Dioxygen mediated hydroacylation of vinyl sulfonates and sulfones on water

Article abstract of DOI:10.1039/b914563j

Herein we report a mild, facile method for the preparation of 1,4-keto-sulfonates and sulfones on water. Further synthetic manipulations can result in products that are not readily accessed by hydroacylation of electron rich alkenes.

Full text of DOI:10.1039/b914563j

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Dioxygen mediated hydroacylation of vinyl sulfonates and
sulfones on waterw
Vijay Chudasama, Richard J. Fitzmaurice, Jenna M. Ahern and Stephen Caddick*
Received (in Cambridge, UK) 20th July 2009, Accepted 28th October 2009
First published as an Advance Article on the web 13th November 2009
DOI: 10.1039/b914563j
Herein we report a mild, facile method for the preparation of
1,4-keto-sulfonates and sulfones on water. Further synthetic
manipulations can result in products that are not readily
accessed by hydroacylation of electron rich alkenes.
(Scheme 1). It should be noted that the reaction requires no
particularly specific conditions, although we have found that it
is important to have a reasonably concentrated reaction
mixture, efficient stirring (stirrer bar) and to ensure that the
reaction is exposed to air (further details in ESIw). Although
we have not examined scalability in detail, we have carried out
the reaction of 1a with 2a on a preparatively useful 2 g scale
with isolated yields of 470%.
The development of new, efficient and environmentally benign
synthetic methodologies for the construction of complex
molecules, and in particular C–C bonds, is an important target
in modern organic synthesis.1–3 In view of this, many recent
methods have focused on the use of sub-stoichiometric
reagents or catalysts which tend to offer enhanced atom-
economy and minimisation of waste.4 Furthermore, significant
advances in the development of aqueous organic transformations
and organocatalysts, which take advantage of the unique
properties of water, have been made in recent years.5–11 Water
is generally perceived as a desirable, ‘green’ solvent for organic
transformations owing to cost, safety and environmental
acceptability.2,3 Furthermore, on water reactions, have been
demonstrated to offer several other advantages as a consequence
of hydrogen bonding and/or hydrophobic effects accelerating
the rate and/or yield of certain chemical reactions.8
In order to gather evidence for the general nature of this
process we examined a small selection of aliphatic aldehydes
(Table 1). Although structurally similar, aldehydes were
specifically chosen to test the limits of our methodology with
respect to aldehyde auto-oxidation rate (Table 2). The yields
for the hydroacylation reactions are comparable to those
utilising peroxide and superior to the analogous reactions in
the 1,4-dioxane conditions that we have previously described.12
The tolerance of the reaction to a-branched and lengthy
alkyl chain aliphatic aldehydes was particularly encouraging.
Moreover, the good yields obtained with the application of
only 2 equivalents of aldehyde with no additional catalyst are
competitive with existing hydroacylation protocols for
electron poor alkenes.13 However, as in our previous study,
we note a disappointing yield for the hydroacylation of vinyl
sulfonate 1a with isobutyraldehyde 2b (Table 1, entry 2).
As with our previously described work we invoke a radical
mechanism based on the observed retardation by addition of
2,6-di-tert-butyl-4-methylphenol (BHT).12 We envisaged that
hydration of aldehyde may play a role and whilst NMR
spectroscopy confirmed that the aldehydes were in equilibrium
with their hydrate 4 under the reaction conditions (Table 1) we
could find no correlation between aldehyde solubility in
water14 or aldehyde hydration on the yield of product 3. In
view of this, and the low conversion observed in the absence of
water for the hydroacylation of 1a with butanal 2a (ca. 25%
in 3 h), we believe water to influence the transformation
through a hydrophobic effect and postulate that the reaction
proceeds via the mechanism given in Scheme 2. The aldehyde
is aerobically transformed to acyl radical 5, which can auto-
oxidise to acid 6 or add to the alkene to form 7. Adduct radical
7 then abstracts an aldehydic hydrogen to form product 3 and
regenerate acyl radical 5. No deuterium incorporation was
observed when reaction of vinyl sulfonate 1a and butanal 2a
was performed in deuterium oxide; this indicates that the
hydrogen atom in 3 is likely to come from abstraction of an
aldehydic C–H.
Recently, we have reported the hydroacylation of electron
poor olefins such as pentafluorophenyl (PFP) vinyl sulfonate
and trichlorophenyl (TCP) vinyl sulfonate with a variety of
aldehydes.12 Although the conditions previously developed
offer an attractive method for hydroacylation of olefins we
have an aspiration to develop reagent-free conditions using
only water and air for carbon–carbon bond formation.
