A novel bis(pinacolato)diboron-mediated N-O bond deoxygenative route to C6 benzotriazolyl purine nucleoside derivatives

Article abstract of DOI:10.1039/c6ob01170e

Reaction of amide bonds in t-butyldimethylsilyl-protected inosine, 2′-deoxyinosine, guanosine, 2′-deoxyguanosine, and 2-phenylinosine with commercially available peptide-coupling agents (benzotriazol-1H-yloxy)tris(dimethylaminophosphonium) hexafluorophosphate (BOP), (6-chloro-benzotriazol-1H-yloxy)trispyrrolidinophosphonium hexafluorophosphate (PyClocK), and (7-azabenzotriazol-1H-yloxy)trispyrrolidinophosphonium hexafluorophospate (PyAOP) gave the corresponding O⁶-(benzotriazol-1-yl) nucleoside analogues containing a C-O-N bond. Upon exposure to bis(pinacolato)diboron and base, the O⁶-(benzotriazol-1-yl) and O⁶-(6-chlorobenzotriazol-1-yl) purine nucleoside derivatives obtained from BOP and PyClocK, respectively, underwent N-O bond reduction and C-N bond formation, leading to the corresponding C6 benzotriazolyl purine nucleoside analogues. In contrast, the 7-azabenzotriazolyloxy purine nucleoside derivatives did not undergo efficient deoxygenation, but gave unsymmetrical nucleoside dimers instead. This is consistent with a prior report on the slow reduction of 1-hydroxy-1H-4-aza and 1-hydroxy-1H-7-azabenzotriazoles. Because of the limited number of commercial benzotriazole-based peptide coupling agents, and to show the applicability of the method when such coupling agents are unavailable, 1-hydroxy-1H-5,6-dichlorobenzotriazole was synthesized. Using this compound, silyl-protected inosine and 2′-deoxyinosine were converted to the O⁶-(5,6-dichlorobenzotriazol-1-yl) derivatives via in situ amide activation with PyBroP. The O⁶-(5,6-dichlorobenzotriazol-1-yl) purine nucleosides so obtained also underwent smooth reduction to afford the corresponding C6 5,6-dichlorobenzotriazolyl purine nucleoside derivatives. A total of 13 examples were studied with successful reactions occurring in 11 cases (the azabenzotriazole derivatives, mentioned above, being the only unreactive entities). To understand whether these reactions are intra or intermolecular processes, a crossover experiment was conducted. The results of this experiment as well as those from reactions conducted in the absence of bis(pinacolato)diboron and in the presence of water indicate that detachment of the benzotriazoloxy group from the nucleoside likely occurs, followed by reduction, and reattachment of the ensuing benzotriazole, leading to products.

Full text of DOI:10.1039/c6ob01170e

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A novel bis(pinacolato)diboron-mediated N–O
bond deoxygenative route to C6 benzotriazolyl
purine nucleoside derivatives†
Cite this: DOI: 10.1039/c6ob01170e
a
a
a
a,b
Vikram Basava, Lijia Yang, Padmanava Pradhan and Mahesh K. Lakshman*
Reaction of amide bonds in t-butyldimethylsilyl-protected inosine, 2’-deoxyinosine, guanosine, 2’-deoxy-
guanosine, and 2-phenylinosine with commercially available peptide-coupling agents (benzotriazol-1H-
yloxy)tris(dimethylaminophosphonium) hexafluorophosphate (BOP), (6-chloro-benzotriazol-1H-yloxy)
trispyrrolidinophosphonium hexafluorophosphate (PyClocK), and (7-azabenzotriazol-1H-yloxy)trispyrrol-
6
idinophosphonium hexafluorophospate (PyAOP) gave the corresponding O -(benzotriazol-1-yl) nucleo-
6
side analogues containing a C–O–N bond. Upon exposure to bis(pinacolato)diboron and base, the O -
6
(
benzotriazol-1-yl) and O -(6-chlorobenzotriazol-1-yl) purine nucleoside derivatives obtained from BOP
and PyClocK, respectively, underwent N–O bond reduction and C–N bond formation, leading to the
corresponding C6 benzotriazolyl purine nucleoside analogues. In contrast, the 7-azabenzotriazolyloxy
purine nucleoside derivatives did not undergo efficient deoxygenation, but gave unsymmetrical nucleo-
side dimers instead. This is consistent with a prior report on the slow reduction of 1-hydroxy-1H-4-aza
and 1-hydroxy-1H-7-azabenzotriazoles. Because of the limited number of commercial benzotriazole-
based peptide coupling agents, and to show the applicability of the method when such coupling agents
are unavailable, 1-hydroxy-1H-5,6-dichlorobenzotriazole was synthesized. Using this compound, silyl-
6
protected inosine and 2’-deoxyinosine were converted to the O -(5,6-dichlorobenzotriazol-1-yl) deriva-
6
tives via in situ amide activation with PyBroP. The O -(5,6-dichlorobenzotriazol-1-yl) purine nucleosides
so obtained also underwent smooth reduction to afford the corresponding C6 5,6-dichlorobenzotriazolyl
purine nucleoside derivatives. A total of 13 examples were studied with successful reactions occurring
in 11 cases (the azabenzotriazole derivatives, mentioned above, being the only unreactive entities).
To understand whether these reactions are intra or intermolecular processes, a crossover experiment was
conducted. The results of this experiment as well as those from reactions conducted in the absence
of bis(pinacolato)diboron and in the presence of water indicate that detachment of the benzotriazoloxy
group from the nucleoside likely occurs, followed by reduction, and reattachment of the ensuing benzo-
triazole, leading to products.
Received 29th May 2016,
Accepted 20th June 2016
DOI: 10.1039/c6ob01170e
www.rsc.org/obc
sides, we and others have been involved with the development
Introduction
of S Ar reactions of nucleosides not involving conventional
N
1
1–19
Nucleosides are central to life processes and, therefore, it is leaving groups such as halides and sulfonates.
Specifi-
not altogether unexpected that modified nucleosides continue cally, our efforts have been directed towards the use of benzo-
to play a major role in biochemistry, biology, as probes of triazole-based peptide-coupling agents for activation of the
1
–10
biological processes, and as pharmaceuticals.
In the amide groups in purine nucleosides. Briefly, reactions of the
context of developing novel approaches to modified nucleo- purinyl amides with (benzotriazol-1-yloxy)tris(dimethyl-
aminophosphonium) hexafluorophosphate (BOP) lead to the
6
O -(benzotriazol-1-yl)purine nucleosides. These compounds
a
Department of Chemistry, The City College of New York, 160 Convent Avenue,
New York, New York 10031, USA. E-mail: mlakshman@ccny.cuny.edu
can either be isolated for subsequent S
N
Ar reaction with
1
1–13,15,16,19
nucleophiles,
or amide activation can be done
b
The Ph.D. Program in Chemistry, The Graduate Center of the City University of
17
in situ followed by reaction with nucleophiles (Scheme 1).
New York, New York, New York 10016, USA
In the course of these investigations we had attempted to
†
Electronic supplementary information (ESI) available: Experimental pro-
6
1
13
use 3′,5′-O-disilyl protected O -(benzotriazol-1-yl)-2′-deoxyino-
cedures, spectroscopic data, and copies of H and C NMR spectra. See DOI:
0.1039/c6ob01170e
1
2
1
sine for Pd-catalyzed C–C bond formation. In this reaction
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Scheme 1 Formation of O -(benzotriazol-1-yl)purine nucleoside derivatives and their conversion to other modified purine nucleosides.
only deoxygenation was observed, leading to the C6 benzotri-
azol-1-yl nucleoside analogue. This had prompted us to con-
sider use of the oxophilic bis(pinacolato)diboron [(pinB)
2
] for
the deoxygenation, and with this reagent the O -(benzotriazol-
-yl) nucleoside was smoothly converted to the benzotriazol-1-
6
1
1
2
yl derivative. This has now prompted us to query whether
such a deoxygenation can be generally accomplished to access
C6 benzotriazolyl nucleosides in a metal-free process. Notably,
other than our previous results on the deoxygenation chem-
istry and two Pd-mediated reactions reported therein for struc-
1
2
ture elucidation purposes, only a solitary example exits on the
20
synthesis of 6-(benzotriazol-1-yl)ribofuranosylpurine. In the
latter work, 6-chloropurine riboside was reacted with 30 mol%
2
0
excess of 1,2,3-benzotriazole, as a melt at 150 °C. Whereas Scheme 2 Four possible approaches to 6-(benzotriazol-1-yl)purine
nucleosides.
this procedure was applicable to the synthesis of the ribonu-
cleosides, its applicability to the synthesis of the more sensi-
tive 2′-deoxyribonucleosides remains unknown. Further, high-
temperature reactions of benzotriazoles can potentially be
could be that nucleoside azides can exist in the alternate tetra-
hazardous due to the possibility for their exothermic
2
4
2
1
zolyl forms.
decomposition.
The failure of the aryne–azide cycloaddition only left
the diboron-mediated deoxygenation of O -(benzotriazol-1-yl)
6
nucleosides to be investigated as the alternate metal-free
approach. In our previous report, under unoptimized con-
ditions, compound 4 was observed to undergo conversion to
Results and discussion
1
2
2 2 3
At the outset we wanted to compare our proposed method for product 5 with (pinB) /Cs CO in PhMe at 100 °C. This
the synthesis of 6-benzotriazolyl purine nucleosides, which formed the basis for our present investigations and optimi-
can also be considered N-aryl benzotriazoles, to other zations (Table 1). Precursors 1 and 4 are readily available via
1
1
approaches. The relevant ones for this comparison are: (a) the our published procedures.
single known example of a neat reaction between 6-chloro-
The results in Table 1 point to several important facts. First,
purine riboside and benzotriazole at 150 °C, (b) aryne–azide base is essential for the reaction (entries 1–3), in the absence
2
0
2
2
cycloaddition, and (c) metal-catalyzed C–N bond formation of which no reaction occurred (entry 4). Cs
2
CO
Between these, only the N1 isomer (entry 1), and although K PO
a) and (b) are comparable to the proposed approach (d) overall yield, formation of the N2 isomer was observed (entry
because they are both metal-free transformations (Scheme 2).
2). It is easy to ascertain structures of the N1 and N2 isomers
3
is best, giving
1
2,23
between benzotriazoles and an aryl halide.
