Preparation of unsymmetrical ketones from tosylhydrazones and aromatic aldehydes via formyl C-H bond insertion

Article abstract of DOI:10.1021/ol5011714

Preparation of ketones by insertion of diazo compounds into the formyl C-H bond of an aldehyde is an attractive procedure, but use of structurally diverse diazo compounds is hampered by preparation and safety issues. A convenient procedure for the synthesis of unsymmetrical ketones from bench-stable tosylhydrazones and aryl aldehydes is reported. The procedure can be performed in one pot from the parent carbonyl compound and needs only a base, with no additional promoters being required.

Full text of DOI:10.1021/ol5011714

Letter
pubs.acs.org/OrgLett
Preparation of Unsymmetrical Ketones from Tosylhydrazones and
Aromatic Aldehydes via Formyl C−H Bond Insertion
Daniel M. Allwood,*,† David C. Blakemore,‡ and Steven V. Ley†
†Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, U.K.
‡Neusentis Chemistry, Pfizer Worldwide Research and Development, The Portway Building, Granta Park, Cambridge, CB21 6GS,
U.K.
S
* Supporting Information
ABSTRACT: Preparation of ketones by insertion of diazo
compounds into the formyl C−H bond of an aldehyde is an
attractive procedure, but use of structurally diverse diazo
compounds is hampered by preparation and safety issues. A
convenient procedure for the synthesis of unsymmetrical ketones
from bench-stable tosylhydrazones and aryl aldehydes is reported.
The procedure can be performed in one pot from the parent
carbonyl compound and needs only a base, with no additional
promoters being required.
etones represent a large and highly diverse class of
compounds which are useful in many areas, including
materials, fragrances, and natural product synthesis. As well as
their biological and structural properties, the intrinsic reactivity
of ketones makes them valuable synthetic intermediates in the
pharmaceutical industry.
Scheme 2. Mechanistic Pathways Following Diazo Addition
to an Aldehyde
K
However, the electrophilicity of the carbonyl group can make
their preparation challenging. As such, the synthesis of ketones
is typically accomplished via controlled addition of an
organometallic reagent to a higher oxidation state partner
such as an ester, acid chloride, or Weinreb amide (Scheme 1, a)
main mechanistic pathways may occur: (1) direct displacement
of N2 by the oxyanion to give an epoxide8 (Scheme 2, red); (2)
1,2-carbon migration to give a substituted aldehyde (Scheme 2,
blue); or (3) a 1,2-hydrogen shift to give the desired ketone
product (Scheme 2, black). The product distribution from this
intermediate is influenced by the nature of the substrate and the
reaction conditions employed.6c,e,i,j,7b,c,g,o,p,8−11
Scheme 1. Typical Strategies for the Synthesis of Ketones
The first practical addition of a diazocarbonyl to an aldehyde
followed by a 1,2-hydrogen shift to give a ketone product was
described by Roskamp12 (Scheme 3a). This process requires a
Lewis acid promoter, and many examples have subsequently
been reported.6h,k,7d,f−o,q−s,13,14 However, for more general
ketone preparation, it is desirable that this mode of reactivity is
also applicable to nonacyl diazo species. Examples involving
these types of substrates are currently under-represented in the
literature. This is undoubtedly due to their problematic
preparation and the toxicity and explosive nature of non-
stabilized diazo intermediates.6k,7p
or by addition to an aldehyde and reoxidation of the
intermediate alcohol (Scheme 1, b).1−4 Both of these
approaches suffer from poor financial, time, step, and redox
economies as well as the requirement for potentially unstable
and air/moisture sensitive organometallic reagents.3−5 There-
fore, a one-step approach from a substrate in the same
oxidation state, such as an aldehyde, represents a highly efficient
and desirable process (Scheme 1, c).
