Zinc mediated direct transformation of propargyl N-hydroxylamines to α,β-unsaturated ketones and mechanistic insight

Article abstract of DOI:10.1016/j.tetlet.2017.01.045

A Lewis acid catalyzed direct transformation of propargyl N-hydroxylamines to α,β-unsaturated ketones in the presence of aqueous Zn(II)-salts has been described. This investigation also provides a novel observation for the stoichiometric role of Zn-halides over what is known to date for catalytic processes. A thorough mechanistic study has been established based on the experiment using¹⁸O-labeled water in optimized reaction conditions; the incorporation of¹⁸O in the desired product was also substantiated by HRMS. This methodology is also a mild, inexpensive, and an efficient approach for this unusual conversion.

Full text of DOI:10.1016/j.tetlet.2017.01.045

Accepted Manuscript
Zinc Mediated Direct Transformation of Propargyl N-hydroxylamines to α,β-
Unsaturated Ketones and Mechanistic Insight
Prasanta Das, Ashton T. Hamme II
PII:
S0040-4039(17)30068-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.01.045
TETL 48548
Reference:
Tetrahedron Letters
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10 January 2017
13 January 2017
Please cite this article as: Das, P., Hamme, A.T. II, Zinc Mediated Direct Transformation of Propargyl N-
hydroxylamines to α,β-Unsaturated Ketones and Mechanistic Insight, Tetrahedron Letters (2017), doi: http://
dx.doi.org/10.1016/j.tetlet.2017.01.045
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Zinc Mediated Direct Transformation of Propargyl
N-hydroxylamines to α,β Unsaturated Ketones and
Mechanistic Insight
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Prasanta Das a, and Ashton T. Hamme IIa,

1
Tetrahedron Letters
Zinc Mediated Direct Transformation of Propargyl N-hydroxylamines to α,β-
Unsaturated Ketones and Mechanistic Insight
Prasanta Dasa,* and Ashton T. Hamme II a, 
a Department of Chemistry & Biochemistry, Jackson State University 1400 J. R. Lynch St, PO Box 17910, Jackson, Ms 39217, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A Lewis acid catalyzed direct transformation of propargyl N-hydroxylamines to α,β-unsaturated
ketones in the presence of aqueous Zn(II)-salts has been described. This investigation also
provides a novel observation for the stoichiometric role of Zn-halides over what is known to
date for catalytic processes. A thorough mechanistic study has been established based on the
experiment using 18O-labeled water in optimized reaction conditions; the incorporation of 18O in
the desired product was also substantiated by HRMS. This methodology is also a mild,
inexpensive, and an efficient approach for this unusual conversion.
Available online
Keywords:
Zinc
Propargyl hydroxylamines
α,β Unsaturated ketones
Mechanistic insight
2009 Elsevier Ltd. All rights reserved.
Since the first discovery in 19111 and further development in
various nucleophilic additions to nitrones,2 propargyl hydroxyl
amines have been understood to be a key milestone in organic
synthesis.3 The C-C triple bond adjacent to N-hydroxylamine
facilitated its versatile modes of action (e.g. oxidative cleavage,4
reduction,5 hydrogenation,6 hydroboration, and cyclization7) to a
wide number of synthetically useful building blocks including
amino acids, isoxazolines, amines, keto-amines, and lactams.
These versatility natures of propargyl hydroxylamines have also
stimulated great interest in discovering its new chemical
transformation. In this direction, Zn(II) based catalysts have been
exploited significantly to promote a broad range of organic
transformations due to its mild reactivity, abundance,
affordability, and environmental friendliness. Most interestingly,
Carreira et al. have demonstrated the catalytic role of Zn(II)-salts
for the transformation of propargyl hydroxyl amines to the
corresponding isoxazolines.7
corporation of 18O-isotope was observed in the desired products.
As several mechanistic pathways have been proposed thus far, a
comprehensive mechanistic understanding is highly warranted.
In earlier report, the N-methyl-4-isoxazolinium, a quaternized
salt of neutral isoxazolines are known to undergo a base mediated
transformation to its enamino ketones and enones through a
deprotonation of 5-CH2 and N-methyl respectively.8 Later a
related observation by Hermecz et al9 described that a tertiary
propargylamine N-oxide undergoes a facile thermal concerted
[2,3] sigmatropic10 transformation in aprotic media (CCl4, THF,
and CH2Cl2) to an intermediate O-propadienyl hydroxylamine
which subsequently underwent a facile1,5 hydrogen shift to
furnish the N-benzylidenemethylamine and propenal. According
Scheme 1. Unusual transformation of propargyl N-hydroxylamines
to α,β-unsaturated ketones.
We herein report a novel and mild behavior of zinc salts for
the aforesaid transformation. It is also important to note that this
is an inexpensive, alternative, and an efficient approach for this
unusual conversion. To the best of our knowledge, other than
what is known in Scheme 1, a similar transformation of either
to this report, even after heating with 18O-labeled water, no in-
———
 Corresponding author. Tel.: +1-601-979-2174; fax: +1-601-979-3674.
e-mail: ashton.t.hamme@jsums.edu ( A.T. Hamme), prasanta.das@jsums.edu (P. Das).

