Phosphabarrelene-modified Rh-catalysts: A new and selective route towards hydroxy-functionalized bicyclic imidazoles via tandem reactions

Article abstract of DOI:10.1039/b911612e

8-Hydroxy-6-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine was formed selectively in high yields from N-(β-methallyl)imidazole by a tandem hydroformylation-cyclization sequence, representing a novel one-pot catalytic synthesis of bicyclic imidazole deriv

Full text of DOI:10.1039/b911612e

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Phosphabarrelene-modified Rh-catalysts: a new and selective route
towards hydroxy-functionalized bicyclic imidazoles via tandem
reactionswz
a
a
a
b
Patrick S. Ba
¨
uerlein, Ismael Arenas Gonzalez, Jarno J. M. Weemers, Martin Lutz,
b
a
a
Anthony L. Spek, Dieter Vogt and Christian Mu
¨
ller*
Received (in Cambridge, UK) 12th June 2009, Accepted 7th July 2009
First published as an Advance Article on the web 23rd July 2009
DOI: 10.1039/b911612e
8
-Hydroxy-6-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine
was formed selectively in high yields from N-(b-methallyl)imidazole
by a tandem hydroformylation–cyclization sequence, representing
a novel one-pot catalytic synthesis of bicyclic imidazole derivatives.
The metal-catalyzed hydroformylation of alkenes is an
industrially important, atom efficient reaction for the production
1
of aldehydes. A developing area is the integration of hydro-
Fig. 1 N-Allyl-imidazole 1 and nagstatin 2.
formylation reactions in tandem or domino-type sequences, in
investigated, which is most likely due to the fact that the
imidazole moiety is much less prone to electrophilic substitution
reactions compared to pyrrole, although the intermolecular
thermal condensation of imidazoles with carbonyl compounds
2
which the initial CO/H addition to an alkene is combined
2
with a subsequent reaction. Yet not trivial to achieve, these
multistep reactions are powerful tools for the construction of
more complex products by making economical use of available
functional groups within the same molecule. In this respect,
vinyl and allyl heteroaromatic substrates are especially inter-
esting and potentially relevant for both pharmaceutical and
fine chemical industry, because the generated frameworks
are often found in biologically active compounds, such as
alkaloids. Vasylyev and Alper recently reported on a rhodium-
catalyzed hydroformylation–silica-promoted deformylation
6
has been reported before. The access to 1,2-fused bicyclic
imidazoles typically requires multistep synthetic protocols and
4
often the presence of strong Lewis acids, such as SnCl or
7
4
TiCl .
During the course of our investigations on functionalized
phosphinine-based heterocycles we anticipated that L1 and L2
might be suitable ligands for reaction sequences under hydro-
8
formylation conditions (Fig. 2). In fact, these types of
3
sequence, leading to hexahydropyrrolo[2,1]oxazoles. The
phosphorus compounds have been shown to be efficient
ligands for the Rh-catalyzed hydroformylation of terminal
formation of 5,6-dihydroindolizines and 5,6,7,8-tetrahydro-
indolizines was observed by Lazzaroni and co-workers after
9
and less reactive internal alkenes before.
hydroformylation of N-(b-methallyl)pyrrole with Rh
as catalyst precursor. Under relatively harsh reaction
conditions (p(CO/H ) 4 100 bar, T 4 100 1C) subsequent
4
(CO)12
We chose the methyl-substituted N-(b-methallyl)imidazole
substrate 3 (Scheme 1) rather than 1, since hydroformylation
2
0
reactions of 1,1 -disubstituted alkenes are almost always
intramolecular cyclization and dehydration and, eventually,
4
hydrogenation occurred.
completely regioselective for the formation of linear versus
10
quaternary aldehydes according to Keulemans empirical rule.
3
Interestingly, analogous reactions starting from N-allyl-
imidazole (1) could lead to bicyclic imidazole derivatives,
which often have antiulcer, anticancer, antidepressant or
5
antimicrobial activity, such as nagstatin 2 (Fig. 1). Surprisingly,
tandem reactions on such substrates have never been
a
Schuit Institute of Catalysis, Laboratory for Homogeneous
Catalysis, Eindhoven University of Technology, 5600 MB Eindhoven,
The Netherlands. E-mail: c.mueller@tue.nl; Fax: +31 40 2455054;
Tel: +31 40 2474679
Fig. 2 Phosphinine L1 and corresponding phosphabarrelene L2.
b
Bijvoet Center for Biomolecular Research, Crystal and Structural
Chemistry, Utrecht University, 3584 CH Utrecht, The Netherlands
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic chemistry.
