Modification of Pyrrolo[2,3-d]pyrimidines by C-H Borylation Followed by Cross-Coupling or Other Transformations: Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

FULL PAPER

DOI: 10.1002/ejoc.201501177

Modification of Pyrrolo[2,3-d]pyrimidines by C–H Borylation Followed by

Cross-Coupling or Other Transformations: Synthesis of 6,8-Disubstituted

7-Deazapurine Bases

[a,b]

[b]

[a,b]

ˇ

ˇ ˇ

Lenka Postová Slavetínská, and Michal Hocek*

Martin Klecka,

Keywords: Synthetic methods / Cross-coupling / C–H activation / Nitrogen heterocycles / Nucleobases / Deazapurines

A

general access to 4-substituted 6-arylpyrrolo[2,3-d]-

ylsulfanyl- or 4-methoxypyrrolo[2,3-d]pyrimidine. The one-

pot borylation/Suzuki coupling reactions were followed

either by demethylation and deprotection to yield deaza-

hypoxanthine bases, or by oxidation of sulfide to sulfone,

amination and deprotection to give deazaadenines. In

pyrimidine (6-substituted 8-aryl-7-deazapurine derivatives)

was developed based on iridium-catalyzed C–H borylations

of pyrrolo[2,3-d]pyrimidines at the 6-position followed by the

Suzuki cross-coupling reactions or other functional group

transformations of the boronates. Biologically relevant 6-aryl- addition, the boronate intermediates were converted into 6-

pyrrolo[2,3-d]pyrimidin-4-amines (8-aryl-7-deazaadenines)

and pyrrolo[2,3-d]pyrimidin-4-ones (–7-deazahypoxanth-

ines) were synthesized starting from SEM-protected 4-meth-

halo- or 6-(trifluoromethyl)pyrrolo[2,3-d]pyrimidine (8-halo-

or 8-trifluoromethyl-7-deazapurine) derivatives.

involve cross-coupling reactions and/or heterocyclizations.

Regioselective cross-coupling reactions were used in the

synthesis of 2,4-disubstituted pyrrolo[2,3-d]pyrimidines^[8]

and, in combination with C–H arylation, for the synthesis

of 2,4,6-triarylpyrrolo[2,3-d]pyrimidines.^[9]A combination

of palladium- and copper-assisted heterocyclization, fol-

lowed by halogenation at the 5-position and Suzuki cou-

pling was used for 4,5,6-trisubstituted derivatives.^[10]We

have recently reported^[11]a chemoselective synthesis of 4,5-

diarylpyrrolo[2,3-d]pyrimidines by using a combination of

the Liebeskind–Srogl and Suzuki coupling reactions. For

the synthesis of 4-substituted 6-arylpyrrolo[2,3-d]pyrimid-

ines (6-substituted 8-aryl-7-deazapurines), palladium-cata-

lyzed heterocyclizations of 5-alkynyl-6-aminopyrimidines^[12]

or heterocyclizations of arylpyrroles^[13]were mostly utilized.

The heterocyclization approaches^[12,13]are more laborious

for the synthesis of larger series of derivatives because sev-

eral steps are typically needed for the preparation of each

compound. On the other hand, regio- or chemoselective

cross-coupling reactions,^[7–11]either alone or in combina-

Introduction

Pyrrolo[2,3-d]pyrimidines (7-deazapurines)^[1]are impor-

tant carba-analogues of biogenic purine bases (to refer to

parent natural purines, we will also use the “purine” no-

menclature and numbering for comparison). Derivatives

bearing multiple substituents at the 2-, 4-, 5-, 6-, and/or 7-

positions of pyrrolo[2,3-d]pyrimidine (2-, 6-, 7-, 8-, and/or

9-positions of 7-deazapurine) have recently attracted signifi-

cant attention as synthetic targets, and many of them dis-

play promising biological effects. 6,7-Disubstituted 7-deaza-

purine ribonucleosides are potent cytostatics,^[2]whereas 7,8-

diaryl-7-deazaadenine derivatives are potent inhibitors of

ACK1 kinase^[3]and 7-alkyl-8-arylsulfanyl-7-deazapurines

are inhibitors of dihydrofolate reductase.^[4]6-Substituted 8-

aryl-7-deazapurine bases (Figure 1) also showed important

biological activities: TWS119 was identified as directing the

differentiation of neuronal cells in mice by GSK-3b inhibi-

tion,^[5]whereas PKI166 and related compounds display an-

titumor activity through inhibition of EGFR-tyrosine kin-

ase^[6]or Bruton’s tyrosine kinase.^[7]Known methods for the

synthesis of substituted pyrrolo[2,3-d]pyrimidines mostly

[a] Department of Organic Chemistry, Faculty of Science, Charles

University in Prague,

Hlavova 8, 12843 Prague-2, Czech Republic

[b] Institute of Organic Chemistry and Biochemistry, Academy of

Sciences of the Czech Republic, Gilead & IOCB Research

Center,

Flemingovo nám. 2, 16610 Prague-6, Czech Republic

E-mail: hocek@uochb.cas.cz

http://ww w .uochb.cas.cz/hocekgroup/

Supporting information and ORCID(s) from the author(s) for

this article are available on the WWW under http://dx.doi.org/

10.1002/ejoc.201501177.

Figure 1. Examples of biologically active 4,6-disubstituted pyr-

rolo[2,3-d]pyrimidines.

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FULL PAPER

tion with C–H activations, enable late-stage diversification products. 7-Benzyl-4-chloropyrrolo[2,3-d]pyrimidine 6 gave

of the substituents in these important heterocycles and thus the desired 6-borylated product 13 in moderate yield (53%),

deserve further development.

whereas the 7-unprotected 4-chloropyrrolo[2,3-d]pyrimidine

C–H activation reactions are currently one of the hottest 7 did not undergo the borylation. Apparently, the iridium-

fields in organic synthesis and they are becoming an indis- catalyzed C–H borylation only works on 7-substituted pyr-

pensable tool in the modification of heterocycles including rolo[2,3-d]pyrimidines bearing functional groups lacking

nucleobases.^[14]Recently, we combined C–H arylations with any acidic protons and/or coordinating nitrogen atoms. On

cross-couplings in the synthesis of substituted^[15]or fused^[16]the other hand, we have no plausible explanation for the

purines and developed C–H borylation,^[17]C–H sulfenyl- lack of reactivity of nucleoside 3.

ation,^[18]and C–H amination^[19]of 7-deazapurines. Iridium-

catalyzed C–H borylation can be combined with the Suzuki

reaction for the synthesis of 4,6-disubstituted pyrrolo[2,3-d]-

pyrimidines (6,8-disubstituted 7-deazapurines) as demon-

strated by several proof-of-principle examples in our pre-

vious preliminary communication.^[17]However, the applica-

tion of the borylation–coupling approach for the synthesis

of biologically relevant deazapurine derivatives, i.e., 7-de-

azaadenine or 7-deazahypoxanthine bases, and the possibil-

ity of applying other transformations of boronates to other

functional groups (aryl, CF₃, halogen) remained to be ad-

dressed. Herein, we report on these issues in this full-paper.

Scheme 1. Borylation of a series of model pyrrolo[2,3-d]pyrimidines

1–11.

To access the biologically relevant substituted 7-deazaad-

enine or 7-deazahypoxanthine bases, a protecting group

must be introduced at the 7-position of the pyrrolo[2,3-d]-

Results and Discussion

Iridium-catalyzed C–H borylation of arenes is an ef- pyrimidine moiety and a suitable functional group must be

ficient single-step method to generate aryl boronates.^[20]In placed at the 4-position. The protecting group must not

our previous work,^[17]we reported that the C–H borylation interfere with the borylation but must be sufficiently stable

of purines did not proceed, presumably because of the and easily removable at the end. Based on our previous ex-

strong coordination of iridium-catalysts to N7 nitrogen of perience with the difficult removal of the N-benzyl group

purine, which prevented the catalytic activity. On the other from pyrrolo[2,3-d]pyrimidines, we choose to use the (tri-

hand, the reaction was successful^[17]in some pyrrolo[2,3-d]- methylsilyl)ethoxymethyl (SEM) group, which is easily re-

pyrimidines (7-deazapurines, lacking this chelating nitro- moved by treatment with trifluoroacetic acid (TFA) fol-

gen). Previously reported^[17]and new results of a systematic lowed by ammonia. As possible transformable or leaving

study of borylation of a series of model pyrrolo[2,3-d]pyr- groups at the 4-position, we considered Cl, OCH₃, SCH₃,

imidines 1–11 are summarized in Scheme 1 and Table 1. and SO₂CH₃, which should be prone to either nucleophilic

Previously, we found^[17]that 4-phenyl-7-benzylpyrrolo[2,3- substitutions or demethylations. The SEM-protected 4-

d]pyrimidine 1 undergoes the iridium-catalyzed borylation chloropyrrolo[2,3-d]pyrimidine 8 was prepared according to

to give 6-borylated product 12 in good yield. However, now a reported procedure^[22]and was converted into 4-methoxy-

we found that neither 7-unsubstituted 4-phenylpyrrolo[2,3- and 4-methylsulfanyl derivatives 9 and 10 by nucleophilic

d]pyrimidine 2 nor nucleoside 3^[21]formed the desired substitution with MeONa or MeSNa, respectively

boronates. 7-Benzylpyrrolo[2,3-d]pyrimidin-4-amine (7-de- (Scheme 2). The sulfide 10 was oxidized to sulfone 11 by

azaadenine) 4 as well as its N-(dimethylamino)methylidene- mCPBA. The corresponding 7-SEM-4-substituted pyrrolo-

protected derivative 5 also did not give any C–H borylation [2,3-d]pyrimidine derivatives 8–11 were then tested in the

Table 1. Direct C–H borylations of pyrrolo[2,3-d]pyrimidines 1–11.

Entry

Starting compound

X

R

Product yield (%)

1

2

3

4

5

6

7

8

1

2

Ph

Me

NH₂

(CH₃)₂NCH=N–

Cl

Bn

H

12 (85)^[a]

no reaction

no reaction^[a]

13 (53)^[a]

no reaction

14 (78)

15 (81)

16 (83)

no reaction

3

2,3,5-tri-O-acetyl-β-d-ribofuranosyl

Bn

4

5

6

7

H

8

SEM

9

10

11

9

OMe

SMe

SO₂Me

10

11

[a] Results previously reported in ref.^[17]

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Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

iridium-catalyzed C–H borylation under the conditions de- tion sequence: C–H borylation/Suzuki cross-coupling with

scribed above (Table 1, entries 8–11). The 4-chloro-, 4- 4-iodoanisole. The borylation was performed as described

methoxy-, and 4-methylsulfanyl-pyrrolo[2,3-d]pyrimidines above and was directly followed by the Suzuki coupling un-

reacted well to give the corresponding boronates 14–16 in der the previously^[17]optimized conditions [Pd(dppf)Cl₂

good yields (78–83%), whereas sulfone 11 did not give any and K₂CO₃in N,N-dimethylformamide (DMF); Scheme 4].

reaction under these conditions.

Unfortunately, the borylation/Suzuki reaction of 4-chloro-

pyrrolo[2,3-d]pyrimidine 8 gave only low yield (20%) of the

desired 6-aryl derivative 18a because the Suzuki cross-cou-

pling step was accompanied by competitive deborylation

back to starting compound 8 (25%) and some other side-

reactions. Therefore, we focused on the one-pot borylation/

arylation of 4-methoxy and 4-methylsulfanyl derivatives 9

and 10. These reactions proceeded smoothly and efficiently

to give the desired SEM-protected 6-arylated pyrrolo[2,3-d]-

pyrimidines 19a (70%) and 20a (79%).

Scheme 2. Reagents and conditions: (i) 1 m MeONa in MeOH

(2 equiv.), acetone, room temp., 18 h; (ii) MeSNa (1.5 equiv.),

MeOH, room temp., 1 h; (iii) mCPBA (2 equiv.), CH₂Cl₂, room

temp., 18 h.

We also explored the possible conversion of boronate 12

into either free boronic acids or trifluoroborates^[23]

(Scheme 3). The reaction of 12 with KHF₂under standard

conditions^[24]gave the desired trifluoroborate 17 in accept-

able yield (68%). However, the oxidation followed by hy-

drolysis under reported conditions,^[24]which was expected

to give the boronic acid, gave only 6-unsubstituted pyr-

rolo[2,3-d]pyrimidine 1 as a product of protodeborylation.

This indicates that the corresponding pyrrolo[2,3-d]pyrim-

idine-6-boronic acid deazapurine-8-boronic acid is too un-

stable to be isolated under these reaction conditions.

Scheme 4. Reagents and conditions: (i) B₂pin₂(1.2 equiv.),

[Ir(COD)OMe]₂(5 mol-%), dtbpy (10 mol-%), THF, 80 °C, 20 h;

(ii) Ar-I (1.1 equiv.), Pd(dppf)Cl₂(5 mol-%; 10 mol-% in case of

20a), K₂CO₃(4 equiv.), DMF, 90 °C, 1 h.

Table 2. Synthesis of 6-arylpyrrolo[2,3-d]pyrimidin-4-ones (8-aryl-

7-deazahypoxanthines).

Scheme 3. Reagents and conditions: (i) KHF₂(6 equiv.), THF/H₂O

(5:3), room temp., 5 h; (ii) NaIO₄(4 equiv.), THF/H₂O (4:1), 1 m

HCl, room temp., 1 h.

Having confirmed the reactivity of the SEM-protected

pyrrolo[2,3-d]pyrimidines 8–10 in C–H borylations

(Table 1, entries 8–10), we tested a two-step, one-pot reac- [a] Overall yield for two steps from 19g. [b] Reaction time 18 h.

Scheme 5. Reagents and conditions: (i) B₂pin₂(1.2 equiv.), [Ir(COD)OMe]₂(5 mol-%), dtbpy (10 mol-%), THF, 80 °C, 20 h; (ii) Ar-X

(1.1 equiv.), Pd(dppf)Cl₂(5 mol-%), K₂CO₃(4 equiv.), DMF, 90 °C, 1 h (or 18 h); (iii) TFA (2 mL), room temp., 1 h, followed by aq.

ammonia (25% [w/w]), room temp., 18 h; (iv) TMSCl (5 equiv.), NaI (5 equiv.), MeCN, 80 °C, 18 h.

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FULL PAPER

Encouraged by these successful reactions, we envisaged silane^[27]generated in situ in acetonitrile to give 6-(hetero)-

the use of the one-pot borylation/arylation of 6-meth- arylpyrrolo[2,3-d]pyrimidin-4-ones [8-(hetero)aryl-7-deaza-

oxypyrrolo[2,3-d]pyrimidine 9 in combination with O-de- hypoxanthines] 22a–h in high yields.

methylation and SEM-deprotection for the synthesis of 6-

To synthesize the corresponding 6-arylpyrrolo[2,3-d]pyr-

aryl-pyrrolo[2,3-d]pyrimidin-4-ones (8-aryl-7-deazahypox- imidin-4-amines (8-aryl-7-deazaadenine bases), we started

anthine bases). We performed a series of one-pot bo- by an analogous one-pot, two-step borylation/arylation of

rylation/Suzuki coupling reactions of methoxypyrrolo[2,3- SEM-protected 4-(methylsulfanyl)pyrrolo[2,3-d]pyrimidine

d]pyrimidine 9 with several aryl iodides (Scheme 5, Table 2). 10. The presence of sulfur meant that 10 mol-% Pd catalyst

Generally, the reactions proceeded very well to give the de- was needed for the Suzuki coupling, but otherwise the reac-

sired SEM-protected 6-(het)aryl-4-methoxypyrrolo[2,3-d]- tion with B₂pin₂followed by cross-coupling with a series of

pyrimidines 19a–h in high yields (Scheme 5, Table 2). In aryl halides proceeded similarly, resulting in high yields of

several cases, the reaction time for the Suzuki reaction was the desired 6-(hetero)aryl products 20a–h (Scheme 6,

increased to 18 h to reach complete conversion. Deprotec- Table 3). In several cases, the reaction time for the Suzuki

tion^[25]of the SEM group treatment with TFA followed by reaction was again increased to 18 h to reach complete con-

aqueous ammonia furnished free 6-(hetero)aryl-4-meth- version. The second step was the oxidation^[28]of methyl-

oxypyrrolo[2,3-d]pyrimidines 21a–f in good yields (65– sulfanyl derivatives 20a–h to methylsulfones 23a–g (which

90%) (Scheme 5, Table 2). In deprotection of aminophenyl- are more reactive electrophiles for nucleophilic substitu-

derivative 19h, the isolated yield of pyrrolo[2,3-d]pyrimidine tion). The reactions proceeded well with the exception of

base 21h was low (22%) due to difficult separation of the derivative 20h (entry 8), which gave an inseparable complex

highly polar derivative by column chromatography. In the mixture. The original procedure (NH₃/MeOH) for amin-

case of compound 19g, deprotection of the SEM group was ation of sulfones^[28]was modified to NH₃/dioxane (to avoid

directly followed by acid hydrolysis^[26]to the free 6-(uracil- formation of methyl ethers observed in methanol), which

5-yl)pyrrolo[2,3-d]pyrimidin-4-one 22i. The final cleavage of gave the desired SEM-protected 6-arylpyrrolo[2,3-d]pyrim-

methyl ethers 21a–h was performed with iodotrimethyl- idin-4-amines 24a–f in good yields. Deprotection of the

Scheme 6. Reagents and conditions: (i) B₂pin₂(1.2 equiv.), [Ir(COD)OMe]₂(5 mol-%), dtbpy (10 mol-%), THF, 80 °C, 20 h; (ii) Ar-X

(1.1 equiv.), Pd(dppf)Cl₂(10 mol-%), K₂CO₃(4 equiv.), DMF, 90 °C, 1 h (or 18 h); (iii) mCPBA (2 equiv.), CH₂Cl₂, room temp., 1 h;

(iv) aq. ammonia (25% w/w), dioxane, 50 °C, 18 h; (v) TFA (2 mL), room temp., 1 h, followed by aq. ammonia (25% w/w), room temp.,

18 h.

Table 3. Synthesis of 6-arylpyrrolo[2,3-d]pyrimidin-4-amines (8-aryl-7-deazaadenines).

[a] Overall yield after acidic deprotection to 25i. [b] 18 h.

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Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

SEM group using TFA followed by aqueous ammonia fur-

nished free 6-substituted pyrrolo[2,3-d]pyrimidin-4-amines

(8-substituted 7-deazaadenines) 21a–f in 65–80% yield. In

the case of compound 24g, deprotection of the SEM group

was directly followed by acid hydrolysis to give the free 6-

(uracil-5-yl)-pyrrolo[2,3-d]pyrimidin-4-amine [8-(uracil-5-

yl)-7-deazaadenine] (25i).

Given that the above reaction sequence did not work for

the preparation 6-(3-aminophenyl)pyrrolo[2,3-d]pyrimidin-

4-amine (25h), we used an alternative synthetic protocol.

The corresponding pyrrolo[2,3-d]pyrimidin-4-one derivative

22h was first chlorinated with POCl₃followed by amination

(NH₃in dioxane) to give the desired pyrrolo[2,3-d]pyrim-

idin-4-amine (deazaadenine) 25h in 40% overall yield

(Scheme 7).

Scheme 8. Reagents and conditions: (A) CuCl₂(3 equiv.), acetone/

H₂O (1:1), 80 °C, 3 h; (B) CuBr₂(3 equiv.), acetone/H₂O (1:1),

80 °C, 3 h; (C) Togni reagent (1.1 equiv.), CuTC (10 mol-%), 1,10-

phenanthroline (20 mol-%), LiOH·H₂O (2 equiv.), CH₂Cl₂, 45 °C,

18 h; (D) Cu(NO₃)₂(2 equiv.), Zn(CN)₂(3 equiv.), CsF (1 equiv.),

acetone/H₂O (2.5:1), 100 °C, 2.5 h.

Scheme 7. Reagents and conditions: (i) POCl₃(5 equiv.),

BnEt₃N⁺Cl (2 equiv.), PhNMe₂(1.1 equiv.), MeCN, reflux, 4 h;

(ii) aq. ammonia (25% w/w), dioxane, 120 °C, 18 h.

Having developed easy access to 6-borylated pyrrolo[2,3-

d]pyrimidines, we also explored the possibility of their con- trifluoromethyl derivative 26l by treatment with the Togni

version into other functional groups. We tested the reac- reagent [(3,3-dimethyl-1-trifluoromethyl)-1,2-benziodoxole],

tions of the 6-borylated 7-benzyl-pyrrolo[2,3-d]pyrimidine CuTC [copper(I)-thiophene-2-carboxylate], and 1,10-phen-

12 generated in situ from 1 and directly functionalized by anthroline,^[31]but the yield was only 34% because of com-

copper-catalyzed substitutions (Scheme 8). Halogenation^[29]petitive protodeborylation. Treatment of 12 with Zn-

of boronate 12 with cupric chloride formed 6-chloropyr- (CN)₂in the presence of Cu(NO₃)₂and CsF^[32]gave 6-

rolo[2,3-d]pyrimidine 26j (46%), whereas analogous bromi- cyano derivative 26m in 58% yield.

nation with cupric bromide gave 6-bromo-derivative 26k

This one-pot, two-step reaction sequence of C–H bor-

(63%). This two-step halogenation at the 6-position is com- ylation/Cu-catalyzed substitution was then applied on

plementary to electrophilic halogenation, which proceeds at SEM-protected 4-chloro- and 4-methoxypyrrolo[2,3-d]pyr-

the 5-position.^[30]Boronate 12 was also converted into 6- imidine 8 and 9. The halogenations and trifluoromethyl-

Scheme 9. Reagents and conditions: (i) B₂pin₂(1.2 equiv.), [Ir(COD)OMe]₂(5 mol-%), dtbpy (10 mol-%), THF, 80 °C, 20 h; (ii) A. CuCl₂

(3 equiv.), acetone/H₂O (1:1), 80 °C, 3 h; B. CuBr₂(3 equiv.), acetone/H₂O (1:1), 80 °C, 3 h; C. Togni reagent (1.1 equiv.), CuTC (10 mol-

%), 1,10-phenanthroline (20 mol-%), LiOH·H₂O (2 equiv.), CH₂Cl₂, 45 °C, 18 h; D. Cu(NO₃)₂(2 equiv.), Zn(CN)₂(3 equiv.), CsF

(1 equiv.), acetone/H₂O (2,5:1), 100 °C, 2 h; (iii) TFA (2 mL), room temp., 1 h, followed by aq. ammonia (25% w/w, room temp., 18 h).

