Synthesis of N6,N6-dialkyladenine nucleosides using hexaalkylphosphorus triamides produced in situ

Article abstract of DOI:10.1002/ejoc.200800752

Reactions between secondary amines and phosphorus trichloride (PCl ₃) leads to the formation of the corresponding tris(dialkylamino) phosphanes or hexaalkylphosphorus triamides [HAPTs: (R₂N) ₃P]. Treatment of silyl-protected 2′-deoxyinosine and acetyl-protected inosine with the HAPTs produced in situ, together with iodine (I₂), leads to the formation of N⁶,N⁶- dialkyladenosine and -2′-deoxyadenosine. In some cases the stoichiometry of the amine is important, as is the use of a tertiary amine base. The effect of amine stoichiometry on the reaction between HAPT and I₂ has been studied by ³¹P{¹H} NMR spectroscopy. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200800752

FULL PAPER
DOI: 10.1002/ejoc.200800752
Synthesis of N6,N6-Dialkyladenine Nucleosides Using Hexaalkylphosphorus
Triamides Produced in Situ
Mahesh K. Lakshman,*[a] Asad Choudhury,[a][‡] Suyeal Bae,[a] Eliezer Rochttis,[a][‡]
Padmanava Pradhan,[a][‡‡] and Amit Kumar[a]
Dedicated to the memory of Dr. John W. Daly (1933–2008)[†]
Keywords: Inosine / Adenosine / Phosphorus triamide / Iodine / Amines
Reactions between secondary amines and phosphorus tri-
chloride (PCl3) leads to the formation of the corresponding
tris(dialkylamino)phosphanes or hexaalkylphosphorus tri-
amides [HAPTs: (R2N)3P]. Treatment of silyl-protected 2Ј-de-
oxyinosine and acetyl-protected inosine with the HAPTs pro-
duced in situ, together with iodine (I2), leads to the formation
of N6,N6-dialkyladenosine and -2Ј-deoxyadenosine. In some
cases the stoichiometry of the amine is important, as is the
use of a tertiary amine base. The effect of amine stoichiome-
try on the reaction between HAPT and I2 has been studied
by 31P{1H} NMR spectroscopy.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
the problems associated with access to electrophilic nucleo-
side precursors, non-aqueous diazotization methods have
been developed.[7] Nevertheless, newer and simpler methods
are needed for the synthesis of N-modified adenine nucleo-
sides.
Introduction
The physiological importance of adenine and modified
adenine nucleosides cannot be overstated. Because of this
high importance, the adenosine core has been the subject
of numerous structural modifications. The emergent com-
pounds have been studied for their wide-ranging effects,
such as modulation of A1, A2 and A3 receptors that control
important biofunctions,[1] and also as antiviral,[2] antican-
cer,[3] and antimalarial[4] pharmacophores. The classical
method for introducing modifications at the exocyclic
amino groups of adenine nucleosides is the SNAr displace-
ment, in which a leaving group at the purine 6-position is
displaced with suitable amines.[5]
One important limitation to the use of SNAr displace-
ment is the availability of suitable nucleoside derivatives,
many of which involve non-trivial synthesis. The most sig-
nificant problem in these processes is the cleavage of the
labile glycosidic bond. Although C-6 sulfonates can be pre-
pared from hypoxanthine nucleosides, competing N-1 and
O-6 sulfonylation occurs.[6] In order to circumvent some of
In this context, the combination of PPh3/I2/amine for the
introduction of morpholinyl, piperidinyl, and imidazolyl
groups at the 6-positions of purine nucleosides has been
reported.[8] This reaction presumably proceeds by formation
of [(Ph3P+I)I–], which reacts at the amide carbonyl group
of the hypoxanthine residue to afford a nucleoside phos-
phonium salt (Scheme 1). Expulsion of Ph3PO from this in-
termediate by the amine then results in the N-modified ade-
nine nucleoside. Along the same lines, treatment of hypo-
xanthine nucleosides with 1H-benzotriazol-1-yloxy-tris(di-
methylamino)phosphonium hexafluorophosphate (BOP)
and amines has been used to synthesize N-substituted ade-
nine nucleosides (Scheme 1).[9] An O-6 phosphonium salt
was proposed as the intermediate in these transformations,
which undergoes reaction with the amine by displacement
of hexamethylphosphoramide [tris(dimethylamino)phos-
phane oxide or HMPA].[9] We have recently analyzed the
mechanism of the reaction between the hypoxanthine core
and BOP and have confirmed that in the absence of an
amine, a nucleoside phosphonium salt is formed en route
to the O6-(benzotriazol-1-yl) nucleoside derivatives.[10]
