Direct and stereoselective alkylation of nitro derivatives with activated alcohols in trifluoroethanol

Article abstract of DOI:10.1002/ejoc.201201345

Herein we disclose the simple, effective, and practical alkylation of nitroalkanes that takes place with benzylic, benzhydrylic, and propargylic alcohols in trifluoroethanol. A variety of different nitroalkanes bearing functional groups can be used in thi

Full text of DOI:10.1002/ejoc.201201345

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201345
Direct and Stereoselective Alkylation of Nitro Derivatives with Activated
Alcohols in Trifluoroethanol
Diego Petruzziello,[a] Andrea Gualandi,[a] Stefano Grilli,[a] and Pier Giorgio Cozzi*[a]
Dedicated to Professor Dieter Seebach on the occasion of his 75th birthday
Keywords: Alkylation / Nucleophilic substitution / Alcohols / Organocatalysis
Herein we disclose the simple, effective, and practical alkyl-
ation of nitroalkanes that takes place with benzylic, benzhy-
drylic, and propargylic alcohols in trifluoroethanol. A variety
of different nitroalkanes bearing functional groups can be
used in this SN1-type reaction to afford the desired products
in quantitative yields. Different chiral nitro derivatives were
submitted to this highly diastereoselective alkylation reac-
tion with selected benzhydrols. A new, effective, and chiral
pyrrolidine organocatalyst was prepared by using this meth-
odology.
city parameters of nitronates. Recently, we established the
possibility to generate stable carbenium ions from alcohols
in alkylation reactions.[12] The possibility to directly use
alcohols in the selective alkylation of nitro compounds is
intriguing and has attracted our attention. In this com-
munication, we report the facile and remarkable reaction of
various nitro compounds with alcohols in CF3CH2OH. In
addition, highly functionalized chiral compounds obtained
by organocatalytic nitro-Michael reactions react with the
selected alcohols with high selectivity.
Introduction
Deprotonated nitroalkanes are an important class of am-
bident anions that are widely used in organic synthesis.[1]
Their application in diverse chemical transformations re-
sults in their frequent use in total synthesis.[2] Recently, ni-
tro derivatives have also found applications in organocata-
lysis,[3] principally in Michael- and Henry-type reactions.[4]
However, the simple alkylation of nitro derivatives is quite
troublesome.[5] In fact, the intrinsic preference for attack
of the oxygen atom of the nitronate anion is so large that
irreversible SN2 reactions with a variety of alkylating agents
generally proceed in this manner.[6] As a consequence of the
failure to achieve C-alkylation of nitronate anions by simple
substitution reactions,[7] Seebach et al. developed a method
Results and Discussion
Trifluoroethanol (TFE) and hexafluoroisopropanol
for the α-alkylation of nitroalkanes that proceeds via dou- (HFIP) are solvents with unique properties.[13] In particular,
bly deprotonated nitroalkanes.[8] By using SOMO concepts, their high ionizing power and low nucleophilicity have
MacMillan recently developed the alkylation of ni- made them the media in which to perform nucleophilic ring
tronates.[9] Generally, in organocatalysis only a handful of opening of oxiranes,[14] intramolecular electrophilic ad-
C–C alkylation reactions occurring with nitro derivatives ditions to C–C bonds,[15] and aromatic electrophilic substi-
have been described.[10] However, Mayr reported SN1-type tution reactions.[16] These reactions are conducted in the ab-
reactions of stabilized benzhydrylium ions with nitro deriv- sence of any other activating agents or Lewis acids. Re-
atives, in which C–C bonds are formed.[11] Good yields of cently, it was shown that HFIP could be employed as a
the C-alkylation products were obtained when solid benzhy- medium and as an activator for a number of classical C–C
drylium tetrafluoroborate was added to solutions of the po- bond-forming reactions by using carbonyl compounds and
tassium nitronate in aqueous acetonitrile. The reactions their acetals.[17]
with carbenium ions were used to establish the nucleophili-
We reasoned that the acidic properties and low nucleo-
philicity of TFE would work to our advantage in the forma-
tion of carbenium ions from benzhydrylic alcohols.[18] We
selected alcohols 1a and 1b, positioned at –7 and –1.5 on
the Mayr scale, respectively, for preliminary investigation
(Table 1).[19] Nitro derivatives 2a–f were shown to give ex-
cellent yields with alcohol 1a. In all cases, no byproducts
derived from O-alkylation were identified in the crude reac-
[a] Dipartimento di Chimica “G. Ciamician”,
ALMA MATER STUDIORUM Università di Bologna,
Via Selmi 2, 40126, Bologna, Italy
Fax: +39-051-2099456
E-mail: piergiorgio.cozzi@unibo.it
Homepage: http://www.unibo.it/docenti/piergiorgio.cozzi
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201345.
Eur. J. Org. Chem. 2012, 6697–6701
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
6697

