1,3-Diamine-Derived Bifunctional Organocatalyst Prepared from Camphor

Article abstract of DOI:10.1002/adsc.201600498

Chiral 1,2-diamines are privileged structural motifs in organocatalysis, whereas efficient 1,3-diamine-derived organocatalysts are very rare. Herein we report a highly efficient camphor-1,3-diamine-derived squaramide organocatalyst. Its catalytic activity

Full text of DOI:10.1002/adsc.201600498

FULL PAPERS
DOI: 10.1002/adsc.201600498
1,3-Diamine-Derived Bifunctional Organocatalyst Prepared from
Camphor
a
a
a
b
ˇ
ˇ
Sebastijan Ricko, Jurij Svete, Bogdan Stefane, Andrej Perdih,
a
a
a,
ˇ
ˇ
ˇ
ˇ
Amalija Golobic, Anze Meden, and Uros Groselj *
a
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia
Fax : (+386)-1-2419-144; phone: (+386)-1-479-8563; e-mail: uros.groselj@fkkt.uni-lj.si
National Institute of Chemistry, Hajdrihova 19, SI-1000 Ljubljana, Slovenia
b
Received: May 11, 2016; Revised: September 13, 2016; Published online: && &&, 0000
th
ˇ
Dedicated to Professor Emeritus Miha Tisler, University of Ljubljana, on the occasion of his 90 birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600498.
Abstract: Chiral 1,2-diamines are privileged structur- to trans-b-nitrostyrene derivatives provides excellent
al motifs in organocatalysis, whereas efficient 1,3-di- enantioselectivities (up to >99% ee).
ACHTUNGTRENNUNGamine-derived organocatalysts are very rare. Herein
we report a highly efficient camphor-1,3-diamine-de-
rived squaramide organocatalyst. Its catalytic activity Keywords: camphor; 1,3-diamines; Michael addition;
in Michael additions of 1,3-dicarbonyl nucleophiles organocatalysis; squaramides
Introduction
has then been expanded by replacing the thiourea
with a squaramide moiety.[2,4] Consequently, amine-
Inspired by the efficiency and selectivity of enzymatic thiourea and amine-squaramide catalysts have
catalysis, the design of organic molecules capable of become work horses of non-covalent organocatalysis.
ꢀ
catalyzing efficient and stereoselective C C bond for- In spite of their tremendous utility, these organocata-
mation is a formidable challenge, which is nowadays lysts are derived from a limited range of chiral struc-
receiving considerable attention.[1] One of the funda- tural scaffolds with the 1,2-diamine moiety as
mental enzymatic catalyst competences that is diffi- a common structural motif.[2–4,11] In contrast, efficient
cult to mimic in synthetic systems is bifunctionality; 1,3- and 1,4-diamine-derived organocatalysts [with the
that is, the ability of a catalyst possessing acid and exception of (BINAM)-based catalysts] are very rare.
base functionality to synergistically activate both the Conformationally flexible guanidine-bisthiourea orga-
nucleophile and the electrophile reacting partners, si- nocatalysts have been used in asymmetric 1,4-type
multaneously.[2–4] The advent of organocatalysis in the Friedel–Crafts reaction of phenols[12a] and phospha-
last decades has provided a boost to the development Michael reaction of diphenyl phosphonate with nitro-
of organocatalyzed synthetic processes for the stereo- olefins.[12b] Ferrocene-based[12c,d] and self-assembled
selective formation of C C and C X bonds including proline-1,3-diamine-thiourea[12e] bifunctional organo-
the construction of useful complex organic frame- catalysts showed high enantioselectivity in Michael
ꢀ
ꢀ
works.[5]
additions of acetylacetone and aldehydes to nitroole-
The possibility to sterically and/or electronically fins. On the other hand, tartaric acid-based 1,4-di-
modulate the structure of chiral 1,2-diamines has ren- amine-thiourea organocatalysts were not effective in
dered them privileged structural motifs in organic the above additions (Figure 1).[12f]
AHCTUNGTRENNUNG
synthesis. They are indispensable in stereoselective
Camphor is one of natureꢀs privileged scaffolds
catalysis ranging from transition metal-catalyzed reac- readily available in both enantiomeric forms. It under-
tions[6,7] to organocatalysis.[2–4,7] Since the pioneering goes a wide variety of chemical transformations which
work of Jacobsen,[8] Schreiner,[9] and Takemoto,[10] bi- functionalize, at first glance, inactivated positions,
functional amine-thioureas have become one of the thus enabling the preparation of structurally and func-
most versatile catalyst types in asymmetric organoca- tionally very diverse products. All of the above fea-
talysis.[2,3] The scope of bifunctional organocatalysis tures make camphor a highly desirable starting mate-
Adv. Synth. Catal. 0000, 000, 0 – 0
1
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Following a literature procedure, camphorsulfonic
acid was transformed into 10-iodocamphor (1),[19]
which was further converted with pyrrolidine into the
amino ketone 2. To the best of our knowledge, the
above transformation represents the easiest way to
prepare 10-aminocamphor derivatives. Subsequent
condensation of 2 with NH2OH, and reduction of
the so-formed oxime 3 yielded a chromatographically
separable mixture of the minor exo- 4 and the
major endo-1,3-diamine 5 in moderate overall yields
(Scheme 1).
Scheme 1. Synthesis of camphor-derived 1,3-diamines 4 and
5.
