Synthesis and matrix metalloproteinase-12 inhibitory activity of ageladine A analogs

DOI: 10.1248/cpb.59.579

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Chemical and Pharmaceutical Bulletin p. 579 - 596 (2011)

Update date:2022-08-02

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Authors:

Ando, Naoki

Terashima, Shiro

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Article abstract of DOI:10.1248/cpb.59.579

Synthesis of the 37 ageladine A analogs was accomplished by employing the total synthetic route of natural ageladine A previously explored by us. From the matrix metalloproteinase-12 (MMP-12) inhibitory activity assay carried out using the novel analogs, it appeared evident that the halogen atom at the 2-position of pyrrole ring was essential for the inhibitory activity and that the introduction of a bromine atom into the 4-position of pyrrole ring is very effective for producing potent activity. In addition, exchange of the pyrrole ring to an imidazole ring was extremely effective in increasing activity, and the analog 29 thus obtained was found to show approximately 4 times more potent activity than natural ageladine A.

Full text of DOI:10.1248/cpb.59.579

May 2011

Regular Article

Chem. Pharm. Bull. 59(5) 579—596 (2011)

579

Synthesis and Matrix Metalloproteinase-12 Inhibitory Activity of

Ageladine A Analogs^1,2)

Naoki ANDO*^,aand Shiro TERASHIMA

^aDiscovery Research Laboratories, Kyorin Pharmaceutical Co., Ltd.; 2399–1 Nogi, Nogi-machi, Shimotsuga-gun, Tochigi

329–0114, Japan: and ^bSagami Chemical Research Institute; 2743–1 Hayakawa, Ayase, Kanagawa 252–1193, Japan.

Received November 16, 2010; accepted February 12, 2011

Synthesis of the 37 ageladine A analogs was accomplished by employing the total synthetic route of natural

ageladine A previously explored by us. From the matrix metalloproteinase-12 (MMP-12) inhibitory activity assay

carried out using the novel analogs, it appeared evident that the halogen atom at the 2-position of pyrrole ring

was essential for the inhibitory activity and that the introduction of a bromine atom into the 4-position of pyrrole

ring is very effective for producing potent activity. In addition, exchange of the pyrrole ring to an imidazole ring

was extremely effective in increasing activity, and the analog 29 thus obtained was found to show approximately 4

times more potent activity than natural ageladine A.

Key words ageladine A; matrix metalloproteinase-12; ageladine A analog

Ageladine A (1), which is a pyrrol-2-aminoimidazole alka- ity performed by using the 37 ageladine A analogs prepared

loid isolated from the marine sponge Agelas nakamurai by by featuring our synthetic route established for 1.¹⁵⁾

Fusetani and colleagues³⁾inhibits various subtypes of matrix

metalloproteinases (MMPs) such as MMP-1, 2, 8, 9, 12, and Results and Discussion

13. Among these MMPs, MMP-12 is considered to be asso-

MMP-12 Inhibitory Activity of Ageladine A Analogs

ciated with inﬂammatory diseases caused by macrophage in- We ﬁrst, attempted to clarify the structural features of agela-

ﬁltration such as skin diseases,^4—6)atherosclerosis,⁷⁾aneu- dine A (1) itself required for its MMP-12 inhibitory activity,

rysms,⁸⁾and cancers.^9—11)We had been studying the possibil- and synthesized the 8 analogs 2—9. The MMP-12 inhibition

ity of using MMP-12 inhibitors against inﬂammatory dis- assay was performed as per the manufacturer’s (BioMol) pro-

eases, but had not been able to ﬁnd a lead compound. Ac- tocol. The results of the MMP-12 inhibitory activity assay of

cordingly, we embarked on evaluating 1 as a new lead com- these analogs are summarized in Table 1. The activity of two

pound for novel MMP-12 inhibitors. Three total syntheses of debromo-analogs 2 and 3 was found to disappear. The N-

1 have been reported by Meketa and Weinreb^12,13)and Shen- methylpyrrole analog 4 showed no activity at all. In addition,

gule and Karuso.¹⁴⁾Recently, we also completed the total the 4 analogs, 5—8 in which the amino or imino groups of

synthesis of 1 based on the biosynthetic route proposed by imidazo[4,5-c]pyridine ring system are methylated and the

Fusetani et al., as shown in Chart 1.^1,15)While our synthetic deamino analog 9 showed weak or no activity. From these re-

route is almost the same as that independently reported by sults, it was supposed that the two bromine atoms and the

Shengule and Karuso,¹⁴⁾it is anticipated to be more efﬁcient three NH groups (1-NH, 14-NH, and 15-NH₂: ageladine A

and practical when taking into account the reagents and numbering) of 1 play an important role in its MMP-12

chemical yields for each step. We wish to report here the inhibitory activity. We paid particular attention to the inﬂu-

structure–activity relationships for MMP-12 inhibitory activ- ence of the bromine atoms, and anticipated that a slight

Reagents and conditions: (a) AcONH₄/MeNO₂, reﬂux, 20 min, 94%; (b) LiAlH₄(3 eq)/THF, 50 °C, 1 h, 67%; (c) 41a/EtOH, 50 °C, 6 h; (d) IBX (1.5 eq)/DMSO, rt,

2 h; (e) MnO₂/CH₂Cl₂, rt, 1 h; (f) BF₃–OEt₂(10 eq)/CH₂Cl₂, rt, overnight; (g) TFA/MeOH, rt, 5 min, 70% (2 steps).

Chart 1. The Synthetic Route of Ageladine A (1) Previously Explored by Us.^1,15)

∗ To whom correspondence should be addressed. e-mail: naoki.andou@mb.kyorin-pharm.co.jp

580

Vol. 59, No. 5

Table 1. MMP-12 Inhibitory Activity of Ageladine A (1) and Its Analogs

2—9

Table 3. MMP-12 Inhibitory Activity of Ageladine A (1) and Its Analogs

29—38

Compound

IC₅₀(mM)

Compound

R¹

R²

R³

IC₅₀(mM)

C–Br

C–Cl

C–H

C–Br

C–H

C–Br

C–H

C–Br

C–H

3.66

0.86

1.64

ꢀ100

15.7

ꢀ100

88.2

ꢀ100

NH₂

NHMe

NH₂

NHMe

NMe₂

3.66

ꢀ100

10.4

C–Br

C–H

56.9

ꢀ100

43.6

C–Br

C–H

Table 2. MMP-12 Inhibitory Activity of Ageladine A (1) and Its Analogs

10—28

contrast, the 3-position of the pyrrole ring was found to show

slightly different substituent effects. The bromine atom was

found to be most promising (see 1, 10, 11, 15, and 17), but

the phenyl and phenethyl groups also showed weak in-

hibitory activity (see 17 and 20). The benzyl, triﬂuo-

romethylphenethyl, and phenylpropyl groups, however, were

not effective. As mentioned above, the 3-position can accept

more different groups than the 2-position, but the number of

acceptable groups seems to be fairly limited. The most inter-

esting effects were obtained by introducing a substituent into

the 4-position of the pyrrole ring. It became obvious that in-

troducing a bromine atom into the 4-position signiﬁcantly in-

creased the inhibitory activity (see 16, 21, and 27). In partic-

ular, 4-bromo-ageladine A 27 showed ca. 3 times more po-

tent inhibitory activity than natural ageladine A (1).

Next, the exchange of the pyrrole ring to various azole

rings such as an imidazole or a tetrazole ring was further ex-

amined because the initial examinations, as shown in Table 1,

suggested that the acidic proton of the pyrrole ring of 1

might play an important role in MMP-12 inhibitory activity.

These results are summarized in Table 3. It was found that

the dibromoimidazole analog 29 shows the most potent in-

hibitory activity among all the synthesized analogs, with its

activity being ca. 4 times stronger than that of 1. In contrast,

the activity of its isomer, 32, was weak. Only analogs having

a halogen atom at the 2-position exhibited inhibitory activity.

It became particularly apparent that having a halogen atom at

Compound

IC₅₀(mM)

3.66

5.02

2.02

ꢀ100

5.02

PhCH₂

Ph(CH₂)₂

o-CF₃-Ph(CH₂)₂

m-CF₃-Ph(CH₂)₂

p-CF₃-Ph(CH₂)₂

Ph(CH₂)₃

18.7

ꢀ100

10.2

Ph(CH₂)₂

2.99

ꢀ100

1.24

ꢀ100

change in the substituent on the pyrrole ring might greatly both the 2- and 3-positions is important to exhibiting activity

inﬂuence the inhibitory activity. We therefore carried out as potent as that of ageladine A (1).

additional synthetic studies of ageladine A analogs to explore

more detailed substituent effects of the pyrrole ring and to ﬁndings were obtained regarding the structure–activity rela-

ﬁnd analogs showing improved inhibitory activity. tionships of 1. First, the proton at the 1-position (NH) and

Summing up the results mentioned above, the following

The results of the examinations regarding more detailed the halogen atom (Br or Cl) at the 2-position are essential.

substituent effects of the pyrrole ring are shown in Table 2. Next, a bromine atom is the most effective at the 3-position,

As for the 2-position of the pyrrole ring, replacement of the but is not essential. Unlike the speciﬁcity required for the 2-

bromine atom with a chlorine atom obviously increased the position, even the 3-phenyl or phenethyl derivatives showed

inhibitory activity (see 11). However, the introduction of activity. Introduction of a bromine atom to the 4-position

other groups such as methyl, and phenyl groups clearly de- strengthens the activity. However, the most potent compound

creased the activity (see 12—14). From these results, it ap- is the imidazole derivative 29, which structurally carries no

peared that the bromine or chlorine atom at the 2-position bromine atom at the corresponding 4-position. It was antici-

plays an important role in MMP-12 inhibitory activity. In pated that these ﬁndings might clarify the importance of

May 2011

581

Reagents and conditions: (a) MeI, NaH/DMF, rt, overnight, 36% for 44a, 27% for 44b; (b) BF₃-Et₂O (10 eq)/CH₂Cl₂, rt, overnight; (c) TFA/MeOH, rt, 5 min, 92%

(2 steps) for 5, 83% (2 steps) for 6, 97% (2 steps) for 7; (d) HCl–MeOH, rt, overnight, 53%; (e) MeI, NaH/DMF, rt, 2 h, 50%.

Chart 2. Synthesis of Ageladine A Analogs (5—7)

acidity of the proton at the 1-position. Thus, the introduction n-butylammonium tribromide (TBABr₃) to give 48a, b, e, f,

of a bromine atom is considered to be effective for enhancing h, i, k, and p. Further bromination of 48f, i, k, and p gave

the acidity of the proton at the 1-position. However, tetrazole rise to 48g, j, l, and q. The phenethyl derivatives 47b—e

or triazole analogs (see 34—38) showing increased acidity were converted to the dibromo-derivatives 48m—o and r

exhibited no or very weak activity. Accordingly, it appears using 2 eq of TBABr₃. Chlorination of 43ac, ad, and ap with

that the presence of halogen atoms at the 2- and 3-positions 2 eq or 1 eq of N-chlorosuccinimide (NCS) afforded 48c, d,

is more important to MMP-12 inhibitory activity than the and s.

strength of acidity of the proton at the 1-position.

The intermediates 43 and 48 synthesized above were de-

Chemistry The synthetic routes for analogs 5—7 are protected by means of one of the 4 following methods

shown in Chart 2. The N-methyl derivatives 5—7 were syn- (method C: BF₃OEt₂; method D: triﬂuoroacetic acid (TFA);

thesized from 43a, which is the intermediate of our total syn- method E: 1) aqueous sodium hydroxide solution (NaOHaq),

thesis of ageladine A (1).^1,15)Methylation of 43a using NaH 2) TFA; method F: 1) hydrogen chloride in methanol (HCl-

and iodomethane produced 44a and 44b in 36% and 27% MeOH), 2) di-tert-butyl dicarbonate (Boc₂O), triethylamine

yields, respectively, after separation by column chromatogra- (TEA), 3) TFA), giving the 33 target ageladine A analogs

phy. In costract, methylation after removal of the tert-butoxy- 2—4, 9—29, 31, and 33—38 (Table 8).

carbonyl (Boc) group provided 46 by way of 45. The N-

The analog 8 was synthesized from 43ca by sequential

methylated compounds 44a, b and 46 were converted to the substitution with dimethylamine and deprotection (Chart 3).

corresponding target analogs 5—7 by the same deprotection The analog 30 was prepared from 48s as shown in Chart 4.

using borontriﬂuoride-etherate (BF₃-OEt₂) as that employed Thus, protection of 48s followed by bromination afforded 51,

for our total synthesis of 1.

which was then transformed to 30 by hydrolysis followed by

The other derivatives were synthesized by applying our deprotection. As shown in Chart 5, synthesis of 32 com-

total synthetic route of 1. The Pictet–Spengler reaction of menced with the less polar regioisomer of 43aw. After

histamine derivatives 40a,^1,15)b, and c¹⁶⁾with aldehydes 41 bromination of 43aw, a two-step deprotection of the dibro-

followed by our original two-step oxidation using IBX and mide 53 afforded 32. Structure determinations of the inter-

activated MnO₂gave imidazo[4,5-c]pyridine derivatives 43 mediates 53 and 54 were not attempted since both of the two

(Tables 4, 5). Run 2 in Table 5 gave 43aw as a mixture of two possible regioisomers converged to 32 as a single product

regioisomers that could be separated by column chromatog- after deprotection.

raphy. However, determinations of their structures were not

On the other hand, the 1H-pyrrol-2-aldehyde derivatives

attempted since removal of the 2-(trimethylsilyl)ethoxymethyl 41a, b, d—o used for the Pictet–Spengler reaction (vide

(SEM) group converged 43aw to a single product 32 (Chart supra) were synthesized by the methods shown in Chart 6.

5). The alkyne derivatives 43aj, ak, al, am, and ao obtained 41c was prepared according to the reported method.¹⁷⁾Thus,

from 40a and 41j—m, o were converted to the phenethyl de- protection of 55¹⁸⁾, 56¹⁹⁾, 58a—c,²⁰⁾and 59²¹⁾with a SEM

rivatives 47a—e by catalytic reduction in good yields as group provided 41a, d, g, i, n, and 60, respectively. The alde-

shown in Table 6.

hyde 41a was further converted to 41f by the regioselective

The various derivatives 43 and 47 were subjected to halo- Suzuki–Miyaura cross-coupling reaction following the pro-

genation to afford 48 as shown in Table 7. Thus, 43ac, a, ae, cedure reported by Handy and Sabatini.²²⁾The 1-methyl de-

ag, ah, ai, an, and 47a were brominated using 1 eq of tetra- rivative 41b was prepared from 41a by the usual procedure.

582

Vol. 59, No. 5

Table 4. Synthesis of the Intermediates 43 for Ageladine A Analogs-1

Aldehyde 41

Run

No.

R¹

No.

R²

No. (yield^a))

NHBoc

C–Br

C–H

C–Me

C–Ph

C–H

C–Br

C–H

ab (22%)

ac (51%)

ad (75%)

ae (45%)

af (52%)

ag (38%)

ah (55%)

ai (69%)

aj (58%)

ak (68%)

al (63%)

am (38%)

an (75%)

ao (17%)^b)

ap (38%)

aq (15%)

ar (48%)

as (20%)

at (76%)

au (75%)

ba (41%)

ca (59%)

SEM

C–Br

C–Me

C–Ph

C–CH₂Ph

—

Ph)

—

21^c)

Ph(o-CF₃))

Ph(m-CF₃))

Ph(p-CF₃))

—

C–(CH₂)₃Ph

—

Ph)

—

C–H

C–Br

C–H

C–Br

SEM

PMB

SEM

C–Br

a) Isolated yield. b) The reaction was performed in reﬂuxing EtOH. Probably due to transesteriﬁcation at higher temperature, the reaction product 43ao was obtained as an

ethyl carbamate instead of a tert-butyl carbamate. c) This reaction was carried out in reﬂuxing 2-methoxyethanol (ca. 125 °C).

Table 5. Synthesis of the Intermediates 43 for Ageladine A Analogs-2

The aldehyde 41h was prepared from 41d by

Suzuki–Miyaura cross-coupling reaction. The Sonogashira

cross-coupling reaction of 41d and 60 gave 41j—m, o, re-

spectively. The synthesis of 41e was performed by bromina-

tion of 57,²⁰⁾followed by protection.

The synthetic routes to the polyazolaldehyde derivatives

41r—u, x, and y are shown in Chart 7. The other polyazol-

aldehydes 41p,²³⁾q,²⁴⁾v,²⁵⁾and w²³⁾were prepared according

to the reported methods. After protection of 61, lithiation of

the 2-position of protected 61 followed by formylation gave

41r. The aldehydes 41s, u, and y were synthesized from

62,²⁶⁾66,²⁷⁾and 67²⁸⁾by a method similar to that used for

41r. Preparation of 41x was achieved starting with the acety-

lene 63. 1,3-Dipolar cycloaddition of 63 with tritylazide gave

64, which was converted into 41x by deprotection. Reduction

of 65²⁹⁾followed by oxidation of the formed alcohol fur-

nished 41t.

Aldehyde 41

Run

No.

No. (yield^a))

av (29%)

aw (22%)^b)

ax (49%)

ay (36%)

Conclusion

As mentioned above, we have succeeded in synthesizing

the 37 ageladine A analogs 2—38 by employing the total

synthetic route of ageladine A (1) previously explored by

us.^1,15)From the MMP-12 inhibitory activity assay carried

out using the novel analogs, it appeared evident that the pro-

ton at the 1-position and the halogen atom at the 2-position

of pyrrole ring were essential for the inhibitory activity and

that the introduction of a bromine atom into the 3- and/or 4-

a) Isolated yield. b) Since 41w was a mixture of two regioisomers, the reaction

product was also obtained as a mixture of two regioisomers. The major less polar prod-

uct 43aw was separated and used for the next bromination.

May 2011

583

Reagents and conditions: (a) 2 M Me₂NH in MeOH, 100 °C (sealed tube), 10 h, 53%; (b) BF₃-Et₂O (10 eq)/CH₂Cl₂, rt. overnight; (c) TFA/MeOH, rt, 5 min, 75%

(2 steps).

Chart 3. Synthesis of 8

Table 7. Synthesis of the Intermediates 48 for Ageladine A Analogs by

Table 6. Synthesis of the Intermediates 47 for Ageladine A Analogs

Halogenations

No.

Run

Method^a)

Run

No. (yield^d))

No.

Ar (position)

No. (yield^a))

43ac

43a

C–Br C–H

C–Br C–Br

C–H

C–Br

C–H

C–Br

C–H

C–Br

C–H

C–Br

C–H

C–Br

a (93%)

b (quant.)

c (19%)

d (91%)

e (98%)

f (81%)

g (94%)

h (96%)

i (88%)

j (93%)

k (91%)

l (98%)

m (93%)

n (78%)

o (78%)

p (90%)

q (92%)

Ph (4-)

a (98%)

b (100%)

c (98%)

o-CF₃-Ph (4-)

m-CF₃-Ph (4-)

p-CF₃-Ph (4-)

Ph (3-)

43ac B^b)C–Cl C–Cl

43ad

43ae

43ag

48f

43ah

43ai

C–Cl C–Br

C–Me C–Br

C–Br C–Me

C–Br C–Ph

C–Br C–CH₂Ph

C–Br C–(CH₂)₂Ph

d (89%)

e (84%^b)^c)

a) Isolated yield. b) Crude yield. c) The crude sample 47e was directly sub-

jected to the next bromination.

10 48i

11 47a

12 48k

13 47b

14 47c

15 47d

16 43an

17 48p

18 47e

19 43ap

position of pyrrole ring was very effective in producing po-

tent activity. It was also found that exchanging a pyrrole ring

for an imidazole ring was quite effective, with the analog 29

thus obtained showing ca. 4 times more potent activity than

natural ageladine A (1). This ﬁnding may suggest that the

strength of the acidity of the proton at the 1-position of the

pyrrole ring would also inﬂuence the MMP-12 inhibitory

activity of 1. These results should be useful for future studies

aimed at identifying even more potent ageladine A analogs.

A^c)C–Br C–(CH₂)₂Ph (o-CF₃) C–Br

A^c)C–Br C–(CH₂)₂Ph (m-CF₃) C–Br

A^c)C–Br C–(CH₂)₂Ph (p-CF₃) C–Br

C–Br C–(CH₂)₃Ph

C–H

C–Br

A^c)C–Br C–Br

C–(CH₂)₂Ph r (84%^e))

C–Cl C–H

s (33%)

a) Method A: TBABr₃(1 eq) was used as a brominating agent. Method B: NCS

(1 eq) was used as a chlorinating agent. b) Two equivalents of NCS were used. c)

Two equivalents of TBABr₃were used. d) Isolated yield. e) Calculated based on

43ao (2 steps).

Experimental

General All melting points were determined with a Yanaco MP-500

melting point apparatus and are uncorrected. Infrared spectra were recorded

with a JASCO FT/IR-5300 spectrometer or a Perkin-Elmer spectrum 100

column chromatography. The following abbreviations were used for solvents

and reagents: acetone (Me₂CO); acetonitrile (MeCN); borontriﬂuoride

diethyletherate (BF₃-OEt₂); N-bromosuccinimide (NBS); n-butyllithium (n-

BuLi); chloroform (CHCl₃); N-chlorosuccinimide (NCS); dichloro-bis(triph-

enylphosphine)palladium (Pd(PPh₃)₂Cl₂); dichloromethane (CH₂Cl₂); diethyl

ether (Et₂O); 4-(N,N-dimethylamino)pyridine (DMAP); N,N-dimethylfor-

mamide (DMF); dimethyl sulfoxide (DMSO); ethanol (EtOH); ethyl acetate

(EtOAc); ethyldiisopropylamine (iPr₂EtN); n-hexane (C₆H₁₄); iodoxybenzoic

acid (IBX); methanol (MeOH); tetrahydrofuran (THF); water (H₂O), di-

tert-butyl dicarbonate (Boc₂O); triethylamine (Et₃N); hydrogen chloride

(HCl); iodomethane (MeI); manganese(IV) oxide (MnO₂); palladium acetate

(Pd(OAc)₂); potassium tert-butoxide (tBuOK); potassium carbonate (K₂CO₃);

pyridinium p-toluenesulfonate (PPTS); sodium borohydride (NaBH₄);

sodium hydride (NaH); sodium hydrogen carbonate (NaHCO₃); sodium hy-

droxide (NaOH); sodium carbonate (Na₂CO₃); sodium sulfate (Na₂SO₄);

tetra-n-butylanmonium tribromide (TBABr₃); tetrakis(triphenylphosphine)-

palladium (Pd(PPh₃)₄); toluene (C₆H₅Me); triﬂuoroacetic acid (TFA); 2-

(trimethylsilyl)ethoxymethyl chloride (SEMCl).

spectrometer. H-NMR spectra were measured with a JEOL JNM-ECA-400

or -ECX-400 (400 MHz) spectrometer. Measurements of ¹³C-NMR spectra

were carried out using a JEOL JNM-ECA-400 or -ECX-400 (100 MHz)

spectrometer. The chemical shifts are expressed in parts per million

(d value) downﬁeld from tetramethylsilane, using tetramethylsilane (dꢁ0)

and/or residual solvents such as chloroform (dꢁ7.26) as an internal stan-

dard. Splitting patterns are indicated as s, singlet; d, doublet; t, triplet; q,

quartet; m, multiplet; br, broad peak. Measurements of mass spectra were

performed with a JEOL JMS-SX102X mass spectrometer. Data for elemen-

tal analyses are within ꢂ0.3% of the theoretical values, and were determined

by a Yanaco CHN-corder MT-6. Unless otherwise noted, all the experiments

were carried out using anhydrous solvents under an atmosphere of argon.

