Diastereodivergent synthesis of chiral vic-disubstituted-cyclobutane scaffolds: 1,3-amino alcohol and 1,3-diamine derivatives - Preliminary use in organocatalysis

Article abstract of DOI:10.1002/ejoc.201201307

The synthesis of chiral cyclobutane containing 1,3-amino alcohols and 1,3-diamines has been accomplished in an efficient and diastereodivergent manner from a common chiral precursor. Regioselective manipulation of functional groups in the prepared products provides an easy entry to several derivatives, such as thioureas. Preliminary results on the use of these compounds as bifunctional organocatalysts are reported. Chiral cyclobutane containing 1,3-amino alcohols and 1,3-diamines have been synthesized from a common chiral precursor. Regioselective transformations of these precursors led to bifunctional thioureas which have been tested as organocatalysts in preliminary experiments Copyright

Full text of DOI:10.1002/ejoc.201201307

Job/Unit: O21307
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Date: 26-11-12 17:55:11
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FULL PAPER
DOI: 10.1002/ejoc.201201307
Diastereodivergent Synthesis of Chiral vic-Disubstituted-Cyclobutane Scaffolds:
1,3-Amino Alcohol and 1,3-Diamine Derivatives – Preliminary Use in
Organocatalysis
Enric Mayans,[a] Albert Gargallo,[a] Ángel Álvarez-Larena,[b] Ona Illa,*[a] and
Rosa M. Ortuño*[a]
Keywords: Synthetic methods / Organocatalysis / Asymmetric catalysis / Michael addition / Regioselectivity / Amino
alcohols / Amines
The synthesis of chiral cyclobutane containing 1,3-amino
alcohols and 1,3-diamines has been accomplished in an ef-
ficient and diastereodivergent manner from a common chiral
precursor. Regioselective manipulation of functional groups
in the prepared products provides an easy entry to several
derivatives, such as thioureas. Preliminary results on the use
of these compounds as bifunctional organocatalysts are re-
ported.
emicals, and iii) monomers in the synthesis of chiral poly-
mers, to name just a few of their applications.[5] As with
amino alcohols, 1,2-diamines are the most abundant di-
amines[6] although there are some examples of 1,3-diamines
as chiral metal ligands.[7] The 1,3-diamine functionality is
also present in the cyclopentane containing structure of
neuraminidase enzyme inhibitors such as the commercial
drug Peramivir™ which displays potent activity against the
influenza viruses.[6e,8]
We recently reported the stereoselective synthesis of all
possible stereoisomers of cyclobutane-1,2-diamines and
some selective transformations,[6f] as part of our research
program based on the synthesis and application of cyclo-
butane derivatives as elements of dendrimers,[9] amino
acids, peptides and other compounds with properties as fol-
damers,[10] organogelators,[11] enzyme inhibitors,[12] organo-
conducting materials[13] and cell penetrating agents.[14] In
this paper, we describe a facile and diastereodivergent entry
to a variety of cyclobutane containing 1,3-amino alcohols,
their conversion into 1,3-diamines and their regioselective
transformations into several derivatives. Some of the deriva-
tives investigated contain a thiourea moiety and an amino
group, making them good candidates for bifunctional or-
ganocatalysts.[15] Preliminary results of assays looking at
the possible application of these compounds in organocata-
lysis are reported herein.
Introduction
Chiral difunctional compounds such as amino alcohols
and diamines are useful scaffolds that have been widely used
in asymmetric synthesis, both as precursors and as chiral
auxiliaries. For amino alcohols, there are many examples
on the synthesis and use of 1,2-derivatives,[1] whereas fewer
examples are known for 1,3-amino alcohols. Nevertheless,
the later have been synthesized through various standard
methods and have been employed as chiral ligands and aux-
iliaries, as phase-transfer catalysts, and as resolution agents,
among other applications.[2] A particular group of these
molecules is characterized by two functional groups linked
to a carbocyclic ring such as cyclohexane and cyclopentane
derivatives; these are the most commonly utilized in the ca-
talysis field and also tend to display interesting biological
activity thus lending themselves to use as antiviral and anti-
tumor agents or antibiotics.[3] In the case of cyclobutanes
with 1,3-amino alcohols, there are fewer examples although
this structural moiety is present in cyclobut-A and cyclobut-
G; both are oxetanocin carbocyclic analogues.[4]
Another class of interesting compounds is represented
by the diamines. As with amino alcohols, optically active
diamines are important molecules for synthetic chemistry.
Such diamines have found use as i) bidentate ligands, ii)
synthetic building blocks for pharmaceuticals and agroch-
[a] Department de Química, Universitat Autònoma de Barcelona,
08193 Cerdanyola del Vallès, Spain
Results and Discussion
E-mail: ona.illa@uab.es
rosa.ortuno@uab.es
Scheme 1 shows the retrosynthetic rationale relating con-
Homepage: http://grupsderecerca.uab.es/rosamortuno
[b] Servei de Difracció de RX, Universitat Autònoma de
Barcelona,
veniently
protected
2-aminocyclobutane-(1R,2S)-1-
carboxylic acid to diastereomeric cis- and trans-1,3-amino
alcohols 1 and 2, and differently substituted 1,3-diamines.
Such amino acid derivatives are suitable precursors in dia-
08193 Cerdanyola del Vallès, Spain
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201307.
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E. Mayans, A. Gargallo, Á. Álvarez-Larena, O. Illa, R. M. Ortuño
FULL PAPER
stereodivergent synthesis of the optically pure target mole- ated with mild acid. Saponification of the methyl ester fol-
cules, and were synthesized, in turn, from a readily available lowed by conversion of the resulting carboxylic acid into a
half ester as described previously.[10c]
transient amide was carried out. Subsequent epimeri-
zation of the α-carboxyl carbon and concomitant hydrolysis
of the amide using 6 m NaOH with heating led to N-pro-
tected trans-amino acid 8.[17] The resultant carboxyl group
was activated as a mixed anhydride by reaction with ethyl
chloroformate and then reduced by addition of LiBH4 in
THF and MeOH, to afford trans-amino alcohol 2 in 60 %
yield. Reaction of 2 with tosyl chloride and DMAP in the
presence of Et3N afforded tosylate 9 in 94 % yield. This is
a key intermediate that allowed regioselective synthesis of
free amines or N-alkyl-substituted derivatives. New prod-
ucts were prepared to illustrate the versatility of these syn-
thetic strategies. For instance, tosylate 9 was treated with
dimethylamine to afford N-monoprotected diamine 10 in
92 % yield. Removal of the N-Boc carbamate was achieved
with TFA to give the corresponding free amine as ammo-
nium trifluoroacetate 11 in 85 % yield. Alternatively, tosyl-
ate 9 reacted with sodium azide in DMF to afford azide 12
in 94 % yield. This azide is another relevant intermediate in
the synthesis of several 1,3-diamine derivatives. Conversion
of the azide to an amino group was achieved both under
Staudinger reaction conditions (addition of aqueous tri-
phenylphosphane followed by treatment with diluted
NaOH) and by hydrogenolysis using Pd(OH)2/C. Monopro-
tected trans-1,3-diamine 13 was obtained in both cases in
44 and 98 % yield, respectively (Scheme 3, conditions a and
b). Moreover, if the hydrogenolysis was carried out in the
presence of a ketone, concomitant reductive amination en-
sued leading to a secondary amine. This observation opens
Scheme 1. General retrosynthesis of cis- and trans-isomers of cyclo-
butane containing 1,3-amino alcohols and 1,3-diamines involving
stereodivergent pathways from chiral cis-amino acid derivatives.
