Stereoselective synthesis of -sulfinylamino isocyanides and 2-imidazolines

Article abstract of DOI:10.1002/ejoc.201402210

An efficient asymmetric synthesis of -sulfinylamino isocyanides is reported on the basis of the highly diastereoselective addition of 9-isocyanofluorene to optically pure N-tert-butanesulfinimines. The resulting optically pure isocyanides readily cyclized to give optically pure 2-imidazolines upon removal of the sulfinyl group. Furthermore, the -sulfinylamino isocyanides were used as chiral inputs in Ugi and Passerini multicomponent reactions to generate new types of (pseudo)peptide scaffolds. Optically pure -sulfinylamino isocyanides are synthesized in a highly diastereoselective addition of 9-isocyanofluorene with N-tert-butanesulfinimines. Follow-up chemistry demonstrates that they are excellent precursors for the preparation of optically pure 2-imidazolines. Furthermore, they are applied in Ugi and Passerini multicomponent reactions; TMSOTf = trimethylsilyl trifluoromethanesulfonate, DIPEA = N,N- diisopropylethylamine. Copyright

Full text of DOI:10.1002/ejoc.201402210

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402210
Stereoselective Synthesis of β-Sulfinylamino Isocyanides and 2-Imidazolines
Guido V. Janssen,[a] Esther Vicente-García,[a] Wouter Vogel,[a] J. Chris Slootweg,[a]
Eelco Ruijter,[a] Koop Lammertsma,*[a] and Romano V. A. Orru*[a]
Keywords: Synthetic methods / Multicomponent reactions / Sulfinimines / Isocyanides / Nitrogen heterocycles / Chirality
An efficient asymmetric synthesis of β-sulfinylamino isocyan-
ides is reported on the basis of the highly diastereoselective
addition of 9-isocyanofluorene to optically pure N-tert-but-
anesulfinimines. The resulting optically pure isocyanides
readily cyclized to give optically pure 2-imidazolines upon
removal of the sulfinyl group. Furthermore, the β-sulfinyl-
amino isocyanides were used as chiral inputs in Ugi and
Passerini multicomponent reactions to generate new types of
(pseudo)peptide scaffolds.
in this field because they allow for the development of dia-
stereoselective MCRs. Furthermore, the isolation of inter-
mediate 6 would provide additional mechanistic evidence
for the proposed reaction pathway. However, the high pro-
pensity of 6 toward cyclization (if R1 = alkyl or aryl)
through intramolecular attack of the nucleophilic amine on
the isocyanide carbon atom results in rapid formation of 2-
imidazolines 8. Reducing the nucleophilicity of the amine
nitrogen atom with a strongly electron-withdrawing group
(EWG) should hamper the cyclization and, thereby make
Introduction
Chiral 2-imidazolines are pharmaceutically privileged
heterocyclic scaffolds. The 2-imidazoline core appears in a
variety of biologically active and medicinal compounds
with antihypertensive,[1] antihyperglycemic,[2] antidepres-
sive,[3] anti-inflammatory,[4] and antitumor activities.[5] The
2-imidazoline core is also popular as the chiral heterocyclic
fragment in several organocatalysts,[6] as chiral ligands in
transition-metal catalysis,[7] and as precursors for N-hetero-
cyclic carbenes.[8]
the isolation of interesting β-amino isocyanides 6 (R1
=
Several synthetic routes are known for the generation of
2-imidazolines. An effective approach was reported in 1977
by Van Leusen and Schöllkopf,[9] who independently dis-
covered a base-promoted reaction between α-lithiated iso-
cyanides and imines. Recently, we reported a more general
multicomponent reaction (MCR) approach for this reaction
that allowed the use of a wide range of amines 1, ketones
or aldehydes 2, and α-acidic isocyanides 3 without the need
for an additional base (Scheme 1).[10] The mechanism most
likely involves a Mannich-type addition of isocyanides 3 to
in situ generated iminium ions 4, which results in intermedi-
ates 6. Rapid cyclization of 6 through nucleophilic attack
of the amine nitrogen atom on the isocyanide carbon atom
followed by a 1,2-proton shift provides 2-imidazolines 8. β-
Amino isocyanide derivatives 6 are synthetically attractive
as inputs for a broad range of isocyanide-based multicom-
ponent reactions, such as the Ugi and Passerini reactions, as
they provide atom and step efficient access to new (pseudo)
peptide scaffolds.[11] Especially chiral isocyanides are useful
EWG) feasible.
