Radical-induced metal-free alkynylation of aldehydes by direct C-H activation

Article abstract of DOI:10.1002/chem.201501094

A direct C(sp²)-H alkynylation of aldehyde C(O)-H bonds with hypervalent iodine alkynylation reagents provides ynones under metal-free conditions. In this method, 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one (TIPS-EBX) constitutes a

Full text of DOI:10.1002/chem.201501094

DOI: 10.1002/chem.201501094
Communication
&
CÀH Activation
Radical-Induced Metal-Free Alkynylation of Aldehydes by Direct
CÀH Activation
Xuesong Liu,[a] Linqian Yu,[a] Mupeng Luo,[a] Jidong Zhu,*[b] and Wanguo Wei*[a]
efficient method to prepare ynones with readily available ma-
Abstract: A direct C(sp2)ÀH alkynylation of aldehyde
terials.
C(O)ÀH bonds with hypervalent iodine alkynylation re-
Recently, direct CÀH alkynylation reactions have gained a lot
agents provides ynones under metal-free conditions. In
of success for the functionalization of a broad range of sub-
this method, 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-
strates.[19] Great efforts on this subject have led to the discov-
3(1H)-one (TIPS-EBX) constitutes an efficient alkynylation
ery of various transition-metal-catalyzed reactions, as well as
reagent for the introduction of the triple bond. The sub-
metal-free conditions. Although much progress has been
strate scope is extended to a variety of (hetero)aromatic,
made in the development of direct CÀH alkynylation of aro-
aliphatic, and a,b-unsaturated aldehydes.
matic C(sp2)ÀH bonds,[19] as well as C(sp3)ÀH bonds,[20] direct
C(sp2)ÀH alkynylation of aldehyde C(O)ÀH, to our knowledge,
has not been well documented. This could be ascribed to the
Ynones are important structural motifs in organic chemistry, as
they serve as key intermediates in the synthesis of various bio-
active molecules.[1] More importantly, they represent a basic
scaffold for the synthesis of various heterocyclic structures,
such as furans,[2] flavones,[3] chromenes,[4] pyrazoles,[5] pyri-
dines,[6] pyrimidines,[7] indenones,[8] and benzodiazepines[9] for
numerous applications. Classical methods for synthesizing
ynones involve the addition of an acetylide anion to carbonyl
electrophiles,[10] Sonogashira coupling of terminal alkynes with
acyl halides,[11] or carbonylative Sonogashira of terminal alkynes
with aryl halides,[12] aryl triflates,[13] or aryl anilines[14] in the
presence of gaseous CO. Other methods, including gold-cata-
lyzed dehydrogenative Meyer–Schuster-like rearrangement,
have also been reported.[15] Huang and co-workers reported
the direct synthesis of ynones from aldehydes by oxidative CÀ
C bond cleavage under aerobic conditions.[16] Very recently, Lei
and co-workers disclosed a one-pot synthesis of ynones by
direct coupling of terminal alkynes with aldehydes by a nucleo-
philic addition/Oppenauer oxidation.[17] During the preparation
of this report, Li and co-workers reported an IrIII- and RhIII-cata-
lyzed CÀH alkynylation of benzaldehydes under chelation assis-
tance.[18] These methods, however, often have limitations with
respect to functional group tolerance, substrate scope, and
practical convenience. Given the recent demand for highly effi-
cient and environmentally friendly processes, there has been
growing interest in the development of a direct, simple, and
high reactivity of the carbonyl group but poor activity of the
formyl CÀH. On the basis of recent advances in metal-catalyzed
or metal-free oxidative cross-coupling reactions involving al-
kynes, we envision that the development of an oxidative alky-
nylation of the aldehyde C(O)ÀH bonds with alkynyl sources
derived from terminal alkynes would provide more efficient
and straightforward routes to ynones.
Aldehydes have been known to easily generate correspond-
ing acyl radicals in the presence of peroxides.[21] The acyl radi-
cal can be used for a variety of direct CÀC bond-formation re-
actions.[22] We were thus interested in whether the generated
acyl radicals could be efficiently trapped by a suitable alkyny-
lating agent to provide a direct synthesis of ynones from readi-
ly available aldehydes. With tert-butyl hydroperoxide (TBHP) as
the oxidant, we began our study with benzaldehyde (1a) as
our model substrate while investigating different alkynylation
reagents in the absence of transition metal salts (Scheme 1).
