Copper-Catalyzed Carbonylative Synthesis of Aliphatic Amides from Alkanes and Primary Amines via C(sp3)-H Bond Activation

Article abstract of DOI:10.1021/acscatal.6b01413

Amides are important intermediates and building blocks in organic synthesis. Among the known preparation procedures, aminocarbonylation is an interesting and powerful tool. However, most of the studies were focused on noble metal-catalyzed synthesis of ar

Full text of DOI:10.1021/acscatal.6b01413

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Letter
Copper-Catalyzed Carbonylative Synthesis of Aliphatic Amides
from Alkanes and Primary Amines via C(sp3)-H Bond Activation
Yahui Li, Fengxiang Zhu, Zechao Wang, and Xiao-Feng Wu
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01413 • Publication Date (Web): 22 Jul 2016
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Copper-Catalyzed Carbonylative Synthesis of Aliphatic Amides from
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Alkanes and Primary Amines via C(sp3)-H Bond Activation
Yahui Li,[a] Fengxiang Zhu,[a] Zechao Wang,[a] and Xiao-Feng Wu*[a,b]
a. Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
b. Department of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou 310018, People’s Republic of China
ABSTRACT: Amides are important intermediates and building blocks in organic synthesis. Among the known preparation procedures,
aminocarbonylation is an interesting and powerful tool. However, most of the studies were focused on noble metal-catalyzed synthesis of
aromatic amides. Herein, we describe an attractive copper-catalyzed synthesis of aliphatic amides from alkanes and amines. A variety of am-
ides were prepared in good yields by carbonylation of the C(sp3)-H bond of alkanes with different amines. Good functional groups tolerance
can be observed.
KEYWORDS: copper catalyst • amides synthesis • carbonylation • amines • alkanes
Amides are important chemicals that prevalent in pharmaceuti-
cals, natural products, and many functional materials.1 Hence, the
development of efficient and selective procedure for new amide
bonds construction is a long-standing task for organic chemists.2
substrates.9 And we recently extended to carbonylative coupling of
cycloalkanes with amides which is stable under oxidative condi-
tions.10 As our continuing interests on developing new carbonyla-
tive coupling reactions and also been attracted by copper catalysts,
we wish to report here an interesting procedure on copper-
catalyzed aminocarbonylation of alkanes. With amines as the reac-
tion partners and copper as the catalyst, the C(sp3)-H bond of simple
alkanes were selectively carbonylated and give the corresponding
aliphatic amides in good yields (Scheme 1, eq. c).
Among the known methodologies, aminocarbonylation is
a
straightforward process for the synthesis of amide moieties.3 De-
pending on the amides needed, by choosing proper amines and
reaction partners, CO as one of the cheapest and most abundant
C1 source can be easily installed into the amide products. However,
by go through literature, main of the reported aminocarbonylation
procedures are based on using C(sp2)-X (X = I, Br, H, etc.) as the
starting materials. With noble metal complex as the catalyst, aro-
matic amides (benzamides) can be selectively produced (Scheme
1, eq. a).4 In comparison, studies on carbonylative transformation
of C(sp3)-X bonds are already become limited which can produce
important aliphatic carbonyl containing compounds (Scheme 1,
eq. b). The developed methods also require noble catalyst and/or
UV irradiation under high CO pressure (50-80 bar).5 Not surprise-
ly, report on aminocarbonylation of C(sp3)-X (X = I, Br, H, etc.)
bonds is even more rare,6 which can be explained by the following
four reasons: 1) the increased difficulty of oxidative addition of
C(sp3)-X (X = I. Br. Cl) bond toward metal center; 2) easier β-
hydrogen elimination of the intermediate complex; 3) easy and fast
nucleophilic substitution reaction of C(sp3)-X (X = I. Br. Cl) and
amines with amines as the reaction partner and also as the base; 4)
the easier oxidation of amines under oxidative conditions. Hence,
aminocarbonylation of C(sp3)-X bonds is remaining challenge.
