Copper(II) acetate catalysed ring-opening cross-coupling of cyclopropanols with sulfonyl azides

Article abstract of DOI:10.1039/c5ra20729k

A copper(ii) acetate catalyzed ring-opening cross-coupling of cyclopropanol with sulfonyl azide has been developed. By this method, various β-amino ketones have been made efficiently in medium to high yields and venerable functional groups such as benzylic C-H, alkyl and aryl bromides, alkyl sulfonate, silyl ether and alkene are compatible with these reaction conditions. Control experiments have precluded the involvement of both radical and simple copper nitrene intermediates and a possible mechanism featuring key steps of ring-opening metalation and alkyl group migratory insertion into copper nitrene has been proposed.

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Journal Name
COMMUNICATION
Copper(II) Acetate Catalysed Ring-Opening Cross-Coupling of
Cyclopropanols with Sulfonyl Azides†
Received 00th January 20xx,
Accepted 00th January 20xx
a,
a
a,
Mei-Hua Shen, * Xiao-Long Lu and Hua-Dong Xu *
DOI: 10.1039/x0xx00000x
www.rsc.org/
A copper(II) acetate catalyzed ring-opening cross-coupling of
cyclopropanol with sulfonyl azide has been developed. By this
O
E+
B-
OH
R
O
E
method, various β-amino ketones have been made efficiently in
medium to high yields and venerable functional groups such as a,
I
R
R
OH
E
2
benzylic C-H, alkyl and aryl bromides, alkyl sulfonate, silyl ether
and alkene are compatible to this reaction conditions. Control
experiments have precluded the involvement of both radical and
simple copper nitrene intermediates and a possible mechanism
1
E+
B-
R
II
OH single electon
oxidant
radical
receptor
featuring key steps of ring-opening metalation and alkyl group
O
O
b,
migratory insertion into copper nitrene has been proposed.
R
R
R
R
X
1
III
3
The energy favouring ring-opening of cyclopropanyl group has
been exploited to develop a plethora of elegant synthetic
1
methodologies. Factors that induce the C-C bond breaking in c,
OH
activator
Nu-
R
R
R
this small ring are extremely diverse depending on the nature
of the ring itself, which is defined by substitution pattern on
the ring, and reaction conditions. For simple cyclopropanol,
the ring opening event normally occurs in a high regioselective
IV
Nu
V
4
1
Scheme 1. Three common ring-opening mechanisms of cyclopropanol
2
fashion due to the effect of hydroxyl group. Roughly, these
reactions fall into three categories in the mechanistic respect:
a) base and electrophile promoted heterolytic cleavage of
The incorporation of a transition metal would expand the
reaction scope and improve their usefulness via the
cyclopropanol ring through the intermediacy of homoenolate
I
intermediary of metal homoenolate M-I. Indeed, both
3
or oxonium ion II (Scheme 1, a); b, single electron oxidation
induced homolytic breaking of C-C bond resulting in β-carbonyl
radical III which can be intercepted by various carbon radical
palladium and copper are reported to mediate ring-opening
coupling reactions of cyclopropanol with carbon-based
6
partners. Very recently, transition metal catalysed conversion
4
receptors (Scheme 1, b); c, activation and removal of the
3 3 2
of cyclopropanol to β-F, β-CF /SCF and β-NR substituted
hydroxyl group to give rise to cyclopropanyl cation IV, which
7
ketones have appeared in literature. On the other hand,
sulfonyl azide has been used in various metal catalysed
transformations via metal nitrene M-VI, metal-nitrene radical
would open up to form more stable allylic cation
5
reactions (Scheme 1, c).
V for further
8
M-VII or other reactive species as key reaction intermediates.
9
In line with our interests in azide chemistry, we are curious
that if the chemistry of cyclopropanol and sulfonyl azide could
interwoven through transition metal catalysis (Figure 1).
