Stereoselective synthesis of 5-substituted pyrrolo[1,2-c]imidazol-3-ones: Access to annulated chiral imidazol(in)ium salts

Article abstract of DOI:10.1021/ol902277y

"Chemical Equation Presented" A two-step synthesis of N-heterocyclic carbene (NHC) precatalysts by diastereoselective or enantioselective lithiation of pyrrolo[1,2-c]imidazol-3-ones followed by POCl₃-induced salt formation is described. The res

Full text of DOI:10.1021/ol902277y

ORGANIC
LETTERS
2010
Vol. 12, No. 1
76-79
Stereoselective Synthesis of 5-Substituted
Pyrrolo[1,2-c]imidazol-3-ones: Access to
Annulated Chiral Imidazol(in)ium Salts
Costa Metallinos* and Shufen Xu
Department of Chemistry, Brock UniVersity, 500 Glenridge AVenue, St. Catharines,
Ontario L2S 3A1, Canada
cmetallinos@brocku.ca
Received October 1, 2009
ABSTRACT
A two-step synthesis of N-heterocyclic carbene (NHC) precatalysts by diastereoselective or enantioselective lithiation of pyrrolo[1,2-c]imidazol-
3-ones followed by POCl3-induced salt formation is described. The resulting 3-chloro-pyrroloimidazol(in)ium salts may be coordinated to
palladium(II) upon NHC generation with t-BuLi at low temperature. The method may facilitate exploitation of these compounds as chiral
organocatalysts or ligands in metal catalysis.
Pyrroloimidazoles (1, Figure 1) resemble plant-derived
pyrrolizidine alkaloids1 (e.g., 2) and constitute a small but
potent class of biologically active molecules. Compounds
with a framework represented by 1 have anxiolytic proper-
ties2 and exhibit nanomolar inhibitory activity against
aldostereone synthase and aromatase.3 As such, they may
be useful in the treatment of hypoalkemia, hypertension, and
congestive heart failure. Previous syntheses of R-arylated
pyrroloimidazoles give racemic products that require resolu-
tion of the constituent enantiomers, which often differ in their
levels of efficacy.3
to chiral N-heterocyclic carbene (NHC) precatalysts such as
triazolium (4) and thiazolium (5) salts.5 However, the related
imidazol(in)ium salts6 (6) are more challenging to prepare
and to date have limited structural diversity because they
originate from syn-1,2-aminoalcohols.7 Development of a
stereoselective synthesis of pyrroloimidazol(in)es, which
contain one or two stereogenic centers R to nitrogen in the
pyrrolidine ring, would provide access to biologically active
compounds and serve to increase the number of annulated
C1-symmetric imidazol(in)ium derived NHCs.8 The latter
may be useful precursors to nucleophilic or transition metal
catalysts.
Compounds with a pyrroloimidazol(in)e skeleton have also
been used as guanidine organocatalysts4 (e.g., 3), although
these do not possess stereogenic centers in the same place
as 1. More appropriate structural comparisons can be made
(5) (a) DiRocco, D. A.; Oberg, K. M.; Dalton, D. M.; Rovis, T. J. Am.
Chem. Soc. 2009, 131, 10872. (b) Rovis, T. Chem. Lett. 2008, 37, 2. (c) de
Alaniz, J. R.; Kerr, M. S.; Moore, J. L.; Rovis, T. J. Org. Chem. 2008, 73,
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5606. (e) Christmann, M. Angew. Chem., Int. Ed. 2005, 44, 2632. (f) Perry,
M. C.; Burgess, K. Tetrahedron: Asymmetry 2003, 14, 951. (g) He, L.;
Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 2825.
(1) Huang, J.-M.; Hong, S.-C.; Wu, K.-L.; Tsai, T.-M. Tetrahedron Lett.
2004, 45, 3047, and references therein.
(2) (a) Fontanella, L.; Corsico, N.; Diena, A.; Occelli, E. Farmaco, Ed.
Sci. 1984, 39, 133. (b) Fontanella, L.; Occelli, E.; Perazzi, A. Farmaco,
Ed. Sci. 1973, 28, 463. (c) Fontanella, L.; Occelli, E. Farmaco, Ed. Sci.
1971, 26, 685.
(6) (a) Nair, V.; Vellalath, S.; Babu, B. P. Chem. Soc. ReV. 2008, 37,
2691. (b) Nair, V.; Babu, B. P; Vellalath, S.; Varghese, V.; Raveendran,
A. E.; Suresh, E. Org. Lett. 2009, 11, 2507. (c) Nair, V.; Vellalath, S.;
Poonoth, M.; Suresh, E. J. Am. Chem. Soc. 2006, 128, 8736. (d) Nair, V.;
Bindu, S.; Sreekumar, V. Angew. Chem., Int. Ed. 2004, 43, 5130.
(7) (a) Struble, J. R.; Kaeobamrung, J.; Bode, J. W. Org. Lett. 2008,
10, 957. (b) Struble, J. R.; Bode, J. W. Tetrahedron 2008, 64, 6961. Review:
(c) Arduengo, A. J.; Iconaru, L. I. Dalton Trans. 2009, 6903.
(3) (a) Ksander, G. M.; Meredith, E.; Monovich, L. H.; Papillon, J.;
Firooznia, F.; Hu, Q. WO 024945 (2007). (b) Browne, L. J.; Gude, C.;
Rodriguez, H.; Steele, R. E. J. Med. Chem. 1991, 34, 725.
(4) Isobe, T.; Fukuda, K.; Ishikawa, T. J. Org. Chem. 2000, 65, 7770.
10.1021/ol902277y  2010 American Chemical Society
Published on Web 12/04/2009