Table 4. One-pot C–H borylation/Cu-catalyzed substitution of SEM-protected pyrrolo[2,3-d]pyrimidines followed by deprotection.

Entry

Starting compd.

Procedure

X

Y

Product yield (%)

1

2

3

4

5

6

7

8

9

A

B

C

D

A

B

Cl

OMe

Cl

Br

CF₃

CN

Cl

Br

CF₃

CN

27j (55)

27k (56)

27l (38)

no reaction

19j (47)

19k (34)

19l (32)

no reaction

28j (66)

28k (75)

28l (73)

–

21j (55)

21k (50)

21l (75)

–

C

D

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FULL PAPER

ations proceeded with modest conversions (probably due to followed by oxidation and amination of sulfone 23l under

partial protodeborylation) to give the desired 6-substituted mild conditions to give SEM-protected pyrrolo[2,3-d]pyr-

products 19j–l and 27j–l in 32–56% yield (Scheme 9, imidin-4-amine 24l in good yield. Final standard deprotec-

Table 4). On the other hand, the cyanation did not proceed tion gave the desired compound 25l in 90% yield.

at all, and only the recovered starting material was ob-

served. Cleavage of SEM groups using TFA followed by

Conclusions

aqueous ammonia furnished the corresponding free 6-sub-

stituted pyrrolo[2,3-d]pyrimidines (8-substituted 7-deaza-

purine bases) 21j–l and 28j–l (Scheme 9, Table 4).

We have developed a general approach for the synthesis

of biologically relevant 4,6-disubstituted pyrrolo[2,3-d]pyr-

imidines (6,8-disubstituted 7-deazapurines). The approach

was based on one-pot, two-step iridium-catalyzed C–H bo-

rylation of 7-substituted or SEM-protected 4-chloro-, 4-

methoxy-, or 4-methylsulfanylpyrrolo[2,3-d]pyrimidines fol-

lowed by palladium-catalyzed Suzuki coupling with aryl

halides. Manipulation of substituents at the 4-position, i.e.,

demethylation of 4-methoxypyrrolo[2,3-d]pyrimidine or

oxidation of 4-(methylsulfanyl)pyrrolo[2,3-d]pyrimidine de-

rivatives to sulfones followed by amination, gave the desired

6-arylpyrrolo[2,3-d]pyrimidin-4-ones (8-aryl-7-deazahypox-

anthines) or pyrrolo[2,3-d]pyrimidin-4-amines (8-aryl-7-de-

azaadenines), respectively, after cleavage of the SEM pro-

tection group. The 6-pinacolboronate intermediates were

also converted into 6-chloro-, 6-bromo, and 6-trifluoro-

methylpyrrolo[2,3-d]pyrimidines (8-chloro-, 8-bromo, and

8-trifluoromethyl-7-deazapurines) by copper-catalyzed dis-

placements. The approach gives easy access to an underex-

plored group of biologically relevant modified pyrrolo[2,3-

d]pyrimidine (7-deazapurine) bases, which could be further

N-alkylated or glycosylated to give a variety of nucleoside

and nucleotide analogues. Application of this methodology

to the synthesis of these derivatives and nucleosides and

biological profiling of the products is underway.

The last goal was the preparation of 6-trifluoromethyl-

pyrrolo[2,3-d]pyrimidin-4-one (8-trifluoromethyl-7-deaza-

hypoxanthine) (22l) and 6-trifluoromethyl-pyrrolo[2,3-d]-

pyrimidin-4-amine

(8-trifluoromethyl-7-deazaadenine)

(25l). The former was easily prepared by cleavage of methyl

ether 21l with iodotrimethylsilane generated in situ (from

TMSCl and NaI) in acetonitrile. The desired compound 22l

was isolated in low yield (30%; Scheme 10).

Scheme 10. Reagents and conditions: (i) TMSCl (5 equiv.), NaI

(5 equiv.), MeCN, 80 °C, 18 h.

More difficult was the preparation of the corresponding

6-trifluoromethyl-pyrrolo[2,3-d]pyrimidin-4-amine

25l

(Scheme 11). An obvious way was through amination of 4-

chloro derivative 28l. However, the reaction did not proceed

under mild conditions, whereas at 120 °C the formation of

unexpected amide 25m was observed due to hydrolysis/am-

monolysis of the CF₃group. Therefore, we used a longer

sequence starting by borylation/trifluoromethylation of 10,

Experimental Section

General: 4-Chloro-7H-pyrrolo[2,3-d]pyrimidine (7) was purchased

from a commercial supplier and used without any further purifica-

tion. 4-Chloro-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-

d]pyrimidine^[22](8) and 4-methyl-7-(2,3,5-tri-O-acetyl-β-d-ribofur-

anosyl)-7H-pyrrolo[2,3-d]pyrimidine^[21](3) were prepared accord-

ing to reported procedures. Anhydrous DMF and THF were used

as received. All compounds were fully characterized by NMR and

spectra were recorded with a 600 MHz (¹H at 600.1 MHz, ¹³C at

150.9 MHz),

a

500 MHz (499.8 or 500.0 MHz for ¹H and

125.7 MHz for ¹³C), or a 400 MHz (¹H at 400 MHz, ¹³C at

100.6 MHz) spectrometer. ¹H and ¹³C resonances were assigned

based on H,C-HSQC and H,C-HMBC spectra. The samples were

measured in CDCl₃or [D₆]DMSO and chemical shifts (in ppm, δ-

scale) are referenced to solvent signal [δ(¹H) = 7.26 ppm, δ(¹H) =

77.0 ppm] or in DMSO [δ(¹H) = 2.50 ppm, δ(¹H) = 39.43 ppm]

Coupling constants (J) are given in Hz. High-performance flash

chromatography (HPFC) was performed on KP-Sil columns. IR

spectra (wavenumbers in cm^–1) were recorded by using the ATR

technique. High-resolution mass spectra were measured by using

the EI ionization technique.

Scheme 11. Reagents and conditions: (i) aq. ammonia (25% w/w),

dioxane, 120 °C, 18 h; (ii) B₂pin₂(1.2 equiv.), [Ir(COD)OMe]₂

(5 mol-%), dtbpy (10 mol-%), THF, 80 °C, 20 h; (iii) Togni reagent

(1.1 equiv.), CuTc (10 mol-%), 1,10-phenanthroline (20 mol-%),

LiOH·H₂O (2 equiv.), CH₂Cl₂, 45 °C, 18 h; (iv) mCPBA (2 equiv.),

CH₂Cl₂, room temp., 1 h; (v) aq. ammonia (25% w/w), dioxane,

50 °C, 18 h; (vi) TFA (2 mL), room temp., 1 h, followed by aq. am-

monia (25% w/w), room temp., 18 h.

4-Methoxy-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-d]-

pyrimidine (9): Protected pyrrolo[2,3-d]pyrimidine 8 (25.54 g,

90 mmol, 1 equiv.) was dissolved in acetone (50 mL), and 1 m solu-

tion of MeONa in MeOH (180 mL, 180 mmol, 2 equiv.) was added

7948

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Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

and the reaction mixture was stirred at room temp. overnight. Sol-

vents were evaporated under reduced pressure and the mixture was

then diluted with water (150 mL) and EtOAc (150 mL). The layers

were separated and the aqueous layer was extracted with EtOAc

(2ϫ150 mL). The combined organic layers were dried with sodium

sulfate (Na₂SO₄), filtered, and concentrated under reduced pressure

to give 9 (24.94 g, 99%) as a yellow oil. ¹H NMR (499.8 MHz, [D₆]-

DMSO): δ = –0.11 (s, 9 H, CH₃Si), 0.79–0.83 (m, 2 H,

SiCH₂CH₂O), 3.48–3.51 (m, 2 H, OCH₂CH₂Si), 4.05 (s, 3 H,

CH₃O), 5.58 (s, 2 H, NCH₂O), 6.57 (d, J_5,6= 3.6 Hz, 1 H, H-5),

7.54 (dd, J_6,5= 3.6, J_6,2= 0.2 Hz, 1 H, H-6), 8.45 (d, J_2,6= 0.2 Hz,

1 H, H-2) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = –1.2

(CH₃Si), 17.3 (SiCH₂CH₂O), 53.7 (CH₃O), 65.7 (OCH₂CH₂Si),

72.8 (NCH₂O), 98.6 (CH-5), 104.8 (C-4a), 127.7 (CH-6), 151.0

851, 842, 755, 656, 525 cm^–1. HRMS (ESI): m/z calcd. for

C₁₃H₂₂O₃N₃SSi 328.1146; found 328.1147.

Borylation of Deazapurines; General Procedure: A pyrrolo[2,3-d]-

pyrimidine 8–11 (1 mmol, 1 equiv.), bispinacolatodiboron (0.305 g,

1.2 mmol, 1.2 equiv.), [Ir(COD)OMe]₂(33 mg, 0.05 mmol, 5 mol-

%), and 4,4Ј-di-tert-butyl-2,2Ј-bipyridine (27 mg, 0.1 mmol,

10 mol-%) were dissolved in anhydrous THF (5 mL) under Ar. The

solution was heated at 80 °C in a septum-sealed flask for 20 h. The

solvent was evaporated and the residue was purified by flash

chromatography in pure dichloromethane. Finally, the crude prod-

uct was rinsed with hexanes and heated at 60 °C under vacuum (6

mTorr) to remove residual pinacol.

4-Chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-[2-(tri-

methylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (14): Start-

ing from 8 (284 mg, 1 mmol), product 14 (322 mg, 78%) was ob-

tained as brownish solid, m.p. 99 °C. ¹H NMR (500 MHz, CDCl₃):

δ = –0.08 (s, 9 H, CH₃Si), 0.85–0.89 (m, 2 H, OCH₂CH₂Si), 1.38

[s, 12 H, (CH₃)₂C], 3.50–3.53 (m, 2 H, OCH₂CH₂Si), 5.89 (s, 2 H,

NCH₂O), 7.23 (s, 1 H, H-5), 8.68 (s, 1 H, H-2) ppm. ¹³C NMR

(125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 17.8 (OCH₂CH₂Si), 24.8

[(CH₃)₂C], 66.3 (OCH₂CH₂Si), 72.6 (NCH₂O), 84.7 [(CH₃)₂C],

112.6 (CH-5), 117.5 (C-4a), 133.0 (C-6), 152.2 (CH-2), 153.3 (C-4),

(CH-2), 152.2 (C-7a), 162.5 (C-4) ppm. IR (KBr): ν = 2950, 2923,

˜

2896, 1592, 1559, 1512, 1476, 1416, 1314, 1236, 1096, 1078, 1060,

863, 842, 764, 731, 647 cm^–1. HRMS (ESI): m/z calcd. for

C₁₃H₂₁O₂N₃NaSi 302.1295; found 302.1295.

4-(Methylsulfanyl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

[2,3-d]pyrimidine (10): Protected pyrrolo[2,3-d]pyrimidine 8 (27 g,

95 mmol, 1 equiv.) was dissolved in methanol (150 mL) and

MeSNa (10 g, 142.5 mmol, 1.5 equiv.) was added. The reaction

mixture was stirred at room temp. for 1 h, then the solvents were

evaporated under reduced pressure and the mixture was diluted

with water (150 mL) and EtOAc (150 mL). The layers were sepa-

rated and the aqueous layer was extracted with EtOAc

(2ϫ150 mL). The combined organic layers were dried with sodium

sulfate (Na₂SO₄), solvents were evaporated, and the residue was

purified by flash chromatography (CH₂Cl₂/EtOAc, 20:1) to give 10

154.0 (C-7a) ppm. IR (KBr): ν = 2989, 2956, 2914, 2893, 1580,

˜

1538, 1428, 1365, 1326, 1254, 1180, 1141, 1087, 866, 827, 746 cm^–1.

HRMS (ESI): m/z calcd. for C₁₈H₃₀O₃N₃BClSi 410.1833; found

410.1831.

4-Methoxy-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-[2-(tri-

methylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (15): Start-

ing from 9 (279 mg, 1 mmol), product 15 (328 mg, 81%) was ob-

1

(25 g, 89%) as a yellowish solid, m.p. 55 °C. H NMR (500 MHz,

tained as a brownish oil. H NMR (500 MHz, CDCl₃): δ = –0.09

CDCl₃): δ = –0.07 (s, 9 H, CH₃Si), 0.88–0.91 (m, 2 H,

OCH₂CH₂Si), 2.71 (s, 3 H, CH₃S), 3.49–3.52 (m, 2 H,

OCH₂CH₂Si), 5.61 (s, 2 H, NCH₂O), 6.56 (d, J_5,6= 3.7 Hz, 1 H,

(s, 9 H, CH₃Si), 0.85–0.88 (m, 2 H, OCH₂CH₂Si), 1.36 [s, 12 H,

(CH₃)₂C], 3.50–3.54 (m, 2 H, OCH₂CH₂Si), 4.11 (s, 3 H, CH₃O),

5.86 (s, 2 H, NCH₂O), 7.17 (s, 1 H, H-5), 8.52 (s, 1 H, H-2) ppm.

^{1 3}C NMR (125.7 MHz, CDCl₃): δ = –1.4 (CH₃Si), 17.8

(OCH₂CH₂Si), 24.8 [(CH₃)₂C], 53.7 (CH₃O), 65.9 (OCH₂CH₂Si),

72.4 (NCH₂O), 84.1 [(CH₃)₂C], 105.7 (C-4a), 112.3 (CH-5), 129.3

H-5), 7.23 (d, J_6,5= 3.7 Hz, 1 H, H-6), 8.69 (s, 1 H, H-2) ppm. ¹³

C

NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 11.8 (CH₃S), 17.7

(OCH₂CH₂Si), 66.4 (OCH₂CH₂Si), 72.8 (NCH₂O), 100.0 (CH-5),

116.1 (C-4a), 129.7 (CH-6), 148.8 (C-7a), 151.2 (CH-2), 161.7 (C-

(C-6), 152.6 (CH-2), 155.1 (C-7a), 163.7 (C-7a) ppm. IR (KBr): ν

˜

4) ppm. IR (KBr): ν = 3105, 3087, 3052, 2956, 2935, 2899, 2875,

˜

= 2977, 2950, 2893, 1682, 1595, 1553, 1524, 1479, 1425, 1374, 1331,

1320, 1260, 1222, 1147, 1090, 970, 860, 836, 797, 761 cm^–1. HRMS

(ESI): m/z calcd. for C₁₉H₃₃O₄N₃BSi 406.2328; found 406.2331.

1550, 1506, 1464, 1446, 1413, 1344, 1251, 1213, 1162, 1096, 1084,

394, 922, 860, 842, 758, 743 cm^–1. HRMS (ESI): m/z calcd. for

C₁₃H₂₂ON₃SSi 296.1247; found 296.1248.

4-(Methylsulfanyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (16):

Starting from 10 (295 mg, 1 mmol), product 16 (350 mg, 83%) was

obtained as a brownish oil. ¹H NMR (500 MHz, CDCl₃): δ = –0.08

(s, 9 H, CH₃Si), 0.85–0.88 (m, 2 H, OCH₂CH₂Si), 1.37 [s, 12 H,

(CH₃)₂C], 2.69 (s, 3 H, CH₃S), 3.50–3.53 (m, 2 H, OCH₂CH₂Si),

5.86 (s, 2 H, NCH₂O), 7.17 (s, 1 H, H-5), 8.70 (s, 1 H, H-2) ppm.

¹³C NMR (125.7 MHz, CDCl₃): δ = –1.4 (CH₃Si), 11.8 (CH₃S),

17.8 (OCH₂CH₂Si), 24.8 [(CH₃)₂C], 66.0 (OCH₂CH₂Si), 72.3

(NCH₂O), 84.3 [(CH₃)₂C], 112.4 (CH-5), 116.0 (C-4a), 130.1 (C-6),

4-(Methylsulfonyl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

[2,3-d]pyrimidine (11): 4-Methylsulfanyl-7H-pyrrolo[2,3-d]pyrimid-

ine 10 (1.48 g, 5 mmol, 1 equiv.) was dissolved in CH₂Cl₂(20 mL),

and m-CPBA (1.72 g, 10 mmol, 2 equiv.) was slowly added (cooling

by water/ice during addition) and the reaction mixture was stirred

at room temp. overnight. Then, 1m NaOH (10 mL) was added to

the mixture to remove residual m-CPBA. The layers were separated

and the aqueous layer was extracted with CH₂Cl₂(2ϫ15 mL). The

combined organic layers were dried with sodium sulfate, solvents

were evaporated, and the residue was purified by flash chromatog-

raphy (HPFC; CHCl₃/MeOH, 20:1) to give 11 (1.28 g, 78%) as a

white solid, m.p. 91 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.05 (s,

9 H, CH₃Si), 0.90–0.93 (m, 2 H, OCH₂CH₂Si), 3.36 (s, 3 H,

CH₃SO₂), 3.51–3.54 (m, 2 H, OCH₂CH₂Si), 5.71 (s, 2 H, NCH₂O),

7.16 (d, J_5,6= 3.7 Hz, 1 H, H-5), 7.59 (d, J_6,5= 3.7 Hz, 1 H, H-6),

8.98 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.5

151.4 (C-7a), 152.2 (CH-2), 163.2 (C-4) ppm. IR (KBr): ν = 2974,

˜

2950, 2929, 2893, 1553, 1527, 1458, 1425, 1371, 1314, 1263, 1222,

1180, 1141, 1084, 857, 839 cm^–1. HRMS (ESI): m/z calcd. for

C₁₉H₃₃O₃N₃BSSi 422.2099; found 422.2099.

7-Benzyl-4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-yltrifluoroborate

(Potassium Salt) (17): To a flask containing 12 (412 mg, 1 mmol,

1 equiv.) and KHF₂(469 mg, 6 mmol), THF (5 mL) and H₂O

(CH₃Si), 17.7 (OCH₂CH₂Si), 39.9 (CH₃SO₂), 67.0 (OCH₂CH₂Si), (3 mL) were added. The reaction mixture was stirred for 5 h at

73.2 (NCH₂O), 101.3 (CH-5), 114.2 (C-4a), 132.1 (CH-6), 150.6 room temperature. The solvents were evaporated and the residue

(CH-2), 154.0 (C-7a), 155.7 (C-4) ppm. IR (KBr): ν = 3111, 3078,

3010, 2953, 2917, 1577, 1550, 1518, 1455, 1443, 1425, 1341, 1323,

1308, 1266, 1248, 1236, 1213, 1123, 1096, 1081, 976, 970, 911, 863,

was purified by flash chromatography (HPFC; EtOAc/MeOH, 9:1)

to give product 17 (266 mg, 68%) as a white solid, m.p. Ͼ 300 °C.

¹H NMR (500 MHz, CD₃OD): δ = 5.67 (s, 2 H, CH₂), 6.86 (H-5),

˜

Eur. J. Org. Chem. 2015, 7943–7961

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7949

M. Klecˇka, L. Posˇtová Slaveˇtínská, M. Hocek

(C-4) ppm. IR (KBr): ν = 2995, 2950, 2893, 2833, 1613, 1595, 1565,

FULL PAPER

7.14–7.15 (m, 1 H, H-p-Bn), 7.18–7.25 (m, 4 H, H-o,m-Bn), 7.52–

˜

7.53 (m, 1 H, H-p-Ph), 7.56–7.58 (m, 2 H, H-m-Ph), 8.06–8.07 (m, 1500, 1476, 1419, 1353, 1320, 1284, 1251, 1213, 1183, 1072, 857,

2 H, H-o-Ph), 8.63 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, 839, 785, 764 cm^–1. HRMS (ESI): m/z calcd. for C₂₀H₂₇O₃N₃NaSi

CD₃OD): δ = 48.7 (CH₂Ph), 104.2 (CH-5), 118.1 (C-4a), 127.7 408.1714; found 408.1714.

(CH-p-Bn), 128.2 (CH-o-Bn), 129.0 (CH-m-Bn), 129.8 (CH-m-Ph),

130.0 (CH-o-Ph), 131.0 (CH-p-Ph), 138.9 (C-i-Ph), 140.3 (C-i-Bn),

149.5 (CH-2), 154.3 (C-7a), 155.8 (C-4) ppm, C-6 was not detected.

¹⁹F NMR (470.3 MHz, CD₃OD): δ = –137.91 ppm. ¹¹B NMR

4-Methoxy-6-(pyridin-2-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (19b): Starting from 9 (1.12 g, 4 mmol)

and 2-iodopyridine (0.47 mL, 4.4 mmol), the reaction was per-

formed according to the General Procedure for 18 h. Purification

was performed by HPFC (EtOAc/hexane, 0–20 %) to give 19b

(160.4 MHz, CD OD): δ = 1.96 ppm. IR (KBr): ν = 3428, 3254,

˜

3

1

3062, 3031, 2949, 1617, 1584, 1562, 1550, 1497, 1474, 1455, 1432,

1148, 1028, 1007, 937, 761, 697 cm^–1. HRMS (ESI): m/z calcd. for

C₁₉H₁₅N₃BF₃Na 376.1203; found 376.1205.

(713 g, 50%) as a yellowish oil. H NMR (600.1 MHz, CDCl₃): δ

= –0.17 (s, 9 H, CH₃Si), 0.79–0.82 (m, 2 H, SiCH₂CH₂O), 3.47–

3.50 (m, 2 H, OCH₂CH₂Si), 4.15 (s, 3 H, CH₃O), 6.20 (s, 2 H,

NCH₂O), 6.95 (s, 1 H, H-5), 7.27 (ddd, J_5,4= 7.2, J_5,6= 4.8, J_5,3

One-Pot C–H Borylation/Suzuki Coupling Sequence; General Pro-

cedure: Pyrrolo[2,3-d]pyrimidine 8–10 (4 mmol, 1 equiv.), bispi-

nacolatodiboron (1.22 g, 4.8 mmol, 1.2 equiv.), [Ir(COD)OMe]₂

(132 mg, 0.2 mmol, 5 mol-%) and 4,4Ј-di-tert-butyl-2,2Ј-bipyridine

(108 mg, 0.4 mmol, 10 mol-%) were dissolved in anhydrous THF

(30 mL) under Ar. The solution was heated at 80 °C in a septum-

sealed vial and stirred under argon for 20 h. The solvent was re-

moved under reduced pressure. The residue was then combined

with aryl halide (4.4 mmol, 1.1 equiv.), Pd(dppf)Cl₂(146 mg,

0.2 mmol, 5 mol-%) and K₂CO₃(2.2 g, 16 mmol, 4 equiv.) in DMF

(30 mL) and stirred under Ar at 90 °C until complete consumption

of staring material (1–18 h) was observed, as monitored by NMR

spectroscopy. The solution was then cooled to room temperature,

and EtOAc (50 mL) and water (50 mL) were added. The aqueous

solution was then extracted with EtOAc (ϫ3) and the combined

organic layers were dried with Na₂SO₄, filtered, and the solvents

were evaporated under vacuum. The crude product was purified by

flash chromatography (hexane/EtOAc).