The cis isomers were obtained starting from orthogonally
protected amino acid 3 (Scheme 2).[10a] The methyl ester of
3 was reduced with LiBH4 in THF at 0 °C in the presence
of substoichiometric MeOH to afford N-protected cis-cy-
clobutane containing 1,3-amino alcohol 1, in 73 % yield.
This yield could be increased to 85 % when LiBH4 in diethyl
ether was used as reducing agent.[16] Notably, alcohol 1 is a
new compound that can be employed as a synthetic inter-
mediate for the preparation of cis-1,3-diamines. Conse-
quently, diamine 6 was prepared as a representative exam-
ple. Thus, mesylate 4 was synthesized in the standard way
and subsequently reacted with pyrrolidine to afford monop-
rotected diamine 5 in 78 % yield over two steps. Although
this transformation is very common with primary mesyl-
ates, it is not trivial to achieve substitution when the mesyl/
tosyloxymethyl group is anchored to the sterically con-
gested cis-1,2-disubstituted cyclobutane moiety and the nu-
cleophile is
a
bulky molecule, such as pyr-
rolidine. Such steric considerations often prevent the de-
sired substitution as recently observed in our laboratory.[16]
Free diamine 6 was obtained in nearly quantitative yield by
hydrogenolysis of the benzyl carbamate in the presence of
Pd(OH)2/C. This diamine was employed in the synthesis of
more elaborately functionalized compounds (vide infra).
Scheme 2. Synthesis of cis-compounds 1 and 5.
N-Protected trans-1,3-amino alcohol 2 could be readily
synthesized following the route outlined in Scheme 3. In
this case, N-Boc precursor 7 was used since the tert-butyl
carbamate is not hydrolyzed under the strongly basic condi-
tions required for epimerization and can be easily elimin- Scheme 3. Synthesis of trans-compounds 2, 11, 13–15.
2
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Chiral Cyclobutane Scaffolds in Organocatalysis
a number of possible strategies by which to achieve further in 78 % yield. In a separate experiment, 6 was refluxed in
functionalization of these scaffolds. Acetone was used as a CH2Cl2 in the presence of 3,5-bis(trifluoromethyl)phenyl
model ketone and, in this way, isopropylamine derivative 14 thioisocyanate to give 17 in 39 % yield. Low yields some-
was obtained in 93 % yield (Scheme 3). Reductive amina- times observed in these kinds of reactions are likely attrib-
tions with aldehydes were carried out with sodium cyano- utable to reversibility issues. Reaction of thioisocyanate 17
borohydride to avoid undesired reduction of the aldehyde with trans-diamine 11 afforded 18a in 37 % yield. In an
under catalytic hydrogenation conditions. The application analogous fashion, highly substituted thiourea 19 and thio-
of benzaldehyde, as a model in such reductive aminations, urea 20 were obtained from corresponding amines (14 or
afforded benzylamine 15 in a non-optimized yield of 38 %. 13) in 46 % and 16 % yield, respectively. Furthermore, easy
To investigate and validate the versatility of these new removal of the Boc group in 20 followed by reductive amin-
synthetic scaffolds for further functionalization, thiourea ation with formaldehyde afforded 18b, the regioisomer of
moieties were incorporated in a regioselective manner. In- 18a, in 18 % non-optimized yield.
spired by Takemoto’s bifunctional chiral thiourea (Fig-
Preliminary studies on the possible application of thio-
ure 1),[15a] which has (R,R)-1,2-cyclohexyldiamine as a chi- ureas 17, 18a, 18b, and 20 as bifunctional organocatalysts
ral scaffold, we undertook the synthesis of related molecules were carried out to investigate i) the influence of the cyclo-
bearing a vic-disubstituted cyclobutane moiety as the chiral butane chirality, ii) the nature of tertiary amine (cyclic or
motif; subsequent efforts entailed the application of these not) and iii) the distance between the thiourea or the amine
new agents in organocatalyzed reactions (Scheme 4).
Figure 1. Takemoto’s bifunctional chiral thiourea.
and the cyclobutane ring on chosen reactions. Conjugate
addition of diethyl malonate to (E)-β-nitrostyrene was se-
lected as a standard reaction.[15a] Experiments with 17 were
performed in solvents of differing polarity including nonpo-
lar solvents such as toluene and dichloromethane, THF as
a low-polarity solvent and dioxane, diglyme, and acetoni-
trile as differently polar solvents. The influence of, i)
number of equivalents of catalyst, ii) temperature, and iii)
reaction time was also investigated for cases giving the best
results (Table 1). Reaction of 17 with 10 mol-% of catalyst
in acetonitrile, diglyme, dioxane or dichloromethane
(Table 1, Entries 1–5) afforded both modest yields and en-
antiomeric ratios (e.r.) The best result in terms of conver-
sion and enantioselectivity was obtained using toluene at
room temperature for 24 h, with an e.r. value of 74:26 in
favor of the S enantiomer being generated in 85 % yield
(Table 1, Entry 6).[18] Variations in temperature (Table 1,
Entries 9 and 10) led to very similar e.r. values but to a
decrease in the yields when an increase in the reaction time
was required. The use of less catalyst (Table 1, Entry 8) re-
sulted in similar reaction enantioselectivity and lower
yields. Consequently, thiourea 17 was shown to be an ef-
ficient organocatalyst accelerating this Michael reaction
and providing 1,4-addition products under similar reaction
conditions and in yields comparable to those previously re-
ported using Takemoto’s thiourea. Nevertheless, 17 was
found to display only modest asymmetric induction in such
reactions.
Bearing in mind the best results obtained with 17, thio-
ureas 18a and 18b were also tested affording the results de-
scribed in Table 1 (Table 1, Entries 11–14). The behaviours
of 18a and 18b in the studied Michael reactions were com-
parable to that observed with 17 highlighting that the pres-
ence of a methylene group as a spacer between the cyclobu-
tane ring and the thiourea or the amine group does not
exert any significant influence upon the reaction. The use
of 18a allowed us to obtain the reaction product in good
yields but with an e.r. inferior to that obtained with 17. In
contrast, N-Boc derivative 20 was a very poor catalyst
Scheme 4. Some examples of further regioselective functionaliza-
tion of diamines.
Thus, cis-diamine 6 was treated with phenyl thioisocyan- (Table 1, Entries 15 and 16). This result was expactable be-
ate in refluxing CH2Cl2 to afford bifunctional thiourea 16 cause of the very weak basicity of the carbamate nitrogen
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E. Mayans, A. Gargallo, Á. Álvarez-Larena, O. Illa, R. M. Ortuño
FULL PAPER
Table 1. Conjugate addition of diethyl malonate to (E)-β-nitrostyr- bond formation. Nevertheless, the active conformation in
ene catalyzed by 17, 18a, 18b, and 20.
solution and in the presence of the substrates can differ
from that adopted in the crystal, as recently described,[20]
and further studies will be carried out to verify or refute
this hypothesis.
