Synthesis of alkyl iodides/nitriles from carbonyl compounds using novel ruthenium tris(2,2,6,6-tetramethyl-3,5-heptanedionate) as catalyst

Article abstract of DOI:10.1016/j.tetlet.2008.09.002

Aldehydes and ketones were hydrogenated to the corresponding alcohols, which were then transformed in situ into their respective iodides and nitriles in good yields. A structurally well-defined O-containing transition metal complex, Ru (TMHD)₃, was found to be the active catalyst for hydrogenation, iodination and cyanation reactions. It has high affinity for the transformation of benzylic alcohols to iodides and nitriles.

Full text of DOI:10.1016/j.tetlet.2008.09.002

Tetrahedron Letters 49 (2008) 6475–6479
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Tetrahedron Letters
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Synthesis of alkyl iodides/nitriles from carbonyl compounds using novel
ruthenium tris(2,2,6,6-tetramethyl-3,5-heptanedionate) as catalyst
Malhari D. Bhor, Anil G. Panda, Nitin S. Nandurkar, Bhalchandra M. Bhanage *
Department of Chemistry, Institute of Chemical Technology, University of Mumbai, N. Parekh Marg, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Revised 29 August 2008
Accepted 1 September 2008
Available online 3 September 2008
Aldehydes and ketones were hydrogenated to the corresponding alcohols, which were then transformed
in situ into their respective iodides and nitriles in good yields. A structurally well-defined O-containing
transition metal complex, Ru (TMHD) , was found to be the active catalyst for hydrogenation, iodination
3
and cyanation reactions. It has high affinity for the transformation of benzylic alcohols to iodides and
nitriles.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Alkyl iodides
Alkyl nitriles
Ru(TMHD)
3
Hydrogenation
Carbonyl compounds
Alkyl halides are versatile intermediates in organic synthesis,
and their transformation to useful compounds is well reported in
the literature. They also serve as important intermediates in the
achieved using different routes including the direct conversion of
aldehydes, oxime ethers, thioamides, carboxylic acids and their
esters, dehydration of aldoximes and amides, oxidation of amines,
reduction of primary aliphatic nitro compounds, enzymatic meth-
1
synthesis of fine chemicals and pharmaceuticals to treat diseases
such as cancer, HIV,3 diabetes4 and arthritis.5 Amongst alkyl
halides, alkyl iodides are of prime importance to synthetic chem-
ists due to their application in substitution, elimination, coupling
reactions, etc. Similarly, alkyl nitriles are useful intermediates for
transformation into various functional groups such as acid, amide,
2
7,8
ods and by application of organoborane/diazoacetonitrile.
Various methods have been demonstrated for the iodination of
9
10
11
alcohols such as BF
3
–Et
2
O/NaI, BF
3
–Et
2
O/CsI, BF
3
–Et
2
O/KI,
PI –Et
4
/DDQ/R N X ,
4
P /
1
2
13
14
15
16
I
C
2
,
Cl
2
SO–DMF/KI, MgI
2
,
HI, ClSiMe
3
/NaI,
/NaI, PPh
and NaI/Amberlyst-15.
R
3
2
2
O or
1
7
18
19
+
À 20
23
6
H
6
/HMPA, CeCl
3
Á7H
2
O/NaI, ZrCl
4
22
3
6
21
amine and amidines, and also into N-containing heterocycles.
3
PPh /DEAD/LiI,
I
2
/petroleum ether
Introduction of the nitrile group into organic compounds can be
Also, there are a few reports on one-pot conversions of alcohols
I
NaI
OH
O
R1
R2
Ru(TMHD)3
Ru(TMHD)3
THF, 400 psi H2
R1
R2
CN
R1
R2
CuCN
1
2
R , R = alkyl, aryl
R1
R2
Scheme 1. Synthesis of alkyl iodides/nitriles from carbonyl compounds.
*
Corresponding author. Tel.: +91 22 24145616; fax: +91 22 24145614.
E-mail address: bhalchandra_bhanage@yahoo.com (B. M. Bhanage).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.002