3
4
gave a good
(
Because we have previously developed the synthesis of on the basis of the symmetry or lack thereof in the benzotri-
6
6
-azidopurine nucleosides from O -(benzotriazol-1-yl) nucleoside azolyl unit. Use of MeCN as solvent for the Cs
2
CO
3
/(pinB)
2
2
4
derivatives, we decided to evaluate the aryne–azide cyclo- combination proved to be inferior (entry 5). In contrast to this,
addition first. 6-Azido-9-(2-deoxy-3,5-di-O-acetyl-β-D-ribofurano- with both K PO and K CO , reactions in MeCN gave good
syl)purine was synthesized as described, and this compound yields, but the N2 isomer was formed in both (entries 6 and 7).
was exposed to benzyne generated from o-(trimethyl- The Cs CO /(pinB) combination in PhMe at 100 °C again pro-
silylphenyl) trifluoromethanesulfonate and CsF in MeCN. In vided an excellent yield of the N1 isomer 5 from precursor 4
contrast to the facile reaction of various organic azides with (entry 8). But the K PO /(pinB) combination in MeCN, which
benzyne, this nucleoside azide did not yield any product either was quite good in the case of the ribose substrate 1, proved to
in the presence or absence of 18-Cr-6. One plausible reason be inferior (entry 9). Use of B (OH) in place of (pinB) , under
3
4
2
3
2
4
2
3
2
3
4
2
2
2
2
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6
a
Table 1 Evaluation of conditions for the deoxygenation of O -(benzotriazol-1-yl)inosine and 2’-deoxyinosine derivatives
Entry
Substrate
Conditions
Result
Total yield
98%
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
4
4
Cs
2
CO
PO , (pinB)
CO , (pinB)
3
, (pinB)
, PhMe, 100 °C
, PhMe, 100 °C
, PhMe, 100 °C
, MeCN, 75 °C
, MeCN, 75 °C
, MeCN, 75 °C
, (pinB) , PhMe, 100 °C
, (pinB) , MeCN, 75 °C
2
, PhMe, 100 °C
2: 98%, 3: 0%
2: 82%, 3: 8%
2: 74%, 3: 0%
2: 0%, 3: 0%
2: 38%, 3: 0%
2: 94%, 3: 4%
2: 81%, 3: 11%
5: 90%, 6: 0%
5: 63%, 6: 6%
b,c
K
K
3
4
2
90%
d
2
3
2
74%e
no base, (pinB)
Cs CO , (pinB)
PO , (pinB)
CO , (pinB)
CO
PO
2
0%
38%
98%c
92%
90%
2
3
2
K
K
3
4
2
2
3
2
Cs
2
3
2
b,c
K
3
4
2
69%
a
Reactions were conducted on 76.5 µmol of the nucleoside at 0.1 M concentration in the reaction solvent, with 2 equiv. of base, and 1.1 equiv. of
b
c
(
pinB) . Yields reported are after chromatographic isolation of products or product mixtures. Reaction did not reach completion. The N1 and
2
d
N2 isomers were collected as a combined fraction and the ratio was assessed by the integration of their purinyl resonances. The reaction was
incomplete, and the starting material and the N1 isomer were collected as a single fraction. The % of the N1 isomer was estimated from the inte-
e
gration of the H-1′ resonances. No reaction was observed and compound 1 was still present.
6
otherwise identical conditions, gave an incomplete reaction derivative 7 to the O -allyl compound 15 was accomplished as
1
5
and multiple products. Thus, this avenue was not pursued.
described. Diazotization-bromination then gave the 2-bromo-
6
25
For further exploration, several precursors (Fig. 1) were pre- O -allyl guanosine derivative 16. Notably, when this reaction
pared by reactions of commercially available nucleosides, pro- was conducted in CH Cl a minor byproduct (17) was observed
2
2
tected as TBDMS ethers, with BOP, PyAOP, and PyClock. that was consistent with the allyl group dibromination, on the
1
Syntheses of compounds 1, 4, 7, and 8 have been published basis of H NMR and HRMS analysis. In CH Br , not only was
2
2
1
1,15
previously,
logous procedures.
In addition to these ten precursors, one more unnatural product formed in CH Cl would not be a problem as this would
and compounds 9–14 were synthesized via ana- the yield of bromide 16 lower (36%) but the amount of the tri-
bromo byproduct 17 also increased (13%). The C2 chlorination
2
2
nucleoside-based ribosyl precursor was synthesized as shown be reactive in the subsequent step. Via a minor modification of
6
26
in Scheme 3. Conversion of O -(benzotriazol-1-yl)guanosine our previous results, C–C cross coupling and deprotection of
Fig. 1 Structures of commercially available peptide coupling agents and precursors prepared with them. PG = TBDMS.
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Scheme 3 Synthesis of an O -(benzotriazol-1-yl)-2-phenylinosine derivative. PG = TBDMS.
6
the O -allyl group was performed in a single step to yield substitution in the product, i.e., we had to query whether the
2
-phenylinosine derivative 18. Finally, reaction of the amide locations of the pyridyl N atom and the Cl atom were identical
group with BOP, using DBU as base, in MeCN gave the desired to those in the precursors or whether some rearrangement had
precursor 19. occurred. With all these considerations, each substrate was
With substrates 1, 4, 7–14, and 19 the next step was an subjected to the deoxygenation conditions and the results
evaluation of the ability of (pinB) /Cs CO to deoxygenate from these experiments are shown in Table 2.
2
2
3
these in PhMe at 100 °C. We were aware that with substrates
As can be seen from Table 2, successful product formation
9
–14, we had to pay particular attention to the benzotriazolyl was observed in nine of the eleven cases (see Fig. 2 for product
6
a
Table 2 Deoxygenation of various O -(benzotriazol-1-yl)purine nucleoside derivatives to 6-(benzotriazolyl)purine nucleosides
Entry
Substrate
N1 isomer
N2 isomer
Other
b
1
1: A = B = CH, Z = H, R = H (ribo)
4: A = B = CH, Z = H, R = H (deoxyribo)
2: 90%
5: 87%
20: 82%
22: 91%
—
24: 11%
27a + b: 64%
28a + b: 84%
29a + b: 84%
30a + b: 79%
31: 89%
—
—
—
—
—
—
b
2
b
3
7: A = B = CH, Z = NH
8: A = B = CH, Z = NH
2
, R = H (ribo)
21: Trace
23: Trace
b
4
2
, R = H (deoxyribo)
b
c
5
9: A = N, B = CH, Z = H, R = H (ribo)
10: A = N, B = CH, Z = H, R = H (deoxyribo)
11: A = B = CH, Z = H, R = 6-Cl (ribo)
12: A = B = CH, Z = H, R = 6-Cl (deoxyribo)
—
—
—
—
—
—
—
25: 25%c
b
6
26: 29%
b
7
—
—
—
—
—
b
d,e
d,e
8
b
9
13: A = B = CH, Z = NH
14: A = B = CH, Z = NH
2
, R = 6-Cl (ribo)
, R = 6-Cl (deoxyribo)
b
1
1
0
1
2
f
19: A = B = CH, Z = Ph, R = H (ribo)
a
b
Yields of the N1 and N2 products are of isolated, purified products. Reactions were conducted at 0.1 M nucleoside (0.167 mmol) in PhMe, with
c
d
2
equiv. of Cs
2
CO
3
, and 1.1 equiv. of (pinB)
2
.
Formation of dimers (25 and 26) was observed in these cases (see text). Two N1 isomers were
e
f
observed (see text). Small amounts of each isomer were separated for characterization. Reaction was conducted with 0.05 mmol of compound
19 at a 0.1 M concentration in PhMe.
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Fig. 2 Structures of products formed from the deoxygenation reactions. PG = TBDMS.
structures). Reactions of precursors 1 and 4 proceeded but definite correlation between a benzotriazolyl doublet (δ =
uneventfully on the larger scales yielding products 2 and 5, 8.72 ppm, J = 8.8 Hz) and a purinyl singlet (δ 8.99 ppm).
respectively. No N2 products were observed. Comparably, reac- Hence, we propose that this compound is the 5-chloro isomer
6
tions of the O -(benzotriazol-1-yl)guanine nucleosides 7 and 8 28a. No NOESY correlation was observed in the case of the
also proceeded well to give the C6 benzotriazolyl products 20 slower-eluting product, which we assign as 28b. That 28b is
and 22. In these cases, trace amounts of what could be N2 also likely a N1 isomer comes from its hydrogenation with
isomers 21 and 23 were observed by TLC. Also, the appearance 10% Pd–C and Et N, in EtOH, at room temperature. From this
3
of symmetrical benzotriazolyl resonances in one chromato- reduction, a 51% yield of compound 5 was obtained, indicat-
graphically obtained fraction from the reaction of precursor 7 ing that 28b is a N1 benzotriazolyl compound (a purple by-
supports this.
3
product, which was sensitive to CDCl , was also obtained in
In contrast to these, in reactions of the 7-azabenzotriazolyl the reduction and it could not be characterized). Comparable
substrates 9 and 10, only a small amount of deoxygenated reduction of 28a also gave compound 5 in 66% yield, and
product 24 was isolated from the deoxyribose precursor 10. In along with the NOESY data above, this supports the assigned
both cases, the major products isolated were dimers 25 and 26 structure. Reduction of product 27b gave a 54% yield of com-
1
1
(see Fig. 2). We have previously independently prepared 26
pound 2, again indicating that this was an N1 isomeric
and identified its formation in a failed C–C cross-coupling product (formation of a purple byproduct occurred and due to
1
2
3
reaction. Here, comparable product 25 was identified from its sensitivity to CDCl it could not be characterized). Struc-
substrate 9. The exact structure of product 24 arising from tures of regioisomeric ribose derivatives 27a and 27b were
compound 10 has not been unequivocally assigned, but the N1 assigned by comparison of the benzotriazolyl and purinyl
structure is proposed because N1 products predominate in all proton resonances to those of the deoxy analogues 28a and
other cases. We also cannot unequivocally comment on the 28b (see Table 3).
location of the pyridyl N atom, i.e., whether A = N and B = CH
or whether A = CH and B = N. In a second reaction of com-
pound 10, use of 2 equiv. of (pinB) only led to an increased
amount of dimer 26 (32%). We have previously shown that
2
Table 3 Chemical shifts of the benzotriazolyl and purinyl proton
resonances in chloro benzotriazolyl products 27–30
a
deoxygenations of 1-hydroxy-1H-4-aza and 1-hydroxy-1H-7-aza-
2
7
benzotriazoles with B (OH) occur slowly. Therefore, dimer
Benzotriazolyl proton
resonances
Purinyl proton
resonances
2
4
Compound
7a
formation, rather than slow deoxygenation may be a compet-
ing reaction.
Monochloro precursors 11–14 can potentially yield three 28a
products, two different N1 isomers and one N2 isomer. Deoxy-
genation of 11 gave two products in 1 : 1.6 ratio and the reac-
2
δ = 8.74, 8.21, 7.64 ppm
δ = 8.72, 8.21, 7.64 ppm
δ = 8.54, 8.17, 7.57 ppm
δ = 8.48, 8.14, 7.52 ppm
δ = 8.85, 8.15, 7.50 ppm
δ = 8.81, 8.12, 7.48 ppm
δ = 8.64, 8.11, 7.46 ppm
δ = 8.59, 8.08, 7.42 ppm
δ = 8.99, 8.63 ppm
δ = 8.99, 8.59 ppm
δ = 8.28 ppm
29a
30a
27b
δ = 8.23 ppm
δ = 9.01, 8.63 ppm
δ = 8.99, 8.58 ppm
δ = 8.29 ppm
tion of 12 also gave two products in 1 : 1.4 ratio. Small 28b
2
3
9b
0b
amounts of products from precursor 12 were separated for
characterization and, first, their NOESY spectra were analyzed.
The chromatographically early-eluting product showed a weak
δ = 8.22 ppm
a
3
Proton NMR spectra were obtained in CDCl .
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Deoxygenation of precursors 13 and 14 each gave two pro- not readily obtained. Thus, it was prepared from the relatively
ducts, in a 1 : 4 and 1 : 1 ratio, respectively. The two products cheap and commercially available 1,2,4-trichlorobenzene (32)
3
2
33
obtained from 14 were inseparable and were characterized as a via nitration (96%) and reaction with hydrazine (56%,
mixture. However, the products arising from 13 were separable Scheme 4). In addition to the routine spectroscopic analyses,
and NOESY spectra of the individual products were analyzed. compound 34 was also assessed by its reduction to 5,6-
Similar to data obtained with 28a and 28b, the chromato- dichloro-1H-benzotriazole (35) under conditions we have
2
7
graphically early-eluting product showed a weak but definite recently reported.
correlation between a benzotriazolyl doublet (δ = 8.54 ppm, J = Next, a series of attempts were directed towards conversion
.3 Hz) and the NH resonance (δ 5.20 ppm). Hence, this of TBDMS-protected inosine (I) and 2′-deoxyinosine (dI) to
9
2
6
product was assigned the 5-chloro structure 29a. By analogy, the O -(5,6-dichloro-1H-benzotriazol-1-yl)inosine derivatives
we surmise 29b to be the 6-chloro isomer. Structures of the via the nucleoside phosphonium salt (Scheme 5). (a) Reaction
inseparable deoxy derivatives 30a and 30b were made by com- of hydroxy benzotriazole 34 with HMPT, I
2
, di-O-silyl dI, DIPEA
parison of chemical shifts of the benzotriazolyl and purinyl in CH Cl at 50 °C resulted in the phosphordiamidite 36
2
2
proton resonances to those of 29a and 29b. Table 3 shows the (Scheme 5) in 42% yield (see the ESI† for data). (b) The same
chemical shifts of the benzotriazolyl and purinyl proton reson- reaction was then conducted stepwise. HMPT was first reacted
6
ances in compounds 27–30. Finally, the deoxygenation of O - with I
2
, followed by the sequential addition of DIPEA and
(benzotriazol-1-yl)-2-phenylinosine 19 derivative proceeded di-O-silyl dI, followed by stirring at room temperature for
efficiently to yield product 31 in excellent yield.