We were inspired by the recent work of Shapiro and
Vigalok11 describing the aerial oxidation of aldehydes to
carboxylic acids and considered that we might be able to
utilise similar conditions for the generation and trapping of
acyl radicals for carbon–carbon formation. Thus we rapidly
identified an operationally simple protocol for the hydroacylation
of vinyl sulfonate 1a with butanal 2a on water at room
temperature to give hydroacylation product 3a in good yield
Scheme 1 Hydroacylation of 1a with 2a on water.
Department of Chemistry, University College London, London,
UK WC1H 0AJ. E-mail: s.caddick@ucl.ac.uk;
Fax: +44 (0)20 7679 4603; Tel: +44 (0)20 7679 7482
w Electronic supplementary information (ESI) available: Details of
experimental procedures and data for novel compounds. See DOI:
10.1039/b914563j
To gain further insight into the rate of the auto-oxidation
process for different aldehydes a brief study was carried out
(Table 2). The results from this study correlate with the
reaction times observed on reaction of the aldehydes with 1a
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Chem. Commun., 2010, 46, 133–135 | 133

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Table 1 Hydroacylation of 1a with aldehydes 2a
b
Yield 3 (%)
Entry
R =
Time/h
Solubilityd/mass%
2 : 4e
1
2
3
4
5
6
7
–(CH2)2CH3, 2a
–CH(CH3)2, 2b
–CH2CH(CH3)2, 2c
–(CH2)4CH3, 2d
–c-C6H11, 2e
3
3
3
6
3
3
6
78, 3a
40, 3b
5.48
4.57
1.78
0.44
—
1 : 1.04
1 : 0.86
1 : 0.66
1 : 0.98
1 : 0.54
1 : 0.03f
1 : 0.12f
c
74, 3c
75, 3d
74, 3e
83, 3f
62, 3g
–CH(C2H5)(CH2)3CH3, 2f
–(CH2)8CH3, 2g
0.05
0.02
a
b
c
Conditions: aldehyde (2 eq.) and alkene (1 eq.) were stirred at 300 rpm in water at 21 1C. 100% conversion of 1a. 60% conversion of 1a.
d
f
Solubility of aldehyde in water at 30 1C.14 e Ratio determined by 1H NMR integration in D2O. Due to poor solubility of aldehyde in D2O, a
DMSO–D2O (1 : 1) mixture was used.
Table 3 Hydroacylation of alkenes 1 with aldehydes 2 on watera
Entry
R =
R0 =
Yield 3b, c(%)
1
2
3
4
5
6
7
8
–(CH2)2CH3, 2a
–c-C6H11, 2e
–(CH2)2CH3, 2a
–c-C6H11, 2e
–(CH2)2CH3, 2a
–c-C6H11, 2e
–(CH2)2CH3, 2a
–c-C6H11, 2e
OEt, 1b
55 (64), 3ab
52 (62), 3eb
52, 3ac
OPh, 1c
Et, 1d
57, 3ec
64, 3ad
d
d
57, 3ed
d
56, 3ae
Ph, 1e
d
61, 3ee
Scheme 2 Postulated mechanism for hydroacylation.
Table 2 Oxidation of aldehyde 2 to acid 6; neat (200 ml)
a
Conditions: aldehyde (5 eq.) and alkene (1 eq.) were stirred at
b
300 rpm in water at 21 1C unless stated otherwise. All reactions
proceeded with 100% conversion of 1. Yields given in parentheses
refer to 1H NMR yields based on pentachlorobenzene as an internal
c
d
standard. Heating to 60 1C was required.
synthetically efficient, it indicates that the trapping of acyl
radical intermediates in the aerial oxidation of aldehydes is not
entirely predicated on a very electron poor vinyl sulfonate.12
Nonetheless, the application of a large excess of one of the
reagents is not unknown in hydroacylation reactions,13 even
those that employ polarity reversal catalysts.15,16
Entry
R =
2 : 6a
1
2
3
4
5
6
7
–CH(CH3)2, 2b
1 : 5.11
1 : 2.16
1 : 1.20
1 : 1.08
1 : 0.66
1 : 0.37
1 : 0.04
–CH(C2H5)(CH2)3CH3, 2f
–CH2CH(CH3)2, 2c
–(CH2)2CH3, 2a
–c-C6H11, 2e
–(CH2)4CH3, 2d
–(CH2)8CH3, 2g
Although an excess of aldehyde was required to permit vinyl
sulfonate 1 to compete effectively with molecular oxygen for
acyl radical 5, it ensured high conversion and minimisation of
the formation of higher order products such as 8. Indeed, in
the case of reaction of 2a with 1b the use of 2 equivalents of 2a
resulted in a 2 : 1 ratio of products 3 and 8. Whereas at a 5 : 1
reaction stoichiometry a 5 : 1 ratio was observed (Table 3,
entry 1). It appears that in the case of the alkenes 1b–1e the
acyl radical trapping and radical chain propagation are less
efficient when compared to 1a. A consequence of the high
reaction stoichiometry is formation of significant amounts of
acid which could be recovered if required in appreciable
amounts (65% based on starting aldehyde for 2e with 1b).
