1,2-Diamine-Derived (thio)Phosphoramide Organocatalysts in Asymmetric Michael Additions

Article abstract of DOI:10.1002/adsc.202000335

Phosphoramides and thiophosphoramides were prepared from optically pure C₂-symmetric 1,2-diamines and were used as chiral organocatalysts in the asymmetric Michael additions of aldehydes and ketones to N-substituted maleimides. The 1,2-diphenylethane-1,2-diamine derived thiophosphoramide, which could be prepared in good yield in a one-step procedure, was found to be more active and selective catalyst in the addition of aldehydes to various maleimide derivatives, when compared to sulfonamides having the same backbone. Products resulted in reactions of ketones with maleimides were also obtained in high yields and enantioselectivities. The thiophosphoramide derivative was also efficient in the asymmetric conjugate addition of carbonyl compounds to β-nitrostyrene and in the reaction of nitromethane with α,β-unsaturated ketones. Based on results obtained with (thio)phosphoramides in asymmetric additions to maleimides it was suggested that a weaker, more flexible hydrogen-bonding of the rigid electrophile to the catalyst is responsible for the improved performance of these bifunctional organocatalysts, as compared with sulfonamides. (Figure presented.).

Full text of DOI:10.1002/adsc.202000335

Title: 1,2-Diamine-derived (thio)phosphoramide organocatalysts in
asymmetric Michael additions
Authors: Viktória Kozma, Ferenc Fülöp, and György Szőllősi
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
1,2-Diamine-derived (thio)phosphoramide organocatalysts in
asymmetric Michael additions
Viktória Kozma,a Ferenc Fülöp,b,c,d and György Szőllősic*
a
Department of Organic Chemistry, University of Szeged, 6720 Szeged, Dóm tér 8, Hungary
Institute of Pharmaceutical Chemistry, University of Szeged, 6720 Szeged, Eötvös utca 6, Hungary
MTA-SZTE Stereochemistry Research Group, University of Szeged, 6720 Szeged, Eötvös utca 6, Hungary
University of Szeged, Interdisciplinary Excellence Centre, Institute of Pharmaceutical Chemistry, 6720 Szeged,
b
c
d
Eötvös utca 6, Hungary
phone: +36-62-544514, e-mail: szollosi@chem.u-szeged.hu
Dedicated to the memory of Prof. Mihály Bartók
Received:
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Phosphoramides and thiophosphoramides were the asymmetric conjugate addition of carbonyl compounds
prepared from optically pure C2-symmetric 1,2-diamines and to -nitrostyrene and in the reaction of nitromethane with
were used as chiral organocatalysts in the asymmetric ,-unsaturated ketones.
Michael additions of aldehydes and ketones to N-substituted
Based on results obtained with (thio)phosphoramides in
maleimides. The 1,2-diphenylethane-1,2-diamine derived asymmetric additions to maleimides it was suggested that a
thiophosphoramide, which could be prepared in good yield weaker, more flexible hydrogen-bonding of the rigid
in a one-step procedure, was found to be more active and electrophile to the catalyst is responsible for the improved
selective catalyst in the addition of aldehydes to various performance of these bifunctional organocatalysts, as
maleimide derivatives, when compared to sulfonamides compared with sulfonamides.
having the same backbone. Products resulted in reactions of
ketones with maleimides were also obtained in high yields
and enantioselectivities.
Keywords: Asymmetric catalysis; Michael addition; 1,2-
Diamines; Thiophosphoramide; Maleimides; Carbonyl
compounds
The thiophosphoramide derivative was also efficient in
organic compounds as catalysts in asymmetric
Michael additions,[3,6] which afforded the desired
products in high yields and optical purities without
metal contaminations following convenient work-up
procedures.
Introduction
Development of efficient chiral catalysts for the
economical synthesis of optically pure compounds is
a challenging task. A variety of chiral metal
complexes and organocatalysts are available for the
stereoselective preparation of optically enriched
chemicals.[1,2] Fine-tuning of the catalysts’ structure
has paramount importance for improving their
performances.[2] Thus, besides studies aimed at
finding novel catalytic materials, research focused on
the effect of structural modification of the catalysts
are equally important.
Asymmetric C‒C bond-forming reactions have
great significance in obtaining the structural
complexity of the optically pure building blocks used
in the pharmaceutical and fine chemical industry.
Among these, conjugate additions are privileged
reactions, owing to the structural diversity of the
employable donors and acceptors.[3,4] Various chiral
metal complexes were found efficient in these
reactions.[5] Since the beginning of the present
century the explosive development of the
organocatalysis led to widespread application of
The stereoselective Michael addition of
nucleophiles to maleimides affords succinimide
derivatives,[7] which are the structural units of several
bioactive natural products, pharmaceuticals and drug
candidates.[8] Special attention has been focused on
the preparation of compounds resulting in reactions
of maleimides and aldehydes or ketones, which may
be further transformed easily in various high value-
added products. These asymmetric Michael additions
may be catalysed by bifunctional primary amine
catalysts bearing a hydrogen-bond (H-bond) donor
unit. Highly efficient chiral catalysts were obtained
from C2-symmetric vicinal primary diamines, such as
cyclohexane-1,2-diamine or 1,2-diphenylethane-1,2-
diamine, following their transformation in
sulfonamide or thiourea derivatives.[9] Compounds
developed so far, bearing various H-bond donor
moieties (Figure 1),[10] showed that tuning the catalyst
structure by proper modifications of these groups
1
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
may lead to improved performances in the
enantioselective conjugate additions to maleimides.
(5, 6 and ent-6) were obtained in good yields (72-
76% after purification by flash-chromatography,
Scheme 1). However, from 1 both 3 and 4 were
isolated only in low yields (11% and 14%), due to
extensive formation of doubly phosphorylated
products. Accordingly, a three-step procedure was
adopted in order to obtain these derivatives in higher
yields. This protocol included the protection of one
amino group as phthalimide,[13] followed by acylation
with the corresponding phosphoric chloride,[12c] and
deprotection using N2H4 hydrate.[13] Although this
procedure included two flash chromatographic
purifications, ent-3 and 4 were isolated in over 50%
overall yields. An additional thiophosphoramide with
a rigid bicyclo[2.2.2]octane moiety (8) was prepared
from
(11S,12S)-11,12-diamino-9,10-dihydro-9,10-
ethanoanthracene (7) in good yield (64%) following
the one-step procedure (Scheme 1).
Figure 1. Structures of chiral bifunctional C2-symmetric
1,2-diamine derivatives used in the asymmetric Michael
additions of aldehydes to maleimides.[9,10]
Recent studies showed that phosphinamides or
(thio)phosphoramides prepared from optically pure
C2-symmetric primary diamines, besides having
antiviral and antifungal effects,[11] are efficient
organocatalysts in asymmetric Michael additions.[12]
These derivatives afforded high yields and good
enantioselectivities in the addition of ketones to -
nitrostyrene. However, the scope of these
bifunctional catalysts has not yet been explored in
detail. Here we disclose results of studies on
extending the applicability of (thio)phosphoramides
prepared from optically pure 1,2-diamines on the
asymmetric addition of carbonyl compounds to
maleimides. Other asymmetric conjugate additions,
such as reactions of carbonyl compounds with -
nitrostyrene and that of nitromethane with ,-
unsaturated ketones were also investigated to test the
versatility of these chiral organocatalysts.
