Synthetic Exploration of α-Diazo γ-Butyrolactams

Article abstract of DOI:10.1002/ejoc.201900133

DIazo transfer reaction onto γ-butyrolactams (activated by α-ethyloxalylation) gave rare α-diazo γ-butyrolactams. Decomposition of the latter by Rh₂(OAc)₄ in the presence of alcohols and water gave products of O–H insertion of the respective metal-cabene species. Silver triflate (1 mol-%) was found to convert the γ-butyrolactams investigated into 1,5-dihydro-2H-pyrrol-2-ones which represent versatile building blocks. Particular instability was noted for α-diazo γ-butyrolactams bearing alkyl or o-substituted aryl substituents on the nitrogen atom. These were found to dimerize in solution or upon storage at room temperature to give fully conjugated bis-hydrazones along with the loss of a nitrogen molecule.

Full text of DOI:10.1002/ejoc.201900133

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Accepted Article
Title: Synthetic exploration of α-diazo γ-butyrolactams
Authors: Daniil Zhukovsky, Dmitry Dar’in, Grigory Kantin, and Mikhail
Krasavin
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10.1002/ejoc.201900133
European Journal of Organic Chemistry
Synthetic exploration of α-diazo γ-butyrolactams
Daniil Zhukovsky[a], Dmitry Dar’in[a], Grigory Kantin[a] and Mikhail Krasavin*[a]
[a] D. Zhukovsky, Dr. D. Dar’in, Dr. G. Kantin, Prof. Dr. M. Krasavin
Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
E-mail: m.krasavin@spbu.ru
http://www.krasavin-group.org/
Supporting information and ORCID(s) from the author(s) for this article are available on the
WWW under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
ABSTRACT
Diazo transfer reaction onto γ-butyrolactams (activated by -ethyloxalylation) gave rare -diazo
γ-butyrolactams. Decomposition of the latter by Rh2(OAc)4 in the presence of alcohols and water
gave products of O-H insertion of the respective metal-cabene species. Silver triflate (1 mol%)
was found to convert the γ-butyrolactams investigated into 1,5-dihydro-2H-pyrrol-2-ones which
represent versatile building blocks. Particular instability was noted for -diazo γ-butyrolactams
bearing alkyl or o-substituted aryl substituents on the nitrogen atom. These were found to
dimerize in solution or upon storage at room temperature to give fully conjugated bis-hydrazones
along with the loss of a nitrogen molecule.
Introduction
α-Diazo monocarbonyl compounds have attracted considerable attention due to their high
reactivity and wealth of possible synthetic transformations.[1–4] Today, however, certain such
compounds remain poorly explored. In particular, five-membered cyclic diazo monocarbonyl
compounds are only sporadically encountered in the literature. Such compounds – as well as the
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10.1002/ejoc.201900133
European Journal of Organic Chemistry
carbene species generated therefrom – are expected to have higher reactivity compared to their
acyclic analogs. This is due to the ring strain causing, in turn, weaker conjugation of the diazo
function (or the resulting carbene center) to the carbonyl group.[5] The reactivity of such diazo
compounds is illustrated by the reported involvement of α-diazo γ-butyrolactones and α-diazo
cyclopentanones in such classic transition metal-catalyzed reactions as cyclopropanation,[6,7]
cyclopropenation,[8] X-H insertion[9–11] and 1,3-dipolar cycloaddition[12] (Scheme 1).
Scheme 1. Examples of transformations of five-membered cyclic α-diazo monocarbonyl
compounds reported in the literature.
At the same time, the information on the reactivity of α-diazo γ-butyrolactams in the literature is
much more limited. Apart from an isolated example of one such compound described within the
scope of
α-diazo-γ-butyrolactone investigation,[5]
α-diazo γ-butyrolactams have been
reported[13] as obtainable by nitrosation of their α-amino γ-butyrolactam precursors and capable
of undergoing 1,3-dipolar cycloaddition with acetylenedicarboxylate.[14]
Considering this apparent void in the synthetically accessible, well-characterized diversity of -
diazo monocarbonyl compounds – as well as our current interest in exploring novel parts of
druglike chemical space by employing functionalized diazo building blocks – we set off to look
for convenient methods to prepare α-diazo γ-butyrolactams and unravel their synthetic potential.
