Synthesis of 5-/8-Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolecular Chemistry

FULL PAPER

DOI: 10.1002/ejoc.201501026

Synthesis of 5-/8-Halogenated or Ethynylated Lipophilic Nucleobases as

Potential Synthetic Intermediates for Supramolecular Chemistry

[a]

Nerea Bilbao, Violeta Vázquez-González, M. Teresa Aranda, and

David González-Rodríguez*^[

a]

Keywords: Supramolecular chemistry / Self-assembly / Alkylation / Cross-coupling / Nucleobases / Nitrogen heterocycles

A series of lipophilic nucleobases that are substituted at the

- (pyrimidines) or 8- (purines) position with either a halogen

atom or a terminal triple bond have been synthesized. The

sequences and reactions studied in this work, which mainly

comprise halogenation, alkylation, Sonogashira coupling,

isocytosine, and uracil derivatives as pyrimidine hetero-

cycles, and guanine, isoguanine, and 2-aminoadenine deriv-

atives as complementary purine bases. Variability was intro-

duced at the N-1/N-9 positions of these pyrimidine/purine

nucleobases, which were functionalized with alkyl or benzyl

5

and trimethylsilylacetylene deprotection, have been care- groups, as well as with protected amine or carboxylic acid

fully optimized, to reach the final compounds in the most

straightforward and convenient way, with the highest pos-

sible purity and yield. These compounds include cytosine,

substituents. The molecules prepared constitute a useful col-

lection of synthetic intermediates for the field of chemical

self-assembly.

Introduction

ment of efficient and reliable synthetic routes to modified

nucleobases, which can act as versatile building blocks in

self-assembly, can be very important and useful for supra-

The strategy of designing chemical moieties with specific

hydrogen-bonding patterns has been used by supramolec-

ular chemists to make one or more molecular components

interact, and thus create well-defined assemblies with di-

verse functions.^[Hydrogen bonding is used here as a

highly selective and directional noncovalent interaction,

whose strength can be tuned depending on the chemical

nature of donor and acceptor functionalities, but also de-

pending on their number and sequence in a particular mo-

lecular fragment. These moieties can be seen as “supra-

molecular directors” that are able to couple specific molec-

ular components in a geometrically defined arrangement,

where, in many cases, hydrogen-bonding interactions coop-

erate with additional weak noncovalent forces such as π–π

[7,8]

molecular chemists.

In this paper, we describe the synthesis of a series of

chemically modified lipophilic natural and unnatural nu-

cleobase derivatives (Figure 1) that are equipped with either

a halogen atom or an ethynyl group, at the 5-position (for

the pyrimidines) or at the 8-position (for the purines). Pyr-

imidine nucleobases comprise cytosine (C), uridine (U), and

isocytosine (iC), whereas the purines prepared in this work

are guanine (G), 2,6-diaminopurine or 2-aminoadenine

1]

[

2]

(AA; hereafter only abbreviated as A), and iso-

guanine (iG). Together, these complementary nucleobases

constitute a useful collection of synthetic intermediates for

supramolecular chemistry. On the one hand, the halogen-

ated position could be used to attach, using one of the large

number of reported metal-catalysed cross-coupling reac-

tions, these units to functional molecules with the aim of

[

3]

stacking, or solvophobic or Coulombic interactions.

Of these supramolecular hydrogen-bonding units, the

naturally occurring DNA bases and synthetic nucleobase

analogues are particularly relevant.^[⁴^,⁵^]Nucleobase deriva-

tives play a crucial role in nature, and have been found to

be clinically useful molecules with diverse biological activi-

ties. N-9-Substituted guanines such as acyclovir represent

an interesting example, because of the potential antiviral

activity of these molecules.^[For these reasons, the develop-

[9]

driving their self-assembly. On the other hand, the rich

reactivity of the terminal triple bond could be used in either

Sonogashira couplings or “click” cycloaddition reactions to

make these six nucleobases convenient “synthons” for the

[10]

preparation of complex organized systems. These hetero-

6]

cycles have been further substituted with lipophilic alkyl or

benzyl groups or with protected amines and carboxylic

acids at N-1 (pyrimidines) or N-9 (purines). In contrast to

[

a] Departamento de Química Orgánica, Facultad de Ciencias,

Universidad Autónoma de Madrid,

[

8]

2

8049 Madrid, Spain

the related nucleosides, where the bulky ribose unit at-

tached at these positions limits aggregation, these simple,

planar groups may help in the production of hierarchical

assemblies where hydrogen bonding is combined with other

E-mail: david.gonzalez.rodriguez@uam.es

http://www.uam.es/proyectosinv/msmn/

Supporting Information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201501026.

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5-/8-Halogenated or Ethynylated Lipophilic Nucleobases

noncovalent interactions acting in orthogonal directions, agents and protocols, such as iodine/iodic acid (I /HIO ),

2

3

such as π–π stacking with other molecules or with planar iodine/periodic acid (I /H IO ), N-iodosuccinimide (NIS),

2

5

6

substrates.

or iodine monochloride (ICl), were tested. Only the best

options for each substrate are reported here. Next, the Son-

ogashira coupling under different conditions was attempted

for each 5-iodopyrimidine. However, none of them (C, U,

or iC) was reactive. We believe that N-1-unsubstituted pyr-

imidines can deactivate the catalytic palladium species thor-

ough chelation by one of their different tautomeric forms,

as has been suggested for other nucleobase derivatives.^[

12]

5-Iodo-substituted pyrimidines were instead subjected first

to an alkylation reaction, which was, in most cases, quite

selective for the N-1 position. The Sonogashira reaction

was carried out on these alkylated iodopyrimidines, and in

all cases this gave excellent yields of the coupled products.

Finally, the TMS protecting group was cleaved in the pres-

ence of tetrabutylammonium fluoride (TBAF).

Cytosine (Scheme 1): a total of six 5-iodo- and 5-ethynyl-

cytosine derivatives were synthesized, each of them with a

different alkyl or benzylic group. Iodination of commer-

cially sourced cytosine (Scheme 1a) was carried out in the

Figure 1. General structures of the pyrimidine (C, U, iC) and pur-

ine (G, A, iG) derivatives targeted in this work.

[

13]

presence of I and HIO . Under these conditions, 5-iodo-

2

3

cytosine (C3) was obtained in close to quantitative yields

by neutralization and straightforward filtration and wash-

ing. This product was then subjected to an alkylation reac-

tion in the presence of the corresponding alkyl/benzyl hal-

ide. These reactions are typically carried out in the presence

of cesium or potassium carbonates, but, in the case of our

iodoalkanes and benzyl halides, the use of these bases did

not give good yields. Instead, the more soluble base

Results and Discussion

As shown in Figure 1, our target nucleobases present

common functional groups, such as the halogen atom or

the ethynyl group at the 5-position of pyrimidines and the

8-position of purines, as well as variable substituents, such

as the diverse lipophilic groups at the 1-position of pyrimid-

ines and the 9-position of purines. Therefore, the ideal,

most convergent synthetic route to these derivatives would

comprise three consecutive steps: 1) halogenation (bromina-

tion or iodination); 2) palladium-catalysed Sonogashira

[

9]

coupling with trimethylsilylacetylene (TMSA), followed

by trimethylsilyl (TMS) deprotection; and 3) nucleophilic

[

11]

substitution with the corresponding alkylating reagent.

Since the variability in our compounds is introduced at the

level of the alkyl substituents, a lower number of products

would need to be synthesized using this sequence. However,

as will be explained below for each nucleobase, different

problems arose during synthesis that made us deviate from

this optimal route. Many intermediates were unreactive un-

der some conditions, and/or showed solubility too low to

be properly purified. The sequences and reactions described

in this work have therefore been carefully optimized to

reach the final compounds in the most straightforward and

convenient way, and with the maximum purity and overall

yield.

Synthesis of Pyrimidines

With the aim of achieving the most convergent route,

iodination of the pyrimidine heterocycles was chosen as the

first reaction in the synthesis of lipophilic C, U, and iC

derivatives. We chose to incorporate iodine rather than

bromine due to the higher reactivity of iodoarenes in metal-

Scheme 1. Synthetic routes to 5-iodo- and 5-ethynyl-cytosines using

the (a) halogenation–alkylation or (b) alkylation–halogenation se-

catalysed cross-coupling reactions. Different iodination quence.

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Scheme 2. Optimized synthetic route to 5-iodo- and 5-ethynyl-uracils.

14]

Bu NOH was used in methanol^[to deprotonate C3 and uct in minor amounts, which could be separated by

4

produce C2_A_l_k₁₀, C2_A_l_k₆, C2_A_l_k₂, C2_B_n₂, and C2_B_n₃in ac- chromatography from the target N-1-alkylated derivative.

ceptable yields. The 1-alkyl-5-iodocytosines were then Compound iC_A_l_k₂was the only product in this work that

transformed into the final 5-ethynyl derivatives using stan- was not transformed into the corresponding 5-ethynyl de-

dard Sonogashira/TMS-deprotection methods.^[

15]

rivative.

We also tested the inverted reaction order, i.e., alkylation

of cytosine followed by halogenation (Scheme 1, b). Besides

being less convergent, this alternative route also presented

other drawbacks. First, the isolation of the halogenated

products was more tedious, and gave lower yields. Second,

the presence of the bulky iodine atom at the C-5 position

in C3 proved to be effective in directing alkylation selec- Scheme 3. Synthetic route to 5-iodoisocytosine iC_A_l_k₂

.

tively to the N-1 position.^[For instance, when the alkyl-

16]

ation reaction was carried out with ethyl iodide directly

with commercially sourced cytosine, a triply alkylated by-

product was also obtained, with ethyl chains at the N-1

Synthesis of Purines

position but also on the amino group. Finally, it was not

The optimized route to 8-halogenated and 8-ethynylated

possible to carry out the halogenation reaction after the purines followed a different synthetic sequence to that used

alkylation for benzyl-substituted derivatives, since they con- for the pyrimidines. We were, of course, interested in achiev-

tain electron-rich aryl groups that would give rise to mix- ing the most convergent path by carrying out the halogen-

[

20]

tures of halogenated products.

ation step

as early as possible in the sequence, as was

Uridine (Scheme 2): the route to the uridine derivatives demonstrated for the pyrimidines. However, although this

started from commercially sourced 5-iodouridine, a com- was accomplished in some cases, the early introduction of

pound that can also be obtained in excellent yields from the halogen atom resulted in a series of secondary problems

[

17]

uridine.

5-Iodouridine was alkylated in the presence of in subsequent reactions that reduced the overall yield. Thus,

Cs CO , which was found to be slightly more efficient than it was preferable to carry out the alkylation reaction as the

2

3

K CO , because of its better solubility in organic solvents. first step in the routes to guanine, 2-aminoadenine, and iso-

2

3

The yields of U2_A_l_k₁₀and U2_A_l_k₆were not very satisfactory, guanine derivatives, despite the higher number of com-

although they are in the same range as those reported for pounds that needed to be synthesized. Then, the alkylated

[

18]

similar alkylation reactions with uridine derivatives. One products were either brominated or iodinated. The prepara-

of the reasons for these relatively low yields is the additional tion of 8-iodopurines was obviously preferred because of

formation of N-3-substituted products and the correspond- the higher reactivity of these compounds in subsequent pal-

1

ing dialkylated products, which were identified by H NMR ladium-catalysed couplings, so their synthesis was opti-

spectroscopy and mass spectrometry, the formation of mized and studied in more detail using different iodination

which competes with alkylation at N-1. Finally, 1-alkyl-5- methods. The iodine substituent could be introduced either

iodouracils were converted into the corresponding 5-ethynyl by electrophilic aromatic substitution in the presence of di-

derivatives through a cross-coupling reaction with TMSA. verse reagents (vide supra), or by deprotonation at the 8-

Traces of deiodinated products were detected in this last position followed by quenching with iodine. The first

reaction.

method, together with bromination with NBS (N-bromo-

Isocytosine (Scheme 3): the unnatural isocytosine ana- succinumide), was not compatible with the benzyl groups,

logue iC_A_l_k₂was also prepared following the halogenation– since they contain electron-rich aromatic rings that are

alkylation sequence. In this case, iodination was carried out more activated towards electrophilic substitution than the

in the presence of N-iodosuccinimide (NIS),^[¹⁹^]since it gave purine ring, as we found out during our tests (see below).

better results than other methods. Alkylation was then car- Similarly to the pyrimidines, the Sonogashira reaction was

ried out using the same procedure as used for the cytosine left as the last step in the synthesis of the 8-ethynylpurines.

derivatives. The base was equipped with a simple ethyl This reaction, as will be explained below, required, in some

group for subsequent sublimation studies under ultrahigh instances, functional group protection of the purine hetero-

vacuum. This reaction also led to the N-3-substituted prod- cycles. Similarly to the pyrimidine bases, all our attempts to

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5-/8-Halogenated or Ethynylated Lipophilic Nucleobases

carry out this palladium-catalysed coupling after the halo- which are sometimes difficult to separate.^[²³^]But probably

genation and before the alkylation were unsuccessful, prob- the most important reason for the difficulty in the synthesis

ably because of deactivation of the catalytic species due to of the guanine derivatives is the requirement to protect or

the higher metal-coordination ability of the N-9-unsubsti- mask the carbonyl group before the palladium-catalysed

tuted derivatives.

cross-coupling reactions. It has previously been reported

Guanine (Schemes 4 and 5): the development of an ef- that the guanine heterocycle has a low reactivity in metal-

[

8,12,24]

ficient synthetic route to 8-ethynyl lipophilic guanines mediated oxidative addition processes.

G1_A_l_k₁₀, G1_A_l_k₂, G1_B_n₂, G1_B_n₃) turned out to be the most ation potential of this base or its ability to coordinate orga-

complex task in this work, and considerable effort was dedi- nometallic catalytic species are cited among the causes that

The low oxid-

(

[

12]

cated to this mission. There are several reasons for this. The would explain such a lack of reactivity. Conversion into

low solubility of guanine or 2-amino-6-hydroxypurine in different functionalized derivatives like 6-alkoxy-,^[

8,24,25]

or

different solvents is one of them. Of all the nucleobases, 6-halogenopurines, which may also show higher selectivities

guanine has the richest supramolecular chemistry,^[

21,22]

and in the alkylation reaction, could be an alternative. Unfortu-

often self-associates in solution to form highly insoluble nately, the use of these starting materials would be more

products or viscous gels. Also, guanine, and purines in ge- expensive, and would increase the number of reaction steps,

neral, consist of mixtures of tautomers, which can lead to which would lead to lower overall yields. Furthermore, pre-

different isomers in the alkylation reactions. The most com- vious methods reported in the literature for the conversion

mon of these are the N-7- and N-9-alkylated products, of 2-amino-6-chloropurine into guanine use vigorous acidic

Scheme 4. Synthetic routes to 8-iodo- and 8-ethynyl-guanines from 2-amino-6-chloropurine.

