Directed C-C bond cleavage of a cyclopropane intermediate generated from: N -tosylhydrazones and stable enaminones: Expedient synthesis of functionalized 1,4-ketoaldehydes

Article abstract of DOI:10.1039/c7cc07178g

An efficient method to construct functionalized 1,4-ketoaldehydes bearing all-carbon α-quaternary centers via regioselective C-C bond activation has been described. The cyclopropanation of bench-stable enaminones with in situ generated diazo reagents from

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Directed C-C Bond Cleavage of Cyclopropane Intermediate
Generated from N-Tosylhydrazones and Stable Enaminones:
Expedient Synthesis of Functionalized 1, 4–Ketoaldehydes †
Meiyan Ni†a, Jianguo Zhang†a, Xiaoyu Lianga, Yaojia Jianga* and Teck-
5
Peng Lohab*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
An efficient method to construct functionalized 1, 4-
ketoaldehydes bearing all-carbon
α-quaternary centers via
10 regioseletive C-C bond activation has been described.
Through cyclopropanation of bench-stable enaminones with
in situ generated diazo reagents from N-tosylhydrazones,
followed by selective C-C bond cleavage of the cyclopropane
ring affords the 1, 4-ketoaldehyde derivatives in good to
15 excellent yields. This method works with broad substrate
scope and high regioseletivity.
Fig. 1 Bioactive molecules carrying 1, 4ꢀketoaldehydes.
40 In our continuing interest in this unique fragment11 and enamine
chemistry,12 we envisage that the reaction of bench stable
enaminones13 with a carbene precursor in the presence of
transition metal catalyst will lead to the formation of strain
cyclopropanyl ring via CꢀC double bond activation (Scheme 1).
45 The obtained strain cyclopropane ring intermediate which upon
CꢀC bond cleavage with the assistance of the electron lone pair
from the amine group will lead to the formation of 1, 4ꢀ
ketoaldehydes. We believe that the carbonyl group at Cꢀ(a) will
help to direct the selective cleavage of the CꢀC bond of the
50 cyclopropane ring due to the stabilization of the anion
intermediate. Herein, we report a new and efficient strategy for
Dioxygenated fragments are featured widely in many natural
products and pharmaceuticals.1 Therefore, there are important
retrons in organic synthesis.2 Although 1, 3ꢀ and 1, 5ꢀ
20 dioxygenated compounds can be easily accessed in organic
synthesis,3 obtaining the 1, 4ꢀdioxygenated compounds is more
challenging which are common skeletons in bioactive molecules
(Fig 1).4 Accordingly, there have been much effort directed
towards the development of new methods for the construction of
25 1, 4ꢀketoaldehyde compounds. Existing methods include the
oxidation of hydroxyl aldehydes or hydroxyl ketones or 1, 4ꢀ
diols5, dearomatization of furan derivatives,6 ozonolysis of γꢀ
ketoalkenes7, intramolecular isomerization8 and intermolecular
coupling of two different carbonyl species.9 Other methods10
30 include the use of nobleꢀmetals as catalysts for the acylation
reaction, small ring opening and TsujiꢀWacker oxidation
reactions. However, despite these advances, existing methods still
have limitations such as using expensive catalysts, harsh reaction
conditions and difficulty in preparing different carbonyl
35 functionalities carrying an alphaꢀquartenary stereogenic center.
the synthesis of 1, 4ꢀketoaldehydes bearing allꢀcarbon
αꢀ
quaternary centers in the presence of cheap copper catalyst
through regioselective CꢀC bond cleavage of the aminoꢀ
55 cyclopropane ring.
a
Institute of Advanced Synthesis, School of Chemistry and Molecular
Engineering, Jiangsu National Synergetic Innovation Center for
Advanced
Materials, Nanjing Tech University, Nanjing 211816
(China)
b
Scheme 1. Our strategy to synthesis of 1, 4ꢀketoaldehydes.
Division of Chemistry and Biological Chemistry, School of Physical
and Mathematical Sciences, Nanyang Technological University,
Singapore 637616 (Singapore)
NꢀTosylhydrazones14 are selected as the carbene sources since
60 they can be easily prepared and the corresponding carbenes can
be generated using copper catalyst. The initial exploration began
Eꢀmail:teckpeng@ntu.edu.sg；iamyjjiang@njtech.edu.cn
† M. N. and J. Z. contributed equally.
