Synthesis of α-Alkynylnitrones via Hydromagnesiation of 1,3-Enynes with Magnesium Hydride

Article abstract of DOI:10.1021/acs.orglett.1c01583

A protocol for the synthesis of α-Alkynylnitrones from 1,3-enynes has been developed. The process is triggered by hydromagnesiation of 1,3-enynes with magnesium hydride (MgH2), which is prepared in situ through solvothermal treatment of magnesium iodide (

Full text of DOI:10.1021/acs.orglett.1c01583

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Letter
Synthesis of α‑Alkynylnitrones via Hydromagnesiation of 1,3-Enynes
with Magnesium Hydride
Yihang Li, Jia Sheng Ng, Bin Wang, and Shunsuke Chiba*
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ABSTRACT: A protocol for the synthesis of α-alkynylnitrones
from 1,3-enynes has been developed. The process is triggered by
hydromagnesiation of 1,3-enynes with magnesium hydride
(MgH2), which is prepared in situ through solvothermal treatment
of magnesium iodide (MgI2) with sodium hydride (NaH) in
tetrahydrofuran. Downstream functionalization of the resulting
propargylmagnesium intermediates with organo nitro compounds
affords α-alkynylnitrones, which could be used as versatile
precursors for the construction of various nitrogen-containing
compounds.
Scheme 1. Hydromagnesiation of 1,3-Enynes and
Downstream Functionalization
mong carbon−carbon unsaturated π-conjugated systems,
1
Areadily accessible 1,3-enynes exhibit versatile reactivity
toward a series of molecular transformations.2 As the current
state-of-the-art methods, transition-metal-catalyzed hydrofunc-
tionalization of 1,3-enynes has been performed typically in a
1,2/1,4-hydrometalation mode, which is followed by down-
stream functionalization with various electrophiles to form
substituted allenes3 or alkynes.4
We have recently disclosed that magnesium hydride
(MgH2),5 generated in situ by the solvothermal treatment of
magnesium iodide (MgI2) with sodium hydride (NaH) in
tetrahydrofuran (THF),6 exhibited unique hydridic reactivity
to induce 1,2/1,4-hydromagnesiation of 1,3-enynes without
the aid of transition-metal catalysts (Scheme 1).7,8 The
resulting organomagnesium intermediates as an equilibrium
mixture of allenyl- and propargylmagnesium species could be
functionalized with electrophiles (E+) such as alkyl and silyl
halides in the presence of copper(I) cyanide (CuCN) as a
catalyst, affording multisubstituted allenes. In the search for
different electrophiles for selective downstream functionaliza-
tion of the organomagnesium intermediates derived from 1,3-
enynes and MgH2, our attention was directed at Bartoli’s
reports about the synthesis of nitrones by the treatment of
Grignard reagents with nitro compounds.9 We surmised if the
downstream treatment of the organomagmesium intermediates
derived from 1,3-enynes and MgH2 with nitro compounds
enables selective propargylic functionalization, thus affording
synthetically useful α-alkynylnitrones. The reaction optimiza-
tion, substrate scope, and synthetic applications of the method
are described herein.
