Metal catalyst-free by design. the synthesis of amides from alkyl iodides, carbon monoxide and amines by a hybrid radical/ionic reaction

Article abstract of DOI:10.1039/a805815f

Amides can be synthesized from alkyl iodides and amines in the presence of CO (20-25 atm), without using transition metal catalyst; the radical cascade is initiated thermally using AIBN and allyltributyltin.

Full text of DOI:10.1039/a805815f

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Metal catalyst-free by design. The synthesis of amides from alkyl iodides,
carbon monoxide and amines by a hybrid radical/ionic reaction
Ilhyong Ryu,*† Kiyoto Nagahara, Nobuaki Kambe, Noboru Sonoda,‡ Sergio Kreimerman and Mitsuo
Komatsu
Department of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
Amides can be synthesized from alkyl iodides and amines in
the presence of CO (20–25 atm), without using transition
metal catalyst; the radical cascade is initiated thermally
using AIBN and allyltributyltin.
tributyltin hydride gave inferior results. On the other hand, in
the presence of 20 mol% of galvinoxyl, the reaction was
inhibited, and 81% of iodide 1a was recovered. These results
convinced us that the pathway by which amide 2 is formed
includes a radical chain transfer.
Transition metal catalysts facilitate many useful synthetic
transformations. However, metal catalyst-free procedures,
which do not require complicated techniques for recovering the
expensive metals and ligands, would have a distinct advantage.1
We recently discovered that irradiation conditions enable us to
synthesize carboxylic acid esters from alkyl iodides, CO, and
ROH.2 This ester synthesis represents an intriguing example of
a reaction which was previously possible only in the presence of
a catalyst, but can now be carried out under metal catalyst-free
conditions. The role of irradiation was unclear, especially as to
whether it was generating an alkyl/iodine radical pair in a non-
chain process or simply initiated a radical chain process. Here
we report the synthesis of amides from alkyl iodides, CO and
amines under thermal initiation conditions [eqn. (1)], expanding
the utility of the metal catalyst-free approach and demonstrating
the involvement of a radical chain transfer step in this hybrid
radical/ionic reaction.
Encouraged by the above results, we then examined the
generality of the amide synthesis using AIBN–allyltin as
thermal initiator. Table 1 shows that amides can be successfully
prepared from RI, medium pressure CO (20–25 atm) and
amines.3 In general triethylamine was added as a base to trap HI,
whereas in entry 3, for convenience 2 equiv. of the amine were
used as both nucleophile and base. Solvents can be varied, and
even in the case where MeOH was used as the solvent, the
amide was the only product of the carbonylation reaction (entry
4). Both primary and secondary amines were useful. In general
carbonylation of tertiary radicals is relatively inefficient
compared with secondary and primary alkyl radicals due to the
facile reverse reaction.4,5 However, the unique radical/ionic
cooperation driving the carbonylation/decarbonylation equilib-
rium in the forward direction could provide an enormous
advantage for the carbonylation of tertiary radicals. Using bis(2-
ethylhexyl)amine, diamide 8 was prepared (entry 7). On the
other hand, when an o-aminobenzyl alcohol was treated with
1d, an N-acylated product 10 was obtained (entry 9). In these
examples, standard flash chromatography on silica gel was used
for the isolation of products, whereas in one case, Renaud’s
recently reported procedure for removing small amounts of tin
residue was tested and found to be convenient (entry 8).6
It should be noted that the use of irradiation conditions, which
