Solvent-free non-covalent organocatalysis: Enantioselective addition of nitroalkanes to alkylideneindolenines as a flexible gateway to optically active tryptamine derivatives

Article abstract of DOI:10.1002/adsc.201100737

A catalytic asymmetric addition of nitroalkanes to alkylideneindolenines, generated in situ from arylsulfonylindoles, is presented. Despite the weakness of the non-covalent H-bond interactions between catalyst and substrates, the performance of the bifunc

Full text of DOI:10.1002/adsc.201100737

FULL PAPERS
DOI: 10.1002/adsc.201100737
Solvent-Free Non-Covalent Organocatalysis: Enantioselective
Addition of Nitroalkanes to Alkylideneindolenines as a Flexible
Gateway to Optically Active Tryptamine Derivatives
Mariafrancesca Fochi,a Lucia Gramigna,a Andrea Mazzanti,a Sara Duce,a,b
Stefano Fantini,a Alessandro Palmieri,c Marino Petrini,c,* and Luca Bernardia,*
a
Department of Organic Chemistry “A. Mangini”, University of Bologna, V. Risorgimento 4, 40136 Bologna, Italy
Fax : (+39)-051-209-3654; phone: (+39)-051-209-3631; e-mail: luca.bernardi2@unibo.it
Department of Organic Chemistry, Universidad Autꢀnoma de Madrid, Cantoblanco, 28049 Madrid, Spain
School of Science and Technology, Chemistry Division, University of Camerino, V. S. Agostino 1, 62032 Camerino, Italy
b
c
Fax : (+39)-0737-402-297; phone: (+39)-0737-402-253; e-mail: marino.petrini@unicam.it
Received: September 22, 2011; Revised: January 17, 2012; Published online: April 24, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100737.
Abstract: A catalytic asymmetric addition of nitroal- vents and reagents, resulting in a truly solvent-free
kanes to alkylideneindolenines, generated in situ reaction. The broad substrate scope shown by the
from arylsulfonylindoles, is presented. Despite the present transformation allowed the preparation of
weakness of the non-covalent H-bond interactions some optically active tryptamine precursors that are
between catalyst and substrates, the performance of not accessible through the previous catalytic asym-
the bifunctional organocatalyst used was found to be metric methods.
essentially unaffected by the polarity of the reaction
medium. Nitroalkanes, mostly used in nearly stoi- Keywords: asymmetric synthesis; nitroalkanes; orga-
chiometric amounts, could thus function both as sol- nocatalysis; solvent-free conditions; tryptamine
Introduction
tivity sometimes observed when increasing reaction
concentration and/or catalyst loading.[5]
According to green chemistry principles, minimisation
During our preliminary studies on the asymmetric
of solvents is one of the most important issues to be addition of nitroalkanes 2 to alkylideneindolenines
considered in the realisation of sustainable chemical (Scheme 1) catalysed by bifunctional organic catalysts
processes.[1] The development of chemical reactions bearing tertiary amines flanked by double H-donors
proceeding efficiently even without solvents (solvent- such as thioureas,[6] uniform enantioselectivities were
free organic synthesis) is thus of high significance. Be- surprisingly observed using a broad range of different
sides, practical advantages of solvent-free organic re- reaction media and concentrations. Even rather
actions are reduction of volumes, increased safety, highly polar and coordinating solvents could in fact
easier work-up procedures, improved reaction kinetics be successfully employed, including aqueous solutions.
