Synthesis and evaluation of 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a] pyridines as potassium-competitive acid blockers

Article abstract of DOI:10.1021/jm7010063

7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological properties were identified that represent interesting candidates for further development as potassium-competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral ketones. The influence of the character of the substituents R³, R⁶, and Ar on the biological activity and the physicochemical properties of the target compounds was examined. In contrast to the parent system (R⁶ = H), compounds in which R⁶ represents a carboxamide residue generally show improved in vivo activity and favorable pK_a/log D values. Whereas variation of R³ is useful to obtain target compounds with modified basicity and lipophilicity, strong inhibition of the H⁺/K⁺-ATPase and potent in vivo activity is observed for R³ = methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion inhibiting action, whereas the (9R)-enantiomers are virtually inactive.

Full text of DOI:10.1021/jm7010063

6240
J. Med. Chem. 2007, 50, 6240-6264
Synthesis and Evaluation of 7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines as
Potassium-Competitive Acid Blockers†
Andreas M. Palmer,* Burkhard Grobbel, Cornelia Jecke, Christof Brehm, Peter J. Zimmermann,
Wilm Buhr, Martin P. Feth, Wolfgang-Alexander Simon, and Wolfgang Kromer
NYCOMED GmbH, Departments of Medicinal Chemistry, Analytical Chemistry, Biochemistry, and Pharmacology,
Byk-Gulden-Str. 2, D-78467 Konstanz, Germany
ReceiVed August 13, 2007
7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines with excellent physicochemical and pharmacological
properties were identified that represent interesting candidates for further development as potassium-
competitive acid blockers (P-CABs). The title compounds were prepared following synthetic pathways that
relied either on a Claisen rearrangement/cross-metathesis reaction or on the (asymmetric) reduction of prochiral
ketones. The influence of the character of the substituents R3, R6, and Ar on the biological activity and the
physicochemical properties of the target compounds was examined. In contrast to the parent system (R6 )
H), compounds in which R6 represents a carboxamide residue generally show improved in vivo activity and
favorable pKa/log D values. Whereas variation of R3 is useful to obtain target compounds with modified
basicity and lipophilicity, strong inhibition of the H+/K+-ATPase and potent in vivo activity is observed for
R3 ) methyl only. Small modifications of the aryl group, e.g., replacement of hydrogen versus a fluoro
atom or a methyl group, are allowed. The (9S)-enantiomers are responsible for the gastric acid secretion
inhibiting action, whereas the (9R)-enantiomers are virtually inactive.
1. Introduction
Gastroesophageal reflux disease (GERDa), the backward flow
of the stomach’s contents into the esophagus, is a digestive
condition that affects 20% of the American population and often
becomes manifest in heartburn, which is characterized by
burning pain that radiates through the chest, neck, and throat.1,2
Peptic ulcer disease, estimated to affect 14.5 million people in
the United States, is a chronic inflammation of the stomach and
duodenum and is responsible for a large economic burden. The
formation of a peptic ulcer is favored by two factors, the
hypersecretion of acid and a weakened resistance of the
protective mucous coating of the stomach and duodenum.3,4 The
inhibition of acid secretion and the neutralization of formed acid
constitute effective approaches for the treatment of both
diseases.1,3 A whole series of compounds that inhibit gastric
acid secretion by blockade of the gastric proton pump enzyme
(H+/K+-ATPase) are known. The compounds designated as
proton pump inhibitors (PPIs), for example, omeprazole, es-
Figure 1. Imidazo[1,2-a]pyridines as potassium-competitive acid
blockers for the treatment of GERD.
omeprazole, lansoprazole, pantoprazole, rabeprazole, and ten-
atoprazole, bind irreversibly to H+/K+-ATPase and have been
available as therapeutics for a long time already. A new class
as potassium-competitive acid blockers (P-CABs) bind revers-
of compounds designated as acid pump antagonists (APAs) or
ibly to H+/K+-ATPase. Although PPIs are considered as the
gold standard for the treatment of acid-related diseases, P-CABs
* To whom correspondence should be addressed. Telephone: +49 7531
might offer some therapeutic advantages, such as better
84 4783. Fax: +49 7531 849 2087. E-mail: andreas.palmer@nycomed.com.
† Design of novel P-CABs, V. Part 1: Zimmerman, P. J.; Buhr, W.;
Brehm, C.; Palmer, A. M.; Feth, M. P.; Senn-Bilfinger, J.; Simon, W. A.
Novel indanyl-substituted imidazo[1,2-a]pyridines as potent reversible
inhibitors of the gastric H+/K+-ATPase. Bioorg. Med. Chem. Lett. 2007,
17, 5374-5378. Part 2: Palmer, A. M.; Grobbel, B.; Brehm, C.; Zimmer-
mann, P. J.; Buhr, W.; Feth, M. P.; Holst, H. C.; Simon, W. A. Preparation
of tetrahydroimidazo[2,1-a]isoquinolines and their use as inhibitors of gastric
acid secretion. Bioorg. Med. Chem. 2007, 15, 7647-7660. Part 3:
Zimmermann, P. J.; Brehm, C.; Buhr, W.; Palmer, A. M.; Volz, J.; Simon,
W. A. Novel imidazo[1,2-a]pyrazine derivatives as potent reversible
inhibitors of the gastric H+/K+-ATPase. Bioorg. Med. Chem. 2007, doi.1016/
j.bmc.2007.09.009. Part 4: Palmer, A. M.; Mu¨nch, G.; Brehm, C.;
Zimmermann, P. J.; Buhr, W.; Feth, M. P.; Simon, W. A. 5-Substituted
1H-pyrrolo[3,2-b]pyridines as inhibitors of gastric acid secretion. Bioorg.
Med. Chem. 2007, doi 10.1016/j.bmc.2007.10.017.
symptom control and faster healing.5-8
In the past 2 decades, one important approach for the
identification of potent P-CABs relied on the structural class
of substituted imidazo[1,2-a]pyridines. The inhibitor SCH 28080
(1) represents the clinical prototype of this series (Figure 1).
SCH 28080 (1) inhibits the gastric proton pump enzyme (H+/
K+-ATPase) by a kinetically competitive and reversible inhibi-
tion mechanism with respect to the potassium ion and shows
excellent antisecretory and cytoprotective properties.9-11 How-
ever, the clinical development of SCH 28080 (1) was stopped
due to extensive metabolism and associated liver toxicity.10
One approach to synthesize advanced chemical analogues of
SCH 28080 was based on results from molecular modeling,
which suggested that in the gas phase, SCH 28080 could adopt
various “folded” conformations (i.e., the phenyl ring is directed
toward and over the imidazo[1,2-a]pyridine ring system) close
to the global minimum of energy.11 On the other hand, single-
crystal X-ray analysis revealed that solid SCH 28080 existed
a Abbreviations: GERD, gastroesophageal reflux disease; PPI, proton
pump inhibitor; APA, acid pump antagonist; P-CAB, potassium competitive
acid blocker; Piv, pivaloyl; TxDMS, thexyldimethylsilyl; TBTU, O-(1H-
benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate; CDI,
carbonyldiimidazole; BINAP, 2,2′-bis(diphenylphosphanyl)-1,1′-binaphthyl;
DPEN, 1,2-diphenylethylenediamine; DAIPEN, 1,1-di-4-anisyl-2-isopropyl-
1,2-ethylenediamine; MTPACl, R-methoxy-R-trifluoromethylphenylacetyl
chloride; CE, capillary electrophoresis; tM, migration time; tR, retention time.
10.1021/jm7010063 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/02/2007

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6241
Scheme 1
in an “extended” conformation (i.e., the phenyl ring is oriented
out and away from the heterocyclic nucleus).9 By synthesis of
simple analogues that imitated these conformations, it was
shown that an “extended” relationship between the phenyl group
and the heterocyclic nucleus was required for effective binding
to H+/K+-ATPase.11 Subsequently, the tricyclic imidazo[1,2-
a]pyridine 2 was synthesized in which the pyrano ring was
considered to enforce this requisite extended relationship and
to mimic a 7-methyl substituent, which would be effective in
overcoming the toxic properties of 1 while its desirable
antisecretory effects were retained (Figure 1).11,12
In the course of our efforts to identify a new generation of
P-CABs, which would be distinguished from former P-CABs
by a high degree of efficacy and safety, we considered the 7H-
8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridine 2 as an interest-
ing lead compound for the synthesis of tricyclic imidazo[1,2-
a]pyridines of the general formula 3 (Figure 1).13-15 Since the
3-cyanomethyl moiety was identified as the metabolic “hot spot”
of SCH 28080 (1), our first goal was to identify potent inhibitors
that are devoid of the 3-cyanomethyl moiety and, as a result,
would not be prone to undergo metabolic degradation by
oxidative decyanation.
One possible problem associated with the replacement of the
cyanomethyl moiety versus another residue at R3 is the alteration
of the pKa value of the heterocyclic system. The imidazo[1,2-
a]pyridine 2 possesses a favorable pKa value of 6.0, which
represents an optimum balance between (a) the request for a
basic compound, since the protonated species is the active form
at the site of action in the parietal cell, and (b) the concept of
developing weakly basic P-CABs that would accumulate in
acidic compartments.8,16 Selective accumulation of the inhibitor
in acidic departments would diminish the interaction with other
enzymes and might translate in to an improved safety profile.
Apart from the option to modify the pKa value by the
character of the substituent R3, we considered the possibility
of adjusting the pKa value by the character of the substituent
R6, e.g., to reduce the pKa value by the presence of an electron-
withdrawing carboxamide substituent.
conversion of substituents R3, R6, and Ar to evaluate the
pharmacological and physicochemical properties of a variety
of compounds 3 and to establish a structure-activity relationship
and (b) the possibility to prepare interesting target compounds
in an enantioselective manner.
2. Chemistry
2.1. Retrosynthesis of 7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridines. In the search for synthetic routes that
allow a flexible and/or enantioselective preparation of 7H-8,9-
dihydropyrano[2,3-c]imidazo[1,2-a]pyridines 3, we examined
the two pathways depicted in Scheme 1. Both approaches use
building blocks of the general formula 4 as starting material.
Pathway a relies on the synthesis of prochiral ketones 7 by
conversion of Mannich bases 5 with pyrrolidine enamines 6,
which can be converted into target compounds 3 by reduction
and subsequent dehydration of the resulting diols 8.12-15,17 In
pathway b, olefins of the general formula 11 are prepared by
the cross-metathesis reaction of imidazopyridine building blocks
9 with styrene derivatives 10.14,15,18 Tricyclic imidazopyridines
3 are obtained from alkenes 11 either in a direct manner by
acid-catalyzed cyclization or by a two-step sequence comprising
hydroboration and dehydration of the resulting diols 8.14,15
Enantioselective synthesis of tricyclic imidazopyridines should
be feasible by applying either pathway, since the key step of
each pathway (ketone reduction/hydroboration) can be per-
formed in an asymmetric manner.19-25
2.2. Preparation of Building Blocks for Pathways a and
b. In order to prepare the building blocks required for both
synthetic approaches, 2-amino-3-benzyloxypyridine (12) was
brominated under acidic conditions (Scheme 2). The resulting
2-amino-3-benzyloxy-5-bromopyridine (13) was transformed
either with 2-bromo-3-butanone or with chloroacetone, furnish-
ing the corresponding imidazo[1,2-a]pyridines 14 and 15. Using
THF as a solvent, the hydrohalide salts of 14 and 15 crystallized
from the reaction mixture and, although long reaction times had
to be taken into account, both derivatives were isolated in good
yield. The carboxamide substituent was introduced by a pal-
ladium-catalyzed amidocarbonylation reaction by applying
Consequently, we searched for synthetic routes toward
tricyclic imidazopyridines of the general formula 3 that would
fulfill the following criteria: (a) the rapid introduction/inter-

6242 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
Scheme 2a
a Reagents and conditions: (i) Br2, HOAc, H2SO4, 0 °C, 2.5 h, 83%. (ii) Bromobutanone, THF, reflux, 6 d, 76%. (iii) Chloroacetone, THF, 60 °C, 11.5
d, 59%. (iv) Pd(OAc)2, PPh3, Et3N, Me2NH (2 N in THF), CO, 120 °C, 18.5 h (16, 76%; 17, 77%). (v) Hydrogenation: Pd/C, H2, MeOH, rt, 2.5-18 h (18,
96%; 19, 98%). Transfer hydrogenation: Pd/C, 1,4-cyclohexadiene, EtOH, reflux, 7 h (18, 77%). (vi) Pd(OAc)2, PPh3, Et3N, EtOH, CO, 120 °C, 17 h, 87%.
(vii) Pd/C, 1,4-cyclohexadiene, EtOH, reflux, 18 h, 80%. (viii) Bromobutanone, THF, reflux, 44 h, 67%. (ix) Pd/C, 1,4-cyclohexadiene, EtOH, reflux, 4 h,
83%.
Scheme 3a
a Reagents and conditions: (i) allyl bromide, K2CO3, DMF, rt, 18.5 h (24, 67%; 25, 70%). (ii) Melting, 160 °C, 0.75 h (26, 76%; 27, 66%).
conditions that had been described in the literature.26 The
carboxamides 16 and 17 were isolated in 76 and 77% yield.
Under similar reaction conditions (when dimethylamine was
substituted versus ethanol), 6-bromoimidazo[1,2-a]pyridine 14
could be transformed into the corresponding ethyl ester 20.26
Finally, the benzyl protective group of intermediates 16, 17,
and 20 was cleaved by catalytic hydrogenation or catalytic
transfer hydrogenation, affording the building blocks 18, 19,
and 21. In the case of the imidazopyridine 18, all reactions were
performed in a multikilogram scale. In the same manner, the
6-unsubstituted imidazopyridine 23 was prepared in two steps
from 2-amino-3-benzyloxypyridine (12): First, the imidazopy-
ridine scaffold was formed by condensation of 12 with 2-bromo-
3-butanone. Second, the benzyloxy protective group was cleaved
by catalytic hydrogenation of 22, affording building block 23.
2.3. Synthesis of tricyclic imidazopyridines by cross
metathesis. We then investigated the cross-metathesis reaction
of 7-allyl-substituted imidazo[1,2-a]pyridines with different
styrene derivatives.18 No conversion was observed, when a
solution of the phenolic imidazopyridine 26 and styrene in
dichloromethane was heated to 40 °C in the presence of second-
generation Grubbs catalyst. Since this was probably due to the
chelating interaction of the ruthenium catalyst with the 8-hy-
droxyimidazo[1,2-a]pyridine moiety, we examined the use of
different protective groups.
First, a pivaloyl protective group was introduced into the
imidazo[1,2-a]pyridine 27 by applying standard conditions. To
our delight, the cross-metathesis reaction of the pivaloic ester
28 with trans-stilbene was now feasible, and the corresponding
olefin 29 was isolated in 53% yield. When the intermediate 29
was subjected to acidic conditions, both cleavage of the
protective group and cyclization occurred, and the pyranoimi-
dazopyridine 30 was isolated in 91% yield. The cross-metathesis/
cyclization reaction could also be conducted in one pot, which
afforded the target compound 30 in 64% yield (Scheme 4).
Subsequently, building blocks 18 and 19 were transformed
into olefins 26 and 27 suitable for cross-metathesis by applying
a two-step sequence comprising an O-allylation reaction and a
Claisen rearrangement (Scheme 3). The latter reaction proceeded
smoothly under solvent-free conditions, when the O-allyl ethers
24 and 25 were heated to a temperature of 160 °C.
Second, we examined the use of the thexyldimethylsilyl

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6243
Scheme 6a
Scheme 4a
a Reagents and conditions: (i) pivaloyl chloride, K2CO3, acetone, rt, 3
h, 72%. (ii) trans-Stilbene, second-generation Grubbs catalyst, CH2Cl2,
40 °C, 18 h, 53%. (iii) 85% H3PO4, 80 °C, 0.75 h, 91%. (iv) trans-stilbene,
second-generation Grubbs catalyst, CH2Cl2, 40 °C, 18 h, then 85% H3PO4,
80 °C, 1 h, 64%.
a Reagents and conditions: (i) NaOH, MeOH, H2O, rt, 1 h, 50 °C, 1 h,
55%. (ii) TBAF, THF, rt, 0.5 h, 81%. (iii) (1) (R)-Alpine-boramine, BF3-
OEt2, THF, rt, 2-2.5 h; (2) addition of 39 or 40, THF, rt, 2-5 h; (3) H2O2,
KOH, EtOH, H2O, 0.25-0.5 h (41a, 50%, 27.8% ee; 42a, 18%, 32.2% ee).
Scheme 5a
ride etherate and was added to a solution of the corresponding
olefin 39 or 40 in THF.25 After a reaction time of 2.5-5 h, the
corresponding alcohol 41a or 42a was obtained by oxidative
workup. The hydroboration reaction proceeded with good
regioselectivity; however, the enantiomeric purity of the alcohols
41a and 42a was low (30% ee). The 3-methyl-substituted
imidazo[1,2-a]pyridine 41a was isolated in 50% yield, whereas
its 3-unsubstituted analogue 42a was obtained in 18% yield only.
2.5. Conversion of the Key Intermediate 30 into 3-Sub-
stituted Tetrahydropyrano[2,3-c]imidazo[1,2-a]pyridines. A
variety of 3-substituted imidazopyridines was prepared by
electrophilic substitution of the 3-H derivative 30 (Scheme 7):
Vilsmeier formylation of 30 afforded the aldehyde 43, which
was transformed further by following one of the three following
pathways: (a) Reduction with sodium borohydride furnished
the alcohol 44. (b) The carboxamides 46 and 47 were secured
by oxidation of the aldehyde 43 to the carboxylic acid 45 and
TBTU-mediated coupling with dimethylamine/2-methoxyethy-
lamine, respectively.27 (c) Grignard addition of propinylmag-
nesium bromide and subsequent oxidation of the propargyl
alcohol 48 afforded the unsaturated ketone 49.
The 3-bromoimidazopyridine 50 was prepared by transforma-
tion of 30 with N-bromosuccinimide. The 3-vinyl substituent
was introduced by Stille coupling of 50 with tributylvinylstan-
nane. Catalytic hydrogenation of the resulting olefin 51 afforded
the 3-ethyl-substituted imidazopyridine 52. The use of Lindlar
catalyst was crucial for the outcome of the hydrogenation
reaction, since more active hydrogenation catalysts (e.g., pal-
ladium on charcoal) not only reduced the carbon-carbon double
bond but also cleaved the pyrano ring.28
a Reagents and conditions: (i) chloro(dimethyl)thexylsilane, imidazole,
DMF, rt, 1 h, 93%. (ii) trans-Stilbene, second-generation Grubbs catalyst,
CH2Cl2, 40 °C, 19 h, 58%. (iii) 2-Methylstyrene, 2-fluorostyrene, or
4-fluorostyrene, second-generation Grubbs catalyst, 40 °C, 4 h-5 d, then
85% H3PO4, 80-100 °C, 1.5-2 h (36, 29%; 37, 56%; 38, 21%).
protective group for the cross metathesis reaction of the 2,3-
dimethylimidazo[1,2-a]pyridine 26 with different styrenes
(Scheme 5). The silyl ether 31 was prepared by imidazole-
catalyzed condensation of the phenolic imidazopyridine 26 with
chlorodimethylthexylsilane. Transformation of 31 with 2-
methylstyrene, 2-fluorostyrene, and 4-fluorostyrene afforded the
corresponding tricyclic imidazopyridines 36-38 in moderate
yields without isolation of the intermediate products 32, 33, and
34 of the cross-metathesis reaction. In the case of trans-stilbene,
the product 35 of the cross-metathesis reaction was isolated in
58% yield.
2.4. Asymmetric Hydroboration of Olefins Obtained by
Cross-Metathesis. The asymmetric hydroboration of olefins 39
and 40, which were prepared from their O-protected precursors
29 and 35 by base/TBAF-mediated cleavage of the protective
group with isopinocampheylborane, was studied next (Scheme
6).25 The hydroborating agent was obtained by treatment of
commercially available (R)-Alpine-boramine with borontrifluo-
Substitution of 30 was also accomplished with other elec-
trophiles, e.g., acetic anhydride or Eschenmoser’s salt, affording
the 3-acetyl derivative 53 and the Mannich base 54.
2.6. Synthesis of Prochiral Ketones and Their Use for the
Preparation of Racemic 7H-8,9-Dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridines. Treatment of the building blocks 18, 21,
and 23, which served as starting materials for the synthesis of
prochiral ketones, with Eschenmoser’s salt furnished the cor-
responding Mannich bases 55, 56, and 57. When these
intermediates were heated in the presence of 1-(1-arylvinyl)-
pyrrolidines, the ketones 61-67 were formed. These reactions
are believed to proceed via the R,â-unsaturated ketones 58-
60, which subsequently react with the corresponding 1-(1-

6244 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
Scheme 7a
a Reagents and conditions: (i) (1) POCl3, DMF, rt, 1 h; (2) 30, DMF, 60 °C, 3 h, 92%. (ii) NaBH4, rt, 0.75 h, 58%. (iii) Sulfamic acid, sodium chlorite,
THF, H2O, 0 °C, 1.25 h, 65%. (iv) (1) TBTU, CH2Cl2, rt, 1 h; (2) amine, rt, 1-1.5 h [46, HNMe2 (2 M in THF), 97%; 47, methoxyethylamine, 70%]. (v)
Propinylmagnesium bromide, THF, -78 °C, 1 h, 0 °C, 2 h, 96%. (vi) MnO2, CH2Cl2, rt, 1 h, 86%. (vii) NBS, CHCl3, CH2Cl2, -78 °C, 0.75 h, 90%. (viii)
Tributyl(vinyl)stannane, (PPh3)2PdCl2, 1,4-dioxane, 100 °C, 3 h, 72%. (ix) Lindlar catalyst (Pd/CaCO3/Pb), H2, MeOH, rt, 4 h, 89%. (x) Ac2O, MsOH,
140 °C, 1.5 d, 46%. (xi) Eschenmoser’s salt, CH2Cl2, rt, 0.5 h, 97%.
Table 1. Conversion of Ketones into Tricyclic Imidazopyridines
82 and 83 were obtained by acid-catalyzed cleavage of their
acetal precursors 80 and 81.
%
target
%
ketone
R6
CONMe2 phenyl
Ar
diol yield compd methoda yield
A variety of other 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-
a]pyridines (85-98) was prepared by TBTU- or CDI-mediated
coupling of different amines with the carboxylic acid 84, which
in turn was obtained by aqueous hydrolysis of its ester precursor
76 (Scheme 11 and Table 2).27
The 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridine 101,
which bears a 4,5-dihydro-1,3-oxazole residue as bioisosteric
replacement of the carboxamide group, was also prepared using
the carboxylic acid 84 as starting material (Scheme 12).30 In a
first step, the N-(2-hydroxyethyl) residue was introduced by
treatment of 84 with thionyl chloride and 2-aminoethanol. In a
second step, the hydroxyl group present in carboxamide 99 was
converted into a leaving group and cyclization to the title
compound 101 was accomplished, albeit in low yield, by heating
of the resulting intermediate 100 in DMF.
2.7. Synthesis of Enantiopure Tricyclic Imidazopyridines
by Asymmetric Reduction of Prochiral Ketones. A variety
of methods are available to reduce ketones in an asymmetric
manner, e.g., enzymatic reduction,19 asymmetric hydrosilyla-
tion,20 or hydroboration using either a chiral boron reagent21 or
an achiral boron reagent in combination with a chiral catalyst.22
The ruthenium-catalyzed hydrogenation23 or transfer hydrogena-
tion24 constitutes one of the most prominent methods for the
synthesis of chiral alcohols. We focused our attention on the
hydrogenation of ketones 61, 82, and 83 using Noyori catalysts
of the type RuCl2[diphosphine][diamine].23 In the case of the
ketone 61, only modest enantioselectivity was achieved using
61
41 76
74
A
B
B
B
B
C
A
A
24
92
62
63
64
65
66
67
CONMe2 2-methylphenyl 68 crude
CONMe2 2-fluorophenyl 69 crude
CONMe2 4-fluorophenyl 70 crude
36
37
38
75
76
77
∑46
∑94
∑85
∑35
69
CONMe2 2-thienyl
71 crude
72 75
73 24
CO2Et
H
phenyl
phenyl
87
a See Scheme 9 for a description of methods A-C
arylvinyl)pyrrolidine, either by hetero-Diels-Alder reaction or
by Michael addition (Scheme 8).17
The ketones 61-67 were transformed into the corresponding
alcohols 41 and 68-73 by reduction with sodium borohydride.
Finally, 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines
36-38, 74, 76, and 77 were secured by Bro¨nsted (phosphoric
acid) or Lewis acid (borontrifluoride etherate) catalyzed cy-
clization of the intermediate diols 41, 68-70, 72, and 73. The
diol 71, bearing a sensitive thiophene residue, was converted
into the corresponding target compound 75 by intramolecular
Mitsunobu reaction (Scheme 9 and Table 1).29
The ester 66 constitutes a useful starting material for the
synthesis of other prochiral ketones (Scheme 10). The carbonyl
function was protected by conversion of ketone 66 into the cyclic
acetal 78. Saponification of the ester function afforded car-
boxylic acid 79, which in turn was subjected to TBTU-mediated
amide coupling.27 Finally, the 6-carboxamide substituted ketones

