One-step synthesis of nitrogen-containing medium-sized rings via α-imino diazo intermediates

Article abstract of DOI:10.1021/ol5012532

Eight- and 9-membered dioxazocines and dioxazonines are readily synthesized starting from N-sulfonyl-1,2,3-triazoles in a single-step procedure. A perfect regioselectivity and generally good yields (up to 92%) are obtained under dirhodium catalysis using

Full text of DOI:10.1021/ol5012532

Letter
pubs.acs.org/OrgLett
One-Step Synthesis of Nitrogen-Containing Medium-Sized Rings via
α‑Imino Diazo Intermediates
Florian Medina,† Celine Besnard,‡ and Jerome Lacour*,†
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́
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†Department of Organic Chemistry, University of Geneva, 30 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
‡Laboratory of Crystallography, University of Geneva, 24 Quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
S
* Supporting Information
ABSTRACT: Eight- and 9-membered dioxazocines and dioxazonines are readily
synthesized starting from N-sulfonyl-1,2,3-triazoles in a single-step procedure. A
perfect regioselectivity and generally good yields (up to 92%) are obtained under
dirhodium catalysis using 1,3-dioxolane and 1,3-dioxane as solvents and reagents.
1,2,3-Triazoles are important building blocks used routinely in
synthetic, biological, and medicinal chemistry.1 These com-
pounds are readily accessible through Huisgen 1,3-dipolar
cycloaddition reactions.2 Previously, it was shown that N-
sulfonyl derivatives of type 1, prepared from sulfonyl azides and
terminal alkynes, decompose under thermal and/or metal-
catalyzed conditions to afford electrophilic α-imino carbenes
(e.g., 2, Scheme 1, eq 1).3,4 These intermediates undergo many
isolated (22%). This result raised our interest as the direct
formation of medium-sized rings is not a trivial matter.8,9 In
addition, it has been shown that α-carbonyl analogues of
intermediates 2 react with THF to form macrocycles rather
than 8-membered rings.10,11 It was then debatable whether a
general medium-size ring synthesis could be achieved using N-
sulfonyl-1,2,3-triazoles 1 and cyclic ethers; other reactants such
as acetals being possibly better reactive partners for the
formation of the 8- and 9-membered rings.12
Care was first taken to reproduce the THF insertion reaction
in the absence of benzonitrile.7b A series of N-sulfonyltriazoles
was prepared following a copper-catalyzed procedure.13 It was
found that compounds 1 are quite sensitive to light and/or
acidic conditions.14 Compound 1b (R = Ph, R′ = p-BrC6H4)
was more stable than others, and it was thus chosen for the
initial trials using a catalytic amount of Rh2(OAc)4 (1 mol %,
Scheme 2). High temperature (100 °C) was necessary to
Scheme 1. Medium-Sized Ring Formation
Scheme 2. Reactivity of Triazole 1b in the Presence of THF
interesting and original processes, from cyclopropanations to
ylide forming reactions and subsequent transformations.5,6
Herein, in a new development in this field, reactions of sulfonyl
triazoles 1 with 1,3-dioxolane and 1,3-dioxane in the presence
of Rh2(OAc)4 (1 or 2 mol %), are shown to generate
unprecedented 8- and 9-membered dioxazocine and dioxazo-
nine adducts. These medium-sized rings 3 and 4 are formed in
generally good yields (up to 92%) and with a perfect
regioselectivity.
As just mentioned, it is known that α-imino carbenes 2 react
with Lewis bases to form reactive ylide intermediates that
undergo further reactions including intermolecular condensa-
tions.6i,7 For instance, when treated with nitriles, intermediates
2 react and form 1,3-imidazoles 5 in good yields and excellent
selectivity (Scheme 1, eq 2).7b Interestingly, when the reaction
was carried with triazole 1a and PhCN in THF as solvent, 8-
membered oxazocine 6a derived from THF insertion was
Received: May 1, 2014
© XXXX American Chemical Society
A
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Letter
achieve full conversion within 5 h. A single product 6b was
identified and isolated (41% yield). While satisfactory, this
result led us to notice a sensitivity of compounds 6 to
purification conditions; extended contact time on chromato-
graphic phases leading to a rearrangement of products 6 into
derivatives of type 7 (Scheme 2). In view of this intrinsic
liability, it was decided to find an alternative reactivity that
would still afford 8- and 9-membered heterocycles but with
better yields and overall stability. Recently, it was shown that α-
diazo-β-ketoesters react in the presence of catalytic amounts of
Rh2(OAc)4 with cyclic acetals to form trioxocines and
trioxonines.12 These medium-sized rings were obtained in
generally good yields (up to 90%) and displayed a surprisingly
high stability. In view of this precedent, the reactivity of N-
sulfonyl triazoles 1 with 1,3-dioxolane and 1,3-dioxane was
considered.