15 minutes. Finally, hydroxybenzotriazole 34 was added, and
All preceding reactions were conducted with substrates pre- the reaction conducted at 50 °C for 20 h. In this event, among
pared from commercially available peptide-coupling agents. several products that formed, two that could be characterized
6
6
A legitimate question, therefore, would be the applicability of were dichlorobenzotriazole 35 and silylated N ,N -dimethyl-2′-
this chemistry to access products where peptide-coupling deoxyadenosine 37. Formation of compound 37 is not entirely
agents are not available. To investigate this there are three unanticipated, as we have previously observed its formation in
3
4
potential approaches, all requiring access to aryl-ring substi- reactions of HMPT and I
2
.
(c) In variations of the procedure
tuted 1-hydroxy-1H-benzotriazoles. (a) The peptide-coupling described in (b), PPh was used in place of HMPT, and reac-
3
reagent is independently synthesized from the hydroxybenzo- tions were conducted at room temperature and at 45 °C. In
triazole and then reacted with the nucleoside, (b) the nucleo- both reactions dichlorobenzotriazole 35 was formed and sig-
side is converted to a phosphonium salt, which is then reacted nificant amounts of the nucleoside precursor were left
with the hydroxybenzotriazole, and (c) a peptide-coupling unreacted.
agent is prepared in situ from the hydroxybenzotriazole and
Because of these unsuccessful attempts, we next focused
then reacted with the nucleoside. Although synthesis of BOP on the use of commercially available bromotripyrrolidino-
and PyAOP are well known and can be applied to the synthesis phosphonium hexafluorophophate (PyBroP) for activating the
2
8,29
of similar compounds,
we excluded option (a) as being purinyl amide and to form the peptide-coupling agent in situ.
6
more labor intensive. We have previously investigated Both reactions can lead to the desired O -(5,6-dichlorobenzo-
approach (b) and initially attempted this.
Synthesis of 1-hydroxy-1H-benzotriazoles are well documen-
1
2,13
triazol-1-yl)inosine derivatives as shown in Scheme 6.
Initial attempts were the conversion of TBMDS-protected
2
1,30 27,31
ted in the literature (Caution!
).
On this basis, we chose dI to the desired product 40 with 3.8 equiv. of PyBroP and
to prepare 5,6-dichloro-1-hydroxy-1H-benzotriazole (34 in 4.5 equiv. of hydroxybenzotriazole 34. In these reactions,
Scheme 4) and test this for additional reactions. Although this expected product 40 predominated. However, in addition,
hydroxybenzotriazole is listed as commercially available, it is various other products were also observed, such as the C6
pyrrolidino nucleoside 38, the C6 benzotriazolyl derivative 39,
and the reduced benzotriazole 35 (all shown in Scheme 5). The
best yield of the desired 40 was 48%. Similarly, reaction of
TBDMS-protected I gave a 49% yield of product 41. Further
experiments revealed that by lowering the amount of PyBroP
to 1.9 equiv., and with 4.5 equiv. of hydroxybenzotriazole 34,
substantial yield improvements and cleaner reactions could be
attained (70% each of 40 and 41). Reactions of 40 and 41 with
(
2 2 3
pinB) and Cs CO under the optimized conditions proceeded
smoothly to provide products 42 and 43 in 61 and 56% yield,
respectively (Scheme 7).
At this point we had shown the generality of this deoxygen-
ative approach to C6 benzotriazolyl purine nucleoside deriva-
tives with substrates obtained from commercially available
benzotriazole-based peptide-coupling agents, analyzed the
isomeric products formed in some cases, and demonstrated
Scheme 4 Synthesis of 5,6-dichloro-1-hydroxy-1H-benzotriazole.
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6
Scheme 5 Products formed in the various attempted conversions of TBDMS-protected I and dI to the O -(5,6-dichlorobenzotriazol-1-yl)inosine
derivatives.
the applicability of the approach when peptide-coupling
agents are unavailable. The next focus was to gain some under-
standing of a plausible mechanistic pathway and there are two
plausible mechanisms. One is an intramolecular process
where the benzotriazolyloxy unit does not become completely
detached from the nucleoside but transfers the oxygen atom to
the diboron. In a second pathway, the benzotriazolyloxy
moiety can become detached from the purine, undergo deoxy-
2
7
genation as hydroxybenzotriazoles do, and then become reat-
tached to the purine.
We reasoned that a crossover experiment involving two pre-
cursors with differently substituted benzotriazoles could shed
light on the underlying mechanism. If an intramolecular
process were operational, then each substrate would yield the
corresponding deoxygenation product, and only two products
would be obtained. However, should the mechanism involve
detachment of the benzotriazolyloxy group from the purine,
then four products could be expected. After TLC analysis of
prospective starting materials and potential products, we
Scheme 6 Use of PyBroP for conversion of TBDMS-protected dI and I
to the corresponding O -(5,6-dichlorobenzotriazol-1-yl) derivatives.
6
6
found that O -(benzotriazol-1-yl)-2′-deoxyinosine derivative 4
6
and O -(5,6-dichlorobenzotriazol-1-yl)inosine derivative 41
would be optimal. An equimolar mixture of compounds 4 and
41 was subjected to the deoxygenation conditions. Four separ-
able products 2, 5, 42, and 43 were obtained (Scheme 8) and
the mole fractions of these were 0.30 : 0.38 : 0.17 : 0.14, respect-
ively. This outcome indicated that the benzotriazolyloxy and
5,6-dichlorobenzotriazolyloxy units likely become detached
from the purine and then undergo deoxygenation. Sub-
sequently, the ensuing reduced benzotriazolyl and 5,6-dichloro-
benzotriazolyl anions can function as nucleophiles, reacting
via the S Ar mechanism with either substrate, again producing
N
N
the two benzotriazolyloxy anions. The N–O reduction/S Ar
process can then continue until each substrate is consumed.
Such a mechanism would readily account for the observed
crossover results. The product distribution shows, as would be
expected, that the dichlorobenzotriazole species is less reactive
than the unhalogenated analogue. The ribose appears less
6
Scheme 7 Deoxygenation of O -(5,6-dichloro-1H-benzotriazol-1-yl)
inosine.
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Scheme 10 Plausible reactions pathways that can result in the
deoxygenation.
dimer formation. Thus, a final experiment was conducted
2
wherein substrate 1 was exposed to (pinB) (1.1 equiv.) and
Cs CO (2 equiv.) in 9 : 1 PhMe–H O at 100 °C. In a 4-hour
2
3
2
reaction time, product 2 was isolated in 81% yield, a result
that is slightly lower than the 90% yield obtained in the
absence of water (entry 1 in Table 2). Contrary to expectation
though, no significant hydrolysis of the substrate to silyl-
protected I was observed. Therefore, at the present time we are
not entirely certain of the mechanism by which the benzotri-
azolyloxy group becomes detached from the purine (perhaps a
very minor hydrolysis reaction), but the crossover experiment
does indicate that such a process could be occurring.
In attempting to elucidate underlying mechanisms, two
plausible pathways can be postulated (a and b in Scheme 10).
It is currently not possible to comment on pathway a involving
a one-step deoxygenation with or without intermediacy of
a benzotriazolyl N-oxide intermediate that can be formed via
rearrangement (shown in the box in Scheme 10).
Scheme 8 The crossover experiment and the products obtained.
reactive than the 2′-deoxy derivative, plausibly for electronic
and steric reasons.
Two final tests were conducted (Scheme 9). In the first, a
reaction of substrate 1 was conducted in the absence of
(
2
pinB) . A 29% yield of the dimer 25 was obtained, indicating
that there is the possibility of a background reaction leading to
the release of the benzotriazolyloxy group. This can then
potentially be a mechanism that initiates the N–O reduction/
SNAr cycle. For this background reaction we then considered
the role of trace amounts of moisture that could hydrolyze the
On the other hand, even if a low concentration of 1H-benzo-
6
O -(benzotriazol-1-yl) substrates, releasing the benzotriazolyl-
−
triazol-1-olate (BtO ) is initially accessible (pathway b), this
oxy group. Such hydrolysis could also readily account for the
2
can undergo reduction with (pinB) . The resulting benzotri-
−
−
azolyl anion (Bt ) can then yield additional BtO by S Ar dis-
N
placement, and the reaction can continue along the sequential
reduction/S Ar reactions. The N3 atom of the benzotriazolyl
N
unit in one substrate can function as a nucleophile in displa-
cing BtO− from another, and this can be one way for the for-
−
mation of BtO . Notably, if a N-oxide intermediate (shown in
the box in Scheme 10) is formed in any pathway, this will also
undergo reduction by (pinB) . Pathway b would be consistent
2
with the crossover results and, in support of this, we have pre-
−
viously shown that benzotriazole is capable of displacing BtO
1
2
2 3
from compound 4. The role of Cs CO in these reactions is
not clear at this time.
Conclusions
Herein we have demonstrated a new approach to the prepa-
ration of C6 benzotriazolyl purine nucleoside derivatives. The
chemistry hinges on an unusual conversion of a C–O–N
2
Scheme 9 Two additional experiments, in the absence of (pinB) , and
in the presence of water.
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linkage to a C–N via the use of (pinB)
2
and Cs
2
CO
3
. Thus, this applicable, and additional results of this chemistry are forth-
is effectively a metal-free C–N bond-forming reaction. The coming from our laboratories.
requisite precursors were readily prepared by reactions of
amide linkages in purine nucleosides with commercially
available, benzotriazole-based peptide coupling agents, or with
in situ-formed reagents when peptide-coupling agents are not
available commercially. Although isomeric N1 benzotriazolyl
Experimental section
General information
products are formed from unsymmetrical benzotriazolyl Thin layer chromatography was performed on 200 µm alumi-
peptide-coupling agents, and traces of N2 products are seen in num-foil-backed silica gel plates, and column chromatography
rare cases, regioisomeric product formation also occurs in was performed using 230–400 mesh silica gel. PhMe was dis-
metal-catalyzed C–N bond-forming reactions of benzotriazoles tilled from sodium, MeCN and DME were distilled from CaH2.
and in aryne–azide cycloadditions leading to N-substituted Et
benzotriazoles. The use of diboron reagents for deoxygen- 6-Azido-9-(2-deoxy-3,5-di-O-acetyl-β-D-ribofuranosyl)purine was
ating N–O bonds can be traced back to the reductions of synthesized as described. O -(Benzotriazol-1-yl) derivatives of
3
N and DIPEA were distilled from CaH
2
and stored over KOH.
2
2,23
2
4
6
4
-methylmorpholine, pyridine, and 4-phenylpyridine N-oxides, inosine, 2′-deoxyinosine, guanosine, and 2′-deoxyguanosine (1,
3
5
11,15
by (pinB)
2
and bis(catecholato)diboron [(catB)
2
]. In these 4, 7, and 8) were synthesized by reported procedures.