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6245
Scheme 10a
Scheme 8a
a Reagents and conditions: (i) 2,2-dimethoxypropane, CH2Cl2, MsOH,
reflux, 6 h, 88%. (ii) KOH, MeOH, H2O, 55 °C, 2 h, 97%. (iii) (1) TBTU,
CH2Cl2, reflux, 2 h; (2) amine, rt, 1 h [80, pyrrolidine; 81, H2NMe (8 M
solution in EtOH)]. (iv) 1 N HCl, THF, 50 °C, 5-7 h (82, ∑46%; 83,
∑73%).
Scheme 11a
a Reagents and conditions: (i) Eschenmoser’s salt, CH2Cl2, rt, 10 min-
2.5 h. (ii) 1-(1-Arylvinyl)pyrrolidine, K2CO3, DMF, 50 °C, 0.5-4 h
[61, 1-(1-phenylvinyl)pyrrolidine, 49%; 62, 1-[1-(2-methylphenyl)vinyl]pyr-
rolidine, 54%; 63, 1-[1-(2-fluorophenyl)vinyl]pyrrolidine, 51%; 64, 1-[1-
(4-fluorophenyl)vinyl]pyrrolidine, 46%; 65, 1-(1-thiophen-2-ylvinyl)pyr-
rolidine, 45%; 66, 1-(1-phenylvinyl)pyrrolidine, 55%]. (iii) 1-(1-
Phenylvinyl)pyrrolidine, toluene, 90-100 °C, 0.25-1 h (61, 79%; 66, 84%;
67, 48%).
a Reagents and conditions (see Table 2): (i) KOH, MeOH, H2O, 50 °C,
2 h, 71%. (ii) Method A, (1), TBTU, CH2Cl2, rt or reflux, 0.75-2 h; (2)
amine, rt or 50 °C, CH2Cl2 or DMF, 0.5-2.5 h; method B, (1) CDI, THF,
40 °C, 2 h; (2) DBU, amine, rt, 1 h-2.5 d.
Scheme 9a
Scheme 12a
a Reagents and conditions (see Table 1): (i) NaBH4, MeOH or EtOH,
rt, 0.5-2.75 h. (ii) Method A, BF3-OEt2, rt, CH2Cl2, 3-5 h; method B,
85% H3PO4, 80 °C, 0.25-1 h; method C, PPh3, DIAD, THF, rt, 0.25 h.
RuCl2[(S)-BINAP][(S,S)-DPEN] as hydrogenation catalyst (37%
ee). The optical purity of the alcohol 41a increased significantly,
when (S)-DAIPEN was used as diamine ligand. The synthesis
of the optical antipode 41b was also feasible, when RuCl2[(R)-
BINAP][(R)-DAIPEN] was employed as hydrogenation catalyst.
To our delight, this methodology could be extended to other
substrates, and the asymmetric hydrogenation of the ketones
82 and 83 afforded the alcohols 102a and 103a in high yields
and good optical purity (Scheme 13). Having the alcohols 41a,
41b, 102a, and 103a in hand, we examined their transformation
into enantiopure 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]-
pyridines by Mitsunobu cyclization. Since the Mitsunobu
reaction proceeds under complete conversion of configuration
at the stereogenic center, complete transfer of the stereochemical
information, which had been introduced by asymmetric hydro-
genation, into the target compound should occur.31 Indeed, when
the alcohols 41a, 41b, 102a, and 103a were treated with
triphenylphosphine and diisopropyl azodicarboxylate, the tri-
cyclic imidazo[1,2-a]pyridines 74a, 74b, 90a, and 86a were
isolated without loss of optical purity (Scheme 13).
a Reagents and conditions: (i) (1) SOCl2, CH2Cl2, DBU, rt, 24 h; (2)
2-aminoethanol, CH2Cl2, rt, 2.5 h, 44%. (ii) SOCl2, rt, 1 h, 70%. (iii) DMF,
150-170 °C, 0.75 h, 14%.
In order to assess the configuration of the stereogenic center,
we used the method described by Mosher et al.32 To this end,
the mixture of the alcohols 41a and 41b obtained by catalytic
hydrogenation of 61 in the presence of RuCl2[(S)-BINAP][(S,S)-
DPEN] was converted into the corresponding silyl ether 104.

6246 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Table 2. Preparation of Target Compounds by Amide Coupling
Palmer et al.
Scheme 14a
a Reagents and conditions: (i) Et3N, TBDMSCl, CH2Cl2, reflux, 5.25
h, 73%. (ii) (S)-(+)-MTPACl, pyridine, CCl4, CH2Cl2, rt, 6 h, 30%; (iii)
CDCl3, rt, 10 d, 72%.
a See Scheme 11 for a description of methods A and B.
Scheme 13a
Figure 2. Assignment of the configuration of the stereogenic center
of the diols 106a and 106b using the method of Mosher et al.
a Reagents and conditions: (i) method A, RuCl2[(S)-BINAP][(S,S)-
DPEN], KOtBu, 2-PrOH, H2, 80 °C, 18 h (41a, 82%, 37% ee); method B,
RuCl2[(S)-BINAP][(S)-DAIPEN], KOtBu, 2-PrOH, H2, rt, 1 d (41a, 92%,
86% ee; 102a, 78%, 87% ee; 103a, 80%, 92% ee). (ii) PPh3, DIAD, THF,
rt, 1-1.5 h (74a, 58%, 85% ee; 90a, 50%, 87% ee; 86a, 14%; 94% ee).
(iii) RuCl2[(R)-BINAP][(R)-DAIPEN], KOtBu, 2-PrOH, H2, rt, 1 d, 87%,
96% ee. (iv) PPh3, DIAD, CH2Cl2, rt, 3 min, 42%, 96% ee.
of the aromatic electron cloud results in an upfield shift of the
1H NMR signal of the methoxy group as compared to the (3S)-
1
diastereomer 106b. In the H NMR spectrum of the diastere-
omeric mixture (106), the signals of the methoxy groups were
observed at 3.43 ppm (major)/3.52 ppm (minor), respectively.
Thus, catalytic hydrogenation under the conditions reported
above mainly furnishes the (3R)-diol 41a. Since the Mitsunobu
etherification proceeds under inversion of configuration of the
stereogenic center, the (9S)-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine 74a is isolated as the major product.31 This
should also apply for the asymmetric reduction of prochiral
ketones of the general formula 7, which are structurally related
to ketone 61.
Upon treatment with (S)-(+)-MTPACl, the protective group was
cleaved and diester 105 was obtained rather than the desired
monoester 106. Fortunately, when a solution of the diester 105
was allowed to stand for 10 days in deuterated chloroform,
selective hydrolysis of the phenolic ester occurred and monoester
106 was obtained in 72% yield (Scheme 14).
Mosher and co-workers have shown that the conformation
depicted in Figure 2 is highly preferred for this class of
compounds.32 In the (3R)-diastereomer 106a, the methoxy
function is located over the aromatic radical. The shielding effect
2.8. Enantiopure Tricyclic Imidazopyridines by HPLC
Separation of the Corresponding Racemates. In order to
secure fast access to a wide variety of enantiopure 7H-8,9-
dihydropyrano[2,3-c]imidazo[1,2-a]pyridines, the separation of

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6247
Table 3. HPLC Separation of Racemic 7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridines into Their Enantiomers
(9S)-enantiomers
(9R)-enantiomers
HPLC conditions
CHIRALPAK
%
yield
mp,
%
mp,
compd
R3
Me
R6
Ar
°C
[R]D20a deg yield
°C
[R]D20a deg
column
eluant
36
(CO)NMe2
o-Me-phenyl
48
47
50
46
48
48
48
46
45
43
48
45
48
48
foam
-49
(0.45)
-84
(0.47)
-72
(0.47)
-65
(0.56)
-54
(0.51)
-82
(0.54)
-30
(0.46)
-53
(0.63)
nd
48
47
50
46
48
48
48
47
45
43
48
45
48
47
foam
39
(0.42)
75
(0.47)
60
(0.39)
62
(0.53)
64
(0.45)
58
(0.52)
25
(0.46)
53
(0.61)
nd
AD-H
n-heptane/EtOH
85:15
n-heptane/EtOH
85:15
n-heptane/EtOH
85:15
n-heptane/EtOH
9:1
37
38
44
50
52
53
74
85
86
89
90
92
98
Me
Me
(CO)NMe2
(CO)NMe2
o-F-phenyl
p-F-phenyl
phenyl
210
255
178
161
211
261
254
349
253
248
269
273
215
210
255
178
162
212
260
254
349
250
247
246
270
215
AD-H
AD-H
AD
CH2OH (CO)NMe2
Br
Et
(CO)NMe2
(CO)NMe2
phenyl
AD
EtOH/MeOH
1:1
EtOH
phenyl
50801
AD-H
AD
(CO)Me (CO)NMe2
phenyl
n-heptane/EtOH
85:15
EtOH/MeOH/Et2NH
5:5:0.1
n-heptane/EtOH
7:3
CH3CN/Et2NH
100:0.1
Me
Me
Me
Me
Me
Me
Me
(CO)NMe2
phenyl
(CO)NH2
phenyl
AD
(CO)NH(Me)
(CO)azetidine
(CO)pyrrolidine
(CO)NH(c-Pr)
phenyl
-56
(0.53)
-50
(0.50)
-60
(0.55)
-50
(0.56)
-64
(0.53)
56
(0.53)
26
(0.50)
45
(0.55)
35
(0.44)
64
ASV
50801
50801
AD-H
AD-H
phenyl
EtOH
phenyl
EtOH
phenyl
n-heptane/EtOH
85:15
n-heptane/EtOH
80:20
(CO)NMe(OMe) phenyl
(0.53)
a The [R]2D0 values of all target compounds were determined in chloroform using the concentration (g/100 cm3) specified in parentheses. In the case of the
target compounds 74a and 74b, dichloromethane was used as solvent.
their racemic precursors using chiral HPLC columns was
investigated as an alternative approach. The conditions for the
separation and the analytical data of the target compounds are
summarized in Table 3: Enantiomeric separation of a number
of tricyclic imidazopyridines bearing different substituents R3
and R6 was accomplished using different CHIRALPAK col-
umns. With exception of target compound 86b (96.5-97.0%
ee), all enantiomers were obtained with an optical purity of
>98% ee.
activity is comparable to that of the corresponding (9S)-
imidazopyridine 36a and its in vivo activity is reduced by a
factor of only 3.
3.1. Influence of the Residue R6 on Physicochemical
Properties and Biological Activity. In the case of the unsub-
stituted derivative 77, the good in vitro activity does not translate
into significant reduction of acid output in the Ghosh Schild
rat (Table 4). Compounds with good in vivo activity and reduced
pKa values are obtained by introduction of an amide residue in
the 6-position. Whereas the pKa value lies in the range of 6.5-
7.1 for all amide residues, lipophilicity and pharmacological
activity strongly depend on the nature of the substituents
attached to the carboxamide residue (Table 4):
3. Biological and Physicochemical Evaluation of the
Target Compounds
The efficacy of all 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-
a]pyridines was assessed using several in vitro and in vivo
models. First, the IC50 value of the inhibition of the gastric
proton pump enzyme (H+/K+-ATPase) isolated from hog gastric
mucosa was determined in a competitive binding assay. Second,
the inhibition of [14C]dimethylaminopyridine accumulation in
intact gastric glands was assessed, which serves as an indirect
parameter for the inhibition of acid secretion in this in vitro
model of the mammalian stomach. Finally, the influence of the
target compounds on the pentagastrin-stimulated acid secretion
of the perfused rat stomach (Ghosh Schild rat) after intraduode-
nal administration was investigated. Furthermore, the basicity
(pKa value) and lipophilicity (log D value) of all racemic 7H-
8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridines was deter-
mined.
The data are summarized in Tables 4-6. In all series, the
pronounced effect of the configuration of the stereogenic center
on the in vitro and in vivo activity is obvious. The (9S)-
enantiomer seems to be responsible for the gastric acid secretion
inhibiting action of the compounds, whereas the (9R)-antipodes
are virtually inactive. The (9R)-imidazopyridine 36b represents
a noteworthy exception of this trend (Table 6): Its in vitro
3.1.1. Hydrogen/Alkyl Aubstitution. Strong inhibition of
H+/K+-ATPase and significant reduction of the [14C]dimethyl-
aminopyridine accumulation in gastric glands is observed, if
the amide residue R6 is unsubstituted or substituted by one or
two methyl groups (85, 86, 74). In all cases, also significant
activity in the Ghosh Schild rat model was observed. Substitu-
tion of the amide residue by two larger alkyl groups results in
decreased pharmacological activity (87). All derivatives show
favorable log D values in the range of 2.5-3.2.
3.1.2. Substitution by Cyclic Amines. If the carboxamide
residue contains a cyclic amine, the pharmacological activity
depends on the ring size and decreases in the order azetidine
(89), pyrrolidine (90), and aziridine (88). On the other hand,
the three derivatives show comparable effects in the gastric
glands model. From the decrease of activity observed for
compound 91 (R6 ) (3-hydroxyazetidino)carboxamide), it can
be concluded that the presence of a polar hydroxyl group seems
to be unfavorable.
3.1.3. Cycloalkyl Substitution. Again, if the carboxamide
residue is substituted by a cycloalkyl residue, the pharmacologi-
cal activity depends on the ring size (cyclopropyl 92 preferred

6248 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
Table 4. Biological and Pharmacological Evaluation of Target Compounds with Different Residues R6
a pIC50 value of the inhibition of H+/K+-ATPase derived from hog gastric mucosa. b pIC50 value of the inhibition of [14C]dimethylaminopyridine accumulation
in intact gastric glands. c Pentagastrin-stimulated acid secretion of the perfused rat stomach: ED50 (µmol/kg) or reduction (%) at dose (µmol/kg). d No
inhibition (n.i.)
over cyclobutyl 93), whereas comparable inhibition in the gastric
glands model is observed. The log D value of the cyclopropyl
carboxamide 92 is acceptable. On the other hand, the cyclobutyl
carboxamide 93 is a rather lipophilic compound.
3.1.4. Aryl Substitution. The increase of lipophilicity is even
more pronounced, if R6 represents an aromatic carboxamide
residue. Both aniline derivatives 94 and 95 reduce the [14C]-
dimethylaminopyridine accumulation in gastric glands in a
significant manner. Despite its high lipophilicity, the aniline
carboxamide 94 shows considerable pharmaceutical activity in
the Ghosh Schild rat.
3.1.5. Other Substituents. Hydrophilic compounds with low
in vitro and in vivo inhibitory activity are obtained if R6
represents a carboxamide residue that contains a basic center
(methansulfonamide 96, piperazine carboxamide 97). In contrast,
the Weinreb amide 98 combines good in vitro and in vivo
activity with favorable physicochemical properties. In compound
101, the carboxamide residue has been replaced by the bioi-
sosteric 4,5-dihydro-1,3-oxazole motif. This modification did
not affect the in vitro activity (101 vs 85). However, the
bioisoster 101 inhibited the acid output in the Ghosh Schild rat
in a less potent manner than carboxamide 85.

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6249
Table 5. Biological and Pharmacological Evaluation of Target Compounds with Different Residues R3
a pIC50 value of the inhibition of H+/K+-ATPase derived from hog gastric mucosa. b pIC50 value of the inhibition of [14C]dimethylaminopyridine accumulation
in intact gastric glands. c Pentagastrin-stimulated acid secretion of the perfused rat stomach: ED50 (µmol/kg) or reduction (%) at dose (µmol/kg). d No
inhibition (n.i.).
Table 6. Biological and Pharmacological Evaluation of Target Compounds with Different Residues Ar
a pIC50 value of the inhibition of H+/K+-ATPase derived from hog gastric mucosa. b pIC50 value of the inhibition of [14C]dimethylaminopyridine accumulation
in intact gastric glands. c Pentagastrin-stimulated acid secretion of the perfused rat stomach: ED50 (µmol/kg) or reduction (%) at dose (µmol/kg). d No
inhibition (n.i.).
The data presented for the ethyl ester 76 illustrates that, in
carboxylic esters. The good in vitro activity of the lipophilic
ester 76 does not translate into significant pharmacological
the case of R6, carboxamide substituents are preferred over

6250 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
effects in the Ghosh Schild rat. This might be due to rapid
metabolic cleavage of 76, furnishing the inactive carboxylic acid
84.
less basic than the parent system and show comparable in vitro
and in vivo activity.
Several target compounds were obtained in an enantiopure
manner, either by chemical synthesis (Noyori reduction of
prochiral ketones) or by HPLC separation. It was found that
the (9S)-enantiomers were responsible for the gastric acid
secretion inhibiting action, whereas the (9R)-enantiomers were
virtually inactive.
3.2. Influence of the Residue R3 on Physicochemical
Properties and Biological Activity. The data presented in Table
5 clearly demonstrate that the nature of the residue R3 exerts a
strong influence on the pKa value and the lipophilicity of the
corresponding tricyclic imidazopyridine. Replacement of the
methyl group (74) versus a hydroxymethyl residue (44) results
in a decrease in basicity of 1.3 log units. A similar effect was
also observed for the alcohol 48. The pKa value can be decreased
even further by introduction of a bromo atom (50; ∆pKa ) 2.5),
an amide residue (46, 47; ∆pKa ) 2.6-2.8), or a carbonyl group
(49, 53; ∆pKa ) 3.4-3.95). Generally, the target compounds
presented in Table 5 show favorable log D values, with the
exception of the rather hydrophilic derivatives 44 and 46.
The character of the residue R3 also possesses a pronounced
influence on the antisecretory activity of the corresponding target
compound. Structural modifications of 74 (R3 ) methyl), e.g.,
homologation of the methyl group (52; R3 ) Et) or replacement
of a hydrogen atom versus a hydroxyl group (44; R3 ) CH2-
OH) or a dimethylamino group (54; R3 ) CH2NMe2), resulted
in compounds with significantly reduced in vitro and in vivo
activity. Also, none of the imidazopyridines 46, 47, 49, 50, and
53, bearing either a 3-bromo, a 3-carboxamide, or a 3-carbonyl
substituent, showed noteworthy activity.
3.3. Influence of the Residue Ar on Physicochemical
Properties and Biological Activity. From the data presented
in Table 6, it can be concluded that small modifications of the
phenyl residue are allowed, like replacement of hydrogen versus
a fluoro atom or introduction of a methyl group in the ortho
position. The derivatives 36, 37, 38, and 74 show comparable
in vitro and in vivo activity. Interestingly, the replacement of
hydrogen versus a fluoro atom or a methyl group does not alter
the lipophilicity of the target compounds (36, 37, 38, 74) but
results in a pronounced decrease of basicity (∆pKa ) 0.4).
Bioisosteric replacement of the phenyl group versus a thiophene
residue furnishes target compound 75, which possesses highly
favorable physicochemical properties. On the other hand,
thiophene derivative 75 shows reduced inhibition of the gastric
proton pump enzyme and less potent reduction of acid output
in the Ghosh Schild rat as compared to its phenyl analogue 74.
In summary, we identified several 7H-8,9-dihydropyrano[2,3-
c]imidazo[1,2-a]pyridines with excellent physicochemical and
pharmacological properties that represent interesting candidates
for further development as potassium-competitive acid blockers.
5. Experimental Section
5.1. Chemistry. General. All chemicals were purchased from
the major chemical suppliers as the highest purity grade and used
without any further purification. 1-(1-Arylvinyl)pyrrolidines were
prepared by titanium tetrachloride mediated condensation of the
corresponding acetophenone derivative with pyrrolidine (see White,
W. A.; Weingarten, H. J. Org. Chem. 1967, 32, 213-214). The
hydrogenation catalysts RuCl2[(S)-BINAP][(S,S)-DPEN] and RuCl2-
[(S)-BINAP][(S)-DAIPEN] are commercially available from Strem
Chemicals or can be prepared according to the procedure given by
Noyori and Ohkuma (Angew. Chem. 2001, 113, 40-75). The
progress of the reaction was monitored on Macherey-Nagel HPTLC
plates (Nano-SIL 20 UV254, 0.20 mm layer, nano-silica gel 60 with
fluorescence indicator UV254) using dichloromethane/methanol as
solvent system. Column chromatography was performed with Merck
silica gel 60 (70-230 mesh ASTM) with the solvent mixtures
specified in the corresponding experiment. Spots were visualized
by iodine vapor or by irradiation with ultraviolet light (254 nm).
Melting points (mp) were taken in open capillaries on a Bu¨chi B-540
melting point apparatus and are uncorrected. 1H NMR spectra were
recorded with a Bruker DRX 200 FT-NMR spectrometer at a
frequency of 200.1 MHz or a Bruker AV 400 FT-NMR spectrom-
eter at a frequency of 400.1 MHz. CDCl3 or DMSO-d6 was used
as solvent. The chemical shifts are reported as parts per million (δ
ppm) with tetramethylsilane (TMS) as an internal standard. High-
resolution mass spectra were obtained on a Bruker Daltonics
MicroTOF Focus instrument using electrospray ionization (ESI
positive). Elemental analysis was performed on a Carlo Erba 1106
C, H, N analyzer. The results of the elemental analyses (see
Supporting Information) suggest that the title compounds contain
variable amounts of crystal water (anhydrous compounds, hemi-
hydrates, hydrates). This might account for the fact that in some
cases melting point deviations between different batches of a title
compound or between racemic title compounds and their corre-
sponding enantiomers were observed. The optical purity of the target
compounds and of selected intermediates was determined by
capillary electrophoresis (CE) and/or high-pressure liquid chroma-
tography (HPLC). The experimental conditions for the separation
of the enantiomers by HPLC are given for each example in the
Experimental Section. The separation by CE was performed using
one of the following experimental setups: instrument, Agilent CE-
3D; capillary, Agilent bubble-cell 64.5 cm × 50 µm (method A),
Agilent bubble-cell 64.5 cm × 75 µm (method B), Agilent barefused
silica bubble 48.5 cm × 50 µm (method C); buffer, Agilent 50
mM sodium phosphate, pH 2.5 (all methods); chiral selector,
Cyclolab 40 mM heptakis(2,3,6-tri-O-methyl)-â-cyclodextrin (all
methods); voltage, 30 kV (all methods); temperature, 10 °C
(methods A and B), 20 °C (method C). The number of the methods
employed for the corresponding analysis is given in parentheses in
the Experimental Section. The purity of the prochiral ketones that
served as substrates for the asymmetric catalytic hydrogenation
reaction was assessed by HPLC. The following experimental
procedure was employed: column, 150 × 4.6 mm XTerra RP 18
5 µm; mobile phase, 0.01 M KH2PO4 (pH 2.0)/acetonitrile/water
90:10:0 (v/v/v) (0 min) to 15:80:5 (v/v/v) (30 min); flow rate, 1.0
4. Conclusion
A variety of tricyclic imidazopyridines were prepared fol-
lowing synthetic pathways that relied either on a Claisen
rearrangement/cross-metathesis reaction or on the preparation/
reduction of prochiral ketones.
The influence of the character of the substituents R3, R6, and
Ar on the biological activity and the physicochemical properties
of the target compounds was examined. In contrast to the parent
system (R6 ) H), compounds where R6 represents a carboxa-
mide residue generally showed improved in vivo activity and
favorable pKa/log D values. SAR data indicate that the car-
boxamide substituent NR31R32 preferrably should be chosen to
be hydrogen, low alkyl, alkoxy, or cyclopropyl. Alternatively,
NR31R32 could represent a cyclic amine. Whereas variation of
R3 is useful to obtain target compounds with modified basicity
and lipophilicity, the character of the substituent R3 is vital for
potent inhibition of the gastric proton pump enzyme. Strong
inhibition of the H+/K+-ATPase and potent in vivo activity was
observed for R3 ) methyl only. Small modifications of the aryl
group, e.g., replacement of hydrogen versus a fluoro atom or a
methyl group are allowed. The corresponding compounds are

