Aerobic cross-dehydrogenative coupling of terminal alkynes and tertiary amines by a combined catalyst of Zn2+ and OMS-2

Article abstract of DOI:10.1039/c4ra05105j

In the presence of ZnBr₂ and a manganese oxide-based octahedral molecular sieve (OMS-2), cross-dehydrogenative coupling of a wide range of terminal alkynes and tertiary amines to propargylamines efficiently proceeded using molecular oxygen as the terminal oxidant. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra05105j

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Aerobic cross-dehydrogenative coupling of
terminal alkynes and tertiary amines by a combined
Cite this: RSC Adv., 2014, 4, 34712
catalyst of Zn2+ and OMS-2†
Received 29th May 2014
Accepted 15th July 2014
*
Xiongjie Jin, Kazuya Yamaguchi and Noritaka Mizuno
DOI: 10.1039/c4ra05105j
www.rsc.org/advances
In the presence of ZnBr2 and a manganese oxide-based octahedral transition metal catalysts have also been applied to the CDC
molecular sieve (OMS-2), cross-dehydrogenative coupling of a wide reactions for synthesis of propargylamines.7m–o Although these
range of terminal alkynes and tertiary amines to propargylamines systems show high catalytic performance, the scope of amine
efficiently proceeded using molecular oxygen as the terminal oxidant. coupling partners is typically limited to only tetrahy-
droisoquinoline derivatives.7m–o Therefore, the development of
new CDC pathways for propargylamines with wide substrate
applicabilities that utilize naturally abundant molecular oxygen
as the terminal oxidant would be of great signicance. Recently,
Propargylamines are key structural motifs in various bioactive
compounds1 and have widely been utilized as synthetic inter-
mediates for nitrogen-containing compounds such as pyr-
we have developed several catalytic CDC-type reactions
azines, oxazoles, and pyrroles.2 To date, various synthetic
procedures for propargylamines have been developed, and the
following four procedures have mostly been utilized; (i) nucle-
ophilic substitution of propargyl halides with amines
(Scheme 1(a)),3 (ii) nucleophilic substitution of a-functionalized
tertiary amines with metal acetylide reagents (Scheme 1(b)),4
(iii) metal-catalyzed nucleophilic addition of terminal alkynes to
iminium species formed by dehydrative condensation of alde-
hydes and amines (Scheme 1(c)),5 and (iv) oxidative cross-
dehydrogenative coupling (CDC)6 of terminal alkynes and
tertiary amines (Scheme 1(d)).7 Although procedures (a–c)
provide excellent approaches to propargylamines, procedure (d)
which proceeds through C–H bond activation and subsequent
C–C bond formation has become a promising alternative for
synthesis of propargylamines due to its high synthetic efficiency
and environmentally benign nature.
including C–N,8a,b P–N,8c Si–N,8d,e and Si–C8f bond forming
reactions. In line with our research interest, we devoted to
develop a novel catalyst system for synthesis of propargylamines
by employing the CDC strategy using molecular oxygen as the
terminal oxidant. Quite recently, we have successfully devel-
oped the OMS-2-promoted aerobic oxidative a-cyanation of
tertiary amines.9,10 This reaction possibly proceeds through the
formation of iminium intermediates by the step-by-step two-
electron oxidation of tertiary amines by OMS-2.10 Thus, we
envisioned that an appropriate metal source, which can
generate metal acetylide species, in combination with OMS-2
With regard to the CDC pathways for propargylamines,
copper-,7a–i iron-,7j,k or silver-catalyzed7l reactions have been
developed in the last decade. However, these catalytic systems
have employed at least stoichiometric amounts of organic
oxidants such as t-BuOOH, (t-BuO)2, N-bromosuccinimide, and
diethyl azodicarboxylate, resulting in generation of vast
amounts of wastes. The photoredox systems in the presence of
Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan. E-mail: tmizuno@mail.ecc.u-tokyo.
ac.jp; Fax: +81-3-5841-7220; Tel: +81-3-5841-7272
† Electronic supplementary information (ESI) available: Experimental details,
data of propargylamines, Tables S1 and S2 and Fig. S1 and S2. See DOI:
10.1039/c4ra05105j
Scheme 1 Synthetic procedures for propargylamines (X ¼ Cl, Br; M ¼
Li, Mg; LG ¼ leaving group).
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would promote CDC of terminal alkynes and tertiary amines (Table 1, entry 9). A remarkable improvement of the yield was
through nucleophilic addition of the metal acetylide species to observed when using cyclopentylmethylether (CPME) as the
the iminium intermediates.
