Trifunctional Squaramide Catalyst for Efficient Enantioselective Henry Reaction Activation

Article abstract of DOI:10.1002/adsc.201600046

A new class of trifunctional squaramide catalyst acting by means of multiple interactions has been found in a study of the Henry reaction. Enantiomerically enriched nitroaldol products were obtained in good yields and high enantioselectivities under mild

Full text of DOI:10.1002/adsc.201600046

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DOI: 10.1002/adsc.201600046
Trifunctional Squaramide Catalyst for Efficient Enantioselective
Henry Reaction Activation
a
a
a,
Juan V. Alegre-Requena, Eugenia MarquØs-López, and Raquel P. Herrera *
a
Laboratorio de Organocatµlisis AsimØtrica, Departamento de Química Orgµnica, Instituto de Síntesis Química y Catµlisis
HomogØnea (ISQCH), CSIC–Universidad de Zaragoza, C/Pedro Cerbuna 12, 50009 Zaragoza, Spain
E-mail: raquelph@unizar.es
Received: January 13, 2016; Revised: March 16, 2016; Published online: May 3, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600046.
Abstract: A new class of trifunctional squaramide actions with the substrates, responsible of the im-
catalyst acting by means of multiple interactions has provement in the reactivity and the enantioselectivi-
been found in a study of the Henry reaction. Enan- ty of this process. Computational calculations sup-
tiomerically enriched nitroaldol products were ob- port a mechanistic hypothesis based on an anion-p
tained in good yields and high enantioselectivities effect, this being the first example reported in asym-
under mild conditions using one of the smallest metric catalysis.
amounts of organocatalyst reported so far for this re-
action (0.25 mol%). The catalyst was able to gener- Keywords: aldehydes; Henry reaction; nitroalkanes;
ate hydrogen bonding and anion-p/hydrogen-p inter- organocatalysis; squaramides; trifunctional catalysts
Introduction
The reaction between an in situ generated nitronate
species and a carbonyl compound, known as the
[4]
Multifunctional scaffolds have received special atten- Henry (nitroaldol) reaction, is an important carbon-
tion in the last decade, with the increasing interest for carbon bond-forming method in organic synthesis.
[5]
the synthesis of more complex catalytic systems with This process represents a powerful and useful tool for
a high organization grade and a multidentate activa- the synthesis of valuable b-nitro alcohols providing,
tion, to offer a cooperative effect resembling the role after further transformations of the versatile nitro
[
1,2]
of enzymes.
These structures could facilitate the group, efficient access to interesting and highly func-
formation of cooperative non-covalent interactions in tionalized intermediates, like b-amino alcohols and a-
[6,7]
a synergic way and thereby significantly improve their hydroxy carboxylic acids.
The Henry reaction may
catalytic activity. This would overcome the drawback be promoted under many different conditions and
of high catalyst loadings that are commonly used in using diverse catalytic systems providing from good-
[3]
[8,9]
organocatalysis, which is still a great challenge.
to-excellent enantioselectivities.
In fact, many ef-
These studies have focused on hydrogen bonding, forts have been invested for improving this method,
electrostatic effects, p-p, cation-p, hydrophobic and and different kinds of organocatalysts have been ex-
Van der Waals forces. All these interactions are be- plored in order to increase the pioneering results re-
[10]
lieved to be involved in stabilizing the transition ported by Nµjera and co-workers in 1994.
states by lowering the energetic barrier with a remark- Therefore, the development of new asymmetric
able increase in the rate of the reaction. These bind- Henry strategies is still important to address the con-
ings could also be responsible of the improvement in struction of interesting building blocks as a crucial
the stereoselectivity of the process by differentially step in total synthesis (Figure 1).
stabilizing the diastereomeric pathways created in the
Herein, we report a new class of trifunctional squar-
transition state between the catalyst and the reacting amide catalysts acting through multidentate activa-
components. Additionally, non-covalent interactions tion, which efficiently catalyzes the asymmetric Henry
operating in a synergic way can afford the conforma- reaction with high yields and high enantioselectivities
tional restriction required to induce high enantiose- (up to 94% ee). A low catalyst loading is required,
lectivity.
routinely 2 mol%, and this can even be decreased to
as low as 0.25 mol% without detriment of the enan-
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Figure 1. Biologically active compounds bearing a b-amino
alcohol motif.