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6251
mL/min; 30 °C. The retention time of the title compounds (detection
at 237-245 nm) is given for each example in the Experimental
Section.
These samples were further purified by treatment with boiling
diethyl ether (200 mL). The title compound was isolated by
filtration, washed with diethyl ether (2 × 40 mL), and dried in
vacuo (24.5 g of a colorless solid which contained 16 mol % of
triphenylphosphine oxide, 76% yield): mp (purified sample)
152 °C; 1H NMR (purified sample, DMSO-d6, 200 MHz) δ ) 2.29,
2.38 (2 s, 6 H), 2.97 (s, 6 H), 5.31 (s, 2 H), 6.69 (d, 1 H), 7.44 (mc,
5 H), 7.94 (d, 1 H); HRMS calcd for C19H22N3O2 m/z (MH+)
324.1707, found 324.1718.
3-Benzyloxy-5-bromopyridin-2-ylamine (13). A four-neck 1000
mL flask was charged with 10% sulfuric acid (500 mL). At ambient
temperature, pyridine 12 (25.0 g, 125 mmol) was added under
stirring. At 0 °C, to the mechanically stirred brown solution was
added a mixture of bromine (24.0 g, 150 mmol) and acetic acid
(82.4 g, 1.37 mol) dropwise over a period of 90 min. The resulting
yellow suspension was stirred for 2.5 h at 0 °C and then poured
onto ice water (500 mL). A pH value of 8 was adjusted by addition
of ammonia solution (25 wt %, 220 mL). The aqueous phase was
extracted with dichloromethane (4 × 1 L). The combined organic
phases were washed with water (300 mL), dried over sodium
sulfate, and concentrated under reduced pressure. The remaining
black solid (34.7 g) was purified by column chromatography [600
g of silica gel; eluant, petroleum ether/ethyl acetate ) 7:3 (v/v)].
The title compound (28.8 g, 83% yield) was isolated as a slightly
8-Benzyloxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic Acid
Dimethylamide (17). Compound 17 was obtained in 77% yield
from 6-bromoimidazo[1,2-a]pyridine 15 by applying a procedure
similar to that described for the preparation of 16 (for further details,
1
see Supporting Information): beige solid; mp 138-140 °C; H
NMR (CDCl3, 200 MHz) δ ) 2.47 (s, 3 H), 2.95 (bs, 6 H), 5.35
(s, 2 H), 6.43 (d, 1 H), 7.40 (mc, 6 H), 7.88 (d, 1 H); HRMS calcd
for C18H20N3O2 m/z (MH+) 310.1550, found 310.1541.
8-Hydroxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxyl-
ic Acid Dimethylamide (18): (a) Transfer Hydrogenation. 1,4-
Cyclohexadiene (6.03 g, 7.12 mL, 75.3 mmol) and palladium
catalyst (10% on charcoal, 0.49 g) were added to a suspension of
8-benzyloxyimidazo[1,2-a]pyridine 16 (4.87 g, containing 16 mol
% of triphenylphosphine oxide, 13.0 mmol) in ethanol (40 mL).
The mixture was refluxed for 7 h, cooled, and filtered. The residue
was washed with dichloromethane (40 mL). The combined organic
phases were concentrated under reduced pressure. The remaining
solid (3.37 g) was washed with acetone/diethyl ether (20 mL/20
mL) and dried in vacuo. This afforded 2.33 g of the title compound
(colorless solid, 77% yield): mp 278 °C (dec); 1H NMR (DMSO-
d6, 200 MHz) δ ) 2.31, 2.37 (2 s, 6 H), 2.99 (s, 6 H), 6.42 (d, 1
H), 7.80 (d, 1 H); HRMS calcd for C12H16N3O2 m/z (MH+)
234.1237, found 234.1229.
1
yellow solid: mp 99 °C; H NMR (CDCl3, 200 MHz) δ ) 4.84
(bs, 2 H), 5.04 (s, 2 H), 7.08 (d, 1 H), 7.40 (mc, 5 H), 7.71 (d, 1
H); HRMS calcd for C12H12BrN2O m/z (MH+) 279.0128, found
279.0099.
8-Benzyloxy-6-bromo-2,3-dimethylimidazo[1,2-a]pyridine (14).
3-Bromo-2-butanone (66.1 g, 46.0 mL, 0.44 mol) was added to a
solution of pyridin-2-ylamine 13 (82.0 g, 0.29 mol) in THF (800
mL). The reaction mixture was refluxed for 48 h and the precipitate
formed was removed by filtration and washed with THF. Water
(800 mL) and dichloromethane (300 mL) were added to the solid,
and the title compound was freed-up from its hydrobromide salt
by addition of 6 N sodium hydroxide solution. The organic phase
was diluted with dichloromethane (500 mL), the phases were
separated, and the aqueous phase was extracted with dichlo-
romethane (2 × 300 mL). The combined organic phases were dried
over sodium sulfate and concentrated in vacuo. The title compound
(50.5 g, 52% yield) was obtained as a colorless solid. The mother
liquor was treated with another portion of 3-bromo-2-butanone (66.1
g, 46.0 mL, 0.44 mol) and was heated to reflux for 4 d further.
The precipitate formed within this period was removed by filtration
and treated as described above. A further 22.6 g of the title
compound was obtained (24% yield, 76% overall yield): mp 172-
(b) Hydrogenation. A solution of 8-benzyloxyimidazo[1,2-a]-
pyridine 16 (37.3 g, 115 mmol) in dry methanol (420 mL) was
treated with hydrogenation catalyst (10 wt % palladium on charcoal,
3.7 g). A hydrogen pressure of 1 bar was applied and the reaction
mixture was stirred for 2.5 h at room temperature. The reaction
mixture was filtered and the filter cake was suspended in dichlo-
romethane (200 mL). The suspension was stirred for several minutes
and filtered, and the combined filtrates were evaporated to dryness.
This afforded 25.9 g of the title compound (colorless solid, 96%
1
173 °C; H NMR (CDCl3, 200 MHz) δ ) 2.34, 2.41 (2 s, 6 H),
1
5.29 (s, 2 H), 6.53 (d, 1 H), 7.40 (mc, 5 H, Ph), 7.57 (d, 1 H);
HRMS calcd for C16H16BrN2O m/z (MH+) 331.0441, found
331.0427.
yield): mp 276-277 °C; H NMR (CDCl3, 200 MHz) δ ) 2.36,
2.40 (2 s, 6 H), 3.10 (s, 6 H), 6.73 (d, 1 H), 7.62 (d, 1 H); HRMS
calcd for C12H16N3O2 m/z (MH+) 234.1237, found 234.1226.
8-Hydroxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic Acid
Dimethylamide (19). Compound 19 was obtained in 98% yield
from 8-benzyloxyimidazo[1,2-a]pyridine 17 by applying a proce-
dure similar to that described for the preparation of 18 (catalytic
hydrogenation) (for further details, see Supporting Information):
8-Benzyloxy-6-bromo-2-methylimidazo[1,2-a]pyridine (15).
Compound 15 was obtained in 59% yield from pyridin-2-ylamine
13 by applying a procedure similar to that described for the
preparation of 14, using chloroacetone instead of 3-bromo-2-
butanone (for further details, see Supporting Information): sticky
yellow solid; 1H NMR (CDCl3, 200 MHz) δ ) 2.43 (s, 3 H), 5.28
(s, 2 H), 6.52 (d, 1 H), 7.37 (mc, 6 H), 7.79 (d, 1 H).
1
beige solid; mp 230-232 °C; H NMR (CDCl3, 200 MHz) δ )
2.44 (s, 3 H), 3.10 (bs, 6 H), 6.74 (d, 1 H), 7.31 (s, 1 H), 7.89 (d,
1 H), 8.96 (bs, 1 H); HRMS calcd for C11H14N3O2 m/z (MH+)
220.1081, found 220.1088.
8-Benzyloxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxy-
lic Acid Dimethylamide (16). A solution of 6-bromoimidazo[1,2-
a]pyridine 14 (27.0 g, 82 mmol) in THF (400 mL) was treated
with palladium acetate (2.7 g, 12 mmol), triphenylphosphine (12.6
g, 48 mmol), triethylamine (26 mL), and dimethylamine (400 mL,
2 M solution in THF, 800 mmol). In an autoclave, the reaction
mixture was subjected to a carbon monoxide pressure of 10 bar
and a temperature of 120 °C. The reaction mixture was kept at this
temperature for 18.5 h, cooled to room temperature, and concen-
trated in vacuo. The oily residue was dissolved in dichloromethane
(400 mL) and water (400 mL). The aqueous phase was extracted
with dichloromethane (2 × 400 mL). The combined organic phases
were filtered, washed with water (2 × 400 mL), dried over sodium
sulfate, and concentrated under reduced pressure. The crude product
(49 g of a brown oil) was purified by column chromatography [1
kg of silica gel; eluant, dichloromethane and, after removal of
triphenylphosphine, dichloromethane/methanol ) 15:1 (v/v)]. Two
batches of the title compound (18.3 g + 13.0 g of a yellow-brown
sticky solid) were obtained, which contained 26/21 mol % of
triphenylphosphine oxide (as determined by 1H NMR spectroscopy).
8-Benzyloxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxy-
lic Acid Ethyl Ester (20). Compound 20 was obtained in 87%
yield from 6-bromoimidazo[1,2-a]pyridine 14 by applying a
procedure similar to that described for the preparation of 16, using
ethanol instead of dimethylamine (for further details, see Supporting
Information): 1H NMR (CDCl3, 200 MHz) δ ) 1.40 (t, 3 H), 2.43,
2.44 (2 s, 6 H), 4.39 (q, 2 H), 5.35 (s, 2 H), 7.03 (d, 1 H), 7.34,
7.52 (2 mc, 5 H), 8.25 (d, 1 H); HRMS calcd for C19H21N2O3 m/z
(MH+) 325.1547, found 325.1562.
8-Hydroxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxyl-
ic Acid Ethyl Ester (21). Compound 21 was obtained in 80% yield
from 8-benzyloxyimidazo[1,2-a]pyridine 20 by applying a proce-
dure similar to that described for the preparation of 18 (catalytic
transfer hydrogenation) (for further details, see Supporting Informa-
tion): mp 241 °C (dec); 1H NMR (DMSO-d6, 200 MHz) δ ) 1.33
(t, 3 H), 2.32, 2.42 (2 s, 6 H), 4.33 (q, 2 H), 6.86 (d, 1 H), 8.26 (d,
1 H); HRMS calcd for C12H15N2O3 m/z (MH+) 235.1077, found
235.1084.

6252 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
8-Benzyloxy-2,3-dimethylimidazo[1,2-a]pyridine (22). Com-
pound 22 was obtained in 67% yield from pyridin-2-ylamine 12
by applying a procedure similar to that described for the preparation
of 14 (for further details, see Supporting Information): colorless
solid; mp 120-122 °C; 1H NMR (DMSO-d6, 200 MHz) δ ) 2.29
(s, 3 H), 2.35 (s, 3 H), 5.27 (s, 2 H), 6.72 (mc, 2 H), 7.42 (mc, 5
H), 7.77 (d, 1 H); HRMS calcd for C16H17N2O m/z (MH+) 253.1335,
found 253.132.
5.98 (mc, 1 H), 7.22 (s, 1 H), 7.53 (s, 1 H), 9.57 (bs, 1 H); HRMS
calcd for C14H18N3O2 m/z (MH+) 260.1394, found 260.1385.
2,2-Dimethylpropionic Acid 7-Allyl-6-dimethylcarbamoyl-2-
methylimidazo[1,2-a]pyridin-8-yl Ester (28). To a suspension of
8-hydroxyimidazo[1,2-a]pyridine 27 (1.00 g, 3.9 mmol) in acetone
(30 mL) were added potassium carbonate (0.53 g, 3.9 mmol) and
pivaloyl chloride (0.93 g, 7.7 mmol). The yellow suspension was
stirred for 3 h at room temperature. After addition of saturated
ammonium chloride solution (20 mL) and water (10 mL), the
reaction mixture was extracted with dichloromethane (3 × 50 mL).
The combined organic phases were dried over sodium sulfate and
concentrated under reduced pressure. The crude product (1.46 g of
a colorless solid) was purified by column chromatography (30 g
of silica gel; eluant, ethyl acetate). The title compound was obtained
in 72% yield (0.96 g of colorless solid): mp 178-180 °C; 1H NMR
(CDCl3, 200 MHz) δ ) 1.48 (s, 9 H), 2.41 (s, 3 H), 2.89 (s, 3 H),
3.08 (s, 3 H), 3.35 (d, 2 H), 5.04 (mc, 2 H), 5.78 (mc, 1 H), 7.28 (s,
1 H), 7.82 (s, 1 H).
2,2-Dimethylpropionic Acid 6-Dimethylcarbamoyl-2-methyl-
7-((E)-3-phenylallyl)imidazo[1,2-a]pyridin-8-yl Ester (29). 7-Al-
lylimidazo[1,2-a]pyridine 28 (9.30 g, 27.1 mmol) was dissolved
in dichloromethane (140 mL) that had been degassed with argon.
After addition of trans-stilbene (19.53 g, 108.4 mmol) and second-
generation Grubbs catalyst (CAS 246047-72-3, 920 mg, 1.08 mmol,
4 mol %), a red solution was obtained. The reaction mixture was
heated to 40 °C and was stirred for 18 h at this temperature. The
crude product obtained on concentration of the green solution was
purified by column chromatography [1.2 kg of silica gel; eluant,
petroleum ether (to remove excess trans-stilbene) and then ethyl
acetate]. A slightly green solid (6.6 g) was isolated, which consisted
of the title compound (90 mol %, 53% yield) and untransformed
starting material 28 (10 mol %, ratio determined by 1H NMR
analysis): 1H NMR (CDCl3, 200 MHz) δ ) 1.49 (s, 9 H), 2.42 (s,
3 H), 2.79 (s, 3 H), 3.01 (s, 3 H), 3.53 (d, 2 H), 6.12 (dt, 1 H), 6.43
(d, 1 H), 7.24 (mc, 6 H), 7.81 (s, 1 H).
2,3-Dimethylimidazo[1,2-a]pyridin-8-ol (23). Compound 23
was obtained in 83% yield from 8-benzyloxyimidazo[1,2-a]pyridine
22 by applying a procedure similar to that described for the
preparation of 18 (catalytic transfer hydrogenation) (for further
1
details, see Supporting Information): mp 210-212 °C; H NMR
(DMSO-d6, 200 MHz) δ ) 2.31 (s, 3 H), 2.35 (s, 3 H), 6.45 (d, 1
H), 6.70 (t, 1 H), 7.65 (d, 1 H), 8.56 (bs, 1 H); HRMS calcd for
C9H11N2O m/z (MH+) 163.0866, found 163.0862.
8-Allyloxy-2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic
Acid Dimethylamide (24). 8-Hydroxyimidazo[1,2-a]pyridine 18
(50.0 g, 0.22 mol) was dissolved in dry DMF (1 L). Potassium
carbonate (29.7 g, 0.22 mol) and allyl bromide (31.2 g, 0.26 mol)
were added, and the reaction mixture was stirred at room temper-
ature for 18.5 h. The solvent was removed under reduced pressure
and the residue was dissolved in saturated ammonium chloride
solution (250 mL) and chloroform (500 mL). The phases were
separated, and the aqueous phase was extracted with chloroform
(2×). The combined organic phases were dried over sodium sulfate
and concentrated under reduced pressure. The residue was purified
by column chromatography [800 g of silica gel; eluant, ethyl acetate/
methanol ) 9:1 (v/v)]. The title compound (40.0 g, 67% yield)
was isolated in the form of a yellow solid. Traces of impurities
(approximately 14 mol %) were visible in the 1H NMR spectrum:
1H NMR (CDCl3, 400 MHz) δ ) 2.39, 2.46 (2 s, 6 H), 3.10 (s, 6
H), 4.80 (dt, 2 H), 5.33 (dd, 1 H), 5.47 (dd, 1 H), 6.14 (ddt, 1 H),
6.53 (d, 1 H), 7.69 (d, 1 H); HRMS calcd for C15H20N3O2 m/z
(MH+) 274.1550, found 274.1543.
8-Allyloxy-2-methylimidazo[1,2-a]pyridine-6-carboxylic Acid
Dimethylamide (25). Compound 25 was obtained in 70% yield
from 8-hydroxyimidazo[1,2-a]pyridine 19 by applying a procedure
similar to that described for the preparation of 24 (for further details,
see Supporting Information): yellowish oil; traces of impurities
2-Methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-
a]pyridine-6-carboxylic Acid Dimethylamide (30): Preparation
from 29. A mixture of 7-((E)-3-phenylallyl)imidazo[1,2-a]pyridine
29 (6.05 g, 14.4 mmol) and 7-allylimidazo[1,2-a]pyridine 28 (0.55
g, 1.6 mmol) was treated with 200 mL of orthophosphoric acid
(85%). The resulting green solution was heated for 50 min to
80 °C. The reaction mixture was cooled to room temperature,
diluted with dichloromethane (200 mL), and neutralized with a 6
N solution of sodium hydroxide at 0 °C. The phases were separated,
and the aqueous phase was extracted with dichloromethane (2 ×
200 mL). The combined organic phases were dried over sodium
sulfate and concentrated under reduced pressure. The crude product
was purified by column chromatography [210 g of silica gel; eluant,
ethyl acetate/methanol ) 9:1 (v/v)]. Evaporation of the correspond-
ing fractions afforded the title compound (4.4 g of a colorless solid,
1
(approximately 5 mol %) were visible in the H NMR spectrum;
1H NMR (CDCl3, 200 MHz) δ ) 2.46 (s, 3 H), 3.09 (s, 6 H), 4.79
(dt, 2 H), 5.33 (dd, 1 H), 5.45 (dd, 1 H), 6.15 (ddt, 1 H), 6.48 (d,
1 H), 7.33 (s, 1 H), 7.87 (d, 1 H); HRMS calcd for C14H18N3O2
m/z (MH+) 260.1394, found 260.1382.
7-Allyl-8-hydroxy-2,3-dimethylimidazo[1,2-a]pyridine-6-car-
boxylic Acid Dimethylamide (26). A flask containing neat
8-allyloxyimidazo[1,2-a]pyridine 24 (40.0 g, 0.15 mol) was put into
an oil-bath that had been preheated to 160 °C. After a period of 50
min at 160 °C, the reaction mixture solidified, forming a dark brown
solid. The crude product was cooled to room temperature and was
treated with a mixture of acetone and diethyl ether [1:1 (v/v), 200
mL], at which point a beige solid precipitated. After a period of 20
min, the precipitate was removed by filtration, washed with diethyl
ether, and dried in vacuo. Thus, 28.0 g of the pure title compound
was isolated. The mother liquor was concentrated under reduced
pressure and the residue (10 g of a brown solid) was purified by
column chromatography [300 g of silica gel; eluant, ethyl acetate/
methanol ) 9:1 (v/v)] yielding another 2.2 g of the title compound
1
91% yield): mp 189 °C, H NMR (CDCl3, 200 MHz) δ ) 2.26
(mc, 2 H), 2.41 (s, 3 H), 2.58, 2.77 (2 mc, 2 H), 2.94 (s, 3 H), 3.12
(s, 3 H), 5.31 (dd, 1 H), 7.40 (mc, 6 H), 7.67 (s, 1 H); HRMS calcd
for C20H22N3O2 m/z (MH+) 336.1707, found 336.1691.
Preparation from 28 (One-Pot Synthesis). In a flame-dried
flask filled with argon, 7-allylimidazo[1,2-a]pyridine 28 (4.80 g,
14.0 mmol) was dissolved in dichloromethane (100 mL) which had
been degassed with argon. After addition of trans-stilbene (10.10
g, 56.0 mmol) and second-generation Grubbs catalyst (CAS 246047-
72-3, 475 mg, 0.56 mmol, 4 mol %), the solution was heated to
40 °C. The reaction mixture was stirred for 18 h at this temperature
and was then concentrated under reduced pressure. A green solid
was obtained which was treated with 100 mL of orthophosphoric
acid (85%). The suspension was heated to 80 °C. After a period of
1 h, a clear solution was obtained which was cooled to room
temperature and poured onto a mixture of ice water (50 mL) and
dichloromethane (50 mL). A pH value of 8 was adjusted by addition
of 6 N sodium hydroxide solution. The phases were separated and
the aqueous phase was extracted with dichloromethane (2 × 20
mL). The combined organic phases were dried over sodium sulfate
and concentrated under reduced pressure. The residue, 16 g of a
1
(30.2 g, 76% overall yield): mp 245-247 °C; H NMR (CDCl3,
200 MHz) δ ) 2.35, 2.44 (2 s, 6 H), 2.87, 3.13 (2 s, 3 H), 3.55 (d,
2 H), 5.02, 5.07 (2 dd, 2 H), 5.97 (mc, 1 H), 7.36 (s, 1 H), 10.76
(bs, 1 H); HRMS calcd for C15H20N3O2 m/z (MH+) 274.1550, found
274.1543.
7-Allyl-8-hydroxy-2-methylimidazo[1,2-a]pyridine-6-carboxy-
lic Acid Dimethylamide (27). Compound 27 was obtained in 66%
yield from 8-allyloxyimidazo[1,2-a]pyridine 25 by applying a
procedure similar to that described for the preparation of 26 (for
further details, see Supporting Information): colorless solid; mp
1
>190 °C (dec); H NMR (CDCl3, 200 MHz) δ ) 2.43 (s, 3 H),
2.88 (s, 3 H), 3.11 (s, 3 H), 3.55 (bd, 2 H), 5.00, 5.07 (2 dd, 2 H),