D. Petruzziello, A. Gualandi, S. Grilli, P. G. Cozzi
SHORT COMMUNICATION
tion mixture. The reactions are very convenient; they are
performed in air at room temperature and generate water
as the only byproduct.[20] In the case of alcohol 1b, a more
electrophilic carbenium ion is produced, and a base additive
was necessary to perform the reaction. We screened various
organic and inorganic bases and found that the addition of
DMAP was necessary to perform the reaction. Notably, the
addition of Brønsted acids and bases to the reaction of ni-
tromethane (5–10 equiv.) with alcohol 1a gave no reaction.
The carbenium ion was isolated as its tetrafluoroborate salt,
but this species was not reactive to nitroethane when the
reaction was performed in the presence of DABCO. With
all acid and base combinations examined, this highlights
the simple conditions that we have found. The reaction
tolerates the presence of many functional groups, and un-
protected primary alcohols can also be present.
Table 1. Addition of alcohols 1a,b to various nitro derivatives 2a–
f in TFE.[a]
Scheme 1. Reaction of alcohols 4a–h with nitroethane in trifluoro-
ethanol.
levels of simple diastereoselection were recorded with alk-
ynyl derivatives. The presence of the pNMe2 substituent as
an activating group was important for the formation of the
desired product in good yield, but it is not mandatory, as
other alcohols able to form stabilized carbenium ions in the
range of –7 and –1 on the Mayr scale could be used.[21] For
example, indolylalkynyl substrates can form carbenium ions
that are quite stable,[22] and they are suitable substrates for
this reaction. In addition, the presence of the activating
pNMe2 moiety is not a limitation for the chemistry, as it is
possible to take advantage of its presence to introduce fur-
ther functional groups, for example, by nickel-[23] or palla-
dium-catalyzed[24] reactions. Other alcohols, such as 1,3-di-
phenylprop-2-en-1-ol, were reactive as well, but the forma-
tion of ether byproducts, obtained by the attack of the
alcohol to the carbenium ion, were the predominant prod-
ucts in these cases. Also, different benzylic substrates (i.e.,
Ar = pNMe2Ph, R = nBu) were reactive under the reaction
conditions, but the formation of alkenes as byproducts,
through elimination of water, was predominant.
Entry
Time [h]
RCH2NO2
Product
Yield[b]
1
2
3
4
5
6
16
20
20
3
20
70
70
23
20
48
48
20
48
20
2a
2b
2c
2d
2e
2f
2a
2b
2c
2c
2d
2e
2e
2f
3aa
3ab
3ac
3ad
3ae
3af
3ba
3bb
3bc
3bc
3bd
3be
3be
3bf
99
99
99
99
95
99
99
99
62
99
99
60
99
65
7[c]
8[c]
9[c]
10[c]
11[c]
12[c]
14[c]
15[c]
[a] The reactions were performed at 25 °C with 1a,b (0.1 mmol)
and nitro derivative 2a–f (3 equiv.), and the reactions were run until
completion, as determined by TLC (16–24 h). [b] Yield after chro-
matographic purification. [c] The reaction was performed at 25 °C
with 1b (1 mmol) and nitro derivative 2a–f (3 equiv.) in the presence
of DMAP (0.2 equiv.) as a catalyst.
Organocatalytic Michael- and Henry-type reactions give
simple stereoselective access to useful densely function-
alized building blocks. Nitro derivatives obtained through
organocatalytic reactions have found increasing applica-
Because many stabilized carbenium ions can be gener- tions in total synthesis. The organocatalyzed Michael ad-
ated within the useful limits of the Mayr scale, as estab- dition of functionalized aldehydes to nitroalkenes is the key
lished with the model substrates, we found that other benz- step in the total synthesis of Tamiflu and ABT 341.[25]
hydrylic, benzylic, and propargylic alcohols reacted under Therefore, we wondered if such enantioenriched and access-
the reaction conditions at 70 °C (Scheme 1).
ible building blocks could be employed in our nitro alkyl-
Asymmetric phenyldimethylaminobenzhydrylic sub- ation reaction performed in TFE. We were pleased to dis-
strates substituted with aryl or heteroaryl groups are reac- cover that the reaction was possible, and it was also highly
tive under the reaction conditions and give the products in diastereoselective. Compounds 6a–c and 7d were obtained
high yields but with poor diastereoselectivities. Moderate through standard organocatalytic procedures described by
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Eur. J. Org. Chem. 2012, 6697–6701