Conclusions
Entry Cat. mol[%] Solvent T[°C] t[h] Yield[%]e.r.[S/R][a]
In summary, the stereocontrolled synthesis of cis- and
42[b]
68[b]
65[b]
65[b]
42[b]
85[b]
59[b]
45[b]
60[b]
61[b]
88[b]
75[b]
61[b]
67[b]
Ͻ 5[c]
Ͻ 5[c]
60:40
68:32
62:38
63:37
68:32
74:26
69:31
71:29
73:27
75:25
52:48
60:40
59:41
64:36
60:40
–
trans-cyclobutane containing 1,3-amino alcohols and 1,3-
diamines has been achieved from a common chiral precur-
sor through the selective and efficient manipulation of func-
tional groups. The versatility of these scaffolds was high-
lighted by several examples of their further functionaliza-
tion to render diastereo- and/or regioisomers as described
herein. Different kinds of thiourea derivatives have been
synthesized and some preliminary experiments have been
carried out to assess their utility as bifunctional organocat-
alysts. It is noteworthy that there are no previous data in
the literature on the use of chiral cyclobutane derivatives in
organocatalysis. Some of these compounds were found to
satisfactorily accelerate the model Michael reaction al-
though the asymmetric induction was modest. Despite this
result, we have gained information about the influence of
stereochemical features on both the reaction acceleration
and the asymmetric induction. All these data will allow us
to design new compounds useful in asymmetric organocata-
lysis. Moreover, the use of the prepared amino alcohols and
diamines to afford candidates for metal ligands and for new
chiral surfactants is under active investigation in our
laboratories.
1
2
3
4
5
6
7
8
17
17
10
10
10
10
10
10
15
5
10
10
10
10
10
10
10
10
CH3CN
diglime
dioxane
THF
25
25
25
25
25
25
25
25
0
–25
25
25
25
25
25
25
24
24
24
24
24
24
24
24
48
48
24
24
24
24
48
48
17
17
17
CH2Cl2
toluene
toluene
toluene
toluene
toluene
CH2Cl2
toluene
CH2Cl2
toluene
CH2Cl2
toluene
17
17
17
9
17
10
11
12
13
14
15
16
17
18a
18a
18b
18b
20
20
[a] Determined by chiral HPLC analysis of the reaction mixture.
[b] Isolated yield. [c] Conversion determined by GC of the reaction
mixture.
and confirmed that the amino group is necessary for the
formation of the malonate-derived enolate.[19]
Otherwise, it appeared that the cis stereochemistry of the
cyclobutane moiety induces better enantioselectivity for
such reactions than does the trans configuration, as de-
duced from comparison of Entries 5 and 6 with Entries 11
and 12 in Table 1 (Table 1, Entries 5, 6, 11 and 12).
To better understand how the stereochemical features of
17 influence its mode of action, we investigated its confor-
mation in the solid state, which was obtained by X-ray dif-
fraction analysis of single crystals (from CH2Cl2-pentane)
(Figure 2). This structure displays the E-conformation for
the thiourea-NH protons and the intramolecular hydrogen
bonding between the pyrrolidine nitrogen atom and neigh-
bouring (S=C)NH. This suggests some level of difficulty for
a double activation of the electrophile by means of two H-
Experimental Section
Materials and Methods: Tetrahydrofuran (THF) was freshly dis-
tilled under a nitrogen atmosphere from sodium/benzophenone.
Dichloromethane was freshly distilled from calcium chloride. All
other chemicals were of commercial grade and used without further
purification unless otherwise stated. 1H NMR and 13C NMR spec-
tra were carried out in deuterated solvents with Bruker Avance 250
and 360 Ultrashield spectrometers. High resolution mass spectra
were recorded with a direct inlet system (ESI). IR spectra were
obtained from samples in neat form with an ATR (Attenuated To-
tal Reflectance) accessory. Melting points were recorded with a Re-
icher Klofler block and values are uncorrected. Purification of the
reaction mixtures was performed by column chromatography with
neutral silica gel (200–400 mesh).
Crystallographic Data: CCDC-903665 contains the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Benzyl N-[(1S,2R)-2-(Hydroxymethyl)cyclobutyl]carbamate (1):
Amino ester 3 (465 mg, 1.8 mmol) was dissolved in THF (23 mL).
The reaction mixture was placed into an ice bath. Then a 2 m solu-
tion of LiBH4 in THF (0.88 mL, 1.8 mmol) was added. After that,
MeOH (0.25 mL, 6.2 mmol) was added dropwise. The reaction
mixture was stirred in the ice bath for further 4 h. Then, a 2 m
solution of LiBH4 in THF (0.13 mL, 0.5 mmol) and MeOH
Figure 2. Structure of 17 as obtained from X-ray diffraction analy-
sis. The H-bond between (S=C)NH and pyrrolidine is marked (dis-
tance in angstroms).
4
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Chiral Cyclobutane Scaffolds in Organocatalysis
(0.04 mL) were added and the mixture was stirred at room temp.
for 2 more h. The reaction progress was monitored by TLC and
when the conversion was complete, MeOH was added until no bub-
bling was observed. Then, water (100 mL) was added and the crude
material was extracted with CH2Cl2 (3ϫ 50 mL). The organic lay-
ers were combined, dried with MgSO4, filtered and the solvent was
evaporated. The crude was purified by column chromatography on
silica gel (hexanes/EtOAc, 3:1) or by crystallization with diethyl
ether/pentanes. In this way, compound 1 was obtained (303 mg,
73 % yield). The same procedure carried out in diethyl ether as a
solvent led to the production of 1 in 85 % yield as a white solid,
m.p. 66–68 °C (n-pentane/diethyl ether). [α]D = –21.6 (c = 1.05,
29.3 (CH2), 23.9 (CH2), 20.4 (CH2) ppm. HRMS (ESI) calcd. for
C17H25N2O2 [M + H]+: 289.1915, found 289.1910.
tert-Butyl N-[(1S,2S)-2-(Hydroxymethyl)cyclobutyl]carbamate (2):
Compound 8 (830 mg, 3.8 mmol) was dissolved in anhydrous THF
(36 mL) under
a nitrogen atmosphere. Ethyl chloroformate
(385 μL, 4.05 mmol) and Et3N (0.89 mL, 6.4 mmol) were added.
The reaction was stirred at room temp. for 40 min. Then the salts
were filtered and washed with THF (10 mL). 2 m LiBH4 in THF
solution (3.87 mL, 7.74 mmol) was added to the filtrate and then
MeOH (0.5 mL, 12.4 mmol) was added dropwise. After 2 h, MeOH
(23.0 mmol) were added. After 5 more h of stirring at room temp.,
more MeOH was added until no gas formation was observed.
Then, water (100 mL) was added and the reaction mixture was ex-
tracted with CH2Cl2 (5ϫ 50 mL). The organic layers were com-
bined, dried with MgSO4, filtered and the solvent evaporated. The
crude reaction was purified by column chromatography on silica
gel (EtOAc/hexanes, 1:2) giving 2 (583 mg, 75 % yield) as a white
solid, m.p. 58–59 °C (EtOAc/hexanes). [α]D = –105 (c = 1.00,
CHCl ). IR (ATR): ν = 3355, 3290, 2946, 2867, 1677 cm–1. 1H
˜
3
NMR (250 MHz, CDCl3, 25 °C): δ = 7.37 (m, 5 H, Ar-H), 5.49
(broad s, 1 H, NH), 5.32 (s, 2 H, CH2Bn), 4.34 (m, 1 H, CHNH),
3.75 (m, 2 H, CH2OH), 2.73 (m, 1 H, CHCH2OH), 2.31 (m, 1 H,
CH2), 1.91 (complex signal group, 2 H, CH2), 1.65 (m, 1 H,
CH2) ppm. 13CNMR (62.5 MHz, CDCl3, 25 °C): δ = 156.9 (C),
136.9 (C), 128.9 (C), 128.5 (C), 67.2 (CH2), 62.9 (CH2), 48.2 (CH),
41.6 (CH), 28.7 (CH2), 18.9 (CH2) ppm. HRMS (ESI) calcd. for
C13H17NNaO3 [M + Na]+: 258.1101, found 258.1100.