Figure 1. Examples of typical 1,2-diamine-thiourea organo-
catalysts and efficient 1,3-diamine analogues.
rial.[13] The first reports on the application of cam-
Next, the title organocatalysts 8–12 were prepared
phor-derived organocatalysts date back to 2005,[14] in 26–84% yields by condensation of diamines 4 and 5
while this topic has recently also been reviewed.[15] with squaramates 6a–c[4e,20] or squarate 7. To have
Structurally, these organocatalysts are divided into access to racemic products for HPLC analysis, a new
two categories. The first, minor one, comprises cata- achiral organocatalyst 13 was also prepared from
lysts with a camphor skeleton as the exclusive chiral squaramate 6a and N,N-dimethylethylenediamine (14)
framework with camphor-derived NHC precursors (Scheme 2). The structures of organocatalysts 9 and
and cyclic hydrazides as typical representatives.[14a,15,16] 10 were confirmed by single crystal X-ray analysis
The vast majority of camphor-based organocatalysts (Figure 2).[21,22]
constitute the second category of mixed bifunctional
Initially, organocatalysts 8–12 (5 mol% used) were
organocatalysts, where the camphor framework is co- tested in the 1,4-addition reaction of acetylacetone
valently connected through a suitable spacer to an a- (15) to trans-b-nitrostyrene (16a) in toluene at 258C
amino acid, most frequently a proline derivative.[15,17]
for 24 h. The results are presented in Table 1. Com-
Within our continuing study on camphor-based di- pound 9 was quickly established as the superior orga-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNGamine-derived bifunctional squaramide organocata- of the above reaction in various solvents (catalyst 9,
lysts prepared from camphor and their application as 258C, 24 h, entries 6–16) revealed that reactions gen-
highly efficient catalysts in Michael additions of 1,3- erally proceeded with excellent conversions (ꢁ97%)
dicarbonyl nucleophiles to trans-b-nitrostyrenes.
and enantioselectivities (ꢁ95% ee), though the con-
version was slower in 1,4-dioxane and MeCN (en-
tries 6 and 14). Diminished enantioselectivities were
observed in MeCN (90% ee) and MeOH (79% ee)
(entries 14 and 13). Reaction in brine gave 17a in
Results and Discussion
First, non-racemic 1,3-diamines 4 and 5 were prepared 96% ee (entry 15), while the neat reaction gave 17a in
in four steps from (1S)-(+)-10-camphorsulfonic acid. 93% ee (entry 16).
Adv. Synth. Catal. 0000, 000, 0 – 0
2
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Scheme 2. Synthesis of squaramide organocatalysts 8–13.
Toluene was chosen as the solvent to be used in fur-
ther transformations. Reactions at lower temperature
(08C and ꢀ258C) were even more enantioselective
(>99% ee), albeit with slower conversion (entries 17
and 18). The conversion was much faster at 808C,
with only slight decrease of enantioselectivity
(entry 19). Lowering the catalyst loading to 0.1 mol%
slowed down the conversion substantially, while enan-
tioselectivity was only slightly decreased (entry 20).[21]
Under the optimum reaction conditions (toluene,
258C, 24 h), the Rawalꢀs squaramide catalyst I,[4e]
Takemotoꢀs thiourea catalyst II,[10a] and Rawal-type
cyclohexane-1,2-diamine-based squaramide catalyst
III[5f] were all outperformed by the catalyst 9 (en-
tries 21–23 vs. entry 2). Notably, the efficacy of cata-
lysts I–III[21] under the above conditions was also in
line with the literature data.[4e,10a,5f]
Figure 2. ORTEP representation of single-crystal X-ray
structure of compound 9. Ellipsoids are plotted at 30%
probability level.[21,22]
Catalyst 9 was then evaluated in the alkylation of
acetylacetone (15) with trans-b-nitrostyrenes 16b–
Adv. Synth. Catal. 0000, 000, 0 – 0
3
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Table 1. Evaluation and optimization of organocatalysts 8–
Table 2. Variation of nitroalkene 16b–s in reactions with ace-
tylacetone (15).[a]
12 in the Michael addition of acetyl
ACHTUNGERTNaNUNG cetone (15) to trans-b-
nitrostyrene (16a).[a]
En-
try
R
Product
Yield
[%][b]
ee
[%]
En- Cat.
try (mol%) vent
Sol-
t [h]/
T [8C] [%]
Conv.
