Copper-catalyzed formylation of alkenyl C-H bonds using BrCHCl2 as a stoichiometric formylating reagent

Article abstract of DOI:10.1039/c8sc00210j

The first example of copper-catalyzed direct formylation of alkenyl C-H bonds for the facile synthesis of α,β-unsaturated aldehydes has been developed. This transformation has demonstrated high reactivity, mild reaction conditions and a broad substrate scope. BrCHCl₂ is expected to be developed as an efficient stoichiometric C1 building block in organic synthesis.

Full text of DOI:10.1039/c8sc00210j

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Copper-catalyzed formylation of alkenyl C-H bonds with BrCHCl2
used as a stoichiometric formylating reagent
Received 00th January 20xx,
Accepted 00th January 20xx
Yan Bao, Gao-Yin Wang, Ya-Xuan Zhang, Kang-Jie Bian, and Xi-Sheng Wang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first example of copper-catalyzed direct formylation of alkenyl of α,β-unsaturated aldehydes. Indeed, the constant
C-H bonds for facile synthesis of α,β-unsaturated aldehydes has exploration of Vilsmeier-Haack reaction has long been
been developed. This transformation has demonstrated high developed as a useful approach to introduce formyl group into
reactivity, mild reaction conditions and broad substrate scope. alkenes.7 On the other hand, using Grubbs II catalyst as the
BrCHCl2 is expected to be developed as an effcient stoichimetric radical initiator succeeded in atom transfer radical addition
C1 bulding block in organic synthesis.
(ATRA) of styrene, which affording the alkenyl aldehyde via the
following elimination of hydrochloric acid under strong acid or
stoichiometric amount of silver salts at high temperature.8
Apart from these intersting progress, both known methods still
suffered from the limited scope of alkenes and requirement of
large amount of poisonous reagents (POCl3 as precusor of
Vilsmeier reagent or CHCl3 as the solvent), which definitely
hampered their practical application in organic synthesis.
Herein, we reported a novel copper-catalyzed formylation of
alkenyl C-H bonds for facile synthesis of α,β-unsaturated
aldehydes, in which high reactivity, mild conditions and broad
substrate scope have been demonstrated. The key to success
is commercially available BrCHCl2 was firstly used as a
stoichiometric formylating reagent instead of CHCl3, which was
normally used as solvent in such reactions, and alkenyl
aldehydes was then furnished by bifunctionalization of alkenes
via a carbocation process and following dehydration.
To develop novel methods for the synthesis of complex
molecules in an efficient and expeditious manner still
represents one kernel study and remains as a major challenge
in organic synthesis. Accordingly, many novel strategies for
quick construction of complex molecular skeleton have been
developed and used for total synthesis of complex
compounds.1,2 Among all these strategies, domino reactions is
emerging as an efficient key reaction to dominate the facile
synthesis of key intermediates in the synthetic route. Of
significant interest are cascade reactions that provide access to
fundamental building blocks in a chemo-selective manner from
readily available starting materials in
a step-economical
fashion.3 As a key material used for cascade transformations,
especially for organocatalyzed domino reactions, α,β-
unsaturated aldehydes have offered
a broad range of
unconventional transformations to make complex molecules
or key intermediates.4 Thus, considerable efforts have been
devoted to developing novel methods for facile synthesis of
α,β-unsaturated aldehydes from readily available simple raw
materials in efficient and quick ways.5
As produced on the large scale industrially and served as an
important feedstock of petrochemical industry, simple alkenes
have long been realized as one of the most widely used raw
material for a great variety of organic transformations.6 And
thus, the direct formylation of simple alkenes thus offers the
most economical and efficient method for facile construction
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai
Road, Hefei, Anhui 230026, China. Email: xswang77@ustc.edu.cn.
Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Scheme 1 Facile synthesis of α,β-unsaturated aldehydes from
alkenes.
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Table 1 Copper-catalyzed formylaion of styrene: optimization Table 2 Substrate scopea
of conditionsa
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), CHBrCl2 (3.0 equiv), Cu
Catalyst (10 mol%), PMDTA (1.0 equiv) and KI (1.0 equiv) in CH3CN (1 mL) at
40 ˚C for 24 h. b Isolated yield by 1HNMR analysis. c KI was not added. d The
mixture of 2a
anhydride 50% ethyl acetate). The yield in the parentheses was isolated
yield of 2a
e TBAI was used instead of KI f NaI was used instead of KI.