and facilitation of one-pot protocols.[2] So far, organo- Unusually high concentrated conditions (>1M) were
catalysis under solvent-free conditions has been also very well tolerated. We rationalised this surpris-
mostly limited to processes involving covalent cata- ing behaviour by considering the very efficient recog-
lyst-substrate(s) intermediates.[3] It is in fact perceived nition of nitro compounds by double H-bond donors,
that aprotic solvents of low polarity are required a linchpin in asymmetric organocatalysis using non-
when coordination of catalyst to substrate(s) is given covalent interactions.[6] Besides, the soft enolisation of
instead by hydrogen bonds, electrostatic or Van der nitroalkanes promoted by these bifunctional catalysts
Waals forces.[4] These weaker, more flexible and less leads to nitronate-catalysts assemblies,[7] wherein elec-
directional interactions (compared to covalent bind- trostatics reinforce the coordination given by the net-
ing), are expected to be much more sensitive to the work of H-bonds (Scheme 1).[8] This arrangement of
polarity and the coordinative properties of the multiple weak interactions was thus rendering the cat-
medium, as highlighted by the decrease in stereoselec- alyst-substrate(s) couple so strongly bound and geo-
metrically well-defined, as to be unperturbed and un-
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Scheme 1. Catalytic asymmetric addition of nitroalkanes 2 to alkylideneindolenines.
affected by its external environment. We quickly rec- reported procedure gives useful enantioselectivities
ognised the potential of this system for the realisation only for phenylnitromethanes, a rather specific class
of an unusual solvent-free asymmetric reaction using of nitroalkanes. This narrow range of accessible com-
H-bond based bifunctional catalysts. In this situation pounds thus leaves space for substantial improvement
an apolar reaction medium should not in fact be in this important transformation.
strictly necessary.[9] As dilution issues should also be
absent, the use of small amounts of the polar nitroal-
kane substrates as reaction media could be envi- Results and Discussion
sioned. However, nitroalkanes are typically used in
large excess (5–10 equiv.) in organocatalytic transfor- We initially investigated the catalytic asymmetric re-
mations,[6,9k] thus posing an additional challenge to action between nitroethane 2a and the p-toluenesul-
this approach. A truly solvent-free reaction obviously fonyl-2-methylindole 1a, in the presence of inorganic
does not involve excess liquid reagents. However, bases for the promotion of sulfinic acid elimination
given the already mentioned benefits of solvent-free and formation of the alkylideneindolenine intermedi-
organic synthesis, we embarked on a detailed investi- ate (Table 1). Reactions were performed under neat
gation, herein presented, on the solvent-free asym- conditions, using an excess of nitroethane 2a as both
metric addition of nitroalkanes 2 to alkylideneindole- solvent and reagent (5 equiv.), and several catalysts
nines, conveniently generated in situ from arylsulfony- 4a–k (Figure 1) featuring tertiary amino moieties
lindoles 1[10] catalysed by bifunctional organic cata- flanked by double hydrogen donors or a single sulfo-
lysts (Scheme 1). Nitroalkanes 2, functioning as both namide donor. Among the different inorganic bases
substrates and reaction media, could be used in tested, solid K3PO4 (1.1 equivalents)[13c] was found to
nearly equimolar amounts in most cases, thus result- be able to promote smoothly the reactions at room
ing in solvent-free reactions.
temperature under these concentrated conditions, af-
After reduction of the nitro group, this transforma- fording the corresponding tryptamine precursor 3aa
tion gives access to optically active tryptamines show- as a diastereomeric mixture (ca. 60:40). Although cat-
casing a chiral centre at the benzylic position. Some alysts 4e and 4f were developed specifically by Chin
of these tryptamines have shown highly significant and Song for reactions at high concentrations, being
biological profiles.[11] The most popular access to unable to self-aggregate,[5] in our case the more popu-
these chiral adducts has until now been the catalytic lar thiourea derived structures 4a and 4b[14] proved to
asymmetric Friedel–Crafts reaction of indoles with ni- be much more efficient in terms of enantioselectivities
troalkenes.[12] The remarkable tolerance of the present (Table 1, entries 1, 2 and 5, 6). Rawalꢂs squaramide[15]
protocol to even secondary nitroalkanes complements catalysts 4c and 4d gave instead intermediate results
the Friedel–Crafts transformation, intrinsically limited (Table 1, entries 3 and 4), whereas Takemotoꢂs cata-
