Aza-Wittig access to chiral imidazol(in)es

Article abstract of DOI:10.1039/b822436f

2-Imidazolines and imidazoles have been accessed by an aza-Wittig sequence featuring novel N-acylation methodology for sulfonamides and optimized conditions for ring closure.

Full text of DOI:10.1039/b822436f

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Aza-Wittig access to chiral imidazol(in)esw
Patrick Loos,ab Matthias Riedrichab and Hans-Dieter Arndt*ab
Received (in Cambridge, UK) 15th December 2008, Accepted 30th January 2009
First published as an Advance Article on the web 20th February 2009
DOI: 10.1039/b822436f
2-Imidazolines and imidazoles have been accessed by an
aza-Wittig sequence featuring novel N-acylation methodology
for sulfonamides and optimized conditions for ring closure.
Imidazole-containing alkaloids comprise a rich group of
bioactive natural products1 and constitute challenging targets
for organic synthesis.2 In contrast, the 4,5-dihydro-1H-imidazole
(‘‘2-imidazoline’’) motif is much less common in nature,3 but
2-imidazolines have been successfully explored in medicinal
chemistry and effector molecules.4 In addition, optically active
imidazolines have been investigated as amide bond isosteres
and chiral templates,5 catalyst precursors,6 and as ligands for
asymmetric catalysis.7
Scheme 1 Regioselective access to imidazol(in)es by aza-Wittig
Enantiopure imidazolines can be prepared from
1,2-diamines,6a,7a,8 amido alcohols,9 and other starting
materials,10 by using (Lewis) acidic activation, intermediate
formation of imidoyl halides or esters, or intramolecular
substitution. Recently, aza-Wittig ring closures11 have emerged
as a powerful means for effecting clean heterocyclizations to
oxazolines and thiazolines, even of sensitive precursors.12 Up
to now, similar transformations leading to the imidazoline
homologs had to employ harsh reaction conditions or special
substrates.13 Here, we report on a general method to furnish
imidazolines and imidazoles from azido peptides under very
mild conditions using aza-Wittig methodology.14
disconnection.
Scheme 2 Synthesis of azido-sulfonamide 9. Reagents and conditions:
(a) TsCl, 1,4-dioxane, aq. Na2CO3, rt; (b) MeOH, SOCl2, rt; (c) TfN3
(6 equiv.), EtN(iPr)2, CH2Cl2–DMF, CuSO4.
Owing to their low electrophilicity, amide carbonyls are
typically inert toward aza-Wittig reactions.11,15 We imagined
that using a chemically stable, electron-withdrawing substituent
X on the nitrogen atom should render the amide carbonyl
susceptible for intramolecular attack of a putative imino-
phosphorane 3 (Scheme 1). By choosing a sulfonyl group for
this purpose, a suitably protected product 1 would arise from
2, which could be liberated and/or further functionalized.
Iminophosphorane 3 should be accessible from azide 5 by
acylation of the NHX moiety (via 4) and Staudinger reaction
with phosphines, thereby enabling assembly from building
blocks with full regio- and stereocontrol (R1/R2).
concomitant loss of the Boc group (8), and transformed into
the corresponding azide 9 using modified Wong conditions
(495% ee by chiral HPLC).16 Azide 9 was found to be rather
sensitive towards exposure to base, and the reaction proceeded
much better when DMF was used as cosolvent.
To the best of our knowledge, N-acylation of sulfonamides
such as 9 is not well documented for more complex acyl donors.
Primary sulfonamides have been subject to acylation with amino
acids, using PyBOP17 or amino acid fluorides.18 N-Acyl
sulfonamides can be formed by ligating thioacids with sulfonyl
azides.19 Precedence for secondary sulfonamide substrates is
very limited;20 hence, suitable conditions had to be found.
Initially, several reagents were screened using the sterically
hindered threonine derivative 10a, with variation of base,
solvent, and temperature. For example, PyBrop or carbodiimides
gave low yields and/or led to extensive racemization or
decomposition. However, clean acylation of 9 to 11 could be
achieved by employing either acid fluorides or uronium-based
coupling reagents. Selected cases are compiled in Table 1.