Scheme 1. Preparation of (thio)phosphoramides from
optically pure C2-symmetric 1,2-diamines.
Results and Discussion
Asymmetric addition of aldehydes to N-
substituted maleimide derivatives
Initially
we
have
attempted
to
prepare
phosphoramides and thiophosphoramides from
optically pure (R,R)-1,2-cyclohexanediamine (1),
(S,S)-1,2-diphenylethane-1,2-diamine (2) and ent-2,
We started our catalytic studies by testing
(thio)phosphoramides 3, ent-3, 4 ‒ 6, ent-6 and 8 as
organocatalysts in the asymmetric conjugate addition
of isobutyraldehyde (9) to N-benzylmaleimide (10a)
leading to the succinimide derivative 11a (Table 1).
by
a
one-step
procedure
using
O,O’-
diethyl(thio)phosphoric chlorides (Scheme 1).[12c] In
reactions of 2 (or ent-2) the corresponding products
2
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
Their performances were compared with the
corresponding chiral diamines (1 or 2) and
sulfonamides:
diaminocyclohexane
toluenesulfonyl)-1,2-diphenylethane-1,2-diamine (13),
ent-13 and (1R,2R)-N-(methanesulfonyl)-1,2-
diphenylethane-1,2-diamine (14). Results
(1R,2R)-N-(p-toluenesulfonyl)-1,2-
(12), (1S,2S)-N-(p-
acceleration of either the enamine intermediate
formation or the iminium ion hydrolysis.[10,12a,14b,15]
However, in this reaction the conversion slightly
decreased under these conditions. Thus, we presume
that acceleration of the above steps does not play role
in determining the overall reaction rate in reaction of
9 with 10a using these catalysts.
Thiophosphoramide 8, with two phenyl rings
cumulated to a bicyclo[2.2.2]octane scaffold, was
slightly less active than 6 and afforded lower ee value
(ee 94%, entry 23). Accordingly, besides the
summarized in Table 1 showed unambiguously, that
the catalyst has to contain a H-bond donor group,
both chiral diamines (1 and 2, entries 1 and 7) were
less efficient than their functionalized derivatives and
provided low ee‘s.
Phosphoramides
3
and
ent-3
and
thiophosphoramide 4 having cyclohexane backbone
were highly active catalysts in the test reaction,
assuring complete conversion of 10a in one hour at
room temperature (rt) (entries 4 – 6). Product 11a
resulted in good yield and in 94% ee’s. The
tosylamide (Ts-amide) 12 was much less efficient,
providing smaller conversion and lower ee (entries 2,
3).
Table
1.
Asymmetric
Michael
addition
of
isobutyraldehyde (9) to N-benzylmaleimide (10a).[a]
Entry
Catalyst Temp Time
Conv
ee
[°C]
[h]
[%][b]
[%][c]
1
2
3
4
5
6
7
8
24
24
24
24
24
24
70
24
70
70
70
70
70
24
50
70
70
70
70
70
70
70
70
5
1
3
1
1
1
42
28
73
99 (82)
99 (83)
99 (82)
89
28 (R)
89 (R)
90 (R)
94 (R)
94 (S)
94 (R)
71 (S)
98 (S)
1
12
12
3
ent-3
4
The organocatalysts with 1,2-diphenylethane
scaffold were less active in this Michael addition
(entries 8 – 22) as compared with 3, ent-3 and 4. The
Ts-amide 13 afforded low conversion at rt in 3 days
(entry 8). However, high ee (98%) was obtained.
Higher conversion, without altering the ee value, was
reached in one day by increasing the reaction
temperature to 70°C (entry 9). Under these conditions
by decreasing the reactants molar ratio (9/10a) from
4/1 to 2/1 and the catalyst amount to 5 mol%, still
good conversions were reached (entries 10, 11). As
expected ent-13 afforded identical results and the
opposite product enantiomer in excess, as compared
with 13 (entry 12). The methanesulfonamide 14 was
slightly more efficient than 13 (entry 13), indicating
that the p-tolyl moiety has no significant influence on
the reaction. As compared to 13, thiophosphoramide
6 was more effective, affording close to full
conversion and high, over 99% ee value at rt in three
days (entry 14). Moreover, this compound afforded
high conversion even at 50°C or complete
transformation of 10a at 70°C following 24 h using
only 2 equivalents (eq.) of 9 (entries 15, 16). The
latter result was also reached with 5 mol% 6 or ent-6
(entries 17, 21). Small decrease in conversion was
detected only when the aldehyde amount was further
decreased to 1.1 eq. (entry 18). Similar result was
obtained with the phosphoramide 5 (entry 22).
24
72
24
24
24
24
24
72
24
24
24
24
24
24
24
24
24
2
43
13
13
13
13
ent-13
14
6
9
94 (80)
92 (77)
80
93 (80)
98 (82)
97 (82)
90
99 (84)
99 (85)
92 (76)
96 (80)
97 (80)
98 (S)
96 (S)
97 (S)
10[d]
11[d,e]
12[d]
13
96 (R)
98 (R)
>99 (S)
>99 (S)
>99 (S)
>99 (S)
>99 (S)
>99 (S)
>99 (S)
14
15[d]
16[d]
17[d,e]
18[e,f]
19[d,e,g]
20[d,e,h]
21[d,e]
22[d,e]
6
6
6
6
6
6
ent-6
5
8
99 (84) >99 (R)
97 (83)
97 (80)
>99 (S)
94 (R)
23[d,e]
[a]
Reaction conditions: 0.03 mmol (10 mol%) catalyst, 0.3
mmol 10a, 1.2 mmol 9, 1 cm3 CHCl3.
[b] Conversion of 10a determined by gas-chromatography
(GC-FID); in brackets are the isolated yields of 11a.
[c] Enantiomeric excess and the absolute configuration of
the excess enantiomer determined by GC-FID.[9j]
[d] Using 0.6 mmol 9.
Next we have changed the solvent from CHCl3 to
toluene with or without acid additives, such as acetic
acid (AcOH), benzoic acid (BzOH), or a combination
of water and AcOH (entries 19, 20). Previous reports
showed that these additives may increase the
conversion in the asymmetric addition of carbonyl
compounds to maleimides and nitroolefins, due to
[e] With 0.015 mmol (5 mol%) catalyst.
[f] Using 0.33 mmol 9.
[g] Reaction in toluene.
[h] Results of reactions in toluene with addition of AcOH or
BzOH (0.03 mmol) or by adding H2O (0.06 mmol) and
AcOH (0.03 mmol).
3
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
these transformations, irrespective of the N-
substituent (Me, Et, Bn, Ph, cyclohexyl or tBu).