CHCl ). IR (ATR): ν = 3364, 2977, 1674, 1519, 1364, 1277, 1161,
˜
3
1050, 870 cm–1. 1H NMR (360 MHz, CDCl3, 25 °C): δ = 5.00
(broad s, 1 H, NH), 3.51 (complex signal group, 3 H, CHN,
CH2OH), 2.31 (m, 1 H, CHCH2OH), 2.18 (m, 1 H, CH2), 1.79
(complex signal group, 2 H, CH2), 1.42 [s, 9 H, C(CH3)3], 1.44–
1.35 (m, 1 H, CH2) ppm. 13C NMR (90 MHz, CDCl3, 25 °C): δ =
156.4 (C), 80.2 (C), 65.7 (CH2), 50.9 (CH), 48.7 (CH), 28.3 (CH3),
25.2 (CH2), 17.2 (CH2) ppm. HRMS (ESI) calcd. for
C10H19NNaO3 [M + Na]+: 224.1257, found 224.1258.
[(1R,2S)-2-(Benzyloxycarbonylamino)cyclobutyl]methyl Methane-
sulfonate (4): Alcohol 1 (300 mg, 1.3 mmol) was dissolved in anhy-
drous CH2Cl2 (10 mL) under a nitrogen atmosphere. The reaction
mixture was placed in an ice bath. Then, Et3N (0.88 mL, 2 mmol)
and mesyl chloride (0.2 mL, 1.7 mmol) were added. The reaction
mixture was stirred for 1 h. After that, water (100 mL) was added
and the crude reaction was extracted with CH2Cl2 (3ϫ 50 mL).
The organic layers were combined, dried with MgSO4, filtered and
solvent was evaporated. The crude product was purified by column
chromatography on silica gel (hexanes/EtOAc, 1:1) or by crystalli-
zation from diethyl ether and pentanes to afford mesylate 4
(397 mg, 98 % yield) as a white solid, m.p. 67–69 °C (n-pentane/
[(1S,2S)-2-(tert-Butoxycarbonylamino)cyclobutyl]methyl 4-Methyl-
benzenesulfonate (9): Compound 2 (283 mg, 1.4 mmol) was dis-
solved in anhydrous CH2Cl2 (5.7 mL) under a nitrogen atmosphere.
Tosyl chloride (548 mg, 2.9 mmol), DMAP (24.4 mg, 0.2 mmol)
and Et3N (0.56 mL, 4.0 mmol) were added and the reaction mix-
ture was stirred at room temp. for 5 h. A saturated aqueous solu-
tion of NH4Cl (50 mL) was then added and the reaction mixture
was extracted with CH2Cl2 (3ϫ 20 mL). The organic layers were
combined, dried with MgSO4, filtered and the solvent evaporated.
The crude reaction was purified by column chromatography on sil-
ica gel (EtOAc/hexanes, 1:4) giving 9 (468 mg, 94 % yield) as a
white solid, m.p. 74–75 °C (EtOAc/hexanes). [α]D = +11.9, (c =
diethyl ether). [α]D = –17.9 (c = 1.00, CHCl ). IR (ATR): ν = 3355,
˜
3
2952, 1677, 1346, 1176 cm–1. H NMR (250 MHz, CDCl3, 25 °C):
1
δ = 7.37 (m, 5 H, Ar-H), 5.11 (complex signal group, 3 H, NH,
CH2Ph), 4.41 (complex signal group, 3 H, CH2OMs, CHNH), 2.96
(complex signal group, 4 H, CHCH2OMs, OSO2CH3), 2.41 (m, 1
H, CH2), 2.03 (complex signal group, 2 H, CH2), 1.71 (m, 1 H,
CH2) ppm. 13C NMR (62.5 MHz, CDCl3, 25 °C): δ = 156.1 (C),
136.8 (C), 129.0 (C), 128.6 (C), 69.5 (CH2), 67.2 (CH2), 47.0 (CH),
39.4 (CH3), 37.7 (CH), 28.5 (CH2), 18.3 (CH2) ppm. HRMS (ESI)
calcd. for C14H19NNaO5S [M + Na]+: 336.0874, found 336.0872.
0.83, CH Cl ). IR (ATR): ν = 3337, 2975, 1695, 1514, 1362, 1174,
˜
2
2
946 cm–1. 1H NMR (360 MHz, CDCl3, 25 °C): δ = 7.75 (d, J =
11.9 Hz, 2 H, Ar-H), 7.34 (d, J = 11.5 Hz, 2 H, Ar-H), 4.80 (m, 1
H, NH), 4.01 (m, 2 H, CH2OTs), 3.73 (m, 1 H, CHN), 2.43 (com-
plex signal group, 4 H, CH3, CHCH2OTs), 2.15 (m, 1 H, CH2),
1.75 (complex signal group, 2 H, CH2), 1.40 [s, 9 H, C(CH3)3], 1.40
(m, 1 H, CH2) ppm. 13C NMR (90 MHz, CDCl3, 25 °C): δ = 155.2
(C), 145.1 (C), 133.4 (C), 130.2 (CH), 128.3 (CH), 79.4 (C), 72.1
(CH2), 48.2 (CH), 44.0 (CH), 28.7 (CH3), 27.6 (CH2), 22.0 (CH3),
18.5 (CH2) ppm. HRMS (ESI) calcd. for C17H25NNaO5S [M +
Na]+: 378.1346, found 378.1345.
Benzyl N-[(1S,2S)-2-(Pyrrolidinylmethyl)cyclobutyl]carbamate (5):
Mesylate 4 (397 mg, 1.3 mmol) was dissolved in anhydrous acetoni-
trile (10 mL) under a nitrogen atmosphere. Then, pyrrolidine
(1.7 mL, 20.7 mmol) was added. The reaction mixture was heated
to reflux for 24 h. After that, the volatiles were evaporated under
vacuum. A saturated aqueous solution of NaHCO3 (100 mL) was
added and the crude reaction was extracted with CH2Cl2 (3ϫ
50 mL). The organic layers were combined, dried with MgSO4, fil-
tered and the solvents evaporated. The product was purified by
column chromatography on silica gel (hexanes/EtOAc, 2:1) to af-
ford 5 (292 mg, 78 % yield) as a yellow oil. [α]D = +72.7, (c = 1.00,
tert-Butyl
N-[(1S,2R)-2-(Dimethylaminomethyl)cyclobutyl]carb-
amate (10): Compound 9 (83 mg, 0.23 mmol) was mixed with a 2 m
solution of NHMe2 in THF (2.33 mL, 4.67 mmol) under a nitrogen
atmosphere. The reaction was stirred at room temp. for 70 h. Then
the volatiles were evaporated under reduced pressure. 1 m solution
CHCl3). IR (ATR):
ν
˜
=
3310, 2952, 1677 cm–1. 1H NMR
(250 MHz, CDCl3, 25 °C): δ = 7.35 (m, 5 H, Ar-H), 5.09 (broad s,
2 H, CH2Ph), 4.22 (complex signal group, 1 H, CHNH), 3.13 (m, of NaOH (10 mL) were added and the product was extracted with
1 H, CHCH2N), 2.69 [m, 1 H, CH2N(CH2)4], 2.50 [complex signal CH2Cl2 (5ϫ 10 mL). The organic layers were combined, dried with
group, 6 H, CH2N(CH2)4, N(CH2CH2)2, CH2], 2.02 (complex sig-
nal group, H, CH2), 1.76 [complex signal group, H,
MgSO4, filtered and the solvent evaporated. The crude reaction
was purified by column chromatography on silica gel (EtOAc with
2
4
N(CH2CH2)2], 1.43 (m, 1 H, CH2) ppm. 13C NMR (62.5 MHz, 3 % of Et3N). In this way, 10 (49 mg, 92 % yield) was obtained as
CDCl3, 25 °C): δ = 156.3 (C), 137.5 (C), 128.8 (C), 128.7 (C), 128.2
(C), 66.5 (CH2), 57.5 (CH2), 54.3 (CH2), 48.2 (CH), 36.4 (CH),
a white solid, m.p. 42–43 °C (EtOAc). [α]D = +19.9 (c = 1.04,
CHCl ). IR (ATR): ν = 3356, 2968, 2945, 2766, 1683, 1530, 1278,
˜
3
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O21307
/KAP1
Date: 26-11-12 17:55:11
Pages: 10
E. Mayans, A. Gargallo, Á. Álvarez-Larena, O. Illa, R. M. Ortuño
(CH2), 28.8 (CH3), 27.3 (CH2), 19.0 (CH2) ppm. HRMS (ESI)