The
cases, the free amines remained complexed to the electrophilic remaining analogues shown in Fig. 1 were synthesized by
6
boron center in the B–O–B product. Silica gel chromatography application of these known routes (see the ESI†). O -Allyl-
was adequate to release the uncomplexed pyridines, but the 4- 2′,3′,5′-tri-O-(t-butyldimethylsilyl)guanosine (15) was prepared
1
5
6
methylmorpholine adduct of (pinB) O was isolated in good from guanosine
and converted to the O -allyl-2-bromo
2
35
yield. In 2011, we comprehensively demonstrated broadly- nucleoside (16) on the basis of our previously published
2
6
applicable synthetic use of (pinB)
reduction of alkyl amino, pyridyl, and anilino N-oxides. The cial suppliers. H NMR spectra were obtained at 500 MHz in
use of B (OH) for reduction of pyridyl N-oxides was demon- CDCl and are referenced to the residual protonated solvent
2 2
and (catB) for the route. All other reagents were used as received from commer-
3
6
1
2
4
3
3
7
13
strated in 2013, and in 2015 we successfully demonstrated resonance. C NMR spectra were obtained at 125 MHz in
a general synthesis of 1H-benzotriazoles from 1-hydroxy-1H- CDCl and are referenced to the solvent resonance. Chemical
3
2
7
benzotriazoles with this reagent.
(OH) was ineffective in comparison to (pinB)
a mechanism standpoint, a crossover experiment indicated to designate resonance multiplicities.
In the present work, shifts (δ) are reported in parts per million (ppm) and coupling
B
2
4
2
. From constants (J) are in hertz (Hz). Standard abbreviations are used
6
that the benzotriazolyloxy group likely becomes detached from
the purine, undergoes reduction with (pinB) , and the (16). A stirred mixture of nucleoside derivative 15 (300.0 mg,
formed benzotriazole can then function as a nucleophile for 0.45 mmol) and SbBr (227.7 mg, 0.63 mmol) in dry CH Cl
O -Allyl-2′,3′,5′-tri-O-(t-butyldimethylsilyl)-2-bromoinosine
2
3
2
2
S Ar displacement. The observation of two isomeric N1-aryl (5 mL) was cooled to −10 °C. To the cooled mixture t-BuONO
N
benzotriazoles from unsymmetrically substituted precursors, (374.0 µL, 3.15 mmol) was added dropwise and the stirring
and the formation of traces of N2 products in some cases is was continued at −10 °C for 3 h. The mixture was then poured
consistent with this mechanistic manifold.
The results described here contribute to an emerging area was washed with CH
on the synthetic applicability of diboron reagents in reductive brine. The aqueous layer was back extracted with CH Cl . The
3
into cold saturated aq. NaHCO , filtered, and the residual solid
2
Cl . The filtrate was washed with water and
2
2
2
2 4
processes. Importantly, as shown here and as we clearly organic layer was dried with anhydrous Na SO , filtered, and evap-
3
6
demonstrated previously, the reductions are generally facile orated under reduced pressure. Purification of the crude material
and insensitive to water. This feature, when combined with the by flash chromatography (SiO , eluted with 5% EtOAc in hexanes)
2
benign nature of the boron-based byproducts, makes such gave 123.0 mg (55% yield) of product 16 (and the C2 chloro ana-
reactions broadly applicable in a variety of contexts. For logue) as a white, fluffy solid. In this reaction compound 17
instance, (pinB)2 has been used for the reduction (26.8 mg, 7% yield) was formed as a minor separable product. R
f
1
of convergine to hippodamine, both ladybeetle alkaloids, (20% EtOAc in hexanes) = 0.64. H NMR of pure 16 (500 MHz,
allowing for an otherwise difficult quantification of these alka- CDCl
3
): δ 8.27 (s, 1H, Ar–H), 6.17–6.12 (m, 1H, vCH), 5.98 (d, J =
loids due to the thermal lability of convergine. Also, (pinB)2, 4.9 Hz, 1H, H-1′), 5.48 (d, J = 17.1 Hz, 1H, vCHtrans), 5.32 (d, J =
and plausibly B (OH) formed from the hydrolysis of (pinB) 10.2 Hz, 1H, vCHcis), 5.10 (d, J = 5.8 Hz, 2H, OCH ), 4.61 (t, J =
3
8
2
4
2
,
2
3
9
have shown biocompatibility in aqueous reactions. It should 4.4 Hz, 1H, H-2′), 4.31 (t, J = 3.9 Hz, 1H, H-3′), 4.16–4.13 (m, 1H,
be noted that despite the recently claimed novelty of amine H-4′), 4.05 (dd, J = 4.4, 11.3 Hz, 1H, H-5′), 3.80 (dd, J = 2.0, 11.3
N-oxide reduction by diboron-based reagents, that report is Hz, 1H, H-5′), 0.95, 0.93, and 0.83 (3s, 27H, t-Bu), 0.15, 0.14, 0.10,
3
9
13
really an application of prior discoveries by others and by 0.09, −0.01, and −0.17 (6s, 18H, SiCH
3
). C NMR (125 MHz,
1
2,35–37
us.
The present results further amplify the utility of CDCl ): δ 160.6, 152.8, 143.2, 141.7, 131.8, 121.4, 119.4, 89.0, 85.4,
3
diboron reducing agents for effecting a range of N–O deoxy- 75.8, 71.6, 68.6, 62.3, 26.1, 25.8, 25.7, 18.5, 18.1, 17.9, −4.3, −4.7,
genations under a variety of conditions. This type of diboron- −4.8, −5.0, −5.4. HRMS (ESI/TOF) calcd for C31
reagent-mediated deoxygenation appears to be quite broadly [M + Na] 751.2712, found 751.2714.
H
57BrN
4
O
5
Si
3
Na
+
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2
6
2
′,3′,5′-Tri-O-(t-butyldimethylsilyl)-2-phenylinosine (18). In was stirred in anhydrous PhMe (1.5 mL) at 100 °C over 4 h,
a clean, dry screw-cap vial containing a stirring bar were under a nitrogen atmosphere. The mixture was cooled, diluted
placed the bromo nucleoside 16 (140.0 mg, 0.192 mmol), PhB- with EtOAc, filtered through Celite, and evaporated under
(
OH)
2
(70.1 mg, 0.575 mmol), and anhydrous
K
3
PO
4
reduced pressure. The crude material was purified by flash
(
122.0 mg, 0.575 mmol). Anhydrous 1,4-dioxane (4 mL) was chromatography (SiO , eluted with 15% EtOAc in hexanes) to
2
1
2
added, the vial was flushed with nitrogen gas for 5 min fol- give 107.4 mg (90% yield) of product 2 as a white, fluffy
lowed by the addition of (dcpf)PdCl
1
2 f
(43.5 mg, 0.0575 mmol). solid. R (20% EtOAc in hexanes) = 0.46. H NMR (500 MHz,
The vial was capped and the mixture was stirred at 100 °C for CDCl ): δ 8.99 (s, 1H, Ar–H), 8.77 (d, J = 8.3 Hz, 1H, Ar–H), 8.61
3
7
h. Then the mixture was cooled to room temperature, filtered (s, 1H, Ar–H), 8.23 (d, J = 8.2 Hz, 1H, Ar–H), 7.68 (t, J = 7.8 Hz,
through Celite, and the filtrate was evaporated to dryness. 1H, Ar–H), 7.52 (t, J = 7.8 Hz, 1H, Ar–H), 6.26 (d, J = 5.4 Hz,
Purification of the crude material by flash chromatography 1H, H-1′), 4.71 (t, J = 4.6 Hz, 1H, H-2′), 4.35 (br s, 1H, H-3′),
(
SiO
2
, eluted with 3% CH
3
OH in CH
2
Cl
2
) gave 124.5 mg (95% 4.19 (br s, 1H, H-4′), 4.03 (dd, J = 3.0, 11.2 Hz, 1H, H-5′), 3.83
(5% (dd, J = 2.0, 11.2 Hz, 1H, H-5′), 0.97, 0.95, and 0.79 (3s, 27H,
yield) of product 18 as a pale-brown, fluffy solid. R
CH OH in CH Cl ) = 0.37. H NMR (500 MHz, C D ): δ 10.30 t-Bu), 0.16, 0.15, 0.12, −0.02, and −0.25 (5s, 18H, SiCH ).
(
f
1
3
2
2
6
6
3
1
3
br s, 1H, NH), 8.23 (s, 1H, Ar–H), 8.06–8.02 (m, 2H, Ar–H),
C NMR (125 MHz, CDCl
3
): δ 154.3, 151.9, 147.8, 146.4, 144.7,
7
.59–7.55 (m, 3H, Ar–H), 6.10 (d, J = 4.4 Hz, 1H, H-1′), 4.54 (t, 132.3, 129.5, 125.7, 123.9, 120.5, 115.3, 88.3, 86.2, 76.3, 72.4,
J = 4.1 Hz, 1H, H-2′), 4.36–4.34 (m, 1H, H-3′), 4.16–4.13 (m, 1H, 62.8, 26.3, 26.0, 25.8, 18.7, 18.2, 18.0, −4.3, −4.4, −4.5, −4.8,
H-4′), 4.00 (dd, J = 3.6, 11.3 Hz, 1H, H-5′), 3.82 (dd, J = 1.9, −5.1, −5.2.
6
1
1.0 Hz, 1H, H-5′), 0.96, 0.94, and 0.82 (3s, 27H, t-Bu), 0.14,
Deoxygenation of O -(benzotriazol-1-yl)-2′-deoxyinosine
13
0
.13, 0.12, 0.10, −0.05, −0.14 (6s, 18H, SiCH3). C NMR derivative (4). As described for the deoxygenation of compound
): δ 158.0, 153.1, 149.2, 139.3, 134.0, 131.8, 1, this reaction was carried out with compound 4 (110.0 mg,
29.2, 127.2, 88.3, 85.2, 76.4, 71.7, 62.4, 26.1, 25.8, 25.7, 20.2, 0.167 mmol), (pinB) (46.1 mg, 0.182 mmol), and Cs CO
8.5, 18.1, 17.9, −4.3, −4.6, −4.9, −5.3. (109.0 mg, 0.335 mmol) in PhMe (1.5 mL) at 100 °C over 4 h.
O -(Benzotriazol-1-yl)-2′,3′,5′-tri-O-(t-butyldimethylsilyl)-2- Purification by flash chromatography (SiO , eluted with 20%
phenylinosine (19). In a clean, dry, screw-cap vial a mixture of and 25% EtOAc in hexanes) gave 84.4 mg (87% yield) of
(125 MHz, CDCl
3
1
1
2
2
3
6
2
1
2
2
-phenylinosine derivative 18 (120.0 mg, 0.175 mmol), BOP product 5 as a white, fluffy solid. R (20% EtOAc in hexanes)
f
1
3
(154.5 mg, 0.349 mmol), and DBU (52.0 µL, 0.349 mmol) was = 0.16. H NMR (500 MHz, CDCl ): δ 9.00 (s, 1H, Ar–H), 8.76
stirred in anhydrous MeCN (1.5 mL) for 24 h, under a nitrogen (d, J = 8.3 Hz, 1H, Ar–H), 8.57 (s, 1H, Ar–H), 8.23 (d, J = 7.8 Hz,
atmosphere. The mixture was diluted with EtOAc and 1H, Ar–H), 7.68 (t, J = 7.5 Hz, 1H, Ar–H), 7.53 (t, J = 7.5 Hz, 1H,
washed with water containing a small amount of NaCl. The Ar–H), 6.64 (app t, J = 6.3 Hz, 1H, H-1′), 4.68–4.65 (m, 1H,
aqueous layer was back extracted with EtOAc, the combined H-3′), 4.10–4.08 (m, 1H, H-4′), 3.90 (dd, J = 3.9, 11.2 Hz,
organic layer was dried with anhydrous Na SO , filtered, and 1H, H-5′), 3.82 (dd, J = 2.9, 11.2 Hz, 1H, H-5′), 2.70 (app quint,
2
4
evaporated under reduced pressure. Purification of the crude
material by flash chromatography (SiO , eluted with 10% H-2′), 0.94 and 0.92 (2s, 18H, t-Bu), 0.13, 0.10, and 0.09
EtOAc in hexanes) gave 49.0 mg (40% yield) of pure product 19 (3s, 12H, SiCH3).