Please see our website (http://www.rsc.org/chemcomm/organic
webtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: A list of all
experimental details. CCDC reference number 736069. For ESI and
crystallographic data in CIF or other electronic format see DOI:
Scheme 1 Rh-catalyzed hydroformylation of 3 and subsequent
cyclization to 5.
10.1039/b911612e
4
944 | Chem. Commun., 2009, 4944–4946
This journal is ꢀc The Royal Society of Chemistry 2009

could easily be synthesized in high yields by reaction of imidazole
11
with 3-chloro-2-methylpropene.
The Rh-catalyzed hydro-
formylations of 3 (S : Rh : L = 1500 : 1 : 20) were performed
at T = 80 1C and p(CO/H = 1 : 1) = 20 bar in toluene.
2
Surprisingly, the Rh-catalyst based on the p-acceptor
phosphinine L1 leads to only 32% conversion after 72 h and
exclusively to the linear aldehyde 4, which shows a characteristic
1
8
3
Fig. 4 H NMR spectrum (400 MHz, CDCl ) of the C –H region of 5.
resonance for the aldehyde-proton at
1
d
t, JH–H = 1.1 Hz) in the H NMR spectrum (Scheme 1).
=
9.7 ppm
(
However, applying the more s-donating phosphabarrelene
L2, almost complete conversion to 4 (98%) could be achieved,
but unfortunately only traces of 5 (B2%) were detected. For
comparison reasons we also applied the bulky phosphite
concentration is reached after 6 h and the final cyclization
product 5 is selectively generated and accumulated within the
reaction time of 45 h. No formation of any byproducts could
be detected. The PPh
the same selectivity under identical reaction conditions but is
-based catalyst Rh/L4 shows essentially
3
t
12
P(OPh-o- Bu)3 (L3) as well as PPh (L4) as ligand. Catalyst
3
ꢁ
1
Rh/L3 showed hardly any conversion (o5%), whereas Rh/L4
led to 92% yield of the aldehyde 4 within 72 hours (B1.5%
of 5, see ESIw). Catalysts based on strong p-acceptor ligands
less active compared to Rh/L2 (TOF = 390 h ). Isolation of
pure 4 and subsequent transformation into 5 (toluene, 120 1C)
further showed that the cyclization step is not metal-catalyzed,
6
(
L1 and L3) are obviously not suitable for the hydroformyla-
as anticipated.
tion of these types of heterocyclic substrates, while catalysts
The bicyclic imidazole 5 was obtained as an off-white solid
9d,13
based on the more s-donating phosphabarrelenes
(L2)
in 80% isolated yield after removal of all volatiles and subsequent
1
recrystallization from toluene. 5 was fully characterized by H
and the strong s-donating PPh show much better results.
3
1
3
and C NMR spectroscopy as well as by elemental analysis.
A possible explanation might be competition for the metal
center between the donor-functionalized substrate present in
large excess and the poor s-donating p-acceptor ligands.
The best performing phosphabarrelene-modified Rh-catalyst
The tandem reaction generates the two stereogenic carbon
6
atoms C and C and thus, the presence of 2 pairs of
8
1
enantiomers is expected. In fact, the H NMR spectrum of
(
Rh/L2) was subsequently applied in the hydroformylation
the product shows two sets of protons of which the set
14
8
assigned to the C –H proton is the most distinctive.
of 3 at T = 120 1C. Under these conditions, 3 is almost
quantitatively converted to 8-hydroxy-6-methyl-5,6,7,8-tetra-
hydroimidazo[1,2-a]pyridine 5 within 45 h (93%, determined
by GC, Scheme 1). Apparently, compound 5 is produced by a
tandem hydroformylation–cyclization sequence, in which the
fused bicyclic imidazole structure is formed by an intra-
Two characteristic resonances and couplings with the two
protons of the adjacent methylene spacer are observed at
3
d = 4.90 ppm (dd, JH–H = 6.6, 10.0 Hz) and d = 5.02 ppm
(t, JH–H = 3.3 Hz), respectively, in a ratio of 2 : 1 (Fig. 4).
3
We were further able to detect the four stereoisomers of 5 in
2
molecular nucleophilic attack of the imidazole C carbon atom
a ratio of 1 : 2 : 2 : 1 by analytical HPLC analysis on a chiral
on the carbonyl group of the aldehyde under formation of an
alcohol. This new one-pot tandem reaction was investigated
by GC-analysis of the product composition during the course
of the reaction and the corresponding distribution-of-species
plot is shown in Fig. 3.
stationary phase, using n-hexane–isopropanol (95 : 5) as eluent
s
(Chiralcel OD–H, t = 12.9 min, t = 19.4 min, t = 25.5 min,
1 2 3
ꢁ1
t = 34.1 min, T = 25 1C, flow-rate 1 mL min , see ESIw).