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a
Table 2. Effects of different sulfony azides in the Ring-Opening Cross-Coupling reaction
Figure 1. Conceptual depiction of interweaving of cyclopropanol chemistry with
sulfonyl azide chemistry by metal catalysis
b
entry
RSO N 5
2
3
product 7a, yield
7aa, 69%
7ab, 56%
7ac, 61%
7ad, 31%
7ae, 18%
7af, 44%
-
1
2
3
4
5
6
7
TsN
3
5a
Our investigation started with catalyst screening for reaction
of phenyl cyclopropanol 1a with tosyl azide 5a (table 1). In
most cases, propiophenone 6a was the only observable
product (see SI-Table 1). To our delight, when a solution of 1a
and 5a in dichloroethane (DCE) was heated to reflux in the
MbsN 5b
3
MsN
3
5c
5d
5e
MtsN
3
TcesN
CamsN
NsN 5g
3
3
5f
3
presence of a catalytic amount Cu(OAc)
coupling product 7aa was isolated in 40% yield along with 6a
table 1, entry 1). Interestingly, while Cu(acac) was slightly
less effective in terms of yield when DCE was used for reaction
media (entry 1 vs 2), CuBr was totally ineffective for the cross-
2
, ring-opening cross
(
2
2
coupling reaction (entry 3) indicating the importance of ligand
effect. Common Copper (I) complexes all failed to deliver 7aa
(
entries 4-6) and only 6a was obtained. When the reaction was
performed in reflux toluene using Cu(OAc) as catalyst, the
yield of cross-coupling product 7aa increased to 69% (entry 7).
More electron deficient Cu(hfacac) showed much poorer
activity than Cu(acac) in toluene (entry 8 vs 9). Toluene was
2
2
a, conditions, 1a (0.5 mmol), 5 (0.75 mmol), Cu(OAc) (0.1 mmol), toluene (2 mL)
o
2
in N , 120 C, 8 h; b, isolated yields
2
2
The effect of sulfonyl azide was also checked with Cu(OAc)
catalyst and toluene as solvent. TsN , MbsN and MsN
afforded corresponding sulfonyl amides in comparable yields
entries 1-3). MtsN , TcesN and CamsN were much inferior
reaction partners for this reaction (entries 4-6), and electron
deficient NsN reacted with 1a to give a complex mixture.
Next the scope of cyclopropanol was investigated with TsN
the amination agent (Table 3). For aryl cyclopropanols 1a-1d
as
2
superior solvent than DCE, THF and chloroform (entries 10-11).
Interestingly, in polar solvents such as acetonitrile, DMF and
DMSO, 1a remained intact under the same conditions (entries
3
3
3
(
3
3
3
12-14).
a
3
Table 1. Optimization of conditions for Ring opening cross-coupling reaction
3
as
,
the yield of corresponding β-tosylamidylaryl ketones increased
from 52% to 76%, suggesting that the electron-donating group
on the phenyl ring favor the ring open/coupling reaction (from
entry 3 to 1, 2 and 4). Substrates with benzylic C-H group
which is potential reactive site in metal catalyzed reactions
involving sulfony azide were also viable for this reaction, as
both 7ea and 7fa were obtained smoothly (entries 5-6) in
comparable yields. 1-Cyclohexylcycplopropanol 1g reacted
b,c
entry
cat
solvent
DCE
temp
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
Products (yield)
1
2
3
4
5
6
7
8
9
Cu(OAc)
2
6a + 7aa (40%)
6a + 7aa (37%)
6a only
Cu(acac)
CuBr
2
DCE
2
DCE
CuCl
CuBr
DCE
6a only
DCE
6a only
3
with TsN in the same conditions to give 7ga in an excellent
CuI
DCE
6a only
yield (entry 7, 95%). Methyl cyclohexylcycplopropanol 1h
afford 7ha in 88% yield (entry 8). The slight decrease in yield
for 7ha than for 7ga might reflect the effect of increased
bulkiness at the alkyl group in 1h. Functional groups such as
alkyl/aryl bromide, alkyl silyl ether, alkylsulfonate and
alkylsulfonamide were all tolerated in this reaction conditions
and related β-tosylamide aryl ketones 7ia-7ma were all
generated in medium to high yields (entries 9-13). It is worth
Cu(OAc)
2
toluene
toluene
toluene
THF
6a + 7aa (69%)
6a + 7aa (51%)
6a + 7aa (15%)
6a + 7aa (29%)
6a + 7aa (27%)
No reaction
No reaction
No reaction
Cu(acac)
2
Cu(hfacac)
2
1
1
1
1
1
0
1
2
3
4
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
CHCl
3
3
CH CN
o
DMF
120 C
o
DMSO
120 C
a Conditions 1a (0.5 mmol), 5a (0.75 mmol), cat (20% mol%), solvent (2 mL), to note that 1n bearing a vulnerable alkene group was also a
heating, 12 h; b isolated yields; c yields for 7aa are reported.
good substrate to give 7na in 57% (entry 14).