These ee values were higher than those reached with
the Ts-amide 12 (Table SI-1, Supporting information).
Figure 2. Effect of 6 amount on the conversion of 10a
(Conv 10a) and ee of 11a in the addition of 9 to 10a.
Reaction conditions: 0.3 mmol 10a, 0.6 mmol 9, solvent: 1
cm3 CHCl3, 70°C, 24 h; open symbols: results obtained
using 13.
Structures of sulfonamides used for comparison:
Results obtained in the reaction of 9 with 10a ‒
10f using 1,2-diphenylethane-1,2-diamine derived
catalysts 5 and 6 are presented in Table 3. Selection
of the presented results was preceded by short
optimizations with each maleimide derivative by
changing the catalyst amount, reactant ratio and
reaction time. High conversions and yields were
obtained in reactions of most maleimides in one day
or less (10b). Similarly with the reaction catalysed by
4, 10f needed longer reaction times to approach full
transformation (entries 11, 12), probably due to steric
hindrances of the bulky tBu group. The
phosphoramide derivative 5 gave smaller conversions
in these reactions as compared with 6. Most
important, excellent enantioselectivities were
obtained in all these reactions. The ee‘s exceeded
those obtained with the sulfonamide 13 (Table SI-2,
Supporting information). The thiophosphoramide 6
provided better ee’s than 5, leading in many reactions
to formation of less than 0.5% of the R enantiomer
(ee > 99%).
Next we have explored the performances of the
(thio)phosphoramides 4, 5 and 6 in the addition of
propionaldehyde (15) to 10a (Table 4). The results
were also compared to those obtained with the
sulfonamides 12 or 13, respectively. Significantly
longer reaction times were necessary for the addition
of 15 to 10a as compared with 9. Similarly with the
addition of 9, the cyclohexane-1,2-diamine derived 4
and 12 were more active than 5, 6 or 13. Almost
complete conversion of 10a was reached with 4 in 5 h
(Table 4, entry 2), whereas under identical conditions,
the conversion was much lower with 12 (entry 1).
With both 4 and 12 the diastereomers of 16 formed in
(thio)phosphoramide group, the hydrocarbon skeleton
of the C2-symmetric 1,2-diamine also plays role in
obtaining high ee value. It must be stressed out that in
the above reactions catalysed by 6, ent-6 or 5 very
high ee values (over 99%) were obtained, thus
optically pure 11a could be isolated in good (82 –
85%) yields.
Owing to the excellent performance of 6, shown
in the addition of 9 to 10a, as compared with the
previously employed 1,2-diphenylethane-1,2-diamine
derivatives,[9,10] we have examined the possibility of
decreasing the organocatalyst amount. The effect of
the 6 amount is presented in Figure 2. Although, 1.6
mol% of 6 was enough to obtain over 60%
conversion in one day using 2 eq. of 9, 2.5 mol%
catalyst was necessary for close to complete
transformation of 10a. However, high ee value (99%)
was obtained even with the lower amount of catalyst.
The time dependence of the ee with 2.5 mol% 6
showed constantly high ee values from the beginning
of the reaction (Figure SI-1, Supporting information).
The higher activities and ee’s obtained in the
reaction
of
9
with
10a
using
the
(thio)phosphoramides 4, 5 and 6, as compared with
the corresponding Ts-amides motivated our study on
extending the scope of these catalysts on reactions of
9 with other N-substituted maleimides.
The 1,2-cyclohexanediamine
derivative
4
provided high conversions of 10a ‒ 10f at rt, thus
succinimide derivatives 11a ‒ 11f were isolated in
good yields (Table 2). The reaction times necessary
to obtain close to complete transformations depended
on the N-substituent. Usually up to 5 h were
sufficient to obtain high conversions; longer time (22
h) was necessary to react the N-tBu derivative 10f
(entry 7). High ee’s (94% – 99%) were obtained in
almost
equal
amounts,
however
the
thiophosphoramide 4 provided slightly better ee.
Table 2. Asymmetric Michael addition of 9 to N-
substituted maleimides 10a – 10f catalysed by 4.[a]
Entry Product Time [h]
Conv [%][b] ee [%][c]
4
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
1
2
1
5
5
3
5
99 (82)
99 (82)
93 (75)
99 (83)
95 (80)
92 (75)
86 (70)
94
99
98
95
96
98
96
3
4
5
6
7
8
8
8
88 (70)
99 (84)
93 (75)
98 (82)
92 (73)
96 (80)
92 (75)
97 (82)
85 (70)
97 (80)
99
>99
>99
>99
99
>99
98
>99
99
11a
11b
11b
11c
11d
11e
11f
11b
11b
11c
11c
11d
11d
11e
11e
11f
11f
5
6
5
6
5
6
5
6
5
6
3[d]
4
24
24
24
24
24
24
96
96
5
6
5
22
7
9[e]
10[e]
11[e]
[a] Reaction conditions: 0.03 mmol (10 mol%) 4, 0.3 mmol
10a – 10f, 1.2 mmol 9, 1 cm3 CHCl3, rt.
12[e]
>99
[b] Conversion of 10a – 10f determined by GC-FID; in
brackets are the isolated yields of 11a – 11f.
[c] Enantiomeric excess (by GC-FID), the configuration of
the excess enantiomer was assigned as R based on
reactions using 12.
[a]
Reaction conditions: 0.015 mmol (5 mol%) catalyst, 0.3
mmol 10a – 10f, 1.2 mmol 9, 1 cm3 CHCl3, 70°C.
[b] Conversion of 10a – 10f determined by GC-FID; in
brackets are the isolated yields of 11a – 11f.
[c] Enantiomeric excess (by GC-FID), the configuration of
the excess enantiomer was S based on reactions using
catalyst 13.
[d] Using 0.015 mmol (5 mol%) 4.
Low conversion was obtained in one week with
[d] Using 0.6 mmol 9.
the
1,2-diphenylethane-1,2-diamine
derived
[e] With 0.03 mmol (10 mol%) catalyst.
sulfonamide 13 at 70°C (entry 3). The
(thio)phosphoramides and led to higher
5
6
Table 4. Asymmetric addition of propionaldehyde (15) to
10a.[a]
conversions (entries 4-6), the latter afforded close to
complete transformation of 10a in five days. In this
reaction a more pronounced difference in the
performance of 5 and 6 may be observed. Both 6 and
13 gave similarly high, 99% ee‘s, whereas the
diastereomeric ratios were low (1.2
–
1.3).