These new nucleoside derivatives are excellent substrates for
modification at C-6. The chemical understanding gained
subsequently led to the development of a second-generation
synthesis of O6-(benzotriazol-1-yl)inosine and -2Ј-deoxy-
[a] Department of Chemistry, The City College and The City Uni-
versity of New York,
160 Convent Avenue, New York, NY 10031-9198, U.S.A.
Fax: +1-212-650-6107
E-mail: lakshman@sci.ccny.cuny.edu
[‡] Undergraduate research participant.
[‡‡] Manager, CCNY high-field NMR facility.
[†] Former laboratory chief (NIDDK) NIH, an exceptional scien-
tist and individual.
Supporting information for this article is available on the
WWW under http://www.eurjoc.org/ or from the author.
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N6,N6-Dialkyladenine Nucleosides
inosine through the use of PPh3/I2/HOBt,[11] as well as poly- pholinyl resonances were clearly visible, but there was an
mer-supported reagents for nucleoside modification.[12] As additional broad resonance at δ = 3.52 ppm. It was the
a result of our interest in understanding whether other presence of this signal that led us to doubt the purity of the
phosphanes can be utilized for modification of purine nu- product obtained.
cleosides at C-6, we became involved in the work described
here (Scheme 1).
Scheme 1. In situ formation of C-6 phosphonium derivatives and
their conversion into adenosine analogues.
Results and Discussion
In our initial experimentation with 3Ј,5Ј-bis-O-(tert-bu-
tyldimethylsilyl)-2Ј-deoxyinosine and the PPh3/I2 combina-
tion, we quickly discovered that the products were contami-
Scheme 2. Initial attempts to convert 1a into the C-6 morpholinyl
and dimethylamino derivatives.
nated by the Ph3P=O byproduct and that separation was
Since N,N-dimethyladenosine is formed in the reaction
between 2Ј,3Ј,5Ј-tri-O-acetylinosine, HMPT, and CX4 (X =
difficult. Scrutiny of the literature (supporting information
to ref.[8b]) indicated a similar problem. We expected that
Br or Cl),[15] we reasoned that the byproduct obtained in
amelioration of this problem could be attained through the
the reaction of 1a might be the N,N-dimethyl-2Ј-deoxyad-
enosine derivative 2a (Scheme 2). Competing formation of
use of a polymer-supported phosphane (Figure 1). To our
surprise, polymer-supported triphenylphosphane from two
dimethylamides in HMPT-mediated conversions of 2,2,2-
different sources[13] proved ineffective for the reaction, and
trihaloethyl esters into amides has been reported in the lit-
so we focused our attention on the family of the proaza-
erature.[16] Our next effort was therefore the synthesis of 2a
by simply replacing morpholine with Me2NH. This reaction
proceeded smoothly, affording the N,N-dimethyl-2Ј-deoxy-
adenosine derivative 2a in good yield. With this authentic
phosphatranes, which have proved to be interesting in other
reactions.[14] These compounds (Figure 1) also proved inef-
fective for conversions, with significant amounts of starting
materials left in many instances.
2a we were able to identify it as the byproduct formed along
with the morpholinyl derivative 2b in the initial reaction
with morpholine (pure 2a displays a broad resonance at δ
= 3.52 ppm that sharpens upon heating to 45 °C).
