Addition of silylated nucleophiles to α-oxoketenes

Article abstract of DOI:10.1039/c5cc10217k

A general evaluation of silylated nucleophiles to intercept transient α-oxoketenes generated by microwave-assisted Wolff rearrangement of 2-diazo-1,3-dicarbonyl compounds is presented. Original scaffolds and synthetic intermediates are accessed in a rapid

Full text of DOI:10.1039/c5cc10217k

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Dudognon, M.
Presset, J. Rodriguez, Y. Coquerel, X. Bugaut and T. Constantieux, Chem. Commun., 2016, DOI:
1
0.1039/C5CC10217K.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Page 1 of 4
Please dCo h ne om t Ca do jmu smt margins
View Article Online
DOI: 10.1039/C5CC10217K
Chemical Communications
COMMUNICATION
Addition of Silylated Nucleophiles to α-Oxoketenes
a
a,b
a
a
a
Yohan Dudognon, Marc Presset, Jean Rodriguez, Yoann Coquerel*, Xavier Bugaut* and
Received 00th January 20xx,
Accepted 00th January 20xx
Thierry Constantieux*a
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
A
general evaluation of silylated nucleophiles to intercept centered nucleophiles to produce the corresponding 1,3-dicarbonyl
transient α-oxoketenes generated by microwave-assisted Wolff products,6,7 and with various unsaturated compounds to afford
rearrangement of 2-diazo-1,3-dicarbonyl compounds is presented. stereodefined polycyclic molecules following pericyclic processes
Original scaffolds and synthetic intermediates are accessed in a (Scheme 1, left).8 Microwave-assisted heating was shown to be
rapid, efficient and easy-to-handle way. Mechanistic studies by highly beneficial in terms of efficiency and practicability in these
DFT calculations and various post-functionalizations are discussed. transformations.9 However, the chemoselective interception of α-
oxoketenes with simple nucleophiles such as dihydrogen, hydrogen
The 1,2-Wolff rearrangement, i.e. the conversion of easily available
azide or ammonia remains unknown (Scheme 1, upper right). We
identified the following issues as possible explanations: (i) reactivity
and chemoselectivity, since the nucleophile has to react with the α-
oxoketene but not with the ketones of the starting materials; (ii)
practicability for reactions at elevated temperature at the lab-scale,
as most of those nucleophiles are gases, often with high toxicities;

-diazocarbonyl derivatives into ketenes with extrusion of
dinitrogen, is a venerable and useful synthetic tool (Scheme 1).1,2 It
has been extensively used for the functionalization and variation of
carbon backbones, especially for the ring contraction of cyclic
molecules and the Arndt-Eistert homologation of carboxylic acids.3
Starting from 2-diazo-1,3-dicarbonyl compounds 1,4 the Wolff
rearrangement produces strongly electrophilic α-oxoketene species
(
iii) product stability since the resulting naked functionalities in the
products (e.g. aldehydes and acyl azides), might be unstable under
the reaction conditions. The alternative anionic species (such as
2
,5 which are usually not isolable and must be generated in situ.
-Oxoketenes can react with a variety of heteroatomic or carbon-
Scheme 1. Previous and new applications of the microwave-assisted Wolff rearrangement
a
Aix Marseille Université, Centrale Marseille, CNRS, iSm2 UMR 7313, 13397,
Marseille, France. E-mail: yoann.coquerel@univ-amu.fr, xavier.bugaut@univ-amu.fr,
thierry.constantieux@univ-amu.fr; Fax: +33 491 289 187; Tel: +33 491 282 874
b
Present address: Université Paris Est, ICMPE (UMR 7182), CNRS, UPEC, F-94320
Thiais, France.
†Electronic Supplementary Information (ESI) available: All spectroscopic data and
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjustmargins

Please dCo h ne om t Ca do jmu smt margins
Page 2 of 4
COMMUNICATION
Journal Name
View Article Online
mineral cyanide or azide sources) can barely be used since they are Pleasingly, analysis of the clean crude reactioDnOmI: 1ix0t.1u0r3e9s/hCo5CwCe1d0o21n7lKy
hardly soluble in the unpolar organic reaction media commonly the masked β-ketoaldehyde 3a as a single diastereomer (98% yield),
used to carry out the Wolff rearrangement.