2
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a
Table 3. Substrate scope for cyclopropanol ring-opening cross-coupling reaction
b
b
entry
cyclopropanol 1
product 7, yield
entry
cyclopropanol 1
product 7, yield
o
2 2
a, conditions, 1a (0.5 mmol), 5 (0.75 mmol), Cu(OAc) (0.1 mmol), toluene (2 mL) in N , 120 C, 8 h; b, isolated yields
Cyclobutanol 8, cyclopentanol 9 and admantanol 10 failed to
undergo analogous ring breaking/coupling reaction when
subjected under the same reaction conditions. These
experiments underscore the necessity of three-membered ring
for the reaction.
To gain more information about this reaction, control
experiments have been carried out (Scheme 2, equations 1-4).
It was found that TEMPO has neglectable effect on this
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reaction. When a mixture of 1a (1 equiv), 5a (1.5 equiv),
TEMPO (2 equiv) and Cu(OAc) was heated in DCE for 8 hours,
aa and 6a were isolated as sole products (Scheme 2, 1), while
increasing the amount of TEMPO to 10 equiv, the formation of
aa was not observed. Interestingly, in the prescence of 2
equiv TEMPO but free of Cu(OAc) 7aa could be isolated in 20%
2
7
7
2
,
yield (Scheme 2, 2). Reaction without sulfonyl azide, phenyl
cyclopropanol 1a was converted to ketone 6a in a high isolated
yield (Scheme 2, 3). In the presence of 1.5 equiv styrene, the
reaction took place as normal and no phenyl tosylaziridine was
observed (Scheme 2, 4). No reaction happened when styrene
and TsN
3 2
was heated with catalytic amount of Cu(OAc)
(
Scheme 2, 5). These results suggested there was no simple
1
0
copper nitrene species TsN=Cu(OAc) in the reaction system.
1
In view our results and literature precedence, a mechanism
1
depicted in scheme 3 was proposed even though a free radical Scheme 3. Proposed mechanisms for Ring-Opening Cross-Coupling reaction of
1
2
alternate couldn’t be excluded at this stage. The catalytic Cylopropanol
circle starts with a Cu(OAc) promoted ring-opening metalation
of cyclopropanol to give alkyl copper(II) homoenolate
Protonation of this species would lead to the side product Conclusions
ketone . On the other hand, Cu(II) species could be
2
1
I.
6
I
In summary, we have described a copper(II) acetate catalysed
ring-opening cross-coupling of cyclopropanol with sulfonyl
azide to produce β-amino ketone. The conditions of this
reaction are mild enough to be compatible with a number of
fragile functionalities.
harnessed by sulfonyl azide 5 either through a transition metal
mediated mechanism or a copper coupled radical process to
construct the key C-N bond giving rise to intermediate II which,
upon release of
Subsequently, ligand exchange would take place with AcOH to
release product and Cu(OAc) to complete the catalytic
2
N , would produce intermediate III.
7
2
circle. This mechanism is also in line with the ineffectiveness of
Cu(I) salts as catalyst for this reaction.
Acknowledgements
The authors wish to thank the Natural Science Foundation of
China (21402014 and 21272077), the Natural Science
Foundation of Jiangsu Province (BK20131143), the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PADA), and Jiangsu Key Laboratory of Advanced
Catalytic Materials and Technology (BM2012110). We also
thank Prof. Lei Zhu at Florida State University for mechanism
discussion.
Notes and references
Note
Sulfonyl azides are known explosive compounds and therefore
special precautions are paid for their preparation and
purification. In some reactions, significant amount of both
TsN
3 2
and TsNH were observed after 8 h heating, suggesting
that some sulfonyl azides are safe for laboratory use at least in
small scale
.
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