Examination of the effect of 6 amount (Figure 3)
showed a slow increase in the conversion at low
amounts of 6 (up to 5 mol%) followed by a more
Entry
Catalyst
Time
[h]
Conv [%]; dr[b]
ee
[%][c]
accentuated
elevation,
whereas
both
the
1[d]
2[d]
3
4
5
5
5
61; 50/50
96 (80); 52/48 94; 95
34; 55/45
66; 55/45
86 (74); 56/44 99; 99
97 (83); 57/43 99; 99
86; 54/46
80; 55/45
87 (74); 56/44 99; 99
92; 91
diastereomeric ratio and the ee’s were unaltered in
the examined concentration range. The peculiarly low
conversions obtained at low catalyst concentrations
may be ascribed to the high 15/6 ratios (over 80),
which may involve the formation of side-products
having as effect the deactivation of the catalyst. In a
reaction using catalyst 6 in toluene both the
conversion and the ee decreased as compared with
CHCl3 (Table 4., entry 7), however, the addition of
acid additives (AcOH or BzOH) or AcOH and water
led to faster reactions, similar with that performed in
CHCl3 (entries 8, 9).
12
4
13
5
6
6
6
6
6
168
120
72
120
120
72
99; 99
98; 98
6
7[e]
8[f]
99; 99
99; 99
9[g]
72
[a]
Reaction conditions: 0.03 mmol (10 mol%) catalyst, 0.3
mmol 10a, 1.2 mmol 15, 1 cm3 CHCl3, 70°C (Bn: benzyl).
[b] Conversion determined by GC-FID, yield of the isolated
product in brackets; dr: diastereomeric ratio (syn/anti).
[c] Enantiomeric excesses of the syn and anti isomers
determined by GC-FID.
Accordingly, results obtained in the Michael
addition of the aldehydes studied above showed the
[d] Reaction at rt (24°C).
[e] Reaction in toluene.
Table 3. Michael addition of 9 to maleimides 10a ‒ 10f
[f] In toluene using 0.03 mmol AcOH or BzOH.
[g] In toluene using 0.03 mmol AcOH and 0.06 mmol H2O.
superior performances of the C2-symmetric 1,2-
diamine
derived
thiophosphoramides,
when
compared with the corresponding sulfonamides. To
test the practical applicability of the former catalysts,
reactions of few N-substituted maleimides were
carried out at higher, 1 mmol scale, using catalyst 6.
Similarly high yields and high optical purities were
obtained by increasing proportionally the solvent and
the 9 amounts without extending the reaction time
(except the reaction of 10b), as shown in Figure 4.
catalysed by 5 and 6.[a]
Entry Product Catalyst Time
[h]
Conv
ee
[%][b]
[%][c]
1[d]
24
24
97 (83)
99 (85)
99
99
11a
11a
5
6
2[d]
5
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
asymmetric reactions (Scheme 2). Our initial attempts
carried out using acetone (17a) as nucleophile under
similar conditions as employed in reactions of
aldehydes (CHCl3, 70°C, 72 h) led to almost
complete recovery of 10a (<5% conversion).
Motivated by results reached in the asymmetric
addition of ketones to -nitrostyrene and maleimides
reported previously,[12a,14-16] we have carried out the
reaction in toluene with the addition of AcOH and
water. High conversion and ee value was obtained in
1 day (Table 5, entry 1). In experiments performed in
toluene or using solely water both the conversions
and ee values decreased (Conv 11%, ee 94% and
Conv 33%, ee 97%, respectively). Adding AcOH or
BzOH the ee‘s were the same as with AcOH and
water, while slightly smaller conversions were
reached (87% and 92%, respectively; in the presence
of BzOH, see entry 2).
Based on these observations the reactions of
maleimides 10a – 10d and ketones 17a – 17f using
catalyst 6 (Scheme 2) were performed in two solvents
(CHCl3 and toluene with addition of AcOH and
water). The best results were selected in Table 5. For
comparison, reactions catalysed with 13 (some with
2) were also carried out (Table SI-3, Supporting
information). High conversions and ee values were
reached in these additions either with catalyst 6 or 13.
In reactions of acetone (products 18aa, 18ba, 18ca,
18da) the ee’s obtained with 6 were slightly higher
than those reached using 13, the N-substituent had
little influence on both the conversions and the ee’s
(entries 1, 7, 8, 17). The R configuration of the chiral
centre was assigned based on reported results
obtained using catalysts ent-13.[16a] Furthermore, high
yield of 18aa was reached in a reaction carried out
with 1 mmol 10a in two days (entry 3).
Figure 3. Effect of 6 amount on the conversion of 10a
(Conv 10a), the dr and ee of 16 in the Michael addition of
15 to 10a. Reaction conditions: 0.3 mmol 10a, 1.2 mmol
15, solvent: 1 cm3 CHCl3, 70°C, 120 h; open symbols:
conversions reached using catalyst 13.
The effect of the catalyst amount in reactions of
17a with 10a or 10d showed that 5 mol% 6 was
sufficient to reach high conversion in the former
reaction in one day, whereas in the latter 15 mol%
was necessary under identical conditions (Figure SI-2,
Supporting information). However, in the reaction of
10d close to complete transformation could be
obtained with low amount of 6 (5 mol%) by
extending the reaction to 48 h (94% conversion). In
both reactions high ee’s were obtained even with the
lowest catalyst amounts.
Figure 4. Products obtained in the Michael addition of 9 to
N-substituted maleimides at 1 mmol scale; reaction
conditions: 0.05 mmol (5 mol%) 6, 1.0 mmol maleimide
derivative, 4.0 mmol 9, 3 cm3 CHCl3, 70°C, 24 h.
Addition of ketones to maleimide derivatives
Asymmetric Michael additions of ketones to
maleimides were seldom reported.[16] Among the few
studies published are three reports using C2-
symmetric diamine derivatives as catalysts and only
one applied chiral sulfonamides, such as 13.[16a] We
continued our study on extending the scope of the
thiophosphoramide catalyst 6 in these demanding
6
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
1
A; 24
A; 24
A; 48
A; 12
B; 72
A; 72
A; 24
A; 24
A; 24
B; 24
A; 72
A; 72
B; 72
A; 120
B; 120
A; 48
A; 48
A; 24
B; 48
A; 72
94 (82)
92 (80)
99 (90)
99 (R)
99 (R)
99 (R)
99; >99
99; >99
98; nd
98 (R)
98 (R)
>99; 99
>99; 99
97; 92
96; 95
98; nd
94; 94
91; 90
98; 98
98 (R)
97; 95
98; nd
99; 98
18aa
18aa
18aa
18ab
18ab
18ac
18ba
18ca
18cb
18cb
18cc
18cd
18cd
18ce
18ce
18cf
2[e]
3[f]
4
98[i] (90); 54/46
92[i] (80); 54/46
80 (70); 85/15
96 (85)
5
6[g]
7
8
90 (80)
9[h]
10[h]
11
12
13
14
15
16
17
18
19
20
99[i] (90); 50/50
85[i] (70); 50/50
92 (81); 75/25
99 (90); 62/38
99 (90); 85/15
75 (60); 58/42
97 (88); 65/35
96 (88); 62/38
99 (90)
18da
18dd
18dd
18df
98 (88); 68/32
99 (90); 86/14
98 (90); 60/40
[a] Reaction conditions: 0.03 mmol (10 mol%) 6, 0.3 mmol
10a – 10d, 1.5 mmol 17a or 1.2 mmol 17b – 17d or 0.6
mmol 17e, 17f, 1 cm3 solvent, 70°C, nd: not determined.