ee
[%]
1
2
3
4
5
6
7
8
4-MeO-C6H4 (16b)
3-MeO-C6H4 (16c)
2-MeO-C6H4 (16d)
2,5-MeO-C6H3 (16e)
4-BnO-C6H4 (16f)
2-BnO-C6H4 (16g)
3,4-BnO-C6H3 (16h)
2-F-C6H4 (16i)
4-Cl-C6H4 (16j)
3-Cl-C6H4 (16k)
2-Cl-C6H4 (16l)
2,4-Cl-C6H3 (16m)
2,6-Cl-C6H3 (16n)
3-Br-C6H4 (16o)
2-Br-C6H4 (16p)
2-furyl (16q)
17b
17c
17d
17e
17f
17g
17h
17i
17j
17k
17l
17m
17n
17o
17p
17q
17r
17s
86 (91)
85 (>99)
89 (92)
86 (>99)
62 (73)
92 (>99)
72 (80)
81 (>99)
79 (>99)
68 (>99)
76 (>99)
73 (>99)
63 (82)
80 (>99)
87 (>99)
54 (97)
99
98
>99
98
92
>99
99
99
>99
96
>99
>99
91
1
2
3
4
5
6
7
8
8 (5)
9 (5)
10 (5)
11 (5)
12 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (5)
9 (0.1)
I[c] (5)
toluene
toluene
toluene
toluene
toluene
24/25
24/25
24/25
24/25
24/25
84
34 (R)
>99 (85)[b] 98 (S)
53
40
81
57
>99
97
98
>99
>99
>99
>99
60
>99
>99
76
96 (S)
90 (S)
82 (S)
97 (S)
96 (S)
96 (S)
98 (S)
95 (S)
98 (S)
96 (S)
79 (S)
90 (S)
96 (S)
93 (S)
>99 (S)
>99 (S)
94 (S)
93 (S)
96 (R)
88 (R)
88 (R)
1,4-dioxane 24/25
CHCl3
EtOAc
THF
CH2Cl2
PhCF3
AcAc
MeOH
MeCN
brine
24/25
24/25
24/25
24/25
24/25
24/25
24/25
24/25
24/25
24/25
24/0
9
9
10
11
12
13
14
15
16
17
18
10
11
12
13
14
15
16
17
18
19
20
21
22
23
94
>99
98
>99
86
neat
1-propyl (16r)
2-propyl (16s)
43 (72)
9 (17)
toluene
toluene
toluene
toluene
toluene
24/ꢀ25 43
[a]
Acetylacetone (15) (0.8 mmol), nitroalkene 16b–
s (0.4 mmol), toluene (1.0 mL); conversion determined
by 1H NMR (CDCl3); ee determined by HPLC.[21]
3/80
24/80
24/25
24
96
31
98
>99
>99
[b]
II[c] (5) toluene
III[c] (5) toluene
Isolated yields; the conversions are given in the brackets.
24/25
[a]
Acetylacetone (15) (0.8 mmol), trans-b-nitrostyrene (16a)
(0.4 mmol), solvent (1.0 mL); conversion determined by
1H NMR (CDCl3); ee determined by HPLC.[21]
Isolated yield.
as in the b-nitrostyrene series 16a–q, while the yields
were lower (entries 17 and 18).
[b]
[c]
I=Rawalꢀs squaramide catalyst;[4e] II=Takemotoꢀs thio-
To further explore the scope of the studied catalytic
urea catalyst;[10a] III=Rawal-type cyclohexane-1,2-dia- system, catalyst 9 was evaluated in 1,4-addition reac-
mine-squaramide catalyst;[5f] the structures of I–III are
tions of nitrostyrenes 16a, 16i, 16l, and 16p with se-
given in the Supporting Information.
lected 1,3-diketones and b-keto esters 18a–h
(Table 3). Once again, almost all reactions proceeded
with excellent conversion, while diastereoselectivity
s under the optimum reaction conditions (toluene, varied with the nucleophile applied; in most cases
258C, 24 h). The results are presented in Table 2. mixtures of diastereomers were formed. Excellent
Generally, the conversions were quantitative (ꢁ97%). diastereoselectivity (dr>94:6) was observed in reac-
A moderate slowdown was observed in the case of tions with ethyl 2-oxocyclopentane-1-carboxylate
electron-donating substituents (entries 1, 3, 5, and 7) (18f) and its 6-membered analogue 18h (entries 9 and
and two ortho-substituents (entry 13). Enantioselec- 13), and in the reaction between a-acetylbutyrolac-
tivities were high (>90% ee), in most cases even ex- tone (18g) and trans-2-bromo-b-nitrostyrene (16p)
cellent (>98% ee). Notably, persistently high selectiv- (entry 12). The ee of the products ranged from 73%
ities were obtained using ortho-monosubstituted ni- to >99%, most of them being ꢁ96% ee. Also here,
trostyrenes (entries 3, 4, 6, 8, 11, 12, and 15). In the the presence of an ortho-substituent in nitrostyrenes
reactions of 15 with aliphatic 1-nitroalkenes 16r and 16i, 16l, and 16p increased the enantioselectivity in
16s, the enantioselectivities were essentially the same comparison to reactions with ortho-unsubstituted ni-
Adv. Synth. Catal. 0000, 000, 0 – 0
4
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Table 3. Variation of nucleophile 18a–h in reactions with nitrostyrenes 16a, i, l, p.[a]
[a]
Nucleophile (0.8 mmol), nitrostyrene (0.4 mmol), toluene (1.0 mL); conversion and dr determined by
1H NMR (CDCl3); ee determined by HPLC.[21]
[b]
Isolated yields; the conversions are given in brackets.
Adv. Synth. Catal. 0000, 000, 0 – 0
5
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Scheme 3. Application of catalyst 9 in some other organic reactions.
trostyrene 16a (entries 3, 6, and 10 vs. 4, 7, 8, 11, and
The kinetic profiles of the model reaction, addition
of acetylacetone (15) to trans-b-nitrostyrene (16a) in
12).
