Rhodium-catalyzed 1,2-addition of Sb-phenyl-1,5-azastibocines to functionalized aldehydes

Article abstract of DOI:10.3987/COM-09-S(S)42

Simple and efficient addition of a phenyl group to aldehydes was accomplished by the rhodium-catalyzed reaction of Sb-phenyl-1,5-azastibocines. Because of the soft nucleophilic character of 1,5-azastibocines, arylation of functionalized aldehydes having ketone, ester, and halogen moieties can be achieved to afford aryl alcohols. The reaction can be carried out under aerobic conditions, in striking contrast to the reactions with hard nucleophiles such as organolithium and Grignard reagents.

Full text of DOI:10.3987/COM-09-S(S)42

HETEROCYCLES, Vol. 80, No. 1, 2010
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HETEROCYCLES, Vol. 80, No. 1, 2010, pp. 163 - 168. © The Japan Institute of Heterocyclic Chemistry
Received, 26th June, 2009, Accepted, 31st August, 2009, Published online, 31st August, 2009
DOI: 10.3987/COM-09-S(S)42
RHODIUM-CATALYZED 1,2-ADDITION OF Sb-PHENYL-1,5-
AZASTIBOCINES TO FUNCTIONALIZED ALDEHYDES
Naoki Kakusawa,a Shuji Yasuike,a,b and Jyoji Kuritaa*
a Faculty of Pharmaceutical Sciences, Hokuriku University, Kanagawa-machi
Ho-3, Kanazawa 920-1181, Japan; E-mail: j-kurita@hokuriku-u.ac.jp
bOrganization for Frontier Research in Pharmaceutical Sciences, Hokuriku
University, Kanagawa-machi Ho-3, Kanazawa 920-1181, Japan
This paper is dedicated to Professor Emeritus Akira Suzuki on the occasion of his
80th birthday.
Abstract – Simple and efficient addition of a phenyl group to aldehydes was
accomplished by the rhodium-catalyzed reaction of Sb-phenyl-1,5-azastibocines.
Because of the soft nucleophilic character of 1,5-azastibocines, arylation of
functionalized aldehydes having ketone, ester, and halogen moieties can be
achieved to afford aryl alcohols. The reaction can be carried out under aerobic
conditions, in striking contrast to the reactions with hard nucleophiles such as
organolithium and Grignard reagents.
Chemoselective addition of aryl anion equivalent to mutifunctionalized carbonyl compounds is one of the
most challenging reactions in organic synthesis, because the direct formation of aryl alcohols is expected
by nucleophilic addition in a single step.1 For arylation of unstable carbonyl compounds with a complex
structure, nucleophiles must be compatible with various functional groups, such as aldehydes, ketones,
esters, nitriles, enones, and halogens. Application of hard organometallic reagents, including
organolithiums and Grignard reagents, will be limited due to their strong nucleophilicity and basicity,
which often bring about undesirable side reactions, such as metallation of other susceptible functional
groups and decomposition of labile target molecules.2 Development of soft nucleophiles is desired, by
which arylation of only specific carbonyl groups will become possible without a tedious
protection-deprotection procedure.3