to a-unsubstituted or mono-substitued tryptamine lyst 4g[16] afforded the adduct 3aa with results compa-
precursors. A catalytic asymmetric protocol under rable, albeit slightly inferior, to those of the quinine-
standard solvent conditions has already been devel- derived thiourea 4a (Table 1, entry 7). We prepared
oped for the addition of nitroalkanes to alkylidenein- the corresponding catalysts 4h and 4i featuring a terti-
dolenines using a bisamidine catalyst.[13] However, the ary nitrogen atom with long alkyl chains. Secondary
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Solvent-Free Non-Covalent Organocatalysis: Enantioselective Addition of Nitroalkanes
Table 1. Representative optimisation results for nitroethane
2a.[a]
amine catalysts bearing long alkyl chains in their
structure have been useful for the development of en-
amine and iminium ion catalysis in aqueous medium,
wherein these long chains serve as reaction environ-
ment.[17] However, in our case this strategy proved to
be unproductive (Table 1, entries 8 and 9). Better re-
sults than with catalyst 4a were instead obtained
simply switching to the corresponding more soluble
dihydroquinine derivative 4j (Table 1, compare en-
tries 1 and 10). At this point, results obtained with
this catalyst 4j under neat conditions were compared
with the behaviour of the same catalyst in toluene as
the solvent. Very similar enantioselectivities were ob-
tained (Table 1, entries 10 and 11), thus demonstrat-
ing that despite the weakness of the non-covalent H-
bond interactions involved, the performance of these
substrate-catalyst assemblies is essentially unaffected
by the polarity of the reaction medium. The surpris-
ingly similar reaction rates of the reaction in toluene
and under neat conditions can instead be rationalised
by considering that the slow step of the whole process
is the formation of the alkylideneindolenine inter-
mediate, occurring at the surface of the solid base and
thus not strongly influenced by the concentration in
the liquid phase. Reaction monitoring by TLC and
1H NMR at different conversions showed in fact the
exclusive presence of starting arylsulfonylindole 1a
and product 3aa in the reaction mixture. No alkyli-
dene intermediate was detected. Rapidity in the enan-
tioselective addition to the rather unstable alkylide-
neindolenine, preventing its decomposition, is indeed
essential for reaction efficiency under these concen-
trated conditions.[18] In order to approach a truly sol-
vent-free reaction, we then decreased the amount of
nitroethane 2a to 1.5 equivalents. Despite the visual
Entry
2a (equiv.)
Cat. 4
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
5
5
5
5
1.5
1.5
1.5
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4j
4j
4k
4k
91
95
90
68
77
80
95
91
86
91
95
88
95
80
87/82
83/76
66/37
30/10
13/7
0/0
86/81
10/10
12/10
94/92
96/94
91/85
95/93
94/93
9
10
11[d]
12
13
14[e]
[a]
Conditions: 1a (0.1 mmol), catalyst 4 (0.01 mmol), nitro-
alkane 2a (see Table), K3PO4 (0.11 mmol), room temper-
ature, 60 h.
[b]
[c]
1
Determined by H NMR on the crude mixture using di-
benzyl as internal standard. 3aa was obtained as a ca.
60:40 diastereomeric mixture in all experiments.
Determined by chiral stationary phase HPLC. The two
values refer to the two diastereoisomers.
Reaction performed in toluene (1.0 mL).
Aqueous K3PO4 (50% w/w, 0.15 mmol) was used as the
base.
[d]
[e]
Figure 1. Bifunctional catalysts tested in the reaction between arylsulfonylindole 1a and nitroethane 2a.
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Table 2. Variation of the arylsulfonyl indole 1.[a]
dehydes, were an initial matter of concern. However,
as shown in Table 2 all substrates 1a–j derived from
the combination of aromatic and aliphatic aldehydes
with 2-methylindole reacted smoothly under the opti-
mised reaction conditions, furnishing the correspond-
ing products 3aa–3ja with good results in terms of
yields and enantiomeric excesses (Table 2, entries 1–
10). Enantioselectivities were particularly good for
the substrates derived from aromatic aldehydes. In
line with the previous literature,[13a–c] arylsulfonyl
indole 1k gave the product 3ka in nearly racemic
form (Table 2, entry 11). The lack of enantioselectivi-
ty for 2-unsubstituted indoles is usually ascribed to
poor geometrical E/Z control in the alkylideneindole-
nine intermediate. Although requiring a substituent at
the 2-position of the indole core, significant structural
variations in this substituent are tolerated by the pres-
ent system. Arylsulfonylindoles 1l and 1m, bearing an
aryl and an ester group, which might serve as handles
for further manipulations, can in fact be productively
engaged in this asymmetric transformation, affording
the corresponding adducts 3la and 3ma with good re-
sults (Table 2, entries 12 and 13).