Scheme 1
. Enantioselective Lithiation of 7 and 9, and
Diastereoselective Lithiation of 14
Figure 1. Examples of compounds with pyrroloimidazol(in)e (1,
3, 6), pyrrolizidine (2), triazoline (4), and thiazoline (5) frameworks.
Previously, we demonstrated that annulated chiral benz-
imidazolium salts could be obtained from 7 (Scheme 1), in
which a fused urea served as a directing group for enanti-
oselective lithiation of the piperidyl ring.9 It was envisioned
that this method could be extended to pyrroloimidazol(in)-
3-ones. This approach is based on the known ability of N-Boc
pyrrolidine (9) to undergo enantioselective lithiation-substitu-
tion with (-)-sparteine to give products in good yields and
enantiomeric purity.10 Recently, this method has become
more versatile by the development of (+)-sparteine sur-
rogates11 (e.g., 12 and 13) and the ability to install aromatic
substituents R to nitrogen.12 Moreover, cyclic carbamates
(e.g., 14) have been shown to undergo diastereoselective
lithiation to give exclusively syn-configured products 15 in
good yields.13
hydrogens of the pyrrolidine ring were 2.51 and 3.69 Å,
respectively. The difference between these distances (1.18
Å) is greater than what was calculated for cyclic carbamate
1413 (0.92 Å based on O· · ·HS ) 2.78 Å and O· · ·HR ) 3.70
Å), suggesting that R-lithiation of 17 would be at least as
selective as 14.
To begin our investigations, the required starting materials
were prepared from t-Bu amide 16 (Scheme 2), which was
obtained from Cbz-protected L-proline by standard meth-
ods.14 Removal of the Cbz group (cyclohexene, Pd/C) and
reduction of the amide (LiAlH4) gave a volatile diamine that,
without purification, was converted to urea 17 with triph-
osgene. The unsaturated congener 19 was prepared by
reduction of 16 with LiAlH4, which gave 18 as an epimeric
mixture of hemiaminals. Addition of dilute acid (0.1 M
aqueous HCl) to this mixture induced elimination of water
to afford urea 19 in good overall yield.
Scheme 2. Synthesis of Chiral Urea 17 and Achiral Urea 19
With respect to diastereoselective lithiation of 17, com-
putational minimization15 indicated that the distances be-
tween the urea oxygen and the pro-S or pro-R R-methylene
(8) For R-chiral annulated NHCs in transition metal catalysis, see: (a)
Metallinos, C.; Du, X. Organometallics 2009, 28, 1233. (b) Metallinos,
C.; Barrett, F. B.; Wang, Y.; Xu, S.; Taylor, N. J. Tetrahedron 2006, 62,
11145. (c) Wu¨rtz, S.; Lohre, C.; Fro¨hlich, R.; Bergander, K.; Glorius, F.
J. Am. Chem. Soc. 2009, 131, 8344. (d) Glorius, F.; Altenhoff, G.; Goddard,
R.; Lehmann, C. Chem. Commun. 2002, 2704. (e) Baskakov, D.; Herrmann,
W. A.; Herdtweck, E.; Hoffmann, S. D. Organometallics 2007, 26, 626.
(9) Metallinos, C.; Dudding, T; Zaifman, J.; Chaytor, J. L.; Taylor, N. J.
J. Org. Chem. 2007, 72, 957.
Accordingly, deprotonation of 17 (1.1 equiv s-BuLi,
TMEDA, Et2O, -78 °C) followed by addition of benzophe-
none gave 20a as a single diastereomer in 60% yield (Scheme
3). Several other substituents were introduced into the
5-position with equal facility, including methyl (55%), allyl
(50%), trimethylsilyl (63%) and trimethylstannyl (55%). All
of the preceding products were obtained as single diastere-
(10) (a) Kerrick, S. T.; Beak, P. J. Am. Chem. Soc. 1991, 113, 9708.
(b) Beak, P.; Kerrick, S. T.; Wu, S.; Chu, J. J. Am. Chem. Soc. 1994, 116,
3231. (c) Hoppe, D.; Hense, T. Angew. Chem., Int. Ed. 1997, 36, 2282.
(11) (a) Stead, D.; O’Brien, P.; Sanderson, A. Org. Lett. 2008, 10, 1409.
(b) Mealey, M. J.; Luderer, M. R.; Bailey, W. F.; Sommer, M. B. J. Org.
Chem. 2004, 69, 6042. (c) O’Brien, P. Chem. Commun. 2008, 655.
(12) (a) Campos, K. R.; Klapars, A.; Waldman, J. H.; Dormer, P. G.;
Chen, C.-Y. J. Am. Chem. Soc. 2006, 128, 3538. (b) O’Brien, P.; Bilke,
J. L. Angew. Chem., Int. Ed. 2008, 47, 2734.
(14) (a) Corma, A.; Iglesias, M.; del Pino, C.; Sa´nchez, F. J. Organomet.
Chem. 1992, 431, 233. (b) Corey, E. J.; Saizo, S.; Bakshi, R. K. J. Org.
Chem. 1988, 53, 2861.
(15) Compound 17 was minimized at the B3LYP/6-31G(d) level as
implemented in Gaussian 03.
(13) Bertini Gross, K. M.; Beak, P. J. Am. Chem. Soc. 2001, 123, 315.
Org. Lett., Vol. 12, No. 1, 2010
77