Scheme 1. General reaction scheme and mechanism for the multi-
component approach.
For this purpose, we envisioned chiral N-tert-butanesulf-
inylimines[12] 9 as suitable imine inputs for this reaction to
obtain either uncyclized β-amino isocyanides 11 or cyclized
2-imidazolines 12 (Scheme 2). In addition to the strong elec-
tron-withdrawing properties of the sulfinyl group, the dis-
tinct chirality of this auxiliary might influence the dia-
stereoselectivity of this reaction. In the past, the chiral sulf-
inyl group of 9 has shown to be a very efficient directing
[a] VU University Amsterdam, Department of Chemistry and
Pharmaceutical Sciences, Amsterdam Institute for Molecules,
Medicines & Systems (AIMMS),
De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
E-mail: k.lammertsma@vu.nl
r.v.a.orru@vu.nl
http://www.chem.vu.nl/en/research/division-organic-chemistry/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402210.
3762
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3762–3766

Synthesis of β-Sulfinylamino Isocyanides and 2-Imidazolines
group in the stereoselective addition of a wide range of Ti(OiPr)4, Sc(OTf)3, and trimethylsilyl trifluoromethane-
nucleophiles to imines 9.[12,13] Because we obtained a mod- sulfonate (TMSOTf) in CH2Cl2 were not effective (Table 1,
erate diastereoselectivity (dr
= 64:36) with α-methyl entries 3–5). To stabilize the cationic intermediate (Figure 1,
benzylamine in our original three-component reaction I), we used THF as the solvent with TMSOTf as the Lewis
(Scheme 1),[10b] we anticipated chiral induction would occur acid. This choice of solvent proved rewarding and rendered
by using chiral imines 9.
14a in 60% yield (Table 1, entry 6). Further improvement
in the yield of isolated 14a to 95% was realized upon using
2 equiv. of TMSOTf (Table 1, entry 7). In both cases, a sin-
gle diastereomer of 14a was obtained, as can be rationalized
by diastereotopic differentiation owing to steric congestion.
This also accounts for the (S) configuration of the newly
formed stereocenter, as depicted in Figure 1 (II).[16] Because
the Si face of imine (R)-9a is shielded upon coordination
with the nonchelating Lewis acid TMSOTf, nucleophilic at-
tack must take place on the less-hindered Re face, which
leads to the expected Cram product.[17]
Scheme 2. Approach to optically active β-amino isocyanides 11.
Results and Discussion
For the initial screening of the reaction conditions, we
chose benzaldehyde-derived sulfinimine (R)-9a[14] and 9-iso-
cyanofluorene 13 as substrates. Not surprisingly, the stan-
dard MCR approach [preformation of imine (R)-9a fol-
lowed by addition of isocyanide 13 without any additives]
in both MeOH and CH2Cl2 was unsuccessful, because the
nitrogen atom of (R)-9a is not sufficiently basic owing to
the strongly electron-withdrawing sulfinyl group. Therefore,
we lithiated isocyanide 13 before addition to imine (R)-9a
at –78 °C, but still no reaction was observed. The logical
next step was to increase the electrophilicity of (R)-9a by
Lewis acid activation, which consequently necessitated the
use of an external base to deprotonate the isocyanide.[15]
This approach proved successful. Indeed, the reaction be-
tween (R)-9a and 13 in the presence of the Lewis acid
BF3·OEt2 and diisopropylethylamine (DIPEA) as base in
CH2Cl2 resulted in the isolation of product 14a in 10%
yield (Table 1, entry 1).
Figure 1. Covalent activation of imine 9a and a rationale behind
the observed diastereoselectivity.
Analysis by IR and NMR spectroscopy provided support
for the formation of desired isocyanide 14a rather than the
2-imidazoline. The IR spectrum showed a strong signal at
ν = 2131 cm–1 and in the 13C NMR spectrum a quaternary
˜
carbon atom was observed at δ = 158.7 ppm, both of which
indicated the presence of an isocyanide. X-ray crystal-struc-
ture determination confirmed the structure of uncyclized
isocyanide (2S)-14a (Figure 2)[18] and thereby its stereo-
selective formation from 13 and (R)-9.