Direct and Stereoselective Alkylation of Nitro Derivatives
Hayashi[26] with high ee values (10:1 to 12:1 syn/anti).[27] stereoisomer) and anti (minor diastereoisomer) forms of the
Flash chromatography purification of these compounds, starting material. In fact, the reaction of 7e (2:1 syn/anti)
performed by our group, resulted in decreased dia- with 1a in TFE at 0 °C was not complete after 24 h, and
stereomeric ratios in comparison to the results obtained by the observed ratio of 9ae was 4:1syn/anti. In contrast, when
Hayashi.[28] When the aldehyde was reduced to the corre- 7f (2:1syn/anti) was treated with 1a in TFE at –20 °C for
sponding alcohol prior to chromatography, the dr values 18 d, the dr of the final mixture (50 % conversion) was 4:1.
obtained were in line with those in Hayashi’s paper. Never- Substrates 7e–g were obtained with a thiourea catalyst by
theless, in both cases, the inseparable mixtures of diastereo- following the protocol established by Jacobsen.[29] As re-
isomers were used in the nitro alkylation reaction to evalu- ported by Jacobsen, the dr obtained in this reaction is mod-
ate the diastereoisomeric stereoselectivity of the reaction.
erate. However, more hindered substrates undergo alkyl-
By employing Hayashi’s protocol, enantiomeric excess ation in TFE in a diastereoselective reaction. No evidence
values up to 99% were obtained, and just two stereoisomers for the presence of the other two diastereoisomers was ob-
1
of the four possible isomers were present in the mixtures tained by H NMR spectroscopy or HPLC–MS (ESI). The
(syn and anti diastereoisomers of the nitro-Michael reac- reaction was also possible with alcohol 4c, but a mixture of
tion). In the alkylation reaction performed in TFE over 20– diastereoisomers was obtained. The reaction of a chiral ni-
70 h, alcohols that were not able to form the carbenium ion tro derivative with alcohols 1a, 1b, and 4c is another exam-
were recovered unconsumed after the reaction, and they do ple of a diastereoselective SN1-type reaction. Quite recently,
not need to be protected. Four diastereoisomers can be Bach exploited diastereoselective alkylations[30] by using
formed by this alkylation reaction performed in TFE: syn– SN1-type reactions[31] in which chiral carbenium ions are
syn, syn–anti, anti–syn, and anti–anti. In all the substrates formed and treated with various nucleophiles. The relative
investigated, we found [in the limits of NMR spectroscopy, anti configuration of the newly formed stereogenic center
GC–MS, and HPLC–MS (ESI)] the predominant presence was established by NOE correlation with 400- and 600-
of two favored diastereoisomers. Starting from a mixture MHz NMR spectrometers on a cyclic product obtained af-
with 10:1dr, it was possible to recognize the presence of ter reduction of the nitro group (Scheme 3, see Supporting
another diastereoisomer as a minor component in the crude Information for full details). The reaction of 7a
reaction mixture (for 8aa and 8ba, Scheme 2). The reaction (3:1syn/anti, 99%ee) in TFE gave corresponding product
was highly diastereoselective, and the stereogenic center 9aa, which was purified by chromatography and treated
formed in the alkylation reaction was obtained with high with Ni-Raney in MeOH at 20 °C in the presence of H2.
stereocontrol (up to 9–10:1anti/syn). The variation in the Corresponding pyrrolidine 10a was isolated in 60 % yield
ratio between the starting and final diastereoisomers is in- with high enantiomeric excess after chromatographic purifi-
ferred by the different reactivities of the syn (major dia- cation.
Scheme 2. Highly diastereoselective addition of enantioenriched nitro derivatives 6a–g and 7d–g to alcohols 1a, 1b, and 4c. Conversions
1
were determined by H NMR spectroscopy.
Eur. J. Org. Chem. 2012, 6697–6701
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6699