FULL PAPER
1166 cm–1. H NMR (360 MHz, CDCl3, 25 °C): δ = 4.77 (broad s,
1 H, NH), 3.72 (m, 1 H, CHNH), 2.52 [m, 1 H, CHCH2N(CH3)2], calcd. for C10H21N2O2 [M + H]+: 201.1601, found 201.1598.
2.28 [complex signal group, 9 H, CH2N(CH3)2, CHCH2N(CH3)2,
CH2], 1.93 (m, 1 H, CH2), 1.68 (m, 1 H, CH2), 1.43 [m, 9 H,
C(CH3)3], 1.43–1.30 (m, 1 H, CH2) ppm. 13C NMR (90 MHz,
CDCl3, 25 °C): δ = 155.3 (C), 79.3 (C), 64.5 (CH2), 50.2 (CH), 46.1
(CH3), 44.6 (CH), 28.7 (CH3), 28.5 (CH2), 21.8 (CH2) ppm. HRMS
(ESI) calcd. for C12H25N2O2 [M + H]+: 229.1911, found 229.1909.
1
tert-Butyl
N-[(1S,2R)-2-(Isopropylamino)methylcyclobutyl]carb-
amate (14): Compound 12 (104 mg, 0.46 mmol) was dissolved in
MeOH (3 mL) and Pd(OH)2/C 20 % weight (42 mg, 40 %) was
added. Acetone (40 μL, 0.69 mmol) was added. The mixture was
stirred under hydrogen pressure (6 atm) for 14 h. The crude reac-
tion was filtered through celite and washed with MeOH (10 mL).
The combined organic layers were evaporated under vacuum. In
this way, 14 (103 mg, 93 % yield) was obtained as a white solid. 1H
NMR (250 MHz, CDCl3, 25 °C): δ = 5.24 (broad s, 1 H, NH), 4.23
(broad s, 1 H, NH), 3.57 (m, 1 H, CHNH), 2.80–2.53 [complex
(1S,2R)-2-(Dimethylaminomethyl)cyclobutyl-1-aminium Trifluoro-
acetate (11): Compound 10 (146 mg, 0.64 mmol) was dissolved in
anhydrous CH2Cl2 (3 mL). Then, TFA (0.64 mL, 8.32 mmol) and
Et3SiH (0.26 mL, 1.6 mmol) were added. The mixture was stirred
at room temp. for 3 h. The volatiles were evaporated under vacuum
and in the dry-freezer. In this way 11 (131 mg, 85 % yield) was
obtained as a colorless oil. [α]D = +18.1 (c = 1.11, MeOH). IR
signal group,
3 H, CH2NH2, CH(CH3)2], 2.31 (m, 1 H,
CHCH2NH) 2.09 (m, 1 H, CH2), 1.78–1.60 (complex signal group,
2 H, CH2), 1.32–1.23 [complex signal group, 10 H, C(CH3)3, CH2],
1.09 [m, 6 H, CH(CH3)2] ppm. 13C NMR (62.5 MHz, CDCl3,
25 °C): δ = 155.7 (C), 79.6 (C), 50.8 (CH), 50.6 (CH), 49.1 (CH),
45.0 (CH2), 28.3 (CH3), 26.3 (CH2), 21.7 (CH3), 21.4 (CH3), 19.2
(CH2) ppm. HRMS (ESI) calcd. for C13H27N2O2 [M + H]+:
242.1994, found 242.1988.
(ATR): ν = 3421, 3001, 1680, 1204, 1132, 892, 836, 799, 723 cm–1.
˜
1H NMR (360 MHz, [D4]methanol, 25 °C): δ = 3.50 (m, 1 H,
CHN), 3.31 (dd, J1 = 6.84 Hz, J2 = 18.7 Hz, 1 H, CH2N), 3.14 (dd,
J1 = 12.9 Hz, J2 = 18.7 Hz, 1 H, CH2N), 2.76 [complex signal
group, 7 H, CHCH2N(CH3)2, CH2N(CH3)2], 2.26–1.93 (complex
signal group, 3 H, CH2, CH2), 1.66 (m, 1 H, CH2) ppm. 13C NMR
(90 MHz, [D4]methanol, 25 °C): δ = 59.6 (CH2), 47.0 (CH under
MeOH signal) 42.2 (CH3), 36.0 (CH), 23.7 (CH2), 20.5 (CH2) ppm.
HRMS (ESI) calcd. for C7H17N2 [M + H]+: 129.1386, found
129.1386.
tert-Butyl N-[(1S,2R)-2-(Benzylamino)methylcyclobutyl]carbamate
(15): Compound 13 (132 mg, 0.66 mmol) were dissolved in MeOH
(0.5 mL) and freshly distilled benzaldehyde (67 μL, 0.66 mmol) was
added. After 3 h 1 m solution of NaCNBH3 in THF (658 μL,
1.9 mmol) was added. The mixture was stirred overnight at room
temp. The crude reaction was concentrated in vacuo and the resi-
due was dissolved in diethyl ether and was extracted with a solution
of HCl at pH = 3 (8 mL). The aqueous layer was washed with
diethyl ether. Then 1 m NaOH (15 mL) was added to the aqueous
layer. The product was extracted from this solution with CH2Cl2
(3ϫ 10 mL). The combined organic layers were dried with MgSO4
and the solvents evaporated under vacuum. In this way, 15 (73 mg,
38 % yield) was obtained as a white solid, m.p. 104–106 °C
tert-Butyl N-[(1S,2R)-2-(Azidomethyl)cyclobutyl]carbamate (12): A
solution of NaN3 (565 mg, 8.7 mmol) in DMF (12.5 mL) was
added to a flask containing 9 (968 mg, 2.72 mmol). The mixture
was heated to 75 °C for three h. Then the reaction mixture was
cooled down to room temp. and EtOAc was added (60 mL). Then,
the crude reaction was washed with water (5ϫ 50 mL). The com-
bined aqueous layers were extracted with EtOAc (100 mL) and this
organic layer was washed again with water (5ϫ 50 mL). The or-
ganic layers were combined, dried with MgSO4, filtered and evapo-
rated under vacuum. The crude reaction was purified by column
chromatography on silica gel (EtOAc/hexanes; 1:9). In this way, 12
(580 mg, 94 % yield) was obtained as a white solid. Note: due to
the intrinsic instability and potential explosive nature of this mole-
cule, only IR and NMR experiments were carried out to character-
ize this intermediate, m.p. 27–29 °C (EtOAc). [α]D = +14.3 (c =
(CH2Cl2). [α]D = +18.4 (c = 1.02, CH Cl ). IR (ATR): ν = 3277,
˜
2
2
3173, 2971, 2921, 2803, 1675, 1560, 1305, 1166, 1013 cm–1. 1H
NMR (250 MHz, CDCl3, 25 °C): δ = 7.35–7.24 (complex signal
group, 5 H, Ar-H), 4.71 (broad s, 1 H, NH), 3.81–3.72 (complex
signal group, 3 H, CH2Ph, CHNH), 2.73 (m, 2 H, CH2NH), 2.36–
2.23 (complex signal group, 2 H, CHCH2NH, CH2), 1.96–1.65
(complex signal group, 2 H, NH, CH2), 1.42–1.23 [complex signal
group, 10 H, C(CH3)3, CH2] ppm. 13C NMR (62.5 MHz, CDCl3,
25 °C): δ = 155.6 (C), 140.4 (C), 128.7 (CH), 128.6 (CH), 127.2
(CH), 79.9 (C), 54.5 (CH2), 53.9 (CH2), 50.9 (CH), 46.4 (CH), 28.7
(CH3), 27.7 (CH2), 19.7 (CH2) ppm. HRMS (ESI) calcd. for
C17H27N2O2 [M + H]+: 291.2067, found 291.2064.
