Indium-employed one-pot sequential double nucleophilic attack on a symmetrical dicarboxaldehyde

Article abstract of DOI:10.1055/s-2004-822931

A novel concept of one-pot sequential double nucleophilic attacks using two different nucleophiles to a molecule having identical functionalities was established via an indium-employed allylation strategy involving an HOAc quenching after the first allylation.

Full text of DOI:10.1055/s-2004-822931

LETTER
1223
Indium-Employed One-Pot Sequential Double Nucleophilic Attack on a
Symmetrical Dicarboxaldehyde
I
ndium-emplo
r
yed One
i
-pot Se
n
quential Dou
i
ble
N
u
v
c
leophilic
A
t
tack sarao Arulananda Babu, Makoto Yasuda, Ikuya Shibata, Akio Baba*
Department of Molecular Chemistry and Handai Frontier Research Center, Graduate School of Engineering, Osaka University,
2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
Fax +81(6)68797387; E-mail: baba@chem.eng.osaka-u.ac.jp
Received 28 February 2004
double allylation strategy. The allylation of aldehydes is a
worthwhile tactic in multi-step organic synthesis.3 Our
strategy engages the addition of HOAc in trapping the
mono allylation product to overcome the difficulty caused
by an unpredictable retro-allylation in the one-pot sequen-
tial double allylation.
Abstract: A novel concept of one-pot sequential double nucleo-
philic attacks using two different nucleophiles to a molecule having
identical functionalities was established via an indium-employed
allylation strategy involving an HOAc quenching after the first
allylation.
Key words: allylation, Barbier type reaction, homoallylic alcohol,
indium, one-pot reaction, terminal selectivity
R2
R1
In synthetic chemical reactions starting from multi-func-
tionalized compounds, each functional group should react
with appropriate reagents in a stepwise approach to obtain
the target molecules. In those cases, synthetic chemists are
involved in discovering the manifold,1 sequential chemi-
cal processes within one pot2 in which the isolation of in-
termediates can be avoided. A typical example of a multi-
step reaction is shown in Scheme 1. In the first step, the
chemoselective treatment of X controls the total success
of the process, and the subsequent reaction with Y affords
the desired product efficiently. A larger difference of re-
activity between FGa and FGb would enhance the selectiv-
ity. In contrast to this situation, the most challenging
problem exists when both functionalities have identical
reactivity. Hence, attacking one of the identical function-
alities located in two terminals of a symmetrical molecule
would be a very important selectivity concept, which may
be called ‘terminal selectivity’.
O
O
+M-O
O–M+
1
3
MnXm
R1
R2
MnXm
+M-O
Terminal selectivity
O
2
Scheme 2
To execute the concept of double nucleophilic attack, it is
necessary to establish the selective mono allylation condi-
tions for the dicarboxaldehyde 4. Initially, we anticipated
treating with one equivalent of an allyl Grignard reagent
to test the selective mono allylation (Scheme 3). How-
ever, it ended up with a modest selectivity in spite of low
yield, which gave us the impetus to look for new options
and reagents to achieve our goal.
HO
X
Y
MgCl
1 equiv
HO
FGa
FGb
FGa
X
FGb
Y
CHO
+
Et2O
0 °C to r.t., 26 h
Y
X
FGa
X
FGb
CHO
4
CHO
33% (5a:6a; 67:33)
HO
FGa FGb; chemoselectivity
FGa = FGb; terminal selectivity
Scheme 3
Scheme 1
Recently, indium metal-promoted reactions have emerged
as appealing processes imparting a wide range of selectiv-
ity.4 With this option, we initially carried out the reactions
of the dicarboxaldehyde 4 (0.2 g) with allyl bromide or al-
lyl iodide (1.6 equiv) and indium (1 equiv) in DMF or
THF–H2O.5 Not surprisingly, poor selectivities were ob-
served (Table 1). It is interesting to find that allyl chloride
in DMF in the presence of NaI furnished good selectivity.
Although additive such as NaI has been reported for the
We aimed to develop a concept of one-pot sequential dou-
ble nucleophilic attack on a symmetrical molecule having
identical functionalities (Scheme 2). In this paper we re-
port our preliminary results of an indium–HOAc based
SYNLETT 2004, No. 7, pp 1223–1226
0
3.
0
6.
2
0
0
4
Advanced online publication: 10.05.2004
DOI: 10.1055/s-2004-822931; Art ID: U06204ST
© Georg Thieme Verlag Stuttgart · New York

