Practical and General Manganese-Catalyzed Carbonylative Coupling of Alkyl Iodides with Amides

Article abstract of DOI:10.1002/cctc.201601712

A selective manganese-catalyzed carbonylative transformation of alkyl iodides and amides was developed. A variety of imides were prepared in moderate to good yields. Alkyl bromides could also be applied by in situ treatment with NaI to give the corresponding alkyl iodides. Notably, no additives or expensive ligands were required here. As the first example of the carbonylative coupling of alkyl iodides with amides, the simple reaction conditions and the advantages of a manganese catalyst make this new general procedure more attractive and practical than conventional techniques. Mechanistically, control experiments and electron paramagnetic resonance spectroscopy studies were also performed, and the radical nature of this new process was proven.

Full text of DOI:10.1002/cctc.201601712

Accepted Article
Title: A Practical and General Manganese-Catalyzed Carbonylative
Coupling of Alkyl Iodides with Amides
Authors: Xiao-Feng Wu, Yahui Li, Fengxiang Zhu, Zechao Wang,
Jabor Rabeah, and Angelika Brückner
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A Practical and General Manganese-Catalyzed Carbonylative
Coupling of Alkyl Iodides with Amides
Yahui Li, Fengxiang Zhu, Zechao Wang, Jabor Rabeah, Angelika Brückner and Xiao-Feng Wu*[a]
Abstract:
A
selective manganese-catalyzed carbonylative
Transition metal-catalyzed carbonylative transformations
have found tremendous applications on the synthesis of a wide
range of carbonyl-containing chemicals.4 Carbonylation
reactions using carbon monoxide (CO) as one of the cheapest
C1 building blocks continues to attract interests of organic
chemists in academic and industrial areas. In the past decades,
main of the achievements on this topic are on noble-metal
catalyzed carbonylative transformations of aryl halides with
various nucleophiles. More specifically, catalysts based on
palladium, ruthenium, and rhodium have been extensively
explored; nucleophiles such as alcohols and amines are more
frequently applied.5 Additionally, free radical carbonylation in the
presence of various radical initiators has also been well
established.6 In general consideration, as one of the most
important intermediates and building blocks in organic synthesis,
the development of new reactions that employ amides as
reactants is worth to pursuit. However, due to the low
nucleophilicity of amides, reports on their applications in
carbonylative coupling reactions are very much limited. In 2002,
Indolese and Schnyder reported an interesting palladium-
catalyzed carbonylative coupling of aryl bromides with primary
amides to the corresponding aromatic imides (Scheme 2, eq.
1).7a Recently, Beller’s group succeeded in using amides as the
reaction partner for hydroamidocarbonylation with alkenes.7b
Various imides were produced in good yields with palladium as
the catalyst (Scheme 2, eq. 2). More recently, our group
reported a novel copper-catalyzed carbonylative coupling of
alkanes with amides via Csp3-H activation (Scheme 2, eq. 3).7c
Moderate to good yields of the desired aliphatic imides can be
produced. Nevertheless, when linear (non-cyclic) alkanes were
applied, regioselectivities between C1, C2 and C3 become
challenge. Theoretically, such a problem can be easily resolved
by using the corresponding alkyl halides as the substrates.
However, due to the limited ability of transition metal catalysts in
Csp3-X (X = I, Br, etc.) bonds activation, the carbonylative
coupling of alkyl halides with amides is still a challenge need to
be overcome (Scheme 2, eq. 4).
transformation of alkyl iodides and amides has been developed. A
variety of imides were prepared in moderate to good yields. Alkyl
bromides can be applied as well by the in situ reacting with NaI to
the corresponding alkyl iodides. Notably, no additive or expensive
ligand is required here. As the first example on carbonylative
coupling of alkyl iodides with amides, the simple reaction conditions
and the advantages of manganese catalyst make this new general
procedure more attractive and practical. Mechanistically, control
experiments and EPR studies were also carried out and the radical
nature of this new process was proven.