tioselectivity. Interestingly, this is one of the lowest
loadings used so far in organocatalysis for this reac-
tion. Moreover, this is the first reported example of
a reaction using squaramides where an anion-p inter-
Figure 2. Representative squaramide-based organocatalysts
tested.
action and a H-p interaction have been found in the the model reaction between 4-nitrobenzaldehyde (2a)
transition state (TS) and could justify the efficiency of and nitromethane (3a) (see the Supporting Informa-
the catalyst used. To the best of our knowledge, this tion for the complete outcomes). After a very exhaus-
kind of activation has not been explored so far in tive screening of the reaction conditions, novel cata-
asymmetric catalysis, and therefore this work could lyst 1j (2 mol%) was found to be the catalyst of
[
11,12]
represent a pivotal contribution in this field.
choice in terms of reactivity and enantioselectivity (>
In this respect, many reactions are efficiently pro- 95% yield, 82% ee, Table 1, entry 1); nitromethane
moted using multifunctional catalysts, where nucleo- with no extra solvent resulted to be the best reaction
phile and electrophile are simultaneously coordinated medium, at À248C. The efficiency of the process was
to the different functional groups present in the cata- further studied for a range of different aldehydes 2a–
[
13]
lyst structure.
In the case of the Henry reaction, o (Table 1).
both components could be efficiently approached in
The Henry reaction took place rendering the de-
the TS following a bifunctional coordination and thus sired b-nitro alcohols 4 in good to excellent yields (up
represent an attractive model to explore this concept. to >95%) and high enantioselectivities (up to 94%)
Based on previous developed studies, we envisaged with very clean reaction crudes. The effectiveness of
the importance of having in the same structure a hy- the developed procedure is well accounted since it
drogen bond moiety and a basic part in order to was successfully applied to a representative set of al-
obtain a more rigid transition state at the moment of dehydes 2a–o. The enantioselectivity was not depen-
the carbon-carbon bond formation. For this aim, we dent on the electronic effects of the aldehydes. How-
[14]
chose squaramide structures 1a–j (Figure 2)
(see ever, the reactivity suggests a close correlation with
the Supporting Information for the rest of tested the electronegativity of the aldehyde since those with
structures and screening), synthesized following our an electron-withdrawing group in the aromatic ring
[
15]
one-pot developed procedure.
exhibited more reactivity. In fact, in the case of alde-
hyde 2n the reaction was slower, although keeping
the good enantioselectivity of the process (entry 14).
At this point, it is important to remark that we have
observed that the presence of traces of acid in the al-
Results and Discussion
We started the investigation of the viability of this dehydes could inactivate the catalyst used at this
process by examining the efficiency of catalysts 1 in small scale, and many of the aldehydes were previous-
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[
a]
Table 1. Scope of the squaramide-catalyzed Henry reaction.
[
b]
[c]
Entry
R
1j [%]
R’
Time [h]
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
4-NO C H (2a)
2
2
2
2
2
2
2
2
2.5
2.5
2
2
2
2
2
2
2
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
24
24
91
86
91
71
86
86
96
96
92
88
92
144
92
88
91
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ha
4ia
4ja
4ka
4la
4ma
4na
4oa
4ab
4bb
>95
>95
81
62
75
96
50
59
50
>95
95
74
55
20
83
94
86
90
86
82
85
82
90
80
92
92
92
84
76
2
6
4
3-NO C H (2b)
2
6
4
4-ClC H (2c)
6
4
3-ClC H (2d)
6
4
4-BrC H (2e)
6
4
4-CNC H (2f)
6
4
1-naphthyl (2g)
Ph (2h)
4-Ph-C H (2i)
6
4
0
1
2
3
4
5
6
7
2-pyridyl (2j)
3-pyridyl (2k)
2-furyl (2l)
2-thiophenyl (2m)
4-MeC H (2n)
6
4
PhCH OCH (2o)
66
75
74
2
2
[
[
d]
e]
[f]
[g]
4-NO C H (2a)
Me (3b)
Me (3b)
72
88
2
6
4
[f]
[g]
3-NO C H (2b)
2
6
4
[a]
Experimental conditions: to a mixture of catalyst 1j (0.0044 mmol) in MeNO (1.1 mL), aldehyde 2a–o (0.22 mmol) was
2
further added in a test tube at À248C.
After isolation by column chromatography.
Determined by chiral HPLC analysis.
dr=1:1.3 anti:syn.
dr=1:1.4 anti:syn.
Yield as mixture of both diasteroisomers.
Enantiomeric excess (ee) for the major diasteroisomer.