D. Petruzziello, A. Gualandi, S. Grilli, P. G. Cozzi
SHORT COMMUNICATION
ation of the carbenium ions formed from the alcohols in a
highly diastereoselective fashion. Hindered secondary
amines can be prepared from these adducts in a straight-
forward manner to give access to functionalized, useful
organocatalytic chiral pyrrolidines. A family of new pyrrol-
idines bearing stereogenic centers and functional groups
can be readily accessed by this methodology.[34]
Scheme 3. Cyclization of derivative 9aa by Ni-Raney in MeOH.
Although the precise role of TFE in the diastereoselec-
tive reaction is not clear at the present time,[32] we can sug-
gest a model for the formation of the major stereoisomer.
We assume that the steric hindrance of the carbenium ion,
generated by the action of TFE, is attacked by the nitro
derivative while avoiding steric interaction with the aryl
groups on the α-carbon atom (Figure 1).
Experimental Section
General Procedure: To a solution of the nitro derivative (3–5 equiv.)
dissolved in TFE (0.2 mL) was added the alcohol (0.1 mmol). The
mixture was stirred at room temperature in a capped vial until the
reaction was complete. After addition of water and evaporation of
TFE under reduced pressure, the aqueous phase was extracted with
Et2O (2ϫ 5 mL). The collected organic layers were dried with an-
hydrous Na2SO4 and concentrated. The residue was purified by
flash chromatography.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures, characterization data, 1H NMR
and 13C NMR spectra, LC–MS data, and HPLC traces.
Acknowledgments
Programma di Ricerca di Rilevante Interesse Nazionale (PRIN),
Bologna University, Fondazione Del Monte, and the European
Commission through project FP7-201431 (CATAFLU.OR) are ac-
knowledged for financial support. Dr. F. Benfatti and Dr. R. Sinisi
are acknowledged for the preliminary investigations of this project.
Mrs. Claire Wilson is acknowledged for proofreading the article.
Figure 1. Stereochemical model for the addition of chiral nitro de-
rivatives to benzhydrylic alcohols.
It is worthy to note that the cyclization procedure gives
simple access to α-substituted pyrrolidines that might serve
as potential organocatalysts. To shown the potentially of
newly synthesized catalysts 10a,[33] we have explored its use
in standard organocatalytic reactions (Scheme 4).
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Direct and Stereoselective Alkylation of Nitro Derivatives
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Received: October 11, 2012
Published Online: October 30, 2012
Eur. J. Org. Chem. 2012, 6697–6701
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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