Entry
1
R1
R2
3 (Yield [%][b]) ee [%][c]
1
1a Ph
1a Ph
1b 4-NO2C6H4 Me
1c 4-t-BuC6H4 Me
1d 4-MeOC6H4 Me
1e 4-PhC6H4
1f 2-ClC6H4
1g 4-ClC6H4
1h n-pentyl
Me
Me
3aa (90)
ent-3aa (98)
3ba (97)
3ca (60)
3da (89)
3ea (74)
3fa (84)
3ga (92)
3ha (74)
3ia (78)
3ja (83)
3ka (65)
3la (68)
95/93
87/78
97/99
95/94
94/88
99/97
97/96
97/96
83/70
82/72
87/71
4/18
2[d,e]
3
4
5
6
7
8
8
Me
Me
Me
Me
Me
Me
H
9[e]
10
11
12
13[f]
1i PhACHTUNGTRENNUNG(CH2)2
1j Cy
1k Ph
1l Ph
1m Ph
Ph
84/62
96/97
CO2Et 3ma (80)
Variation of the nitroalkane partner was then sur-
veyed, using the parent arylsulfonylindole 1a. As
shown in Table 3, primary nitroalkanes 2b–e could be
used with very good results (Table 3, entries 1–4),
with the exception of phenylnitromethane 2e
(Table 3, entry 5). Less obviously, the optimised reac-
tion conditions could also be directly translated to the
more hindered secondary nitroalkanes 2f–h as nucleo-
philes, giving the corresponding products 3af–3ah
with moderate to good yields and enantioselectivities
(Table 3, entries 6–10). By using mechanical stirring
(instead of magnetic) for a more efficient mixing of
the solid mixture, the reaction with 2-nitropropane 2f
[a]
Conditions: arylsulfonylindole 1a–l (0.10 mmol), catalyst
4k (0.010 mmol, 10 mol%), nitroethane 2a (0.15 mmol,
1.5 equiv.), K3PO4 (0.11 mmol, 1.1 equiv.), room tempera-
ture, 60 h.
Isolated yield after chromatography on silica gel. Ad-
ducts were isolated as diastereomeric mixtures (ca. 60:40
in all cases).
Determined by chiral stationary phase HPLC. The two
values refer to the two diastereoisomers.
Dihydroquinidine-derived catalyst.
[b]
[c]
[d]
[e]
[f]
2 equiv. of 2a were used.
1 mL of 2a, 20 mol% 4k, Na2CO3 as the base, 508C.
appearance of the reaction as a mixture of different could also be performed on a preparative scale with
solids, adduct 3aa formed smoothly with comparable comparable results (Table 3, entry 7).