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According to Pauling’s electron negativity,4 the carbon atom of the Sb-C bond is slightly negatively
charged, so organoantimony compounds exhibit soft nucleophilic characteristics. For example,
pentaarylstiboranes, one of the most reactive hypervalent organoantimony compounds, can react with
various acyl chlorides and aldehydes which are activated with Lewis acids. In this reaction, aryl groups
on pentaarylstiborane are considered to behave as aryl anion equivalents.5 Taking advantage of this soft
nucleophilic property of organoantimony compounds, we have previously reported 1,4-addition of
Sb-aryl-1,5-azastibocines to electron-deficient olefins under a rhodium catalyst.6 The result implies that
not only the aryl group on the 1,5-azastibocine furnishes soft nucleophilic properties, but also the
antimony atom bears highly reactive hypervalent characteristics. Indeed, the antimony atom in
1,5-azstibocine exhibits tetravalent psuedo-trigonal bipyramidal structure with intramolecular
coordination between antimony and nitrogen, as shown compound 1 in Table 1 and 2.7 As a part of our
continuous study on organoantimony compounds as useful organic reagents,8 we next planned the
1,2-addition of 1,5-azastibocines to carbonyl compounds.
Researches on 1,2-addition using main group compounds to aldehydes have been flourishing recently. 9
Organo-boron,10 -aluminum,11 -stannum,12 and -silicon13 compounds have been reacted with aldehyde in
the presence of transition metal catalysts, such as rhodium and palladium, to afford aryl alcohols. These
main group compounds are generally stable in air and water. The high stability and reactivity of main
group compounds under ambient conditions could possibly provide a straightforward method for
1,2-addition of aldehydes and might be a promising alternative for organolithium and Grignard reagents
which require strict anhydrous conditions along with an inert atmosphere.
The reaction of Sb-phenyl-1,5-azastibocine (1) with benzaldehyde (2a) was chosen as the model reaction
to investigate suitable reaction conditions. The mixture was refluxed in 1,2-DCE (dichloroethane) under
aerobic conditions without a transition metal catalyst, but no reaction occurred (Table 1, entry 1).
However, we found that rhodium catalysts, especially [RhCl(cod)]2, promoted the 1,2-addition to give the
expected benzhydrol (3a) in 70% yield in an atmospheric environment (entry 9) and that similar reactions
using nickel and palladium catalysts gave no product (entries 2-6).
The effect of phosphine ligand was investigated to facilitate the arylation of 2a. The addition of 5 mol%
of triphenylphosphine (TPP) improved the yield of 3a to 84% yield (entry 11). In contrast, the yield of 3a
was decreased by the further addition of TPP (10 mol%) and the reaction was completely inhibited by
excess addition of TPP (20 mol%) (entries 12, 13). As Ueda and Miyaura have reported, the
electron-donating phosphine ligand is considered to enhance the nucleophilicity of the aryl group on a
rhodium catalyst; however, excess phosphine ligand may block the aldehyde to coordinate with rhodium
metal.14 Thus, addition of an appropriate amount of phosphine ligand (5 mol%) might keep the balance
between the high nucleophilicity of the aryl group and effective coordination of aldehydes to the rhodium

HETEROCYCLES, Vol. 80, No. 1, 2010
165
catalyst. Electron-rich monodentate phosphines, such as tris(methoxyphenyl)phosphines and
tri(n-butyl)phosphine, were excellent ligands for the present reaction, but bulky phosphines and bidentate
phosphines with a large bite angle were not effective (entries 14−21).
Table 1. Investigation of various transition metal catalysts and phosphine ligands
t-Bu
[RhCl(cod)]2 (5 mol%)
O
N
OH
Ph
3a
Ph
H
Sb
Ph
1,2-DCE, 80 C
°
1
2a
Ph
Phosphine ligand
Entry
Catalyst
Time (h)
Yield (%)
(5 mol%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
----
----
----
----
----
----
----
----
----
----
24
24
24
24
24
24
7
7
7
7
0
0
0
0
0
0
NiCl2(PPh3)2
[Ni(cod)]2
Pd(OAc)2
PdCl2(PPh3)2
Pd(PPh3)4
RhCl(PPh3)3
[Rh(OH)(cod)]2
[RhCl(cod)]2
Rh(cod)2BF4
[RhCl(cod)]2
47
65
70
65
84
35
0
91
89
90
50
76
79
76
68
----
Ph3P
5
5
5
5
Ph3P (10 mol%)
Ph3P (20 mol%)
(2-MeOC6H4)3P
(4-MeOC6H4)3P
n-Bu3P
t-Bu3P
5
5
5
4
Cy3P
dppe
dppf
±BINAP
5
5
5
We also screened suitable solvents under similar reaction conditions using Ph3P (5 mol%) as the
phosphine ligand. Polar solvents, such as NMP (N-methyl-2-pyrrolidinone) and DMF, were the preferred
solvents in the 1,4-conjugate addition of 1,5-azastibocines with electron-deficient olefins;6 however, they
were unsuitable for the present 1,2-addition, e.g., NMP (5 h, 33%) and DMF (9 h, 0%). In hydrocarbon
solvents, such as benzene (7 h, 56%) and hexane (7 h, 39%), 3a was formed in moderate yield. The
arylation proceeded smoothly in ethereal solvents such as 1,2-DME (7 h, 78%), 1,4-dioxane (4 h, 68%).
Consequently, the best result was obtained when 1,2-DCE was employed (5 h, 84%) as a solvent.
However, other halogen solvents, such as chloroform (5 h, 40%) and carbon tetrachloride (5 h, 2%), gave