omers, which entails a diastereomeric ratio (dr) of >95:5 for
the R-lithio intermediate before electrophile quench. The syn
relative stereochemistry of products 20a, 20b, 20c, and 20e
were verified by NOESY or 1-D NOE spectroscopy, which
is consistent with the stereochemistry of products 15. That
the R-carbanion of 17 had configurational stability at -78
°C was demonstrated by transmetalation of stannane 20e (n-
BuLi, Et2O, 4.5 h), which upon Me2SO4 quench gave syn-
20b exclusively.
stannyl derivatives 21b-d in higher enantiomeric purity
(94:6 to 99:1 er; 88-98% ee) and yields ranging from
63-76%. Phenylation according to the procedure described
for N-Boc pyrrolidine12 afforded 21e in lower yield (30%)
but similar enantiomeric purity (93.5:6.5 er; 87% ee).
The absolute stereochemistry of 21b was determined by
reduction of the enamine (NaBH3CN, MeOH/AcOH, reflux),
which gave a mixture of anti- and syn-20b. Syn-20b had
20
the same specific rotation ([R]D -4) as 20b derived from
20
17 ([R]D -4.4). The relative stereochemistry of anti-20b
was verified by 1-D NOE experiments.16 In addition,
transmetalation of stannane 21d (n-BuLi, THF, -100 °C)
and quench with Me2SO4 gave 21b with the same optical
rotation as 21b made directly from 19. Based on these results
and the expectation that the enantioselectivity during (-)-
sparteine-mediated lithiation of 19 arises from an asymmetric
deprotonation step,10 the same relative stereochemistry may
be tentatively assigned to all products 21a-e.
Scheme 3. Diastereoselective Lithiation of 17
Scheme 5. (-)-Sparteine-Mediated Lithiation of 19
a via CuCN · 2LiCl transmetalation.
For enantioselective lithiation of 19, several alkyllithium-
ligand-solvent combinations were evaluated by examining
the product of benzophenone quench of the putative R-car-
banion (21a, Scheme 4). The best result was obtained using
i-PrLi/(-)-sparteine in MTBE solvent, which provided 21a
in 67% yield and 90.5:9.5 enantiomeric ratio (81% ee). The
combination of i-PrLi and (+)-sparteine surrogate 13 in Et2O
afforded the antipode of 21a in 60% yield and 14.5:85.5 er
(71% ee).
a via CuCN · 2LiCl transmetalation. b After transmetalation (n-BuLi,
THF, -100 °C, 1 h) and Me2SO4 quench. c via ZnCl2 transmetalation and
Pd(OAc)2/HBF4 · P(t-Bu)3 coupling.
Preliminary experiments indicate that ureas 20b, 19, and
21b may be converted to imidazol(in)ium salts with phos-
phorus oxychloride (Scheme 6).17 For example, a heated
solution of 20b in POCl3 produced chiral imidazolinium 22,
isolated as the tetraphenylborate salt. Likewise, sequential
treatment of 19 or 21b with POCl3 and NaBPh4 gave the
3-chloroimidazolium salts 23a,b, which were immediate
precursors to Pd(II) complexes 24a,b by chlorine-lithium
exchange with t-BuLi at low temperature.18
Scheme 4
.
Optimization Experiments for Enantioselective
Lithiation of 19
In conclusion, it has been shown that 5-substituted
pyrroloimidazol(in)ium precatalysts can be prepared in two
(16) The pyrrolidine methyl group in syn-20b has a 13C NMR chemical
shift of 18.2 ppm compared to 22.5 ppm in anti-20b. The difference in
resonance frequency can be attributed to a γ-effect and may be used to
assign syn and anti streochemistry in these ureas and related chiral bicyclic
ketones with a high degree of confidence. See: (a) Hudlicky, T.; Koszyk,
F. J.; Kutchan, T. M.; Sheth, J. P J. Org. Chem. 1980, 45, 5020. (b)
Hudlicky, T.; Koszyk, F. J.; Dochwat, D. M.; Cantrell, G. L. J. Org. Chem.
1981, 46, 2911.
(17) Review: Crouch, D. R. Tetrahedron 2009, 65, 2387.
(18) Snead, D. R.; Ghiviriga, I.; Abboud, K. A.; Hong, S. Org. Lett.
2009, 11, 3274.
Applied to other electrophiles (Scheme 5), the optimum
i-PrLi/(-)-sparteine/MTBE conditions gave Me, allyl, and
78
Org. Lett., Vol. 12, No. 1, 2010