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D. González-Rodríguez et al.

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Scheme 5. Attempted synthesis of 8-bromo- and 8-ethynylguanines from guanine.

or basic conditions, which are not compatible with sensitive considered with the aim of reducing the reactivity of this

functional groups. position in the halogenation step. This particular protecting

First, we tried using 2-amino-6-chloropurine as the start- group was chosen because of several additional advantages

ing material, and we evaluated different routes and se- in the synthetic route: it imparts solubility to the hetero-

quences from this commercially available derivative cyclic ring, and can be efficiently deprotected in the pres-

[

30]

(

Scheme 4). Our initial idea was to carry out the whole ence of fluoride in the very last step of the route,

along

[

30]

three-step reaction sequence directly on derivatives of this with the TMSA group. Compound G7 was thus synthe-

kind. Since our attempts to halogenate this substrate under sized, and then subjected to a halogenation reaction. Elec-

different conditions were unsuccessful, we started the route trophilic iodination was first tested, but this gave negative

by alkylating 2-amino-6-chloropurine with diverse iodoalk- results, and the starting material was recovered in all cases.

anes, to give G5_A_l_k₁₀and G5_A_l_k₂, and with the correspond- Bromination in the presence of Br did not work either. In

2

[

26]

ing benzyl bromide, to give G5_B_n₃

.

The benzyl halide led contrast, bromination with NBS led to G6, which could be

[27]

mainly to a single N-9-alkylation product,

whereas 1- subsequently alkylated. It is worth noting that the alkyl-

iododecane and 1-iodoethane, presumably due to their ation reaction of this substrate gave complete regioselectiv-

lower steric hindrance, produced mixtures of N-7- and N- ity for N-9 for both alkyl and benzylic halides, leading to

9-substituted products in an approximate 1:4 ratio, al- G3_A_l_k₁₀and G3_B_n₂. However, despite the convergent nature

though the overall yields were still very satisfactory. of this route, we were still not very satisfied, since the first

Next, we tested the halogenation of G5_A_l_k₁₀. Only NBS- two reactions (nucleophilic aromatic substitution and

mediated bromination worked in our hands. However, treat- bromination) proceeded with low to moderate yields, and

ment of this substrate with NBS unexpectedly gave a mix- were not very reproducible, and the products obtained (i.e.,

ture of brominated products, mainly consisting of our target G7 and G6) could not easily be isolated from traces of im-

2-amino-8-bromo-6-chloropurine, and 2-amino-6,8-di- purities. It is also important to note that G6 was unreactive

bromopurine, in which the 6-chloro atom was replaced by in palladium-catalysed couplings, either in Sonogashira re-

bromine. Unfortunately, this mixture could not be sepa- actions with TMSA, or in Stille reactions in the presence

rated, and the formation of this dibrominated by-product of ethynyltributylstannane. Altering the sequence by alkyl-

could not be avoided by changing the reaction conditions. ation of G7 led to more easily isolable products. The use of

The mixture was subjected to a Sonogashira coupling to see 1-iododecane or 1-iodoethane in this reaction led now to a

whether one of the 6- or 8-positions reacted selectively, or ca. 1:1 mixture of N-7- and N-9-substituted products, which

whether the products of the Sonogashira reaction could be is surprising in view of the higher regioselectivities obtained

separated by chromatography. Despite all our attempts un- in the alkylation reactions of G6 and of 2-amino-6-chloro-

der different conditions and with different palladium cata- purine (see above). Bromination of G4_A_l_k₁₀and G4_A_l_k₂led

lysts, the two positions seemed to be equally reactive, and to the 8-bromopurines G3_A_l_k₁₀and G3_A_l_k₂in quite good

our target compound could not be separated from the mix- yields.

ture of ethynylated products. On the other hand, hydrolysis

of the mixture of brominated products under acidic condi- our target lipophilic guanines is shown in the central region

Nevertheless, the best route we found for the synthesis of

[

28]

tions led to mixtures of 8- and 6-oxopurines.

of Scheme 4. Alkylation was first carried out on 2-amino-

To circumvent these problems, substitution of the 6- 6-chloropurine using K CO or Cs CO as the base, as de-

2

3

2

3

chloro atom with a 2-trimethylsilylethoxy group^[was next scribed above. This reaction gave rather soluble products in

29]

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5-/8-Halogenated or Ethynylated Lipophilic Nucleobases

good yields. These could be easily purified, and then sub- lected from the various options available, but compound

jected to nucleophilic aromatic substitution with the 2-tri- G11 was still unreactive in Pd-catalysed Sonogashira or

methylsilylethoxy group to give compounds G4_A_l_k₁₀

,

Stille reactions under any of the conditions we tried. There-

G4_A_l_k₂, and G4_B_n₃. As mentioned above, the G4_A_l_k₁₀and fore, G11 was subjected first to an alkylation reaction with

G4_A_l_k₂products could be brominated at the 8-position in either ethyl iodide, 3,4,5-tris(dodecyloxy)benzyl bromide, or

the presence of NBS, but treatment of G4_B_n₃with NBS tert-butyl bromoacetate. Unexpectedly, in all cases, this nu-

(1 equiv.) led instead to the selective bromination of the aro- cleophilic substitution reaction gave very low regioselectiv-

matic benzyl moiety. Iodination was then tested using a dif- ity, leading to mixtures of mono- and dialkylated products

ferent approach that involved deprotonation at the guanine that complicated the purification process. Compound G11

8-position in the presence of LDA (lithium diisoprop- was alkylated at both the imidazole ring and at the amide

ylamide), and quenching of the resulting anion with iod- protecting group. Not only that, despite the high steric hin-

[

31]

ine.

Product G2_B_n₃was generated in this way in accept- drance of the diphenylcarbamoyl group, the N-7-substi-

able yield. This iodination procedure is, of course, also com- tuted product turned out to be one of the major by-prod-

patible with the alkylated purines. Finally, bromo deriva- ucts in this reaction. Only the target compound (i.e., G10_E_s)

tives G3_A_l_k₁₀, G3_A_l_k₂, and G3_B_n₂, and iodoguanine G2_B_n₃could be isolated in pure form in 28% yield from this mix-

were subjected to a Sonogashira coupling under the usual ture.

conditions, followed by deprotection of the alkyne TMS

group, to give G1_A_l_k₁₀, G1_A_l_k₂, G1_B_n₂, and G1_B_n₃

2-Aminoadenine (Scheme 6): two alkylated adenine de-

rivatives were prepared from commercially sourced 2,6-di-

.

The synthesis of 9-alkyl-8-ethynylguanines was also at- aminopurine. All our attempts to either iodinate or brom-

tempted using guanine as a convenient starting material, inate this starting material were unsuccessful. Instead, the

[

37]

primarily due to its low cost (Scheme 5). However, the ex- alkylation reaction was carried out as the first step of the

tremely low solubility of this heterocyclic reagent had to be synthetic route. K CO proved to be the best base for these

2

3

overcome first. The literature offers different methods to reactions as it is easily handled and inexpensive, and gave

transiently transform guanine into products that are soluble good yields. Compounds A4_A_l_k₁₀and A4_A_l_k₂were prepared

[

32]

enough to carry out several synthetic transformations.

in this way. Next, the halogenation reaction was optimized.

[

38]

Among the different methods we tested, we chose protec- Iodination in the presence of periodic acid

was chosen

tion of the 2-amine as an isobutyryl amide, due to the ac- over bromination with NBS, not only for the reasons stated

ceptable solubility and ease of isolation of the product. above, but also because of the poor yields and low reliability

Compound G13 was thus synthesized in 80% yield in the of the latter reaction, even when recrystallized NBS was

presence of isobutyric anhydride.^[This product could be used. It is worth mentioning that none of the guanine deriv-

halogenated in the presence of bromine and sodium acet- atives tested could be iodinated under these conditions.

ate^[to give G12 in good yields. Direct attempts to carry Compounds A2_A_l_k₁₀, A2_A_l_k₂, and A3_A_l_k₁₀were then sub-

out a Sonogashira reaction with TMSA on compound G12 jected to the Sonogashira–TMS-cleavage protocol, leading

were unsuccessful in our hands, despite the fact that a re- to A1_A_l_k₁₀and A1_A_l_k₂in good yields.

33]

34]

lated procedure was recently reported starting from similar

Isoguanine (Scheme 6): the unnatural isoguanine nucleo-

[

35]

substrates;

only the starting material was recovered. We base could be obtained from 2,6-diaminopurine in a single

thought that protection of the 6-carbonyl group in G12 step by selective hydrolysis at C-2 via a diazonium interme-

[

39]

could increase its reactivity in palladium-catalysed cou- diate. For the sake of simplicity and convergence, we car-

[

12]

[36]

plings. A diphenylcarbamoyl protecting group was se- ried out this process after the cross-coupling reaction of the

Scheme 6. Optimized synthetic route to 8-iodo- and 8-ethynyl-diaminopurine and 8-ethynylisoguanine.

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iodinated A2 derivatives, and before TMS deprotection, benzyl chloride,^[⁴¹^]and 3,4,5-tris(dodecyloxy)benzyl bromide^[⁴²^]has

been reported elsewhere.

since the terminal ethynyl group was found to interfere with

^t^hⁱ^s^r^e^a^c^tⁱ^oⁿ^.^C^o^m^p^o^uⁿ^dⁱ^G¹Alk2 was isolated in 73% over-

all yield from A2_A_l_k₂after TMS cleavage in the presence of

K CO .

Synthesis of Cytosine Derivatives

-Iodocytosine (C3): Compound C3 was synthesized according to

5

2

3

[13]

a literature procedure adapted to our molecule. Cytosine (10.0 g,

9

1

0.0 mmol), iodine (34.3 g, 135.0 mmol), and iodic acid (22.2 g,

26.0 mmol) were stirred in acetic acid (300 mL) at 40 °C over-

Conclusions

night. When the reaction was complete, the mixture was cooled

and treated with Na (satd. aq.; 200 mL) until a white suspen-

sion was obtained. The mixture was then neutralized with NaOH

2 2 3

S O

In this work, we have prepared a series of lipophilic nu-

cleobases, including natural and unnatural derivatives, sub- (6 m aq.; 900 mL). The resulting white solid was collected by fil-

stituted at the 5-position (pyrimidines) or 8-position (pur- tration, and washed with slightly basified water until the filtered

ines) with either a halogen atom or a terminal triple bond. water had neutral pH. The solid was dried under reduced pressure

1

to give C3 (20.6 g, 96%). H NMR (300 MHz, [D

6

]DMSO): δ =

These include cytosine, isocytosine, and uracil derivatives

as pyrimidine heterocycles, and guanine, isoguanine, and 2-

aminoadenine derivatives as complementary purine bases.

The N-1/N-9 position of these compounds was function-

alized with alkyl or benzyl groups, as well as with amine or

carboxylic acid precursors. Such functional groups can

make the nucleobases more soluble in organic solvents, and

can direct nucleobase assembly in organic solvents or onto

surfaces; these phenomena are being studied in our group

at the moment. The synthetic sequences leading to the final

ethynylated compounds were optimized for each base, pay-

1

2

0.76 (br. s, 2 H, N H), 7.76 (s, 1 H, 6-H), 6.48 (br. s, 2 H, NH )

ppm. C NMR (75 MHz, CDCl ): δ = 164.4, 155.8, 149.4,

3

5.2 ppm. HRMS (ESI ): calcd. for C

1

3

+

5

4 5 3

H N OI [M + H] 237.9471;

found 237.9464.

Standard Procedure A for the Nucleobase Alkylation Reaction: The

corresponding iodoalkane or benzyl bromide/chloride (1.2 equiv.;

indicated in each case) was added dropwise to a suspension of the

nucleobase starting material (1 equiv.) and a base (1.2 equiv.; indi-

cated in each case) in dry DMF (volume indicated in each case).

The mixture was stirred under argon at 40 °C for a period of time

(

indicated in each case) until the reaction was complete, as indi-

ing attention to convergence, convenience, ease of purifica- cated by TLC. Work-up and purification methods are indicated in

tion, and overall yields. Our results indicate that the each case.

choice of reaction conditions and of the order in which the

1

-Decyl-5-iodocytosine (C2Alk10): Compound C2Alk10 was synthe-

halogenation, alkylation, and Sonogashira steps are carried

out is not always trivial, and that each base requires a par-

ticular optimized protocol.

[14]

sized according to a literature procedure

ecule. Compound C2Alk10 could be obtained following Standard

Procedure A using C3 (10.0 g, 42.2 mmol), Bu NOH (1.0 m solu-

adapted to our mol-

4

The molecules prepared in this work can be regarded as tion in MeOH; 50.6 mL, 50.6 mmol), 1-iododecane (11.0 mL,

a relevant collection of “supramolecular synthons” to 50.6 mmol), and DMF (150 mL). The reaction was complete after

1

2 h. Then, the reaction mixture was poured into water (150 mL)

which a wide diversity of functional units may be attached

by means of metal-catalysed cross-coupling or “click” reac-

tions, in order to guide their organization.

and the precipitated solid was collected by filtration, washed with

water, and dried. The resulting solid was washed with acetonitrile

to give C2Alk10 (9.8 g, 62%).

Compound C2Alk10 could also be obtained by stirring C4Alk10

(

15.7 g, 62.5 mmol), iodine (10.1 g, 40.5 mmol), and iodic acid

13.2 g, 76.0 mmol) in acetic acid (400 mL) at 40 °C overnight.

Experimental Section

General Information: Chemicals were purchased from commercial

suppliers, and were used without further purification. Solid, hygro-

scopic reagents were dried in a vacuum oven before use. N-Bromo-

succinimide (NBS) was recrystallized twice from water. Reaction

solvents were thoroughly dried before use using standard methods.

