Functionalisation of aldehydes via aerobic hydroacylation of azodicarboxylates 'on' water

Article abstract of DOI:10.1039/c0cc04520a

Herein we report the functionalisation of aldehydes via hydroacylation of azodicarboxylates. A range of functionalised aldehydes are employed as the limiting reagent including chiral non-racemic aldehydes bearing α-stereocentres which are functionalised giving access to enantiomerically pure products. The resultant hydrazides can be employed as acyl donors in the synthesis of amides.

Full text of DOI:10.1039/c0cc04520a

View Online / Journal Homepage / Table of Contents for this issue
Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2011, 47, 3269–3271
www.rsc.org/chemcomm
COMMUNICATION
Functionalisation of aldehydes via aerobic hydroacylation of
azodicarboxylates ‘on’ waterw
Vijay Chudasama, Jenna M. Ahern, Dipti V. Dhokia, Richard J. Fitzmaurice and
Stephen Caddick*
Received 20th October 2010, Accepted 21st December 2010
DOI: 10.1039/c0cc04520a
Herein we report the functionalisation of aldehydes via
hydroacylation of azodicarboxylates. A range of functionalised
aldehydes are employed as the limiting reagent including chiral
non-racemic aldehydes bearing a-stereocentres which are
functionalised giving access to enantiomerically pure products.
The resultant hydrazides can be employed as acyl donors in the
synthesis of amides.
clean aerobic activation protocol can be readily converted into
amides.
Investigations were initiated with an optimisation of the
functionalisation of butanal 1a with diethyl azodicarboxylate
(DEAD) to afford hydrazide 2a. Application of our previously
optimised conditions for hydroacylation of electron deficient
double bonds ‘on’ water (Table 1, entry 1) afforded hydrazide
2a in excellent yield, 92%, based on DEAD as the limiting
reagent in 6 h.10 However, the large excess of butanal 1a
employed (2 eq.) precludes the use of the methodology for the
functionalisation of valuable aldehydes. Although reduction
of the 1a : DEAD ratio to 1.5 : 1 afforded hydrazide 2a
in similarly high yield (Table 1, entry 2), stoichiometric
reaction conditions gave hydrazide 2a in a relatively modest
isolated yield, 70%, with significant quantities of diethyl
hydrazinedicarboxylate observed in the crude 1H NMR
spectrum (Table 1, entry 3). Pleasingly, increasing the amount
of DEAD afforded hydrazide 2a in excellent yield, 90%, based
on butanal 1a as the limiting reagent (Table 1, entry 4). Whilst
employing butanal 1a as the limiting reagent no evidence of
the formation of butanoic acid, from aerobic oxidation of
butanal 1a, or telomeric products, from reaction of multiple
equivalents of DEAD with butanal 1a, were observed. Similarly
to related processes,10–12 the formation of hydrazide 2a
was completely inhibited by 2,6-di-tert-butyl-4-methylphenol
(BHT), implicating a radical intermediate in the reaction of
butanal 1a with DEAD.
The drive to develop ever more efficient and environmentally
benign synthetic methodologies for the construction of complex
molecules is a major focus in modern organic synthesis.1,2
Thus, the development of methods to affect the hydroacylation
of double and triple bonds has received much attention in
recent years, often employing metals in sub-stoichiometric
quantities.3–5 Although examples of hydroacylation reactions
employing near stoichiometric amounts of aldehyde have been
reported,6 most examples employ the aldehyde in significant
excess.7–9
We have described simple methods for the hydroacylation
of carbon–carbon double bonds via interception of acyl radicals
generated by aldehyde auto-oxidation with a range of electron
deficient alkenes to synthesise unsymmetrical ketones in organic
solvent and ‘on’ water.10–12 Recently, methods to affect the
hydroacylation of azodicarboxylates to generate hydrazides
under similar conditions have been reported.13,14 However,
approaches to date focus on the functionalisation of azodi-
carboxylates employing excess aldehyde.
Herein, we describe the functionalisation of aldehydes with
azodicarboxylates where the aldehyde is employed as the
limiting reagent. Thus our previously developed, catalyst-free
conditions for aerobic hydroacylation were applied to the
synthesis of hydrazides from functionalised aldehydes using
a single equivalent of aldehyde. We also highlight for the first
time the prospect for carrying out hydroacylation with chiral
aldehydes and show that the hydrazides generated by our
Table 1 Optimisation of reaction of butanal 1a with DEAD ‘on’
watera
Entry
1a/eq.
DEAD/eq.
Time/h
Yieldb 2a/%
1
2
3
4
2.0
1.5
1.0
1.0
1.0
1.0
1.0
1.2
6
12
16
16
92
90
70
90
Department of Chemistry, University College London, London,
WC1H 0AJ, UK. E-mail: VPEnterprise@ucl.ac.uk;
Fax: +44 (0)20 7679 9852; Tel: +44 (0)20 7679 9851
w Electronic supplementary information (ESI) available: Details of
experimental procedures and spectral data for compounds 2, 3, 6 and 7.
See DOI: 10.1039/c0cc04520a
a
Conditions: 1a (1 mmol), DEAD (1.2 mmol), H2O (500 mL),
b
21 1C. Isolated yield.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3269–3271 3269