magnesium intermediates I, generated by the reaction of 1a
with sodium hydride (NaH, 1.5 equiv) and magnesium iodide
(MgI2, 2 equiv) at 100 °C for 2 h, with nitrobenzene (2a) (2
equiv) at −78 °C followed by aqueous workup with an
aqueous ammonium chloride (NH4Cl) solution provided the
desired α-alkynylnitrone 3aa in 68% NMR yield (63% isolated
yield) along with N-propargylhydroxylamine 4aa in 9% NMR
Received: May 10, 2021
Published: June 14, 2021
At the outset of the project, we optimized the reaction
conditions using 1,3-enyne 1a and nitrobenzene (PhNO2, 2a)
as the model substrates (Table 1). Treatment of organo-
https://doi.org/10.1021/acs.orglett.1c01583
© 2021 American Chemical Society
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a
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Organo Nitro Compounds 2
b
b
entry
1
2
additive (equiv)
yield of 3aa (%)
yield of 4 (%)
c
none
none
68 (63)
9
10
−
−
−
d
61
66
70
76 (73)
76 (72)
3
4
5
6
TMEDA (1.5)
DMAP (1.5)
Et3N (1.5)
Et3N (1)
Et3N (1)
c
c
−
−
e
c
7
(78)
a
Reaction conditions: 1a (0.5 mmol), NaH (1.5 equiv), MgI2 (2
equiv), THF (2.5 mL, 0.2 M), 100 °C (sealed, oil bath) for 2 h; then
additive (1−1.5 equiv) at room temperature (24 °C) for 1 h; then
PhNO2 2a (2 equiv), −78 °C (dry ice/acetone bath) for 3 h before
workup with a saturated aqueous NH4Cl solution. Abbreviations:
TMEDA, tetramethylethylenediamine; DMAP, 4-dimethylaminopyr-
b
idine. 1H NMR yields based on the internal standard were recorded.
c
d
Isolated yields in parentheses. The amination step was conducted
a
e
Reaction conditions: 1a (0.5 mmol), NaH (1.5 equiv), MgI2 (2
equiv), THF (2.5 mL, 0.2 M), 100 °C (sealed, oil bath) for 2 h; then
Et3N (1 equiv) at room temperature (24 °C) for 1 h; then nitro
compounds 2 (2 equiv) at −78 °C (dry ice/acetone bath) for 1.5−3 h
before workup with a saturated aqueous NH4Cl solution (see the
Supporting Information for details). Isolated yields of 3 were
using 1.2 equiv of 2a for 4.5 h. The reaction was performed using 7
mmol of 1a.
yield, which was formed probably via over-reduction of
tetrahedral intermediate II by the remaining magnesium
hydride (entry 1).9b Reduction of the amount of nitrobenzene
(2a) to 1.2 equiv diminished the yield of 3aa (entry 2). We
observed that addition of tertiary amines (1−1.5 equiv) to a
solution of the organomagnesium intermediates prior to the
treatment with nitrobenzene (2a) could suppress the over-
reduction (entries 3−6), where tertiary amines might serve as a
chelating ligand to the magnesium cations.10 Among the
tertiary amine additives screened, use of triethylamine (Et3N)
was found to be optimal to provide nitrone 3aa as the sole
product in good yields (entries 5 and 6). The reaction of 1a on
a 7 mmol scale did not diminish the isolated yield of 3aa,
proving the scalability of the process (entry 7).
The synthesis of α-alkynylnitrones has been underdevel-
oped, and successful examples are limited to the oxidative
cross-coupling between aldonitrones and alkynyl Grignard
reagents reported by Studer.11,12 Therefore, we next examined
the substrate scope with respect to the nitro compounds for
the synthesis of α-alkynylnitrones 3 from 1,3-enyne 1a
(Scheme 2). Various nitroarenes, including electron-rich (for
2b), electron-deficient (for 2c and 2d), and sterically hindered
(for 2e−2g) forms, were found to be compatible for the
downstream functionalization to give the corresponding N-
arylnitrones 3ab−3ag generally in good yields.13 As for
nitroalkanes, use of 2-methyl-2-nitropropane (2h) allowed
for installation of a removable tert-butyl group on the nitrogen
of nitrone 3ah. Similarly, employment of nitrocyclopentane
(2i) resulted in the smooth introduction of a cyclo-pentyl
b
recorded. The reaction was conducted using 1 mmol of 1a.
c
Nitroalkane 2h or 2j was added at 0 °C (ice/water bath), and the
reaction mixture was stirred at the same temperature for 20 h.
d
Nitrocyclopentane (2i) was added at 24 °C, and the reaction
mixture was stirred at the same temperature for 20 h.
group (for 3ai), while the reaction with nitromethane (2j)
resulted in the formation of N-methylnitrone 3aj in moderate
yield.