[b] Solvent used and reaction time [h]; A: toluene + 0.03
mmol AcOH + 0.06 mmol H2O; B: CHCl3.
[c] Conversion determined by GC-FID, isolated yields in
brackets; dr: diastereomeric ratio (syn/anti).[16]
[d] Enantiomeric excesses of both enantiomer pairs (if two
chiral centres are formed) by GC-FID; the configuration
was identified based on a previous report.[16a]
[e] Reaction in toluene with 0.03 mmol BzOH.
[f] Using 1 mmol 10a and 5 mmol 17a in 3 cm3 solvent.
[g] Reaction at rt.
[h] Using 0.015 mmol (5 mol%) 6.
[i] Cca. 2% of regioisomers with the following structures
Scheme 2. Products obtained in the Michael addition of
ketones to N-substituted maleimides using 6.
Both catalysts, 13 and 6, provided similarly high
(over 99%) ee in less than one day when ketone 17b
was employed (entries 4, 9). Reactions of this ketone
was also significantly faster in toluene than in CHCl3
(entries 5, 10), providing identical ee values in both
solvents. Reactions of cycloaliphatic ketones 17c –
17f needed longer time to obtain almost complete
transformations of the maleimides, attributable to the
steric hindrances of the cycloaliphatic rings (entries 6,
11 – 16, 18 – 20). Similar conversions and yields
were obtained in these reactions using 6 and 13 as
catalysts, accompanied by high ee’s (97 – 99%),
except 17e. Moreover, the diastereomeric ratio
increased from 1 ‒ 1.2 (obtained with 17b) up to 5.6
(85/15) in reactions of cyclopentanone (17c) and
cyclohexanone (17d).
are formed:
Summing up, based on the above results one may
conclude that the thiophosphoramide derivative
prepared from (S,S)-1,2-diphenylethane-1,2-diamine
is an efficient catalyst in the enantioselective
conjugate addition of carbonyl compounds to N-
substituted maleimides.
Addition of carbonyl compounds to -nitrostyrene
The asymmetric organocatalyzed conjugate addition
of carbonyl compounds to nitroolefins is a convenient
preparation procedure of optically pure -
nitroaldehydes and ketones, which may be
transformed in valuable nitrogen containing
pharmaceutical intermediates.[14] Recently it was
Table 5. Michael addition of ketones to N-substituted
maleimides catalysed by 6.[a]
reported
the
application
of
some
ee [%][d]
(thio)phosphoramides in the asymmetric addition of
ketones (mostly 17a) to nitroolefins.[12,14] However,
the diamine derivatives used in the present work with
Produ Solvent;
time[b]
ct
Conv [%];
dr (syn/anti)[c]
7
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
the exception of 4[12b] were not yet tested, although
other derivatives, among which sulfonamides, proved
to be efficient.[17] Thus, our investigation was
extended on using the above employed
(thio)phosphoramides in the addition of 17a and 9 to
-nitrostyrene (19).
8[e]
6
6
6
6
A; 24
A; 48
A; 24
B; 48
87 (80)
98 (90)
67
95 (R)
96 (R)
95 (R)
93 (R)
9[f]
10[g]
11
68
[a]
Reaction conditions: 0.04 mmol (10 mol%) catalyst, 0.4
mmol 19, 2 mmol 17a, 1 cm3 solvent, 70°C.
[b] Solvent; A: toluene + 0.04 mmol AcOH + 0.08 mmol
H2O, B: CHCl3.
Reactions were performed in two solvents, i.e.
toluene (in the presence of AcOH and water) and
CHCl3. Selected results obtained in the addition of
17a to 19 are presented in Table 6. Contrary to the
addition of aldehydes to maleimides, in this reaction
the catalysts having 1,2-cyclohexane backbone (12,
ent-3, 4) were less active, than the 1,2-diphenylethane
derivatives (13, 5, 6). With the formers the ee values
[c] Conversion of 19 determined by GC-FID, yields of the
isolated products in brackets.
[d] Enantiomeric excess and the absolute configuration of
the excess enantiomer determined by GC-FID.[12a,17d]
[e] Using 0.02 mmol (5 mol%) catalyst.
[f] Reaction at 50°C.
[g] Without using AcOH and water additives.
were
also
lower.
Nevertheless,
the
(thio)phosphoramides ent-3 and 4 (entries 2, 3)
provided better ee’s than 12 (entry 1). In contrast, 10
mol% of the 1,2-diphenylethane-1,2-diamine
derivatives afforded high conversions in one day
(entries 5 – 7). Good ee values (94 – 95%) were
obtained with 13 and 6, the latter also provided the
highest yield. Decrease of the 6 amount to 5 mol%
led to the same ee value (95%) and slightly lower
conversion (entry 8), whereas decrease of the reaction
temperature to 50°C afforded close to complete
transformation of 19 in two days and small increase
in the ee (96%, entry 9). In reactions carried out in
toluene without additives (entry 10) or in CHCl3
(entry 11) the conversion of 19 decreased.
Addition of nitromethane to ,-unsaturated
ketones
The Michael additions examined above proceed
through activation of the Michael donors by
formation of the corresponding enamines. In
continuation we have attempted the use of the
thiophosphoramide 6 in conjugate additions occurring
through formation of iminium ion upon condensation
of the catalyst with an appropriate Michael acceptor.
As test reactions additions of nitromethane (22) to
trans-4-phenylbut-3-en-2-one (23) and 2-cyclohexen-
1-one (25) were selected. The most efficient
stereoselective catalysts employed in these reactions
were 2-pyrrolidine, cyclohexane-1,2-diamine and
cinchona alkaloid derivatives, respectively. Reactions
catalysed by the former two occur through iminium
ion transition states.[3,20] Until now 1,2-
diphenylethane-1,2-diamine derived catalysts have
not yet been tested in these transformations.
In the addition of 22 to 23 the thiophosphoramide
6 was found to be efficient (Table 7), affording over
90% conversions in four or three days using 10 or 15
mol% 6, respectively (entries 5, 6), whereas 13 was
less active (entries 2, 3). The ee values obtained with
these catalysts were high (up to 95%); 6 afforded the
same value as 13 when 15 mol% was used. Lower
conversions were obtained in CHCl3 than in toluene
Although, amino acids, oligopeptides and various
optically pure pyrrolidine derivatives were found
efficient in the asymmetric addition of aldehydes to
19,[14,18] studies on using C2-symmetric diamine
derivatives as catalysts have been seldom reported.[19]
Investigation of the conjugate addition of 9 to 19
confirmed
the
better
activity
of
the
thiophosphoramide 6 as compared with 13 (Scheme
3), although both provided low conversions even with
20 mol% catalyst in 6 days. Similarly high ee’s were
reached with both 6 and 13, respectively. Contrary to
the previous reaction of 19, these experiments
proceeded better in CHCl3, as compared with toluene
even when additives were used in the latter solvent
(not shown).