[
[
[
[
[
[
b]
c]
d]
e]
f]
g]
ly treated in order to avoid such inactivation. This
We continued our investigations by exploring the
fact is in agreement with the lack of background for effect of some designed changes in the structure of
this reaction in the absence of a base. The absolute the catalyst, in order to understand the role played by
configuration of final adducts 4 was determined by novel catalyst 1j, which bears different functionalities
comparison of their optical rotation values with those (Scheme 1). Thus, catalyst 1k, which has the opposite
previously reported in the literature for the same configuration (S) on the binaphthyl scaffold compared
products and it was found to be S (see the Experi- to catalyst 1j (R), was prepared in order to study the
mental Section for optical rotation values).
possible match/mismatch effect. Interestingly, no re-
We further evaluated the grade of effectiveness of versal of the sense in the asymmetric induction was
the catalytic system by lowering even more the cata- observed, giving rise to the same absolute enantiomer
lyst loading for four representative aldehydes (2a, b, f, in the final product. However, final product 4ba was
and p) (Table 2).
achieved with a lower ee value compared to catalyst
As disclosed in Table 2, interestingly, we were able 1j (81% vs. 94% ee). This suggests that the sense of
to decrease the catalyst loading to 0.25 mol%, one of the enantioinduction of this process seems to be di-
the lowest values used in a Henry protocol and one of rectly depending on the 2-(1-piperidinyl)cyclohexyl-
the lowest amounts employed so far in organocataly- amine moiety, but the different value of enantioselec-
[3]
sis. In all cases, the same enantioselectivity was tivity obtained reveals an influence of the binaphthyl
found, although after longer reaction times. It is ring in the different reaction pathways.
worth noting that this system allows for scaling up the
The reaction using catalyst 1l (with an OMe group
reaction, since the same excellent results, in terms of instead of a free OH) leads to the same good results
enantioselectivity and reactivity, were afforded when obtained with catalyst 1j. Therefore, it seems that the
it was set up to obtain 1 gram of final product binaphthyl skeleton could be crucial in stabilizing the
(
Table 2, entry 7).
TS to properly induce better enantioselectivity, even
when the participation of the OR (R=H or Me)
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[
a]
Table 2. Study of the catalyst loading for the Henry reaction.
[
b]
[c]
Entry
1
R
1j [%]
Time [h]
Yield [%]
ee [%]
4-NO C H (2a)
4-NO C H (2a)
4-NO C H (2a)
3-NO C H (2b)
3-NO C H (2b)
3-NO C H (2b)
3-NO C H (2b)
4-CNC H (2f)
1
24
76
92
24
76
95
96
95
100
92
45
120
>95
>95
86
>95
>95
92
>95
>95
>95
59
>95
>95
82
82
82
94
94
94
94
82
82
82
86
86
2
6
4
[
[
d]
e]
2
3
4
5
6
7
8
9
1
1
1
0.5
0.25
1
0.5
0.25
0.25
1
0.5
0.25
0.5
0.25
2
6
4
2
6
4
2
6
4
[
[
[
d]
e]
f]
2
6
4
2
6
4
2
6
4
6
4
[
d]
4-CNC H (2f)
4-CNC H (2f)
6
4
[
[
[
e]
0
1
2
6
4
d]
e]
F C (2p)
5
5
F C (2p)
5
5
[a]
Experimental conditions: to a mixture of catalyst 1j in MeNO (1.1 mL), aldehyde 2a, b, f, p (0.22 mmol) was further
2
added in a test tube at À248C. After the reaction time, adduct 4 was isolated by flash chromatography.
[
[
[
[
[
b]
After isolation by column chromatography.
c]
d]
e]
f]
Determined by chiral HPLC analysis.
Conditions for the use of 0.44 mmol of aldehyde.
Conditions for the use of 0.88 mmol of aldehyde.
Reaction performed at higher scale to obtain 1 gram of product.
other squaramides whose structures only differ in
their aromatic moieties, such as 1a–c and 1e (Support-
ing Information, entry 6 in Table S2 and entries 1, 7
and 8 in Table S3, respectively). This fact confirms the
necessity of the complete binaphthyl structure in cata-
lyst 1j for the success of the process.
In order to explain the role of the multifunctional
catalyst 1j, based on the experimental results and
computational calculations (see the Supporting Infor-
mation), a reasonable reaction pathway is proposed
for the Henry reaction between 4-cyanobenzaldehyde
(
2f) and nitromethane (3a) (only the rate-limiting
step is shown for simplicity) (Figure 3).