Imides are produced as important intermediates in the bulk and
fine chemical industries. They are used as detergents,
pharmaceutical intermediates, agrochemicals and also various
bio-active molecules.1 Selected examples of valuable imides
compounds are shown in Scheme 1, include Pioglitazone
(Actos),2a which is a prescription drug to treat diabetes,
Lenalidomide (Revlimid),2a which is intended as a treatment for
multiple myeloma, tetraacetylethylenediamine (TAED) is used as
aperoxide bleach activator in detergents,2b Diacetazotol
(Dermagan), which stimulates wound epithelization, Formothion
is a chemical compound used in acaricides and insecticides and
also the anxiolytic drug Aniracetam (Ampamet).2c Traditional
procedures for the synthesis of imides are based on the
nucleophilic substitution of activated carboxylic acid derivatives,
such as, acid chlorides or anhydrides, with amides in the
presence of base or acid under cautious conditions.3 Due to the
availability and stability of the substrates applied and also
limitations on the functional group tolerance, the development of
new methodologies for imides synthesis are still under demand.
Scheme 1. Selected examples of bio-active imides derivatives.
[a]
Y. Li, F. Zhu, Z. Wang, Dr. J. Rabeah, Prof. Dr. A. Brückner, Prof.
Dr. X.-F. Wu
Leibniz-Institut für Katalyse e.V. an der Universität Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: Xiao-Feng.Wu@catalysis.de
Prof. Dr. X.-F. Wu, Department of Chemistry, Zhejiang Sci-Tech
University, Xiasha Campus, Hangzhou 310018, People’s Republic
of China
Supporting information for this article is given via a link at the end of
the document.
Scheme 2. Carbonylation reactions with amides as the reaction partner.
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On the other hand, manganese salts are abundant, cheap
and environmental benign. In organic synthesis, manganese
salts have been extensively applied as catalysts in fine and bulk
chemicals preparation.8 To our surprise, the reports on applying
manganese catalysts in carbonylative transformations are still
limited.9 Taking all the above discussed challenges into
consideration and also based on our continues research
interests, we report here the first example on carbonylative of
alkyl iodides with amides. With manganese as the catalyst,
various imides were prepared in good yields from ready
available alkyl halides and amides. Excellent selectivity and
functional group tolerance can be observed in the new
be decreased to 15 bar without losing reaction efficiency and the
result can be obtained at 80 C. At this stage, we found by the
combination of Mn2(CO)10 (3 mol%) and K2CO3 (2 equiv.) in
PhCF3 at 80 oC under 15 bar CO, 85 % of the desired imide can
be isolated (Table 1, entry 16).
o
Table 2. Manganese-catalyzed carbonylative synthesis of imides from
alkyl iodides.[a]
procedure.
Table 1. Screening of reaction conditions.[a]
Entry
1
Catalyst
Solvent
Benzotrifluoride
Benzotrifluoride
Benzotrifluoride
Benzotrifluoride
Benzotrifluoride
Benzotrifluoride
Cyclohexane
1,4-Dioxane
Toluene
Yield[b]
-
MnF2
2
MnCl2
-
3
Pd(OAc)2
Mn(acac)2
Mn(CO)5Br
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
Mn2(CO)10
-
4
trace
65%
77%
47%
43%
31%
30%
trace
trace
65%
85%
63%
85%
57%
5
6
7
8
9
10
11
12
13
14[c]
15[d]
16[e]
17[f]
CH3CN
DMSO
DMF
THF
Benzotrifluoride
Benzotrifluoride
Benzotrifluoride
Benzotrifluoride
a
1-Iodobutane (0.5 mmol), amide (1.5 equiv.), catalyst (3 mol%; 6 mol% for
monomer catalysts), K2CO3 (2 equiv.), CO (20 bar), benzotrifluoride (2 mL),
b
c
120 oC, 12 h. Isolated yields. 120 oC, CO (15 bar), 24 h .d 120 oC, CO (10
bar), 24 h. e 80 oC, CO (15 bar), 24 h. f 60 oC, CO (15 bar), 24h.