Japp ∼ 6.4 Hz, 1H, H-2′), 2.54 (ddd, J = 3.3, 6.1, 13.1 Hz, 1H,
2
1
3
C NMR (125 MHz, CDCl ): δ 153.9,
3
as a white, fluffy solid. (An equal amount of product contain- 151.8, 147.7, 146.4, 144.3, 132.2, 129.5, 125.7, 124.1, 120.5,
ing trace amounts of impurities was also obtained. The more 115.2, 88.4, 84.8, 72.3, 63.0, 41.6, 26.1, 25.9, 18.6, 18.2, −4.5,
polar starting material was isolated by elution with 90% EtOAc −4.6, −5.2, −5.3.
1
6
in acetone.) R
f
(10% EtOAc in hexanes) = 0.27. H NMR
): δ 8.52 (s, 1H, Ar–H), 8.15 (dd, J = 1.5, 8.0 Hz, (7). As described for the deoxygenation of compound 1, this
H, Ar–H), 7.92–7.90 (m, 1H, Ar–H), 7.05–7.01 (m, 3H, Ar–H), reaction was carried out with compound 7 (124.4 mg,
.94 (dd, J = 2.6, 6.5 Hz, 1H, Ar–H), 6.89–6.86 (m, 2H, Ar–H), 0.167 mmol), (pinB) (46.1 mg, 0.182 mmol), and Cs CO
.22 (d, J = 3.6 Hz, 1H, H-1′), 4.74 (t, J = 3.9 Hz, 1H, H-2′), 4.55 (109.0 mg, 0.335 mmol) in PhMe (1.5 mL) at 100 °C over 4 h.
Deoxygenation of O -(benzotriazol-1-yl)guanosine derivative
(
500 MHz, C D
6 6
2
6
6
2
2
3
(t, J = 4.8 Hz, 1H, H-3′), 4.25–4.28 (m, 1H, H-4′), 3.99 (dd, J = Purification by flash chromatography (SiO , eluted with 20%
2
4
0
−
1
1
6
.0, 11.3 Hz, 1H, H-5′), 3.74 (dd, J = 2.2, 11.4 Hz, 1H, H-5′), EtOAc in hexanes) gave 100.0 mg (82% yield) of product 20 as
.98 and 0.91 (2s, 27H, t-Bu), 0.11, 0.10, 0.08, 0.01, −0.016, a pale-brown, fluffy solid. A trace amount of N2 isomer 21
1
3
0.023 (6s, 18H, SiCH3). C NMR (125 MHz, C D ): δ 159.2, was observed in this reaction. R (30% EtOAc in hexanes) =
6
6
f
1
58.5, 154.9, 143.9, 136.6, 130.6, 128.4, 128.3, 128.0, 127.7, 0.40. H NMR (500 MHz, CDCl
3
): δ 8.59 (d, J = 8.3 Hz, 1H,
27.6, 124.1, 120.5, 119.2, 110.0, 108.6, 89.2, 84.5, 76.2, 71.2, Ar–H), 8.30 (s, 1H, Ar–H), 8.20 (d, J = 8.3 Hz, 1H, Ar–H), 7.63 (t,
1.9, 26.0, 25.8, 25.6, 18.4, 18.0, 17.9, −4.4, −4.7, −4.8, −4.9, J = 7.4 Hz, 1H, Ar–H), 7.49 (t, J = 7.4 Hz, 1H, Ar–H), 6.08 (d, J =
−
5.5, −5.6. HRMS (ESI/TOF) calcd for C40
H
61
N
7
O
5
Si
3
Na 5.4 Hz, 1H, H-1′), 5.28 (br s, 2H, NH
H-2′), 4.31 (t, J = 4 Hz, 1H, H-3′), 4.15–4.13 (m, 1H, H-4′), 3.98
Representative procedure: deoxygenation of O -(benzotri- (dd, J = 3.4, 11.3 Hz, 1H, H-5′), 3.81 (dd, J = 2.7, 11.5 Hz, 1H,
azol-1-yl)inosine derivative (1). In a clean, dry, screw-cap vial a H-5′), 0.95, 0.94, and 0.82 (3s, 27H, t-Bu), 0.15, 0.14, 0.12, 0.00,
2
), 4.59 (t, J = 4.9 Hz, 1H,
+
[M + Na] 826.3934, found 826.3925.
6
1
3
mixture of compound 1 (121.9 mg, 0.167 mmol), (pinB)
2
−0.03, and −0.16 (6s, 18H, SiCH
3
). C NMR (125 MHz,
(
46.1 mg, 0.182 mmol), and Cs CO (109.0 mg, 0.335 mmol) CDCl ): δ 158.9, 156.2, 148.1, 146.2, 141.4, 132.0, 128.9, 125.3,
2
3
3
Org. Biomol. Chem.
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1
20.3, 118.1, 115.0, 87.5, 85.6, 76.2, 72.2, 62.8, 26.1, 25.9, 25.7, pound 24 as an off-white, fluffy solid. R
f
of 26 (50% EtOAc
1
8.6, 18.1, 17.9, −4.3, −4.5, −4.6, −4.9, −5.2, −5.3. HRMS in hexanes) = 0.17. H NMR of 26 (500 MHz, CDCl ): δ 8.98 (s,
3
+
(ESI/TOF) calcd for C34
H
58
N
8
O
4
Si
3
Na [M + Na] 749.3787, 1H, Ar–H), 8.50 (s, 1H, Ar–H), 8.25 (s, 1H, Ar–H), 8.14 (s, 1H,
found 749.3781.
Ar–H), 6.56 (t, J = 6.4 Hz, 1H, H-1′), 6.42 (t, J = 6.4 Hz, 1H,
6
Deoxygenation of O -(benzotriazol-1-yl)-2′-deoxyguanosine H-1′), 4.64–4.59 (m, 2H, H-3′), 4.06–4.02 (m, 2H, H-4′),
derivative (8). As described for the deoxygenation of compound 3.89–3.84 (m, 2H, H-5′), 3.80–3.77 (dd, J = 2.6, 11.4 Hz, 2H,
7
0
, this reaction was carried out with compound 8 (102.6 mg, H-5′), 2.67 (app quint, Japp ∼ 6.5 Hz, 1H, H-2′), 2.56 (app quint,
.167 mmol), (pinB)2 (46.1 mg, 0.182 mmol), and Cs CO Japp ∼ 6.4 Hz, 1H, H-2′), 2.50 (ddd, J = 3.9, 6.4, 13.0 Hz, 1H,
2
3
(
109.0 mg, 0.335 mmol) in PhMe (1.5 mL) at 100 °C over 4 h. H-2′), 2.45 (ddd, J = 3.9, 6.2, 13.0 Hz, 1H, H-2′), 0.92, 0.917,
Purification by flash chromatography (SiO , eluted with 30% 0.914, and 0.89 (4s, 36H, t-Bu), 0.12, 0.11, 0.10, 0.09, 0.08,
EtOAc in hexanes) gave 90.9 mg (91% yield) of product 22 as and 0.07 (6s, 36H, SiCH ). HRMS of 26 (ESI/TOF) calcd for
2
3
+
an off-white, fluffy solid. A trace amount of N2 isomer 23 was
44 78 8 7 4
C H N O Si Na [M + Na] 965.4968, found 965.4963. Com-
1
1
observed in this reaction. R (40% EtOAc in hexanes) = 0.37. pound 26 is known in the literature.
f
R
f
of 24 (50% EtOAc in
1
1
H NMR (500 MHz, CDCl ): δ 8.58 (d, J = 8.3 Hz, 1H, Ar–H), hexanes) = 0.07. H NMR of 24 (500 MHz, CDCl ): δ 9.09 (d, J =
3
3
8
7
.28 (s, 1H, Ar–H), 8.21 (d, J = 8.3 Hz, 1H, Ar–H), 7.64 (t, J = 8.3 Hz, 1H, Ar–H), 8.99 (s, 1H, Ar–H), 8.88 (d, J = 4.4 Hz, 1H,
.6 Hz, 1H, Ar–H), 7.50 (t, J = 7.7 Hz, 1H, Ar–H), 6.47 (t, J = 6.6 Ar–H), 8.62 (s, 1H, Ar–H), 7.62 (dd, J = 4.4, 8.3 Hz, 1H, Ar–H),
Hz, 1H, H-1′), 5.24 (br s, 2H, NH ), 4.63–4.60 (m, 1H, H-3′), 6.64 (t, J = 6.6 Hz, 1H, H-1′), 4.67–4.65 (m, 1H, H-3′), 4.11–4.08
2
4
.06–4.04 (m, 1H, H-4′), 3.86–3.78 (m, 2H, 2H-5′), 2.60 (app (m, 1H, H-4′), 3.90 (dd, J = 3.9, 11.2 Hz, 1H, H-5′), 3.81 (dd, J =
quint, Japp ∼ 6.7 Hz, 1H, H-2′), 2.46 (ddd, J = 3.4, 5.8, 13.2 Hz, 2.5, 11.2 Hz, 1H, H-5′), 2.68 (app quint, Japp ∼ 6.5 Hz, 1H,
1
0
1
8
H, H-2′), 0.94 and 0.92 (2s, 18H, t-Bu), 0.13, 0.12, 0.10, and H-2′), 2.54 (ddd, J = 3.4, 5.9, 13.2 Hz, 1H, H-2′), 0.94 and 0.91
1
3
.09 (4s, 12H, SiCH
3
). C NMR (125 MHz, CDCl
3
): δ 158.9, (2s, 18H, t-Bu), 0.13 and 0.10 (2s, 12H, SiCH
Si Na [M + Na] 605.2816,
8.0, 83.8, 113.8, 72.2, 62.9, 41.0, 26.0, 25.8, 24.9, 18.4, 18.0, found 605.2814. A C NMR spectrum could not be obtained
3
). HRMS of 24
+
55.9, 146.2, 141.2, 132.0, 129.0, 125.3, 120.2, 118.1, 114.9, (ESI/TOF) calcd for C27
H
42
N
8
O
3
2
1
3
−
4.6, −4.7, −5.3, −5.4. HRMS (ESI/TOF) calcd for because of low quantity of the material isolated.
+
6
C
28
H
44
N
8
O
3
Si
2
Na [M + Na] 619.2973, found 619.2979.
