A novel rearrangement reaction of β-diazo-α-ketoacetals

Article abstract of DOI:10.1016/j.tetlet.2009.03.025

Treatment of pyruvate ketal-derived diazoacetoacetates or vinyldiazoketones with rhodium(II) complexes at elevated temperatures results in an unusual skeletal rearrangement to afford eight-membered ring lactones.

Full text of DOI:10.1016/j.tetlet.2009.03.025

Tetrahedron Letters 50 (2009) 3568–3570
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel rearrangement reaction of b-diazo-a-ketoacetals
Marvis O. Erhunmwunse a,b, Patrick G. Steel a,
*
a Department of Chemistry, University of Durham, Science Laboratories, South Road Durham, DH1 3LE, UK
b Department of Chemistry, Faculty of Physical Sciences, University of Benin, P.M.B. 1154, Benin City, Nigeria
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of pyruvate ketal-derived diazoacetoacetates or vinyldiazoketones with rhodium(II) com-
plexes at elevated temperatures results in an unusual skeletal rearrangement to afford eight-membered
ring lactones.
Received 14 January 2009
Revised 26 February 2009
Accepted 6 March 2009
Available online 11 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium carbenoid
Wolff rearrangement
Ketal
Lactone
Ketene
a
-Diazocarbonyl compounds are exceptionally valuable re-
OTBS
CH3
agents for organic synthesis undergoing a wide range of transfor-
mations including insertion reactions, cyclopropanation, ylide
formation and Wolff rearrangements.1 Within the first of these
reaction classes there have been many developments that enable
selective insertion reactions to be undertaken in both an inter-
and intramolecular fashion. In this respect we have exploited such
advances in a study aimed at developing methodology for the syn-
thesis of highly substituted cyclic ethers through a tandem C–H
insertion-acetal bond cleavage sequence, Scheme 1.2 Whilst this
proved to be effective we sought to enhance this process by incor-
poration of an additional carbenoid stabilising group that would
also provide direct entry to a tetrasubstituted THF on acetal frag-
mentation. In this Letter, we describe our initial attempts to
achieve this which have led to the discovery of an unusual rear-
rangement pathway which provides access to a novel medium ring
lactone system.
O
N2
HO
O
O
R
CH3
H
4
O
R
1
Rh2(OAc)4
DCM, rt
Et3SiH, BF3•OEt2
-78 ºC
OTBS
O
i. NaBH4, MeOH
O
CH3
O
R
CH3
R
ii. TBSOTf, 2,6-lutidine
DCM
O
O
3
2
Scheme 1.
We commenced this study by preparing suitable substrates
focusing on diazoacetoacetate 7 and the donor–acceptor stabilised
system represented by vinyl diazoketone 8, Scheme 2. The former
could be prepared from the pyruvate-derived acetal 5 in a short se-
quence of steps involving conversion to the aldehyde 6 and then a
one-pot tandem aldol condensation–oxidation using an ethyl
diazoacetate, DBU and IBX combination.3 The vinyl diazoketone 8
was prepared in a longer sequence involving addition of allyl mag-
nesium bromide to the aldehyde 6, oxidation and diazo transfer
using p-acetamidobenzenesulfonyl azide (ABSA). During the oxida-
tion step partial isomerisation of the double bond occurred to form
the corresponding ,b-unsaturated ketone. This, however, was of
little consequence as, in the presence of a mild base, diazo transfer
occurred exclusively at the kinetically favoured -position.
Our first attempts to promote the desired insertion reaction fo-
cused on diazoacetoacetate 7. Whilst using rhodium(II) acetate,
Rh2(OAc)4, as the catalyst at room temperature led only to recov-
ered starting material, slow addition of 7 to a solution of rho-
dium(II) heptafluorobutyrate [Rh2(pfb)4] led to the isolation of
bicycle 9, arising from enolate capture of an oxonium generated
by initial hydride transfer to the rhodium carbenoid, Scheme 3.4
a
a
* Corresponding author.