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6253
green solid, was purified by column chromatography [320 g of silica
gel; eluant, petroleum ether (to remove excess trans-stilbene) and
then ethyl acetate/methanol ) 100:2 (v/v)]. The title compound
9-(2-Fluorophenyl)-2,3-dimethyl-7H-8,9-dihydropyrano[2,3-
c]imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (37):
Preparation from 31. In a flame-dried flask filled with argon,
7-allylimidazo[1,2-a]pyridine 31 (2.00 g, 4.8 mmol) was dissolved
in dichloromethane (50 mL) that had been degassed with argon.
After addition of 2-fluorostyrene (2.94 g, 24.1 mmol) and second-
generation Grubbs catalyst (CAS 246047-72-3, 162 mg, 0.19 mmol,
4 mol %), the solution was heated to 40 °C. The reaction mixture
was stirred for 17 h at this temperature and then concentrated under
reduced pressure. A suspension of the residue in 25 mL of
orthophosphoric acid (85%) was stirred at 100 °C (preheated oil
bath). After a period of 2 h, a clear solution was obtained that was
poured onto ice water (70 mL) and dichloromethane (100 mL). A
pH value of 8 was adjusted by addition of 6 N sodium hydroxide
solution. The phases were separated, and the aqueous phase was
extracted with dichloromethane (2 × 50 mL). The combined organic
phases were dried over sodium sulfate and concentrated under
reduced pressure. The black, solid residue (5.6 g) was purified by
column chromatography [225 g of silica gel; eluant, ethyl acetate/
triethylamine ) 100:1 (v/v)]. After removal of the solvent, the pure
title compound (1.0 g of a colorless solid, 56% yield) was
obtained: mp 202 °C; 1H NMR (CDCl3, 200 MHz) δ ) 2.27 (mc,
2 H), 2.36, 2.41 (2 s, 6 H), 2.61 (mc, 1 H), 2.82 (mc, 1 H), 2.95,
3.14 (2 s, 6 H), 5.60 (dd, 1 H), 7.09 (mc, 2 H), 7.27 (mc), 7.44 (s,
1 H), 7.60 (dt, 1 H); HRMS calcd for C21H23FN3O2 m/z (MH+)
368.1769, found 368.1758.
1
(3.0 g, 64% yield) was isolated as a green foamy solid. H NMR
(CDCl3, 200 MHz) δ ) 2.26 (mc, 2 H), 2.41 (s, 3 H), 2.58, 2.77 (2
mc, 2 H), 2.94 (s, 3 H), 3.12 (s, 3 H), 5.31 (dd, 1 H), 7.40 (mc, 6
H), 7.67 (s, 1 H); HRMS calcd for C20H22N3O2 m/z (MH+)
336.1707, found 336.1701.
7-Allyl-8-[dimethyl(1,1,2-trimethylpropyl)silanyloxy]-2,3-di-
methylimidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide
(31). In a flame-dried flask filled with argon, a suspension of
8-hydroxyimidazo[1,2-a]pyridine 26 (3.60 g, 13.2 mmol) in dry
DMF (50 mL) was treated with imidazole (1.52 g, 22.3 mmol) and
chlorodimethylthexylsilane (slow addition of 4.40 mL, 4.00 g, 22.4
mmol). A brown solution was obtained, which was stirred for 1 h
at room temperature. The reaction mixture was poured onto a
mixture of ice (20 g), saturated ammonium chloride solution (30
mL), and dichloromethane (50 mL). The biphasic mixture was
stirred for several minutes, the phases were separated, and the
aqueous phase was extracted with dichloromethane (2 × 15 mL).
The combined organic phases were washed with water (20 mL),
dried over sodium sulfate, and concentrated under reduced pressure.
The residue, 7.5 g of a yellow-brown oil, was purified by column
chromatography [150 g of silica gel; eluant, petroleum ether/ethyl
acetate ) 8:2 (v/v)]. This afforded the title compound in 93% yield
1
(5.10 g of a colorless solid): mp 93-95 °C; H NMR (CDCl3,
200 MHz) δ ) 0.41 (s, 6 H), 0.96 (d, 6 H), 1.02 (s, 6 H), 1.83
(septet, 1 H), 2.31, 2.36 (2 s, 6 H), 2.84, 3.08 (2 s, 6 H), 3.50 (mc,
2 H), 4.96 (mc, 2 H), 5.84 (mc, 1 H), 7.36 (s, 1 H).
Preparation from 69. The crude diol 69 (2.1 g) was dissolved
in orthophosphoric acid (85 wt %, 20 mL). The suspension was
heated at 80 °C (preheated oil bath). After a period of 30 min, a
clear solution was obtained. After a reaction time of 1 h, the hot
solution was poured onto ice water (100 mL) and dichloromethane
(100 mL). The pH value of the biphasic mixture was adjusted to 8
by addition of 6 N sodium hydroxide solution. The phases were
separated, and the aqueous phase was extracted with dichlo-
romethane (2 × 40 mL). The combined organic phases were dried
over sodium sulfate and concentrated under reduced pressure. A
slightly yellow foamy solid remained which was dried in vacuo.
The title compound was obtained in 94% yield (1.94 g): mp
8-[Dimethyl(1,1,2-trimethylpropyl)silanyloxy]-2,3-dimethyl-
7-((E)-3-phenylallyl)imidazo[1,2-a]pyridine-6-carboxylic Acid
Dimethylamide (35). In a flame-dried flask filled with argon,
7-allyl-imidazo[1,2-a]pyridine 31 (5.00 g, 12.0 mmol) was dissolved
in dry dichloromethane (200 mL) that had been degassed with
argon. trans-Stilbene (8.70 g, 48.3 mmol) and second-generation
Grubbs catalyst (CAS 246047-72-3, 0.40 g, 0.5 mmol, 3.9 mol %)
were added, and the obtained red solution was heated to reflux for
19 h. The dark-brown reaction mixture was concentrated to a
volume of 80 mL and loaded onto a column filled with 200 g of
silica gel. The title compound was eluted using a mixture of
petroleum ether and ethyl acetate [7:3 (v/v)]. The solvent was
removed and the oily residue was dried in vacuo. A pale-red foam
(3.70 g) was obtained [mixture of the title compound (93 wt %,
58% yield) and dimethyl(1,1,2-trimethylpropyl)silanol (7 wt %)].
Compound 35: 1H NMR (CDCl3, 200 MHz) δ ) 0.44 (s, 6 H),
0.97 (d, 6 H), 1.03 (s, 6 H), 1.88 (septet, 1 H), 2.31, 2.37 (2 s, 6
H), 2.75, 3.03 (2 s, 6 H), 3.69 (bs, 2 H), 6.20 (dt, 1 H), 6.37 (d, J
) 15.8 Hz, 1 H), 7.22 (mc, 5 H), 7.34 (s, 1 H). Dimethyl(1,1,2-
trimethylpropyl)silanol: 1H NMR (CDCl3, 200 MHz) δ ) 0.13 (s,
6 H), 0.87 (s, 6 H), 0.90 (d, 6 H), 1.64 (mc).
1
203 °C; H NMR (CDCl3, 200 MHz) δ ) 2.23, 2.36, 2.41 (mc, 2
s, 8 H), 2.61 (mc, 1 H), 2.83, 2.95 (mc, s, 4 H), 3.14 (s, 3 H), 5.60
(dd, 1 H), 7.09 (mc, 2 H), 7.27 (mc), 7.44 (s, 1 H), 7.60 (dt, 1 H);
HRMS calcd for C21H23FN3O2 m/z (MH+) 368.1769, found
368.1766. Anal. (C21H22FN3O2) C, H, N, F.
9-(4-Fluorophenyl)-2,3-dimethyl-7H-8,9-dihydropyrano[2,3-
c]imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (38):
Preparation from 31. Compound 38 was obtained in 21% yield
from 7-allylimidazo[1,2-a]pyridine 31 by applying a procedure
similar to that described for the preparation of 37, using 4-fluo-
rostyrene instead of 2-fluorostyrene (for further details, see Sup-
1
porting Information): slightly green solid, mp 267-268 °C; H
NMR (CDCl3, 200 MHz) δ ) 2.24 (mc, 2 H), 2.36, 2.41 (2 s, 6
H), 2.68 (mc, 2 H), 2.93, 3.13 (2 s, 6 H), 5.27 (dd, 1 H), 7.04 (t, 2
H), 7.43 (mc, 3 H); HRMS calcd for C21H23FN3O2 m/z (MH+)
368.1769, found 368.1751. Anal. (C21H22FN3O2) C, H, N, F.
Preparation from 70. Compound 38 was obtained in 85%
overall yield from diol 70 by applying a procedure similar to that
described for the preparation of 37 (for further details, see
2,3-Dimethyl-9-(2-methylphenyl)-7H-8,9-dihydropyrano[2,3-
c]imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (36):
Preparation from 31. Compound 36 was obtained in 29% yield
from 7-allylimidazo[1,2-a]pyridine 31 by applying a procedure
similar to that described for the preparation of 37, using 2-methyl-
styrene instead of 2-fluorostyrene (for further details, see Supporting
Information): foamy solid; 1H NMR (CDCl3, 200 MHz) δ ) 2.18
(mc, 2 H), 2.36, 2.37, 2.40 (3 s, 9 H), 2.78, 2.99 (mc, s, 5 H), 3.15
(s, 3 H), 5.42 (dd, 1 H), 7.20 (mc, 3 H), 7.43 (s, 1 H), 7.56 (mc, 1
H); HRMS calcd for C22H26N3O2 m/z (MH+) 364.2020, found
364.2016. Anal. (C22H25N3O2) H. C: calcd, 72.70; found, 71.82.
N: calcd, 11.56; found, 10.76.
Preparation from 68. Compound 36 was obtained in 46%
overall yield from diol 68 by applying a procedure similar to that
described for the preparation of 37 (for further details, see
Supporting Information): mp 198 °C; 1H NMR (CDCl3, 200 MHz)
δ ) 2.18 (mc, 2 H), 2.36, 2.37, 2.40 (3 s, 9 H), 2.78, 2.99 (mc, s,
5 H), 3.15 (s, 3 H), 5.42 (dd, 1 H), 7.20 (mc, 3 H), 7.43 (s, 1 H),
7.56 (mc, 1 H); HRMS calcd for C22H26N3O2 m/z (MH+) 364.2020,
found 364.2008. Anal. (C22H25N3O2) H. C: calcd, 72.70; found,
71.80. N: calcd, 11.56; found, 11.06.
1
Supporting Information): colorless solid; mp 260 °C; H NMR
(CDCl3, 200 MHz) δ ) 2.24 (mc, 2 H), 2.36, 2.41 (2 s, 6 H), 2.68
(mc, 2 H), 2.93, 3.13 (2 s, 6 H), 5.27 (dd, 1 H), 7.04 (t, 2 H), 7.43
(mc, 3 H). Anal. (C21H22FN3O2) C, H, N, F.
8-Hydroxy-2,3-dimethyl-7-((E)-3-phenylallyl)imidazo[1,2-a]-
pyridine-6-carboxylic Acid Dimethylamide (39). In a flask filled
with argon, silyl ether 35 (1.10 g, 2.2 mmol) was dissolved in dry
THF (20 mL). After slow addition of a 1 M solution of tetrabu-
tylammonium fluoride in THF (3.30 mL, 3.3 mmol) a dark-green
solution was obtained, which was stirred for 30 min at room
temperature. The reaction mixture was poured onto a mixture of
ice (10 g), saturated ammonium chloride solution (15 mL), and
dichloromethane (30 mL). The biphasic mixture was stirred for
several minutes, the phases were separated, and the aqueous phase

6254 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
was extracted with dichloromethane (3 × 10 mL). The combined
organic phases were washed with water (20 mL), dried over sodium
sulfate, and concentrated under reduced pressure. The oily residue
(1.5 g) was purified by column chromatography [15 g of silica gel;
eluant, dichloromethane and then dichloromethane/methanol ) 20:1
(v/v)]. A green solid (900 mg) was obtained, which was suspended
in diethyl ether (10 mL), isolated by filtration, washed with diethyl
ether (10 mL), and dried in vacuo. The pure title compound (630
mg of a slightly gray solid) was isolated in 81% yield: mp 183-
monoisopinocampheylborane] were combined. A suspension of
alkene 39 (0.42 g, 1.2 mmol) in dry THF (15 mL) was added slowly
at room temperature, at which point a yellow solution was obtained.
After a reaction time of 5 h, the solution was poured onto a cold
mixture of aqueous potassium hydroxide solution (230 mg in 1.6
mL of water), ethanol (4 mL), and hydrogen peroxide (30 wt % in
water, 1.6 mL). After a period of 30 min, the reaction mixture was
poured onto saturated ammonium chloride solution (20 mL) and
dichloromethane (40 mL). The phases were separated, and the
aqueous phase was extracted with dichloromethane (1 × 10 mL).
The combined organic phases were washed with water, dried over
sodium sulfate, and concentrated under reduced pressure. The crude
product (1.9 g of a yellow oil) was purified by column chroma-
tography [40 g of silica gel; eluant, dichloromethane (to remove
isopinocampheol) and then dichloromethane/methanol ) 20:1 (v/
v)]. Evaporation of the corresponding fractions furnished a solid
(320 mg), which was washed with acetone (1 mL), isolated by
filtration, and dried in vacuo. The title compound was isolated in
50% yield (0.22 g of a colorless solid, optical purity 27.8% ee):
mp 216-218 °C (after crystallization from acetone); determination
of the optical purity by CE, tM [(3S)-enantiomer] ) 18.3 min/36.1
area %, tM [(3R)-enantiomer] ) 18.6 min/63.9 area %, 27.8% ee
1
185 °C; H NMR (CDCl3, 200 MHz) δ ) 2.32, 2.35 (2 s, 6 H),
2.76, 2.96 (2 s, 6 H), 3.48 (d, 2 H), 5.26 (bs), 6.23, 6.34 (mc, d, 2
H), 7.27 (mc, 5 H), 7.69 (s, 1 H); HRMS calcd for C21H24N3O2 m/z
(MH+) 350.1863, found 350.1853. Anal. (C21H23N3O2) H, N. C:
calcd, 72.18; found, 71.54.
8-Hydroxy-2-methyl-7-((E)-3-phenylallyl)imidazo[1,2-a]pyri-
dine-6-carboxylic Acid Dimethylamide (40). Pivaloic acid ester
29 was dissolved in methanol (200 mL). After dropwise addition
of a 6 N sodium hydroxide solution (12 mL), the reaction mixture
was stirred for 1 h at room temperature and for 1 h at 50 °C. The
dark solution was concentrated to a volume of 30 mL. Water (30
mL) and dichloromethane (50 mL) were added, and the biphasic
mixture was neutralized by addition of 6 N hydrochloric acid. The
phases were separated, and the aqueous phase was extracted with
dichloromethane (3 × 15 mL). The combined organic phases were
washed with water (20 mL), dried over sodium sulfate, and
evaporated to dryness. A dark solid (5 g) was obtained, which was
dissolved in a hot mixture of dichloromethane (20 mL) and acetone
(60 mL). The stirred solution was allowed to cool to room
temperature, at which point crystallization took place. Stirring was
continued for 1 h at room temperature. The precipitate was isolated
by filtration, washed with diethyl ether (10 mL), and dried in vacuo.
The title compound was isolated in the form of a colorless solid
1
(A); H NMR (DMSO-d6, 200 MHz) δ ) 1.81 (mc, 2 H), 2.30,
2.33 (2 s, 6 H), 2.50 (bmc), 2.78, 2.91 (2 s, 6 H), 4.49 (t, 1 H),
5.69 (bs), 7.25 (mc, 5 H), 7.59 (s, 1 H); HRMS calcd for C21H26N3O3
m/z (MH+) 368.1969, found 368.1952.
Synthesis via Asymmetric Keto Reduction with RuCl2[(S)-
BINAP][(S,S)-DPEN]. The ketone 61 (2.00 g, 5.5 mmol), potas-
sium tert-butylate (0.74 g, 6.6 mmol), and RuCl2[(S)-BINAP][(S,S)-
DPEN] (CAS 329736-05-2, 110 mg, 0.11 mmol, S/C ) 60:1) were
dissolved in dry 2-propanol (150 mL) that had been degassed with
argon. The homogeneous brown solution was transferred into a 300
mL autoclave, pressurized with hydrogen (45 bar), and heated to
80 °C. The reaction mixture was kept at 80 °C for 18 h, cooled to
room temperature, and concentrated under reduced pressure. The
residue was dissolved in water (50 mL) and the pH value of the
solution was adjusted to 7.5 by addition of 2 N hydrochloric acid
(2.4 mL). The aqueous phase was extracted with dichloromethane
(3 × 100 mL). The pH value was readjusted and the extraction
was repeated two more times. The combined organic phases were
dried over sodium sulfate and concentrated under reduced pressure.
The residue, a green-brown solid, was purified by column chro-
matography [100 g of silica gel; eluant, dichloromethane/methanol
) 15:1 (v/v)]. The title compound was obtained as a gray solid
(1.64 g, 36.8% ee, 82% yield) (the optical purity was determined
at the stage of the silyl ether 104): 1H NMR (DMSO-d6, 200 MHz)
δ ) 1.81 (mc, 2 H), 2.30, 2.33 (2 s, 6 H), 2.50 (bmc), 2.78, 2.91 (2
s, 6 H), 4.49 (t, 1 H), 7.25 (mc, 5 H), 7.59 (s, 1 H).
Synthesis via Asymmetric Keto Reduction with RuCl2[(S)-
BINAP][(S)-DAIPEN]. In a flame-dried flask filled with argon,
the ketone 61 (10.00 g, 27.4 mmol) was suspended in dry
2-propanol (400 mL) that had been degassed with argon. After
addition of potassium tert-butylate (3.70 g, 30.2 mmol), stirring
was continued until a yellow solution was obtained (approximately
30 min). The hydrogenation catalyst RuCl2[(S)-BINAP][(S)-
DAIPEN] (CAS 212143-24-3, 240 mg, 0.21 mmol, S/C ) 130:1)
was added. The resulting red-yellow solution was stirred for 15
min at room temperature and was transferred under inert conditions
into a 1 L autoclave equipped with a glass inlay. The reaction
mixture was pressurized with hydrogen (40 bar) and was stirred
for 24 h at room temperature. The brown solution was concentrated
to a volume of 50 mL and poured onto a cold mixture of saturated
ammonium chloride solution (120 mL) and dichloromethane (250
mL). A neutral pH value was adjusted by addition of 6 N
hydrochloric acid. The phases were separated, and the aqueous
phase was extracted with dichloromethane (2 × 40 mL). The
combined organic phases were washed with water (30 mL), dried
over sodium sulfate, and concentrated under reduced pressure. The
residue, a green oil (15 g), was purified by column chromatography
[150 g of silica gel; eluant, dichloromethane/methanol ) 20:1 (v/
v)]. Evaporation of the corresponding fractions afforded
1
(2.6 g, 55% yield): mp 188-190 °C; H NMR (DMSO-d6, 200
MHz) δ ) 2.35 (s, 3 H), 2.75 (s, 3 H), 2.94 (s, 3 H), 3.48 (d, 2 H),
6.28 (mc, 2 H), 7.26 (mc, 5 H), 7.59 (s, 1 H), 7.97 (s, 1 H); HRMS
calcd for C20H22N3O2 m/z (MH+) 336.1707, found 336.1682.
8-Hydroxy-7-(3-hydroxy-3-phenylpropyl)-2,3-dimethylimidazo-
[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (41). Over a
period of 20 min, sodium borohydride (0.40 g, 10.6 mmol) was
added to a solution of the ketone 61 (3.10 g, 8.5 mmol) in methanol
(30 mL). The reaction mixture was stirred for 40 min at ambient
temperature. Another portion of sodium borohydride (0.10 g, 2.6
mmol) was added and stirring was continued for another 30 min.
The reaction mixture was then poured on a mixture of saturated
ammonium chloride solution (50 mL), ice (20 g), and dichlo-
romethane (100 mL). The phases were separated, and the aqueous
phase was extracted with dichloromethane (3 × 20 mL). The
combined organic phases were washed with saturated ammonium
chloride solution (2 × 20 mL) and water (2 × 20 mL), dried over
sodium sulfate, and evaporated to dryness. The residue was treated
with acetone (12 mL). A colorless precipitate was formed that was
washed with acetone and diethyl ether and dried. The title
compound (2.10 g, 67% yield) was isolated as a colorless solid.
The mother liquor (0.8 g) was purified by column chromatography
[silica gel; eluant, dichloromethane/2-propanol ) 20:1 (v/v)],
yielding another 0.29 g (9% yield) of the title compound: mp 219-
1
221 °C (after crystallization from acetone); H NMR (DMSO-d6,
200 MHz) δ ) 1.81 (mc, 2 H), 2.30, 2.33 (2 s, 6 H), 2.50 (bmc),
2.78, 2.91 (2 s, 6 H), 4.49 (t, 1 H), 5.69 (bs), 7.25 (mc, 5 H), 7.59
(s, 1 H); HRMS calcd for C21H25N3O3 m/z (MH+) 368.1969, found
368.1968.
8-Hydroxy-7-((R)-3-hydroxy-3-phenylpropyl)-2,3-dimethyl-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide
(41a): Synthesis via Asymmetric Hydroboration. A flame-dried
flask filled with argon was charged with (R)-Alpine-boramine (CAS
67826-92-0, 1.50 g, 3.6 mmol). After addition of dry THF (8 mL),
a colorless solution was obtained, which was treated with boron
trifluoride diethyl etherate (0.92 mL, 1.03 g, 7.3 mmol). The solution
was stirred for 2 h at room temperature. A colorless precipitate
was obtained, which was removed by filtration and washed with
cold THF (6 mL, argon atmosphere). The filtrates [containing (-)-

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6255
the title compound (9.30 g of a pale-green solid, 92% yield, optical
purity 85.8% ee): determination of the optical purity by CE, tM
[(3S)-enantiomer] ) 20.2 min/7.1 area %, tM [(3R)-enantiomer] )
5 H), 7.81 (s, 1 H); HRMS calcd for C21H24N3O3 m/z (MH+)
366.1812, found 366.1800. Anal. (C21H23N3O3·0.5H2O) C, H, N.
6-Dimethylcarbamoyl-2-methyl-9-phenyl-7H-8,9-dihydropy-
rano[2,3-c]imidazo[1,2-a]pyridine-3-carboxylic Acid (45). A
solution of the aldehyde 43 (1.10 g, 3.0 mmol) in THF (30 mL)
and water (20 mL) was treated with sulfamic acid (0.50 g, 5.1
mmol) and cooled to 0 °C. An aqueous solution (5 mL) of sodium
chlorite (80% purity, 0.47 g, 4.2 mmol) was added dropwise. The
reaction mixture was stirred for 1.25 h at 0 °C. After addition of
an aqueous solution (5 mL) of sodium sulfite (0.65 g, 5.2 mmol),
stirring was continued for 5 min. The reaction mixture was extracted
with dichloromethane (2 × 50 mL). The organic phases were dried
over sodium sulfate and concentrated under reduced pressure. The
residue (750 mg) was dissolved in dichloromethane (10 mL) and
water (10 mL). A pH value of 8 was adjusted by addition of 2 N
sodium hydroxide solution (0.6 mL). The phases were separated,
and the aqueous phase was extracted with dichloromethane (2 ×
10 mL). The organic phases were discarded, and the aqueous phase
was acidified to pH 5 by addition of 2 N hydrochloric acid (1 mL).
The aqueous phase was extracted with dichloromethane (2 × 20
mL), diluted with saturated sodium chloride solution (5 mL), and
extracted again with another portion of dichloromethane. The
combined dichloromethane phases were dried over sodium sulfate
and concentrated under reduced pressure to yield the title compound
(450 mg of a colorless solid, 39% yield). The aqueous phase was
concentrated to a volume of 5 mL. After addition of dichlo-
romethane (10 mL), the pH value was readjusted to 5 by addition
of 2 N hydrochloric acid (0.5 mL). Following the procedure
described above, another 300 mg of the title compound was obtained
1
20.5 min/92.9 area %, 85.8% ee (A); H NMR (DMSO-d6, 200
MHz) δ ) 1.81 (mc, 2 H), 2.30, 2.33 (2 s, 6 H), 2.50 (bmc), 2.78,
2.91 (2 s, 6 H), 4.49 (t, 1 H), 5.69 (bs), 7.25 (mc, 5 H), 7.59 (s, 1
H); HRMS calcd for C21H26N3O3 m/z (MH+) 368.1969, found
368.1959.
8-Hydroxy-7-((S)-3-hydroxy-3-phenylpropyl)-2,3-dimethyl-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (41b).
Compound 41b was obtained in 87% yield from ketone 61 by
applying a procedure similar to that described for the preparation
of 41a, using RuCl2[(R)-BINAP][(R)-DAIPEN] (CAS 329735-86-
6) instead of RuCl2[(S)-BINAP][(S)-DAIPEN] (for further details,
see Supporting Information): colorless solid; mp 215-217 °C (after
crystallization from acetone); determination of the optical purity
by CE, tM [(3S)-enantiomer] ) 18.5 min/97.7 area %, tM [(3R)-
enantiomer] ) 19.0 min/2.3 area %, 95.5% ee (A); 1H NMR
(DMSO-d6, 200 MHz) δ ) 1.81 (mc, 2 H), 2.30, 2.33 (2 s, 6 H),
2.50 (bmc), 2.78, 2.91 (2 s, 6 H), 4.49 (t, 1 H), 5.43 (bs), 7.25 (mc,
5 H), 7.59 (s, 1 H); HRMS calcd for C21H26N3O3 m/z (MH+)
368.1969, found 368.1963.
8-Hydroxy-7-((R)-3-hydroxy-3-phenylpropyl)-2-methylimidazo-
[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (42a). Com-
pound 42a was obtained in 18% yield from alkene 40 by applying
a procedure similar to that described for the preparation of 41a
(asymmetric hydroboration) (for further details, see Supporting
Information): colorless solid; mp 223-224 °C; determination of
the optical purity by CE, tM [(3S)-enantiomer] ) 17.6 min/33.2
area %, tM [(3R)-enantiomer] ) 17.8 min/64.8 area %, 32.2% ee
(A); 1H NMR (DMSO-d6, 200 MHz) δ ) 1.81 (mc, 2 H), 2.33 (s,
mc, 4 H), 2.65 (mc), 2.77, 2.89 (2 s, 6 H), 4.50 (t, 1 H), 7.25 (mc,
5 H), 7.55 (s, 1 H), 7.88 (s, 1 H); HRMS calcd for C20H24N3O3
m/z (MH+) 354.1812, found 354.1810.
1
(26% yield): mp 138 °C; H NMR (CDCl3, 200 MHz) δ ) 2.31
(mc, 2 H), 2.69, 2.74 (mc, s, 4 H), 2.91, 2.96 (mc, s, 4 H), 3.16 (s,
3 H), 5.33 (dd, 1 H), 7.29 (mc), 7.43 (mc, 2 H), 8.93 (s, 1 H).
2-Methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-
a]pyridine-3,6-dicarboxylic Acid Bis(dimethylamide) (46). A
solution of carboxylic acid 45 (0.120 g, 0.32 mmol) in dichlo-
romethane (20 mL) was treated with TBTU (0.107 g, 0.33 mmol).
The suspension was stirred for 1 h at room temperature. A 2 M
solution of dimethylamine in THF (0.32 mL, 0.64 mmol) was added
and stirring was continued for 1.5 h at room temperature. The
reaction mixture was quenched by addition of water (20 mL). The
phases were separated, and the aqueous phase was extracted with
dichloromethane (2 × 10 mL). The combined organic phases were
dried over sodium sulfate and concentrated under reduced pressure.
This afforded the title compound in 97% yield (124 mg of a
3-Formyl-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (43). A
flask containing dry DMF (10 mL) was cooled to 0 °C, and
phosphorus oxychloride (1.14 g, 7.4 mmol) was added. The cooling
bath was removed and the solution was stirred for 1 h at room
temperature. The red reaction mixture was treated with a solution
of 7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridine 30 (1.00 g,
3.0 mmol) in dry DMF (10 mL) and was heated to 60 °C. After a
period of 3 h, the reaction mixture was poured on ice water (50
mL), neutralized by addition of 2 N sodium hydroxide solution,
and extracted with dichloromethane (3 × 40 mL). The combined
organic phases were dried over sodium sulfate and concentrated in
vacuo. The title compound (1.0 g, 92% yield) was obtained as a
1
yellowish solid): mp 190 °C; H NMR (CDCl3, 200 MHz) δ )
2.26 (mc, 2 H), 2.47 (s, 3 H), 2.61 (mc, 1 H), 2.80 (mc), 2.95 (s, 3
H), 3.10, 3.12 (2 s, 9 H), 5.33 (dd, 1 H), 7.39 (mc, 5 H), 8.06 (s,
1 H); HRMS calcd for C23H27N4O3 m/z (MH+) 407.2078, found
407.2066.
1
brown solid: mp 222-224 °C; H NMR (CDCl3, 200 MHz) δ )
2.31 (mc, 2 H), 2.72 (s, mc, 4 H), 2.89, 2.95 (mc, s, 4 H), 3.15 (s,
3 H), 5.34 (dd, 1 H), 7.39 (mc, 5 H), 9.09 (s, 1 H), 9.99 (s, 1 H);
HRMS calcd for C21H22N3O3 m/z (MH+) 364.1656, found 364.1651.
2-Methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-
a]pyridine-3,6-dicarboxylic Acid 3-[(2-Methoxyethyl)amide]
6-Dimethylamide (47). Compound 47 was obtained in 70% yield
from carboxylic acid 45 by applying a procedure similar to that
described for the preparation of 46 (for further details, see
3-Hydroxymethyl-2-methyl-9-phenyl-7H-8,9-dihydropyrano-
[2,3-c]imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide
(44). A suspension of the aldehyde 43 (1.00 g, 2.8 mmol) in dry
ethanol (30 mL) was treated with sodium borohydride (52 mg, 1.37
mmol). The reaction mixture was stirred for 40 min at room
temperature. A clear solution was obtained which was poured on
water (20 mL) and dichloromethane (50 mL). The phases were
separated, and the aqueous phase was extracted with dichlo-
romethane (2 × 20 mL). The combined organic phases were dried
over sodium sulfate and concentrated under reduced pressure. A
yellowish, foamy solid remained which was crystallized from
acetone (5 mL). The colorless precipitate was isolated by filtration
and dried in vacuo, yielding 420 mg of the pure title compound
(42% yield). The mother liquor was concentrated and the residue
was purified by column chromatography [silica gel; eluant, ethyl
acetate/methanol ) 10:1 (v/v)]. This furnished a further 160 mg
1
Supporting Information): colorless solid; mp 208 °C; H NMR
(CDCl3, 200 MHz) δ ) 2.27 (mc, 2 H), 2.61, 2.71 (mc, s, 4 H),
2.84, 2.96 (mc, s, 4 H), 3.11 (s, 3 H), 3.42 (s, 3 H), 3.64 (mc, 4 H),
5.32 (dd, 1 H), 6.23 (bt, 1 H), 7.39 (mc, 5 H), 9.01 (s, 1 H). Anal.
(C24H28N4O4) H. C: calcd, 66.04; found, 65.23. N: calcd, 12.84;
found, 12.34.
3-(1-Hydroxy-2-butynyl)-2-methyl-9-phenyl-7H-8,9-dihydro-
pyrano[2,3-c]imidazo[1,2-a]pyridine-6-carboxylicAcidDimethyl-
amide (48). In a flame-dried flask filled with argon, aldehyde 43
was suspended in dry THF (50 mL). The suspension was cooled
to -78 °C and propinylmagnesium bromide (11.0 mL of a 0.5 M
solution in THF, 5.5 mmol) was added using a syringe. The reaction
mixture was stirred for 1 h at -78 °C and for 2 h at 0 °C and then
quenched by addition of water (30 mL) and dichloromethane (70
mL). The phases were separated, and the aqueous phase was
extracted with dichloromethane (2 × 50 mL). The combined organic
phases were washed with water (20 mL) and saturated sodium
1
of the title compound (yellow solid, 16% yield): mp 186 °C; H
NMR (CDCl3, 200 MHz) δ ) 2.30, 2.37 (mc, s, 5 H), 2.68 (mc, 2
H), 2.90, 3.10 (2 s, 6 H), 4.85 (s, 2 H), 5.30 (dd, 1 H), 7.38 (mc,

