Nucleic acid related compounds. 118. Nonaqueous diazotization of aminopurine derivatives. Convenient access to 6-halo- and 2,6-dihalopurine nucleosides and 2′-deoxynucleosides with acyl or silyl halides

Article abstract of DOI:10.1021/jo020625a

Treatment of 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2-amino-6-chloropurine (1) with TMS-Cl and benzyltriethylammonium nitrite (BTEA-NO₂) in dichloromethane gave the crystalline 2,6-dichloropurine nucleoside 2, and acetyl chloride/BTEA-NO₂ was equally effective (～85%, without chromatography). TMS-Br/tert-butyl nitrite/dibromomethane gave crystalline 2-bromo-6-chloro analogue 3 (85%). (Chloro or bromo)-dediazoniation of 3′,5′-di-O-acetyl-2′-deoxyadenosine (4) gave the 6-[chloro (5, 63%) or bromo (6, 80%)]purine deoxynucleosides, and 2′,3′,5′-tri-O-acetyladenosine (8) was converted into the 6-chloropurine nucleoside 9 (71%).

Full text of DOI:10.1021/jo020625a

phoryl halides8,11 or Vilsmeier-Haack reagents7,8). Con-
version of 6-(oxo f halo)purine derivatives with a positive
halogen source and hexamethylphosphorus triamide
(HMPT) gave 6-(bromo or chloro)purine ribonucleosides,9
but failed with an acid-sensitive 2′-deoxynucleoside.9b We
have communicated a new functionalization of 6-oxopu-
rine nucleoside and 2′-deoxynucleoside derivatives, which
provides 6-(imidazol-1-yl) compounds in excellent yields.12
The imidazolyl group can be substituted by common
nucleophiles, but it is not displaced as readily as a
halogen. Halo-dediazoniation provides economical access
to base-functionalized nucleosides in comparison with
lithiation/stannylation procedures.13
Nu cleic Acid Rela ted Com p ou n d s. 118.
Non a qu eou s Dia zotiza tion of Am in op u r in e
Der iva tives. Con ven ien t Access to 6-Ha lo-
a n d 2,6-Dih a lop u r in e Nu cleosid es a n d
2′-Deoxyn u cleosid es w ith Acyl or Silyl
Ha lid es1
Paula Francom† and Morris J . Robins*
Department of Chemistry and Biochemistry,
Brigham Young University, Provo, Utah 84602-5700
morris_robins@byu.edu
Nitrosylation of weakly basic amines is often rate
limiting in dediazoniation, and nitrosyl halides are potent
nitrosylating agents.3b Nitrosyl halides are likely gener-
ated in situ during nonaqueous diazotization of aminopu-
rine nucleosides with antimony trihalides and a nitrite
source.4,5 However, diazotization/dediazoniation mecha-
nisms can be complex and are influenced to a significant
degree by minor changes in reaction conditions.5 Anti-
mony(III) halides are effective catalysts for diazotization/
halo-dediazoniation, and have Lewis acidic properties as
well as serving as halogen donors. Because antimony
compounds are toxic and SbCl3 has been shown to bind
to DNA,14 efficient halo-dediazoniation procedures that
do not employ SbX3 are needed.5
Received September 30, 2002
Abstr a ct: Treatment of 9-(2,3,5-tri-O-acetyl-â-D-ribofuran-
osyl)-2-amino-6-chloropurine (1) with TMS-Cl and benzyl-
triethylammonium nitrite (BTEA-NO2) in dichloromethane
gave the crystalline 2,6-dichloropurine nucleoside 2, and
acetyl chloride/BTEA-NO2 was equally effective (∼85%,
without chromatography). TMS-Br/tert-butyl nitrite/dibro-
momethane gave crystalline 2-bromo-6-chloro analogue 3
(85%). (Chloro or bromo)-dediazoniation of 3′,5′-di-O-acetyl-
2′-deoxyadenosine (4) gave the 6-[chloro (5, 63%) or bromo
(6, 80%)]purine deoxynucleosides, and 2′,3′,5′-tri-O-acetyl-
adenosine (8) was converted into the 6-chloropurine nucleo-
side 9 (71%).