Herein, we present our preliminary results in this regard.
Results and discussion
Direct transfer of the diazo function onto a lactam moiety can be significantly facilitated by 2-
acylation. While trifluoroacetylation has been reported as a viable means to activate lactams
toward diazotransfer,[5] we turned our attention to -oxalylation reaction. Deacetylative diazo
transfer reaction has been described for -oxalylated cyclic ketones[15] and for lactams, ethyl
oxalylation protocol has also been described in the literature.[16] Oxalylation is a markedly
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10.1002/ejoc.201900133
European Journal of Organic Chemistry
cheaper alternative to the traditionally employed trifluoroacetlation[17,18] or to diazo transfer onto
non-acylated monocarbonyl substrates which requires the use of strong bases such LDA[19,20] or
NaHMDS.[21] To our delight, -oxalylation of lactams 1 worked rather well according to the
literature protocol[17] and delivered target -oxalyl derivatives 2 in generally good yields
(Scheme 2).
Scheme 2. -Oxalylation of lactams 1a-j.
Diazo transfer onto substrates 2a-j was achieved using the conventional protocol employing 4-
nitrobenzenesulfonyl azide and DBU[22,23] (Scheme 3). -Diazo lactams 3a-j were all found
unstable to isolation on silica gel (vide infra) and therefore were isolated by column
chromatography on neutral alumina.
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10.1002/ejoc.201900133
European Journal of Organic Chemistry
Scheme 3. Preparation of -diazo lactams 3a-j.
a compounds were insufficiently stable to allow for full characterization.
13
All synthesized compounds were characterized by NMR spectroscopy. However, the C NMR
spectra of compounds 3a-d not be obtained as at concentrations typically used for recording 13C
NMR spectra, these compounds dimerized to give respective bis-hydrazones 4a-d. Bis-
hydrazones 4b and 4d were isolated and their structure was confirmed by analytical data. Such
dimerization of diazo compounds is a known pathway[24,25] accompanied by the loss of a
nitrogen molecule (Scheme 4). Dimerization also took place while storing there compounds in
the neat form; in this case, the oil-like compounds 3a-d visibly solidified over time to form
crystalline bis-hydrazones 4a-d.
Interestingly, instability toward dimerization appears to be characteristic only for N-alkyl (3a-c)
or o-substituted N-aryl (3d) -diazo lactams. Their N-phenyl counterpart (3e) was found to
remain intact in boiling acetone over 3 h. Likewise, all other -diazo lactams 3e-j were found
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10.1002/ejoc.201900133
European Journal of Organic Chemistry
stable to storage at 4 ºC over several months. This difference in stability can be rationalized by
the weaker electron-withdrawing character of the carbonyl group in 3a-d due to greater basicity
of the lactam nitrogen for electronic (3a-c) or steric (3d) reasons (cf. unstable 3d to its stable p-
substituted isomer 3g), which has the observed overall destabilizing effect.
Scheme 4. Observed dimerization of -diazo lactams 3b and 3d
The instability of -diazo -butyrolactams toward isolation on silica gel was noted above. The
main decomposition product was identified as respective 3-pyrrolin-2-one, presumably formed
on decomposition of the diazo function into the respective carbene followed by 1,2-hydride shift
(as reported for -diazocarbonyl compounds under transition metal catalysis).[26] Alternatively,
this transformation may proceed via protonation of the -diazocarbonyl moiety followed by
elimination of a nitrogen molecule. 3-Pyrrolin-2-ones are versatile substrates for addition of
organometallic compounds,[27–30] Michael addition[31–33] and 1,3-dipolar cycloaddition.[34–36] At
the same time, the principal methods employed in their preparation are olefin metathesis[37–39]
and oxidative elimination of -phenylselenyl lactams.[40-41] We reasoned that the discovered
facile formation of 3-pyrrolin-2-ones from -diazo--butyrolactams could be viewed, in
principle, as an alternative method of preparation of these important building blocks.