Throughout this study, Merck precoated TLC plates (Silica gel 60 F₂₅₄, 0.25

mm) were used for thin layer chromatographic (TLC) analysis, and all of the

spots were visualized using UV light followed by coloring with phospho-

molybdic acid or anisaldehyde. Silica gel 60N (40—50 mm, neutral; Kanto

Chemical Co., Inc., Tokyo, Japan) or Chromatorex^®NH DM2035 (200—

350 mesh; Fuji Silysia Chemical, Ltd., Aichi, Japan) was used for the ﬂash

4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-car-

584

Vol. 59, No. 5

Table 8. Synthesis of Ageladine A Analogs 2—4, 9—29, 31, and 33—38

Run

Method^a)

R¹

R²

No. (yield^b))

43ad

48a

43ab

43ba

48c

48d

43ae

48e

43af

48f

48g

48h

48i

48j

48k

48l

48m

48n

48o

48p

48q

48b

48r

43ar

43aq

43av

43at

43as

43ax

43ay

43au

C–H

C–Br

C–Cl

C–Me

C–Ph

C–Br

C–H

C–Br

C–H

C–Br

C–H

NH₂

2 (82%)

3 (86%)

4 (82%)

C–H

C–Br

C–H

C–Br

C–H

C–Br

C–H

C–Br

C–H

C–Br

C–(CH₂)₂Ph

C–Br

C–Cl

C–Br

C–Me

C–Ph

C–CH₂Ph

C–(CH₂)₂Ph

C–(CH₂)₂Ph–o-CF₃

C–(CH₂)₂Ph–m-CF₃

C–(CH₂)₂Ph–p-CF₃

C–(CH₂)₃Ph

9 (67%)

NH₂

10 (91%)

11 (23%)

12 (64%)

13 (61%)

14 (65%)

15 (84%)

16 (34%)

17 (75%)

18 (68%)

19 (71%)

20 (71%)

21 (49%)

22 (74%)

23 (61%)

24 (44%)

25 (69%)

26 (59%)

27 (72%)

28 (79%)

29 (64%)

31 (33%)

33 (46%)

34 (73%)

35 (56%)

36 (46%)

37 (9%)

C–(CH₂)₃Ph

C–Br

C–H

C–Br

38 (58%)

a) Method C: 1) BF₃OEt₂, 2) Na₂CO₃aq, 3) TFA, method D: 1) TFA, 2) Na₂CO₃aq, 3) TFA, method E: 1) NaOHaq, 2) TFA, method F: 1) HCl-MeOH, 2) Boc₂O, Et₃N, 3)

TFA. b) Isolated yield.

Reagents and conditions: (a) Boc₂O, DMAP (cat.)/MeCN, rt, overnight, 93%; (b) NBS/MeCN, rt, 3 d, 72%; (c) NaOHaq/EtOH, 80 °C, 8 h; (d) TFA/CH₂Cl₂, rt,

overnight, 59% (2 steps).

Chart 4. Synthesis of 30

May 2011

585

Reagents and conditions: (a) NBS/CHCl₃, rt, overnight, 81%; (b) NaOHaq/EtOH, 80 °C, 8 h; c) TFA/CH₂Cl₂, rt, overnight, 78% (2 steps).

Chart 5. Synthesis of 32

Reagents and conditions: (a) i) SEMCl, tBuOK/DMF, 0 °C, 1 h, 89% for 41a, 92% for 41d, 80% for 41e (2 steps), 91% for 41g, 43% for 41i, 51% for 41n, 89% for

60; (b) MeI, tBuOK/DMF, 0 °C, 1 h, 98%; (c) PhB(OH)₂, Pd(OAc)₂, K₂CO₃/DMF, 100 °C, 7—8 h, 70%; (d) PhB(OH)₂, Pd(PPh₃)₄, K₂CO₃/DMF, 100 °C, 8 h, 52%; (e)

PdCl₂(PPh₃)₂, CuI, TEA/DMF, 100 °C, 5 h, 60% for 41j, 59% for 41k, 53% for 41l, 54% for 41m, 96% for 41o; (f) NBS/THF, ꢃ78 °C.

Chart 6. Synthesis of the Pyrrole-2-aldehyde Derivatives 41a, b, d—o

Hz), 7.13 (1H, dd, Jꢁ1.8, 0.9 Hz), 9.53 (1H, d, Jꢁ0.9 Hz). LR-MS (CI^ꢄ)

m/z: 304 [MꢄH^ꢄ]. HR-MS (CI^ꢄ) m/z: Calcd for C₁₁H₁₉BrNO₂Si (MꢄH^ꢄ)

304.0368, Found 304.0322.

baldehyde (41a) To a solution of 55 (1.0 g, 4.0 mmol) in DMF (20 ml) was

added tBuOK (466 mg, 4.2 mmol) at 0 °C. After stirring at room temperature

for 30 min, SEMCl (0.77 ml, 4.4 mmol) was added to the reaction mixture at

0 °C, and the whole was stirred at the same temperature for 1 h. The reaction

was quenched by adding H₂O at 0 °C, and the mixture was extracted with

EtOAc. The organic extracts were combined, washed with H₂O and brine,

dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated in vacuo. Pu-

riﬁcation of the residue by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ

10/1) afforded 41a (1.35 g, 89%) as a light brown oil. IR (ATR): 2953, 1671,

4-Methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-carbalde-

hyde (41g) Treatments of 58a (450 mg, 4.1 mmol) with tBuOK (554 mg,

4.9 mmol) and SEMCl (0.874 ml, 4.9 mmol) carried out in a similar manner

to that described for 41a gave 41g (894 mg, 91%) as a colorless oil after

puriﬁcation by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ50/1). IR

(ATR): 2953, 1663, 1248, 1083, 832, 751 cm^ꢃ1. ¹H-NMR (CDCl₃) d: ꢃ0.03

(9H, s), 0.88—0.92 (2H, m), 2.11 (3H, s), 3.51—3.56 (2H, m), 5.64 (2H, s),

6.77 (1H, d, Jꢁ1.5 Hz), 6.92 (1H, t, Jꢁ0.9 Hz), 9.50 (1H, d, Jꢁ0.9 Hz). LR-

MS (EI^ꢄ) m/z: 239 [M^ꢄ]. HR-MS (EI^ꢄ) m/z: Calcd for C₁₂H₂₁NO₂Si (M^ꢄ)

239.1342, Found 239.1378.

4-Benzyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-carbalde-

hyde (41i) The same treatments of 58b (560 mg, 3.0 mmol) with tBuOK

(678 mg, 6.0 mmol) and SEMCl (1.07 ml, 6.0 mmol) as those described for

41a gave 41i (411 mg, 43%) as a pale yellow solid after puriﬁcation by col-

umn chromatography (SiO₂₁, C₆H₅Me/EtOAcꢁ50/1). IR (ATR): 2952, 1663,

1084, 833, 763, 701 cm^ꢃ1. H-NMR (CDCl₃) d: ꢃ0.04 (9H, s), 0.86—0.90

(2H, m), 3.51—3.55 (2H, m), 3.83 (2H, s), 5.64 (2H, s), 6.78 (1H, d, Jꢁ1.8

Hz), 6.91 (1H, dd, Jꢁ1.8, 0.9 Hz), 7.20—7.23 (3H, m), 7.28—7.32 (2H, m),

1399, 1371, 1310, 1248, 1091, 832 cm^ꢃ1. H-NMR (CDCl₃) d: ꢃ0.03 (9H,

s), 0.88—0.92 (2H, m), 3.57—3.61 (2H, m), 5.81 (2H, s), 7.02 (1H, s), 9.40

(1H, s). Low resolution (LR)-MS (electrospray ionization (ESI)^ꢄ) m/z: 382

[MꢄH^ꢄ]. High resolution (HR)-MS (ESI^ꢄ) m/z: Calcd for C₁₁H₁₈Br₂NO₂Si

(MꢄH^ꢄ) 381.94736, Found 381.94819.

4-Bromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-carbalde-

hyde (41d) Treatments of 56 (1.74 g, 10 mmol) with tBuOK (1.23 g, 11

mmol) and SEMCl (1.95 ml, 11 mmol) carried out in the same manner as de-

scribed for 41a gave 41d (2.79 g, 92%) as a colorless oil after puriﬁcation by

column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ20/1). IR (ATR): 2953, 1668,

1375, 1248, 1083, 832, 738 cm^ꢃ^{1 1}H-NMR (CDCl₃) d: ꢃ0.02 (9H, s),

0.88—0.94 (2H, m), 3.52—3.57 (2H, m), 5.67 (2H, s), 6.95 (1H, d, Jꢁ1.8

586

Vol. 59, No. 5

Reagents and conditions: (a) i) SEMCl, tBuOK/DMF, 0 °C, 1 h; ii) nBuLi, DMF/THF, ꢃ78 °C (for crude product) (this sample contained some unidentiﬁed by-prod-

ucts (ca. 10%); (b) nBuLi, DMF/THF, ꢃ78 °C-rt, 45%; (c) trytylazide, CuI, diisopropylethylamine/DMF, 40 °C, 44 h, 93%; (d) PPTS (cat.)/acetone, rt, 2 d, 46%; (e) i)

NaBH₄/MeOH, 0 °C, 30 min; ii) MnO₂/CH₂Cl₂, rt, 4 h, 80%; (f) nBuLi, HCO₂Et/THF, ꢃ98 °C-rt, 73%; (g) nBuLi, TMEDA, HCO₂Et/THF, ꢃ98 °C-rt (a mixture of 41u

and 67 (3 : 1) was obtained. This was directly used for the next reaction.).

Chart 7. Synthesis of the Azole-aldehyde Derivatives 41r—u, x, y

9.50 (1H, d, Jꢁ0.9 Hz). LR-MS (ESI^ꢄ) m/z: 316 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ)

Calcd for C₁₈H₂₆NO₂Si m/z: 316.17328 (MꢄH^ꢄ), Found 316.17404.

phy (SiO₂, C₆H₁₄/EtOAcꢁ50/1) afforded 41e (245 mg, 80%) as a red oil. ¹H-

NMR (CDCl₃) d: ꢃ0.03 (9H, s), 0.86—0.90 (2H, m), 2.35 (3H, s), 3.52—

3.57 (2H, m), 5.78 (2H, s), 6.91 (1H, s), 9.41 (1H, s). LR-MS (EI^ꢄ) m/z: 317

[M^ꢄ]. HR-MS (EI^ꢄ) m/z: Calcd for C₁₂H₂₀BrNO₂Si (M^ꢄ) 317.0447, Found

317.0446.

4-(3-Phenylpropyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrole-2-

carbaldehyde (41n) Simlar treatments of 58c (1.32 g, 6.2 mmol) with

tBuOK (1.04 g, 9.3 mmol) and SEMCl (1.64 ml, 9.3 mmol) to those de-

scribed for 41a gave 41n (1.09 g, 51%) as a pale yellow oil after puriﬁcation

by column chromatography (SiO₂₁, toluene/EtOAcꢁ50/1). IR (ATR): 2936,

4-Bromo-5-phenyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-

carbaldehyde (41f) To a solution of 41a (448 mg, 1.2 mmol) in DMF

1663, 1084, 833, 749, 697 cm^ꢃ1. H-NMR (CDCl₃) d: ꢃ0.04 (9H, s), 0.89 (5 ml) were added phenylboronic acid (215 mg, 1.8 mmol), Pd(OAc)₂(13.1

(2H, t, Jꢁ8.3 Hz), 1.87—1.95 (2H, m), 2.50 (2H, t, Jꢁ7.6 Hz), 2.66 (2H, t, mg, 0.059 mmol) and K₂CO₃(405 mg, 2.9 mmol), and the reaction mixture

Jꢁ7.6 Hz), 3.53 (2H, t, Jꢁ8.3 Hz), 5.65 (2H, s), 6.80 (1H, d, Jꢁ1.8 Hz), was stirred at 100 °C for 7.5 h. The reaction mixture was diluted with

6.94 (1H, br s), 7.17—7.21 (3H, m), 7.27—7.31 (2H, m), 9.52 (1H, d, Jꢁ EtOAc, and the whole was ﬁltered through a pad of celite. The ﬁltrate was

0.9 Hz). LR-MS (ESI^ꢄ) m/z: 344 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) Calcd for

washed with H₂O and brine, dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated in vacuo. Puriﬁcation of the residue by column chromatogra-

phy (SiO₂, C₆H₁₄/EtOAcꢁ30/1) afforded 41f (311 mg, 70%) as a light brown

oil. IR (ATR): 2952, 1668, 1458, 1399, 1248, 1207, 1075, 832, 760,

C₂₀H₃₀NO₂Si m/z: 344.20458 (MꢄH^ꢄ), Found 344.20497.

3-Bromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-carbalde-

hyde (60) Treatments of 59 (4.00 g, 23 mmol) with tBuOK (2.84 g, 25

mmol) and SEMCl (4.48 ml, 25 mmol) carried out in the same manner as de-

scribed for 41a gave 60 (6.28 g, 89%) as a pale yellow oil after puriﬁcation

by column chromatography (SiO₂, C₆H₅Me/EtOAcꢁ50/1). This compound

was used for the next step at once since it was unstable. ¹H-NMR (CDCl₃) d:

ꢃ0.02 (9H, s), 0.89—0.93 (2H, m), 3.53—3.57 (2H, m), 5.67 (2H, s), 6.34

(1H, d, Jꢁ2.8 Hz), 7.09 (1H, dd, Jꢁ2.8, 0.9 Hz), 9.73 (1H, d, Jꢁ0.9 Hz).

4,5-Dibromo-1-methyl-1H-pyrrol-2-carbaldehyde (41b) To a solution

697 cm^ꢃ1. H-NMR (CDCl₃) d: ꢃ0.05 (9H, s), 0.82—0.86 (2H, m), 3.47—

3.51 (2H, m), 5.56 (2H, s), 7.08 (1H, s), 7.47—7.54 (5H, m), 9.58 (1H, s).

LR-MS (EI^ꢄ) m/z: 379 [M^ꢄ]. HR-MS (EI^ꢄ) m/z: Calcd for C₁₇H₂₂BrNO₂Si

(M^ꢄ) 379.0603, Found 379.0626.

4-Phenyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-carbalde-

hyde (41h) The same treatments of 41d (609 mg, 2.0 mmol) with phenyl-

boronic acid (610 mg, 5.0 mmol), Pd(PPh₃)₄(116 mg, 0.10 mmol) and

of 55 (1.00 g, 4.0 mmol) in DMF (20 ml) was added tBuOK (466 mg, 4.2 K₂CO₃(1.38 g, 10 mmol) as those described for 41f gave 45h (314 mg, 52%)

mmol) at 0 °C. After stirring at room temperature for 30 min, MeI (0.369 ml, as a colorless oil after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/

5.9 mmol) was added to the reaction mixture at 0 °C, and the whole was

stirred at the same temperature for 1 h. The reaction was quenched by

adding H₂O at 0 °C. The precipitates appeared were collected by ﬁltration,

washed with H₂O, and dried in vacuo to afford 41b (1.03 g, 98%) as a light

brown solid. This sample was directly used for the next reaction without fur-

ther puriﬁcation.¹H-NMR (CDCl₃) d: 4.00 (3H, s), 6.96 (1H, s), 9.35 (1H, s).

4-Bromo-5-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-

EtOAcꢁ30/1). IR (ATR): 2953, 1663, 1371, 1248, 1087, 832, 755,

692 cm^ꢃ1. H-NMR (CDCl₃) d: ꢃ0.02 (9H, s), 0.91—0.95 (2H, m), 3.58—

3.62 (2H, m), 5.75 (2H, s), 7.24—7.28 (2H, m), 7.39 (2H, t, Jꢁ7.9 Hz),

7.44—7.45 (1H, m), 7.51—7.54 (2H, m), 9.64 (1H, d, Jꢁ0.9 Hz). LR-MS

(EI^ꢄ) m/z: 301 [M^ꢄ]. HR-MS (EI^ꢄ) m/z: Calcd for C₁₇H₂₃NO₂Si 301.1498

(M^ꢄ), Found 301.1525.

4-(Phenylethynyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-car-

carbaldehyde (41e) To a solution of 57 (109 mg, 1.0 mmol) in THF baldehyde (41j) To a solution of 41d (2.65 g, 8.7 mmol) in DMF (50 ml)

(10 ml) was added NBS (178 mg, 1.0 mmol) at ꢃ78 °C under an argon atmo- were added Pd(PPh₃)₂Cl₂(306 mg, 0.44 mmol), copper(I) iodide (83.0 mg,

sphere. The mixture was stirred at the same temperature for 2 h, diluted with 0.44 mmol), phenylacetylene (5.74 ml, 52 mmol) and Et₃N (25 ml), and the

C₆H₁₄, washed with H₂O and brine, dried over anhydrous Na₂SO₄, reaction mixture was stirred at 100 °C for 8 h. The reaction mixture was di-

ﬁltered, and then concentrated in vacuo. Puriﬁcation of the residue by col-

luted with EtOAc, and the whole was ﬁltered through a pad of celite. The ﬁl-

umn chromatography (SiO₂, C₆H₁₄/EtOAcꢁ5/1) afforded crude 4-bromo-5- trate was washed with H₂O and brine, dried over anhydrous Na₂SO₄, ﬁltered,

methyl-1H-pyrrol-2-carbaldehyde as a red powder. To a solution of the pow-

der in DMF (4 ml) was added tBuOK (114 mg, 1.0 mmol) at 0 °C. After stir-

ring at room temperature for 30 min, SEMCl (0.181 ml, 1.0 mmol) was

added to the reaction mixture at 0 °C, and the whole was stirred at the same

and then concentrated in vacuo. Puriﬁcation of the residue by column chro-

matography (SiO₂, C₆H₁₄/EtOAcꢁ50/1—40/1) afforded 41j (1.70 g, 60%) as

a brown oil. IR (ATR): 2952, 2217, 1667, 1367, 1248, 1085, 831, 753,

690 cm^ꢃ1. H-NMR (CDCl₃) d: ꢃ0.01 (9H, s), 0.90—0.95 (2H, m), 3.55—

temperature for 1 h. The reaction was quenched by adding H₂O at 0 °C, and 3.59 (2H, m), 5.70 (2H, s), 7.11 (1H, d, Jꢁ1.8 Hz), 7.31—7.37 (4H, m),

the mixture was extracted with EtOAc. The organic extracts were combined,

washed with H₂O and brine, dried over anhydrous Na₂SO₄, ﬁltered, and then

concentrated in vacuo. Puriﬁcation of the residue by column chromatogra-

7.48—7.51 (2H, m), 9.58 (1H, d, Jꢁ0.9 Hz). LR-MS (EI^ꢄ) m/z: 325 [M^ꢄ].

HR-MS (EI^ꢄ) m/z: Calcd for C₁₉H₂₃NO₂Si (M^ꢄ) 325.1498, Found 325.1530.

4-(2-(Triﬂuoromethyl)phenylethynyl)-1-(2-(trimethylsilyl)ethoxymethyl)-

May 2011

587

1H-pyrrol-2-carbaldehyde (41k) Treatments of 41d (599 mg, 2.0 mmol)

with Pd(PPh₃)₂Cl₂(105 mg, 0.15 mmol), copper(I) iodide (28.6 mg, 0.15

mmol), (2-(triﬂuoromethyl)phenyl)acetylene (2.04 g, 12 mmol) and iPr₂EtN

(10 ml) carried out in the same manner as described for 41j gave 41k

(455 mg, 59%) as a brown oil after puriﬁcation by column chromatography

The reaction was quenched by adding H₂O, and the whole was extracted

with EtOAc. The organic extracts were combined, washed with H₂O and

brine, dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated in vacuo.

Puriﬁcation of the residue by column chromatography (SiO₂, CH₂Cl₂–C₆H₁₄/

EtOAcꢁ2/1) afforded 41s (649 mg, 45%) as a white solid. This sample was

(SiO₂, C₆H₁₄/EtOAcꢁ40/1-30/1). IR (ATR): 2954, 1670, 1315, 1166, 1129, directly used for the next reaction without further puriﬁcation. ¹H-NMR

1089, 1056, 832, 760 cm^ꢃ1. ¹H-NMR (CDCl₃) d: ꢃ0.01 (9H, s), 0.91—0.95 (CDCl₃) d: 7.08—7.15 (6H, m), 7.31—7.38 (9H, m), 8.10 (1H, s), 9.14

(2H, m), 3.56—3.60 (2H, m), 5.71 (2H, s), 7.13 (1H, d, Jꢁ1.8 Hz), 7.38— (1H, s).

7.42 (2H, m), 7.51 (1H, td, Jꢁ7.6, 0.6 Hz), 7.62 (1H, d, Jꢁ7.6 Hz), 7.67

4-Diethoxymethyl-1-trityl-1H-1,2,3-triazole (64) To a solution of

(1H, d, Jꢁ7.6 Hz), 9.60 (1H, d, Jꢁ1.2 Hz). LR-MS (ESI^ꢄ) m/z: 394 [Mꢄ tritylazide (2.00 g, 7.0 mmol) and 63 (3.0 ml, 21 mmol) in DMF (14 ml) were

H^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₀H₂₃F₃NO₂Si (MꢄH^ꢄ) 394.14501,

Found 394.14524.

