Periselectivity switch of acylketenes in cycloadditions with 1-azadienes: Microwave-assisted diastereoselective domino three-component synthesis of α-spiro-Δ-lactams

Article abstract of DOI:10.1021/ol101938r

The microwave-assisted Wolff rearrangement of cyclic 2-diazo-1,3-diketones in the presence of primary amines and α,β-unsaturated aldehydes provides a straightforward three-component stereoselective access to a variety of α-spiro-Δ-lactams following an imination/Wolff rearrangement/[2 + 4] cycloaddition domino sequence. With aniline derivatives, a complementary aza-Wittig/Wolff rearrangement/[2 + 4] sequence was developed. These reactions feature an unprecedented reactivity of acylketenes as dienophiles in 6π electrocyclic processes.

Full text of DOI:10.1021/ol101938r

ORGANIC
LETTERS
2010
Vol. 12, No. 18
4212-4215
Periselectivity Switch of Acylketenes in
Cycloadditions with 1-Azadienes:
Microwave-Assisted Diastereoselective
Domino Three-Component Synthesis of
r-Spiro-δ-lactams
Marc Presset, Yoann Coquerel,* and Jean Rodriguez*
Institut des Sciences Mole´culaires de Marseille, iSm2-UMR CNRS 6263, Aix-Marseille
UniVersite´, Centre Saint Je´roˆme, SerVice 531, 13397 Marseille cedex 20, France
yoann.coquerel@uniV-cezanne.fr; jean.rodriguez@uniV-cezanne.fr
Received August 17, 2010
ABSTRACT
The microwave-assisted Wolff rearrangement of cyclic 2-diazo-1,3-diketones in the presence of primary amines and r,ꢀ-unsaturated aldehydes
provides a straightforward three-component stereoselective access to a variety of r-spiro-δ-lactams following an imination/Wolff rearrangement/
[2 + 4] cycloaddition domino sequence. With aniline derivatives, a complementary aza-Wittig/Wolff rearrangement/[2 + 4] sequence was
developed. These reactions feature an unprecedented reactivity of acylketenes as dienophiles in 6π electrocyclic processes.
Ketenes1 are excellent partners in cycloaddition reactions.2
For example, their [2 + 2] cycloadditions with imines
(Staudinger reaction)3 or alkenes4 are the most popular routes
to ꢀ-lactams and cyclobutanones, respectively. Ketenes react
preferentially with 1,3-(hetero)dienes to give four-membered
rings following [2 + 2] cycloadditions,5 and there have been
only a few examples of ketenes being good dienophiles in
[4 + 2] cycloadditions.6 Both the [2 + 2] and [4 + 2]
cycloadditions can take place across either the CdC or the
CdO bond of the ketene.7 In cycloadditions involving
acylketenes,8 the situation is somewhat different. In their s-Z
(1) (a) Tidwell, T. T. Ketenes II; John Wiley & Sons: Hoboken, NJ,
2006. (b) Tidwell, T. T. Eur. J. Org. Chem. 2006, 563.
(2) Hyatt, J. A.; Raynolds, P. W. Org. React. 1994, 45, 159.
(3) (a) Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J.
Org. Chem. 1999, 3223. (b) Singh, G. S. Tetrahedron 2003, 59, 7631. (c)
Venturini, A.; Gonza´lez, J. Mini-ReV. Org. Chem. 2006, 3, 185. (d) Brandi,
A.; Cicchi, S.; Cordero, F. M. Chem. ReV. 2008, 108, 3988. (e) Coss´ıo,
F. P.; Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41, 925. (f) Aranda,
M. T.; Perez-Faginas, P.; Gonzalez-Muniz, R. Curr. Org. Chem. 2009, 6,
325.