4
In order to gain more information on the stereochemistry of
the products we made use of the rather large differences in
retention times and were able to separate and characterize all
four stereoisomers independently. As anticipated, fractions
The substrate 3 is rapidly consumed at the beginning of
ꢁ1
the reaction with a turnover frequency (TOF) of 700 h
determined at 20% conversion). The maximum aldehyde
1
(
1 + 4 show identical H NMR spectra and the distinctive
8
triplet at d = 5.02 ppm for the C -proton, while identical
Fig. 5 Stereoisomers of 5 and corresponding Newman-projections;
8
1
Fig. 3 Distribution-of-species plot for the tandem hydroformylation–
cyclization sequence of substrate 3. S : Rh : L2 = 1500 : 1 : 20, cRh = 1 mM,
(a) anti configuration leading to a triplet for C –H in the H NMR
spectrum (HPLC fractions 1 + 4); (b) syn configuration (dd, HPLC
fractions 2 + 3).
V = 8 mL, T = 120 1C, p = 20 bar (CO/H
2
= 1 : 1).
This journal is ꢀc The Royal Society of Chemistry 2009
Chem. Commun., 2009, 4944–4946 | 4945

spectroscopy in combination with chiral HPLC analysis and
the bicyclic nature of the product could unambiguously be
confirmed by X-ray crystal structure determination. The full
substrate and product scope is currently under investigation in
1
5
our laboratories.
C.M. gratefully acknowledges the Netherlands Organization
for Scientific Research (NWO-CW) for financial support. The
authors thank Ton Staring for technical assistance.
Notes and references
Fig. 6 Hydrogen bonding of 5 in the crystal. Displacement ellipsoids
1
P. W. N. M. van Leeuwen and C. Claver, Rhodium
Catalyzed Hydroformylation, Kluwer Academic Publishers,
Dordrecht, 2000; P. W. N. M. van Leeuwen, Homogeneous
Catalysis: Understanding the Art, Kluwer Academic Publishers,
Dordrecht, 2004.
are shown at the 50% probability level. Only the major stereoisomer
5
(S,R) of the mixture is shown.
1
H NMR spectra with the characteristic doublet of doublets at
d = 4.90 ppm was observed for fractions 2 + 3 (see ESIw).
From the Newman-projections of all four stereoisomers it
becomes obvious that the anti products are expected to show a
¨
2 See for example: P. Eilbracht, L. Barfacker, C. Buss, C. Hollmann,
B. E. Kitsos-Rzychon, C. L. Kranemann, T. Rische,
R. Roggenbuck and A. Schmidt, Chem. Rev., 1999, 99, 3329;
B. Breit, Acc. Chem. Res., 2003, 36, 264; M. L. Clarke, Curr.
Org. Chem., 2005, 9, 701; D. E. Fogg and E. N. dos Santos, Coord.
8
1
2
triplet for the C –H proton of the A B spin system in the H
ˇ
Chem. Rev., 2004, 248, 2365; S. T. Kemme, T. Smejkal and
B. Breit, Adv. Synth. Catal., 2008, 350, 989; T. Spangenberg,
B. Breit and A. Mann, Org. Lett., 2009, 11, 261.
NMR spectrum (Fig. 5a). This pair can consequently be
assigned to fractions 1 and 4 in the HPLC chromatogram.
In contrast, the pair of enantiomers with syn configuration
8
Fig. 5b) should result in a doublet of doublets for the C –H
3 M. Vasylyev and H. Alper, Angew. Chem., Int. Ed., 2008, 48, 1287.
4 R. Lazzaroni, R. Settambolo, A. Caiazzo and L. Pontorno,
J. Organomet. Chem., 2000, 601, 320; R. Settambolo, A. Caiazzo
and R. Lazzaroni, Tetrahedron Lett., 2001, 42, 4045;
S. Rocchiccioli, G. Guazzelli, R. Lazzaroni and R. Settambolo,
J. Heterocycl. Chem., 2007, 44, 479.
(
1
proton of the ABX spin system in the corresponding H NMR
spectrum, and can therefore be assigned to fractions 2 and 3.
Moreover, the Newman-projections indicate the preferred
formation of the syn-configured enantiomers as both the
5
Nagstatin is a naturally occurring carbohydrate mimic isolated
from the fermentation broth of Streptomyces amakusaensis with N-
acetyl-b-D-glucosaminidase inhibiting properties. It has potential
as an anticancer and antidiabetic agent.
