Reductive Coupling of Acid Chlorides with Nitriles Promoted by Titanium Tetraiodide. A Rapid Access to α-Imino Ketones

Article abstract of DOI:10.1246/cl.2003.1088

Reductive coupling reactions of carboxylic acid chlorides and alkyl nitriles were efficiently promoted by titanium tetraiodide to give α-imino ketones in good yields.

Full text of DOI:10.1246/cl.2003.1088

1088
Chemistry Letters Vol.32, No.11 (2003)
Reductive Coupling of Acid Chlorides with Nitriles Promoted by Titanium Tetraiodide.
A Rapid Access to ꢀ-Imino Ketones
Makoto Shimizu,ꢀ Nobuyuki Manabe, and Hiroshi Goto
Department of Chemistry for Materials, Mie University, Tsu 514-8507
(Received September 12, 2003;CL-030858)
Reductive coupling reactions of carboxylic acid chlorides
and alkyl nitriles were efficiently promoted by titanium tetraio-
dide to give ꢀ-imino ketones in good yields.
Table 1. Comparison of reaction conditionsa
O
O
TiI4 / CH3CN
Quench
Ph
2a
Ph
Cl
−40 °C − rt , Time
NH
2a/%b
1a
Reductive coupling reaction of carbonyl compounds is one
of the most useful methods for the construction of carbon frame-
works.1 Such reactions often use low valent metals as reducing
reagents, because the reactions in most cases proceed via a single
electron transfer mechanism. Whereas it has already been report-
ed that the reductive coupling of nitriles with ketones are pro-
moted by low valent titanium2 or samarium3 to give ꢀ-hydroxy
ketones, acid chlorides undergo a coupling reaction with ketones
in the presence of samarium diiodide in acetonitrile to give also
ꢀ-hydroxy ketones.4 Although nitriles were used as solvents in
the latter reaction, coupling products arising from nitriles were
not obtained. If nitriles work as substrates for the coupling reac-
tion with acid chlorides, ꢀ-imino carbonyl compounds would be
formed, which are useful synthetic intermediates for several or-
ganic transformations.5,6 We have been interested in reactions
using titanium tetraiodide, which possesses good reducing abil-
ity,7 and have already reported selective reductions8 involving
carbon–carbon bond formations such as the pinacol coupling re-
action.9 We have now found that titanium tetraiodide promotes
the reductive coupling reaction of carboxylic acid chlorides with
alkyl nitriles to give ꢀ-imino ketones (Eq 1), and wish to de-
scribe herein such a reaction in detail.
Entry
TiI4/equiv.
Time/h
18.0
21.0
22.5
23.0
20.0
21.5
22.0
22.0
22.0
Quench with
1
2
3
4
5
6
7
8
9
1.0
2.0
3.0
4.0
5.0
2.0
2.0
2.0
2.0
aq NaHCO3
aq NaHCO3
aq NaHCO3
aq NaHCO3
aq NaHCO3
CH3COCl
(CH3CO)2O
TMSCl
(CF3CO)2O
33
43
44
31
32
36
52
40
28
aReaction was carried out according to the typical procedure.11
bIsolated yield.
Table 2. Reductive coupling reaction of various nitriles and
carboxylic acid chloridesa
O
O
(CH3CO)2O
(5.0 eq)
TiI4 (2.0 eq) / R2CN
R2
NH
R1
Cl
R1
rt , 6 h
t, Time
1
2
Entry
1
2
3
4
5
6
7
8
R1
R2
t/ꢂC Time/h 2/%b
Ph
Ph
Ph
CH3
C2H5
C3H7
ꢁ40–rt
ꢁ78–rt
ꢁ78–rt
21.0
22.0
23.0
21.0
20.5
21.0
23.0
23.0
21.5
22.0
22.0
21.5
22.0
21.5
22.0
23.0
24.0
24.0
52
54
25
61
20
40
12
0
42
69
66
71
55
23
43
21
11
35
O
O
R2
Reductive Coupling
R2CN
R1
R1
Cl
+
(1)
Ph
Ph
Ph
Ph
Ph
Ph
(CH3)2CH ꢁ70–rt
NH
1
(CH3)3C
ClCH2
Cl2CH
Cl3C
rt
2
When benzoyl chloride was treated with 1 equiv. of titanium
ꢁ60–rt
ꢁ30–rt
ꢁ40–rt
tetraiodide in acetonitrile, ꢀ-imino ketone 2a was formed. The
amount of titanium tetraiodide and the reaction temperature
were first screened, and the results are summarized in Table 1.1
The reaction using 2.0 equiv. of titanium tetraiodide gave
the ꢀ-imino ketone 2a in 43% yield (Entry 2). However, the
use of an increased amount of titanium tetraiodide did not no-
ticeably increase the yields (Entries 3–5). Regarding the reaction
temperature, the best of yield was obtained when the reaction
was carried out at ꢁ40 ꢂC to room temperature. In an effort to
increase the product yields, the quenching procedure was exam-
ined. Among the procedures, quenching the reaction with acetic
anhydride was found to be effective, giving the coupling product
in 52% yield (Entry 7).10 Under the optimum conditions, reac-
tions with various aliphatic nitriles were carried out, and the re-
sults are summarized in Table 2.
