Copper-catalyzed carbon-carbon bond cleavage of primary propargyl alcohols: β-carbon elimination of hemiaminal intermediates

Article abstract of DOI:10.1039/c5cy00783f

The copper-catalyzed cleavage of carbon-carbon bonds in primary propargyl alcohols under oxygen was investigated. This process involves the formation and fragmentation of hemiaminals from aldehydes (oxidized alcohols) and amines. This reaction mechanism was supported by the formation of N-formyl amines and GC experimental results.

Full text of DOI:10.1039/c5cy00783f

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Copper-Catalyzed Carbon-Carbon Bond Cleavage of Primary
Propargyl Alcohols: β-Carbon Elimination of Hemiaminal
Intermediates
Received 00th January 20xx,
Accepted 00th January 20xx
Ye-Won Kang,a Yu Jin Cho,a Kwang-Youn Ko,c and Hye-Young Jang*a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
The copper-catalyzed cleavage of carbon-carbon bonds in primary intermediates. In this study, we present this new fragmentation
propargyl alcohols under oxygen was investigated. This process mechanism, which favors cleavage of the relatively robust C-C bond
involves the formation and fragmentation of hemiaminals from over β-hydrogen elimination or C-N bond cleavage (Scheme 1, eq
aldehydes (oxidized alcohols) and amines. This reaction 3).9 The resulting alkynyl copper species were isolated as triazoles
mechanism was supported by the formation of N-formyl amines via cycloaddition with azides.10
and GC experimental results.
Previous reports
The transition-metal-catalyzed cleavage of the σ C-C bond is a
OH
R'
metal catalyst
challenging subject in organic chemistry due to the inertness of
species. Current protocols include ring-opening of strained C-C
bonds, C-C bond cleavage of ketones, and β-carbon elimination of
tertiary alcohols and propargyl amines.1,2,3,4 In particular, transition-
metal-catalyzed C(sp)-C(sp3) bond breaking of tert-propargyl
alcohols via β-alkynyl elimination has proven favorable given the
facile release of corresponding ketone. Rhodium and palladium
complexes are commonly used to activate these species, allowing
the resulting alkynyl-metal species to be used in subsequent
reactions like alkene/alkyne couplings and rearrangements (Scheme
1, eq 1).3 In addition, copper complexes have shown catalytic
activity in the dealkynylation of propargyl amines and α- and β-
hydroxy propargyl alcohols (Scheme 1, eq 1 and 2).2 However,
aside from this one amine case, this class of reaction is restricted to
the aforementioned alcohols. To the best of our knowledge, metal-
catalyzed β-alkynyl elimination of primary propargyl alcohols has
not been reported.5
R
M
(1)
R
R''
M = Rh and Pd with 3° alcohols
M = Cu with α-and β−hydroxy propargyl alcohols
R'
copper catalyst
R
(2)
R
R
Cu
NR''2
OH
O
This work
copper catalyst
NHR2
(3)
Cu
R
H
O
[O]
OCu
NR2
R
R
NR2
hemiaminal
Scheme 1 Metal-catalyzed β-alkynyl elimination.
The transition-metal-catalyzed formation of amides through the
oxidation or dehydrogenation of alcohols or aldehydes with amines
is generally thought to proceed through hemiaminal
intermediates.6,7 These metal-bound hemiaminals usually undergo
β-hydrogen elimination to afford the target. While we were
studying the copper-catalyzed oxidation of alcohols, 8 we observed
a new catalytic property of copper salts which allow them to
promote β-carbon elimination of propargyl alcohols via these
Testing began with the reaction of phenyl propargyl alcohol 1a in
the presence of Cu(OAc)2 (5 mol%) and 2,2,6,6-
tetramethylpiperidinyloxy (TEMPO, 5 mol%) at 100 °C under 1 atm
of oxygen (see Table 1). Compound 1a afforded 1b in 83% yield
after 18 h (Table 1, entry 1). When TEMPO was not included, 1b
was obtained in 13% yield; this suggests that oxidation to the
aldehyde was incomplete, and that TEMPO is required to ensure
that this important process with respect to dealkynylation proceeds
under these conditions (Table 1, entry 2).11,12 Similarly, in the
absence of O2, 1b was not formed and 1a remained mostly
unoxidized. The common ligands 1,10-phenanthroline and 2,2'-
bipyridine showed no increase in yield (Table 1, entries 3 and 4).
Meanwhile, replacing the catalyst with the copper salts CuCl2,
Cu(OTf)2 and Cu(acac)2 gave yields of 50, 36, and 7%, respectively
(Table 1, entries 5-7). Morpholine was also replaced with methyl
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benzyl amine, piperidine, and pyrrolidine which afforded 1b in 19,
52, and 42% yield, respectively (Table 1, entries 8-10). In the
absence of copper catalysts, 1b did not form (Table 1, entry 11).
