Cl2 (a:b)
–78 °C, 18–22 h
1a
Bn
Bn
Bn
Bn
2a
PyBidine (L1)
pybim (L2)
Entry
Ligand
Metal salt
X (equiv)
Ratio a/b
Yield (%)
ee (%)
1
2
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
Cu(OTf)2
CuI
0
1:1
1:1
1:1
1:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
3:1
41
85
25a
70
82
67
85
83
72
87
15a
76
5
13
17
18
49
51
78
36
71
36
31
27
0
3
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Co(OAc)2·4H2O
Ni(OAc)2·4H2O
Zn(OAc)2
0
4
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
5
6
7
8
9
NiCl2·6H2O
10
11
12
NiI2
Ni(ClO4)2·6H2O
Ni(OAc)2·4H2O
a Low conversion yield.
be employed as substrates, giving the corresponding prod-
ucts in good yields with moderately high ee values (en-
tries 9 and 10).
Table 2 Asymmetric Iodolactonization Using PyBidine-Ni(OAc)2
Catalyst
I
PyBidine (10.5 mol%)
O
R
O
O
To investigate how the catalyst controls asymmetric iodo-
lactonization, we conducted an ESI-MS study (Figure 1).
The catalyst solution gave an ion peak (m/z = 820.3151)
corresponding to [PyBidine-Ni(OAc)]+. When substrate
1a was added to the catalyst solution, a new ion peak was
observed (m/z = 950.3934) that was assigned as [PyBi-
dine-Ni(O2C(CH2)3C(=CH2)Ph)]+. The ESI-MS study
strongly suggests exchange of the counter anion in the cat-
alyst with the carboxylic acid 1a.
The 1H NMR spectrum of a CDCl3 solution of the original
substrate 1a exhibited three series of methylene signals
between δ = 1.7 and 2.7 ppm. When 1a was mixed with
PyBidine-Ni(OAc)2 catalyst at room temperature, all
three methylene signals underwent significant up-field
shifts accompanied by pronounced broadening, due to the
effect of the paramagnetic Ni(II) complex. Additional in-
formation was obtained by instead adding the PyBidine-
Zn(OAc)2 catalyst (Figure 2); when 1a was mixed with
this catalyst at room temperature, all three methylene sig-
nals again underwent significant up-field shifts, to the re-
gion δ = 1.5–2.4 ppm.
Ni(OAc)2⋅4H2O (10 mol%)
( )n
R
OH
NIS (1.1 equiv), I2 (0.2 equiv)
toluene–CH2Cl2 (a:b)
–78 °C, 18–22 h
( )n
Entry
R
n
Ratio a/b Yield (%) ee (%)
1
2a
3b
4
Ph
Ph
1
0
1
1
1
1
1
1
1
1
3:1
3:1
2:1
3:1
3:1
1:0
3:1
3:1
3:1
3:1
85
76
81
67
95
82
78
45
82
79
78
53
64
75
89
87
72
75
48
57
4-ClC6H4
4-FC6H4
5
4-MeC6H4
4-MeOC6H4
3-MeC6H4
2-naphthyl
n-octyl
6
7
8
9
10
c-hexyl
a Reaction time: 4 h.
b Reaction time: 48 h.
Each peak in this spectrum was unequivocally assigned on
the basis of 2D NMR experimental data (see the Support-
ing Information). Since the presence of either Brønsted or
Lewis acids typically results in a down-field shift of the
found to increase the enantioselectivity, resulting in prod-
ucts with up to 89% ee (entries 5 and 6). These results
show that 5-alkyl-substituted hexenoic-5-acids may also
Synlett 2013, 24, 2045–2048
© Georg Thieme Verlag Stuttgart · New York

LETTER
Ni-Carboxylate in Iodolactonization with PyBidine-Ni(OAc)2
2047
PyBidine-Ni(OAc)2-catalyzed asymmetric iodolactoniza-
tion was developed, as summarized in Scheme 1.
I
H
N
R
O
O
O
O
I2
+
+
O
R
OH
PyBidine–
Ni(OAc)2
I2
N
O
O
AcOH
+
AcOH
O
O
I
*
ONi
*
ONi
R
R
(B)
(A)
O
I2
I3
I
N
I2
N
N
O
O
O
O
O
Scheme 1 Proposed catalytic cycle for asymmetric iodolactoniza-
tion promoted by PyBidine-Ni(OAc)2
The catalytic cycle begins with an anion exchange be-
tween PyBidine-Ni(OAc)2 and the alkenylcarboxylic acid
substrate (Scheme 1). In the newly produced chiral nickel-
alkenylcarboxylate (A), the π electrons of the double bond
are electronically enriched compared with the original
free alkenoic acid. Based on previous reports, molecular
iodine adds to the N-iodosuccinimide to form the more re-
active N-I3-succinimide species,5,10 and the electronically
enriched double bond in the nickel-alkenylcarboxylate
readily reacts with this activated iodinium species to gen-
erate intermediate B. This latter species subsequently un-
dergoes intramolecular cyclization in an enantioselective
manner through nucleophilic attack of the chiral nickel-
carboxylate group to form the optically active gluconolac-
tone, with concurrent regeneration of the PyBidine-
Ni(OAc)2 catalyst and the catalytic I2.
