A simple, user-friendly process for the homologation of aldehydes using tosylhydrazone salts

Article abstract of DOI:10.1016/S0040-4039(00)01856-6

Aldehydes can be homologated to ketones in moderate to good yields using aryldiazomethanes generated in situ from tosylhydrazones. Chiral aldehydes can be employed with almost complete retention of configuration. The tosylhydrazones can also be generated in situ from the corresponding aldehyde leading to a one-pot process for coupling two different carbonyl compounds to give ketones. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01856-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10327–10331
A simple, user-friendly process for the homologation of
aldehydes using tosylhydrazone salts
Varinder K. Aggarwal,a,* Javier de Vicente,a Beatrice Pelotier,a Ian P. Holmesa and
Roger V. Bonnertb
aDepartment of Chemistry, University of Sheffield, Sheffield S3 7HF, UK
bAstraZeneca R&D Charnwood, Medicinal Chemistry, Bakewell Road, Loughborough, Leics LE11 5RH, UK
Received 30 August 2000; revised 10 October 2000; accepted 19 October 2000
Abstract
Aldehydes can be homologated to ketones in moderate to good yields using aryldiazomethanes
generated in situ from tosylhydrazones. Chiral aldehydes can be employed with almost complete retention
of configuration. The tosylhydrazones can also be generated in situ from the corresponding aldehyde
leading to a one-pot process for coupling two different carbonyl compounds to give ketones. © 2000
Elsevier Science Ltd. All rights reserved.
Homologation of aldehydes and ketones by carbon insertion methods is a valuable tool in
organic synthesis.1–6 Most methods employ diazoalkanes,2–6 but these processes are limited due
to competing reactions such as multiple homologation, and oxirane formation. The extent of
such competing processes has been limited using hindered aluminium-based Lewis acids.5 A
further practical limitation of this methodology is the need to synthesise and handle diazocom-
pounds, which, since they are invariably toxic and unstable, precludes their use on a large scale.
As an alternative to the use of diazoalkanes, Katritzky1a,b has reported the use of 1-(arylmethyl)-
benzotriazoles for homologation of carbonyl compounds which works effectively because the
benzotriazole moiety is both an anion stabilising group and leaving group. However, high
temperatures are required in this process (65–210°C). We have recently reported a new method
for the epoxidation of carbonyl compounds using catalytic amounts of sulfides and diazocom-
pounds.7 Cognisant of the practical limitations surrounding the use and handling of diazocom-
pounds we sought and developed a method for generating such reactive intermediates in situ and
successfully applied this method to catalytic asymmetric epoxidation,8 aziridination8 and
cyclopropanation8 (Scheme 1). We also considered the potential application of this new
* Corresponding author. Current address: Department of Chemistry, Bristol University, Cantock’s Close, Bristol BS8
1TS, UK. E-mail: v.aggarwal@bristol.ac.uk
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01856-6

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Scheme 1. In situ generation of diazocompound and applications to epoxidation (X=O), aziridination (X=NTs) and
cyclopropanation (X=CH2) and proposed application to homologation of carbonyl compounds
protocol for generating diazocompounds towards a user-friendly method for homologation of
carbonyl compounds and in this paper report our success in achieving this objective.
Aryldiazomethanes have been employed in the homologation of aldehydes using an iron-
based Lewis acid4a and LiBr in Et2O.4b We therefore began our studies using our in situ method
for generating PhCHN2 and tested the reaction in a several ethereal solvents in the presence of
an excess of LiBr (ether was reported to be best).
Only moderate yields of the homologated ketone were obtained even though the hydrazone
had been completely consumed (Table 1, entries 1–3). THF appeared to be the optimum solvent
and so further studies were conducted in this solvent. We decided to confirm that all the
additives were required (entries 4, 5), but were surprised to find that the homologation reaction
actually performed better in the absence of both LiBr and the PTC. Thus, only the reagents
required in the coupling were necessary for the reaction. We subsequently investigated the effect
of solvent on the yield of the reaction (entries 6–11) and found that THF and THF/H2O gave
the highest yields. These solvents were therefore selected for further optimisation. As it was
found that significant amounts of the aldehyde remained we decided to increase the quantity of
the tosylhydrazone salt and also tested the Li salt as well (entries 12–17). Improved yields were
indeed obtained with increased loadings of the tosylhydrazone salt but the yields plateaued at
1.5 equivalents. No improvements were obtained using the lithium derivative and so the
optimum conditions were as shown in entry 15. We also determined that 10% water in THF was
optimum (entries 18 and 19).
During the course of the reactions a steady state concentration of the diazocompound is
formed as shown by the gradual change in colour of the reaction mixture from colourless to
pink and finally back to colourless at the end. Phenyldiazomethane is a deep red liquid.
Careful analysis of the reactions conducted in THF and in THF/H2O revealed significant
differences in the efficiency and selectivity of the reaction (Scheme 2). In THF reactions were less
efficient (a substantial amount of aldehyde remained), but only the product of H-migration 2
was observed. In contrast, in THF/H2O, reactions were considerably more efficient (no aldehyde
remained), but phenyl migration competed with H-migration and the aldehyde that formed was
further homologated to give 3. In homologation of aldehydes with diazocompounds, the main
product results from H-migration, but a protic solvent promotes aryl6 and alkyl5a migrations (as
observed). Thus, for cleaner reactions aprotic solvents should be employed but higher yields can
be achieved in the presence of proton donors.