Nitrosyl chloride, as a component of aqua regia, was
recorded in eighth-century Arabic literature,15 and in situ
generation of NOCl with acetyl chloride and nitrous acid
or alkyl nitrites replaced aqua regia a millenium later.16
Generation of NOCl with AlCl3, PCl3, AsCl3, or TiCl4 is
known,17,18 and such sources have been used for in situ
diazotization of aliphatic amines.19 Generation of NOCl
from silicon chlorides and alkyl nitrites was noted in
early patent literature,15 and TMS-Cl/MX has been used
for halo-dediazoniation of aryl triazenes.20 TMS-Cl, NaNO2,
and phase transfer agents have been used for deoxima-
tion of aldehyde and ketone oximes21a as well as halo-
In tr od u ction
Nonaqueous diazotization/halo-dediazoniations2,3 pro-
vide efficient transformations of (amino f halo)purine
nucleosides.4,5 Halogen-functionalized derivatives can be
converted into biologically important analogues by nu-
cleophilic aromatic displacement6-9 and organometallic
cross-coupling chemistry.10 Halo-dediazoniations of ami-
nopurines can be performed under milder conditions4,5
than halo-deoxygenation of oxopurine derivatives (phos-
† Present address: Biota, Inc., Carlsbad, CA.
(1) (a) Patent application filed. (b) Paper 117: Miles, R. W.; Nielsen,
L. P. C.; Ewing, G. J .; Yin, D.; Borchardt, R. T.; Robins, M. J . J . Org.
Chem. 2002, 67, 8258-8260.
(10) (a) Matsuda, A.; Shinozaki, M.; Yamaguchi, T.; Homma, H.;
Nomato, R.; Miyasaka, T.; Watanabe, Y.; Abiru, T. J . Med. Chem. 1992,
35, 241-252. (b) Lakshman, M. K.; Keeler, J . C.; Hilmer, J . H.; Martin,
J . Q. J . Am. Chem. Soc. 1999, 121, 6090-6091. (c) Hocek, M.; Holy´,
A.; Votruba, I.; Dvorˇa´kova´, H. Collect. Czech. Chem. Commun. 2001,
66, 483-499. (d) Ve´liz, E. A.; Stephens, O. M.; Beal, P. A. Org. Lett.
2001, 3, 2969-2972.
(2) Bunnett’s nomenclature3 is used. Replacement of a diazonium
species by another group is termed dediazoniation regardless of
mechanism. The name of the entering group is added as a prefix (e.g.,
chloro-dediazoniation and bromo-dediazoniation).
(3) (a) Zollinger, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 141-
150. (b) Zollinger H. Diazo Chemistry I. Aromatic and Heteroaromatic
Compounds; VCH: New York, 1994.
(11) Gerster, J . F.; Robins, R. K. J . Org. Chem. 1966, 31, 3258-
3262.
(12) Lin, X.; Robins, M. J . Org. Lett. 2000, 2, 3497-3499.
(13) Kato, K.; Hayakawa, H.; Tanaka, H.; Kumamoto, H.; Shindoh,
S.; Shuto, S.; Miyasaka, T. J . Org. Chem. 1997, 62, 6833-6841.
(14) Huang, H.; Shu, S. C.; Shih, J . H.; Kuo, C. J .; Chiu, I. D.
Toxicology 1998, 129, 113-123.
(4) (a) Robins, M. J .; Uznanski, B. Can. J . Chem. 1981, 59, 2608-
2611. (b) Robins, M. J .; Wnuk, S. F. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, UK, 1995;
Vol. 1, pp 205-206. (c) Nair, V.; Richardson, S. G. Synthesis 1982,
670-672.
(5) For background discussion and references see: Francom, P.;
J aneba, Z.; Shibuya, S.; Robins, M. J . J . Org. Chem., 2002, 67, 6788-
6796.