2
Tetrahedron Letters
propargyl hydroxylamine or its isoxazoline intermediate
zinc halides have a higher propensity to manifest this unusual
transformation over other zinc salts. Based on the NMR ratio
between major/minor products and the corresponding isolated
yields, it is also obvious that ZnI2 is better than other halides
(ZnCl2 and ZnBr2). Further reaction of 1 with Zn(OAc)2.2H2O
and Zn(NO3)2.6H2O produced the required compound 2 as the
major product in 27% and 20% yields respectively after 24h of
reflux (entries 4 and 9, Table 1). In case of Zn(OH)2,
Zn(SO4)2.7H2O, and ZnO, we isolated compound 2 along with
compound 3 in a 1:1 ratio from trace to 50% yields, and we also
recovered the starting material in most of the cases. Particularly,
when Zn(ClO4)2.6H2O was employed as a catalyst, no trace of
compound 2 or 3 was isolated, instead, decomposition of the
starting material was observed. Based on the data from Table 1,
ZnI2 (entry 3) was found to be the superior Lewis acid promoter
for the formation of 2.
remains unexplored due to the prevalence in developing a
catalytic method over stoichiometric one. However, we believe
that this finding as well as mechanistic insight would be the
guiding factor for understanding the unusual nature of Zn(II)-salt
in the presence of water and would allow the synthetic access to
construct useful building blocks as well.
It is important to highlight that continuing our ongoing
spiroisoxazoline work,11 we were synthesizing isoxazolines
following one of the Carreira’s methods,7 using commercial
grade hydrated ZnI2 in stoichiometric amount, we realized an out
of the ordinary reaction rather than the desired one. Further
investigation of this reaction, led us to report this communication
accentuating the unprecedented behavior of Zn(II)/H2O for the
transformation of propargyl hydroxylamine to the corresponding
α,β-unsaturated ketone. It is worth mentioning that according to
Carriera’s recent work, Zn(II)-catalyzed transformation of
propargyl hydroxylamine to the corresponding 2,3-
dihydroisoxazoles required inert reaction conditions, and even
after a prolonged reaction time, there was no report of product
other than the formation of 2,3-dihydroisoxazoles. Based upon
the preliminary observation, we focused our interests on
optimizing the reaction conditions (ZnI2, CH2Cl2/H2O, and
reflux). In the context of our investigation, we first examined the
reactivity of various Zn(II)-salts that can promote this sort of
transformation. When 1 was treated with stoichiometric amount
of various Zn(II)-salts in the presence of water and under reflux
conditions, we realized the formation of desired product 2.
However, we also observed the formation of a cyclic isoxazoline
3 (minor product, up to 50% yield) in some cases along with the
major unsaturated ketone 2 (Table 1) We also observed a polar
compound in TLC which was later characterized as benzyl
hydroxylamine.
In order to further optimize other experimental parameters
(e.g. solvent, equiv, and reaction time), and to find optimal
reaction conditions, we chose a range of solvents such as CH2Cl2,
toluene, CH3CN, and THF (Table 2). Of the aforementioned
solvents, CH2Cl2 was found to be the best solvent. The time
dependent experiment showed that the usual reaction time is 2-4
hours for the maximum transformation. However, the extended
period of reaction time has no significant improvement on yield.
To understand the stoichiometric and catalytic behaviors of ZnI2,
we performed the reaction under various loading (from 10 to 100
mol%). We also realized that catalytic loading (10 mol%, entry 7,
Table 2) dawdled down the reaction time to the completion and
respectively the yield of the desired product 2. However, in the
presence of stoichiometric amount of ZnI2 (1 equiv), both the
reaction time and the isolated yields were affected significantly.
In order to fine tune and determine the optimal amount of ZnI2,
we further reduced the loading of ZnI2 to 0.5 equiv; the reaction
was monitored by frequently checking the TLC. In this setting,
the reaction usually takes 2-4 h to reach its completion.
Table 1
Product ratios and isolated yields for Zn(II) promoted decomposition
of propargyl hydroxylamines (1).a
Table 2
Optimization of other parameters for ZnI2 mediated decomposition
of propargyl hydroxylamine (1).a
aGeneral procedure: 1 (0.122 mmol), Zn(II)-salt (1 eqiv), H2O (1eq),
c
CH2Cl2 (2 mL), under reflux. bNMR ratios of crude 2 and 3.
Isolated yield of 2. d No purification was attempted due to the lack of
characteristic TLC indications for 2 or 3
aGeneral procedure: 1 (0.122 mmol), Zn(II)-salt (0.1-1 equiv), H2O
(1 equiv), CH2Cl2 (2 mL) for the given temperature and time.
bIsolated yield of 2. c In absence of water.
The ratio (2:3) was determined by NMR spectroscopy from
the crude reaction mixture. The ratio between integrated signals
at δ 6.7 ppm for α,β-unsaturated ketone 2 and δ 5.5 ppm for
isoxazoline 3 enabled us to determine the optimized reaction
conditions. As depicted in entries 1-3, Table 1, it is apparent that
Under optimized reaction conditions, the substrate scope was
also explored in order to understand reaction compatibility and
efficacy (Table 3). Subsequently, a plethora of tri-substituted
propargyl hydroxylamines were generated from diethyl zinc-