6
476
M. D. Bhor et al. / Tetrahedron Letters 49 (2008) 6475–6479
25
Table 1
to nitriles using HCN/PPh
3
/DEAD,24 acetone cyanohydrin, CCl
4
/
Optimization of the hydrogenation of benzaldehydea
26
27
PPh
DDQ, Me
3
/NaCN,
n-Bu
3
P/CCl
4
/KCN/18-crown-6,
PPh
,
3
4
/n-Bu NCN/
2
8
29
30
31
Entry
Catalyst
Solvent
Temperature (°C)
Time (h)
Yieldb (%)
3
SiCl/NaI/NaCN, TsIm/NaCN, NH
3
/I
2
NH /1,3-diio-
3
3
2
do-5,5-dimethyl hydantoin, etc. However, these methods suffer
from major disadvantages such as the presence of hazardous and
toxic I and HCN vapours, risk of explosion in the case of DEAD,
2
lower yields, harsh reaction conditions, non-commercially avail-
able materials and tedious work-up procedures, for example, in
Influence of catalyst
1
2
3
4
5
RuCl
Ru(acac)
Ru(TMHD)
Ru(TMOD)
Pd(TMHD)
3
THF
THF
THF
THF
THF
80
80
80
80
80
4
4
4
4
4
18
70
96
85
65
3
3
3
2
3 3
the separation of Ph P@O, unreacted Ph P and products.
Influence of solvent
Thus, developing novel and greener methods, which have high-
er efficiency, selectivity, less toxicity and easy to handle and com-
mercially available materials, is still a challenging task. Previously,
we reported metal-TMHD catalyzed transformations in organic
The use of 2,2,6,6-tetramethyl-3,5-heptanedione
TMHD) as a ligand resulted in excellent yields of products and
6
7
8
9
Ru(TMHD)
3
3
3
3
CH
DMF
Toluene
3
CH OH
3
CN
80
80
80
80
4
4
4
4
62
71
82
79
Ru(TMHD)
Ru(TMHD)
Ru(TMHD)
3
3
Influence of temperature
synthesis.
1
1
0
1
Ru(TMHD)
Ru(TMHD)
3
3
THF
THF
60
90
4
4
80
97
(
such reactivity could be attributed to the fact that a good balance
exists between the steric and electronic properties of the complex.
Moreover, it is also a good substitute for various phosphine-based
protocols.
Influence of time
1
1
1
2
3
4
Ru(TMHD)
Ru(TMHD)
Ru(TMHD)
3
3
3
THF
THF
THF
80
80
80
2
3
5
72
84
98
In continuation of our work on hydrogenation reactions,34 and
a
Benzaldehyde (5 mmol), catalyst (1 mol %), solvent (20 ml), 400 psi
00 rpm.
GC yield.
H
2
,
33
exploring metal-TMHD as a catalyst for organic reactions, we
herein report a novel methodology for the synthesis of alkyl io-
5
b
dides/nitriles via hydrogenation using Ru(TMHD)
3
as the catalyst
Table 2
a,35
Hydrogenation of carbonyl compounds
Entry
Carbonyl compound
Product
Time (h)
Yieldb (%)
96
1
CHO
CH OH
4
4
4
4
5
5
2
2
3
4
5
6
HO
Cl
CHO
CHO
HO
Cl
CH OH
92
90
95
72
86
2
CH OH
2
H CO
CHO
H CO
CH OH
3
3
2
CHO
CH2OH
CHO
O
CH OH
2
O
S
7
8
9
5
5
5
82
92
90
CHO
S
CH OH
2
O
C
OH
CH3
CH3
O
C
OH
C
H

M. D. Bhor et al. / Tetrahedron Letters 49 (2008) 6475–6479
6477
Table 2 (continued)
Entry
Carbonyl compound
Product
Time (h)
4
Yieldb (%)
88
1
0
1
O
OH
1
O
OH
4
6
85
79
1
2
O
OH
a
3 2
Carbonyl compound (5 mmol), Ru(TMHD) 1 mol %, THF 20 ml, 400 psi H , 500 rpm, 80 °C.
GC yield.
b
(
Scheme 1).33e Using this method, carbonyl compounds were
3
good yields. The Ru(TMHD) catalyst was found to be highly active
hydrogenated to the corresponding alcohols, which were then
transformed in situ into their respective iodides and nitriles in
for both steps and hence the reactions could be carried out in a
sequential manner. To begin with, the catalytic activity, choice of
Table 3
Synthesis of alkyl iodides36
Entry
Carbonyl compound
Time (h)
—
Alcohol
Time (h)
6
Alkyl iodide
Yielda (%)
84
Ref.
10
1
—
OH
OH
I
I
2
3
4
5
6
CHO
4
4
4
4
5
5
6
82
80
78
81
77
61
10
10
10
10
10
10
HO
CHO
CHO
HO
8
HO
OH
I
Cl
Cl
Cl
10
8
OH
I
H CO
H CO
H CO
CHO
3
3
3
OH
I
O
C
OH
I
10
10
C
H
C
H
7
OH
I
CHO
a
Isolated yield.