E-mail address: p.g.steel@durham.ac.uk (P.G. Steel).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.025

M. O. Erhunmwunse, P. G. Steel / Tetrahedron Letters 50 (2009) 3568–3570
3569
MeO
O
O
H
O
2'
1'
H
Ph
CH3
O
H
2
O
8
5
H
CH3
4
6
O
i. LiAlH4, Et2O
H
ii. (COCl)2, DMSO, Et3N, CH2Cl2
11
90%
Figure 1. Selected HMBC correlations for 11.
H
O
O
nal, provided much clearer correlations in the various 2D NMR
experiments undertaken. Notably, a significant NOESY correlation
was observed between H-10 and the 4-CH3 signal, consistent with
a cis alkene and thereby confirming the cyclic nature of the lactone.
Further evidence was obtained from HSQC and HMBC experiments,
with the HMBC correlations of C-2 to 8-H, C-4 to 6-H, C-2 to 10-H
and C-3 to both 20-H and 4-CH3 providing strong support for the
proposed structure, Figure 1. As for lactone 10, the 4-CH3 signal
in the 1H NMR spectra exhibited a marked shift to higher frequency
appearing at d 2.11 whilst the IR spectrum showed bands consis-
tent with an ester (lactone) and C@C unsaturation at 1714 and
1617 cmꢀ1, respectively. Final evidence in support of the lactone
structure was provided by the high resolution mass spectral anal-
ysis of 11 (ESI) m/z (MNa+) = 267.0993 which was consistent with
the proposed molecular formula of C15H16O3Na. A search of various
databases revealed that this structure was novel with the closest
analogy being found in the fungal natural products barceloneic lac-
tone 12, isolated from a fungus of the genus Phoma in a screen for
protein-farnesyl transferase (PFT-ase) inhibitors,6 and penicillide
13 and dehydropenicillide 14, found in the ascomycetous fungus
Talaromyces derxii,7 Figure 2. Since synthetic approaches to these
compounds have not been reported we felt that a brief examina-
tion of the scope and mechanism of this rearrangement was mer-
ited. Replacing benzene by higher boiling toluene as the solvent
had no effect on the reaction outcome. By-passing the slow addi-
tion process and simply heating 7 with Rh2(pfb)4 in refluxing tolu-
ene afforded a mixture of 9 (45%) and 10 (22%). That the formation
of the former simply represented a background reaction occurring
prior to reaching the critical reaction temperature for the rear-
rangement was confirmed by repeating this process in a micro-
wave reactor. Under these conditions a cleaner reaction, with no
evidence for the formation of 9, could be achieved at much lower
reaction temperatures (70 °C) and shorter reactions times
(10 min). Whilst heating is essential, it is not a sole requirement,
as all attempts to achieve this transformation in the absence of a
Ph
CH3
O
6
EtO2CCHN2, DBU
IBX, DMSO
89%
i. AllylMgBr, THF (94%)
ii. (COCl)2, DMSO, Et3N, CH Cl2 (76%)
iii. ABSA, DBU, MeCN (920%)
N2
O
N2
O
EtO2C
O
O
Ph
Ph
CH3
CH3
O
O
8
7
Scheme 2.
Given the enhanced electrophilicity of Rh2(pfb)4, such an out-
come is not surprising but did confirm that generation of the inter-
mediate carbenoid was accessible. Consequently we explored the
use of other ligands and reaction conditions. One such variation
was to attempt the reaction at elevated temperatures. Whilst pro-
longed heating in dichloromethane led to extensive decomposi-
tion, reaction with Rh2(OAc)4 in refluxing benzene for a 2 h
period resulted in clean conversion to a new compound isolated
as a colourless oil in 40% yield.5 This however was clearly not the
desired bicyclic acetal as analysis of the 13C NMR spectrum indi-
cated two ester carbonyl signals (d 168.1 and d 166.2) that were
clearly conjugated to an alkene (d 168.5). Moreover, the 1H chem-
ical shift for the methyl group (d 2.29) suggested that this too was
coupled to the conjugated system. Combined with mass spectral
data (ES+) which suggested a molecular ion of m/z = 291 (MNa+)
led to the suggestion that the unusual lactone system 10 had been
produced. Stronger evidence for such a proposal came from the
similar reaction of vinyldiazoketone 8 which afforded the analo-
gous lactone 11. This compound, having only a single carbonyl sig-
O
EtO
R
H
O
O
N2
O
OH
Rh2(pfb)4,CH2Cl2, rt
O
CH3
CH3
O
O
Ph
Ph
(R = CO2Et)
40%
O
O
H
H
CH3
O
7 R = CO2Et
9
H3CO
OMe
8 R = CH=CH2
OH
12
Rh2(OAc)4
PhH, reflux
40%
O
O
OMe
O
O
O
O
R
O
O
OH
Ph
CH3
O
OH
OH
OH
10 R = CO2Et (40%)
11 R = CH=CH2 (45%)
13
14
Scheme 3.