The two experiments above indicated that the HMPT/I2
combination could be used to produce effective activation
of the C-6 amide linkage with no problems associated with
Figure 1. Reagents that were initially tested.
product isolation and purification. However, a problem that
We then reasoned that increasing the ease of removal of remained to be solved was the competing formation of 2a.
the resultant phosphane oxide might allow circumvention This reaction could potentially be more significant if
of the problem. Tris(dimethylamino)phosphane (HMPT) amines with nucleophilicities lower than that of dimeth-
was not only expected to display enhanced nucleophilicity ylamine were to be used.
in its reaction with I2, but the formed HMPA should poten-
At this juncture we reasoned that specific tris(dialkyl-
tially be removable by washing with water. It was with this amino)phosphanes or hexaalkylphosphorus triamides
in mind that we embarked on subsequent experimentation, (HAPTs) could potentially be prepared from individual
the results of which are reported here.
amines and used in combination with I2 for activation of
On the basis of the above considerations, we initially sub- the C-6 amide carbonyl group. The ensuing nucleoside
jected 3Ј,5Ј-bis-O-(tert-butyldimethylsilyl)-2Ј-deoxyinosine phosphonium salts could then be subjected to subsequent
(1a) to treatment with HMPT/I2/morpholine/iPr2NEt (DI- displacement reactions with the amines used for forming
PEA) in toluene at 90 °C (Scheme 2). This reaction pro- the specific HAPT. In such an event, there would be only
ceeded smoothly and appeared clean by TLC. However, the one possible amine nucleophile in the reaction.
1H NMR spectrum of the product from this reaction was
interesting. The signals for the purine, saccharide, and mor- ino)- and tris(piperidino)phosphanes have been prepared by
In this context, HAPT derivatives such as tris(pyrrolid-
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M. K. Lakshman et al.
FULL PAPER
treatment of PCl3 with pyrrolidine and piperidine, respec- Table 1. Initial reactions of hydroxy-protected 2Ј-deoxyinosine and
tively.[17] In our experiments, we decided to conduct the en-
inosine with HAPT formed in situ, I2 and secondary amine.
tire operation – consisting of: (a) formation of the HAPT,
(b) activation of the C-6 amide, and (c) the amination reac-
tion – as a one-pot process without isolation of the individ-
ual tris(dialkylamino)phosphanes. We chose secondary
amines for the current work for two reasons: primary
amines could potentially form polymeric products with
PCl3, and reactions between HAPTs and primary amines
could lead to iminophosphoranes [(R2N)3P=NR].[18] With
secondary amines these potentially complicating problems
can be avoided. Finally, in initial experiments, we opted to
use the secondary amine itself as base. Our overall logic is
represented in Scheme 3. As can be seen from this scheme,
a total of 9 mol-equiv. of the amine would be needed per
mol-equiv. of PCl3.
Scheme 3. Plausible synthesis of adenine nucleosides through in
situ formation of HAPT [(R2N)3P].
[a] Yield is of isolated, purified products. [b] Reaction with a 2 
solution of Me2NH in THF.
On the basis of these considerations, the initial condi-
tions we opted for were 2.6–3.0 mol-equiv. PCl3/20–30 mol-
equiv. secondary amine/2.2 mol-equiv. I2 with toluene
(PhMe) as solvent. Under these conditions, 3Ј,5Ј-bis-O-
(tert-butyldimethylsilyl)-2Ј-deoxyinosine (1a) and 2Ј,3Ј,5Ј-
tri-O-acetylinosine (1b) were converted into a series of N,N-
disubstituted adenine derivatives (Table 1).
Despite the simplicity of the reaction and the overall rea-
sonable results obtained (Table 1), difficulties were faced in
some reactions. For example, the reaction involving pyrrol-
idine and 1b did not yield tractable product. This led us to
question the underlying reasons, one of which was the pos-
sible competitive formation of tetrakis(dialkylamino)phos-
phonium salts (Scheme 4). Such salts have been described
in the literature.[19]
Scheme 4. Plausible reaction of HAPT with I2 and subsequent con-
version into a tetrakis(dialkylamino)phosphonium salt.