Column chromatography was carried out on silica gel Merck-60

When the reaction was complete, the mixture was cooled, and the

insoluble iodic acid was removed by filtration. The resulting mix-

ture was extracted with ethyl acetate, and the organic phase was

washed with water (3ϫ 400 mL), NaHCO

Na (satd. aq.; 400 mL), and brine (400 mL). The organic

layer was dried with MgSO , and concentrated in vacuo. The re-

3

(satd. aq.; 3ϫ 400 mL),

2 2 3

S O

4

(

230–400 mesh, 60 Å), and TLC was carried out on aluminium

sulting solid was washed with diethyl ether to give C2Alk10 (15.8 g,

81%) as a bright beige solid. m.p. 163–165 °C. H NMR (300 MHz,

1

sheets precoated with silica gel 60 F254 (Merck). High-resolution

mass spectra (HRMS) were determined with a VG AutoSpec in-

[D

6

]DMSO): δ = 8.07 (s, 1 H, 6-H), 7.58 (br. s, 1 H, NH

2

), 6.43

19), 1.6–1.4 (m, 2 H,

14CH ), 0.85 (t,

) ppm. C NMR (75 MHz, CDCl ): δ =

164.8, 155.4, 150.9, 55.0, 50.5, 31.8, 29.5, 29.4, 29.3, 29.23, 29.17,

1

2 2 9

strument (FAB) or an Applied Biosystems QSTAR instrument (br. s, 1 H, NH ), 3.7–3.6 (m, 2 H, N CH C H

1

(ESI) in the positive mode. MALDI-TOF MS spectra were deter-

N CH

2

CH

2

C

8

H

17), 1.4–1.1 (m, 14 H, N C

2

H

4

C

7

H

3

1

3

mined with a Bruker Ultraflex III instrument equipped with a

nitrogen laser operating at 337 nm. NMR spectra were recorded

J = 7.0 Hz, 3 H, CH

3

+

25 3

with a Bruker AC-300 (300 MHz) instrument. The temperature was 26.5, 22.6, 14.1 ppm. HRMS (ESI ): calcd. for C14H N OI [M +

+

actively controlled to be 298 K. Chemical shifts are reported in

ppm using the signals of the deuterated solvent as the internal stan-

dard [CHCl , calibrated at δ = 7.26 ppm ( H) and 77.0 ppm ( C);

3

H] 378.1036; found 378.1028.

-Hexyl-5-iodocytosine (C2Alk6): Compound C2Alk6 could be ob-

tained following Standard Procedure using C3 (5.0 g,

1.1 mmol), Bu NOH (1.0 m solution in MeOH; 25 mL,

1

13

A

1

13

DMSO calibrated at δ = 2.50 ppm ( H) and 39.5 ppm ( C)].

2

4

Compounds G8Alk10, G9Alk10, and G3Bn2 were not isolated. The

25.3 mmol), 1-iodohexane (4 mL, 25.3 mmol), and DMF (75 mL).

The reaction was complete after 8 h. The reaction mixture was then

poured into water (75 mL) and the precipitated solid was collected

[40]

synthesis and characterization of compounds 5-iodocytosine C3,

19]

[33]

5

-iodoisocytosine iC3,^[

guanine G13,

3,5-bis(dodecyloxy)-

7166

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7160–7175

5-/8-Halogenated or Ethynylated Lipophilic Nucleobases

by filtration, washed with water, and dried. The resulting solid was

purified by column chromatography on silica gel (CHCl /MeOH, and the solution was added by cannula to the reaction mixture.

0:1) to give C2Alk6 (4.0 g, 59%) as a pale solid. m.p. 165–166 °C. The resulting solution was stirred for 12 h. After the reaction was

), 7.54 (s, 1 complete, the solvent was evaporated under reduced pressure. The

benzene (3.36 g, 4.64 mmol) was dissolved in dry DMF (50 mL),

3

5

1

H NMR (300 MHz, CDCl

3 2

): δ = 8.39 (br. s, 1 H, NH

1

H, 6-H), 5.54 (br. s, 1 H, NH

1

N C

2

), 3.73 (m, 2 H, N CH

CH ), 1.4–1.2 (m,

), 0.87 (t, J = 6.6 Hz, 3 H, CH

2

C

6

5

H

11), residue was purified by column chromatography (CHCl

H, 20:1) to give C2Bn3 (2.8 g, 76%) as a white solid. m.p. 115–117 °C.

3

) ppm. C NMR ): δ = 9.10 (br. s, 1 H, C NH-H), 7.48

3

/MeOH,

1

.8–1.6 (m,

2

CH

H, N CH

2

C

4

H

9

1

13

1

4

2

H

4

C

3

H

6

3

H NMR (300 MHz, CDCl

(s, 1 H, 6-H), 6.46 (s, 2 H, Ar-2,4,6), 5.65 (s, 1 H, C NH-H), 4.82

4

6

(75 MHz, [D ]DMSO): δ = 163.9, 154.6, 151.9, 55.0, 48.6, 30.8,

+

1

2

[

8.6, 25.5, 21.9, 13.8 ppm. HRMS (ESI ): calcd. for C10

H

17

N

3

OI

(s, 2 H, N CH

OCH CH ), 1.24 [m, 34 H, OCH

O(CH

1

5

2

), 3.92 (t, J = 6.3 Hz, 6 H, OCH

CH (CH CH

] ppm. C NMR (75 MHz, CDCl ): δ = 165.0, 155.1,

53.6, 148.3, 138.4, 130.6, 107.1, 90.2, 84.0, 77.3, 75.0, 73.4, 69.3,

2.7, 32.0, 30.4, 29.8, 29.7, 29.5, 26.17, 22.74, 14.2 ppm. HRMS

2

), 1.75 (m, 6 H,

M + H]⁺322.0410; found 322.0405.

)

9

], 0.86 [m, 9 H,

2

3

1

3

2

)

11CH

3

1

-Ethyl-5-iodocytosine (C2Alk2): Compound C2Alk2 could be ob-

using C3 (10.0 g,

NOH (1.0 m solution in MeOH; 50.6 mL,

0.6 mmol), 1-iododecane (11 mL, 50.6 mmol), and DMF

tained following Standard Procedure

4

5

A

2.2 mmol), Bu

4

+

3 4

ESI ): calcd. for C47H82IN O

[M + H]⁺880.5422; found

(

8

80.5454.

(

150 mL). The reaction was complete after 5 h. The solvent was

evaporated, and the crude solid was purified by column chromatog-

raphy on silica gel (CHCl /MeOH, 20:1). A final recrystallization

1-[2-(tert-Butylcarbamate)ethyl]-5-iodocytosine (C2Am): A suspen-

sion of C3 (3.0 g, 12.65 mmol) and Cs CO (4.9 g, 15.19 mmol) in

3

2

3

from acetonitrile gave C2Alk2 (2.2 g, 40%) as a white solid.

dry DMF (75 mL) was stirred at room temperature for 1.5 h. Then

a solution of 2-(Boc-amino)ethylbromide (3.4 g, 15.19 mmol) in dry

DMF (5 mL) was added by cannula, and the resulting suspension

was stirred at room temperature for 12 h. Once the reaction was

complete, the resulting solid was collected by filtration, washed

Compound C2Alk2 could also be obtained by stirring C4Alk2 (1.0 g,

7

8

.2 mmol), iodine (2.8 g, 11.1 mmol), and iodic acid (1.5 g,

.8 mmol) in acetic acid (20 mL) at 40 °C. The reaction was com-

plete after 4 h. Then, the reaction mixture was cooled to room tem-

perature, and the insoluble iodic acid was removed by filtration.

with water, and dried under vacuum to give C2Am (3.92 g, 82%) as

1

a white solid. m.p. 231–233 °C. H NMR (300 MHz, CDCl

3

): δ =

The mixture was extracted with CHCl

washed with water (3ϫ 10 mL), NaHCO

Na (satd. aq.; 10 mL), and brine (10 mL). The organic layer

was dried with MgSO , and concentrated in vacuo. The resulting

solid was purified by column chromatography on silica gel (CHCl

MeOH, 20:1) to give C2Alk2 (0.7 g, 36%) as a white solid. m.p. 203–

3

, and the organic phase was

4

7

.80 (s, 1 H, 6-H), 7.60 (s, 1 H, C NH-H), 6.85 (br. s, 1 H,

N CH CH -NH), 6.43 (br. s, 1 H, C NH-H), 3.66 (d, J = 5.8 Hz,

2 2

3

(satd. aq.; 3ϫ 10 mL),

1

4

2 2 3

S O

1

2

9

1

H, N CH

H, OC(CH

55.6, 154.6, 152.1, 55.0, 48.7, 39.5, 38.5, 28.2 ppm. HRMS (ESI ):

[M + H]⁺381.0418; found 381.0403.

2

CH

2

), 3.14 (d, J = 5.8 Hz, 2 H, N CH

2

CH

2

), 1.35 [s,

4

1

3

)

3

] ppm. C NMR (75 MHz, [D

6

]DMSO): δ = 164.0,

3

/

+

calcd. for C11

Standard Procedure B for the Sonogashira Coupling^[⁴¹^]with TMSA

) ppm. C NMR and Subsequent Deprotection of the Alkyne TMS Group: A dry

]DMSO): δ = 163.9, 154.4, 151.6, 55.2, 43.8, THF/NEt (4:1) solvent mixture was subjected to deoxygenation

4 3

H18IN O

1

2

7

2

(

1

04 °C. H NMR (300 MHz, [D

.61 (br. s, 1 H, NH ), 6.46 (br. s, 1 H, NH

), 1.13 (t, J = 7.0 Hz, 3 H, CH

3

6

]DMSO): δ = 8.09 (s, 1 H, 6-H),

2

), 3.67 (q, J = 7.0 Hz,

1

13

H, N CH

2

CH

3

75 MHz, [D

4.5 ppm. HRMS (ESI ): calcd. for C

found 265.9781.

6

3

+

6

H

9

N

3

OI [M + H] 265.9784;

by three freeze-pump-thaw cycles with argon. Then, this solvent

was added to a mixture of the appropriate halogenated base

(

3 2 2

1 equiv.), CuI (0.01 equiv.), and Pd(PPh ) Cl (0.02 equiv.). The

1

-[3,5-Bis(dodecyloxy)benzyl]-5-iodocytosine (C2Bn2): Following

mixture was stirred at room temperature for a few minutes. Then,

trimethylsilylacetylene (TMSA; 2 equiv.) was added dropwise. The

reaction mixture was stirred under argon at a given temperature

for a period of time (indicated in each case) until the reaction was

complete, as indicated by TLC. Then, the mixture was filtered

through Celite, and the solvent was evaporated under vacuum.

Standard Procedure A for the alkylation reaction, Bu NOH (1.0 m

4

solution in MeOH; 2.26 mL, 2.26 mmol) was added to a suspension

of C3 (500 mg, 2.26 mmol) in dry DMF (25 mL). The resulting

mixture was stirred at 40 °C for 1 h. Then 1-(chloromethyl)-3,5-

bis(dodecyloxy)benzene (1.34 g, 2.72 mmol) was added, and the re-

sulting solution was stirred at 40 °C for 16 h. Once the reaction

was complete, the solvent was evaporated under reduced pressure.

The crude material was dissolved in CH

tion was washed with water (3ϫ 10 mL), and brine (10 mL). The

organic phase was dried with MgSO , and concentrated in vacuo.

The residue was purified by column chromatography (CHCl

The resulting crude material was placed in a round-bottomed flask

equipped with a magnetic stirrer bar. THF was added, and the

mixture was stirred at room temperature until the solid was dis-

2 2

Cl (10 mL), and this solu-

4

solved.

Then,

hydrated

tetrabutylammonium

fluoride

3

/

(TBAF·3H O; 1 equiv.) was slowly added at 0 °C, and the mixture

2

MeOH, 50:1) to give C2Bn2 (234 mg, 40%) as a white solid. m.p. was stirred at room temperature until TLC indicated that the reac-

1

6

25–127 °C. H NMR (300 MHz, CDCl

.42 (d, J = 2.1 Hz, 3 H, Ar-2,4,6), 4.89 (s, 2 H, N CH

), 1.75 (p, J = 6.8 Hz, 6 H, OCH

.61–1.06 [m, 36 H, OCH CH (CH CH ], 1.06–0.78 [m, 6 H, the resulting solid was washed with cold acetonitrile.

O(CH ): δ = 163.7, 161.0,

] ppm. ¹³C NMR (75 MHz, CDCl

55.7, 150.6, 137.9, 106.9, 101.2, 77.2, 68.4, 55.8, 52.6, 32.1, 29.8,

9.8, 29.8, 29.7, 29.6, 29.5, 29.4, 26.2, 22.8, 14.3 ppm. HRMS

3

): δ = 7.51 (s, 1 H, 6-H), tion was complete (approximately 1 h in all cases). The solvent was

1

2

), 3.91 (t, evaporated under reduced pressure, and the product was purified

CH ), by column chromatography (eluent indicated in each case). Finally,

J = 6.5 Hz, 4 H, OCH

2

1

2

)

9

3

2

)

11CH

3

1

-Decyl-5-ethynylcytosine (C1Alk10): Compound C1Alk10 was pre-

pared following Standard Procedure B. Compound C2Alk10 (10.0 g,

6.5 mmol), Pd(PPh Cl (372.1 mg, 0.53 mmol), and CuI

50.4 mg, 0.27 mmol) were dissolved in the THF/NEt mixture

125 mL). Then TMSA (9.8 mL, 53.0 mmol) was added. The reac-

(9.2 g,

29.2 mmol) was added to a THF (130 mL) solution of the crude

mixture. Compound C1Alk10 was purified by column chromatog-

raphy on silica gel (CHCl /EtOAc, 20:1). A final recrystallization

from acetonitrile gave C1Alk10 (4.7 g, 65%) as a brown solid. m.p.

1

2

(

2

(

3

)

2

+

59 3 3

ESI ): calcd. for C35H N O I [M + H] 696.3595; found

3

696.3581.

1

-[3,4,5-Tris(dodecyloxy)benzyl]-5-iodocytosine (C2Bn3): Following tion was complete after 12 h. Then, TBAF·3H

NOH (1.0 m solution in MeOH;

.22 mL, 4.22 mmol) was added to a solution of C3 (1.0 g,

2

O

Standard Procedure A, Bu

4

3

.22 mmol) in dry DMF (100 mL), and the mixture was stirred for

0 min at 50 °C. Then, 1-(bromomethyl)-3,4,5-tris(dodecyloxy)-

3

Eur. J. Org. Chem. 2015, 7160–7175

www.eurjoc.org

7167

D. González-Rodríguez et al.

FULL PAPER

1

139–141 °C. H NMR (300 MHz, [D

6

]DMSO): δ = 8.05 (s, 1 H, 6- 1-[3,4,5-Tris(dodecyloxy)benzyl]-5-ethynylcytosine (C1Bn3): Follow-

H), 7.50 (br. s, 1 H, NH

2

), 6.66 (br. s, 1 H, NH

2

), 4.30 (s, 1 H, ing Standard Procedure B, TMSA (1.4 mL, 2.27 mmol) was added

19), 1.6–1.4 (m, 2 H, to a solution of C2Bn3 (500 mg, 0.568 mmol), [Pd(Ph ]Cl

), 0.85 (t, (7.71 mg, 0.011 mmol), and CuI (1.07 mg, 0.006 mmol) in THF/

1

CϵCH), 3.7–3.6 (m, 2 H, N CH

2

C

9

1

H

3

)

2

1

N CH

2

CH

2

C

8

H

17), 1.3–1.1 (m, 14 H, N C

2

H

4

C

7

H

14CH

3

J = 6.6 Hz, 3 H, CH

3

) ppm. ¹³C NMR (75 MHz, [D

6 3

]DMSO): δ = NEt (5 mL), and the mixture was stirred at 40 °C overnight. Once

1

2

C

64.9, 154.8, 148.8, 89.5, 83.7, 74.9, 50.6, 31.8, 29.4, 29.3, 29.2,

the reaction was complete, the solvent was evaporated. The re-

sulting crude material was suspended in THF (10 mL), and

+

9.12, 29.10, 26.4, 22.6, 14.0 ppm. HRMS (ESI ): calcd. for

H

26

N

3

O [M + H]⁺276.2070; found 276.2079.