(6) (a) Brady, W. T.; Shieh, C. H. J. Org. Chem. 1983, 48, 2499. (b)
Moore, H. W.; Hughes, G.; Srinivasachar, K.; Fernandez, M.; Nguyen,
N. V.; Schoon, D.; Tranne, A. J. Org. Chem. 1985, 50, 4231. (c) Elliot,
M. C.; Monk, A. E.; Kruiswijk, E.; Hibbs, D. E.; Jenkins, R. L.; Jones,
D. V. Synlett 1999, 1379. (d) Jayakumar, S.; Singh, P.; Mahajan, M. P.
Tetrahedron 2004, 60, 4315. (e) Kobayashi, S.; Semba, T.; Takahashi, T.;
Yoshida, S.; Dai, K.; Otani, T.; Saito, T. Tetrahedron 2009, 65, 920. (f)
Marton, A.; Paˆrvulescu, L.; Draˇghici, C.; Varga, R. A.; Gheorghiu, M. D.
Tetrahedron 2009, 65, 7504.
(4) (a) Brady, W. T. Tetrahedron 1981, 37, 2949. (b) Bellus, D.; Ernst,
B. Angew. Chem., Int. Ed. 1988, 27, 797.
(7) (a) Yamabe, S.; Dai, T.; Minato, T.; Machiguchi, T.; Hasegawa, T.
J. Am. Chem. Soc. 1996, 118, 6518. (b) Machiguchi, T.; Hasegawa, T.;
Ishiwata, A.; Terashima, S.; Yamabe, S.; Minato, T. J. Am. Chem. Soc.
1999, 121, 4771. (c) Machiguchi, T.; Okamoto, J.; Morita, Y.; Hasegawa,
T.; Yamabe, S.; Minato, T. J. Am. Chem. Soc. 2006, 128, 44. (d) Ussing,
B. R.; Hang, C.; Singleton, D. A. J. Am. Chem. Soc. 2006, 128, 7594.
(5) For examples of application, see: (a) Coquerel, Y.; Greene, A. E.;
Depre´s, J.-P. Org. Lett. 2003, 5, 4453. (b) Carret, S.; Blanc, A.; Coquerel,
Y.; Berthod, M.; Greene, A. E.; Depre´s, J.-P. Angew. Chem., Int. Ed. 2005,
44, 5130.
10.1021/ol101938r  2010 American Chemical Society
Published on Web 08/24/2010

conformation, acylketenes behave almost exclusively as 1,3-
oxadienes in inverse demand hetero-Diels-Alder reactions.9
Examples of [2 + 2] cycloadditions to the ketene function
of acylketenes are rare, and with the exception of their
cyclodimerization, examples of 6π electrocyclic events
involving the CdC bond of acylketenes as dienophiles are
unknown.8 We report herein that under microwave irradiation
in situ generated 1-azadienes10 react smoothly with cyclic
acylketene dienophiles Via [2 + 4] cycloaddition to produce
diastereoselectively a variety of R-spiro-δ-lactams in a single
multiple bond-forming transformation.11,12
We recently became interested in applications of the
microwave-assisted Wolff rearrangement13 of 2-diazo-cy-
cloalkan-1,3-diones as a very convenient source of cyclic
acylketenes,14 notably a three-component approach to 1,3-
oxazin-4-ones involving the in situ formation of the dieno-
philic CdN double bond.14b The projected extension of this
methodology to 2-vinyl-1,3-oxazin-4-ones (e.g., 8a) using
R,ꢀ-unsaturated aldehydes has revealed an unprecedented
periselectivity switch of acylketenes. The microwave irradia-
tion at 140 °C for 15 min of a 1:1:1 mixture of the diazo
compound 1a, benzylamine (2a), and cinnamaldehyde (3a)
unexpectedly furnished the R-spiro-δ-lactam product 4a as
a single diastereomer in 74% yield, resulting from a formal
[2 + 4] cycloaddition between the CdC bond of the
acylketene 5a as dienophile and the 1-azadiene 6a generated
in situ (Scheme 1). As anticipated, the formation of the
believed to involve first the reversible formation of the
zwitterionic intermediates 7exo and 7endo. The second step,
which can be viewed as a reversible six-electron disrotatory
electrocyclization, would lead to the spiro compound 4a from
7exo, whereas the oxazinone 8a would derive from 7endo. From
these considerations, the periselectivity of the reaction, i.e.,
[2 + 4] versus [4 + 2] cyclization, would be determined by
the relative enthalpies of formation of the two compounds
4a and 8a, respectively, with preferential formation of the
former.15 The reversible formation of 2-vinyl-1,3-oxazin-
4-ones 8 as depicted in Scheme 1 was unambiguously
demonstrated: oxazinone 8j obtained as a minor byproduct
when the reaction of entry 9 (Table 1) is performed at 140
°C (Vide infra) was converted into the spiro product 4j
(conversion 100%, isolated yield 25%) together with 2-me-
thylcinnamaldehyde (ca. 20%) and degradation after 15 min
at 160 °C. A 3,3-sigmatropic rearrangement, which could
also account for the conversion of 8j into 4j, is not consistent
with the observed regeneration of the aldehyde under the
reaction conditions.