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
View Online
We then took the opportunity to investigate the function-
alisation of a range of structurally diverse aldehydes with both
DEAD and diisopropyl azodicarboxylate (DIAD), to give
hydrazides 2 and 3 respectively. Pleasingly, functionalisation
of butanal 1a, with DIAD gave hydrazide 3a in an analogous
yield to that observed with DEAD (Table 2, entry 1).
Previously, our aerobic activation methodology has shown
poor applicability to isobutanal 1b as it is rapidly auto-
oxidised to its corresponding acid in air.10 However, in this
case, isobutanal 1b was readily functionalised with both
DEAD and DIAD, to give hydrazides 2b and 3b, in good
yields (Table 2, entry 2). Moreover, pivaldehyde 1c, which has
previously shown a tendency to undergo rapid decarbonyl-
ation, was also efficiently converted to its corresponding hydra-
zides 2c and 3c at room temperature (Table 2, entry 3).12 In
addition, good yields were also observed upon function-
alisation of an aromatic aldehyde, 4-fluorobenzaldehyde 1d,
with both DEAD and DIAD (Table 2, entry 4). At this juncture,
since hydroacylation reactions with DIAD generally gave higher
yields (Table 2, entries 1–4), subsequent reactions were carried
out employing DIAD as the acceptor. Functionalisation of
electron neutral and electron rich aromatic aldehydes 1e and
1f with DIAD was successful in generating the corresponding
hydrazides 3e and 3f, however, functionalisation of 4-methoxy-
benzaldehyde 1f was only affected in a modest yield (Table 2,
entries 5 and 6). The functional group tolerance and mild
nature of the aerobic hydroacylation of azodicarboxylates as a
methodology for the functionalisation of aldehydes is clearly
highlighted in the high yields, 70–80%, obtained for the reaction
of aldehydes 1g–k bearing ester, epoxide, acetal and, most
pleasingly, alkene functional groups with DIAD to afford a
range of functionalised hydrazides (Table 2, entries 7–11).
We envisaged that the nature of the aerobic hydroacylation
of azodicarboxylates would permit functionalisation of alde-
hydes bearing a-stereocenters whilst preserving enantiomeric
excess of the starting aldehyde. Thus, we were delighted to
observe that when enantio enriched aldehydes 1l and 1m were
treated with DIAD ‘on’ water their corresponding hydrazides
3l and 3m could be readily isolated in excellent yields (Table 2,
entries 12 and 13) and with essentially complete retention of
enantiomeric excess, as determined by HPLC (see ESIw). To
the best of our knowledge, this represents the first example of
hydroacylation achieved with a chiral aldehyde with retention
of enantiomeric excess.
Table 2 Aerobic hydroacylation of DEAD and DIAD with
aldehydes 1a
Isolated yield/%
i
2, R2 = Et 3, R2 = Pr
Entry Aldehyde R1
1
2
1a
1b
90
72
91
79
3
4
1c
1d
64
62
69
75
5
6
1e
1f
—
—
79
44
7
8
1g
1h
—
—
80
74
9
1i
—
70
10
11
1j
—
—
75
55
1k
12
1l
—
—
61b
88b
We then sought to explore the reactivity of hydrazides 2 and 3.
Attempts to convert hydrazide 2a with LiCl, under classical
Krapcho decarboxylation conditions, to its corresponding
unsubstituted hydrazide afforded a mixture of compounds
containing hydrazide 4 and heterocycle 5 derived from mono
decarboxylation of 2a (Scheme 1). Attempts to decarboxylate
imide 3a under Krapcho conditions afforded only diisopropyl
hydrazinedicarboxylate, presumably derived from an addition–
elimination reaction of chloride with hydrazide 3a. This led us
to examine the efficacy of hydrazides 3 as acyl donors for the
formation of amides. Thus treatment of hydrazide 3a with
2.5 equivalents of n-hexylamine or allylamine in CH2Cl2 for 16 h
afforded the corresponding amides 6 and 7 in excellent yields,
96% and 95%, respectively, with concurrent isolation of
diisopropyl hydrazinedicarboxylate (Scheme 1). Additionally,
13
1m
a
Conditions: 1 (1 mmol), DEAD (1.2 mmol), H2O (500 mL), 21 1C,
b
24–96 h. 3l 99% ee, 3m 98% ee (see ESIw).
hydrazide 3m can be readily converted under similar conditions,
to its corresponding benzyl amide 8 in good yield, 87%, with
retention of stereochemical information at the a carbon (see
ESIw). Although this mode of reactivity is well established,
such as in the cleavage of phthalimides with amines,15–18 the
conversion of hydrazides 3a and 3m to their corresponding
amides represents, to the best of our knowledge, the first
c
3270 Chem. Commun., 2011, 47, 3269–3271
This journal is The Royal Society of Chemistry 2011