TBAF·3H

was complete, the solvent was evaporated, and the resulting residue

was purified by column chromatography (CHCl /MeOH, 50:1) to

give C1Bn3 (340 mg, 77%) as a pale solid. m.p. 94–96 °C. H NMR

2

O (625 mg, 0.625 mmol) was added. When the reaction

16

1-Hexyl-5-ethynylcytosine (C1Alk6): Compound C1Alk6 was pre-

3

pared following Standard Procedure B. Compound C2Alk6 (3.7 g,

1

11.6 mmol), Pd(PPh

3

)

2

Cl

2

(162 mg, 0.23 mmol), and CuI (22 mg,

mixture (70 mL).

4

(

300 MHz, CDCl

3

): δ = 7.47 (s, 1 H, 6-H), 6.87 (br. s, 1 H, C NH-

0.12 mmol) were dissolved in the THF/NEt

3

4

H), 6.49 (s, 2 H, Ar-2,6), 5.67 (br. s, 1 H, C NH-H), 4.87 (s, 2 H,

Then TMSA (3.3 mL, 23.1 mmol) was added. The reaction was

complete after 12 h. Then, TBAF·3H O (3.7 g, 11.6 mmol) was

added to a THF (60 mL) solution of the crude mixture. Compound

1

N CH

CϵCH), 1.89–1.52 (m,

OCH CH (CH CH ], 1.03–0.67 [m, 9 H, O(CH

C NMR (75 MHz, CDCl ): δ = 165.0, 155.1, 153.6, 148.3, 138.4,

2

), 3.93 (td, J = 6.5, 2.2 Hz, 6 H, OCH

H, OCH CH ), 1.28 [m, 64 H,

] ppm.

2

), 3.32 (s, 1 H,

2

8

2

)

9

3

2 3

)11CH

C1Alk6 was purified by column chromatography on silica gel

13

3

(CHCl

3

/MeOH, 50:1). A final recrystallization from acetonitrile

1

2

C

30.6, 107.1, 90.2, 84.0, 77.3, 75.0, 73.4, 69.3, 52.7, 32.0, 30.4, 29.8,

1

gave C1Alk6 (2.1 g, 81%) as an ochre solid. m.p. 163–164 °C.

NMR (300 MHz, CDCl

NH ), 5.64 (br. s, 1 H, NH

1

H

+

9.7, 29.5, 26.2, 22.7, 14.2 ppm. HRMS (ESI ): calcd. for

3

): δ = 7.54 (s, 1 H, 6-H), 6.89 (br. s, 1 H,

_[_M₊_H_]+ 778.6456; found 778.6464.

49

H

84

N

3

O

4

1

2

), 3.77 (m, 2 H, N CH

2

C

5

H

11), 3.35 (s,

1

H, CϵCH), 1.8–1.6 (m, 2 H, N CH

2

CH

2

C

4

H

9

), 1.4–1.2 (m, 6 H, 1-[2-(tert-Butylcarbamate)ethyl]-5-ethynylcytosine (C1Am): Follow-

1

13

N C

2

H

4

C

3

H

6

CH

3

), 0.88 (t, J = 6.6 Hz, 3 H, CH

3

) ppm. C NMR ing Standard Procedure B, C2Am (3.0 g, 7.9 mmol), Pd(PPh

(140 mg, 0.2 mmol), and CuI (20 mg, 0.1 mmol) were dissolved in

the THF/NEt mixture. TMSA (3.4 mL, 23.9 mmol) was added,

3 2 2

) Cl

(75 MHz, CDCl

3

): δ = 164.7, 154.8, 149.1, 89.2, 83.7, 75.0, 50.7,

+

31.4, 29.2, 26.2, 22.5, 14.0 ppm. HRMS (FAB ): calcd. for

3

C

12

H

18

N

3

O [M + H]⁺220.1450; found 220.1445.

and the mixture was heated at 40 °C for 12 h. When the reaction

was complete, the solvent was evaporated. The resulting crude ma-

1-Ethyl-5-ethynylcytosine (C1Alk2): Compound C1Alk2 was prepared

terial and TBAF·3H

THF (1:1), and the mixture was stirred at room temperature for

h until the reaction was complete. The solvent was then evapo-

rated under reduced pressure. The resulting solid was purified by

column chromatography (CHCl /MeOH, 20:1) to give C1Am

2 2 2

O (2.7 g, 8.9 mmol) were dissolved in CH Cl /

following Standard Procedure B. Compound C2Alk2 (1.5 g,

5.7 mmol), Pd(PPh

3

)

2

Cl

2

(79.5 mg, 0.11 mmol), and CuI (10.8 mg,

mixture (15 mL).

1

0.06 mmol) were dissolved in the THF/NEt

3

Then TMSA (2 mL, 11.3 mmol) was added. The reaction was com-

plete after 12 h. Then, TBAF·3H O (1.8 g, 5.7 mmol) was added

to a THF (50 mL) solution of the crude mixture. Compound C1Alk2

was purified by column chromatography on silica gel (CHCl

EtOAc, 20:1). A final recrystallization from acetonitrile gave C1Alk2

3

2

1

(

1.57 g, 71%) as a pale brown solid. m.p. 205–206 °C. H NMR

300 MHz, [D ]DMSO): δ = 7.77 (s, 1 H, 6-H), 7.51 (br. s, 1 H,

C NH-H), 6.85 (br. s, 1 H, N CH

6

3

/

4

1

2

CH

2

-NH), 6.64 (br. s, 1 H,

4

1

C NH-H), 4.30 (s, 1 H, CϵCH), 3.69 (m, 2 H, N CH

2

CH

2

), 3.16

] ppm. C NMR

]DMSO): δ = 164.6, 155.6, 154.0, 150.5, 87.7, 85.6,

1

(

5

(

0.51 g, 55%) as a white solid. m.p. 196–197 °C. H NMR

300 MHz, CDCl ): δ = 7.79 (br. s, 1 H, NH ), 7.55 (s, 1 H, 6-H),

.76 (br. s, 1 H, NH ), 3.84 (q, J = 7.2 Hz, 2 H, N CH

s, 1 H, CϵCH), 1.32 (t, J = 7.2 Hz, 3 H, CH

) ppm. ¹³C NMR

75 MHz, CDCl ): δ = 164.7, 154.6, 148.6, 89.7, 83.8, 74.9, 45.6,

4.6 ppm. HRMS (ESI ): calcd. for C

found 164.0822.

1

13

(

7

m, 3 H, N CH

75 MHz, [D

7.8, 75.9, 49.1, 28.1, 1.9 ppm. HRMS (FAB ): calcd. for

_[_M₊_H_]+ 279.1457; found 279.1457.

2 2 3 3

CH ), 1.34 [s, 9 H, OC(CH )

3

2

6

1

2

CH

3

), 3.35

+

3

13 18 4 3

C H N O

3

+

1

8

H

10

N

3

O [M + H] 164.0818;

1-Decylcytosine (C4Alk10): Compound C4Alk10 was synthesized ac-

cording to a literature procedure^[adapted to our molecule. Com-

pound C4Alk10 was obtained following Standard Procedure A using

14]

1

-[3,5-Bis(dodecyloxy)benzyl]-5-ethynylcytosine (C1Bn2): Following

Standard Procedure B, C2Bn2 (1.1 g, 1.58 mmol), CuI (0.03 mg,

.0158 mmol), and Pd(Ph Cl (22 mg, 0.032 mmol) were dis-

solved in the THF/NEt mixture (15 mL). Then, TMSA (0.6 mL,

.74 mmol) was added, and the mixture was stirred at 40 °C over-

cytosine (10.0 g, 90 mmol), Bu

08 mL, 108 mmol), 1-iododecane (19 mL, 108 mmol), and DMF

500 mL). The reaction was complete after 12 h. Then, the reaction

4

NOH (1.0 m solution in MeOH;

1

(

0

3

)

2

3

mixture was poured into water (150 mL), and the precipitated solid

was collected by filtration, washed with water, and dried. The re-

sulting solid was washed with acetonitrile to give C4Alk10 (15.8 g,

4

night. Once the reaction was complete, the solvent was evaporated

under reduced pressure. The residue was dissolved in THF (15 mL),

and TBAF·3H O (553 mg, 1.58 mmol) was added. Once the depro-

2

tection was complete, the solvent was removed under reduced pres-

sure. The crude material was purified by column chromatography

1

7

(

7

0%) as a pale solid. H NMR (300 MHz, [D

6

]DMSO): δ = 7.54

), 5.61 (d, J =

19), 1.53 (m, 2 H,

14CH ), 0.85 (t,

]DMSO): δ = 165.8, 155.8,

46.0, 93.0, 48.6, 38.5, 31.2, 28.9, 28.6, 25.9, 22.0, 13.9 ppm.

d, J = 7.0 Hz, 1 H, 6-H), 6.91 (br. s, 2 H, NH

2

.0 Hz, 1 H, 5-H), 3.59 (m, 2 H, N CH C H

2 9

17), 1.3–1.1 (m, 14 H, N C

H, CH ) ppm. C NMR (75 MHz, [D

1

N CH

3

1

2

CH

2

C

8

H

2

H

4

C

7

H

3

(CHCl

3

/MeOH, 100:1). Subsequent recrystallization from CHCl

3

/

13

3

6

MeCN gave C1Bn2 (902 mg, 82%) as a pale brown solid. m.p. 103–

1

4

105 °C. H NMR (300 MHz, CDCl

3

): δ = 8.41 (br. s, 1 H, C NH-

+

_O_[_M₊_H_]+ 252.2070; found

26 3

H N

HRMS (ESI ): calcd. for C14

52.2082.

C

4

H), 7.51 (s, 1 H, 6-H ), 6.40 (s, 3 H, Ar-2,4,6), 6.20 (s, 1 H, C NH-

2

1

H), 4.89 (s, 2 H, N CH

H, CϵCH), 1.74 (dt, J = 8.3, 6.5 Hz, 6 H, OCH

m, 36 H, OCH CH (CH CH ], 1.00–0.75 [m, 6 H, O(CH

] ppm. ¹³C NMR (75 MHz, CDCl

): δ = 163.8, 161.1, 148.9,

2

), 3.91 (t, J = 6.5 Hz, 4 H, OCH

2

), 3.36 (s,

1

[

CH

2

CH ), 1.62–1.11

2

1-Ethylcytosine (C4Alk2): Compound C4Alk2 was obtained following

Standard Procedure A using cytosine (5.0 g, 45 mmol), Bu NOH

2

)

9

3

2

)

11

-

4

3

(1.0 m solution in MeOH; 54 mL, 54 mmol), 1-iodoethane (4.5 mL,

1

2

C

37.1, 107.1, 101.3, 84.9, 77.3, 74.1, 68.4, 52.8, 32.1, 29.8, 29.7,

54 mmol), and DMF (150 mL). The reaction was complete after

+

9.6, 29.5, 29.4, 26.2, 22.84, 14.3 ppm. HRMS (ESI ): calcd. for 12 h. After solvent evaporation, the crude solid was purified by

H

60

N

3

O

3

[M + H]⁺594.4629; found 594.4667.

column chromatography on silica gel (CHCl /MeOH, 20:1). A final

3

37

7168

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7160–7175

5-/8-Halogenated or Ethynylated Lipophilic Nucleobases

recrystallization from acetonitrile gave C4Alk2 (1.2 g, 19%) as a

white solid. ¹H NMR (300 MHz, [D

]DMSO): δ = 7.59 (d, J =

(15 mL) solution of the crude mixture. The crude material was

6

purified by column chromatography on silica gel (CHCl

3

/hexane,

7

5

.0 Hz, 1 H, 6-H), 7.02 (br. s, 2 H, NH

2

), 5.64 (d, J = 7.0 Hz, 1 H, 100:1) to give U1Alk6 (216 mg, 49%) as a white solid. m.p. 149–

1

3

-H), 3.65 (q, J = 7.0 Hz, 2 H, N CH

2

CH

3

), 1.13 (t, J = 7.0 Hz, 3

]DMSO): δ = 165.5, 155.2, 7.49 (s, 1 H, 6-H), 3.74 (t, J = 7.0 Hz, 2 H, N CH

151 °C. H NMR (300 MHz, CDCl

3

): δ = 8.31 (br. s, 1 H, N H),

) ppm. ¹³C NMR (75 MHz, [D

1

C

5

H

11), 3.21 (s,

H, CH

45.9, 93.3, 43.7, 14.5 ppm. HRMS (ESI ): calcd. for C

M + H]⁺140.0818; found 140.0813.

3

6

2

+

1

[

6

H

10

N

3

O

1 H, CϵCH), 1.8–1.6 (m, 2 H, N CH

2

CH

2

C

4

H

9

), 1.4–1.2 (m, 6 H,

1

13

N C

2

H

4

C

3

H

6

CH

3 3

), 0.89 (t, J = 6.7 Hz, 3 H, CH ) ppm. C NMR

(

4

75 MHz, [D

6

]DMSO): δ = 161.9, 149.8, 148.1, 98.7, 82.1, 74.5,

Synthesis of the Uracil Derivatives

-Decyl-5-iodouracil (U2Alk10): Compound U2Alk10 was obtained

following Standard Procedure using 5-iodouracil (5.0 g,

(8.2 g, 25.2 mmol), 1-iododecane (5.4 mL,

5.2 mmol), and DMF (100 mL). The reaction was complete after

h. The solvent was evaporated, and the crude material was dis-

+

9.4, 31.2, 29.0, 26.0, 22.4, 13.9 ppm. HRMS (ESI ): calcd. for

1

+

C

12

H

17

N

2

O

2

[M + H] 221.1284; found 221.1281.