Table 6. Asymmetric Michael addition of acetone (17a) to
-nitrostyrene (19).[a]
Entry Catalyst Solvent[b]; Conv [%][c] ee [%][d]
time [h]
1
2
3
4
5
6
7
A; 24
A; 24
A; 24
B; 24
A; 24
A; 24
A; 24
58
44
68 (S)
73 (R)
77 (S)
76 (S)
94 (R)
90 (R)
95 (R)
12
ent-3
4
4
13
5
Scheme 3. Asymmetric addition of 9 to 19. Reaction
conditions: 0.08 mmol (20 mol%) 6 or 13, 0.4 mmol 19, 2
mmol 9, 1 cm3 CHCl3 (isolated yield of 21 in brackets).
60 (45)
32
93 (82)
99 (90)
99 (90)
6
8
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
with the use of additives. It is worth noting that in
this reaction the opposite enantiomer of 3-phenyl-4-
nitropentane-2-one (S-20) in the same optical purity
was prepared, as compared with the addition 17a to
19 by applying the same organocatalyst (6).
The addition of 22 to the cycloaliphatic 2-
cyclohexen-1-one (24) proceeded faster than the
previous reaction with both 13 and 6 reaching over
90% conversions of 24 in one day in toluene in the
presence of AcOH and water (Table 8). Both
catalysts afforded identically high ee values (97%).
Entry Catalyst Solvent
Conv [%][b]
ee [%][c]
1
2
3
CHCl3
A
CHCl3
A
35
97 (82)
34
97
97
97
97
13
13
6
4
94 (80)
6
[a]
Reaction conditions: 0.03 mmol (10 mol%) catalyst, 0.3
mmol 24, 3 mmol 22, 0.5 cm3 solvent, A: toluene + 0.03
mmol AcOH + 0.06 mmol H2O, 70°C, 24 h.
[b] Conversion determined by GC-FID, yield of the isolated
product in brackets.
[c] Enantiomeric excesses determined by GC-FID, the
absolute configuration of the excess enantiomer was S.[20]
Interpretation of the results
(thio)phosphoramides, as compared with the
corresponding sulfonamides in additions of carbonyl
compounds to maleimides, also accompanied by
increase in the ee values. The phosphoramide group’s
acidity is lower than that of the sulfonamide,
similarly with the corresponding acids.[21] Moreover,
the thiophosphoramide has the lowest acidity among
these derivatives. As the latter compound afforded
both the highest activities and enantioselectivities in
the additions of 9 to maleimides, in these reactions a
weaker H-bonding of the Michael acceptor assures a
catalytically more efficient interaction. Similar
behaviour was observed in the reaction of 9 with 19
using carboxamides vs sulfonamides.[22]
Additions of carbonyl compounds to activated olefins
catalysed by primary amines proceed through
enamine intermediates (EA), as illustrated in Scheme
4. H-bond donor groups activate the Michael acceptor
(such as the N-substituted maleimides) by increasing
its electrophilicity and also orientates the reacting
species, directing the formation of the C‒C bond
(TS1). The present results indicated higher activity of
Table 7. Asymmetric Michael addition of nitromethane
The inverse order of the acidity strength of the H-
bond donor group as compared to the obtained
conversions indicates that this group is not directly
involved in the acid-accelerated reversible formation
of the enamine (EA) or the hydrolysis of the imine
(IM) intermediate formed from iminium species
(Scheme 4, TS2). However, the reaction of 9 with
10a occurred readily without adding acid, whereas in
reactions of ketones acid and water additives
improved the conversion.
(22) to trans-4-phenylbut-3-en-2-one (23).[a]
Entry Catalyst; Solvent
amount[b]
time
[h]
Conv
ee
[%][c]
[%][d]
1
2
3
4
5
13; 10
13; 10
13; 15
6; 10
6; 10
6; 15
CHCl3
A
A
CHCl3
A
A
96
96
72
96
96
72
43
66
77 (50)
50
91 (77)
94 (80)
95
95
95
93
94
95
Besides increasing the rate, the higher ee values
obtained with the (thio)phosphoramides indicate, that
tuning the acidity of the amide group affected the step
in which the chiral centre is formed (Scheme 4, step
III.). Accordingly, a more stereospecific interaction in
the TS1 occurs when the H-bond is weaker. This
observation is in contrast with results obtained using
thiourea derivatives, which provided high
enantioselectivities as a consequence of a double H-
bonding of the electrophile.[9] A probable explanation
is that the more flexible bond between the
thiophosphoramide moiety and the maleimide allows
better arrangement of the activated electrophile.
Differences in reactions catalysed by 6 and 13
were observed when we have determined the relative
concentrations of the intermediates by electrospray-
6
[a]
Reaction conditions: 0.3 mmol 23, 3 mmol 22, 0.5 cm3
solvent, 70°C, A: toluene + 0.03 mmol AcOH + 0.06 mmol
H2O.
[b] Amount of catalyst used [mol%].
[c] Conversion determined by GC-FID, yield of the isolated
product in brackets.
[d] Enantiomeric excess determined by GC-FID, the
configuration of the excess enantiomer was S.[12a,17d]
Table 8. Asymmetric conjugate addition of nitromethane
(22) to 2-cyclohexen-1-one (24).[a]
ionization
mass-spectrometry
(ESI-MS).
A
mechanistic study of the reaction of 9 and 10b by
ESI-MS measurements was published by Kokotos
using amino acid catalysts.[23]
9
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
Scheme 4. Catalytic cycle of the asymmetric Michael addition of 9 to maleimides promoted by (S,S)-1,2-diphenylethane-
1,2-diamine-derived bifunctional catalysts.
70
m/z 605+H+
60
Addition of 9 to the solution of 6 or 13 resulted in
complete transformation of these amines to the
50
corresponding enamines (M 420+H+ and 418+H+) in
less than one day (for ESI-MS spectra see the
Supporting information). Following addition of 10a
to these solutions the appearance of the imines (IM;
M 607+H+ and 605+H+) was detected after another
day. However, the relative abundance of the IM
formed from 13 was much lower as compared to that
resulted from 6 (14% vs 56%, see Figure 5), and
these relative concentrations didn’t change
significantly after another day. Addition of 10a to a
solution of the organocatalysts allowed the detection
of 13-10a and 6-10a molecular associates of low
intensities (M 553+H+ and 551+H+, see the
Supporting information). However, the abundance of
the former was higher, confirming the stronger H-
bonding of the maleimide to the sulfonamide 13 as
compared with the phosphoramide 6. By adding 9 the
amounts of IM formed were close to that obtained
previously using the opposite addition order (Figure 5,
6(a)).
40
30
20
10
0
m/z 607+H+
13
6(a)
6
The significantly higher amount of IM
intermediate accumulated during the reaction
catalysed by 6 as compared to 13 indicated a faster
C‒C bond forming
Figure 5. Relative abundances of the imines formed in
reactions of 9 with 10a catalysed by 13 and 6 after 1 and 2
days at rt; below the ESI-MS spectrum recorded after 1
day reaction. Reaction conditions: 0.015 mmol 13 or 6 in
0.5 cm3 CHCl3, 0.15 mmol 9, 0.15 mmol 10a added after
18 h; (a) 10a was added 18 h before introducing 9.
