Synthesis of Nitro Alcohols by Riboflavin Promoted Tandem Nef-Henry Reactions on Nitroalkanes

Article abstract of DOI:10.1002/adsc.202001344

We disclose a unprecedented riboflavin promoted Nef reaction of primary nitroalkanes coupled with a nitroaldol reaction. This tandem process allows the synthesis of functionalized nitro alcohols under mild reaction conditions. Secondary nitroalkanes fail to give the expected nitroaldol products although they are consumed under the reaction conditions. (Figure presented.).

Full text of DOI:10.1002/adsc.202001344

Title: Synthesis of Nitro Alcohols by Riboflavin Promoted Tandem Nef-
Henry Reactions on Nitroalkanes
Authors: Gabriele Lupidi, Alessandro Palmieri, and Marino Petrini
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10.1002/adsc.202001344
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Synthesis of Nitro Alcohols by Riboflavin Promoted Tandem
Nef-Henry Reactions on Nitroalkanes
Gabriele Lupidi,a Alessandro Palmieri,a,* and Marino Petrini a,*
a
School of Science and Technology, Chemistry Division, University of Camerino, Via S. Agostino 1, 62032 Camerino,
Italy. E-mail: alessandro.palmieri@unicam.it; marino.petrini@unicam.it.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
elimination step generating nitrite anions and iminium
Abstract. We disclose
a
unprecedented riboflavin
promoted Nef reaction of primary nitroalkanes coupled ions which upon hydrolysis afford the parent carbonyl
derivatives (Scheme 1).[7] Re-oxidation of the flavin
with a nitroaldol reaction. This tandem process allows the
synthesis of functionalized nitro alcohols under mild
reaction conditions. Secondary nitroalkanes fail to give the
expected nitroaldol products although they are consumed
under the reaction conditions.
reduced form is usually provided by molecular
oxygen restoring the catalyst activity. This approach
has been never applied to set up a synthetic
methodology for the catalytic or promoted Nef
reaction, although various studies open up interesting
perspectives for the development of this nitro to
carbonyl conversion.[8]
Keywords: Flavins; Henry reaction; Nef reaction;
Nitroalkanes; Tandem reactions.
The flourishing chemistry of nitro compounds is still
of notable synthetic interest as evidenced by the large
number of processes employing nitro-containing
derivatives as pivotal intermediates.[1] The carbanion
stabilizing property of the nitro group through the
formation of nitronate anions, has been using for a
long time to generate new carbon-carbon bonds
exploiting the Henry nitroaldol process as well as
conjugate additions to electron-poor alkenes.[2] The
easy reduction of the nitro moiety is probably one of
the most viable and exploited functional group
transformations used to access amino derivatives.[3]
The nitro to carbonyl conversion, widely known as
the Nef reaction, is another process frequently used to
install aldehydes, ketones and carboxylic acids in
structural frameworks embedding nitro groups.[4] This
transformation was originally designed as an
hydrolytic cleavage, under strongly acidic conditions,
of a preformed nitronate anion.[5] However, along the
years the carbon-nitrogen double bond cleavage has
been more efficiently achieved under oxidative
conditions or by partial reduction of the nitro group
using transition metal salts. The original hydrolytic
procedure is indeed seldom applied for synthetic
purposes because of the harsh conditions required.
The ability of some nitroalkane oxidases (NAO) in
converting primary and secondary nitroalkanes into
the corresponding carbonyls and nitrite anions has
been known since the early 1950s.[6] The activity of
these enzymes seems associated to the flavoprotein
systems which flavin moiety is able to interact with
nitroalkanes through a diaza-conjugate addition-
Scheme 1. Enzymatic catalytic cycle evidenced for the
nitroalkane oxidase (NAO) assisted bio-Nef reactions.
In a very recent paper, various flavinium salts have
been proposed as catalysts to generate nitrite anions
from nitromethane.[9] The nitrite anions thus formed
have been used to support further NOx/TEMPO
catalytic cycles for the selective oxidation of alcohols,
diols and ethers. The flavinium salts employed in this
process, although quite efficient, are not
commercially available and must be prepared from a
multistep synthesis. In the search for a simple flavin
derivative retaining the reactivity features of
enzymatic NAO systems our attention was captured
by riboflavin, also referred as vitamin B2, a
1
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10.1002/adsc.202001344
Advanced Synthesis & Catalysis
commercially available and relatively inexpensive Table 1. Optimization of the reaction conditions.[a]
compound.[10] In this communication we present the
preliminary results obtained in the utilization of
riboflavin as promoter of the nitro to carbonyl
conversion which in our conditions is coupled to a
Henry reaction allowing the synthesis of nitro
alcohols. To the best of our knowledge, this is the
first example in which an efficient biomimetic Nef
reaction is realized using commercially available
cheap reagents.