Synthesis of the Isocytosine Derivatives

_-_I_o_d_o_i_s_o_c_y_t_o_s_i_n_e₍_i_C₃₎_:[19] Isocytosine (1.0 g, 9.0 mmol) was sus-

pended in AcOH/H O (1:1; 35 mL). The reaction mixture was

stirred at 50 °C for 15 min. Then N-iodosuccinimide (2.4 g,

A

2

4

2 3

1 mmol), Cs CO

5

2

solved in CHCl

3

(200 mL). This solution was washed with water

(3ϫ 100 mL) and brine (100 mL). The organic layer was dried with

1

2

0.8 mmol) was added, and the mixture was stirred at 100 °C for

h. When the reaction was complete, the mixture was cooled to

MgSO

4

, and concentrated in vacuo. The crude solid was purified

/MeOH, 200:1) to

by column chromatography on silica gel (CHCl

give U2Alk10 (3.6 g, 45%) as a white solid. m.p. 148–149 °C.

NMR (300 MHz, [D

3

room temperature. The resulting cream-coloured solid was col-

1

H

lected by filtration, and washed with water to give iC3 (1.7 g, 81%).

3

6

]DMSO): δ = 11.58 (br. s, 1 H, N H), 8.20 (s,

1

H NMR (300 MHz, [D

s, 1 H, 6-H), 6.71 (br. s, 2 H, NH ) ppm. C NMR (75 MHz, [D ]-

2 6

]DMSO): δ = 11.26 (br. s, 1 H, N H), 7.93

3

6

1

H, 6-H), 3.64 (t, J = 6.9 Hz, 2 H, N CH

2

C

9

H

19), 1.55 (m, 2 H,

14CH ), 0.85 (t,

]DMSO): δ =

60.8, 150.7, 150.0, 67.5, 49.1, 31.7, 29.3, 29.2, 29.1, 29.00, 28.96,

13

(

1

N CH

J = 6.9 Hz, 3 H, CH

1

2

CH

2

C

8

H

17), 1.3–1.1 (m, 14 H, N C

2

H

4

C

7

H

3

+

DMSO): δ = 161.5, 159.6, 156.6, 71.0 ppm. HRMS (ESI ): calcd.

for C H N

4 5 3

) ppm. ¹³C NMR (75 MHz, [D

_O_I_[_M₊_H_]+ 237.9471; found 237.9464.

3

6

+

1-Ethyl-5-iodoisocytosine (iC2Alk2): Compound iC2Alk2 was ob-

tained following Standard Procedure A using iC3 (1.7 g, 7.3 mmol),

Bu NOH (1.0 m solution in MeOH; 8.8 mL, 8.8 mmol), 1-iodo-

4

ethane (0.72 mL, 8.8 mmol), and DMF (30 mL). The resulting

solution was stirred at room temperature for 2 h, until the reaction

was complete. The solvent was evaporated, and the crude material

24 2 2

6.2, 22.5, 13.5 ppm. HRMS (FAB ): calcd. for C14H N O I [M

+

H] 379.0883; found 379.0881.

-Hexyl-5-iodouracil (U2Alk6): Compound U2Alk6 was obtained fol-

lowing Standard Procedure using 5-iodouracil (3.0 g,

(4.9 g, 15.1 mmol), 1-iodohexane (2.2 mL,

1

A

1

4

2 3

2.6 mmol), Cs CO

5.1 mmol), and DMF (200 mL). The reaction was complete after

h. The solvent was evaporated, and the crude solid was purified

was dissolved in CHCl

water (3ϫ 20 mL), and brine (20 mL). The organic layer was dried

with MgSO , and concentrated in vacuo. The crude solid was puri-

fied by column chromatography on silica gel (CHCl /MeOH,

00:1). A final recrystallization from acetonitrile gave iC2Alk2

3

(40 mL). This solution was washed with

by column chromatography on silica gel (CHCl

3

/MeOH, 200:1) to

4

1

give U2Alk6 (0.64 g, 16%) as a white solid. H NMR (300 MHz,

3

CDCl ): δ = 8.20 (br. s, 1 H, N H), 7.60 (s, 1 H, 6-H), 3.73 (t, J =

1

(

4

CH

3

1

7

1

.4 Hz, 2 H, N CH

2

C

5

H

11), 1.7–1.6 (m, 2 H, N CH

CH ), 0.90 (t, J = 7.0 Hz, 3 H, CH

): δ = 169.5, 154.3, 148.9, 67.3,

2

CH

2

C

4

H

9

),

1

0.67 g, 35%) as a white solid. m.p. 181–182 °C. H NMR

300 MHz, CDCl ): δ = 7.98 (s, 1 H, 6-H), 5.19 (br. s, 2 H, NH ),

), 1.35 (t, J = 7.3 Hz, 3 H,

) ppm. C NMR (75 MHz, CDCl ): δ = 159.4, 158.9, 155.2,

OI [M +

1

.3–1.2 (m, 6 H, N C

ppm. C NMR (75 MHz, CDCl

2

H

4

C

3

H

6

3

)

3

2

13

3

1

2 3

.06 (q, J = 7.3 Hz, 2 H, N CH CH

+

4

C

9.2, 31.2, 29.1, 26.0, 22.4, 13.9 ppm. HRMS (ESI ): calcd. for

13

3

+

10

H

16

N

2

O

2

I [M + H] 323.0251; found 323.0249.

+

6 9 3

8.5, 29.7, 12.1 ppm. HRMS (ESI ): calcd. for C H N

+

1

-Decyl-5-ethynyluracil (U1Alk10): Compound U1Alk10 was prepared H] 265.9784; found 265.9786.

following Standard Procedure B. U2Alk10 (3.2 g, 8.4 mmol),

Pd(PPh Cl (117.6 mg, 0.17 mmol), and CuI (15.9 mg,

.08 mmol) were dissolved in the THF/NEt mixture (60 mL).

Then TMSA (3.1 mL, 16.8 mmol) was added. The reaction was

complete after 12 h. Then, TBAF·3H O (2.7 g, 8.4 mmol) was

Standard Procedure C for the Carbonyl Group Protection of the

Guanine Derivatives: In a two-necked round-bottomed flask,

equipped with a basic reflux set-up and a magnetic stirrer bar, acti-

vated NaH (4 equiv.) was placed under argon. Dry solvent (indi-

cated in each case) was added, and the mixture was stirred. Then,

3

)

2

0

3

2

added to a THF (60 mL) solution of the crude mixture. The crude

material was purified by column chromatography on silica gel (hex-

2-trimethylsilylethanol (2 equiv.) was added dropwise, and the mix-

ture was stirred under reflux for 2.5 h. The mixture was then cooled

to room temperature, and the nucleobase (1 equiv.) was added care-

fully. The resulting mixture was stirred under reflux overnight, until

TLC indicated that the reaction was complete. Work-up and purifi-

cation methods are indicated in each case.

1

ane/EtOAc, 4:1) to give U1Alk10 (461 mg, 65%) as a white solid. H

3

NMR (300 MHz, CDCl

3

): δ = 8.16 (br. s, 1 H, N H), 7.49 (s, 1 H,

1

6-H), 3.74 (t, J = 6.7 Hz, 2 H, N CH

2

C

9

H

19), 3.21 (s, 1 H, CϵCH),

17), 1.3–1.2 (m, 14 H,

14CH ), 0.88 (t, J = 6.7 Hz, 3 H, CH ) ppm. C NMR

3 3

1

N C

.8–1.6 (m,

2

H, N CH

2

CH

2

C

8

H

1

13

2

H

4

C

7

H

(75 MHz, [D

6

]DMSO): δ = 161.6, 149.5, 148.0, 98.7, 82.1, 74.4,

Synthesis of the Guanine Derivatives

4

9.4, 31.8, 29.7, 29.44, 29.37, 29.2, 29.1, 26.3, 22.6, 14.1 ppm.

_-_A_m_i_n_o_-₆_-_[₂_-₍_t_r_i_m_e_t_h_y_l_s_i_l_y_l₎_e_t_h_o_x_y_]_p_u_r_i_n_e₍_G₇₎_:[29] Compound G7

was prepared following Standard Procedure using NaH

118.3 mmol, 2.8 g) and dry dioxane (125 mL). Then, 2-trimethyl-

silylethanol (8.5 mL, 59.2 mmol) was added dropwise. Later, 2-

amino-6-chloropurine (5.0 g, 29.6 mmol) was added. The reaction

2

+

HRMS (ESI ): calcd. for C16

H

25

N

2

O

2

[M + H] 277.1910; found

C

+

2

77.1910; calcd. for C16

99.1750.

H

24

N

2

O

2

Na 299.1729 [M + Na] ; found

(

1

-Hexyl-5-ethynyluracil (U1Alk6): Compound U1Alk6 was prepared

following Standard Procedure B. U2Alk6 (0.64 g, 2.0 mmol), was completed overnight. The mixture was concentrated in vacuo,

Pd(PPh Cl (27.9 mg, 0.04 mmol), and CuI (3.8 mg, 0.02 mmol) the residue was dissolved in water (100 mL), and this solution was

were dissolved in the THF/NEt

0.6 mL, 4.0 mmol) was added. The reaction was complete after

h. Then, TBAF·3H O (0.6 g, 2.0 mmol) was added to a THF

3

)

2

3

mixture (20 mL). Then TMSA

washed with diethyl ether (2ϫ 50 mL). Acetic acid was added to

the aqueous phase until pH 6, and the resulting solid was collected

by filtration. The crude solid was dried, and passed through a silica

(

8

2

Eur. J. Org. Chem. 2015, 7160–7175

www.eurjoc.org

7169

D. González-Rodríguez et al.

FULL PAPER

plug (CHCl

3

/MeOH, 10:1). A final recrystallization from MeOH/

pressure, and the crude product was purified by column

1

water gave G7 (2.9 g, 48%) as a white solid. m.p. 184–185 °C. H

chromatography (cyclohexane/EtOAc, 4:1) to give G5Bn3 (4.6 g,

9

1

NMR (300 MHz, [D

s, 1 H, 8-H), 6.15 (br. s, 2 H, NH

OCH CH TMS), 1.13 (t, J = 7.0 Hz, 2 H, OCH

s, 9 H, Si(CH

] ppm. ¹³C NMR (75 MHz, [D

59.9, 159.6, 156.0, 138.4, 113.0, 63.3, 17.1, –1.3 ppm. HRMS

6

]DMSO): δ = 12.36 (br. s, 1 H, N H), 7.77 48%) as a white solid. m.p. 92–94 °C. H NMR (300 MHz, CDCl

3

):

(

2

), 4.49 (t, J = 7.0 Hz, 2 H,

CH TMS), 0.07 C NH

]DMSO): δ = 1.72 (m, 6 H, OCH

CH ], 0.86 [t, J = 6.6 Hz, 9 H, O(CH

(75 MHz, CDCl ): δ = 159.3, 154.0, 153.7, 151.4, 142.3, 138.5,

129.9, 125.2, 106.6, 77.2, 73.6, 69.4, 47.6, 32.0, 30.4, 29.84, 29.80,

δ = 7.70 (br. s, 1 H, 8-H), 6.43 (s, 2 H, Ar-2,6), 5.34 (br. s, 2 H,

2

9

2

), 5.10 (s, 2 H, N CH

CH ), 1.55–1.05 [m, 60 H, OCH

] ppm. C NMR

2

), 3.90 (q, J = 7.0 Hz, 6 H, OCH

2

),

[

3

)

3

6

2

CH (CH

2

)

9

-

1

3

1

3

2 3

)11CH

+

(ESI ): calcd. for C10

H

18

N

5

OSi [M + H] 252.1275; found

3

252.1299.

+

2

C

9.74, 29.52, 29.47, 26.2, 22.8, 14.2 ppm. HRMS (ESI ): calcd. for

Standard Procedure D for the Bromination Reaction of the Purine

Derivatives: NBS (1.1 equiv.) was added over a period of time (indi-

cated in each case) to a solution of the nucleobase (1 equiv.) in a

solvent (indicated in each case). The reaction mixture was stirred

for a period of time (indicated in each case) at room temperature

until the reaction was complete, as indicated by TLC. Work-up and

purification methods are indicated in each case.

[M + H]⁺812.6178; found 812.6206.

48

H

83ClN

5 3

O

2-Amino-9-decyl-6-[2-(trimethylsilyl)ethoxy]purine

Compound G4Alk10 could be obtained following Standard Pro-

cedure A using G7 (1.5 g, 6.0 mmol), K CO (1.0 g, 7.2 mmol), 1-

(G4Alk10):^[³⁰^]

2

3

iododecane (1.5 mL, 7.2 mmol), and DMF (20 mL). The reaction

was complete after 8 h. The solvent was evaporated, and the crude

3

solid was purified by column chromatography on silica gel (CHCl /

MeOH, 100:1) to give G4Alk10 (0.97 g, 42%) as a white solid.

2

-Amino-8-bromo-6-[2-(trimethylsilyl)ethoxy]purine (G6): Com-

pound G6 was prepared following Standard Procedure D. Com-

pound G7 (0.10 g, 0.4 mmol) was dissolved in acetonitrile (3 mL),

and NBS (0.08 g, 0.4 mmol) was added over a period of 30 min.

The reaction was complete after 3 h. The mixture was then filtered

through a filter paper, and the filtrate was concentrated under re-

duced pressure. The crude solid was purified by column chromatog-

Compound G4Alk10 could also be obtained following Standard Pro-

cedure C using NaH (0.19 g, 0.7 mmol) and 2-trimethylsilylethanol

(0.15 mL, 1.0 mmol) in dry THF (5 mL). Then, G5Alk10 (0.16 g,

0.5 mmol) was added. The reaction was completed overnight. The

reaction mixture was concentrated in vacuo, dissolved in ethyl acet-

ate (20 mL) and washed with water (3ϫ 10 mL). The organic layer

raphy on silica gel (CHCl

3

/MeOH, 50:1) to give G6 (40 mg, 35%)

as a yellow solid. H NMR (300 MHz, [D ]DMSO): δ = 13.09 (br.