Prior work from this laboratory17–20 has shown that
sulfonates are useful alternatives to sulfonyl chlorides in the
a
Ratio of aldehyde 2 to acid 6 after 2 h stirring at 300 rpm determined
through comparison of the 1H NMR integration. It should also be
noted that not stirring significantly slowed the rate of auto-oxidation.
in that the aldehydes that auto-oxidised at the slowest rate
required prolonged reaction times (Table 1, entries 4 and 7,
and Table 2, entries 6 and 7). Moreover, the low conversion
observed for isobutyraldehyde could be attributed to its
propensity to rapidly auto-oxidise (Table 2, entry 1).
We have extended the olefin tolerance to both ethyl and
phenyl vinyl sulfonates and, most pleasingly, vinyl sulfones
(Table 3). Although this required the use of 5 equivalents
of aldehyde and needs further optimisation to make it
ꢀc
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134 | Chem. Commun., 2010, 46, 133–135

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well documented,24 the elimination conditions were applied to
sulfones 3ad and 3ae (Table 4, entries 7–10) and were success-
ful, albeit in poorer yields. We believe the inferior yields
observed for b-keto-sulfones 3ad and 3ae highlight a specific
advantage of b-keto-sulfonates 3a, 3ab and 3ac.
In summary, we have developed a novel method for the
effective hydroacylation of vinyl sulfonates and sulfones on
water using only air to promote C–H activation. The
previously unexplored b-keto-PFP-sulfonates, which have
Scheme 3 Synthesis of sultam 10, where R1 = nBu and R2 = nhexyl.
been prepared via
a relatively efficient hydroacylation
synthesis of sulfonamides. However b-keto-sulfonates offer
specific opportunities for additional transformations. Thus
using a modification of our usual protocol,19,20 we were able
to convert b-keto-sulfonate 3a into sulfonamide 9 in good
yield. Moreover, due to the presence of the b-keto function-
ality, we were also able to synthesise sultam 10 (Scheme 3) in
excellent yield through a reductive cyclisation of 9 under acidic
conditions.
pathway, show promise as reagents for b-keto-sulfonamide
and sultam formation. Their ability to also undergo efficient
elimination, and hence for the in situ generation of enones,
provides opportunities for the synthesis of molecules that may
not be readily accessible via the hydroacylation of electron rich
alkenes.
We gratefully acknowledge the EPSRC and UCL for
funding and the EPSRC Mass Spectrometry Service for
provision of spectra.
Furthermore, treatment of 3a with DBU led to clean
elimination to the enone (not shown) demonstrating an overall
conversion of an aldehyde to an enone via hydroacylation and
elimination. We envisage that this hydroacylation–elimination
approach is complementary to current methods for the
generation of enones from aldehydes and avoids the use of
potent nucleophiles and oxidising conditions commonly
employed.21 The opportunities afforded by the vinyl sulfonate
and hence b-keto-sulfonate derived from hydroacylation are
enhanced by this elimination protocol, because the enone can
undergo a wide range of conjugate addition reactions.22 For
example, in the alkene hydroacylation arena, there is a
significant limitation associated with electron rich alkenes.16
Thus, using a simple sequence involving hydroacylation,
elimination and addition, it should be possible to access a
variety of unsymmetrical functionalised ketones from
aldehydes which would offer a significant challenge to current
alkene hydroacylation methodologies.16 In order to demon-
strate this concept we have made b-keto-sulfides, the synthesis
of which, to the best of our knowledge, has not been reported
by direct hydroacylation of vinyl sulfides.23 Thus, treatment of
sulfonates 3a, 3ab and 3ac with DBU and a thiol in dichloro-
methane led to a smooth and high yielding transformation to
11, presumably via an elimination–addition sequence (Table 4,
entries 1–6). As the elimination of sulfones to give alkenes is
Notes and references
1 P. T. Anastas and M. M. Kirchhoff, Acc. Chem. Res., 2002, 35, 686.
2 C. J. Li, Chem. Rev., 1993, 93, 2023.
3 U. M. Lindstrom, Chem. Rev., 2002, 102, 2751.
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5 A. El-Batta, C. C. Jiang, W. Zhao, R. Anness, A. L. Cooksy and
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6 D. Gonzalez-Cruz, D. Tejedor, P. de Armas and F. Garcia-
Tellado, Chem.–Eur. J., 2007, 13, 4823.