4-(3-(Triﬂuoromethyl)phenylethynyl)-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-carbaldehyde (41l) Treatments of 41d (913 mg, 3.0 mmol)

with Pd(PPh₃)₂Cl₂(105 mg, 0.15 mmol), copper(I) iodide (28.6 mg, 0.15

added copper(I) iodide (1.34 g, 7.0 mmol) and iPr₂EtN (9.2 ml, 53 mmol),

and the mixture was stirred at 40 °C for 44 h. The reaction was quenched by

adding H₂O, and the whole was extracted with EtOAc. The organic extracts

were combined, washed with H₂O and brine, dried over anhydrous Na₂SO₄,

ﬁltered, and concentrated in vacuo. The residue was puriﬁed by column

mmol), (3-(triﬂuoromethyl)phenyl)acetylene (3.06 g, 18 mmol) and Et₃N chromatography (SiO₂, C₆H₁₄/EtOAcꢁ6/1—5/1) to give 64 (2.69 g, 93%) as

(10 ml) carried out in a similar manner to that described for 41j gave 41l

(620 mg, 53%) as a brown oil after puriﬁcation by column chromatography

(SiO₂, C₆H₁₄/EtOAcꢁ50/1—40/1). IR (ATR): 2954, 1671, 1324, 1164,

a pale yellow solid. IR (ATR): 2974, 2899, 1493, 1444, 1113, 1047, 1019,

744, 696 cm^ꢃ^{1 1}H-NMR (CDCl₃) d: 1.21 (6H, t, Jꢁ7.0 Hz), 3.56—3.72

(4H, m), 5.73 (1H, s), 7.11—7.15 (6H, m), 7.29—7.36 (9H, m), 7.50 (1H, s).

1124, 1070, 833, 799, 694 cm^ꢃ1. ¹H-NMR (CDCl₃) d: ꢃ0.01 (9H, s), 0.91— LR-MS (EI^ꢄ) m/z: 413 [M^ꢄ], 243. HR-MS (EI^ꢄ) m/z: Calcd for C₂₆H₂₇N₃O₂

0.95 (2H, m), 3.55—3.59 (2H, m), 5.71 (2H, s), 7.12 (1H, d, Jꢁ1.8 Hz), (M^ꢄ) 413.2103, Found 413.2132.

7.39 (1H, dd, Jꢁ1.8, 0.9 Hz), 7.47 (1H, t, Jꢁ7.9 Hz), 7.57 (1H, d, Jꢁ7.9

1-Trityl-1H-1,2,3-triazol-4-carbaldehyde (41x) To a solution of 64

Hz), 7.65 (1H, d, Jꢁ7.9 Hz), 7.75 (1H, s), 9.60 (1H, d, Jꢁ0.9 Hz). LR-MS (2.48 g, 6.0 mmol) in Me₂CO (400 ml) was added PPTS (151 mg, 0.60

(ESI^ꢄ) m/z: 394 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₀H₂₃F₃NO₂Si mmol), and the reaction mixture was stirred at room temperature for 2 d.

394.14501 (MꢄH^ꢄ), Found 394.14534.

4-(4-(Triﬂuoromethyl)phenylethynyl)-1-(2-(trimethylsilyl)ethoxymethyl)-

The reaction was quenched by adding aqueous NaHCO₃solution, and the

whole was extracted with EtOAc. The organic extracts were combined,

1H-pyrrol-2-carbaldehyde (41m) The same treatments of 41d (913 mg, washed with brine, dried over anhydrous Na₂SO₄, ﬁltered, and concentrated

3.0 mmol) with Pd(PPh₃)₂Cl₂(105 mg, 0.15 mmol), copper(I) iodide (28.6

mg, 0.15 mmol), (4-(triﬂuoromethyl)phenyl)acetylene (3.06 g, 18 mmol) and

Et₃N (10 ml) as those described for 41j gave 41m (635 mg, 54%) as a brown

oil after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ

in vacuo. The residue was puriﬁed by column chromatography (SiO₂, C₆H₁₄/

EtOAcꢁ9/1) to give 41x (934 mg, 46%) as a white solid. IR (ATR): 3466,

3060, 1698, 1490, 1445, 1274, 1183, 1038, 760, 746, 697 cm^ꢃ^{1 1}H-NMR

(CDCl₃) d: 7.09—7.13 (6H, m), 7.33—7.39 (9H, m), 8.07 (1H, s), 10.18

50/1—40/1). IR (ATR): 2955, 1671, 1320, 1164, 1105, 1065, 833 cm^ꢃ1.¹H- (1H, s). LR-MS (EI^ꢄ) m/z: 339 [M^ꢄ], 282, 243, 165. HR-MS (EI^ꢄ) m/z:

NMR (CDCl₃) d: ꢃ0.01 (9H, s), 0.91—0.95 (2H, m), 3.55—3.60 (2H, m), Calcd for C₂₂H₁₇N₃O (M^ꢄ) 339.1372, Found 339.1354.

5.71 (2H, s), 7.12 (1H, d, Jꢁ1.8 Hz), 7.39 (1H, dd, Jꢁ1.8, 0.9 Hz), 7.59 (4H,

3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-carbaldehyde (41t)

s), 9.60 (1H, d, Jꢁ0.9 Hz). LR-MS (EI^ꢄ) m/z: 393 [M^ꢄ]. HR-MS (EI^ꢄ) m/z: To a solution of 65 (2.00 g, 6.1 mmol) in MeOH (60 ml) was added NaBH₄

Calcd for C₂₀H₂₂F₃NO₂Si 393.1372 (M^ꢄ), Found 393.1381.

(1.16 g, 31 mmol) at 0 °C, and the reaction mixture was stirred at room tem-

perature for 30 min. The reacton was quenched by adding saturated NH₄Claq

at 0 °C, and the miture was extracted with EtOAc. The organic extracts were

combined, washed with brine, dried over anhydrous Na₂SO₄, ﬁltered, and

3-(Phenylethynyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-car-

baldehyde (41o) Similar treatments of 60 (1.00 g, 3.29 mmol) with

Pd(PPh₃)₂Cl₂(116 mg, 0.17 mmol), copper(I) iodide (31.4 mg, 0.17 mmol),

phenylacetylene (2.16 ml, 20 mmol) and Et₃N (10 ml) to those described for concentrated in vacuo to give (3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-tria-

41j gave 41o (1.03 g, 96%) as a brown oil after puriﬁcation by column chro-

zol-5-yl)methanol as a white solid. ¹H-NMR (CDCl₃) d: 2.80 (1H, br s),

matography (SiO₂, C₆H₁₄/EtOAcꢁ50/1). IR (ATR): 2952, 1659, 1483, 1426, 3.80 (3H, s), 4.69 (2H, d, Jꢁ5.2 Hz), 5.30 (2H, s), 6.88 (2H, dt, Jꢁ8.6,

1364, 1332, 1247, 1094, 833, 754, 689 cm^ꢃ^{1 1}H-NMR (CDCl₃) d: ꢃ0.02 2.1 Hz), 7.24 (2H, dt, Jꢁ8.6, 2.1 Hz). To a solution of the methanol deriva-

(9H, s), 0.90—0.94 (2H, m), 3.54—3.59 (2H, m), 5.72 (2H, s), 6.45 (1H, d, tive in CH₂Cl₂(100 ml) was added activated MnO₂(11.3 g), and the mixture

Jꢁ2.8 Hz), 7.10 (1H, dd, Jꢁ2.8, 0.9 Hz), 7.34—7.37 (3H, m), 7.50—7.54 was stirred at room temperature for 4 h. The reaction mixture was ﬁltered

(2H, m), 9.95 (1H, d, Jꢁ0.9 Hz). LR-MS (ESI^ꢄ) m/z: 326 [MꢄH^ꢄ]. HR-MS through a pad of celite, and the ﬁltrate was concentrated in vacuo to give 41t

(ESI^ꢄ) m/z: Calcd for C₁₉H₂₄NO₂Si (MꢄH^ꢄ) 326.15763, Found 326.15686.

(1.47 g, 80%) as a white solid. This compound was directly used for the next

4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-imidazol-2-car- reaction without further puriﬁcation. IR (ATR): 2925, 2892, 2841, 1708,

baldehyde (41r) To a solution of 61 (1.00 g, 3.28 mmol) in DMF (30 ml) 1612, 1513, 1456, 1251, 1030, 776, 758, 700 cm^ꢃ1.¹H-NMR (CDCl₃) d:

was added tBuOK (442 mg, 3.9 mmol) at 0 °C. After stirring at room tem-

perature for 30 min, SEMCl (0.639 ml, 3.6 mmol) was added to the reaction

mixture at 0 °C, and the whole was stirred at the same temperature for 1 h.

The reaction was quenched by adding H₂O at 0 °C, and the mixture was ex-

3.79 (3H, s), 5.63 (2H, s), 6.86 (2H, dt, Jꢁ8.6, 2.1 Hz), 7.34 (2H, dt, Jꢁ8.6,

2.1 Hz), 9.90 (1H, s). LR-MS (EI^ꢄ) m/z: 295 [M^ꢄ], 216, 121. HR-MS (EI^ꢄ)

m/z: Calcd for C₁₁H₁₀BrN₃O₂(M^ꢄ) 294.9956, Found 294.9975.

5-Bromo-2-trityl-2H-1,2,3-triazol-4-carbaldehyde (41y) To a solution

tracted with EtOAc. The organic extracts were combined, washed with H₂O of 66 (1.41 g, 3.0 mmol) in THF (30 ml) was added dropwise n-BuLi (1.6

and brine, dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated in mol/l in C₆H₁₄, 2.05 ml, 3.3 mmol) at ꢃ98 °C, and the mixture was stirred at

vacuo. The residue was dissolved in THF (30 ml), and n-BuLi (1.61 mol/l in the same temperature for 10 min. Ethyl formate (3.0 ml) was added to the

C₆H₁₄, 2.04 ml, 3.3 mmol) was added dropwise to the solution at ꢃ78 °C, mixture. The mixture was stirred at the same temperature for 30 min, and

and the mixture was stirred at the same temperature for 1 h. To the mixture

was added DMF (3.0 ml) at the same temperature, and the mixture was

slowly warmed to room temperature. The reaction was quenched by adding

a saturated ammonium chloride solution, and the whole was extracted with

EtOAc. The organic extracts were combined, washed with H₂O and brine,

dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated in vacuo. Pu-

riﬁcation of the residue by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ

then slowly warmed to room temperature. The reaction was quenched by

adding saturated NH₄Claq, and exracted with EtOAc. The organic extracts

were combined, washed with brine, dried over anhydrous Na₂SO₄, ﬁltered,

and concentrated in vacuo. The residue was puriﬁed by column chromato-

graphy (SiO₂, C₆H₁₄/EtOAcꢁ9/1—8/1) to give 41y (917 mg, 73%) as a pale

yellow powder. IR (ATR): 1704, 1444, 1273, 1136, 880, 747, 697 cm^ꢃ1.¹H-

NMR (CDCl₃) d: 7.09—7.13 (6H, m), 7.31—7.37 (9H, m), 10.06 (1H, s).

20/1—10/1) afforded crude 41r (984 mg, ꢅ78%: this sample was contami- LR-MS (EI^ꢄ) m/z: 417 [M^ꢄ], 310, 282, 243, 167. HR-MS (EI^ꢄ) m/z: Calcd

nated with some unidentiﬁed by-products (ca. 10%)) as a light brown oil and

for C₂₂H₁₆BrN₃O (M^ꢄ) 417.0477, Found 417.0513.

1-(4-Methoxybenzyl)-1H-tetrazol-5-carbaldehyde (41u) To a solution

was directly used for the next reaction without further puriﬁcation. ¹H-NMR

(CDCl₃) d: ꢃ0.02 (9H, s), 0.90—0.96 (2H, m), 3.58—3.63 (2H, m), 5.83 67 (951 mg, 5.0 mmol) in THF (50 ml) and N,N,N,N-tetramethylethylenedi-

(2H, s), 9.61 (1H, s). amine (5.0 ml) was added dropwise n-BuLi (1.6 mol/l in C₆H₁₄, 3.4 ml,

1-Trityl-1H-1,2,4-triazol-5-carbaldehyde (41s) To a solution of 62 5.5 mmol) at ꢃ98 °C, and the mixture was stirred at the same temperature

(1.33 g, 4.3 mmol) in THF (20 ml) was added dropwise n-BuLi (1.61 mol/l in for 5 min. After ethyl formate (5.0 ml) was added to the reaction mixture, the

C₆H₁₄, 3.45 ml, 5.6 mmol) at ꢃ78 °C, and the mixture was stirred at the

same temperature for 1 h. To the mixture was added DMF (3.0 ml) at the

same temperature, and the mixture was slowly warmed to room temperature.

whole was stirred at the same temperature for 30 min, and then warmed to

room temperature slowly. The reaction was quenched by adding saturated

NH₄Claq, the whole was extracted with EtOAc. The organic extracts were

588

Vol. 59, No. 5

combined, washed with brine, dried over anhydrous Na₂SO₄, ﬁltered, and

concentrated in vacuo. The residue was puriﬁed by column chromatography

(SiO₂, C₆H₁₄/EtOAcꢁ1/1) to give a mixture of 41u and 67 (2 : 1). Since 41u

was found to be fairly unstable, this mixture was directly used for the next

followed by dehydrogenation using IBX (375 mg, 1.3 mmol) and activated

MnO₂(2.3 g) to those described for 43ad gave 43af (271 mg, 52%) as a pale

yellow solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/

EtOAcꢁ4/1). mp: 110—112 °C (from C₆H₁₄–EtOAc). IR (KBr): 3390,

reaction without further puriﬁcation. ¹H-NMR (CDCl₃) d: 3.79 (3H, s), 5.81 2953, 1716, 1633, 1571, 1474, 1252, 1155, 1081, 861, 835, 771, 700 cm^ꢃ1

(2H, s), 6.87 (2H, dt, Jꢁ9.4, 2.5 Hz), 7.36 (2H, dt, Jꢁ9.4, 2.5 Hz), 10.26 ¹H-NMR (CD₃OD) d: ꢃ0.28 (9H, s), 0.46 (2H, t, Jꢁ8.6 Hz), 1.58 (9H, s),

(1H, s). LR-MS (EI^ꢄ) m/z: 218 [M^ꢄ], 161. HR-MS (EI^ꢄ) m/z: Calcd for 2.96 (2H, t, Jꢁ8.6 Hz), 5.61 (2H, br s), 6.91 (1H, br s), 7.42 (1H, d, Jꢁ5.5

C₁₀H₁₀N₄O₂(M^ꢄ) 218.0804, Found 218.0836.

Hz), 7.42—7.54 (5H, m), 8.25 (1H, br s). LR-MS (ESI^ꢄ) m/z: 584 [MꢄH^ꢄ].

HR-MS (ESI^ꢄ) m/z: Calcd for C₂₇H₃₅BrN₅O₃Si (MꢄH^ꢄ) 584.16925, Found

584.17389.

tert-Butyl [4-(4-Methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-

2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ag) The same treat-

ments of 40a^1,15)(323 mg, 1.4 mmol) with 41g (376 mg, 1.6 mmol) followed

tert-Butyl [4-(4-Bromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-

2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ad)

A solution of

40a^1,15)(226 mg, 1.0 mmol) and 41d (350 mg, 1.2 mmol) in EtOH (5 ml) was

stirred at 50 °C for 4 h. The mixture was concentrated in vacuo, and the

residue was puriﬁed by column chromatography (NH-SiO₂, EtOAc) to give

the 4,5,6,7-tetrahydroderivative of 43ad as a yellow amorphous solid. ¹H- by dehydrogenation using IBX (602 mg, 2.2 mmol) and activated MnO₂

NMR (CD₃OD) d: 0.01 (9H, s), 0.83—0.96 (2H, m), 1.51 (9H, s), 2.59— (5.0 g) as those described for 43ad gave 43ag (244 mg, 38%) as a pale yel-

2.63 (2H, m), 2.93 (1H, dt, Jꢁ12.5, 5.0 Hz), 3.05—3.11 (1H, m), 3.50— low amorphous solid after puriﬁcation by column chromatography (SiO₂,

3.62 (2H, m), 5.09 (1H, s), 5.24 (1H, d, Jꢁ11.0 Hz), 5.33 (1H, d, Jꢁ11.0

C₆H₁₄/EtOAcꢁ4/1—3/1). IR (ATR): 3393, 2952, 1712, 1631, 1568, 1249,

Hz), 5.80 (1H, Jꢁ1.8 Hz), 6.89 (1H, Jꢁ1.8 Hz). LR-MS (ESI^ꢄ) m/z: 512 1154, 1069, 859, 831, 766 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.60

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₁H₃₅BrN₅O₃Si (MꢄH^ꢄ) (2H, t, Jꢁ8.3 Hz), 1.57 (9H, s), 2.15 (3H, s), 3.17 (2H, br s), 5.59 (2H, br s),

512.16925, Found 512.16973. To a solution of the 4,5,6,7-tetrahydroderiva-

tive (258 mg, 0.50 mmol) in DMSO (2.5 ml) was added IBX (211 mg, 0.76

mmol), and the mixture was stirred at room temperature for 2 h. The reac-

tion was quenched by adding H₂O and an aqueous NaOH solution (1.0 mol/l,

3.0 ml, 3.0 mmol), and the mixture was extracted with EtOAc. The organic

extracts were combined, washed with H₂O and brine, dried over anhydrous

6.63 (1H, br s), 6.82 (1H, br s), 7.35 (1H, d, Jꢁ5.5 Hz), 8.20 (1H, br s). LR-

MS (ESI^ꢄ) m/z: 444 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₂H₃₄N₅O₃Si

(MꢄH^ꢄ) 444.24309, Found 444.24362.

tert-Butyl [4-(4-Phenyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-

2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ah) Similar treat-

ments of 40a^1,15)(339 mg, 1.5 mmol) with 41h (543 mg, 1.8 mmol) followed

Na₂SO₄, ﬁltered, and then concentrated in vacuo. To a solution of the residue by dehydrogenation using IBX (630 mg, 2.3 mmol) and activated MnO₂

in CH₂Cl₂(10 ml) was added activated MnO₂(1.4 g), and the mixture was

stirred at room temperature for 1 h. The reaction mixture was ﬁltered

through a pad of celite, and the ﬁltrate was concentrated in vacuo. The

residue was puriﬁed by column chromatography (NH-SiO₂, C₆H₁₄/EtOAcꢁ

1/1) to give 43ad (192 mg, 75%) as a pale yellow solid. IR (KBr): 3388,

(4.0 g) to those described for 43ad gave 43ah (419 mg, 55%) as a brown

amorphous solid after puriﬁcation by column chromatography (SiO₂,

C₆H₁₄/EtOAcꢁ4/1—3/1). IR (KBr): 3391, 2952, 1719, 1632, 1592, 1570,

1508, 1420, 1370, 1251, 1155, 1086, 861, 835, 754, 693 cm^ꢃ^{1 1}H-NMR

(CD₃OD) d: ꢃ0.24 (9H, s), 0.64 (2H, t, Jꢁ7.9 Hz), 1.57 (9H, s), 3.18—3.28

2952, 1719, 1633, 1571, 1252, 1155, 1083, 836 cm^ꢃ1. ¹H-NMR (CD₃OD) d: (2H, m), 5.74 (2H, br s), 7.15 (1H, t, Jꢁ7.3 Hz), 7.17 (1H, br s), 7.32 (2H, t,

ꢃ0.23 (9H, s), 0.62 (2H, t, Jꢁ8.1 Hz), 1.57 (9H, s), 3.22 (2H, t, Jꢁ8.1 Hz), Jꢁ7.3 Hz), 7.39 (1H, d, Jꢁ5.5 Hz), 7.42 (1H, br s), 7.60 (2H, d, Jꢁ7.3 Hz),

5.68 (2H, br s), 6.86 (1H, br s), 7.07 (1H, br s), 7.38 (1H, d, Jꢁ5.5 Hz), 8.22 8.24 (1H, s). LR-MS (ESI^ꢄ) m/z: 506 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd

(1H, s). LR-MS (ESI^ꢄ) m/z: 508 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for for C₂₇H₃₆N₅O₃Si (MꢄH^ꢄ) 506.25874, Found 506.25888.

C₂₁H₃₁BrN₅O₃Si (MꢄH^ꢄ) 508.13795, Found 508.13726.

tert-Butyl [4-(4-Benzyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-

tert-Butyl [4-(4,5-Dibromo-1-methyl-1H-pyrrol-2-yl)-1H-imidazo[4,5- 2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ai) Treatments of

c]pyridin-2-yl]carbamate (43ab) Treatments of 40a^1,15)(324 mg, 1.4 mmol)

with 41b (459 mg, 1.7 mmol) followed by dehydrogenation using IBX

40a^1,15)(339 mg, 1.5 mmol) with 41i (395 mg, 1.3 mmol) followed by dehy-

drogenation using IBX (526 mg, 1.9 mmol) and activated MnO₂(3.0 g) car-

(145 mg, 0.52 mmol) and activated MnO₂(1.0 g) carried out in the same ried out in the same manner as described for 43ad gave 43ai (450 mg, 69%)

manner as described for 43ad gave 43ab (117 mg, 22%) as a pale yellow as a light brown amorphous solid after puriﬁcation by column chromatogra-

solid after puriﬁcation by column chromatography (NH-SiO₂, C₆H₁₄/ phy (SiO₂, C₆H₁₄/EtOAcꢁ3/1—2/1). IR (ATR): 3388, 2951, 1713, 1631,

EtOAcꢁ1/1). IR (KBr): 3358, 2986, 1716, 1632, 1571, 1465, 1272, 1254, 1566, 1249, 1153, 1082, 833 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: ꢃ0.24 (9H, s),

1156 cm^ꢃ1.¹H-NMR (CD₃OD) d: 1.59 (9H, s), 3.79 (3H, s), 6.85 (1H, br s), 0.57—0.62 (2H, m), 1.57 (9H, s), 3.18 (2H, t, Jꢁ8.1 Hz), 3.86 (2H, s), 5.60

7.41 (1H, d, Jꢁ5.5 Hz), 8.23 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 470 (2H, br s), 6.62 (1H, br s), 6.81 (1H, br s), 7.12—7.28 (5H, m), 7.34 (1H, d,

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₆H₁₇Br₂N₅O₂(MꢄH^ꢄ) Jꢁ5.8 Hz), 8.19 (1H, br s). LR-MS (ESI^ꢄ) m/z: 520 [MꢄH^ꢄ]. HR-MS

469.98273, Found 469.98284.