= 1.4 Hz, 1 H, H-5-py), 7.77 (ddd, J_4,3= 8.0, J_4,5= 7.2, J_4,6

=

1.8 Hz, 1 H, H-4-py), 7.80 (ddd, J_3,4= 8.0, J_3,5= 1.4, J_3,6= 1.0 Hz,

1 H, H-3-py), 8.45 (d, J_2,6= 0.2 Hz, 1 H, H-2), 8.69 (ddd, J_6,5= 4.8,

J_6,4= 1.8, J_6,3= 1.0 Hz, 1 H, H-6-py) ppm. ¹³C NMR (150.9 MHz,

CDCl₃): δ = –1.6 (CH₃Si), 17.7 (SiCH₂CH₂O), 53.8 (CH₃O), 66.1

(OCH₂CH₂Si), 71.4 (NCH₂O), 101.1 (CH-5), 105.4 (C-4a), 122.5

(CH-5-py), 123.0 (CH-3-py), 136.8 (CH-4-py), 147.8 (C-6), 149.4

(CH-6-py), 151.3 (C-2-py), 151.8 (CH-2), 154.7 (C-7a), 163.2 (C-

4) ppm. HRMS (ESI): m/z calcd. for C₁₈H₂₄O₂N₄NaSi 379.1560;

found 379.1561.

4-Methoxy-6-(thiophen-2-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (19c): Starting from 9 (1.12 g, 4 mmol)

and 2-iodothiophene (0.49 mL, 4.4 mmol), the reaction was per-

formed according to the General Procedure for 1 h. Purification

was performed by HPFC (EtOAc/hexane, 0–20 %) to give 19c

1

(939 mg, 65%) as a yellowish oil. H NMR (500 MHz, CDCl₃): δ

= –0.05 (s, 9 H, CH₃Si), 0.95–0.98 (m, 2 H, OCH₂CH₂Si), 3.67–

3.70 (m, 2 H, OCH₂CH₂Si), 4.14 (s, 3 H, CH₃O), 5.71 (s, 2 H,

NCH₂O), 6.72 (s, 1 H, H-5), 7.13 (dd, J_4,5= 5.1, J_4,3= 3.6 Hz, 1

H, H-4-thienyl), 7.39 (dd, J_5,4= 5.1, J_5,3= 1.2 Hz, 1 H, H-5-thi-

enyl), 7.59 (dd, J_3,4= 3.6, J_3,5= 1.2 Hz, 1 H, H-3-thienyl), 8.49 (s,

1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si),

17.9 (OCH₂CH₂Si), 53.7 (CH₃O), 66.4 (OCH₂CH₂Si), 70.7

(NCH₂O), 99.1 (CH-5), 105.4 (C-4a), 126.6 (CH-5-thienyl), 127.6

(CH-3-thienyl), 128.1 (CH-4-thienyl), 132.8 and 132.9 (C-6,C-2-thi-

4-Chloro-6-(4-methoxyphenyl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (18a): Starting from 8 (1.14 g, 4 mmol)

and 4-iodoanisole (1.03 g, 4.4 mmol), the reaction was performed

according to the General Procedure for 1 h. Purification was per-

formed by HPFC (EtOAc/hexane, 0–20 %) to give 18a (312 mg,

20%) as a yellowish oil. ¹H NMR (500 MHz, CDCl₃): δ = –0.03

(s, 9 H, CH₃Si), 0.96–0.99 (m, 2 H, OCH₂CH₂Si), 3.72–3.76 (m, 2

H, OCH₂CH₂Si), 3.88 (s, 3 H, CH₃O), 5.61 (s, 2 H, NCH₂O), 6.63

(s, 1 H, H-5), 7.02–7.04 (m, 2 H, H-m-Ph), 7.71–7.73 (m, 2 H, H-

o-Ph), 8.65 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ

= –1.4 (CH₃Si), 18.0 (OCH₂CH₂Si), 55.4 (CH₃O), 67.0

(OCH₂CH₂Si), 71.0 (NCH₂O), 98.6 (CH-5), 114.3 (CH-m-Ph),

117.7 (C-4a), 122.8 (C-i-Ph), 130.9 (CH-o-Ph), 143.7 (C-6), 150.5

(CH-2), 151.0 (C-4), 153.4 (C-7a), 160.5 (C-p-Ph) ppm. IR (KBr):

enyl), 151.2 (CH-2), 154.0 (C-7a), 162.7 (C-4) ppm. IR (KBr): ν =

˜

2956, 2896, 2866, 1595, 1553, 1473, 1458, 1413, 1356, 1344, 1320,

1248, 1207, 1081, 857, 833, 782, 764, 698 cm^–1. HRMS (ESI): m/z

calcd. for C₁₇H₂₄N₃O₂SiS 362.1359; found 362.1370.

6-(Furan-2-yl)-4-methoxy-7-[2-(trimethylsilyl)ethoxymethyl]-7H-

pyrrolo[2,3-d]pyrimidine (19d): Starting from 9 (1.12 g, 4 mmol) and

2-bromofuran (0.39 mL, 4.4 mmol), the reaction was performed ac-

cording to the General Procedure for 18 h. Purification was per-

formed by HPFC (EtOAc/hexane, 0–20 %) to give product 19d

ν = 2956, 2899, 2833, 1607, 1538, 1500, 1347, 1248, 1180, 1165,

˜

1084, 857, 842 cm^–1. HRMS (ESI): m/z calcd. for C₁₉H₂₅O₂N₃ClSi

390.1399; found 390.1404.

1

(621 mg, 45%) as a brown oil. H NMR (500 MHz, CDCl₃): δ =

–0.08 (s, 9 H, CH₃Si), 0.89–0.94 (m, 2 H, OCH₂CH₂Si), 3.60–3.64

(m, 2 H, OCH₂CH₂Si), 4.14 (s, 3 H, CH₃O), 5.79 (s, 2 H, NCH₂O),

6.53 (dd, J_4,3= 3.5, J_4,5= 1.8 Hz, 1 H, H-4-furyl), 6.84 (s, 1 H, H-

5), 6.93 (dd, J_3,4= 3.5, J_3,5= 0.8 Hz, 1 H, H-3-furyl), 7.54 (dd, J_5,4

= 1.8, J_5,3= 0.8 Hz, 1 H, H-5-furyl), 8.48 (s, 1 H, H-2) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 18.0 (OCH₂CH₂Si),

53.7 (CH₃O), 66.4 (OCH₂CH₂Si), 70.7 (NCH₂O), 99.1 (CH-5),

105.4 (C-4a), 126.6 (CH-5-thienyl), 127.6 (CH-3-thienyl), 128.1

(CH-4-thienyl), 132.8 and 132.9 (C-6,C-2-thienyl), 151.2 (CH-2),

4-Methoxy-6-(4-methoxyphenyl)-7-[2-(trimethylsilyl)ethoxymeth-

yl]-7H-pyrrolo[2,3-d]pyrimidine (19a): Starting from 9 (1.12 g,

4 mmol) and 4-iodoanisole (1.03 g, 4.4 mmol), the reaction was

performed according to the General Procedure for 1 h. Purification

was performed by HPFC (EtOAc/hexane, 0–20 %) to give 19a

1

(1.08 g, 70%) as a yellowish oil. H NMR (500 MHz, CDCl₃): δ =

–0.03 (s, 9 H, CH₃Si), 0.94–0.98 (m, 2 H, OCH₂CH₂Si), 3.70–3.74

(m, 2 H, OCH₂CH₂Si), 3.87 (s, 3 H, CH₃O-p), 4.14 (s, 3 H, CH₃O-

4), 5.58 (s, 2 H, NCH₂O), 6.56 (s, 1 H, H-5), 6.99–7.01 (m, 2 H,

H-m-C₆H₄OMe), 7.67–7.68 (m, 2 H, H-o-C₆H₄OMe), 8.49 (s, 1 H,

H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.4 (CH₃Si), 18.0

(OCH₂CH₂Si), 53.7 (CH₃O-4), 55.3 (CH₃O-p), 66.6 (OCH₂CH₂Si),

70.8 (NCH₂O), 97.8 (CH-5), 105.5 (C-4a), 114.2 (CH-m-

154.0 (C-7a), 162.7 (C-4) ppm. IR (KBr): ν = 2956, 2929, 2866,

˜

2848, 1595, 1589, 1565, 1476, 1461, 1419, 1353, 1329, 1248,

1216, 1090, 866, 839, 776 cm^–1. HRMS (ESI): m/z calcd. for

C₁₇H₂₃O₃N₃NaSi 368.1401; found 368.1401.

C₆H₄OMe), 123.9 (C-i-C₆H₄OMe), 130.7 (CH-o-C₆H₄OMe), 140.2 4-Methoxy-6-(thiophen-3-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-

(C-6), 150.7 (CH-2), 153.95 (C-7a), 160.0 (C-p-C₆H₄OMe), 162.5 7H-pyrrolo[2,3-d]pyrimidine (19e): Starting from 9 (1.12 g, 4 mmol)

7950

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

and 3-iodothiophene (0.45 mL, 4.4 mmol), the reaction was per-

formed according to the General Procedure for 1 h. Purification

was performed by HPFC (EtOAc/hexane, 0–20 %) to give 19e

(1.11 g, 77%) as a yellowish solid, m.p. 55 °C. ¹H NMR (500 MHz,

NCH₂O), 6.61 (s, 1 H, H-5), 6.83 (ddd, J_6Ј,5Ј= 8.0, J_6Ј,2Ј= 2.4 Hz,

J_6Ј,4Ј= 1.0 Hz, 1 H, H-6Ј), 7.14 (m, 1 H, H-2Ј), 7.19 (ddd, J_4Ј,5Ј

7.6, J_4Ј,2Ј= 1.6 Hz, J_4Ј,6Ј= 1.0 Hz, 1 H, H-4Ј), 7.27 (t, J_5Ј,4Ј= J_5Ј,6Ј

=

7.8 Hz, 1 H, H-5Ј), 8.50 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = –0.04 (s, 9 H, CH₃Si), 0.96–0.99 (m, 2 H, CDCl₃): δ = –1.4 (CH₃Si), 18.0 (OCH₂CH₂Si), 53.8 (CH₃O), 66.6

OCH₂CH₂Si), 3.72–3.76 (m, 2 H, OCH₂CH₂Si), 4.18 (s, 3 H, (OCH₂CH₂Si), 70.9 (NCH₂O), 98.5 (CH-5), 105.5 (C-4a), 116.0

CH₃O), 5.70 (s, 2 H, NCH₂O), 6.69 (s, 1 H, H-5), 7.43 (dd, J_5,4

5.0, J_5,2= 2.9 Hz, 1 H, H-5-thienyl), 7.46 (dd, J_4,5= 5.0, J_4,2

=

(CH-6Ј), 116.4 (CH-2Ј), 120.6 (CH-4Ј), 129.7 (CH-5Ј), 132.5 (C-

3Ј), 140.3 (C-6), 145.2 (C-1Ј), 150.9 (CH-2), 154.0 (C-7a), 162.7 (C-

1.3 Hz, 1 H, H-4-thienyl), 7.88 (dd, J_2,5= 2.9, J_2,4= 1.3 Hz, 1 H,

4) ppm. IR (KBr): ν = 3434, 3318, 3207, 2956, 1592, 1556, 1476,

˜

H-2-thienyl), 8.51 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, 1329, 1207, 1072, 1057, 866, 842, 797 cm^–1. HRMS (ESI): m/z

CDCl₃): δ = –1.4 (CH₃Si), 18.0 (OCH₂CH₂Si), 54.3 (CH₃O), 66.5

(OCH₂CH₂Si), 70.9 (NCH₂O), 98.1 (CH-5), 105.3 (C-4a), 124.4

(CH-2-thienyl), 126.3 (CH-5-thienyl), 128.2 (CH-4-thienyl), 131.6

(C-3-thienyl), 135.6 (C-6), 150.2 (CH-2), 153.4 (C-7a), 162.4 (C-

calcd. for C₁₉H₂₇O₂N₄Si 371.1899; found 371.1898.

6-(4-Methoxyphenyl)-4-(methylsulfanyl)-7-[2-(trimethylsilyl)eth-

oxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (20a): Starting from 10

(1.18 g, 4 mmol), 4-iodoanisole (1.03 g, 4.4 mmol) and Pd(dppf)Cl₂

(292 mg, 0.4 mmol, 10 mol-%), the reaction was performed accord-

ing to the General Procedure for 1 h. Purification was performed

by HPFC (EtOAc/hexane, 0–20%) to give 20a (1.27 g, 79%) as a

yellowish solid, m.p. 144 °C. ¹H NMR (500 MHz, CDCl₃): δ =

4) ppm. IR (KBr): ν = 3102, 2953, 2902, 2857, 1601, 1571, 1562,

˜

1470, 1413, 1392, 1347, 1317, 1299, 1257, 1230, 1204, 1078, 1054,

946, 925, 863, 836, 812, 779, 764 cm^–1. HRMS (ESI): m/z calcd. for

C₁₇H₂₄N₃O₂SiS 362.1359; found 362.1346.

6-(Furan-3-yl)-4-methoxy-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyr- –0.03 (s, 9 H, CH₃Si), 0.95–0.98 (m, 2 H, OCH₂CH₂Si), 2.72 (s, 3

rolo[2,3-d]pyrimidine (19f): Starting from 9 (1.12 g, 4 mmol) and 3-

bromofuran (0.4 mL, 4.4 mmol), the reaction was performed ac-

cording to the General Procedure for 1 h. Purification was per-

H, CH₃S), 3.71–3.74 (m, 2 H, OCH₂CH₂Si), 3.87 (s, 3 H, CH₃O),

5.58 (s, 2 H, NCH₂O), 6.54 (s, 1 H, H-5), 7.00–7.01 (m, 2 H, H-m-

Ph), 7.69–7.71 (m, 2 H, H-o-Ph), 8.69 (s, 1 H, H-2) ppm. ¹³C NMR

formed by HPFC (EtOAc/hexane, 0–20 %) to give 19f (802 mg, (125.7 MHz, CDCl₃): δ = –1.4 (CH₃Si), 11.9 (CH₃S), 18.0

1

58%) as a brown oil. H NMR (500 MHz, CDCl₃): δ = –0.05 (s, 9 (OCH₂CH₂Si), 55.4 (CH₃O), 66.7 (OCH₂CH₂Si), 70.6 (NCH₂O),

H, CH₃Si), 0.93–0.96 (m, 2 H, OCH₂CH₂Si), 3.65–3.68 (m, 2 H,

98.3 (CH-5), 114.2 (CH-m-Ph), 116.1 (C-4a), 123.5 (C-i-Ph), 130.7

OCH₂CH₂Si), 4.13 (s, 3 H, CH₃O), 5.67 (s, 2 H, NCH₂O), 6.62 (s, (CH-o-Ph), 141.3 (C-6), 150.4 (C-7a), 150.8 (CH-2), 160.1 (C-p-

1 H, H-5), 6.77 (dd, J_4,5= 1.9, J_4,2= 0.9 Hz, 1 H, H-4-furyl), 7.51

(t, J_5,4= J_5,2= 1.7 Hz, 1 H, H-5-furyl), 7.99 (dd, J_2,5= 1.5, J_2,4

Ph), 160.4 (C-4) ppm. IR (KBr): ν = 3066, 2953, 2902, 2842, 1616,

˜

=

1503, 1422, 1344, 1317, 1263, 1248, 1192, 1141, 1126, 1078, 1057,

863, 851, 836, 755, 534 cm^–1. HRMS (ESI): m/z calcd. for

C₂₀H₂₇O₂N₃NaSSi 424.1486; found 424.1486.

0.9 Hz, 1 H, H-2-furyl), 8.47 (s, 1 H, H-2) ppm. ¹³C NMR

(125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 18.0 (OCH₂CH₂Si), 53.7

(CH₃O), 66.3 (OCH₂CH₂Si), 70.6 (NCH₂O), 97.5 (CH-5), 105.4

(C-4a), 110.5 (CH-4-furyl), 116.8 (C-3-furyl), 131.7 (C-6), 141.0

(CH-2-furyl), 143.5 (CH-5-furyl), 150.8 (CH-2), 153.9 (C-7a), 162.5

4-(Methylsulfanyl)-6-(pyridin-2-yl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (20b): Starting from 10 (1.18 g,

4 mmol), 2-iodopyridine (0.47 mL, 4.4 mmol) and Pd(dppf)Cl₂

(292 mg, 0.4 mmol, 10 mol-%), the reaction was performed accord-

ing to the General Procedure for 18 h. Purification was performed

by HPFC (EtOAc/hexane, 0–20%) to give 20b (954 mg, 64%) as a

(C-4) ppm. IR (KBr): ν = 2947, 2893, 1769, 1598, 1559, 1476, 1419,

˜

1329, 1251, 1213, 1081, 875, 857, 836, 779, 761 cm^–1. HRMS (ESI):

m/z calcd. for C₁₇H₂₄N₃O₃Si 346.1587; found 346.1589.

4-Methoxy-6-(2,4-dimethoxypyrimidin-5-yl)-7-[2-(trimethylsilyl)- yellowish oil. ¹H NMR (500 MHz, CDCl₃): δ = –0.16 (s, 9 H,

ethoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (19g): Starting from 9

(1.12 g, 4 mmol) and 5-iodo-2,4-dimethoxypyrimidine (1.17 g,

4.4 mmol), the reaction was performed according to the General

Procedure for 18 h. Purification was performed by HPFC (EtOAc/

hexane, 0–20%) to give 19g (1.1 g, 66%) as a yellowish solid, m.p.

CH₃Si), 0.80–0.83 (m, 2 H, OCH₂CH₂Si), 2.73 (s, 3 H, CH₃S),

3.48–3.51 (m, 2 H, OCH₂CH₂Si), 6.17 (s, 2 H, NCH₂O), 6.94 (s, 1

H, H-5), 7.28 (ddd, J_5,4= 7.5, J_5,6= 4.8, J_5,3= 1.2 Hz, 1 H, H-5-

py), 7.79 (btd, J_4,5= J_4,3= 7.7, J_4,6= 1.8 Hz, 1 H, H-4-py), 7.85

(dt, J_3,4= 8.0, J_3,5= J_3,6= 1.1 Hz, 1 H, H-3-py), 8.70 (ddd, J_6,5

=

79 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.11 (s, 9 H, CH₃Si), 4.8, J_6,4= 1.8 Hz, J_6,3= 1.0 Hz, 1 H, H-6-py), 8.72 (s, 1 H, H-

0.79–0.83 (m, 2 H, OCH₂CH₂Si), 3.45–3.48 (m, 2 H, OCH₂CH₂Si), 2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.6 (CH₃Si), 11.9

4.00 (s, 3 H, CH₃O-4Ј), 4.06 (s, 3 H, CH₃O-2Ј), 4.13 (s, 3 H, CH₃O- (CH₃S), 17.7 (OCH₂CH₂Si), 66.3 (OCH₂CH₂Si), 71.2 (NCH₂O),

4), 5.53 (s, 2 H, NCH₂O), 6.61 (s, 1 H, H-5), 8.44 (s, 1 H, H-6Ј),

101.4 (CH-5), 115.8 (C-4a), 122.8 (CH-5-py), 123.3 (CH-3-py),

136.8 (CH-4-py), 138.2 (C-6), 149.5 (CH-6-py), 150.9 and 151.1 (C-

8.50 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.6

(CH₃Si), 17.8 (OCH₂CH₂Si), 53.7 (CH₃O-4), 54.3 (CH₃O-2Ј), 55.1 7a, C-2-py), 151.7 (CH-2), 161.9 (C-4) ppm. IR (KBr): ν = 3052,

˜

(CH₃O-4Ј), 66.3 (OCH₂CH₂Si), 71.2 (NCH₂O), 101.4 (CH-5), 2953, 2932, 2893, 1589, 1556, 1455, 1443, 1416, 1350, 1269, 1251,

105.4 (C-4a), 107.1 (C-5Ј), 130.8 (C-6), 151.4 (CH-2), 153.8 (C-

7a), 159.8 (CH-6Ј), 162.8 (C-4), 165.5 (C-2Ј), 168.8 (C-4Ј) ppm. IR

1177, 1075, 937, 917, 860, 836, 770 cm^–1. HRMS (ESI): m/z calcd.

for C₁₈H₂₄N₄OSSi 372.1440; found 372.1442.

(KBr): ν = 2986, 2956, 2896, 2866, 1610, 1598, 1473, 1380, 1356,

˜

4-(Methylsulfanyl)-6-(thiophen-2-yl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (20c): Starting from 10 (1.18 g,

4 mmol), 2-iodothiophene (0.49 mL, 4.4 mmol) and Pd(dppf)Cl₂

(292 mg, 0.4 mmol, 10 mol-%), the reaction was performed accord-

ing to the General Procedure for 1 h. Purification was performed

by HPFC (EtOAc/hexane, 0–20%) to give 20c (1.05 g, 69%) as a

yellowish solid, m.p. 92 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.04

(s, 9 H, CH₃Si), 0.95–0.98 (m, 2 H, OCH₂CH₂Si), 2.72 (s, 3 H,

CH₃S), 3.67–3.71 (m, 2 H, OCH₂CH₂Si), 5.72 (s, 2 H, NCH₂O),

6.69 (s, 1 H, H-5), 7.15 (dd, J_4,5= 5.1, J_4,3= 3.7 Hz, 1 H, H-4-

1320, 1290, 1251, 1213, 1078, 1018, 866, 833 cm^–1. HRMS (ESI):

m/z calcd. for C₁₉H₂₈N₅O₄Si 418.1911; found 418.1898.