Deoxygenation
of
O -(6-chlorobenzotriazol-1-yl)inosine
6
Attempted deoxygenation of O -(7-azabenzotriazol-1-yl) derivative (11). As described for the deoxygenation of com-
inosine derivative (9). As described for the deoxygenation of pound 1, this reaction was carried out with compound 11
compound 1, this reaction was attempted with compound 9 (127.6 mg, 0.167 mmol), (pinB) (46.1 mg, 0.182 mmol), and
58.8 mg, 81.0 µmol), (pinB)2 (22.24 mg, 87.6 µmol), and Cs CO (109.0 mg, 0.335 mmol) in PhMe (1.5 mL) at 100 °C for
2
(
2
3
2 3 2
Cs CO (52.6 mg, 0.161 mmol) in PhMe (0.75 mL) at 100 °C 4 h. Purification by flash chromatography (SiO , eluted with
over 4 h. Evaporation of the reaction mixture and purification 15% EtOAc in hexanes) gave isomer 27a (31.1 mg) and 27b
by flash chromatography (SiO , eluted with 40% EtOAc in (48.3 mg), each as an off-white, fluffy solid, for an overall yield
2
1
hexanes) gave 24.6 mg (25% yield) of compound 25 as an oily of 64%. R
product. R (40% EtOAc in hexanes) = 0.84. H NMR (500 MHz, 27a (500 MHz, CDCl ): δ 8.99 (s, 1H, Ar–H), 8.74 (d, J = 9.3 Hz,
f 3
f
of 27a (20% EtOAc in hexanes) = 0.55. H NMR of
1
CDCl ): δ 8.99 (s, 1H, Ar–H), 8.60 (s, 1H, Ar–H), 8.26 (s, 1H, 1H, Ar–H), 8.63 (s, 1H, Ar–H), 8.21 (s, 1H, Ar–H), 7.64 (d, J =
3
Ar–H), 8.25 (s, 1H, Ar–H), 6.17 (d, J = 3.4 Hz, 1H, H-1′), 6.02 (d, 8.7 Hz, 1H, Ar–H), 6.27 (d, J = 5.5 Hz, 1H, H-1′), 4.70 (app t, J =
J = 3.9 Hz, 1H, H-1′), 4.57 (t, J = 3.6 Hz, 1H, H-2′), 4.50 (t, J = 4.9 Hz, 1H, H-2′), 4.34 (t, J = 3.2 Hz, 1H, H-3′), 4.20–4.18 (m,
4
4
.2 Hz, 1H, H-2′), 4.37 (t, J = 4.4 Hz, 1H, H-3′), 4.33 (t, J = 1H, H-4′), 4.03 (dd, J = 3.5, 11.2 Hz, 1H, H-5′), 3.83 (d, J = 11.5
.4 Hz, 1H, H-3′), 4.18–4.14 (m, 2H, H-4′), 4.06–4.01 (m, 2H, Hz, 1H, H-5′), 0.97, 0.96, and 0.79 (3s, 27H, t-Bu), 0.17, 0.16,
1
3
3
H-5′), 3.83–3.79 (m, 2H, H-5′), 0.96, 0.93, 0.86, and 0.85 (4s, 0.13, −0.02, and −0.25 (5s, 18H, SiCH ). C NMR of 27a
5
4H, t-Bu), 0.15, 0.14, 0.12, 0.11, 0.10, 0.03, −0.04, −0.07 (8s, (125 MHz, CDCl ): δ 154.4, 151.8, 147.3, 147.0, 144.9, 131.4,
3
1
3
3
6H, SiCH
3
). C NMR (125 MHz, CDCl
3
): δ 155.1, 153.5, 152.2, 130.9, 130.2, 123.8, 119.9, 116.2, 88.3, 86.2, 76.4, 72.3, 62.8,
1
8
2
47.8, 147.1, 145.9, 144.9, 138.9, 129.9, 124.9, 89.0, 88.7, 85.0, 26.3, 25.9, 25.7, 18.7, 17.9, −4.3, −4.4, −4.5, −4.9, −5.1, −5.2.
4.9, 83.5, 76.4, 71.2, 71.0, 62.1, 62.0, 26.1, 25.9, 25.74, 25.7, HRMS of 27a (ESI/TOF) calcd for C H O ClN Si Na
3
4
56
4
7
3
+
5.0, 18.6, 18.1, 17.9, −4.2, −4.3, −4.6, −4.8, −5.28, −5.33. [M + Na] 768.3282, found 768.3282. R
f
of 27b (20% EtOAc
in hexanes) = 0.42. H NMR of 27b (500 MHz, CDCl ):
δ 9.01 (s, 1H, Ar–H), 8.85 (s, 1H, Ar–H), 8.63 (s, 1H, Ar–H),
+
1
HRMS (ESI/TOF) calcd for C56
1
H
106
N
8
O
9
Si
6
Na [M + Na]
3
225.6596, found 1225.6604.
6
Attempted deoxygenation of O -(7-azabenzotriazol-1-yl)-2′- 8.15 (d, J = 8.8 Hz, 1H, Ar–H), 7.50 (d, J = 7.2 Hz, 1H, Ar–H),
deoxyinosine derivative (10). As described for the deoxygena- 6.27 (d, J = 5.5 Hz, 1H, H-1′), 4.71 (t, J = 4.9 Hz, 1H, H-2′), 4.35
tion of compound 1, this reaction was attempted with com- (t, J = 3.4 Hz, 1H, H-3′), 4.20–4.18 (m, 1H, H-4′), 4.04 (dd, J =
pound 10 (48.3 mg, 80.7 µmol), (pinB)
and Cs CO (52.6 mg, 0.161 mmol) in PhMe (0.75 mL) at 0.96, and 0.79 (3s, 27H, t-Bu), 0.17, 0.16, 0.13, −0.02, and
00 °C over 4 h. Evaporation of the reaction mixture and purifi- −0.25 (5s, 18H, SiCH3). C NMR of 27b (125 MHz, CDCl3):
cation by preparative TLC (1 mm, 20 × 20 cm SiO plate eluted δ 154.2, 151.6, 147.1, 144.7, 144.6, 135.8, 132.5, 126.6, 123.6,
2
(22.2 mg, 87.6 µmol), 3.3, 11.0 Hz, 1H, H-5′), 3.82 (d, J = 11.5 Hz, 1H, H-5′), 0.97,
2
3
1
3
1
2
with 60% EtOAc in hexanes) gave 22.0 mg (29% yield) of com- 121.0, 115.1, 88.1, 86.0, 76.1, 72.2, 62.6, 26.1, 25.8, 25.5, 18.5,
pound 26 as an oily product, and 5.0 mg (10% yield) of com- 18.0, 17.7, −4.5, −4.6, −4.7, −5.1, −5.3, −5.4. HRMS of 27b
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+
(
ESI/TOF) calcd for C34
H
56
O
4
ClN
7
Si
3
Na [M + Na] 768.3282, 26.1, 25.9, 25.7, 18.6, 18.1, 17.9, −4.3, −4.5, −4.6, −4.9, −5.2,
−5.3. HRMS of 29a (ESI/TOF) calcd for C H O ClN Si
found 768.3282.
3
4
58
4
8
3
6
+
Deoxygenation of O -(6-chlorobenzotriazol-1-yl)-2′-deoxyino- [M + H] 761.3572, found 761.3567. R
f
of 29b (20% EtOAc
sine derivative (12). As described for the deoxygenation of com- in hexanes) = 0.30. H NMR of 29b (500 MHz, CDCl ): δ 8.64
pound 1, this reaction was carried out with compound 12 (d, J = 1.7 Hz, 1H, Ar–H), 8.29 (s, 1H, Ar–H), 8.11 (d, J = 8.2 Hz,
105.8 mg, 0.167 mmol), (pinB) (46.1 mg, 0.182 mmol), and 1H, Ar–H), 7.46 (dd, J = 1.6, 8.8 Hz, 1H, Ar–H), 6.07 (d, J =
Cs CO (109.0 mg, 0.335 mmol) in PhME (1.5 mL) at 100 °C 5.4 Hz, 1H, H-1′), 5.22 (s, 2H, NH ), 4.57 (t, J = 4.4 Hz, 1H,
1
3
(
2
2
3
2
for 4 h. Purification by flash chromatography (SiO , eluted H-2′), 4.31–4.30 (m, 1H, H-3′), 4.15–4.13 (m, 1H, H-4′), 3.98
2
with 20% EtOAc in hexanes) gave isomers 28a (27.2 mg), 28b (dd, J = 3.3, 11.5 Hz, 1H, H-5′), 3.81 (dd, J = 2.2, 11.5 Hz, 1H,
(
14 mg), and a mixture of 28a + 28b (45.6 mg), each as an off- H-5′), 0.96, 0.95, and 0.83 (3s, 27H, t-Bu), 0.16, 0.15, 0.12, 0.00,
1
3
white, amorphous solid, for an overall yield of 64%. R of 28a and −0.16 (5s, 18H, SiCH3). C NMR of 29b (125 MHz,
f
1
(
50% EtOAc in hexanes) = 0.79. H NMR of 28a (500 MHz, CDCl
CDCl ): δ 8.99 (s, 1H, Ar–H), 8.72 (d, J = 8.8 Hz, 1H, Ar–H), 8.59 121.0, 118.0, 115.0, 87.5, 85.7, 76.2, 72.2, 62.7, 26.1, 25.9,
s, 1H, Ar–H), 8.21 (s, 1H, Ar–H), 7.64 (dd, J = 2.0, 8.8 Hz, 1H, 25.7, 18.6, 18.1, 17.9, −4.3, −4.5, −4.6, −4.9, −5.2, −5.3. HRMS
3
): δ 158.8, 156.4, 147.7, 144.7, 141.7, 135.4, 132.5, 126.4,
3
(
+
58 4 8 3
Ar–H), 6.64 (t, J = 6.4 Hz, 1H, H-1′), 4.66–4.64 (m, 1H, H-3′), of 29b (ESI/TOF) calcd for C34H O ClN Si [M + H] 761.3572,
4
3
6
0
.09–4.07 (m, 1H, H-4′), 3.89 (dd, J = 3.9, 11.3 Hz, 1H, H-5′), found 761.3577.
6
.81 (dd, J = 3.0, 11.2 Hz, 1H, H-5′), 2.68 (app quint, Japp Deoxygenation of O -(6-chlorobenzotriazol-1-yl)-2′-deoxy-
∼
.5 Hz, 1H, H-2′), 2.54 (ddd, J = 3.5, 5.8, 12.9 Hz, 1H, H-2′), guanosine derivative (14). As described for the deoxygenation
.94 and 0.91 (2s, 18H, t-Bu), 0.13, 0.10, and 0.09 (3s, 12H, of compound 1, this reaction was carried out with compound
1
3
SiCH3). C NMR of 28a (125 MHz, CDCl ): δ 153.8, 151.7, 14 (108.4 mg, 0.167 mmol), (pinB) (46.1 mg, 0.182 mmol), and
3
2
1
8
−
47.1, 146.8, 144.4, 131.3, 130.8, 130.1, 123.8, 119.7, 116.1, Cs
2
CO
3
(109.0 mg, 0.335 mmol) in PhMe (1.5 mL) at 100 °C for
8.3, 84.8, 72.1, 62.8, 41.5, 26.0, 25.8, 18.4, 18.0, −4.6, −4.7, 4 h. Purification by flash chromatography (SiO
5.3, −5.4. HRMS of 28a (ESI/TOF) calcd for C H O ClN Si 25% EtOAc in hexanes) gave 83 mg (79% yield) a 1 : 1 mixture of
of 28b (50% EtOAc in 30a + 30b as an off-white, fluffy solid. R (30% EtOAc in
): δ 8.99 (s, hexanes) = 0.37, 0.30. H NMR (500 MHz, CDCl ): δ 8.59 (d, J =
2
, eluted with
2
8
43
3
7
2
+
[M + H] 616.2654, found 616.2643. R
f
f
1
1
hexanes) = 0.69. H NMR of 28b (500 MHz, CDCl
3
3
1
8
H, Ar–H), 8.81 (d, J = 1.0 Hz, 1H, Ar–H), 8.58 (s, 1H, Ar–H), 1.1 Hz, 1H, Ar–H), 8.48 (d, J = 8.7 Hz, 1H, Ar–H), 8.23 (s, 1H, Ar–
.12 (d, J = 8.8 Hz, 1H, Ar–H), 7.48 (dd, J = 1.4, 8.8 Hz, 1H, H), 8.22 (s, 1H, Ar–H), 8.14 (s, 1H, Ar–H), 8.08 (d, J = 8.3 Hz, 1H,
Ar–H), 6.63 (t, J = 6.6 Hz, 1H, H-1′), 4.66–4.64 (m, 1H, H-3′), Ar–H), 7.52 (dd, J = 1.1, 8.8 Hz, 1H, Ar–H), 7.42 (dd, J = 1.6,
4
3
6
.09–4.07 (m, 1H, H-4′), 3.89 (dd, J = 4.2, 11.0 Hz, 1H, H-5′), 8.8 Hz, 1H, Ar–H), 6.43 (t, J = 6.0 Hz, 2H, H-1′), 5.32 and 5.27
.80 (dd, J = 2.9, 11.2 Hz, 1H, H-5′), 2.69 (app quint, Japp (2s, 4H, NH ), 4.62–4.60 (m, 2H, H-3′), 4.04–4.02 (m, 2H, H-4′),
.4 Hz 1H, H-2′), 2.53 (ddd, J = 3.4, 5.9, 13.1 Hz, 1H, H-2′), 0.93 3.84–3.73 (m, 4H, H-5′), 2.60 (app quint, Japp ∼ 4.4 Hz, 2H,
∼
2
and 0.90 (2s, 18H, t-Bu), 0.12, 0.09, and 0.08 (3s, 12H, SiCH ). H-2′), 2.45–2.40 (m, 2H, H-2′), 0.92 and 0.90 (2s, 36H, t-Bu),
3
1
3
13
C NMR of 28b (125 MHz, CDCl
44.3, 135.8, 132.5, 126.6, 123.6, 121.0, 115.1, 88.2, 84.7, 72.1, CDCl
2.8, 41.4, 25.9, 25.7, 18.4, 17.9, −4.7, −4.8, −5.4, −5.5. HRMS 141.4, 135.5, 132.5, 131.0, 130.6, 129.7, 126.4, 121.0, 119.6,
3
): δ 153.7, 151.6, 147.1, 144.7, 0.12, 0.08, and 0.07 (3s, 24H, SiCH
3
). C NMR (125 MHz,
1
6
3
): δ 158.9, 158.8, 156.0, 147.6, 147.5, 146.7, 144.7, 141.5,
+
of 28b (ESI/TOF) calcd for C28
H
42
O
3
ClN
7
Si
2
Na [M + Na]
118.0, 117.9, 115.8, 114.9, 88.0, 83.8, 62.9, 41.1, 26.0, 25.8, 18.4,
6
38.2468, found 638.2467.