(ESI^ꢄ) m/z: Calcd for C₂₈H₃₈N₅O₃Si (MꢄH^ꢄ) 520.27439, Found 520.27439.

tert-Butyl [4-(4-(Phenylethynyl)-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43aj) Treat-

ments of 40a^1,15)(474 mg, 2.1 mmol) with 41j (707 mg, 2.3 mmol) followed

by dehydrogenation using IBX (879 mg, 3.1 mmol) and activated MnO₂

(5.0 g) carried out in a similar manner to that described for 43ad gave 43aj

(647 mg, 58%) as a light brown amorphous solid after puriﬁcation by col-

tert-Butyl [4-(1-(2-(Trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-1H-

imidazo[4,5-c]pyridin-2-yl]carbamate (43ac) Treatments of 40a^1,15)

(390 mg, 1.7 mmol) with 41c¹⁷⁾(435 mg, 1.9 mmol) followed by dehydro-

genation using IBX (417 mg, 1.5 mmol) and activated MnO₂(2.6 g) carried

out in a similar manner to that described for 43ad gave 43ac (350 mg, 51%)

as a pale yellow solid after puriﬁcation by column chromatography (NH-

SiO₂, C₆H₁₄/EtOAcꢁ1/1). IR (ATR): 3404, 2892, 1704, 1634, 1567, 1480, umn chromatography (SiO₂, C₆H₁₄/EtOAcꢁ10/1—4/1). IR (ATR): 3391,

1418, 1246, 1146, 1086, 835, 715 cm^ꢃ1. H-NMR (CD₃OD) d: ꢃ0.25 (9H, 2951, 2216, 1714, 1630, 1567, 1248, 1153, 1082, 859, 833, 754 cm^ꢃ1. H-

s), 0.60 (2H, t, Jꢁ7.9 Hz), 1.57 (9H, s), 3.19 (2H, t, Jꢁ7.9 Hz), 5.69 (2H, s),

6.29 (1H, s), 6.77 (1H, br s), 7.06 (1H, s), 7.36 (1H, d, Jꢁ5.5 Hz), 8.22 (1H,

s). LR-MS (ESI^ꢄ) m/z: 430 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₂₁H₃₂N₅O₃Si (MꢄH^ꢄ) 430.22744, Found 430.22818.

NMR (CD₃OD) d: ꢃ0.22 (9H, s), 0.62—0.66 (2H, m), 1.58 (9H, s), 3.26

(2H, br s), 5.73 (2H, br s), 6.99 (1H, br s), 7.24—7.35 (4H, m), 7.40 (1H, d,

Jꢁ5.5 Hz), 7.45 (1H, d, Jꢁ6.7 Hz), 8.23 (1H, br s). LR-MS (ESI^ꢄ) m/z: 530

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₉H₃₆N₅O₃Si (MꢄH^ꢄ) 530.25874,

tert-Butyl [4-(4-Bromo-5-methyl-1-(2-(trimethylsilyl)ethoxymethyl)- Found 530.25854.

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ae) The

tert-Butyl [4-(4-(2-(Triﬂuoromethyl)phenylethynyl)-1-((2-(trimethyl-

same treatments of 40a^1,15)(275 mg, 1.2 mmol) with 41e (426 mg, 1.3 mmol) silyl)ethoxy)methyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]

followed by dehydrogenation using IBX (512 mg, 1.83 mmol) and activated

MnO₂(3.8 g) as those described for 43ad gave 43ae (286 mg, 45%) as a

light brown amorphous solid after puriﬁcation by column chromatography

carbamate (43ak) The same treatments of 40a^1,15)(226 mg, 1.0 mmol)

with 41k (450 mg, 1.1 mmol) followed by dehydrogenation using IBX

(420 mg, 1.5 mmol) and activated MnO₂(3.0 g) as those described for 43ad

(SiO₂, C₆H₁₄/EtOAcꢁ10/1—4/1). IR (ATR): 3385, 2951, 1714, 1630, 1567, gave 43ak (405 mg, 68%) as a brown amorphous solid after puriﬁcation by

1248, 1153, 1075, 858, 833, 761 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.26 (9H, s), column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ4/1—3/1). IR (ATR): 3390,

0.56 (2H, t, Jꢁ8.3 Hz), 1.57 (9H, s), 2.35 (3H, s), 3.06—3.11 (2H, m), 5.69 2951, 2216, 1714, 1631, 1570, 1316, 1250, 1155, 1132, 1084, 834 cm^ꢃ1. ¹H-

(2H, br s), 6.76 (1H, br s), 7.38 (1H, d, Jꢁ5.5 Hz), 8.22 (1H, br s). LR-MS

(ESI^ꢄ) m/z: 522 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₂H₃₃BrN₅O₃Si (2H, br s), 5.76 (2H, br s), 7.02 (1H, br s), 7.36 (1H, br s), 7.40 (1H, d,

(MꢄH^ꢄ) 522.15360, Found 522.15397.

Jꢁ5.5 Hz), 7.44 (1H, t, Jꢁ7.6 Hz), 7.57 (1H, t, Jꢁ7.6 Hz), 7.65 (1H, d,

NMR (CD₃OD) d: ꢃ0.21 (9H, s), 0.64 (2H, t, Jꢁ7.9 Hz), 1.57 (9H, s), 3.27

tert-Butyl [4-(4-Bromo-5-phenyl-1-(2-(trimethylsilyl)ethoxymethyl)- Jꢁ7.6 Hz), 7.69 (1H, d, Jꢁ7.6 Hz), 8.24 (1H, br s). LR-MS (ESI^ꢄ) m/z: 598

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43af) Simi-

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₃₅F₃N₅O₃Si (MꢄH^ꢄ)

598.24612, Found 598.24677.

lar treatments of 40a^1,15)(202 mg, 0.89 mmol) with 41f (340 mg, 0.89 mmol)

May 2011

589

tert-Butyl [4-(4-(3-(Triﬂuoromethyl)phenylethynyl)-1-(2-(trimethyl-

silyl)ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]

carbamate (43al) Similar treatments of 40a^1,15)(226 mg, 1.0 mmol) with

41l (600 mg, 1.5 mmol) followed by dehydrogenation using IBX (420 mg,

tert-Butyl [4-(4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-imida-

zol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ar) Treatments of

40a^1,15)(280 mg, 1.2 mmol) with 41r (476 mg, 1.2 mmol) followed by dehydro-

genation using IBX (521 mg, 1.9 mmol) and activated MnO₂(5.0 g) carried

1.5 mmol) and activated MnO₂(3.0 g) to those described for 43ad gave 43al out in the same manner as described for 43ad gave 43ar (352 mg, 48%) as a

(374 mg, 63%) as a brown amorphous solid after puriﬁcation by column pale yellow solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/

chromatography (SiO₂, C₆H₁₄/EtOAcꢁ4/1—3/1). IR (ATR): 3388, 2952, EtOAcꢁ3/1). IR (ATR) 3376, 2957, 1713, 1629, 1569, 1517, 1483, 1462,

2213, 1713, 1626, 1591, 1568, 1326, 1246, 1154, 1125, 1087, 834 cm^ꢃ1. ¹H- 1367, 1246, 1148, 1090, 1057, 860, 832, 770, 681 cm^ꢃ1. ¹H-NMR (CD₃OD)

NMR (CD₃OD) d: ꢃ0.22 (9H, s), 0.62—0.66 (2H, m), 1.57 (9H, s), 3.26 d: ꢃ0.17 (9H, s), 0.83 (2H, br s), 1.61 (9H, s), 3.62 (2H, br s), 6.38 (2H,

(2H, t, Jꢁ7.9 Hz), 5.75 (2H, br s), 7.03 (1H, br s), 7.39 (1H, br s), 7.40

br s), 7.43 (1H, br s), 8.33 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 587

(1H, d, Jꢁ5.5 Hz), 7.52—7.60 (2H, m), 7.69—7.71 (2H, m), 8.24 (1H, br s). [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₀H₂₉Br₂N₆O₃Si (MꢄH^ꢄ)

LR-MS (ESI^ꢄ) m/z: 598 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for 587.04371, Found 587.04317.

C₃₀H₃₅F₃N₅O₃Si (MꢄH^ꢄ) 598.24612, Found 598.24620.

tert-Butyl [4-(1-Trityl-1H-1,2,4-triazol-5-yl)-1H-imidazo[4,5-c]pyridin-2-

yl]carbamate (43as) Treatments of 40a^1,15)(376 mg, 1.7 mmol) with 41s

(599 mg, 1.8 mmol) followed by dehydrogenation using IBX (697 mg, 2.5

mmol) and activated MnO₂(5.2 g) carried out in a similar manner to that de-

scribed for 43ad gave 43as (181 mg, 20%) as a white powder after puriﬁca-

tion by column chromatography (NH-SiO₂, C₆H₁₄/EtOAcꢁ10/1). IR (ATR):

tert-Butyl [4-(4-(4-(Triﬂuoromethyl)phenylethynyl)-1-(2-(trimethyl-

silyl)ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]

carbamate (43am) Treatments of 40a^1,15)(384 mg, 1.7 mmol) with 41m

(635 mg, 1.6 mmol) followed by dehydrogenation using IBX (678 mg,

2.4 mmol) and activated MnO₂(6.0 g) carried out in the same manner as de-

scribed for 43ad gave 43am (364 mg, 38%) as a light brown amorphous

solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ

3369, 2981, 1724, 1633, 1568, 1475, 1245, 1149, 750, 699 cm^ꢃ1. H-NMR

(CD₃OD) d: 1.54 (9H, s), 7.25—7.30 (6H, m), 7.35—7.42 (9H, m), 7.47

10/1—4/1). IR (ATR): 3388, 2952, 2218, 1713, 1633, 1570, 1322, 1250, (1H, d, Jꢁ5.5 Hz), 8.30 (1H, d, Jꢁ5.5 Hz), 8.39 (1H, s). LR-MS (ESI^ꢄ) m/z:

1155, 1125, 1066, 836 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: ꢃ0.22 (9H, s), 0.64 544 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₂H₃₀N₇O₂(MꢄH^ꢄ)

(2H, t, Jꢁ8.1 Hz), 1.58 (9H, s), 3.26 (2H, br s), 5.76 (2H, br s), 7.03 (1H,

br s), 7.38 (1H, br s), 7.40 (1H, d, Jꢁ5.5 Hz), 7.63 (4H, s), 8.24 (1H, br s).

LR-MS (ESI^ꢄ) m/z: 598 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₃₀H₃₅F₃N₅O₃Si (MꢄH^ꢄ) 598.24612, Found 598.24563.

544.24610, Found 544.24644.

tert-Butyl [4-(3-Bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)-

1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43at) The same treatments

of 40a^1,15)(1.35 g, 6.0 mmol) with 41t (1.45 g, 4.9 mmol) followed by dehy-

drogenation using IBX (2.06 g, 7.4 mmol) and activated MnO₂(15.0 g) as

those described for 43ad gave 43at (1.87 g, 76%) as a white powder after

trituration with C₆H₁₄-EtOAc (1/1). IR (ATR): 3380, 1979, 1725, 1571,

tert-Butyl [4-(4-(3-Phenylpropyl)-1-(2-(trimethylsilyl)ethoxymethyl)-1H-

pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43an) Treatments

of 40a^1,15)(790 mg, 3.5 mmol) with 41n (1.00 g, 2.9 mmol) followed by de-

hydrogenation using IBX (1.22 g, 4.4 mmol) and activated MnO₂(5.0 g) car- 1512, 1246, 1151, 764 cm^ꢃ^{1 1}H-NMR (DMSO-d₆) d: 1.56 (9H, s), 3.71

ried out in a similar manner to that described for 43ad gave 43an (1.19 g, (3H, s), 6.15 (2H, br s), 6.86 (2H, d, Jꢁ7.3 Hz), 7.30 (2H, br s), 7.58 (1H, d,

75%) as a light brown amorphous solid after puriﬁcation by column chro- Jꢁ5.2 Hz), 8.43 (1H, br s), 11.29 (2H, br s), 11.51 (1H, br s). LR-MS (ESI^ꢄ)

matography (SiO₂, C₆H₁₄/EtOAcꢁ4/1—3/1). IR (ATR): 3393, 2930, 1711, m/z: 500 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₁H₂₃BrN₇O₃(MꢄH^ꢄ)

1630, 1566, 1249, 1152, 1081, 833, 697 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.25

500.10457, Found 500.10460.

tert-Butyl [4-(1-(4-Methoxybenzyl)-1H-tetrazol-5-yl)-1H-imidazo[4,5-

(9H, s), 0.58—0.62 (2H, m), 1.55 (9H, s), 1.90—1.97 (2H, m), 2.55 (2H, t,

Jꢁ7.3 Hz), 2.68 (2H, t, Jꢁ7.3 Hz), 3.20 (2H, t, Jꢁ8.3 Hz), 5.62 (2H, br s), c]pyridin-2-yl]carbamate (43au) Similar treatments of 40a^1,15)(623 mg,

6.65 (1H, br s), 6.85 (1H, br s), 7.11—7.26 (5H, m), 7.34 (1H, d, Jꢁ5.5 Hz), 2.8 mmol) with crude 41u (ꢅ5 mmol) to those described for 43ad gave the

8.21 (1H, br s). LR-MS (ESI^ꢄ) m/z: 548 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: 4,5,6,7-tetrahydroderivative of 43au (1.02 g, 87%). Subsequent dehydro-

Calcd for C₃₀H₄₂N₅O₃Si (MꢄH^ꢄ) 548.30569, Found 548.30505.

genation of the 4,5,6,7-tetrahydroderivative (800 mg, 1.9 mmol) using IBX

(781 mg, 2.8 mmol) and activated MnO₂(4.8 g) gave 43au (588 mg, 75%) as

a white powder after trituration with C₆H₁₄. IR (ATR): 3375, 2979, 1721,

Ethyl [4-(3-(Phenylethynyl)-1-(2-(trimethylsilylethoxy)methyl)-1H-

pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ao) Treatments

of 40a^1,15)(530 mg, 2.3 mmol) with 41o (762 mg, 2.34 mmol) in reﬂuxing

EtOH instead of EtOH at 50 °C followed by dehydrogenation using IBX

(983 mg, 3.5 mmol) and activated MnO₂(1.0 g) carried out in a similar man-

1637, 1572, 1514, 1464, 1247, 1150, 770 cm^ꢃ^{1 1}H-NMR (DMSO-d₆) d:

1.56 (9H, s), 3.71 (3H, s), 6.30 (2H, br s), 6.86 (2H, d, Jꢁ7.6 Hz), 6.94 (2H,

d, Jꢁ8.9 Hz), 7.30 (2H, br s), 7.64 (1H, d, Jꢁ5.2 Hz), 8.48 (1H, br s), 11.67

ner to that described for 43ad gave 43ao (197 mg, 17%) as a brown amor- (2H, br s). LR-MS (ESI^ꢄ) m/z: 423 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

phous solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/

C₂₀H₂₃N₈O₃(MꢄH^ꢄ) 423.18931, Found 423.18926.

EtOAcꢁ1/1—2/3). IR (ATR): 3369, 2951, 2209, 1725, 1637, 1572, 1519,

tert-Butyl [4-(1-Trityl-1H-imidazol-4-yl)-1H-imidazo[4,5-c]pyridin-2-

yl]carbamate (43av) Treatments of 40a^1,15)(290 mg, 1.3 mmol) with 41v²⁴⁾

(433 mg, 1.3 mmol) followed by dehydrogenation using IBX (538 mg, 1.9

mmol) and activated MnO₂(3.0 g) carried out in the same manner as de-

1472, 1424, 1240, 1091, 827, 752, 690 cm^ꢃ1. H-NMR (CD₃OD) d: ꢃ0.28

(9H, s), 0.56 (2H, t, Jꢁ8.1 Hz), 1.21 (3H, br s), 3.16 (2H, t, Jꢁ8.1 Hz), 4.15

(2H, br s), 5.60 (2H, br s), 6.48 (1H, d, Jꢁ2.4 Hz), 7.10—7.12 (3H, m),

7.20—7.23 (3H, m), 7.50 (1H, d, Jꢁ5.5 Hz), 8.37 (1H, d, Jꢁ5.5 Hz). LR- scribed for 43ad gave crude 43av (200 mg, 29%) as a pale yellow solid. This

MS (ESI^ꢄ) m/z: 502 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₇H₃₂N₅O₃Si sample was used for the next deprotection without further puriﬁcation since

(MꢄH^ꢄ) 502.22744, Found 502.22714.

it was unsable.

tert-Butyl [4-(1-(2-(Trimethylsilyl)ethoxymethyl)-1H-imidazol-2-yl)-

1H-imidazo[4,5-c]pyridin-2-yl]carbamate (43ap) The same treatments

of 40a^1,15)(262 mg, 1.2 mmol) with 41p²²⁾(342 mg, 1.5 mmol) followed by

dehydrogenation using IBX (487 mg, 1.7 mmol) and activated MnO₂(6.0 g)

tert-Butyl [4-(1-(2-(Trimethylsilyl)ethoxymethyl)-1H-imidazol-4-yl)-1H-

imidazo[4,5-c]pyridin-2-yl]carbamate and tert-Butyl [4-(1-(2-(Trimethylsi-

lyl)ethoxymethyl)-1H-imidazol-5-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carba-

mate (43aw and 43awꢀ or vice versa) Treatments of 40a^1,15)(500 mg, 2.2

as those described for 43ad gave 43ap (192 mg, 38%) as a white solid after mmol) with 41w²²⁾(500 mg, 2.2 mmol) followed by dehydrogenation using

puriﬁcation by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ1/1—1/2). IR

IBX (930 mg, 3.3 mmol) and activated MnO₂(5.0 g) carried out in a similar

manner to that described for 43ad gave less polar 43aw (206 mg, 22%) and

(ATR): 3374, 2953, 1714, 1633, 1569, 1470, 1246, 1157, 1073, 828 cm^ꢃ1

¹H-NMR (CD₃OD) d: ꢃ0.17 (9H, s), 0.82 (2H, br s), 1.60 (9H, s), 3.57 (2H, more polar 43awꢆ (116 mg, 12%) both as a white powder after separation by

br s), 6.21 (2H, br s), 7.28 (1H, br s), 7.40 (2H, d, Jꢁ1.2 Hz), 8.32 (1H, t, Jꢁ column chromatography (NH-SiO₂, C₆H₁₄/EtOAcꢁ1/1–AcOEt). 43aw: H-

5.2 Hz). LR-MS (ESI^ꢄ) m/z: 431 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for NMR (CD₃OD) d: ꢃ0.21 (9H, s), 0.66—0.71 (2H, m), 1.57 (9H, s), 3.36

C₂₀H₃₁N₆O₃Si (MꢄH^ꢄ) 431.22269, Found 431.22246.

(2H, t, Jꢁ8.1 Hz), 5.97 (2H, br s), 7.40 (1H, d, Jꢁ5.2 Hz), 7.82 (1H, br s),

tert-Butyl [4-(1-Trityl-1H-imidazol-2-yl)-1H-imidazo[4,5-c]pyridin-2- 7.95 (1H, br s), 8.25 (1H, d, Jꢁ5.2 Hz). 43awꢆ: ¹H-NMR (CD₃OD) d: ꢃ0.01

yl]carbamate (43aq) Similar treatments of 40a^1,15)(466 mg, 2.0 mmol)

with 41q²³⁾(667 mg, 2.0 mmol) followed by dehydrogenation using IBX

(375 mg, 1.3 mmol) and activated MnO₂(3.0 g) to those described for 43ad

gave 43aq (74.0 mg, 15%) as a light brown powder after puriﬁcation by col-

umn chromatography (NH-SiO₂, EtOAc). IR (ATR): 3386, 2931, 1719,

(9H, s), 0.94 (2H, d, Jꢁ7.9 Hz), 1.61 (9H, s), 3.63 (2H, t, Jꢁ7.9 Hz), 5.47

(2H, s), 7.33 (1H, d, Jꢁ5.5 Hz), 7.94 (1H, br s), 7.97 (1H, s), 8.18 (1H, d,

Jꢁ5.5 Hz). Less polar 43aw obtained as a predominantproduct was directly

subjected to the next bromination.

tert-Butyl [4-(1-Trityl-1H-1,2,3-triazol-4-yl)-1H-imidazo[4,5-c]pyridin-2-

1628, 1567, 1447, 1249, 1153, 747, 700 cm^ꢃ1. H-NMR (CD₃OD) d: 1.59

yl]carbamate (43ax) A solution of 40a^1,15)(660 mg, 2.9 mmol) and 41x

(9H, s), 6.93—7.29 (19H, m), 7.36—7.38 (1H, m). LR-MS (ESI^ꢄ) m/z: 543 (934 mg, 2.8 mmol) in EtOH (40 ml) was stirred overnight at 50 °C. The re-

[MꢄH^ꢄ], 301. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₃H₃₁N₆O₂(MꢄH^ꢄ) action mixture was concentrated in vacuo, and the residue was triturated

543.25085, Found 543.25078.

with C₆H₁₄–EtOAc to give the 4,5,6,7-tetrahydroderivative of 43ax (1.16 g,

590

Vol. 59, No. 5

77%) as a light brown powder. ¹H-NMR (CD₃OD) d: 1.50 (9H, s), 2.62 (2H, trated in vacuo. The residue was puriﬁed by column chromatography (SiO₂,

br s), 2.99—3.05 (1H, m), 3.10—3.16 (1H, m), 5.12 (1H, s), 7.06—7.13 C₆H₁₄/EtOAcꢁ4/1—3/1) to give 47a (319 mg, 98%) as a light brown amor-

(6H, m), 7.29—7.38 (9H, m), 7.52 (1H, s). To a solution of the 4,5,6,7-

tetrahydroderivative (500 mg, 0.91 mmol) in DMSO (8.0 ml) was added IBX

(384 mg, 1.4 mmol), and the mixture was stirred at room temperature for 1 h.

The reaction was quenched by adding H₂O and an aqueous NaOH solution

(1.0 mol/l, 5.0 ml, 5.0 mmol), and the mixture was extracted with EtOAc.