6
478
M. D. Bhor et al. / Tetrahedron Letters 49 (2008) 6475–6479
solvent, reaction time and temperature were studied for the hydro-
genation step. The results are summarized in Table 1.
hyde was selectively hydrogenated to cinnamyl alcohol in 72%
yield (entry 5). Heterocyclic aldehydes such as furyl and thienyl
were also hydrogenated to alcohols in 86% and 82% yields, respec-
tively (entries 6 and 7). Ketones including acetophenone and ben-
zophenone were hydrogenated to the corresponding alcohols in
92% and 90% yields (entries 8 and 9). Cyclohexanone, cyclopenta-
none and 9-fluorenone were also hydrogenated to the correspond-
ing alcohols in 79–88% yields (entries 10–12).
Thus, after completion of the hydrogenation reaction, the
resulting mixture was treated with NaI or CuCN to afford alkyl io-
dides or nitriles in good yields (Tables 3 and 4).
Benzaldehyde was converted effectively to benzyl iodide in 82%
yield within 6 h after hydrogenation to benzyl alcohol (Table 3, en-
try 2). It was observed that a comparable yield of benzyl iodide was
obtained to that when commercially available benzyl alcohol was
Catalyst screening showed that Ru(TMHD)
lyst for hydrogenation of carbonyl compounds at 80 °C. RuCl
was poorly active, whereas Ru(acac) was found to give a 70% yield
of benzyl alcohol (entry 2). Ru(TMHD) was also compared with
3
was the best cata-
3
3
3
the Ru complex of 2,7,7-trimethyl-3,5-octanedione (TMOD), which
gave an 85% yield (entry 4). This result could be attributed to the
fact that the TMHD ligand increases the bulk of the complex and
results in high stability thereby increasing the catalytic efficiency
of the catalyst. Pd(TMHD)
of benzyl alcohol (entry 5). Ru(TMHD)
2
was also screened and gave a 65% yield
catalyst was found to give
3
good yields in the iodination and cyanation reactions compared to
that of other hydrogenation catalysts used in the present study,
which gave 40–60% yields of iodides/nitriles. The influence of sol-
vent has a great impact as it should be compatible for all the steps.
THF was found to be an excellent solvent for hydrogenation, iodin-
ation and cyanation and was used for further study. When metha-
nol was used as the solvent, acetal formation was observed,
whereas with acetonitrile, DMF and toluene, unreacted benzalde-
hyde was observed (entries 6–9). Hydrogenation at a lower tem-
perature 60 °C, gave a satisfactory yield, whereas increasing the
temperature to 90 °C did not improve the result (entries 3, 10
and 11). The influence of time shows that hydrogenation was com-
plete in 4 h.
3
treated with sodium iodide in the presence of Ru(TMHD) (entry
1). Similarly, substituted benzaldehydes such as 4-hydroxy, 4-
chloro and 4-methoxy were transformed into the corresponding
iodides after hydrogenation in good yield (entries 3–5). Benzophe-
none was hydrogenated to benzhydrol, which was then converted
to its iodide in 77% yield (entry 6). Cinnamaldehyde was trans-
formed into cinnamyl iodide in 61% yield after selective hydroge-
nation to cinnamyl alcohol (entry 7). These results indicate that
iodination of benzylic alcohols occurs smoothly in the presence
3
of Ru(TMHD) giving high yields of aliphatic iodides.
Carbonyl compounds such as aldehydes and ketones were
hydrogenated to the corresponding alcohols in short reaction times
Benzaldehyde was converted to phenylacetonitrile in 84% yield
within 10 h after hydrogenation to benzyl alcohol (Table 4, entry
2). A comparable yield of phenylacetonitrile obtained when com-
mercially available benzyl alcohol was treated with cuprous cya-
(Table 2). Benzaldehydes having substituents such as 4-hydroxy, 4-
chloro and 4-methoxy were hydrogenated to the corresponding
benzyl alcohols in 90–95% yields (entries 2–4). Selective hydroge-
3
nide in the presence of Ru(TMHD) as catalyst (entry 1).
34c
nation of cinnamaldehyde is a challenging task.
Cinnamalde-
Similarly, 4-methoxybenzaldehyde was transformed into the cor-
Table 4
Synthesis of alkyl nitriles37
Entry
Carbonyl compound
Time (h)
—
Alcohol
Time (h)
10
Alkyl nitrile
Yielda (%)
87
Ref.
27
1
—
OH
OH
CN
CN
2
3
4
5
6
CHO
4
4
5
5
5
4
10
11
12
12
10
13
84
82
75
58
78
70
27
28
28
27
28
28
H CO
H CO
H CO
CHO
3
3
3
OH
CN
O
C
OH
CN
C
H
C
H
OH
CN
CHO
O
C
CN
OH
CH3
CH3
CH3
7
O
OH
CN
a
Isolated yield.

M. D. Bhor et al. / Tetrahedron Letters 49 (2008) 6475–6479
6479
responding nitrile after hydrogenation in good yield (entry 3). Ben-
zophenone, cinnamaldehyde, acetophenone and cyclohexanone
were converted to their respective nitriles, yields of 58% to 78%
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3
tion metal complex Ru(TMHD) was found to show good catalytic
activity in hydrogenation, iodination and cyanation reactions un-
der mild conditions in a sequential one-pot fashion. Alkyl iodides
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3
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1
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(
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hydrogenation was transferred into a two-necked flask and cuprous cyanide
9
53.
(
896 mg, 10 mmol) was added. The resulting mixture was stirred at 80 °C for
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the desired time (Table 4). The reaction mixture was cooled, diluted with water
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vacuo to afford the product in good yield.
1
5. Stone, H.; Shechter, H. Org. Synth. 1963, 4, 323.