Table 1. Screening of Lewis acids and reaction conditions.
Entry
LA[a]
Solvent
T [°C]
t [h]
Yield[b] [%]
1
2
3
4
BF3·OEt2
AlCl3
Ti(OiPr)4
Sc(OTf)3
TMSOTf
TMSOTf
TMSOTf
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
r.t.
r.t.
r.t.
16
16
16
16
3
3
3
10
26
–
–
–
60
95
r.t.
5
–78
–78
–78
6
7[c]
THF
[a] LA = Lewis acid. [b] Yield of isolated product. [c] TMSOTf
(2 equiv.).
Figure 2. Molecular structure of (2S)-14a. Hydrogen atoms and a
cocrystalized CH2Cl2 molecule are omitted for clarity, and dis-
placement parameters are drawn at the 50% probability level.
To optimize the reaction, we tested several Lewis acids
in combination with DIPEA. The yield of 14a was im-
With the optimized conditions (Table 1, entry 7), we ex-
proved to 26% with AlCl3 (Table 1, entry 2), whereas plored the scope of the reaction for a variety of aromatic
Eur. J. Org. Chem. 2014, 3762–3766
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3763

K. Lammertsma, R. V. A. Orru et al.
SHORT COMMUNICATION
(R)-N-tert-butanesulfinimines 9b–j (Table 2). 2-Naphthyl Upon using more hindered acids [R1 = Et, cyclohexyl (Cy),
derivative (R)-9b diastereoselectively gave (2S)-14b in 66% tBu], corresponding Passerini products 15b–d were likewise
yield (Table 2, entry 1) and both electron-rich and electron- obtained in 26–54% yield (Table 3, entries 2–4). The lower
poor imines (R)-9c–g reacted smoothly to give correspond- yield may be due to the steric bulk and acidity of the car-
ing products (2S)-14c–g as single diastereomers in reason- boxylic acids, which suggests a relationship between acidity
able to good yields (52–85%; Table 2, entries 2–6). Also, 2- and steric hindrance on the reaction rate. Although the
furyl- and 2-thienyl-substituted imines (R)-9h and (R)-9i Passerini products were successfully isolated, the reduced
gave corresponding heteroaromatic products (2S)-14h and reaction rate and substrate size did not have any influence
(2S)-14i stereoselectively in satisfactory yields (Table 2, en- on the stereochemical outcome of the reaction, as com-
tries 7 and 8). However, reaction of 3-pyridyl-substituted pounds 15b–d were all isolated as 1:1 diastereomeric mix-
imine (R)-9j with 13 did not give the desired product, prob- tures.
ably owing to competition for coordination of the Lewis
Table 3. Passerini reactions with (2S)-14a.
acid between the sulfinyl group and the pyridine nitrogen
atom, which thereby led to side reactions.[19] The use of
other α-acidic isocyanides such as p-nitrobenzyl isocyanide
and methyl α-phenyl isocyanoacetate did not lead to the
desired products.
Table 2. Diastereoselective formation of (2S)-14b–j.
Entry
Product
R1
dr[a]
Yield[b] [%]
1
2
3
4
15a
15b
15c
15d
Me
Et
Cy
tBu
50:50
50:50
50:50
50:50
57
54
42
26
[a] Determined by analysis of the crude reaction mixture by
1H NMR spectroscopy. [b] Yield of isolated product.
Entry Product[a]
R1
dr[b]
ee[c]
[%]
Yield[d]
[%]
The use of (2S)-14a in the Ugi four-component transfor-
mation also lacked chiral induction (Table 4). Thus, reac-
tion of (2S)-14a with isobutyraldehyde, p-methoxybenzyl-
amine, and acetic acid in methanol resulted in the isolation
of Ugi product 16a as a 1:1 diastereomeric mixture in 68%
yield (Table 4, entry 1). Reactions of (2S)-14a with benzyl-
amine, isobutyraldehyde, and cyclohexanecarboxylic acid or
acetic acid also afforded 1:1 diastereomeric mixtures of 16b
(60%) and 16c (56%), respectively (Table 4, entries 2 and
3).