which was identified by comparison with known related
Despite the widespread application of silylated nucleophiles in compounds.17 This methodology could be applied to the synthesis
organic chemistry (hydrosilylation,10 Mukaiyama aldol reaction,11 of various cyclic masked β-ketoaldehydes by ring contraction
Peterson elimination,12 Hiyama-Denmark cross-coupling13 etc...), (products 3b to 3g), such as functionalized thiolanone 3e, oxindole
they have hardly been reacted with ketene species. Indeed, there 3f and benzoxofurane 3g. The acyclic products 3h and 3i could also
are only
a single example of trapping of a ketene with be prepared from the corresponding acyclic diazo compounds.
hexamethyldisilazane (HMDS) to afford the corresponding primary Notably, all those compounds were obtained with good to excellent
amide in a context of total synthesis,14 and a study on the yields in a practical and expeditious manner (reaction time = 3 min,
hydrosilylation of bench-stable polyfluoroketenes under Pt- no work-up, no purification). Generally, only the (E)-diastereomer
catalysis.15 Additionally, a recent report presents the coupling of was observed, but for several examples, the (Z) diastereomer could
1
,3-dioxin-2-ones with silyl enol ethers.16 In the present work, we also be detected. The use of less nucleophilic silicium hydrides
describe the first chemoselective addition of a variety of easy-to- (Ph SiH, Ph SiH and (EtO) SiH) resulted in complex reaction
3
2
2
3
handle silylated nucleophiles to α-oxoketenes generated by mixtures.18 Remarkably, with this methodology, the position of the
microwave-assisted Wolff rearrangement of either acyclic or cyclic protected aldehyde functionality in compounds 3a-c and 3e is fully
2
-diazo-1,3-dicarbonyl compounds, to prepare building blocks that controlled since the starting diazo compounds are symmetric
are hard or impossible to access by alternative existing methods molecules, whereas other existing methods to prepare this motif,
Scheme 1, bottom right). Triethylsilane and trimethylsilyl azide such as the formylation of enolate, are plagued with problems of
(
were used as sources of hydride and azide, to synthesize masked β- regioselectivity.17h
ketoaldehydes 3 and a β-ketoacyl azide 5, respectively. In addition,
The outcome of the reaction raised mechanistic considerations,
HMDS acted as a liquid anhydrous ammonia surrogate and
trimethylsilyldiazomethane as a source of methylene to afford upon
desilylation primary β-ketoamides 4 and fused bicylic furan-3-ones
which were investigated by computational DFT methods in the case
of the model reaction between the conformationally constrained -
oxoketene A and trimethylsilane (Figure 1).19 In early calculations,
both the endo and exo direct 1,2-hydrosilylation of the ketene
carbonyl group reaction paths were computed, and the formation
of (E) isomer C was found both kinetically and thermodynamically
6, respectively. In these reactions, the silyl group remarkably
enabled the in situ protection of sensitive functionalities avoiding
their degradation during the reaction.
We started our investigation by mixing triethylsilane and 2-diazo- favored over the (Z) isomer B at the studied level of theory (Figure
5
,5-dimethylcyclohexane-1,3-dione in toluene at 160 °C under 1a). However, in both cases activation barriers are high (134 and
-1
microwave irradiation during 3 minutes (Table 1).
110 kJ.mol , respectively), and an alternative reaction pathway was
investigated (Figure 1b). The hydrosilylation reactions described in
Table 1 are believed to occur via a three-step mechanism: (i) a
concerted kinetically favored 1,4-hydrosilylation of the -oxoketene
produces intermediate D through a six-membered transition state
TSAD;20 (ii) a 1,5-shift of the silyl group from the ketone enol ether
oxygen atom to the aldehyde one in D is possible through another
six-membered transition state TSDB to give the (Z) isomer B; (iii) the
thermodynamic (E) isomer product C can be obtained by an
isomerization of the (Z) isomer B. The unusual B  C isomerization
has a reasonable energy barrier due to the marked polarization of
the enol ether double bond with a “push-pull” motif allowing for a
transition state similar to an enolate/silyl-stabilized oxonium
system.21,22
Table 1. Synthesis of masked β-ketoaldehydes by triethylsilane additiona
We then turned our attention to nitrogen-centered silylated
nucleophiles, using HMDS and trimethylsilyl azide (TMSN ). The
3
reactions of representative -oxoketenes with HMDS afforded
relatively complex crude reaction mixtures, which after purification
by silica gel chromatography delivered the corresponding cyclic and
acyclic primary β-ketoamides 4a-4e in satisfactory yields (Table 2).23
a
A solution of diazo compound (0.25 mmol, 1 equiv) and triethylsilane (1 equiv) was
b
stirred at 160 °C for 3 min in toluene (2 mL). The reactions were conducted on a 1
mmol scale. The reactions were conducted on a 0.5 mmol scale. d The reactions were
c
conducted at 200 °C for 3 min.