3
mediated nucleophilic addition of several substituted alkynes to
disubstituted nitrones (aliphatic or aromatic substituted)
following a reported procedure.12 Having in hand a variety of tri-
substituted propargyl hydroxylamines, we then performed the
aforementioned reaction by following our optimized reaction
conditions (ZnI2 0.5 equiv, CH2Cl2/H2O, reflux 2-12 h). As
shown in Table 3, it is clearly evident that a wide range of
alkynes are compatible with this reaction environment, and the
desired products were isolated in good yields.
addition of H2O might be hindered in the presence of bulky
substituent.
8,9
Based on literature precedence, we at this point speculated
that the formation of α,β-unsaturated ketone could be facilitated
by N-O bond cleavage of a cyclic isoxazoline intermediate
followed by an elimination of benzyl amine. It is worth noting
that the N-O bond cleavage will provide the unsaturated ketone
where the 16O-atom comes from hydroxylamine. Regardless, the
formation of isoxazolines, the stoichimetric zinc salt could also
facilitate the elimination of the hydroxylamine via a proposed
nucleophilic attack by H2O to the terminal alkyne might result an
allenol formation which could further tautomerize to give the
desired product where the O-atom in the product comes from
water. In order to understand the role of water and to establish a
plausible mechanistic pathway, we next envisioned running a
couple of reactions shown in Scheme 2 using 18O-labeled water.
This modification was also executed separately for propargyl
hydroxylamine and its corresponding cyclic isoxazolines
(obtained by Carreira’s method)7 as well. In both cases, we
observed the 18O isotope incorporation in the product which was
further corroborated by HRMS. This observation not only
enlightens our understanding, it also enabled us to propose novel
pathways for this type of unusual transformation.
Table 3
Substrate scope for the decomposition of propargyl hydroxylamine.
aGeneral procedure: 10 mol % of ZnI2 and 10 mol% of DMAP were
added to a solution of propargylic N-hydroxylamine in CH2Cl2 at 23
°C. After 4h at rt, usual workup and purification provided the desired
product.
Scheme 2. Unusual transformation of propargyl N-hydroxylamines
to α,β-unsaturated ketones.
As depicted in Scheme 3, where propargyl amine is the
starting material, we propose that ZnI2 first coordinates to the
triple bond b followed by a nucleophilic oxidative addition of
H2O to furnish intermediate d in the presence of excess ZnI2. The
intermediate d then undergoes a reductive elimination and
protonation to form the alleneol e with further rearrangement to
α,β-unsaturated ketone f (Scheme 3). It is important to note that
this plausible elimination resembles the reported process where
an elimination of an imine has been shown from a propargyl
secondary amine through an allene intermediate.9
aGeneral procedure: alkyne (1 mmol), nitrone (1.1 mmol), toluene (4
mL), diethylzinc (1M in hexane, 0.2 mmol), under N2 atmosphere at
rt provided isolated yield. bGeneral procedure: propargyl
hydroxylamine (1 equiv), ZnI2 (0.5 equiv), H2O (1equiv.), CH2Cl2
(2 mL), under reflux condition provided isolated yield.
We also investigated the effect of functional group tolerance
by incorporating -OTBS, -CO2Et, -Ph, or methyl groups on the
terminal alkyne. It is worth mentioning that bulky substituents
(e.g. –TMS or –CO2 Bu) based alkynes have a negative effect on
the reaction and no trace of desired product has been isolated.
This is due to the fact that the proposed nucleophilc oxidative
Scheme 3. Plausible mechanism for the decomposition of propargyl
hydroxylamine.
t