), 4.47 (t, J = 7.0 Hz, 2 H,

TMS), 1.11 (t, J = 7.0 Hz, 2 H, OCH CH TMS), 0.06 ane, 5:1) to give G4Alk10 (71 mg, 35%) as a white solid. H NMR

s, 9 H, Si(CH ]DMSO): δ = (300 MHz, [D ]DMSO): δ = 7.82 (s, 1 H, 8-H), 6.28 (br. s, 2 H,

] ppm. ¹³C NMR (75 MHz, [D

59.5, 159.8, 156.1, 121.5, 114.7, 63.6, 40.4, 17.0, –1.3 ppm. HRMS NH ), 4.49 (m, 2 H, OCH CH TMSЈ), 3.97 (t, J = 7.2 Hz, 2 H,

19), 1.8–1.6 (m, 2 H, N CH

14CH ), 1.1–1.0 (m, 2 H, OCH

J = 7.1 Hz, 3 H, CH ), 0.06 [s, 9 H, Si(CH

75 MHz, CDCl ): δ = 161.4, 159.2, 153.9, 139.1, 115.8, 64.8, 43.5,

1.8, 29.8, 29.44, 29.40, 29.2, 29.0, 26.6, 22.6, 17.6, 14.0, 1.41 ppm.

1

6

was dried with MgSO

was purified by column chromatography on silica gel (CHCl

4

and concentrated in vacuo. The crude solid

/hex-

9

s, 1 H, N H), 6.33 (br. s, 2 H, NH

OCH CH

[

2

3

1

2

3

)

3

6

1

2

+

9

(ESI ): calcd. for C10

H

17

N

5

OSiBr [M + H] 330.0380; found

N CH

H, N C

2

C

9

H

2

CH

2

C

8

H

17), 1.3–1.1 (m, 2

CH TMS), 0.84 (t,

3 3

)

] ppm. ¹³C NMR

9

3

30.0395.

2

H

4

C

7

H

3

2

3

2

-Amino-6-chloro-9-decylpurine (G5Alk10): Compound G5Alk10 was

(

3

obtained following Standard Procedure A using 2-amino-6-chloro-

purine (8.0 g, 47 mmol), K CO (7.8 g, 56.4 mmol), 1-iododecane

12 mL, 56.4 mmol), and DMF (110 mL). The solvent was evapo-

rated, and the crude solid was purified by column chromatography

on silica gel (CHCl /MeOH, 50:1) to give G5Alk10 (12.4 g, 85%) as

a white solid. H NMR (300 MHz, [D ]DMSO): δ = 8.13 (s, 1 H, Compound G4Alk2 could be obtained following Standard Pro-

), 4.02 (t, J = 7.0 Hz, 2 H, cedure A using G7 (1.0 g, 3.9 mmol), K CO (0.6 g, 4.7 mmol), 1-

17), 1.3–1.1 (m, 14 iodoethane (0.4 mL, 4.7 mmol) and DMF (20 mL). The reaction

3

2

3

+

38 5

H N

OSi [M + H]⁺392.2840; found

HRMS (ESI ): calcd. for C20

92.2849.

(

3

(G4Alk2):^[³⁰^]

3

2-Amino-6-[2-(trimethylsilyl)ethoxy]-9-ethylpurine

1

6

8

2

N H), 6.87 (br. s, 2 H, C NH

N CH

H, N C

NMR (75 MHz, [D

2

3

9

2

C

9

H

19), 1.8–1.6 (m, 2 H, N CH

14CH ), 0.84 (t, J = 7.0 Hz, 3 H, CH

]DMSO): δ = 159.7, 154.0, 149.3, 143.2, 123.4, solid was purified by column chromatography on silica gel (CHCl

3.0, 31.2, 28.9, 28.8, 28.6, 28.4, 25.9, 22.0, 13.9 ppm. HRMS MeOH, 50:1) to give G4Alk2 (0.35 g, 32%) as a white solid.

2 2 8

CH C H

9

13

2

H

4

C

7

H

3

) ppm.

C

was complete after 8 h. The solvent was evaporated, and the crude

6

3

/

4

+

(ESI ): calcd. for C15

H

25

N

5

Cl [M + H] 310.1793; found 310.1801.

Compound G4Alk2 could also be obtained following Standard Pro-

2

-Amino-6-chloro-9-ethylpurine (G5Alk2):^[²⁶^]Compound G5Alk2 was cedure C using NaH (0.86 g, 35.8 mmol) and 2-trimethylsilyl-

obtained following Standard Procedure A using 2-amino-6-chloro-

purine (3.0 g, 17.7 mmol), K CO (2.9 g, 21.2 mmol), 1-iodoethane

1.7 mL, 21.2 mmol), and DMF (60 mL). The solvent was evapo-

rated, and the crude solid was purified by column chromatography

on silica gel (CHCl /MeOH, 50:1) to give G5Alk2 (2.6 g, 74%) as a

white solid. H NMR (300 MHz, [D ]DMSO): δ = 8.14 (s, 1 H, ganic layer was dried with MgSO

), 4.07 (q, J = 7.3 Hz, 2 H, crude solid was purified by column chromatography on silica gel

ethanol (2.6 mL, 17.9 mmol) in dry THF (50 mL). Then, G5Alk2

(1.77 g, 9.0 mmol) was added. The reaction was completed over-

night. The reaction mixture was concentrated in vacuo, the residue

2

3

(

was dissolved in CHCl

diethyl ether (30 mL), and then with water (3ϫ 30 mL). The or-

, and concentrated in vacuo. The

3

(50 mL), this solution was washed with

3

1

6

4

8

2

N H), 6.91 (br. s, 2 H, C NH

2

9

13

N CH

2

CH

3

), 1.36 (t, J = 7.3 Hz, 3 H, CH

]DMSO): δ = 159.7, 153.9, 149.3, 142.9, 123.4, 38.2,

4.9 ppm. HRMS (ESI ): calcd. for C

found 198.0542.

-Amino-9-[3,4,5-tris(dodecyloxy)benzyl]-6-chloropurine (G5Bn3): A

suspension of 2-amino-6-chloropurine (2.0 g, 11.79 mmol) and

CO (1.9 g, 14.15 mmol) in dry DMF (130 mL) was stirred at

0 °C for 30 min. Then 1-(bromomethyl)-3,4,5-tris(dodecyloxy)-

3 3

) ppm. C NMR (CHCl /hexane, 100:1) to give G4Alk2 (633 mg, 25%) as a white

1

(

1

75 MHz, [D

6

solid. H NMR (300 MHz, CDCl

3

): δ = 7.60 (s, 1 H, 8-H), 4.77

CH TMS), 4.10 (q, J =

), 1.48 (t, J = 7.0 Hz, 3 H, CH

+

7

H

9

N

5

Cl [M + H] 198.0540;

(br. s, 2 H, NH ), 4.6–4.5 (m, 2 H, OCH

7.0 Hz, 2 H, N CH

m, 2 H, OCH

75 MHz, CDCl

8.9, 16.7, 0.0 ppm. HRMS (ESI ): calcd. for C12

2

9

2

CH

TMS), 0.09 [s, 9 H, Si(CH

3

1

), 1.3–1.2

3

(

2

CH

2

3

) ] ppm. C NMR

2

(

1

3

): δ = 162.6, 160.9, 155.0, 140.0, 116.8, 66.0, 39.7,

+

H

22

N

5

OSi [M +

K

4

2

3

+

H] 280.1588; found 280.1586.

benzene (10.3 g, 14.15 mmol) was added, and the mixture was

heated at 40 °C overnight. The solvent was removed under reduced

2-Amino-6-[2-(trimethylsilyl)ethoxy]-9-[3,4,5-tris(dodecyloxy)benz-

yl]purine (G4Bn3): Compound G4Bn3 was obtained following Stan-

7170

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7160–7175

5-/8-Halogenated or Ethynylated Lipophilic Nucleobases

dard Procedure A using NaH (800 mg, 33.37 mmol), 2-(trymethyl- 2-Amino-8-iodo-6-[2-(trimethylsilyl)ethoxy]-9-[3,4,5-tris(dodecyl-

silyl)ethanol (1.2 mL, 8.14 mmol), and G5Bn3 (3.4 g, 4.17 mmol) in oxy)benzyl]purine (G2Bn3): Following Standard Procedure E, LDA

dry dioxane (60 mL). The mixture was heated at reflux overnight was prepared from diisopropylamine (1.6 mL, 11.82 mmol) and

until the reaction was complete. The resulting mixture was concen-

trated in vacuo, and the residue was purified by column chromatog-

raphy on silica gel (cyclohexane/EtOAc, 4:1) to give G4Bn3 (2.23 g,

nBuLi (2.5 m solution in THF; 7.88 mL, 7.88 mmol) in THF

(21 mL). The mixture was stirred at 0 °C for 45 min, then it was

cooled to –78 °C, and a solution of G4Bn3 (1.41 g, 1.58 mmol) in

THF (21 mL) was added by cannula. The resulting mixture was

1

6

2%) as a white solid. H NMR (300 MHz, CDCl

3

): δ = 7.55 (s, 1

), 5.02 (br. s, 2

), 4.03–3.68 (m, 6 H, (10 mL) was added. Once the reaction was complete, saturated

), 1.56–1.11 [m, 62 H, NH Cl (10 mL) was added, and the mixture was allowed to slowly

], 1.01–0.77 [m, 9 H, O(CH ], 0.09 [s, reach room temperature. The phases were separated, and the aque-

): δ = 161.7, 159.6, ous phase was extracted with CH Cl (3ϫ 15 mL). The combined

39.2, 138.3, 130.8, 115.8, 106.5, 77.2, 73.6, 69.4, 65.1, 47.2, 32.1, organic layers were washed with Na (satd. aq.; 1ϫ 30 mL),

0.5, 29.84, 29.78, 29.5, 26.2, 22.8, 17.8, 14.2, –1.3 ppm. HRMS NaHCO (satd. aq.; 1ϫ 30 mL), and brine (1ϫ 30 mL). The or-

ganic layer was dried with MgSO , and the solvent was evaporated.

9

H, 8-H), 6.45 (s, 2 H, Ar-2,6), 5.12 (s, 2 H, N CH

2

stirred at –78 °C for 5 h. A solution of I (1.19 g, 4.7 mmol) in THF

2

6

H, C NH

OCH ), 1.88–1.55 (m, 6 H, OCH

OCH CH (CH CH

H, Si(CH ] ppm. C NMR (75 MHz, CDCl

2

), 4.74–4.39 (m, 2 H, C OCH

2

CH

2

4

2

)

9

3

2 3

)11CH

13

9

1

3

)

3

2

2 2 3

S O

3

+

(

ESI ): calcd. for C53

H

96

N

5

O

4

Si [M + H] 894.7226; found

4

894.7217.

The resulting solid was purified by column chromatography (cyclo-

hexane/EtOAc, 5:1) to give G2Bn3 (977 mg, 60%) as a white solid.

2

-Amino-8-bromo-9-decyl-6-[2-(trimethylsilyl)ethoxy]purine

1

m.p. 77–79 °C. H NMR (300 MHz CDCl

3

2

): δ = 6.46 (s, 2 H, Ar-

(

G3Alk10): Compound G3Alk10 was obtained following Standard

9

2

,6), 5.07 (s, 2 H, N CH

2

), 5.00 (s, 2 H, C NH

2

), 4.59–4.43 (m, 2

), 1.70 (q, J = 6.9 Hz, 6 H,

CH (CH CH ],

], 0.05 [d, J = 1.3 Hz, 9 H, Si(CH

ppm. C NMR (75 MHz, CDCl ): δ = 160.0, 159.3, 155.0, 153.2,

Procedure D using G4Alk10 (0.63 g, 2.3 mmol) in CCl (10 mL), and

4

6

H, C OCH

OCH CH

.99–0.73 [m, 9 H, O(CH

2

), 4.01–3.72 (m, 6 H, OCH

2

), 1.24 [d, J = 5.8 Hz, 63 H, OCH

NBS (0.44 g, 2.5 mmol), added over a period of 30 min. The reac-

tion was complete after 3 h. The crude mixture was filtered through

a filter paper, and the filtrate was concentrated under reduced pres-

sure. The crude solid was then purified by column chromatography

2

)

9

3

0

2

)

11CH

3

)

1

3

3^]

3

137.9, 130.5, 118.5, 106.2, 97.0, 73.3, 69.1, 65.0, 48.5, 31.9, 30.3,

on silica gel (CHCl

3

/hexane, 100:1) to give G3Alk10 (0.87 g, 80%).

H NMR (300 MHz, [D ]DMSO): δ = 6.48 (br. s, 2 H, NH ), 4.48

m, 2 H, OCH CH TMS), 3.97 (t, J = 7.2 Hz, 2 H, N CH

.8–1.6 (m, 2 H, OCH CH 1 7 ), 1. 4–1.1 (m, 14 H,

), 1.1–1.0 (m, 2 H, OCH CH TMS), 0.84 (t, J =

), 0.06 [s, 9 H, Si(CH

): δ = 160.1, 159.0, 154.7, 135.2, 116.0, 65.0, 44.1,

1.9, 29.7, 29.5, 29.4, 29.3, 29.1, 26.5, 22.7, 17.6, 14.1, 1.42 ppm.

1

29.68, 29.65, 29.62, 29.60, 29.58, 29.59, 29.53, 29.4, 29.3, 26.0, 22.6,

6

2

+

9

17.6, 14.0, –1.5 ppm. HRMS (ESI ): calcd. for C H IN O Si [M*

+

(

1

OC

6

2

C

9

H

19),

53 94

5

4

+

H] 1020.6192; found 1020.6210.

2

2 8

C H

2

H

4

C

7

H

14CH

9

3

2

13

9-Decyl-8-ethynylguanine (G1Alk10): Compound G1Alk10 was pre-

pared following Standard Procedure B. Compound G3Alk10 (2.3 g,

.7 Hz, 3 H, N C

9

H

19CH

3

3 3

) ] ppm. C NMR

(75 MHz, CDCl

3

4

.9 mmol), Pd(PPh

3

)

2

Cl

2

(68.6 mg, 0.10 mmol), and CuI (9.3 mg,

mixture (20 mL).

3

+

0.05 mmol) were dissolved in the THF/NEt

3

HRMS (ESI ): calcd. for C20

found 470.1941.