However, the reaction of benzaldehyde with phenylacetylene
[a] X. Liu, L. Yu, M. Luo, Prof. W. Wei
Shanghai Advanced Research Institute, Chinese Academy of Sciences
99 Haike Road, Shanghai 201210 (P. R. China)
E-mail: weiwg@sari.ac.cn
[b] Prof. J. Zhu
Interdisciplinary Research Center on Biology and Chemistry
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
354 Lingling Road, Shanghai 200032 (P. R. China)
E-mail: zhujd@sioc.ac.cn
Scheme 1. Oxidative CÀH alkynylation of benzaldehyde. Reaction conditions:
Benzaldehyde 1a (0.50 mmol), alkyne (0.60 mmol), TBHP (0.75 mmol), 1,2-di-
chloroethane (5.0 mL), 1108C, N2, 12 h, in Schlenk tubes. [a] Yield of product
isolated by column chromatography. TBHP=tert-butyl hydroperoxide (70%
aqueous solution).
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201501094.
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conducted in 1,2-dichloroethane at 1108C in the presence of
TBHP under N2 atmosphere did not form the desired cross-cou-
pling product in any detectable amount. Other terminal al-
kynes, such as 1-heptyne, also failed to give any coupling
products. Considering the undesired terminal alkyne homocou-
pling under oxidative conditions,[23] we investigated various
preactivated alkynylating reagents, such as alkynyl halides[24]
and benziodoxolone-based hypervalent iodine reagents[25] as
coupling partners. After considerable efforts, benziodoxolone-
derived hypervalent iodine reagents were found to be optimal
and furnished desired coupling products. Gratifyingly, when 1-
yield of 2a was obtained (Table 1, entry 12). During our stud-
ies, we found that metal catalysts, such as [{RhCp*Cl2}2],
Pd(OAc)2, Cu(OAc)2, AuCl3, had adverse effects on the reaction
and only trace amounts of the desired product were formed
(Table 1, entries 13–16). Similarly, when AgNO3 (Table 1,
entry 17) was employed, the reaction process was also dramat-
ically affected and only 36% of alkynylation adduct was ob-
tained. This observation suggests that the reaction may pro-
ceed through a different mechanism from conventional metal-
catalyzed CÀH alkynylations.[18,27] Encouraged by this result, we
initiated an attempt to synthesize ynones directly from alde-
hydes and alkynyl source derived from terminal alkynes under
metal-free conditions.
[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one
(TIPS-
EBX)[26] was employed, the desired ynone 2a was obtained in
63% isolated yield (Scheme 1; G=TIPS).
With the optimized reaction conditions in hand, we convert-
ed a variety of commercially aromatic aldehydes into the corre-
sponding ynones to examine the scope of the direct alkynyla-
tion protocol (Table 2). Simple alkyl- and alkoxy-substituted ar-
omatic aldehydes were successfully coupled with TIPS-EBX to
afford the corresponding ynones in good to excellent yields
(2a–c, 52–91% yield). Unfortunately, when electron-withdraw-
While further optimizing the reaction conditions, we discov-
ered that the right choices of solvent, reaction temperature,
and oxidant were crucial to minimizing formation of the unde-
sired side product. The reaction worked in a broad range of
solvents (Table 1, entries 1–5), with toluene giving the best re-
Table 1. Optimization of the direct CÀH alkynylation.[a]
Table 2. Scope of the alkynylation of (hetero)aryl aldehydes.[a,b]
Entry
Solvent
Oxidant
Catalyst
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
DCE
dioxane
THF
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
BPO
–
110
110
85
72(63)
34
–
–
–
–
–
–
–
–
–
–
–
<5
<5
85(72)
90(76)
31
25
0
<5
63
99(91)
<5
<5
<5
<5
36
CH3CN
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
85
110
130
130
130
130
130
130
130
MnO2
H2O2
9
10
11
12
13
14
15
16
17
K2S2O8
TBPB
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
[{RhCp*Cl2}2] 130
Pd(OAc)2
Cu(OAc)2
AuCl3
130
130
130
130
AgNO3
[a] Reaction conditions: benzaldehyde 1a (0.30 mmol), TIPS-EBX
(0.36 mmol), oxidant (0.45 mmol), catalyst (10 mol%), solvent (3.0 mL), N2,
12 h in Schlenk tubes; [b] yields were determined by HPLC analysis with
Ph3P as the internal standard; yields of isolated products given in paren-
theses. DCE=1,2-dichloroethane, BPO=benzoyl peroxide, TBPB=tert-
butyl peroxybenzoate, DTBP=di-tert-butyl peroxide.