When freshly prepared, preformed amino acid fluoride
delivered the amide 11 in acceptable yield and purity
(dr 4 97 : 3).18 Both soluble organic as well as solid inorganic
base could be used (see entries a and b). Unfortunately,
TFFH-mediated formation21 of the acid fluoride in situ gave
inferior results (entry c). First experiments with the uronium salt
To explore the feasibility of this strategy, we investigated
the chiral diaminopropionic acid derivative 9 (Scheme 2)
in analogy to substrates useful for the formation of
peptide-embedded thiazolines and oxazolines.12c Conversion
of commercially available (S)-Na-Boc-diaminopropionic acid
6 into its Nb-sulfonamide 7 proceeded swiftly under standard
conditions. Acid 7 was esterified using MeOH–SOCl2 with
a Technische Universitat Dortmund, Fakultat Chemie,
Otto-Hahn-Str. 6, D-44221 Dortmund, Germany
¨
¨
b Max-Planck-Institut fur Molekulare Physiologie, Otto-Hahn-Str. 11,
D-44227 Dortmund, Germany.
¨
E-mail: hans-dieter.arndt@mpi-dortmund.mpg.de
w Electronic supplementary information (ESI) available: General proce-
dures and 1H-NMR spectra of 11, 12, 13, 16. See DOI: 10.1039/b822436f
ꢀc
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Table 1 Optimization of sulfonamide N-acylation
Table 2 Acylations under optimized conditions and aza-Wittig ring
closure to 2-imidazolines
Entry
X
Reagenta
Base
Solvent
Yield
Methoda
A
Yield of 11
Yield of 12
a
b
c
d
e
f
F
F
—
—
EtN(iPr)2
Cs2CO3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
59%
51%
28%
14%
22%
85%
71%
Entry
a
R =
OH
OH
OH
OH
OH
TFFH
HATU
HATU
HATU
HBTU
Cs2CO3
EtN(iPr)2
EtN(iPr)2
Cs2CO3
Cs2CO3
85%
97%b
CH2Cl2
CH2Cl2
g
a
Abbreviations:
TFFH
=
tetramethylfluoroformamidinium
2-(10H-70-azabenzotriazol-10-yl)-
b
A
85%
94%b
hexafluorophosphate; HATU
1,1,3,3-tetramethyluronium
2-(10H-benzotriazol-10-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate.
=
hexafluorophosphate;
HBTU
=
c
A
A
85%
99%
46%
80%
HATU using standard conditions22 were not very encouraging,
and solvent influence was minute (entries d, e). However, after
some experimentation it was found that switching from a soluble
organic to the insoluble inorganic base Cs2CO3 led to surprisingly
clean transformations, with excellent yields of amide 11a
(entry f).23 Interestingly, K2CO3 gave inferior results (not shown),
indicating that a soluble sulfonamide anion might be involved in
the reaction. Switching to the less labile HOBt-derived active ester
(entry g) did not improve the outcome of the reaction, showing
that both high electrophilicity of the acyl donor as well as
sufficient base strength to deprotonate the sulfonamide are
important for optimal conversion. Notably, racemization was
not observed under these conditions (dr 4 97 : 3).
d
91%b
e
f
A
85%
64%
85%
B
B
97%
80%
91%b
76%b
g
This method was applied to a diverse selection of acyl donors
(Table 2). In general, many types of substrates (hindered/
unhindered, polar/non-polar, aliphatic/aromatic) performed
well and gave the corresponding amides 11 in excellent yields
(entries a–e). However, for Ala and Phe (entries f, g) the
conversion was unsatisfactory, which may be attributed to
premature cleavage of the intermediate active ester by the rather
nucleophilic Cs2CO3, or formation of unreactive oxazolone
intermediates. Gratifyingly, preformed acid fluorides delivered
the amides with high efficiency in these cases.