The organic extracts were combined, washed with H₂O and brine, dried over

anhydrous Na₂SO₄, ﬁltered, and then concentrated in vacuo. To a solution of

the residue in CH₂Cl₂(20 ml) was added activated MnO₂(3.0 g), and the

phous solid. IR (ATR): 3393, 2950, 1713, 1631, 1567, 1249, 1153, 1082,

859, 833 cm^ꢃ1. H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.57—0.61 (2H, m),

1.57 (9H, s), 2.82 (2H, t, Jꢁ7.6 Hz), 2.92 (2H, t, Jꢁ7.6 Hz), 3.13—3.17

(2H, m), 5.58 (2H, br s), 6.66 (1H, br s), 6.78 (1H, br s), 7.10—7.14 (1H, m),

7.22—7.25 (4H, m), 7.35 (1H, d, Jꢁ5.5 Hz), 8.21 (1H, d, Jꢁ5.5 Hz). LR-

MS (ESI^ꢄ) m/z: 534 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₉H₄₀N₅O₃Si

534.29004 (MꢄH^ꢄ), Found 534.29014.

tert-Butyl [4-(4-(2-(Triﬂuoromethyl)phenethyl)-1-(2-(trimethylsilyl)-

mixture was stirred at room temperature for 2 h. The reaction mixture was ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carba-

ﬁltered through a pad of celite, and the ﬁltrate was concentrated in vacuo. mate (47b) Treatments of 43ak (387 mg, 0.65 mmol) with 10% Pd/C (39

The residue was triturated with C₆H₁₄–EtOAc (1 : 1) to give 43ax (312 mg, mg) under a hydrogen atmosphere carried out in the same manner as de-

63%) as a pale yellow powder. IR (ATR): 3394, 2977, 1711, 1577, 1441, scribed for 47a gave 47b (390 mg, 100%) as a pale yellow amorphous solid

1251, 1152, 697 cm^ꢃ1

¹H-NMR (DMSO-d₆) d: 1.52 (9H, s), 7.13—7.15 after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ3/1). IR

(6H, m), 7.39 (1H, d, Jꢁ5.5 Hz), 7.43—7.47 (9H, m), 8.13 (1H, s), 8.21 (ATR): 3389, 2951, 1713, 1631, 1567, 1311, 1250, 1153, 1119, 1082,

(1H, d, Jꢁ5.5 Hz), 11.61 (1H, br s), 11.76 (1H, br s). LR-MS (ESI^ꢄ) m/z: 833 cm^ꢃ1. H-NMR (CD₃OD) d: ꢃ0.24 (9H, s), 0.59—0.63 (2H, m), 1.57

544 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₂H₃₀N₇O₂(MꢄH^ꢄ)

(9H, s), 2.82 (2H, t, Jꢁ7.6 Hz), 3.10 (2H, t, Jꢁ7.6 Hz), 3.19 (2H, t,

Jꢁ8.3 Hz), 5.62 (2H, br s), 6.70 (1H, br s), 6.86 (1H, s), 7.32—7.37 (2H, m),

544.24610, Found 544.24644.

tert-Butyl [4-(5-Bromo-2-trityl-2H-1,2,3-triazol-4-yl)-1H-imidazo[4,5- 7.45—7.53 (2H, m), 7.64 (1H, d, Jꢁ7.6 Hz), 8.22 (1H, d, Jꢁ4.9 Hz).

c]pyridin-2-yl]carbamate (43ay) Treatments of 40a^1,15)(226 mg, 1.0 LR-MS (ESI^ꢄ) m/z: 602 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

mmol) with 41y (502 mg, 1.2 mmol) followed by dehydrogenation using

IBX (228 mg, 0.82 mmol) and activated MnO₂(3.6 g) carried out in the same

manner as described for 43ad gave 43ay (215 mg, 36%) as a pale yellow

C₃₀H₃₉F₃N₅O₃Si (MꢄH^ꢄ) 602.27742, Found 602.27753.

tert-Butyl [4-(4-(3-(Triﬂuoromethyl)phenethyl)-1-(2-(trimethylsilyl)-

ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carba-

powder after triturate with C₆H₁₄–EtOAc (1/1). IR (ATR): 3387, 2979, 1720, mate (47c) Treatments of 43al (359 mg, 0.60 mmol) with 10% Pd/C

1571, 1249, 1150, 698 cm^ꢃ1. H-NMR (DMSO-d₆) d: 1.47 (9H, s), 7.09— (36 mg) under a hydrogen atmosphere carried out in a similar manner to that

7.49 (15H, m), 8.25 (1H, d, Jꢁ5.5 Hz), 8.35 (1H, d, Jꢁ5.5 Hz), 11.08 (1H,

described for 47a gave 47c (353 mg, 98%) as a yellow amorphous solid after

br s), 11.53 (1H, br s). LR-MS (ESI^ꢄ) m/z: 622 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) puriﬁcation by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ3/1). IR

m/z: Calcd for C₃₂H₂₉BrN₇O₂(MꢄH^ꢄ) 622.15661, Found 622.15646.

4-(4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-

1H-imidazo[4,5-c]pyridine (43ba) A solution of commercially available

40b (565 mg, 5.1 mmol) and 41a (1.95 g, 5.1 mmol) in 2-methoxyethanol

(10 ml) was heated at reﬂux for 18 h. The reaction mixture was concentrated

in vacuo and the residue was puriﬁed by column chromatography (NH-SiO₂,

(ATR): 3393, 2950, 1711, 1631, 1567, 1328, 1250, 1155, 1123, 1074,

825 cm^ꢃ1. H-NMR (CD₃OD) d: ꢃ0.26 (9H, s), 0.56—0.60 (2H, m), 1.57

(9H, s), 2.87 (2H, t, Jꢁ7.0 Hz), 3.03 (2H, t, Jꢁ7.0 Hz), 3.13—3.17 (2H, m),

5.60 (2H, br s), 6.81 (1H, br s), 7.35 (1H, d, Jꢁ5.5 Hz), 7.40—7.53 (4H, m),

8.21 (1H, m). LR-MS (ESI^ꢄ) m/z: 602 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd

for C₃₀H₃₉F₃N₅O₃Si (MꢄH^ꢄ) 602.27742, Found 602.27813.

EtOAc/MeOHꢁ50/1) to give the 4,5,6,7-tetrahydroderivative of 43ba

tert-Butyl [4-(4-(4-(Triﬂuoromethyl)phenethyl)-1-(2-(trimethylsilyl)-

(1.93 g, 80%) as a yellow amorphous solid. H-NMR (CDCl₃) d: 0.01 (9H, ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carba-

s), 0.90—0.95 (2H, m), 2.66 (2H, t, Jꢁ5.2 Hz), 3.01 (1H, dt, Jꢁ12.8, 5.2 mate (47d) The same treatments of 43am (355 mg, 0.59 mmol) with 10%

Hz), 3.10—3.16 (1H, m), 3.59—3.63 (2H, m), 5.23 (1H, s), 5.38 (1H, d, Jꢁ Pd/C (35 mg) under a hydrogen atmosphere as those described for 47a gave

11.0 Hz), 5.55 (1H, d, Jꢁ11.0 Hz), 5.92 (1H, s), 7.48 (1H, s). LR-MS (ESI^ꢄ) 47d (319 mg, 89%) as a pale yellow amorphous solid after puriﬁcation by

m/z: 475 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₆H₂₅Br₂N₄OSi (MꢄH^ꢄ) column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ6/1—3/1). IR (ATR): 3395,

475.01644, Found 475.01606. To a solution of the 4,5,6,7-tetrahydroderiva-

tive (90.0 mg, 0.19 mmol) in DMSO (1.0 ml) was added IBX (79.5 mg,

0.28 mmol), and the mixture was stirred at room temperature for 2 h. The re-

action was quenched by adding H₂O and an aqueous NaOH solution

(1.0 mol/l, 3.0 ml, 3.0 mmol), and the mixture was extracted with EtOAc.

2950, 1711, 1631, 1567, 1324, 1250, 1154, 1121, 1067, 824 cm^ꢃ1. ¹H-NMR

(CD₃OD) d: ꢃ0.27 (9H, s), 0.57 (2H, t, Jꢁ8.1 Hz), 1.57 (9H, s), 2.88 (2H, t,

Jꢁ7.3 Hz), 3.03 (2H, t, Jꢁ7.3 Hz), 3.12 (2H, t, Jꢁ8.1 Hz), 5.57 (2H, br s),

6.69 (1H, br s), 6.77 (1H, s), 7.35 (1H, d, Jꢁ5.5 Hz), 7.41 (2H, d, Jꢁ7.9 Hz),

7.53 (2H, d, Jꢁ7.9 Hz), 8.21 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 602

The organic extracts were combined, washed with H₂O and brine, dried over [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₃₉F₃N₅O₃Si (MꢄH^ꢄ)

anhydrous Na₂SO₄, ﬁltered, and then concentrated in vacuo. To a solution of

602.27742, Found 602.27685.

the residue in CH₂Cl₂(10 ml) was added activated MnO₂(0.50 g), and the

Ethyl [4-(3-Phenethyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-

mixture was stirred overnight at room temperature. The reaction mixture yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (47e) Similar treatments

was ﬁltered through a pad of celite, and the ﬁltrate was concentrated in

vacuo. The residue was puriﬁed by column chromatography (NH-SiO₂,

C₆H₁₄/EtOAcꢁ1/1) to give 43ba (45.7 mg, 51%) as an orange amorphous

of 43ao (195 mg, 0.39 mmol) with 10% Pd/C (20 mg) under a hydrogen

atmosphere to those described for 47a gave crude 47e (216 mg, 84%) as a

brown amorphous solid after concentration of the ﬁltrate in vacuo. This

sample was directly used for the next bromination without further puriﬁca-

solid. IR (ATR): 2951, 1580, 1466, 1247, 1090, 1060, 833, 743 cm^ꢃ1. H-

NMR (CD₃OD) d: ꢃ0.29 (9H, s), 0.54—0.58 (2H, m), 3.14—3.18 (2H, m), tion. ¹H-NMR (CD₃OD) d: ꢃ0.21 (9H, s), 0.58 (2H, t, Jꢁ8.1 Hz), 1.34 (3H,

5.90 (2H, br s), 7.05 (1H, br s), 7.57 (1H, br s), 8.34 (1H, br s), 8.39 (1H, d,

Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 471 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd

for C₁₆H₂₁Br₂N₄OSi (MꢄH^ꢄ) 470.98514, Found 470.98511.

t, Jꢁ7.3 Hz), 2.72 (4H, t, Jꢁ7.3 Hz), 3.14 (2H, br s), 4.30 (2H, q, Jꢁ7.3

Hz), 5.28 (2H, br s), 6.18 (1H, br s), 6.89—7.06 (6H, m), 7.45 (1H, d, Jꢁ5.5

Hz), 8.26 (1H, d, Jꢁ5.5 Hz).

2-Bromo-4-(4,5-dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-

pyrrol-2-yl)-1H-imidazo[4,5-c]pyridine (43ca) Treatments of 40c¹⁶⁾

(415 mg, 1.6 mmol) with 41a (667 mg, 1.7 mmol) followed by dehydrogena-

tion using IBX (664 mg, 2.4 mmol) and activated MnO₂(4.0 g) carried out in

the same manner as described for 43ad gave 43ca (510 mg, 59%) an a or-

tert-Butyl [4-(5-Bromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-

2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48a) To a solution of

43ac (175 mg, 0.41 mmol) in MeOH (10 ml) was added TBABr₃(196 mg,

0.41 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 h.

After adding Et₃N (0.50 ml) at 0 °C, the mixture was diluted with EtOAc,

ange solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/ washed with brine, and concentrated in vacuo. The residue was puriﬁed by

EtOAcꢁ1/1). IR (ATR): 3156, 2949, 1588, 1465, 1389, 1309, 1239, 1061, column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ3/1) to give 48a (155 mg,

1041, 857, 835, 750 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.58—0.62 93%) as a white powder. IR (ATR): 3396, 2947, 2891, 1702, 1636, 1567,

(2H, m), 3.20 (2H, t, Jꢁ8.3 Hz), 5.84 (2H, s), 7.03 (1H, s), 7.53 (1H, d, Jꢁ 1440, 1256, 1153, 1085, 834, 720 cm^ꢃ1. H-NMR (CD₃OD) d: ꢃ0.26 (9H,

5.5 Hz), 8.28 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 549 (MꢄH^ꢄ). HR-MS

(ESI^ꢄ) m/z: Calcd for C₁₆H₂₀Br₃N₄OSi (MꢄH^ꢄ) 548.89565, Found

548.89476.

tert-Butyl [4-(4-Phenethyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-

2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (47a) A suspension of

43aj (322 mg, 0.61 mmol) and 10% Pd/C (16 mg) in EtOH (10 ml) was

stirred at room temperature for 5 h under a hydrogen atmosphere. The reac-

tion mixture was ﬁltered through a pad of celite, and the ﬁltrate was concen-

s), 0.57 (2H, t, Jꢁ8.1 Hz), 1.57 (9H, s), 3.14 (2H, t, Jꢁ8.1 Hz), 5.80 (2H,

br s), 6.36 (1H, br s), 6.81 (1H, br s), 7.40 (1H, d, Jꢁ5.5 Hz), 8.22 (1H, s).

LR-MS (ESI^ꢄ) m/z: 508 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₂₁H₃₁BrN₅O₃Si (MꢄH^ꢄ) 508.13795, Found 508.13873.

tert-Butyl [4-(3,4,5-Tribromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-

pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48b) Treatments

of 43a (150 mg, 0.26 mmol) with TBABr₃(129 mg, 0.27 mmol) carried out

in the same manner as described for 48a gave 48b (174 mg, ca. 100%) as a

May 2011

591

tert-Butyl [4-(4-Benzyl-5-bromo-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48i) Treat-

ments of 43ai (440 mg, 0.85 mmol) with TBABr₃(408 mg, 0.85 mmol) car-

ried out in the same manner as described for 48a gave 48i (444 mg, 88%) as

a white solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/

EtOAcꢁ4/1—2/1). IR (ATR): 3384, 2951, 1710, 1631, 1566, 1250, 1153,

1072, 826, 710 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.55—0.59 (2H,

m), 1.56 (9H, s), 3.15 (2H, t, Jꢁ7.6 Hz), 3.85 (2H, br s), 5.78 (2H, br s), 6.71

(1H, br s), 7.12—7.25 (5H, m), 7.37 (1H, d, Jꢁ5.5 Hz), 8.20 (1H, br s).

LR-MS (ESI^ꢄ) m/z: 598 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₂₈H₃₇BrN₅O₃Si (MꢄH^ꢄ) 598.18490, Found 598.18466.

tert-Butyl [4-(4-Benzyl-3,5-dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48j) Treat-

ments of 48i (200 mg, 0.33 mmol) with TBABr₃(182 mg, 0.38 mmol) car-

ried out in a similar manner to that described for 48a gave 48j (211 mg,

93%) as a white solid after puriﬁcation by column chromatography (SiO₂,

C₆H₁₄/EtOAcꢁ2/1). IR (ATR): 3372, 2950, 1710, 1635, 1569, 1250, 1147,

1060, 834 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.22 (9H, br s), 0.55 (2H, t, Jꢁ8.3

Hz), 1.56 (9H, s), 3.08 (2H, br s), 3.92 (2H, br s), 5.40 (2H, br s), 7.15 (1H, t,

Jꢁ7.3 Hz), 7.23 (2H, t, Jꢁ7.3 Hz), 7.30 (2H, d, Jꢁ7.3 Hz), 7.51 (1H, d, Jꢁ

5.5 Hz), 8.30 (1H, br s). LR-MS (ESI^ꢄ) m/z: 676 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ)

m/z: Calcd for C₂₈H₃₆Br₂N₅O₃Si (MꢄH^ꢄ) 676.09542, Found 676.09520.

tert-Butyl [4-(5-Bromo-4-phenethyl-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48k) The

same treatments of 47a (299 mg, 0.56 mmol) with TBABr₃(284 mg, 0.59

mmol) as those described for 48a gave 48k (290 mg, 91%) as a pale yellow

amorphous solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/

EtOAcꢁ5/1—4/1). IR (ATR): 3391, 2949, 1713, 1630, 1567, 1248, 1153,

1087, 859, 833, 697 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.26 (9H, s), 0.54—0.58

(2H, m), 1.57 (9H, s), 2.79 (2H, br s), 2.90 (2H, t, Jꢁ7.6 Hz), 3.09—3.13

(2H, m), 5.76 (2H, br s), 6.66 (1H, br s), 7.11—7.15 (1H, m), 7.20—7.26

(4H, m), 7.39 (1H, d, Jꢁ5.5 Hz), 8.17 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ)

m/z: 612 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₉H₃₉BrN₅O₃Si (MꢄH^ꢄ)

612.20055, Found 612.20057.

pale yellow amorphous solid after puriﬁcation by column chromatography

(SiO₂, C₆H₁₄/EtOAcꢁ1/1). IR (KBr): 3383, 2954, 1721, 1637, 1574, 1513,

1472, 1370, 1250, 1157, 1089, 861, 834, 770 cm^ꢃ1. H-NMR (CD₃OD) d:

ꢃ0.22 (9H, s), 0.56 (2H, t, Jꢁ8.3 Hz), 1.57 (9H, s), 3.09 (2H, br s), 5.39

(2H, br s), 7.54 (1H, d, Jꢁ5.2 Hz), 8.31 (1H, br s). LR-MS (ESI^ꢄ) m/z: 664

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₁H₂₉Br₃N₅O₃Si (MꢄH^ꢄ)

663.95898, Found 663.95572.

tert-Butyl [4-(4,5-Dichloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-

pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48c) To a solu-

tion of 43ac (274 mg, 0.64 mmol) in THF (7.0 ml) was added NCS (170 mg,

1.3 mmol). The mixture was stirred at room temperature for 2 d, and concen-

trated in vacuo. The residue was puriﬁed by column chromatography (SiO₂,

C₆H₁₄/EtOAcꢁ4/1—3/1) to give 48c (59.6 mg, 19%) as a pale yellow amor-

phous solid. IR (ATR): 3383, 2952, 1714, 1629, 1568, 1481, 1248, 1152,

1078, 859, 832, 768 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.59 (2H, t,

Jꢁ8.1 Hz), 1.57 (9H, s), 3.17 (2H, t, Jꢁ8.1 Hz), 5.83 (2H, br s), 6.91 (1H,

br s), 7.41 (1H, d, Jꢁ5.5 Hz), 8.22 (1H, br s). LR-MS (ESI^ꢄ) m/z: 498

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₁H₃₀Cl₂N₅O₃Si (MꢄH^ꢄ)

498.14950, Found 498.14982.

tert-Butyl [4-(4-Bromo-5-chloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-

pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48d) Treatments

of 43ad (218 mg, 0.42 mmol) with NCS (56.2 mg, 0.42 mmol) carried out in

the same manner as described for 48c gave 48d (209 mg, 91%) as a light

brown amorphous solid after puriﬁcation by column chromatography (SiO₂,

C₆H₁₄/EtOAcꢁ1/1). IR (ATR): 3382, 2951, 1715, 1629, 1568, 1476, 1248,

1152, 1079, 858, 832, 768 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.59

(2H, t, Jꢁ8.1 Hz), 1.57 (9H, s), 3.17 (2H, t, Jꢁ8.1 Hz), 5.84 (2H, br s), 6.95

(1H, br s), 7.41 (1H, d, Jꢁ5.5 Hz), 8.23 (1H, br s). LR-MS (ESI^ꢄ) m/z: 542

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₁H₃₀BrClN₅O₃Si (MꢄH^ꢄ)

542.09898, Found 542.09858.

tert-Butyl 4-(3,4-Dibromo-5-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-

H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48e) Treat-

ments of 43ae (100 mg, 0.19 mmol) with TBABr₃(101 mg, 0.21 mmol) car-

ried out in the same manner as described for 48a gave 48e (113 mg, 98%) as

a colorless amorphous solid after puriﬁcation by column chromatography

(SiO₂, C₆H₁₄/EtOAcꢁ3/1—2/1). IR (ATR): 3376, 2952, 1718, 1634, 1568,

1248, 1151, 1077, 859, 830 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.24 (9H, s), 0.53

(2H, t, Jꢁ8.3 Hz), 1.57 (9H, s), 2.40 (3H, s), 2.99 (2H, br s), 5.29 (2H, br s),

7.52 (1H, d, Jꢁ5.5 Hz), 8.31 (1H, br s). LR-MS (ESI^ꢄ) m/z: 600 [MꢄH^ꢄ].

HR-MS (ESI^ꢄ) m/z: Calcd for C₂₂H₃₂Br₂N₅O₃Si (MꢄH^ꢄ) 600.06412, Found

600.06419.

tert-Butyl [4-(3,5-Dibromo-4-phenethyl-1-(2-(trimethylsilyl)etho-

xymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate

(48l) Similar treatments of 48k (100 mg, 0.16 mmol) with TBABr₃(86.3

mg, 0.18 mmol) to those described for 48a gave 48l (111 mg, 98%) as a col-

orless amorphous solid after puriﬁcation by column chromatography (SiO₂,

C₆H₁₄/EtOAcꢁ4/1—3/1). IR (ATR): 3378, 2950, 1718, 1634, 1571, 1249,

1152, 1075, 831, 697 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.23 (9H, s), 0.54 (2H,

t, Jꢁ8.3 Hz), 1.57 (9H, s), 2.84 (4H, br s), 3.03 (2H, br s), 5.36 (2H, br s),

7.14—7.18 (1H, m), 7.21—7.28 (4H, m), 7.52 (1H, d, Jꢁ5.5 Hz), 8.32 (1H,

br s). LR-MS (ESI^ꢄ) m/z: 690 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₂₉H₃₈Br₂N₅O₃Si (MꢄH^ꢄ) 690.11107, Found 690.11073.

tert-Butyl [4-(5-Bromo-4-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48f) Treat-

ments of 43ag (221 mg, 0.50 mmol) with TBABr₃(265 mg, 0.55 mmol) car-

ried out in a similar manner to that described for 48a gave 48f (211 mg,

81%) as a pale yellow amorphous solid after puriﬁcation by column chro-

matography (SiO₂, C₆H₁₄/EtOAcꢁ5/1—4/1). IR (ATR): 3392, 2951, 1714,

tert-Butyl [4-(3,5-Dibromo-4-(2-(triﬂuoromethyl)phenethyl)-1-(2-

(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-

2-yl]carbamate (48m) Treatments of 47b (380 mg, 0.63 mmol) with TBABr₃

(641 mg, 1.3 mmol) carried out in the same manner as described for 48a

gave 48m (447 mg, 93%) as a pale yellow amorphous solid after puriﬁcation

by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ4/1—3/1). IR (ATR):

1630, 1567, 1248, 1153, 1087, 859, 833, 766 cm^ꢃ1. H-NMR (CD₃OD) d:

ꢃ0.26 (9H, s), 0.56 (2H, t, Jꢁ8.3 Hz), 1.57 (9H, s), 2.11 (3H, s), 3.12 (2H,

t, Jꢁ8.3 Hz), 5.74 (2H, br s), 6.73 (1H, br s), 7.38 (1H, d, Jꢁ5.5 Hz), 8.22

(1H, br s). LR-MS (ESI^ꢄ) m/z: 522 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₂₂H₃₃BrN₅O₃Si (MꢄH^ꢄ) 522.15360, Found 522.15388.