Figure 2. Structurally related natural products.

3570
M. O. Erhunmwunse, P. G. Steel / Tetrahedron Letters 50 (2009) 3568–3570
O
CO2Et
O
O
CO2Et
R3
N2
Rh2(pfb)4 (5 mol%), PhMe
MW, 70 ºC,10 min
R1
R2
R3
O
R1
O
O
R2
15 R1 = 4-NO2C6H4, R2 = H, R3 =CH3 (47%)
16 R1 = Ph, R2 = H, R3 = Ph (28%)
17 R1 = CH3, R2 = NO2, R3 =CH3 (30%)
Scheme 4.
Rh(II) complex failed leading to a complex product mixture with
no evidence for any lactone formation. Similarly, all attempts to
reproduce this transformation using diazoketone 1 which lacks
the additional stabilising element failed leading only to extensive
decomposition. However, variation in both components of the ace-
tal is tolerated leading to similar yields of products in all cases,
Scheme 4.8
to medium ring lactones found in a range of naturally occurring
compounds. We are actively exploring the potential for this trans-
formation to be applied to the synthesis of these structures and
will report on these studies in due course.
Acknowledgements
To account for these observations we propose a pathway in
which initial carbene generation is achieved under promotion by
the Rh(II) complex, Scheme 5. At room temperature this reacts to
afford the ‘O insertion’ product 21. However, at higher tempera-
tures, potentially through dissociation of the metal carbenoid 19
to afford the free carbene, a Wolff rearrangement can occur leading
to the ketene 22.9 In the absence of a stabilising group (alkene or
ester unit) this is unstable and undergoes decomposition at these
elevated temperatures, cf. compound 1. However, when substi-
tuted this is sufficiently long-lived to allow a formal 1,3 shift of
one of the acetal oxygen atoms to occur to give the observed lac-
tones.10 In support of such a hypothesis, heating of acetal 7 with
Rh2(pfb)4 in a mixture of toluene and methanol (1:1) afforded
the diester 25 along with trace amounts of lactone 10.
We thank Drs. A. M. Kenwright and M. Jones for assistance with
NMR and mass spectrometry experiments, respectively and The
Commonwealth Scholarship Commission (NGCA-2006-64) and
University of Benin, Nigeria for financial support (Scholarship to
M.O.E.).
References and notes
1. For leading reviews of this field see: (a) Zhang, Z. H.; Wang, J. B. Tetrahedron
2008, 64, 6577–6605; (b) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417–
424; (c) Wee, A. G. H. Curr. Org. Synth. 2006, 3, 499–555; (d) Davies, H. M. L.;
Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861–2903; (e) Ye, T.; McKervey, M. A.
Chem. Rev. 1994, 94, 1091–1160.
2. Garbi, A.; Mina, J. G.; Steel, P. G.; Longstaff, T.; Vile, S. Tetrahedron Lett. 2005, 46,
7175–7178.
3. Erhunmwunse, M. O.; Steel, P. G. J. Org. Chem. 2008, 73, 8675–8677.
4. (a) Clark, J. S.; Dossetter, A. G.; Wong, Y. S.; Townsend, R. J.; Whittingham, W.
G.; Russell, C. A. J. Org. Chem. 2004, 69, 3886–3898; (b) Clark, J. S.; Dossetter, A.
G.; Russell, C. A.; Whittingham, W. G. J. Org. Chem. 1997, 62, 4910–4911; (c)
Wardrop, D. J.; Velter, A. I.; Forslund, R. E. Org. Lett. 2001, 3, 2261–2264; (d)
Wardrop, D. J.; Forslund, R. E. Tetrahedron Lett. 2002, 43, 737–739.