enantiomeric excess (Table 1, entry 12). Remarkably,
Nitromethane 2i showed instead a very different
even this very small amount of liquid nitroethane 2a behaviour. Under conditions suitable for both pri-
is able to homogenise sufficiently the system, consid- mary and secondary nitroalkanes, nitromethane 2i fur-
ering that all other reagents and products are solid. nished the corresponding product 3ai in much re-
Even better results were obtained using the corre- duced yield, although the enantiomeric excess was
sponding urea-derived catalyst 4k (Table 1, entry 13). good (Scheme 2, top). This sharp decrease in yield is
Worth noting, the use of an aqueous base did not in- due in part to the decreased reactivity of nitrome-
fluence the enantioselectivity obtained, thus further thane 2i, slowing down the rate of the addition to the
highlighting the tolerance of this catalytic system to alkylideneindolenine. This rather unstable intermedi-
different reaction environments (Table 1, entry 14).[19] ate[10d] accumulates in the reaction mixture and de-
Using these conditions (Table 1, entry 13), variation composes prior to the catalytic addition. A second
in the structure of both sulfonylindole 1 and nitroal- reason is the formation of the dimeric product 3ai’ in-
kane 2 was explored. Initially, different arylsulfonylin- corporating one nitromethane and two indole units,
doles 1a–m, derived from different aldehydes and in- deriving from attack of the adduct 3ai to a second al-
doles, were reacted with nitroethane 2a (Table 2). The kylideneindolenine electrophile (Scheme 2, top). An
presumably different solubility of the solid arylsulfo- additional optimisation round was thus undertaken
nylindoles 1 into the little amount of nitroethane (see the Supporting Information). Final optimised
used, together with increased instability of the alkyli- conditions, preventing both side processes, entailed
dene indolenines derived from aliphatic enolisable al- the use of excess nitromethane 2i in the presence of
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Solvent-Free Non-Covalent Organocatalysis: Enantioselective Addition of Nitroalkanes
Table 3. Variation of the nitroalkane 2.[a]
Entry
2
R1
R2
3 (Yield [%][b]) ee [%][c]
1
2
2b Et
H
H
H
H
H
3ab (98)
3ac (99)
ent-3ac (73)
3ad (81)
3ae (65)
96/95
96/94
95/99
>99/>99
77/75
91
91
79
98
98
2c
2c
n-pentyl
n-pentyl
3[d]
4[e]
5[f]
6
2d Cy
2e Ph
2f
2f
2f
2g
2h
Me
Me
Me
Me 3af (85)
Me 3af (68)
Me ent-3af (75)
3ag (65)
7[e,g]
8[d,e]
9
G
E
Figure 2. X-ray ORTEP structure for the major diastereoiso-
mer of compound 3ga.
10[e]
3ah (66)
[a]
Conditions: sulfonylindole 1a (0.10 mmol), catalyst 4k
(0.010 mmol, 10 mol%), nitroalkane 2b–h (0.15 mmol,
1.5 equiv.), K3PO4 (0.11 mmol, 1.1 equiv.), room tempera-
ture, 60 h.
Isolated yield after chromatography on silica gel. 3ab–
3ae were obtained as diastereomeric mixtures (ca. 60:40
in all cases).
Determined by chiral stationary phase HPLC. The two
values refer to the two diastereoisomers.
Dihydroquinidine catalyst.
Na2CO3 as the inorganic base at 508C. These condi-
tions could be successfully applied with good results
to a few substrates 1a, d, f, j (Scheme 2, bottom).
The relative and absolute configuration for the
major diastereoisomer of adduct 3ga was unambigu-
ously determined as (1S,2S) by anomalous X-ray dif-
fractometric analysis (Figure 2, for details see the
Supporting Information).[20]
By comparing the optical rotation and HPLC data
of compound 3ai with literature values (see the Sup-
porting Information), it was possible to verify that
this compounds features the same 1S configuration at
the benzylic chiral centre. Attack at the Si-face of the
prochiral E-alkylideneindolenine intermediate by the
catalyst 4k-nitronate ion pair accounts for the ob-
served stereoselectivity in both cases, and can be vi-
sualised with the transition state model depicted in
Figure 3, derived from available computational stud-
ies on related systems.[7] As previously mentioned
(Scheme 1), soft enolisation of the nitroalkane gener-
ates a nitronate coordinated by multiple H-bonds
[b]
[c]
[d]
[e]
[f]
2 equiv. of nitroalkane were used.
K2CO3 (5 equiv.) was used as the base.
Reaction on 1.0 mmol scale, at 308C, mechanical stirring.
[g]
Scheme 2. Catalytic enantioselective addition of nitrome-
thane 2i.
Figure 3. Transition state model.