6256 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
chloride solution (20 mL), dried over sodium sulfate, and concen-
trated in vacuo. A yellow foamy solid (1.07 g of a diasteromeric
mixture of the title compound, 96% yield) was isolated: 1H NMR
(CDCl3, 200 MHz) δ ) 1.84, 1.85 (2 s), 2.25 (mc, 2 H), 2.39 (s, 3
H), 2.60, 2.81 (2 mc, 2 H), 2.93, 2.96 (2 s, ∑ 3 H), 3.12 (s, 3 H),
3.74 (mc), 5.30 (mc, 1 H), 5.85 (mc, 1 H), 7.38 (mc, 5 H), 8.14,
8.15 (2 s, ∑ 1 H); HRMS calcd for C24H26N3O3 m/z (MH+)
404.1969, found 404.1970.
2-Methyl-3-(1-oxo-2-butynyl)-9-phenyl-7H-8,9-dihydropyrano-
[2,3-c]imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide
(49). A solution of alcohol 48 (500 mg, 1.24 mmol) in dichlo-
romethane (20 mL) was treated with manganese dioxide (4.0 g, 46
mmol). The suspension was stirred for 1 h at room temperature
and then filtered over Celite. Concentration of the filtrate yielded
a yellow foamy solid, which was purified by column chromatog-
raphy (silica gel; eluant, ethyl acetate). After evaporation of the
corresponding fractions, the title compound was isolated in 86%
yield (430 mg of a yellow solid): mp 216-217 °C; 1H NMR
(CDCl3, 200 MHz) δ ) 2.16 (s, 3 H), 2.30 (mc, 2 H), 2.70
(mc, 1 H), 2.90, 2.91, 2.94 (s, mc, s, 7 H), 3.14 (s, 3 H), 3.48 (s),
5.34 (dd, 1 H), 7.39 (mc, 5 H), 9.28 (s, 1 H); HRMS calcd
for C24H24N3O3 m/z (MH+) 402.1812, found 402.1810. Anal.
(C24H23N3O3‚H2O) C, H, N.
3-Bromo-2-methyl-9-phenyl-7H-8,9-dihydro-pyrano[2,3-c]-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (50).
7H-8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridine 30 (2.00 g, 6.0
mmol) was dissolved in a mixture of chloroform (10 mL) and
dichloromethane (10 mL). The solution was cooled to -78 °C and
N-bromosuccinimide (1.06 g, 6.0 mmol) was added. The reaction
mixture was stirred for 45 min at -78 °C. The cooling bath was
removed and saturated sodium bicarbonate solution (15 mL) was
added. The phases were separated, and the aqueous phase was
extracted with dichloromethane (10 mL). The combined organic
phases were dried over sodium sulfate and concentrated under
reduced pressure. A light green foamy solid (2.7 g) was isolated,
which was purified by column chromatography [80 g of silica gel;
eluant, ethyl acetate/petroleum ether ) 6:4 (v/v)]. The title
compound was isolated as a beige solid (1.75 g, 71% yield).
Futhermore, 0.5 g of a mixture of the title compound (96 wt %)
and succinimide (4 wt %) was isolated (19% yield): mp 167-168
°C; 1H NMR (CDCl3, 200 MHz) δ ) 2.28 (mc, 2 H), 2.45 (s, 3 H),
2.69 (mc, 2 H), 2.93, 3.14 (2 s, 6 H), 5.32 (dd, 1 H), 7.38 (mc, 5
H), 7.65 (s, 1 H). Anal. (C20H20BrN3O2) C, H, N, Br.
2-Methyl-9-phenyl-3-vinyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (51). In
a flame-dried flask filled with argon, 3-bromo-7H-8,9-dihydropy-
rano[2,3-c]imidazo[1,2-a]pyridine 50 (1.60 g, 3.9 mmol) was
dissolved in dry 1,4-dioxane (50 mL). The solution was treated
with tributylvinylstannane (1.48 g, 4.7 mmol) and bis(triph-
enylphosphino)palladium chloride (270 mg, 0.38 mmol) and stirred
at a temperature of 100 °C (preheated oil bath). After 2 h, another
portion of tributylvinylstannane (0.70 g, 2.2 mmol) and bis-
(triphenylphosphino)palladium chloride (140 mg, 0.20 mmol) was
added. The reaction was continued for 1 h at 100 °C. The reaction
mixture was cooled to room temperature and concentrated in the
presence of silica gel (3 g). The crude product was purified by
column chromatography [120 g of silica gel; eluant, petroleum ether,
then petroleum ether/ethyl acetate ) 1:1 (v/v), and then petroleum
ether/ethyl acetate ) 2:8 (v/v)]. In order to achieve further
purification, the title compound obtained after chromatography (1.3
g) was dissolved in ethyl acetate (20 mL) and water (15 mL). The
pH was adjusted to 1.5 by addition of 2 N hydrochloric acid. The
phases were separated, and the aqueous phase was extracted with
ethyl acetate (10 mL). The organic phase was discarded and
dichloromethane (20 mL) was added to the aqueous phase. The
pH value was adjusted to 8 by addition of 2 N sodium hydroxide
solution. The phases were separated, and the aqueous phase was
extracted with dichloromethane (2 × 10 mL). The combined organic
phases were dried over sodium sulfate and concentrated under
reduced pressure. This afforded the pure title compound in 72%
yield (1.0 g of a yellow solid): 1H NMR (CDCl3, 200 MHz) δ )
2.30 (mc, 2 H), 2.54, 2.63 (s, mc, 4 H), 2.79 (mc, 1 H), 2.92, 3.13
(2 s, 6 H), 5.34 (dd, 1 H), 5.42 (d, 1 H), 5.56 (d, 1 H), 6.78 (dd,
1 H), 7.38 (mc, 5 H), 7.75 (s, 1 H).
3-Ethyl-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (52). 3-Vi-
nyl-7H-8,9-dihydropyrano[2,3-c]imidazo[1,2-a]pyridine 51 (0.280
g, 0.77 mmol) was dissolved in dry methanol (20 mL). After
addition of Lindlar catalyst (Pd/CaCO3/Pb, 56 mg, 20 wt %), a
hydrogen pressure of 1 bar was applied. The reaction mixture was
stirred for 2 h at room temperature and another 28 mg (10 wt %)
of catalyst was added. The hydrogenation was continued for 2 h.
The catalyst was removed by filtration, the filtrate was concentrated,
and the remaining yellow solid was dried in vacuo. The title
1
compound was isolated in 89% yield (250 mg): mp 230 °C; H
NMR (CDCl3, 200 MHz) δ ) 1.20 (t, 3 H), 2.26 (mc, 2 H), 2.41
(s, 3 H), 2.57 (mc, 1 H), 2.73, 2.84, 2.92 (mc, q, s, 6 H), 3.13 (s, 3
H), 5.32 (dd, 1 H), 7.38 (mc, 6 H). Anal. (C22H25N3O2) H. C: calcd,
72.70; found, 72.03. N: calcd, 11.56; found, 11.05.
3-Acetyl-2-methyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (53). 7H-
8,9-Dihydropyrano[2,3-c]imidazo[1,2-a]pyridine 30 (1.10 g, 3.3
mmol) was dissolved in acetic anhydride (50 mL). After addition
of methanesulfonic acid (0.38 g, 3.9 mmol), the solution was heated
for 1.5 d at 140 °C. The reaction mixture was concentrated and
saturated sodium bicarbonate solution (90 mL) was added in order
to adjust the pH value to 7-8. The aqueous phase was extracted
with dichloromethane (2 × 70 mL, 1 × 30 mL). The combined
organic phases were dried over sodium sulfate and concentrated
under reduced pressure. The brown residue was purified by column
chromatography (silica gel; eluant, ethyl acetate), yielding 0.57 g
of the title compound (colorless solid, 46% yield): mp 249-
1
251 °C; H NMR (CDCl3, 200 MHz) δ ) 2.29 (mc, 2 H), 2.61-
3.00, 2.61, 2.80, 2.94 (m, 3 s, 11 H), 3.14 (s, 3 H), 5.34 (dd, 1 H),
7.38 (mc, 5 H), 9.32 (s, 1 H); HRMS calcd for C22H24N3O3 m/z
(MH+) 378.1812, found 378.1793.
3-Dimethylaminomethyl-2-methyl-9-phenyl-7H-8,9-dihydro-
pyrano[2,3-c]imidazo-[1,2-a]pyridine-6-carboxylic Acid Di-
methylamide, Iodide Salt (54). 7H-8,9-Dihydropyrano[2,3-c]-
imidazo[1,2-a]pyridine 30 (0.250 g, 0.75 mmol) was dissolved in
dry dichloromethane (10 mL), and Eschenmoser’s salt (0.138 g,
0.75 mmol) was added. The reaction mixture was stirred for 30
min at room temperature and then evaporated to dryness. This
afforded the title compound in 97% yield (377 mg of a colorless
solid): mp 183-184 °C; 1H NMR (DMSO-d6, 200 MHz) δ ) 2.14,
2.27 (2 mc, 2 H), 2.40 (s, 3 H), 2.55 (bs), 2.77, 2.90 (bs, s, 10 H),
3.04 (s, 3 H), 4.64 (bs, 2 H), 5.31 (dd, 1 H), 7.43 (mc, 5 H), 8.29
(s, 1 H), 9.59 (bs, 1 H); HRMS calcd for C23H29N4O2 m/z (MH+)
393.2285, found 393.2282.
7-Dimethylaminomethyl-8-hydroxy-2,3-dimethylimidazo[1,2-
a]pyridine-6-carboxylic Acid Dimethylamide (55). Over a period
of 30 min, Eschenmoser’s salt (5.6 g, 30 mmol) was added to a
solution of 8-hydroxyimidazo[1,2-a]pyridine 18 (5.5 g, 24 mmol)
in dichloromethane (100 mL). The reaction mixture was stirred for
70 min at ambient temperature (formation of a yellow precipitate)
and then poured on cooled, saturated sodium hydrogencarbonate
solution (50 mL). The aqueous phase was extracted with dichlo-
romethane (6 × 20 mL). The combined organic phases were washed
with water (30 mL), dried over sodium sulfate, and evaporated to
dryness. The title compound (6.5 g, 95% yield) was isolated as a
colorless solid: mp 210 °C (dec); 1H NMR (DMSO-d6, 200 MHz)
δ ) 2.25 (s, 6 H), 2.29 (s, 3 H), 2.34 (s, 3 H), 2.85 (s, 3 H), 2.99
(s, 3 H), 3.53 (s, 2 H), 7.62 (s, 1 H); HRMS calcd for C15H23N4O2
m/z (MH+) 291.1816, found 291.1804.
7-Dimethylaminomethyl-8-hydroxy-2,3-dimethylimidazo[1,2-
a]pyridine-6-carboxylic Acid Ethyl Ester (56). Compound 56 was
obtained in 93% yield from 8-hydroxyimidazo[1,2-a]pyridine 21
by applying a procedure similar to that described for the preparation
of 55 (for further details, see Supporting Information): 1H NMR
(CDCl3, 200 MHz) δ ) 1.41 (t, 3 H), 2.40 (s, 12 H), 4.19 (s, 2 H),
4.37 (q, 2 H), 8.04 (s, 1 H).

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6257
7-Dimethylaminomethyl-8-hydroxy-2,3-dimethylimidazo[1,2-
a]pyridine (57). Compound 57 was obtained in 62% yield from
8-hydroxyimidazo[1,2-a]pyridine 23 by applying a procedure
similar to that described for the preparation of 55 (for further details,
see Supporting Information). The crude title compound was
subjected directly to the next reaction step (synthesis of the ketone
67).
crude product (5 g of a brown solid) was purified by column
chromatography (silica gel; eluant, dichloromethane). The title
compound (3.2 g, 79% yield) was obtained as a brownish foam;
1
traces of impurities were visible in the H NMR spectrum of this
compound: 1H NMR (DMSO-d6, 200 MHz) δ ) 2.32 (s, 3 H),
2.36 (s, 3 H), 2.82 (mc, 2 H), 2.89 (s, 3 H), 3.01 (s, 3 H), 3.21 (mc,
2 H), 7.59 (mc, 3 H), 7.95 (d, 2 H), 7.99 (s, 1 H); HRMS calcd for
C21H24N3O3 m/z (MH+) 366.1812, found 366.1815.
8-Hydroxy-2,3-dimethyl-7-(3-oxo-3-phenylpropyl)imidazo-
[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (61): Method
A. (a) In a flame-dried flask filled with argon, a suspension of
8-hydroxyimidazo[1,2-a]pyridine 18 (50.0 g, 214 mmol) in dry
dichloromethane (1.2 L) was treated with Eschenmoser’s salt (40.3
g, 218 mmol). The reaction mixture was stirred for 1 h at room
temperature. In the beginning, a clear solution was obtained; within
10 min, the formation of a precipitate was observed. The solvent
was then removed under reduced pressure. (b) The rotary evaporator
was filled with argon. The residue (hydroiodide salt of compound
55) was dissolved in dry DMF (1.1 L), which had been preheated
to 50 °C. An almost clear solution was obtained, which was treated
with potassium carbonate (30.4 g, 220 mmol) and 1-(1-phenylvinyl)-
pyrrolidine (CAS 3433-56-5, 82.5 g, purity 90 wt %, 428 mmol).
In a preheated oil bath, the brown solution was stirred for 30 min
at 50 °C and then poured onto a stirred mixture of ammonium
chloride (130 g), water (200 mL), ice (300 g), and dichloromethane
(600 mL). Stirring was continued for several minutes and the pH
value was adjusted to pH ) 8 by addition of 6 N hydrochloric
acid. The phases were separated, and the aqueous phase was
extracted with dichloromethane (3 × 100 mL). The combined
organic phases were washed with water (2 × 100 mL), dried over
sodium sulfate, and concentrated under reduced pressure (DMF was
removed at a temperature of 60 °C). A dark-brown, oily residue
(80 g) was obtained which was dried in vacuo. (c) The residue
(crude title compound) was purified by filtration over silica gel
[500 g; eluant, ethyl acetate and then ethyl acetate/methanol ) 8:2
(v/v)]. A red-brown solid was isolated (60 g of crude title
compound, HPLC purity 88.08%) which was dried in vacuo,
dissolved in methanol (200 mL), and treated with fumaric acid (25.5
g, 220 mmol). The brown suspension was stirred for 20 min at
40 °C, at which point a clear solution was obtained. The solution
was concentrated under reduced pressure until a dense suspension
was formed. Acetone (120 mL) was added and the mixture was
concentrated again until a dense suspension was formed. The slurry
was diluted with acetone (150 mL) and stirred at 40 °C (30 min),
room temperature (19 h), and 0 °C (2 h). The salt of the title
compound with fumaric acid (molar ratio 1:1) was isolated by
filtration, washed with acetone (20 mL) and diethyl ether (50 mL),
and dried in vacuo (51 g of a colorless solid, 49% yield, mp 196-
198 °C). (d) The salt of the title compound with fumaric acid (50
g, 104 mmol) was added portionwise to a mixture of sodium
bicarbonate (42 g, 500 mmol), water (400 mL), and dichlo-
romethane (400 mL). The biphasic mixture was stirred for 5 min.
The phases were separated, and the aqueous phase was extracted
with dichloromethane (2 × 50 mL). The organic phases were
washed with water (2 × 100 mL), dried over sodium sulfate, and
concentrated under reduced pressure. This afforded the title
compound in the form of a colorless, foamy solid (37.7 g, 99%
8-Hydroxy-2,3-dimethyl-7-[3-(2-methylphenyl)-3-oxopropyl]-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (62).
Compound 62 was obtained in 54% yield from 8-hydroxyimidazo-
[1,2-a]pyridine 18 by applying a procedure similar to that described
for the preparation of 61 (method A), using 1-[1-(2-methylphenyl)-
vinyl]pyrrolidine (CAS 156004-72-7) instead of 1-(1-phenylvinyl)-
pyrrolidine (for further details, see Supporting Information): col-
orless solid; mp 179-180 °C/182-183 °C; HPLC purity batch 1,
97.3%, batch 2, 99.6% (tR ) 10.7 min); 1H NMR (DMSO-d6, 200
MHz) δ ) 2.32, 2.35, 2.41 (3 s, 9 H), 2.79, 2.88 (mc, s, 5 H), 3.01,
3.08 (s, mc, 5 H), 5.45 (bs), 7.37 (mc, 3 H), 7.71 (mc, 2 H); HRMS
calcd for C22H26N3O3 m/z (MH+) 380.1969, found 380.1957. Anal.
(C22H25N3O3·H2O) C, H, N.
7-[3-(2-Fluorophenyl)-3-oxopropyl]-8-hydroxy-2,3-dimethyl-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (63).
Compound 63 was obtained in 51% yield from 8-hydroxyimidazo-
[1,2-a]pyridine 18 by applying a procedure similar to that described
for the preparation of 61 (method A), using 1-[1-(2-fluorophenyl)-
vinyl]pyrrolidine (CAS 237436-15-6) instead of 1-(1-phenylvinyl)-
pyrrolidine (for further details, see Supporting Information): beige
1
solid; mp 196 °C; HPLC purity 98.12% (tR ) 9.4 min); H NMR
(DMSO-d6, 200 MHz) δ ) 2.32, 2.35 (2 s, 6 H), 2.89 (bmc, s, 5
H), 2.99 (s, 3 H), 3.18 (bmc, 2 H), 5.48 (bs), 7.33 (mc, 2 H), 7.65,
7.69(mc, s, 2 H), 7.81 (dt, 1 H); HRMS calcd for C21H23FN3O3
m/z (MH+) 384.1718, found 384.1705.
7-[3-(4-Fluorophenyl)-3-oxopropyl]-8-hydroxy-2,3-dimethyl-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (64).
Compound 64 was obtained in 46% yield from 8-hydroxyimidazo-
[1,2-a]pyridine 18 by applying a procedure similar to that described
for the preparation of 61 (method A), using 1-[1-(4-fluorophenyl)-
vinyl]pyrrolidine (CAS 237436-54-3) instead of 1-(1-phenylvinyl)-
pyrrolidine (for further details, see Supporting Information): beige
solid: mp 221 °C; HPLC purity 97.83% (tR ) 9.9 min); 1H NMR
(DMSO-d6, 200 MHz) δ ) 2.32, 2.35 (2 s, 6 H), 2.85, 2.88 (mc, s,
5 H), 3.00 (s, 3 H), 3.19 (t, 2 H), 6.42 (bs, 1 H), 7.34 (t, 2 H), 7.70
(s, 1 H), 8.05 (q, 2 H); HRMS calcd for C21H23FN3O3 m/z (MH+)
384.1718, found 384.1722.
8-Hydroxy-2,3-dimethyl-7-(3-oxo-3-thiophen-2-ylpropyl)imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (65). Com-
pound 65 was obtained in 45% yield from the crude intermediate
55 by applying a procedure similar to that described for the
preparation of 61 (method A), using 1-(1-thiophen-2-ylvinyl)-
pyrrolidine instead of 1-(1-phenylvinyl)pyrrolidine (for further
details, see Supporting Information): beige solid; mp 234 °C; HPLC
1
purity 99.04% (tR ) 8.3 min); H NMR (DMSO-d6, 200 MHz) δ
) 2.32, 2.36 (2 s, 6 H), 2.81, 2.89 (mc, s, 5 H), 3.01 (s, 3 H), 3.14
(t, 2 H), 5.85 (bs), 7.24 (dd, 1 H), 7.71 (s, 1 H), 7.93 (dd, 1 H),
8.00 (dd, 1 H); HRMS calcd for C19H22N3O3S m/z (MH+) 372.1376,
found 372.1364.
1
yield, 49% overall yield). The sample was pure by means of H
NMR spectroscopy and showed an HPLC purity of 99.07% (tR )
9.4 min): mp 115-117 °C; 1H NMR (CDCl3, 200 MHz) δ ) 2.32,
2.37 (2 s, 6 H), 2.95 (s), 3.05 (bs), 3.14 (s, Σ 8 H), 3.42 (mc, 2 H),
7.29 (s, 1 H), 7.47 (mc, 3 H), 8.00 (mc, 2 H); HRMS calcd for
C21H24N3O3 m/z (MH+) 366.1812, found 366.1821.
Method B. In a flame-dried flask under argon, intermediate 55
(free base, 3.2 g, 11 mmol) and 1-(1-phenylvinyl)pyrrolidine (3.1
g, 18 mmol) were dissolved in absolute toluene (50 mL). The
solution was heated to 105 °C. After 15 min the reaction mixture
was cooled to 0 °C and poured on a mixture of ice-water (50 mL)
and dichloromethane (50 mL). The brown organic phase was
removed and the aqueous phase was extracted with dichlo-
romethane. The combined organic phases were washed with water
(20 mL), dried over sodium sulfate, and evaporated to dryness. The
8-Hydroxy-2,3-dimethyl-7-(3-oxo-3-phenylpropyl)imidazo-
[1,2-a]pyridine-6-carboxylic Acid Ethyl Ester (66): Method A.
Compound 66 was obtained in 55% yield from 8-hydroxy-imidazo-
[1,2-a]pyridine 21 by applying a procedure similar to that described
for the preparation of 61 (method A) (for further details, see
Supporting Information): colorless solid; mp 172-174 °C; HPLC
purity 98.33% (tR ) 14.1 min); 1H NMR (DMSO-d6, 200 MHz) δ
) 1.29 (t, 3 H), 2.34, 2.41 (2 s, 6 H), 3.23 (s, 4 H), 4.29 (q, 2 H),
6.30 (bs, 1 H), 7.51 (t, 2 H), 7.64 (t, 1 H), 7.98 (d, 2 H), 8.19 (s,
1 H); HRMS calcd for C21H23N2O4 m/z (MH+) 367.1652, found
367.1657.
Method B. Compound 66 was obtained in 84% yield from
intermediate 56 by applying a procedure similar to that described
for the preparation of 61 (method B) (for further details, see