9
CH3OCH2 ꢁ50–rt
(CH3)2CH ꢁ70–rt
(CH3)2CH ꢁ70–rt
(CH3)2CH ꢁ70–rt
(CH3)2CH ꢁ70–rt
(CH3)2CH ꢁ70–rt
(CH3)2CH ꢁ70–rt
10
11
12
13
14
15
16
17
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-CH3C6H4
4-CH3OC6H4
2-Naphthyl
trans-PhCH=CH (CH3)2CH ꢁ70–rt
CH2=CH
(CH3)2CH ꢁ70–rt
18 trans-C3H7CH=CH (CH3)2CH ꢁ70–rt
aReaction was carried out according to the typical procedure.11
bIsolated yield.
acetonitrile and methoxyacetonitrile, also proceeded to give the
coupling products in moderate yields, whereas trichloroacetoni-
trile did not give the desired product (Entries 6–9). When unsat-
urated nitriles such as acrylonitrile and crotononitrile were used,
The reaction in isobutyronitrile gave the best yield of 61%
(Entry 4). Pivalonitrile, a bulky nitrile, gave a lower yield (Entry
5). Reactions in nitriles possessing heteroatoms, such as chloro-
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.11 (2003)
1089
(1998).
S. M. Ruder, Tetrahedron Lett., 33, 2621 (1992).
the coupling reaction did not proceed. The reaction of aromatic
acid chloride in most cases gave the good yields of the products.
In particular, better yields were obtained using the aromatic acid
chlorides possessing electron withdrawing groups (Entries 10–
12). Although the yields were not always good, unsaturated acid
chlorides gave coupling products without affecting the double
bonds (Entries 16–18). However, the aliphatic acid chlorides
were not good substrates for the present reaction.
4
5
a) Y. Niwa and M. Shimizu, J. Am. Chem. Soc., 125, 3720
(2003). b) Y. Niwa, K. Takayama, and M. Shimizu, Bull.
Chem. Soc. Jpn., 75, 1819 (2002). c) M. Shimizu and Y.
Niwa, Tetrahedron Lett., 42, 2829 (2001). d) Y. Niwa, K.
Takayama, and M. Shimizu, Tetrahedron Lett., 42, 5473
(2001).
6
7
8
a) M. Shimizu, K. Tsukamoto, T. Matsutani, and T.
Fujisawa, Tetrahedron, 54, 10265 (1998). b) M. Shimizu,
K. Tsukamoto, and T. Fujisawa, Tetrahedron Lett., 38,
5193 (1997).
a) M. Shimizu, T. Sahara, and R. Hayakawa, Chem. Lett.,
2001, 792. b) R. Hayakawa, T. Sahara, and M. Shimizu, Tet-
rahedron Lett., 41, 7939 (2000). c) M. Shimizu, K. Shibuya,
and R. Hayakawa, Synlett, 2000, 1437.
a) M. Shimizu and T. Sahara, Chem. Lett., 2002, 888. b) M.
Shimizu, Y. Takeuchi, T. Sahara, Chem. Lett., 2001, 1196. c)
M. Shimizu, F. Kobayashi, R. Hayakawa, Tetrahedron, 57,
9591 (2001). d) R. Hayakawa, H. Makino, and M. Shimizu,
Chem. Lett., 2001, 756. e) R. Hayakawa and M. Shimizu,
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2000, 724.
