Iridium-Catalyzed β-Alkynylation of Aliphatic Oximes as Masked Carbonyl Compounds and Alcohols

Article abstract of DOI:10.1002/anie.202002948

An Ir-catalyzed C(sp³)?H alkynylation of aliphatic ketones, aldehydes, and alcohols was achieved by using the corresponding oxime derivatives and a Ir^III catalyst. This general reaction is selective towards primary C(sp³)?H bonds and can be used for the late-stage C?H alkynylation of complex molecules.

Full text of DOI:10.1002/anie.202002948

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Accepted Article
Title: Iridium-Catalyzed β-Alkynylation of Aliphatic Oximes as Masked
Carbonyl Compounds and Alcohols
Authors: Antonio M. Echavarren, Eric Tan, and Margherita Zanini
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202002948
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10.1002/anie.202002948
Angewandte Chemie International Edition
Iridium-Catalyzed -Alkynylation of Aliphatic Oximes as Masked
Carbonyl Compounds and Alcohols
Eric Tan,† Margherita Zanini,† and Antonio M. Echavarren*
Dedicated to the memory of our colleague and friend Prof. Dr. Kilian Muñiz
Abstract: The Ir-catalyzed C(sp3)–H alkynylation of aliphatic ketones,
aldehydes, and alcohols has be performed in a general manner through
their corresponding oxime derivatives in the presence of a Ir(III) catalyst.
The reaction is selective towards primary C(sp3)–H bonds and can be
used for the late-stage C-H alkynylation of complex molecules.
Scheme 1. Strategies in metal-catalyzed C(sp3)–H alkynylation.
Ketoximes have been used as directing group in C(sp3)–H
functionalization in the context of C–H oxygenation,[13] amidation,[14]
amination,[15] arylation,[16] and iodination[17] with different transition
metals as catalysts. We envisioned that the alkynylation of oximes
derived from aldehydes, ketones, or alcohols[18] could significantly
broaden the scope of the functionalization of C(sp3)–H bonds. With
this aim, we have developed an iridium-catalyzed alkynylation
directed by oximes, which in contrast to previous examples occurs
exclusively at primary C(sp3)–H (Scheme 2). We also report
examples of a similar process in which N-heterocycles are used as
directing groups.
Alkynes are ubiquitous functional groups of high synthetic
versatility,[1] which are also present as part of drugs,[2] natural
products,[3] and organic materials.[4] The chemistry of alkynes has
gained particular momentum in recent years due to the
development of catalysts based on gold(I), platinum(II) and other
electrophilic metals that trigger a wide variety of highly selective
transformations in complex molecular settings.[5] Therefore, the
development of methods for the selective introduction of alkynes in
organic molecules is of the highest interest. To this end, classical
cross coupling approaches require the pre-functionalization of the
starting material with halides, pseudoaldehydes[6] or unsaturated
bonds. In recent years, the so-called inverse-Sonogashira reaction
emerged for the direct alkynylation of activated [7] and unactivated
C(sp2)–H bonds[8] C–H bonds using transition-metal catalysts.
In contrast, the direct alkynylation of more challenging C(sp3)–
H bonds remains underdeveloped. C(sp3-H) alkynylation can
proceed via a radical pathway (Scheme 1, a), which requires either
activation via 1,5-HAT from nitrogen in gamma position to the
reactive center[9] or the presence of a heteroatom alpha to the C-H
bond to achieve good reagioselectivty[10,11]. Alternatively, C(sp3-H)
alkynylation through a C-H activation pathway requires the
presence of a β-chelating carboxylic acid derivative or heterocycle
TIPS
TIPS
O
H
RO
O
1) oxime formation
N
R
2) [Ir]
R
R
R’
Br
TIPS
R’
R’
TIPS
TIPS
HO
R
H
N
1) oxime formation
HO
R
O
2) [Ir]
R’
R'
R
Br
TIPS
R'
Scheme 2: Ir-catalyzed C(sp3)–H alkynylation of oximes derived from ketones,
aldehydes, and alcohols.