To quickly explore the scope and limitations in or- the presence of catalyst 9, were determined by
ganic synthesis, squaramide 9 was used as catalyst in 1H NMR using different concentrations of the catalyst
five other reactions. Notably, only preliminary reac- 9 and reactants 15 and 16a. Reactions were performed
tions were preformed devoid of optimization of the in a rotating NMR tube in 0.75 mL of CDCl3 at
reaction conditions. The results are presented in 302 K. The results are shown in Figure 3. First, the re-
Scheme 3. Promising results (>50% yield, >50% ee) action was carried out under standard conditions (st)
were obtained in the 1,2-addition of 15 to isatin imine using 2.67 mol% catalyst loading and two-fold excess
23, and C-alkylation of 3-hydroxypyrrole 30 [Eqs. (2) acetylacetone (15) ([9]st =1.8ꢂ10ꢀ3 M, [15]st =0.14M,
*
and (5)]. On the other hand, Michael addition of 4- and [16a]st =0.07M) ( ). The reversed stoichiometry
hydroxycoumarin (20) to enone 21 and Friedel–Crafts of reactants using a two-fold excess of b-nitrostyrene
&
aminoalkylation of 4-hydroxyindole (25) with 23 were (16a) ( ) did not affect the reaction rate as evidenced
&
*
not enantioselective, whereas 1,4-addition of nitrome- by almost identical kinetic profiles ( , ). With stan-
thane (27) to chalcone (28) was enantioselective dard concentrations of reactants, [15]st and [16a]st, and
albeit with low conversion [Eqs. (1), (3), and (4)].[21]
by lowering the catalyst loading to 1.35 mol% ( ) and
~
Adv. Synth. Catal. 0000, 000, 0 – 0
6
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
Figure 3. Kinetic profiles of the reaction 15+16a!17a in
CDCl3 catalyzed with 9. Standard conditions: [15]st =0.14M,
[16a]st =0.07M, and [9]st =1.8ꢂ10ꢀ3 M ( ). Inversed condi-
*
&
tions: [16a]=0.14M, [15]=0.07, [9]st ( ). 1.35 mol% 9: [9]=
9ꢂ10ꢀ4 M, [15]st, [16a]st ( ). 0.67 mol% 9: [9]=4.5ꢂ10ꢀ4 M,
~
^
[15]st, [16a]st ( ). The relative conversion of 16a was deter-
mined by integrating the vinylic signal at 7.54 ppm (d, J=
13.7 Hz) and by integrating the signal of the product 17a at
3.88 ppm (d, J=10.0 Hz).[21]
^
*
0.67 mol% ( ), the reaction became much slower ( ,
[21]
~
^
,
).
Next, the dependences of the initial reaction rates
(v0) of the model reaction on the concentrations of
the catalyst and the reactants, [9], [15], and [16a]
1
were determined by H NMR by monitoring forma-
tion of the product 17a. The logarithmic initial reac-
tion rates (ln v0) were plotted against logarithmic con-
centrations (ln c) as shown in Figure 4 (Plots A–C).[21]
When catalyst loading was varied at standard concen-
trations of the reactants, [15]st =0.14M and [16a]st =
0.07M, a nice linearity between ln v0 and ln [9] was
obtained and the reaction rate showed first-order de-
pendence in the concentration of catalyst 9 (Figure 4,
Plot A). Using standard concentrations of the catalyst
and the electrophile, [9]st =1.8ꢂ10ꢀ3 M and [16a]st, the
0.5-order dependence on the nucleophile 15 was de-
termined in the concentration range [15]=0.07–
Figure 4. Logarithmic plots of initial reaction rates (ln v0)
against concentration (ln c) of the catalyst 9 (Plot A), acetyl-
AHCTUNGTRENNUNG
acetone (15) (Plot B), and nitrostyrene (16a) (Plot C).[21]
0.26M, where the reaction has non-saturation kinetics urements were performed in a rotating NMR tube in
(Figure 4, Plot B). Kinetic measurements with varia- CDCl3 at 302 K. The concentrations of rac-17a and 9
ble concentrations of the electrophile [16a]=0.017– were the same ([rac-17a]=[9]=0.018M). The racemic
0.14M and with standard concentrations [9]st and product rac-17a underwent the reversible process af-
[15]st revealed the first-order dependence of the initial fording acetylacetone (15) and trans-b-nitrostyrene
rate on the concentration of 16a (Figure 4, Plot C).[21] (16a) in 8% conversion within 15 h. Consequently, the
These order dependences were in line with the recent- remaining Michael adduct 17a present in the reaction
ly published results on the kinetics of bifunctional mixture was enantiomerically enriched (7% ee) to-
squaramide-catalyzed reactions, hence, the reaction wards the (R)-enantiomer meaning that the (S)-enan-
most probably follows a bifunctional mechanism with tiomer was selectively subjected to the retro-Michael
ꢀ
involvement of the ternary complex in the C C bond process. According to the principle of microscopic re-
formation as the rate-determining step.[23]
versibility, these observations indicate that the stereo-
Finally, the catalytic retro-Michael reaction on the determining transition states for forward and back-
racemic product rac-17a was also tested. The meas- ward reaction are the same.[24]
Adv. Synth. Catal. 0000, 000, 0 – 0
7
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
To gain further insight into the mechanistic aspects bonded to the squaramide unit of 9 and nitrostyrene
and plausible origin of the high enantioselectivity of (16a) H-bonded to the protonated pyrrolidine residue
the 1,3-diamine-derived organocatalyst 9, density of the catalyst 9. Within the four proposed transition
functional theory (DFT) calculations were performed states, the (S)-TS1 is energetically most favorable.