10329
Table 1
Optimisation of reactiona
Entry
Salt 1 (equiv.)
Solvent
Et2O
1,4-Dioxane
THF
THF
THF
1,4-Dioxane
MeCN
DMSO
DMF
MeOH
THF/H2O (9:1)
THF
THF
PTC (equiv.)
0.1
0.1
0.1
0
0
0
0
0
0
0
0
0
0
0
0
0
LiBr (equiv.)
Yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1
1
1
1
1
1
1
1
10
10
10
10
0
0
0
0
0
0
0
0
0
0
0
0
0
6
29
38
36
52
9
47
11
11
42
50
49
49
42
59
59
54
51
27
1
1
1
1.5
2.0
1.5-Li
1.5
2.0
1.5-Li
1.5
1.5
THF
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (9:1)
THF/H2O (19:1)
THF/H2O (4:1)
0
0
0
0
0
a Experimental procedure: to a suspension of Na/Li-1 in the solvent chosen was added PhCHO under nitrogen at
rt. The mixture was stirred at 50°C until all the hydrazone was consumed (followed by TLC) and disappearance of
the red colour of the phenyldiazomethane (normally occurred after 48 h). After work up the resulting oil was analysed
1
by GC and H NMR.
b Yields calculated by GC using dibenzyl ether as internal standard.
Scheme 2. Effect of water on the reaction
The optimum conditions were tested with a range of aldehydes and several different
tosylhydrazone salts (Table 2). In most cases good yields of the homologated products derived
from H-migration were obtained together with variable but much smaller amounts of products
derived from R1 migration.
The process is further illustrated by the homologation of glyceraldehyde acetonide (Scheme 3).
Although the homologated product was only obtained in moderate yield it was formed with
high enantiomeric excess9 and obtained directly and simply.

10330
Table 2
Homologation of a range of aldehydes with various tosylhydrazone saltsa
R1
R2
Yield 2a–jb
Yield 3a–jb
p-MeC6H4
o-MeC6H4
p-MeOC6H4
p-NO2C6H4
p-ClC6H4
2-Furyl
n-C7H15
c-C6H11
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
52
48
20
15
17
21
22
0
32
21
13
12
38 (45% ald)
78
39
58
46
62
41
33
p-ClC6H4
o-MeC6H4
Ph
a Experimental procedure: to a suspension of 1 (1.5 mmol) in THF/H2O 9:1 (3.3 mL) was added aldehyde (1 mmol)
under nitrogen at rt. The mixture was stirred at 50°C until all the hydrazone was consumed (followed by TLC) and
disappearance of the red colour of the phenyldiazomethane (normally 48 h).
b Isolated yields.
Scheme 3. Homologation using a chiral aldehyde
Finally, we have discovered that the process can be simplified further by generating the
tosylhydrazone salt in situ from the corresponding aldehyde using very simple reagents without
significantly compromising the yield of the homologated ketone (Scheme 4). Thus, two different
aldehydes can be coupled together in one pot to give ketones.
Scheme 4. One pot homologation process

10331
Note added in proof: Related work on aldehyde homologations using tosyl hydrazone salts has
recently appeared: Angle, S. R.; Neitzel, M. L. J. Org. Chem. 2000, 65, 6458–6461.
Acknowledgements
We thank AstraZeneca for support of a studentship (J.G.F.) and the EPSRC for support.
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