After obtaining 1b in a good yield, other propargyl alcohols
including aromatic and aliphatic groups were checked. Depending
on the substituent of propargyl alcohols, different copper salts,
additives, and the solvent were required (supporting information).
Table 1 Optimization of the conversion of 1a to 1b and examples of dimers
catalyst (5 mol%)
Ph
Scheme 2 The control experiment and proposed mechanism for the formation of
1b from 1a.
ligand (5 mol%)
additives
Ph
Ph
OH
1a
1b
O2, toluene (0.5 M)
100 C, 18 h
The dimerization yield varied significantly depending on the copper
salt and amine additive used (Table 1). It is possible that the yield of
1b might not accurately reflect dealkynylation efficiently; therefore,
the cycloaddition of alkynes and azides was tested, since this
cycloaddition occurs even in the absence of catalysts.
additives
(equiv)
entry catalyst
ligand
Yield
1
2
TEMPO
--
morpholine (1.5)
morpholine (1.5) 13%
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
83%
3
phenanthroline morpholine (1.5)
56%
23%
4
bipyridine
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
TEMPO
morpholine (1.5)
β-Alkynyl elimination of 1a was followed by cycloaddition with
benzylazide 1c under the optimized conditions. As shown in Table 2,
triazole 1d was formed in 73, 50, 50, 83%, using Cu(OAc)2, CuCl2,
Cu(OTf)2, Cu(acac)2, respectively (Table 2, entries 1-4). Triazole 1d
was obtained as the major product, showing that this reaction
proceeds even in the presence of oxidant.13 Additionally, unlike the
oxidative dimerization results, the cycloaddition yields were not
greatly affected by changing amines (Table 2, entries 4-7). The best
yield was obtained using Cu(acac)2 and methyl benzyl amine (Table
2, entry 5).
5
morpholine (1.5) 50%
6
morpholine (1.5)
morpholine (1.5)
MeNHBn (1.5)
piperidine (1.5)
pyrrolidine (1.5)
morpholine (1.5)
Cu(OTf)2
Cu(acac)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
--
36%
7%
7
8
19%
52%
42%
--
9
10
11
F
OMe
F
MeO
2b
66%
3b
68%
Cu(OAc)2, pyrrolidine, 0.25 M
Cu(acac)2, pyrrolidine, 0.25 M
Me
Me
4b
75%
Table 2 Optimization of the conversion of 1a to 1d
Cu(OAc)2, pyrrolidine, 0.25 M
C7H15
C7H15
5b
75%
6b
55%
catalyst (5 mol%)
N
Bn
N
N
Ph
TEMPO (5 mol%)
additives
BnN3
+
Cu(acac)2, MeNHBn, 0.25 M
Cu(acac)2, morpholine, 0.5 M
OH
Ph
1a
1c
1d
O2, toluene (0.5 M)
100 C, 18 h
Presumably, 1b was formed by the copper-catalyzed Glase-Hay
coupling of phenylacetylene which is formed by the β-alkynyl
elimination of 1a. To confirm this hypothesis, the reaction of 1a was
monitored by gas chromatography (supporting information), and a
control experiment using phenylpropiolaldehyde was carried out;
during GC analysis, phenylacetylene, phenylpropiolaldehyde, 1b,
additives
(equiv)
entry catalyst
Yield
1
2
3
4
5
6
7
morpholine (1.5)
morpholine (1.5)
morpholine (1.5)
Cu(OAc)2
CuCl2
73%
50%
50%
Cu(OTf)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
Cu(acac)2
morpholine (1.5) 83%
and
phenylpropiolaldehyde was converted to 1b in 65% yield (Scheme
2). Compound 1a was completely oxidized to
N-formyl
morpholine
were
all
observed,
and
MeNHBn (1.5)
piperidine (1.5)
pyrrolidine (1.5)
85%
80%
77%
phenylpropiolaldehyde within 2 h. Concurrently, it undergoes β-
alkynyl elimination, in which the formyl group is transferred to
morpholine to afford N-formyl morpholine. The resulting
phenylacetylene then undergoes oxidative dimerization to afford 1b
through copper-catalyzed oxidation.
To better understand the β-alkynyl elimination mechanism, we
performed several control experiments (Scheme 3). Frist, we tested
the β-alkynyl elimination of 1a in the absence of amines (eq 1). The
desired product 1d was isolated in 52% yield, suggesting that β-
alkynyl elimination occurs but is less efficient. Presumably, a part of
1a functions as an alcohol nucleophile to form the hemiacetal
intermediate, which can undergo dealkylation, but at a lower yield.