The O atom of the aldehyde, which is developing
a negative charge during the advance of the reaction,
and the H atom of the aldehyde are interacting with
the p-system of the catalyst in the most energetically
favorable reaction pathway (see the Supporting Infor-
mation for additional TSs).
In order to support these p interactions, the elec-
Scheme 1. Additional squaramide-based organocatalysts 1k– tronic density maps of the non-covalent interactions
m tested.
for TSa-c have been also calculated (Figure 4,
Figure 5, and Figure 6). These maps show hydrogen
bonds between the aldehyde and the squaramide
group in the process is still unclear at this stage. Inter- moiety through double hydrogen bonding with the
estingly, when we performed the reaction with cata- NH groups and between the basic nitrogen atom on
lyst 1m (with a naphthyl moiety instead of the bi- the piperidine and the nitromethane. These non-cova-
naphthyl fragment present in 1j), the reactivity and lent interactions are represented in blue color.
the enantioselectivity of the process drastically drop-
Moreover, the p interactions between the aldehyde
ped (10% yield, 60% ee). Also, catalyst 1j showed and the binaphthyl moiety are also disclosed. These
much better results compared to those obtained with interactions are shown in green color, being weaker
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Figure 3. TSa: catalyst-substrate complex before nitronate attack, TSb: transition state (TS) of the nitronate attack, and TSc:
catalyst-intermediate product complex after the nitronate attack. All DFT calculations were carried out with Gaussian 09
[
16]
software at the IEFPCM-SMD(MeNO )/wB97XD/6-31G(d) level (see the Supporting Information for more information
2
about computational details).
Figure 6. Electronic density map of TSc: green and blue re-
Figure 4. Electronic density map of system TSa: green and
blue regions represent attractive VdW interactions. Grid
[
17]
[
17]
gions represent attractive VdW interactions. Grid data for
[18]
sign(l2)1 and RDG was generated using Multiwfn.
image was created using VMD.
The
data for sign(l2)1 and RDG was generated using Mul-
[
19]
[
18]
[19]
tiwfn. The image was created using VMD.
than those represented in blue color (Figure 4,
Figure 5, and Figure 6).
Thus, catalyst 1j could be acting in a trifunctional
fashion. First, the aldehyde would be activated by the
squaramide moiety through double hydrogen bonding
with the NH groups. At the same time, the p-system
of the binaphthyl scaffold would stabilize the TS and
would activate the aldehyde for the subsequent
attack. Additionally, the basic nitrogen atom on the
piperidine ring would activate the nitromethane, al-
lowing the attack of the nitronate form over the Re
face of the aldehyde. This attack would afford the S
absolute configuration in all final products, which is
consistent with the observed results. Moreover, this
attack would be in agreement with the control of the
Figure 5. Electronic density map of TSb: green and blue re-
[17]
gions represent attractive VdW interactions. Grid data for
[
18]
sign(l2)1 and RDG was generated using Multiwfn. The sense in the enantioinduction by the 2-(1-piperidinyl)-
[19]
image was created using VMD.
cyclohexylamine moiety.
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Beyond the steric influence caused by the binaphth- reported in the
d
scale relative to residual CHCl
3
(
7.26 ppm), MeCN (1.94 ppm) and DMSO (2.50 ppm) for
yl moiety that can orientate the disposition of the re-
agents in the TS, we believe that the non-covalent in-
teractions between this group and the aldehyde influ-
ence both the reactivity and the enantioselectivity of
the process. This anion-p interaction would stabilize
1
H NMR and to the central line of CDCl (77 ppm), CD CN
1.24 ppm) and DMSO-d (39.43 ppm) for C-APT-NMR.
3
3
1
3
(
6
Materials
[
20]
[21]
[22]
[23]
[22]
[22]
[22]
the energetic barrier of the TS, increasing the reaction Spectral data for 1b, 1c, 1d, 1e, 1f, 1g, 1h,
[
24]
[21]
[21]
[21]
[21]
[21]
rate of the process and, consequently, the origin of 1i, 1j, 1n, 1o, 1p, and 1q are consistent with
the catalysis would also rely in this weak but efficient values previously reported in the literature. For the synthesis
and spectra of catalysts 1k–m see the Supporting Informa-
tion.