Electronic Supplementary Information (ESI) available: Detailed
experimental procedures analytical data, See DOI: 10.1039/b000000x/
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the desired products in good to excellent yields (3eaꢀ3ha). It is
worth to note that the chloro, bromo and iodo functionalities are
useful synthetic functional groups in coupling reactions15, and
40 this allows possible transformations to other functional 1, 4ꢀ
ketoaldehydes. Naphthyl substrate also proceeded efficiently to
give the corresponding product in 94% yield (3ia). Obvious steric
effect was observed when different aliphatic enaminones were
explored. Examination of different R1 revealed the efficiency of
45 the reaction in the order of primary, secondary, followed by
tertiary alkyl groups: 3ja, 70%; 3ka, 54%; 3la, 58%; 3ma, 29%.
Notably, the strainedꢀring cyclopropanyl substitution is well
tolerated in this catalytic conditions. Heteroꢀaromatic ring
substrates were examined to test the possible competition reaction
50 of sp2 CꢀH bonds of enamine with heteroꢀaromatic rings.
Gratifyingly, this reaction did not affect the heteroꢀaromatic ring,
affording the products in good to excellent yields. The results
have been achieved for electronꢀrich five memberꢀrings in 88%
and 93% yields (3oaꢀ3pa) while electronꢀdeficient pyridinyl
55 group gave the product in 61% yield (3na). When the
enaminones bearing multiple double bonds were used in the
reaction, the reaction proceeded in high regioselectivity, reacting
only with the enamine moiety rather than the conjugated (3qaꢀ
3ra) or unconjugated double bonds (3sa). Alkynyl substitution
60 also remained intact under the reaction condition albeit in lower
yield (3ta).
by reacting enaminone 1a with Nꢀtosylhydrazone 2a in the
o
presence of CuI and LiOtBu in DCE at 80 C (Table 1, entry 1).
To our delight, the desired 2ꢀmethylꢀ4ꢀoxoꢀ2, 4ꢀdiphenylbutanal
3aa could be obtained albeit in low yield (11%). The structure
was determined by NMR spectra and one of the products
structure 3ba was further confirmed by single crystal Xꢀray
analysis (See SI). Continuing screening the reaction conditions
revealed that the solvent and base had a significant influence on
the reaction efficiency. For instance, using K2CO3 in toluene
10 furnished the desired 1, 4ꢀketoaldehyde in 47% yield (Table 1,
entry 3 and SI). Various common copper salts were examined as
catalysts (See SI). Both Cu(I) and Cu(II) were found to promote
the reactions in good efficiency (Table 1, entries 4ꢀ7). Among
them, the more basic copper catalyst Cu(OH)2 was found to
15 afford the product in the highest yield (88% yield) (Table 1, entry
7). Further optimization of the reaction conditions revealed that
when enaminone 1a was reacted with Nꢀtosylhydrazone 2a using
10 mol% Cu(OH)2 and 2.0 equiv. K2CO3 in toluene at 80 oC
under Ar atmosphere, the desired product was obtained in 94%
20 isolated yield (Table 1, entry 8).
5
Table 1. Optional reaction conditions.a
Table 2. Substrate scope for reaction of enaminonesa ,b
O
NNHTs
Cu(OH)2, K2CO3
O
Ph
R1
N
O
+
Ph
R1
PhCH3, 80 o
C
1
3
2a
entry
metal
base
solvent
DCE
Yield (%)b
O
O
O
O
Ph
Ph
O
Ph
Ph
O
O
O
1
2
3
4
5
6
7
8
CuI
LiOtBu
LiOtBu
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
11
33
O2N
NC
MeO
CuI
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
PhCH3
3ca,78%
3aa, 96%
3ba, 81%
3da, 97%
CuI
47
O
O
O
O
Ph
Ph
Ph
Ph
O
O
O
O
Cu(TC)
CuOAc
Cu(OAc)2
Cu(OH)2
68
F
Cl
Br
I
71
3ha, 82%
3ea, 90%
3ga, 97%
3fa, 91%
47
O
Ph
O
O
88
96/94d
Ph
Ph
O
O
Ph
O
O
O
c
Me
Cu(OH)2
3la, 58%
3ja, 70%
3ka, 54%
3ia, 94%
a Conditions: A mixture of 1a (0.1 mmol, 1 equiv), 2a (0.2 mmol, 2
equiv), base (0.20 mmol, 2.0 equiv), catalyst (20 mol %) and solvent (2
O
O
O
O
Ph
Ph
Ph
Ph
O
O
O
o
O
O
N
O
mL) were sealed in Schlenk tube under Ar atmosphere at 80 C and the
S
mixture was stirred for 24h or until the 1a was consumed completely.