3376, 2952, 1718, 1571, 1311, 1249, 1151, 1121, 831 cm^ꢃ^{1 1}H-NMR

(CD₃OD) d: ꢃ0.23 (9H, s), 0.55 (2H, t, Jꢁ8.1 Hz), 1.57 (9H, s), 2.85 (2H,

br s), 3.06 (4H, br s), 5.37 (2H, br s), 7.34—7.42 (2H, m), 7.52—7.55 (2H,

m), 7.65 (2H, d, Jꢁ7.6 Hz), 8.33 (1H, br s). LR-MS (ESI^ꢄ) m/z: 758 [Mꢄ

H^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₃₇Br₂F₃N₅O₃Si (MꢄH^ꢄ)

758.09845, Found 758.09866.

tert-Butyl [4-(3,5-Dibromo-4-(3-(triﬂuoromethyl)phenethyl)-1-(2-

(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-

2-yl]carbamate (48n) Treatments of 47c (345 mg, 0.57 mmol) with TBABr₃

(579 mg, 1.2 mmol) carried out in a similar manner to that described for 48a

gave 48n (339 mg, 78%) as a pale yellow amorphous solid after puriﬁcation

by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ4/1—3/1). IR (ATR):

3379, 2952, 1718, 1571, 1329, 1250, 1154, 1124, 1072, 832 cm^ꢃ1. ¹H-NMR

(CD₃OD) d: ꢃ0.24 (9H, s), 0.53 (2H, t, Jꢁ8.3 Hz), 1.57 (9H, s), 2.87 (2H,

br s), 3.01 (4H, br s), 5.36 (2H, br s), 7.44—7.53 (5H, m), 8.32 (1H, br s).

LR-MS (ESI^ꢄ) m/z: 758 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₃₀H₃₇Br₂F₃N₅O₃Si (MꢄH^ꢄ) 758.09845, Found 758.09875.

tert-Butyl 4-(3,5-Dibromo-4-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48g) The

same treatments of 48f (100 mg, 0.19 mmol) with TBABr₃(101 mg, 0.21

mmol) as those described for 48a gave 48g (108 mg, 94%) as a colorless

amorphous solid after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/

EtOAcꢁ3/1). IR (ATR): 3378, 2951, 1718, 1634, 1569, 1248, 1152, 1068,

858, 830 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.24 (9H, s), 0.54 (2H, t, Jꢁ8.3 Hz),

1.57 (9H, s), 2.11 (3H, br s), 3.05 (2H, br s), 5.37 (2H, br s), 7.51 (1H, d, Jꢁ

5.5 Hz), 8.31 (1H, br s). LR-MS (ESI^ꢄ) m/z: 600 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ)

m/z: Calcd for C₂₂H₃₂Br₂N₅O₃Si (MꢄH^ꢄ) 600.06412, Found 600.06447.

tert-Butyl [4-(5-Bromo-4-phenyl-1-(2-(trimethylsilyl)ethoxymethyl)-

1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48h) Simi-

lar treatments of 43ah (151 mg, 0.30 mmol) with TBABr₃(151 mg,

0.31 mmol) to those described for 48a gave 48h (167 mg, 96%) as a white

powder after puriﬁcation by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ

4/1). mp: 157—159 °C (from C₆H₁₄–EtOAc). IR (KBr): 3404, 2964, 1705,

1637, 1561, 1474, 1269, 1253, 1155, 1087, 859, 835, 755, 697 cm^ꢃ^{1 1}H-

tert-Butyl [4-(3,5-Dibromo-4-(4-(triﬂuoromethyl)phenethyl)-1-(2-

(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-

2-yl]carbamate (48o) The same treatments of 47d (259 mg, 0.43 mmol)

with TBABr₃(435 mg, 0.90 mmol) as those described for 48a gave 48o

(256 mg, 78%) as a pale yellow amorphous solid after puriﬁcation by col-

umn chromatography (SiO₂, C₆H₁₄/EtOAcꢁ4/1). IR (ATR): 3390, 2926,

NMR (CD₃OD) d: ꢃ0.24 (9H, s), 0.61 (2H, t, Jꢁ7.9 Hz), 1.57 (9H, s), 3.20

(2H, t, Jꢁ7.9 Hz), 5.89 (2H, br s), 7.07 (1H, br s), 7.27 (1H, t, Jꢁ7.3 Hz),

7.39 (2H, t, Jꢁ7.3 Hz), 7.43 (1H, d, Jꢁ5.5 Hz), 7.64—7.67 (2H, m), 8.26

(1H, br s). LR-MS (ESI^ꢄ) m/z: 584 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₂₇H₃₅BrN₅O₃Si (MꢄH^ꢄ) 584.16925, Found 584.16867.

592

Vol. 59, No. 5

1714, 1569, 1325, 1249, 1153, 1118, 1103, 1065, 829 cm^ꢃ1

¹H-NMR

Jꢁ8.1 Hz), 1.47 (9H, s), 3.23 (2H, t, Jꢁ8.1 Hz), 3.35 (3H, s), 3.71 (3H, s),

5.96 (2H, s), 7.11 (1H, s), 7.50 (1H, d, Jꢁ5.8 Hz), 8.39 (1H, d, Jꢁ5.8 Hz).

(CD₃OD) d: ꢃ0.24 (9H, s), 0.53 (2H, t, Jꢁ7.9 Hz), 1.57 (9H, s), 2.89 (2H,

br s), 3.00 (4H, br s), 5.33 (2H, br s), 7.40 (2H, d, Jꢁ7.9 Hz), 7.53 (1H, d, Jꢁ LR-MS (ESI^ꢄ) m/z: 614 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

5.5 Hz), 7.56 (2H, d, Jꢁ7.9 Hz), 8.32 (1H, br s). LR-MS (ESI^ꢄ) m/z: 758 C₂₃H₃₄Br₂N₅O₃Si (MꢄH^ꢄ) 614.07977, Found 614.07726.

[MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₃₇Br₂F₃N₅O₃Si (MꢄH^ꢄ)

758.09845, Found 758.09818.

4-(4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-

1H-imidazo[4,5-c]pyridin-2-amine (45) To a solution of 43a (392 mg,

0.67 mmol) in MeOH (5.0 ml) was added 20% HCl–EtOH (10 ml), and the

reaction mixture was stirred overnight at room temperature. The whole was

tert-Butyl [4-(5-Bromo-4-(3-phenylpropyl)-1-(2-(trimethylsilyl)-

ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carba-

mate (48p) Similar treatments of 43an (1.15 g, 2.1 mmol) with TBABr₃concentrated in vacuo, and aqueous 10% Na₂CO₃solution (10 ml) was

(1.01 g, 2.1 mmol) to those described for 48a gave 48p (1.18 g, 90%) as a

pale yellow amorphous solid after puriﬁcation by column chromatography

added to the residue. The mixture was stirred at room temperature for 1 h.

Precipitates were collected by ﬁltration, dried, and puriﬁed by column chro-

(SiO₂, C₆H₁₄/EtOAcꢁ5/1—2/1). IR (ATR): 3375, 2920, 1705, 1636, 1569, matography (NH-SiO₂, EtOAc/MeOHꢁ10/1) to afford 45 (172 mg, 53%) as

1248, 1157, 827 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: ꢃ0.26 (9H, s), 0.57 (2H, t, a pale yellow powder. IR (ATR): 2950, 1640, 1552, 1435, 1248, 1066,

Jꢁ8.1 Hz), 1.55 (9H, s), 1.89—1.96 (2H, m), 2.54 (2H, t, Jꢁ7.0 Hz), 2.67 832 cm^ꢃ1. ¹H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.54—0.58 (2H, m), 3.07—

(2H, t, Jꢁ7.6 Hz), 3.14 (2H, t, Jꢁ8.1 Hz), 5.76 (2H, br s), 6.77 (1H, br s),

3.11 (2H, m), 5.69 (2H, s), 6.70 (1H, s), 7.20 (1H, d, Jꢁ5.5 Hz), 8.14 (1H, d,

7.11—7.25 (5H, m), 7.38 (1H, d, Jꢁ5.5 Hz), 8.22 (1H, br s). LR-MS (ESI^ꢄ) Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 486 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd

m/z: 626 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₄₁BrN₅O₃Si (MꢄH^ꢄ) for C₁₆H₂₂Br₂N₅OSi (MꢄH^ꢄ) 485.99604, Found 485.99600.

626.21620, Found 626.21553.

4-(4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-1-

methyl-1H-imidazo[4,5-c]pyridin-2-amine (46) Treatments of 45 (260

mg, 0.44 mmol) with NaH (60% in oil, 14.2 mg, 0.36 mmol) and MeI (0.022

ml, 0.36 mmol) carried out in the same manner as described in 44a gave 46

(80.7 mg, 50%) as a colorless amorphous solid after puriﬁcation by column

chromatography (NH-SiO₂, C₆H₁₄/EtOAcꢁ1/1—1/3). IR (ATR): 3440,

tert-Butyl [4-(3,5-Dibromo-4-(3-phenylpropyl)-1-(2-(trimethylsilyl)-

ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carba-

mate (48q) Treatments of 48p (231 mg, 0.37 mmol) with TBABr₃

(196 mg, 0.41 mmol) carried out in the same manner as described for 48a

gave 48q (239 mg, 92%) as a pale yellow amorphous solid after puriﬁcation

by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ2/1). IR (ATR): 3378,

2951, 1657, 1543, 1464, 1245, 1092, 1070, 859, 833, 798 cm^ꢃ^{1 1}H-NMR

2947, 1717, 1634, 1570, 1250, 1153, 832 cm^ꢃ1

¹H-NMR (CD₃OD) d:

(CD₃OD) d: ꢃ0.23 (9H, s), 0.64—0.68 (2H, m), 3.20—3.25 (2H, m), 3.59

(3H, s), 5.98 (2H, s), 6.06 (2H, br s), 6.99 (1H, d, Jꢁ5.5 Hz), 7.03 (1H, s),

8.26 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 500 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ)

m/z: Calcd for C₁₇H₂₄Br₂N₅OSi (MꢄH^ꢄ) 500.01169, Found 500.01106.

4-(4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-pyrrol-2-yl)-

N,N-dimethyl-1H-imidazo[4,5-c]pyridin-2-amine (49) A mixture of 43ca

(220 mg, 0.40 mmol) and dimethylamine (2 mol/l in MeOH, 10 ml, 20 mmol)

was heated at 100 °C in a sealed tube for 10 h. The reaction mixture was

concentrated in vacuo, and the residue was puriﬁed by column chromatogra-

ꢃ0.24 (9H, s), 0.54 (2H, t, Jꢁ8.3 Hz), 1.56 (9H, s), 1.92 (2H, br s), 2.60

(2H, br s), 2.69 (2H, t, Jꢁ7.9 Hz), 3.08 (2H, br s), 5.37 (2H, br s), 7.12—

7.27 (5H, m), 7.51 (1H, d, Jꢁ5.5 Hz), 8.29 (1H, br s). LR-MS (ESI^ꢄ) m/z:

704 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₄₀Br₂N₅O₃Si (MꢄH^ꢄ)

704.12672, Found 704.12752.

tert-Butyl [4-(4,5-Dibromo-3-phenethyl-1-(2-(trimethylsilyl)-

ethoxymethyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carba-

mate (48r) Treatments of crude 47e with TBABr₃(413 mg, 0.39 mmol)

carried out in a similar manner to that described for 48a gave 48r (216 mg, phy (NH-SiO₂, C₆H₁₄/EtOAcꢁ1/1) to afford 49 (201 mg, 53%) as a pale yel-

84% from 43ao) as a light brown amorphous solid after puriﬁcation by col-

umn chromatography (SiO₂, C₆H₁₄/EtOAcꢁ5/1—3/1). IR (ATR): 3383,

low amorphous solid. IR (ATR): 3268, 2949, 1626, 1603, 1572, 1434, 1409,

1248, 1062, 915, 833, 755 cm^ꢃ1

¹H-NMR (CD₃OD) d: ꢃ0.23 (9H, s),

2950, 1725, 1631, 1572, 1520, 1474, 1454, 1425, 1237, 1090, 1073, 831, 0.55—0.59 (2H, m), 3.11—3.15 (2H, m), 3.18 (6H, s), 5.66 (2H, s), 6.75

768, 697 cm^ꢃ1. H-NMR (CD₃OD) d: ꢃ0.22 (9H, s), 0.55 (2H, br s), 1.35 (1H, s), 7.22 (1H, d, Jꢁ5.5 Hz), 8.11 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z:

(3H, t, Jꢁ7.0 Hz), 2.62 (2H, t, Jꢁ7.6 Hz), 2.81 (2H, t, Jꢁ7.6 Hz), 3.06 (2H, 514 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₈H₂₆Br₂N₅OSi (MꢄH^ꢄ)

br s), 4.31 (2H, q, Jꢁ7.0 Hz), 5.35 (2H, br s), 6.77 (2H, d, Jꢁ7.0 Hz), 6.90— 514.02734, Found 514.02695.

6.99 (3H, m), 7.49 (1H, d, Jꢁ5.5 Hz), 8.27 (1H, d, Jꢁ5.5 Hz). LR-MS

(ESI^ꢄ) m/z: 662 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₂₇H₃₄Br₂N₅O₃Si

(MꢄH^ꢄ) 662.07977, Found 662.08011.

tert-Butyl [4-(5-Chloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-imida-

zol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (48s) The same treat-

tert-Butyl 2-(di(tert-butoxycarbonyl)amino)-4-(5-chloro-1-(2-(trimethylsi-

lyl)ethoxymethyl)-1H-imidazol-2-yl)-1H-imidazo[4,5-c]pyridin-1-

carboxylate (50) To a solution of 48s (135 mg, 0.29 mmol) in MeCN

(3.0 ml) were added Boc₂O (316 mg, 1.5 mmol) and DMAP (10 mg). The

mixture was strirred overnight at room temperature and concentrated in

ments of 43ap (431 mg, 1.0 mmol) with NCS (147 mg, 1.1 mmol) in CCl₄vacuo. The residue was puriﬁed by column chromatography (SiO₂, C₆H₁₄/

(10 ml) as those described for 48c gave 48s (152 mg, 33%) as a white pow- EtOAcꢁ3/1—3/2) to afford 50 (180 mg, 93%) as a light brown amorphous

der after trituration with CH₂Cl₂. IR (ATR): 3378, 2899, 1716, 1570, 1464, solid. IR (ATR): 2980, 1756, 1369, 1338, 1247, 1144, 1118, 1099, 836

1246, 1154, 1077, 923, 830, 677 cm^ꢃ1. ¹H-NMR (DMSO-d₆) d: ꢃ0.21 (9H, cm^ꢃ^{1 1}H-NMR (CDCl₃) d: ꢃ0.14 (9H, s), 0.72 (2H, t, Jꢁ8.1 Hz), 1.41

s), 0.78 (2H, t, Jꢁ7.9 Hz), 1.53 (9H, s), 3.55 (2H, t, Jꢁ7.9 Hz), 6.32 (2H, s),

(18H, s), 1.69 (9H, s), 3.39 (2H, t, Jꢁ8.1 Hz), 5.95 (2H, s), 7.28 (1H, s),

7.43 (1H, s), 7.47 (1H, d, Jꢁ5.5 Hz), 8.30 (1H, d, Jꢁ5.5 Hz), 11.55 (1H, 7.94 (1H, d, Jꢁ5.5 Hz), 8.61 (1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 665

br s), 11.79 (1H, br s). LR-MS (ESI^ꢄ) m/z: 465 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₄₆ClN₆O₇Si (MꢄH^ꢄ)

m/z: Calcd for C₂₀H₃₀ClN₆O₃Si (MꢄH^ꢄ) 465.18372, Found 465.18429.

tert-Butyl [4-(4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-

pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-(methyl)carbamate (44a)

665.28858, Found 665.28773.

tert-Butyl 4-(4-Bromo-5-chloro-1-(2-(trimethylsilyl)ethoxymethyl)-1H-

imidazol-2-yl)-2-(di(tert-butoxycarbonyl)amino)-1H-imidazo[4,5-

and tert-Butyl [4-(4,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H- c]pyridin-1-carboxylate (51) To a solution of 50 (190 mg, 0.29 mmol) in

pyrrol-2-yl)-1-methyl-1H-imidazo[4,5-c]pyridin-2-yl]-(methyl)carba-

mate (44b) To a solution of 43a (260 mg, 0.44 mmol) in DMF (3.0 ml)

was added NaH (60% in oil, 19.5 mg, 0.49 mmol), and the reaction mixture

was stirred at room temperature for 1 h. To the mixture was added MeI

(0.033 ml, 0.53 mmol) at 0 °C, and the whole was stirred at the same temper-

ature for 1 h. The reaction was quenched by adding H₂O at 0 °C, and the

mixture was extracted with EtOAc. The organic extracts were combined,

MeCN (3.0 ml) was added NBS (76.4 mg, 0.43 mmol). The mixture was

stirred at room temperature for 3 d and then concentrated in vacuo. The

residue was puriﬁed by column chromatography (SiO₂, C₆H₁₄/EtOAcꢁ4/1—

3/1) to afford 51 (153 mg, 72%) as a colorless oil. IR (ATR): 2980, 1760,

1369, 1336, 1240, 1142, 1117, 1098, 834 cm^ꢃ1. ¹H-NMR (CDCl₃) d: ꢃ0.15

(9H, s), 0.64—0.68 (2H, m), 1.42 (18H, s), 1.69 (9H, s), 3.24—3.29 (2H,

m), 5.75 (2H, s), 7.97 (1H, d, Jꢁ5.5 Hz), 8.68 (1H, d, Jꢁ5.5 Hz). LR-MS

washed with H₂O and brine, dried over anhydrous Na₂SO₄, ﬁltered, and then (ESI^ꢄ) m/z: 743 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₃₀H₄₅BrClN₆O₇Si

concentrated in vacuo. Puriﬁcation of the residue by column chromatogra-

phy (NH-SiO₂, C₆H₁₄/EtOAcꢁ10/1—3/1) to give 44a (94.7 mg, 36%) as a

(MꢄH^ꢄ) 743.19909, Found 743.19920.

tert-Butyl [4-(2,5-Dibromo-1-(2-(trimethylsilyl)ethoxymethyl)-1H-imi-

colorless amorphous solid and 44b (73.1 mg, 27%) as a colorless oil. 44a; dazol-4- or 5-yl)-1H-imidazo[4,5-c]pyridin-2-yl]carbamate (53) To a

IR (ATR): 3376, 2952, 1706, 1538, 1424, 1339, 1143, 1090, 834 cm^ꢃ1. H- solution of 43aw (90 mg, 0.21 mmol) in CHCl₃(3.0 ml) was added NBS

NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.59 (2H, t, Jꢁ8.1 Hz), 1.69 (9H, s), 3.17 (112 mg, 0.63 mmol), and the mixture was stirred overnight at room temper-

(2H, t, Jꢁ8.1 Hz), 3.57 (3H, s), 5.92 (2H, s), 7.07 (1H, s), 7.40 (1H, d, Jꢁ

ature. The whole was directly puriﬁed by column chromatography (SiO₂,

5.2 Hz), 8.23 (1H, d, Jꢁ5.2 Hz). LR-MS (ESI^ꢄ) m/z: 600 [MꢄH^ꢄ]. HR-MS

C₆H₁₄/EtOAcꢁ1/1) to afford 53 (100 mg, 81%) as a white powder. This

(ESI^ꢄ) m/z: Calcd for C₂₂H₃₂Br₂N₅O₃Si (MꢄH^ꢄ) 600.06412, Found sample was directly subjected to the next deprotection. H-NMR (CD₃OD)

600.06323. 44b; IR (ATR): 2951, 1720, 1579, 1525, 1461, 1330, 1248,

d: ꢃ0.22 (9H, s), 0.58 (2H, d, Jꢁ8.3 Hz), 1.57 (9H, s), 3.11—3.16 (2H, m),

1148, 1091, 834 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: ꢃ0.25 (9H, s), 0.61 (2H, t, 5.44 (2H, s), 7.57 (1H, d, Jꢁ5.5Hz), 8.34 (1H, d, Jꢁ5.5 Hz).

May 2011

593

4-(5-Bromo-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-amine

ꢀMethod Cꢁ To a solution of 48a (100 mg, 0.20 mmol) in CH₂Cl₂(5.0 ml)

was added BF₃-OEt₂(0.25 ml, 2.0 mmol) under an argon atmosphere, and

the mixture was stirred at room temperature for 18 h. The reaction was

(3) 1411, 1177, 1116, 824, 806, 723 cm^ꢃ1. H-NMR (CD₃OD) d: 7.45 (1H, s),

7.80 (1H, d, Jꢁ6.4 Hz), 8.29 (1H, d, Jꢁ6.4 Hz), 8.68 (1H, s). ¹³C-NMR

(CD₃OD) d: 103.1, 108.3, 110.5, 118.0, 125.7, 135.0, 136.0, 136.8, 144.1,

148.5. LR-MS (ESI^ꢄ) m/z: 341 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

quenched by adding aqueous 10% Na₂CO₃solution, and the reaction mix- C₁₀H₇Br₂N₄(MꢄH^ꢄ) 340.90375, Found 340.90286.

ture was extracted with EtOAc. The combined extracts were washed with

4-(4,5-Dichloro-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-amine

H₂O and brine, dried over anhydrous Na₂SO₄, ﬁltered, and then concentrated (10) The same treatments of 48c (83.0 mg, 0.17 mmol) with BF₃–OEt₂

in vacuo. The residue was dissolved in MeOH, and the methanolic solution

(0.210 ml, 1.7 mmol) and TFA (0.10 ml) as those described for 3 gave 10-

was ﬁltered through a pad of NH-SiO₂(washed with MeOH); the ﬁltrate was 2TFA (75.3 mg, 91%) as a pale yellow powder after trituration with

then concentrated in vacuo. The residue was dissolved in MeOH (2.0 ml),

CH₂Cl₂–MeOH. mp 150 °C (decomp., from MeOH–CH₂Cl₂). IR (KBr):

and TFA (0.10 ml) was added to the MeOH solution. The acidic methanolic

3455, 1686, 1648, 1212, 1126, 1035, 724 cm^ꢃ1. H-NMR (CD₃OD) d: 7.14

solution was concentrated in vacuo. Trituration of the residue with CH₂Cl₂(1H, s), 7.43 (1H, d, Jꢁ6.4 Hz), 8.06 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR (DMSO-

gave 3-2TFA (85.4 mg, 86%) as a yellow powder. mp: 115 °C (decomp.,

d₆) d: 104.7, 110.0, 113.3, 115.1, 116.0, 118.0, 120.9, 121.7, 126.8, 158.7.

from MeOH–CH₂Cl₂). H-NMR (CD₃OD) d: 6.42 (1H, d, Jꢁ4.0 Hz), 7.11

LR-MS (ESI^ꢄ) 268 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₀H₈Cl₂N₅

(1H, d, Jꢁ4.0 Hz), 7.38 (1H, d, Jꢁ6.4 Hz), 8.00 (1H, d, Jꢁ6.4 Hz). ¹³C- (MꢄH^ꢄ) 268.01568, Found 268.01564.