Next, the substituent compatibility on the 1,3-enynes 1 was
investigated using nitrobenzene (2a) for the downstream
functionalization (Scheme 3). As for substituent R1 (Scheme
3A), the method was amenable to efficient installation of a
series of aryl (for 3ba−3ga) and heteroaryl (for 3ha and 3ia)
groups. Alkyl-substituted alkynylnitrone 3ja could be synthe-
sized in 59% yield. It should also be noted that the protocol
was compatible with employment of silyl-substituted enyne 1k,
affording 3ka in 70% yield. We found that the method can
engage internal alkenes having alkyl substituents as the R2 to
provide nitrones 3la−3na in good to moderate yields (Scheme
3B).
Having developed the method for the construction of α-
alkynylnitrones 3, we next directed our attention to
demonstrating their derivatization (Scheme 4). Hydride
reduction of N-phenyl nitrone 3aa with lithium borohydride
(LiBH4) afforded N-propargylhydroxylamine 4aa in good yield
(Scheme 4A).14 Subsequent treatment of 4aa with iron (Fe)
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a
Scheme 3. Scope of 1,3-Enynes 1
Scheme 4. Derivatization of α-Alkynylnitrones 3
a
Reaction conditions: 1 (0.5 mmol), NaH (1.5 equiv), MgI2 (2
equiv), THF (2.5 mL, 0.2 M), 100 °C (sealed, oil bath) for 2.5−14 h;
then Et3N (1 equiv) at room temperature (24 °C) for 1 h; then
PhNO2 2a (2 equiv) at −78 °C (dry ice/acetone bath) for 3 h before
workup with a saturated aqueous NH4Cl solution. Isolated yields of 3
b
were recorded. Hydromagnesiation was conducted using NaH (1.5
equiv) and MgI2 (1.5 equiv).
powder in acetic acid (AcOH) induced deoxygenation to form
propargylamine 5aa while keeping the alkynyl moiety intact.
On the contrary, reduction of N-tert-butyl nitrone 3ah with
LiBH4 became sluggish, affording the corresponding hydroxyl-
amine 4ah in 24% yield. In turn, we found that reduction of
3ah by the NaH/ZnCl2 system, which was recently developed
for the controlled reduction of carboxamides and carbonitriles
by our group,15 directly provides propargylamine 5ah in 60%
yield. Conversion of N-tert-butyl nitrone 3ah into isoxazole 6
was successfully implemented by following Studer’s protocol11
that employs boron trichloride (BCl3) in 1,2-dichloroethane
(Scheme 4B). One of the features of the method presented
here is its ability in the facile installation of an alkene tether on
the α-alkynylnitrone scaffolds (e.g., synthesis of 3af and 3na),
which could be utilized for the ensuing intramolecular 1,3-
dipolar [3+2] cycloaddition.16,17 Thus, solvothermal treatment
of 3na in chlorobenzene (PhCl) at 80 °C resulted in smooth
cycloaddition to form diastereomerically pure bicyclic
isoxazolidine 7. The reductive N−O bond fission of 7 with
Fe powder in AcOH delivered polysubstituted cyclopentane 8.
Similarly, intramolecular 1,3-diploar [3+2] cycloaddition of 3af
proceeded selectively via transition state 9 to form tetrahydro-
1,4-epoxybenzo[b]azepine 10 as the major product, along with
the formation of 4,5-dihydro-3H-1,4-methanobenzo[c][1,2]-
oxazepane 10′ in 8% yield via another twisted transition state,
9′ (Scheme 4D). The reductive N−O bond cleavage of 10
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(b) Negishi, E.; Anastasia, L. Palladium-Catalyzed Alkynylation.
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This work has demonstrated the synthesis of α-alkynylni-
trones from 1,3-enynes via hydromagnesiation with magne-
sium hydride followed by downstream treatment with nitro
compounds. The process operates under transition-metal free
conditions, offering concise access to synthetically valuable α-
alkynylnitrones. Given the broad substrate scope of this
protocol and the synthetic potentials of α-alkynylnitrones, we
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01583.
