Synthesis with perfect atom economy: Generation of diazo ketones by 1,3-dipolar cycloaddition of nitrous oxide at cyclic alkynes under mild conditions

Article abstract of DOI:10.1002/anie.201101326

A cascade of five steps, transforms cyclooctynes in the presence of nucleophiles NuH and nitrous oxide, into the depicted products (see scheme). In another example, nitrous oxide was added at a cycloalkyne at -25 °C to generate the corresponding diazo ket

Full text of DOI:10.1002/anie.201101326

DOI: 10.1002/anie.201101326
Nitrogen Heterocycles
Synthesis with Perfect Atom Economy: Generation of Diazo Ketones
by 1,3-Dipolar Cycloaddition of Nitrous Oxide at Cyclic Alkynes under
Mild Conditions**
Klaus Banert* and Oliver Plefka
In memory of Adolf Krebs
conditions. By using these processes in the range ꢀ258C to
Nitrous oxide is well-known as cheap nontoxic gas utilized not
only in medicine and food technology but also as oxidizing
reagent,[1,2] for example, in the transformation of benzene
derivatives into phenols[1,3] and in the epoxidation of olefins.[4]
In some other selective oxidation processes, such as the
synthesis of cyclohexanone from cyclohexene and nitrous
oxide,[5] a 1,3-dipolar cycloaddition at alkenes 1a to generate
short-lived 4,5-dihydro-1,2,3-oxadiazoles 2a was postulated
to explain the final products 5a (Scheme 1).[6] Intermediates
2a and 3a are also plausible when Wagner–Meerwein
rearrangement to yield 6a or cleavage into 7a and 8a
followed by formation of cyclopropane 9a via the corre-
sponding carbene was observed.[5a,7] In the case of alkynes 1b,
treatment with nitrous oxide should lead to 1,2,3-oxadiazoles
2b and diazo carbonyl compound 3b.[8] Under the reaction
conditions, most probably, ketenes 4b were produced by
Wolff rearrangement and isolated as dimers or trapped by
nucleophilic addition of water, alcohols, or amines.[9] All these
results indicated that nitrous oxide acted in cycloaddition
reactions as a 1,3-dipole of the diazonium betaine type, based
on Huisgenꢀs classification.[10] This mechanistic interpretation
was also supported by quantum chemical calculations.[7e,11]
However, the very low reactivity of nitrous oxide, which
required drastic, potentially dangerous, and technically
demanding reaction conditions,[5a,7a,9] did not allow nitrogen-
containing products, such as 2, 3, or 8a, to be detected.
Herein, we show that the addition of nitrous oxide at
cyclic alkynes to generate diazo ketones is possible under mild
ambient temperature, the first sequential products containing
all three atoms of nitrous oxide are be prepared.
A slow reaction leading to ester 12[12] in 77% yield was
observed when we treated a solution of the cycloalkyne 10[13]
in methanol with nitrous oxide (50 bar)[14] at room temper-
ature (Scheme 2). We assume that diazo ketone 11 was
formed by strain-promoted 1,3-dipolar cycloaddition and
subsequent ring opening of the corresponding 1,2,3-oxadia-
zole. However, the intermediate 11 clearly underwent a rapid
Wolff rearrangement to produce the ring-contracted ketene,
which was trapped by the nucleophilic addition of methanol
to afford 12. Thus, we were not able to detect 11 directly.
Surprisingly, the stability of 11 seems to be lower than that of
20a, which is in contrast to the properties of other cyclic a-
diazo ketones with adjacent benzo units.[15] The cycloheptyne
derivative 13, first synthesized by Krebs et al.,[16] proved to be
even more reactive. Substrate 13 was consumed within less
than 60 min if subjected to an excess of nitrous oxide (50 bar)
in chloroform at ambient temperature. When this trans-
formation was performed at ꢀ258C, the diazo compound 14
was obtained in 95% yield and could be analyzed at the same
1
temperature by H and 13C NMR spectroscopy for the first
time. If the solution of 14 was warmed to room temperature,
the known ketene 15,[16b,17] diketone 16,[16,17] and the re-
arrangement product 17[16b,17] were formed rapidly as the main
products.[18] Previously, diazo ketone 14 was generated only
in situ owing to its low stability, which was explained by the
conformation of the seven-membered ring that excludes
resonance stabilization because the diazo and carbonyl
functions are orthogonal to one another.[17,19]
When cyclooctyne (18a)[20] or cycloocten-5-yne (18b)[21]
were treated with nitrous oxide in the presence of nucleo-
philes NuH, the reaction sequences did not stop at diazo
ketones 20 and did not precede via ketenes of type 4b
(Scheme 3).[22] Instead we obtained the stable products 19,
which clearly include two molecules of 18, all three atoms of
nitrous oxide, and the nucleophile NuH. Most probably, after
cycloaddition of nitrous oxide and ring opening, the corre-
sponding diazo compounds 20 very rapidly[23] underwent