As the start of this project, we chose 1-iodobutane and
caprolactam as the model substrates to establish this new
carbonylation procedure. Upon the variation of reaction
conditions, different reaction outcomes could be obtained (Table
1). Among the different metal catalyst precursors (Table 1,
entries 1-6), Mn2(CO)10 showed the best result (77% isolated
yield; Table 1, entry 6). Notably, Pd(OAc)2 a powerful catalyst in
carbonylative aryl halides transformation, could not give trace of
the desired product (Table 1, entries 3). Among the other tested
manganese salts, no reaction occurred with MnCl2, MnF2, or
Mn(acac)2 as the catalyst and 65% of the desired imide can be
obtained with Mn(CO)5Br as the catalyst. Subsequent
optimization studies were focused on using Mn2(CO)10 as the
catalyst and various solvents were checked (Table 1, entries 7-
13). Good yields could be obtained with benzotrifluoride or THF
as the solvent. Then, fine turnings were performed with PhCF3
as the solvent (Table 1, entries 14-17). The pressure of CO can
a
Alkyl halide (0.5 mmol), amide (0.75 mmol), Mn2(CO)10 (3 mol%), K2CO3 (0.75
mmol), CO (15 bar), benzotrifluoride (2 mL), 80 oC, 24 h. b Isolated yields. c 1
mmol NaI. d 0.6 mmol NaI.
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With the optimized reaction conditions in hand, we
examined the scope and limitation of this procedure with a range
of alkyl halides. As shown in Table 2, not only primary, but also
secondary and tertiary alkyl iodides are all shown to be proper
substrates here. Good to excellent yields of the desired imides
were produced by reacting butyl iodide and 2-iodobutane with
caprolactam (yield of isolated 3a and 3b, 85% and 92%
Subsequently, different amides were tested with iodobutane
(Table 3). In general, moderate to good yields can be obtained
in all the tested cases without further optimization. In addition to
amides, lactams can be applied as well. However, primary
amides were shown to be non-suitable coupling partners here.
Finally, to illustrate the synthetic potential of this method, we
performed a gram-scale synthesis of the imide 3r with 81 %
overall yield upon isolation (Scheme 3).
respectively).
1-Iodoadamantane
can
be
transformed
successfully as well and gave the corresponding imide in 73%
yield (Table 2, entry 3). Then other alkyl halides were reacted.
As shown, the reactions of iodoethane (1d) and 1-iodo-propane
(1e) with amides gave the desired products in moderate yield
(Table 2, 3d and 3e, 53% and 55% yields, respectively). Also,
long chain alkyl halides can be tolerated well in the reaction. For
example, when we use 1-iodo-octane and 1-iodo-hexane as the
substances, good yields can be obtained (Table 2, 3f and 3g,
72% and 86% yields, respectively). Chloro-substituted
substrates can also be tolerated and provide the desired imide in
moderate yield (Table 2, 3i). Alkyl bromides, such as 1-bromo-
butane, 2-bromo-butane and 1-bromo-octane, can be efficiently
transformed under our conditions as well with NaI as the additive
(Table 2, 1k-1m). Here, alkyl bromides were in situ transformed
into the corresponding alkyl iodides after reacted with NaI.
Scheme 3. Gram-scale synthesis of imides 3r.
In order to get some insight into the reaction pathway, 2
equivalents of TEMPO were added to our standard reactions,
and no desired product could be detected (Scheme 4).
Therefore, a radical pathway was suggested.
Scheme 4. Reaction with TEMPO.
Table 3. Manganese-catalyzed carbonylative synthesis of imides from
amides.[a]
Figure 1. EPR spectra of a) Mn2(CO)10, caprolactam and butyl iodide in
cyclohexane after catalytic test at 65 oC and 20 bar CO; a) experiment; b) in
the presence of DMPO as a spin trap.
a
Figure 2. EPR spectrum (measured at 20 oC) of the spin adduct formed after
adding DMPO to the reaction mixture of Mn2(CO)10, and butyl iodide in
cyclohexane reacted at 65 oC for 10 mins under 20 bar CO. (the background
Alkyl halide (0.5 mmol), amide (0.75 mmol), Mn2(CO)10 (3mol%), K2CO3 (0.75
b
c
mmol), CO (15 bar), benzotrifluoride (2 mL), 80 oC, 24 h. Isolated yields.