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
View Online
4 D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev., 2010,
110, 624–655.
5 C. H. Jun, E. A. Jo and J. W. Park, Eur. J. Org. Chem., 2007,
1869–1881.
6 Y. Shibata and K. Tanaka, J. Am. Chem. Soc., 2009, 131,
12552–12553.
7 Y. J. Kim and D. Lee, Org. Lett., 2004, 6, 4351–4353.
8 M. E. Gonzalez-Rosende, J. Sepulveda-Arques, E. Zaballos-
Garcia, L. R. Domingo, R. J. Zaragoza, W. B. Jennings,
S. E. Lawrence and D. O’Leary, J. Chem. Soc., Perkin Trans. 2,
1999, 73–79.
9 E. Zaballos-Garcia, M. E. Gonzalez-Rosende, J. M. Jorda-Gregori,
J. Sepulveda-Arques, W. B. Jennings, D. Oleary and S. Twomey,
Tetrahedron, 1997, 53, 9313–9322.
10 V. Chudasama, R. J. Fitzmaurice, J. M. Ahern and S. Caddick,
Chem. Commun., 2010, 46, 133–135.
Scheme 1 Reactions of hydrazides 2a, 3a and 3m.
11 V. Chudasama, R. J. Fitzmaurice and S. Caddick, Nat. Chem.,
2010, 2, 592–596.
12 R. J. Fitzmaurice, J. M. Ahern and S. Caddick, Org. Biomol.
Chem., 2009, 7, 235–237.
reported example of the use of acyl hydrazinedicarboxylates as
acyl donors.
In conclusion, we have described a benign, atom economic
method for the functionalisation of aldehydes via the hydro-
acylation of azodicarboxylates at room temperature ‘on’ water.
The use of aldehyde as the limiting reagent, which is in sharp
contrast to previous approaches, offers the opportunity for the
effective manipulation of a variety of valuable functionalised
aldehydes and tolerance to a range of useful functional groups
has been demonstrated. The application of this methodology to
aldehydes bearing a-stereocentres suggests that this methodology
offers excellent synergy with the ever expanding arena of
organocatalysis. Moreover, conversion of the intermediate acyl
hydrazinedicarboxylates to their corresponding amides, via
aminolysis, represents an overall oxidation of aldehydes to amides,
which is both mild and high yielding and offers a complementary
approach to the metal catalysed oxidation of imines.19–27
We gratefully acknowledge UCL, BBSRC, EPSRC,
GlaxoSmithKline for financial support.
13 B. Ni, Q. Y. Zhang, S. Garre and A. D. Headley, Adv. Synth.
Catal., 2009, 351, 875–880.
14 Q. Zhang, E. Parker, A. D. Headley and B. Ni, Synlett, 2010,
2453–2456.
15 M. Bibian, S. El-Habnouni, J. Martinez and J. A. Fehrentz,
Synthesis, 2009, 1180–1184.
16 I. Bouillon, N. Brosse, R. Vanderesse and B. Jamart-Gregoire,
Tetrahedron, 2007, 63, 2223–2234.
17 N. Brosse, M. F. Pinto and B. Jamart-Gregoire, Eur. J. Org.
Chem., 2003, 4757–4764.
18 N. A. Rodios and N. E. Alexandrou, Synthesis, 1982, 824–826.
19 J. H. Dam, G. Osztrovszky, L. U. Nordstrom and R. Madsen,
Chem.–Eur. J., 2010, 16, 6820–6827.
20 S. Muthaiah, S. C. Ghosh, J. E. Jee, C. Chen, J. Zhang and
S. H. Hong, J. Org. Chem., 2010, 75, 3002–3006.
21 S. De Sarkar and A. Studer, Org. Lett., 2010, 12, 1992–1995.
22 S. De Sarkar, S. Grimme and A. Studer, J. Am. Chem. Soc., 2010,
132, 1190–1191.
23 C. W. Qian, X. M. Zhang, Y. Zhang and Q. Shen, J. Organomet.
Chem., 2010, 695, 747–752.
24 Y. J. Wu, S. W. Wang, L. J. Zhang, G. S. Yang, X. C. Zhu,
Z. H. Zhou, H. Zhu and S. H. Wu, Eur. J. Org. Chem., 2010,
326–332.
25 J. F. Wang, J. M. Li, F. Xu and Q. Shen, Adv. Synth. Catal., 2009,
351, 1363–1370.
26 J. M. Li, F. Xu, Y. Zhang and Q. Shen, J. Org. Chem., 2009, 74,
2575–2577.
27 C. Fang, W. X. Qian and W. L. Bao, Synlett, 2008, 2529–2531.
Notes and references
1 R. A. Sheldon, Green Chem., 2008, 10, 359–360.
2 P. T. Anastas and M. M. Kirchhoff, Acc. Chem. Res., 2002, 35,
686–694.
3 M. C. Willis, Chem. Rev., 2010, 110, 725–748.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 3269–3271 3271