37 5

H N OSiBr [M + H] 470.1945;

Then TMSA (1.80 mL, 9.8 mmol) was added. The reaction was

complete after 12 h. Then, the reaction mixture was concentrated

under reduced pressure, the residue was dissolved in THF (30 mL),

2

(

-Amino-8-bromo-6-[2-(trimethylsilyl)ethoxy]-9-ethylpurine

G3Alk2): Compound G3Alk2 was obtained following Standard Pro-

cedure D using G4Alk2 (0.63 g, 2.3 mmol) in CCl (10 mL), and

and TBAF·3H

evaporated, and the dark brown oil was purified by column

chromatography on silica gel (CHCl /MeOH, 30:1) to give G1Alk10

2

O (3.4 g, 10.8 mmol) was added. The solvent was

4

NBS (0.44 g, 2.5 mmol), added over a period of 30 min. The reac-

tion was complete after 4 h. The crude mixture was filtered through

a filter paper, and the filtrate was concentrated under reduced pres-

sure. The crude solid was then purified by column chromatography

3

1

(

1.1 g, 70 %) as a pale yellow solid. m.p. Ͼ 250 °C. H NMR

1

300 MHz, [D

6

]DMSO): δ = 10.68 (br. s, 1 H, N H), 6.59 (br. s, 2

H, NH

2

), 4.70 (s, 1 H, CϵCH), 3.97 (t, J = 6.9 Hz, 2 H,

on silica gel (CHCl

3

/hexane, 100:1) to give G3Alk2 (0.60 g, 72%) as

a white solid. H NMR (300 MHz, [D ]DMSO): δ = 6.48 (br. s, 2

H, NH ), 4.48 (m, 2 H, OCH CH TMS), 4.02 (q, J = 7.1 Hz, 2

), 1.26 (t, J = 7.2 Hz, 3 H, CH ), 1.11 (m, 2 H,

TMS), 0.06 [s, 9 H, Si(CH

] ppm. ¹³C NMR (75 MHz,

): δ = 159.8, 159.2, 154.5, 123.7, 114.1, 63.8, 55.6, 17.0, 14.4,

9

N CH

2

C

9

H

19), 1.8–1.6 (m, 2 H, N CH

14CH ), 0.83 (t, J = 6.9 Hz, 3 H, CH

]DMSO): δ = 156.2, 84.8, 73.6, 42.7, 31.2,

2 2 8

CH C H17), 1.3–1.1 (m, 14

1

6

9

13

H, N C

NMR (75 MHz, [D

8.85, 28.78, 28.6, 28.4, 25.8, 22.0, 13.9 ppm. HRMS (ESI ): calcd.

_O_[_M₊_H_]+ 316.2131; found 316.2146.

for C17

2

H

4

C

7

H

3

) ppm.

C

2

6

9

H, N CH

OCH CH

CDCl

2

CH

3

+

2

3 3

)

26 5

H N

3

+

21 5

H N

OSiBr [M + H]⁺

–

3

1.3 ppm. HRMS (ESI ): calcd. for C12

58.0693; found 358.0693.

9

-Ethyl-8-ethynylguanine (G1Alk2): Compound G1Alk2 was prepared

following Standard Procedure B. Compound G3Alk2 (0.57 g,

1.6 mmol), Pd(PPh Cl (22.0 mg, 0.03 mmol), and CuI (3.0 mg,

0.02 mmol) were dissolved in the THF/NEt mixture (15 mL).

Standard Procedure E for the Iodination Reaction of the Guanine

Derivatives: A solution of LDA freshly prepared from diisopropyl-

amine (7.5 equiv.) and nBuLi (2.5 m, 5.0 equiv.) in THF (volume

indicated in each case) was added to a solution of the nucleobase

)

3 2

2

3

Then TMSA (0.6 mL, 3.2 mmol) was added. The reaction was

complete after 8 h. Then, the reaction mixture was concentrated

under reduced pressure, the residue was dissolved in THF (20 mL),

(1 equiv.) in THF (volume indicated in each case) at –78 °C. After

4

h, a solution of I (3.0 equiv.) in THF (volume indicated in each

2

and TBAF·3H

evaporated, and the dark brown oil was purified by column

chromatography on silica gel (CHCl /MeOH, 10:1) to give G1Alk2

(270 mg, 83%) as a pale yellow solid. m.p. Ͼ 250 °C. H NMR

2

O (1.1 g, 3.5 mmol) was added. The solvent was

case) was added, and the mixture was stirred at –78 °C until the

reaction was complete, as indicated by TLC. The mixture was left

to warm up to 0 °C, then it was quenched with NH

The aqueous phase was separated, and extracted with CH

combined organic layers were concentrated under reduced pressure,

the residue was dissolved in CH

with Na (satd. aq.), NaHCO

ganic layer was then dried with MgSO

3

1

4

Cl (satd. aq.).

1

2

Cl . The

(300 MHz, [D

6

]DMSO): δ = 10.71 (br. s, 2 H, NH ), 6.61 (br. s, 2

H, NH ), 4.71 (s, 1 H, CϵCH), 4.01 (q, J = 7.0 Hz, 2 H,

2

9

13

2

Cl

2

, and this solution was washed

N CH

2

CH

3

), 1.27 (t, J = 7.0 Hz, 3 H, CH

3

) ppm. C NMR

2

S

2

O

3

(satd. aq.) and brine. The or-

(75 MHz, [D

6

]DMSO): δ = 156.2, 154.2, 150.7, 128.8, 116.5, 84.8,

+

4

, and concentrated in vacuo.

73.4, 37.7, 14.8 ppm. HRMS (ESI ): calcd. for C

9

H

10

N

5

O [M +

7171

+

Purification methods are indicated in each case.

H] 204.0879; found 204.0878.

Eur. J. Org. Chem. 2015, 7160–7175

www.eurjoc.org

D. González-Rodríguez et al.

FULL PAPER

9

-[3,4,5-Tris(dodecyloxy)benzyl]-8-ethynylguanine (G1Bn3): Com-

a suspension of G12 (6.37 g, 21.22 mmol), DMAP (4-dimethyl-

pound G1Bn3 was prepared following Standard Procedure B for a

Sonogashira coupling reaction. Compound G2Bn3 (977 mg,

aminopyridine; 51.53 mg, 0.42 mmol), and diphenylcarbamoyl

chloride (5.89 g, 42.44 mmol) in CHCl (300 mL) under argon. The

3

0.95 mmol), Pd(PPh

3

)

2

Cl

2

(13.3 mg, 0.019 mmol), and CuI (1.8 mg,

resulting mixture was stirred at reflux overnight. Then, the mixture

0.0095 mmol) were dissolved in the THF/NEt

3

mixture (10 mL). was filtered, and the solvent was removed under reduced pressure.

Then TMSA (0.7 mL, 0.67 mmol) was added, and the mixture was

stirred at 40 °C for 24 h. Once the reaction was complete, the sol-

The crude material was purified by column chromatography

(CHCl /MeOH, 100:1) to give G11 (8.17 g, 78%) as a white solid.

m.p. 140–141 °C. H NMR (300 MHz, [D

3

1

vent was evaporated in vacuo. TBAF·3H

2

O (659 mg, 2.09 mmol)

6

]DMSO): δ = 12.16 (br.

s, 1 H, N H), 11.89 (s, 1 H, N H), 7.51–7.28 (m, 10 H, Ph), 2.77

(sept, J = 6.9 Hz, 1 H, CHiPr), 1.16 (d, J = 6.9 Hz, 6 H, CH iPr)

]DMSO): δ = 180.4, 153.2, 150.1,

148.3, 146.8, 141.1, 139.9, 129.6, 129.4, 128.5, 127.9, 127.9, 126.8,

1

9

was added to a solution of the crude material in THF (10 mL).

The residue was purified by column chromatography on silica gel

3

1

3

(

CHCl

3

/MeOH, 100:1). A final recrystallization from CHCl

3

/

ppm. C NMR (75 MHz, [D

6

MeCN gave G1Bn3 (598 mg, 77%) as a pale brown solid. m.p. 148–

1

+

1

6

49 °C. H NMR (300 MHz, CDCl

3

): δ = 11.81 (br. s, 1 H, N H), 126.0, 119.9, 118.9, 79.1, 34.9, 18.9, 18.7 ppm. HRMS (ESI ):

2

Br [M + H]⁺495.0774; found 495.0758.

.64 (br. s, 2 H, C NH-H), 6.54 (s, 2 H, Ar-2,6), 5.13 (s, 2 H, calcd. for C22

H

20

N

6

O

3

9

N CH

1

CH

(

6

(

2

), 3.89 (t, J = 6.4 Hz, 6 H, OCH

.72 (m, 6 H, OCH CH ), 1.54–1.07 [m, 60 H, OCH

_]_p_p_m_.₁3C NMR

], 0.87 [td, J = 6.7, 2.1 Hz, 9 H, O(CH

): δ = 154.6, 153.3, 138.1, 130.9, 106.6, 77.3, 73.5,

9.2, 32.1, 30.5, 29.9, 29.8, 29.7, 29.5, 26.3, 22.8, 14.3 ppm. HRMS

2

), 3.37 (s, 1 H, CϵCH),

6

2

8

-Bromo-9-(2-tertbutylacetyl)-O -diphenylcarbamoyl-N -isobutyryl-

guanine (G10Es): Following Standard Procedure A, a solution of

G11 (2.35 g, 4.74 mmol) and K CO (0.8 g, 5.8 mmol) in dry DMF

60 mL) was stirred for 30 min. Then, tert-butyl-bromoacetate

2

CH (CH ) -

2

2 9

3

2 3

)11CH

2

3

76 MHz, CDCl

3

(

+

(839 μL, 5.68 mmol) was added, and the resulting mixture was

stirred at 40 °C for 24 h. When the reaction was complete, the sol-

ESI ): calcd. for C50

H

84

N

5

O

4

[M + H] 818.6517; found 818.6540.

-[3,5-Bis(dodecyloxy)benzyl]-8-ethynylguanine (G1Bn2): Following

CO (144 mg,

.044 mmol), and 1-(chloromethyl)-3,5-bis(dodecyloxy)benzene

516 mg, 1.04 mmol) were dissolved in dry DMF (10 mL), and the

9

vent was evaporated, and the residue was dissolved in CHCl

3

Standard Procedure A, G6 (288 mg, 0.87 mmol), K

2

3

(

15 mL). The organic layer was washed with water (2ϫ 15 mL),

1

(

4

and brine (20 mL), and dried with MgSO . The solvent was re-

moved under reduced pressure to give G10Es (0.81 g, 28%) as a

white solid. m.p. 102–104 °C. ¹H NMR (300 MHz, CDCl

): δ =

.75 (s, 1 H, NHCOiPr), 7.49–7.08 (m, 10 H, Ph), 4.88 (s, 2 H,

mixture was heated at 40 °C overnight. Once the reaction was com-

plete, the solvent was removed under reduced pressure. The re-

3

7

sulting crude material was passed through a silica plug (CHCl

MeOH, 100:1).

3

/

CH

2

), 3.24 (sep, J = 6.8 Hz, 1 H, CHiPr), 1.40 (s, 9 H, CH

3

tBu),

iPr) ppm. C NMR (75 MHz, [D ]-

DMSO): δ = 176.1, 166.2, 158.3, 153.4, 151.8, 147.0, 129.1, 127.6,

26.9, 125.6, 124.1, 116.8, 82.3, 63.6, 34.9, 27.7, 19.0 ppm. HRMS

1

3

1.27 (d, J = 6.8 Hz, 6 H, CH

3

6

Following Standard Procedure B for a Sonogashira coupling, the

residue was dissolved in the THF/NEt mixture with Pd(Ph Cl

12.3 mg, 0.0175 mmol) and CuI (1.7 mg, 0.009 mmol). Then,

3

)

2

1

(

+

_B_r_[_M₊_H_]+ 609.1455; found

30 6 5

H N O

(

6

ESI ): calcd. for C28

09.1459.

TMSA (0.3 mL, 2.33 mmol) was added. The resulting mixture was

stirred at 40 °C overnight. Once the reaction was complete, the sol-

vent was removed under reduced pressure. The resulting crude ma-

Synthesis of the Adenine Derivatives

,6-Diamino-9-decylpurine (A4Alk10): Compound A4Alk10 was ob-

terial was dissolved in THF (10 mL), and TBAF·3H

.74 mmol) was added. Once the deprotection was complete, the

solvent was removed under reduced pressure, and the crude prod-

uct was purified by column chromatography (CHCl /MeOH, 100:1)

2

O (548 mg,

2

1

tained following Standard Procedure A using 2,6-diaminopurine

5.0 g, 33 mmol), K CO (5.5 g, 40 mmol), 1-iododecane (8.6 mL,

0 mmol), and DMF (100 mL). The reaction was completed over-

night. The solvent was evaporated, and the crude material was dis-

solved in CHCl (200 mL) and washed with water (3ϫ 100 mL)

and brine (100 mL). The organic layer was dried with MgSO , and

concentrated in vacuo. The crude solid was purified by column

chromatography on silica gel (CHCl /MeOH, 50:1) to give A4Alk10

6.7 g, 69%) as a white solid. H NMR (300 MHz, [D ]DMSO): δ

), 5.75 (br. s, 2 H,

19), 1.8–1.6 (m, 2 H,

14CH ), 0.84 (t,

]DMSO): δ =

60.2, 156.1, 151.2, 137.6, 113.2, 42.4, 31.3, 29.3, 29.0, 28.8, 28.7,

(

2

3

4

to give G1Bn2 (219.3 mg, 77%) as a pale brown solid. m.p. 88–

1

8

6

9 °C. H NMR (300 MHz, CDCl

3

): δ = 11.90 (br. s, 1 H, N H),

9

3

.57–6.24 (m, 3 H, Ar-2,4,6), 5.16 (s, 2 H, N CH

2

), 3.86 (t, J =

4

.5 Hz, 5 H, OCH

CH ), 1.26 [m, 39 H, OCH

H, O(CH

62.6, 155.8, 153.7, 150.3, 138.4, 130.7, 107.1, 77.2, 73.5, 69.4, 56.3,

2.6, 36.6, 32.0, 31.5, 30.4, 29.84, 29.82, 29.80, 29.78, 29.75, 29.7,

2

), 3.35 (s, 1 H, CϵCH), 1.88–1.58 (m, 6 H,

CH (CH CH ], 0.98–0.72 [m,

_]_p_p_m_.1 C NMR (75 MHz, CDCl

): δ = 163.9,

OCH

2

)

9

3

6

1

5

2

)

11CH

3

1

(

=

6

8

6

7.69 (s, 1 H, N H), 6.61 (br. s, 2 H, C NH

2

9

+

C NH

N CH

2

), 3.92 (t, J = 6.7 Hz, 2 H, N CH

2

9

C

9

H

9.7, 29.5, 29.48, 29.5, 26.2, 22.8, 14.2 ppm. HRMS (ESI ): calcd.

9

+

2

CH

2

C

8

H

17), 1.3–1.1 (m, 14 H, N C

2

H

4

C

7

H

3

for C38

H

60

N

5

O

3

[M + H] 634.4690; found 634.4688.

1

3

3 6

J = 6.5 Hz, 3 H, CH ) ppm. C NMR (75 MHz, [D

2

8

-Bromo-N isobutyrylguanine (G12): Br

2

(2 mL, 52.96 mmol) was

1

2

+

2

[33]

added to a suspension of N -isobutyrylguanine

(5.85 g,

+

27 6

8.6, 26.1, 22.1, 14.0 ppm. HRMS (ESI ): calcd. for C15H N [M

H] 291.2291; found 291.2302.