4
Tetrahedron Letters
10. Johnstone, R. A. W. Mech. Mol. Migr. 1969, 2, 249–266.
On the other hand, in the case of isoxazoline g, ZnI2 might
11. (a) Das, P.; Valente, E. J.; Hamme II, A. T. Eur. J. Org. Chem. 2014,
2659–2663; (b) Das, P and Hamme II, A. T. Eur. J. Org. Chem. 2015,
5159–5166; (c) Das, P.; Omollo, A. O.; Sitole, L. J.; McClendon, E.;
Valente, E. J.; Raucher, D.; Walker, L. R.; Hamme II, A. T.
Tetrahedron Lett. 2015, 56, 1794–1797.
12. (a) Ohemeng, K. A.; Podlogar, B. L.; Nguyen, V. N.; Bernstein, J. I.;
Krause, H. M.; Hilliard, J. J.; Barrett, J. F. J. Med. Chem. 1997, 40,
3292–3296; (b) Kawase, M.; Kikugawa, Y. J. Chem. Soc. Perkin 1,
1979, 643–645; (c) Dondoni, A.; Franco, S.; Junquera, F.; Merchan, F.
L.; Merino, P.; Tejero, T. Synthetic Communications 1994, 24, 2537–
2550.
be playing the role as a Lewis acid and coordinated with N- and
O- atoms where the O-vinyl center becomes electrophilic as
shown in intermediate h in Scheme 4. As a result, facilitating a
similar oxidative addition of H2O, followed by a migration of
double bond and elimination of hydroxylamine provided the
desired unsaturated system j (Scheme 4).
Scheme 4. Plausible mechanism for the decomposition of
isoxazoline.
In conclusion, we documented the Zn(II)/H2O-mediated mild
and efficient reaction condition for a smooth transformation of
the propargyl hydroxylamine to unusual α,β-unsaturated ketone.
This reaction can be performed for a wide range of substrates
with few limitations as explained in the text. We believe that this
observation not only grasps reader’s attention due to its novel
mechanistic pathway, it also facilitates the accumulation of many
important building blocks of synthetic and medicinal interest.
Acknowledgments
The project described was supported by NIH/NIGMS (Award
Number: 5 SC3 GM094081-06), and the Analytical and NMR
CORE facilities were supported by the RCMI-Center for
environmental Health (Award Number: 5G12MD007581).
Supplementary Material
1
Supplementary data (compound data including H NMR, 13C
NMR, IR, HRMS and X-ray) associated with this article can be
found, in the online version, at
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6
Tetrahedron
Highlights

Direct Transformation of Propargyl N-
hydroxylamines to unsaturated ketones

Zn(II)/H2O-mediated mild and efficient
reaction condition

This reaction can be performed for a wide
range of substrates with few limitations