1
2
3
4
5
6
7
8
9
(2S)-14b
(2S)-14c
(2S)-14d
(2S)-14e
(2S)-14f
(2S)-14g
(2S)-14h
(2S)-14i
(2S)-14j
2-naphthyl
4-MeOC6H4 Ͼ99:1
4-O2NC6H4 Ͼ99:1
4-NCC6H4
4-ClC6H4
4-F3CC6H4
2-furyl
2-thienyl
3-pyridyl
Ͼ99:1
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
Ͼ99
–
66
85
67
52
75
52
79
57
–
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
Ͼ99:1
–
[a] The stereochemistry of 14b–i was tentatively assigned as the
same as (2S)-14a by analogy. This was further supported by similar
optical rotations for all products (see the Supporting Information
Table 4. Ugi reactions with (2S)-14a.
1
for details). [b] Determined by analysis by H NMR spectroscopy
and HPLC on a chiral stationary phase. [c] Determined by HPLC
on a chiral stationary phase. [d] Yield of isolated product.
We continued our investigations and explored follow-up
chemistry with optically pure isocyanide (2S)-14a. Two
MCRs, the Ugi and Passerini reactions, were chosen as suit-
able reactions. The formation of a new stereocenter in both
MCRs allowed us to investigate the influence of the chiral-
ity of isocyanide (2S)-14a on the diastereoselectivity. Al-
though diastereoselectivity has been observed in isocyanide-
based MCRs with the use of chiral substrates other than
isocyanides,[20] the successful application of chiral isocyan-
ides remains scarce.[21]
To examine the stereochemical influence on the Passerini
reaction, optically pure (2S)-14a was treated with isobutyr-
aldehyde and four different carboxylic acids (Table 3). Al-
beit slowly (7 d),[22] the reaction of (2S)-14a with isobutyr-
Entry
Product
R1
R2
dr[a]
Yield[b] [%]
1
2
3
16a
16b
16c
Me
Me
Cy
OMe
H
H
50:50
50:50
50:50
68
60
56
[a] Determined by analysis of the crude reaction mixture by
1H NMR spectroscopy. [b] Yield of isolated product.
Finally, we examined the transformation of isocyanides
aldehyde and acetic acid in CH2Cl2 gave product 15a in (2S)-14 into corresponding 2-imidazolines 17 (Table 5). Be-
57% yield as a 1:1 diastereomeric mixture (Table 3, entry 1). cause the nucleophilicity of the sulfonamide nitrogen atom
3764
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Eur. J. Org. Chem. 2014, 3762–3766

Synthesis of β-Sulfinylamino Isocyanides and 2-Imidazolines
on TLC. Then, the reaction was quenched at –78 °C by the addition
of a saturated solution of NH4Cl to the vigorously stirred reaction
mixture. After the frozen mixture was warmed to room tempera-
ture, the layers were separated, and the aqueous layer was extracted
twice with CH2Cl2. The combined organic layer was washed with
brine, dried with Na2SO4, and concentrated in vacuo. Crude prod-
uct 14 was then purified by column chromatography.
is likely inadequate to induce cyclization, we reasoned that
removal of the sulfinyl group would be sufficient to facili-
tate ring closure. Deprotection of sulfinyl groups is typically
accomplished by treatment with an excess amount of HCl
in an ethereal solvent to afford the amine as the HCl salt.[23]
Thus, (2S)-14a was smoothly deprotected with HCl
(3 equiv.) in Et2O and rapid cyclization was induced upon
treatment with triethylamine in CH2Cl2 to quantitatively
give optically pure 2-imidazoline (S)-17a (Table 5, entry 1).
Likewise, p-methoxyphenyl- and 2-thienyl-substituted iso-
cyanides (2S)-14c and (2S)-14i afforded quantitatively cy-
clized products (S)-17c and (S)-17i, respectively, as single
enantiomers. Similar treatment of p-nitrobenzyl-substituted
isocyanide (2S)-14d also gave quantitative cyclization to
imidazoline 17d, but, surprisingly, as a mixture of enantio-
mers (94 %ee). We presume that the proton attached to the
stereogenic center, which carries the electron-withdrawing
p-nitrophenyl group, is relatively easily abstracted by Et3N,
which leads to partial racemization.