Formation of a ketone from an aldehyde requires formal
insertion of a functionalized carbon atom into the aldehyde
formyl C−H bond and is commonly achieved using diazo
compounds.6,7
Indeed, addition of a diazo compound to an aldehyde
produces a diazonium alkoxide (Scheme 2, a), from which three
Received: April 23, 2014
© XXXX American Chemical Society
A
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Letter
a
Scheme 3. Selected Studies in the Reaction of Diazo Species
with Aldehydes to Furnish Ketones
Table 1. Optimization of Reaction Conditions
b
entry
1
base
solvent
equiv ald. time (h) yield (%)
1
1a
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
K2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
1.0
1.0
1.0
1.0
1.1
1.2
1.0
1.0
1.0
1.0
1.0
6
6
0
80
80
0
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
3
18
1
4
5
6
79
80
18
6
6
6
7
6
8
1,2-DCE
6
9
MeCN
6
44
29
61
10
11
PhCF3
6
1,2-DME
6
a
Reaction conditions: 0.5 mmol of 1, 0.75 mmol of base, 2 mL of
b
solvent, sealed tube, 110 °C. Isolated yield.
attempt using K2CO3 at 110 °C in dioxane provided complete
conversion of tosylhydrazone, but no evidence of product
formation (Table 1, entry 1). Pleasingly, however, a change of
base to Cs2CO3 provided the required product in 80% yield
(Table 1, entry 2). This excellent yield is noteworthy, since a
Lewis acid promoter is normally required for conversion in this
type of process13,16 and aryl aldehydes have been shown to
preferentially deliver 1,2-carbon migration over 1,2-hydrogen
migration products.6i,11 We have previously described the
influence of modulating arylsulfonylhydrazone electronics on
the rate of diazo release in coupling reactions.21 Use of an
electron-rich PMP sulfonylhydrazone 1b slows release of the
diazo species, although in this instance it provided an identical
yield of the product (Table 1, entry 3). As observed in our
previous study, the electron-deficient 4-nitro analogue 1c
decomposed within 1 h and no product was isolated (Table 1,
entry 4).21 The yield obtained was shown to be insensitive to
the stoichiometry of the aldehyde (Table 1, entries 5−6).
Consequently, a 1:1 ratio of tosylhydrazone to aldehyde was
retained in further experiments. A short screen of solvents with
a similar boiling point to dioxane led to no further increase in
yield (Table 1, entries 7−11).
With optimized conditions in hand (Table 1, entry 2), a
range of aryl aldehydes were assessed for their performance in
the reaction (Scheme 4).22 High yields were obtained for
electron-neutral (2−3), electron-rich (4), and electron-poor
(5) substrates. Brominated ketone 6 and an ester-containing
ketone (11), which would both be challenging to prepare using
organometallic methodology, were prepared cleanly in 77% and
79% yields, respectively. An ortho-substituted example was
similarly successful in good yield (7). Likewise, acetal (8) and
nitrile (10) functionalities were well-tolerated, giving excellent
yields of product. Finally, a range of heterocyclic aldehydes also
performed well, giving good-to-excellent yields of ketone
products (9, 12−15). In some examples, slightly improved
yields could be achieved by using 1.2 equiv of the aldehyde and
progressing the reaction for 18 h.
In one notable example, Anselme described the reaction of
aryldiazomethanes with aldehydes promoted by LiBr.15 Yields
were moderate-to-excellent, but limitations of the process
included the requirement for 10 equiv of LiBr, poor
performance on sterically crowded substrates, necessity for
exclusion of light, and long reaction times (Scheme 3b). A
subsequent report by Kingsbury employed catalytic Sc(OTf)3
to couple unstabilized alkyl and aryl diazo compounds with aryl
and alkyl aldehydes in low-to-excellent yields in under 30 min
(Scheme 3c).16 However, a major drawback to both of these
processes lies in the aforementioned preparation and handling
of potentially toxic and explosive diazo species.6k,7p
In an attempt to avoid these issues, two simultaneous reports
described the use of aryl tosylhydrazones17 (Scheme 3d) or aryl
tosylhydrazone metal salts18 (Scheme 3e) as in situ diazo
sources for subsequent aldehyde insertion reactions. In the first
example, MeOH or EtOH was used since protic solvents were
known to promote diazo insertion reactions.19 However, side
reactions of the diazo species with the solvent led to difficult
product purification and a large excess of the tosylhydrazone
was required to generate satisfactory yields. In the other report,
water was used as a protic cosolvent in order to drive the
reaction to full conversion and higher yields, but this also led to
increased formation of carbon migration and homologated
products.6h,20 In addition to these common problems, these
processes only work with aryl tosylhydrazones and both require
very long reaction times.