Experimental procedures and spectral data (PDF)
FAIR data, including the primary NMR FID files, for
compounds 1a−1n, 3aa−3aj, 3ba−3na, 4aa, 4ah, 5aa,
5ah, 6−8, 10, 10′, and 11 (ZIP)
Accession Codes
CCDC 2080264−2080265 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(7) Wang, B.; Li, Y.; Pang, J. H.; Watanabe, K.; Takita, R.; Chiba, S.
Hydromagnesiation of 1,3-Enynes by Magnesium Hydride for
Synthesis of Tri- and Tetra-substituted Allenes. Angew. Chem., Int.
Ed. 2021, 60, 217−221.
AUTHOR INFORMATION
Corresponding Author
■
(8) For anti-hydromagnesiation of arylalkynes by magnesium
hydride, see: Wang, B.; Ong, D. Y.; Li, Y.; Pang, J. H.; Watanabe,
K.; Takita, R.; Chiba, S. Stereo-controlled anti-hydromagnesiation of
aryl alkynes by magnesium hydrides. Chem. Sci. 2020, 11, 5267−5272.
(9) (a) Bartoli, G.; Marcantoni, E.; Petrini, M. Nitrones from
Addition of Benzyl and Allyl Grignard Reagents to Alkyl Nitro
Compounds: Chemo-, Regio-, and Stereoselectivity of the Reaction. J.
Org. Chem. 1992, 57, 5834−5840. (b) Bartoli, G.; Marcantoni, E.;
Petrini, M.; Dalpozzo, R. Reaction of Aryl and Alkyl Nitro
Compounds with 2-Butenylmagnesium Chloride: Synthesis of a
New Class of Nitrones. J. Org. Chem. 1990, 55, 4456−4459.
(10) (a) Pinkus, A. G. Three-Coordinate Magnesium. Coord. Chem.
Rev. 1978, 25, 173−197. (b) Evans, D. F.; Khan, M. S. Studies on
Grignard Reagents. Part II. NNN′N′-Tetraethylethylenediamine
Grignard Adducts. J. Chem. Soc. A 1967, 0, 1648−1649. (c) Toney,
J.; Stucky, G. D. On the Association of the Grignard Reagent. Chem.
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(11) (a) Murarka, S.; Studer, A. Transition Metal-Free TEMPO-
Catalyzed Oxidative Cross-Coupling of Nitrones with Alkynyl-
Grignard Reagents. Adv. Synth. Catal. 2011, 353, 2708−2714.
(b) Murarka, S.; Studer, A. Zinc Triflate Catalyzed Aerobic Cross-
Dehydrogenative Coupling (CDC) of Alkynes with Nitrones: A New
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(12) There is one report about the synthesis of α-alkynylnitrone by
employing dehydrative condensation between alkynylketones and
hydroxylamines. However, it potentially reaches completion with the
1,4-addition of hydroxylamines to alkynylketones, especially in the
presence of water: Padwa, A.; Wong, G. S. K. 1,3-Dipolar
Cycloaddition of Nitrones Derived from the Reaction of Acetylenes
with Hydroxylamines. J. Org. Chem. 1986, 51, 3125−3133.
(13) The structure of nitrone 3ab was confirmed by X-ray
crystallographic analysis. See the Supporting Information for details.
It should be noted that all of the α-alkynylnitrones 3 were formed as a
Shunsuke Chiba − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371;
orcid.org/0000-0003-2039-023X; Email: shunsuke@
ntu.edu.sg
Authors
Yihang Li − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371
Jia Sheng Ng − Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371
Bin Wang − Division of Chemistry and Biological Chemistry,
School of Physical and Mathematical Sciences, Nanyang
Technological University, Singapore 637371
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01583
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by funding from Nanyang
Technological University (NTU) and the Singapore Ministry
of Education (Academic Research Fund Tier 2, MOE2019-T2-
1-089).
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