Figure 1 ESI-MS study on the interaction of catalyst with 1a
This hypothetical mechanism for nickel-carboxylate me-
diated iodolactonization also provides a reasonable expla-
nation for the observed enantioface selection, as shown in
Figure 3.13 When the nickel-carboxylate is generated on
the (S,S)-diphenylethylenediamine-derived PyBidine-
Ni(OAc)2 complex, the reactive iodinium species will ap-
proach from the second quadrant when forming B, ensur-
ing that subsequent iodocylization leads to the formation
of the S-configuration-enriched iodolactone.14
Figure 2 1H NMR spectra of (a) 1a and (b) a 1:1 mixture of 1a with
PyBidine-Zn(OAc)2
NMR signals of a compound due to a reduction in electron
density, we attributed the observed up-field shifts upon
addition of PyBidine-Zn(OAc)2 to the formation of car-
boxylate anion species. The addition of the catalyst also
caused the coupling pattern of the α-protons of the carbox-
ylic acid group of 1a to transform from a simple triplet
into a pair of double-double doublets (ddd). This observa-
tion strongly suggests the incorporation of 1a into the
asymmetric environment of the chiral catalyst through the
formation of a metal carboxylate.
In conclusion, we have successfully demonstrated an
asymmetric iodolactonization reaction by using our newly
developed PyBidine-Ni(OAc)2 catalyst.15 The work
shows that the formation of an intermediate nickel-
carboxylate species is a vital step in the enantioselective
reaction. Based on this working hypothesis, the develop-
ment of more efficient catalysts with applications in
Based on the ESI-MS and 1H NMR data provided in Fig-
ure 1 and Figure 2, a plausible reaction mechanism for the
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2045–2048

2048
T. Arai et al.
LETTER
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Ph
N
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Ph
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N
Ph
Ph
H
O
N
N
Ni
H
N
C
O-
Ph
Figure 3 Enantioface selection in PyBidine-Ni(OAc)2-catalyzed
asymmetric iodolactonization
asymmetric halocyclization is in progress in our laborato-
ry.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and Tech-
nology (Japan), by the Chiba University Iodine Research Project,
and by the Workshop on Chirality in Chiba University (WCCU).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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m
iotSrat
ungIifoop
r
t
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carboxylate was proposed, although the basis of metal-
carboxylate formation is unclear. See: Lee, H. J.; Kim, D. Y.
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NMR (500 MHz, CDCl3): δ = 7.41–7.33 (m, 5 H), 3.58 (dd,
J = 12.3, 11.2 Hz, 2 H), 2.57–2.33 (m, 4 H), 1.84–1.80 (m,
1 H), 1.60–1.56 (m, 1 H); 13C NMR (125 MHz, CDCl3): δ =
170.5, 140.3, 129.1, 128.5, 125.3, 84.5, 32.1, 29.1, 17.8,
16.6; HRMS: m/z [M + H]+ calcd for C12H14O2I: 317.0033;
found: 317.0031; 78% ee; [α]D24 +27.5 (c = 1.2, CHCl3);
enantiomeric excess was determined by HPLC analysis with
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1.0 mL/min; 250 nm): Rt = 14.2 (major enantiomer), 15.8
(minor enantiomer) min.
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(15) Enantioselective Iodolactonization Catalyzed by
PyBidine-Ni(OAc)2 Complex; General Procedure: A
mixture of PyBidine (7.3 mg, 0.0105 mmol) and
Ni(OAc)2·4H2O (2.5 mg 0.01 mmol) was stirred at r.t. for 3 h
in anhydrous CH2Cl2 (1.0 mL). After cooling the mixture to
–78 °C, a carboxylic acid (0.1 mmol) in toluene (3.0 mL)
was slowly added and the mixture was stirred for 0.5 h at the
same temperature. I2 (5.0 mg, 0.02 mmol) and NIS (24.6 mg,
0.11 mmol) were added and the mixture was stirred for 22–
48 h. The reaction was quenched by the addition of saturated
aq Na2SO3 and 1 M aq NaOH, and extracted with CH2Cl2
(3×). The collected organic layer was dried over Na2SO4.
After removal of the solvent under reduced pressure, the
residue was purified by silica-gel column chromatography
(hexane–EtOAc, 6:1) to afford the iodolactone. The
enantiomeric excess of the product was determined by
HPLC analysis.
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