(15) Beckham, L. J .; Fessler, W. A.; Kise, M. A. Chem. Rev. 1951,
48, 319-396.
(16) (a) Weber, C. O. Ber. 1902, 35, 1947-1951. (b) Klages, A. Ber.
1902, 35, 2245-2262.
(6) J ohnson, J . A., J r.; Thomas H. J .; Schaeffer, H. J . J . Am. Chem.
Soc. 1958, 80, 699-702.
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(18) Partington, J . R.; Whynes, A. L. J . Chem. Soc. 1949, 3135-
3141.
(7) Robins, M. J .; Basom, G. L. Can. J . Chem. 1973, 51, 3161-3169
and references therein.
(19) Doyle, M. P.; Bosch, R. J .; Seites, P. G. J . Org. Chem. 1978, 43,
4120-4125.
(20) Ku, H.; Barrio, J . R. J . Org. Chem. 1981, 46, 5239-5241.
(21) (a) Lee, J . G.; Kwak, K. H.; Hwang, J . P. Tetrahedron Lett. 1990,
31, 6677-6680. (b) Lee, J . G.; Cha, H. T. Tetrahedron Lett. 1992, 33,
3167-3168.
(8) Srivastava, P. C.; Robins, R. K.; Meyer, R. B., J r. In Chemistry
of Nucleosides and Nucleotides; Townsend, L. B., Ed.; Plenum: New
York, 1988; Vol. 1, pp 113-281.
(9) (a) Ve´liz, E. A.; Beal, P. A. Tetrahedron Lett. 2000, 41, 1695-
1697. (b) Ve´liz, E. A.; Beal P. A. J . Org. Chem. 2001, 66, 8592-8598.
10.1021/jo020625a CCC: $25.00 © 2003 American Chemical Society
Published on Web 12/31/2002
666
J . Org. Chem. 2003, 68, 666-669

SCHEME 1a
TABLE 1. P r od u cts fr om Ha lo-d ed ia zon ia tion s of 1
products (%)
reagent
solvent
2
3
9
TMS-Cl/TBN
TMS-Br/TBN
CH2Br2
CH2Cl2
72
16
15
69
2.5
SCHEME 2a
a
Reagents and conditions: (a) TMS-Cl/BTEA-NO2/CH2Cl2 (83%);
(b) TMS-Cl/BTEA-NO2/NaNO2/CH2Cl2 (86%); (c) AcCl/BTEA-NO2/
CH2Cl2/0-5 °C (84%); (d) TMS-Br/TBN/CH2Br2 (85%).
dediazoniation of anilines.21b Olah reported generation
of nitryl chloride from NaNO3/TMS-Cl, and nitrations
with NO2Cl were catalyzed by AlCl3.22 Facilitation of
halo-dediazoniation of arylamines occurs with tetraalkyl-
ammonium halides.21,23,24
We have employed SbX3 and nitrite sources for
nucleosides,4a,b,5 but nitrosyl halides have rarely been
used in nucleoside chemistry.8,25 Chlorine, tert-butyl
nitrite (TBN), and copper(I) chloride26 were used for
chloro-dediazoniation of a 2-amino-6-chloropurine nucleo-
side, and adenosine and guanosine derivatives underwent
fluoro-dediazoniation with tert-butylthionitrites and
NaBF4.27 We now report nonaqueous halo-dediazonia-
tions of aminopurine nucleosides with convenient reagent
combinations for generation of NOCl or NOBr in situ.
Efficient chloro-dediazoniation of 9-(2,3,5-tri-O-acetyl-
â-D-ribofuranosyl)-2-amino-6-chloropurine28,29 (1) (Scheme
1) was effected with TMS-Cl (9 equiv) and benzyltriethyl-
ammonium nitrite (BTEA-NO2) (3 equiv) in CH2Cl2 at
ambient temperature. The process was rapid (<30 min),
and crystalline 9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-
2,6-dichloropurine4c,5 (2) (83%, without chromatography)
was obtained. Comparable yields were obtained at 0 °C.