–
3
OH and –CH groups are located in the preferred equatorial
position of the annulated ring.
From the mixture of stereoisomers single crystals suitable
for X-ray diffraction were formed by slow crystallization of
6 A. M. Roe, J. Chem. Soc., 1963, 2195.
7
D. H. Hua, F. Zhang and J. Chen, J. Org. Chem., 1994, 59, 5084;
F. Aldabbagh and W. R. Bowman, Tetrahedron, 1999, 55, 4109;
H.-C. Kan, M-C. Tseng and Y.-H. Chu, Tetrahedron, 2007, 63,
1644.
5
from toluene. The crystal structure unambiguously confirms
the bicyclic nature of the anticipated imidazole derivative.
Due to the centrosymmetry of the space group the crystal
structure is racemic, but on individual crystallographic
sites a mixture of the syn products is found in a ratio
8 C. Mu
¨
ller, E. A. Pidko, D. Totev, M. Lutz, A. L. Spek, R. A. van
ller,
Santen and D. Vogt, Dalton Trans., 2007, 5372; C. Mu
¨
E. A. Pidko, A. J. P. M. Staring, M. Lutz, A. L. Spek,
R. A. van Santen and D. Vogt, Chem.–Eur. J., 2008, 14, 4899.
9 B. Breit, Chem. Commun., 1996, 2071; B. Breit, R. Winde,
T. Mackewitz, R. Paciello and K. Harms, Chem.–Eur. J., 2001,
5
(S,R) : 5(R,S) = 0.756(4) : 0.244(4) and consequently on
an inverted site of 0.244(4) : 0.756(4) (see also ESIw). The
molecular structure of the major enantiomer 5(S,R) is depicted
in Fig. 6 and shows hydrogen bonding between the –OH group
and the basic nitrogen atom N4 of an adjacent molecule and
7
, 3106; B. Breit and E. Fuchs, Chem. Commun., 2004, 694;
E. Fuchs, M. Keller and B. Breit, Chem.–Eur. J., 2006, 12, 6930;
P. Le Floch, Coord. Chem. Rev., 2006, 250, 627; P. Le Floch, Sci.
Synth., 2005, 15, 1097; C. Mu
5505; See also: M. Blug, C. Guibert, X.-F. Le Goff, N. Me
and P. Le Floch, Chem. Commun., 2009, 201.
¨
ller and D. Vogt, Dalton Trans., 2007,
7a
´
zailles
vice versa. This stabilizing effect might explain the fact that
5
does not undergo spontaneous elimination of H O as
2
1
0 For the formation of quaternary aldehydes see: A. I. M. Keulemans,
A. Kwantes and T. van Bavel, Recl. Trav. Chim. Pays-Bas, 1948, 67,
4
observed for related compounds. Furthermore, it can be seen
that the hydrogen atoms H6, H7a and H7b adopt the typical
positions for the syn product (vide supra).
298; M. L. Clarke and G. J. Roff, Chem.–Eur. J., 2006, 12, 7978;
M. L. Clarke and G. J. Roff, Green Chem., 2007, 9, 792.
1 3 was synthesized according to a modified literature procedure:
G. Guazzelli, R. Settambolo and R. Lazzaroni, Synth. Commun.,
2007, 37, 1211.
1
In summary we have developed a new route towards
functionalized bicyclic imidazole derivatives consisting of a
one-pot tandem reaction sequence under hydroformylation
conditions. 8-Hydroxy-6-methyl-5,6,7,8-tetrahydroimidazo-
1
1
1
1
2 P. W. N. M. van Leeuwen and C. F. Roobeek, J. Organomet.
Chem., 1983, 258, 343.
3 C. Wallis, P. G. Edwards, M. Hanton, P. D. Newman, A. Stasch,
G. Jones and R. P. Tooze, Dalton Trans., 2009, 2170.
4 S. Mitsui, A. Kasahara and K. Hanaya, Bull. Chem. Soc. Jpn.,
[
1,2-a]pyridine was formed selectively in high yield by
hydroformylation of N-(b-methallyl)imidazole using
phosphabarrelene-modified Rh-catalyst and subsequent intra-
a
1
968, 41, 2526–2528.
5 Preliminary results also show the efficient conversion of
N-(b-methallyl)benzimidazole and N-(a-methallyl)imidazole to
cyclic heterocycles and will be reported elsewhere.
molecular cyclization. The stereochemistry of the generated
1
pairs of enantiomers was investigated by H NMR
2
4
946 | Chem. Commun., 2009, 4944–4946
This journal is ꢀc The Royal Society of Chemistry 2009