Scheme 1. General carbonylative coupling reactions.
Initially, we chosen cyclohexane and aniline as the model sub-
strates in the presence of 20 bar of CO and the effects of copper
catalysts were tested (Table 1, entries 1-9). Under our former
reaction conditions, only 19% of the desired N-
phenylcyclohexanecarboxamide can be produced (Table 1, entry
1). Nitrobenzene, nitrosobenzene, azobenzene and other non-
charactable could be detected with the full conversion of aniline.
Nevertheless, these results proven our hypothesis and encouraged
us to move forward. In the other tested copper salts, improved
yields can be achieved in general and the best selectivity can be
obtained with CuF2 as the catalyst (Table 1, entry 8). Excitingly,
67% of N-phenylcyclohexanecarboxamide was isolated and with
good reproducibility. In the case with Pd(OAc)2 as the catalyst,
On the other hand, copper salts have advantages include non-
expensive and low toxicity which have been extensively applied as
catalysts and additives in organic synthesis.7 In some topics, such as
oxidation reactions, the catalysis behavior of copper catalyst is
comparable or even better then palladium catalysts.8 However, in
the area of carbonylative coupling transformations, copper catalyst
is still in its infancy while palladium catalysts are already matured.
The few reports on copper-catalyzed carbonylative coupling reac-
tions are limited with aryl iodides or diaryliodonium salts as the
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Table 2. Cu-catalyzed carbonylative synthesis of aliphatic amides.[a]
only trance of the desired amide can be detected together with the
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aniline oxidation by-products (Table 1, entry 10). Additionally, in
the absence of a copper catalyst or ligand, no desired product can
be observed. Screening of other nitrogen ligands (pyridine, bipyri-
dine, TMEDA, DMEDA, DMPA, L-proline) revealed that 1,10-
phenanthroline hydrate is the most effective ligand for delivering
the desired amide product. Then we tested the influences of reac-
tion temperature, additives and CO pressure on this aminocar-
bonylation reaction (Table 1, entries 11-15). Dramatic yields de-
creasing were observed when K2CO3 or AcOH was added into the
reaction mixture (Table 1, entries 12 and 13; 26% and 23% yields
respectively). Interestingly, moderate yields can still be obtained
under lower CO pressure (10 bar; Table 1, entry 11), lower tem-
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perature (100 C; Table 1, entry 14) and lower catalyst loading (5
mol%; Table 1, entry 15). It’s meaningful to mention that full
conversion of aniline could be observed in all the reactions per-
formed.
Table 1. Cu-catalyzed amide synthesis: Optimization reaction conditions.[a]
Entry
Catalyst
Yield[b]
1
2
CuBr(Me2S)
Cu(acac)2
CuBr2
19%
42%
36%
48%
18%
27%
42%
67%[c]
24%
trace
48%
26%
23%
54%
65%
3
4
Cu(CH3CN)4PF6
Cu(CF3CO2)2
CuI
5
6
7
CuCl
8
CuF2
9
Cu(OTf)2
Pd(OAc)2
CuF2
10
11[d]
12[e]
13[f]
14[g]
15[h]
CuF2
CuF2
CuF2
CuF2
[a] 2 (0.5 mmol), CuF2 (10 mol%), 1,10-phen (10 mol%), DTBP (0.75 mmol),
CO (20 bar), cyclohexane (1.5 mL), 120 oC, 24 h. [b] Isolated yields.
[a] Aniline (0.5 mmol), catalyst (10 mol%), ligand (10 mol%), DTBP (0.75
mmol; 1.5 equiv.), CO (50 bar), cyclohexane (1.5 mL), 24 h. [b] GC yields
with hexadecane as the internal standard. [c] Isolated yields. [d] CO (10 bar).