TMS-Cl (3.5 equiv) and BTEA-NO2 (1.5 equiv) with
powdered NaNO2 (5 equiv) gave 2 (86%) within 1 h. By
contrast, another method for nonaqueous chloro-dedi-
azoniation of 1 employed Cl2/TBN/CuCl in a strongly
exothermic reaction, and removal of colloidal material by
filtration was required prior to crystallization of 2.26
We found that 1 underwent efficient bromo-dediazo-
niation with TMS-Br and TBN. Competing redox with
nitrite anion and TMS-Br precluded the use of NaNO2.
Crystalline 2-bromo-6-chloropurine nucleoside 34c,5 (85%,
without chromatography) was obtained with TMS-Br
(9 equiv)/TBN (20 equiv)/CH2Br2/ambient temperature
within 1 h.
a
Reagents and conditions: (a) TMS-Cl/BTEA-NO2/CH2Cl2/0 °C
(63%); (b) TMS-Br/TBN/CH2Br2/0-5 °C (80%); (c) (i) NaOH/H2O,
(ii) XAD-4 (80%); (d) AcCl/BTEA-NO2/CH2Cl2/0 °C (71%); (e) SOCl2/
BTEA-NO2/-78 °C to ambient temperature (62%).
for 2 and 8.14 for 3). Products were separated (prepara-
tive TLC) and quantitated (UV), and their identities were
confirmed (MS). Treatment of 1 with TMS-X (9 equiv)
and TBN (20 equiv) in CH2X′2 at ambient temperature
for 3 h gave results summarized in Table 1.
Yields of (reagent and solvent)-derived halo-dediazo-
niation products were remarkably constant in both
reactions. Products in which halogen was derived from
TMS-X exceeded the solvent-derived halo-dediazoniation
products by a factor of ∼4.5. Nitrosyl halides decompose
by both homolytic and heterolytic pathways, which pre-
cludes mechanistic inferences regarding these halo-dedi-
azoniations. However, enhanced formation of products
derived from TMS-X versus those from solvent is analo-
gous to our results with TBN/(SbBr3 and/or BTEA-Br).5
Halo-dediazoniation with likely in situ generation of
NOCl or NOBr also was effective at C6 of acetylated
adenosine derivatives. Chloro-dediazoniation of the acid-
labile 3′,5′-di-O-acetyl-2′-deoxyadenosine30 (4) (TMS-Cl/
BTEA-NO2/CH2Cl2/0 °C/3 h) (Scheme 2) gave 9-(3,5-
di-O-acetyl-2-deoxy-â-D-erythro-pentofuranosyl)-6-chloro-
purine (5) (63%). Bromo-dediazoniation of 4 (TMS-Br/
TBN/CH2Br2/0-5 °C/5-7 h) proceeded more cleanly to
give the important intermediate 9-(3,5-di-O-acetyl-2-
deoxy-â-D-erythro-pentofuranosyl)-6-bromopurine5,9b (6)
(80%). Minor quantities (<15%) of 6-oxopurine deriva-
We determined ratios of halo-dediazoniation products
1
with competing halogen sources (TMS-X/CH2X′2) by H
NMR analysis of purified mixtures (H8 signals at δ 8.27
(22) Olah, G. A.; Ramaiah, P.; Sandford, G.; Orlinkov, A.; Prakash,
G. K. S. Synthesis 1994, 468-469.
(23) Gao, X.; J ones, R. A. J . Am. Chem. Soc. 1987, 109, 1275-1278.
(24) Barbero, M.; Degani, I.; Dughera, S.; Fochi, R. J . Org. Chem.
1999, 64, 3448-3453.
(25) Sigel, H.; Brintzinger, H. Helv. Chim. Acta 1965, 48, 433-437.
(26) Niiya, K.; Olsson, R. A.; Thompson R. D.; Silvia, S. K.; Ueeda,
M. J . Med. Chem. 1992, 35, 4557-4561.
(29) Robins, M. J .; Uznanski, B. Can. J . Chem. 1981, 59, 2601-
2607.