/2aa was dehydrated by T3P (1-Propanephosphonic acid cyclic
.
PMDTA.; 1,1,4,7,7-pentamethyl-diethylenetriamin.
Our initial investigation commenced with 4-methoxystrene
(
1a) as the pilot substrate, and bromodichloromethane as the
stoichiometric formylating reagent in the presence of a
catalytic amount of copper catalyst (10 mol%) and 1.0 equiv of
PMDTA (1,1,4,7,7-pentamethyl-diethylenetriamin) in CH3CN at
40 °C (Table 1). Unfortunately, none of the desired product 2a
was obtained when CuBr was used as the catalyst. Considering
the halogen atom exchange may improve the reactivity of
CHBrCl2,9 to our delight, the addition of 1.0 equiv of KI into the
reaction system afforded 2a successfully, albeit with
a
a General conditions:
1
(0.2 mmol), Cu(OH)2 (10 mol%), CHBrCl2 (3.0 equiv),
relatively low yield (23%, entry 2). Additionally, carefully
examination of copper catalysts were next performed, which
indicated Cu(OH)2 gave the best result with 31% yield (entry 4).
Meanwhile, further investigation of various solvents gave no
improvement of yield and CH3CN was still the best choice.
While trace amount of bifunctionalized alcohol 2aa was
isolated as a byproduct, it was conjectured that water worked
as the hydroxyl source for this bifunctional reaction. As we
expected, up to 28% yield of 2aa was obtained along with 24%
yield of 2a when water was used directly as the solvent. To
further improve the yield, the co-solvent has been investigated
and CH3CN/H2O (1/1) gave the dichloromethylated alcohol 2aa
in 74% yield along with the aldehyde 2a in 7% yield. Actually,
after simple work-up without purification and further
dehydration with T3P, 2a was finally furnished in 80% yield
(Entry 8). Considering the key role of PMDTA played in this
transformation,10 other bases have also been screened instead
PMDTA (1.0 equiv) and NaI (1.0 equiv) in CH3CN/H2O (v:v = 1:1, 1 mL) at 40
˚C for 24 h, then dehydrated by T3P (3.0 equiv.) in EtOAc at 100 °C; for 2x-
y, 1 (0.2 mmol), Cu(hfacac)2·xH2O (10 mol%), CHBrCl2 (3.0 equiv), PMDTA
(1.0 equiv) and KI (1.0 equiv) in CH3CN (1 mL) at 80 ˚C for 24 h, and
b
aldehydes 2x-y were obtained directly. Isolated yields were reported. 80
˚C.
of PMDTA, while giving none of the desired product 2a (Table
1, entries 11-13). Notably, by the replacement of KI with NaI,
the yield of 2a was further improved to 90% after this two-step
formylation of styrene (entry 15). Finally, control experiment
indicated that none of the desired product was obtained
without the addition of copper catalyst or base (For details,
see the supporting information).
With the optimized conditions in hand, we next investigated
the scope of alkenes (Table 2). Initially, the study of
substituent effect on the aryl rings of styrene derivatives
2 | J. Name., 2012, 00, 1-3
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showed both electron-donating groups, such as 4-Methoxy, 4-
Phenoxy, 4-Methyl and 4-Methylthio 1a ), and weak
electron-withdrawing (1f ) groups, such as Fluorine, Chlorine,
(
-d
-h
Bromine, were all compatible with this catalytic system and
able to furnish the desired products in moderate to high yields.
Not surprisingly, the substrates with electron-withdrawing
groups installed on the aryl rings gave normally lower yields
and required relatively higher reaction temperature (2f-h).
Meanwhile, a variety of styrene derivatives with ortho-, meta-,
as well as para-substituents were smoothly formylated to
afford the corresponding α,β-unsaturated aldehydes 2i-k in
acceptable yields.
The ortho-chloro- and meta-methyl-substituted styrenes (1g
,
1k), styrene (1e) and 2-vinylnaphthalene (1l) also required a
much higher temperature and gave moderate yields. Although
the ortho- and meta-Methoxystyrene (1i-j) did not need high
temperature, but the yields of reaction were only moderate.