We recently found that the combination of a Cp*Rh(III) catalyst
and bromo-alkyne is a highly active system for the alkynylation of
a broad-range of aromatic and olefinic C(sp2)–H bonds.[ 19 ]
However, our attempt to extend these procedures to aliphatic
C(sp3)–H bonds in oxime 1a proved unsuccessful (Table 1, entry
1). The solution was found by using Cp*Ir(III) catalyst and TIPS-
protected bromo alkyne 2a (Table 1, entry 2), with AgSbF6, Ag2CO3
and LiOAc as additives in 1,2-dichloroethane (DCE) as solvent.
Under this condition, product 3a resulting from the alkynylation at
the methyl group was obtained in 78% yield. Control experiments
showed the essential role of all reaction components (Table 1,
entries 3-4). Other metal catalysts used in C–H functionalization
were inactive (Table 1, entry 5).[20] The use of other silver salts
(Table 1, entry 6), lower catalyst loading (Table 1, entry 7), lower
or higher temperature (Table 1, entry 8) or other solvents (Table 1,
entries 9-11) gave 3a in lower yields. No conversion was observed
with bromo- or iodo-alkynes 2b-d (Table 1, entry 12).
(Scheme 1, b),[12]
.
Table 1. Ir-catalyzed C(sp3)–H alkynylation of 1a with 2a.[a]
TIPS
[] E. Tan, M. Zanini, Prof. A. M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ), Barcelona Institute
of Science and Technology
MeO
MeO
N
N
Br
TIPS (2a)
(1.2 equiv)
Me
Av. Països Catalans 16, 43007 Tarragona (Spain)
Departament de Química Analítica i Química Orgànica, Universitat
Rovira i Virgili, C/ Marcel·li Domingo s/n, 43007 Tarragona (Spain)
E-mail: aechavarren@iciq.es
[Cp*IrCl2]2 (7 mol %), AgSbF6 (30 mol %)
Ag2CO3 (1 equiv), LiOAc (30 mol %)
1a
3a
DCE, 70 ºC, 14 h
† These authors contributed equally to this work.
entry
1
Deviation from optimized condition
yield 3a (%)[a]
Supporting information for this article is available on the WWW under
http://www.angewandte.org or from the author.
[Cp*RhCl2] instead of [Cp*IrCl2]
0
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10.1002/anie.202002948
Angewandte Chemie International Edition
Oximes derived from alcohols could also be alkynylated in the
presence of iridium catalyst under identical conditions (Scheme 4).
Among the different alcohol derivatives tested with 1-
methylcyclohexanol, the oxime derived from cyclopentanone 4a
gave the highest yield of alkynylated derivative 5a (89%). Products
derived from primary (5d), secondary (5e-m), and tertiary (5n-o)
alcohols could be alkynylated in 44-80% yield. All the reactions
display an exquisite selectivity towards the activation of the C–H
bond that would form the 5-membered iridacycle as demonstrated
in the formation of 5f in which the methyl in -position to the alcohol
is selectively alkynylated over the one in -position. Interestingly,
this selectivity is maintained in presence of C(sp2)–H bond in -
position (5k). The presence of an ether (5i), aromatic ring (5j), or
bulky adamantyl group (5m) does not erode the selectivity of the
transformation.
2
3
4
5
None
80 (78)[b]
Without [Cp*IrCl2]
0
0
0
Without Ag2CO3, LiOAc, or AgSbF6
With MnBr(CO)5, Cp*Co(CO)I2, Pd(OAc)2, or
[RuCl2(p-cymene)]2 instead of [Cp*IrCl2]
6
7
With AgNO3 or Ag2O instead of Ag2CO3
With 3 or 5 mol % of catalyst instead of 7 mol %
At 25 ºC or 80 ºC
0
25 or 50
60
8
9
With THF instead of DCE
50
10
11
With tert-amyl alcohol instead of DCE
20
With DCE/TFE (1/1) or DCE/HFIP (1/1) instead of
DCE
50 or 40
12
With 2b-d
0
[a] Yield determined by 1H NMR with biphenyl as internal standard. [b] Isolated
yields in parentheses.
Under the optimized conditions, oxime ethers 1a-c led to 3a-c
in similar yields (70-78%) (Scheme 3), whereas the free oxime, the
acetoxime and the O-allyl oxime of 2-methylcyclohexanone failed
to provide the -alkynylated products. In the case of 1b, no
alkynylation at the methyl of the ethoxy group of the oxime was
observed. The methoximes of 2-methyl-2-cycloxanone (1d), 2,5-
dimethylbenzoquinone (1e), and (+)-trans-dihydrocarvone (1f)
gave 3d-f in moderate yields. The alkynylation of the methoxime of
(R)-carvone (1g) afforded 3g in good yield in a 6 mmol scale.