(30) van der Wenden, E. M.; von Frijtag Drabbe Ku¨nzel, J . K.;
Mathot, R. A. A.; Danhof, M.; IJ zerman, A. P.; Soudijn, W. J . Med.
Chem. 1995, 38, 4000-4006.
(27) Kim, Y. H.; Lee, C. H.; Chang, K. Y. Tetrahedron Lett. 1990,
31, 3019-3022.
(28) Gerster, J . F.; J ones, J . W.; Robins, R. K. J . Org. Chem. 1963,
28, 945-948.
J . Org. Chem, Vol. 68, No. 2, 2003 667

tives were produced with halo-dediazoniations at C6 as
previously noted.5 This bromo-dediazoniation of the acid-
sensitive 2′-deoxynucleoside (4 f 6) gave yields compa-
rable to those reported by Ve´liz and Beal for conversion
of protected inosine into a 6-bromopurine ribonucleoside
derivative with HMPT/(NBS or CBr4),9 whereas the latter
conditions caused glycosyl bond cleavage with a protected
2′-deoxyinosine.9b
Montgomery and Thomas31 identified polymerization
of 9-(â-D-ribofuranosyl)-6-chloropurine in aqueous base
(displacement of chloride by sugar hydroxyl groups), and
the enhanced SNAr reactivity of 6-bromopurine derivative
6 was recently noted.9b We deprotected 6 with alcoholic
ammonia at lowered temperatures,5 but accompanying
displacement of bromide by sugar hydroxyl groups can
occur. We investigated deacetylation with NaOH/H2O/
DME or Dowex 1 (OH-)/H2O/DME, but observed (TLC)
minor conversion of 6 to 2′-deoxyinosine and/or other
byproducts. Clean deprotection was effected by treatment
of 6 on a large surface (flask) with dilute NaOH/H2O (0.01
M, 5 equiv) followed by adsorption of the product on a
polystyrene resin (Amberlite XAD-4). Elution with ac-
etonitrile and flash evaporation of volatiles at lowered
temperatures gave the elusive 2′-deoxynucleoside 75
without significant side reactions. This procedure5 allows
isolation of other 6-halopurine nucleosides (>80% yields)
as clean powders.
We investigated acetyl chloride and BTEA-NO2 for in
situ generation of NOCl. It had been shown that different
ratios of nitrite, acetate, and substrate determined
proportions of NOCl, AcONO, and N2O3 in solution, and
these affected nitrosylation pathways.32 An approxi-
mately equimolar ratio of AcCl/BTEA-NO2 was effective
for chloro-dediazoniation of (2 or 6)-aminopurine nucleo-
sides. Treatment of 2′,3′,5′-tri-O-acetyladenosine33 (8)
with a 5-fold excess of AcCl/BTEA-NO2 in CH2Cl2 at 0-5
°C for 3 h gave 9-(2,3,5-tri-O-acetyl-â-D-ribofuranosyl)-
6-chloropurine5,28 (9) (71%). Yields were decreased with
larger quantities of AcCl or BTEA-NO2. Treatment of 1
under analogous conditions gave 2 (83%, without chro-
matography) (Scheme 1).
We also evaluated thionyl chloride for in situ genera-
tion of NOCl. Moss and Matsuo34 had treated alkane
diazoates with SOCl2 and obtained alkyl chlorides, N2,
and SO2. Our treatment of 8 with BTEA-NO2 (3 equiv)
in SOCl2 gave 9 (62%) plus the 6-oxo byproduct (2′,3′,5′-
tri-O-acetylinosine33). This procedure did not work well
at the gram scale, and extensive glycosyl bond cleavage
occurred with 8/TBN/SOCl2.
Exp er im en ta l Section
UV spectra were recorded with solutions in EtOH unless
otherwise indicated. 1H NMR spectra (Me4Si/CDCl3) were re-
corded at 200 MHz unless otherwise indicated. “Apparent” peak
shapes are in quotation marks when first-order splitting would
be more complex or when peaks were poorly resolved. Mass
spectra (MS) were determined with FAB (glycerol) or CI (CH4
or isobutane). Chemicals and solvents were of reagent quality.