to find the most favored transition state and to com- This might be explained by the almost staggered
pare the results with our experimental data.[21] DFT alignment of reactants and a short distance (~0.3 nm)
calculations were carried out for the catalyst 9 and between the pyrrolidineꢀs H–N+ and the oxygen atom
substrates 15 and 16a leading to the product 17a, of the nitro group both stabilizing (S)-TS1 by dipole-
taking into the account that both reactants can form dipole interactions (Figure 5).[21] Formation of the (S)-
H-bonds with the squaramide unit of the catalyst 9.[25] isomer of 17a via energetically most favorable transi-
Accordingly, all possible orientations leading to the tion state (S)-TS1 suggests that the reaction proceeds
(R)- and the (S)-isomer were considered and investi- through TS1 following Takemotoꢀs pathway.[10b] This
gated.[21] Figure 5 shows the four transition state struc- is somewhat surprising, since the alternative Pꢃpai–
tures, (S)-TS1, (R)-TS1, (S)-TS2, and (R)-TS2 that Soꢄs pathway[26] through TS2 seems to be dominant
were allocated during the extensive computational for 1,2-diamino catalysis.[25,26] The most favorable
scan of the conformational space available to these transition state (S)-TS1 deriving the (S)-isomer of 17a
transition states.
is in complete agreement with the experimental ob-
The first pair of transition state structures, (S)-TS1 servations. The corresponding transition state (R)-
and (R)-TS1, corresponds to the Takemoto model:[10b] TS1 leading to the (R)-isomer is 3.97 kcalmolꢀ1
nitrostyrene 16a is docked via H-bonds to the squara- higher in energy that corresponds to >99% ee of the
mide unit of the catalyst 9, whereas the enolate form (S)-isomer selectivity. Transition states (S)-TS2 and
of the nucleophile 15 is H-bonded to the protonated (R)-TS2 are 7.86 and 3.78 kcalmolꢀ1 higher in energy,
pyrrolidine part of the catalyst 9. The second pair of respectively.[21] The observed theoretical data are in
transition state structures, (S)-TS2 and (R)-TS2, fol- line with the results reported by Pꢃpai and Soꢄs
lows the Pꢃpai–Soꢄs model[26] with enolate 15 H- et al.[25,26] on a similar catalytic system and support an
idea that application of a single reactivity model
might not be generalized sufficiently for the realiza-
tion of the stereoselectivity outcome of Michael addi-
tions catalyzed by squaramide-derived organocata-
lysts.
Conclusions
A new class of chiral squaramide catalysts based on
a camphor-derived 1,3-diamine scaffold was devel-
oped. Organocatalysts 8–12 are easily available from
(1S)-(+)-10-camphorsulfonic acid. Catalyst 9 shows
excellent conversions and enantioselectivities (up to
>99%) in 1,4-additions of 1,3-dicarbonyls to trans-b-
nitrostyrene acceptors. It is distinguished by its toler-
ance towards moisture and air. The kinetic measure-
ments were in agreement with known results on the
kinetics of the bifunctional squaramide-catalyzed re-
actions, thus supporting a bifunctional reaction mech-
anism.[23] DFT calculations performed on the M06-
2X/6-311+ +G(d,p) level of theory fully corroborate
the experimentally observed (S)-stereoselectivity of
the catalyst 9. The DFT calculation also suggests that
the reaction goes by the Takemoto pathway[10b]
through (S)-TS1. Accordingly, this is the very first
time when the original mechanistic proposal seems to
be working. The preliminary testing of catalyst 9 in
some other reactions also showed promising activities,
thus indicating the potential of this class of 1,3-di-
AHCTUNGTREGUNaNN mine building blocks for the development of new
Figure 5. Diagram presentations of the structures of the op-
timized transition states (S)-TS1, (R)-TS1, (S)-TS2, and (R)-
TS2 for the reaction 15+16a!17a in the presence of the
catalyst 9. The DDG values are given for the reaction in tol-
uene.
(organo)catalysts. The synthetic method allows for
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
1276, 1170, 1129, 1001, 952, 896, 871, 843, 822, 731, 722, 707,
681, 617 cmꢀ1. 1H NMR (500 MHz, DMSO-d6): d=0.85 (s,
3H, Me), 0.90 (s, 3H, Me), 0.87–0.99 (m, 1H), 1.08–1.32 (m,
5H), 1.37–1.48 (m, 1H), 1.57 (t, J=4.4 Hz, 1H), 1.73–1.83
(m, 1H), 1.85–1.95 (m, 1H), 2.00 (d, J=12.6 Hz, 1H), 2.05–
2.15 (m, 2H), 2.18–2.28 (m, 2H), 2.28–2.39 (m, 1H), 2.73 (d,
J=12.5 Hz, 1H), 4.57–4.67 (m, 1H), 4.84 (dd, J=15.3,
5.8 Hz, 1H), 4.93 (dd, J=15.0, 7.2 Hz, 1H), 7.41 (d, J=
10.2 Hz, 1H, NH), 7.58 (s, 1H, NH), 8.06 (s, 1H, 1H of
Arl), 8.11 (s, 2H, 2H of Arl); 13C NMR (126 MHz, DMSO-
d6): d=18.8, 20.1, 23.0, 25.4, 28.4, 37.5, 44.0, 45.5, 48.9, 51.9,
54.9, 57.0, 57.4, 121.2, 123.3 (q, J=272.8 Hz), 128.8 (d, J=
4.0 Hz), 130.48 (q, J=32.7 Hz), 143.0, 165.5, 169.5, 182.3,
182.9.
easy diversification of the core scaffold by attachment
of different primary and tertiary amino residues at
positions 10 and 2 with endo- and exo-configuration.
Studies on optimization of the synthesis, preparation
of novel camphor-1,3-diamine based organocatalysts,
and their application in different asymmetric transfor-
mations, i.e., 30!31 are underway and will be report-
ed it a subsequent communication.