120 oC.
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signals originated from DMPO sample was subtracted since commercial
DMPO often have varying amounts of paramagnetic impurities).
yields from readily available alkyl halides and amides. Notably,
this is the first report on carbonylative coupling of alkyl halides
with amides. Mechanistically, control experiments and EPR
studies confirm the radical nature of this new process. This
procedure is expected to complement the current methods for
carbonylation reactions in organic synthesis.
Additionally, EPR investigations with 5,5-dimethyl-1-
pyrroline N-oxide as a spin trap to detect the short lived radicals
were performed as well. A catalytic test was performed in
cyclohexane for 2h at 65 oC (reaction mixture containing
Mn2(CO)10, caprolactam and butyl iodide in cyclohexane under
pressure of CO (20 bar). After that, about 0.5 ml from the
reaction mixture was transferred into EPR tube under inert
atmosphere and measured directly. The EPR spectrum of the
reaction mixture did not show any signal (Figure 1, a), probably
due to the short life of the radicals. However, the EPR
measurement of the reaction mixture in the presence of 5,5-
dimethyl-1-pyrroline-N-oxide (DMPO) as a spin trap for 10
minutes shows a complex spectrum due to the superimposed of
several radical signals (Figure 1, b) suggesting that the catalytic
reaction is proceeds via radical pathway. To prove that the
catalytic reaction initiates by the reaction of alkyl iodide with the
thermally generated •Mn(CO)5 radical (by thermolysis of
Mn2(CO)10 dimer) to produce an alkyl radical, EPR investigation
was performed in the presence of DMPO similar to that
mentioned above but in the absence of caprolactam. The EPR
measurement of the reaction mixture after subtraction the
background signals originated from DMPO (commercial DMPO
often have varying amounts of paramagnetic impurities) shows a
six line spectra at g = 2.007 (aN = 14.1 G and aH = 20.2 G,
Figure 2) due to the formation of spin adduct (DMPO/ •R). This
EPR experiment provides definitive proof for •R production.
Based on our results, a possible reaction mechanism is
proposed in Scheme 5. The catalytic reaction starts with
thermally induced thermolysis of Mn-Mn bond in Mn2(CO)10
dimer (A) to generate •Mn(CO)5 radical (B),10 (B) abstracts
iodine atom from alkyl iodide (C) to generate an alkyl-centered
radical (D) and form I-Mn(CO)5 (E). The alkyl-centered radical
(D) was detected by in situ EPR study using DMPO as a spin
trap. The alkyl radical (D) undergoes carbonylation by reaction
with I-Mn(CO)5 (E) and provides acyl manganese RCOMn(CO)4-
I intermediate (F).11 Then complex F reacts with amide (G) to
produce the final carbonylation product (H) and regenerate
complex B under the assistant of base and ready for the next
catalytic cycle.
Acknowledgements
The authors thank the Chinese Scholarship Council for financial
Support. We also appreciate the general supports from
Professor Matthias Beller in LIKAT. The analytic supports of Dr.
W. Baumann, Dr. C. Fisher, S.Buchholz, and S. Schareinaare
gratefully acknowledged.
Keywords: manganese catalyst • amides • carbonylation •
imides • alkyl halide
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Yahui Li, Fengxiang Zhu, Zechao Wang,
Jabor Rabeah, Angelika Brückner and
Xiao-Feng Wu*
Page No. – Page No.
A novel and practical manganese-catalyzed carbonylative transformation of alkyl halides
and amides has been developed. Primary, secondary and tertiary alkyl halides (X= I, Br)
were carbonylated with a wide variety of amides and gave the corresponding imides in
moderate to good yields. Notably, this is the first report on carbonylative coupling of alkyl
halides with amides.
A Practical and General Manganese-
Catalyzed Carbonylative Coupling of
Alkyl Iodides with Amides
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