2
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjustmargins

Page 3 of 4
Please dCo h ne om t Ca do jmu smt margins
Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C5CC10217K
Figure 1. a) Model study for the direct 1,2-hydrosilylation pathway. b) Simplified model study for the 1,4-hydrosilylation / 1,5-shift of the Me
3
Si group / isomerization
pathway. The energy profiles were obtained by DFT calculations at the B3LYP/6-311++G(d,p) level of theory with the IEFPCM solvation model (free energies in
-1
kJ.mol ; see Supporting Information for full details)
Table 2. Synthesis of β-ketoamides by HMDS additiona
TMSCF
because of its too weak nucleophilicity (not depicted). On the
opposite, TMSCHN behaved as a convenient source of methylene
Table 3): indeed, after initial nucleophilic trapping, the second
3
, only the -oxoketene dimer was obtained, presumably
2
(
diazo function underwent an insertion reaction to deliver original
fused bicylic furan-3-ones 6a-c, whose synthesis has scarcely been
reported,24 with satisfactory yield after purification by silica gel
chromatography. It is worth noting that related preliminary
evaluation of the coupling between two different diazo species can
be found in the literature but yields of products were low because
of other competing pathways.25 The present results highlight the
beneficial effect of the silyl group to prevent over-reaction of the
product under the reaction conditions. Moreover this
transformation represents
different diazo compounds.
Table 3. Synthesis of bicylicfuran-3-ones by TMSCHN
2
additiona
a selective cross-coupling of two
aA solution of diazo compound (0.1 mmol, 1 equiv) and HMDS (1 equiv) was stirred at
1
60 °C for 3 min in toluene (2 mL). Yields of isolated pure products after purification by
b
c
flash chromatography on silica gel. This reaction was conducted on a 0.5 mmol scale.
This reaction was conducted on a 0.25 mmol scale.
3
The reaction with TMSN was less straightforward but, after
optimization of the reaction conditions involving the portionwise
addition of the diazo compound obtained from dimedone, the
previously unknown masked β-ketoacyl azide 5 was obtained
diastereoselectively with 86% yield (Scheme 2).19
aA solution of diazo compound (0.1 mmol, 1 equiv) and TMSCHN
(1 equiv) was stirred
2
at 160 °C for 3 min in toluene (2 mL). Yields of isolated pure products after purification
b
by flash chromatography on silica gel. This reaction was conducted on a 0.5 mmol
c
scale. This reaction was conducted on a 0.25 mmol scale.
Scheme 2. Addition of TMSN
3
With this set of original structures in hand, we briefly investigated
To complete the study, carbon-centered silylated nucleophiles were their potential post-functionalization to obtain more structurally
investigated through the reactions with trimethylsilyl cyanide diverse scaffolds. Starting from masked β-ketoaldehyde 3a, Michael
(
TMSCN),
trimethyl(trifluoromethyl)silane
(TMSCF
3
)
and addition on methyl vinyl ketone in slightly basic hydro-organic
). With TMSCN, the expected reaction conditions19 delivered with good yield product 7, which
trimethylsilyldiazomethane (TMSCHN
2
product could be observed but it was not possible to optimize the could be further functionalized into spiro-cyclohexenone 8 by
reaction to a reasonable level of selectivity. As to the reaction with Robinson annulation, also with good yield.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjustmargins

Please dCo h ne om t Ca do jmu smt margins
Page 4 of 4
COMMUNICATION
Journal Name
Martinez and F. Lamaty, in Stereoselective SynthVeieswisAroticfleDOrnulignse
and Natural Products, eds. V. Andrushko and N. Andrushko,
DOI: 10.1039/C5CC10217K
John Wiley & Sons, Hoboken, NJ, 2013, Chap. 5, pp. 145-166.