Experimental Section
General
Solvents for extractions and chromatography were of techni-
cal grade and were distilled prior to use. Extracts were dried
over technical grade Na2SO4. Melting points were deter-
mined on a Kçfler micro hot stage and on SRS OptiMelt
MPA100 – Automated Melting Point System (Stanford Re-
search Systems, Sunnyvale, California, USA). The NMR
spectra were obtained on a Bruker Avance DPX 300 at
300 MHz for 1H and 75.5 MHz for 13C nucleus, and on
a Bruker UltraShield 500 plus (Bruker, Billerica, Massachu-
setts, USA) at 500 MHz for 1H and 126 MHz for 13C nucleus,
using DMSO-d6 and CDCl3 with TMS as the internal stan-
dard, as solvents. Mass spectra were recorded on an Agilent
6224 Accurate Mass TOF LC/MS (Agilent Technologies,
Santa Clara, California, USA), IR spectra on a Perkin–
Elmer Spectrum BX FTIR spectrophotometer (Perkin–
Elmer, Waltham, Massachusetts, USA). Microanalyses were
performed on a Perkin–Elmer CHN Analyzer 2400 II (Per-
kinElmer, Waltham, Massachusetts, USA). Column chroma-
tography (CC) was performed on silica gel [Silica gel 60,
particle size: 0.035–0.070 mm (Sigma–Aldrich, St. Louis,
Missouri, USA)]. HPLC analyses were performed on an
Agilent 1260 Infinity LC (Agilent Technologies, Santa
Clara, California, USA) using CHIRALPAK AD-H
(0.46 cm øꢂ25 cm) and CHIRALCEL OD-H (0.46 cm øꢂ
25 cm) chiral columns (Chiral Technologies, Inc., West
Chester, Pennsylvania, USA). Organocatalyzed reactions
General Procedure for the Organocatalyzed
Asymmetric Michael Addition of 1,3-Dicarbonyl
Nucleophiles to Nitroalkene Acceptors
To a solution/suspension of nitroalkene acceptor (0.4 mmol)
and the tested organocatalyst 8–12 (0.1–5 mmol%) in anhy-
drous solvent (1 mL) under argon at the designated temper-
ature (T=ꢀ258C to 808C) the 1,3-dicarbonyl nucleophile
was added (0.8 mmol) and the resulting reaction mixture
was stirred for 3–24 h. The reaction was quenched by pass-
ing it as quickly as possible through a short pad of silica gel
60 (length 3–4 cm, diameter=2 cm) using a mixture of
EtOAc and petroleum ether in a ratio of 1:1 to cut off the
organocatalyst used. Volatile components were evaporated
under vacuum. The residue was used to determine the reac-
tion conversion and diastereomer ratio by means of
1H NMR analysis and the enantiomer excess of the products
by means of HPLC analysis. The novel organocatalyzed
products were isolated by column chromatography (silica
gel 60, mobile phase). Fractions containing the pure product
were combined and volatile components evaporated under
vacuum followed by full characterization.
General Procedure for the Preparation of Racemic
were performed on EasyMax 102 Advanced synthesis work- Mixtures
station (Mettler-Toledo, LLC).
All the chemicals used are commercially available and
were purchased from Sigma–Aldrich (St. Louis, Missouri,
USA). The source of chirality: (1S)-(+)-10-camphorsulfonic
acid (1), product number C2107 Aldrich, assay: ꢁ99.0%,
[a]2D0: +19.98 (c=5 in H2O), mp 196–2008C (dec.).
To a solution/suspension of nitroalkene acceptor (0.4 mmol)
and achiral organocatalyst 13 (0.0244 mmol, 10 mg) in
CH2Cl2 (2 mL) at room temperature the 1,3-dicarbonyl com-
pound was added (0.8 mmol) and the resulting reaction mix-
ture was stirred at room temperature for 24 h. Volatile com-
ponents were evaporated under vacuum and the residue was
purified by column chromatography (Silica gel 60, mobile
phase). Fractions containing the pure racemic product(s)
were combined and volatile components evaporated under
vacuum followed by HPLC analysis.
Synthesis of Organocatalyst 9
To a solution of endo-1,3-diamine 5 (4.542 mmol, 1.01 g) in
anhydrous MeOH (25 mL) under argon squaramide 6a
(4.954 mmol, 1.75 g) was added and the reaction mixture
was stirred at room temperature for 48 h. The resulting pre-
cipitate was collected by filtration and washed with cooled
Et2O (08C, 2ꢂ20 mL) to give product 9 as a white solid;
yield: 2.068 g (3.805 mmol, 84%); mp 226–2298C. [a]rD:t::
ꢀ37.9 (c=0.34, CH2Cl2:MeOH=1:1). Anal.: C27H31F6N3O2
requires: C 59.66, H 5.75, N 7.73; found: C 59.74, H 5.52, N
7.68%; EI-HR-MS: m/z=544.2393 (MH+); C27H32F6N3O2
requires: 544.2393 (MH+); IR: nmax =3306, 3215, 2956, 2875,
2800, 1801, 1657, 1539, 1489, 1457, 1417, 1381, 1343, 1301,
Acknowledgements
Financial support from the Slovenian Research Agency
through grant P1-0179 is gratefully acknowledged.
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
References
2005, 127, 119–125; c) H. Miyabe, Y. Takemoto, Bull.