pounds of general structure 6, which are relatively uncommon
and challenging to make by conventional routes.7 Additional
work is underway to explore the utility of these materials as
precursors to chiral “frustrated” Lewis pairs,19 nucleophiles
and ligands in asymmetric catalysis. Procedures to remove
and/or replace the N-t-Bu group20 with other substituents are
also being studied. The outcomes of these investigations will
be reported as results permit.
Scheme 6
.
Conversion of Pyrroloimidazol(in)ones to NHC
Precursors 22, 23a, and 23b
Acknowledgment. We thank NSERC Canada for support
of our research program. Prof. Travis Dudding and Keivan
Taban (Brock University) are thanked for computational
modeling of 17. Josh Zaifman (Brock University) is thanked
for assisting in the preparation of 21e. We are grateful to
Tim Jones and Razvan Simionescu (Brock University) for
assistance with spectroscopic data collection.
Supporting Information Available: Experimental pro-
1
cedures, H and 13C NMR spectra, NOESY/NOE spectra,
plus the minimized structure of 17. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL902277Y
steps by stereoselective lithiation-electrophile quench of
pyrrolo[1,2-c]imidazol(in)-3-ones 17 or 19, followed by
POCl3-induced salt formation. These results establish a new
method to access enantiomerically enriched R-chiral com-
(19) (a) Chase, P. A.; Stephan, D. W. Angew. Chem., Int. Ed. 2008, 47,
7433. (b) Holschumacher, D.; Bannenberg, T.; Hrib, C. G.; Jones, P. G.;
Tamm, M. Angew. Chem., Int. Ed. 2008, 47, 7428.
(20) Wen, Y.; Zhao, B.; Shi, Y. Org. Lett. 2009, 11, 2365.
Org. Lett., Vol. 12, No. 1, 2010
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