In order to test this working hypothesis, we conducted
We interpreted this unexpected difficulty as follows. two experiments. In one case, piperidine (6 mol-equiv.) was
When excesses of fairly nucleophilic amines are utilized, carefully added at 0 °C to a well-stirred solution of PCl3 in
there can be two competing processes: (a) reaction of the anhydrous toluene. After the mixture had been brought to
nucleoside O-6 with the iodo-HAPT intermediate formed room temperature and stirred for about 30 min, I2 (1.2 mol-
from the reaction between the HAPT and I2, and (b) reac- equiv.) was added. The suspension was stirred at room tem-
tion between the amine and the iodo-HAPT intermediate perature for about 23 h and then filtered. The filtrate, when
produced. It is conceivable that in the present cases the tet- concentrated to dryness and analyzed by 31P{1H} NMR
rakis(dialkylamino)phosphonium species represents a dead- spectroscopy (Figure 2A), showed a predominant reso-
end intermediate that does not react at the O-6 atom of the nance at δ = 26.55 ppm (relative to 85% H3PO4 as external
nucleoside.
reference). A second experiment was conducted in a similar
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N6,N6-Dialkyladenine Nucleosides
manner with the exception that excess piperidine (30 mol- cies, the reaction with the nucleoside was conducted in the
equiv.) was used. 31P{1H} NMR analysis (Figure 2B) presence of a tertiary amine: iPr2NEt. The tertiary amine
showed an entirely different resonance at δ = 20.69 ppm.
not only acts as proton sponge but can also liberate free
secondary amine from the initially formed hydrochloride
salt for the final displacement step. A brief analysis of sol-
vents [toluene (PhMe), 1,2-dimethoxyethane (DME), and
CH2Cl2] was also conducted at this stage in order to opti-
mize the reactions. The results of these experiments are
shown in Table 2.
Table 2. Modified conditions tested for the synthesis of N,N-modi-
fied adenine nucleoside derivatives.
Figure 2. 31P{1H} NMR spectra (in CDCl3) of the reaction mixture
obtained with (A) PCl3 + piperidine (6 mol-equiv.) + I2 (1.2 mol-
equiv.), and (B) PCl3 + piperidine (30 mol-equiv.) + I2 (1.2 mol-
equiv.).
The results clearly indicated the formation of a new
phosphorus-containing species when a large excess of piper-
idine was present. To verify these results further, another
experiment was conducted (see scheme above Figure 3). A
toluene solution of commercially available bromotripyrrol-
idinophosphonium hexafluorophosphate (PyBroP) was ex-
posed to pyrrolidine (15 mol-equiv.) for about 20 h. The re-
action mixture was concentrated to dryness and analyzed
by 31P{1H} NMR spectroscopy. The initial 31P resonance
of PyBroP at δ = 27.93 ppm (Figure 3A) was replaced by
new resonances, with the major one at δ = 25.14 ppm (Fig-
ure 3B).
[a] Where reported, yield is of isolated, purified product. [b] Inc. =
incomplete reaction, about 80% 1b remained. [c] About 20% 1b
was still present on workup.
From Table 2 it is clear that in many cases complete reac-
tion can be attained in the presence of the tertiary amine.
As can be seen in Entries 1, 2, 4 and 5, complete reaction
with the nucleosides can be accomplished in the presence
of iPr2NEt but with only 18 mol-equiv. of the secondary
amine. DME proved to be a good solvent for the reaction
between 1b and pyrrolidine (Entry 5), a reaction that was
generally problematic/low-yielding.
