A useful method for the conversion of olefins to nitro olefins

Article abstract of DOI:10.1021/acs.orglett.1c00868

Triflyl nitrate is easily generated from tetra-n-butylammonium nitrate in CH2Cl2 solution and serves as an effective nitrating agent for a wide range of unsaturated substrates to form nitro olefins.

Full text of DOI:10.1021/acs.orglett.1c00868

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Letter
A Useful Method for the Conversion of Olefins to Nitro Olefins
G. Sudhakar Reddy and E. J. Corey*
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ABSTRACT: Triflyl nitrate is easily generated from tetra-n-butylammonium
nitrate in CH2Cl2 solution and serves as an effective nitrating agent for a wide
range of unsaturated substrates to form nitro olefins.
e recently reported an effective and convenient
conversion of cyclopentene (1) to 1-nitrocyclopentene
(2) and the use of the latter as a key intermediate for the
enantioselective synthesis of the chiral C2-symmetric azate-
traquinane 3 (Scheme 1).1 As pointed out previously, this
Table 1. Nitration of Selected Monocyclic Substrates to
Form Conjugated Nitro Olefins
W
Scheme 1. 1-Nitrocyclopentene (2); Preparation En Route
to Azatetraquinane 3
route to 2 is operationally simpler than previous preparations
which have drawbacks, including the need for multiple steps or
the use of NO2 under pressure or ultrasound irradiation.2 The
conversion of 1 to 2 likely involves the mixed anhydride
CF3SO2ONO2 as a reactive intermediate.3 In this paper, we
report on the application of this reagent to the generation of a
wide range of nitro olefins and demonstrate the scope and
simplicity of this approach to nitration. In general, the nitration
reactions were conducted by slow addition of 1.1 equiv of
triflic anhydride to a solution of tetra-n-butylammonium
nitrate (1.1 equiv) and tetra-n-butylammonium triflate (0.5
equiv) in methylene chloride at 30 °C with stirring and
temperature maintenance with a water bath. The addition of
tetra-n-butylammonium triflate to the reaction mixture
improves the yield of product, possibly because it can serve
as a proton acceptor from an intermediate β-nitro carbocation.
Seven representative examples are presented in Table 1 with
isolated yields ranging between 70 and 80%. Pure product was
readily obtained by flash column chromatography on silica.
Further details can be found in the Supporting Information. It
is noteworthy that the nitration was successful not only with
the five- to eight-membered cycloalkenes (entries 1−4) but
also with the much less nucleophilic substrates shown in Table
1, entries 5−7. However, 1-nitrocyclopentene (2) was much
Received: March 12, 2021
Published: April 13, 2021
https://doi.org/10.1021/acs.orglett.1c00868
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3399−3402
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less reactive than substrates 10, 12, and 14 when subjected to
the nitration conditions shown in Table 1 and was recovered
unchanged (98%). The preparation of the products 2, 5, 7, and
9 had previously been reported by other methods.4
We have also observed that allylic nitration products can be
formed from certain trisubstituted electron-rich olefins. In the
case of these more reactive substrates, the reaction is best
conducted at −30 °C using 1.3−2 equiv of tetra-n-
butylammonium nitrate in CH2Cl2 and without added tetra-
n-butylammonium triflate. It is noteworthy that the nitration of
E,E-farnesol BOC ester (20) afforded the allylic nitro product
21 without the formation of cyclization or other products
involving the internal double bonds (Table 2). It is likely that
(24) was nitrated efficiently at the hindered C-12 position to
form the previously unknown 12-nitro derivative 25. On the
other hand, the nitration of cholesteryl benzoate (26) turned
out to be more complex, due to the formation of the
rearrangement product 27 instead of the more obvious 6-
nitrocholesterol benzoate (Scheme 3). The structure of 27 was
Scheme 3. Nitration−Rearrangement of Cholesteryl
Benzoate (26)
Table 2. Conversion of Trisubstituted Olefins to Allylic
Nitro Olefins
established by 2-D NMR structural analysis, as detailed in the
Supporting Information, and also the chemical transformations
to alcohol 28 and ketone 29 which are shown in Scheme 3. It
is clear that the rearrangement of the C19 angular methyl group
of 26 to C5 of the intermediate 6α-nitro-C5-carbocation is fast
enough to outcompete loss of a proton from C6.
Another fascinating aspect of the nitration methodology
described herein emerged from the study of phenyl-substituted
olefins. The results with a series of such substrates are
summarized in Table 3. These nitration reactions with
Table 3. Ortho-Selective Nitration of Conjugated Styrene
Derivatives
the initial β-nitro carbocation is deprotonated very rapidly
because of the high concentration of anions in the reaction
mixture. It is possible that the position selectivity leading to 21
may be due to a prevailing compact conformation of 20 in the
salt-rich medium that effectively buries the internal CC.
The balance between the formation of conjugated and allylic
nitro alkene formation is actually substrate dependent as
shown by the two examples in Scheme 2. As indicated in this
scheme, the sesquiterpene cedrene (22) was converted cleanly
to the conjugated nitro olefin 23. Similarly, β-amyrin benzoate
Scheme 2. Examples of Nitration of More Complex
Substrates
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Author
substrates 30, 32, 34, 36, and 38 occurred exclusively at the
ortho carbon on the aromatic ring; no product of olefinic or
para-carbon attack could be detected. Products 31, 33, 35, 37,
and 39 were identical with previously reported compounds by
1H, 13C NMR and melting point comparison.5 One possible
explanation for this high ortho vs para selectivity, as outlined in
Scheme 4, involves the cycloaddition of the nitronium ion
G. Sudhakar Reddy − Department of Chemistry and Chemical
Biology, Harvard University, Cambridge, Massachusetts
02138, United States; orcid.org/0000-0001-8301-2207
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00868
Notes
Scheme 4. Possible [4 + 2]-Cycloaddition Pathway for
The authors declare no competing financial interest.
Ortho-Position Selective Nitration of 40 to 42
ACKNOWLEDGMENTS
■
We are grateful to Pfizer, Inc., and Bristol-Myers Squibb for
financial support.
REFERENCES
+
■
(NO2 ) intermediate to the ortho position and the olefinic
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carbon α to the electron-withdrawing group (EWG) of 40 to
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relevant that methyl 3-phenylpropionate (43) undergoes
nitration selectively at the para position to form 44 (Scheme
5).
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Scheme 5. Para-Selective Nitration of 43
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The nearly 20 examples described herein for the nitration of
a range of olefins by the triflic anhydride−tetra-n-butylammo-
nium nitrate combination demonstrate the utility and
simplicity of this approach to a wide range of nitro olefins. It
is effective for both π-basic and electron-deficient olefins, as
demonstrated by the results summarized in Table 1. The
method can be recommended as convenient, easily executed,
and relatively safe. It is well suited for laboratory-scale
preparations.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00868.
Experimental procedures and characterization data for
novel reactions and products including copies of 1H and
13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
E. J. Corey − Department of Chemistry and Chemical Biology,
Harvard University, Cambridge, Massachusetts 02138,
United States; orcid.org/0000-0002-1196-7896;
Email: corey@chemistry.harvard.edu
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