effect. This interaction ensures a more energetically
favorable TS where the chiral catalyst remains in
close proximity to the electrophile during the enantio-
Representative Procedure for the Squaramide-
Organocatalyzed Henry Reaction of Aldehydes
selectivity-determining step of the catalytic cycle. The
presence of these secondary bindings is able to pro-
vide a higher degree of organization in the transition
To a mixture of catalyst 1j (0.0044 mmol unless otherwise
state, necessary for a high enantioinduction. More- stated in Table 1) and MeNO2 (1.1 mL), aldehyde 2a–o
over, the lower enantioselectivity observed with cata- (0.22 mmol) was added in a test tube at À248C. After the
lyst 1m compared with 1j, would also be in agreement reaction time (see Table 1 and Table2), adducts 4 were iso-
lated by flash chromatography (SiO , using hexane:EtOAc
with the importance of the presence of the binaphthyl
scaffold to organize a more stable TS.
2
9
:1 to hexane:EtOAc 7:3). Yields and enantioselectivities
are reported in Table 1. If acid traces were observed in the
aldehydes by NMR, these aldehydes were previously puri-
fied by column chromatography (very short column, eluted
with CH Cl or MeCN) or extraction (dissolving these alde-
Conclusions
2
2
hydes in CH Cl and washing with a 0.3M solution of
2
2
In conclusion, a new class of chiral squaramide cata-
NaOH). Then, the CH Cl was evaporated under vacuum
2
2
lysts acting by mean of multiple interactions has been and the aldehydes were used within 2–5 min to avoid acid
developed to efficiently catalyze the Henry reaction formation.
[
25]
with very good results. Novel trifunctional catalyst 1j
is able to generate hydrogen bonding and anion-p in-
teractions with the substrates, which are responsible
of the improvement in the reactivity and the stereose-
lectivity of the process. This active catalyst was found
to provide excellent values of enantioselectivity and
reactivity even at 0.25 mol% catalyst loading, one of
the lowest amounts for this reaction using organocata-
(S)-2-Nitro-1-(4-nitrophenyl)ethanol (4aa):
Following
the general procedure, compound 4aa was obtained after
2
4 h of reaction at À248C as a dark green oil; yield: >95%
yield. The ee of the product was determined to be 83% by
HPLC using a Daicel Chiralpak IA column (n-hexane/i-
PrOH=80:20, flow rate 1 mLmin , l=230.3 nm): t
À1
=
major
28
1
5.6 min; t
=12.1 min. [a] : +23.2 (c 1.30, CHCl , 82%
D
minor 3
23
[25]
ee) {lit., [a] : À30.4 (c 0.53, CHCl ) for (R)-4aa, 88% ee}.
D
3
[
26]
(
S)-2-Nitro-1-(3-nitrophenyl)ethanol (4ba):
Following
lysts. A unique example of anion-p effect has been the general procedure, compound 4ba was obtained after
described for the first time in asymmetric catalysis, 24 h of reaction at À248C as a dark green solid; yield:
and this feature makes catalyst 1j a plausible trifunc- >95%. The ee of the product was determined to be 94% by
HPLC using a Daicel Chiralpak IB column (n-hexane/i-
tional catalyst. Further investigations of the efficacy
À1
PrOH=80:20, flow rate 1 mLmin , l=281.7 nm): t
=
of this organocatalyst in other catalytic asymmetric
reactions, as well as additional computational and
NMR studies, are ongoing in our lab in order to sup-
port the singular activation mode proposed herein.
major
2
3
1
0.5 min; t
=9.9 min. [a] : +27.2 (c 0.33, CHCl , 94%
D
minor 3
26
[
26]
ee) {lit., [a] : À27.4 (c 0.87, CH Cl ) for (R)-4ba, 96% ee}.
D
2
2
[
25]
(
S)-1-(4-Chlorophenyl)-2-nitroethanol (4ca):
Following
the general procedure, and purifying the aldehyde by
column chromatography (eluted with CH Cl ), compound
2
2
4
ca was obtained after 91 h of reaction at À248C as a dark
brown oil; yield: 81%. The ee of the product was deter-
Experimental Section
mined to be 86% by HPLC using a Daicel Chiralpak IB
À1
column (n-hexane/i-PrOH=90:10, flow rate 1 mLmin , l=
General Experimental Methods
2
D
3
2
30.1 nm): tmajor =12.6 min; t
=11.1 min. [a] : +27.2 (c
minor
25] 22
[
Purification of reaction products was carried out either by
filtration or by flash chromatography using silical-gel
0.31, CHCl , 86% ee) {lit., [a] : À38.8 (c 0.55, CHCl ) for
3
D
3
(R)-4ca, 90% ee}.