NMR (CD₃OD) d: 104.9, 106.4, 114.2, 114.4, 125.2, 129.7, 132.3, 136.6,

4-(4-Bromo-5-chloro-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-

146.8, 160.7. LR-MS (ESI^ꢄ) m/z: 278 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd amine (11) Similar treatments of 48d (170 mg, 0.31 mmol) with BF₃–OEt₂

for C₁₀H₉BrN₅(MꢄH^ꢄ) 278.00413, Found 278.00488.

(0.393 ml, 3.1 mmol) and TFA (0.10 ml) to those described for 3 gave 11-

2TFA (39.2 mg, 23%) as a pale yellow powder after trituration with CH₂Cl₂–

MeOH. mp: 130 °C (decomp., from MeOH–CH₂Cl₂). IR (KBr): 3147, 2923,

4-(4-Bromo-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-amine (2)

Treatments of 43ad (145 mg, 0.29 mmol) with BF₃-OEt₂(0.358 ml, 2.9

mmol) and TFA (0.10 ml) carried out in the same manner as described for 3

gave 2-2TFA (118 mg, 82%) as a pale yellow amorphous solid. IR (KBr):

3343, 3190, 1671, 1639, 1438, 1205, 1146, 725 cm^ꢃ1. ¹H-NMR (CD₃OD) d:

1719, 1664, 1474, 1438, 1202, 1135, 794, 724 cm^ꢃ1. H-NMR (CD₃OD) d:

7.16 (1H, s), 7.42 (1H, d, Jꢁ6.4 Hz), 8.06 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR

(CD₃OD) d: 98.3, 105.3, 114.8, 121.0, 123.5, 128.6, 133.0, 136.6, 146.9,

7.15 (1H, d, Jꢁ1.5 Hz), 7.24 (1H, d, Jꢁ1.5 Hz), 7.39 (1H, d, Jꢁ6.4 Hz), 160.7. LR-MS (ESI^ꢄ) m/z: 312 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

8.00 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR (CD₃OD) d: 99.6, 104.9, 113.8, 124.5, C₁₀H₈BrClN₅(MꢄH^ꢄ) 311.96516, Found 311.96500.

125.1, 129.8, 132.3, 137.0, 146.6, 160.6. LR-MS (ESI^ꢄ) m/z: 278 [MꢄH^ꢄ].

HR-MS (ESI^ꢄ) m/z: Calcd for C₁₀H₉BrN₅278.00413 (MꢄH^ꢄ), Found

278.00450.

4-(4-Bromo-5-methyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-

amine (12) Treatments of 43ae (140 mg, 0.27 mmol) with BF₃–OEt₂

(0.34 ml, 2.7 mmol) and TFA (0.10 ml) carried out in the same manner as de-

4-(4,5-Dibromo-1H-pyrrol-2-yl)-N-methyl-1H-imidazo[4,5-c]pyridin- scribed for 3 gave 12-2TFA (88.9 mg, 64%) as a pale yellow amorphous

2-amine (5) Treatments of 44a (70.0 mg, 0.12 mmol) with BF₃–OEt₂

(0.146 ml, 1.2 mmol) and TFA (0.10 ml) carried out in a similar manner to

solid after trituration with CH₂Cl₂–MeOH. IR (ATR): 3149, 1707, 1655,

1431, 1185, 1135, 796, 721 cm^ꢃ1. H-NMR (CD₃OD) d: 2.36 (3H, s), 7.09

that described for 3 gave 5-2TFA (63.7 mg, 92%) as a yellow amorphous

(1H, s), 7.34 (1H, d, Jꢁ6.7 Hz), 7.96 (1H, d, Jꢁ6.7 Hz). ¹³C-NMR (CD₃OD)

solid. IR (KBr): 3406, 1654, 1431, 1203, 1140 cm^ꢃ1. H-NMR (CD₃OD) d: d: 11.9, 99.3, 104.6, 114.6, 122.2, 130.0, 132.2, 134.1, 135.9, 146.3, 160.2.

3.13 (3H, s), 7.17 (1H, s), 7.40 (1H, d, Jꢁ6.4 Hz), 8.04 (1H, d, Jꢁ6.4 Hz). LR-MS (ESI^ꢄ) m/z: 292 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

¹³C-NMR (CD₃OD) d: 29.6, 102.3, 104.7, 107.4, 114.7, 117.4, 125.4, 127.5, C₁₁H₁₁BrN₅(MꢄH^ꢄ) 292.01978, Found 292.02030.

132.3, 146.6, 160.7. LR-MS (ESI^ꢄ) m/z: 370 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z:

Calcd for C₁₁H₁₀Br₂N₅(MꢄH^ꢄ) 369.93030, Found 369.99450.

4-(4-Bromo-5-phenyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-

amine (14) Treatments of 43af (226 mg, 0.39 mmol) with BF₃–OEt₂

4-(4,5-Dibromo-1H-pyrrol-2-yl)-1-methyl-1H-imidazo[4,5-c]pyridin- (0.49 ml, 3.9 mmol) and TFA (0.10 ml) carried out in a similar manner to

2-amine (6) The same treatments of 46 (72.0 mg, 0.14 mmol) with BF₃– that described for 3 gave 14-2TFA (146 mg, 65%) as a yellow powder after

OEt₂(0.181 ml, 1.4 mmol) and TFA (0.10 ml) as those described for 3 gave trituration with CH₂Cl₂–MeOH. mp: 130 °C (decomp., from MeOH–

6-2TFA (71.2 mg, 83%) as a yellow powder after trituration with CH₂Cl₂.

CH₂Cl₂). IR (KBr): 3104, 1711, 1654, 1474, 1194, 1137, 722 cm^ꢃ^{1 1}H-

mp: 160 °C (decomp. from CH₂Cl₂). IR (ATR): 3131, 2892, 1655, 1426, NMR (CD₃OD) d: 7.28 (1H, s), 7.39 (1H, d, Jꢁ6.4 Hz), 7.42 (1H, tt, Jꢁ7.3,

1177, 1124, 831, 791, 721 cm^ꢃ1. H-NMR (CD₃OD) d: 3.73 (3H, s), 7.19

1.2 Hz), 7.50 (2H, t, Jꢁ7.3 Hz), 7.81—7.84 (2H, m), 8.03 (1H, d, Jꢁ

(1H, s), 7.51 (1H, d, Jꢁ6.4 Hz), 8.08 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR (CD₃OD)

6.4 Hz). ¹³C-NMR (CD₃OD) d: 98.2, 104.8, 116.5, 124.2, 127.8, 129.0,

d: 30.1, 102.4, 103.8, 107.8, 115.1, 125.7, 128.6, 132.3, 136.5, 146.7, 160.8. 129.4, 129.9, 131.5, 132.3, 134.7, 137.1, 146.4, 160.6. LR-MS (ESI^ꢄ) m/z:

LR-MS (ESI^ꢄ) m/z: 370 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for 354 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₆H₁₃BrN₅(MꢄH^ꢄ)

C₁₁H₁₀Br₂N₅(MꢄH^ꢄ) 369.93030, Found 369.93090.

354.03543, Found 354.03625. Anal. Calcd for C₁₆H₁₂BrN₅–2C₂HF₃O₂, C,

41.26%, H, 2.42%, N, 12.03%, Found: C, 41.16%, H, 2.42%, N, 12.30%.

4-(5-Bromo-4-phenyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-

amine (17) Treatments of 48h (167 mg, 0.29 mmol) with BF₃–OEt₂(0.36

ml, 2.9 mmol) and TFA (0.10 ml) carried out in the same manner as de-

scribed for 3 gave 17-2TFA (134 mg, 75%) as a yellow powder after tritura-

4-(4,5-Dibromo-1H-pyrrol-2-yl)-N,1-dimethyl-1H-imidazo[4,5-c]

pyridin-2-amine (7) Similar treatments of 44b (60.0 mg, 0.0975 mmol)

with BF₃-OEt₂(0.122 ml, 0.98 mmol) and TFA (0.10 ml) to those described

for 3 gave 7-2TFA (57.8 mg, 97%) as a yellow amorphous solid. IR (KBr):

3448, 3284, 1697, 1686, 1649, 1625, 1426, 1204, 1138 cm^ꢃ^{1 1}H-NMR

(CD₃OD) d: 3.20 (3H, s), 3.69 (1H, s), 7.21 (1H, s), 7.50 (1H, d, Jꢁ6.4 Hz),

tion with CH₂Cl₂–MeOH. mp: 220 °C (decomp. from MeOH–CH₂Cl₂). IR

8.08 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR (CD₃OD) d: 29.9, 30.0, 102.2, 103.2, (KBr): 3067, 1713, 1668, 1457, 1202, 1142, 996 cm^ꢃ1. H-NMR (CD₃OD)

107.4, 115.0, 125.4, 127.5, 132.0, 136.2, 146.7, 160.2. LR-MS (ESI^ꢄ) m/z: d: 7.32 (1H, tt, Jꢁ7.3, 1.2 Hz), 7.35 (1H, s), 7.41 (1H, d, Jꢁ6.4 Hz), 7.43

384 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₂H₁₂Br₂N₅(MꢄH^ꢄ)

(2H, t, Jꢁ7.3 Hz), 7.63—7.66 (2H, m), 8.04 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR

(DMSO-d₆) d: 102.6, 104.7, 113.1, 114.6, 117.5, 124.3, 124.7, 126.8, 127.1,

383.94595, Found 383.94957.

4-(4,5-Dibromo-1H-pyrrol-2-yl)-N,N-dimethyl-1H-imidazo[4,5- 127.4, 128.6, 133.1, 133.4, 158.9. LR-MS (ESI^ꢄ) m/z: 354 [MꢄH^ꢄ]. HR-

c]pyridin-2-amine (8) Treatments of 49 (192 mg, 0.37 mmol) with BF₃– MS (ESI^ꢄ) m/z: Calcd for C₁₆H₁₃BrN₅(MꢄH^ꢄ) 354.03543, Found

OEt₂(0.468 ml, 3.7 mmol) and TFA (0.10 ml) carried out in the same man-

ner as described for 3 gave 8-2TFA (172 mg, 75%) as a yellow powder after

trituration with CH₂Cl₂. mp: 140 °C (decomp., from CH₂Cl₂). IR (ATR):

354.03540. Anal. Calcd for C₁₆H₁₃BrN₅–2C₂HF₃O₂–H₂O, C, 40.02%, H,

2.69%, N, 11.67%, Found: C, 40.13%, H, 2.59%, N, 11.74%.

4-(3,4,5-Tribromo-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-amine

(27) Treatments of 48b (144 mg, 0.22 mmol) with BF₃–OEt₂(0.271 ml,

3117, 1784, 1633, 1198, 1134, 791, 691 cm^ꢃ1. H-NMR (CD₃OD) d: 3.30

(6H, s), 7.18 (1H, s), 7.40 (1H, d, Jꢁ6.4 Hz), 8.04 (1H, d, Jꢁ6.4 Hz). ¹³H- 2.2 mmol) and TFA (0.10 ml) carried out in a similar manner to that de-

NMR (CD₃OD) d: 38.6, 102.4, 104.8, 107.6, 115.2, 125.5, 127.9, 132.2, scribed for 3 gave 27-TFA (86.1 mg, 72%) as a pale yellow powder after trit-

137.5, 147.3, 160.9. LR-MS (ESI^ꢄ) m/z: 384 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: uration with CH₂Cl₂. mp: 185 °C (decomp. from CH₂Cl₂). IR (KBr): 3333,

Calcd for C₁₂H₁₂Br₂N₅(MꢄH^ꢄ) 383.94595, Found 383.94591. Anal. Calcd 3179, 1681, 1661, 1636, 1433, 1205, 1184, 1115, 720 cm^ꢃ1

¹H-NMR

for C₁₂H₁₁Br₂N₅–2C₂HF₃O₂: C, 31.34; H, 2.14; N, 11.42. Found: C, 31.11; (CD₃OD) d: 7.53 (1H, d, Jꢁ6.4 Hz), 8.24 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR

H, 2.05; N, 11.58.

(CD₃OD) d: 103.0, 104.3, 106.7, 108.5, 116.8, 119.7, 122.4, 126.4, 135.4,

4-(4,5-Dibromo-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridine (9) Treat-

162.3. LR-MS (ESI^ꢄ) m/z: 434 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

ments of 43ba (84.4 mg, 0.179 mmol) with BF₃-OEt₂(0.225 ml, 1.8 mmol) C₁₀H₇Br₃N₅(MꢄH^ꢄ) 433.82516, Found 433.82799.

and TFA (0.10 ml) carried out in a similar manner to that described for 3

gave 9-2TFA (67.9 mg, 67%) as a pale yellow powder after trituration with

CH₂Cl₂. mp: 200 °C (decomp. from CH₂Cl₂). IR (ATR): 2785, 1671, 1612, CH₂Cl₂(3.0 ml) was added TFA (3.0 ml), and the mixture was stirred

4-(3,4-Dibromo-5-methyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-

2-amine (13) ꢀMethod Dꢁ To a solution of 48e (94.1 mg, 0.16 mmol) in

594

Vol. 59, No. 5

overnight at room temperature. The reaction mixture was concentrated in c]pyridin-2-amine (21) The same treatments of 48l (90.07 mg, 0.13

vacuo, and the residue was dissolved in MeOH (5.0 ml). To the mixture was

added aqueous 10% Na₂CO₃solution (3.0 ml), and the whole was extracted

with EtOAc. The combined extracts were washed with H₂O and brine, dried

over anhydrous Na₂SO₄, ﬁltered, and then concentrated in vacuo. The

residue was dissolved in MeOH (3.0 ml), and TFA (0.15 ml) was added to

mmol) with TFA (3.0 ml) as those described for 13 gave 21-2TFA (44.3 mg,

49%) as a pale yellow amorphous solid after trituration with CH₂Cl₂–

MeOH. IR (ATR): 3172, 1656, 1631, 1422, 1202, 1181, 1114, 718 cm^ꢃ1. ¹H-

NMR (DMSO-d₆) d: 2.26—2.72 (2H, m), 2.76—2.81 (2H, m), 7.18—7.32

(5H, m), 7.50 (1H, d, Jꢁ6.1 Hz), 7.75 (2H, br s), 8.26 (1H, d, Jꢁ6.1 Hz),

the MeOH solution. The acidic methanolic solution was concentrated in 12.73 (1H, br s). ¹³C-NMR (DMSO-d₆) d: 27.7, 35.3, 100.0, 102.4, 112.6,

vacuo. Trituration of the residue with MeOH–CH₂Cl₂gave 13-2TFA (56.8 115.6, 118.6, 121.5, 121.9, 122.2, 126.1, 128.28, 128.34, 128.36, 128.41,

mg, 61%) as a pale yellow amorphous solid. IR (ATR): 3168, 1657, 1631,

1178, 1120, 719 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 2.39 (3H, s), 7.49 (1H, d, C₁₈H₁₆Br₂N₅(MꢄH^ꢄ) 459.97725, Found 459.97738.

Jꢁ6.4 Hz), 8.18 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR (CD₃OD) d: 12.5, 101.4,

4-(3,5-Dibromo-4-(2-(triﬂuoromethyl)phenethyl)-1H-pyrrol-2-yl)-1H-

140.6. LR-MS (ESI^ꢄ) m/z: 460 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

102.6, 107.4, 118.6, 127.6, 133.5, 134.0, 135.5, 150.8, 161.9. LR-MS imidazo[4,5-c]pyridin-2-amine (22) Similar treatments of 48m (231 mg,

(ESI^ꢄ) m/z: 370 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₁H₁₀Br₂N₅

(MꢄH^ꢄ) 369.93030, Found 369.93036.

0.30 mmol) with TFA (3.0 ml) to those described for 13 gave 22-2TFA

(171 mg, 74%) as a yellow amorphous solid after trituration with CH₂Cl₂–

MeOH. IR (ATR): 3331, 3161, 1651, 1630, 1312, 1171, 1102, 720 cm^ꢃ1. ¹H-

NMR (CD₃OD) d: 2.82—2.88 (2H, m), 3.04 (2H, t, Jꢁ7.9 Hz), 7.38 (2H, t,

Jꢁ7.9 Hz), 7.51 (1H, d, Jꢁ6.7 Hz), 7.53 (1H, t, Jꢁ7.9 Hz), 7.66 (1H, d, Jꢁ

7.9 Hz), 8.20 (1H, d, Jꢁ6.7 Hz). LR-MS (ESI^ꢄ) m/z: 528 [MꢄH^ꢄ]. HR-MS

(ESI^ꢄ) m/z: Calcd for C₁₉H₁₅Br₂F₃N₅(MꢄH^ꢄ) 527.96463, Found

527.96461.

4-(4,5-Dibromo-1-methyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-

2-amine (4) Treatments of 43ab (90.0 mg) with TFA (3.0 ml) carried out

in the same manner as described for 13 gave 4-2TFA (94.3 mg, 82%) as a

pale yellow amorphous solid after trituration with CH₂Cl₂–MeOH. IR

(KBr): 3351, 3166, 1672, 1431, 1202, 1139, 722 cm^ꢃ1. H-NMR (CD₃OD)

d: 3.69 (3H, s), 6.80 (1H, s), 7.54 (1H, d, Jꢁ6.4 Hz), 8.22 (1H, d, Jꢁ6.4

Hz). ¹³C-NMR (CD₃OD) d: 36.4, 100.4, 108.1, 111.6, 116.7, 125.7, 128.1,

135.5, 136.7, 150.5, 161.8. LR-MS (ESI^ꢄ) m/z: 370 [MꢄH^ꢄ]. HR-MS

(ESI^ꢄ) m/z: Calcd for C₁₁H₁₀Br₂N₅(MꢄH^ꢄ) 369.93030, Found 369.93000.

4-(5-Bromo-4-methyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-

amine (15) Treatments of 48f (85.0 mg, 0.16 mmol) with TFA (3.0 ml)

carried out in a similar manner to that described for 13 gave 15-2TFA (71.4

mg, 84%) as a pale yellow amorphous solid after trituration with CH₂Cl₂–

4-(3,5-Dibromo-4-(3-(triﬂuoromethyl)phenethyl)-1H-pyrrol-2-yl)-1H-

imidazo[4,5-c]pyridin-2-amine (23) Treatments of 48n (223 mg, 0.29

mmol) with TFA (3.0 ml) carried out in the same manner as described for 13

gave 23-2TFA (136 mg, 61%) as a yellow amorphous solid after trituration

with CH₂Cl₂–MeOH. IR (ATR): 3335, 3162, 1650, 1631, 1329, 1201, 1119,

720 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 2.84—2.88 (2H, m), 2.98 (2H, t, Jꢁ7.3

Hz), 7.43—7.49 (4H, m), 7.50 (1H, d, Jꢁ6.4 Hz), 8.19 (1H, d, Jꢁ6.4 Hz).

MeOH. IR (ATR): 3140, 2928, 1716, 1648, 1463, 1439, 1177, 1128, 792, LR-MS (ESI^ꢄ) m/z: 528 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

721 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 2.11 (3H, s), 7.00 (1H, s), 7.35 (1H, d, C₁₉H₁₅Br₂F₃N₅(MꢄH^ꢄ) 527.96463, Found 527.96521.

Jꢁ6.7 Hz), 7.96 (1H, d, Jꢁ6.7 Hz). ¹³C-NMR (CD₃OD) d: 11.6, 104.7,

4-(3,5-Dibromo-4-(4-(triﬂuoromethyl)phenethyl)-1H-pyrrol-2-yl)-1H-

106.5, 114.1, 122.5, 124.0, 129.7, 132.1, 136.2, 146.4, 160.5. LR-MS imidazo[4,5-c]pyridin-2-amine (24) Treatments of 48o (247 mg, 0.33

(ESI^ꢄ) m/z: 292 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₁H₁₁BrN₅

(MꢄH^ꢄ) 292.01978, Found 292.02019.

mmol) with TFA (3.0 ml) carried out in a similar manner to that described

for 13 gave 24-2TFA (108 mg, 44%) as a yellow amorphous solid after tritu-

ration with CH₂Cl₂–MeOH. IR (ATR): 3355, 3167, 1659, 1633, 1324, 1178,

1115, 1066, 710 cm^ꢃ1. ¹H-NMR (CD₃OD) d: 2.84—2.88 (2H, m), 2.98 (2H,

t, Jꢁ7.5 Hz), 7.38 (2H, d, Jꢁ8.3 Hz), 7.49 (1H, d, Jꢁ6.4 Hz), 7.56 (2H, d,

4-(3,5-Dibromo-4-methyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-

2-amine (16) The same treatments of 48g (86.6 mg, 0.14 mmol) with TFA

(3.0 ml) as those described for 13 gave 16-2TFA (29.3 mg, 34%) as a pale

yellow amorphous solid after trituration with CH₂Cl₂–MeOH. IR (ATR): Jꢁ8.3 Hz), 8.18 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR (CD₃OD) d: 28.5, 36.2, 101.9,

3147, 1655, 1632, 1421, 1172, 1122, 718 cm^ꢃ1. H-NMR (CD₃OD) d: 2.10

105.5, 107.8, 121.2, 124.2, 124.6, 126.2, 126.3, 127.2, 129.3, 129.6, 130.4,

(3H, s), 7.49 (1H, d, Jꢁ6.4 Hz), 8.18 (1H, d, Jꢁ6.4 Hz). ¹³C-NMR (CD₃OD)

134.3, 146.9, 162.2. LR-MS (ESI^ꢄ) m/z: 528 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z:

d: 11.1, 102.5, 104.9, 107.9, 120.8, 121.6, 127.3, 134.3, 135.5, 151.5, 162.2. Calcd for C₁₉H₁₅Br₂F₃N₅(MꢄH^ꢄ) 527.96463, Found 527.96446.