CH2Cl2 and CH2Br2 were dried by reflux over and distillation
from CaH2. Benzyltriethylammonium nitrite (BTEA-NO2) was
prepared from BTEA-Cl by ion exchange [Dowex 1 × 2 (Cl-) +
1 M NaNO2/H2O (until no AgCl with 2% AgNO3/EtOH) f Dowex
1 × 2 (NO2-); BTEA-NO2/H2O solution was evaporated, EtOH/
toluene was added and evaporated in vacuo (5×), and the
granular solid was stored over P2O5 with protection from light].
Filtration chromatography was performed with silica gel (60-
200 mesh). TLC was performed with silica gel on aluminum
plates (CHCl3/MeOH, 95:5, unless otherwise indicated). “Cold”
or “cooled” indicates use of an ice-water bath. Substrates 1,29
4,30 and 833 were prepared as described.
9-(2,3,5-Tr i-O-a cetyl-â-D-r ibofu r a n osyl)-2,6-d ich lor op u -
r in e (2). Meth od A: TMS-Cl (1.14 mL, 978 mg, 9.0 mmol) was
added dropwise to a stirred solution of 1 (428 mg, 1.0 mmol) in
CH2Cl2 (30 mL) under N2. BTEA-NO2 (714 mg, 3.0 mmol) in
CH2Cl2 (10 mL) was added dropwise (1 drop/2 s) and the solution
was stirred at ambient temperature for 30 min (TLC). The
solution was diluted (CH2Cl2, 200 mL) and washed (5% NaHCO3/
H2O, 5 × 100 mL). The combined aqueous phase was extracted
(CH2Cl2, 2 × 100 mL), and the combined organic phase was dried
(MgSO4) and filtered. Volatiles were evaporated, Et2O was added
to and evaporated (3 ×) from the yellow oil, and the residue was
recrystallized (EtOH) to give 2 (373 mg, 83%) as pale-yellow
crystals with mp, UV, 1H NMR, and MS data as reported.5
Meth od B: TMS-Cl (444 µL, 380 mg, 3.50 mmol) was added
dropwise to a stirred mixture of 1 (428 mg, 1.0 mmol) and
powdered NaNO2 (345 mg, 5.0 mmol) in CH2Cl2 (25 mL) under
N2. BTEA-NO2 (357 mg, 1.5 mmol) in CH2Cl2 (5 mL) was added
dropwise (1 drop/s) and the solution was stirred at ambient
temperature for 1 h (TLC). The mixture was cooled for 15 min
and added dropwise to a cold, vigorously stirred mixture of
saturated NaHCO3/H2O (200 mL)//CH2Cl2 (200 mL). The aque-
ous layer was extracted (CH2Cl2), and the combined organic
phase was washed (H2O) and dried (MgSO4). Volatiles were
evaporated, and the yellow oil was recrystallized (BuOH) to give
2 (384 mg, 86%).
Meth od C: A solution of AcCl/CH2Cl2 (1 M, 2.5 mL, 2.5 mmol)
was added to dried CH2Cl2 (10 mL) under N2, and the solu-
tion was cooled for 15 min. BTEA-NO2 (535.5 mg, 2.25 mmol)
in CH2Cl2 (5 mL) was then added dropwise (1 drop/2 s) to the
cold, stirred solution of AcCl/CH2Cl2. A cold solution of 1 (214
mg, 0.5 mmol) in dried CH2Cl2 (5 mL) was then added dropwise
to the cooled, stirred AcCl/BTEA-NO2/CH2Cl2 solution (TLC,
hexanes/EtOAc, 3:7). Immediate workup and recrystallization
(method B) gave 2 (187 mg, 84%).