[e] K2CO3 (1 equiv.). [f] CH3CO2H (1 equiv.). [g] 100 oC. [h] Catalyst (5 mol%),
ligand (5 mol%).1,10-Phen = 1,10-phenanthroline hydrate.
To reveal the generality of this method, aniline and benzylic
amines were also tested (Table 3), these substrates are more in-
tended to be oxidized compared with aliphatic amines tested. To
our delight, aniline was smoothly transformed into the desired
amide in 67% yield (Table 3, entry 1). Various benzyl amines can
be reacted as well and give the corresponding amides in moderate
to good yields (Table 3, entries 2-8). For example, (4-
bromophenyl)-methanamine and 1-(4-chlorophenyl)ethan-1-
amine can successfully give the wanted products which are ready
for further modification via cross-coupling reactions. Notably,
enantioenriched substrate can be applied as well and keep excellent
chirality in the final product (Table 3, entry 8).
With the optimized reaction conditions in hand, we examined
the scope of the reaction with a range of amines. As shown in Table
2, various aliphatic amines were successfully applied. Good yields
of the desired amides can be produced by reacting pentylamine,
hexylamine and octylamine with cyclohexane (Table 2, entries 1-
3). Branched amines can be applied as reaction partners as well and
give the corresponding aliphatic amides in good to excellent yields
(Table 2, entries 4-8). Cyclohexylamine and amantadine can pro-
vide the desired amides in 65-68% yields (Table 2, entries 7-8).
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Table 4. Cu-catalyzed synthesis of amides from alkanes.[a]
Table 3. Cu-catalyzed synthesis of amides from aromatic and benzyl
amines.[a]
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[a] 2 (0.5 mmol), CuF2 (10 mol%), 1,10-phen (10 mol%), DTBP (0.75 mmol), CO
(20 bar), alkane (1.5 mL), 120 oC, 24 h. [b] Isolated yields.
In order to get insight into the reaction mechanism, an experi-
ment with TEMPO was carried out and shown in Scheme 2. When
4 equivalents of TEMPO were added to the standard reaction
mixture, no desired amide product can be obtained. And a product
from the reaction between cyclohexane and TEMPO was found in
GC-MS analysis.
[a] 2 (0.5 mmol), CuF2 (10 mol%), 1,10-phen (10 mol%), DTBP (0.75 mmol), CO
(20 bar), cyclohexane (1.5 mL), 120 oC, 24 h. [b] Isolated yields.
Scheme 2. Control experiment.
Additionally, alkane derivatives were tested under our standard
reaction conditions (Table 4). Cyclopentane and cycloheptane
worked well under our reaction conditions and give the corre-
sponding amides in 57-66% yields (Table 4, entries 1-2). Non-
cyclic alkanes were applied as well, and moderate selectivity can be
obtained in general. The reaction of 3-ethylpentane occurred pref-
erentially at secondary and primary C-H bonds over the tertiary C-
H bond (Table 4, entry 3). In the case of using pentane and hexane
as the reactants and solvents, moderate to good yields of the corre-
sponding amides can be isolated with moderate selectivity (Table
4, entries 4-5). Remarkably, around 5% of the C3 product of pen-
tane can be detected in the crude NMR. Due to the low amount, we
did not isolate it.
Based on our results, a possible reaction mechanism is been pro-
posed (Scheme 3). The reaction started with a copper(II)-
catalyzed or thermal hemolytic cleavage of a peroxide to generate
the tert-butoxy radical, which reacts with cyclohexane and sequen-
tial oxidation of the copper(II) species to give the Cu(III)-
cyclohexane species B. Then complex B go X ligand exchange with
amine to produce Cu(III) intermediate C with alkyl and amine X
ligands. Subsequent CO coordination and insertion forms the
intermediate D or D’, which then afford the final aminocarbonyla-
tion product E after reductive elimination and along with a Cu (I)
intermediate which can be oxidized by tBuO radical into the active
Cu (II) species for the next catalytic cycle.