1.01, CHCl ). IR (ATR): ν = 3338, 2978, 2091, 1683, 1511, 1365,
˜
3
1251, 1013 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 4.99
(broad s, 1 H, NH), 3.78 (m, 1 H, CHNH), 3.31 (m, 2 H, CH2N3),
2.39–2.12 (complex signal group, 2 H, CHCH2N3, CH2), 1.87–1.61
(complex signal group 2 H, CH2), 1.38 [m, 10 H, C(CH3)3,
CH2] ppm. 13C NMR (62.5 MHz, CDCl3, 25 °C): δ = 155.3 (C),
79.6 (C), 54.6 (CH2), 49.2 (CH), 45.0 (CH), 28.7 (CH3), 27.7 (CH2),
19.4 (CH2) ppm.
1-Phenyl-3-[(1R,2S)-2-(pyrrolidinylmethyl)cyclobutyl]thiourea (16):
Compound 5 (300 mg, 1.04 mmol) was dissolved in the minimum
amount of ethanol. Then, Pd(OH)2/C (80 mg) was added. The reac-
tion mixture was hydrogenated over 12 h under 6 atmospheres pres-
sure. Then the crude reaction was filtered through celite and the
resulting celite pad washed with copious amounts of MeOH. The
solvent was evaporated under vacuum giving 6 (157 mg, 98 % yield)
as a yellow oil. This product was used in the following step without
tert-Butyl N-[(1S,2R)-2-(Aminomethyl)cyclobutyl]carbamate (13):
Compound 12 (291 mg, 1.28 mmol) was dissolved in THF (5 mL)
and Pd(OH)2/C 20 % weight (116 mg, 40 %) was added. The mix-
ture was stirred under hydrogen pressure (6 atm) for 5 h. The crude
reaction was filtered through celite and washed with THF (20 mL).
The combined organic layers were evaporated under vacuum. 13
(251 mg, 98 % yield) was obtained as a white solid. [α]D –30.3 (c =
1
further purification. H NMR (250 MHz, CDCl3, 25 °C): δ = 6.11
(broad s, 2 H, NH2), 3.99 (broad s, 1 H, CHNH2), 3.85 (m, 1 H,
CHCH2N), 3.11 [complex signal group, 4 H, CH2N, N(CH2-
CH2)2], 2.89 [complex signal group, 2 H, N(CH2CH2)2], 2.38 (m, 2
1.28, CHCl ). IR (ATR): ν = 3360, 3340, 3170, 2977, 1680, 1537,
˜
3
1291, 1170, 875 cm–1. 1H NMR (250 MHz, CDCl3, 25 °C): δ = 4.88
(broad s, 1 H, NH), 3.72 (m, 1 H, CHNH), 2.75 (m, 2 H,
CH2NH2), 2.20 (complex signal group, 4 H, CHCH2NH2, CH2),
1.89–1.59 (complex signal group, 2 H, CH2), 1.43–1.27 [complex
H, CH2), 2.01 [complex signal group,
CH2)2] ppm.
6 H, CH2, N(CH2-
Freshly prepared amine 6 (150 mg, 1 mmol) was dissolved in anhy-
signal group, 10 H, C(CH3)3, CH2] ppm. 13C NMR (62.5 MHz, drous CH2Cl2 (12 mL) under a nitrogen atmosphere. Then, phenyl
CDCl3, 25 °C): δ = 155.6 (C), 80.0 (C), 50.3 (CH), 49.0 (CH), 46.2 isothiocyanate (0.12 mL, 1 mmol) was added. The reaction mixture
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O21307
/KAP1
Date: 26-11-12 17:55:11
Pages: 10
Chiral Cyclobutane Scaffolds in Organocatalysis
was refluxed for 18 h. After that, the volatiles were evaporated un-
der vacuum. The crude reaction was purified by column
chromatography on silica gel (from pure CH2Cl2 to a mixture of
CH2Cl2/MeOH/Et3N, 100:5:1) yielding 16 (225 mg, 78 % yield) as
a white solid, m.p. 146–148 °C (n-pentane). [α]D = +32.5 (c = 1.00,
thiocyanate (86 μL, 0.47 mmol) were added. The reaction mixture
was refluxed for 28 h under a nitrogen atmosphere. Then the vola-
tiles were evaporated and the crude reaction was purified by col-
umn chromatography on silica gel (EtOAc/hexanes, 1:5). In this
way, 19 (85 mg, 46 % yield) was obtained as a pale yellow solid,
m.p. 73–75 °C (EtOAc). [α]D = –11.5 (c = 0.98, CHCl3). IR (ATR):
CHCl ). IR (ATR): ν = 3355, 3310, 2965, 1465, 1394, 1274,
˜
3
1128 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 9.57 (broad s,
ν = 3260, 2977, 1679, 1510, 1367, 1273, 1165, 1127, 1043, 780, 700,
1
˜
1
1 H, NH), 7.39–7.22 (m, 5 H, Ar-H), 4.73 (broad s, 1 H, NH), 3.26
(m, 1 H, CHN), 2.71 (complex signal group, 2 H, CH2N,
CHCH2N), 2.18 [complex signal group, 7 H, CH2N, N(CH2-
CH2)2, CH2], 1.44 [complex signal group, 6 H, N(CH2CH2)2,
680 cm–1. H NMR (250 MHz, CDCl3, 25 °C): δ = 8.80 (broad s,
1 H, NH), 7.88 (s, 2 H, Ar-H), 7.66 (s, 1 H, Ar-H), 5.80 [sept, J =
6.8 Hz, 1 H, CH(CH3)2], 4.84 (broad s, 1 H, NH), 4.14 (d, J =
15.9 Hz, 1 H, CH2NH), 3.65 (m, 1 H, CHNHBoc), 3.41 (dd, J =
CH2] ppm. 13C NMR (62.5 MHz, CDCl3, 25 °C): δ = 180.1 (C), 15.9 Hz, JЈ = 8.7 Hz, 1 H, CH2NH), 2.62 (m, 1 H, CHCH2N), 2.20
137.6 (C), 130.0 (C), 126.8 (C), 125.1 (C), 58.1 (CH2), 53.8 (CH2), (m, 2 H, CH2), 1.69 (m, 2 H, CH2), 1.21–1.17 [complex signal
52.3 (CH), 35.6 (CH), 29.6 (CH2), 23.4 (CH2), 20.0 (CH2) ppm. group, 15 H, C(CH3)3, CH(CH3)2] ppm. 13C NMR (62.5 MHz,
HRMS (ESI) calcd. for C16H24N3S [M + H]+: 290.1685, found
289.1679.