[
27]
(0.063–0.200 mm). Analytical thin layer chromatography
(S)-1-(3-Chlorophenyl)-2-nitroethanol (4da):
Following
was performed on 0.25 mm silical gel 60-F plates. The ESI
ionization method and mass analyzer type MicroTof-Q were
the general procedure, and purifying the aldehyde 2d by
basic washing, compound 4da was obtained after 86 h of re-
action at À248C as a dark brown oil; yield: 62%. The ee of
the product was determined to be 90% by HPLC using
1
used for the ESI measurements. H NMR spectra were re-
13
corded at 300 and 400 MHz; C-APT-NMR spectra were re-
corded at 75 and 100 MHz; CDCl , CD CN and DMSO-d
were used as the deuterated solvents. Chemical shifts were
a Daicel Chiralpak IB column (n-hexane/i-PrOH=90:10,
3
3
6
À1
flow rate 1 mLmin , l=226.2 nm): t
=11.8 min; tminor =
major
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2
D
4
[27]
27
D
1
+
0.3 min. [a] : +24.8 (c 1.4, CHCl , 90% ee) {lit., [a] :
EtOAc 7:3 to hexane:EtOAc 2:8) after 92 h of reaction at
À248C as a dark brown oil; yield: 95%. The ee of the prod-
uct was determined to be 92% by HPLC using a Daicel
3
31.17 (c 1.0, CHCl ) for 95% ee}.
S)-1-(4-Bromophenyl)-2-nitroethanol (4ea):
3
[28]
(
Following
the general procedure, and purifying the aldehyde 2e by
Chiralpak IA column (n-hexane/i-PrOH=90:10, flow rate
À1
column chromatography (eluted with CH Cl ), compound
1 mLmin , l=240.2 nm): t
=24.3 min; tminor =28.3 min.
2
2
major
2
9
4
ea was obtained after 91 h of reaction at À248C as a dark
[a] : +35.1 (c 0.23, MeCN, 92% ee).
D
[
34]
brown oil; yield: 75%. The ee of the product was deter-
(R)-1-(Furan-2-yl)-2-nitroethanol (4la):
Following the
mined to be 86% by HPLC using a Daicel Chiralpak IA
general procedure, and purifying the aldehyde 2l by column
chromatography (eluted with CH Cl ), compound 4la was
À1
column (n-hexane/i-PrOH=90:10, flow rate 1 mLmin , l=
2
2
2
D
3
2
0
(
37.2 nm): tmajor =14.9 min; t
=12.2 min. [a] : +20.1 (c
obtained after 88 h of reaction at À248C as a dark brown
oil; yield: 74%. The ee of the product was determined to be
92% by HPLC using a Daicel Chiralpak IA column (n-
minor
28] 23
[
.27, CHCl , 86% ee) {lit., [a] : À68.6 (c 1.40, CHCl ) for
3
D
3
R)-4ea, 89% ee}.
S)-4-(1-Hydroxy-2-nitroethyl)benzonitrile (4fa):
[
29]
À1
(
Fol-
hexane/i-PrOH=90:10, flow rate 1 mLmin , l=224.8 nm):
2
D
9
lowing the general procedure, compound 4fa was isolated
by flash chromatography after 71 h of reaction at À248C as
a pale brown solid; yield: >95%. The ee of the product was
determined to be 82% by HPLC using a Daicel Chiralpak
tmajor =10.9 min;
t
=10.2 min. [a] : +36.3 (c 0.16,
minor
[
29]
23
CHCl , 92% ee) {lit., [a] : À36.7 (c 2.72, CHCl ) for (S)-
3
D
3
4la, 85% ee}.
[
34]
(R)-2-Nitro-1-(thiophen-2-yl)ethanol (4ma):
Following
À1
IB column (n-hexane/i-PrOH=90:10, flow rate 1 mLmin ,
the general procedure, and purifying the aldehyde 2m by
2
D
4
l=243.5 nm): tmajor =27.6 min; t
=25.3 min. [a] : +36.3
column chromatography (eluted with CH Cl ), compound
minor
30] 20
2
2
[
(
c 0.74, CHCl , 81% ee) {lit., [a] : À32.8 (c 0.50, CH Cl )
4ma was obtained after 92 h of reaction at À248C as a dark
brown oil; yield: 55% yield. The ee of the product was de-
termined to be 92% by HPLC using a Daicel Chiralpak IB
3
D
2
2
for (R)-4fa, 90% ee}.
S)-1-(Naphthalen-1-yl)-2-nitroethanol (4ga): Following
[25]
(
À1
the general procedure, and purifying the aldehyde 2g by
basic washing, compound 4ga was obtained after 86 h of re-
action at À248C as a dark brown oil; yield: 50%. The ee of
the product was determined to be 85% by HPLC using
column (n-hexane/i-PrOH=90:10, flow rate 1 mLmin , l=
2
D
9
246.6 nm): tmajor =12.0 min; t
=11.4 min. [a] : +35.9 (c
minor
28]
23
[
0.08, CHCl , 90% ee) {lit., [a] : À26.4 (c 3.11, CHCl ) for
3
D
3
(S)-4ma, 86% ee}.
[
35]
a Daicel Chiralpak IB column (n-hexane/i-PrOH=90:10,
(S)-2-Nitro-1-p-tolylethanol (4na): Following the gener-
al procedure, and purifying the aldehyde 2n by column chro-
matography (eluted with CH Cl ), compound 4na was ob-
À1
flow rate 1 mLmin , l=254.0 nm): t
=14.5 min; t
=
major
minor
27
[25]
21
1
1.6 min. [a] : +19.1 (c 0.85, CHCl , 85% ee) {lit., [a] :
D
3
D
2
2
+
24.5 (c 0.53, CHCl , for (S)-4ga, 88% ee}.
tained after 6 days of reaction at À248C as a dark brown
oil; yield: 20% yield. The ee of the product was determined
to be 84% by HPLC using a Daicel Chiralpak IB column
3
[31]
(
S)-2-Nitro-1-phenylethanol (4ha): Following the gener-
al procedure, and purifying the aldehyde 2h by basic wash-
ing, compound 4ha was obtained after 86 h of reaction at
À248C as a dark brown oil; yield: 59%. The ee of the prod-
uct was determined to be 82% by HPLC using a Daicel
À1
(n-hexane/i-PrOH=95:5, flow rate 1 mLmin , l=220 nm):
1
D
8
tmajor =19.8 min;
t
=17.0 min. [a] : +26.8 (c 0.25,
minor
[
35]
20
CHCl , 84% ee) {lit.,
[a] : +34.1 (c=1.90, CHCl ) for
3
D
3
Chiralpak IB column (n-hexane/i-PrOH=90:10, flow rate
(S)-4na, 84% ee}.
(R)-1-(Benzyloxy)-3-nitropropan-2-ol (4oa):
the general procedure, compound 4oa was isolated by flash
chromatography after 92 h of reaction at À248C as a dark
brown oil; yield: 66%. The ee of the product was deter-
mined to be 76% by HPLC using a Daicel Chiralpak IB
À1
[36]
1
mLmin , l=248.1 nm): t
=11.3 min; t
=10.1 min.
Following
major
minor
[31] 21
2
5
[a] : +11.9 (c 1.1, CH Cl , 82% ee) {lit., [a] : À41.6 (c
D
2
2
D
1.03, CH Cl ) for (R)-4ha, 94% ee}.
2 2
[31]
(
S)-1-([1,1’-Biphenyl]-4-yl)-2-nitroethanol (4ia): Follow-
ing the general procedure, compound 4ia was isolated by
flash chromatography after 96 h of reaction at À248C as
À1
column (n-hexane/i-PrOH=95:5, flow rate 1 mLmin , l=
227.7 nm): tmajor =22.6 min; t
[31]
24
D
a yellow solid; yield: 50%; mp 127–1298C. The ee of the
=25.0 min. [a] : +7.8 (c
minor
[
37]
product was determined to be 90% by HPLC using a Daicel
0.25, CHCl , 76% ee) {lit., [a] : +1.5 (c 0.9, CH Cl ) for
3
D
2
2
Chiralpak IB column (n-hexane/i-PrOH=90:10, flow rate
(R)-4oa, 80% ee}.
(S)-2-Nitro-1-(perfluorophenyl)ethanol (4pa): Following
the general procedure, compound 4pa was isolated by flash
À1
[37]
1
mLmin , l=231.2 nm): t
=16.3 min; t
=13.3 min.
major
minor
[31]
23
2
3
[a] : +25.8 (c 0.47, CHCl , 88% ee) {lit., [a] : À36.1 (c
D
3
D
1.35, CH Cl ) for (R)-4ia, 91% ee}.
chromatography (SiO , using hexane:EtOAc 95:5 to hex-
2
2
2
[32]
(
S)-2-Nitro-1-(pyridin-2-yl)ethanol (4ja):
Following the
ane:EtOAc 9:1) after 120 h of reaction at À248C as
a yellow oil; yield: >95%. The ee of the product was deter-
mined to be 86% by HPLC using a Daicel Chiralpak IA
column (n-hexane/i-PrOH=95:5, flow rate 1 mLmin , l=
232.8 nm): tmajor =10.9 min; t
general procedure, and purifying the aldehyde 2j by column
chromatography (eluted with MeCN), compound 4ja was
À1
isolated by flash chromatography (SiO , using hexane:
2
2
8
EtOAc 8:2 to hexane:EtOAc 1:1) after 96 h of reaction at
À248C as a dark brown oil; yield: >95%. The ee of the
product was determined to be 80% by HPLC using a Daicel
=12.4 min. [a] : +2.8 (c
minor
D
[
37]
1.1, CHCl , 86% ee) {lit.,
[a]D +8.9 (c 0.8, CH Cl ) for
3
2 2
(S)-4oa, 90% ee}.
2-Nitro-1-(4-nitrophenyl)propan-1-ol (4ab):
the general procedure, compound 4ab was isolated by flash
chromatography (SiO , using hexane:EtOAc 95:5 to hex-
[
34,38]
Chiralpak IA column (n-hexane/i-PrOH=90:10, flow rate
Following
À1
1
[
mLmin , l=218.4 nm): t
=12.1 min; tminor =15.3 min.
major
2
4
a] : +49.8 (c 0.16, CHCl , 80% ee).
S)-2-Nitro-1-(pyridin-3-yl)ethanol (4ka): Following the
D
3
2
[33]
(
ane:EtOAc 9:1) after 88 h of reaction at À248C as a dark
[
34,38]
general procedure, and purifying the aldehyde 2k by column
chromatography (eluted with MeCN), compound 4ka was
green solid; yield: 75%.
The diastereomeric ratio (anti/
1
syn, 1:1.3) was determined by H NMR. The ee of the prod-
ucts was determined to be 72% (syn isomer) by HPLC using
isolated by flash chromatography (SiO , using hexane:
2
Adv. Synth. Catal. 2016, 358, 1801 – 1809
1807
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FULL PAPERS
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a Daicel Chiralpak IA column (n-hexane/iPrOH=90:10,
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À1
flow rate 1 mLmin , l=242.0 nm): t
=29.9 min; tminor
=
major
2
5.9 min; for the syn diastereoisomer.
[34,38]
2-Nitro-1-(3-nitrophenyl)propan-1-ol (4bb):
Following
the general procedure, compound 4bb was isolated by flash
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1
[34,38]
1
:1.4) was determined by H NMR.
The ee of the prod-
ucts was determined to be 87% (syn isomer) by HPLC using
a Daicel Chiralpak IB column (n-hexane/i-PrOH=95:5,
À1
flow rate 1 mLmin , l=238.4 nm): t
=35.6 min; tminor =
major
31.5 min; for the syn diastereoisomer.
Acknowledgements
8220–8236; d) J. V. Alegre-Requena, Synlett 2014, 25,
2
98–299; e) P. Chauhan, S. Mahajan, U. Kaya, D. Hack,
We thank the Ministerio de Economia y Competitividad
MINECO, Project CTQ2013-44367-C2–1-P), the University
D. Enders, Adv. Synth. Catal. 2015, 357, 253–281.
15] J. V. Alegre-Requena, E. MarquØs-López, R. P. Her-
rera, RSC Adv. 2015, 5, 33450–33462.
(
[
[
of Zaragoza (JIUZ-2014-CIE-07), the High Council of Sci-
entific Investigation (CSIC) (PIE-201580I010) and Govern-
ment of Aragon DGA (Research Group E-104) for financial
support of our research. J. V. A.-R. thanks the DGA for a pre-
doctoral contract.
16] All calculations were carried out with the Gaussian 09
suite of programs: M. J. Frisch, G. W. Trucks, H. B.
Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson,
H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F.
Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M.
Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai,
T. Vreven Jr, J. A. Montgomery, J. E. Peralta, F.
Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
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iels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski,
D. J. Fox, Gaussian 09, Revision A.1, Gaussian, Inc.,
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