bYields were determined by 1H NMR vs an internal standard, c10 mol %
catalystꢀloading, dYields were isolated, Cu(TC) = Copper(I) thiopheneꢀ
2ꢀcarboxylate, DCE = dichloroethane.
3ma, 29%
3pa, 93%
3oa, 88%
3na, 61%
O
O
Ph
Ph
O
O
Ph
O
Ph
O
O
Ph
Ph
3sa, 75%
3ta, 41%
3qa, 64%
3ra, 52%
25
With the optimized reaction conditions in hand, we proceeded to
survey the scope of the reactions with different enaminones 1
(Table 2). Generally, the reactions tolerated a broad range of
substituted enaminones to afford the corresponding 1, 4ꢀ
65 aConditions: 0.2 mmol 1 and 0.4 mmol 2a with 10 mol% Cu(OH)2
and 2.0 eq. K2CO3 were stirred in 4 mL dry toluene under Ar
protection at 80 oC. bIsolated yields.
30 ketoaldehyes in good to excellent yields. Investigation the
electronic influence of the phenyl group showed that although
both electronꢀwithdrawing (3ba and 3ca) and electronꢀdonating
(3da) groups performed well and resulted in good yields,
electronꢀrich enaminone seems to work better (97% yield).
35 Halogen substituents (F, Cl, Br and I) at the paraꢀposition of
phenyl group worked well under standard conditions affording
Next, we turn our attention to investigate the scope of Nꢀ
70 tosylhydrazones under the same reaction conditions. (Table 2).
With regard to the substituent effect on the phenyl ring, various
functional groups containing hydrazones were examined in this
transformation. The halogen substituents on the paraꢀsite of
phenyl ring were well tolerated and gave the desired products up
75 to 92% yield (3abꢀ3ae). The electronic effect to this protocol was
2
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DOI: 10.1039/C7CC07178G
observed as the orthoꢀ, metaꢀ and paraꢀMeO substitutions (3agꢀ
3ah) gave better results to electronꢀwithdrawing groups (3aiꢀ
3ak). Multiple substitutions on the phenyl ring had less influence
on the reaction and gave the 2ꢀ(2, 4ꢀdichlorophenyl)ꢀ2ꢀmethylꢀ4ꢀ
oxoꢀ4ꢀphenylbutanal in 92% yield (3al). Heterocycles could also
survived under this standard reaction condition albeit in lower
yield (3am). In addition to simple phenyl acetone derived Nꢀ
tosylhydrazones, other substituents such as ethyl group also
proceeded well and gave the desired 1, 4ꢀketoaldehydes in 88%
mechanism. D2O exchange experiment was explored and found
35 that the Dꢀlabeling product was detected in methylene CꢀH bond.
Additionally, O18 was also found in the 1, 4ꢀkeoaldehydes product
when H2O18 was used in the catalytic system. These results
supported our proposed mechanism (Scheme 2, b).
5
10 yield (3an). It is worth to note that cyclic ketone derived Nꢀ
tosylhydrazones (3aoꢀ3ap) could also afford the desired products
in good yields, thus offering an efficient approach for the
construction of natural products containing spiroꢀring structure.
Finally, aldehyde derived Nꢀtosylhydrazones were also examined
15 in the reaction condition, the results revealed that various 2ꢀ
monoꢀsubstituted 1, 4ꢀketoaldehydes could be obtained in
moderate to good yields (3aq-3at). Unfortunately, no desired
product was obtained when aliphatic Nꢀtosylhydrazones were
used as the substrates (3av-3ay).
20 Table 3. Substrates scope for Nꢀtosylhydrazones a, b
O
R1
O
R2
NNHTs
Cu(OH)2, K2CO3
+
O
Ph
N
R1 R2
PhCH3, 80 o
C
Ph
3
1a
2
40
F
Br
Cl
I
Scheme 2. Proposed reaction mechanism and isotopic labeling study
.
