Acyl hydrazides as acyl donors for the synthesis of diaryl and aryl alkyl ketones

Article abstract of DOI:10.1039/c3cc47967f

In this communication we describe a novel strategy for the formation of valuable diaryl and aryl alkyl ketones from acyl hydrazides. A wide variety of ketones are prepared and the mild reaction conditions allow for the use of a range of functionalities, especially in the synthesis of diaryl ketones.

Full text of DOI:10.1039/c3cc47967f

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Acyl hydrazides as acyl donors for the synthesis
of diaryl and aryl alkyl ketones†
Cite this: Chem. Commun., 2014,
50, 743
Ahmed R. Akhbar,a Vijay Chudasama,*a Richard J. Fitzmaurice,a Lyn Powellb and
Stephen Caddick*a
Received 16th October 2013,
Accepted 22nd November 2013
DOI: 10.1039/c3cc47967f
www.rsc.org/chemcomm
In this communication we describe a novel strategy for the formation of
valuable diaryl and aryl alkyl ketones from acyl hydrazides. A wide variety
of ketones are prepared and the mild reaction conditions allow for the use
of a range of functionalities, especially in the synthesis of diaryl ketones.
Diaryl and aryl alkyl ketones are important intermediates in the
synthesis of various pharmaceuticals, natural products, agro-
chemicals and other functional materials.1 They are synthesised by
Fig. 1 Comparison between Weinreb amides and acyl hydrazides.
numerous protocols, perhaps the most common of which is Friedel– acyl hydrazides via the hydroacylation of azo-dicarboxylates.6e In
Crafts acylation.1 Although this method has been useful for the that report, we highlighted that acyl hydrazides may be employed
synthesis of many ketones, it suffers from poor functional group as acyl donors for the synthesis of amides.6e Given the similarities
tolerance, has untunable regioselectivity and requires the use of a between acyl hydrazides and Weinreb amides, the fact they have
stoichiometric amount of Lewis acid.2 Another common method to plenty of sites available for forming a stable metal chelate and
access ketones is the oxidation of secondary alcohols. However, this have been shown to be highly stable and effective acyl donors, we
protocol often requires the use of a stoichiometric amount of oxidant were intrigued as to whether acyl hydrazides could serve as
and is commonly limited by poor functional group tolerance.3 The effective acyl donors for the synthesis of ketones. Such a trans-
reaction of carboxylic acid derivatives such as anhydrides and acid formation would be highly desirable due to the facile and mild
chlorides with organometallic reagents tend to suffer from over- way in which aldehydes can be readily transformed into acyl
addition (resulting in the formation of tertiary alcohol products) and hydrazides in a single step.6e The conversion of an aldehyde to a
poor chemoselectivity.4 However, a notable exception in this class of Weinreb amide, in contrast, typically requires multiple steps and
derivatives are Weinreb amides.5 Treatment of a Weinreb amide relatively harsh reaction conditions.5b
with a suitable organometallic reagent provides ketones in high
Investigations to explore the feasibility of converting acyl
yields without significant over-addition. This selectivity is as a result hydrazides into ketones were initiated by reaction of acyl hydrazide
of the formation of a stable, metal-chelate tetrahedral intermediate 1a with n-PnMgBr 2a (Table 1). Initially, we applied typical Weinreb
under the reaction conditions, which prevents over addition of ketone synthesis reaction conditions (ꢀ10 1C, THF, 1.2 eq. of
nucleophile (Fig. 1).5 The tetrahedral intermediate is subsequently RMgX) to affect formation of ketone 3aa.5b Encouragingly, reaction
destroyed upon work-up to afford ketone.5
under these conditions afforded ketone 3aa, albeit in low yield,
We have previously described simple and efficient methods 21% (Table 1, entry 1). Also isolated from the reaction mixture were
for the hydroacylation of various radical acceptors using atmo- secondary and tertiary alcohols, 4 and 5, in 14% and 28% yield,
spheric oxygen as radical initiator.6 Most recently, we reported a respectively (Table 1, entry 1). Formation of secondary alcohol 4
highly efficient method for the functionalisation of aldehydes to may be rationalised by b-hydride elimination of a Grignard reagent
complexed to ketone 3aa.7 Tertiary alcohol 5 is likely to have
a Department of Chemistry, University College London, London, WC1H 0AJ, UK.
E-mail: VPEnterprise@ucl.ac.uk, v.chudasama@ucl.ac.uk; Tel: +44 (0)20 3108 5071
b AstraZeneca, Charter Way, Silk Road Business Park, Macclesfield, Cheshire,
SK10 2NA, UK
† Electronic supplementary information (ESI) available: 1H and 13C NMR spectra
for all novel compounds and compounds prepared by a novel protocols. See DOI:
10.1039/c3cc47967f
formed by addition of n-PnMgBr 2a to ketone 3aa formed in the
reaction conditions.