6-(3-Aminophenyl)-4-methoxy-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (19h): Starting from 9 (1.12 g, 4 mmol)

and 3-iodoaniline (0.53 mL, 4.4 mmol), the reaction was performed

according to the General Procedure for 1 h. Purification was per-

formed by HPFC (EtOAc/hexane, 0–20%) to give 19h (1.1 g, 74%)

1

as a yellowish solid, m.p. 113 °C. H NMR (500 MHz, CDCl₃): δ

= –0.04 (s, 9 H, CH₃Si), 0.93–0.96 (m, 2 H, OCH₂CH₂Si), 3.69–

3.73 (m, 2 H, OCH₂CH₂Si), 4.14 (s, 3 H, CH₃O), 5.61 (s, 2 H, thienyl), 7.42 (dd, J_5,4= 5.1, J_5,3= 1.2 Hz, 1 H, H-5-thienyl), 7.63

Eur. J. Org. Chem. 2015, 7943–7961

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7951

M. Klecˇka, L. Posˇtová Slaveˇtínská, M. Hocek

FULL PAPER

(dd, J_3,4= 3.7, J_3,5= 1.2 Hz, 1 H, H-3-thienyl), 8.68 (s, 1 H, H-

(OCH₂CH₂Si), 66.4 (OCH₂CH₂Si), 70.4 (NCH₂O), 97.9 (CH-5),

110.5 (CH-4-furyl), 116.0 (C-4a), 116.6 (C-3-furyl), 132.9 (C-6),

2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 11.9

(CH₃S), 17.9 (OCH₂CH₂Si), 66.5 (OCH₂CH₂Si), 70.5 (NCH₂O), 141.4 (CH-2-furyl), 143.6 (CH-5-furyl), 150.4 (C-7a), 150.9 (CH-

99.4 (CH-5), 115.9 (C-4a), 127.1 (CH-5-thienyl), 128.0 (CH-3-thi-

enyl), 128.2 (CH-4-thienyl), 132.5 (C-2-thienyl), 134.0 (C-6), 150.5

2), 160.5 (C-4) ppm. HRMS (ESI): m/z calcd. for C₁₇H₂₃N₃O₂SSi

361.1280; found 361.1278.

(C-7a), 151.2 (CH-2), 160.9 (C-4) ppm. IR (KBr): ν = 3081, 3066,

˜

6-(2,4-Dimethoxypyrimidin-5-yl)-4-(methylsulfanyl)-7-[2-(trimeth-

ylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (20g): Starting

from 10 (1.18 g, 4 mmol), 5-iodo-2,4-dimethoxypyrimidine (1.17 g,

4.4 mmol) and Pd(dppf)Cl₂(292 mg, 0.4 mmol, 10 mol-%), the re-

action was performed according to the General Procedure for 18 h.

Purification was performed by HPFC (EtOAc/hexane, 0–20%) to

give 20g (676 mg, 39%) as a white solid, m.p. 134 °C. ¹H NMR

(500 MHz, CDCl₃): δ = –0.10 (s, 9 H, CH₃Si), 0.80–0.83 (m, 2 H,

OCH₂CH₂Si), 2.72 (s, 3 H, CH₃S), 3.45–3.48 (m, 2 H,

OCH₂CH₂Si), 4.01 (s, 3 H, CH₃O-4Ј), 4.07 (s, 3 H, CH₃O-2Ј), 5.53

(s, 2 H, NCH₂O), 6.59 (s, 1 H, H-5), 8.45 (s, 1 H, H-6Ј), 8.70 (s, 1

H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si),

11.9 (CH₃S), 17.7 (OCH₂CH₂Si), 54.4 (CH₃O-4Ј), 55.2 (CH₃O-2Ј),

66.4 (OCH₂CH₂Si), 71.0 (NCH₂O), 101.8 (CH-5), 106.8 (C-5Ј),

115.9 (C-4a), 132.0 (C-6), 150.1 (C-7a), 151.3 (CH-2), 159.8 (CH-

2953, 2926, 2893, 1559, 1485, 1458, 1440, 1407, 1356, 1260, 1248,

1174, 1057, 928, 854, 839, 785, 755, 728 cm^–1. HRMS (ESI): m/z

calcd. for C₁₇H₂₄ON₃S₂Si 378.1125; found 378.1126.

6-(Furan-2-yl)-4-(methylsulfanyl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (20d): Starting from 10 (1.18 g,

4 mmol), 2-bromofuran (0.39 mL, 4.4 mmol) and Pd(dppf)Cl₂

(292 mg, 0.4 mmol, 10 mol-%), the reaction was performed accord-

ing to the General Procedure for 1 h. Purification was performed

by HPFC (EtOAc/hexane, 0–20%) to give 20d (897 mg, 62%) as a

yellowish solid, m.p. 100 °C. ¹H NMR (500 MHz, CDCl₃): δ =

–0.07 (s, 9 H, CH₃Si), 0.91–0.94 (m, 2 H, OCH₂CH₂Si), 2.73 (s, 3

H, CH₃S), 3.60–3.64 (m, 2 H, OCH₂CH₂Si), 5.80 (s, 2 H, NCH₂O),

6.55 (dd, J_4,3= 3.5, J_4,5= 1.8 Hz, 1 H, H-4-furyl), 6.83 (s, 1 H, H-

5), 6.98 (dd, J_3,4= 3.5, J_3,5= 0.8 Hz, 1 H, H-3-furyl), 7.56 (dd, J_5,4

= 1.8, J_5,3= 0.8 Hz, 1 H, H-5-furyl), 8.67 (s, 1 H, H-2) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 11.9 (CH₃S), 17.8

(OCH₂CH₂Si), 66.3 (OCH₂CH₂Si), 70.9 (NCH₂O), 97.7 (CH-5),

110.1 (CH-3-furyl), 111.9 (CH-4-furyl), 115.9 (C-4a), 130.8 (C-6),

143.3 (CH-5-furyl), 145.6 (C-2-furyl), 150.4 (C-7a), 151.1 (CH-2),

6Ј), 161.3 (C-4), 165.6 (C-2Ј), 168.7 (C-4Ј) ppm. IR (KBr): ν =

˜

2953, 2932, 1613, 1568, 1553, 1476, 1407, 1377, 1302, 1248, 1189,

1078, 1066, 863, 842 cm^{– 1}. HRMS (ESI): m/z calcd. for

C₁₉H₂₇N₅O₃SSi 433.1604; found 433.1602.

6-(3-Aminophenyl)-4-(methylsulfanyl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (20h): Starting from 10 (1.18 g,

4 mmol), 3-iodoaniline (0.53 mL, 4.4 mmol) and Pd(dppf)Cl₂

(292 mg, 0.4 mmol, 10 mol-%), the reaction was performed accord-

ing to the General Procedure for 1 h. Purification was performed

by HPFC (EtOAc/hexane, 0–20%) to give 20h (1.21 g, 78%) as a

yellowish solid, m.p. 109 °C. ¹H NMR (500 MHz, CDCl₃): δ =

–0.03 (s, 9 H, CH₃Si), 0.93–0.97 (m, 2 H, OCH₂CH₂Si), 2.73 (s, 3

H, CH₃S), 3.70–3.73 (m, 2 H, OCH₂CH₂Si), 5.61 (s, 2 H, NCH₂O),

161.2 (C-4) ppm. IR (KBr): ν = 2944, 2923, 2893, 2872, 1562, 1524,

˜

1464, 1443, 1425, 1407, 1344, 1269, 1248, 1213, 1186, 1162, 1075,

1015, 946, 928, 866, 833, 770, 761, 734 cm^–1. HRMS (ESI): m/z

calcd. for C₁₇H₂₄O₂N₃SSi 362.1353; found 362.1354.

4-(Methylsulfanyl)-6-(thiophen-3-yl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (20e): Starting from 10 (1.18 g,

4 mmol), 3-iodothiophene (0.45 mL, 4.4 mmol) and Pd(dppf)Cl₂

(292 mg, 0.4 mmol, 10 mol-%), the reaction was performed accord-

ing to the General Procedure for 18 h. Purification was performed

by HPFC (EtOAc/hexane, 0–20%) to give 20e (1.06 g, 70%) as a

yellowish solid, m.p. 99 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.03

(s, 9 H, CH₃Si), 0.96–1.00 (m, 2 H, OCH₂CH₂Si), 2.73 (s, 3 H,

CH₃S), 3.72–3.75 (m, 2 H, OCH₂CH₂Si), 5.68 (s, 2 H, NCH₂O),

6.64 (s, 1 H, H-5), 7.44 (dd, J_5,4= 5.0, J_5,2= 2.9 Hz, 1 H, H-5-

thienyl), 7.49 (dd, J_4,5= 5.0, J_4,2= 1.3 Hz, 1 H, H-4-thienyl), 7.91

(dd, J_2,5= 2.9, J_2,4= 1.3 Hz, 1 H, H-2-thienyl), 8.68 (s, 1 H, H-

2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.4 (CH₃Si), 11.9

(CH₃S), 18.0 (OCH₂CH₂Si), 66.6 (OCH₂CH₂Si), 70.5 (NCH₂O),

98.4 (CH-5), 115.9 (C-4a), 124.7 (CH-2-thienyl), 126.3 (CH-5-thi-

enyl), 128.2 (CH-4-thienyl), 131.5 (C-3-thienyl), 136.2 (C-6), 150.3

6.58 (s, 1 H, H-5), 6.75 (ddd, J_6Ј,5Ј= 8.0, J_6Ј,2Ј= 2.4 Hz, J_6Ј,4Ј

1.0 Hz, 1 H, H-6Ј), 7.07–7.08 (m, 1 H, H-2Ј), 7.13 (ddd, J_4Ј,5Ј

7.6, J_4Ј,2Ј= 1.7 Hz, J_4Ј,6Ј= 0.9 Hz, 1 H, H-4Ј), 7.25 (t, J_5Ј,4Ј= J_5Ј,6Ј

=

7.8 Hz, 1 H, H-5Ј), 8.70 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = –1.4 (CH₃Si), 11.9 (CH₃S), 18.0 (OCH₂CH₂Si), 66.7

(OCH₂CH₂Si), 70.7 (NCH₂O), 98.9 (CH-5), 115.6 and 115.7 (CH-

2Ј,6Ј), 116.0 (C-4a), 119.7 (CH-4Ј), 129.7 (CH-5Ј), 132.1 (C-3),

141.6 (C-6), 146.6 (C-1Ј), 150.4 (C-7a), 150.8 (CH-2), 160.7 (C-

4) ppm. IR (KBr): ν = 3324, 2950, 1610, 1553, 1538, 1479, 1464,

˜

1437, 1353, 1251, 1171, 1060, 851, 833, 785 cm^–1. HRMS (ESI):

m/z calcd. for C₁₉H₂₇ON₄SSi 387.1669; found 387.1670.

Oxidation to Sulfones; General Procedure: A 4-MeS-pyrrolo[2,3-d]-

pyrimidine 20a–h and 23l (2 mmol, 1 equiv.) was dissolved in

CH₂Cl₂(10 mL) and m-CPBA (900 mg, 4 mmol, 2 equiv.) was

slowly added (water/ice bath during addition) and the reaction mix-

ture was stirred at room temp. overnight. Then 1m NaOH (10 mL)

was added to the mixture to remove residual m-CPBA. The layers

were separated and the aqueous layer was extracted with CH₂Cl₂

(2ϫ25 mL). The combined organic layers were dried with sodium

sulfate, solvents were evaporated, and the residue was purified by

flash chromatography (HPFC; CHCl₃/MeOH, 20:1).

(C-7a), 150.9 (CH-2), 160.7 (C-4) ppm. IR (KBr): ν = 3102, 3043,

˜

2953, 2920, 2896, 2863, 1550, 1461, 1347, 1269, 1242, 1177, 1081,

917, 860, 836, 776 cm^{– 1}. HRMS (ESI): m/z c al cd . for

C₁₇H₂₃N₃OSiS₂377.1052; found 377.1053.

6-(Furan-3-yl)-4-(methylsulfanyl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (20f): Starting from 10 (1.18 g,

4 mmol), 3-bromofuran (0.4 mL, 4.4 mmol) and Pd(dppf)Cl₂

(292 mg, 0.4 mmol, 10 mol-%), the reaction was performed accord-

ing to the General Procedure for 18 h. Purification was performed

by HPFC (EtOAc/hexane, 0–20%) to give 20f (721 mg, 50%) as a

6-(4-Methoxyphenyl)-4-(methylsulfonyl)-7-[2-(trimethylsilyl)eth-

yellowish solid. ¹H NMR (500 MHz, CDCl₃): δ = –0.05 (s, 9 H, oxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (23a): Starting from pyr-

CH₃Si), 0.94–0.97 (m, 2 H, OCH₂CH₂Si), 2.73 (s, 3 H, CH₃S), rolo[2,3-d]pyrimidine 20a (803 mg, 2 mmol) and m-CPBA (900 mg,

3.65–3.68 (m, 2 H, OCH₂CH₂Si), 5.67 (s, 2 H, NCH₂O), 6.60 (s, 1 4 mmol), the reaction was performed according to the General Pro-

H, H-5), 6.80 (dd, J_4,5= 1.9, J_4,2= 0.9 Hz, 1 H, H-4-furyl), 7.53

cedure to give 23a (668 mg, 77%) as a white solid, m.p. 147 °C. ¹H

(bt, J_5,2= J_5,4= 1.7 Hz, 1 H, H-5-furyl), 8.02 (dd, J_2,5= 1.6, J_2,4NMR (500 MHz, CDCl₃): δ = –0.01 (s, 9 H, CH₃Si), 0.98–1.01

= 0.9 Hz, 1 H, H-2-thienyl), 8.67 (s, 1 H, H-2) ppm. ¹³C NMR (m, 2 H, OCH₂CH₂Si), 3.36 (s, 3 H, CH₃SO₂), 3.74–3.78 (m, 2 H,

(125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 12.0 (CH₃S), 17.9 OCH₂CH₂Si), 3.89 (s, 3 H, CH₃O), 5.67 (s, 2 H, NCH₂O), 7.03–

7952

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Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

7.05 (m, 2 H, H-m-Ph), 7.14 (s, 1 H, H-5), 7.77–7.78 (m, 2 H, H- 144.7 (CH-5-furyl), 150.2 (CH-2), 154.4 (C-4), 155.8 (C-7a) ppm.

o-Ph), 8.95 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ

HRMS (ESI): m/z calcd. for C₁₇H₂₃O₄N₃NaSSi 416.1071; found

= –1.4 (CH₃Si), 18.0 (OCH₂CH₂Si), 40.1 (CH₃SO₂), 55.4 (CH₃O), 416.1070.

67.2 (OCH₂CH₂Si), 70.9 (NCH₂O), 99.0 (CH-5), 114.4 (CH-m-Ph),

4-(Methylsulfonyl)-6-(thiophen-3-yl)-7-[2-(trimethylsilyl)ethoxy-

114.5 (C-4a), 122.3 (C-i-Ph), 131.0 (CH-o-Ph), 147.1 (C-6), 149.9

(CH-2), 153.8 (C-4), 156.0 (C-7a), 160.9 (C-p-Ph) ppm. IR (KBr):

methyl]-7H-pyrrolo[2,3-d]pyrimidine (23e): Starting from pyr-

rolo[2,3-d]pyrimidine 20e (755 mg, 2 mmol) and m-CPBA (900 mg,

4 mmol), the reaction was performed according to the General Pro-

cedure to give 23e (507 mg, 62%) as a yellow solid, m.p. 178 °C.

¹H NMR (500 MHz, CDCl₃): δ = –0.02 (s, 9 H, CH₃Si), 0.99–1.03

(m, 2 H, OCH₂CH₂Si), 3.37 (s, 3 H, CH₃SO₂), 3.74–3.77 (m, 2 H,

OCH₂CH₂Si), 5.78 (s, 2 H, NCH₂O), 7.24 (s, 1 H, H-5), 7.49 (dd,

J_5,4= 5.0, J_5,2= 2.9 Hz, 1 H, H-5-thienyl), 7.57 (dd, J_4,5= 5.0, J_4,2

= 1.3 Hz, 1 H, H-4-thienyl), 8.07 (dd, J_2,5= 2.9, J_2,4= 1.3 Hz, 1

H, H-2-thienyl), 8.95 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = –1.4 (CH₃Si), 18.0 (OCH₂CH₂Si), 40.1 (CH₃SO₂), 67.1

(OCH₂CH₂Si), 70.8 (NCH₂O), 99.1 (CH-5), 114.3 (C-4a), 126.6

(CH-2-thienyl), 126.9 (CH-5-thienyl), 128.2 (CH-4-thienyl), 130.5

(C-3-thienyl), 141.8 (C-6), 150.1 (CH-2), 154.3 (C-4), 155.8 (C-

ν = 3132, 3010, 2953, 2929, 2899, 1473, 1413, 1344, 1302, 1245,

˜

1174, 1138, 1123, 1066, 1015, 869, 845, 782, 755, 761, 537 cm^–1.

HRMS (ESI): m/z calcd. for C₂₀H₂₇O₄N₃NaSSi 456.1384; found

456.1384.

4-(Methylsulfonyl)-6-(pyridin-2-yl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (23b): Starting from pyr-

rolo[2,3-d]pyrimidine 20b (745 mg, 2 mmol) and m-CPBA (900 mg,

4 mmol), the reaction was performed according to the General Pro-

cedure to give 23b (528 mg, 65%) as a white solid, m.p. 109 °C. ¹H

NMR (500 MHz, CDCl₃): δ = –0.17 (s, 9 H, CH₃Si), 0.78–0.80

(m, 2 H, OCH₂CH₂Si), 3.37 (s, 3 H, CH₃SO₂), 3.44–3.47 (m, 2 H,

OCH₂CH₂Si), 6.34 (s, 2 H, NCH₂O), 7.37 (ddd, J_5,4= 7.5, J_5,6

=

7a) ppm. IR (KBr): ν = 3102, 3007, 2953, 2929, 2896, 1583, 1550,

˜

4.8 Hz, J_5,3= 1.2 Hz, 1 H, H-5-py), 7.48 (s, 1 H, H-5), 7.85 (btd,

J_4,5= J_4,3= 7.7, J_4,6= 1.8 Hz, 1 H, H-4-py), 7.91 (dt, J_3,4= 7.9,

1467, 1350, 1311, 1251, 1135, 1126, 1072, 863, 833, 776, 534 cm^–1.

HRMS (ESI): m/z calcd. for C₁₇H₂₃N₃O₃SiS₂409.0950; found

409.0948.

J_3,5= J_3,6= 1.1 Hz, 1 H, H-3-py), 8.75 (ddd, J_6,5= 4.8 Hz, J_6,4

=

1.8 Hz, J_6,3= 0.9 Hz, 1 H, H-6-py), 9.01 (s, 1 H, H-2) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = –1.6 (CH₃Si), 17.7 (OCH₂CH₂Si),

40.0 (CH₃SO₂), 66.7 (OCH₂CH₂Si), 71.7 (NCH₂O), 101.9 (CH-5),

113.8 (C-4a), 123.8 (CH-5-py), 124.0 (CH-3-py), 137.1 (CH-4-py),

143.2 (C-6), 149.6 (CH-6-py), 150.1 (C-2-py), 151.0 (CH-2), 155.5

6-(Furan-3-yl)-4-(methylsulfonyl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (23f): Starting from pyrrolo[2,3-d]pyr-

imidine 20f (633 mg, 1.75 mmol) and m-CPBA (784 mg, 3.5 mmol),

the reaction was performed according to the General Procedure to

give 23f (430 mg, 62 %) as a white solid. ¹H NMR (500 MHz,

CDCl₃): δ = –0.03 (s, 9 H, CH₃Si), 0.96–0.99 (m, 2 H,

OCH₂CH₂Si), 3.36 (s, 3 H, CH₃SO₂), 3.67–3.70 (m, 2 H,

(C-4), 156.2 (C-7a) ppm. IR (KBr): ν = 2950, 2899, 1476, 1347,

˜

1323, 1302, 1248, 1135, 1063, 1051, 863, 791, 767, 528 cm^–1. HRMS

(ESI): m/z calcd. for C₁₈H₂₄N₄O₃SiS 404.1338; found 404.1335.

OCH₂CH₂Si), 5.78 (s, 2 H, NCH₂O), 6.88 (dd, J_4,5= 1.9, J_4,2

0.9 Hz, 1 H, H-4-furyl), 7.19 (s, 1 H, H-5), 7.57 (bt, J_5,2= J_5,4

=

4-(Methylsulfonyl)-6-(thiophen-2-yl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (23c): Starting from pyr-

rolo[2,3-d]pyrimidine 20c (755 mg, 2 mmol) and m-CPBA (900 mg,

4 mmol), the reaction was performed according to the General Pro-

cedure to give 23c (717 mg, 89%) as a yellow solid, m.p. 107 °C.

¹H NMR (500 MHz, CDCl₃): δ = –0.03 (s, 9 H, CH₃Si), 0.98–1.01

(m, 2 H, OCH₂CH₂Si), 3.37 (s, 3 H, CH₃SO₂), 3.70–3.73 (m, 2 H,

1.7 Hz, 1 H, H-5-furyl), 8.15 (dd, J_2,5= 1.5, J_2,4= 0.9 Hz, 1 H, H-

2-thienyl), 8.93 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃):

δ = –1.4 (CH₃Si), 17.9 (OCH₂CH₂Si), 40.0 (CH₃SO₂), 66.9

(OCH₂CH₂Si), 70.7 (NCH₂O), 98.6 (CH-5), 110.4 (CH-4-furyl),

114.3 (C-4a), 116.0 (C-3-furyl), 138.8 (C-6), 142.6 (CH-2-furyl),

144.1 (CH-5-furyl), 150.0 (CH-2), 154.1 (C-4), 155.8 (C-7a) ppm.

HRMS (ESI): m/z calcd. for C₁₇H₂₃N₃O₄SiS 393.1179; found

393.1177.

OCH₂CH₂Si), 5.82 (s, 2 H, NCH₂O), 7.20 (dd, J_4,5= 5.1, J_4,3

=

3.7 Hz, 1 H, H-4-thienyl), 7.27 (s, 1 H, H-5), 7.53 (dd, J_5,4= 5.1,

J_5,3= 1.2 Hz, 1 H, H-5-thienyl), 7.77 (dd, J_3,4= 3.7, J_3,5= 1.2 Hz,

1 H, H-3-thienyl), 8.95 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz,

CDCl₃): δ = –1.4 (CH₃Si), 17.9 (OCH₂CH₂Si), 40.1 (CH₃SO₂), 67.0

(OCH₂CH₂Si), 70.8 (NCH₂O), 99.8 (CH-5), 114.3 (C-4a), 128.5

(CH-4-thienyl), 128.9 (CH-5-thienyl), 129.5 (CH-3-thienyl), 131.2

(C-2-thienyl), 139.9 (C-6), 150.3 (CH-2), 154.3 (C-4), 155.9 (C-

6-(2,4-Dimethoxypyrimidin-5-yl)-4-(methylsulfonyl)-7-[2-(trimeth-

ylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-d]pyrimidine (23g): Starting

from pyrrolo[2,3-d]pyrimidine 20g (650 mg, 1.5 mmol) and m-

CPBA (672 mg, 3 mmol), the reaction was performed according to

the General Procedure to give 23g (598 mg, 86%) as a white solid,

m.p. 122 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.08 (s, 9 H,

CH₃Si), 0.82–0.85 (m, 2 H, OCH₂CH₂Si), 3.37 (s, 3 H, CH₃SO₂),

3.48–3.51 (m, 2 H, OCH₂CH₂Si), 4.03 (s, 3 H, CH₃O-4Ј), 4.09 (s,

3 H, CH₃O-2Ј), 5.63 (s, 2 H, NCH₂O), 7.19 (s, 1 H, H-5), 8.50 (s,

1 H, H-6Ј), 8.98 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃):

δ = –1.5 (CH₃Si), 17.8 (OCH₂CH₂Si), 40.0 (CH₃SO₂), 54.5 (CH₃O-

4Ј), 55.3 (CH₃O-2Ј), 67.0 (OCH₂CH₂Si), 71.4 (NCH₂O), 102.7

(CH-5), 105.9 (C-4a), 114.0 (C-5Ј), 138.1 (C-6), 150.6 (CH-2), 155.0

(C-4), 155.3 (C-7a), 160.1 (CH-6Ј), 166.0 (C-2Ј), 168.6 (C-4Ј) ppm.