Herein, we disclose for the rst time aerobic CDC of terminal (Table 1, entry 12, Table S2†). Other solvents such as tri-
alkynes and tertiary amines to produce propargylamines in the uorotoluene, N-methylpyrrolidone, dimethylformamide,
solvent instead of toluene, and 3aa was obtained in 85% yield
presence of a combined catalyst of Zn2+ (typically ZnBr2) and dimethylacetamide, 1,4-dioxane, dimethylsulfoxide, and dieth-
OMS-2 (Scheme 1(e)).11 Various kinds of propargylamines could ylcarbonate gave lower yields of 3aa than CPME (Table S2†).
successfully be synthesized by the present CDC. In this reaction, Only 16% yield of 3aa was obtained when the CDC reaction was
molecular oxygen could be used as the terminal oxidant, and carried out under 1 atm of Ar, indicating that molecular oxygen
OMS-2 could be reused several times.
is the terminal oxidant (Table 1, entry 13). Both ZnBr2 and OMS-
Initially, the CDC reaction of phenylacetylene (1a) and N,N- 2 were the indispensable components, and the reaction hardly
dimethylcyclohexylamine (2a) to N-methyl-N-(3-phenylprop-2- proceeded in the absence of ZnBr2 or OMS-2 (Table 1, entries 14
yn-1-yl)cyclohexylamine (3aa) was carried out in the presence and 16). OMS-2 showed higher performance than the
of various kinds of metal catalysts and OMS-2 under 1 atm of commercially available activated MnO2 and b-MnO2. t-BuOOH
O2.‡ Among various zinc catalysts examined such as ZnCl2, was not the effective oxidant. The present CDC reaction was
Zn(OTf)2 (OTf ¼ triate), ZnF2, ZnI2, and ZnBr2 in toluene signicantly suppressed by the presence of a radical scavenger
(Table 1, entries 1–5), ZnBr2 showed the best performance, of dibutylhydroxytoluene (BHT) (Table 1, entry 15), suggesting
giving 3aa in 59% yield (Table 1, entry 5). In this case, the that radical intermediates are included in the present CDC.
alkynylation exclusively took place at the methyl position
Aer the CDC reaction of 1a and 2a, OMS-2 could easily be
without methine alkynylation. Other metal catalysts such as retrieved from the reaction mixture by simple ltration with
InCl3, NiCl2$6H2O, FeCl3, CuCl2$2H2O, CoCl2, and MgCl2 gave >97% recovery. The retrieved OMS-2 could be reused several
lower yields of 3aa in comparison with ZnBr2 (Table 1, entries 6– times for the same reaction though its performance gradually
11). When CuCl2$2H2O was employed, a signicant amount of decreased (fresh: 85% yield of 3aa for 8 h, the 1st reuse: 87%,
1,4-diphenylbutadiyne derived from the copper-catalyzed the 2nd reuse: 75%, and the 3rd reuse: 72%, see Fig. S1†).
Glaser–Hay homocoupling of 1a was formed as the byproduct
Next, the substrate scope of the present Zn2+-OMS-2-
mediated CDC of terminal alkynes and tertiary amines was
investigated. Under the optimized reaction conditions, various
kinds of structurally diverse propargylamines could be synthe-
sized from terminal alkynes and tertiary amines (Scheme 2 and
Fig. S2†). All products could readily be isolated (see the ESI† for
detailed procedures and compound data), and the yields of
isolated products are shown in Scheme 2.
Table 1 The CDC of phenylacetylene (1a) and N,N-dimethylcyclo-
hexylamine (2a) with various metal catalystsa
Aromatic alkynes with electron-donating as well as electron-
withdrawing substituents were all efficiently reacted with 2a to
give the corresponding propargylamines (Scheme 2, entries 1–
10). In the present system, the steric effect of substituents on
aromatic rings is likely negligible because the CDC reactions of
2-, 3-, and 4-ethynyltoluenes were almost equally effective
(Scheme 2, entries 2–4). In the case of halo-substituted aromatic
alkynes, the reaction smoothly proceeded without dehalogena-
tion (Scheme 2, entries 6–8). Thus, it would be possible to utilize
these halo-functionalities for further derivatization of these
propargylamines. Heteroaromatic alkynes such as 3-ethynylth-
iophene and 3-ethynylpyridine were also applicable to the
present CDC (Scheme 2, entries 11 and 12). In addition, the
reaction of an enyne and 2a efficiently proceeded to give the
corresponding propargylamines (Scheme 2, entry 13). Not only
aromatic alkynes but also an aliphatic one could act as the
coupling partner while the yield of the desired product was low
(Scheme 2, entry 14). As for the amine coupling partners,
various aliphatic tertiary amines could be applied to the present
CDC reaction, and in all these cases the alkynylation exclusively
occurred at the methyl positions even in the presence of
methylene and methine positions (Scheme 2, entries 15–18).