Figure 1. Anisotropic displacement ellipsoids plot of the crystal
structure of 3b. Thermal ellipsoids are drawn at 50% probability.
this result in hand, the influence of the sulfonyl group on the
reactivity was investigated. Triazole 1c carrying also an
electron-withdrawing group (R′ = p-NO2C6H4, Scheme 3)
was found to react under the same conditions and afforded
desired product 3c; the moderate solubility of 1c in 1,3-
dioxolane being probably the reason for the moderate yield
(64%). Triazoles with donating groups on the sulfonyl moiety
were also tested. Substrates 1a, 1d, 1e, 1f, and 1g were all
reactive, and reactions proceeded generally well (76−85%
yields). Clearly, steric hindrance does not perturb the reactivity
as products 3e and 3f were obtained in 77 and 85% yields,
respectively (R′ = mesityl, 1-naphthyl). The phenyl group at
carbon-4 of triazoles 1 was also modified. Substrates 1h, 1i, and
1j afforded the corresponding products in good to excellent
yields (78−91%); the nature of the substituent (Me, CF3) on
the aromatic moiety or the presence of a vinylic group have
little influence on the outcome.
Then, reactions with 1a−j were repeated in dry 1,3-dioxane
as solvent to afford products of type 4 (Scheme 4). It was,
however, necessary to modify the protocol in some cases. In
fact, some of the 9-membered dioxazonine adducts seemed
unstable under the reaction conditions, decomposing to some
extent before full conversion of the triazole substrates. In these
instances noted in Scheme 4, care was taken to shorten the
reaction time by increasing the catalyst loading to 2 mol %.
Then, products 4 were generally obtained in good yields (81−
86%). A poorer reactivity was however noticed in the case of 4b
and 4c carrying electron-withdrawing groups (73 and 59%,
respectively). Also, even after adjusting the reaction conditions,
it was not possible to isolate product 4j (Scheme 4).
In practice, after a few experiments made to determine the
optimal conditions (see the Supporting Information), reactions
were performed in dry 1,3-dioxolane as solvent by treatment of
solutions of triazoles 1 (1.0 equiv) with Rh2(OAc)4 (1 mol %)
(Scheme 3).15,16 Complete consumption of 1b was again
achieved in 5 h at 100 °C. Analysis of the reaction mixture
indicated the formation of one major product (3b, 92%). Based
1
on detailed H, 13C, and IR analyses, only an original cyclic
dioxazocine structure was consistent with the data, the motif
being confirmed by X-ray diffraction studies (Figure 1). With
a
Scheme 3. Eight-Membered Dioxazocine Synthesis
A mechanistic rationale coherent with the above-detailed
experimental results is proposed in Scheme 5.12 Most likely, as
detailed in the introduction, the reaction pathway involves the
generation of electrophilic α-imino carbenes of type 2 (Scheme
5). Nucleophilic attack of an oxygen atom from the cyclic
acetals generates the corresponding oxonium ylide of type 8.
Then, the lone-pair of the unbound oxygen atom provokes an
opening of the acetal ring leading to the formation of
unsaturated oxocarbenium ions of type 9. This intermediate 9
is then ideally suited to undergo favored 8- or 9-endo-trig
cyclization reactions responsible for the formation of the
medium-sized products.17,18 In addition, this rationale explains
the regiochemistry and the perfect selectivity; ring-opening and
-closing reactions always occur after the ylide formation at the
acetal carbon preferentially.
With this rationale in mind, reactions were performed with
unsymmetrical 4-methyl-1,3-dioxane 10 and 4-methyl-1,3-
dioxolane 11; the extra methyl group leading possibly to
1
regioisomers (Scheme 6). Interestingly, with 10 as solvent, H
NMR analysis of the crude reaction mixture indicated the
exclusive formation of a single regioisomer 12b1, which was
isolated in good yield (79%). Its structure was assigned by
a
All yields correspond to isolated yields.
B
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Letter
a
Scheme 4. Nine-Membered Dioxazonine Synthesis
Scheme 6. Reactions with Unsymmetrical Acetals
respectively. The structures were assigned by NMR spectros-
copy, and in the case of 13b1, the attribution was confirmed by
X-ray analysis (see Figure S1, Supporting Information).