Perhaps as expected, the addition of greater equivalents of 2a led
to an increase in the amount of tertiary alcohol, with no ketone
being observed at all (Table 1, entry 2). We rationalised that reaction
at a lower temperature would give better opportunity for a complex
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Table 1 Optimisation of reaction of acyl hydrazide 1a with 2a
Table 2 Reaction of acyl hydrazides 1a–l with 2a–b
Isolated yield 3/%, R0 =
Entry
1
Acyl hydrazide 1, R =
Temp. Time
Conversion
2a (eq.) 1aa (%) 3aaa (%) 4a (%) 5a (%)
Entry (1C)
(h)
78, 3aa
77, 3ba
78, 3ab
87, 3bb
1
2
3
4
5
6
7
8
ꢀ10
ꢀ10
ꢀ40
ꢀ40
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
ꢀ78
0.5
0.5
0.5
0.5
0.5
0.5
1
2
3
0.5
0.5
0.5
0.5
0.5
1.2
2
84
100
64
21
0
14
12
10
11
2
28
42
10
21
0
1.2
2
1.2
2
41
32
21
64
61
60
62
78
72
71
69
72
2
95
34
74
4
5
2
1
2
77
3
4
71, 3ca
68, 3da
73, 3cb
70, 3db
2
2
75
80
3
4
2
2
9
10
11
12
13
14
2.5
3
4
89
91
92
7
7
8
3
6
6
5
6
94
100
12
11
5
8
Determined by integration of 19F NMR relative to trifluorotoluene as
an internal standard.
a
5
6
7
79, 3ea
72, 3fa
76, 3ga
71, 3eb
92, 3fb
72, 3gb
formed by addition of a Grignard onto an acyl hydrazide to be
persistent. To investigate this, reaction of 1a with 1.2 and 2 equivalents
of 2a was carried at ꢀ40 1C and ꢀ78 1C (Table 1, entries 3–6). Most
pleasingly, decreasing the reaction temperature resulted in a
decrease in the amount of 4 and 5, and a gradual increase in
yield of ketone with maximum yield, 64%, being observed with
2 equivalents of 2a at ꢀ78 1C. In an attempt to further increase
conversion and yield of ketone 3aa, the effect of increasing
reaction time was explored (Table 1, entries 7–9). However, this
had little effect on conversion and yield, with comparable yields
being observed for reaction at ꢀ78 1C for 0.5 to 3 h. In a further
attempt to increase yield of ketone, the use of a greater equiva-
lents of 2a was explored (Table 1, entries 10–14). Gratifyingly, this
afforded increasingly higher conversion of acyl hydrazide 1a
(i.e. from 80% to 100%) with an excellent yield of ketone, 78%,
being observed with 2.5 equivalents of 2a (Table 1, entry 10).
Although using greater than 2.5 equivalents gave higher conversion,
there was no increase in the yield of ketone (Table 1, entries 11–14).
We next applied our optimised conditions to the reaction of
acyl hydrazide 1a with phenyl magnesium bromide 2b to evaluate
the applicability of the conditions for the formation of diaryl
8
36, 3ha
44, 3ia
0, 3ja
74, 3hb
73, 3ib
77, 3jb
9
10
11
12
0, 3ka
76, 3kb
76, 3lb
74, 3la
a
b
Conditions: ꢀ78 1C, THF, 30 min. ꢀ78 1C to 0 1C, THF, 1 h.
ketones. Unfortunately, this only afforded a low yield of ketone (1a–l) were prepared using our previously reported facile method
3ab, 7%, due to low conversion of 1a, 12%, perhaps as 2b is a less for the hydroacylation of DIAD in good yields.6e Each acyl hydrazide
potent nucleophile than 2a. To combat this, addition of 2b at was then reacted with n-pentyl magnesium bromide 2a and phenyl
ꢀ78 1C was followed by warming to 0 1C. Pleasingly, this afforded magnesium bromide 2b (Table 2) under the optimised conditions
ketone 3ab in 78% yield (Table 2, entry 1).
developed for the formation of aryl alkyl and diaryl ketones, respec-
With optimised conditions in-hand we took the opportunity to tively. Encouragingly, good to excellent yields were observed for
investigate the applicability of our protocol for the formation of reaction of 2a and 2b with electron poor (Table 2, entries 1 and 2),
ketones from various aryl acyl hydrazides. All starting hydrazides electron neutral (Table 2, entry 3), and electron rich (Table 2, entry 4)
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Fig. 2 Formation of various ketones using our protocol.
aryl acyl hydrazides. It was also pleasing that bromo- and iodo-
functionalised aryl acyl hydrazides were tolerant of the reaction con-
ditions and afforded ketones in good yields (Table 2, entries 5–7).