1224
S. A. Babu et al.
LETTER
Table 1 Establishment of Mono Allylation and the Effect of Allyl Halide/Solvent/Additivea
R1
R1
R2
R2
HO
HO
HO
R2
R1
X
CHO
5a,6a: R1 = R2 = H
5b,6b: R1 = R2 = Me
5c,6c: R1 = Me, R2 = CH2CH2CH=C(Me)2
+
solvent/additive
In, r.t.
CHO
CHO
R1
R2
6a–c
4
5a–c
Entry
Halide
Equiv
Solvent
Additive
Time (h)
Yield (%)
Ratio (5:6) b
1
2
3
1.6
1.6
1.6
THF–H2O
DMF
DMF
None
None
Nal
19
24
2
28
52
74
78:22
63:37
57:43
Br
4
1.6
DMF
None
2
81
58:42
I
5
6
1.6
1.8
DMF
DMF
None
Nal
45
96
<5
68
–
Cl
>95:5
7
8
9
1.6
1.6
1.6
THF–H2O
DMF
DMF
None
None
Nal
23
48
1.5
<5
11
84
–
Br
>95:5
>95:5
10
1.6
DMF
Nal
48
27
>95:5
Cl
11
12
1.7
1.7
DMF
DMF–H2O
Nal
Nal
19
15
33
84
>95:5
>95:5
Br
a All reactions were performed with 1.5 mmol of aldehyde in 7–9 mL of solvent at 26–28 °C.
b Ratio based on NMR spectra of crude reaction mixtures.
selective mono allylation of 1,2-diones with allyl bro- Encouraged by the mono allylation condition, we next be-
mide, we observed only non-selective reactions (entry came concerned with the main objective of the sequential
3).6a It is interesting to note that the reaction involving reaction; treating two different allyl sources such as pre-
allyl chloride furnished good selectivity in the presence of nyl bromide and allyl bromide with the dicarboxaldehyde
NaI, and the prolonged reaction time accounts for the 4 in one-pot. To a DMF solution containing the dicarbox-
gradual generation of allylic indium source to afford the aldehyde 4 and NaI were added prenyl bromide and indi-
mono allylation product 5a.7 Similarly, the reaction in- um powder. After stirring for 1.5 hours at room
volving prenyl chloride gave good selectivity but a poor temperature, NaI, allyl bromide and indium powder were
yield of product 5b was obtained, perhaps due to its very added to the reaction mixture. The stirring was continued
low reactivity. Consequently, in the presence of NaI in for a further 2 hours, this reaction gave us a disappointing
DMF we established very good mono allylation selectivi- result. Formation of a mixture of products 7a and 6a in the
ties in the case of prenyl bromide8 as well as geranyl ratio of 67:33 was observed (Scheme 4).
bromide furnishing the products 5b (84%) and 5c (84%,
The formation of 6a may be due to considerable retro-al-
entries 9 and 12).6b,c In the case of geranyl bromide a small
lylation of the transient intermediate homoallyloxy metal
amount of water (0.4 mL) essentially promoted the
reaction.
species 2 (Scheme 2) when the next highly reactive allylic
indium is introduced. To overcome this retro-allylation,
our strategy is after completing the first nucleophilic at-
tack to quench the metal-adduct 2 by a protic reagent, then
HO
HO
Br
CHO
Br
(1.65 equiv)
In (1 equiv)
to introduce the second nucleophile. We found that
quenching the first step allylation by HOAc and subse-
quent introduction of the next nucleophile furnished the
unsymmetrical allylation product 7a with a high degree of
selectivity and yield.9,10 The presence of protic species
will not affect the second allylation since an indium-pro-
moted Barbier type allylation is well known to tolerate the
(1.6 equiv)
+
In (1 equiv)
HOAc
30 min
NaI (1.6 equiv)
DMF (7 mL)
1 h
NaI (1.65 equiv)
2 h
CHO
HO
HO
6a
4
7a
81% (7a:6a; >95:5)
83% (7a:6a; 67:33) without HOAc
Scheme 4
Synlett 2004, No. 7, 1223–1226 © Thieme Stuttgart · New York