7 S. Y. Jung and R. A. Marcus, J. Am. Chem. Soc., 2007, 129, 5492.
8 S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb and
K. B. Sharpless, Angew. Chem., Int. Ed., 2005, 44, 3275.
9 M. C. Pirrung and K. Das Sharma, J. Am. Chem. Soc., 2004, 126, 444.
10 M. C. Pirrung, Chem.–Eur. J., 2006, 12, 1312.
11 N. Shapiro and A. Vigalok, Angew. Chem., Int. Ed., 2008, 47, 2849.
12 R. J. Fitzmaurice, J. M. Ahern and S. Caddick, Org. Biomol.
Chem., 2009, 7, 235.
13 For lead references to hydroacylation strategies see:
M. Christmann, Angew. Chem., Int. Ed., 2005, 44, 2632;
D. Seebach, Angew. Chem., Int. Ed. Engl., 1979, 18, 239;
C. Chatgilialoglu, D. Crich, M. Komatsu and I. Ryu, Chem.
Rev., 1999, 99, 1991.
14 R. M. Stephenson, J. Chem. Eng. Data, 1993, 38, 630.
15 H. S. Dang and B. P. Roberts, J. Chem. Soc., Perkin Trans. 1,
1998, 67.
16 S. Tsujimoto, T. Iwahama, S. Sakaguchi and Y. Ishii, Chem.
Commun., 2001, 2352; S. Tsujimoto, S. Sakaguchi and Y. Ishii,
Tetrahedron Lett., 2003, 44, 5601.
17 S. Caddick, J. D. Wilden and D. B. Judd, J. Am. Chem. Soc., 2004,
126, 1024.
Table 4 In situ elimination–thiolation of 3
18 S. Caddick, J. D. Wilden, H. D. Bush, S. N. Wadman and B. Judd,
Org. Lett., 2002, 4, 2549.
19 J. D. Wilden, D. B. Judd and S. Caddick, Tetrahedron Lett., 2005,
46, 7637.
20 S. Caddick, J. D. Wilden and D. B. Judd, Chem. Commun., 2005,
2727.
21 For examples see: R. T. Lewis, W. B. Motherwell and M. Shipman,
J. Chem. Soc., Chem. Commun., 1988, 948; E. Negishi, S. Ma,
T. Sugihara and Y. Noda, J. Org. Chem., 1997, 62, 1922.
22 For example see: P. Perlmutter, Conjugate Addition Reactions in
Organic Synthesis, Tetrahedron Organic Chemistry Series, Pergamon,
Oxford, 1992, vol. 9.
23 We note that Willis and co-workers have reported the synthesis of
b-keto-sulfides via metal catalysed alkene and alkyne hydroacyl-
ation incorporating the sulfide into the aldehyde component, see
for example: G. L. Moxham, H. Randell-Sly, S. K. Brayshaw,
A. S. Weller and M. C. Willis, Chem.–Eur. J., 2008, 14, 8383.
24 For example see: B. R. Langlois, T. Billard, J.-C. Mulatier and
C. Yezeguelian, J. Fluorine Chem., 2007, 128, 851.
Entry
R =
R0 =
Yield 9 (%)
1
2
3
4
5
6
7
8
9
10
–OPFP, 3a
–(CH2)5CH3
–CH2C6H4CH3
–(CH2)5CH3
–CH2C6H4CH3
–(CH2)5CH3
–CH2C6H4CH3
–(CH2)5CH3
–CH2C6H4CH3
–(CH2)5CH3
–CH2C6H4CH3
98, 11a
97, 11b
89, 11a
90, 11b
92, 11a
90, 11b
46, 11a
34, 11b
78, 11a
75, 11b
–OEt, 3ab
–OPh, 3ac
–Et, 3ad
–Ph, 3ae
ꢀc
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Chem. Commun., 2010, 46, 133–135 | 135