Although there are several arguments on the reaction mech-
anism and more experiments appear to be needed, two possible
pathways of the present coupling reaction are shown in
Scheme 1. An initial iodination of the carbonyl group of the car-
boxylic acid chloride gives the iodinated intermediate 3, which
is attacked by the iodide anion from titanium tetraiodide to form
an anionic species.12 A similar attack of halide anions was ob-
served in the reaction of ꢀ-halo ketones with metal halides.13
This anionic species in turn undergoes an addition reaction with
nitrile to form the coupling product (Eq 2). Another involves an
acyl titanium speceis 4 derived from the reduction of the acid
chloride 1 with a low valent titanium species followed by cou-
pling with nitrile (Eq 3). We are currently investigating the true
reactive intermediate in more detail.
9
I3
Ti
I
10 The added acetic anhydride may remove the amine impuri-
ties derived from reduction of imino and/or nitrile speceis.
11 A typical procedure is as follows: Isobutyronitrile (1.0 mL)
was added to TiI4 (0.5 mmol) at room temperature under
an argon atmosphere, and the solution was stirred at that tem-
perature for 10 min. To it was added a solution of benzoly
chloride (35.1 mg, 0.25 mmol) in isobutyronitrile (1.0 mL)
at ꢁ70 ꢂC. After the mixture was allowed to warm to room
temperature during 21 h, acetic anhydride (0.12 mL,
1.25 mmol) was added to it, and the mixture was stirred for
6 h at room temperature. Sat. aqueous NaHCO3 and 10%
aqueous NaHSO3 were added successively. The mixture
was filtered through a Celite pad and extracted with ethyl
acetate (10 mL ꢃ 3). The combined organic extracts were
dried over anhydrous Na2SO4, and concentrated in vacuo.
Purification on buffered silica gel TLC gave the adduct
(26.8 mg, 61%) as a yellow powder. Mp 149–150 ꢂC;IR
(CHCl3) 3398, 3028, 1695, 1592, 1465, 1381, 1239, 1194,
I3TiO
R1
I
R2
C
O
N
TiI4
R1
Cl
Cl
3
I
I
I
I
I
I
TiI3
Ti
Ti
O
O
H+
I
R2
R2
R1
O
R1
(2)
(3)
R1
N
Cl
NH
N
2
Cl
TiI3
C
R2
I2
I
O
O
O
1) R2CN
2) H+
R2
NH
Ti (II) or (III)
R1
R1
TiLn
R1
Cl
1
4
2
1
1156, 1103, 898 cmꢁ1; H NMR (270 MHz, CDCl3) ꢁ 1.26
Scheme 1.
In conclusion, we have shown that reductive coupling reac-
(d, J ¼ 6:93 Hz, 6H), 3.67 (sept, J ¼ 6:93 Hz, 1H), 7.47–
7.63 (m, 3H), 7.88–7.90 (m, 2H), 8.88 (br, 1H); 13C NMR
(126 MHz, CDCl3) ꢁ 18.7, 34.9, 127.7, 128.9, 133.0,
133.1, 165.3, 180.2. The buffered silica gel was prepared
by suspending 93 g of silica gel (Merck 60F254) in 230 mL
of a phosphate buffer solution (pH 7.0) for 2 h and dried.
12 G. W. Kabalka and Z. Wu, Tetrahedron Lett., 41, 579
(2000).
tions of carboxylic acid chlorides proceed with aliphatic nitriles
to give ꢀ-imino ketones using the mild reducing ability of tita-
nium tetraiodide. Although the product yields are moderate by
the present procedure, these coupling products are not readily
obtained from the reactions mediated by low valent metal re-
agents possessing strong reducing ability.
13 a) C. Rener, W. Huayue, and Z. Yongmin, J. Chem. Res.,
Synop., 1999, 666. b) T. Tsuritani, S. Ito, H. Shinokubo,
and K. Oshima, J. Org. Chem., 65, 5066 (2000). c) K.
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References and Notes
1
2
3
G. M. Robertson, in ‘‘Comprehensive Organic Synthesis,’’
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Published on the web (Advance View) October 27, 2003;DOI 10.1246/cl.2003.1088