Although ortho-substitution was not so well tolerated on application
of 2a, good yields were observed for the synthesis of diaryl ketones
(Table 2, entries 8 and 9). Owing to the mildness of the reaction
conditions required for effective conversion, we appraised the use of
acyl hydrazides bearing functionalities that were not tolerant of
Weinreb amide ketone synthesis conditions, i.e. nitro- and cyano-
groups (Table 2, entries 10 and 11). Although no product was isolated
on reaction with n-PnMgBr 2a, diaryl ketones 3jb and 3kb were
isolated in excellent yields on application of PhMgBr 2b, demonstrat-
Scheme 1 Reaction of: (a) hydrazide 1a with 2a then MeI, and with 2a
ing to some extent the mildness of our protocol. We also show that a followed by 2b; (b) hydrazide 12 with 2a; and (c) carbamate 13 with 2a.
heterocyclic acyl hydrazide, 1l, gave good yields of aryl alkyl and
diaryl ketone upon reaction with n-PnMgBr 2a and PhMgBr 2b,
with n-PnMgBr 2a (1 eq.) followed by addition of PhMgBr 2b
respectively (Table 2, entry 12).
(1.5 eq.). This afforded primarily diaryl ketone 3ab, 71%, and a
Having demonstrated good tolerance of acyl hydrazides for
modest amount of 3aa.
the formation of diaryl and aryl alkyl ketones on application
We next evaluated the importance of deprotonation for efficient
of Grignards 2a and 2b, we explored the tolerance of other
ketone synthesis to transpire by reaction of methylated hydrazide 12
Grignard reagents (Fig. 2). To do this, acyl hydrazide 1a was
with 1.5 equivalents of 2a (Scheme 1b). This resulted in a poor yield
reacted with alkynyl, thiophenyl and isopropyl magnesium
of ketone, 38%, with a significant amount of tertiary alcohol being
bromides. Gratifyingly, this afforded excellent yields of ketones
observed (20%), perhaps indicating that deprotonation is important
6–8, thus demonstrating the flexibility of our protocol with
for efficient ketone formation to ensue. Finally, we synthesised
respect to the nature of the Grignard reagent.
carbamate 13 and reacted it with 1.5 equivalents of 2a to determine
In order for the yield of ketone to be so high we rationalised that
if carbonyl complexation may play a key role in forming a stable
there must be some complexation to stabilise the adduct formed
intermediate, especially in view of a report on the reaction of
upon nucleophilic addition to acyl hydrazide. We rationalised that
Grignard reagents with N-Boc protected b-, g- and d-lactams for
complexation could be affected through one of three possibilities
the synthesis of ketones.8 However, reaction of 13 with 2a only
(Fig. 3): (i) deprotonated hydrazide, 9; (ii) ester carbonyl, 10; or
afforded ketone in 36% yield, again due to the formation of a
(iii) N-lone pair, 11.
significant amount of tertiary alcohol (Scheme 1c). Thus, it seems
To appraise the feasibility of each of these postulated inter-
reasonable to conclude the high yield of ketone observed in our
mediates we initially explored whether an acyl hydrazide would be
protocol is most likely due to the formation of a persistent inter-
deprotonated under the reaction conditions owing to the acidity of
mediate of the form of 9 (see Fig. 3).
the N–H bond. To do this, acyl hydrazide 1a was reacted with a
In summary, the work described herein represents, to the best of
single equivalent of Grignard 2a, followed by addition of methyl
our knowledge, the first examples of the use of acyl hydrazides as
iodide, all at ꢀ78 1C, and then quenching with ammonium chloride
acyl donors for the synthesis of ketones. This is particularly exciting
(Scheme 1a). As this resulted in the formation of a significant
in view of the facile manner in which acyl hydrazides may be pre-
amount of methylated hydrazide 12, 87%, we felt it appropriate to
pared from various aldehydes6e,9 or otherwise.10 Moreover, ketone
conclude that an acyl hydrazide would be significantly deprotonated
formation has been shown to proceed under mild conditions, which
under the reaction conditions, thus disfavouring the likelihood of
has allowed for the tolerance of sensitive functional groups such as
intermediate 11. Further support for the first equivalent of Grignard
nitrile and nitro for the synthesis of diaryl ketones, and various
acting as base was obtained by reaction of acyl hydrazide 1a
Grignard reagents. We will now seek to evaluate the applicability of
our protocol for the formation of dialkyl ketones, and especially
those derived from enantiopure alkyl acyl hydrazides.
Notes and references
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Fig. 3 Potential stable intermediates.
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