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the pressure was carefully released. After removal of solvent under
reduced pressure, pure product was obtained by column chromatog-
raphy on silica gel (eluent: pentane/ethyl acetate = 10:1).
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REFERENCES
[1]
(a) Novel Synthetic Chemistry of Ureas and Amides (Hutchby,
7
8
9
M.), Springer, 2013. (b) Mintzer, M. A.; Simanek, E. E. Chem. Rev. 2009,
109, 259-302.
[2]
(a) Carey, J. S.; Laffan, D.; Thomson, C.; M. Williams, T. Org.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Biomol. Chem. 2006, 4, 2337-2347. (b) Cupido, T.; Tulla-Puche, J.; Speng-
ler, J.; Albericio, F. Curr. Opin. Drug Discovery Dev. 2007, 10, 768-783.
[3]
(a) Brennführer, A.; Neumann, H.; Beller, M. Angew. Chem. Int.
Ed. 2009, 48, 4114-4133. (b) Fujiwara, Y.; Takaki, K.; Taniguchi, Y. Synlett
1996, 7, 591-599.
[4]
For selected reports on aminocarbonylation for benzamides
synthesis, see: (a) Schoenberg, A.; Heck, R. F. J. Org. Chem. 1974, 39,
3327-3331. (b) Hosoi, K.; Nozaki, K.; Hiyama, T. Org. Lett. 2002, 4, 2849-
2851. (c) Cunico, R. F.; Maity, B. C. Org. Lett. 2002, 4, 4357-4359. (d)
Yamazaki, K.; Kondo, Y. J. Comb. Chem. 2004, 6, 121-125. (e) Schnyder,
A.; Indolese, A. F. J. Org. Chem. 2002, 67, 594-597. (f) Morera, E.; Ortar,
G. Tetrahedron Lett. 1998, 39, 2835-2838. (g) Ueda, K.; Sato, Y.; Mori, M.
J. Am. Chem. Soc. 2000, 122, 10722-10723. (h) Liang, Z.; Zhang, J.; Liu, Z.;
Wang, K.; Zhang, Y. Tetrahedron 2013, 69, 6519-6526. (i) Orito, K.;
Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.; Yuguchi, M.;
Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126, 14342-14343. (j)
Haffemayer, B.; Gulias, M.; Gaunt, M. J. Chem. Sci. 2011, 2, 312-315.
Scheme 3. Proposed reaction mechanism.
In conclusion, a novel copper-catalyzed aminocarbonylation re-
action of alkanes with amines has been developed. With copper salt
as the catalyst, various aliphatic amides were prepared in good
yields by carbonylative activation of the C(sp3)-H bond of alkanes.
Notably, this is the first report on copper-catalyzed aminocarbonyl-
ation reaction for aliphatic amides synthesis.
[5]
For leading reviews on radical carbonylation, see: (a) Schiesser,
C. H.; Wille, U.; Matsubara, H.; Ryu, I. Acc. Chem. Res. 2007, 40, 303-313.
(b) Sumino, S.; Fusano, A.; Fukuyama, T.; Ryu, I. Acc. Chem. Res. 2014, 47,
1563-1574. (c) Ryu, I.; Sonoda, N. Angew. Chem. Int. Ed. 1996, 35, 1050-
1066. (d) Ryu, I. Chem. Rec. 2002, 2, 249-258. for reports on carbonylation
of cycloalkanes with alkenes, see: (e) Ryu, I.; Tani, A.; Fukuyama, T.;
Ravelli, D.; Fagnoni, M.; Albini, A. Angew. Chem. Int. Ed. 2011, 50, 1869-
1872. (f) Okada, M.; Fukuyama, T.; Yamada, K.; Ryu, I.; Ravelli, D.;
Fagnoni, M. Chem. Sci. 2014, 5, 2893-2898.