6258 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
Supporting Information): brownish foam (90% purity according
to 1H NMR analysis); 1H NMR (CDCl3, 200 MHz) δ ) 1.39 (t, 3
H), 2.39 (s, 6 H), 3.46 (mc, 4 H), 4.39 (q, 2 H), 7.46 (mc, 3 H),
8.03 (d, 2 H), 8.10 (s, 1 H); HRMS calcd for C21H23N2O4 m/z
(MH+) 367.1652, found 367.1653.
3-(8-Hydroxy-2,3-dimethylimidazo[1,2-a]pyridin-7-yl)-1-phe-
nylpropan-1-one (67). Compound 67 was obtained in 48% yield
from intermediate 57 by applying a procedure similar to that
described for the preparation of 61 (method B) (for further details,
see Supporting Information). The crude title compound was
obtained as a brownish foam and was immediately subjected to
the next reaction step (reduction to the diol 73). HRMS calcd for
C18H19N2O2 m/z (MH+) 295.1441, found 295.1433.
8-Hydroxy-7-[3-hydroxy-3-(2-methylphenyl)propyl]-2,3-di-
methylimidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide
(68). Compound 68 was obtained from ketone 62 by applying a
procedure similar to that described for the preparation of 41 (for
further details, see Supporting Information). The crude title
compound was isolated in the form of a yellow foam, which was
directly used as starting material for the synthesis of 36. 1H NMR
(CDCl3 + traces of MeOD, 200 MHz) δ ) 2.00 (bmc, 2 H), 2.16
(s, 3 H), 2.35 (s, 3 H), 2.55 (s, 3 H), 2.91, 3.05, 3.12 (s, bmc, s, 8
H), 4.81 (dd, 1 H), 7.07 (mc, 4 H), 7.51 (d, 1 H); HRMS calcd for
C22H28N3O3 m/z (MH+) 382.2125, found 382.2112.
7-[3-(2-Fluorophenyl)-3-hydroxypropyl]-8-hydroxy-2,3-di-
methylimidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide
(69). Compound 69 was obtained from ketone 63 by applying a
procedure similar to that described for the preparation of 41 (for
further details, see Supporting Information). The crude title
compound (colorless solid) was directly used as starting material
for the synthesis of 37. 1H NMR (CDCl3, 200 MHz) δ ) 1.90 (mc,
2 H), 2.35, 2.56 (2 s, 6 H), 2.80, 2.95 (bs, s, 4 H), 3.14 (s, 3 H),
3.35 (mc, 1 H), 4.90 (dd, 1 H), 6.88 (mc, 1 H), 7.09, 7.14 (mc, s, 3
H), 7.59 (mc, 1 H); HRMS calcd for C21H25FN3O3 m/z (MH+)
386.1874, found 386.1855.
1 H), 6.64 (d, 1 H), 7.27 (mc, 5 H), 7.58 (d, 1 H); HRMS calcd for
C18H21N2O2 m/z (MH+) 297.1598, found 297.1580.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (74). Lewis
Acid Catalyzed Cyclization. Compound 74 was obtained in 24%
yield from diol 41 by applying a procedure similar to that described
for the preparation of 76 (for further details, see Supporting
Information): colorless solid; mp 245-247 °C; 1H NMR (DMSO-
d6, 200 MHz) δ ) 2.12 (mc, 1H), 2.25 (s, bs, 4 H), 2.34 (s, 3 H),
2.49 (bs), 2.75 (mc, 1 H), 2.86, 3.00 (2 s, 6 H), 5.26 (d, 1 H), 7.40
(mc, 5 H), 7.80 (s, 1 H). Anal. (C21H23N3O2·0.5H2O) H, N. C: calcd,
70.37; found, 70.84.
Broensted Acid Catalyzed Cyclization. Over a period of 15
min, portions of diol 41 (12.5 g, 34.0 mmol) were dissolved in
orthophosphoric acid (85 wt %, 100 mL). The reaction mixture
was heated at 80 °C (preheated oil bath). After a reaction time of
0.25 h, the reaction was quenched with ice and a pH value of 6.5
was adjusted by addition of 6 N sodium hydroxide solution. The
aqueous solution was extracted with dichloromethane (3×). The
combined organic phases were dried over sodium sulfate and
concentrated under reduced pressure. The residue was purified by
column chromatography [silica gel; eluant, ethyl acetate/methanol
) 9:1 (v/v)]. The corresponding fractions were concentrated to a
volume of 50 mL, and diisopropyl ether (200 mL) was added. After
a period of 0.5 h, the title compound was isolated by filtration (10.9
1
g of a colorless solid, 92% yield): mp 253-254 °C; H NMR
(DMSO-d6, 200 MHz) δ ) 2.12 (mc, 1H), 2.25 (s, bs, 4 H), 2.34
(s, 3 H), 2.49 (bs), 2.75 (mc, 1 H), 2.86, 3.00 (2 s, 6 H), 5.26 (d,
1 H), 7.40 (mc, 5 H), 7.80 (s, 1 H).
(9S)-2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (74a). In
a flame-dried flask filled with argon, (R)-diol 41a (9.10 g, 24.8
mmol, 85.9% ee) was suspended in dry THF (330 mL). After
addition of triphenylphosphine (19.50 g, 74.3 mmol) and dropwise
addition of DIAD (15.20 g, 75.1 mmol), a dark-green solution was
obtained, which was stirred for 80 min at room temperature. The
reaction mixture was concentrated under reduced pressure and the
residue (50 g of a green oil) was purified by column chromatog-
raphy [250 g of silica gel; eluant, ethyl acetate, then ethyl acetate/
methanol ) 20:1 (v/v)]. A colorless solid (6.5 g) was obtained
which was suspended in diethyl ether (30 mL). The precipitate was
isolated by filtration, washed with diethyl ether (20 mL), and dried
in vacuo, yielding 5.0 g of the title compound (58% yield, optical
purity 85.2-85.4% ee): mp 258-260 °C; determination of the
optical purity by HPLC (column, 250 × 4.6 mm CHIRALPAK
AD-H 5 µm; mobile phase, ethanol/methanol ) 1:1 (v/v) with 0.1%
of diethylamine; flow rate, 1 mL/min; 35 °C; detection at 243 nm),
tR [(9R)-enantiomer] ) 4.0 min/7.3 area %, tR [(9S)-enantiomer]
) 4.4 min/92.7 area %, 85.4% ee; determination of the optical purity
by CE, tM [(9S)-enantiomer] ) 19.5 min/92.6 area %, tM [(9R)-
enantiomer] ) 20.3 min/7.4 area %, 85.2% ee (A); 1H NMR
(DMSO-d6, 400 MHz) δ ) 2.12 (mc, 1H), 2.25 (s, bs, 4 H), 2.34
(s, 3 H), 2.49 (bs), 2.75 (mc, 1 H), 2.86, 3.00 (2 s, 6 H), 5.26 (d,
1 H), 7.40 (mc, 5 H), 7.80 (s, 1 H). Anal. (C21H23N3O2) C, H, N.
7-[3-(4-Fluorophenyl)-3-hydroxypropyl]-8-hydroxy-2,3-di-
methylimidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide
(70). Compound 70 was obtained from ketone 64 by applying a
procedure similar to that described for the preparation of 41 (for
further details, see Supporting Information). The crude title
compound (colorless solid) was directly used as starting material
1
for the synthesis of 38. H NMR (CDCl3 + traces of MeOD, 200
MHz) δ ) 1.97 (bmc, 2 H), 2.35 (s, 3 H), 2.56 (s, 3 H), 2.92, 3.14,
3.20 (2 s, bmc, 8 H), 4.55 (dd, 1 H), 6.92 (t, 2 H), 7.17 (s, 1 H),
7.29 (mc, 2 H).
8-Hydroxy-7-(3-hydroxy-3-thiophen-2-ylpropyl)-2,3-dimethyl-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (71).
Compound 71 was obtained from ketone 65 by applying a procedure
similar to that described for the preparation of 41 (for further details,
see Supporting Information). The title compound (colorless solid)
was directly used as starting material for the synthesis of 75: mp
157 °C; 1H NMR (CDCl3, 200 MHz) δ ) 2.09 (mc, 2 H), 2.31 (s,
3 H), 2.48 (bs, 4 H), 2.91 (s, 3 H), 3.14, 3.33 (s, bs, 4 H), 4.80 (t,
1 H), 6.87 (mc, 2 H), 7.11 (mc, 2 H); HRMS calcd for C19H24N3O3S
m/z (MH+) 374.1533, found 374.1536.
8-Hydroxy-7-(3-hydroxy-3-phenylpropyl)-2,3-dimethylimidazo-
[1,2-a]pyridine-6-carboxylic Acid Ethyl Ester (72). Compound
72 was obtained in 75% yield from ketone 66 by applying a
procedure similar to that described for the preparation of 41 (for
further details, see Supporting Information): almost colorless foam;
1H NMR (CDCl3, 200 MHz) δ ) 1.40 (t, 3 H), 2.13 (mc, 2 H),
2.40 (s, 3 H), 2.52 (s, 3 H), 3.26 (mc, 1 H), 3.50 (mc, 1 H), 4.39 (q,
2 H), 4.61 (dd, 1 H), 7.24 (mc, 5 H), 7.95 (s, 1 H); HRMS calcd
for C21H25N2O4 m/z (MH+) 369.1809, found 369.1791.
(9R)-2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (74b).
Compound 74b was obtained in 42% yield from (S)-diol 41b
(95.4% ee) by applying a procedure similar to that described for
the preparation of 74a, using dichloromethane instead of THF as
solvent (for further details, see Supporting Information): mp 257-
259 °C; determination of the optical purity by HPLC (column, 250
× 4.6 mm CHIRALPAK AD-H 5 µm; mobile phase, ethanol/
methanol ) 1:1 (v/v) with 0.1% of diethylamine; flow rate, 1 mL/
min; 35 °C; detection at 243 nm), tR [(9R)-enantiomer] ) 3.9 min/
97.8 area %, tR [(9S)-enantiomer] ) 4.4 min/2.2 area %, 95.6%
ee; determination of the optical purity by CE, tM [(9S)-enantiomer]
) 18.3 min/2.1 area %, tM [(9R)-enantiomer] ) 18.6 min/97.9 area
7-(3-Hydroxy-3-phenylpropyl)-2,3-dimethylimidazo[1,2-a]py-
ridin-8-ol (73). Compound 73 was obtained in 24% yield from
ketone 67 by applying a procedure similar to that described for the
preparation of 41 (for further details, see Supporting Information):
colorless solid; mp 183-185 °C; 1H NMR (DMSO-d6, 200 MHz)
δ ) 1.85 (mc, 2 H), 2.24 (s, 3 H), 2.33 (s, 3 H), 2.63 (mc), 4.54 (t,
1
%, 95.8% ee (A); H NMR (DMSO-d6, 200 MHz) δ ) 2.14 (mc,
1H), 2.26 (s, mc, 4 H), 2.35 (s, 3 H), 2.47 (mc), 2.78, 2.87 (mc, s,
4 H), 3.01 (s, 3 H), 5.26 (dd, 1 H), 7.42 (mc, 5 H), 7.79 (s, 1 H);

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6259
HRMS calcd for C21H24N3O2 m/z (MH+) 350.1863, found 350.1859.
Anal. (C21H23N3O2) C, H, N.
at room temperature and the precipitate that formed was isolated
by filtration. The filter cake was washed with water (until the filtrate
showed a neutral pH value) and acetone (5 mL) and was dried in
vacuo. The title compound was isolated in 97% yield (1.6 g of
2,3-Dimethyl-9-thiophen-2-yl-7H-8,9-dihydropyrano[2,3-c]-
imidazo[1,2-a]pyridine-6-carboxylic Acid Dimethylamide (75).
Compound 75 was obtained in 35% yield from diol 71 by applying
a procedure similar to that described for the preparation of 74a
(for further details, see Supporting Information): colorless solid;
1
colorless solid): mp 240-242 °C; H NMR (DMSO-d6 + traces
of MeOD, 200 MHz) δ ) 1.99 (mc, 1 H), 2.51 (mc), 3.06 (s, 3 H),
3.23 (mc, 2 H), 7.52 (mc, 3 H), 7.74 (mc, 2 H), 8.68 (s, 1 H); HRMS
calcd for C20H21N2O4 m/z (MH+) 353.1496, found 353.1490.
(9-Methoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydropyrano-
[2,3-c]imidazo[1,2-a]pyridin-6-yl)pyrrolidin-1-ylmethanone (80).
In a flask filled with argon, a suspension of carboxylic acid 79
(2.00 g, 5.7 mmol) in dry dichloromethane (35 mL) was treated
with TBTU (2.10 g, 6.5 mmol). The reaction mixture was refluxed
for 2 h and then allowed to cool to room temperature. After addition
of pyrrolidine (0.43 g, 0.50 mL, 6.0 mmol), a yellow solution was
obtained, which was stirred for 1 h at room temperature. The
reaction mixture was poured onto ice water (30 mL) and the stirred
biphasic mixture was neutralized by addition of saturated sodium
bicarbonate solution. The phases were separated, and the aqueous
phase was extracted with dichloromethane (2 × 10 mL). The
combined organic phases were washed with water (20 mL), dried
over sodium sulfate, and concentrated under reduced pressure. The
residue (4 g of a yellow oil) was purified by column chromatog-
raphy [90 g of silica gel; eluant, dichloromethane/methanol ) 100:2
(v/v)]. A colorless foamy solid (1.9 g) was isolated, which was a
mixture of the title compound (67 mol %), benzotriazol-1-ol (22
mol %), and tetramethylurea (11 wt %) (as judged by the 1H NMR
spectrum): 1H NMR (DMSO-d6, 200 MHz) δ ) 1.87, 2.07 (2 mc,
5 H), 2.36, 2.42 (2 s, 6 H), 2.55 (mc), 2.69 (tetramethylurea), 2.86,
3.02 (mc, s, 4 H), 3.26 (mc), 3.50 (t, 2 H), 7.48 [mc, 3 H (title
compound), 2 H (benzotriazol-1-ol)], 7.64, 7.72 [2 mc, 2 H (title
compound), 1 H (benzotriazol-1-ol)], 7.98 [d, 1 H (benzotriazol-
1-ol)], 8.11 (s, 1 H); HRMS calcd for C24H28N3O3 m/z (MH+)
406.2125, found 406.2123.
1
mp 241 °C; H NMR (DMSO-d6, 200 MHz) δ ) 2.25, 2.26, 2.34
(s, mc, s, 8 H), 2.53 (mc), 2.73, 2.87 (mc, s, 4 H), 3.01 (s, 3 H),
5.56 (dd, 1 H), 7.08 (dd, 1 H), 7.23 (bd, 1 H), 7.57 (dd, 1 H), 7.79
(s, 1 H); HRMS calcd for C19H22N3O2S m/z (MH+) 356.1427, found
356.1418.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Ethyl Ester (76). In a flame-
dried flask set under argon, a solution of diol 72 (250 mg, 0.68
mmol) in dichloromethane (15 mL) was treated with an excess of
boron trifluoride etherate (1.71 mL, 13.6 mmol). The solution was
stirred for 4 h at ambient temperature. The reaction mixture was
quenched at 0 °C by addition of saturated ammonium chloride
solution (20 mL). The pH was adjusted to 7 using 6 N sodium
hydroxide solution (3 mL). The aqueous phase was extracted with
dichloromethane (3 × 20 mL). The combined organic phases were
washed with 20 mL of water and dried over sodium sulfate. After
evaporation of the solvent, the residue (245 mg of a colorless solid)
was purified by column chromatography [silica gel; eluant,
petroleum ether/ethyl acetate ) 1:1 (v/v)]. The title compound
(164 mg, 69% yield) was obtained as a colorless solid: mp 146-
147 °C; 1H NMR (CDCl3, 200 MHz) δ ) 1.41 (t, 3 H), 2.26, 2.42
(mc, s, 8 H), 3.16 (mc, 2 H), 4.38 (q, 2 H), 5.28 (dd, 1 H), 7.37
(mc, 5 H), 8.22 (s, 1 H); HRMS calcd for C21H23N2O3 m/z (MH+)
351.1703, found 351.1719.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine (77). Compound 77 was obtained in 87% yield from
diol 73 by applying a procedure similar to that described for the
preparation of 76 (for further details, see Supporting Information).
9-Methoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-
c]imidazo[1,2-a]pyridine-6-carboxylic Acid Methylamide (81).
Compound 81 was obtained as mixture with benzotriazol-1-ol (39
mol %) and tetramethylurea (8 mol %) from carboxylic acid 79 by
applying a procedure similar to that described for the preparation
of 80, using methylamine instead of pyrrolidine (for further details,
see Supporting Information): 1H NMR (DMSO-d6, 200 MHz) δ
) 1.92 (mc, 1 H), 2.39, 2.45 (2 s, mc, 7 H), 2.69 (tetramethylurea),
2.80 (d, mc, 4 H), 3.03, 3.05 (s, mc, 4 H), 7.48 [mc, 3 H (title
compound), 2 H (benzotriazol-1-ol)], 7.67, 7.72 [2 mc, 2 H (title
compound), 1 H (benzotriazol-1-ol)], 7.99 [d, 1 H (benzotriazol-
1-ol)], 8.21 (s, 1 H), 8.47 (bq, 1 H); HRMS calcd for C21H24N3O3
m/z (MH+) 366.1812, found 366.1804.
[8-Hydroxy-2,3-dimethyl-7-(3-oxo-3-phenylpropyl)imidazo-
[1,2-a]pyridin-6-yl]pyrrolidin-1-ylmethanone (82). A solution of
the crude acetal 80 (1.80 g) in THF (25 mL) was treated with 1 N
hydrochloric acid (10 mL) and was heated to 50 °C for 5 h. The
reaction mixture was allowed to cool to room temperature, poured
onto a mixture of ice water (25 mL) and dichloromethane (30 mL),
and neutralized by addition of 2 N sodium hydroxide solution. The
phases were separated, and the aqueous phase was extracted with
dichloromethane (2 × 15 mL). The combined organic phases were
washed with water (20 mL), dried over sodium sulfate, and
concentrated in vacuo. The title compound (1.2 g, HPLC purity
98.42%) was further purified by column chromatography [50 g of
silica gel; eluant, ethyl acetate/methanol ) 10:1 (v/v)]. This afforded
the pure title compound in 46% overall yield [1.03 g of a colorless
solid, HPLC purity 99.55% (tR ) 10.9 min)]: mp 257-258 °C;
1H NMR (DMSO-d6, 200 MHz) δ ) 1.84 (mc, 4 H), 2.32, 2.36 (2
s, 6 H), 2.87 (mc, 2 H), 3.24 (mc, 4 H), 3.46 (mc, 2 H), 6.85 (bs, 1
H), 7.52 (t, 2 H), 7.64 (t, 1 H), 7.77 (s, 1 H), 7.96 (d, 2 H); HRMS
calcd for C23H26N3O3 m/z (MH+) 392.1969, found 392.1955.
8-Hydroxy-2,3-dimethyl-7-(3-oxo-3-phenylpropyl)imidazo-
[1,2-a]pyridine-6-carboxylic Acid Methylamide (83). Compound
83 was obtained in an overall yield of 73% from crude acetal 81
by applying a procedure similar to that described for the preparation
of 82 (for further details, see Supporting Information): yellow solid;
1
beige solid: mp 163-165 °C; H NMR (DMSO-d6, 200 MHz) δ
) 2.14, 2.25 (mc, s, 5 H), 2.34 (s, 3 H), 2.66 (mc, 1 H), 2.94 (mc,
1 H), 5.23 (dd, 1 H), 6.63 (d, 1 H), 7.43 (mc, 5 H), 7.71 (d, 1 H);
HRMS calcd for C18H19N2O m/z (MH+) 279.1492, found 279.1479.
9-Methoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-
c]imidazo[1,2-a]pyridine-6-carboxylic Acid Ethyl Ester (78). 2,2-
Dimethoxypropane (8.6 g, 10.1 mL, 83 mmol) was added to a
solution of ketone 66 (2.00 g, 5.5 mmol) in dry dichloromethane
(25 mL). After slow addition of methanesulfonic acid (0.68 g, 0.46
mL, 7.1 mmol), a dark brown solution was obtained, which was
refluxed for 6 h. The reaction mixture was cooled and poured onto
a stirred mixture of saturated sodium bicarbonate solution (25 mL)
and dichloromethane (20 mL). The biphasic mixture was stirred
for several minutes, and the phases were separated. The aqueous
phase was extracted with dichloromethane (2 × 15 mL). The
combined organic phases were washed with water (20 mL), dried
over sodium sulfate, and concentrated under reduced pressure. The
brown residue (3 g) was treated with diethyl ether (15 mL) and the
resulting slurry was stirred for 15 min. The precipitate was isolated
by filtration, washed with diethyl ether (5 mL), and dried in vacuo.
The title compound (1.85 g of a colorless solid) was isolated in
1
88% yield: mp 184-186 °C; H NMR (DMSO-d6, 200 MHz) δ
) 1.35 (t, 3 H), 1.90 (mc, 1 H), 2.34, 2.37, 2.43 (s, mc, s, 7 H),
2.99, 3.12 (s, mc, 5 H), 4.33 (q, 2 H), 7.49 (mc, 3 H), 7.63 (mc, 2
H), 8.36 (s, 1 H); HRMS calcd for C22H25N2O4 m/z (MH+)
381.1809, found 381.1803.
9-Methoxy-2,3-dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-
c]imidazo[1,2-a]pyridine-6-carboxylic Acid (79). To a suspension
of ester 78 (1.80 g, 4.7 mmol) in methanol (40 mL) was added an
aqueous solution of potassium hydroxide (0.56 g, 10.0 mmol, in 5
mL of water). The resulting red suspension was heated to 55 °C.
After 30 min, a clear solution was obtained which was kept at
55 °C for 90 min. The reaction mixture was cooled and concentrated
under reduced pressure. The wet residue was dissolved in water
(40 mL) and 2 N hydrochloric acid was added to the stirred solution
until a pH value of 2 was obtained. Stirring was continued for 1 h