7a) ppm. IR (KBr): ν = 3004, 2959, 2929, 2893, 1544, 1485, 1413,

˜

1353, 1302, 1248, 1138, 1123, 1069, 863, 839, 779, 764, 534 cm^–1.

HRMS (ESI): m/z calcd. for C₁₇H₂₄O₃N₃³²S₂²⁸Si 410.1023; found

410.1022.

6-(Furan-2-yl)-4-(methylsulfonyl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (23d): Starting from pyrrolo[2,3-d]pyr-

imidine 20d (723 mg, 2 mmol) and m-CPBA (900 mg, 4 mmol), the

reaction was performed according to the General Procedure to give

23d (600 mg, 76 %) as a yellow solid, m.p. 146 °C. ¹H NMR

(500 MHz, CDCl₃): δ = –0.06 (s, 9 H, CH₃Si), 0.93–0.96 (m, 2 H,

OCH₂CH₂Si), 3.36 (s, 3 H, CH₃SO₂), 3.62–3.65 (m, 2 H,

IR (KBr): ν = 3031, 3007, 2953, 2923, 2890, 1601, 1550, 1470, 1401,

˜

1380, 1344, 1320, 1248, 1081, 866, 839, 776, 761, 531 cm^–1. HRMS

(ESI): m/z calcd. for C₁₉H₂₇N₅O₅SSi 465.1502; found 465.1505.

OCH₂CH₂Si), 5.91 (s, 2 H, NCH₂O), 6.60 (dd, J_4,3= 3.5, J_4,5

=

1.8 Hz, 1 H, H-4-furyl), 7.16 (dd, J_3,4= 3.5, J_3,5= 0.7 Hz, 1 H, H-

3-furyl), 7.39 (s, 1 H, H-5), 7.64 (dd, J_5,4= 1.8, J_5,3= 0.7 Hz, 1 H,

6-(Trifluoromethyl)-4-(methylsulfonyl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (23l): Starting from pyr-

H-5-furyl), 8.93 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): rolo[2,3-d]pyrimidine 20l (218 mg, 0.6 mmol) and m-CPBA

δ = –1.5 (CH₃Si), 17.7 (OCH₂CH₂Si), 40.1 (CH₃SO₂), 66.8

(OCH₂CH₂Si), 71.3 (NCH₂O), 98.1 (CH-5), 112.3 (CH-4-furyl),

(207 mg, 1.2 mmol), the reaction was performed according to the

General Procedure to give 23l (168 mg, 71%) as a white solid, m.p.

112.6 (CH-3-furyl), 114.3 (C-4a), 136.0 (C-6), 144.6 (C-2-furyl), 145 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.04 (s, 9 H, CH₃Si),

Eur. J. Org. Chem. 2015, 7943–7961

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7953

M. Klecˇka, L. Posˇtová Slaveˇtínská, M. Hocek

FULL PAPER

0.92–0.95 (m, 2 H, OCH₂CH₂Si), 3.38 (s, 3 H, CH₃SO₂), 3.58–3.62

NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 17.9 (OCH₂CH₂Si),

66.4 (OCH₂CH₂Si), 70.6 (NCH₂O), 98.7 (CH-5), 102.9 (C-4a),

(m, 2 H, OCH₂CH₂Si), 5.86 (s, 2 H, NCH₂O), 7.61 (q, J_5,F

=

1.1 Hz, 1 H, CH-5), 9.11 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, 126.6 (CH-5-thienyl), 127.6 (CH-3-thienyl), 128.2 (CH-4-thienyl),

CDCl₃): δ = –1.5 (CH₃Si), 17.7 (OCH₂CH₂Si), 39.8 (CH₃SO₂), 67.4 132.4 (C-6), 132.6 (C-2-thienyl), 150.9 (CH-2), 152.3 (C-7a), 155.6

(OCH₂CH₂Si), 72.0 (NCH₂O), 104.1 [q, J_C,F= 4.3 Hz, CH-5], (C-4) ppm. IR (KBr): ν = 3455, 3291, 3159, 3090, 2950, 2914, 1643,

˜

111.7 (C-4a), 120.0 (q, J_C,F= 270.2 Hz, CF₃), 131.8 (q, J_C,F

=

1592, 1547, 1476, 1311, 1248, 1081, 863, 854, 833, 707 cm^–1. HRMS

39.5 Hz, C-6), 152.9 (CH-2), 155.1 (C-7a), 158.4 (C-4) ppm. ¹⁹F (ESI): m/z calcd. for C₁₆H₂₂N₄OSiS 346.1284; found 346.1286.

NMR (470.3 MHz, CDCl₃): δ = –56.86 (s, 1 F, F-2) ppm. IR (KBr):

6-(Furan-2-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-

ν = 2956, 2926, 2893, 1547, 1431, 1371, 1344, 1320, 1233, 1180,

˜

d]pyrimidine-4-amine (24d): Starting from pyrrolo[2,3-d]pyrimidine

23d (393 mg, 1 mmol), the reaction was performed according to the

General Procedure to give 24d (280 mg, 85%) as a yellowish solid,

m.p. 153 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.07 (s, 9 H,

CH₃Si), 0.91–0.94 (m, 2 H, OCH₂CH₂Si), 3.61–3.64 (m, 2 H,

OCH₂CH₂Si), 5.64 (br. s, 2 H, NH₂), 5.75 (s, 2 H, NCH₂O), 6.53

(dd, J_4,3= 3.4, J_4,5= 1.8 Hz, 1 H, H-4-furyl), 6.72 (s, 1 H, H-5),

1159, 1138, 1093, 863, 836, 528 cm^–1. HRMS (ESI): m/z calcd. for

C₁₄H₂₀O₃N₃F₃NaSSi 418.0839; found 418.0838.

Amination of Sulfones to 7-Deazaadenines; General Procedure: A 4-

methylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine 23a–g and 23l

(1 mmol) were dissolved in 1,4-dioxane (5 mL) and aq. ammonia

(25% w/w, 5 mL) was added. The reaction mixture was stirred at

50 °C overnight, the solvents were evaporated, and the residue was

purified by flash chromatography (HPFC; EtOAc/MeOH, 20:1).

6.92 (dd, J_3,4= 3.4, J_3,5= 0.8 Hz, 1 H, H-3-furyl), 7.53 (dd, J_5,4

=

1.8, J_5,3= 0.8 Hz, 1 H, H-5-furyl), 8.31 (s, 1 H, H-2) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 17.8 (OCH₂CH₂Si),

66.2 (OCH₂CH₂Si), 71.0 (NCH₂O), 96.9 (CH-5), 102.9 (C-4a),

109.2 (CH-3-furyl), 111.8 (CH-4-furyl), 129.3 (C-6), 142.9 (CH-5-

furyl), 145.7 (C-2-furyl), 151.0 (CH-2), 152.2 (C-7a), 155.9 (C-

4) ppm. HRMS (ESI): m/z calcd. for C₁₆H₂₃O₂N₄Si 331.1585;

found 331.1585.

6-(4-Methoxyphenyl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-

pyrrolo[2,3-d]pyrimidine-4-amine (24a): Starting from pyrrolo[2,3-

d]pyrimidine 23a (434 mg, 1 mmol), the reaction was performed

according to the General Procedure to give 24a (308 mg, 83%) as

a white solid, m.p. 142 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.03

(s, 9 H, CH₃Si), 0.94–0.98 (m, 2 H, OCH₂CH₂Si), 3.70–3.74 (m, 2

H, OCH₂CH₂Si), 3.87 (s, 3 H, CH₃O), 5.19 (br. s, 2 H, NH₂), 5.54 6-(Thiophen-3-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

(s, 2 H, NCH₂O), 6.38 (s, 1 H, H-5), 6.99–7.01 (m, 2 H, H-m-Ph), [2,3-d]pyrimidine-4-amine (24e): Starting from pyrrolo[2,3-d]pyrim-

7.65–7.67 (m, 2 H, H-o-Ph), 8.35 (s, 1 H, H-2) ppm. ¹³C NMR idine 23e (410 mg, 1 mmol), the reaction was performed according

(125.7 MHz, CDCl₃): δ = –1.4 (CH₃Si), 18.0 (OCH₂CH₂Si), 55.3

to the General Procedure to give 24e (292 mg, 84%) as a white

(CH₃O), 66.5 (OCH₂CH₂Si), 70.6 (NCH₂O), 97.1 (CH-5), 103.1 solid, m.p. 159 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.04 (s, 9

(C-4a), 114.1 (CH-m-Ph), 124.0 (C-i-Ph), 130.6 (CH-o-Ph), 139.2 H, CH₃Si), 0.96–0.99 (m, 2 H, OCH₂CH₂Si), 3.72–3.75 (m, 2 H,

(C-6), 151.8 (CH-2), 152.6 (C-7a), 156.0 (C-4), 159.9 (C-p-Ph) ppm. OCH₂CH₂Si), 5.42 (br. s, 2 H, NH₂), 5.64 (s, 2 H, NCH₂O), 6.53

IR (KBr): ν = 3324, 3138, 2950, 2917, 2899, 1664, 1592, 1553, (s, 1 H, H-5), 7.42 (dd, J_5,4= 5.0, J_5,2= 2.9 Hz, 1 H, H-5-thienyl),

˜

1455, 1440, 1314, 1248, 1222, 1084, 860, 833, 749, 737 cm^–1. HRMS

(ESI): m/z calcd. for C₁₉H₂₇O₂N₄Si 371.1898; found 371.1898.

7.44 (dd, J_4,5= 5.0, J_4,2= 1.4 Hz, 1 H, H-4-thienyl), 7.84 (dd, J_2,5

= 2.9, J_2,4= 1.3 Hz, 1 H, H-2-thienyl), 8.34 (s, 1 H, H-2) ppm. ¹³

C

NMR (125.7 MHz, CDCl₃): δ = –1.4 (CH₃Si), 18.0 (OCH₂CH₂Si),

66.5 (OCH₂CH₂Si), 70.6 (NCH₂O), 97.4 (CH-5), 102.9 (C-4a),

124.0 (CH-2-thienyl), 126.2 (CH-5-thienyl), 128.1 (CH-4-thienyl),

131.8 (C-3-thienyl), 134.5 (C-6), 151.2 (CH-2), 152.4 (C-7a), 155.8

6-(Pyridin-2-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

[2,3-d]pyrimidine-4-amine (24b): Starting from pyrrolo[2,3-d]pyrim-

idine 23b (404 mg, 1 mmol), the reaction was performed according

to the General Procedure to give 24b (320 mg, 94%) as a yellowish

solid, m.p. 137 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.15 (s, 9

H, CH₃Si), 0.82–0.85 (m, 2 H, OCH₂CH₂Si), 3.52–3.55 (m, 2 H,

OCH₂CH₂Si), 5.51 (br. s, 2 H, NH₂), 6.09 (s, 2 H, NCH₂O), 6.85

(s, 1 H, H-5), 7.26 (ddd, J_5,4= 7.4, J_5,6= 4.8 Hz, J_5,3= 1.2 Hz, 1

(C-4) ppm. IR (KBr): ν = 3446, 3288, 3135, 3102, 2950, 2917, 2890,

˜

1634, 1595, 1556, 1470, 1302, 1293, 1251, 1081, 860, 836 cm^–1

.

HRMS (ESI): m/z calcd. for C₁₆H₂₂N₄OSiS 346.1284; found

346.1283.

H, H-5-py), 7.76 (btd, J_4,5= J_4,3= 7.7, J_4,6= 1.8 Hz, 1 H, H-4- 6-(Furan-3-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-

py), 7.82 (dt, J_3,4= 8.0, J_3,5= J_3,6= 1.1 Hz, 1 H, H-3-py), 8.37 (s,

1 H, H-2), 8.68 (ddd, J_6,5= 4.8, J_6,4= 1.8 Hz, J_6,3= 1.0 Hz, 1 H,

d]pyrimidine-4-amine (24f): Starting from pyrrolo[2,3-d]pyrimidine

23f (394 mg, 1 mmol), the reaction was performed according to the

1

H-6-py) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.6 (CH₃Si), General Procedure to give 24f (248 mg, 71%) as a white solid. H

17.7 (OCH₂CH₂Si), 66.2 (OCH₂CH₂Si), 71.2 (NCH₂O), 100.6 NMR (500 MHz, CDCl₃): δ = –0.05 (s, 9 H, CH₃Si), 0.93–0.97 (m,

(CH-5), 102.9 (C-4a), 122.5 (CH-5-py), 122.8 (CH-3-py), 136.7 (C-

2 H, OCH₂CH₂Si), 3.65–3.69 (m, 2 H, OCH₂CH₂Si), 5.57 (br. s, 2

6), 136.8 (CH-4-py), 149.5 (CH-6-py), 150.9 (C-2-py), 152.0 (CH- H, NH₂), 5.63 (s, 2 H, NCH₂O), 6.51 (s, 1 H, H-5), 6.76 (dd, J_4,5

2), 153.2 (C-7a), 156.4 (C-4) ppm. IR (KBr): ν = 3309, 3114, 3043,

= 1.9, J_4,2= 0.9 Hz, 1 H, H-4-furyl), 7.51 (t, J_5,2= J_5,4= 1.7 Hz,

1 H, H-5-furyl), 7.97 (dd, J_2,5= 1.5, J_2,4= 0.9 Hz, 1 H, H-2-thi-

enyl), 8.31 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ =

–1.4 (CH₃Si), 17.9 (OCH₂CH₂Si), 66.3 (OCH₂CH₂Si), 70.5

(NCH₂O), 97.1 (CH-5), 102.9 (C-4a), 110.4 (CH-4-furyl), 116.7 (C-

3-furyl), 131.1 (C-6), 141.0 (CH-2-furyl), 143.5 (CH-5-furyl), 150.6

(CH-2), 152.2 (C-7a), 155.5 (C-4) ppm. HRMS (ESI): m/z calcd.

for C₁₆H₂₃O₂N₄Si 331.1585; found 331.1585.

˜

2950, 1673, 1595, 1589, 1562, 1556, 1455, 1323, 1248, 1096, 1069,

863, 839, 761 cm^–1. HRMS (ESI): m/z calcd. for C₁₇H₂₃N₅OSi

341.1672; found 341.1671.

6-(Thiophen-2-yl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

[2,3-d]pyrimidine-4-amine (24c): Starting from pyrrolo[2,3-d]pyrim-

idine 23c (410 mg, 1 mmol), the reaction was performed according

to the General Procedure to give 24c (316 mg, 91%) as a yellowish

solid, m.p. 151 °C. ¹H NMR (500 MHz, CDCl₃): δ = –0.04 (s, 9 6-(2,4-Dimethoxypyrimidin-5-yl)-7-[2-(trimethylsilyl)ethoxymeth-

H, CH₃Si), 0.94–0.98 (m, 2 H, OCH₂CH₂Si), 3.67–3.70 (m, 2 H,

OCH₂CH₂Si), 5.58 (br. s, 2 H, NH₂), 5.68 (s, 2 H, NCH₂O), 6.59

yl]-7H-pyrrolo[2,3-d]pyrimidine-4-amine (24g): Starting from pyr-

rolo[2,3-d]pyrimidine deazapurine 23g (465 mg, 1 mmol), the reac-

(s, 1 H, H-5), 7.14 (dd, J_4,5= 5.1, J_4,3= 3.6 Hz, 1 H, H-4-thienyl), tion was performed according to the General Procedure to give 24g

1

7.38 (dd, J_5,4= 5.1, J_5,3= 1.2 Hz, 1 H, H-5-thienyl), 7.58 (dd, J_3,4(374 mg, 93%) as a white solid, m.p. 104 °C. H NMR (500 MHz,

= 3.6, J_3,5= 1.2 Hz, 1 H, H-3-thienyl), 8.33 (s, 1 H, H-2) ppm. ¹³

C

CDCl₃): δ = –0.10 (s, 9 H, CH₃Si), 0.80–0.83 (m, 2 H,

7954

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

OCH₂CH₂Si), 3.47–3.49 (m, 2 H, OCH₂CH₂Si), 4.01 (s, 3 H, 12.64 (v. br. s., 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]-

CH₃O-4Ј), 4.07 (s, 3 H, CH₃O-2Ј), 5.50 (s, 2 H, NCH₂O), 5.58 (br. DMSO): δ = 53.6 (CH₃O), 97.4 (CH-5), 105.8 (C-4a), 120.2 (CH-

s, 2 H, NH₂), 6.51 (s, 1 H, H-5), 8.35 (s, 1 H, H-2), 8.43 (s, 1 H,

H-6Ј) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 17.8

(OCH₂CH₂Si), 54.4 (CH₃O-4Ј), 55.1 (CH₃O-2Ј), 66.3

3-py), 123.0 (CH-5-py), 136.5 (C-6), 137.4 (CH-4-py), 149.7 (CH-

6-py), 149.9 (C-2-py), 151.6 (CH-2), 153.6 (C-7a), 162.7 (C-4) ppm.

IR (KBr): ν = 3066, 3007, 2983, 2935, 2857, 2797, 1601, 1589, 1580,

˜

(OCH₂CH₂Si), 71.1 (NCH₂O), 101.0 (CH-5), 102.9 (C-4a), 107.0 1479, 1458, 1443, 1410, 1329, 1278, 1242, 1180, 1126, 979, 887,

(C-5Ј), 130.1 (C-6), 151.0 (CH-2), 152.1 (C-7a), 155.7 (C-4), 159.8 842, 752 cm^–1. HRMS (ESI): m/z calcd. for C₁₂H₁₀ON₄Na

(CH-6Ј), 165.5 (C-2Ј), 168.8 (C-4Ј) ppm. IR (KBr): ν = 3437, 3413,

249.0747; found 249.0746.

˜

3339, 3219, 3138, 2959, 2896, 1646, 1610, 1586, 1559, 1473, 1398,

1377, 1299, 1251, 1087, 1015, 866, 833 cm^–1. HRMS (ESI): m/z

calcd. for C₁₈H₂₆N₆O₃Si 402.1836, found 402.1835.

4-Methoxy-6-(thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (21c):

Starting from pyrrolo[2,3-d]pyrimidine 19c (724 mg, 2 mmol), the

reaction was performed according to the General Procedure to give

6-(Trifluoromethyl)-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo- 21c (416 mg, 90%) as a yellowish solid, m.p. 227 °C. ¹H NMR

[2,3-d]pyrimidine-4-amine (24l): Starting from pyrrolo[2,3-d]pyrim-

idine deazapurine 23l (130 mg, 0.33 mmol), the reaction was per-

formed according to the General Procedure to give 24l (100 mg,

90%) as a white solid, m.p. 140 °C. H NMR (500 MHz, CDCl₃):

δ = –0.06 (s, 9 H, CH₃Si), 0.90–0.93 (m, 2 H, OCH₂CH₂Si), 3.57–

(500.0 MHz, [D₆]DMSO): δ = 4.04 (s, 3 H, CH₃O), 6.68 (s, 1 H,

H-5), 7.15 (dd, J_4,5= 5.1, J_4,3= 3.6 Hz, 1 H, H-4-thienyl), 7.58 (br.

d, J_5,4= 5.1 Hz, 1 H, H-5-thienyl), 7.62 (br. d, J_3,4= 3.6 Hz, 1 H,

H-3-thienyl), 8.38 (s, 1 H, H-2), 12.60 (br. s, 1 H, NH) ppm. ¹³C

NMR (125.7 MHz, [D₆]DMSO): δ = 53.8 (CH₃O), 95.0 (CH-5),

1

3.60 (m, 2 H, OCH₂CH₂Si), 5.71 (s, 2 H, NCH₂O), 5.80 (br. s, 2 106.0 (C-4a), 125.3 (CH-3-thienyl), 126.6 (CH-5-thienyl), 128.6

H, NH₂), 6.96 (q, J_5,F= 1.1 Hz, 1 H, H-5), 8.40 (s, 1 H, H-2) ppm.

^{1 3}C NMR (125.7 MHz, CDCl₃): δ = –1.6 (CH₃Si), 17.7

(OCH₂CH₂Si), 66.8 (OCH₂CH₂Si), 71.6 (NCH₂O), 101.1 (C-4a),

102.5 (q, J_C,F= 4.4 Hz, CH-5), 120.7 (q, J_C,F= 268.7 Hz, CF₃),

125.1 (q, J_C,F= 39.3 Hz, C-6), 152.5 (C-7a), 153.1 (CH-2), 157.0

(C-4) ppm. ¹⁹F NMR (470.3 MHz, CDCl₃): δ = –56.03 (s, 1 F, F-

(CH-4-thienyl), 131.8 (C-6), 134.6 (C-2-thienyl), 151.2 (CH-2),

153.8 (C-7a), 162.3 (C-4) ppm. IR (KBr): ν = 3210, 3123, 3069,

˜

2988, 2947, 2875, 2842, 1610, 1592, 1562, 1485, 1407, 1344, 1329,

1299, 1216, 1183, 1123, 973, 890, 773, 695 cm^–1. HRMS (ESI): m/z

calcd. for C₁₁H₁₀ON₃S 232.0539; found 232.0539.

6-(Furan-2-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (21d): Start-

ing from pyrrolo[2,3-d]pyrimidine 19d (345 mg, 1 mmol), the reac-

tion was performed according to the General Procedure to give 21d

(172 mg, 80%) as a white solid, m.p. 243 °C. ¹H NMR (500.0 MHz,

2) ppm. IR (KBr): ν = 3135, 2953, 2929, 1655, 1601, 1562, 1544,

˜

1365, 1314, 1251, 1180, 1129, 1120, 869, 836 cm^–1. HRMS (ESI):

m/z calcd. for C₁₃H₂₀ON₄F₃Si 333.1353; found 333.1353.