ASSOCIATED CONTENT
Supporting Information: General procedure, NMR data and spectrum
are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
E-mail: Xiao-Feng.Wu@catalysis.de
[6]
(a) Yoo, E. J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
17378-17380. (b) Li, S.; Chen, G.; Feng, C.-G.; Gong, W.; Yu, J.-Q. J. Am.
Chem. Soc. 2014, 136, 5267-5270. (c) McNally, A.; Haffemayer, B.;
Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510, 129-133. (d) Hasegawa,
N.; Charra, V.; Inoue, S.; Fukumoto, Y.; Chatani, N. J. Am. Chem. Soc.
2011, 133, 8070-8073. (e) Wang, C.; Zhang, L.; Chen, C.; Han, J.; Yao, Y.;
Zhao, Y. Chem. Sci. 2015, 6, 4610-4614. For reports on carbonylation of
C(sp3)-H bond of benzylic substrates, see: (f) Xie, P.; Xie, Y.; Qian, B.; Zhou,
H.; Xia, C.; Huang, H. J. Am. Chem. Soc. 2012, 134, 9902-9905. (g) Xie, P.;
Xia, C.; Huang, H. Org. Lett. 2013, 15, 3370-3373. (h) Liu, H.; Laurenczy,
G.; Yan, N.; Dyson, P. J. Chem. Commun. 2014, 50, 341-343. For a general
review on C(sp3)-X bond carbonylations, see: (i) Wu, L.; Fang, X.; Liu, Q.;
Jackstell, R.; Beller, M.; Wu, X.-F. ACS Catal. 2014, 4, 2977-2989.
ACKNOWLEDGMENT
The authors thank the Chinese Scholarship Council for financial Sup-
port. We also thank the financial supports from NSFC (21472174) and
Zhejiang Natural Science Fund for Distinguished Young Scholars
(LR16B020002). The analytic supports of Dr. W. Baumann, Dr. C.
Fisher, S. Buchholz, and S. Schareina are gratefully acknowledged. We
also appreciate the generous supports from Professor Matthias Beller in
LIKAT.
General procedure:
[7]
Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski, M.
A 4 mL screw-cap vial was charged with CuF2 (5.05 mg, 10 mol%),
1,10-phenanthroline hydrate (9.9 mg, 10 mol%), aniline (0.5 mmol),
cyclohexane (1.5 mL) and an oven-dried stirring bar. The vial was
closed by Teflon septum and phenolic cap and connected with atmos-
phere with a needle. After cyclohexane (1.5 mL), DTBP (0.75 mmol)
were injected by syringe, the vial was fixed in an alloy plate and put into
Paar 4560 series autoclave (500 mL) under argon atmosphere. At
room temperature, the autoclave is flushed with carbon monoxide for
three times and 20 bar of carbon monoxide was charged. The autoclave
was placed on a heating plate equipped with magnetic stirring and an
C. Chem. Rev. 2013, 113, 6234-6458.
[8]
1766.
[9]
McCann, S. D.; Stahl, S. S. Acc. Chem. Res. 2015, 48, 1756–
(a) Liu, J. M.; Zhang, R. Z.; Wang, S. F.; Sun, W.; Xia, C. G. Org.
Lett. 2009, 11, 1321-1324. (b) Tambade, P.; Patil, Y.; Nandurkar, N.;
Bhanage, B. Synlett, 2008, 886-888. (c) Kang, S.-K.; Yamaguchi, T.; Kim,
T.-H.; Ho, P.-S. J. Org. Chem. 1996, 61, 9082-9083. (d) Romano, U.; Tesel,
R.; Rebora, P.; Mauri, M. Ind. Eng. Chem. Prod. Res. Dev. 1980, 19, 396-403.
[10] Li, Y.; Dong, K.; Zhu, F.; Wang, Z.; Wu, X.-F. Angew. Chem. Int.
Ed. 2016, 55, 7227-7230.
o
aluminum block. The reaction is allowed to be heated under 120 C for
24 hours. Afterwards, the autoclave is cooled to room temperature and
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