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3a in modest yield and the major product was Sb-chloro-1,5-azastibocine, probably derived from
homolytic cleavage of the Sb-phenyl bond of 1,5-azastibocine, followed by chlorine abstraction from
chloroform and carbon tetrachloride.
Under the optimized conditions examined here,15 we next examined the reaction of 1 with various
aromatic (2a−h) and aliphatic aldehydes (2i, j) to reveal the generality and electronic effect of the present
reaction. Electronically neutral and deficient aromatic aldehydes (2a−e) underwent 1,2-addition
efficiently to afford benzhydrols (3a−e) in excellent yield (Table 2, entries 1−5). Even electron rich and
sterically hindered o-substituted aldehydes (2f−h) gave the corresponding 1,2-adducts (3f−h) in
satisfactory yield (entries 6−8). When the aryl bromide was treated with phenyllithium or
phenylmagnesium bromide, a halogen-metal exchange reaction could occur; however, the reaction of
1,5-azastibocine with p-bromobenzaldehyde (2e) gave the 1,2-adduct (3e) with the halogen moiety
unchanged (entry 5). Ketone and ester moieties tolerated the reaction conditions, so no care was needed to
protect these carbonyl groups in the formal nucleophilic addition of aryl anion equivalent to aldehyde
(entries 2, 3). Aliphatic aldehydes (2i, j) were moderately reactive substrates and the reaction required a
prolonged reaction time; however, it is noteworthy that no aldol product was observed even in the
presence of α-hydrogen in the present arylation.
Table 2. Reaction of Sb-phenyl-1,5-azastibocine (1) with various aldehydes (2a-j)
t-Bu
[RhCl(cod)]2 (5 mol%)
n-Bu3P (5 mol%)
O
N
OH
Ph
3a-j
H
R
R
Sb
1,2-DCE, 80 C
°
1
2a-j
Ph
Aldehyde
Yield (%)
90
Entry
Time (h)
5
Entry
Aldehyde
Time (h) Yield (%)
a:
f:
g:
h:
i:
5
4
73
70
85
54
1
2
3
4
CHO
CHO
6
7
8
9
Me
CHO
Ac
b:
c:
d:
2.5
86
83
90
MeO
CHO
Me
3.5
3
5
AcO
F3C
CHO
CHO
CHO
16
CHO
5
e:
5
86
10
j:
PhCH2CHO
5
68
Br
CHO

HETEROCYCLES, Vol. 80, No. 1, 2010
167
These results suggest that Sb-aryl-1,5-azastibocine can behave as a soft nucleophile which reacts only
with aldehyde with high functional compatibility. The catalytic cycle of arylation with 1,5-azastibocine
might be similar to that with other main group compounds10, 16 and the details of the mechanism and
compatibility with other functional groups will be discussed in due course.
ACKNOWLEDGEMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for
the Promotion of Science (JSPS) (to J. K.); the “Academic Frontier” Project for Private Universities from
the Ministry of Education, Culture, Sports, Sciences and Technology of Japan (to S. Y.). Financial
support was also provided by the Specific Research Fund of Hokuriku University (to N. K.). All are
gratefully acknowledged.
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