To our interests, heteroarene-derived styrene substrates,
including 2-vinylthiophene 1p and 3-vinylbenzothiophene 1q
,
were also well tolerated in this novel transformation with
synthetically useful yields (2p, 63%; 2q, 75%). Just as expected,
1,1-diphenylethenes 1r
trapper than styrene, generated the tri-substituted
unsaturated aldehyde 2r in relatively higher yields (Table 2, methanol as the cation scavenger afforded the corresponding
2r ). Of note was that formylation of tri- substituted internal bifunctional product 2ab in 72% yield, which further verify this
styrene 1u also proceeded smoothly to give the corresponding Scheme 2 Mechanistic studies. a For details of isolation of 2aa, see
tetra-substituted vinyl aldehyde with a pretty good yield (2u
-t, normally worked as better radical
-t
-t
,
83%). Importantly, subjection of 1,2-dihydronaphthalene 1v
into the optimized conditions resulted in the formylation of C-
H bond in cyclic double bonds successfully. It was also
noteworthy that the conjugated alkene 1w underwent the
reaction efficiently, with an acceptable yield (2w, 50%) and a
good E/Z selectivity (8:1). To our satisfaction, N-vinyl
substrates could also been directly formylated at the end of
terminal alkenes to afford β-aminoacrylaldehyde with
moderated yields, by simply deviating the conditions to a
combination of Cu(hfacac)2 •xH2O, KI and CH3CN.
To gain some insights into the mechanism of this
transformation, a series of control experiments were then
performed accordingly. First, the reaction was completely
quenched when 1.0 equivalent of 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) was added into the standard
conditions. Meanwhile, subjection of 1.0 equivalent of
butylated hydroxytoluene (BHT) into the standard conditions
the supporting information.
Scheme 3 Proposed mechanism.
possibility.11
On the basis of our preliminary results and previous reports,12
a plausible mechanism involving a •CHCl2 radical is proposed
as shown in the Scheme 3. The copper salt is reduced to
generate low-valent Cu complex, which can transfer a single
electron to the CHBrCl2 and then produce a free radical •CHCl2
afforded the corresponding dichloromethyl adduct
3 in 58%
yield. Both results indicated that this transformation may
processed via a radical path. To further verify this speculation,
the well known radical clock, 1-(1-cyclopropylvinyl)-4-
(
B
), Subsequently, The radical reacts with the styrene. The
•CHCl2 addition-compound can be oxidized by high-valent
Cu compelx to cationic intermediate . At last, the high-valent
methoxybenzene
4, had been synthesized and added into this
D
catalytic system, furnishing the cycle-opening product
5
in 65%
E
yield, strengthening the surmise of the dichloromethyl radical
(•CCl2H) being involved in the catalytic cycle.
Cu complex is reduced to low-valent Cu complex to complete
the catalytic cycle. There are two possible pathways for the
As alcohol 2aa was isolated as the key intermediate along with
vinyl aldehyde 2a in the model reaction (Eq. 4, Scheme 2), a
possible carbocation process was suggested to be involved in
the catalytic cycle. Indeed, the replacement of H2O with
sequential transformation of cation
a, Deprotonation to regenerate C=C bond, and
the following hydrolysis of dichloromethyl group to aldehyde.
E
to vinyl aldehyde
F: Path
F
is obtained by
Path b, cation
E
is captured by H2O to give the alcohol
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intermediate
sequentially hydrolysis of dichloromethyl group to afford F 13
Scheme 4 Formylation of estrone derivative
G, followed by dehydration with T3P and
.
6.
To demonstrate the synthetic potential of this transformation,
we had applied this two-step transformation to the late-stage
formylation of complex biologically active molecules. As shown
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ü
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7
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Conclusions
In summary, we have developed a novel copper-catalyzed
formylation of alkenyl C-H bonds for facile synthesis of α,β-
unsaturated aldehydes. This transformation has demonstrated
high reactivity, mild conditions and broad substrate scope. It is
the utmost factor that commercially available BrCHCl2 was
used as a stoichiometric formylating reagent instead of CHCl3,
and mechanistic studies indicated that alkenyl aldehydes was
furnished by bifunctionalization of alkenes via a carbocation
process and following dehydration. Further application of this
method for modification of bioactive molecules and BrCHCl2 as
an interesting C1 building block in organic synthesis are still
underway in our laboratory.
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Acknowledgment
We gratefully acknowledge the Strategic Priority Research
Program of the Chinese Academy of Sciences (Grant No.
XDB20000000), the National Basic Research Program of China
(973 Program 2015CB856600), and the National Science
Foundation of China (21522208, 21772187) for financial
support.
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The first example of copper-catalyzed formylation of alkenyl C-H bonds with BrCHCl2
used as a stoichiometric formylating reagent for facile synthesis of α,β-unsaturated
aldehydes has been developed.