Phenylpropiolaldehyde and 1c were also tested in the absence of
amines and alcohols, and formed only regioisomer mixtures of 1e
(eq 2). The reaction of phenylpropiolaldehyde with 1c in the
presence of amine provided 1d in 50% yield (eq 3). After the
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oxidation of 1a by Cu(OAc)2 and O2, reduced copper salts become
the active species in the second step (non-oxidative reaction);
therefore, the CuOAc-catalyzed reaction in the absence of oxygen
was carried out to form 1d in 75% yield (eq 4). The reaction of
phenylpropiolaldehyde with 1c in the presence of pentanol affords
1d in 74% yield (eq 5). Based on these results, it appears that both
amines and alcohols facilitate the β-alkynyl elimination via
hemiaminal or hemiacetal intermediates. In the absence of copper
catalysts, the reaction of phenylacetylene and 1c afforded a
regioisomer mixture of 1d and 1d' in 59% yield. The formation of 1d
as a single regioisomer under our reaction conditions implies that
copper catalysts are involved in both dealkynylation and
cycloaddition.
Scheme 4 Proposed reaction mechanism for triazole formation.
Next, the scope of the reaction was examined (Figure 1). Since the
dealkynylation yield could not be directly measured under the
standard conditions, the yield for acetylene cycloaddition was used
to provide an estimate. Halogen-substituted phenyl propargyl
alcohols were converted to triazoles 2d and 3d in 77 and 85% yield,
respectively. Meanwhile, para-, meta-, and ortho-substituted
phenyl propargyl alcohols afforded 4d, 5d, and 6d in 78, 85, and 78%
yield, respectively. Cyclohexene-substituted propargyl alcohols also
participated in the reaction to form 7d in 57% yield. Overall,
cyclohexyl, cyclopropyl, and pentyl propargyl alcohols underwent
dealkynylation smoothly. Trimethylsilyl propargyl alcohol also
showed good conversion, giving a yield of 81% with benzylazide. In
addition to benzylazide 1c, octylazide was tested to form 12d in 93%
yield.
Cu(OAc)2 (5 mol%)
N
Bn
N
N
Ph
TEMPO (5 mol%)
O2, toluene (0.5 M)
100 C, 18 h
BnN3
(1)
+
OH
Ph
1a
1c
1d
Yield = 52%
Cu(OAc)2 (5 mol%)
TEMPO (5 mol%)
O2, toluene (0.5 M)
100 C, 18 h
N
N
N
Bn
Bn
Bn
N
(2)
N
N
N
N
N
Ph
+ BnN3
+
+
O
Ph
OHC
Ph
Ph
CHO
1c
1d
1e
not formed
Yield = 85%
Cu(OAc)2 (5 mol%)
TEMPO (5 mol%)
N
Bn
Bn
N
N
Ph
Ph
(3)
+ BnN3
O
O
O
MeNHBn
(1.5 equiv)
Ph
O2, toluene (0.5 M)
100 C, 18 h
1c
1d
Yield = 50%
CuOAc (5 mol%)
TEMPO (5 mol%)
MeNHBn (1.5 equiv)
N2, toluene (0.5 M)
100 C, 18 h
N
N
N
(4)
+ BnN3
Ph
1c
1d
Yield = 75%
Cu(OAc)2 (5 mol%)
TEMPO (5 mol%)
pentanol (1.5 equiv)
O2, toluene (0.5 M)
100 C, 18 h
N
Bn
N
N
Ph
+ BnN3
(5)
(6)
Ph
1c
1d
Yield = 74%
N
N
Bn
Bn
N
N
N
N
+ BnN3
+
Ph
toluene (0.5 M)
100 C, 18 h
Ph
Ph
1d'
1d 1d'
1c
1d
Yield = 59% (
:
= 2:1)
Scheme 3 Control experiments.
A reaction mechanism for the dealkynylation of 1a is proposed in
Scheme 4. Propargyl alcohol 1a undergoes oxidation to form
intermediate I, which reacts with morpholine (or alcohols) to afford
the key hemiaminal (hemiacetal) intermediate II. At this stage,
dealkynylation occurs to afford intermediate III and formamide
(formacetate). This intermediate then undergoes cycloaddition with
benzylazide to form the corresponding triazoles.
Figure 1 Substrate Scope.
Conclusions
We have presented the copper-catalyzed C-C bond cleavage of
primary propargyl alcohols under mild aerobic oxidative
conditions. This reaction proceeds through hemiaminal
intermediates that form through the oxidation of propargyl
alcohols and the subsequent nucleophilic addition of amines to
aldehydes. Hemiaminals are known to undergo both
β-
hydrogen elimination and the C-N bond cleavage; however, in
this case, the less polar C-C bond was cleaved to generate the
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