6260 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
1
mp 284-286 °C; HPLC purity 99.57% (tR ) 8.8 min); H NMR
ee) by applying a procedure similar to that described for the
preparation of 74a (for further details, see Supporting Informa-
tion): mp 261-263 °C; determination of the optical purity by HPLC
(column, 250 × 4.6 mm CHIRALPAK AD-H 5 µm; mobile phase,
ethanol/methanol ) 1:1 (v/v) with 0.1% of diethylamine; flow rate,
0.8 mL/min; 35 °C; detection at 245 nm), tR [(9R)-enantiomer] )
4.1 min/2.9 area %, tR [(9S)-enantiomer] ) 4.4 min/97.1 area %,
94.2% ee; determination of the optical purity by CE, tM [(9S)-
enantiomer] ) 18.6 min/97.1 area %, tM [(9R)-enantiomer] ) 19.9
min/2.9 area %, 94.2% ee (A); 1H NMR (DMSO-d6, 200 MHz) δ
) 2.07 (mc, 1H), 2.26 (s, mc, 4 H), 2.37 (s, 3 H), 2.74, 2.77 (mc,
d, 4 H), 3.00 (mc, 1 H), 5.24 (dd, 1 H), 7.42 (mc, 5 H), 7.91 (s, 1
H), 8.32 (bq, 1 H); HRMS calcd for C20H22N3O2 m/z (MH+)
336.1707, found 336.1696.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Diethylamide (87). Compound
87 was obtained in 78% yield from carboxylic acid 84 by applying
a procedure similar to that described for the preparation of 86, using
diethylamine instead of methylamine (for further details, see
Supporting Information): colorless solid; mp 178-180 °C; 1H NMR
(DMSO-d6, 300 MHz) δ ) 1.02 (t, 3 H), 1.17 (t, 3 H), 2.11 (mc,
1 H), 2.26, 2.29 (s, mc, 4 H), 2.35 (s, 3 H), 2.45 (mc), 2.75 (mc, 1
H), 3.19 (bq, 2 H), 3.45 (bs, 2 H), 5.27 (dd, 1 H), 7.42 (mc, 5 H),
7.78 (s, 1 H); HRMS calcd for C23H28N3O2 m/z (MH+) 378.2176,
found 378.2154. Anal. (C23H27N3O2·0.5H2O) C, H, N.
(DMSO-d6, 200 MHz) δ ) 2.32, 2.38 (2 s, 6 H), 2.76 (d, 3 H),
2.98 (mc, 2 H), 3.25 (mc, 2 H), 5.95 (bs, 1 H), 7.52 (t, 2 H), 7.64
(t, 1 H), 7.82 (s, 1 H), 7.98 (d, 2 H), 8.34 (bq, 1 H); HRMS calcd
for C20H22N3O3 m/z (MH+) 352.1656, found 352.1641.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid (84). A suspension of ester 76
(16.7 g, 48 mmol) in methanol (170 mL) and water (35 mL) was
treated with potassium hydroxide (4.5 g, 80 mmol) and heated to
50 °C. After a reaction time of 2 h, the methanol was removed in
vacuo. Water (400 mL) and dichloromethane (300 mL) was added,
the pH was adjusted to 4.8 (isoelectric point of the title compound)
by addition of 6 N hydrochloric acid, and stirring was continued
for 30 min. A precipitate was formed which slowly dissolved after
addition of dichloromethane (100 mL) and methanol (100 mL).
The phases were separated, and the aqueous phase was extracted
with dichloromethane (2 × 50 mL). The combined organic phases
were dried over sodium sulfate and concentrated to a volume of
50 mL. Upon addition of diethyl ether (100 mL), a colorless
precipitate was formed. Stirring was continued for 30 min at 0 °C.
The precipitate was isolated by filtration and dried in vacuo, yielding
9.1 g of the pure title compound (58% yield). The aqueous phase
was saturated with sodium chloride and extracted with chloroform
(1 × 400 mL, 2 × 100 mL). The combined organic phases were
dried over sodium sulfate and concentrated in vacuo. This afforded
another batch of the title compound (2.0 g, 13% yield): mp 318-
320 °C; 1H NMR (DMSO-d6, 200 MHz) δ ) 2.09 (mc, 1 H), 2.28
(s, mc, 4 H), 2.40 (s, 3 H), 3.10 (mc, 2 H), 5.25 (dd, 1 H), 7.43 (mc,
5 H), 8.32 (s, 1 H); HRMS calcd for C19H19N2O3 m/z (MH+)
323.1390, found 323.1383. Anal. (C19H18N2O3·0.5H2O) C, H, N.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Amide (85). A suspension of
carboxylic acid 84 (500 mg, 1.54 mmol) in dichloromethane (20
mL) was treated with TBTU (504 mg, 1.57 mmol). The reaction
mixture was heated for 1 h at 40 °C and then allowed to cool to
room temperature. Ammonia gas was bubbled through the suspen-
sion over a period of 30 min. The reaction mixture was poured
onto water (20 mL), dichloromethane (30 mL) was added, and a
pH value of 6 was adjusted by addition of 2 N hydrochloric acid.
In order to facilitate the separation of the phases, a 10 mL portion
of methanol was added. The phases were separated, and the aqueous
phase was extracted with dichloromethane (2 × 10 mL). The
combined organic phases were dried over sodium sulfate and
concentrated in vacuo. The title compound (310 mg, 64% yield)
was isolated in the form of a colorless solid: mp 346-348 °C; 1H
NMR (DMSO-d6, 200 MHz) δ ) 2.09 (mc, 1 H), 2.26 (mc, s, 4
H), 2.38 (s, 3 H), 2.97 (mc, 2 H), 5.24 (dd, 1 H), 7.41 (bs, mc, 6
H), 7.85 (bs, 1 H), 7.98 (s, 1 H); HRMS calcd for C19H20N3O2 m/z
(MH+) 322.1550, found 322.1541.
(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridin-6-yl)aziridin-1-ylmethanone (88). Compound 88
was obtained in 15% yield from carboxylic acid 84 by applying a
procedure similar to that described for the preparation of 86, using
aziridine instead of methylamine (for further details, see Supporting
Information): colorless solid; mp 180-181 °C; 1H NMR (CDCl3,
200 MHz) δ ) 2.23 (mc, 12 H), 3.08 (mc, 2 H), 5.29 (dd, 1 H),
7.39 (mc, 5 H), 8.31 (s, 1 H); HRMS calcd for C21H22N3O2 m/z
(MH+) 348.1707, found 348.1699.
(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]-imidazo-
[1,2-a]pyridin-6-yl)azetidin-1-ylmethanone (89). Compound 89
was obtained in 88% yield from carboxylic acid 84 by applying a
procedure similar to that described for the preparation of 86, using
azetidine instead of methylamine (for further details, see Supporting
1
Information): colorless solid; mp 254 °C; H NMR (CDCl3, 200
MHz) δ ) 2.29, 2.37, 2.41 (mc, 2 s, 10 H), 2.76 (mc, 1 H), 2.99
(mc, 1 H), 4.18 (bs, 4 H), 5.30 (dd, 1 H), 7.38 (mc, 6 H); HRMS
calcd for C22H24N3O2 m/z (MH+) 362.1863, found 362.1852. Anal.
(C22H23N3O2·0.5H2O) C, H, N.
(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridin-6-yl)pyrrolidin-1-ylmethanone (90). Compound 90
was obtained in 45% yield from carboxylic acid 84 by applying a
procedure similar to that described for the preparation of 86, using
pyrrolidine instead of methylamine (for further details, see Sup-
porting Information): mp 274 °C; 1H NMR (CDCl3, 200 MHz) δ
) 1.97 (mc, 4 H), 2.26, 2.36, 2.41 (mc, 2 s, 8 H), 2.62 (mc, 1 H),
2.84 (mc, 1 H), 3.24 (mc, 2 H), 3.65 (t, 2 H), 5.31 (dd, 1 H), 7.38
(mc, 6 H); HRMS calcd for C23H26N3O2 m/z (MH+) 376.2020, found
376.2011. Anal. (C23H25N3O2) C, H, N.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Methylamide (86). Carboxylic
acid 84 (1.50 g, 4.6 mmol) and TBTU (1.40 g, 4.4 mmol) were
suspended in dichloromethane (50 mL). After a reaction time of 1
h at room temperature, methylamine (8.0 M solution in ethanol, 2
mL, 16 mmol) was added. Within 30 min, a clear solution was
obtained, which was stirred for 2 h at room temperature. The
reaction mixture was poured onto water (20 mL), the phases were
separated, and the aqueous phase was extracted with dichlo-
romethane (10 mL). The combined organic phases were washed
with water (10 mL), dried over sodium sulfate, and concentrated
in vacuo. The residue (1.1 g) was purified by column chromatog-
raphy [silica gel; eluant, dichloromethane/methanol ) 15:1 (v/v)].
Evaporation of the corresponding fractions afforded the title
compound (0.90 g of a colorless solid, 58% yield): mp 255-
(9S)-(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridin-6-yl)pyrrolidin-1-ylmethanone (90a). Com-
pound 90a was obtained in 50% yield from (R)-diol 102a (87.4%
ee) by applying a procedure similar to that described for the
preparation of 74a (for further details, see Supporting Informa-
tion): mp 268-270 °C; determination of the optical purity by HPLC
(column, 250 × 4.6 mm CHIRALPAK OD-H 5 µm; mobile phase,
n-hexane/2-propanol ) 9:1 (v/v); flow rate, 1 mL/min; 35 °C;
detection at 220 nm), tR [(9R)-enantiomer] ) 35.5 min/6.3 area %,
tR [(9S)-enantiomer] ) 43.1 min/93.7 area %, 87.4% ee; determi-
nation of the optical purity by CE, tM [(9S)-enantiomer] ) 19.7
min/93.6 area %, tM [(9R)-enantiomer] ) 20.4 min/6.4 area %,
1
257 °C; H NMR (DMSO-d6, 200 MHz) δ ) 2.09 (mc, s), 2.26
(mc, s, 4 H), 2.37 (s, 3 H), 2.78 (mc, d, 4 H), 3.00 (mc, 1 H), 5.24
(dd, 1 H), 7.41 (mc, 5 H), 7.92 (s, 1 H), 8.32 (q, 1 H); HRMS
calcd for C20H22N3O2 m/z (MH+) 336.1707, found 336.1704.
(9S)-2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imi-
dazo[1,2-a]pyridine-6-carboxylic Acid Methylamide (86a). Com-
pound 86a was obtained in 14% yield from (R)-diol 103a (92.0%
1
87.2% ee (A); H NMR (DMSO-d6, 200 MHz) δ ) 1.85 (mc, 4
H), 2.13 (mc, 1H), 2.25 (s, mc, 4 H), 2.35 (s, 3 H), 2.50 (mc), 2.81
(mc, 1 H), 3.26 (mc, 2 H), 3.48 (t, 2 H), 5.25 (dd, 1 H), 7.42 (mc,
5 H), 7.84 (s, 1 H); HRMS calcd for C23H26N3O2 m/z (MH+)
376.2020, found 376.2010.

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6261
(3-Hydroxyazetidin-1-yl)(2,3-dimethyl-9-phenyl-7H-8,9-dihy-
dropyrano[2,3-c]imidazo[1,2-a]pyridin-6-yl)methanone (91). Com-
pound 91 was obtained in 36% yield from carboxylic acid 84 by
applying a procedure similar to that described for the preparation
of 86, using 3-hydroxyazetidine instead of methylamine (for further
details, see Supporting Information): colorless solid; mp 306-
308 °C; 1H NMR (DMSO-d6, 200 MHz) δ ) 2.10 (mc, 1 H), 2.26
(s, mc, 4 H), 2.37 (s, 3 H), 2.66 (mc, 1 H), 2.92 (mc, 1 H), 3.85
(mc, 2 H), 4.23 (mc, 2 H), 4.50 (mc, 1 H), 5.26 (dd, 1 H), 5.75 (mc,
1 H), 7.42 (mc, 5 H), 7.85 (s, 1 H); HRMS calcd for C22H24N3O3
m/z (MH+) 378.1812, found 378.1798.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Cyclopropylamide (92). Com-
pound 92 was obtained in 45% yield from carboxylic acid 84 by
applying a procedure similar to that described for the preparation
of 86, using cyclopropylamine instead of methylamine (for further
details, see Supporting Information): colorless solid; mp 260 °C;
1H NMR (DMSO-d6, 200 MHz) δ ) 0.57 (mc, 2 H), 0.70 (mc, 2
H), 2.06 (mc, 1 H), 2.26 (s, mc, 4 H), 2.37 (s, 3 H), 2.66-3.08 (m,
3 H), 3.17 (d, MeOH), 4.07 (q, MeOH), 5.23 (dd, 1 H), 7.42 (mc,
5 H), 7.86 (s, 1 H), 8.42 (d, 1 H); HRMS calcd for C22H24N3O2
m/z (MH+) 362.1863, found 362.1853. Anal. (C22H23N3O2·0.5H2O)
C, H, N.
5 H), 5.28 (dd, 1 H), 7.44 (mc, 5 H), 8.14 (s, 1 H); HRMS calcd
for C20H21N3O4S m/z (MH+) 400.1326, found 400.1318.
(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridin-6-yl)piperazin-1-ylmethanone (97). Compound 97
was obtained in 13% yield from carboxylic acid 84 by applying a
procedure similar to that described for the preparation of 96, using
piperazine instead of methanesulfonamide (for further details, see
1
Supporting Information): H NMR (DMSO-d6, 200 MHz) δ ) 2.16,
2.25, 2.35 (mc, 2 s, 8 H), 2.73 (bs, overlay with DMSO signal),
3.20 (bs, overlay with water signal), 3.58 (bs, 2 H), 5.27 (dd, 1 H),
7.43 (mc, 6 H), 7.76 (s, 1 H); HRMS calcd for C23H27N4O2 m/z
(MH+) 391.2129, found 391.2121. Anal. (C23H26N4O2·0.5H2O) C,
H, N.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Methoxymethylamide (98).
Compound 98 was obtained in 33% yield from carboxylic acid 84
by applying a procedure similar to that described for the preparation
of 86, using N,O-dimethylhydroxylamine instead of methylamine
(for further details, see Supporting Information): colorless solid;
mp 192-193 °C (enantiomers 98a and 98b, mp 215-216 °C); 1H
NMR (DMSO-d6, 200 MHz) δ ) 2.12 (mc, 1 H), 2.26 (mc, s, 4
H), 2.36 (s, 3 H), 2.54 (mc), 2.81 (mc, 1 H), 3.26 (s, 3 H), 3.57 (s,
3 H), 5.26 (dd, 1 H), 7.42 (mc, 5 H), 7.92 (s, 1 H); HRMS calcd
for C21H24N3O3 m/z (MH+) 366.1812, found 366.1820.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Cyclobutylamide (93). Com-
pound 93 was obtained in 47% yield from carboxylic acid 84 by
applying a procedure similar to that described for the preparation
of 86, using cyclobutylamine instead of methylamine (for further
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid (2-Hydroxyethyl)amide (99).
A mixture of carboxylic acid 84 (0.50 g, 1.6 mmol) and thionyl
chloride (0.34 mL, 0.55 g, 4.6 mmol) was diluted with dry
dichloromethane (7 mL). The suspension was treated with DBU
(0.24 mL, 0.24 g, 1.6 mmol) and stirred for 24 h at room
temperature. The light-brown reaction mixture was evaporated to
dryness and the residue was dissolved in dry dichloromethane (15
mL). The resulting suspension was cooled to 0 °C and a solution
of 2-aminoethanol (0.17 mL, 0.17 g, 2.8 mmol) in dichloromethane
(5 mL) was added. The reaction mixture was stirred for 2.5 h at
room temperature. The precipitate was removed by filtration. The
filtrate was concentrated in vacuo and the brown residue (0.9 g)
was purified by column chromatography [36 g of silica gel; eluant,
ethyl acetate/methanol ) 10:1 (v/v)]. Evaporation of the corre-
sponding fractions yielded the pure title compound (0.25 g of a
1
details, see Supporting Information): mp 257-258 °C; H NMR
(CDCl3, 200 MHz) δ ) 1.79 (mc), 1.90-2.50, 2.33, 2.40 (m, 2 s,
12 H), 2.84 (mc, 1 H), 3.01 (mc, 1 H), 4.55 (mc, 1 H), 5.22 (dd, 1
H), 6.50 (d, 1 H), 7.39 (mc, 6 H); HRMS calcd for C23H26N3O2
m/z (MH+) 376.2020, found 376.2025.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid Phenylamide (94). Compound
94 was obtained in 39% yield from carboxylic acid 84 by applying
a procedure similar to that described for the preparation of 86, using
aniline instead of methylamine (for further details, see Supporting
Information): colorless solid; mp 285-287 °C; 1H NMR (DMSO-
d6, 200 MHz) δ ) 2.09 (mc, 1 H), 2.29 (mc, s, 4 H), 2.41 (s, 3 H),
2.77 (mc, 1 H), 3.06 (mc, 1 H), 5.28 (dd, 1 H), 7.11 (t, 1 H), 7.42
(mc, 7 H), 7.73 (d, 2 H), 8.14 (s, 1 H), 10.37 (s, 1 H); HRMS calcd
for C25H24N3O2 m/z (MH+) 398.1863, found 398.1851.
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid (4-Ethoxyphenyl)amide (95).
Compound 95 was obtained in 49% yield from carboxylic acid 84
by applying a procedure similar to that described for the preparation
of 86, using 4-ethoxyaniline instead of methylamine (for further
details, see Supporting Information): mp 223 °C; 1H NMR (CDCl3,
200 MHz) δ ) 1.42 (t, 3 H), 2.11 (mc, 1 H), 2.27, 2.33, 2.39 (s,
mc, s, 7 H), 2.89 (mc, 1 H), 3.10 (mc, 1 H), 4.04 (q, 2 H), 5.14 (dd,
1 H), 6.87 (d, 2 H), 7.25 (mc), 7.38 (mc, 2 H), 7.44 (s, 1 H), 7.64
(d, 2 H), 8.71 (bs, 1 H). Anal. (C27H27N3O3) H, N. C: calcd, 73.45;
found, 73.00.
1
colorless solid, 44% yield): mp 209-210 °C; H NMR (CDCl3,
200 MHz) δ ) 1.92 (mc), 2.27 (mc, s, 4 H), 2.41 (s, 3 H), 2.68
(mc, 2 H), 3.46 (mc, 2 H), 3.71 (mc, 2 H), 4.97 (dd, 1 H), 7.14 (bt,
1 H), 7.27 (s), 7.42 (mc, 5 H).
2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carboxylic Acid (2-Chloroethyl)amide (100).
A solution of (2-hydroxyethyl)carboxamide 99 (0.30 g, 0.8 mmol)
in thionyl chloride (0.40 mL, 0.65 g, 5.5 mmol) was stirred for 1
h at room temperature. It was then diluted with dichloromethane
(30 mL) and water (5 mL) and a neutral pH value was adjusted by
addition of saturated sodium bicarbonate solution. The phases were
separated, and the aqueous phase was extracted with dichlo-
romethane (20 mL). The combined organic phases were dried over
sodium sulfate, concentrated under reduced pressure, and dried in
vacuo. The title compound was obtained in 70% yield (0.22 g of a
colorless solid): 1H NMR (CDCl3, 200 MHz) δ ) 2.14 (mc), 2.32,
2.38 (2 s, mc, 7 H), 2.85 (mc, 1 H), 3.08 (mc, 1 H), 3.75 (s, 4 H),
5.21 (dd, 1 H), 6.90 (bs, 1 H), 7.36 (mc, 5 H), 7.60 (s, 1 H).
6-(4,5-Dihydrooxazol-2-yl)-2,3-dimethyl-9-phenyl-7H-8,9-di-
hydropyrano[2,3-c]imidazo[1,2-a]pyridine (101). Three samples
of (2-chloroethyl)carboxamide 100 (3 × 70 mg, 0.55 mmol) were
transferred into microwave tubes and dissolved in dry DMF (3 ×
3 mL). The yellow solution was heated to 150 °C for 20 min and
to 170 °C for another 20 min. The reaction mixtures were combined
and evaporated to dryness. The residue was purified by column
chromatography [22 g of silica gel; eluant, ethyl acetate/methanol
) 100:3 (v/v)]. Evaporation of the corresponding fractions furnished
a red solid (106 mg, mixture of title compound with untransformed
starting material as indicated by TLC analysis), which was further
purified by preparative HPLC. The title compound was isolated in
14% yield (27 mg of a colorless solid): 1H NMR (CDCl3, 200
N-(2,3-Dimethyl-9-phenyl-7H-8,9-dihydropyrano[2,3-c]imidazo-
[1,2-a]pyridine-6-carbonyl)methanesulfonamide (96). A suspen-
sion of carboxylic acid 84 (0.80 g, 2.5 mmol) in dry THF (30 mL)
was treated with N,N′-carbonyldiimidazole (0.80 g, 4.9 mmol). After
a reaction time of 2 h at 40 °C a brown solution was obtained.
DBU (0.75 g, 4.9 mmol) and methanesulfonamide (0.47 g, 4.9
mmol) was added and stirring was continued for 1 h at room
temperature. The reaction mixture was poured onto water (30 mL)
and dichloromethane (50 mL), the phases were separated, and the
aqueous phase was extracted with dichloromethane (30 mL). The
combined organic phases were dried over sodium sulfate and
concentrated in vacuo. The residue (1.5 g of a brown foamy solid)
was purified by column chromatography [45 g of silica gel; eluant,
dichloromethane/methanol ) 100:3 (v/v)]. The corresponding
fractions were evaporated and the title compound was isolated (0.70
1
g, 71% yield): mp 210 °C; H NMR (DMSO-d6, 200 MHz) δ )
2.09 (mc, 1 H), 2.30 (s, mc, 4 H), 2.41 (s, 3 H), 3.00, 3.10 (s, mc,