Deprotection of SEM Group; General Procedure: A SEM-protected

pyrrolo[2,3-d]pyrimidine 19a–h, 19j–l, 24a–g, 24l, or 27j–l was dis-

solved in trifluoroacetic acid (2 mL) and the reaction mixture was

stirred at room temp. for 30 min. The mixture was then diluted

with NaHCO₃(to pH 7) and EtOAc (25 mL) was added. The layers

were separated and the aqueous layer was extracted with EtOAc

(ϫ2). The combined organic layers were dried with sodium sulfate,

and concentrated under reduced pressure to give a solid. Aq. am-

monia (25% w/w, 15 mL) was added and the mixture was stirred

at room temp. overnight to form white precipitate of product,

which was isolated by filtration.

[D₆]DMSO): δ = 4.04 (s, 3 H, CH₃O), 6.64 (dd, J_4,3= 3.4, J_4,5=

1.8 Hz, 1 H, H-4-furyl), 6.67 (s, 1 H, H-5), 6.99 (dd, J_3,4= 3.4, J_3,5

= 0.8 Hz, 1 H, H-3-furyl), 7.79 (dd, J_5,4= 1.8, J_5,3= 0.8 Hz, 1 H,

H-5-furyl), 8.38 (s, 1 H, H-2), 12.59 (v. br. s., 1 H, NH) ppm. ¹³C

NMR (125.7 MHz, [D₆]DMSO): δ = 53.6 (CH₃O), 96.7 (CH-5),

105.5 (C-4a), 107.5 (CH-3-furyl), 112.2 (CH-4-furyl), 128.4 (C-6),

143.6 (CH-5-furyl), 146.7 (C-2-furyl), 151.1 (CH-2), 153.5 (C-7a),

162.2 (C-4) ppm. IR (KBr): ν = 3117, 3075, 2989, 2941, 2893, 2818,

˜

1598, 1586, 1524, 1482, 1458, 1410, 1344, 1326, 1296, 1248, 1183,

1132, 1075, 1006, 973, 884, 830, 764, 740, 656 cm^–1. HRMS (ESI):

m/z calcd. for C₁₁H₁₀O₂N₃216.0768; found 216.0768.

4-Methoxy-6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (21a):

Starting from pyrrolo[2,3-d]pyrimidine 19a (772 mg, 2 mmol), the

reaction was performed according to the General Procedure to give

21a (458 mg, 90 %) as a white solid, m.p. 278 °C. ¹H NMR

(600.1 MHz, CDCl₃): δ = 3.80 (s, 3 H, CH₃O-p), 4.04 (s, 3 H,

CH₃O-4), 6.83 (s, 1 H, H-5), 7.01–7.03 (m, 2 H, H-m-C₆H₄OMe),

7.85–7.87 (m, 2 H, H-o-C₆H₄OMe), 8.36 (s, 1 H, H-2), 12.41 (br.

s, 1 H, NH) ppm. ¹³C NMR (150.9 MHz, CDCl₃): δ = 53.5 (CH₃O-

4-Methoxy-6-(thiophen-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (21e):

Starting from pyrrolo[2,3-d]pyrimidine 19e (723 mg, 1 mmol), the

reaction was performed according to the General Procedure to give

21e (414 mg, 90 %) as a white solid, m.p. 232 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 4.04 (s, 3 H, CH₃O), 6.85 (s, 1 H,

H-5), 7.66 (dd, J_5,4= 5.1, J_5,2= 2.9 Hz, 1 H, H-5-thienyl), 7.69

(dd, J_4,5= 5.1, J_4,2= 1.4 Hz, 1 H, H-4-thienyl), 8.00 (dd, J_2,5

=

2.9, J_2,4= 1.4 Hz, 1 H, H-2-thienyl), 8.37 (s, 1 H, H-2), 12.47 (br.

4), 55.4 (CH₃O-p), 93.6 (CH-5), 106.0 (C-4a), 114.6 (CH-m- s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 53.4

C₆H₄OMe), 123.9 (C-i-C₆H₄OMe), 126.9 (CH-o-C₆H₄OMe), 136.8 (CH₃O), 94.8 (CH-5), 105.6 (C-4a), 121.1 (CH-2-thienyl), 126.1

(C-6), 150.3 (CH-2), 153.7 (C-7a), 159.4 (C-p-C₆H₄OMe), 161.8 (C- (CH-4-thienyl), 127.5 (CH-5-thienyl), 133.0 and 133.2 (C-6,C-3-thi-

4) ppm. IR (KBr): ν = 3150, 3013, 2995, 2941, 2842, 1622, 1598,

enyl), 150.6 (CH-2), 153.4 (C-7a), 162.1 (C-4) ppm. IR (KBr): ν =

˜

1544, 1503, 1482, 1332, 1254, 1177, 1126, 1024, 976, 890, 827,

3216, 3126, 3081, 3066, 3016, 2983, 2944, 2863, 1610, 1592, 1562,

773 cm^–1. HRMS (ESI): m/z calcd. for C₁₄H₁₄O₂N₃256.1081; 1479, 1341, 1323, 1180, 1126, 973, 899, 878, 770, 653 cm^–1. HRMS

found 256.1081.

(ESI): m/z calcd. for C₁₁H₁₀ON₃S 232.0539; found 232.0539.

4-Methoxy-6-(pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (21b): 6-(Furan-3-yl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (21f): Start-

Starting from pyrrolo[2,3-d]pyrimidine 19b (356 mg, 1 mmol), the

reaction was performed according to the General Procedure to give

21b (192 mg, 85 %) as a white solid, m.p. Ͼ350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 4.06 (s, 3 H, CH₃O), 7.20 (s, 1 H,

H-5), 7.34 (ddd, J_5,4= 7.5, J_5,6= 4.8 Hz, J_5,3= 1.1 Hz, 1 H, H-5-

py), 7.89 (td, J_4,5= J_4,3= 7.8, J_4,6= 1.8 Hz, 1 H, H-4-py), 8.06 (dt,

J_3,4= 8.0, J_3,5= J_3,6= 1.1 Hz, 1 H, H-2-furyl), 8.41 (s, 1 H, H-2),

8.64 (ddd, J_6,5= 4.8, J_6,4= 1.8 Hz, J_6,3= 1.0 Hz, 1 H, H-6-py),

ing from pyrrolo[2,3-d]pyrimidine 19f (691 mg, 2 mmol), the reac-

tion was performed according to the General Procedure to give 21f

(281 mg, 65%) as a white solid, m.p. 218 °C. ¹H NMR (500.0 MHz,

[D₆]DMSO): δ = 4.04 (s, 3 H, CH₃O), 6.79 (d, J_5,NH= 2.1 Hz, 1

H, H-5), 7.05 (dd, J_4,5= 1.9, J_4,2= 0.8 Hz, 1 H, H-4-furyl), 7.77

(t, J_5,2= J_5,4= 1.7 Hz, 1 H, H-5-furyl), 8.21 (br. dd, J_2,5= 1.5, J_2,4

= 0.8 Hz, 1 H, H-2-furyl), 8.36 (s, 1 H, H-2), 12.37 (br. s, 1 H,

NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 53.4 (CH₃O),

Eur. J. Org. Chem. 2015, 7943–7961

www.eurjoc.org

7955

M. Klecˇka, L. Posˇtová Slaveˇtínská, M. Hocek

94.8 (CH-5), 105.5 (C-4a), 108.4 (CH-4-furyl), 118.4 (C-3-furyl), (C-2-py), 152.1 (C-7a), 153.0 (CH-2), 157.9 (C-4) ppm. IR (KBr):

FULL PAPER

129.7 (C-6), 139.8 (CH-2-furyl), 144.5 (CH-5-furyl), 150.5 (CH-2), ν = 3398, 3078, 2971, 2923, 2845, 2809, 1637, 1622, 1595, 1580,

˜

153.4 (C-7a), 161.8 (C-4) ppm. IR (KBr): ν = 3216, 3174, 3141,

1464, 1443, 1359, 1284, 758 cm^–1. HRMS (ESI): m/z calcd. for

˜

3129, 3001, 2944, 2899, 2860, 1604, 1586, 1491, 1338, 1332, 1159,

1129, 1072, 973, 872, 767, 650, 588 cm^–1. HRMS (ESI): m/z calcd.

for C₁₁H₁₀O₂N₃216.0768; found 216.0768.

C₁₁H₁₀N₅212.0931; found 212.0931.

6-(Thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25c): Start-

ing from pyrrolo[2,3-d]pyrimidine 24c (347 mg, 1 mmol), the reac-

tion was performed according to the General Procedure to give 25c

(160 mg, 74 %) as a greyish solid, m.p. 345 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 6.73 (s, 1 H, H-5), 6.96 (br. s, 2 H,

NH₂), 7.11 (dd, J_4,5= 5.1, J_4,3= 3.6 Hz, 1 H, H-4-thienyl), 7.46

–7.50 (m, 2 H, H-3,5-thienyl), 8.03 (s, 1 H, H-2), 12.06 (br. s, 1 H,

NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 96.4 (CH-5),

6-(3-Aminophenyl)-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (21h):

Pyrrolo[2,3-d]pyrimidine 19h (1.02 g, 2.75 mmol) was used accord-

ing to the General Procedure. Crude product was purified by

chromatography on silica gel (CHCl₃/MeOH, 10:1) to give 21h

(147 mg, 22 %) as a yellowish solid, m.p. 296 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 4.04 (s, 3 H, CH₃O), 5.15 (br. s, 2

H, NH₂), 6.57 (ddd, J_6Ј,5Ј= 7.8, J_6Ј,2Ј= 2.2 Hz, J_6Ј,4Ј= 1.2 Hz, 1 103.5 (C-4a), 123.5 (CH-3-thienyl), 125.0 (CH-5-thienyl), 128.3

H, H-6Ј), 6.71 (s, 1 H, H-5), 7.02–7.06 (m, 2 H, H-2Ј,4Ј), 7.09 (t, (CH-4-thienyl), 128.5 (C-6), 135.4 (C-2-thienyl), 151.9 (C-7a), 152.4

J_5Ј,4Ј= J_5Ј,6Ј= 7.9 Hz, 1 H, H-5Ј), 8.36 (s, 1 H, H-2), 12.38 (br. s,

(CH-2), 157.2 (C-4) ppm. IR (KBr): ν = 3464, 3300, 3117, 3108,

˜

1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 53.5

3096, 2988, 1637, 1586, 1556, 1485, 1314, 764, 698 cm^–1. HRMS

(CH₃O), 94.1 (CH-5), 105.8 (C-4a), 110.9 (CH-2Ј), 113.5 (CH-4Ј), (ESI): m/z calcd. for C₁₀H₉N₄S 217.0542; found 217.0543.

114.3 (CH-6Ј), 129.6 (CH-5Ј), 131.8 (C-3Ј), 137.8 (C-6), 149.2 (C-

6-(Furan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25d): Pyr-

1Ј), 150.5 (CH-2), 153.6 (C-7a), 162.0 (C-4) ppm. IR (KBr): ν =

˜

rolo[2,3-d]pyrimidine 24d (248 mg, 0.75 mmol) was deprotected ac-

cording to the General Procedure. Crude product was purified by

chromatography on silica gel (CHCl₃/MeOH, 10:1) to give 25d

(119 mg, 79%) as a white solid, m.p. 300 °C. ¹H NMR (500.0 MHz,

[D₆]DMSO): δ = 6.59 (dd, J_4,3= 3.4, J_4,5= 1.8 Hz, 1 H, H-4-furyl),

3330, 3225, 3126, 1983, 2947, 1598, 1586, 1479, 1355, 1126,

776 cm^–1. HRMS (ESI): m/z calcd. for C₁₃H₁₃ON₄241.1084; found

241.1084.

6-(Uracil-5-yl)-pyrrolo[2,3-d]pyrimidin-4-one (22i): Pyrrolo[2,3-

d]pyrimidine 19g (731 mg, 1.75 mmol) was deprotected according

to the General Procedure directly followed by heating to reflux in

a solution of THF/dioxane/HCl (1:1:1, 9 mL) for 2 h. The reaction

mixture was evaporated and ethanol (5 mL) was added. The mix-

ture was then kept in a refrigerator overnight to furnish 22i

(416 mg, 97 %) as yellowish crystals, m.p. Ͼ 350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 7.00 (d, J_5,NH= 2.3 Hz, 1 H, H-5),

6.76 (d, J_5,NH= 1.9 Hz, 1 H, H-5), 6.83 (dd, J_3,4= 3.4, J_3,5

=

0.9 Hz, 1 H, H-3-furyl), 7.00 (br. s, 2 H, NH₂), 7.72 (dd, J_5,4= 1.8,

J_5,3= 0.9 Hz, 1 H, H-5-furyl), 8.03 (s, 1 H, H-2), 11.99 (br. s, 1 H,

NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 95.4 (CH-5),

103.3 (C-4a), 105.8 (CH-3-furyl), 112.0 (CH-4-furyl), 125.5 (C-6),

142.8 (CH-5-furyl), 147.5 (C-2-furyl), 151.7 (C-7a), 152.4 (CH-2),

157.4 (C-4) ppm. IR (KBr): ν = 3461, 3309, 3150, 3117, 3102, 2980,

˜

7.83 (s, 1 H, H-2), 7.97 (d, J_6Ј,NH= 6.1 Hz, 1 H, H-6Ј), 11.31 (dd, 2839, 1640, 1592, 1574, 1476, 1302, 1015, 767 cm^–1. HRMS (ESI):

J_NH,6Ј= 6.1, J_NH,NH= 1.8 Hz, 1 H, NH-1Ј), 11.39 (d, J_NH,NH

1.8 Hz, 1 H, NH-3Ј), 11.85 (v. br. s, 1 H, NH-3), 11.90 (d, J_NH,5

=

m/z calcd. for C₁₀H₉ON₄201.0771; found 201.0771.

6-(Thiophen-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25e): Pyr-

rolo[2,3-d]pyrimidine 24e (260 mg, 0.75 mmol) was deprotected ac-

cording to the General Procedure. Crude product was purified by

chromatography on silica gel (CHCl₃/MeOH, 10:1) to give 25e

(117 mg, 72 %) as a white solid, m.p. Ͼ 350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 6.74 (d, J_5,NH= 2.2 Hz, 1 H, H-5),

6.91 (br. s, 2 H, NH₂), 7.48 (dd, J_4,5= 5.0, J_4,2= 1.3 Hz, 1 H, H-

4-thienyl), 7.64 (dd, J_5,4= 5.0, J_5,2= 2.9 Hz, 1 H, H-5-thienyl),

7.82 (dd, J_2,5= 2.9, J_2,4= 1.3 Hz, 1 H, H-2-thienyl), 8.02 (s, 1 H,

H-2), 11.92 (br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]-

DMSO): δ = 96.0 (CH-5), 103.4 (C-4a), 119.6 (CH-2-thienyl), 125.5

(CH-4-thienyl), 127.5 (CH-5-thienyl), 130.1 (C-6), 133.8 (C-3-thi-

2.3 Hz, 1 H, NH-7) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ =

101.4 (CH-5), 104.9 (C-5Ј), 108.6 (C-4a), 126.8 (C-6), 137.7 (CH-

6Ј), 143.9 (CH-2), 148.7 (C-7a), 150.7 (C-2Ј), 158.5 (C-4), 162.6 (C-

4Ј) ppm. IR (KBr): ν = 3261, 3219, 3183, 3156, 3114, 3063, 2908,

˜

1706, 1682, 1583, 1565, 1524, 1416, 1257, 1227, 1192, 914, 824,

782, 555 cm^–1. HRMS (ESI): m/z calcd. for C₁₀H₇O₃N₅²³Na

268.0441; found 268.0442.

6-(4-Methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25a):

Starting from pyrrolo[2,3-d]pyrimidine 24a (148 mg, 0.4 mmol), the

reaction was performed according to the General Procedure to give

25a (77 mg, 80 %) as a white solid, m.p. 324 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 3.79 (s, 3 H, CH₃O), 6.76 (d, J_5,NHenyl), 151.7 (C-7a), 152.1 (CH-2), 157.3 (C-4) ppm. IR (KBr): ν =

˜

= 2.2 Hz, 1 H, H-5), 6.88 (br. s, 2 H, NH₂), 7.00–7.02 (m, 2 H, H-

3467, 3297, 3111, 3087, 3025, 2905, 1646, 1595, 1562, 1485, 1320,

m-Ph), 7.69–7.71 (m, 2 H, H-o-Ph), 8.01 (s, 1 H, H-2), 11.87 (br. 791, 761 cm^–1. HRMS (ESI): m/z calcd. for C₁₀H₉N₄S 217.0542;

d, J_NH,5= 2.0 Hz, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]- found 217.0543.

DMSO): δ = 55.4 (CH₃O), 94.8 (CH-5), 103.8 (C-4a), 114.6 (CH-

6-(Furan-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25f): Pyr-

m-Ph), 124.7 (C-i-Ph), 126.2 (CH-o-Ph), 133.8 (C-6), 151.8 (CH-

rolo[2,3-d]pyrimidine 24f (247 mg, 0.75 mmol) was deprotected ac-

2), 152.0 (C-7a), 157.1 (C-4), 158.9 (C-p-Ph) ppm. HRMS (ESI):

cording to the General Procedure. Crude product was purified by

m/z calcd. for C₁₃H₁₃ON₄241.1084; found 241.1084.

chromatography on silica gel (CHCl₃/MeOH, 10:1) to give 25f

6-(Pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25b): Start-

ing from pyrrolo[2,3-d]pyrimidine 24b (256 mg, 0.75 mmol), the re-

action was performed according to the General Procedure to give

25b (117 mg, 74 %) as a white solid, m.p. 326 °C. ¹H NMR

(98 mg, 65 %) as a white solid, m.p. Ͼ 350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 6.63 (d, J_5,NH= 2.1 Hz, 1 H, H-5),

6.84 (dd, J_4,5= 1.9, J_4,2= 0.9 Hz, 1 H, H-4-furyl), 6.88 (br. s, 2 H,

NH₂), 7.75 (t, J_5,4= J_5,2= 1.7 Hz, 1 H, H-5-furyl), 8.01 (s, 1 H,

(500.0 MHz, [D₆]DMSO): δ = 7.08 (br. s, 2 H, NH₂), 7.23 (br. s, 1 H-2), 8.10 (dd, J_2,5= 1.6, J_2,4= 0.9 Hz, 1 H, H-2-furyl), 11.81 (br.

H, H-5), 7.25–7.28 (m, 1 H, H-5-py), 7.82–7.88 (m, 2 H, H-3,4-py), s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 95.9

8.07 (s, 1 H, H-2), 8.59 (dt, J_6,5= 4.7, J_6,4= J_6,3= 1.4 Hz, 1 H, H-

(CH-5), 103.3 (C-4a), 108.6 (CH-4-furyl), 118.9 (C-3-furyl), 126.5

(C-6), 138.9 (CH-2-furyl), 144.5 (CH-5-furyl), 151.7 (C-7a), 152.0

6-py), 12.08 (br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]-

DMSO): δ = 99.2 (CH-5), 103.8 (C-4a), 119.1 (CH-3-py), 122.2 (CH-2), 157.0 (C-4) ppm. IR (KBr): ν = 3458, 3297, 3168, 3117,

˜

(CH-5-py), 133.5 (C-6), 137.3 (CH-4-py), 149.7 (CH-6-py), 150.2

2893, 2929, 2860, 1643, 1592, 1577, 1482, 1335, 1320, 779,

7956

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

770 cm^–1. HRMS (ESI): m/z calcd. for C₁₀H₉ON₄201.0771; found

12.89 (v.br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO):

201.0771.

δ = 53.9 (CH₃O), 96.6 (CH-5), 105.3 (C-4a), 122.9 (C-6), 151.3

(CH-2), 152.1 (C-7a), 161.5 (C-4) ppm. IR (KBr): ν = 3174, 3129,

˜

6-(Uracil-5-yl)-pyrrolo[2,3-d]pyrimidin-4-amine (25i): Pyrrolo[2,3-

d]pyrimidine 24g (302 mg, 0.75 mmol) was deprotected according

to the General Procedure directly followed by heating to reflux in

a solution of THF/dioxane/HCl (1:1:1, 9 mL) for 24 h. The reaction

mixture was evaporated and ethanol (5 mL) was added. The mix-

ture was then kept in a refrigerator overnight to furnish 25i

(141 mg, 77 %) as yellowish crystals, m.p. Ͼ350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 7.52 (d, J_5,NH= 2.2 Hz, 1 H, H-5),

3084, 3055, 2962, 2938, 2893, 2869, 2821, 2744, 2711, 2678, 2660,

1601, 1583, 1488, 1458, 1413, 1347, 1326, 1305, 114, 1096, 970, 940,

893, 815, 791, 653 cm^–1. HRMS (ESI): m/z calcd. for C₇H₇ON₃Cl

184.0272; found 184.0272.

6-Bromo-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (21k): Starting

from pyrrolo[2,3-d]pyrimidine 19k (347 mg, 1.25 mmol), the reac-

tion was performed according to the General Procedure to give 21k

8.15 (d, J_6Ј,NH= 6.1 Hz, 1 H, H-6Ј), 8.32 (s, 1 H, H-2), 11.48 (d, (142 mg, 50%) as a white solid, m.p. 234 °C. ¹H NMR (500.0 MHz,

J_NH,NH= 1.8 Hz, 1 H, NH-3Ј), 11.51 (dd, J_NH,6Ј= 6.1, J_NH,NH

=

[D₆]DMSO): δ = 4.01 (s, 3 H, CH₃O), 6.60 (s, 1 H, H-5), 8.36 (s, 1

H, H-2), 12.84 (v. br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz,

[D₆]DMSO): δ = 53.6 (CH₃O), 100.1 (CH-5), 105.9 (C-4a), 109.3

1.8 Hz, 1 H, NH-1Ј), 12.81 (d, J_NH,5= 2.2 Hz, 1 H, NH-7) ppm.

¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 100.9 (CH-5), 102.1 (C-

4a), 103.8 (C-5Ј), 130.7 (C-6), 139.2 (CH-6Ј), 142.3 (CH-2), 148.5

(C-6), 150.8 (CH-2), 153.3 (C-7a), 160.0 (C-4) ppm. IR (KBr): ν =

˜

(C-7a), 150.4 (C-4), 150.5 (C-2Ј), 162.2 (C-4Ј) ppm. IR (KBr): ν =

3697, 3129, 3087, 3049, 2988, 2959, 2938, 2866, 2818, 1607, 1589,

1479, 1461, 1413, 1347, 1326, 1141, 979, 896 cm^–1. HRMS (ESI):

m/z calcd. for C₇H₇ON₃⁷⁹Br 227.9767; found 227.9768.