Chem. Soc. Jpn. 2008, 81, 785–795; d) Y. Takemoto,
Chem. Pharm. Bull. 2010, 58, 593–601.
[1] a) J. Seayad, B. List, Org. Biomol. Chem. 2005, 3, 719–
724; b) P. I. Dalko, L. Moisan, Angew. Chem. 2004, 116,
5248–5286; Angew. Chem. Int. Ed. 2004, 43, 5138–5175;
c) K. N. Houk, B. List, Acc. Chem. Res. 2004, 37, 487–
487.
[11] a) P. Melchiorre, Angew. Chem. 2012, 124, 9886–9909;
Angew. Chem. Int. Ed. 2012, 51, 9748–9770; b) L.
Zhang, N. Fu, S. Luo, Acc. Chem. Res. 2015, 48, 986–
997.
[2] a) Stereoselective Organocatalysis, (Ed.: R. Rios), John
Wiley & Sons, Hoboken, 2013; b) G. Jakab, P. R.
Schreiner, in: Comprehensive Enantioselective Organo-
catalysis, (Ed.: P. I. Dalko), Wiley-VCH, Weinheim,
2013, pp 315–342.
[12] a) Y. Sohtome, B. Shin, N. Horitsugi, R. Takagi, K. No-
guchi, K. Nagasawa, Angew. Chem. 2010, 122, 7457–
7461; Angew. Chem. Int. Ed. 2010, 49, 7299–7303; b) Y.
Sohtome, N. Horitsugi, R. Takagi, K. Nagasawa, Adv.
Synth. Catal. 2011, 353, 2631–2636; c) W. Yao, M.
Chen, X. Liu, R. Jiang, S. Zhang, W. Chen, Catal. Sci.
Technol. 2014, 4, 1726–1729; d) X. Ren, C. He, Y. Feng,
Y. Chai, W. Yao, W. Chen, S. Zhang, Org. Biomol.
Chem. 2015, 13, 5054–5060; e) W.-H. Wang, T. Abe, X.-
B. Wang, K. Kodama, T. Hirose, G.-Y. Zhang, Tetrahe-
dron: Asymmetry 2010, 21, 2925–2933; f) M. B. Lauber,
R. Frçhlich, J. Paradies, Synthesis 2012, 44, 3209–3215.
[13] a) T. Money, Remote functionalization of camphor: ap-
plication to natural product synthesis, in: Org. Synth.:
Theory Appl. 1996, 3, 1–83; b) T. Money, Nat. Prod.
Rep. 1985, 2, 253–289.
[3] For recent reviews on bifunctional amine-thioureas,
see: a) M. S. Taylor, E. N. Jacobsen, Angew. Chem.
2006, 118, 1550–1573; Angew. Chem. Int. Ed. 2006, 45,
1520–1543; b) Z. Zhang, P. R. Schreiner, Chem. Soc.
Rev. 2009, 38, 1187–1198; c) S. J. Connon, Synlett 2009,
354–376; d) W.-Y. Siau, J. Wang, Catal. Sci. Technol.
2011, 1, 1298–1310; e) S. Narayanaperumal, D. G.
Rivera, R. C. Silva, M. W. Paixao, ChemCatChem 2013,
5, 2756–2773; f) O. V. Serdyuk, C. M. Heckel, S. B. Tso-
goeva, Org. Biomol. Chem. 2013, 11, 7051–7071.
[4] For recent reviews on bifunctional amine-squaramides,
see: a) F. E. Held, S. B. Tsogoeva, Catal. Sci. Technol.
2016, 6, 645–667; b) P. Chauhan, S. Mahajan, U. Kaya,
D. Hack, D. Enders, Adv. Synth. Catal. 2015, 357, 253–
281; c) J. Alemꢃn, A. Parra, H. Jiang, K. A. Jørgensen,
Chem. Eur. J. 2011, 17, 6890–6899. For examples of
squaramide-derived organocatalysts. see: d) Y. Zhu,
J. P. Malerich, V. H. Rawal, Angew. Chem. 2010, 122,
157–160; Angew. Chem. Int. Ed. 2010, 49, 153–156;
e) J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am.
Chem. Soc. 2008, 130, 14416–14417.
[14] a) M. Lemay, W. W. Ogilvie, Org. Lett. 2005, 7, 4141–
4144; b) S. Rajaram, M. S. Sigman, Org. Lett. 2005, 7,
5473–5475.
ˇ
[15] U. Groselj, Curr. Org. Chem. 2015, 19, 2048–2074.
[16] a) Y. Li, Z. Feng, S.-L. You, Chem. Commun. 2008,
2263–2265; b) Q. Li, W.-Y. Wong, W.-H. Chan,
A. W. M. Lee, Adv. Synth. Catal. 2010, 352, 2142–2146;
c) Y. Li, X.-Q. Wang, C. Zheng, S.-L. You, Chem.
Commun. 2009, 5823–5825; d) Z.-Q. Rong, M.-Q. Jia,
S.-L. You, Org. Lett. 2011, 13, 4080–4083.
[5] For selected examples of construction of multiple ste-
reogenic centers by organocatlysis see: a) P. Chauhan,
S. Mahajan, C. C. J. Loh, G. Raabe, D. Enders, Org.
Lett. 2014, 16, 2954–2957; b) M. Bluemel, P. Chauhan,
R. Hahn, G. Raabe, D. Enders, Org. Lett. 2014, 16,
6012–6015; c) C. C. J. Loh, P. Chauhan, D. Hack, C.