were employed in our previous study,2 can also be used for the
amide synthesis, and are especially useful for the reaction of
primary alkyl iodides.7 Scheme 1 illustrates the three step
R
NR′R′′
radical initiator
+
+
(1)
R-I
CO
R′R′′NH
O
Thermally initiated conditions for the catalyst-free synthesis
of amides were examined for the conversion of 2-iodooctane 1a,
diethylamine, and CO into N,N-diethyl amide 2 [eqn. (2)]. No
reaction took place under thermal conditions without a radical
initiator. However, the results with conventional radical
initiators, such as AIBN and BPO, were disappointing, since
only low yields of the desired 2 were obtained. For example,
when a hexane solution of 1a and Et2NH was heated under 25
atm of CO at 80 °C for 8 h in the presence of AIBN (30 mol%),
2 was obtained in 10% yield. A dramatic increase in the yield of
2 up to 91% was achieved when both AIBN (25 mol%) and
allyltributyltin (10 mol%) were used. The combination of AIBN
and tris(trimethylsilyl)silane also gave a good result but AIBN–
initiation process
Initiator
CO
In-I
In
•
R-I
R
•
•
R
radical chain
process
O
25 atm,
80 °C, 8 h
NEt2
I
(2)
+
+ Et2NH
CO
triethylamine
hexane
O
1a
no initiator
AIBN (30 mol%)
BPO (20 mol%)
2
R-I
0%
10%
17%
91%
5%
80%
43%
ionic
process
2 R'2NH
– R'2NH • HI
R
NR'2
R
I
AIBN (25 mol%), allyltributyltin (10 mol%)
AIBN (25 mol%), allyltributyltin (10 mol%), galvinoxyl (20 mol%)
AIBN (25 mol%), (TMS)3SiH (20 mol%)
O
O
AIBN (30 mol%), Bu3SnH (30 mol%)
Scheme 1
Chem. Commun., 1998
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Table 1 Amide synthesis via catalyst-free carbonylation of alkyl iodidesa
mechanism: (i) radical initiation via either irradiation or thermal
initiator, (ii) radical chain propagation, composed of two
reversible type radical reactions (carbonylation and iodine atom
transfer), and (iii) ionic quenching to shift the equilibria of the
reversible radical reactions.
In this study, we have achieved a new metal-free synthesis of
amides from organic iodides, CO and amines using AIBN and
allyltributyltin, which previously could only be accomplished in
the presence of a transition metal catalyst.8 We are now
examining the applications of this approach to bifunctional
substrates which hold promise for the synthesis of a variety of
nitrogen heterocycles and designed polyamides.
This work was supported by a Grant-in Aid for Scientific
Research on Priority Areas (No. 09238232) from the Ministry
of Education, Science, Sports and Culture of Japan. Thanks are
due to the Instrumental Analysis Center, Faculty of Engineer-
ing, Osaka University, for assistance in obtaining 600 MHz
NMR, HRMS and elemental analyses. I. R. thanks the
Sumitomo Foundation for financial support. K. N. is grateful to
JSPS Research Fellowships for Young Scientists. S. K. thanks
the Ministry of Education, Science, Sports and Culture of Japan
for the scholarship.
Amine (equiv.)/
solvent/conditions Product
Yield
(%)b
Entry Alkyl iodide
Et2NH (0.9)
Et3N (1.3)
NEt2
hexane (0.5 ml)
80 °C, 8 h
1
I
89
CO (25 atm)
O
1a
2
n-C6H13NH2 (1.1)
Et3N (1.1)
H
hexane (0.5 ml)
80 °C, 8 h
N
60c
2
3
1a
CO (20 atm)
O
3
OEt
Et2NH (2.3)
hexane (0.5 ml)
80 °C, 8 h
OEt
I
NEt2
82
CO (20 atm)
O
4 (trans:cis = 85:15)
1b
O
piperazine
Et3N (3.0)
MeOH (1 ml)
80 °C, 10h
CO (20 atm)
N
4d
57
96
N
I
Notes and References
1c
O
5
† E-mail: ryu@chem.eng.osaka-u.ac.jp
‡ Present Address: Department of Applied Chemistry, Faculty of Engineer-
ing, Kansai University, Suita, Osaka 564-0073, Japan
PhNH2 (1.0)
Et3N (1.3)
H
MeCN (0.5 ml)
80 °C, 8 h
N
5
Ph
I
CO (20 atm)
O
1 For recent progress in the efficient recovery of catalysts including
fluorous biphasic systems, see J. A. Gladysz, Science, 1994, 266, 55; I. T.