O
O
O
O
To further demonstrate the synthetic utility of our developed
protocol, the reaction was performed on 10 mmol scale of
45 emaninone (Scheme 3). To our delight, the reaction proceeded
smoothly and generated the corresponding product in 2.20 gram
(87%) under the standard catalytic conditions. The 1, 4ꢀ
ketoaldehydes obtained are versatile intermediates in organic
synthesis. For example, the carbonyl groups could be easily
50 reduced to 1, 4ꢀdiol 4aa in 97% isolated yield (Scheme 3, a).
Selectively reaction of the formyl group using ethyl 2ꢀ
(diethoxyphosphoryl)acetate afforded the ethyl (E)ꢀ4ꢀmethylꢀ6ꢀ
oxoꢀ4,6ꢀdiphenylhexꢀ2ꢀenoate 5aa in 89% yield (Scheme 3, b).
An interesting cyclobutylene derivatives 6aa could be obtained
55 through intramolecular McMurry coupling reactions (Scheme 3,
c).16 Finally, it can also easily be halogenated with HBr in DMSO
to afford 3ꢀbromoꢀ2ꢀmethylꢀ4ꢀoxoꢀ2, 4ꢀdiphenylbutanal 7aa
(Scheme 3, d).17
O
O
O
O
3ae, 70%
Ph
Ph
Ph
Ph
Ph
3ad, 89%
3ab, 71%
3ac, 92%
CN
OMe
OMe
O
O
O
OMe
O
O
O
O
Ph
O
Ph
Ph
Ph
3af
, 95%
3ag, 84%
3ah, 82%
3ai, 43%
Cl
NO2
CF3
S
O
Cl
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
Ph
3am, 22%
Ph
3al
, 92%
3aj, 68%
3ak
, 73%
O
O
Ph
O
O
O
O
Ph
O
O
3an, 88%
3ap, 40%
3aq, 79%
3ao, 57%
F
Br
CF3
O
O
O
O
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
3ar, 73%
3at, 74%
3as, 79%
3au, 42%
Ph
Ph
O
O
O
O
O
O
Ph
Ph
Ph
3ay, 0%
3av, 0%
3ax, 0%
3aw, 0%
On the basis of the above results, a tentative mechanism is
proposed for the reaction of enaminone with Nꢀtosyl hydrazones
under Cu(OH)2/K2CO3 conditions (Scheme 2, a). Initially, copper
25 carbenoidꢀA is formed from the in situ generated diazo precursor
Nꢀtosyl hydrazine 2a. The resulting carbenoidꢀA underwent
cyclopropanation reaction with enaminone 1a to afford
intermediate B. Due to ring strain and with the assistance of the
nitrogen lone pairs, the CꢀC bond was regioselectively cleavaged
60 Scheme 3. Diverse transformations of 1, 4ꢀketoaldehydes.
30 at the
αꢀposition of the carbonyl group to give ylide C, which
In summary, a new and efficient method has been developed
subsequently underwent hydrolysis to afford the desired 1, 4ꢀ
ketoaldehyde 3aa and its enol form 3aa’. The isotopic labeling
experiments were then performed to probe the proposed
for the synthesis of 1, 4ꢀketoaldehydes bearing allꢀcarbon
αꢀ
quaternary centers. The special features of this method are (1) it
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65
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a
wide substrate scope tolerating diverse
functionalities. (2) the reaction is performed using cheap copper
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versatile and can be easily converted to a wide variety of useful
synthetic building blocks. Isotopic labeling experiments
supported our proposed reaction mechanism. Further studies on
the catalytic and asymmetric protocol of this reaction as well as
the application of this unique cascade transformations will be
reported in due course.
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10 Acknowledgement
The authors gratefully acknowledge funding from the National
Natural Science Foundation of China (21502089), Jiangsu
Province Funds Surface Project (BK 20161541) and the Starting
Funding of Research (39837107) from Nanjing Tech University.
15 We also thank the financial support by SICAM Fellowship by
Jiangsu National Synergetic Innovation Center for Advanced
Materials. Dr. Li Yongxing (NTU) is thanked for single crystal
Xꢀray diffraction analysis.
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