Finally, to gather further information on the reactivity and
develop an even better understanding, two 4-alkyl-N-sulfonyl-
triazoles 1k (R = t-butyl) and 1l (R = n-butyl) were prepared
and tested with 1,3-dioxolane as solvent (Scheme 7). In line
Scheme 7. Reactivity of the 4-Alkyl-N-sulfonyl-1,2,3-triazoles
a
b
All yields correspond to isolated yields. Reaction performed with 2
mol % of Rh2(OAc)4 instead.
Scheme 5. Mechanistic Rationale
with literature precedents,20 substrate 1k did not afford the 8-
membered heterocycle but only product 14 of 1,2-methyl shift
(87% yield, Scheme 7). Gratifyingly, crude NMR analysis of the
reaction involving 1l showed the presence of both the product
of 1,2-hydride shift 15 but also this time of dioxazocine 3l in a
1:2 ratio (Scheme 7). Purification of the crude afforded
however only a small amount of 3l (9%). These reactions thus
confirm the existence of rapid alkyl and hydride shifts21 when
the N-sulfonyltriazoles are substituted with alkyl groups and
treated with Rh2(OAc)4. Clearly, with the α-imino carbene
derived from 1l, the intramolecular shift (→15) is less favored
than the intermolecular attack from dioxolane (→3l). With the
carbene derived from 1k, the steric hindrance of the tert-butyl
group favors the intramolecular process as only product 14 can
be detected.
In conclusion, the one-pot synthesis of nitrogen-containing
8- and 9-membered dioxazocines and dioxazonines has been
achieved under dirhodium catalysis using N-sulfonyl-1,2,3-
triazoles as substrates. Perfect regioselectivity was noticed for
the medium-size ring formation that can be explained by a clear
mechanistic rationale. It was, however, shown that only 4-aryl
(and 4-vinyl) triazoles are directly amenable for this trans-
formation.
NMR spectroscopy. This result indicates that the less hindered
oxygen atom (without the adjacent methyl substituent) reacts
first with the carbene 2.19 The second O atom, next to the
methyl group, then helps generate the electrophilic oxocarbe-
nium intermediate of type 9 that is trapped to form the product
with the observed regioselectivity. With 4-methyl-1,3-dioxolane
11, the situation was less favorable as a 2:1 mixture of
regioisomers was obtained. Adducts 13b1 and 13b2 were
isolated by flash chromatography in 54% and 26% yields,
C
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(d) Yadagiri, D.; Anbarasan, P. Chem.Eur. J. 2013, 19, 15115−
15119. (e) Miura, T.; Tanaka, T.; Yada, A.; Murakami, M. Chem. Lett.
2013, 42, 1308−1310. (f) Jung, D. J.; Jeon, H. J.; Kim, J. H.; Kim, Y.;
Lee, S.-g. Org. Lett. 2014, 16, 2208−2211.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
(9) According to Baldwin’s rule, the formation of 6a from the
corresponding ylide intermediate should be disfavored as it involves in
its most direct pathway an intramolecular 5-endo-tet cyclization. See
the discussion in refs 11 and 12.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jerome.lacour@unige.ch.
Notes
(10) (a) Cenini, S.; Cravotto, G.; Giovenzana, G. B.; Palmisano, G.;
Tollari, S. Tetrahedron 1999, 55, 6577−6584. (b) Zeghida, W.;
Besnard, C.; Lacour, J. Angew. Chem., Int. Ed. 2010, 49, 7253−7256.
The authors declare no competing financial interest.
(c) Vishe, M.; Hrdina, R.; Guen
Synth. Catal. 2013, 355, 3161−3169.
́ ́
ee, L.; Besnard, C.; Lacour, J. Adv.
ACKNOWLEDGMENTS
■
(11) Macrocyclization reactions are also observed using Pd(II)
catalysts with diazocarbonyles in THF; see: Kitamura, M.; Kisanuki,
M.; Kanemura, K.; Okauchi, T. Org. Lett. 2014, 16, 1554−1557.
(12) Ballesteros-Garrido, R.; Rix, D.; Besnard, C.; Lacour, J. Chem.
Eur. J. 2012, 18, 6626−6631.
We thank the University of Geneva and the Swiss National
Science Foundation for financial support. We acknowledge the
contributions of the Sciences Mass Spectrometry (SMS)
platform at the Faculty of Sciences, University of Geneva.
(13) Raushel, J.; Fokin, V. V. Org. Lett. 2010, 12, 4952−4955.
(14) Adducts 1 are however stable for months when stored in the
dark at 4 °C.
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