LETTER
Indium-Employed One-Pot Sequential Double Nucleophilic Attack
1225
protic conditions. This is the reason why the quenching Subsequently, we performed interesting reactions of pre-
process is successfully applicable in this one-pot reaction. nyl bromide and propargylic sources such as 1-bromobut-
2-yne or 1-bromopent-2-yne to give the novel bis-ho-
moallylic-allenic alcohols 7d,e. In line with these experi-
Encouraged by the success of the prenylation–allylation
reaction, we further investigated various combinations of
ments, the combinations of geranylation–allylation as
allylic nucleophiles in the one-pot reaction (Table 2).11
well as geranylation–prenylation gave the products 7f–h,
Combination of prenylation–geranylation afforded a
novel unsymmetrical bis-homoallylic alcohol 7c (80%).
respectively. In the case of geranyl bromide as the first nu-
cleophile, addition of a small amount of water (0.4 mL)
Table 2 One-pot Sequential Double Nucleophilic Attack on a Symmetrical Dicarboxaldehyde
R1
R2
R1X/Indium
R2X/Indium
Acetic acid
O
O
HO
OH
4 or 8
7
Entry
1
Bis-aldehyde
R1X
R2X
Producta
Yield (%)
81
7a
7b
Br
Br
HO
OH
OH
OHC
CHO
4
4
2
3
72
80
Br
Br
HO
Br
4
7c
HO
OH
Br
Br
4
5
6
4
4
4
7d
7e
7f
74
72
83
Br
Br
HO
HO
OH
OH
•
•
Br
Br
Br
HO
OH
Br
7
8
9
4
4
Geranyl bromide
Geranyl bromide
Geranyl bromide
7g
7h
7i
83
85
73
HO
HO
OH
OH
Br
Br
OHC
CHO
OH
OH
OH
8
10
8
Geranyl bromide
7j
71
Br
OH
a Isolated as a mixture of diastereomers in the ratio of 1:1, in addition stereoisomers in the ratio of ca. 75:25 were observed in the case of geranyl
bromide as the nucleophile.
Synlett 2004, No. 7, 1223–1226 © Thieme Stuttgart · New York