Spiro compounds are of broad scientific interest due to
their unique chemical and conformational features as well
as the biological properties often associated with the asym-
metric spiro carbon atom. They have attracted considerable
attention from the synthetic community.16 In the case of
complex bioactive molecules containing a spiranic subunit,
it often occurs that simplified analogues retaining essentially
the spiro structural domain exhibit a comparable, and
sometimes better, biological profile as the parent com-
pounds.17 With in mind the application of this new reaction
to the synthesis of hitherto unknown small bioactive R-spiro-
δ-lactam molecules,18 we explored its scope and limits.
Scheme 1
.
Periselectivity Switch of Acylketenes in 6π
Electrocyclizations
(11) For a complementary synthetic approach to R-spirolactams involv-
ing a single multiple-bond forming reaction, see: Boddaert, T.; Coquerel,
Y.; Rodriguez, J. AdV. Synth. Catal. 2009, 351, 1744.
(12) For reviews on multicomponent reactions with 1,3-dicarbonyls, see:
(a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004,
4957. (b) Lie´by-Muller, F.; Simon, C.; Constantieux, T.; Rodriguez, J. QSAR
Comb. Sci. 2006, 5-6, 432. (c) Bonne, D.; Coquerel, Y.; Constantieux, T.;
Rodriguez, J. Tetrahedron: Asymmetry 2010, 21, 1085.
(13) Kirmse, W. Eur. J. Org. Chem. 2002, 2193.
(14) (a) Presset, M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem. 2009,
74, 415. (b) Presset, M.; Coquerel, Y.; Rodriguez, J. Org. Lett. 2009, 11,
5706.
(15) The enthalpies of formation obtained from DFT (B3LYP/6-311G**)
calculations (Gaussian) showed a preference of 9.9 kcal/mol for the
formation of the R-spiro-δ-lactam product 4 over the 2-vinyl-1,3-oxazin-
4-one product 8 from methylamine, aldehyde 3a, and the diazo compound
1c. A full theoretical study (DFT) of the periselectivities in acylketene
cycloadditions is in progress and will be reported in due time.
(16) (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007. (b) Pradhan, R.;
Patra, M.; Behera, A. K.; Mishra, B. K.; Behera, R. K. Tetrahedron 2006,
62, 779. (c) Sinibaldi, M.-E.; Canet, I. Eur. J. Org. Chem. 2008, 4391. (d)
Raju, B. R.; Saikia, A. K. Molecules 2008, 13, 1942. (e) Kotha, S.; Deb,
A. C.; Lahiri, K.; Manivannan, E. Synthesis 2009, 165.
1-azadiene is faster than the formation of the acylketene by
Wolff rearrangement under the reaction conditions, thus
avoiding the nucleophilic addition of the amine to the
acylketene leading to a ꢀ-ketoamide product.14a According
to the stepwise mechanism generally admitted for the
Staudinger reaction, the reaction presented in Scheme 1 is
(17) Nicolaou, K. C.; Wu, T. R.; Sarlah, D.; Shaw, D. M.; Rowcliffe,
E.; Burton, D. R. J. Am. Chem. Soc. 2008, 130, 11114.