Lehmann, D. Enders, Adv. Synth. Catal. 2014, 356,
3181–3186; d) P. Chauhan, G. Urbanietz, G. Raabe, D.
Enders, Chem. Commun. 2014, 50, 6853–6855; e) P.
Chauhan, S. Mahajan, G. Raabe, D. Enders, Chem.
Commun. 2015, 51, 2270–2272; f) D. Mailhol, M. del
Mar Sanchez Duque, W. Raimondi, D. Bonne, T. Con-
stantieux, Y. Coquerel, J. Rodriguez, Adv. Synth. Catal.
2012, 354, 3523–3532.
[17] For selected examples, see: a) Y.-m. Chen, P.-H. Lee, J.
Lin, K. Chen, Eur. J. Org. Chem. 2013, 2699–2707;
b) Y. Zhou, Q. Liu, Y. Gong, Org. Biomol. Chem. 2012,
10, 7618–7627; c) Y.-F. Ting, C. Chang, R. J. Reddy,
D. R. Magar, K. Chen, Chem. Eur. J. 2010, 16, 7030–
7038; d) D. R. Magar, C. Chang, Y.-F. Ting, K. Chen,
Eur. J. Org. Chem. 2010, 2062–2066; e) C. Chang, S.-H.
Li, R. J. Reddy, K. Chen, Adv. Synth. Catal. 2009, 351,
1273–1278.
ˇ
ˇ
[18] a) U. Groselj, A. Golobic, K. Stare, J. Svete, B. Stanov-
ˇ
ˇ
nik, Chirality 2012, 24, 307–317; b) U. Groselj, S. Ricko,
J. Svete, B. Stanovnik, Chirality 2012, 24, 412–419; c) S.
ˇ
ˇ
ˇ
Ricko, A. Golobic, J. Svete, B. Stanovnik, U. Groselj,
Chirality 2015, 27, 39–52.
[6] D. Steinborn, Fundamentals of Organometallic Cataly-
[19] a) J. D. Loudon, J. Chem. Soc. 1933, 823–825; b) F. W.
Lewis, G. Egron, D. H. Grayson, Tetrahedron: Asym-
metry 2009, 20, 1531–1535; c) M. J. Spallek, G. Storch,
O. Trapp, Eur. J. Org. Chem. 2012, 3929–3945.
[20] a) K. S. Rao, R. Trivedi, M. L. Kantam, Synlett 2015,
26, 221–227; b) Y. Qian, G. Ma, A. Lv, H.-L. Zhu, J.
Zhao, V. H. Rawal, Chem. Commun. 2010, 46, 3004–
3006.
[21] For details see the Supporting Information.
[22] Structural and other crystallographic data have been
deposited. CCDC 1476085 and CCDC 1476086 contain
the supplementary crystallographic data for compounds
9 and 10, respectively, of this paper. These data can be
obtained free of charge from The Cambridge Crystallo-
sis, Wiley-VCH, Weinheim, 2016.
[7] a) Y. L. Bennani, S. Hanessian, Chem. Rev. 1997, 97,
3161–3195; b) R. Noyori, T. Ohkuma, Angew. Chem.
2001, 113, 40–75; Angew. Chem. Int. Ed. 2001, 40, 40–
73; c) W. Notz, F. Tanaka, C. F. Barbas III, Acc. Chem.
Res. 2004, 37, 580–591; d) J. Duan, P. Li, Catal. Sci.
Technol. 2014, 4, 311–320.
[8] M. S. Sigman, E. N. Jacobsen, J. Am. Chem. Soc. 1998,
120, 4901–4902.
[9] P. R. Schreiner, A. Wittkopp, Org. Lett. 2002, 4, 217–
220.
[10] a) T. Okino, Y. Hoashi, Y. Takemoto, J. Am. Chem.
Soc. 2003, 125, 12672–12673; b) T. Okino, Y. Hoashi, T.
Furukawa, X. Xu, Y. Takemoto, J. Am. Chem. Soc.
Adv. Synth. Catal. 0000, 000, 0 – 0
10
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
asc.wiley-vch.de
graphic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
[25] B. Kꢄtai, G. Kardos, A. Hamza, V. Farkas, I. Pꢃpai, T.
Soꢄs, Chem. Eur. J. 2014, 20, 5631–5639.
[23] E. Varga, L. T. Mika, A. Csꢃmpai, T. Holczbauer, G.
Kardos, T. Soꢄs, RSC Adv. 2015, 5, 95079–95086.
[24] D. G. Blackmond, O. K. Matar, J. Phys. Chem. B 2008,
112, 5098–5104.
[26] a) A. Hamza, G. Schubert, T. Soꢄs, I. Pꢃpai, J. Am.
Chem. Soc. 2006, 128, 13151–13160; b) B. Tan, Y. Lu,
X. Zeng, P. J. Chua, G. Zhong, Org. Lett. 2010, 12,
2682–2685.
Adv. Synth. Catal. 0000, 000, 0 – 0
11
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!

FULL PAPERS
12 1,3-Diamine-Derived Bifunctional Organocatalyst Prepared
from Camphor
Adv. Synth. Catal. 2016, 358, 1 – 12
ˇ
ˇ
Sebastijan Ricko, Jurij Svete, Bogdan Stefane,
ˇ
ˇ
Andrej Perdih, Amalija Golobic, Anze Meden,
ˇ
ˇ
Uros Groselj*
Adv. Synth. Catal. 0000, 000, 0 – 0
12
ꢁ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!