The initial goal of our research was to establish a new
protocol for the conversion of nitroalkanes into the
corresponding carbonyl derivatives. For this purpose
Entry Base (eq)
Promoter
(eq)
Yield
(%)
we firstly made to react nitroalkane 4a in the presence
of cetyltrimethylammonium hydroxide (CTAOH) and
riboflavin 1 in water as solvent. According to the
result reported in Table1, entry 1, nitro alcohol 5a
was isolated as single product in low yield after
stirring for 4 h at room temperature. The observed
nitro alcohol clearly arises from a fast nitroaldol
reaction between the initially formed aldehyde and
the residual nitroalkane. The combined action of the
base and riboflavin is essential for the formation of
the nitro alcohol since in absence of one of the two
reagents only the unreacted nitroalkane is recovered
from the reaction mixture. Considering the nature of
the general mechanism portrayed in Scheme 1, it is
assumed as a possible cause of the reduced yield
observed, a failure in the oxidation step which should
regenerate riboflavin from its reduced form. However,
repeating the reaction under oxygen atmosphere was
unsuccessful in increasing the yield of the nitro
alcohol (Table 1, entry 2). Conversely, a notable
improvement was observed by increasing the amount
of riboflavin, revealing that the catalytic cycle is not
operative and that 1 must be considered as an actual
reagent (Table 1, entry 3). Since the use of sodium
hydroxide was ineffective in this reaction, other
quaternary ammonium hydroxides were tested and we
finally found in tetrahexylammonium hydroxide
(THAOH) the best base for this conversion (Table 1,
entry 4). Structurally modified flavin reagents such as
acetylated riboflavin 2 and commercially available
isoalloxazin 3 have been tested to verify a possible
improvement. However compound 2 was less
effective than riboflavin and isoalloxazin 3 totally
failed in leading to the expected product 5a (Table 1,
entries 5-6). The devised procedure for the Nef
reaction occurs under very mild reaction conditions
avoiding further oxidation of the intermediate
aldehyde which is often observed using oxidative
methods.[11] Furthermore, the subsequent nitroaldol
process avoids the isolation of the aldehyde
increasing the level of efficiency of the whole
process. The optimized reaction conditions have been
then applied to a series of nitroalkane derivatives 4
leading to nitro alcohols 5 in satisfactory yields
(Table 2). Linear nitroalkanes efficiently afford the
corresponding nitro alcohols 5a-d containing simple
alkyl chains, phenyl ring and terminal unsaturation.
1
2
3
4
5
6
CTAOH (0.55)
1 (1.0)
1 (1.0)
1 (2.0)
1 (2.0)
2 (2.0)
3 (2.0)
26
26
61
75
53
n.r.
CTAOH (0.55), O2 (1 bar)
CTAOH (0.55)
THAOH (0.55)
THAOH (0.55)
THAOH (0.55)
[a] Reaction conditions: 4a (0.6 mmol), base, promoter in
water (1 mL), room temperature,
cetyltrimethylammonium hydroxide. THAOH: tetrahexyl-
ammonium hydroxide.
4 h. CTAOH:
Table 2. Scope of the reaction.[a]
[a] Reaction conditions: nitroalkane 4 (0.6 mmol), riboflavin
(0.6 mmol), THAOH (0.33 mmol) in water (1 mL) at rt for
4 h. Nitro alcohols have been isolated as an almost
equimolar amount of diastereoisomers. Reaction carried
out on a 3 mmol of substrate.
[b]
2
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10.1002/adsc.202001344
Advanced Synthesis & Catalysis
A slight erosion in the chemical yield has been competitive nitroaldol reaction with 4a and 4p.
observed increasing the scale of the process to 3 Secondary nitroalkanes, although reactive in the
mmol in the preparation of compound 5b. The devised reaction conditions, do not provide neither the
reaction of functionalized 2-nitroethylbenzenes, also ketone derivatives nor the nitroaldol products.
nicely proceeds toward the formation of nitro alcohols
5g-j. In this specific case the tandem process prevents
from the direct utilization of arylacetaldehydes, the
products of the Nef reaction of 2-nitroethylbenzenes,
which are quite sensitive compounds.[12] Of particular
interest is the reaction of nitroalkanes bearing
electrophilic fuctionalities such as ester or cyano
groups
which
in
our
conditions
afford
polyfunctionalized derivatives 5e,f. Both these nitro
alcohols are amenable of further synthetic
manipulation involving selective functional group
transformations. Finally, nitroethyl-1,3-dioxolane and
3-phthalimido-1-nitropropane can be converted into
nitro alcohols 5k,l embedding masked carbonyl and
amino functions. The nitro alcohols 5 prepared by this
procedure are obtained as an equimolar mixture of the
two possible diastereoisomers. This trend has been
previously observed in the Henry reaction involving
nitroalkanes and alkanals using quaternary
ammonium salts.[13] Interestingly, the reaction of
arylnitromethanes 4m-o under our reaction conditions
led to the exclusive formation of isoxazolidine N-
oxides 6 under unoptimized conditions (Scheme 2).