18.0, −4.6, −4.7, −5.3, −5.5. HRMS (ESI/TOF) calcd for
6
+
Deoxygenation of O -(6-chlorobenzotriazol-1-yl)guanosine C H O ClN Si [M + H] 631.2758, found 631.2745.
2
8
44
3
8
2
6
derivative (13). As described for the deoxygenation of com-
Deoxygenation
of
O -(benzotriazol-1-yl)-2′,3′,5′-tri-O-
pound 1, this reaction was carried out with compound 13 (t-butyldimethylsilyl)-2-phenylinosine (19). As described for the
130.2 mg, 0.167 mmol), (pinB) (46.1 mg, 0.182 mmol), and deoxygenation of compound 1, this reaction was carried out
(
2
Cs
4
1
2
CO
h. Purification by flash chromatography (SiO
5% EtOAc in hexanes) gave isomers 29a (19.1 mg), 29b at 100 °C for 4 h. Purification by flash chromatography (SiO2,
3
(109.0 mg, 0.335 mmol) in PhMe (1.5 mL) at 100 °C for with compound 19 (40.0 mg, 0.05 mmol), (pinB)
2
(13.7 mg,
2
, eluted with 0.054 mmol), and Cs CO (32.4 mg, 0.1 mmol) in PhMe (1 mL)
2
3
(
46.4 mg) and a mixture of 29a + 29b (46.4 mg), each as an off- eluted with 20% and 25% EtOAc in hexanes) gave 35.1 mg
white to white fluffy solid, for an overall yield of 84%. R of 29a (89% yield) of product 31 as a pale pink, fluffy solid. R (20%
20% EtOAc in hexanes) = 0.42. H NMR of 29a (500 MHz, EtOAc in hexanes) = 0.47. H NMR (500 MHz, C D ): δ 8.78 (d,
f
f
1
1
(
6
6
3
CDCl ): δ 8.54 (d, J = 9.3 Hz, 1H, Ar–H), 8.28 (s, 1H, Ar–H), 8.17 J = 7.4 Hz, 2H, Ar–H), 8.71 (d, J = 8.3 Hz, 1H, Ar–H), 8.63 (s,
(d, J = 1.7 Hz, 1H, Ar–H), 7.57 (dd, J = 1.6, 8.8 Hz, 1H, Ar–H), 1H, Ar–H), 7.97 (d, J = 8.3 Hz, 1H, Ar–H), 7.42 (t, J = 7.8 Hz,
6
4
1
1
0
.07 (d, J = 5.4 Hz, 1H, H-1′), 5.20 (s, 2H, NH ), 4.56 (t, J = 2H, Ar–H), 7.30 (t, J = 7.4 Hz, 1H, Ar–H), 7.23 (t, J = 7.8 Hz, 1H,
2
.7 Hz, 1H, H-2′), 4.30 (t, J = 3.8 Hz, 1H, H-3′), 4.13–4.15 (m, Ar–H), 7.01 (t, J = 7.6 Hz, 1H, Ar–H), 6.42 (d, J = 4.4 Hz, 1H,
H, H-4′), 3.98 (dd, J = 3.3, 11.5 Hz, 1H, H-5′), 3.81 (dd, J = 2.2, H–1′), 4.91 (t, J = 4.2 Hz, 1H, H–2′), 4.60 (t, J = 4.2 Hz, 1H, H–
1.5 Hz, 1H, H-5′), 0.96, 0.95, and 0.82 (3s, 27H, t-Bu), 0.15, 3′), 4.33–4.31 (m, 1H, H–4′), 4.03 (dd, J = 3.5, 11.2 Hz, 1H, H–
1
3
.14, 0.12, 0.00, and −0.16 (5s, 18H, SiCH
3
). C NMR of 29a 5′), 3.78 (dd, J = 1.5, 11.3 Hz, 1H, H–5′), 1.02, 0.98, and 0.93
(
1
125 MHz, CDCl
3
): δ 158.9, 156.4, 147.6, 146.8, 141.6, 131.0, (3s, 27H, t-Bu), 0.16, 0.15, 0.11, 0.05, 0.00, and −0.01 (6s, 12H,
1
3
30.7, 129.6, 119.6, 117.9, 115.9, 87.4, 85.8, 76.3, 72.3, 62.8, SiCH3). C NMR (125 MHz, C D ): δ 158.5, 155.0, 147.9, 146.6,
6 6
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1
2
3
44.4, 137.9, 132.2, 130.4, 128.5, 128.4, 128.0, 127.8, 127.6, anhydrous DME (3 mL) were added Et N (195.8 µL,
24.8, 123.6, 120.1, 114.5, 88.7, 84.9, 76.2, 71.7, 62.2, 25.9, 1.404 mmol) and MeCN (1.5 mL), and the mixture was
5.7, 25.6, 18.3, 18.0, 17.8, 1.0, −4.4, −4.8, −4.9, −5.6, −5.62. stirred at room temperature for 15 min. PyBroP (276.3 mg,
+
HRMS (ESI/TOF) calcd for C40
H
62
O
4
N
7
Si
3
[M + H] 788.4166, 0.59 mmol) was added and the stirring was continued at room
found 788.4151.
temperature for 15 min. 3′,5′-Di-O-TBDMS-protected 2′-deoxy-
Synthesis of 5,6-dichloro-1-hydroxy-1H-benzotriazole (34)
Step 1: preparation of 1,2,4-trichloro-5-nitrobenzene (33). In a the dropwise addition of DIPEA (198.0 µL, 1.135 mmol).
inosine (150.0 mg, 0.312 mmol) was added, followed by
3
2
clean, dry, round-bottomed flask a mixture of KNO (8.34 g, The mixture was stirred at room temperature for 20 h and then
3
8
2.5 mmol) in conc. H
stirring. To this stirring mixture was added 1,2,4-trichloro- chromatography (SiO
benzene (6.9 mL, 55.5 mmol) dropwise. The mixture was then gave 146.0 mg (70% yield) of product 40 as a yellow, fluffy
2
SO
4
(110 mL) was cooled at 0 °C with evaporated under reduced pressure. Purification by flash
2
, eluted with 15% EtOAc in hexanes)
1
warmed to 50 °C for 3 h. The mixture was cooled to 0 °C and solid. R
f
(20% EtOAc in hexanes) = 0.43. H NMR (500 MHz,
neutralized with 2 M aq. NaOH. The crystals formed were fil- CDCl ): δ 8.55 (s, 1H, Ar–H), 8.41 (s, 1H, Ar–H), 8.26 (s, 1H,
3
tered, washed with water, and crystallized from petroleum Ar–H), 7.64 (s, 1H, Ar–H), 6.55 (t, J = 6.3 Hz, 1H, H-1′),
ether to yield compound 33 as fine, pale-yellow crystals. To 4.65–4.63 (m, 1H, H-3′), 4.07–4.05 (m, 1H, H-4′), 3.92 (dd, J =
remove impurity traces, further purification was done by flash 3.9, 11.0 Hz, 1H, H-5′), 3.80 (dd, J = 3.1, 11.3 Hz, 1H, H-5′),
chromatography (SiO , eluted with hexanes) to give 12.0 g 2.64 (app quint, Japp ∼ 6.3 Hz, 1H, H-2′), 2.52 (ddd, J = 4.4, 6.0,
2
(
f
96% yield) of compound 33. R (20% EtOAc/hexanes) = 0.71. 13.2 Hz, 1H, H-2′), 0.92 (1s, 18H, tert-Bu), 0.11 and 0.109 (2s,
1
13
H NMR (500 MHz, DMSO-d
6
): δ 8.49 (s, 1H, Ar–H), 8.25 (s, 1H, 12H, SiCH
3 3
). C NMR (125 MHz, CDCl ): δ 158.6, 153.7, 151.2,
1
3
Ar–H). C NMR (125 MHz, DMSO-d ): δ 146.4, 136.5, 132.8, 143.9, 142.2, 134.2, 130.0, 128.1, 121.5, 119.8, 110.1, 88.2, 85.1,
6
1
31.2, 127.1, 124.9.
Step 2: conversion of 33 to 34. In a clean, dry, round- HRMS (ESI/TOF) calcd for C28
bottomed flask equipped with a stirring bar were placed com- 688.2028, found 688.2029.
71.6, 62.6, 41.7, 26.0, 25.7, 18.4, 18.0, −4.6, −4.8, −5.4, −5.5.
H
41Cl
2
N
7
O
4
2
Si Na [M + Na]
6
pound 33 (3.3 g, 14.6 mmol), EtOH (33 mL), PhMe (16.5 mL),
Na CO (2.01 g, 18.9 mmol), and water (1.8 mL) in that order. silyl)inosine (41). As described for the preparation of com-
To the gently stirring mixture was added hydrazine (4.57 g, pound 40, this synthesis was performed with 5,6-dichloro-
45.7 mmol) and the mixture was heated to reflux at 100 °C 1-hydroxy-1H-benzotriazole (34, 286.4 mg, 1.404 mmol), an-
for 20 h. The mixture was cooled to room temperature and the hydrous DME (3 mL), Et N (195.0 µL, 1.404 mmol), CH CN
O -(5,6-Dichlorobenzotriazol-1-yl)-2′,3′,5′-tri-O-(t-butyldimethyl-
2
3
1
3
3
flask was transferred to an ice-cold water bath. Upon acidifica- (1.5 mL), PyBroP (276.3 mg, 0.59 mmol), 2′,3′,5′-tri-O-TBDMS-
tion to pH 2 with 1 M HCl a precipitate formed, which was fil- protected inosine (190.6 mg, 0.312 mmol), and DIPEA
tered, and washed with cold water. The crude material was (198.0 µL, 1.815 mmol). After addition of the last reagent the
recrystallized from 1 : 1 H O/EtOH to give 1.678 g (56% yield) mixture was stirred at room temperature for 7 h and evapor-
2
of product 34 as a pale-brown powder. R
f
(10% CH
) = 0.60. H NMR (500 MHz, DMSO-d ): δ 14.05 (br s, graphy (SiO
H, OH), 8.40 (s, 1H, Ar–H), 8.09 (s, 1H, Ar–H). C NMR 174.0 mg (70% yield) of product 41 as an off-white, fluffy solid.