CDCl3, 25 °C): δ = 181.4 (C), 156.6 (C), 142.5 (C), 131.9 (q, 1 C),
128.5 (CH), 125.8 (CH), 119.6 (C), 80.8 (C), 52.1 (CH), 49.9 (CH),
48.7 (CH2), 42.6 (CH), 28.3 (CH3), 24.8 (CH3), 24.3 (CH3), 21.7
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2S)-2-(pyrrolidinylmethyl)-
cyclobutyl]thiourea (17): Amine 6 (132 mg, 0.85 mmol), freshly pre-
pared as described above, was dissolved in anhydrous CH2Cl2
(7 mL) under a nitrogen atmosphere. Then, 3,5-bis(trifluorometh-
yl)phenyl isothiocyanate (0.15 mL, 0.85 mmol) was added. The re-
action mixture was refluxed for 24 h. After that, the volatiles were
evaporated under vacuum. The crude reaction was purified by col-
umn chromatography on silica gel (EtOAc with 2 % Et3N) yielding.
17 (143 mg, 39 % yield) as a white solid, m.p. 125–127 °C (n-pent-
(CH2),
20.0
(CH2) ppm.
HRMS
(ESI)
calcd.
for
C22H29F6N3NaO2S [M + Na]+: 536.1777, found 536.1785.
Thiourea 20: Compound 13 (264 mg, 1.32 mmol) was dissolved in
anhydrous CH2Cl2 (10 mL) and 3,5-bis(trifluoromethyl)phenyl iso-
thiocyanate (0.6 mL, 4.09 mmol) were added. The reaction mixture
was refluxed for 24 h under a nitrogen atmosphere. Then the vola-
tiles were evaporated and the crude reaction was purified by col-
umn chromatography on silica gel (hexanes/EtOAc/Et3N, 8:1:0.4)
yielding 20 (99 mg, 16 % yield) as a pale yellow solid, m.p. 61–
ane). [α]D = +8.0 (c = 1.00, CHCl ). IR (ATR): ν = 3355, 3310,
˜
3
2965, 1465, 1394, 1274, 1128 cm–1. 1H NMR (250 MHz, [D4]meth-
anol, 25 °C): δ = 8.04 (broad s, 2 H, Ar-H), 7.54 (s, 1 H, Ar-H),
4.77 (complex signal group, 3 H, 2ϫ NH, CHN), 2.78 (complex
signal group, 2 H, CHCH2N, CHCH2N), 2.43 [complex signal
group, 6 H, CHCH2N, N(CH2CH2)2, CH2], 2.00 (complex signal
group, 2 H, CH2), 1.62 [complex signal group, 5 H, N(CH2CH2)2,
CH2] ppm. 13C NMR (62.5 MHz, [D4]methanol, 25 °C): δ = 181.3
(C), 135.0–117.0 (various C plus coupled signals of CF3), 56.6
(CH2), 54.1 (CH2), 51.1 (CH), 37.9 (CH), 26.9 (CH2), 23.2 (CH2),
20.8 (CH2) ppm. HRMS (ESI) calcd. for C18H22F6N3S [M + H]+:
426.1442, found 426.1436.
63 °C (CH2Cl2). [α]D = –27.5 (c = 1.2, CHCl ). IR (ATR): ν =
˜
3
3215, 2934, 1675, 1502, 1471, 1369, 1274, 1166, 1126, 1019, 884,
700, 680 cm–1. H NMR (360 MHz, CDCl3, 25 °C): δ = 8.17 (s, 2
1
H, Ar-H), 7.62 (s, 1 H, Ar-H), 3.75 (complex signal group, 2 H,
NHBoc, CH2NH), 3.57 (m, 1 H, CH2NH), 2.50 (m, 1 H,
CHCH2N), 2.18 (m, 1 H, CHNHBoc), 1.85 (m, 2 H, CH2), 1.38
[complex signal group, 11 H, C(CH3)3, CH2] ppm. 13C NMR
(90 MHz, CDCl3, 25 °C): δ = 181.3 (C), 156.4 (C), 141.8 (C), 131.1
(q, 1 C), 124.8 (CH), 121.8 (CH), 116.2 (C), 78.7 (C), 49.4 (CH2),
43.9 (CH), 29.3 (CH), 27.4 (CH3), 25.6 (CH2), 18.3 (CH2) ppm.
HRMS (ESI) calcd. for C19H23F6N3NaO2S [M + Na]+: 494.1307,
found 494.1305.
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1S,2R)-2-(dimethylamino-
methyl)cyclobutyl]thiourea (18a): Compound 11 (133 mg,
0.55 mmol) was dissolved in a 1 m NaOH solution (7 mL). The free
amine was extracted with CH2Cl2 (5ϫ 10 mL). The organic layers
were combined, dried with MgSO4, filtered and evaporated to ob-
tain 70 mg of the free amine as an off-white solid. This solid was
1-[3,5-Bis(trifluoromethyl)phenyl]-3-[(1R,2S)-2-(dimethylamino)-
cyclobutylmethyl]thiourea (18b): Compound 20 (67 mg, 0.14 mmol)
was dissolved in anhydrous CH2Cl2 (3 mL) and TFA (143 μL,
1.85 mmol) and triethylsilane (56 μL, 0.36 mmol) were added. The
reaction mixture was stirred at room temp. for 3 h. The volatiles
were then evaporated and the acetate salt dissolved in 1 m NaOH
solution (5 mL) and the aqueous layer was extracted with CH2Cl2
(3ϫ 10 mL). The combined organic layers were dried with MgSO4
and the solvent was evaporated under reduced pressure. This crude
material was dissolved in AcCN (3 mL) and a 37 % aqueous solu-
tion of formaldehyde (71 μL, 0.91 mmol) was added. After 25 min,
a 1 m solution of NaCNBH3 in THF (263 μL, 0.78 mmol) was
added followed, 15 min later, by AcOH (7.5 μL, 0.14 mmol). The
resulting solution was stirred at room temp. overnight. Volatile
compounds were evaporated and 1 m NaOH solution was added
(5 mL). Then the aqueous layer was extracted with CH2Cl2 (3ϫ
10 mL). The combined organic layers were dried and the solvent
was removed under reduced pressure. Product 18b was purified by
semi-preparative thin layer chromatography on silica gel (EtOAc/
3 % of Et3N). In this way, 18b (9.4 mg, 18 % yield) was obtained
then dissolved in anhydrous CH2Cl2 (5 mL) in
a nitrogen
atmosphere and 3,5-bis(trifluoromethyl)phenyl isothiocyanate
(0.398 mL, 2.20 mmol) was added. The mixture was refluxed for
16 h. Then the volatiles were evaporated and crude reaction was
purified by column chromatography on silica gel (CHCl3 with 5 %
of a 32 % aqueous solution of NH3) yielding 18a (82 mg, 37 %
yield) as a white solid, m.p. 159–161 °C (CH2Cl2/n-pentane). [α]D
= –60.7 (c = 1.02, MeOH). IR (ATR): ν = 3206, 2920, 1375, 1274,
˜
1
1161, 1120, 879, 678 cm–1. H NMR (360 MHz, CDCl3, 25 °C): δ
= 7.93 (s, 2 H, Ar-H), 7.64 (s, 1 H, Ar-H), 6.61 (broad s, 1 H,
NH), 3.71 (m, 1 H, CHN), 2.57–2.29 [complex signal group, 10 H,
CHCH2N(CH3)2, CH2N(CH3)2, CH2N(CH3)2], 2.01 (m, 2 H,
CH2), 1.27–1.39 (m, 2 H, CH2) ppm. 13C NMR (90 MHz CDCl3,
25 °C): δ = 182.3 (C), 142.5 (C), 131.9 (q, 1 C), 124.6 (CH), 121.8
(C), 118.3 (CH), 64.1 (CH2), 54.6 (CH), 45.7 (CH3), 43.2 (CH),
26.4 (CH2), 19.0 (CH2) ppm. HRMS (ESI) calcd. for C16H20F6N3S
[M + H]+: 400.1277, found 400.1282.