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with the catalyst. This highly defined assembly reacts dary nitroalkanes gives access to tryptamines that are
selectively with the alkylideneindolenine, eventually not accessible through the previously reported cata-
activated by a hydrogen bond interaction. Whereas lytic asymmetric methods [Eq. (1)].[12,13a]
coordination of the alkylideneindolenine electrophile
to the ammonium proton is only speculative, the for-
mation of a triply coordinated nitronate-catalyst as- Experimental Section
sembly evolving to the transition state seems highly
plausible. As subjecting the major diastereisomer of Typical Procedure for the Organocatalytic
3ga to the reaction conditions did not result in observ- Enantioselective Addition of Nitroalkanes 2 to 3-(1-
able epimerisation, the low diastereomeric ratio ob- Arylsulfonylalkyl)indoles 1
served when primary nitroalkanes 2a–e were used in
the reaction cannot be ascribed to thermodynamic
To a 10-mL test tube equipped with a magnetic stirring bar,
3-(1-arylsulfonylalkyl)indole 1a (37.5 mg, 0.10 mmol), cata-
equilibration of the products 3aa–ma and 3ab–ae. The
low diastereoselectivity of the reaction is instead due
to the inability of catalyst 4k in controlling the prochi-
ral face of the nitronate reacting with the alkylide-
neindolenine.
Reduction of the nitro moiety in adducts 3af and
3ai, to give the corresponding highly valuable trypt-
lyst 4k (5.8 mg, 0.01 mmol, 10 mol%), nitroethane 2a
(11.3 mL, 0.15 mmol) and K3PO4 (0.11 mmol, 23 mg) were
sequentially added. The mixture was stirred at room temper-
ature for 60 h, then saturated NH4Cl solution (1.0 mL) was
added. The organic product was extracted with toluene (2ꢃ
1.0 mL),[20] filtered through a plug of silica gel and the plug
washed with Et2O (2ꢃ). After evaporation of the solvents,
1
the residue was analysed by H NMR spectroscopy to deter-
ACHTUNGTRENNUNGamines, was straightforward. After derivatisation with
mine the conversion and the diastereomeric ratio of the
product. Finally, the residue was purified by chromatogra-
phy on silica gel (n-hexane/CH2Cl2, 2:3) giving the product
3aa as an off-white solid as a diastereomeric mixture
(68:32); yield: 90%. The enantiomeric excess of the product
was determined by chiral stationary phase HPLC (Chiralpak
AD-H, n-hexane/i-PrOH 90:10, 0.75 mLminÀ1, l=254 nm):
major diastereoisomer: tmaj =19.2 min, tmin =29.1 min, 95%
ee; minor diastereoisomer: tmaj =18.0 min, tmin =23.9 min,
93% ee. 1H NMR (CDCl3, 400 MHz): d=7.89 (br s, 1H
maj), 7.77 (br d, J=8.2 Hz, 1H min), 7.74 (br s, 1H min),
7.61 (br d, J=7.5 Hz, 1H maj), 7.45 (br d, J=7.23 Hz, 2H
min), 7.40 (br d, J=8.0, 2H maj), 7.34–7.06 (various m, 6H
maj+6H min), 5.90–5.76 (m, 1H maj+1H min), 4.77 (d,
J=11.2 Hz, 1H maj), 4.68 (d, J=11.8 Hz, 1H min), 2.40 (s,
3H maj), 2.35 (s, 3H min), 1.65 (d, J=6.5 Hz, 3H min), 1.52
(d, J=6.6 Hz, 3H maj); 13C NMR (CDCl3, 100 MHz): d=
140.3 (maj), 139.7 (min), 135.3 (maj), 135.2 (min), 132.6
(maj), 132.2 (min), 128.8 (min), 128.6 (maj), 128.2 (min),
127.3 (maj), 127.0 (min), 126.9 (maj), 126.6 (maj), 126.5
(min), 121.3 (maj), 121.0 (min), 119.8 (maj), 119.5 (min),
118.8 (min), 118.6 (maj), 110.7 (maj), 110.6 (min), 109.8
(min), 109.4 (maj), 86.2 (maj), 85.6 (min), 48.4 (min), 47.6
(maj), 19.6 (min), 19.3 (maj), 12.1 (maj), 12.0 (min); MS
(EI): m/z=294 (15, M+), 220 (100, MÀC2H4NO2).
TsCl to facilitate isolation by chromatography on
silica gel, compounds 5af and 5ai were obtained in ex-
cellent yields and with enantiomeric excesses compa-
rable to those of the starting 3af and 3ai [Eq. (1) and
Eq. (2)].