˜

3318, 3267, 3150, 3043, 2956, 2851, 2788, 2729, 1709, 1676, 1595,

1574, 1446, 1442, 1245, 1224, 1216, 770 cm^–1. HRMS (ESI): m/z

calcd. for C₁₀H₉O₂N₆245.0782; found 245.0782.

4-Methoxy-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (21l):

Pyrrolo[2,3-d]pyrimidine 19l (420 mg, 1.2 mmol) was deprotected

according to the General Procedure. Crude product was purified

by chromatography on silica gel (CHCl₃/MeOH, 10:1) to give 21l

4,6-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (28j): Pyrrolo[2,3-d]pyr-

imidine 27j (318 mg, 1 mmol) was deprotected according to the Ge-

neral Procedure. Crude product was purified by chromatography

on silica gel (CHCl₃/MeOH, 10:1) to give 28j (124 mg, 66%) as a

1

(198 mg, 75%) as a white solid, m.p. 190 °C. H NMR (500 MHz,

1

white solid, m.p. 250 °C. H NMR (500.0 MHz, [D₆]DMSO): δ =

[D₆]DMSO): δ = 3.44 (s, 3 H, CH₃O), 7.10 (q, J_5,F= 1.3 Hz, 1 H,

6.72 (s, 1 H, H-5), 8.60 (s, 1 H, H-2), 12.48 (v. br. s, 1 H, NH) ppm.

¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 97.3 (CH-5), 117.3 (C-

4a), 127.6 (C-6), 149.4 (C-4), 150.9 (CH-2), 151.4 (C-7a) ppm. IR

H-5), 8.54 (s, 1 H, H-2), 13.36 (br. s, 1 H, NH) ppm. ¹³C NMR

(125.7 MHz, [D₆]DMSO): δ = 54.1 (CH₃O), 100.6 (q, J_C,F

=

3.7 Hz, CH-5), 104.0 (C-4a), 121.2 (q, J_C,F= 267.8 Hz, CF₃), 124.0

(KBr): ν = 3126, 3072, 2962, 2935, 2794, 2678, 2651, 1610, 1565, (q, J_C,F= 39.2 Hz, C-6), 153.3 (C-7a), 153.7 (CH-2), 163.9 (C-

˜

1497, 1443, 1338, 1260, 1213, 988, 872, 815 cm^–1. HRMS (ESI):

4) ppm. ¹⁹F NMR (470.3 MHz, [D₆]DMSO): δ = –56.00 (s, 1 F,

m/z calcd. for C₆H₃N₃Cl₂186.9704; found 186.9705.

CF ) ppm. IR (KBr): ν = 3111, 3081, 2998, 2956, 2854, 2827, 2732,

˜

3

2678, 2630, 1592, 1556, 1491, 1413, 1335, 1320, 1296, 1254, 1192,

1177, 1126, 1084, 967, 893, 845, 788, 719, 659 cm^–1. HRMS (ESI):

m/z calcd. for C₈H₇ON₃F₃218.0536; found 218.0534.

6-Bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (28k): Pyrrolo[2,3-

d]pyrimidine 27k (363 mg, 1 mmol) was deprotected according to

the General Procedure. Crude product was purified by chromatog-

raphy on silica gel (CHCl₃/MeOH, 10:1) to give 28k (174 mg, 75%)

6-(Trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine-4-amine (25l): Pyr-

1

as a white solid, m.p. 258 °C. H NMR (500.0 MHz, [D₆]DMSO): rolo[2,3-d]pyrimidine 24l (100 mg, 0.3 mmol) was deprotected ac-

δ = 6.80 (s, 1 H, H-5), 8.58 (s, 1 H, H-2), 13.43 (v. br. s, 1 H, cording to the General Procedure. Crude product was purified by

NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 101.2 (CH-

chromatography on silica gel (CHCl₃/MeOH, 10:1) to give 25l

(55 mg, 90 %) as a white solid, m.p. Ͼ350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 7.09 (q, J_5Ј,F= 1.4 Hz, 1 H, H-5),

5), 114.4 (C-6), 117.6 (C-4a), 149.1 (C-4), 150.8 (CH-2), 152.5 (C-

7a) ppm. IR (KBr): ν = 3123, 3090, 3069, 3022, 2950, 2920, 2875,

˜

2803, 1604, 1559, 1494, 1422, 1335, 1263, 1210, 988, 866, 806 cm^–1. 7.32 (br. s, 2 H, NH₂), 8.14 (s, 1 H, H-2), 12.68 (br. s, 1 H,

HRMS (ESI): m/z calcd. for C₆H₃N₃ClBr 230.9199; found

230.9200.

NH) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 101.6 (C-4a),

101.7 (q, J_C,F= 3.8 Hz, CH-5), 120.8 (q, J_C,F= 38.8 Hz, C-6),

121.5 (q, J_C,F= 266.9 Hz, CF₃), 151.9 (C-7a), 154.6 (CH-2), 158.7

(C-4) ppm. ¹⁹F NMR (470.3 MHz, [D₆]DMSO): δ = –55.67 (s, 1 F,

4-Chloro-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine (28l): Pyr-

rolo[2,3-d]pyrimidine 27l (246 mg, 0.7 mmol) was deprotected ac-

cording to the General Procedure. Crude product was purified by

chromatography on silica gel (CHCl₃/MeOH, 10:1) to give 28l

(113 mg, 73%) as a white solid, m.p. 191 °C. ¹H NMR (500.0 MHz,

[D₆]DMSO): δ = 7.30 (q, J_5,F= 1.3 Hz, 1 H, H-5), 8.79 (s, 1 H, H-

2), 13.92 (v. br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]-

DMSO): δ = 101.4 (br. q, J_C,F= 3.7 Hz, CH-5), 115.8 (C-4a), 120.7

(br. q, J_C,F= 268.8 Hz, CF₃), 127.4 (q, J_C,F= 39.7 Hz, C-6), 152.4

(C-7a), 153.3 (CH-2), 153.4 (C-4) ppm. ¹⁹F NMR (470.3 MHz,

CF ) ppm. IR (KBr): ν = 3494, 3072, 2983, 2920, 2845, 2809, 2735,

˜

3

2669, 1661, 1586, 1380, 1329, 1204, 1177, 1120, 1081 cm^–1. HRMS

(ESI): m/z calcd. for C₇H₆N₄F₃203.0539; found 203.0538.

Deprotection of the OMe Group to give Pyrrolo[2,3-d]pyrimidin-4-

ones; General Procedure: To a stirred mixture of a 4-methoxy-7H-

pyrrolo[2,3-d]pyrimidine 21a–f, 21h, or 21l (0.50 mmol, 1 equiv.)

and NaI (272 mg, 2.5 mmol, 5 equiv.) in anhydrous MeCN (5 mL),

TMSCl (438 μL, 2.5 mmol, 5 equiv.) was slowly added and the mix-

ture was stirred at 80 °C for 18 h. The precipitate was filtered off,

washed carefully with MeCN, and dissolved in water, and pH of

the solution was adjusted to 7 using solid K₂CO₃. The product

precipitated and was filtered off.

[D ]DMSO): δ = δ = –56.66 (s, 1 F, CF ) ppm. IR (KBr): ν = 3093,

˜

6

3

3081, 2992, 2863, 2809, 2758, 2696, 1598, 1577, 1547, 1416, 1314,

1257, 1245, 1222, 1180, 1141, 979, 872 cm^–1. HRMS (ESI): m/z

calcd. for C₇H₃N₃ClF₃220.9968; found 220.9969.

6-Chloro-4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (21j): Pyrrolo[2,3-

d]pyrimidine 19j (471 mg, 1.5 mmol) was deprotected according to

the General Procedure. Crude product was purified by chromatog-

6-(4-Methoxyphenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22a):

Starting from pyrrolo[2,3-d]pyrimidine 21a (128 mg, 0.5 mmol), the

reaction was performed according to the General Procedure to give

22a (103 mg, 85%) as a greyish solid, m.p. Ͼ 300 °C. ¹H NMR

raphy on silica gel (CHCl₃/MeOH, 10:1) to give 21j (150 mg, 55%)

1

as a white solid, m.p. 235 °C. H NMR (500.0 MHz, [D₆]DMSO): (500 MHz, CDCl₃): δ = 3.78 (s, 3 H, CH₃O), 6.79 (d, J_5,NH

=

δ = 4.01 (s, 3 H, CH₃O), 6.52 (s, 1 H, H-5), 8.38 (s, 1 H, H-2),

2.4 Hz, 1 H, H-5), 6.97–6.99 (m, 2 H, H-m-C₆H₄OMe), 7.75–7.76

Eur. J. Org. Chem. 2015, 7943–7961

www.eurjoc.org

7957

M. Klecˇka, L. Posˇtová Slaveˇtínská, M. Hocek

FULL PAPER

(m, 2 H, H-o-C₆H₄OMe), 7.84 (bd, J_2,NH= 3.2 Hz, 1 H, H-2), H-2-thienyl), 7.86 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, [D₆]-

11.81 (br. s, 1 H, NH-3), 12.22 (br. d, J_NH,5= 2.4 Hz, 1 H, NH- DMSO): δ = 99.2 (CH-5), 109.0 (C-4a), 119.3 (CH-2-thienyl), 125.9

7) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –55.3 (CH₃O), 97.9

(CH-4-thienyl), 127.2 (CH-5-thienyl), 129.8 (C-6), 133.6 (C-3-thi-

(CH-5), 109.2 (C-4a), 114.5 (CH-m-C₆H₄OMe), 124.3 (C-i- enyl), 144.1 (CH-2), 149.3 (C-7a), 158.8 (C-4) ppm. IR (KBr): ν =

˜

C₆H₄OMe), 126.2 (CH-o-C₆H₄OMe), 133.4 (C-6), 143.2 (CH-2), 3201, 3186, 3174, 3129, 3081, 3060, 2989, 2914, 2854, 1673, 1655,

149.2 (C-7a), 158.3 (C-4), 158.8 (C-p-C₆H₄OMe) ppm. IR (KBr):

1586, 1568, 1541, 1446, 1422, 1245, 1207, 1186, 1084, 961, 917,

857, 761, 600 cm^–1. HRMS (ESI): m/z calcd. for C₁₀H₆ON₃S

216.0237; found 216.0238.

ν = 3192, 3111, 3093, 3028, 3001, 2962, 2899, 2863, 2836, 1664,

˜

1610, 1527, 1497, 1380, 1299, 1281, 1263, 1242, 1183, 1024, 914,

839, 809, 776, 620 cm^–1. HRMS (ESI): m/z calcd. for C₁₃H₁₂O₂N₃

242.0924; found 242.0925.

6-(Furan-3-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22f): Starting

from pyrrolo[2,3-d]pyrimidine 21f (215 mg, 1 mmol), the reaction

was performed according to the General Procedure to give 22f

(160 mg, 80 %) as a greyish solid, m.p. Ͼ 350 °C. ¹H NMR

6-(Pyridin-2-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22b): Start-

ing from pyrrolo[2,3-d]pyrimidine 21b (113 mg, 0.5 mmol), the re-

action was performed according to the General Procedure to give

22b (75 mg, 71 %) as a greyish solid, m.p. Ͼ300 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 6.69 (s, 1 H, H-5), 6.97 (dd, J_4,5

=

1.9, J_4,2= 0.9 Hz, 1 H, H-4-furyl), 7.72 (t, J_5,4= J_5,2= 1.7 Hz, 1

H, H-5-furyl), 7.84 (s, 1 H, H-2), 8.10 (dd, J_2,5= 1.5, J_2,4= 0.9 Hz,

1 H, H-2-furyl) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 99.1

(CH-5), 108.8 (CH-4-furyl), 108.8 (C-4a), 118.6 (C-3-furyl), 126.4

(C-6), 138.8 (CH-2-furyl), 143.7 (CH-2), 144.3 (CH-5-furyl), 149.0

(500.0 MHz, [D₆]DMSO): δ = 7.17 (s, 1 H, H-5), 7.27 (ddd, J_5,4

7.5, J_5,6= 4.8 Hz, J_5,3= 1.1 Hz, 1 H, H-5-py), 7.83 (ddd, J_4,3

=

8.0, J_4,5= 7.5 Hz, J_4,6= 1.8 Hz, 1 H, H-4-py), 7.89 (s, 1 H, H-2),

7.94 (dt, J_3,4= 8.0, J_3,5= J_3,6= 1.1 Hz, 1 H, H-3-py), 8.58 (ddd,

J_6,5= 4.8, J_6,4= 1.8 Hz, J_6,3= 1.0 Hz, 1 H, H-6-py), 11.89 (br. s,

1 H, NH-3), 12.48 (br. s, 1 H, NH-7) ppm. ¹³C NMR (125.7 MHz,

[D₆]DMSO): δ = 101.8 (CH-5), 109.4 (C-4a), 119.4 (CH-3-py),

122.3 (CH-5-py), 133.2 (C-6), 137.2 (CH-4-py), 144.5 (CH-2), 149.5

(CH-6-py), 149.7 (C-7a), 149.9 (C-2-py), 158.6 (C-4) ppm. IR

(C-7a), 158.3 (C-4) ppm. IR (KBr): ν = 3105, 3037, 2965, 2848,

˜

2806, 2717, 2663, 1679, 1562 cm^–1. 1601, 1559, 1425, 1389, 1242,

1213. HRMS (ESI): m/z calcd. for C₁₀H₇N₃O₂201.0538; found

201.0540.

6-(3-Aminophenyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22h):

Starting from pyrrolo[2,3-d]pyrimidine 21h (120 mg, 0.5 mmol), the

reaction was performed according to the General Procedure to give

22h (85 mg, 75 %) as a greyish solid, m.p. Ͼ 350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 5.10 (br. s, 2 H, NH₂), 6.50 (ddd,

J_6Ј,5Ј= 7.9, J_6Ј,2Ј= 2.2 Hz, J_6Ј,4Ј= 1.1 Hz, 1 H, H-6Ј), 6.67 (d, J_5,NH

(KBr): ν = 3111, 3043, 2956, 2908, 2854, 2830, 1667, 1595, 1568,

˜

1529, 1467, 1443, 1428, 1257, 1210, 1156, 919, 878, 836, 752 cm^–1.

HRMS (ESI): m/z calcd. for C₁₁H₈ON₄Na 235.0590; found

235.0590.

6-(Thiophen-2-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22c):

Starting from pyrrolo[2,3-d]pyrimidine 21c (231 mg, 1 mmol), the

reaction was performed according to the General Procedure to give

= 2.2 Hz, 1 H, H-5), 6.94–6.97 (m, 2 H, H-2Ј,4Ј), 7.05 (t, J_5Ј,4Ј

=

J_5Ј,6Ј= 8.0 Hz, 1 H, H-5Ј), 7.84 (s, 1 H, H-2), 11.82 (br. s, 1 H,

NH-3), 12.19 (br. s, 1 H, NH-7) ppm. ¹³C NMR (125.7 MHz, [D₆]-

DMSO): δ = 98.4 (CH-5), 109.1 (C-4a), 110.3 (CH-2Ј), 112.8 (CH-

4Ј), 113.6 (CH-6Ј), 129.5 (CH-5Ј), 132.1 (C-3Ј), 134.3 (C-6), 143.6

1

22c (195 mg, 90%) as a yellowish solid, m.p. Ͼ 350 °C. H NMR

(500.0 MHz, [D₆]DMSO): δ = 6.62 (s, 1 H, H-5), 7.08–7.10 (m, 1

H, H-4-thienyl), 7.45–7.48 (m, 2 H, H-3,5-thienyl), 7.86 (s, 1 H, H-

2) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ = 99.0 (CH-5),

109.1 (C-4a), 123.4 (CH-3-thienyl), 125.0 (CH-5-thienyl), 128.2

(CH-4-thienyl), 128.6 (C-6), 135.2 (C-2-thienyl), 144.1 (CH-2),

(CH-2), 149.1 and 149.2 (C-1Ј,7a), 158.4 (C-4) ppm. IR (KBr): ν =

˜

3401, 3321, 3219, 3147, 3028, 2959, 2899, 2854, 1673, 1613, 1595,

1482, 1263, 1239, 919, 773 cm^–1. HRMS (ESI): m/z calcd. for

C₁₂H₁₁ON₄227.0927; found 227.0930.

149.6 (C-7a), 158.4 (C-4) ppm. IR (KBr): ν = 3198, 3138, 3105,

˜

3072, 3037, 2959, 2911, 2845, 1673, 1589, 1535, 1494, 1431, 1386,

1254, 1195, 919, 856, 770, 683 cm^–1. HRMS (ESI): m/z calcd. for

C₁₀H₆ON₃S 216.0237; found 216.0239.

6-(Trifluoromethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22l):

Starting from pyrrolo[2,3-d]pyrimidine 21l (163 mg, 0.75 mmol),

the reaction was performed according to the General Procedure to

1

give 22l (45 mg, 30%) as a greyish solid, m.p. Ͼ350 °C. H NMR

6-(Furan-2-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22d): Starting

from pyrrolo[2,3-d]pyrimidine 21d (65 mg, 0.3 mmol), the reaction

was performed according to the General Procedure to give product

22d (55 mg, 92 %) as a greyish solid, m.p. Ͼ 350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 6.57 (dd, J_4,3= 3.4, J_4,5= 1.8 Hz, 1

H, H-4-furyl), 6.61 (s, 1 H, H-5), 7.79 (dd, J_3,4= 3.4, J_3,5= 0.8 Hz,

1 H, H-3-furyl), 7.69 (dd, J_5,4= 1.8, J_5,3= 0.8 Hz, 1 H, H-5-furyl),

7.84 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, [D₆]DMSO): δ =

97.9 (CH-5), 105.3 (CH-3-furyl), 108.9 (C-4a), 112.0 (CH-4-furyl),

125.8 (C-6), 142.4 (CH-5-furyl), 144.4 (CH-2), 147.8 (C-2-furyl),

(500.0 MHz, [D₆]DMSO): δ = 6.88 (s, 1 H, H-5), 7.88 (s, 1 H, H-

2), 11.76 (v. br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]-

DMSO): δ = 103.1 (CH-5), 107.9 (C-4a), 122.2 (br. q, J_C,F

=

266.8 Hz, CF₃), 123.2 (m, C-6), 144.6 (m, CH-2), 151.6 (m, C-7a),

158.9 (C-4) ppm. ¹⁹F NMR (470.3 MHz, CDCl₃): δ = –55.36 (s, 1

F, F-2) ppm. IR (KBr): ν = 3075, 2995, 2920, 2830, 1691, 1592,

˜

1532, 1389, 1219, 1207, 1177, 1123 cm^–1. HRMS (ESI): m/z calcd.

for C₇H₄ON₃F₃Na 226.0199; found 226.0198.

One-Pot C–H Borylation/Substitution Sequence; General Procedures

149.9 (C-7a), 159.1 (C-4) ppm. IR (KBr): ν = 3189, 3120, 3078,

˜

Procedure A: Pyrrolo[2,3-d]pyrimidine 1, 8, or 9 (2 mmol, 1 equiv.),

bispinacolatodiboron (0.61 g, 2.4 mmol, 1.2 equiv.), [Ir(COD)-

OMe]₂(66 mg, 0.1 mmol, 5 mol-%), and 4,4Ј-di-tert-butyl-2,2Ј-bi-

pyridine (54 mg, 0.2 mmol, 10 mol-%) were dissolved in anhydrous

THF (15 mL) under Ar. The solution was heated at 80 °C in a

3040, 2971, 2914, 2890, 2833, 2818, 2773, 2708, 1652, 1595, 1565,

1518, 1431, 1389, 1257, 1216, 1012, 919, 890, 839, 773, 731,

620 cm^–1. HRMS (ESI): m/z calcd. for C₁₀H₇O₂N₃Na 224.0430;

found 224.0431.

6-(Thiophen-3-yl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (22e): septum-sealed vial and stirred under argon for 20 h. The solvent

Starting from pyrrolo[2,3-d]pyrimidine 21e (231 mg, 1 mmol), the

reaction was performed according to the General Procedure to give

22e (152 mg, 70%) as a greyish solid, m.p. Ͼ 350 °C. ¹H NMR

was removed under reduced pressure and the crude mixture was

then dissolved in acetone (10 mL). A solution of CuCl₂(807 mg,

6.0 mmol, 3 equiv.) in water (10 mL) was added and the mixture

was heated for 4 h at 80 °C. The solution was cooled to room tem-

perature, diluted with EtOAc (25 mL) and with a saturated aq.

solution of NH₄Cl (25 mL). The aqueous solution was then ex-

(500.0 MHz, [D₆]DMSO): δ = 6.80 (s, 1 H, H-5), 7.60 (dd, J_4,5

5.0, J_4,2= 1.5 Hz, 1 H, H-4-thienyl), 7.61 (dd, J_5,4= 5.0, J_5,2

=

2.7 Hz, 1 H, H-5-thienyl), 7.84 (dd, J_2,5= 2.7, J_2,4= 1.5 Hz, 1 H,

7958

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7943–7961

Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

tracted three times with EtOAc and the combined organic layers

were dried with Na₂SO₄, filtered, and the solvents were evaporated

under vacuum. The crude product was purified by flash chromatog-

raphy (HPFC; hexane/EtOAc).

o,m,p-Bn), 7.51–7.58 (m, 3 H, H-m,p-Ph), 8.08–8.10 (m, 2 H, H-o-

Ph), 8.97 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ =

46.9 (CH₂Ph), 103.4 (CH-5), 116.0 (C-6), 116.9 (C-4a), 127.4 (CH-

o-Bn), 127.9 (CH-p-Bn), 128.8 (CH-m-Bn), 128.9 (CH-o-Ph), 129.0

(CH-m-Ph), 130.4 (CH-p-Ph), 136.0 (C-i-Bn), 151.2 (CH-2), 152.1

(C-7a), (C-4 and C-i-Ph not detected) ppm. HRMS (ESI): m/z

calcd. for C₁₉H₁₅N₃Br 364.0444; found 364.0444.

Procedure B: Performed as described in Procedure A, but using

CuBr₂(1.34 g, 6.0 mmol, 3 equiv.) instead of CuCl₂.