another 1,3-dipolar cycloaddition to bring about short-lived
3H-pyrazoles 21 that isomerized to the aromatic heterocycles
22 by 1,5-acyl migration.[24] Finally, nucleophilic attack should
lead from 22 to esters and amides of type 19. Polycyclic 1-acyl-
1H-pyrazoles react easily with alcohols or amines to yield the
corresponding acylated products,[25] and some of them are
highly sensitive to hydrolysis.[24] Nevertheless we isolated the
[*] Prof. Dr. K. Banert, O. Plefka
Chemnitz University of Technology, Organic Chemistry
Strasse der Nationen 62, 09111 Chemnitz (Germany)
Fax: (+49)371-531-21229
E-mail: klaus.banert@chemie.tu-chemnitz.de
Homepage: http://www.tu-chemnitz.de/chemie/org/indexe.html
[**] We gratefully acknowledge financial support from the Deutsche
Forschungsgemeinschaft (BA 903/10-3). O.P. thanks the Studen-
tenwerk Chemnitz–Zwickau for a fellowship of the Freistaat
Sachsen. We are grateful to Dr. M. Hagedorn for experimental
support and assistance with the manuscript. Prof. A. Krebs and
Prof. H. Detert gave us highly useful tips for the synthesis of
cycloalkynes. We thank Prof. M. Oestreich for support with the MS
experiments. Strained Rings, Part 2; for Part 1, see: M. Al-Omari, K.
Banert, M. Hagedorn, Angew. Chem. 2006, 118, 315–317; Angew.
Chem. Int. Ed. 2006, 45, 309–311.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201101326.
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Communications
Scheme 1. Postulated 1,3-dipolar cycloaddition of nitrous oxide at alkenes 1a or alkynes 1b and the corresponding secondary reactions.
with moisture, for exam-
ple, in an attempt at pu-
rification by chromatogra-
phy, 22a was hydrolyzed
to the corresponding 7-
(pyrazol-3-yl)heptanoic
acid.
We assumed that the
first step in the formation
of diazo ketones, such as
20, is rate-determining
and that the rate of this
cycloaddition process to
generate 1,2,3-oxadiazoles
Scheme 2. Reactions of cycloalkynes 10 and 13 with nitrous oxide.
can be strongly influenced
by substituents in posi-
tion 3 of 18a. Thus, we treated the cycloalkynes
23a[27,28] and 23b[29] with nitrous oxide in the presence
of nucleophiles, such as methanol and aniline
(Scheme 4). Both substrates 23 are significantly less
reactive than the parent compound 18a. However, the
reactivity of 23a, bearing a weak acceptor substituent
(CHOMe) at the triple bond, is less than that of 23b
which has the more bulky isopropyl group. This outcome
indicates that sterically demanding as well as electron-
withdrawing substituents decrease the rate of the cyclo-
addition step. This effect of electron-withdrawing sub-
stituents, observable in the case of acceptor-substituted
alkynes, was predicted by quantum chemical calcula-
tions.[11b,d] The diazo ketone, resulting from cycloaddi-
tion of nitrous oxide at 23b followed by ring opening,
underwent Wolff rearrangement via the corresponding
ketene, and led to the expected amide 27b, which does
not give any information on the regiochemistry of the
first step. Surprisingly, 23a did not yield a ring-con-
tracted ester, and 26a was formed instead. In a control
experiment with 23a in methanol (air, 55 bar, 608C),
generation of 26a without nitrous oxide was ruled out. Thus,
we suggest that 26a was produced from 23a via the hetero-
cycle 24a and the carbene 25a, which isomerized to 26a by
hydrogen shift. The regiochemistry of the postulated cyclo-
addition reaction 23a!24a seems to be compatible with
Scheme 3. Cascade reactions of cycloalkynes 18 with nitrous oxide.
tricyclic compound 22a after treatment of 18a with nitrous
oxide (50 bar) in solvents such as dichloromethane, chloro-
form, or tetrachloromethane, at ambient temperature. The
same 1-acyl-1H-pyrazole was also formed when 18a was
subjected to 20a[26] in chloroform. However, after contact
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Scheme 4. Reactions of substituted cyclooctynes 23 with nitrous oxide.
quantum chemical calculations.[11i] However, these calcula-
tions include p-electron-withdrawing substituted alkynes
instead of acetylenes with substituents showing an electron-
accepting inductive effect.
In summary, we have found convincing evidence that
treatment of alkynes with nitrous oxide precedes via 1,3-
dipolar cycloaddition and subsequent ring opening to give
diazo ketones, which can be analyzed in one special case or
utilized in cascade reactions to synthesize pyrazole deriva-
tives with perfect atom economy.
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Received: February 22, 2011
Published online: May 25, 2011
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Keywords: cascade reactions · nitrogen heterocycles ·
.
reaction mechanisms · rearrangements · strained compounds
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