LR-MS (ESI^ꢄ) m/z: 370 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₁₁H₁₀Br₂N₅(MꢄH^ꢄ) 369.93030, Found 369.93003.

4-(5-Bromo-4-(3-phenylpropyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-

c]pyridin-2-amine (25) The same treatments of 48p (315 mg, 0.50 mmol)

4-(4-Benzyl-5-bromo-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2- with TFA (5.0 ml) as those described for 13 gave 25-2TFA (218 mg, 69%) as

amine (18) Similar treatments of 48i (240 mg, 0.40 mmol) with TFA (3.0 a yellow amorphous solid after trituration with CH₂Cl₂. IR (ATR): 3062,

ml) to those described for 13 gave 18-2TFA (170 mg, 68%) as a pale yellow

2930, 1711, 1650, 1462, 1188, 1133, 722 cm^ꢃ^{1 1}H-NMR (CD₃OD) d:

amorphous solid after trituration with CH₂Cl₂. IR (ATR): 3124, 2927, 1706, 1.91—1.98 (2H, m), 2.53 (2H, t, Jꢁ7.6 Hz), 2.68 (2H, t, Jꢁ7.6 Hz), 7.06

1651, 1460, 1191, 1137, 721 cm^ꢃ1. ¹H-NMR (CD₃OD) d: 3.84 (2H, s), 6.95 (1H, s), 7.13—7.27 (5H, m), 7.36 (1H, d, Jꢁ6.4 Hz), 7.97 (1H, d, Jꢁ6.4

(1H, s), 7.16—7.30 (5H, m), 7.34 (1H, d, Jꢁ6.7 Hz), 7.92 (1H, d, Jꢁ6.7

Hz). LR-MS (ESI^ꢄ) m/z: 368 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₁₇H₁₅BrN₅(MꢄH^ꢄ) 368.05108, Found 368.05123. Anal. Calcd for

Hz). LR-MS (ESI^ꢄ) m/z: 396 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₁₉H₁₉BrN₅(MꢄH^ꢄ) 396.08238, Found 396.08261.

4-(3,5-Dibromo-4-(3-phenylpropyl)-1H-pyrrol-2-yl)-1H-imidazo[4,5-

C₁₇H₁₄BrN₅–2C₂HF₃O₂–1.5H₂O: C, 40.47%, H, 3.07%, N, 11.24%, Found: c]pyridin-2-amine (26) Similar treatments of 48q (370 mg, 0.52 mmol)

C, 40.44%, H, 2.84%, N, 11.42%. with TFA (5.0 ml) to those described for 13 gave 26-TFA (182 mg, 59%) as a

4-(4-Benzyl-3,5-dibromo-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2- pale yellow amorphous solid after trituration with CH₂Cl₂. IR (ATR) 3337,

amine (19) Treatments of 48i (230 mg, 0.34 mmol) with TFA (3.0 ml) car- 3167, 2937, 1661, 1633, 1201, 1170, 1114, 702 cm^ꢃ1. ¹H-NMR (CD₃OD) d:

ried out in the same manner as described for 13 gave 19-TFA (135 mg, 71%) 1.86—1.94 (2H, m), 2.58 (2H, t, Jꢁ7.6 Hz), 2.69 (2H, t, Jꢁ7.6 Hz), 7.13—

as a yellow amorphous solid after trituration with CH₂Cl₂. IR (ATR): 3339,

7.27 (5H, m), 7.49 (1H, d, Jꢁ6.4 Hz), 8.17 (1H, d, Jꢁ6.4 Hz). LR-MS

3158, 1662, 1201, 1177, 1132, 719 cm^ꢃ1. H-NMR (CD₃OD) d: 3.90 (2H, (ESI^ꢄ) m/z: 474 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₉H₁₈Br₂N₅

s), 7.14—7.30 (5H, m), 7.51 (1H, d, Jꢁ6.4 Hz), 8.18 (1H, d, Jꢁ6.4 Hz). LR- (MꢄH^ꢄ) 473.99290, Found 473.99244. Anal. Calcd for C₁₉H₁₇Br₂N₅-

MS (ESI^ꢄ) m/z: 446 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₇H₁₄Br₂N₅

C₂HF₃O₂: C, 42.81%, H, 3.08%, N, 11.89%, Found: C, 42.88%, H, 3.09%,

(MꢄH^ꢄ) 445.96160, Found 445.96117. Anal. Calcd for C₁₇H₁₃Br₂N₅– N, 11.87%.

C₂HF₃O₂: C, 40.67%, H, 2.51%, N, 12.48%, Found: C, 40.74%, H, 2.47%,

N, 12.31%.

4-(4,5-Dibromo-1H-imidazol-2-yl)-1H-imidazo[4,5-c]pyridin-2-amine

(29) Treatments of 43ar (100 mg, 0.17 mmol) with TFA (3.0 ml) carried

out in the same manner as described for 13 gave 29-2TFA (64.2 mg, 64%) as

a pale yellow powder after trituration with CH₂Cl₂–MeOH. IR (ATR): 3329,

2973, 1708, 1671, 1476, 1444, 1316, 1184, 1135, 1005, 834, 791, 761, 720,

707 cm^ꢃ1. ¹H-NMR (CD₃OD) d: 7.41 (1H, d, Jꢁ5.8 Hz), 8.38 (1H, d, Jꢁ5.8

Hz). ¹³C-NMR (CD₃OD) d: 107.5, 112.1, 126.9, 130.7, 140.7, 142.8, 145.0,

4-(5-Bromo-4-phenethyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-c]pyridin-2-

amine (20) Treatments of 48k (90.0 mg, 0.15 mmol) with TFA (3.0 ml)

carried out in a similar manner to that described for 13 gave 20-2TFA

(63.4 mg, 71%) as a pale yellow amorphous solid after trituration with

CH₂Cl₂–MeOH. IR (ATR): 3017, 1650, 1626, 1433, 1185, 1132, 721 cm^ꢃ1

¹H-NMR (CD₃OD) d: 2.27—2.81 (2H, m), 2.91 (2H, t, Jꢁ7.8 Hz), 6.98 155.3. LR-MS (ESI^ꢄ) m/z: 357 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

(1H, s), 7.13—7.26 (5H, m), 7.35 (1H, d, Jꢁ6.4 Hz), 7.95 (1H, d, Jꢁ6.4 C₉H₇Br₂N₆(MꢄH^ꢄ) 356.90989, Found 356.90979. Anal. Calcd for

Hz). ¹³C-NMR (CD₃OD) d: 29.5, 37.4, 104.7, 106.3, 124.2, 126.7, 127.0, C₉H₆Br₂N₆–2C₂HF₃O₂: C, 26.64%, H, 1.38%, N, 14.34%, Found: C,

129.3, 129.5, 129.8, 132.1, 136.3, 142.6, 146.5, 160.4. LR-MS (ESI^ꢄ) m/z: 26.26%, H, 1.27%, N, 14.05%.

382 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₈H₁₇BrN₅(MꢄH^ꢄ)

382.06673, Found 382.06675.

4-(3,5-Dibromo-4-phenethyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-

4-(1H-Imidazol-2-yl)-1H-imidazo[4,5-c]pyridin-2-amine (31) Treat-

ments of 43aq (74.0 mg, 0.14 mmol) with TFA (3.0 ml) carried out in a simi-

lar manner to that described for 13 gave 31-2TFA (19.2 mg, 33%) as a light

May 2011

595

459.97725, Found 459.97668.

brown amorphous solid after trituration with CH₂Cl₂. IR (ATR): 3105, 3012,

1712, 1616, 1435, 1174, 1137, 829, 753, 719, 635 cm^ꢃ1. ¹H-NMR (CD₃OD)

d: 7.39 (1H, d, Jꢁ5.5 Hz), 7.53 (2H, s), 8.26 (1H, d, Jꢁ5.5 Hz). LR-MS

(ESI^ꢄ) m/z: 201 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₉H₉N₆(MꢄH^ꢄ)

201.08887, Found 201.08811. Anal. Calcd for C₉H₉N₆–2C₂HF₃O₂–0.2H₂O:

C, 36.16%, H, 2.43%, N, 19.46%, Found: C, 35.99%, H, 2.35%, N, 19.32%.

4-(1H-Imidazol-4-yl)-1H-imidazo[4,5-c]pyridin-2-amine (33) The same

treatments of 43av (38.8 mg, 0.072 mmol) with triﬂuoroacetic acid (2.0 ml)

as those described for 13 gave 33-2TFA (14.2 mg, 46%) as a light brown

amorphous solid after trituration with CH₂Cl₂. IR (ATR): 3089, 2875, 1667,

4-(4-Bromo-5-chloro-1H-imidazol-2-yl)-1H-imidazo[4,5-c]pyridin-2-

amine (30) Treatments of 52 (160 mg, 0.22 mmol) with an aqueous NaOH

solution (3.0 ml, 3.0 mmol, 1.0 mol/l) followed by deprotection of the SEM

group using TFA (3.0 ml) carried out in the same manner as described for 28

gave 30-2TFA (64.0 mg, 59%) as a pale yellow amorphous solid after tritu-

ration with CH₂Cl₂–MeOH. IR (ATR): 3358, 3113, 1711, 1677, 1478, 1192,

1146, 993, 720 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 7.41 (1H, d, Jꢁ5.5 Hz),

8.38(1H, d, Jꢁ5.5 Hz). LR-MS (ESI^ꢄ) m/z: 313 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ)

m/z: Calcd for C₉H₇BrClN₆(MꢄH^ꢄ) 312.96041, Found 312.95984.

1634, 1426, 1194, 1118, 795, 721, 628 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 7.45

4-(2,5-Dibromo-1H-imidazol-4-yl)-1H-imidazo[4,5-c]pyridin-2-amine

(32) Treatments of 54 (100 mg, 0.17 mmol) with an aqueous NaOH solu-

tion (1.0 mol/l, 3.0 ml, 3.0 mmol) followed by deprotection of the SEM

group using TFA (3.0 ml) carried out in a similar manner to that described

for 28 gave 32-2TFA (70.2 mg, 78%) as a pale yellow amorphous solid after

trituration with CH₂Cl₂. IR (ATR): 2797, 1703, 1655, 1430, 1175, 1129,

(1H, d, Jꢁ6.4 Hz), 8.13 (1H, s), 8.15 (1H, d, Jꢁ6.4 Hz), 8.27 (1H, d,

Jꢁ0.9 Hz). LR-MS (EI^ꢄ) m/z: 200 [M^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₉H₈N₆(M^ꢄ) 200.0810, Found 200.0779.

4-(5-Bromo-4H-1,2,4-triazol-3-yl)-1H-imidazo[4,5-c]pyridin-2-amine

(34) To a solution of 43at (610 mg, 1.2 mmol) in CH₂Cl₂(15 ml) was

added TFA (10 ml) at 0 °C. The mixture was stirred at room temperature for

2 h, and then concentrated in vacuo. To the residue was added TFA (10 ml),

and the solution was stirred at room temperature for 48 h, and concentrated

in vacuo. The residue was triturated with CH₂Cl₂to give 34-TFA (351 mg,

73%) as a white amorphous solid. IR (ATR): 3318, 3066, 2684, 1698, 1661,

720 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 7.94 (1H, d, Jꢁ6.4 Hz), 8.26 (1H, d, Jꢁ

6.4 Hz). ¹³C-NMR (CD₃OD) d: 108.7, 120.9, 128.0, 132.0, 137.1, 150.7,

160.8, 161.5, 161.9. LR-MS (ESI^ꢄ) m/z: 357 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ)

Calcd for C₉H₇Br₂N₆m/z: 356.90989 (MꢄH^ꢄ), Found 356.90985.

4-(4H-1,2,4-Triazol-3-yl)-1H-imidazo[4,5-c]pyridin-2-amine (35) The

same treatments of 43as (173 mg, 0.32 mmol) with an aqueous NaOH solu-

tion (1.0 mol/ml, 10 ml, 10 mmol) followed by deprotection of the trityl

group using TFA (3.0 ml) in as those described for 28 gave 35-TFA (56.2

mg, 56%) as a light brown powder after trituration with CH₂Cl₂. mp: 233 °C

(decomp., from CH₂Cl₂), IR (ATR): 3114, 2930, 1709, 1671, 1490, 1174,

1614, 1331, 1182, 1127, 721 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 7.52 (1H, d,

Jꢁ6.1 Hz), 8.31 (1H, d, Jꢁ6.1 Hz). LR-MS (ESI^ꢄ) m/z: 280 [MꢄH^ꢄ]. HR-

MS (ESI^ꢄ) m/z: Calcd for C₈H₇BrN₇(MꢄH^ꢄ) 279.99463, Found

279.99415. Anal. Calcd for C₈H₆BrN₇–C₂HF₃O₂–H₂O: C, 29.14%, H,

2.20%, N, 23.79%, Found: C, 29.20%, H, 2.09%, N, 24.05%.

1127, 796, 722 cm^ꢃ^{1 1}H-NMR (CD₃OD) d: 7.53 (1H, d, Jꢁ6.4 Hz), 8.23

4-(1H-1,2,3-Triazol-4-yl)-1H-imidazo[4,5-c]pyridin-2-amine (36)

ꢀMethod Fꢁ A solution of 43ax (260 mg, 0.48 mmol) in 10% HCl–MeOH

(20 ml) was stirred at room temperature for 8 h, and concentrated in vacuo.

The residue was triturated with CH₂Cl₂to give a white power, and the pow-

der was dissolved in 6 mol/l HCl (10 ml). The solution was stirred at 60 °C

for 15 h, and concentrated in vacuo. To a solution of the residue in MeOH

(10 ml) were added TEA (0.5 ml) and Boc₂O (200 mg). The mixture was

stirred overnight at room temperature, and concentrated in vacuo. The

residue was triturated with H₂O and CH₂Cl₂to give tert-butyl 2-amino-4-

(1H, d, Jꢁ6.4 Hz), 8.77 (1H, s). LR-MS (ESI^ꢄ) m/z: 202 [MꢄH^ꢄ]. HR-MS

(ESI^ꢄ) m/z: Calcd for C₈H₈N₇(MꢄH^ꢄ) 202.08412, Found 202.08347.

4-(5-Bromo-1H-1,2,3-triazol-4-yl)-1H-imidazo[4,5-c]pyridin-2-amine

(37) Similar treatments of 43ay (200 mg, 0.32 mmol) with an aqueous

NaOH solution (1.0 mol/ml, 5.0 ml, 5.0 mmol) followed by deprotection of

the trityl group using TFA (3.0 ml) to those described for 28 gave 37-TFA

(11.2 mg, 9%) as a pale yellow amorphous solid after trituration with

CH₂Cl₂. IR (ATR): 3364, 3082, 2927, 2702, 1680, 1619, 1197, 1180, 1146,

722 cm^ꢃ1. ¹H-NMR (CD₃OD) d: 7.53 (1H, d, Jꢁ6.1 Hz), 8.39 (1H, d, Jꢁ6.1

Hz). LR-MS (ESI^ꢄ) m/z: 280 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for

C₈H₇BrN₇(MꢄH^ꢄ) 279.99463, Found 279.99384.

(1H-1,2,3-triazol-4-yl)-1H-imidazo[4,5-c]pyridin-1-carboxylate as

a light

brown powder. To a solution of the carboxylate derivative in MeOH (8.0 ml)

was added TFA (4.0 ml). The mixture was stirred overnight at room temper-

ature, and then concentrated in vacuo. The residue was triturated with

MeOH–CH₂Cl₂to give 36-TFA (70.1 mg, 46%) as a white amorphous solid.

4-(1H-Tetrazol-5-yl)-1H-imidazo[4,5-c]pyridin-2-amine (38) Treat-

ments of 43au (575 mg, 1.4 mmol) with an aqueous NaOH solution (1.0

mol/ml, 10 ml, 10 mmol) carried out in the same manner as described for 28

gave the de-tert-butoxycarbonyl derivative (385 mg, 88%) as a white pow-

der. Subsequent deprotection of the de-tert-butoxycarbonyl derivative

(85.0 mg, 0.26 mmol) using TFA (3.0 ml) gave 38 (35.2 mg, 66%) as a light

brown solid after trituration with CH₂Cl₂. mp: 250 °C (decomp., from

IR (ATR): 3154, 2914, 1660, 1196, 1127, 801, 720 cm^ꢃ^{1 1}H-NMR

(CD₃OD) d: 7.51 (1H, d, Jꢁ6.4 Hz), 8.21 (1H, d, Jꢁ6.4 Hz), 8.74 (1H, s).

LR-MS (ESI^ꢄ) m/z: 202 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₉H₈N₇

(MꢄH^ꢄ) 202.08412, Found 202.08402. Anal. Calcd for C₉H₇N₇–C₂HF₃O₂–

0.2H₂O: C, 37.67%, H, 2.66%, N, 30.75%, Found: C, 37.39%, H, 2.66%, N,

30.53%.

MeOH), IR (ATR): 3408, 3061, 2665, 1662, 1572, 1418, 1322, 812 cm^ꢃ1

¹H-NMR (DMSO-d₆) d: 7.39 (1H, d, Jꢁ6.4 Hz), 7.54 (2H, br s), 8.12 (1H, d,

Jꢁ6.4 Hz). LR-MS (ESI^ꢄ) m/z: 203 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd

for C₇H₇N₈(MꢄH^ꢄ) 203.07937, Found 203.07985. Anal. Calcd for

C₇H₆N₈–0.6H₂O: C, 39.47%, H, 3.41%, N, 52.61%, Found: C, 39.69%, H,

3.14%, N, 52.48%.

4-(4,5-Dibromo-3-phenethyl-1H-pyrrol-2-yl)-1H-imidazo[4,5-

c]pyridin-2-amine (28) ꢀMethod Eꢁ To a solution of 48r (120 mg,

0.18 mmol) in EtOH (5.0 ml) was added an aqueous NaOH solution (3.0 ml,

3.0 mmol, 1.0 mol/l). The reaction mixture was stirred at 80 °C for 8 h, and

then concentrated in vacuo. To the residue was added H₂O, and the whole

was extracted with EtOAc. The organic extracts was conbined, washed H₂O

and brine, dried over anhydrous Na₂SO₄, ﬁltered, and concentrated in vacuo.

The residue was puriﬁed by column chromatography (NH-SiO₂, EtOAc/

MeOHꢁ10/1) to give the deethoxycarbonyl derivative (89.0 mg, 83%) as a

MMP-12 Inhibition Assay The MMP-12 inhibition assay was per-

formed as per the manufacturer’s (BioMol) protocol. Human MMP-12 cat-

alytic domain (residues 84—255) obtained from Biomol (Plymouth Meet-

ing, PA, U.S.A.) was diluted in assay buffer (50 m^MTris pH 7.5, 0.05% Brij-

35, 10 m^MCaCl₂, 1 mM DTNB) to a concentration of 0.007 U/ml. The MMP-

12 solution (44 ml) was premixed with 1 ml of inhibitors dissolved in DMSO

in a 384-well plate, and the mixture was incubated for 20 min at room tem-

perature. Then, 5 ml of 1 mM MMP chromogenic substrate (thiopeptolide)

obtained from Biomol was added to the mixture and the reaction mixture

was incubated for 30—80 min at 37 °C. The reaction was terminated by

adding 7 ml of 0.2 M EDTA (pH 8.0). The intensity of the color developed by

the digested substrate was measured at 405 nm.

colorless amorphous solid. H-NMR (CD₃OD) d: ꢃ0.19 (9H, s), 0.57 (2H,

dd, Jꢁ8.9, 7.6 Hz), 2.58 (2H, br s), 2.78 (2H, br s), 3.09 (2H, t, Jꢁ8.3 Hz),

5.34 (2H, br s), 6.79 (2H, d, Jꢁ6.4 Hz), 6.95—7.03 (3H, m), 7.24 (1H, d,

Jꢁ5.5 Hz), 8.14 (1H, d, Jꢁ5.5 Hz). To a solution of the deethoxycarbonyl

derivative in CH₂Cl₂(3.0 ml) was added TFA (3.0 ml). The reaction mixture

was stirred overnight at room temperature, and then concentrated in vacuo.

The residue was dissolved in EtOAc, washed with queous 10% Na₂CO₃so-

lution, H₂O and brine, dried over anhydrous Na₂SO₄, ﬁltered, and then con-

centrated in vacuo. The residue was dissolved in MeOH, and the methanolic

solution was ﬁltered through a pad of NH-SiO₂(washed with MeOH), and

the ﬁltrate was concentrated in vacuo. The residue was dissolved in MeOH

(5.0 ml), and TFA (0.12 ml) was added to the MeOH solution. The acidic

methanolic solution was concentrated in vacuo. Trituration of the residue

with CH₂Cl₂gave 28-2TFA (81.0 mg, 95%) as a pale yellow amorphous

Acknowledgements We are grateful to Drs. T. Ishizaki and Y. Fukuda,

Kyorin Pharmaceutical Co. Ltd., for their many valuable suggestions and en-

couragement. We would also like to thank Dr. Y. Kohno, Kyorin Pharmaceu-

tical Co., Ltd., for his helpful suggestions and discussions. The MMP-12 in-

hibition assay was performed by Dr. Emme C. K. Lin, ActivX Biosciences,

to whom our thanks are also due.

solid. IR (ATR): 3084, 1654, 1576, 1544, 1429, 1189, 1134, 799, 723 cm^ꢃ1

¹H-NMR (CD₃OD) d: 2.70 (2H, t, Jꢁ6.1 Hz), 3.06 (2H, t, Jꢁ6.1 Hz),

6.65—6.67 (2H, m), 6.73 (1H, tt, Jꢁ7.3, 1.2 Hz), 6.80 (2H, tt, Jꢁ7.3, 1.2

Hz), 7.35 (1H, d, Jꢁ6.4 Hz), 7.97 (1H, d, Jꢁ6.4 Hz). LR-MS (ESI^ꢄ) m/z:

460 [MꢄH^ꢄ]. HR-MS (ESI^ꢄ) m/z: Calcd for C₁₈H₁₆Br₂N₅(MꢄH^ꢄ)

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DOI: 10.1248/cpb.59.579

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Article abstract of DOI:10.1248/cpb.59.579

Full text of DOI:10.1248/cpb.59.579

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