Procedure C: Pyrrolo[2,3-d]pyrimidine 1, 8, 9, or 10 (2 mmol,

1 equiv.), bispinacolatodiboron (0.61 g, 2.4 mmol, 1.2 equiv.),

[Ir(COD)OMe]₂(66 mg, 0.1 mmol, 5 mol-%), and 4,4Ј-di-tert-

butyl-2,2Ј-bipyridine (54 mg, 0.2 mmol, 10 mol-%) were dissolved

in anhydrous THF (10 mL) under Ar. The solution was heated at

80 °C in a septum-sealed vial and stirred under argon for 20 h. The

solvent was removed under reduced pressure, then the crude mix-

ture was dissolved in CH₂Cl₂(8 mL). The solution was transferred

by using a syringe into an oven-dried sealed bomb that was placed

with CuTc (38 mg, 0.2 mmol, 10 mol-%), 1,10-phenanthroline

(72 mg, 0.4 mmol, 20 mol-%), LiOH·H₂O (168 mg, 4 mmol,

2 equiv.) and Togni’s reagent (726 mg, 2.2 mmol, 1.1 equiv.) under

Ar. The reaction system was quickly degassed through three freeze-

pump-thaw cycles and refilled with Ar. The reaction was stirred at

45 °C for 18 h. The solution was then cooled to room temperature,

and CH₂Cl₂(25 mL) and a saturated solution of NH₄Cl (25 mL)

were added. The aqueous solution was then extracted two times

with CH₂Cl₂and the combined organic layers were dried with

Na₂SO₄, filtered, and the solvents were evaporated under vacuum.

The crude product was purified by flash chromatography (HPFC;

hexane/EtOAc).

7-Benzyl-4-phenyl-6-(trifluoromethyl)-7H-pyrrolo[2,3-d]pyrimidine

(26l): Starting from 1 (285 mg, 1 mmol), the reaction was per-

formed according to General Procedure C to give 26l (120 mg,

1

34%) as a white solid. H NMR (499.8 MHz, CDCl₃): δ = 5.68 (s,

2 H, CH₂Ph), 7.18–7.19 (m, 2 H, H-o-Bn), 7.26–7.31 (m, 3 H, H-

m,p-Bn), 7.30 (q, J_H,F= 1.1 Hz, 1 H, H-5), 7.54–7.61 (m, 3 H, H-

m,p-Ph), 8.10–8.12 (m, 2 H, H-o-Ph), 9.10 (s, 1 H, H-2) ppm. ¹³C

NMR (125.7 MHz, CDCl₃): δ = 46.8 (CH₂Ph), 103.7 (q, J_C,F

=

4.3 Hz, CH-5), 116.9 (C-4a), 120.7 (q, J_C,F= 269.2 Hz, CF₃), 126.9

(CH-o-Bn), 127.8 (CH-p-Bn), 128.1 (q, J_C,F= 38.1 Hz, C-6), 128.6

(CH-m-Bn), 128.9 (CH-o-Ph), 129.0 (CH-m-Ph), 130.8 (CH-p-Ph),

136.3 (C-i-Bn), 137.2 (C-i-Ph), 153.2 (C7a), 154.1 (CH-2), 160.2

(C-4) ppm. ¹⁹F{¹H} NMR (470.3 MHz, CDCl₃): δ = –55.79 ppm.

HRMS (ESI): m/z calcd. for C₂₀H₁₅N₃F₃354.1213; found

354.1214.

7-Benzyl-6-cyano-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (26m):

Starting from 1 (143 mg, 0.5 mmol), the reaction was performed

according to General Procedure D to give 26m (90 mg, 58%) as a

1

white solid, m.p. 123 °C. H NMR (499.8 MHz, CDCl₃): δ = 5.65

(s, 2 H, CH₂Ph), 7.31–7.33 (m, 1 H, H-p-Bn), 7.35–7.36 (m, 2 H,

H-m-Bn), 7.42–7.44 (m, 2 H, H-o-Bn), 7.49 (s, 1 H, H-5), 7.56–7.59

(m, 3 H, H-m,p-Ph), 8.06–8.08 (m, 2 H, H-o-Ph), 9.14 (s, 1 H, H-

2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 47.6 (CH₂Ph), 111.2

(C-6), 112.4 (CH-5), 112.5 (CN), 114.0 (C-4a), 128.2 (CH-o-Bn),

128.50 (CH-p-Bn), 128.95 (CH-m-Bn), 128.98 (CH-o-Ph), 129.12

(CH-m-Ph), 131.1 (CH-p-Ph), 135.5 (C-i-Bn), 136.8 (C-i-Ph), 151.8

(C-7a), 154.9 (CH-2), 160.7 (C-4) ppm. HRMS (ESI): m/z calcd.

for C₂₀H₁₅N₄311.1291; found 311.1290.

Procedure D: Pyrrolo[2,3-d]pyrimidine 1 (0.5 mmol, 1 equiv.), bis-

pinacolatodiboron (152 mg, 0.6 mmol, 1.2 equiv.), [Ir(COD)OMe]₂

(17 mg, 0.025 mmol, 5 mol-%), and 4,4Ј-di-tert-butyl-2,2Ј-bipyr-

idine (13 mg, 0.05 mmol, 10 mol-%) were dissolved in anhydrous

THF (5 mL) under Ar. The solution was heated at 80 °C in a sep-

tum-sealed vial and stirred under argon for 20 h. The solvent was

removed under reduced pressure, then the residue was dissolved in

acetone (10 mL) and Cu(NO₃)₂·3H₂O (242 mg, 1 mmol, 2 equiv.),

Zn(CN)₂(176 mg, 1.5 mmol, 3 equiv.), and CsF (76 mg, 0.5 mmol,

1 equiv.) were added to the reaction vessel followed by H₂O (4 mL).

The flask was sealed with a Teflon-lined cap, and the green suspen-

sion was stirred vigorously at 100 °C for 2.5 h. The solution was

cooled to room temp., and EtOAc (15 mL) and a saturated solution

of NH₄Cl (15 mL) were added. The aqueous solution was then ex-

tracted three times with EtOAc and the combined organic layers

were dried with Na₂SO₄, filtered, and the solvents were evaporated

under vacuum. The crude product was purified by flash chromatog-

raphy (HPFC; hexane/EtOAc).

4,6-Dichloro-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo[2,3-d]-

pyrimidine (27j): Starting from 8 (568 mg, 2 mmol), the reaction

was performed according to General Procedure A to give 27j

(350 mg, 55%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃):

δ = –0.06 (s, 9 H, CH₃Si), 0.90–0.94 (m, 2 H, OCH₂CH₂Si), 3.58–

3.61 (m, 2 H, OCH₂CH₂Si), 5.70 (s, 2 H, NCH₂O), 6.62 (s, 1 H,

H-5), 8.65 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ =

–1.5 (CH₃Si), 17.7 (OCH₂CH₂Si), 67.1 (OCH₂CH₂Si), 70.8

(NCH₂O), 99.0 (CH-5), 117.1 (C-4a), 129.2 (C-6), 150.9 (C-4),

151.7 (CH-2), 154.5 (C-7a) ppm. IR (KBr): ν = 3114, 2950, 2920,

˜

7-Benzyl-6-chloro-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (26j): Start-

ing from 1 (285 mg, 1 mmol), the reaction was performed according

to General Procedure A to give 26j (146 mg, 46%) as a yellowish

2896, 2866, 1592, 1577, 1541, 1503, 1455, 1446, 1419, 1383, 1344,

1254, 1248, 1207, 1186, 1126, 1093, 911, 860, 839, 779, 755 cm^–1.

HRMS (ESI): m/z calcd. for C₁₂H₁₇ON₃Cl₂NaSi 340.0410; found

340.0410.

1

solid, m.p. 118 °C. H NMR (500 MHz, CDCl₃): δ = 5.58 (s, 2 H,

CH₂-Bn), 6.82 (s, 1 H, H-5), 7.26–7.34 (m, 5 H, H-o,m,p-Bn), 7.48–

7.58 (m, 3 H, H-m,p-Ph), 8.06–8.08 (m, 2 H, H-o-Ph), 8.98 (s, 1 H,

H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 45.7 (CH₂-Bn),

99.0 (CH-5), 115.2 (C-4a), 127.4 (CH-o-Bn), 127.9 (CH-p-Bn),

128.6 (C-6), 128.7 (CH-o-Ph), 128.7 (CH-m-Bn), 128.9 (CH-m-Ph),

130.2 (CH-p-Ph), 136.3 (C-i-Bn), 137.8 (C-i-Ph), 151.5 (C-7a),

151.8 (CH-2), 156.3 (C-4) ppm. HRMS (ESI): m/z calcd. for

C₁₉H₁₅N₃Cl 320.0949; found 320.0949.

6-Bromo-4-chloro-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

[2,3-d]pyrimidine (27k): Starting from 8 (568 mg, 2 mmol), the reac-

tion was performed according to General Procedure B to give 27k

1

(403 mg, 56%) as a white solid, m.p. 49 °C. H NMR (500 MHz,

CDCl₃): δ = –0.06 (s, 9 H, CH₃Si), 0.90–0.94 (m, 2 H,

OCH₂CH₂Si), 3.57–3.60 (m, 2 H, OCH₂CH₂Si), 5.71 (s, 2 H,

NCH₂O), 6.77 (s, 1 H, H-5), 8.64 (s, 1 H, H-2) ppm. ¹³C NMR

7-Benzyl-6-bromo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidine (26k): (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 17.7 (OCH₂CH₂Si), 67.0

Starting from 1 (285 mg, 1 mmol), the reaction was performed ac-

cording to General Procedure B to give 26k (229 mg, 63%) as a

yellowish solid, m.p. 110 °C. ¹H NMR (499.8 MHz, CDCl₃): δ =

(OCH₂CH₂Si), 71.9 (NCH₂O), 103.1 (CH-5), 116.6 (C-6), 118.0 (C-

4a), 150.8 (C-4), 151.2 (CH-2), 152.2 (C-7a) ppm. IR (KBr): ν =

˜

3105, 2956, 2917, 2902, 2881, 2866, 1583, 1541, 1485, 1458, 1434,

5.60 (s, 2 H, CH₂Ph), 6.98 (s, 1 H, H-5), 7.26–7.33 (m, 5 H, H- 1416, 1386, 1350, 1257, 1248, 1180, 1090, 1075, 1033, 911, 860,

Eur. J. Org. Chem. 2015, 7943–7961

www.eurjoc.org

7959

M. Klecˇka, L. Posˇtová Slaveˇtínská, M. Hocek

FULL PAPER

839, 779, 749 cm^–1. HRMS (ESI): m/z calcd. for C₁₂H₁₈ON₃BrClSi

362.0086, found 362.0086.

4-(Methylsulfanyl)-6-(trifluoromethyl)-7-[2-(trimethylsilyl)ethoxy-

methyl]-7H-pyrrolo[2,3-d]pyrimidine (20l): Starting from 10

(1116 mg, 4 mmol), the reaction was performed according to Gene-

ral Procedure C to give 20l (472 mg, 34%) as a colorless oil. ¹H

NMR (500 MHz, CDCl₃): δ = –0.06 (s, 9 H, CH₃Si), 0.90–0.93

(m, 2 H, OCH₂CH₂Si), 2.72 (s, 3 H, CH₃S), 3.56–3.59 (m, 2 H,

OCH₂CH₂Si), 5.75 (s, 2 H, NCH₂O), 7.01 (q, J_5,F= 1.1 Hz, 1 H,

H-5), 8.76 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ =

– 1 . 6 ( CH₃S i) , 1 1. 9 ( CH₃S ), 17 . 7 (O CH₂CH₂Si), 66.8

(OCH₂CH₂Si), 71.5 (NCH₂O), 103.1 (q, J_C,F= 4.3 Hz, CH-5),

4-Chloro-6-(trifluoromethyl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (27l): Starting from 8 (568 mg,

2 mmol), the reaction was performed according to General Pro-

cedure C to give 27l (264 mg, 38%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃): δ = –0.06 (s, 9 H, CH₃Si), 0.91–0.94 (m, 2

H, OCH₂CH₂Si), 3.57–3.61 (m, 2 H, OCH₂CH₂Si), 5.79 (s, 2 H,

NCH₂O), 7.12 (q, J_5,F= 1.1 Hz, 1 H, H-5), 8.79 (s, 1 H, H-2) ppm.

^{1 3}C NMR (125.7 MHz, CDCl₃): δ = –1.6 (CH₃Si), 17.7

(OCH₂CH₂Si), 67.2 (OCH₂CH₂Si), 72.0 (NCH₂O), 103.6 (q, J_C,F

= 4.4 Hz, CH-5), 115.6 (C-4a), 120.2 (q, J_C,F= 269.3 Hz, CF₃),

129.0 (q, J_C,F= 39.7 Hz, C-6), 154.0 (C-7a), 153.4 (CH-2), 154.6

(C-4) ppm. ¹⁹F NMR (470.3 MHz, CDCl₃): δ = –56.61 (s, 1 F, F-

113.8 (C-4a), 120.6 (q, J_C,F= 269.1 Hz, CF₃), 126.5 (q, J_C,F

=

39.2 Hz, C-6), 150.4 (C-7a), 153.2 (CH-2), 164.7 (C-4) ppm. ¹⁹F

NMR (470.3 MHz, CDCl₃): δ = –56.20 (s, 1 F, F-2) ppm. IR (KBr):

ν = 2953, 2923, 2890, 1556, 1443, 1368, 1275, 1251, 1183, 1153,

˜

1129, 1090, 860, 833 cm^{– 1}. HRMS (ESI): m/z calcd. for

2) ppm. IR (KBr): ν = 3950, 2929, 2899, 1592, 1553, 1544, 1446,

˜

C₁₄H₂₁ON₃F₃SSi 364.1121; found 364.1123.

1431, 1413, 1371, 1353, 1248, 1189, 1147, 1096, 860, 842 cm^–1

.

4-Amino-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (25m): A solu-

tion of 28l (111 mg, 0.5 mmol) and aq. ammonia (25% w/w, 5 mL)

in dioxane (5 mL) was stirred in an autoclave at 120 °C for 18 h.

The solvents were then evaporated and the residue was purified

by flash chromatography (HPFC; CHCl₃/MeOH, 5:1) to give 25m

(45 mg, 50 %) as a white powder, m.p. Ͼ 350 °C. ¹H NMR

(500.0 MHz, [D₆]DMSO): δ = 7.08 (s, 1 H, H-5), 7.16 (br. s, 2 H,

NH₂-4), 7.35 and 7.70 (2ϫbr. s, 2ϫ 1 H, CONH₂), 8.07 (s, 1 H,

H-2), 11.82 (br. s, 1 H, NH) ppm. ¹³C NMR (125.7 MHz, [D₆]-

DMSO): δ = 103.05 (C-4a and CH-5), 128.4 (C-6), 151.4 (C-7a),

HRMS (ESI): m/z calcd. for C₁₃H₁₈ON₃ClF₃Si 352.0854; found

352.0855.

6-Chloro-4-methoxy-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

[2,3-d]pyrimidine (19j): Starting from 9 (1116 mg, 4 mmol), the re-

action was performed according to General Procedure A to give

19j (590 mg, 47 %) as a white solid, m.p. 80 °C. ¹H NMR

(500 MHz, CDCl₃): δ = –0.07 (s, 9 H, CH₃Si), 0.90–0.93 (m, 2 H,

OCH₂CH₂Si), 3.57–3.60 (m, 2 H, OCH₂CH₂Si), 4.10 (s, 3 H,

CH₃O), 5.66 (s, 2 H, NCH₂O), 6.51 (s, 1 H, H-5), 8.47 (s, 1 H, H-

2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 17.7

(OCH₂CH₂Si), 53.8 (CH₃O), 66.6 (OCH₂CH₂Si), 70.5 (NCH₂O),

97.8 (CH-5), 105.0 (C-4a), 124.8 (C-6), 151.3 (CH-2), 152.1 (C-7a),

154.2 (CH-2), 158.9 (C-4), 162.5 (CO) ppm. IR (KBr): ν = 3428,

˜

3404, 3330, 3177, 3108, 2995, 2908, 2782, 1694, 1655, 1628, 1598,

1538, 1437, 1386, 1335 cm^–1. HRMS (ESI): m/z calcd. for

C₇H₈ON₅178.0723; found 178.0721.

161.9 (C-4) ppm. IR (KBr): ν = 3261, 3102, 3060, 3001, 2953, 2923,

˜

6-(3-Aminophenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (25h): A

mixture of pyrrolo[2,3-d]pyrimidin-4-one 22h (57 mg, 0.25 mmol),

benzyltriethylammonium chloride (114 g, 0.5 mmol), and N,N-di-

methylaniline (35 μL, 0.275 mmol) in anhydrous MeCN (2.5 mL)

was stirred at room temp., then phosphorus oxychloride (115 μL,

1.25 mmol) was added. The mixture was stirred at 100 °C for 6 h,

then the solvents were evaporated under reduced pressure and the

residue was diluted with water and neutralized with aqueous am-

monia to pH 7. The crude intermediate was filtered, washed with

cold water, then with hydrochloric acid and again with cold water.

After drying under reduced pressure, the intermediate was placed

in steel bomb and aq. ammonia (25 % w/w, 2 mL) in dioxane

(2 mL) was added. The mixture was stirred at 120 °C for 18 h, then

the solvents were evaporated and the residue was purified by flash

chromatography (HPFC; CHCl₃/MeOH, 5:1) to give 25h (22 mg,

40%) as a brown solid, m.p. Ͼ350 °C. ¹H NMR (500.0 MHz, [D₆]-

DMSO): δ = 6.53 (ddd, J_6Ј,5Ј= 8.0, J_6Ј,2Ј= 2.2 Hz, J_6Ј,4Ј= 1.0 Hz,

1 H, H-6Ј), 6.83 (d, J_5,NH= 1.9 Hz, 1 H, H-5), 6.92–6.96 (m, 2 H,

H-2Ј,4Ј), 7.08 (bt, J_5Ј,4Ј= J_5Ј,6Ј= 7.9 Hz, 1 H, H-5Ј), 7.32 (br. s, 2

H, NH₂-4), 8.09 (s, 1 H, H-2), 12.07 (br. s, 1 H, NH) ppm. ¹³C

NMR (125.7 MHz, [D₆]DMSO): δ = 96.1 (CH-5), 103.5 (C-4a),

110.3 (CH-2Ј), 112.9 (CH-4Ј), 113.9 (CH-6Ј), 129.6 (CH-5Ј), 132.2

(C-3Ј), 135.5 (C-6), 149.2 (C-1Ј), 149.8 (CH-2), 151.3 (C-7a), 155.7

2899, 2869, 1712, 1685, 1661, 1595, 1559, 1503, 1479, 1464, 1410,

1377, 1314, 1245, 1230, 1099, 1060, 917, 860, 839, 794, 755 cm^–1.

HRMS (ESI): m/z calcd. for C₁₃H₂₀O₂N₃ClNaSi 336.0906; found

336.0906.

6-Bromo-4-methoxy-7-[2-(trimethylsilyl)ethoxymethyl]-7H-pyrrolo-

[2,3-d]pyrimidine (19k): Starting from 9 (1116 mg, 4 mmol), the re-

action was performed according to General Procedure B to give

19k (490 mg, 34 %) as a white solid, m.p. 82 °C. ¹H NMR

(500 MHz, CDCl₃): δ = –0.06 (s, 9 H, CH₃Si), 0.90–0.93 (m, 2 H,

OCH₂CH₂Si), 3.56–3.60 (m, 2 H, OCH₂CH₂Si), 4.11 (s, 3 H,

CH₃O), 5.67 (s, 2 H, NCH₂O), 6.65 (s, 1 H, H-5), 8.45 (s, 1 H, H-

2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.5 (CH₃Si), 17.7

(OCH₂CH₂Si), 53.8 (CH₃O), 66.6 (OCH₂CH₂Si), 71.6 (NCH₂O),

102.1 (CH-5), 106.0 (C-4a), 111.8 (C-6), 151.3 (CH-2), 152.9 (C-

7a), 161.7 (C-4) ppm. IR (KBr): ν = 3099, 2953, 2914, 1896, 1863,

˜

1595, 1473, 1461, 1416, 1383, 1353, 1317, 1242, 1227, 1093, 911,

842 cm^–1. HRMS (ESI): m/z calcd. for C₁₃H₂₀O₂N₃BrNaSi

380.0400; found 380.0401.

4-Methoxy-6-(trifluoromethyl)-7-[2-(trimethylsilyl)ethoxymethyl]-

7H-pyrrolo[2,3-d]pyrimidine (19l): Starting from 9 (1116 mg,

4 mmol), the reaction was performed according to General Pro-

cedure C to give 19l (472 mg, 34%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃): δ = –0.07 (s, 9 H, CH₃Si), 0.90–0.93 (m, 2 H,

OCH₂CH₂Si), 3.56–3.59 (m, 2 H, OCH₂CH₂Si), 4.14 (s, 3 H,

CH₃O), 5.75 (s, 2 H, NCH₂O), 7.02 (q, J_5,F= 1.2 Hz, 1 H, H-5),

8.58 (s, 1 H, H-2) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = –1.6

(CH₃Si), 17.7 (OCH₂CH₂Si), 54.0 (CH₃O), 66.7 (OCH₂CH₂Si),

71.6 (NCH₂O), 102.9 (q, J_C,F= 4.5 Hz, CH-5), 103.8 (C-4a), 120.7

(q, J_C,F= 268.7 Hz, CF₃), 125.9 (q, J_C,F= 39.2 Hz, C-6), 153.7

(CH-2), 153.9 (C-7a), 164.2 (C-4) ppm. ¹⁹F NMR (470.3 MHz,

CDCl₃): δ = –56.07 (s, 1 F, F-2) ppm. HRMS (ESI): m/z calcd. for

C₁₄H₂₁O₂N₃F₃Si 348.1350; found 348.1351.

(C-4) ppm. IR (KBr): ν = 3348, 3120, 2956, 2926, 2851, 1673, 1619,

˜

1601, 1538, 1488, 1317, 1287, 764 cm^–1. HRMS (ESI): m/z calcd.

for C₁₂H₁₂N₅226.1087; found 226.1086.

Supporting Information (see footnote on the first page of this arti-

1

cle): Copies of H and ¹³C NMR spectra of the products.

Acknowledgments

This work was supported by institutional support of the Charles

University, Prague and the Academy of Sciences of the Czech Re-

7960

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7943–7961

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Received: September 10, 2015

Published Online: November 17, 2015

Eur. J. Org. Chem. 2015, 7943–7961

www.eurjoc.org

7961

Article Doi

Modification of Pyrrolo[2,3-d]pyrimidines by C-H Borylation Followed by Cross-Coupling or Other Transformations: Synthesis of 6,8-Disubstituted 7-Deazapurine Bases

DOI: 10.1002/ejoc.201501177

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