6262 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
MHz) δ ) 2.30, 2.40, 2.41 (mc, 2 s, 8 H), 3.15 (mc, 2 H), 4.09
(mc, 2 H), 4.38 (mc, 2 H), 5.30 (dd, 1 H), 7.39 (mc, 5 H), 8.09 (s,
1 H); HRMS calcd for C21H22N3O2 m/z (MH+) 348.1707, found
348.1723.
105: 1H NMR (CDCl3, 200 MHz) δ ) 2.00-2.60 (bs), 2.34, 2.37
(2 s, Σ 10 H), 2.73 (s, 3 H), 2.87, 2.97 (2 s, Σ 3 H), 3.44, 3.48 (2
s, ∑ 3 H), 3.79, 3.85 (2 s, ∑ 3 H), 5.61 (bt, 1 H), 7.30 (mc, 10 H),
7.54 (mc, 3 H), 7.63 (s, 1 H), 8.06 (mc, 2 H).
[8-Hydroxy-7-((R)-3-hydroxy-3-phenylpropyl)-2,3-dimethyl-
imidazo[1,2-a]pyridin-6-yl]pyrrolidin-1-ylmethanone (102a). Com-
pound 102a was obtained in 78% yield from ketone 82 by applying
a procedure similar to that described for the preparation of 41a
(asymmetric hydrogenation with RuCl2[(S)-BINAP][(S)-DAIPEN])
(for further details, see Supporting Information): pale-green solid;
mp 252-254 °C; determination of the optical purity by CE, tM
[(3S)-enantiomer] ) 20.2 min/6.3 area %, tM [(3R)-enantiomer] )
(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropionic Acid 3-(6-
Dimethylcarbamoyl-8-hydroxy-2,3-dimethylimidazo[1,2-a]pyri-
din-7-yl)-1-phenylpropyl Ester (106). A solution of the diaster-
eomeric mixture of the diester 105 (42 mg, 0.05 mmol) in deuterated
chloroform was allowed to stand for 10 d at room temperature.
The solvent was removed under reduced pressure and the crude
product was purified by column chromatography [2 × 6 g of silica
gel; eluant, dichloromethane/methanol ) 15:1 (v/v)]. A mixture of
the diastereomeric esters of 106 was isolated in 72% yield: 1H
NMR (DMSO-d6, 400 MHz) δ ) 2.05 (bs, 1 H), 2.17 (bs, 1 H),
2.29, 2.32 (2 s, 6 H), 2.48 (bs), 2.71, 2.75 (2 s, ∑ 3 H), 2.82, 2.84
(2 s, ∑ 3 H), 3.43, 3.52 (2 s, ∑ 3 H), 5.98 (mc, 1 H), 7.41 (mc, 10
H), 7.61, 7.62 (2 s, ∑ 1 H).
1
20.4 min/93.7 area %, 87.4% ee (A); H NMR (DMSO-d6, 200
MHz) δ ) 1.77 (mc, 6 H), 2.30, 2.33 (2 s, 6 H), 2.55 (mc), 3.13,
3.34 (2 t, 4 H), 4.49 (t, 1 H), 5.93 (bs), 7.25 (mc, 5 H), 7.65 (s, 1
H); HRMS calcd for C23H28N3O3 m/z (MH+) 394.2125, found
394.2107.
8-Hydroxy-7-((R)-3-hydroxy-3-phenylpropyl)-2,3-dimethyl-
imidazo[1,2-a]pyridine-6-carboxylic Acid Methylamide (103a).
Compound 103a was obtained in 80% yield from ketone 83 by
applying a procedure similar to that described for the preparation
of 41a (asymmetric hydrogenation with RuCl2[(S)-BINAP][(S)-
DAIPEN]) (for further details, see Supporting Information): color-
less solid; mp 250-252 °C; determination of the optical purity by
CE, tM [(3S)-enantiomer] ) 19.2 min/4.0 area %, tM [(3R)-
5.2. Biochemistry. Determination of Inhibitory Activity in a
Competitive Binding Assay against H+/K+-ATPase from Hog
Gastric Mucosa. Given data are the mean IC50 values from two
or three independent determinations. The malachite green assay
modified from Yoda and Hokin (Biochem. Biophys. Res. Commun.
1970, 40, 880-886) was used for the determination of H+/K+-
ATPase IC50 (Lanzetta, P. A.; Alvarez, L. J.; Reinach, P. S.; Candia,
O. A. Anal. Biochem. 1979, 100, 95-97). Pipes [piperazine-1,4-
bis(2-ethanesulfonic acid)], sucrose, nigericin, Na-ATP, and
malachite green were purchased from Sigma-Aldrich, and Tris [tris-
(hydroxymethyl)aminomethane], KCl, and ammonium heptamo-
lybdate tetrahydrate were from Merck, and MgCl2 was from Fluka.
Final assay concentrations: 4 mM Pipes/8 mM Tris buffer pH 7.4,
0.25 M sucrose, 1 mM KCl, 1 mM MgCl2, 0.5-1 µg/100 µL
nigericin (1:1 ratio with enzyme), 0.5-1 µg/100 µL enzyme
(dependent on K+-stimulated, specific activity), and 1 mM Na-
ATP (high grade); reaction volume, 101 µL. Malachite green
reagent was prepared by mixing 2 parts of malachite green stock
solution (1.2 M in H2O, protected from light and used within 12
weeks) with 1 part of ammonium heptamolybdate tetrahydrate stock
solution (42 g/L in 4 N HCl) and was kept for 30 min at room-
temperature prior to use. A Pipes/Tris buffer based solution with
sucrose and MgCl2 was prepared. Nigericin and enzyme were added
to reach the final concentrations mentioned above; 80 µL/well of
this mixture was placed into 96-well flat bottom plates (clear,
polystyrol, Greiner bio-one), and 10 µL/well of KCl (1 mM final)
was used for stimulation of the H+/K+-ATPase activity. Test
substances were dissolved as 10 mM solutions in 100% DMSO,
and 1 µL of substance solution was added in dilutions ranging from
1 × 10-4 to 1 × 10-9 M (final). The enzymatic reaction was started
by addition of 10 µL ATP (1 mM final). The assay was incubated
for 30 min at room temperature. The reaction was stopped by
addition of 150 µL of malachite green reagent and incubated for
another 15 min prior to photometric reading of the plate at 680 nm
in a PowerWave HT Microplate spectral photometer (BioTek). The
results were analyzed with GraphPad Prism software (Version 4.02)
to calculate IC50 values by sigmoidal curve fitting. “Enzyme” refers
to H+/K+-ATPase-containing vesicles prepared from hog gastric
mucosa as described previously (Rabon, E. C.; Im, W. B.; Sachs,
G. Methods Enzymol. 1988, 157, 649-654).
1
enantiomer] ) 19.6 min/96.0 area %, 92.0% ee (A); H NMR
(DMSO-d6, 200 MHz) δ ) 1.81 (mc, 2 H), 2.30, 2.35 (2 s, 6 H),
2.72, 2.73 (mc, d, 5 H), 4.47 (t, 1 H), 5.66 (bs), 7.33 (mc, 5 H),
7.71 (s, 1 H), 8.26 (bq, 1 H); HRMS calcd for C20H24N3O3 m/z
(MH+) 354.1812, found 354.1801.
8-(tert-Butyldimethylsilanyloxy)-7-(3-hydroxy-3-phenylpropyl)-
2,3-dimethylimidazo[1,2-a]pyridine-6-carboxylic Acid Dimethyl-
amide (104). The diol 41 (200 mg, 0.54 mmol, product of the
asymmetric hydrogenation of ketone 61 with RuCl2[(S)-BINAP]-
[(S,S)-DPEN]) was dissolved in dichloromethane (10 mL). Tri-
ethylamine (110 mg, 151 µL, 1.09 mmol) and a solution of tert-
butyldimethylchlorosilane (179 mg, 1.19 mmol) in dichloromethane
(5 mL) were added. The reaction mixture was heated to reflux for
5.25 h and then quenched by addition of saturated ammonium
chloride solution (10 mL). The phases were separated, and the
aqueous phase was extracted with dichloromethane (2 × 10 mL).
The combined organic phases were dried over sodium sulfate and
concentrated under reduced pressure. A green oil (296 mg)
remained, which was purified by column chromatography (20 g of
silica gel; eluant, ethyl acetate). The title compound was isolated
in 73% yield (190 mg): determination of the optical purity by
HPLC (column, 250 × 4.6 mm CHIRALPAK AD-H 5 µm (two
columns), mobile phase, n-hexane/2-propanol ) 83:17 (v/v); flow
rate, 1 mL/min; 35 °C; detection at 220 nm), tR [(3R)-enantiomer]
) 10.0 min/68.4 area %, tR [(3S)-enantiomer] ) 10.6 min/31.6 area
1
%, 36.8% ee; H NMR (CDCl3, 200 MHz) δ ) 0.33, 0.44 (2 s, 6
H), 1.02 (s, 9 H), 2.00 (mc, 2 H), 2.33, 2.37 (2 s, 6 H), 2.65 (mc,
2 H), 2.88, 3.11 (2 s, 6 H), 4.58 (dd, 1 H), 7.26 (mc, 5 H), 7.38 (s,
1 H).
(R)-3,3,3-Trifluoro-2-methoxy-2-phenylpropionic Acid 6-Di-
methylcarbamoyl-2,3-dimethyl-7-[3-phenyl-3-((R)-3,3,3-trifluoro-
2-methoxy-2-phenylpropionyloxy)propyl]imidazo[1,2-a]pyridin-
8-yl Ester (105). (S)-(+)-MTPACl (95 mg, 0.38 mmol) was
dissolved in pyridine (810 µL) and carbon tetrachloride (810 µL).
A solution of the protected diol 104 (100 mg, 0.21 mmol, containing
the two enantiomers in a 7:3 ratio) in dichloromethane (500 µL)
was added. The reaction mixture was stirred for 6 h at room
temperature and then diluted with water (5 mL) and chloroform
(10 mL). The phases were separated, and the aqueous phase was
extracted with chloroform (2 × 10 mL). The organic phases were
washed with saturated sodium chloride solution (5 mL), dried over
sodium sulfate, and concentrated under reduced pressure. The crude
product was dried thoroughly and then purified by column
chromatography [10 g of silica gel; eluant, ethyl acetate/petroleum
ether ) 7:3 v/v)]. A yellowish oil (50 mg, 30% yield) was isolated
that was characterized as diastereomeric mixture of the diester
[14C]Dimethylaminopyridine Accumulation in Intact Gastric
Glands. Gastric acid secretion is stimulated by gastrin, histamine,
and acetylcholine via the receptors on the parietal or the entero-
chromaffin-like cell. These physiologic stimuli influence the
intracellular cyclic AMP and Ca2+ levels, thus leading to relocation
and activation of H+/K+-ATPase. Instead of the physiologic
agonists, the membrane-permeant dibutyryl-cyclic AMP was used
to stimulate receptor-independent acid secretion in isolated gastric
glands. Accumulation of the weak base [14C]dimethylaminopyridine
(14C-AP) in the acidic compartment of the canaliculi serves as an
indirect measure of acid secretion and forms the basis of measure-
ment of acid secretion in this in vitro model of the mammalian
stomach. Intact gastric glands were prepared from anesthesized New
Zealand rabbits (weight 2-3 kg) by high-pressure perfusion of the

Dihydropyranoimidazopyridines as P-CABs
Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24 6263
stomach, separation of the fundic mucosa, and subsequent colla-
genase digestion of fragments of the mucosa [Berglindh, T;
Helander, H. F.; Obrink, K. J. Acta Physiol. Scand. 1976, 97 (4),
401-414. Berglindh, T.; Obrink, K. J. Acta Physiol. Scand. 1976,
96 (2), 150-159]. After the gastric glands were washed several
times, they were suspended in Krebs-Henseleit solution containing
2 mg/mL rabbit serum albumin and 2 mg/mL glucose. Glands were
incubated for 30 min at 37 °C in a shaker bath (200 osc/min) in
the presence of 0.125 µM 14C-AP (113 µCi/µmol) at pH 7.4. Glands
were stimulated with 1 mM dibutyryl cAMP in the absence or
presence of the corresponding inhibitor (concentration range 3 nM-
100 µM). The reaction was stopped by centrifugation (10 s at
20 000g). After centrifugation, the accumulation of 14C-AP in the
glands was calculated as follows: radioactivity was measured in
an aliquot of the supernatant (200 µL) and in the precipitate after
dissolution in 1 mL of 1 N NaOH. In order to calculate the amount
of protein, the Eppendorf tubes were weighed empty, with protein
(wet weight), and with freeze-dried protein (dry weight). This ratio
of supernatant and pellet protein radioactivity was used to calculate
the accumulation of 14C-AP in the glands. The inhibitor concentra-
tion required to achieve 50% inhibition (IC50) of 14C-AP accumula-
tion was determined by fitting the equation for the expected
inhibition pattern to the data points.
J.; Tam, K. Lipophilicity profiles: Theory and Measurement, in
Pharmakokinetic Optimization in Drug Research: Biological,
Physicochemical and Computational Strategies; Testa, B., van de
Waterbeemd, H., Folkers, G., Guy, R., Eds.; VHCA: Zurich, 2001;
pp 275-304.
Acknowledgment. We are grateful to Ms. Gabriela Mu¨nch
for chemical assistance, Ms. Brigitte Boessenecker for the
determination of pKa and log D values, Ms. Tanja Ramisch for
the assessment of compound purities by HPLC, Dr. Cristina
Suteu (Chiral Technologies Europe) for the enantiomeric
separation of selected target compounds by chiral HPLC, Ms.
M. David and Ms. I. Hartig-Beecken for the in vitro evaluation
of the target compounds, and Mr. W. Prinz for the realization
of pharmacological tests.
Supporting Information Available: Detailed protocols for the
preparation of all target compounds and intermediates whose
synthesis is described in a general manner only in the Experimental
Section and assessment of purity of all target compounds by HPLC
and/or elemental analysis. This material is available free of charge
via the Internet at http://pubs.acs.org.
5.3. Pharmacology. Inhibition of Pentagastrin-Stimulated
Acid Secretion of the Perfused Rat Stomach (Ghosh Schild Rat).
The abdomen of anesthetized rats (CD rat, female, 200-250 g;
1.5 g/kg i.m. urethane) was opened after tracheotomy by a median
upper abdominal incision and a PVC catheter was fixed transorally
in the esophagus and another via the pylorus such that the ends of
the tubes just projected into the gastric lumen. The catheter leading
from the pylorus led outward into the right abdominal wall through
a side opening. After thorough rinsing (about 50-100 mL), warm
(37 °C) physiological NaCl solution was continuously passed
through the stomach (0.5 mL/min, pH 6.8-6.9; Braun-Unita I).
The pH (pH meter 632, glass electrode EA 147; φ ) 5 mm,
Metrohm) was adjusted by titration with a freshly prepared 0.01 N
NaOH solution to pH 7 (Dosimat 665 Metrohm), the secreted HCl
was determined in the effluent in each case collected at an interval
of 15 min. The gastric secretion was stimulated by continuous
infusion of 1 µg/kg (1.65 mL/h) of iv pentagastrin (left femoral
vein) about 30 min after the end of the operation (i.e., after
determination of 2 preliminary fractions). The substances to be
tested were administered intraduodenally in a 2.5 mL/kg liquid
volume 60 min after the start of the continuous pentagastrin
infusion. The body temperature of the animals was kept at a constant
37.8-38 °C by infrared irradiation and heat pads (automatic,
stepless control by means of a rectal temperature sensor).
5.4. Physical Chemistry. General. The determination of dis-
sociation constants (pKa) and lipophilicity [log P, log D (pH 7.4)]
were performed on a Sirius GL pKa analyzer specifically designed
for pH-metric pKa and 1-octanol/water partition coefficient mea-
surements (Sirius Analytical Instruments Ltd., Forest Row, UK).
Determination of Dissociation Constants. The pKa values of
the investigated compounds were determined by potentiometric
cosolvent titrations in 0.15 mol/L KCl solutions in the pH range of
2.0-11.0 at 25 °C using methanol as cosolvent in varying portions
and 0.5 mol/L KOH and HCl as titrants, respectively. Linear
extrapolation to 0% cosolvent-content was performed by the
Yasuda-Shedlovsky plot method implemented in the software
RefinementPro 2 from SIRIUS (Avdeef, A.; Box, K. J.; Comer, J.
E. A., Gilges, M.; Hadley, M.; Hibbert, C.; Patterson, W.; Tam, K.
Y. J. Pharm. Biomed. Anal. 1999, 20, 631-641).
References
(1) Heartburn, hiatal hernia, and gastroesophageal reflux disease
(GERD); NIH Publication No. 03-0882; June 2003; http://diges-
tive.niddk.nih.gov/ddiseases/pubs/gerd/index.htm.
(2) Locke, G. R., 3rd; Talley, N. J.; Fett, S. L.; Zinsmeister, A. R.;
Melton, L. J. 3rd Prevalence and clinical spectrum of gastroesoph-
ageal reflux: A population-based study in Olmsted County, Min-
nesota. Gastroenterology 1997, 112, 1448-1456.
(3) H. pylori and peptic ulcer; NIH Publication No. 05-4225; October
2004; http://digestive.niddk.nih.gov/ddiseases/pubs/hpylori/index. htm.
(4) Lethbridge-Cejku, M.; Vickerie, J. Summary health statistics for U.
S. adults: National health interview survey, 2003. Natl. Center Health
Stat., Vital Health Stat. 2005, 10 (225).
(5) Parsons, M. E.; Keeling, D. J. Novel approaches to the pharmacologi-
cal blockade of gastric acid secretion. Expert Opin. InVestig. Drugs
2005, 14, 411-421.
(6) Fass, R.; Shapiro, M.; Dekel, R.; Sewell, J. Systematic review:
Proton-pump inhibitor failure in gastro-oesophageal reflux diseases
Where next? Aliment. Pharmacol. Ther. 2005, 22, 79-94.
(7) Vakil, N. Review article: New pharmacological agents for the
treatment of gastro-oesophageal reflux disease. Aliment. Pharmacol.
Ther. 2004, 19, 1041-1049.
(8) Andersson, K.; Carlsson, E. Potassium-competitive acid blockade:
A new therapeutic strategy in acid-related diseases. Pharmacol.
Therap. 2005, 108, 294-307.
(9) Kaminski, J. J.; Bristol, J. A.; Puchalski, C.; Lovey, R. G.; Elliott,
A. J.; Guzik, H.; Solomon, D. M.; Conn, D. J.; Domalski, M. S.;
Wong, S.-C.; Gold, E. H.; Long, J. F.; Chiu, P. J. S.; Steinberg, M.;
McPhail, A. T. Antiulcer agents. 1. Gastric antisecretory and
cytoprotective properties of substituted imidazo[1,2-a]pyridines. J.
Med. Chem. 1985, 28, 876-892.
(10) Kaminski, J. J.; Hilbert, J. M.; Pramanik, B. N.; Solomon, D. M.;
Conn, D. J.; Rizvi, R. K.; Elliott, A. J.; Guzik, H.; Lovey, R. G.;
Domalski, M. S.; Wong, S.-C.; Puchalski, C.; Gold, E. H.; Long, J.
F.; Chiu, P. J. S.; McPhail, A. T. Antiulcer agents. 2. Gastric
antisecretory, cytoprotective, and metabolic properties of substituted
imidazo[1,2-a]pyridines and analogues. J. Med. Chem. 1987, 30,
2031-2046.
(11) Kaminski, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi, R. K.; Conn,
D. J.; Elliott, A. J.; Lovey, R. G.; Guzik, H.; Chiu, P. J. S.; Long, J.
F.; McPhail, A. T. Antiulcer agents. 4. Conformational considerations
and the antiulcer activity of substituted imidazo[1,2-a]pyridines and
related analogues. J. Med. Chem. 1989, 32, 1686-1700.
(12) Gold, E. H.; Kaminski, J. J.; Puchalski, C. Antiulcer tricyclic imidazo-
[1,2-a]pyridines. Patent application US 4468400, 1984.
(13) Zimmermann, P. J.; Simon, W.-A.; Postius, S.; Kromer, W.; Buhr,
W.; Senn-Bilfinger, J. Tricyclic imidazopyridines. Patent application
WO 03/014123, 2003.
(14) Buhr, W.; Chiesa, M. V.; Zimmermann, P. J.; Brehm, C.; Simon,
W.-A.; Kromer, W.; Postius, S.; Palmer, A. Tricyclic imidazopy-
ridines for use as gastric secretion inhibitors, Patent application WO
2005/058325, 2005.
Determination of Distribution Coefficients. The distribution
coefficients between 1-octanol and aqueous KCl solution were
determined at 25 °C by potentiometric titrations in the pH range
of 2.0-11.0. The titrations were performed in mixtures of 0.15
mol/L KCl solution and water-saturated 1-octanol with varying
1-octanol portions using 0.5 mol/L KOH and HCl as titrants,
respectively. The dependence of log D values on pH was obtained
by least-squares fitting of the experimental data to a theoretical
function of the distribution coefficient D (RefinementPro2): Comer,
(15) Chiesa, M. V.; Zimmermann, P. J.; Brehm, C.; Simon, W.-A.;
Kromer, W.; Postius, S.; Palmer, A.; Buhr, W. Tricyclic imidazopy-
ridines. Patent application WO 2005/090358, 2005.

6264 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 24
Palmer et al.
(16) Kaminski, J. J.; Wallmark, B.; Briving, C.; Andersson, B. M.
Antiulcer agents. 5. Inhibition of gastric H+/K+-ATPase by substi-
tuted imidazo[1,2-a]pyridines and related analogues and its implica-
tion in modeling the high affinity potassium ion binding site
of the gastric proton pump enzyme. J. Med. Chem. 1991, 34, 533-
541.
(17) Bu¨yu¨kkidan, B.; Bilgic¸, S.; Bilgic¸, O. The synthesis of some chromans
via o-quinone-methide intermediates. Synth. Commun. 2001, 31,
1263-1270.
(18) (a) Van de Weghe, P.; Eustache, J.; Cossy, J. Metathesis reactions.
General considerations. Curr. Top. Med. Chem. 2005, 5, 1461-1472.
(b) Vernall, A. J.; Abell, A. D. Cross metathesis of nitrogen-
containing systems. Aldrichimica Acta 2003, 36, 93-105. (c) Connon,
S. J.; Blechert, S. Recent developments in olefin cross-metathesis.
Angew. Chem. Int. Ed. 2003, 42, 1900-1923.
(19) Nakamura, K.; Yamanaka, R.; Matsuda, T.; Harada, T. Recent
developments in asymmetric reduction of ketones with biocatalysts.
Tetrahedron: Asymmetry 2003, 14, 2659-2681.
(24) (a) Palmer, M. J.; Wills, M. Asymmetric transfer hydrogenation of
CdO and CdN bonds. Tetrahedron: Asymmetry 1999, 10, 2045-
2061. (b) Noyori, R.; Yamakawa, M.; Hashiguchi, S. Metal-ligand
bifunctional catalysis: A nonclassical mechanism for asymmetric
hydrogen transfer between alcohols and carbonyl compounds. J. Org.
Chem. 2001, 66, 7931-7944.
(25) (a) Brown, H. C.; Jadhav, P. K.; Mandal, A. K. Hydroboration. 62.
Monoisopinocampheylborane, an excellent chiral hydroborating agent
for trans-substituted and trisubstituted alkenes. Evidence for a strong
steric dependence in such asymmetric hydroborations. J. Org. Chem.
1982, 47, 5074-5083. (b) Brown, H. C.; Ramachandran, P. V.
Versatile R-pinene-based borane reagents for asymmetric syntheses.
J. Organomet. Chem. 1995, 500, 1-19.
(26) (a) Head, R. A.; Ibbotson, A. Palladium catalysed synthesis of N-
and S-heterocyclic esters. Tetrahedron Lett. 1984, 25, 5939-5942.
(b) Horino, H.; Sakaba, H.; Arai, M. Facile preparation of 6-bro-
mopyridine-2-carboxamide and pyridine-2,6-dicarboxamide: Partial
aminocarbonylation of 2,6-dibromopyridine. Synthesis 1989, 715-
718.
(20) (a) Lipshutz, B. H.; Lower, A.; Kucejko, R. J.; Noson, K. Applications
of asymmetric hydrosilylations mediated by catalytic (DTBM-
SEGPHOS)CuH. Org. Lett. 2006, 8, 2969-2972. (b) Riant, O.;
Mostefai, N.; Courmarcel, J. Recent advances in the asymmetric
hydrosilylation of ketones, imines, and electrophilic double bonds.
Synthesis 2004, 18, 2943-2958.
(27) Montalbetti, C. A. G. N.; Falque, V. Amide bond formation and
peptide coupling. Tetrahedron 2005, 61, 10827-10852.
(28) Ghosh, A. K.; Krishnan, K. Chemoselective catalytic hydrogenation
of alkenes by Lindlar catalyst. Tetrahedron Lett. 1998, 39, 947-
948.
(21) Brown, H. C.; Chandrasekharan, J.; Ramachandran, P. V. Chiral
synthesis via organoboranes. 14. Selective reductions. 41. Diisopi-
nocampheylchloroborane, an exceptionally efficient chiral reducing
agent. J. Am. Chem. Soc. 1988, 110, 1539-1546.
(29) Bachki, A.; Foubelo, F.; Yus, M. Organolithium reagents from alkyl
phenyl ethers. Tetrahedron Lett. 1998, 39, 7759-7762.
(30) Seijas, J. A.; Va´zquez-Tato, M. P.; Mart´ınez, M. M.; Santiso, V.
Synthesis of anacardic acids by nucleophilic substitution on 2-ary-
loxazolines. Tetrahedron Lett. 2004, 45, 1937-1939.
(22) (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. Highly enantioselective
borane reduction of ketones catalyzed by chiral oxazaborolidines.
Mechanism and synthetic applications. J. Am. Chem. Soc. 1987, 109,
5551-5553. (b) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.
P.; Singh, V. K. A stable and easily prepared catalyst for the
enantioselective reduction of ketones. Applications to multistep
syntheses. J. Am. Chem. Soc. 1987, 109, 7925-7926. (c) Corey, E.
J.; Helal, C. J. Reduction of carbonyl compounds with chiral
oxazaborolidine catalysts: A new paradigm for enantioselective
catalysis and a powerful new synthetic method. Angew. Chem. Int.
Ed. 1998, 37, 1986-2012.
(23) (a) Noyori, R.; Ohkuma, T. Asymmetric catalysis by architectural
and functional molecular engineering: Practical chemo- and stereo-
selective hydrogenation of ketones. Angew. Chem., Int. Ed. 2001,
40, 40-73. (b) Sandoval, C. A.; Ohkuma, T.; Mun˜iz, K.; Noyori, R.
Mechanism of asymmetric hydrogenation of ketones catalyzed by
BINAP/1,2-diamine-ruthenium(II) complexes. J. Am. Chem. Soc.
2003, 125, 13490-13503.
(31) (a) Shi, Y.-J.; Hughes, D. L.; McNamara, J. M. Stereospecific
synthesis of chiral tertiary alkyl-aryl ethers via Mitsunobu reaction
with complete inversion of configuration. Tetrahedron Lett. 2003,
44, 3609-3611. (b) Dirlam, N. L.; Moore, B. S.; Urban, F. J. Novel
synthesis of the aldose reductase inhibitor sorbinil via amidoalky-
lation, intramolecular oxazolidin-5-one alkylation, and chymotrypsin
resolution. J. Org. Chem. 1987, 52, 3587-3591.
(32) (a) Dale, J. A.; Mosher, H. S. Nuclear magnetic resonance enantiomer
reagents. Configurational correlations via nuclear magnetic resonance
chemical shifts of diastereomeric mandelate, O-methylmandelate, and
R-methoxy-R-trifluoromethylphenylacetate (MTPA) esters. J. Am.
Chem. Soc. 1973, 95, 512-519. (b) Dale, J. A.; Dull, D. L.; Mosher,
H. S. R-Methoxy-R-trifluoromethylphenylacetic acid, a versatile
reagent for the determination of enantiomeric composition of alcohols
and amines. J. Org. Chem. 1969, 34, 2543-2549.
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