Interestingly, (L)-fenchone derivative 1h leads to 3h by selective
alkynylation at the bridgehead methyl group.[21] Methoximes of
acyclic ketones and aldehydes 1i-m also provided the
corresponding alkynylated products 3i-m.
Scheme 4. Ir-catalyzed C(sp3)–H alkynylation of oximes derived from alcohols.
Yields are for isolated products. [a] Dialkynylated product also isolated in 21%
yield. [b] Obtained as a mixture 3:1 of mono:di-alkynylated peoducts. [c] Yield
corrected for conversion (57%).
Substrates bearing functional groups such as a carboxylic acid,
ester, ketone, amide, amine or O-thiocarbamate β to a primary
C(sp3)–H bond did not react under our standard conditions.[22]
However, nitrogen heterocycles such as pyridines 6a-c, pyrazole
6d or pyrazine 6e led to C–H alkynylation products 7a-e at 120 °C
in good yields (Scheme 5).
Scheme 3. Ir-catalyzed C(sp3)–H alkynylation of oximes derived from ketones
and aldehydes. Yields are for isolated products. [a] Reaction performed with 6
mmol (1.1 g, 6 mmol) of methyl oxime under standard conditions.
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10.1002/anie.202002948
Angewandte Chemie International Edition
83% yield; and then reduced in presence of Zn powder to give 10e
in 72% yield.
Scheme 5. Iridium-catalyzed C(sp3)–H alkynylation directed by nitrogen
heterocycles.
The reaction was applied for the late-stage functionalization of
ketoximes derived from natural products 8a-c (Scheme 6). Thus,
the ketoxime derivative of (-)-santonin (8a) was alkynylated to form
3n in 77 % yield. Oleanolic acid (8b) was converted into a
separable mixture of products 3o and 3o’ in 35% and 20%,
respectively by a series of standard transformations followed by
alkynylation. Similarly, lanosterol (8c) was transformed into 3p,
obtained as 4:1 diasteromeric mixture in 63% yield.
Scheme 7. (a) Deprotection of alkynes. (b) Cleavage of oximes. TBAF =
tetrabutylammonium fluoride.
In summary, we have developped a method for the β-
alkynylation of aldehydes, ketones, and alcohols using oximes as
directing groups. The reaction is selective towards primary C(sp3)–
H bonds and tolerates the presence of functional groups such as
ester, ether or alkenes. Cyclic and acyclic aliphatic substrates,
including derivatives of natural products were successful
substrates. Basic heterocycles such as pyridine, pyrazole, or
pyrazine could also be used as directing groups. Extension of this
method for the alkynylation of other substrates is now under
development in our group.
Scheme 6. Functionalization of santonin (8a), oleanolic acid, (8b) and lanosterol
(8c) via their methoxime derivatives. [a] 1.7:1 mixture of diastereomers. [b] 4:1
mixture of diastereomers.
Acknowledgements
The silyl groups in 3g and 5a were cleanly removed with TBAF
in 85% and 95% yield, respectively (Scheme 7, a). Deprotection of
the methoxime 3a to the corresponding ketone 9a was achieved in
81% yield by treatment with formaldehyde under acidic conditions
(Scheme 7, b). Oximes 5 were reduced to the alcohol either with
LiAlH4 (89% yield for 10a) or NaCNBH3 in presence of an excess
of Zn powder (76-79% yield for 10b-d). This procedure can be
performed stepwise via hydroxylamine 11, which was isolated in
We thank the Ministerio de Ciencia e Innovación (MCI)/
Agencia Estatal de Investigación (AEI)/FEDER, UE (CTQ2016-
75960-P), the AGAUR (2017 SGR 1257), and CERCA,
Program/Generalitat de Catalunya and Caixa-Severo Ochoa
predoctoral fellowship to M.Z. for financial support. We also thank
the CELLEX-ICIQ HTE laboratory.
Keywords: Iridium · C–H functionalization · Alkynylation · Oximes
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