1
1
0 Y. Nakajima and S. Shimada, RSC Adv., 2015, 5, 20603-20616.
1 (a) T. Mukaiyama, K. Narasaka and K. Banno, Chem. Lett.,
1
973, 1011-1014; (b) J. Matsuo and M. Murakami, Angew.
Scheme 3. Post-functionalization of masked β-ketoaldehyde 3a
Chem. Int. Ed., 2013, 52, 9109-9118.
1
2 (a) D. J. Peterson, J. Org. Chem., 1968, 33, 780-784; (b) L. F. v.
Staden, D. Gravestock and D. J. Ager, Chem. Soc. Rev., 2002,
31, 195-200.
In conclusion, we have successfully developed a versatile method
for the addition of silylated nucleophiles to α-oxoketenes generated
by microwave-assisted Wolff rearrangement of 2-diazo-1,3- 13 (a) Y. Hatanaka and T. Hiyama, J. Org. Chem., 1988, 53, 918-
9
20; (b) H. F. Sore, W. R. J. D. Galloway and D. R. Spring,
dicarbonyl compounds to synthesize valuable building blocks that
are hard or impossible to access by existing methods. This
methodology is a rapid, efficient and user-friendly way to prepare
original scaffolds and synthetic intermediates that are likely to find
interesting applications in synthetic organic chemistry. Additionally,
DFT calculations are in agreement with an initial 1,4-hydrosilylation
Chem. Soc. Rev., 2012, 41, 1845-1866.
1
1
4 L. N. Mander and M. M. McLachlan, J. Am. Chem. Soc., 2003,
125, 2400-2401.
5 (a) A. Y. Volkonskii, E. M. Kagramanova, E. I. Mysov and N. E.
Mysova, Russ. Chem. Bull., 2004, 53, 1693-1699. (b) A. Y.
Volkonskii, E. M. Kagramanova, E. I. Mysov and N. D.
Kagramanov, Russ. Chem. Bull., 2010, 59, 569-576.
with participation of the ketone’s oxygen atom. Our current efforts 16 Q. Wang and B. List, Synlett, 2015, 26, 1525-1527.
1
7 (a) P. J. Stang and W. L. Treptow, J. Med. Chem., 1981, 24
,
aim to find applications for these promising substrates in
enantioselective organocatalysis.
4
68-472; (b) M. J. Suto, K. M. Tramposch, M. Wierzba, A. J.
Solo and W. Duax, J. Org. Chem., 1987, 52, 2263-2273; (c) L.
F. Tietze, A. Bergmann, G. Brill, K. Brüggemann, U. Hartfiel
and E. Voß, Chem. Ber., 1989, 122, 83-94; (d) E. Krawczyk and
A. Skowrońska, Heteroat. Chem, 2000, 11, 353-361; (e) P. T.
O'Sullivan, W. Buhr, M. A. M. Fuhry, J. R. Harrison, J. E.
Davies, N. Feeder, D. R. Marshall, J. W. Burton and A. B.
Holmes, J. Am. Chem. Soc., 2004, 126, 2194-2207; (f) L. Wan
We thank R. Rosas, Dr. N. Vanthuyne and M. Jean, and the whole
team of Spectropole (www.spectropole.fr). Financial support from
Aix Marseille Université, Centrale Marseille and the CNRS is
acknowledged.
and M. A. Tius, Org. Lett., 2007, 9, 647-650; (g) E. M. B. l.
Janke, S. Schlund, A. Paasche, B. Engels, R. d. Dede, I.
Hussain, P. Langer, M. Rettig and K. Weisz, J. Org. Chem.,
Notes and references
2
009, 74, 4878-4881; (h) N. Höttecke, H. Reinke, C. Fischer
1
2
L. Wolff, Justus Liebigs Ann. Chem., 1902, 325, 129-195.
(a) W. Kirmse, Eur. J. Org. Chem., 2002, 2193-2256; (b) Y.
Coquerel and J. Rodriguez, in Molecular Rearrangements in
Organic Synthesis, Ed.: C. Rojas, John Wiley & Sons,
Hoboken, NJ, 2015, Chap. 3, pp. 59-84.
and P. Langer, Z. Naturforsch., 2009, 64b, 699-706; (i) T. S. I.
Franczyk II, D. R. Hill, A. R. Haight, M. A. McLauglin, S.