5. All new compounds had satisfactory analytical and spectroscopic data.
6. Jayasuriya, H.; Ball, R. G.; Zink, D. L.; Smith, J. L.; Goetz, M. A.; Jenkins, R. G.;
Nallinomstead, M.; Silverman, K. C.; Bills, G. F.; Lingham, R. B.; Singh, S. B.;
Pelaez, F.; Cascales, C. J. Nat. Prod. 1995, 58, 986–991.
7. Suzuki, K.; Nozawa, K.; Udagawa, S.; Nakajima, S.; Kawai, K. Phytochemistry
1991, 30, 2096–2098.
8. Typical experimental procedure: (Z)-4-methyl-7-phenyl-3-vinyl-7,8-dihydro-
1,5-dioxocin-2(6H)-one 11: rhodium(II) perfluorobutyrate, Rh2(CO2C3F7)4
(5 mol %) solution in toluene (10 ml) placed in a microwave vial (20 ml) was
In conclusion, we have discovered a novel rearrangement of
acetal-containing diazocarbonyl compounds that provide access
R
R
O
O
[Rh]
[Rh]
N2
R2
R2
O
O
R1
R1
O
O
18
19
70 ºC
rt
[Rh]
O
R
argon flushed and maintained at 70 °C. After 2 min,
a solution of vinyl
O
diazoketone 8 (0.10 g, 0.37 mmol) in toluene (5 ml) was added and it was
immediately placed into the reactor. The vial was then immediately placed into
the reactor and heated at 70 °C for 15 min to give complete reaction
(determined by monitoring a series of trial reactions, involving variations of
time and temperature). The reaction mixture was then allowed to attain room
temperature, silica gel was added and the solvent was evaporated under
reduced pressure. The crude residue was then purified by flash column
chromatography on silica gel (ether/petroleum ether: 2/8) to give the title
R
R2
R2
O
O
O
20
R1
R1
O
22
lactone 11 as a colourless oil (0.04 g, 45%).
m
max (ATR): 1714 (C@O, lactone), 1617
(C@C), 1494, 1390, 1302, 1258, 1173, 1012, 896, 764, 700, 616 cmꢀ1
.
dH
O
R
O
(700 MHz, CDCl3): 7.37–7.35 (2H, m, Ar-H), 7.31–7.30 (3H, m, Ar-H), 6.43 (1H,
dd, J 17.1, 11.1, CH@CH2), 5.27 (1H, d, J 17.1, CH@CH2), 5.13 (1H, d, J 11.1,
CH@CH2), 4.54–4.91 (2H, m, 8-H), 4.37 (1H, dd, J 13.5, 3.4, 6-H), 4.24 (1H, dd, J
13.5, 6.8, 6-H), 3.35–3.31 (1H, m, 7-H), 2.11 (3H, s, 4-CH3). dC (175 MHz; CDCl3):
169.7 (C-2), 157.4 (C-4, enol ether), 137.6 (ipso Ar-C), 131.0 (CH@CH2), 128.9 (Ar-
C), 128.1 (Ar-C), 127.8 (Ar-C), 114.2 (CH@CH2), 105.3 (C-3), 68.0 (C-8), 67.4 (C-6),
47.2 (C-7), 19.0 (4-CH3). m/z (ES+): 308 (M+Na++CH3CN, 20%), 267 (M+Na+, 20),
245 (M+H+, 60). HRMS (ES+) found: 267.0993 (C15H16O3Na requires 267.0992).
H
R
O
R1
R2
R2
O
R1
O
O
21
23
9. For
a similar example of Wolff rearrangements occurring at elevated
temperatures see: Boukraa, M.; Dayoub, W.; Doutheau, A. Lett. Org. Chem.
2006, 3, 204–206.
O
EtO2C
O
CO2Me
R2
O
10. A referee has suggested an alternative pathway involving hydrolysis of the
ketene to afford a dioxane-2-acetic acid derivative. Subsequent b-elimination
of the dioxolane leads to a hydroxy acid intermediate which can then undergo
cyclisation to give the observed lactone. Whilst we cannot definitively rule out
such a pathway, we note that the lactone products can be observed directly in
the reaction mixture even in the absence of any potential water source, that is,
prior to the addition of the silica gel.
R
R1
R1
R2
O
O
24
25
Scheme 5.