as a colorless oil. [α]D = +46.1 (c = 1.04, CH Cl ). IR (ATR): ν =
˜
2
2
3180, 2946, 1594, 1518, 1470, 1391, 1272, 1130, 1110, 899,
687 cm–1. 1H NMR (360 MHz, CDCl3, 25 °C): δ = 8.68 (s, 1 H,
NH), 8.02 (s, 2 H, Ar-H), 7.64 (s, 1 H, Ar-H), 7.13 (broad s, 1 H,
NH), 3.76 (m, 1 H, CHN), 3.61 (m, 1 H, CH2NH), 3.51 (m, 1 H,
Thiourea 19: Compound 14 (86 mg, 0.36 mmol) was dissolved in
anhydrous CH2Cl2 (4 mL) and 3,5-bis(trifluoromethyl)phenyl iso-
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Job/Unit: O21307
/KAP1
Date: 26-11-12 17:55:11
Pages: 10
E. Mayans, A. Gargallo, Á. Álvarez-Larena, O. Illa, R. M. Ortuño
FULL PAPER
F. Fülöp, Amino Acids 2011, 41, 597–608; i) Z. Szakonyi, K.
Csillag, F. Fülöp, Tetrahedron: Asymmetry 2011, 22, 1021–
1027.
a) N. Katagiri, H. Sato, C. Kaneko, Chem. Pharm. Bull. 1990,
38, 288–290; b) A. Rustullet, R. Alibés, P. de March, M. Fig-
ueredo, J. Font, Org. Lett. 2007, 9, 2827–2830; c) B. Darses,
A. E. Greene, S. C. Coote, J.-F. Poisson, Org. Lett. 2008, 10,
821–824; d) A. Ebead, R. Fournier, E. Lee-Ruff, Nucleosides
Nucleotides Nucleic Acids 2011, 30, 391–404.
CH2NH), 2.94 (m, 1 H, CHCH2N), 2.61 [d, J = 3.8 Hz, 6 H,
N(CH3)2], 2.06 (m, 2 H, CH2), 1.85 (m, 1 H, CH2), 1.59 (m, 1 H,
CH2) ppm. 13C NMR (90 MHz, CDCl3, 25 °C): δ = 181.9 (C),
140.2 (C), 132.1 (q, 1 C), 123.4 (C), 121.6 (CH), 118.2 (CH), 67.3
(CH), 48.0 (CH3), 47.6 (CH3), 46.6 (CH2), 37.9 (CH), 20.5 (CH2),
17.6 (CH2) ppm. HRMS (ESI) calcd. for C16H20F6N3S [M + H]+:
400.1277, found 400.1285.
[4]
General Procedure for the Organocatalyzed Conjugate Addition Re-
actions: A typical experiment with organocatalyst 17 is described.
(E)-β-nitrostyrene (35.1 mg, 0.24 mmol) was dissolved in toluene
(0.5 mL) and diethyl malonate then added (75 μL, 0.49 mmol), fol-
lowed by the desired amount of catalyst 17 (5 or 10 mol-%). The
reaction was stirred for 24 or 48 h at room temp., 0 °C or –25 °C.
Then the crude reaction was analyzed by gas chromatography (con-
ditions: 70 °C for 3 min; 25 °C/min ramp up to 300 °C; 300 °C for
5 min) to determine the yield. Retention times: diethyl malonate:
7 min; (E)-β-nitrostyrene: 9.2 min; diethyl 2-(2-nitro-1-phenyleth-
yl)malonate: 11.8 min. The crude reaction was purified by column
chromatography on silica gel (EtOAc/hexanes, 1:9) to obtain pure
diethyl 2-(2-nitro-1-phenylethyl)malonate.[20] Then, if the mobile
phase was changed to EtOAc/2 % of Et3N, the catalyst can be reco-
vered. The purified product was analyzed by HPLC using a Daicel
AD-H column, hexane/iPrOH, 80:20, 1 mL/min, retention times:
10.0 min [(R), minor], 27 min [(S), major].[18,21]
[5]
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Supporting Information (see footnote on the first page of this arti-
1
cle): Selected HPLC chromatograms and copies of the H and 13C
[9]
NMR spectra.
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Acknowledgments
We acknowledge financial support from the Spanish Ministerio de
Ciencia e Innovación (MICINN) (grant number CTQ2010-15408/
BQU) and Generalitat de Catalunya (grant number 2009SGR-733).
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[15]
[16]
[17]
8
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Job/Unit: O21307
/KAP1
Date: 26-11-12 17:55:11
Pages: 10
Chiral Cyclobutane Scaffolds in Organocatalysis
[18] Absolute configuration was determined by comparison with
data reported in: D. Almas¸i, D. A. Alonso, E. Gómez-Bengoa,
C. Nájera, J. Org. Chem. 2009, 74, 6163–6168.
[19] A. Hamza, G. Schubert, T. Sóos, I. Papai, J. Am. Chem. Soc.
2006, 128, 13151–13160.
[21]
NMR spectroscopic data are consistent with those described
in: D. M. Barnes, J. Ji, M. G. Fickes, M. A. Fitzgerald, S. A.
King, H. E. Morton, F. A. Plagge, M. Preskill, S. H. Wagaw,
S. J. Wittenberger, J. Zhang, J. Am. Chem. Soc. 2002, 124,
13097–13105 ppm.
[20] K. M. Lippert, K. Hof, D. Gerbig, D. Ley, H. Hausmann, S.
Guenther, P. R. Schreiner, Eur. J. Org. Chem. 2012, 30, 5919–
5927.
Received: October 3, 2012
Published Online: ᭿
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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9

Job/Unit: O21307
/KAP1
Date: 26-11-12 17:55:11
Pages: 10
E. Mayans, A. Gargallo, Á. Álvarez-Larena, O. Illa, R. M. Ortuño
FULL PAPER
Chiral Cyclobutane Organocatalysts
E. Mayans, A. Gargallo, Á. Álvarez-
Larena, O. Illa,* R. M. Ortuño* .... 1–10
Diastereodivergent Synthesis of Chiral vic-
Disubstituted-Cyclobutane Scaffolds: 1,3-
Amino Alcohol and 1,3-Diamine Deriva-
tives – Preliminary Use in Organocatalysis
Chiral cyclobutane containing 1,3-amino
alcohols and 1,3-diamines have been syn-
thesized from a common chiral precursor.
Regioselective transformations of these
precursors led to bifunctional thioureas
which have been tested as organocatalysts
in preliminary experiments
Keywords: Synthetic methods / Organocat-
alysis / Asymmetric catalysis / Michael ad-
dition / Regioselectivity / Amino alcohols /
Amines
10
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