(8) (a) Wentrup, C.; Heilmayer, W.; Kollenz, G. Synthesis 1994, 1219.
(b) Kollenz, G.; Ebner, S. In Science of Synthesis: Houben-Weyl Methods
of Molecular Transformations; Danheiser, R., Ed.; Georg Thieme Verlag:
Stuttgart, Germany, 2006, Vol. 23, Chapter 9, pp 271-349. (c) Reber, K. P.;
Tilley, S. D.; Sorensen, E. J. Chem. Soc. ReV. 2009, 38, 3022.
(9) Birney, D. M.; Wagenseller, P. E. J. Am. Chem. Soc. 1994, 116,
6262.
(18) For recent representative examples of de novo biologically active
R-spiro-δ-lactams, see: (a) Craig, C. A. (Merck & Co) WO-A1 2010033421,
2010. (b) Selnick, H. G.; Bell, I. M.; Mcwherter, M.; Staas, D. D.; Stachel,
S. J.; Steele, T.; Stump, C.; Wood, M. R.; Zartman, C. B. (Merck & Co)
WO-A2 2009120652, 2009. (c) Nakagawa, A.; Uno, S.; Makishima, M.;
Miyachi, H.; Hashimoto, Y. Bioorg. Med. Chem. 2008, 16, 7046. (d) Meng,
X.; Maggs, J. L.; Pryde, D. C.; Planken, S.; Jenkins, R. E.; Peakman, T. M.;
Beaumont, K.; Kohl, C.; Park, B. K.; Stachulski, A. V. J. Med. Chem. 2007,
50, 6165.
(10) Groenendaal, B.; Ruijter, E.; Orru, R. V. A. Chem. Commun. 2008,
5474.
Org. Lett., Vol. 12, No. 18, 2010
4213

In the above three-component reaction, the in situ forma-
tion of the 1-azadiene 6a generates water, which can undergo
undesired competitive addition to the acylketene. Thus,
during the optimization process, an alternative one-pot
stepwise protocol was developed involving first the formation
of the 1-azadiene 6a [from 2a + 3a (1:1) in toluene at 140
°C under microwave irradiation for 15 min] and removal of
all volatiles under vacuum,19 followed by addition of the
diazo compound 1a and an additional 15 min of dielectric
heating (see Supporting Information for details). Under these
optimized one-pot conditions, the spiro compound 4a could
be isolated in 99% yield. The reaction was found to be very
general under both conditions (multicomponent or one-pot
stepwise), leading to the spiro products 4 from a variety of
diazo compounds 1, primary amines 2, and R,ꢀ-unsaturated
aldehydes 3 in fair to high yields (Table 1). In the few cases
in which some minor amount of 2-vinyl-1,3-oxazin-4-one 8
was obtained together with the desired spiro compound 4
after 15 min at 140 °C, the reaction temperature was
increased to 160-200 °C to give only the spiro product 4
(entries 5, 9, 14-16). The six- and seven-membered diazo
compounds 1a-d could be used with comparable efficiencies
(entries 2-5). With the chiral acylketene derived from 1b
(entry 3) or an enantiopure primary branched amine (entry
8), a modest chiral induction was observed, but an encourag-
ing diastereoselectivity was obtained in the reaction with (-)-
perillaldehyde (entry 16). Of importance, the reaction proved
highly chemoselective, and functionalized amines containing
a terminal double bond (entries 2-4, 11, 15, and 16) or a
1,3-diene moiety (entries 1, 10, 12, and 14), as well as an
aldehyde containing an extra double bond (entry 15) or a
1,3-diene group (entry 10), could be used without production
of side products resulting from competitive cycloadditions
at these insaturations. These functional groups should prove
useful in further postcondensation reactions.