Horváth and J. Rábai, Science, 1994, 266, 72; J. J. J. Juliette, I. T. Horváth
and J. A. Gladysz, Angew. Chem., Int. Ed. Engl., 1997, 36, 1610. Also see
a related review: D. P. Curran, Angew. Chem., Int. Ed., 1998, 37,
1174.
1d
1d
6
Et2NH (0.9)
Et3N (1.5)
hexane (0.5 ml)
80 °C, 8 h
CO (20 atm)
NEt2
80
6
2 K. Nagahara, I. Ryu, M. Komatsu and N. Sonoda, J. Am. Chem. Soc.,
1997, 119, 5465.
O
7
3 General procedure: A magnetic stirring bar, AIBN (0.3 mmol), hexane
(0.5 ml), allyltributyltin (0.1 mmol), alkyl iodide 1a (1 mmol),
triethylamine (1.3 mmol) and amine (1.2 mmol) were placed in a 50 ml
stainless steel autoclave with a glass liner. The autoclave was closed,
purged twice with CO, pressurized with 25 atm of CO and then heated
with stirring at 80 °C for 8 h. Excess CO was discharged at room
temperature. Washing the crude mixture with MeCN (10 ml) followed by
precipitation of ammonium salts in Et2O (40 ml), filtration, evaporation
of filtrate and column chromatography on silica gel gave pure amide 2.
4 Rapid decarbonylation rates (105 to 106 s21 at room temp.) of pivaloyl
radical are known, see: Y. P. Tsentalovich and H. Fischer, J. Chem. Soc.,
Perkin Trans. 2, 1994, 729; C. E. Brown, A. G. Neville, D. M. Rayner,
K. U. Ingold and L. Lusztyk, Aust. J. Chem., 1995, 48, 363; C.
Chatgilialoglu, C. Ferreri, M. Lucarini, P. Pedrielli and G. F. Pedulli,
Organometallics, 1995, 14, 2672.
bis(2-ethylhexyl)-
amine (0.5)
Et
Et3N (1.5)
N
hexane (0.5 ml)
80 °C, 8 h
CO (20 atm)
7
8
97
Bu
2
I
I
O
1e
8
Bu2NH (1.0)
Et3N (1.3)
hexane (0.5 ml)
90 °C, 8 h
NBu2
74e
CO (20 atm)
O
1f
9
5 I. Ryu and N. Sonoda, Angew. Chem., Int. Ed. Engl., 1996, 35, 1050.
6 P. Renaud, E. Lacôte and L. Quaranta, Tetrahedron Lett., 1998, 39,
2123.
7 Reaction of primary alkyl iodides under thermal initiation conditions
suffers from direct aminolysis.
8 For examples of amide synthesis by catalytic carbonylation, see A.
Schoenberg and R. F. Heck, J. Org. Chem., 1974, 39, 3327; T. Kobayashi
and M. Tanaka, J. Organomet. Chem., 1982, 231, C12; T. Kobayashi and
M. Tanaka, J. Organomet. Chem., 1982, 233, C64; F. Ozawa, H. Soyama,
T. Yamamoto and A. Yamamoto, Tetrahedron Lett.,1982, 23, 3383; T.
Kondo, Y. Sone, Y. Tsuji and Y. Watanabe, J. Organomet. Chem., 1994,
473, 163. Also see a related review: A. Yamamoto, Bull. Chem. Soc. Jpn.,
1995, 68, 433.
o-amino benzyl-
alcohol(1.0)
Et3N (1.3)
O
MeCN (0.5 ml)
80 °C, 10 h
9
1d
52
N
H
CO (25 atm)
HO
10
a In general reactions were conducted on 1 mmol scale with AIBN (20–30
mol%)–allyltributyltin (10%) as initiator. For typical procedure: see ref. 3.
Yields after isolation by chromatography on silica gel. N-Hexyl-
N-(1-methylheptyl)amine was formed as a by-product by direct aminolysis.
d Molar ratio: 1c:piperazine:Et3N = 2.5:1.0:3.0. e Renaud’s NaOH workup
(ref. 6) was performed to eliminate tin residues.
b
c
Received in Cambridge, UK, 27th July 1998; 8/05815F
1954
Chem. Commun., 1998