producibility, highest yield, and broadest scope (entry 5). With
TBHP as an oxidant, the yield of 2a was improved to 90%
when the reaction temperature was raised to 1308C in
a Schlenk tube (Table 1, entry 6). Oxidant screening (Table 1,
entries 6–12) indicated that di-tert-butyl peroxide (DTBP) was
superior to TBHP, benzoyl peroxide (BPO), K2S2O8, MnO2, H2O2,
and tert-butyl peroxybenzoate (TBPB). When the reaction was
carried out at 1308C over 12 h in the presence of DTBP, 99%
[a] Reaction conditions: (hetero)aryl aldehyde 1 (0.30 mmol), TIPS-EBX
(0.36 mmol), DTBP (0.45 mol), toluene (3.0 mL), 1308C, N2, 12 h, in Schlenk
tubes; [b] yield of product isolated by column chromatography.
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ing groups such as halo-, cyano-, nitro- or carboxyl- groups
were introduced into the aromatic ring, the reaction became
sluggish and only trace amounts of coupling products were
formed (data not shown here). Notably, aryl aldehydes bearing
a neighboring OH or NHBoc substituent were well tolerated,
providing the corresponding ynones in decent yields (2d,e,
47–52% yield; Table 2). These functional groups are valuable
as they are potential substrates for further transformations.[3,4]
Furthermore, aromatic ring can be extended to various aro-
matic heterocycles (2g–i, 40–73% yield; Table 2). Gratifyingly,
direct alkynylation of furan–, thiophene–, pyrrole–, isoxazole–,
benzofuran–, benzothiophene–, and indole–aldehydes with
TIPS-EBX proceeded to give the desired ynones in moderate to
excellent yields (2j–r, 50–94% yield). N-Methyl indole-3-alde-
hyde proved to be a superior substrate and provided ynone
2r in quantitative yield. These heteroaromatic ynones should
be highly useful scaffolds for medicinal chemistry.[1]
Table 3. Scope of the alkynylation of aliphatic aldehydes.[a,b]
Encouraged by the successful alkynylation of (hetero)aryl al-
dehydes, we explored the scope of the reaction extensively by
applying various aliphatic aldehydes. The first set of reactions
was carried out using 1-heptanal and TIPS-EBX under the
above-optimized conditions. However, the reaction became
sluggish, affording the desired ynone 3a in only 23% yield.
Compared with (hetero)aryl aldehydes, aliphatic aldehydes
more easily undergo side oxidation and thermal decarboxyla-
tion. We therefore conducted a quick screening for milder con-
ditions (see the Supporting Information for details). We were
pleased to find that the yield of 3a could be improved to 57%
by lowering the reaction temperature to 858C and prolonging
the reaction time to 24 h, while utilizing TBHP in CH3CN as
a more compatible reaction system at the lower temperature.
The generality of this methodology is demonstrated in Table 3.
Various aliphatic aldehydes, including those bearing primary,
secondary, and tertiary alkyl groups, were transformed into the
corresponding ynones in moderate yield (3a–e, 24–57% yield).