10
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
rate in the former reaction. This results in a higher
concentration of the intermediate IM which follows
to be hydrolysed, a step not affected by the catalyst
structure, however influenced by the concentration of
the IM intermediate. Thus, these results suggest that
the better performance, i.e. significantly higher
activity, of the thiophosphoramide as compared to
sulfonamides may derive from the looser H-bond of
the electrophile, as supposed previously.
nucleophile 22, with negligible steric effect is
anchored by H-
The significantly lower activity of the
organocatalysts with 1,2-diphenylethane as compared
with the 1,2-cyclohexane scaffold revealed the
importance of the C2-symmetric diamine backbone.
The steric constraints exerted by phenyl rings
decreased the accessibility of the catalyst, as
compared with the cyclohexane moiety, however,
also ensured higher ee values. Nevertheless, opposite
order of activities were noted in the reaction of 17a
and 19, owing to the flexibility of the nitroolefin, as
compared with the more rigid cyclic maleimide. The
-unbranched aldehyde 15 reacted much slower than
Figure 6. Probable transition states in reactions of 17a
with 19 (A) and 22 with 23 (B) catalysed by 6.
bonding (Figure 6 (B)). The origin of the higher
activity may also reside in different strengths of the
H-bonding with the two catalysts, i.e. the flexibility
of the nucleophilic species and faster release of the
product in reactions catalysed by 6 as compared to 13.
Similarly to the reaction of ketones with maleimides,
in these reactions the structure of the ketone had
significant effect on the rate, as illustrated by the time
necessary to transform 23 and 24. As in reactions of
the latter no difference was observed between the two
organocatalysts one may presume the better
accessibility of the iminium ion by the H-bonded 22
in the transition state as compared with 23.
9
possibly as
a
consequence of the lower
nucleophilicity of the enamine intermediate. However,
the similarly high ee values reached with 15 indicated
that the more appropriate orientation of the
maleimides is at the origin of the better stereocontrol
reached with the thiophosphoramide (as compared to
sulfonamide). This is also confirmed by the high ee’s
obtained with various N-substituted maleimides. In
reactions of these derivatives with 9 the substituent
influenced mostly the rate, i.e. the time necessary to
reach close to complete transformations of
maleimides, probably by affecting their access to the
active sites.
Conclusions
Reactions of ketones and maleimides was sluggish
without acid additives possibly due to slow EA
formation or IM hydrolysis (Scheme 4, steps I. and
V.). Acceleration of these steps by addition of an acid
and water led to formation of products in shorter
reactions, with the formation of the C‒C bond taking
over the rate determination. The steric effect of the
ketone structure was indicated by the time necessary
to obtain high conversion and the diastereomeric ratio
obtained with various ketones. This had as a
consequence the smaller influence of the catalyst H-
bond donor group, i.e. lower differences in the ee’s
obtained with 6 and 13, especially in reactions of
bulkier ketones.
The better performance of the thiophosphoramide
derivatives as compared to sulfonamides was also
traceable in reaction of carbonyl compounds with -
nitrostyrene, reactions proceeding also through
enamine intermediates. The higher flexibility of the
nitroolefin 19 as compared with the maleimide cyclic
structure may give a reasonable explanation on the
slightly lower ee’s obtained in these reactions. Hence,
these reactions proceed through a similar mechanism
via a possible transition state shown in Figure 6 (A).
Significantly improved conversions were obtained
with 6 as compared with 13 in the addition of
nitromethane to 23 proceeding through iminium ion-
type transition state. In these reactions the
The present study aimed at tuning the structure of
chiral C2-symmetric diamines derived bifunctional
organocatalysts for application in the asymmetric
Michael addition of carbonyl compounds to
maleimides by using (thio)phosphoramide moieties as
hydrogen-bond donor groups. It was found that
phosphoramides and especially thiophosphoramides
are more efficient in the addition of aldehydes to
various N-substituted maleimides, as compared with
the corresponding sulfonamides. The use of 1,2-
diphenylethane-1,2-diamine
derived
thiophosphoramide, which could be prepared in good
yield in a one-step procedure, afforded optically pure
products in high yields and also allowed the use of
low amount, down to 2.5 mol%, of catalyst. In
reactions of ketones and maleimides addition of water
and acids was necessary to accelerate the enamine
intermediate formation and to obtain the chiral
adducts in high yields and enantioselectivities in
shorter reactions. The structure of the carbonyl
compound influenced the diastereomeric ratios and
the time necessary to reach complete conversions.
The applicability of the thiophosphoramide
derivative was also investigated in other asymmetric
conjugate additions. This organocatalyst proved to be
more active and stereoselective in additions of
carbonyl compounds to -nitrostyrene than the
11
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
(total reaction time 20 h). To the resulted slurry 40 cm3
water was added, the organic phase was separated, the
aqueous phase was washed twice with 25 cm3 CH2Cl2 and
the unified organic phases were dried over sicc. Na2SO4.
The crude product obtained following evaporation of the
solvent was purified by flash chromatography eluted using
CH2Cl2/MeOH 25/1 mixture. 1.095 g (yield 75%) of
product 6 was obtained as white crystalline material (for
spectroscopic data see the Supporting information).
The other compounds obtained via one-step procedure
were prepared similarly at 2 or 4 mmol scale using the
corresponding diamine and chloro(thio)phosphate; yields:
11% (3), 14% (4), 72% (5), 76% (ent-6) and 64% (8).
corresponding para-toluenesulfonamide, whereas in
reactions of nitromethane to ,-unsaturated ketones
higher
or
similar
yields
and
identical
enantioselectivities were reached.
The superiority of the chiral thiophosphoramide
organocatalysts in Michael additions, as compared
with sulfonamides was rationalized suggesting a
weaker hydrogen-bonding of the activated olefins to
the catalyst using the former derivatives. Besides an
increase in the rate this interaction allows a more
appropriate arrangement of the activated electrophile.
Experimental Section
Three-steps preparation method
Preparation of O,O-diethyl[(1R,2R)-2-aminocyclohexyl]-
phosphoramidothioate (4).
Materials and methods
(1) In a 100 cm3 two-necked round bottom glass flask
7.5 mmol (1.4267 g) para-toluenesulfonic acid
monohydrate was dehydrated by refluxing in 40 cm3
xylene for 2 h using a water separator. The solution was
cooled to room temperature, 7.5 mmol (0.8564 g) (1R,2R)-
cyclohexane-1,2-diamine (1) and 7.5 mmol (1.1109 g)
phthalic anhydride were added and the solution was stirred
at 160°C for 3 h. The mixture was cooled to room
temperature and the crystalized material was filtered,
washed with 10 cm3 cold toluene and dried, to obtain
Optically pure 1,2-diamines: 1, ent-1, 2, ent-2 and 7;
sulfonamides 12, 13, ent-13 and 14 and reagents: O,O’-
diethyl
chlorophosphate
and
O,O’-diethyl
chlorothiophosphate were purchased from Sigma-Aldrich
and used as received. Carbonyl compounds: 9, 15, 17a ‒
17f; N-substituted maleimides: 10a ‒ 10f, trans--
nitrostyrene (19), nitromethane (22), trans-4-phenylbut-3-
en-2-one (23) and 2-cyclohexen-1-one (24) were
commercial products (Sigma-Aldrich) and were used
without purification. Solvents, reagents and additives of
analytical grades were used in all reactions.