a
Reagents and conditions: A: carboxylic acid, HATU, Cs2CO3, CH2Cl2,
b
0 1C; B: acid fluoride, EtN(iPr)2, CH2Cl2, 25 1C. PPh3 (1.5 equiv.),
THF, reflux, 2.5–6 h. PPh3 (1.2 equiv.), 2,6-lutidine, 80 1C, 2–6 h.
c
(entries c, e). Not unexpectedly, varying the phosphine did not
improve this outcome.12c In a solvent screen it was found that
conducting the ring closure reaction in 2,6-lutidine would lead
to better reaction rates and cleaner products (entries c, e).
Despite the elevated temperature, epimerizations or eliminations
were not observed. The reason of this rather specific solvent
effect remains under study. Currently, we speculate that the
basic medium neutralizes adventitious acid which otherwise
might deactivate the intermediate iminophosphorane 3 by
protonation.24
Oxidation12c,14b to the imidazole could then be smoothly
achieved using DBU and BrCCl3 (Table 3).25 Sterically
hindered as well as oxidation prone precursors (e.g. 12c) could
be transformed to the imidazole amino acids 13 in very good
yields without formation of side products (entries a–c). On the
other hand, it would be desirable if oxidation of the ring could
be achieved by making use of the high oxidation state of the
sulfonyl substituent. First attempts to trigger its elimination
with strong bases (KOtBu, DBN, DABCO) were not met with
success. To our surprise, treating 2-imidazoline 12f with an
excess of DBU led to clean formation of the imidazole 16 in
acceptable yield (entry d).
Ring closure of the activated amides 11 to the 2-imidazolines
was investigated next. To our delight, initial experiments showed
that conversion to the 2-imidazolines 12 was smooth using our
previously disclosed conditions.12c Imidazoline formation
occurred at ambient or elevated temperature in THF with
PPh3, generally with good to excellent yields (Table 2).23
All compounds could be isolated and were shown to be
diastereomerically pure by 1H-NMR. Notably, imidazolines with
little steric shielding (12f, 12g) were quite prone to hydrolysis of
the activated amidine function, suffering ring opening to a
primary sulfonamide. Both acid and wet silica were found to
easily trigger this process, but not base. This illustrates that the
mild conditions of the aza-Wittig ring closure are ideally suited to
directly access even sensitive 2-imidazolines.
In cases of pronounced steric hindrance and low electro-
philicity the reaction rates were slow under standard aza-Wittig
ring-closure conditions, which was reflected in modest yields
ꢀc
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Table 3 Generating imidazole amino acids from 2-imidazolinesa
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Entry
2-Imidazoline
Method
Product
Yield
a
b
c
12a
12c
12f
12f
a
a
a
b
13a
13c
13f
16
87%
90%
76%
49%
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a
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0 1C - rt.
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In conclusion, we have shown that imidazolines can be
efficiently formed by intramolecular aza-Wittig ring closures
of N-acylated azido sulfonamides under essentially neutral
conditions, with complete regiocontrol. Substrates were
assembled by sulfonamide N-acylation, enabling liberal
structural variation in the target molecules. Reaction
conditions could be found that deliver the target heterocycles
with neglible epimerization. It is expected that substrate
reactivity can be fine-tuned further by variation of the
sulfonamide group. Together with flexible deprotective or
non-deprotective tailoring, this method should be helpful for
flexible access to key imidazolines and imidazoles in medicinal
chemistry, library generation, and target oriented synthesis.
Funding by the Deutsche Forschungsgemeinschaft (AR493/1-1
and -2 to H.-D. A.) and the Fonds der Chemischen Industrie is
highly appreciated. The authors thank Prof. Dr H. Waldmann for
support and MSc B. van Vliet for donating acid 10d.
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23 For a general procedure see the supporting information.
24 Further research is currently being undertaken to clarify this point.
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ꢀc
This journal is The Royal Society of Chemistry 2009
1902 | Chem. Commun., 2009, 1900–1902