This result is probably due to the preliminary
formation of nitroalkene 7 which upon conjugate
addition of phenylnitromethane gives 1,3-dinitro
compound 8.[14] The latter intermediate under basic
conditions affords 6 through an intramolecular
displacement of the nitrite anion by the nitronate
group.[15]
Scheme 3. Crossed experiment with 3-phenylnitropropane
and 1-nitrohexane
Surprisingly, it was observed disappearance of the
starting materials but no compounds arising from the
Nef or any other process have been detected. A
possible explanation for this behavior lies in the
possibility that the Michael adduct of secondary
nitroalkanes with the riboflavin is enough stable to
prevent loss of the nitrite anion to generate the
reactive iminium ion.[16] In order to gain further
elements supporting this hypothesis, a mixture of
nitropentane and 2-nitropropane were made to react
under the usual reaction conditions (Scheme 4). The
only product isolated from the reaction mixture was
nitro alcohol 5b arising from the reaction of
nitropentane albeit in reduced yield compared to that
reported in Table 2. The cross nitroaldol product
obtained by the reaction between 2-nitropropane and
pentanal, generated from the Nef reaction of 1-
nitropentane, was not observed. This finding would
apparently support the scavenging of riboflavin by 2-
nitropropane limiting the efficiency of the reaction of
nitropentane.
Scheme 2. Synthesis of isoxazoline N-oxides 6 from
arylnitromethanes 4m-o.
A crossed reaction has been also attempted between
primary nitroalkanes 4a and 4p evidencing the
formation of a mixture of three of the four possible
products. Interestingly, product 5a arising from the
homo reaction of 4a was not observed (Scheme 3).
The absence of nitro alcohol 5a in the reaction
mixture may reflect the lower reactivity of 3-
phenylpropanal compared to hexanal in the
Scheme 4. Crossed experiment with nitropentane and 2-
nitropropane.
3
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10.1002/adsc.202001344
Advanced Synthesis & Catalysis
Riboflavin (0.6 mmol, 2 eq.) was then added and the
resulting mixture was stirred at room temperature for 4
hours. Upon completion, the mixture was diluted with
CH2Cl2 (4 mL) and washed with brine (3×2 mL). The
aqueous phase was further extracted with CH2Cl2 (4×20
mL), and the combined organic phases were dried over
Na2SO4, filtered and concentrated to dryness under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate, 9:1).
However, a LC-MS analysis of the solid portion of
the reaction with nitrocyclohexane did not evidence
neither the presence of nitroalkane-riboflavine
adducts nor the reduced form of riboflavine. An
extensive decomposition of reduced riboflavine could
explain the failure of the oxidative last step of the
catalytic cycle. According to the experimental
observations the plausible mechanism is portrayed in
Scheme 5. The nitronate anion generated from
nitroalkane 4 by basic treatment attacks the riboflavin
1 leading to adduct 11. This intermediate, upon loss
of a nitrite anion, generates the iminium ion 12 which
Acknowledgements
We acknowledge financial support from University of Camerino
(FAR program) and MIUR (PRIN 2017, NATURECHEM project
upon hydrolysis affords the reduced form of grant n.2017A5HXFC).
riboflavin 13 and the aldehyde. Compund 13 is not
oxidized to riboflavin maybe because of its
decomposition thus disrupting a possible catalytic References
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In conclusion, we have disclosed for the first time a
riboflavin-promoted Nef reaction on primary
nitroalkanes which coupled with a tandem Henry
reaction allows the efficient synthesis of nitro
alcohols. A wide range of functionalized primary
nitroalkanes can be used for this purpose while
secondary nitrolakanes, although reactive fail to
afford the expected nitro alcohols. Further studies to
elucidate the mechanistic aspects of this process are
currently underway.
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Experimental Section
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with magnetic stirring bar, tetrahexylammonium hydroxide
(THAOH) was added (0.33 mmol, obtained diluting 0.3
mL of THAOH 40% water solution in 0.7 mL of water).
4
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10.1002/adsc.202001344
Advanced Synthesis & Catalysis
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phenylnitromethane with ammonium persulfate: A. H.
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5
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10.1002/adsc.202001344
Advanced Synthesis & Catalysis
COMMUNICATION
Synthesis of Nitro Alcohols by Riboflavin
Promoted Tandem Nef-Henry Reactions on
Nitroalkanes
Adv. Synth. Catal. Year, Volume, Page – Page
Gabriele Lupidi, Alessandro Palmieri,* and Marino
Petrini.*
6
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