This methyl selectivity is possibly due to the stereoelectronically
controlled deprotonation of amine cation radicals (step 2 in
Scheme 3).12 As for the stereoelectronically controlled
Conv. (%)
Entry
Catalyst
1a
2a
Yield of 3aa (%)
1
2
3
4
5
6
7
8
ZnCl2
Zn(OTf)2
ZnF2
ZnI2
ZnBr2
InCl3
NiCl2$6H2O
FeCl3
CuCl2$2H2O
CoCl2
MgCl2
ZnBr2
61
24
12
29
72
37
21
23
98
58
23
95
28
8
36
32
23
29
43
29
22
28
41
37
28
56
8
51
8
1
4
59
24
7
8
9b
10
11
12c
13c,d
14c,e
15c,f
16c
37
43
7
85
16
1
ZnBr2
ZnBr2
ZnBr2
None
2
11
23
68
10
14
<1
a
Reaction conditions: catalyst (metal: 5 mol%), OMS-2 (100 mg), 1a (1.0
mmol), 2a (2.0 mmol), toluene (2 mL), 100 ꢀC, O2 (1 atm), 4.5 h.
b
Conversion and yield were determined by GC analysis.
1,4-
c
d
Diphenylbutadiyne was formed in 43% yield. CPME (2 mL), 8 h. Ar
(1 atm). e Without OMS-2. f BHT (2.0 mmol).
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coupling product could be obtained though the yield was only
6% for 24 h. In this case, no product derived from the alkyny-
lation of triethylamine was produced. These results indicates
that the basicity of amines (for deprotonation of terminal
alkynes) and steric effect of substituents of amines (stereo-
electronic effect) are very signicant for the present CDC
reaction.
The plausible reaction mechanism for the present Zn2+
-
OMS-2-mediated CDC is shown in Scheme 3. Firstly, the single-
electron transfer (SET) from a tertiary amine to OMS-2 generates
an amine cation radical species A (step 1). Then, the successive
deprotonation of the cation radical species A (step 2) and the
second SET give an iminium intermediate B (step 3). In the
previous work, we have successfully detected the iminium
intermediate by NMR analysis during the reaction of a tertiary
amine in the presence of OMS-2 and LiBF4.10 The above-
mentioned stereoelectronic effect also supports this mecha-
nism. Meanwhile, a zinc acetylide species C can be formed from
a terminal alkyne, and the tertiary amine likely act as a base to
promote the deprotonation of the terminal alkyne (step 4).13
Finally, the nucleophilic attack of the acetylide species C to the
iminium intermediate B gives the corresponding propargyl-
amines as the nal product (step 5). The reduced OMS-2 can be
reoxidized by molecular oxygen.9
In summary, we have successfully developed the Zn2+-OMS-
2-mediated CDC reaction of terminal alkynes and tertiary
amines to propargylamines. Various kinds of structurally
diverse propargylamines could be synthesized. The present
CDC reaction could employ molecular oxygen as the terminal
Scheme 2 Scope of the present CDC of terminal alkynes and tertiary
amines. Reaction conditions: 1 (1.0 mmol), 2 (2.0 mmol), ZnBr2 (5
mol%), OMS-2 (100 mg), CPME (2 mL), 100 ꢀC, under O2 (1 atm). Yields
(based on 1) of isolated products are shown. a ZnBr2 (20 mol%).
oxidant which provides
propargylamines.
a
green synthetic route to
Notes and references
‡ A typical procedure for CDC of terminal alkynes and tertiary amines: into a Pyrex
glass reactor (volume: ca. 20 mL) were successively placed ZnBr2 (11.3 mg, 0.05
mmol), OMS-2 (100 mg), 1 (1 mmol), 2 (2 mmol), CPME (2 mL), and a Teon-
coated magnetic stir bar, and the reaction mixture was purged with oxygen gas,
and then vigorously stirred at 100 ꢀC. Aer the reaction was completed, an
internal standard (diphenyl) was added to the reaction mixture, and the conver-
sions of 1 and 2 and the product yield were determined by GC analysis. As for
isolation of propargylamine products, an internal standard was not added. Aer
the reaction, OMS-2 was ltered off (>97% recovery), and then the ltrate was
concentrated by evaporation of CPME. The crude product was subjected to
column chromatography on silica gel (typically using n-hexane/diethylether as the
eluent), giving the pure propargylamines. The products were identied by GC-MS
and NMR (1H and 13C) analyses.
Scheme 3 A plausible reaction mechanism for the present CDC of
terminal alkynes and tertiary amines.
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