2.9675
g
(yield
95%)
N-[(1R,2R)-2-
ammoniumcyclohexyl]-phthalimide para-toluenesulfonate.
(2) 4 mmol (1.666 g) of the material obtained in the
previous step was suspended in 30 cm3 sat. Na2CO3
aqueous solution and stirred for 2 h at rt. The aqueous
solution was washed three times with 20 cm3 EtOAc, the
unified organic solutions were dried over sicc. Na2SO4 and
the solvent was evaporated. The material was identified by
GC-MSD analysis and was used in the following step
without further purification. The obtained material was
reacted with diethyl chlorothiophosphate as described in
the one-step procedure. It was dissolved in 15 cm3 dry
CH2Cl2 followed by addition of 4 mmol (0.560 cm3) Et3N.
The flask was flushed with N2 and the solution was cooled
to 0°C. To this solution 4 mmol (0.630 cm3) O,O’-diethyl
chlorothiophosphate dissolved in 25 cm3 dry CH2Cl2 was
added dropwise in 2 h. The solution was let to warm up
slowly to room temperature and stirred for another 18 h.
To the resulted slurry 40 cm3 water was added, the organic
phase was separated, the aqueous phase was washed twice
with 25 cm3 CH2Cl2 and the unified organic phases were
dried over sicc. Na2SO4. The crude product obtained
following evaporation of the solvent was purified by flash
chromatography eluted with hexane/ethyl acetate (EtOAc)
1/5 mixture. 1.110 g (yield 70%) of a pale yellow viscous
oil was obtained.
Gas-chromatographic analysis of the reaction
products were carried out using Agilent Techn. 6890 N
GC-5973 MSD (GC-MSD) equipped with a 30 m long HP-
1MS capillary columns for mass spectrometric
identification of the products. For quantitative analysis
Agilent 7890A GC-FID or Agilent 6890N-FID
chromatographs equipped with chiral capillary columns
(Cyclosil-B, 30 m x 0.25 mm ID, J&W or Hydrodex g-
TBDAc, 25 m x 0.25 ID, Macherey-Nagel) was used. 1H
and 13C NMR spectra of the purified products were
recorded on Bruker Avance DRX 400 or Bruker Ascend
500 spectrometers using CDCl3 solvent. For identification
of the newly prepared organocatalysts and for the
mechanistic investigations the ESI-MS spectra were
recorded using LCQ Fleet Ion Trap LC/MS (Thermo Sci.)
instrument using direct injection. Products were isolated by
flash chromatography on silica gel 60, 40-63 μm. The
purity of the fractions were checked by thin-layer
chromatography on Kieselgel-G (Merck Si 254 F) layers.
Optical rotations of the compounds were measured using
Perkin-Elmer 341 polarimeter.
Preparation of (thio)phosphoramides
One-step preparation method
(3) The material obtained in the previous step (2.8
mmol) was dissolved in 15 cm3 EtOH in a 50 cm3 flask
and 1 cm3 hydrazine hydrate was added. The solution was
refluxed for 2 h, cooled to room temperature, the
precipitate was dissolved in 20 cm3 CHCl3, filtered and
washed twice with 20 cm3 CHCl3. From the unified
organic phases the solvent was evaporated and the crude
product was purified by flash chromatography eluted with
CHCl3/MeOH 20/1 mixture. 0.619 g of 4 (yield 83%) was
obtained as light beige crystals (see the Supporting
information). The overall yield of 4 following three-steps
was 55%.
Preparation of O,O-diethyl[(1S,2S)-2-amino-1,2-diphenyl-
ethyl]phosphoramidothioate (6).
In a 100 cm3 three-necked round bottom glass flask to a
solution of
4
mmol (849.2 mg) (1S,2S)-1,2-
diphenylethane-1,2-diamine (2) in 15 cm3 dry CH2Cl2 4
mmol (0.560 cm3) Et3N was added. The flask was flushed
with N2 and the solution was cooled to 0°C. To this
solution
4
mmol
(0.630
cm3)
O,O’-diethyl
chlorothiophosphate dissolved in 25 cm3 dry CH2Cl2 was
added dropwise in 2 h. The solution was let to warm up
slowly to room temperature and stirred for another 18 h
12
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10.1002/adsc.202000335
Advanced Synthesis & Catalysis
Compound ent-3 was also prepared using the three-step
procedure from ent-1 and diethyl chlorophosphate in 52%
overall yield.
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Michael additions: general procedure
The reactions were carried out in 4 cm3 closed glass vials.
The solutions were stirred magnetically (600 rpm)
immersed in an oil bath set to the desired temperature. In a
typical reaction the given amount of catalyst was dissolved
in the corresponding solvent, additives were added if
needed followed by introducing the given amounts of
maleimide derivative (or other activated olefin) and finally
the carbonyl compound. The vial was closed and was
introduced in the oil bath (except when the experiments
were carried out at rt). Following the given reaction time 1
cm3 saturated aq. NH4Cl was added, the organic phase was
separated and the aqueous phase was washed three times
with 1 cm3 organic solvent. The unified organic phases
were dried on sicc. MgSO4 and analysed by gas-
chromatography following filtration and addition of 25
mm3 n-decane internal standard (GC-MSD and GC-FID).
The solvent was evaporated and the adducts were purified
by flash chromatography using hexane/EtOAc mixtures for
determination of the yields and characterization. Reactions
at 1 mmol scale were carried out similarly using 8 cm3
vials and the amounts given in Figure 4 or Table 5, entry 3.
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spectra and GC-FID chromatograms of the obtained
products see the Supporting information.
Conversions (Conv [%]), diastereomeric ratios
(syn/anti, where applicable) and enantioselectivities (as
enantiomeric excess, ee [%]) were calculated based on the
relative concentrations determined by gas-chromatography
(see the Supporting Information). The absolute
configuration of the excess enantiomers were assigned
based on chromatographic analysis of products resulted in
reactions using catalysts described in the literature.
Acknowledgements
Financial support of the Ministry of Human Capacities, Hungary
through grants 20391-3/2018/FEKUSTRAT and NTP-NFTÖ-19
(V. Kozma) is acknowledged.
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15
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FULL PAPER
1,2-Diamine-derived (thio)phosphoramide
organocatalysts in asymmetric Michael additions
Adv. Synth. Catal. Year, Volume, Page – Page
Viktória Kozma, Ferenc Fülöp, György Szőllősi*
16
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