In order to address these shortfalls in current methods, we
have developed a safe and convenient procedure for the C−H
insertion of bench-stable alkyl tosylhydrazones into aryl
aldehydes (Scheme 3f). Products of this type are challenging
to prepare using traditional multistep routes, owing to the
nature of the reagents required to bring about such trans-
formations.3,4
Our investigations began by performing a screen of
conditions using Boc-piperidinone tosylhydrazone 1a and 4-
chlorobenzaldehyde as a model system (Table 1). An initial
To evaluate the tosylhydrazone component of the reaction, a
range of alkyl tosylhydrazones were prepared and subjected to
the reaction conditions with 4-chlorobenzaldehyde as a
B
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Scheme 4. Isolated Yields from Reaction of 1a with a Range
of Aryl Aldehydes
Scheme 6. Preparation of Deuterated 4-Chlorobenzaldehyde
29 and Subsequent Reaction with 1a To Give Deuterium-
Labelled Product 30
group (30, Scheme 6). A subsequent reaction run for 18 h
revealed a lower D/H ratio. Therefore, we postulate that the
reaction occurs via a 1,2-hydrogen shift16 (Scheme 6a) and that
the product then enolizes under the reaction conditions,
partially eroding the level of deuterium incorporation.
For practical reasons, we also established that the procedure
can be performed as a one-pot reaction. Reaction of a 1:1
stoichiometry of 1-Boc-4-piperidinone and tosylhydrazide in
MeOH for 3 h, removal of the solvent, and subjection of the
resulting residue to the ketone synthesis conditions with 4-
chlorobenzaldehyde gave a 77% yield of the homologated
ketone product, 2 (Scheme 7). Since the majority of
tosylhydrazones can be prepared without purification in a
similar manner, a one-pot procedure is a viable option in most
cases.
a
Reaction performed with 1.2 equiv of aldehyde for 18 h.
common partner (Scheme 5). High yields were obtained for
heterocyclic (2, 16−17) and carbocyclic (18−19) products.
Scheme 5. Isolated Yields from Reaction of a Range of
Tosylhydrazones (1a,1d−1n) with 4-Chlorobenzaldehyde
Scheme 7. One-Pot Reaction of 1-Boc-4-piperidinone To
Form 2
In summary, we present a safe and convenient procedure for
the synthesis of unsymmetrical ketones from bench-stable
saturated tosylhydrazones and aryl aldehydes, which avoids the
preparation and handling of toxic and explosive diazo
compounds. The reaction provides moderate-to-excellent yields
of a wide variety of products, uses a 1:1 stoichiometric ratio of
the reaction partners, requires no additional promoters or
catalysts other than Cs2CO3 as a base, and can be performed as
a one-pot procedure.
a
Reaction performed with 1.2 equiv of aldehyde for 18 h.
Isopropyl (21), isobutyl (23), neopentyl (24), and other
branched alkyl groups (20, 22) could also be introduced in
moderate-to-good yield. Finally, products derived from 1,3-aryl
(25) and 1,2-aryl tosylhydrazones (26) were obtained in good
yield under these conditions. Reactions using benzylic (1,1-aryl)
tosylhydrazones led to complex mixtures of products,
presumably due to a switch in reaction mechanism caused by
the change in electronic nature of the substrate.
In order to probe the mechanism of the transformation,
deuterated aldehyde 29 was prepared via a three-step sequence
(Scheme 6). Submission of this aldehyde to the reaction
conditions with 1a gave the ketone product in 78% yield with
56% deuterium incorporation at the position α to the carbonyl
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data, structural assign-
ment, and NMR spectra for all synthesized compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
C
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Letter
(r) Li, W.; Wang, J.; Hu, X.; Shen, K.; Wang, W.; Chu, Y.; Lin, L.; Liu,
X.; Feng, X. J. Am. Chem. Soc. 2010, 132, 8532−8533. (s) Gao, L.;
Kang, B. C.; Hwang, G.-S.; Ryu, D. H. Angew. Chem., Int. Ed. 2012, 51,
8322−8325.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: dma33@cam.ac.uk.
Notes
(8) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Eur. J. Org.
Chem. 2002, 1562−1565.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
This work was supported by a postdoctoral fellowship from
Pfizer (D.M.A.) and the B.P. 1702 professorship (S.V.L.).
■
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