9-(2,3,5-Tr i-O-a cetyl-â-D-r ibofu r a n osyl)-2-br om o-6-ch lo-
r op u r in e (3). TMS-Br (1.2 mL, 1.38 g, 9.0 mmol) was added
dropwise to a stirred solution of 1 (428 mg, 1.0 mmol) in
CH2Br2 (30 mL) under N2. TBN (2.4 mL, 2.06 g, 20 mmol) was
added dropwise, and stirring was continued at ambient tem-
perature for 1 h (TLC). Workup (as for 2, method B) and
recrystallization (EtOH) gave 3 (416 mg, 85%) with mp and
spectral data as reported.5
9-(3,5-Di-O-a cetyl-2-d eoxy-â-D-er yth r o-p en tofu r a n osyl)-
6-ch lor op u r in e (5). TMS-Cl (3.81 mL, 3.26 g, 30 mmol) was
added dropwise to a cold (0 °C), stirred solution of 4 (335 mg,
1.0 mmol) in dried CH2Cl2 (30 mL) under N2. BTEA-NO2 (2.38
g, 10 mmol) in dried CH2Cl2 (10 mL) was added dropwise, the
flask was sealed (glass or Teflon stopper), and stirring was
continued for 1-2 h with cooling (TLC showed conversion of 4
f 5 plus a minor product). The solution was added dropwise to
a vigorously stirred mixture of cold, saturated NaHCO3/H2O (200
mL)//CH2Cl2 (200 mL). The organic layer was washed (H2O and
brine), dried (MgSO4), and filtered through 20 g of silica gel in
In summary, we have likely effected in situ generation
of NOCl/CH2Cl2 or NOBr/CH2Br2 from (Me3SiX or AcCl)
and (TBN or BTEA-NO2). Our procedures provide ef-
ficient halo-dediazoniation of protected (2 or 6)-aminopu-
rine nucleosides as well as the acid-sensitive 2′-deoxy-
nucleosides. These reactions are cost-effective and proceed
at or below ambient temperature with convenient re-
agents and standard laboratory equipment and condi-
tions.
(31) Montgomery, J . A.; Thomas, H. J . J . Org. Chem. 1971, 36,
1962-1967.
(32) Casado, J .; Castro, A.; Mosquera, M.; Prieto, M. F. R.; Tato, J .
V. Monatsh. Chem. 1984, 115, 669-682.
(33) Bredereck, H.; Martini, A. Chem. Ber. 1947, 80, 401-405.
(34) Moss, R. A.; Matsuo, M. Tetrahedron Lett. 1976, 1963-1966.
668 J . Org. Chem., Vol. 68, No. 2, 2003

a fritted glass funnel. Product was eluted (CH2Cl2/MeOH, 99.9:
0.1), and volatiles were evaporated to give 5 (223 mg, 63%) as a
pale-yellow solid foam: UV max 264 nm (ꢀ 9700), min 225 nm;
1H NMR δ 2.06, 2.13 (2 × s, 2 × 3H), 2.61-2.72 (ddd, J ) 14.2,
6.2, 2.8 Hz, 1H), 2.90 (“quint”, J ) 6.4 Hz, 1H), 4.31-4.43 (m,
3H), 5.42-5.44 (m, 1H), 6.47 (“t”, J ) 5.8 Hz, 1H), 8.30, 8.75 (2
× s, 2 × 1H); LRMS (CI) m/z 355/357 (MH+ [C14H1635/37ClN4O5]
) 355/357). Anal. Calcd for C14H15ClN4O5: C, 47.40; H, 4.26; N,
15.79. Found: C, 47.42; H, 4.35; N, 15.77.
9-(3,5-Di-O-a cetyl-2-d eoxy-â-D-er yth r o-p en tofu r a n osyl)-
6-br om op u r in e (6). TMS-Br (396 µL, 459 mg, 3.0 mmol) was
added dropwise to a cold (0 °C), stirred solution of 4 (335 mg,
1.0 mmol) in CH2Br2 (40 mL) under N2. TBN (2.4 mL, 2.06 g,
20 mmol) was added dropwise, the flask was sealed (glass or
Teflon stopper), and stirring was continued at 0-5 °C for 5-7 h
(TLC showed conversion of 4 f 6 plus a minor product). Workup
and evaporation of volatiles (as for 5) gave 65,9b (319 mg, 80%)
as a pale-yellow oil with UV and 1H NMR data as reported.5
HRMS (FAB) m/z 399.0313 (MH+ [C14H1679BrN4O5] ) 399.0304).