26.48 mmol) and NaOAc (6.29 g, 52.96 mmol) in AcOH (70 mL).

+

The mixture was stirred at 80 °C overnight. Once the reaction was

complete, the mixture was cooled to room temperature. The re-

2,6-Diamino-9-ethylpurine (A4Alk2): Compound A4Alk2 was ob-

sulting solid was collected by filtration, and washed with H

EtOH to give G12 (6.37 g, 80 %) as a white solid. H NMR

2

O, and

tained following Standard Procedure A using 2,6-diaminopurine

3.0 g, 20 mmol), K CO (3.3 g, 24 mmol), 1-iodoethane (2 mL,

4 mmol), and DMF (150 mL). The reaction was completed over-

1

(

2

3

1

(

1

300 MHz, [D

6

]DMSO): δ = 13.88 (br. s, 1 H, N H), 12.09 (br. s,

H, N H), 11.60 (s, 1 H, NHCOiPr), 2.75 (sep, J = 6.8 Hz, 1 H,

CHiPr), 1.12 (d, J = 6.8 Hz, 6 H, CH

iPr) ppm. ¹³C NMR

75 MHz, [D ]DMSO): δ = 180.0, 154.3, 153.0, 147.2, 39.5, 34.7,

2

9

night. The crude mixture was concentrated under reduced pressure,

and the crude solid was purified by column chromatography on

3

(

1

3

6

1

silica gel (CHCl

3

/MeOH, 10:1) to give A4Alk2 (2.4 g, 67%).

H

+

[M + H]⁺

9.0 ppm. HRMS (FAB ): calcd. for C

00.0096; found 300.0092.

9

H

11BrN

5

O

2

8

NMR (300 MHz, [D

6

]DMSO): δ = 7.71 (s, 1 H, N H), 6.64 (br. s,

6

2

H, C NH

2

), 5.77 (br. s, 2 H, C NH

), 1.32 (t, J = 7.3 Hz, 3 H, CH

(75 MHz, [D ]DMSO): δ = 160.2, 156.0, 151.3, 137.0, 113.3, 37.3,

2

), 3.97 (q, J = 7.3 Hz, 2 H,

6

2

9

13

8

-Bromo-O -diphenylcarbamoyl-N -isobutyrylguanine (G11): N CH

2

CH

3

) ppm. C NMR

DIPEA (diisopropylethylamine; 5.4 mL, 31.38 mmol) was added to

6

7172

www.eurjoc.org

Eur. J. Org. Chem. 2015, 7160–7175

5

1

-/8-Halogenated or Ethynylated Lipophilic Nucleobases

+

[M + H]⁺179.1039;

5.3 ppm. HRMS (ESI ): calcd. for C

7

H

11

N

6

3

purified by column chromatography on silica gel (CHCl /MeOH,

found 179.1038.

20:1) to give A1Alk10 (130 mg, 51%) as a white solid.

2

,6-Diamino-8-bromo-9-decylpurine (A3Alk10): Compound A3Alk10

Compound A1Alk10 could also be obtained following Standard Pro-

cedure B with A3Alk10 (0.91 g, 2.5 mmol), Pd(PPh Cl (36.1 mg,

.05 mmol), and CuI (4.9 mg, 0.02 mmol) dissolved in the THF/

was obtained following Standard Procedure D using A4Alk10 (4.9 g,

6.9 mmol) in acetonitrile (80 mL) and NBS (3.6 g, 18.6 mmol),

3

)

2

1

0

which was added over a period of 4 h. The reaction was completed

overnight. Then, the crude mixture was concentrated under re-

duced pressure. The crude solid was purified by column chromatog-

NEt

3

mixture (10 mL). Then TMSA (0.9 mL, 5.0 mmol) was

added. The reaction was complete after 12 h. The mixture was con-

centrated under reduced pressure, the residue was dissolved in THF

raphy on silica gel (CHCl

3

/MeOH, 30:1) to give A3Alk10 (0.8 g,

(

15 mL), and TBAF·3H

material was purified by column chromatography on silica gel

CHCl /MeOH, 20:1) to give A1Alk10 (130 mg, 82%) as a white so-

2

O (0.9 g, 2.8 mmol) was added. The crude

1

13%) as an ochre solid. m.p. 140–142 °C. H NMR (300 MHz, [D

6

]-

),

H,

6

2

DMSO): δ = 6.77 (br. s, 2 H, C NH

2

), 5.87 (br. s, 2 H, C NH

H, N CH 19), 1.68 (m,

14CH ), 0.82 (t,

]DMSO): δ =

60.3, 155.0, 152.7, 121.0, 113.5, 43.0, 31.2, 28.8, 28.7, 28.6, 28.5,

2

(

3

9

3

.90 (t,

J

=

7.1 Hz,

17), 1.3–1.1 (m, 14 H, N C

J = 7.1 Hz, 3 H, CH

) ppm. ¹³C NMR (75 MHz, [D

2

C

9

H

2

1

lid. m.p. 144–145 °C. H NMR (300 MHz, [D

(

3

N CH

J = 6.9 Hz, 3 H, CH

6

]DMSO): δ = 6.86

), 4.69 (s, 1 H, CϵCH),

19), 1.71 (m, H,

14CH ), 0.84 (t,

]DMSO): δ =

9

N CH

2

CH

2

C

8

H

2

H

4

C

7

H

3

6

2

br. s, 2 H, C NH

.98 (t,

2

), 5.94 (br. s, 2 H, C NH

2

9

3

6

J

=

6.9 Hz,

2

H, N CH

17), 1.4–1.1 (m, 14 H, N C

C

H

2

9

1

2

9

2

CH

2

C

8

H

2

H

4

C

7

H

3

+

5.9, 22.0, 13.9 ppm. HRMS (ESI ): calcd. for C15

H

26BrN

6

[M +

13

3

) ppm. C NMR (75 MHz, [D

6

+

H] 369.1396; found 369.1411.

1

2

C

61.2, 156.1, 151.4, 129.0, 113.1, 84.7, 74.0, 42.4, 31.3, 28.95, 28.90,

+

8.7, 28.6, 26.0, 22.1, 13.9 ppm. HRMS (ESI ): calcd. for

2

9

,6-Diamino-9-decyl-8-iodopurine (A2Alk10):^[³⁸^]Iodine (2.3 g,

.3 mmol) was added to a suspension of H IO (1.4 g, 6.2 mmol)

[M + H]⁺315.2291; found 315.2289.

17

H

27

N

6

5

6

in MeOH (10 mL) at room temperature. After 10 min, a solution

of A2Alk10 (1.8 g, 6.2 mmol) in MeOH (10 mL) was added at room

temperature. The reaction mixture was stirred at 70 °C for 5 h. Af-

ter the reaction was complete, the mixture was allowed to cool

2

,6-Diamino-9-ethyl-8-ethynylpurine (A1Alk2): Compound A1Alk2

was prepared following Standard Procedure B. Compound A2Alk2

(0.45 g, 1.5 mmol), Pd(PPh

(2.8 mg, 0.01 mmol) were dissolved in the THF/NEt

(35 mL). Then, TMSA (0.4 mL, 3.0 mmol) was added. The reac-

3

)

2

Cl

2

(20.6 mg, 0.03 mmol), and CuI

3

mixture

down to room temperature, and Na

added. The mixture was extracted with CH

organic phase was washed with water (20 mL) and brine (20 mL).

The organic layer was dried with MgSO , and concentrated in

vacuo. The crude solid was purified by column chromatography on

silica gel (CHCl /MeOH, 50:1) to give A2Alk10 (1.3 g, 50%) as a

2

S

2

O

5

(satd. aq.; 10 mL) was

2

Cl (30 mL), and the

2

tion was complete after 12 h. The mixture was concentrated under

reduced pressure, the residue was dissolved in THF (35 mL), and

TBAF·3H

was purified by column chromatography on silica gel (CHCl

MeOH, 10:1) to give A1Alk2 (146 mg, 48%) as a white solid. m.p.

Ͼ 250 °C. H NMR (300 MHz, CDCl

C NH

N CH

4

2

O (0.55 g, 1.65 mmol) was added. The crude material

3

/

3

1

white solid. H NMR (300 MHz, [D

6

]DMSO): δ = 6.74 (br. s, 2

), 3.86 (t, J = 7.3 Hz, 2 H,

CH 17), 1.3–1.1 (m, 14

1

3

): δ = 5.41 (br. s, 2 H,

), 4.18 (q, J = 7.2 Hz, 2 H,

), 3.42 (s, 1 H, CϵCH), 1.42 (t, J = 7.2 Hz, 3 H, CH

]DMSO): δ = 161.2, 156.1, 151.1,

6

2

H, C NH

2

), 5.81 (br. s, 2 H, C NH

19), 1.7–1.6 (m, 2 H, N CH

2

6

2

), 4.77 (br. s, 2 H, C NH

CH

2

9

N CH

2

C

9

H

2

2 8

C H

9

2

3

)

9

13

H, N C

NMR (75 MHz, [D

4.3, 31.3, 29.1, 28.88, 28.87, 28.7, 28.6, 26.0, 22.1, 13.9 ppm.

2

H

4

C

7

H

14CH

3

), 0.84 (t, J = 6.9 Hz, 3 H, CH

3

) ppm.

C

1

3

ppm. C NMR (75 MHz, [D

28.4, 113.1, 84.7, 73.9, 37.3, 14.9 ppm. HRMS (ESI ): calcd. for

[M + H]⁺203.1039; found 203.1040.

6

]DMSO): δ = 160.2, 154.8, 152.8, 116.2, 95.8,

+

1

4

9 11 6

C H N

+

6

HRMS (ESI ): calcd. for C15H26IN [M + H] 417.1258; found

4

17.1275.

Synthesis of the Isoguanine Derivative

-Ethyl-8-ethynylisoguanine (iG1Alk2):^[³⁹^a^]Compound iG1Alk2 was

prepared from A2Alk2 (0.15 g, 0.5 mmol) following the same pro-

cedure as used for A1Alk2. But before TMS deprotection, the crude

mixture after the Sonogashira coupling was suspended in THF/

2,6-Diamino-9-ethyl-8-iodopurine (A2Alk2): Compound A2Alk2

9

(1.0 g, 5.6 mmol), iodine (1.3 g, 2.1 mmol), and H

5

IO (1.3 g,

6

5.6 mmol) were stirred in DMF (30 mL) at 70 °C for 24 h. After

the reaction was complete, the reaction mixture was concentrated

in vacuo. The crude material was dissolved in CHCl (50 mL), and

this solution was washed with Na (satd. aq.; 40 mL), water

40 mL), and brine (40 mL). The organic layer was dried with

3

H

2

O (1:1; 18 mL). Then, a solution of NaNO

in H O (2 mL) was added. The mixture was heated at 50 °C,

AcOH/H O (1:1; 0.5 mL) was slowly added. The reaction mixture

was stirred at 50 °C for 2 h. Once the reaction was complete, the

mixture was allowed to cool down to room temperature, and NH

2

(0.15 g, 2.2 mmol)

2 2 5

S O

(

2

4

MgSO , and concentrated under reduced pressure. The crude solid

was purified by column chromatography on silica gel (CHCl

MeOH, 10:1) to give A2Alk2 (0.6 g, 37%) as a white solid. m.p. 242–

2

3

/

3

1

was added until pH 8. The reaction mixture was concentrated un-

der reduced pressure.

243 °C. H NMR (300 MHz, [D

6

]DMSO): δ = 6.77 (br. s, 2 H,

), 5.87 (br. s, 2 H, C NH ), 3.92 (q, J = 7.4 Hz, 2 H,

CH ), 1.23 (t, J = 7.0 Hz, 3 H, CH

]DMSO): δ = 160.3, 154.9, 152.5, 116.3, 95.4, 38.8,

6

2

C NH

N CH

2

9

13

2

3

) ppm. C NMR

2 3

Then, K CO (0.15 g, 1.1 mmol) was added to a MeOH (10 mL)

(75 MHz, [D

6

+

solution of the resulting crude solid. The reaction mixture was

stirred at room temperature for 1 h until completion. The solvent

was evaporated, and the crude solid was purified by column

7 10 6

15.0 ppm. HRMS (ESI ): calcd. for C H N I [M + H] 305.0006;

found 305.0001.

2

,6-Diamino-9-decyl-8-ethynylpurine (A1Alk10): Compound A1Alk10

chromatography on silica gel (CHCl

(81 mg, 73%) as a pale yellow solid. m.p. Ͼ 250 °C. H NMR

3

/MeOH, 20:1) to give iG1Alk2

1

was prepared following Standard Procedure B. Compound A2Alk10

3

(0.34 g, 0.8 mmol), Pd(PPh

(1.5 mg, 0.01 mmol) were dissolved in the THF/NEt

(13 mL). Then TMSA (0.3 mL, 1.6 mmol) was added. The reaction

3

)

2

Cl

2

(11.4 mg, 0.02 mmol), and CuI

(300 MHz, [D

6

]DMSO): δ = 11.0 (br. s, 1 H, N H), 7.90 (br. s, 2

3

mixture

H, NH ), 4.80 (s, 1 H, CϵCH), 3.97 (q, J = 7.2 Hz, 2 H,

2

9

13

N CH

2

CH

3

), 1.26 (t, J = 7.2 Hz, 3 H, CH

3

) ppm. C NMR

was complete after 12 h. The mixture was concentrated under re-

duced pressure, the residue was dissolved in THF (15 mL), and

TBAF·3H O (0.3 g, 0.9 mmol) was added. The crude material was

2

(75 MHz, [D

14.7, 8.7 ppm. HRMS (ESI ): calcd. for C

204.0879; found 204.0879.

6

]DMSO): δ = 130.3, 85.5, 79.2, 73.2, 56.1, 45.9, 37.5,

+

9

H

10 5

N O [M + H]

Eur. J. Org. Chem. 2015, 7160–7175

www.eurjoc.org

7173

D. González-Rodríguez et al.

FULL PAPER

[

16] D. L. Helfer II, R. S. Hosmane, N. J. Leonard, J. Org. Chem.

Acknowledgments

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Funding from the European Research Council (ERC) (ERC-StG

1

2

(

79548) and Ministerio de Economía

MINECO) (CTQ2011-23659) is gratefully acknowledged. V. V.-G.

is grateful for an FPI fellowship from MINECO.

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Article Doi

Synthesis of 5-/8-Halogenated or Ethynylated Lipophilic Nucleobases as Potential Synthetic Intermediates for Supramolecular Chemistry

DOI: 10.1002/ejoc.201501026

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