Brief screening of catalysts capable of causing the conversion of 3e into its 3-pyrrolin-2-one
counterpart (5e) revealed AgOTf (1 mol %) being the most appropriate catalyst for this
transformation (Table 1).
Table 1. Optimization of the 1,2-hydride shift reaction conditions
№
Catalyst
Time
Conversion, %a
Yield, %a
1
2
Silica, 500 % wt.
TFA, 10 mol %
16 h
100
100
45
41
10 min
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10.1002/ejoc.201900133
European Journal of Organic Chemistry
3
4
Ag2O, 10 mol %
AgOTf, 1 mol %
24 h
40
100b
100
10 min
100
a Yield and conversion were determined by 1H NMR spectroscopy.
b Yield calculated based on incomplete conversion.
The newly optimized conditions were applied to the preparation of a short array of 1-aryl 3-
pyrrolin-2-ones 5e-j all of which were obtained in nearly quantitative yield (Scheme 5).
Scheme 5. Preparation of pyrrolinones
Having established (and, to some degree, exploited) the limits of stability of the newly
synthesized -diazo--butyrolactams 3, we were keen to explore their performance in the
reaction of insertion of the respective metal cabene species into O-H bonds, which are typical
reactions of -diazo carbonyl compounds catalyzed, in particular, by dirhodium tetraacetate[40–
[44,45]
43]. It should be noted that BF3∙OEt2, another common catalyst for such transformations
,
was not found applicable in this case as it rapidly converted lactams 3 into 3-pyrrolin-2-ones 5.
The Rh2(OAc)4-catalyzed reaction of -diazo -butyrolactams 3e-j with a range of aliphatic
alcohols (as well as water) indeed proved to be rather facile an high-yielding, except for the
sterically demanding tert-butyl alcohol which gave no desired product 6g. Less sterically
demanding yet still bulky cyclohexanone gave respective O-H insertion product 6h in noticeably
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European Journal of Organic Chemistry
modest yield. Notably, reaction with CD3OD led to the introduction of the four deuterium atoms
into the product molecule (6c) which can be rationalized by the initial oxonium ylide formation
followed by 1,2-deuterium shift (Scheme 6).
Scheme 6. Rh2(OAc)4-catalyzed O-H insertion reactions of -diazo -butyrolactams 3c-j.
a acetone was used as a solvent
b RʹOH was used as a solvent
c dichloromethane was used as a solvent
Conclusion
In this Communication, we described a facile preparation of a series of -diazo -butyrolactams
by direct deacylative diazo transfer onto N-substituted -butyrolactams activated by -
oxalylation. The products obtained differ in stability, where N-aryl -diazo--butyrolactams (in
which the basicity of the lactam nitrogen is likely reduced) are much more stable compared to
their counterparts carrying an alkyl or an o-substituted aryl group on the nitrogen atom. The
latter decompose via dimerization accompanied by extrusion of a nitrogen molecule. Even the
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European Journal of Organic Chemistry
stable N-aryl -diazo -butyrolactams were found to rapidly convert into 3-pyrrolen-2-ones; this
nearly quantitative transformation can be used for preparation of these versatile building blocks.
Rh(II)-catalyzed decomposition of N-aryl -diazo -butyrolactams in presence of aliphatic
alcohols and water at room temperature leads to rapid and high-yielding O-H insertion reaction
which is typical of diazo compound reaction toolkit. These findings expand the current toolbox
of -diazo monocarbonyl compounds into druglike lactam scaffold space.
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, analytical data, copies of the 1H and 13C NMR spectra.
AUTHOR INFORMATION
Corresponding Author
* E-mail: m.krasavin@spbu.ru.
ORCID
Dmitry Dar’in: 0000-0002-0413-7413
Mikhail Krasavin: 0000-0002-0200-4772.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Foundation for Basic Research (project grant 19-03-
00775). We thank Research Centre for Magnetic Resonance and the Center for Chemical
Analysis and Materials Research of Saint Petersburg State University Research Park for
obtaining the analytical data.
KEYWORDS: -diazo lactams, 3-pyrrolen-2-ones, 1,2-hydride shift, diazo transfer reaction, O-
H insertion, γ-butyrolactams.
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