Anal. Calcd for C14H15BrN4O5‚0.5H2O: C, 41.18; H, 3.92; N,
13.73. Found: C, 41.00; H, 3.79; N, 13.79.
6-Br om o-9-(2-d e oxy-â-D -er yt h r o-p e n t ofu r a n osyl)p u -
r in e (7). Volatiles were evaporated from a solution of 6 (299
mg, 0.75 mmol) in CH2Cl2 (75 mL) in a 2000-mL flask to form a
thin film. NaOH/H2O (0.01 M, 380 mL, 3.8 mmol) was added,
and the solution was stirred at ambient temperature for 1-2 h
(maximum 2 h, byproduct formation occurs; TLC, CHCl3/MeOH,
9:1). Adsorption on Amberlite XAD-4 resin (145 mL) and
processing (see method 55) gave 7 (189 mg, 80%) as an off-white
solid. A sample was chromatographed (silica gel; CH2Cl2/
Me2CO, 1:1) to give 7 as a white powder with UV and 1H
NMR data as reported.5 HRMS (FAB) m/z 315.0106 (M+
[C10H1179BrN4O3] ) 315.0093). Anal. Calcd for C10H11BrN4O3:
C, 38.11; H, 3.52; N, 17.78. Found: C, 38.30; H, 3.60; N, 17.54.
9-(2,3,5-Tr i-O-a cetyl-â-D-r ibofu r a n osyl)-6-ch lor op u r in e
(9). Meth od A: BTEA-NO2 (595 mg, 2.5 mmol) in CH2Cl2 (5 mL)
was added dropwise to a cold (0 °C), stirred solution of AcCl (225
µL, 250 mg, 3.2 mmol) in CH2Cl2 (2.5 mL) under N2. A solution
of 8 (197 mg, 0.5 mmol) in CH2Cl2 (5 mL) was added dropwise
to the dark-orange solution, and stirring was continued at 0 °C
for 4 h (TLC showed conversion of 8 f 9 plus a minor product).
The solution was added dropwise to a vigorously stirred mixture
of cold, saturated NaHCO3/H2O (200 mL)//CH2Cl2 (200 mL). The
aqueous layer was extracted (CH2Cl2), and the combined organic
phase was dried (MgSO4) and filtered through silica gel (15 g)
in a fritted glass funnel. Product was eluted (CH2Cl2/MeOH,
99.9:0.1), and volatiles were evaporated to give 95 (147 mg,
71%) as a pale-yellow solid foam: UV (MeOH) max 264 nm
(ꢀ 9700), min 227 nm; LRMS (FAB) m/z 413/415 (MH+
[C16H1835/37ClN4O7] ) 413/415).
Meth od B: BTEA-NO2 (357 mg, 1.5 mmol) and 8 (196 mg,
0.5 mmol) were cooled (-78 °C) under N2. SOCl2 (15 mL) was
added dropwise with stirring, the dark-orange solution was
allowed to warm slowly to ambient temperature, and stirring
was continued for 4 h (TLC showed conversion of 8 f 9 plus a
minor product). The solution was added dropwise to a vigorously
stirred mixture of saturated Na2CO3/H2O (250 mL)//CH2Cl2 (250
mL). The organic layer was washed (H2O and brine), and the
combined aqueous phase was extracted (CH2Cl2). The combined
organic phase was dried (MgSO4) and volatiles were evaporated
to give 9 (128 mg, 62%) as a white solid foam.
Ack n ow led gm en t. We thank the Brigham Young
University gift funds for support and Mrs. J eanny K.
Gordon for assistance with the manuscript.
J O020625A
J . Org. Chem, Vol. 68, No. 2, 2003 669