Shekhar, S. Yu, J. Mei and L. Wang, WO 2009/155386(A1),
2009; (j) R. Dede, A. Riahi, M. Shkoor, M. A. Yawer, I.
Hussain, N. Kelzhanova, Z. A. Abilov, A. Falodun, H. Görls and
P. Langer, Z. Naturforsch., 2013, 68b, 1021-1030; (k) F.
Erben, V. Specowius, J. Wölfling, G. Schneider and P. Langer,
Helv. Chim. Acta, 2013, 96, 924-930.
3
4
F. Arndt, B. Eistert, Ber., 1935, 68b, 200-208.
M. Presset, D. Mailhol, Y. Coquerel, J. Rodriguez, Synthesis,
2
011, 16, 2549-2552.
5
Reviews: (a) C. Wentrup, W. Heilmayer and G. Kollenz, 18 M. Horn, L. H. Schappele, G. Lang-Wittkowski, H. Mayr and A.
Synthesis, 1994, 12, 1219-1248; (b) G. Kollenz and S. Ebner,
R. Ofial, Chem. Eur. J., 2013, 19, 249-263.
in Science of Synthesis: Houben-Weyl Methods of Molecular 19 See supporting information for further details.
Transformations, Danheiser, R., Ed., Georg Thieme Verlag, 20 The possible pseudopericyclic character of this process could
Stuttgart, Germany, 2006, Vol. 23, pp. 271-349; (c) K. P.
Reber, S. D. Tilley and E. J. Sorensen, Chem. Soc. Rev., 2009,
explain its low activation barrier. For a review, see: P. v. R.
Schleyer, J. I. Wu, F. P. Cossio and I. Fernandez, Chem. Soc.
Rev., 2014, 43, 4909-4921.
3
8
, 3022-3034; (d) A. Ford, H. Miel, A. Ring, C. N. Slattery, A.
R. Maguire and M. A. McKervey, Chem. Rev., 2015, 115
981-10080.
(a) M. Presset, Y. Coquerel and J. Rodriguez, J. Org. Chem.,
,
21 (E/Z) isomerization of silyl enol ether has already been
documented. See for example: J. L. Duffy, T. P. Yoon and D.
A. Evans, Tetrahedron Lett., 1995, 36, 9245-9248.
9
6
2
009, 74, 415-418; (b) T. Boddaert, Y. Coquerel and J. 22 The possible biradical character of TSBC has been evaluated
Rodriguez, Eur. J. Org. Chem., 2011, 5061-5070; (c) J.-C.
Castillo, M. Presset, R. Abonia, Y. Coquerel and J. Rodriguez,
Eur. J. Org. Chem., 2012, 2338-2345.
Y. Coquerel, K. Mohanan, M. Presset, D. Mailhol and J.
Rodriguez, Chem. Eur. J., 2012, 18, 9217-9220.
(a) M. Presset, Y. Coquerel and J. Rodriguez, Org. Lett., 2009,
via a UB3LYP calculation and found unfavorable (+43.1
kJ.mol-1).
23 A small amount (5-10%) of the corresponding β-ketonitriles
was also isolated from these reactions.
7
8
24 R. Dolmazon, J. Heterocycl. Chem., 1988, 25, 751-757 and
related articles from the same group.
11, 5706-5709; (b) M. Presset, Y. Coquerel and J. Rodriguez, 25 (a) L. Capuano, R. Zander and P. Zenner, Chem. Ber., 1979,
Org. Lett., 2010, 12, 4212-4215; (c) M. Presset, K. Mohanan,
M. Hamann, Y. Coquerel and J. Rodriguez, Org. Lett., 2011,
112, 3753-3758; (b) L. Capuano and T. Tammer, Chem. Ber.,
1981, 114, 456-467.
1
3
, 4124-4127; (d) J. Galvez, J.-C. Castillo, J. Quiroga, M.
Rajzmann, J. Rodriguez and Y. Coquerel, Org. Lett., 2014, 16
126-4129; (e) P. Neupane, L. Xia and Y. R. Lee, Adv. Synth.
Catal., 2014, 356, 2566-2574.
,
4
9
(a) C. O. Kappe, D. Dallinger and S. S. Murphree, Practical
Microwave Synthesis for Organic Chemists, Wiley-VCH,
Weinheim, 2009; (b) Y. Coquerel, E. Colacino, J. Rodriguez, J.
4
| J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjustmargins