Bifunctional Squaramide Organocatalysts for the Asymmetric Addition of Formaldehyde tert-Butylhydrazone to Simple Aldehydes

Article abstract of DOI:10.1002/chem.201801052

The nucleophilic addition of formaldehyde tert-butylhydrazone to simple aldehydes (a formal hetero-carbonyl–ene reaction) can be performed with good reactivity and excellent enantioselectivity by virtue of the dual hydrogen-bonding activation exerted by amide–squaramide organocatalysts. The resulting hydroxydiazenes (azo alcohols) were isolated in high yields as enantiomerically enriched azoxy compounds after a regioselective azo-to-azoxy transformation. Subsequent derivatization provides an entry to relevant amino alcohols, oxazolidinones, and derivatives thereof.

Full text of DOI:10.1002/chem.201801052

A Journal of
Accepted Article
Title: Bifunctional Squaramide Organocatalysts for the Asymmetric
Addition of Formaldehyde tert-Butyl Hydrazone to Simple
Aldehydes
Authors: José M. Lassaletta, Esteban Matador, María de Gracia
Retamosa, David Monge, Javier Iglesias-Sigüenza, and
Rosario Fernández
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content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201801052
Link to VoR: http://dx.doi.org/10.1002/chem.201801052
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Bifunctional Squaramide Organocatalysts for the Asymmetric
Addition of Formaldehyde tert-Butyl Hydrazone to Simple
Aldehydes
Esteban Matador,[a] María de Gracia Retamosa,[b] David Monge,*[a] Javier Iglesias-Sigüenza, [a] Rosario
Fernández*[a] and José M. Lassaletta*[b]
A)
B)
O
Abstract: The nucleophilic addition of formaldehyde tert-butyl
hydrazone to simple aldehydes (a formal hetero-carbonyl-ene
reaction) can be performed with good reactivities and excellent
enantioselectivities by virtue of the dual H-bonding activation exerted
NR´R´´
R
NR´R´´
N
N
H
Brönsted acids
N
X
+
X
N
R
H
BIMBOLs,
phosphoric or
dicarboxylic acids
Ar
DAHs
O
Ar
by
amide-squaramide
organocatalysts.
The
resulting
tBu
N
tBu
hydroxydiazenes (azo alcohols) were isolated in high yields as
enantiomerically enriched azoxy compounds after a regioselective
azo-to-azoxy transformation. Subsequent derivatizations provide an
entry to relevant amino alcohols, oxazolidinones and derivatives
thereof.
NH
H
O
N
N
H-bonding catalysis
Bis-ureas
+
O
HO
R
R
Z
H
Z
FTBH
O
Two-point interaction; activated
CF3
O
Introduction
N
H
N
H
F3C
H
N
H
N
H
Hydrazones have been frequently exploited as versatile
reagents in organic synthesis; primarily for the generation of
molecular complexity from simple starting materials and,
O
O
Z
O
CF3
H
R
F3C
N
N
additionally,
enabling
distinctive
functional
group
tBu
interconversions.[1] Acting as mild carbon π-nucleophiles, their
additions to C=X (X = C, N, O) bonds are useful C–C bond
forming reactions for the synthesis of enantiomerically pure
compounds, including highly functionalized amines and
alcohols.[2] The development of asymmetric catalytic versions of
these reactions was initially hindered for the sensitivity of these
reagents toward most Lewis acidic metal complexes,[3] but the
milder nature of organocatalytic activation strategies appeared
to solve these compatibility issues.[4] Thus, LUMO-lowering
activation of imines by axially chiral BINOL, phosphoric or
dicarboxylic acid derivatives allowed 1,2-addition of N,N-
dialkylhydrazones (DAHs) to yield enantiomerically enriched α-
aminohydrazones (Scheme 1, A).[5] Dual H-bonding activation by
thioureas was also identified as a proper strategy for the
conjugate addition of DAHs to β,γ-unsaturated α-ketoesters.[6]
However, none of these catalysts provided satisfactory results
tBu
N
C)
tBu
NH
This work
N
O
R
N
H-bonding catalysis
Squaramides ?
+
HO
H
H
R
H
FTBH
Single-point interaction; lower reactivity
Scheme 1. Organocatalytic asymmetric 1,2-additions of hydrazones to imines
and carbonyl compounds.
for 1,2-addition of DAHs to carbonyl compounds. Alternatively,
we have exploited the distinct properties of formaldehyde tert-
butyl hydrazone (FTBH) in reactions with activated carbonyl
compounds (α-keto esters,[7] α-keto phosphonates[8] and
isatins[9]) to afford highly functionalized β-hydroxy diazenes
(Scheme 1, B).Dual activation by axially chiral BINAM bis-ureas,
behaving as bifunctional organocatalysts, proved to be key to
achieve good catalytic activities and stereocontrol. Accordingly,
FTBH would be activated by one of the urea’s carbonyl groups
via NH–O hydrogen bond, and guided to the reachable carbonyl
face of the dicarbonyl substrate which, employing two interaction
points, would be activated by the second urea moiety acting this
time (as usually) as a double H-bond donor. Aimed to expand
the scope of this strategy, we next investigated enantioselective
reactions with single carbonyl compounds (simple aldehydes
and ketones). These are a priori more challenging substrates for
two main reasons: First, the lower electrophilicity of the carbonyl
[a]
E. Matador, Dr. D. Monge, Dr. Javier Iglesias-Sigüenza, Dr. R.
Fernández
Departamento de Química Orgánica, Universidad de Sevilla and
Centro de Innovación Avanzada (ORFEO-CINQA)
C/ Prof. García González, 1, 41012 Sevilla, Spain
E-mail: dmonge@us.es, ffernan@us.es
[b]
Dr. M. G. Retamosa, Dr. J. M. Lassaletta
Instituto de Investigaciones Químicas (CSIC-US) and Centro de
Innovación en Química Avanzada (ORFEO-CINQA)
Avda. Américo Vespucio, 49, 41092 Sevilla, Spain
E-mail: jmlassa@iiq.csic.es.
Supporting information for this article is available via a link at the
end of the document.
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Table 1. Optimization of the reaction of 1a with 2a.[a]
group in these substrates will presumably make necessary to
use more active (acidic) catalysts, but the compatibility with the
hydrazone reagent could be compromised. Second, the
geometry of the catalyst-substrate complex should be fixed
using a single interaction site, in contrast with the above-
mentioned precedents. In fact, intensive efforts performed with
BINOL/BINAM derived H-bonding catalysts or common
bifunctional thiourea organocatalysts revealed either low-to-
moderate catalytic activity or led to products with negligible
levels of enantioselectivity, highlighting the importance of
auxiliary interacting groups (Z=O) to facilitate the desired
stereocontrol (see Supporting information for details). To
overcome these difficulties, we envisioned that more acidic H-
bonding squaramides[10] might provide a better activation of
single carbonyl compounds and additionally, the distinctive more
canted NH groups might also help fixing the geometry of the
complex, thereby enabling a better enantiocontrol. In this paper,
we disclose the asymmetric addition of FTBH to simple
aldehydes employing bifunctional amide-squaramides (Scheme
1, C).
Entry
1
Catalyst
Solvent
Toluene
Toluene
Toluene
Toluene
TBME
T (°C)
Conv. (%)[b]
ee (%)[c]
-
--
--
I
rt
95 (90)
55
2
5
-
3
5
95
39
50[d]
70
52
72
76
41
72
66
36
55
23
90
90
4
II
5
80
5
II
5
55
6
II
CH3CN
CH2Cl2
CF3-Ph
CF3-Ph
CF3-Ph
CF3-Ph
CF3-Ph
CF3-Ph
CF3-Ph
CF3-Ph
CF3-Ph
5
48
7
II
5
78
8
II
5
95
9
III
IV
V
VI
VII
VIII
II
5
>99
95
10
11
12
13
14
15
16[e]
5
5
92
5
96
5
94
5
88
Results and Discussion
–10
–10
92
II
94 (90)
p-Chlorobenzaldehyde 2a,
a
relatively reactive aromatic
aldehyde, was chosen as a model substrate for preliminary
experiments. For comparative purposes, the reactivity of simple
formaldehyde hydrazones 1a-c with 2a was analyzed (Scheme
2). Not surprisingly, the N-anisyl-derivative 1b and N,N-dimethyl
hydrazone 1c showed no reactivity, neither under thermal nor
catalytic conditions.[11] In sharp contrast, tert-butyl hydrazone 1a
smoothly added to 2a in toluene at room temperature (full
conversion to 3a in ca. 60 hours). The thermal reaction proved
to be reversible and, hence, diazene 3a did not resist
chromatographic purification. Fortunately, in situ oxidation of
crude diazene 3a with magnesium monoperoxyphthalate
(MMPP) afforded a stable azoxy compound 4a with complete
regioselectivity (oxidation exclusively at the more hindered N)
and 90% isolated yield after two steps (entry 1, Table 1). Cooling
to 5 °C slowed down the uncatalyzed reaction (55% conversion
to 3a after 60 hours, entry 2) and, therefore, these conditions
were used in further studies for the evaluation of different
organocatalysts (see the Supporting Information). After
[a] Unless otherwise stated, all reactions were performed at 0.1 mmol scale
using 10 mol% catalyst loading at 0.3M (reaction time of the addition step =
60 hours). [b] Conversion to 3a estimated by 1H-NMR (in parenthesis,
isolated yield of 4a after column chromatography). [c] Determined by HPLC.
[d] Non-reproducible result. [e] Reaction was performed at 0.5M.
preliminary screening of diverse bifunctional (thio)ureas with
different chiral scaffolds and functionalities, only amino acid
derived thioureas afforded a moderate level of asymmetric
induction, reaching up to 39% ee (entry 3) by using amide-
thiourea I (Figure 1). In the seeking of more active and selective
catalysts, analogous squaramide II was synthesized and
analyzed.[12] A better enantioselection was reached (up to 50%
ee, entry 4); however, reaction conversions remained lower than
expected and could not be regularly reproduced, reaching high
values (up to 80%) only in isolated experiments. As the low
solubility of II in toluene (<3 mg/mL at rt) was considered as a
possible explanation,[13] a survey of different solvents [TBME,
CH3CN, CH2Cl2 (entries 5-7) among others] was performed.
CH2Cl2 performed better, leading to high conversion and a
promising 72% ee (entry 7), but again solubility issues (≈3
mg/mL at rt) hampered a further optimization. Finally, α,α,α-
trifluorotoluene (TFT)[14] emerged as the best option, leading to
better and reproducible results. The higher solubility of II (≈15
mg/mL at rt) in this solvent granted homogeneous reactions in
which higher conversions (95%) and enantioselectivities (up to
76% ee) were obtained (entry 8). Next, the catalytic performance
of several bifunctional amide-squaramides (II-VIII, Figure 1) was
tBu
R1
N
O
N
Cat.
(10 mol %)
N
R2
N
HO
+
Toluene
R1 = tBu
R2 = H
H
H
Cl
H
1a, R1 = tBu, R2 = H
1b, R1 = p-MeOPh, R2 = H
1c, R1 = R2 = Me
2a
Cl
3a
tBu
N
N
O
HO
MMPP, MeOH
comparatively
analyzed.
A
significant
decrease
in
H
enantioselectivity was observed by using phenylalanine
derivative III (41% ee, entry 9) instead of tert-leucine-derived II
(76 % ee, entry 8), highlighting the better conformational control
exerted by tert-butyl group in the chiral amide fragment. This
Cl
4a
Scheme 2. Model reaction of hydrazones 1 with 2a.
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tBu
N
tBu
NH
O
O
S
O
i) II (5-10 mol%), TFT
ArF
+
Ph
N
N
N
O
O
ArF
N
N
H
R
ii) MMPP, MeOH
N
H
N
H
N
HO
R
H
Ph
Ph
O
H
H
2
I
II
O
H
1a
Ph
4
O
O
tBu
N
O
O
tBu
Ph
N
Ph
4a: R = p-Cl
4b: R = m-Cl
4c: R = o-Cl
4d: R = o-F
4e: R = o-Br
4f: R = p-NO2
N
ArF
N
N
ArF
N
H
N
H
O
N
N
H
N
H
HO
HO
Ph
IV
MeO
O
III
O
Ph
H
H
Ph
R
F
CF3
O
O
4g
tBu
N
tBu
tBu
N
ArF
=
N
ArF
N
N
N
O
O
X
O
CF3
N
H
N
H
N
F
HO
HO
HO
V
Me
O
O
O
H
H
H
Br
F
X
Cl
ArF
N
H
N
H
4h
4i: X = F
4j: X = Cl
4k
N
VI
tBu
N
tBu
N
tBu
N
O
Ph
O
O
O
O
F
F
F
N
N
N
O
O
O
HO
HO
HO
F
MeO
N
N
N
N
N
N
H
H
H
H
H
Ph
ArF
H
H
Ph
VII
O
F
VIII
O
Me
Ph
Ph
4n
4l
4m
tBu
N
tBu
N
tBu
Figure 1. Selected amide-thiourea/squaramide organocatalysts tested.
N
N
N
N
O
O
O
HO
HO
HO
X
observation is in accordance with 1H-NMR spectra for both
catalysts in DMSO at 303 K, showing (Z)/(E)-amide rotamers in
4:1 (III) and 6:1 (II) ratios (see the Supporting Information).
The dialkylamino group had a significant influence in the
stereochemical outcome of the reaction. Squaramide IV, bearing
a relatively flexible dibenzylamino group, afforded similar results
(entry 10) to II, while introduction of a bulkier bis(naphthalen-1-
ylmethyl)amino group in squaramide V slightly diminished its
catalytic activity and enantioinduction ability (entry 11).
Squaramide VI, containing a rigid cyclic amino group derived
H
H
H
4q: X = O
4r: X = S
tBu
4p
4o
N
O
N
tBu
tBu
N
HO
N
N
O
H
N
O
HO
HO
Ph
H
H
N
H
OH
4s
4t
4u
O
from (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline, exhibited
a
N
tBu
N
tBu
tBu
N
tBu
good catalytic activity but low enantioselectivity (entry 12).
N
N
N
O
N
O
Having established the best amide unit, we analyzed the
influence of the H-bonding donor group by comparing
squaramide II [bearing a bis(trifluoromethyl)phenyl substituent]
O
HO
HO
HO
Ph
O
H
H
H
with
VII
(pentafluorophenyl
derivative)
and
VIII
4v
4w
4x
[bis(trifluoromethyl)benzyl derivative]. As predicted, the results
allow to establish a direct correlation between the H-bond donor
capability of the catalysts [II > VII > VIII (inferred from chemical
Scheme 3. Scope of the addition of 1a to aldehydes 2.
that aryl-substituted azoxy compounds 4a-p can be obtained in
good to excellent yields and high enantioselectivities (81-96%
ee) in most cases. A correlation between the reaction rate and
the electronic properties of the aryl group was observed:
electron-poor aldehydes 2a-k reacted at −10/−20 °C for 60–72
hours (entries 1-11), while benzaldehyde (2l) and more electron-
rich substrates (2m-p) required longer reaction times for
completion (entries 12-16). Remarkably, an excellent
enantiocontrol was observed for ortho/para- and ortho/ortho-di
halogenated benzaldehydes (2h-k), leading to highly
enantioenriched derivatives 4h-k (94-96% ee). 2-Furyl and 2-
1
shift of NH protons in H-NMR, see the Supporting Information)]
and the observed enantioselectivity, which drops to 55% (entry
13) and 23% ee (entry 14) for less acidic VII and VIII,
respectively. Using the best catalyst II, further optimization of
temperature and concentration was carried out (entries 15 and
16). Thus, performing the addition reaction at –10 °C (0.5M)
followed by in situ oxidation yielded 4a in 90% yield and 90%
ee.[15]
The scope of the reaction was then explored with
representative aromatic, heteroaromatic and aliphatic aldehydes
(Scheme 3). The collected data summarized in Table 2 show
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Table 2. Scope of the addition of 1a to aldehydes 2.[a]
group that might act as an auxiliary H-bond acceptor, afforded
4x with 76% yield and an excellent 94% ee (entry 24).
Remarkably, it was possible to reduce the catalyst loading to 5
mol% without compromising the either the chemical yield or the
reaction time, and with a minor impact in the enantioselectivity,
as shown for representative examples (entries 1-6 and 8-11). To
further explore the efficiency of the catalytic system, the
synthesis of 4a (94%, 90% ee), 4i (98%, 94% ee), 4l (95%, 86%
ee) and 4t (80%, 75% ee) were performed on a 1 mmol scale.
The catalyst II survived the oxidative reaction conditions and
could be recovered (85-90% after chromatographic purification)
and reused.
Product 4a was crystallized and its structure elucidated by X-
ray diffraction analysis (Figure 2),[16] unequivocally confirming
the absolute (S) configuration of the newly created stereogenic
center and the assigned regioselectivity of the N-oxidation. The
absolute configuration of other adducts 4 were assigned by
Entry
1
4
T (°C)
−10
−10
−10
−10
−10
−10
−10
−20
−20
−20
−20
−10
−10
−10
−10
−10
−10
−10
−10
−20
−20
−20
−10
−10
t (h)[b]
72
72
60
60
72
60
60
60
60
60
60
80
92
80
80
92
60
92
96
96
96
96
168
60
yield (%)[c],[d]
96 (95)
94 (94)
96 (96)
99 (97)
99 (94)
94 (93)
90
ee (%)[d],[e]
91 (90)
87 (86)
91 (86)
92 (88)
90 (87)
92 (92)
88
4a[f]
4b
4c
4d
4e
4f
2
3
4
5
6
7
4g
4h
4i
8
99 (98)
99 (98)
93 (90)
99 (97)
95
94 (92)
96 (94)
94 (92)
95 (93)
88
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23[h]
24
4j
4k
4l
analogy assuming
a uniform reaction pathway (See
stereochemical model, vide infra). Azoxy alcohols 4 are
valuable derivatives considering the growing interest in
bioactive azoxy compounds,[17] which contrast with the lack
of methodologies for their stereo and regioselective
synthesis. Additionally, some useful transformations of adducts
4m
4n
4o
4p
4q
4r
77
81
85
90
92
84
4
are presented in Scheme 4. For example, under SN2
52
82
Mitsunobu reaction conditions, the hydroxyl group was efficiently
substituted by a protected amino group, as exemplified for the
synthesis of 5. Additionally, the direct conversion of the azoxy
76
94
77
92
4s[g]
90
>99
O2
N1
4t
84
75
4u
4v
4w
4x
75
84
N2
79
81
55
90
76
94
Cl1
O1
[a] Unless otherwise indicated, all reactions were performed at 0.2 mmol scale
using II (10 mol%) as the catalyst. [b] Reaction time of the addition step. [c]
Isolated overall yield after column chromatography. [d] In parenthesis, data for
reactions performed with 5 mol% catalyst. [e] Determined by HPLC. [f] This
result is slightly better than for the reaction performed at 0.1 mmol scale
(compare with Table 1, entry 16). [g] 9:1 dr. [h] 2 eq. of 1a were sequentially
added after 96 and 120 hours, respectively.
Figure 2. X-Ray structure of (S)-4a. H atoms (except H1 and H7) are omitted
for clarity. Thermal ellipsoids drawn at 50% probability.
tBu
N
N
O
NH2
HO
R
H2, Ni raney
MeOH
thienyl heteroaromatic derivatives afforded also the expected
products 4q,r with high enantioselectivities (94 and 92% ee,
respectively: entries 17 and 18). Double addition of 1a to
terephthalaldehyde 2s generated two stereogenic centers to
yield bis-azoxy compound 4s with good diastereoselectively (9:1
dr) and excellent enantioselectivity (entry 19). Aldehydes
bearing representative alkyl chains [R = Bn (2t), R = i-Pr (2u)
and R = heptyl (2v), (entries 20-22)] were also well tolerated;
reactions with 1a at −20 °C for 96 hours gave products 4t-v in
good yields and moderate to good enantioselectivities (75-84%
ee). Cyclopropyl-substituted aldehyde 2w was the less reactive
substrate within this series, giving 4w with a modest 55% yield
but in higher 90% ee (entry 23). Finally, 2x, bearing a benzyloxy
HO
R
H
H
6
4
BTC, DIPEA
CH2Cl2
PPh3, Phthalimide
DEAD, THF
R = 4-Cl-C6H4
O
tBu
N
O
NH
O
N
O
N
R
H
O
H
7d: R = 2-F-C6H4, 63%, 88% ee
7g: R = 2-F-5-MeO-C6H3, 65%, 83% ee
7i: R = 2,6-F2-C6H3, 55%, 93% ee
Cl
5: 75%, 91% ee
Scheme 4. Synthetic transformations of azoxy compounds 4.
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tBu
N
N
compound 4 into free amino alcohols 6 was performed by
applying standard hydrogenation conditions [Ni-raney, H2 (25-50
mbar), room temperature]. This unprecedented transformation,
which formally involves three consecutive steps [Hydrogenolytic
N–O bond cleavage (azoxy-to-azo compound reduction), N=N
bond hydrogenation (azo-to-hydrazine reduction) and N–N bond
hydrogenolysis (hydrazine-to-amine)] afforded amino alcohols
6[18] which were subsequently protected by reaction with
triphosgene to yield the corresponding oxazolidinones[19] 7 in
good overall yields and enantioselectivities (Scheme 4).
tBu
NH
O
F
HO
Cat. (10 mol %)
N
+
H
TFT, -10 °C
10 h
H
H
F
F
F
2i
1a
3i
O
O
O
N
O
N
Me
N
Ph
tBu
Me
ArF
N
ArF
N
tBu
N
Ph
O
Ph
H
H
H
H
O
X
II
>90% conv.
IX
<30% conv.
Ph
<30% conv.
Mechanistic aspects
Scheme 5. Model reaction to assess the bifunctional activity of II.
Squaramide II is believed to act in a bifunctional fashion, as
previously
proposed
for
BINAM-bis-urea/dicarbonyl
compound/1a systems.6a Consistent with structure/activity and
selectivity relationships [see the screening of organocatalysts
(Chart 1, Table 1) and the Supporting Information], the
experimental
data
allowed
to
identify
3,5-
bis(trifluoromethyl)phenyl-substituted squaramide and tert-
leucine-derived amide fragments as key elements for a plausible
cooperative catalysis. To assess the organocatalytic activity of II,
2,6-difluorobenzaldehyde 2i was chosen as substrate. The
presence of fluorine atoms in ortho- and para- positions
facilitates the monitoring of the reaction mixture by recording, in
relatively short reaction times, 19F NMR spectra of the mixture
(Figure 3). Reactions of 1a with 2i in α,α,α-trifluorotoluene at
−10 °C using catalyst II, and resembling monofunctional units IX
(achiral squaramide) and X (achiral amide) were comparatively
analyzed (Scheme 5) revealing a much higher catalytic activity
of II (>90% conv. after 10 hours) in comparison with fragments
IX (<30% conv.) and X (<30% conv.), acting either alone or
combined (IX + X).[20]
Figure 4. Conversion over time for the 1a + 2i → 3i transformation in the
presence of bifunctional amide-squaramide II, achiral squaramide IX, amide X,
and the mixture IX + X. All reactions were monitored in TFT at 263 K by 19F-
NMR (500 MHz).
The evolution of these reactions over time (Figure 4) shows
also a maximum differentiation at the beginning of the process
[>80% conv. after 3 hours (II) vs <15% IX, X or (IX + X)]. These
results highlight the importance of the so-called ‘entropic gain’
facilitated by bifunctional catalysts in which two or more
activating functionalities work in close proximity in the same
molecule. Consequently, a model to explain the high selectivity
and the observed absolute configuration is proposed (Scheme
6). In this model, the aldehyde is activated by double H-bonding
by the squaramide moiety, while the amide carbonyl group
serves as an H-bond acceptor for the hydrazone NH group.
Simultaneous activation/positioning of both reagents while
minimizing steric repulsions during the C–C bond formation is
consistent with an anti approach of azomethine carbon to the Re
face of the aldehyde carbonyl. A slightly negative nonlinear
effect (see the Supporting Information) suggests
a more
Figure 3. 19F NMR spectra obtained for the reaction 1a + 2i → 3i catalyzed by
II in α,α,α-trifluorotoluene at −10 °C. Hollow arrows show the decay of the
signals corresponding to 2i and the rise of the signals corresponding to 3i.
complex scenario involving self-aggregates, with different solid-
solution phase behavior.[21] Indeed, enantiopure catalyst (S)-II
and racemic catalyst (rac)-II show very different solubilities (≈15
mg of (S)-II/mL TFT at rt; ≈28 mg of (rac)-II/mL TFT at rt).
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O
O
N
A)
O2
O3
C26
C24
Me
ArF
O
N
C17
N
Ph
H
H
C16
O
(II)n
N2
Ph
N3
C21
off-cycle precipitate
O
N
C25
N1
C15
O1
Me
H2
ArF
H3
N
H
N
Ph
H
O
Ph
homochiral self-aggregate
O
N
O
N
B)
Me
ArF
N
Ph
tBu
Z
H
H
O
II
Ph
1a
2
N
O
O
OH
R
H
H
ArF
tBu
N
H
N
Me
3: Z = N
MMPP
4: Z = N
N
H
Ph
O
Ph
O
O
H
N
H
H
H
R
N
Anti relative position
Scheme 6. Proposed catalytic cycle and stereochemical model.
Moreover, all attempts to crystalize racemic catalyst led to
precipitate forms not suitable for X-ray diffraction studies while
crystals obtained for enantiopure catalyst (S)-II show a perfect
packing based on linear head-to-tail ladder networks (See
homochiral self-aggregate in Scheme 6, and X-ray structure).[21]
However, the effect observed is relatively low as reactions
become completely homogeneous upon mixing of reagents.
To gain some insight into reagents-catalyst interactions,
additional NMR experiments were performed. However, non-
confident data were collected due to solubility issues.[22]
Moreover, we tried to co-crystallize (S)-II with several aldehydes.
Nevertheless, squaramide (S)-II crystallized instead and its
monomeric structure was analyzed by X-ray diffractometry
(Figure 5).[23] As usual, the squaramide ring adopts an anti/anti
conformation, with the bis-trifluoromethyl-phenyl ring slightly
twisted [torsion angle: C(24)-N(3)-C(25)-C(26) = −35.0(7)°] with
respect to the cyclobutendione unit. The co-planarity and
directionality of the two NH groups [torsion angles: H(2)-N(2)-
C(21)-C(24) = 4.7(5)°; H(3)-N(3)-C(24)-C(21) = −5.3(3)°] might
ensure their participation in the aldehyde carbonyl group
activation with a minimal entropic cost. In the chiral amide
fragment, the preferred conformation places the tert-butyl group
almost perpendicular to the squaramide plane [torsion angle:
Figure 5. A) X-Ray structure of II. H atoms (except H1 and H7) are omitted for
clarity. Thermal ellipsoids drawn at 50% probability. B) Head-to-tail H-bonding
interactions in the solid state (three monomers shown).
Conclusions
In summary, amide-squaramide catalysts enabled the highly
enantioselective addition of formaldehyde tert-butyl hydrazone
(FTBH) to simple aldehydes. The use of α,α,α-trifluorotoluene
was essential to ensure homogeneous reaction media which led
to good and reproducible results. Experimental data suggest that
the ability of the squaramide group to behave as efficient H-bond
donor and the presence of a H-bond acceptor in tert-leucine
derived amide fragment of catalyst II are key for the dual
activation of the reactants, leading to enantioenriched products
via
a highly ordered complex that explains the observed
stereochemistry. The presented approach allows for an efficient
route to asymmetric functionalization of simple aldehydes
affording a broad spectrum of optically active alcohols and
derivatives thereof.
C(17)-C(16)-N(2)-C(21)
= 105.6(5)°]. Importantly, the low
dihedral O(1)-C(15)-C(16)-N(2) angle of −41.9(6)° places the
amide carbonyl group [C(15)=O(1)] in a convenient orientation to
drive the approach of the hydrazone to aldehyde.
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12915. (b) J. A. Carmona, G. de Gonzalo, I. Serrano, A. M. Crespo-
Peña, M. Šimek, D. Monge, R. Fernández, J. M. Lassaletta, Org.
Biomol. Chem. 2017, 15, 2993-3005.
Experimental Section
General procedure for the catalytic enantioselective reactions of
[8]
[9]
I. Serrano, D. Monge, E. Álvarez, R. Fernández, J. M. Lassaletta,
Chem. Commun. 2015, 51, 4077-4080.
tert-butyl hydrazone 1a with aldehydes
regioselective N-oxidation:
2
and subsequent
D. Monge, A. M. Crespo-Peña, E. Martín-Zamora, E. Álvarez, R.
Fernández, J. M. Lassaletta, Chem. Eur. J. 2013, 19, 8421-8425.
Freshly distilled formaldehyde tert-butyl hydrazone 1a (34 µL, 0.3 mmol)
was added to a solution of aldehydes 2 (0.2 mmol) and catalyst II (0.02
mmol, 12 mg) in α,α,α-trifluorotoluene (0.4 mL) at the temperature
specified for each substrate (see Table 2). The mixture was stirred until
consumption of the starting material (1H-NMR monitoring). After this time,
MeOH (0.4 mL) and MMPP (360 mg, 0.6 mmol) were subsequently
added and the reaction mixture was allowed to warm up to rt for
completion (1-2 hours). The mixture was then diluted with H2O (3 mL)
and extracted with CH2Cl2 (3 x 5 mL). The combined organic layers were
washed with brine (1 x 20 mL), dried over MgSO4 and concentrated
under reduced pressure. The resulting residue was purified by flash
chromatography (Cy/CH2Cl2/AcOEt 1/8/1) to afford azoxy compounds 4.
Enantiomeric excess was determined by HPLC analysis.
[10] For selected reviews, see: (a) J. Alemán, A. Parra, H. Jiang, K. A.
Jørgensen, Chem. Eur. J. 2011, 17, 6890-6899. (b) X. Han, H.-B. Zhou,
C. Dong, Chem. Rec. 2016, 16, 897-906. For discussion on
squaramide acidities, see: (c) X. Ni, X. Li, Z. Wang, J.-P. Cheng, Org.
Lett. 2014, 16, 1786-1789. For seminal paper, see: (d) J. P. Malerich, K.
Hagihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416-14417.
For selected applications in asymmetric organocatalysis, see: (e) F. F.
Wolf, H. Klare, B. Goldfuss, J. Org. Chem. 2016, 81, 1762-1768. (f) H.
Y. Bae, C. E. Song, ACS Catal. 2015, 5, 3613-3619. (g) R. S.
Tukhvatshin, A. S. Kucherenko, Y. V. Nelyubina, S. G. Zlotin, ACS
Catal. 2017, 7, 2981-2989. (h) F. Manoni, S. J. Connon, Angew. Chem.
Int. Ed. 2014, 53, 2628-2632. For examples involving mono-carbonyl
substrates: (i) J. V. Alegre-Requena, E. Marqués-López, P. J. S. Miguel,
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Acknowledgements
[11] N,N′-Bis[3,5-bis(trifluoromethyl)phenyl] thiourea (Schreiner thiourea: A.
Wittkopp and P. R. Schreiner, Chem. Eur. J., 2003, 9, 407) was used
as an achiral catalysts in preliminary reactivity experiments.
This work was supported by the Spanish MINECO (CTQ2016-
76908-C2-1-P, CTQ2016-76908-C2-2-P), European FEDER
funds and the Junta de Andalucía (Grant 2012/FQM1078). We
also thank general NMR services of the University of Sevilla.
[12] Examples of related bifunctional amide-squaramides in asymmetric
organocatalysis: (a) V. Kumarand, S. Mukherjee, Chem Commun. 2013,
49, 11203-11205. (b) H. Zhang, S. Lin, E. N. Jacobsen, J. Am. Chem.
Soc. 2014, 136, 16485-16488. (c) K. Bera, I. N. N. Namboothiri, Org.
Biomol. Chem. 2014, 12, 6425-6431.
Keywords: H-bonding organocatalysis, bifunctional catalysis,
squaramides, azoxy compounds, oxazolidinones
[13] The reason for the low solubility of squaramides in nonpolar solvents is
that they frequently self-aggregate through dual H-bonds into head-to-
tail ladder networks. See: (a) A. Portell, R. Barbas, D. Braga, M. Polito,
C. Puigjanerand, R. Prohens, CrystEngComm, 2009, 11, 52-54. (b) A.
Portell, M. Font-Bardia, A. Bauzá, A. Frontera, R. Prohens, Cryst.
Growth Des. 2014, 14, 2578-2587. (c) A. Portell, M. Font-Bardia, A.
Bauzá, A. Frontera, R. Prohens, CrystEngComm, 2016, 18, 6437-6443.
[14] α,α,α-Trifluorotoluene is similar to CH2Cl2 in diverse reactions, see: A.
Ogawa, and T. Kaname, ‘α,α,α-Trifluorotoluene’ in Encyclopedia of
Reagents for Organic Synthesis 2005, John Wiley and Sons. Doi:
[1]
[2]
(a) R. Fernández, J. M. Lassaletta, Synlett, 2000, 1228-1240. (b) R.
Brehme, D. Enders, R. Fernández, J. M. Lassaletta, Eur. J. Org. Chem.
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(a) R. Fernández, E. Martín-Zamora, C. Pareja, J. Vázquez, E. Díez, A.
Monge, J. M. Lassaletta, Angew. Chem. Int. Ed. Eng. 1998, 37, 3428-
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5207.
10.1002/047084289X.rn00653. Dielectric constants: CH2Cl2
= 9.04;
α,α,α-trifluorotoluene = 9.18. Dipole moments: CH2Cl2 = 1.89; α,α,α-
trifluorotoluene = 2.86.
[3]
Some exceptions: (a) D. Monge, E. Martín-Zamora, J. Vázquez, M.
Alcarazo, E. Álvarez, R. Fernández, J. M. Lassaletta, Org. Lett. 2007, 9,
2867-2870. (b) S. Breitler, E. M. Carreira, J. Am. Chem. Soc. 2015, 137,
5296-5299.
[15] Employing these optimized conditions, analogous thiourea I afforded 4a
in 50% yield and 78% ee.
[16] CCDC 1825088 contains the supplementary crystallographic data for
(S)-4a.
[4]
[5]
Hydrazones in asymmetric organocatalysis: M. G. Retamosa, E.
Matador, D. Monge, J. M. Lassaletta, R. Fernández, Chem. Eur. J.
2016, 22, 13430-13445.
[17] Bioactive azoxy compounds: a) the antimicrobial and cytotoxic
elaiomycins: L. Ding, B. L. T. Ndejouong, A. Maier, H. H. Fiebigand, C.
Hertweck, J. Nat. Prod. 2012, 75, 1729-1734. b) the antibiotic
valanimycin: R. P. Garg, X. L. L. Qian, L. B. Alemany, S. Moran, R. J.
Parry, Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 6543-6547. c) and the
antifungal agent maniwamycin A: M. Nakayama, Y. Takahashi, H. Itoh,
K. Kamiya, M. Shiratsuchi, G. Otani, J. Antibiot. 1989, 42, 1535-1540.
[18] Amino alcohols are also important building blocks. As representative
example, 6i was isolated (50% yield, 93% ee) and fully characterized
(See the Supporting Information).
(a) D. J. Dixon, A. L. Tillman, Synlett, 2005, 17, 2635-2638. (b) M.
Rueping, E. Sugiono, T. Theissmann, A. Kuenkel, A. Kçckritz, A. Pews-
Davtyan, N. Nemati, M. Beller, Org. Lett. 2007, 9, 1065-1068. (c) T.
Hashimoto, M. Hirose, K. Maruoka, J. Am. Chem. Soc. 2008, 130,
7556-7557. (d) T. Hashimoto, H. Kimura, K. Maruoka, Angew. Chem.
Int. Ed. 2010, 49, 6844-6847. (e) Recent example on the asymmetric
1,2-addition of N-monoalkylhydrazones (MAHs) to yield β-amino N,N´-
dialkyldiazenes: Y. Wang, Q. Wang, J. Zhu, Angew. Chem. Int. Ed.
2017, 56, 5612-5615.
[19] Oxazolidinones in medicinal chemistry: (a) T. A. Mukhtar, G. D. Wright,
Chem. Rev. 2005, 105, 529-542. (b) M. R. Barbachyn, C. W. Ford,
Angew. Chem. Int. Ed. 2003, 42, 2010-2023. (c) H. Kakeya, M.
Morishita, K. Kobinata, M. Osono, M. Ishizuka, J. Osada, J. Antibiot.
[6]
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R. P. Herrera, D. Monge, E. Martín-Zamora, R. Fernández, J. M.
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(a) A. M. Crespo-Peña, D. Monge, E. Martín-Zamora, E. Álvarez, R.
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1998, 51, 1126-1128. (d) M. F. Gordeev, Y. Y. Zhengyu, J. Med. Chem.
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[20] For
a
discussion on multiple vs multifunctional catalysis, see: S.
[22] NMR titration experiments in α,α,α-trifluorotoluene, employing signal
suppression techniques, were not satisfactory. NMR titration
experiments in CD2Cl2, afforded erratic results due to precipitation of II
at concentrations representative of catalyst loading and even below.
[23] CCDC 1825081 contains the supplementary crystallographic data for
(S)-II.
Piovesana, D. M. S. Schietroma, M. Bella, Angew. Chem. Int. Ed. 2011,
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non-linear effect due to the presence of soluble off-cycle catalyst
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Jacobsen, J. Am. Chem. Soc. 2016, 138, 7860-7863. (b) D. Ford, D.
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Esteban Matador, María de Gracia
Retamosa, David Monge,* Javier
Iglesias-Sigüenza, Rosario Fernández*
and José M. Lassaletta*
Page No. – Page No.
Bifunctional Squaramide
Text for Table of Contents
Organocatalysts for the Asymmetric
Addition of Formaldehyde tert-Butyl
Hydrazone to Simple Aldehydes
Bifunctional
catalysts
enantioselective
amide-squaramide
enabled
the
highly
of
addition
formaldehyde tert-butyl hydrazone to
simple aldehydes. The use of α,α,α-
trifluorotoluene was essential to afford
good
and
reproducible
results.
Subsequent derivatizations provide an
entry to relevant amino alcohols,
oxazolidinones
thereof.
and
derivatives
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