General Procedure for the Passerini Reactions with (2S)-14a: In a
round-bottomed flask, the carboxylic acid (1.1 equiv.) and aldehyde
(1.1 equiv.) were dissolved in CH2Cl2. The resulting solution was
stirred for 30 min followed by the addition of the isocyanide
(1.0 equiv.). The reaction mixture was stirred for 3 days at room
temperature. Evaporation of the solvent followed by column
chromatography afforded Passerini product 15.
General Procedure for the Ugi Reactions with (2S)-14a: In a round-
bottomed flask, the amine (1.5 equiv.) and aldehyde (1.5 equiv.)
were dissolved in MeOH, which was followed by the addition of
Na2SO4. The resulting suspension was stirred for 4 h before the
carboxylic acid (1.5 equiv.) was added. This mixture was stirred for
1 h, after which the isocyanide (1.0 equiv.) was added. The resulting
mixture was stirred for 3 days at room temperature before evapora-
tion of the solvent, which was followed by column chromatography
to afford Ugi product 16.
Table 5. Transformation of (2S)-14 into 2-imidazolines (S)-17.
General Procedure for the Transformation of Isocyanides (2S)-14
into Optically Pure 2-Imidazolines (S)-17: In a flame-dried flask
under inert atmosphere, the isocyanide (1.0 equiv.) was dissolved in
Et2O. HCl (2 m in Et2O, 3 equiv.) was dropwise added to the solu-
tion. The resulting suspension was stirred for 30 min. Next, the
mixture was filtered, and the residue was dissolved in CH2Cl2. Et3N
(3.0 equiv.) was added, and the mixture was stirred for 15 min.
Then, the reaction mixture was washed twice with water and brine,
dried with Na2SO4, and concentrated in vacuo to yield pure 2-imid-
azoline (2S)-17.
Entry Product
R1
ee[a]
Yield[b] [%]
1
2
3
4
(S)-17a
(S)-17c
17d
Ph
Ͼ99
Ͼ99
94
quant.
quant.
quant.
quant.
4-MeOC6H4
4-NO2C6H4
2-thienyl
Supporting Information (see footnote on the first page of this arti-
cle): General information, detailed experimental procedures, copies
of the 1H NMR and 13C NMR spectra, copies of the HPLC traces,
and experimental details of the X-ray crystal structure determi-
nation.
(S)-17i
Ͼ99
[a] Determined by HPLC on a chiral stationary phase. [b] Yield of
isolated product.
Conclusions
Acknowledgments
In conclusion, we reported the fully diastereoselective ad-
dition of 9-isocyanofluorene to chiral N-sulfinylimines to
afford novel chiral β-sulfinylamino isocyanides. Excellent
selectivities and good yields were obtained for a range of
aromatic N-sulfinylimines. We demonstrated the applica-
bility of these β-amino isocyanides in the Ugi and Passerini
reactions. Finally, we also showed that the N-sulfinylimines
are excellent precursors for the efficient synthesis of op-
tically pure 2-imidazolines.
The Dutch National Research School Combination Catalysis
(NRSC-C) is gratefully acknowledged for financial support. Dr.
Chris Frampton (SAFC Pharmorphix) and Dr. Christophe M. L.
van de Velde (University of Antwerp) are kindly acknowledged for
measurement and interpretation of the crystal structure. The au-
thors thank Sanne Bouwman and Elwin Janssen for HRMS mea-
surements and Dr. F. J. J. de Kanter for assistance with NMR spec-
troscopy.
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General Procedure for the Diastereoselective Addition of 13 to Sulf-
inimines 9: In a flame-dried flask under inert atmosphere, imine 9
(1.0 equiv.) was dissolved in THF, and the solution was cooled to
–78 °C. TMSOTf (2.0 equiv.) was added, and the mixture was
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K. Lammertsma, R. V. A. Orru et al.
SHORT COMMUNICATION
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[14] Optically pure N-tert-butanesulfinylimines 9 (Ͼ99 %ee) were
conveniently prepared from commercially available starting
Received: March 6, 2014
Published Online: May 12, 2014
3766
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