Preparative Scale Procedure for Compound 3af
Conclusions
To a 25-mL round-bottom flask equipped with a mechanical
Exploiting the efficient recognition of the nitro stirrer, were sequentially added 2-methyl-3-[phenyl-
AHCTUNGTREG(NNUN tosyl)methyl]-1H-indole 1a (375.4 mg, 1.0 mmol), catalyst
moiety by bifunctional organocatalysts, it was possible
to develop the catalytic asymmetric addition of nitro-
alkanes to alkylideneindolenines under solvent-free
conditions.[21] The reaction employs readily available
and bench stable catalysts and substrates, rendering
feasible the addition to rather unstable alkylidenein-
dolenines through their generation in situ. Reduction
of the nitro group in the adducts gives highly valuable
enantioenriched protected tryptamines. Remarkably,
4k (58.0 mg, 0.10 mmol, 10 mol%), 2-nitropropane 2f
(180 mL, 2.0 mmol), and finely ground K3PO4 (233.5 mg,
1.1 mmol). The mixture was mechanically stirred at 308C for
60 h, then saturated NH4Cl solution (10 mL) was added and
the product was extracted with CH2Cl2 (3ꢃ10 mL). The
combined organic phases were dried over Na2SO4, filtered
and evaporated under reduced pressure. Finally, the residue
was purified by chromatography on silica gel (n-hexane/
CH2Cl2, 2:3) giving (S)-2-methyl-3-(2-methyl-2-nitro-1-phe-
the tolerance of this reaction manifold also to secon- nylpropyl)-1H-indole 3af as an off-white solid; yield: 210 mg
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Solvent-Free Non-Covalent Organocatalysis: Enantioselective Addition of Nitroalkanes
(68%); mp 106–1088C; [a]2D0: À81 (c 0.425, CH2Cl2). The
enantiomeric excess of the product was determined by
chiral stationary phase HPLC (Chiralpak AS, n-hexane/i-
Lee, J. E. Lee, S. H. Youk, J. Chin, C. E. Song, Angew.
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PrOH 90:10, 1.0 mLminÀ1, l=254 nm): tmaj =9.4 min, tmin
=
1
10.2 min, 91% ee). H NMR (CDCl3, 400 MHz): d=7.95 (br
s, 1 H, NH), 7.39 (d, J=7.8 Hz, 1H, HAr), 7.34–7.14 (m, 6H,
HAr), 7.11 (dt, J=7.4, 1.2 Hz, 1H, HAr), 7.01 (dt, J=7.4,
1.2 Hz, 1H, HAr), 5.30 (s, 1H, benzylic H), 2.42 (s, 3H,
indole CH3), 1.19 (s, 3H, propyl CH3), 1.67 (s, 3H, propyl
CH3); 13C NMR (CDCl3, 100 MHz): d=139.5 (CAr), 135.4
(CAr), 134.1 (CAr), 128.35 (CAr), 128.3 (CAr), 127.6 (CAr),
126.45 (CAr), 121.1 (CAr), 120.5 (CAr), 119.6 (CAr), 110.5
(CAr), 110.1 (CAr), 92.9 (CNO2), 50.1 (benzylic C), 29.0
(propyl CH3), 23.2 (propyl CH3), 12.85 (indole CH3); MS
(EI): m/z=308 (7, M+), 261 (90, MÀHNO2), 220 (100,
MÀC3H6NO2); HR-MS (EI): m/z=308.15266, calcd. for
C19H20N2O2: 308.15248.
Acknowledgements
We acknowledge financial support from University of Bolo-
gna, Polo Scientifico-Didattico di Rimini, University of Ca-
merino and FIRB National Project ꢀMetodologie di nuova
generazione nella formazione di legami carbonio-carbonio
e carbonio-eteroatomo in condizioni eco-sostenibiliꢁ. S. D.
thanks University of Madrid and Comunidad Autꢂnoma de
Madrid for a fellowship. M. F. and L. B. thank Dr. Mauro
Comes-Franchini and Prof. Alfredo Ricci for support.
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