125 MHz, DMSO-d ): δ 141.8, 130.8, 127.7, 127.02, 120.7, (Trace amounts of 38 and 39 were observed and removed chro-
3
OH in ated under reduced pressure. Purification by flash chromato-
1
CH
2
Cl
2
6
2
, eluted with 5% and 10% EtOAc in hexanes) gave
13
1
(
6
1
1
[
11.3, 124.9. HRMS (ESI/TOF) calcd for
C
6
H
3
OCl
2
N
3
Na matographically.) R
f
(15% EtOAc in hexanes) = 0.64. H NMR
+
M + Na] 225.9545, found 225.9546.
Reduction of 5,6-dichloro-1-hydroxy-1H-benzotriazole (34) (s, 1H, Ar–H), 7.63 (s, 1H, Ar–H), 6.15 (d, J = 3.9 Hz, 1H, H-1′),
to 5,6-dichloro-1H-benzotriazole (35). To mixture of 4.57 (t, J = 3.9 Hz, 1H, H-2′), 4.34 (t, J = 4.4 Hz, 1H, H-3′),
50.0 mg, 4.19–4.17 (m, 1H, H-4′), 4.05 (dd, J = 3.4, 11.7 Hz, 1H, H-5′),
N (41.0 µL, 3.82 (d, J = 11.7 Hz, 1H, H-5′), 0.97, 0.93, and 0.82 (3s, 27H,
.294 mmol), and the mixture was stirred at room temperature t-Bu), 0.17, 0.16, 0.11, 0.10, 0.004, and −0.15 (6s, 18H, SiCH ).
C NMR (125 MHz, CDCl ): δ 158.7, 154.1, 151.5, 144.3, 142.4,
(500 MHz, CDCl ): δ 8.64 (s, 1H, Ar–H), 8.41 (s, 1H, Ar–H), 8.26
3
a
5
,6-dichloro-1-hydroxy-1H-benzotriazole
(34,
0
.245 mmol) in CH CN (1 mL) was added Et
3
3
0
3
1
3
for 30 min. To this mixture was added B (OH) (26.3 mg,
2
4
3
0
.294 mmol) and the mixture was stirred at 50 °C for 30 min. 134.4, 130.1, 128.2, 121.6, 110.2, 89.1, 85.6, 76.7, 71.6, 62.3,
The mixture was cooled and evaporated under reduced 26.3, 26.0, 25.8, 18.7, 18.2, 18.0, −4.2, −4.5, −4.6, −4.8, −5.2,
pressure. Purification of the crude material by flash chromato- −5.3, −11.7. HRMS (ESI/TOF) calcd for C H Cl N O Si Na
3
4
55
2
7
5
3
+
graphy (SiO
2
, eluted with 40% EtOAc in hexanes) to gave [M + Na] 818.2842, found 818.2862.
6
3
3.3 mg (72% yield) of 5,6-chloro-1-hydroxy-1H-benzotriazole
Deoxygenation of O -(5,6-dichlorobenzotriazol-1-yl)-3′,5′-di-
(
35) as a pale-yellowish-brown powder. R (10% CH OH in O-(t-butyldimethylsilyl)-2′-deoxyinosine (40). As described for
f
3
1
CH
2
Cl
2
) = 0.63. H NMR (500 MHz, DMSO-d
6
): δ 16.05 (s, 1H, the deoxygenation of compound 1, this reaction was carried
NH), 8.34 (s, 2H, Ar–H). HRMS (ESI/TOF) calcd for C
6
H
4
Cl
2
N
3
out with compound 40 (100.0 mg, 0.15 mmol), (pinB)
(41.3 mg, 0.163 mmol), and Cs CO (97.7 mg, 0.29 mmol) in
2
+
[
M + H] 187.9777, found 187.9779.
2
3
6
O -(5,6-Dichlorobenzotriazol-1-yl)-3′,5′-di-O-(t-butyldimethyl- PhMe (1.5 mL) at 100 °C for 4 h. Purification by flash chrom-
silyl)-2′-deoxyinosine (40). To a stirred solution of 5,6-dichloro- atography (SiO , eluted with 20% and 30% EtOAc in hexanes)
-hydroxy-1H-benzotriazole (34, 286.0 mg, 1.404 mmol) in gave 60.0 mg (61% yield) of product 42 as a yellow, fluffy solid.
2
1
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1
R
f
(20% EtOAc in hexanes) = 0.25. H NMR (500 MHz, CDCl
δ 9.01 (s, 1H, Ar–H), 8.94 (s, 1H, Ar–H), 8.60 (s, 1H, Ar–H), 8.33
s, 1H, Ar–H), 6.64 (t, J = 6.6 Hz, 1H, H-1′), 4.67–4.65 (m, 1H,
3
):
3 C. Simons, Nucleoside Mimetics: Their Chemistry and Bio-
logical Properties, Gordon and Breach, Amsterdam, 2001.
4 Perspectives in Nucleoside and Nucleic Acid Chemistry,
ed. M. V. Kisakürek and H. Rosemeyer, Verlag Helvetica
Chimica Acta, Zurich and Wiley-VCH, Weinheim, 2000.
5 R. J. Suhadolnik, Nucleosides as Biological Probes, Wiley,
New York, 1979.
(
H-3′), 4.10–4.08 (m, 1H, H-4′), 3.90 (dd, J = 3.6, 11.2 Hz, 1H,
H-5′), 3.82 (d, J = 11 Hz, 1H, H-5′), 2.68 (app quint, Japp ∼ 3.3
Hz, 1H, H-2′), 2.54 (ddd, J = 3.4, 6.7, 12.9 Hz, 1H, H-2′), 0.94
3
and 0.91 (2s, 18H, t-Bu), 0.13, 0.10, and 0.10 (3s, 12H, SiCH ).
+
HRMS (ESI/TOF) calcd for C H Cl N O Si [M
+
H]
6 Antiviral Nucleosides: Chiral Synthesis and Chemotherapy,
ed. C. K. Chu, Elsevier, Amsterdam, 2003.
2
8
42
2
7
3
2
6
50.2259, found 650.2260.
6
Deoxygenation of O -(5,6-dichlorobenzotriazol-1-yl)-2′,3′,5′-
tri-O-(t-butyldimethylsilyl)inosine (41). As described for the
deoxygenation of compound 1, this reaction was carried out
with compound 41 (119.5 mg, 0.15 mmol), (pinB)
.163 mmol), and Cs CO (97.7 mg, 0.29 mmol) in PhMe
7 N. Venkatesan, Y. J. Seo, E. K. Bang, S. M. Park, Y. S. Lee
and B. H. Kim, Bull. Korean Chem. Soc., 2006, 27, 613–630.
8 L. I. Wiebe, Braz. Arch. Biol. Technol., 2007, 50, 445–459.
9 D. E. Bergstrom, Curr. Protoc. Nucleic Acids Chem., 2009, 37,
1.4:1.4.1–1.4:1.4.32.
2
(41.3 mg,
0
2
3
(1.5 mL) at 100 °C for 4 h. Purification by flash chromato- 10 S. G. Srivatsan and A. A. Sawant, Pure Appl. Chem., 2011, 83,
graphy (SiO
2
, eluted with 10% EtOAc in hexanes) gave 61.1 mg
213–232.
(
56% yield) of product 43 as a pale-yellow powder. R (15% 11 S. Bae and M. K. Lakshman, J. Am. Chem. Soc., 2007, 129,
f
1
EtOAc in hexanes) = 0.46. H NMR (500 MHz, CDCl
3
): δ 9.00 (s,
782–789.
1
H, Ar–H), 8.99 (s, 1H, Ar–H), 8.64 (s, 1H, Ar–H), 8.32 (s, 1H, 12 S. Bae and M. K. Lakshman, J. Org. Chem., 2008, 73, 1311–
Ar–H), 6.26 (d, J = 5.4 Hz, 1H, H-1′), 4.69 (t, J = 4.6 Hz, 1H, 1319.
H-2′), 4.34–4.33 (m, 1H, H-3′), 4.20–4.18 (m, 1H, H-4′), 4.03 13 S. Bae and M. K. Lakshman, J. Org. Chem., 2008, 73, 3707–
dd, J = 3.6, 11.4 Hz, 1H, H-5′), 3.83 (d, J = 11.7 Hz, 1H, H-5′), 3713.
.97, 0.95, and 0.78 (3s, 27H, t-Bu), 0.17, 0.16, 0.12, −0.03, and 14 S. Bae and M. K. Lakshman, Org. Lett., 2008, 10, 2203–
(
0
−
0.26 (5s, 18H, SiCH
3
). HRMS (ESI/TOF) calcd for
2206.
+
C
34
H
56Cl
2
N
7
O
4
Si
3
[M + H] 780.3073, found 780.3073.
15 M. K. Lakshman and J. Frank, Org. Biomol. Chem., 2009, 7,
2933–2940.
Crossover experiment involving compounds 4 and 41. As
described for the deoxygenation of compound 1, a mixture of 16 S. Satishkumar, P. K. Vuram, S. S. Relangi, V. Gurram,
compounds 4 (50.0 mg, 83.7 µmol), 41 (66.7 mg, 83.7 µmol),
H. Zhou, R. J. Kreitman, M. M. Martínez Montemayor,
L. Yang, M. Kaliyaperumal, S. Sharma, N. Pottabathini and
M. K. Lakshman, Molecules, 2015, 20, 18437–18463.
(
pinB)2 (46.1 mg, 0.182 mmol), and Cs CO (109 mg,
2 3
0
.335 mmol) in PhMe (1.5 mL) was stirred at 100 °C for 4 h.
The mixture was cooled and evaporated under reduced 17 Z.-K. Wan, E. Binnun, D. P. Wilson and J. Lee, Org. Lett.,
pressure. Chromatographic separation by preparatory TLC 2005, 7, 5877–5880.
1 mm, 20 × 20 cm SiO plate eluted with 30% EtOAc in 18 Z.-K. Wan, S. Wacharasindhu, C. G. Levins, M. Lin,
hexanes) gave compounds 43 (15.4 mg), 2 (28.8 mg), 42
15.1 mg), and 5 (30.2 mg). R values (30% EtOAc in hexanes)
(
2
K. Tabei and T. S. Mansour, J. Org. Chem., 2007, 72, 10194–
10210.
(
f
of 43: 0.82, 2: 0.70, 42: 0.53, and 5: 0.34.
19 T. D. Ashton and P. J. Scammells, Aust. J. Chem., 2008, 61,
49–58.
2
2
2
0 G.-R. Qu, H.-L. Zhang, H.-Y. Niu, Z.-K. Xue, X.-X. Lv and
H.-M. Guo, Green Chem., 2012, 14, 1877–1879.
1 M. Malow, K. D. Wehrstedt and S. Neuenfeld, Tetrahedron
Lett., 2007, 48, 1233–1235.
2 See for leading examples: (a) F. Shi, J. P. Waldo, Y. Chen
and R. C. Larock, Org. Lett., 2008, 10, 2409–2412;
Acknowledgements
Support of this work by NSF Grant CHE-1265687 (MKL) and a
PSC CUNY award is gratefully acknowledged. Infrastructural
support at CCNY was provided by NIH grant G12MD007603
from the National Institute on Minority Health and
Health Disparities. We thank AllyChem for generous samples
of (pinB) , (catB) , and B (OH) .
(
b) L. Campbell-Verduyn, P. H. Elsinga, L. Mirfeizi,
R. A. Dierckx and B. L. Feringa, Org. Biomol. Chem., 2008, 6,
461–3463.
3
2
2
2
2
2
2
3 (a) J. C. Antilla, J. M. Baskin, T. E. Barder and
S. L. Buchwald, J. Org. Chem., 2004, 69, 5578–5587;
(b) S. Ueda, M. Su and S. L. Buchwald, Angew. Chem., Int.
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