Furthermore, a,b-alkenyl aldehydes are compatible and lead to
acceptable yields (3 f–h, 20–34% yield). Interestingly, the reac-
tion was also effective for a,b-alkynyl aldehydes, albeit provid-
ing the corresponding a,b-alkynyl ketones in lower yields (3i
and j, 15 and13% yield, respectively). The scope of the substi-
tuted EBX reagents was also investigated. Interestingly, unlike
(hetero)aryl aldehydes, aliphatic aldehydes were found to react
smoothly with 1-(phenylethynyl)-1,2-benziodoxol-3(1H)-one
(Ph-EBX), 1-[(trimethylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one
(TMS-EBX), and 1-(tert-butylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-
one (tBu-EBX) under the above-optimized conditions, provid-
ing the corresponding ynones in moderate to excellent yields
(3k–r, 26–73%). Various alkyl-substituted aldehydes were
tested to prove the generality of this reaction.
[a] Reaction conditions: aldehyde 1 (0.30 mmol), G-EBX (0.36 mmol), TBHP
(0.45 mol), CH3CN (3.0 mL), 858C, 24 h, under N2, in Schlenk tubes;
[b] yield of product isolated by column chromatography.
TEMPO adduct 5 was isolated in 45% yield, albeit with lower
conversion. These observations provide evidence of acyl radical
is most likely involved in this transformation (Scheme 2),[28] and
the reaction may proceed through a similar radical-induced
mechanism as proposed by Li et al.[28a]
The above results not only demonstrate the generality of al-
dehydes oxidative cross-coupling with TIPS-EBX, but also pro-
vide a unique approach to alkynes with the potential for fur-
ther derivatization. The TIPS group can be easily removed in
the presence of tetra-n-butylammonium fluoride (TBAF)/HOAc
To gain insights into the reaction mechanism, we performed
a couple of competition experiments. When the reaction of
benzaldehyde 1a with TIPS-EBX was conducted under the op-
timized conditions in the presence of a radical scavenger,
2,2,6,6-tetramethylpiperidin-1-yl)oxy (TEMPO), the alkynylation
was totally inhibited, and the acyl radical adduct 4 was isolated
in quantitative yield. Likewisely, when an aliphatic aldehyde,
cyclohexyl aldehyde 1d was applied, the corresponding acyl-
Scheme 2. Control experiments with TEMPO.
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Information for selected examples), which can undergo further
transformations, such as the Sonogashira cross-coupling and
click reaction. Consequently, the C(sp2)ÀH activation–alkynyla-
tion presented herein has the potential to achieve a privileged
position as a novel tool for various applications in synthetic
chemistry, chemical biology, and materials science.
In summary, we have developed a novel aldehyde C(O)ÀH
activation–alkynylation reaction utilizing the benziodoxolone-
based alkyne-transfer reagent TIPS-EBX, which provides
a direct and efficient entry to various ynones in moderate to
good yields. The generality of this approach was well demon-
strated with various types of aldehydes, including (hetero)aro-
matic aldehydes, aliphatic aldehydes and a,b-unsaturated alde-
hydes. Our work represents the first example of acetylene in-
corporation to aldehydes under metal-free conditions, which
constitutes an important advance in the field of hypervalent
iodine chemistry and direct CÀH activation. Further studies on
the use of hypervalent iodine reagents in catalytic alkynylation
reactions and on the applications of terminal and silyl-protect-
ed alkynes are also underway.
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Acknowledgements
This study was financially supported by the National Natural
Science Foundation of China (Grant No. 21202100) and The
Strategic Priority Research Program of the Chinese Academy of
Sciences (Grant No. XDA01040302).
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Keywords: aldehydes
hypervalent iodine · radicals
·
alkynylation
·
CÀH activation
·
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Received: March 20, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
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Communication
COMMUNICATION
Direct C(sp2)ÀH activation of aldehyde
C(O)ÀH bonds with hypervalent alkynyl
iodides (G-EBX) provides ynones under
metal-free conditions. 1-[(Triisopropylsi-
lyl)ethynyl]-1,2-benziodoxol-3(1H)-one
(TIPS-EBX) constitutes an efficient alky-
nylation reagent for the introduction of
the triple bond.
&
CÀH Activation
X. Liu, L. Yu, M. Luo, J. Zhu,* W. Wei*
&& – &&
Radical-Induced Metal-Free
Alkynylation of Aldehydes by Direct
CÀH Activation
&
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Chem. Eur. J. 2015, 21, 1 – 6
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!