Table 1. Scope and Limitsa
With aniline derivatives, no spiro product was formed
under both reaction conditions, possibly because of failures
in generating the corresponding imines. This limitation was
bypassed by a consecutive aza-Wittig20/Wolff rearrangement/
[2 + 4] cycloaddition sequence allowing the efficient
synthesis of the desired spirolactams 10 bearing an aryl
substituent at the nitrogen atom (Scheme 2). The reaction
of aryl azides 9 with trimethylphosphine produced the
corresponding phosphazenes, which were directly treated
with 1 equiv of cinnamaldehyde or benzalacetone in the same
reaction vessel and submitted to microwave irradiation to
provide the 1-azadienes. To these materials was added the
diazo compound, still in the same reactor, and the mixture
was submitted again to microwave irradiation to give the
expected spiro compounds 10a-e in modest to good yields.
The structure of 10c was confirmed by X-ray diffraction
analysis. This consecutive sequence was found nicely
complementary to the above-described multicomponent
or one-pot reaction,21 allowing the synthesis of N-aryl-
substituted products, as well as the introduction of an
a Unless stated otherwise, all reactions were performed with 1 equiv of each
reaction partner in anhydrous toluene (0.4 M) at 140 °C in sealed tubes under
microwave irradiation. b Yields for isolated product(s) after silica gel flash
chromatography. MC refers to the multicomponent protocol, and SW refers to the
one-pot stepwise protocol. See Supporting Information for details. c Reaction
performed at 200 °C. d Reaction performed at 160 °C. e The formation of the
1-azadiene was incomplete from 1H NMR analysis.
(19) In this case, the formation of the 1-azadiene was found quantitative
1
by H NMR analysis.
(20) Palacios, F.; Alonso, C.; Aparicio, D.; Rubiales, G.; de los Santos,
J. M. Tetrahedron 2007, 63, 523.
4214
Org. Lett., Vol. 12, No. 18, 2010

(multicomponent, consecutive, or one-pot reactions) from
simple substrates involving an imination (or aza-Wittig)/
Wolff rearrangement/[2 + 4] cycloaddition sequence. These
unprecedented transformations, based on the peculiar reactiv-
ity of acylketenes as dienophiles in [2 + 4] cycloadditions,
nicely combine excellent “economy” (step, atom [waste], raw
material, time and energy) with a broad scope of substrates,
which makes this approach very attractive for the generation
of libraries of synthetically and biologically valuable R-spiro-
δ-lactam compounds. From a more fundamental point of
view, the herein disclosed reactivity of acylketenes as
dienophiles in 6π electrocyclic processes considerably
broadens the scope of their chemistry, and was demonstrated
to result from a thermodynamic control.
Scheme 2
.
Consecutive aza-Wittig/Wolff Rearrangement/
[2 + 4] Cycloaddition Sequence
additional alkyl substituant (R4) on the double bond of the
δ-lactam ring when an R,ꢀ-unsaturated ketone was used in
the aza-Wittig reaction.
Acknowledgment. M.P. thanks the ENS Cachan for a
fellowship award, and we warmly thank Dr. M. Rajzmann
(Aix-Marseille Universite´) for helpful assistance with theo-
retical calculations. Financial support from the French
Research Ministry, the Universite´ Paul Ce´zanne, and the
CNRS is gratefully acknowledged.
In summary, a series of R-spiro-δ-lactams 4 and 10 was
prepared efficiently and with high diastereoselectivity by
microwave-assisted multiple bond-forming transformations
Supporting Information Available: Experimental pro-
cedures and characterization data for all compounds and the
crystallographic data for compound 10c in CIF format. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) For efforts to clarify the terminologies of multiple bond-forming
transformations, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed.
1993, 32, 131. (b) Tietze, L. F. Chem. ReV. 1996, 96, 115. (c) Coquerel,
Y.; Boddaert, T.; Presset, M.; Mailhol, D.; Rodriguez, J. In Ideas in
Chemistry and Molecular Sciences: AdVances in Synthetic Chemistry;
Pignataro, B., Ed.; Wiley-VCH: Weinheim, Germany, 2010; Chapter 9, pp
187-202.
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