1226
S. A. Babu et al.
LETTER
(5) The reaction was sluggish and even dropwise addition of
was essential, and later HOAc was added to quench the
first geranylation before introducing second nucleophiles.
Furthermore, treatment of 1,3-benzenedicarboxaldehyde
(8) with geranyl bromide and the second allylic sources
such as allyl bromide or 3-bromo-2-methylpropene also
afforded the respective products 7i, and 7j; in these reac-
tions a considerable amount of bis-geranylation product
was obtained. In all of the reactions we obtained 1:1 mix-
ture of diastereomers; in addition, in the reactions involv-
ing geranyl bromide, the formation of stereoisomers in the
ratio of ca. 75:25 was observed. These results show that
the sequential introduction of two nucleophiles to obtain
the unsymmetrical bis-homoallylic as well as homoallyl-
ic-allenic alcohols within one-pot is possible.
prenyl bromide did not furnish good results.
(6) (a) Nair, V.; Ros, S.; Jayan, C. N.; Viji, S. Synthesis 2003,
2542. (b) Perhaps the success for the mono allylation
(Table 1) could be due to the relatively low reactivity of allyl
chloride as well as dilute reaction medium; however, in the
case of prenyl halides, both prenyl chloride and bromide
seem to be less reactive towards indium to form the
respective allylicindium. (c) From the results presented in
Table 1 (entries 5, 6 as well as 8, 9) addition of NaI enhances
the yield of products 5a–c, and it reveals that halide
exchange (Cl–/Br– of allyl/prenyl halide into the
corresponding allyl/prenyl iodide) takes place.
(7) It is well known that halide exchange is very fast, but we
observed the slow and gradual conversion of allyl chloride
into allyl iodide under the conditions as monitored by the 1H
NMR spectrum at regular intervals over 24 h by shaking NaI
with allyl chloride in DMF-d7.
(8) Mono prenylation of aliphatic dialdehyde such as
glutaraldehyde (50% aq solution) was established, however,
cyclic product 6-(1,1-dimethylallyl)tetrahydropyran-2-ol
was obtained. Double allylation of aliphatic dialdehydes will
be revealed in full account elsewhere.
(9) We performed the quenching with other protic sources such
as H2O and aq HCl; however, in these conditions we
observed the formation of mixtures of allylation products.
(10) When acetic acid was added immediately after the addition
of indium in the first step, this experiment revealed the
formation of a bis-prenylation product as well as 7a.
(11) General Procedure for the Double Nucleophilic
Allylation. To a DMF (7 mL) solution containing the
dicarboxaldehyde 4 (0.2 g), NaI (1.6 equiv) were added
prenyl bromide (1.6 equiv) and indium powder (1 equiv).
The reaction mixture was stirred for 1 h at r.t.; then HOAc
(0.6 mL) was added and the stirring was continued for 30–45
min. After this period, to the above reaction mixture were
added NaI (1.65 equiv), allyl bromide (1.65 equiv), indium
powder (1 equiv) and stirred for further 2–3 h. Followed by
this period, the reaction mixture was treated with H2O and
extracted with Et2O, followed by concentration to afford a
crude reaction mixture. The obtained mixture was subjected
to column chromatographic purification to furnish the pure
products. All new compounds exhibited spectral data
consistent with their structures. Representative
In conclusion, a novel concept for the one-pot double nu-
cleophilic attack on a dicarboxaldehyde with two different
allylic or propargylic reagents has been developed, which
is coupled with the simplicity of the procedure. Currently,
we are involved in further elaboration and application of
these new and exciting one-pot sequential reactions to the
other systems.
Acknowledgment
This work was supported by a Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science, and
Technology, Japan. Thanks are due to Mr. H. Moriguchi, Faculty of
Engineering, Osaka University, for assistance in obtaining MS
spectra.
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spectroscopic data of 1-[4-(1-hydroxybut-3-enyl)-
phenyl]-2,2-dimethylbut-3-en-1-ol (7a). IR:(neat): 3398,
2978, 1639, 1415, 1052, 914 cm–1. 1H NMR (270 MHz,
CDCl3): d = 7.22 (4 H, s, arom-CH), 5.87 (1 H, dd, J1 = 18.0
Hz, J2 = 10.5 Hz, =CH), 5.80–5.68 (1 H, m), 5.13–4.99 (4 H,
m), 4.65 (1 H, t, J = 6.5 Hz, HOCH), 4.36 (1 H, s, HOCH),
2.50 (2 H, br s, OH), 2.45 (2 H, t, J = 6.8 Hz), 0.97 (3 H, s,
CH3), 0.92 (3 H, s, CH3). 13C NMR (67.9 MHz, CDCl3):
d = 144.84 (=CH), 142.78 (quart-C), 139.88 (quart-C),
134.34 (=CH), 127.62 (=CH), 124.80 (=CH), 118.02
(=CH2), 113.59 (=CH2), 80.31 (HOCH), 73.00 (HOCH),
43.63 (CH2), 42.07 (quart-C), 24.30 (CH3), 21.10 (CH3). MS
(CI): m/z (%) = 247 (1) [M+ + 1], 229 (84), 211 (14), 187 (6),
159 (100), 131 (2). HRMS (CI): m/z calcd for C16H23O2:
247.1698. Found: 247.1693 [M+ + 1].
Synlett 2004, No. 7, 1223–1226 © Thieme Stuttgart · New York