As shown in Scheme 5, the imidazol-1-yl nucleoside 2e
can also be synthesized from 1a by use of PCl3 (3 mol-
equiv.)/imidazole (30 mol-equiv.)/I2 (2.2 mol-equiv.). The re-
action of 1a, which was conducted in 1,2-dichloroethane
(DCE) for better solubility of imidazole, proceeded to com-
pletion at room temperature in 72 h (63% yield). In contrast
to this successful reaction of disilyl derivative 1a, the corre-
sponding treatment of triacetate 1b was unsuccessful. We
then investigated the use of Et2NH as the nucleophile
(Scheme 5). In this case, surprisingly, successful reaction
was observed with the triacetate 1b (82% yield of 3e), but
Figure 3. 31P{1H} NMR spectra (in CDCl3) of (A) PyBroP and (B)
PyBroP + pyrrolidine (15 mol-equiv.). (The PF6 resonance is not
shown, but it appears at δ = –143.97 ppm in each case.).
–
Having gained a better understanding of the underlying the reaction with the disilyl derivative 1a was unsuccessful.
chemical processes involved in these transformations, we In contrast, O6-(benzotriazol-1-yl)-3Ј,5Ј-bis-O-(tert-butyldi-
decided to evaluate reactions that only involved stoichio- methylsilyl)-2Ј-deoxyinosine underwent smooth reaction
metric ratios of PCl3 and the secondary amine (PCl3/amine, with Et2NH, leading to the diethylamino product.[20]
1:6). This should in principle result in the formation of the
In order to determine what role if any the 2Ј-substituent
HAPT and amine hydrochloride. Then, in order to prevent plays, we conducted two additional experiments on the tri-
formation of the tetrakis(dialkylamino)phosphonium spe- silyl-protected inosine 1c (Scheme 5). We chose to conduct
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M. K. Lakshman et al.
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Conclusions
Although we and others have developed the use of Pd-
catalyzed amination methods for nucleoside modifica-
tion,[22] the SNAr displacement approach continues to play
an important role. In this paper we have studied the use of
tris(dialkylamino)phosphanes (HAPTs) generated in situ
for the conversion of protected inosine and 2Ј-deoxyinosine
derivatives into adenosine analogues. In several instances,
excess secondary amine can be used for the formation of
the HAPT, as well as as a base and nucleophile. However,
it appears that the formation of tetrakis(dialkylamino)phos-
phonium salts can become a competing process with the
strongly nucleophilic[23] and sterically less demanding
amines. Both silyl and acetyl protecting groups are suitable
for these reactions, although some differences in reactivity
Scheme 5. Synthesis of the C-6 imidazol-1-yl and diethylamino de-
rivatives. Conditions: (a) PCl3 (3 mol-equiv.)/imidazole (30 mol-
equiv.)/I2 (2.2 mol-equiv.), DCE, room temp.; (b) PCl3 (3 mol-
equiv.)/Et2NH (30 mol-equiv.)/I2 (2.2 mol-equiv.), PhMe, room
temp.; (c) PCl3 (3 mol-equiv.)/imidazole (30 mol-equiv.)/I2 (2.2 mol-
equiv.), DCE, 90 °C; (d) PCl3 (3 mol-equiv.)/Et2NH (30 mol- were observed. In a distantly related reaction, adenine has
equiv.)/I2 (2.2 mol-equiv.), DCE, 90 °C.
been produced in 16% yield upon heating of hypoxanthine
with (MeO)3P=O at 100 °C, followed by treatment with
NH4Cl/K2CO3 at 100 °C.[24] The leaving group proposed in
that reaction was dimethyl phosphate, whereas in the pres-
reactions with imidazole (with which 1b did not yield any
product) and Et2NH (with which 1a did not yield any prod-
uct). In these reactions, the imidazolyl product 4a was ob-
ent case a phosphoramide species is the likely leaving group.
In comparison of this method to our recently reported
chemistry using O6-(benzotriazol-1-yl)inosine deriva-
tained in 47% yield within 36 h, and the diethylamino prod-
tives,[10–12] this method offers a one-step conversion of hy-
uct 4b was obtained in 81% yield within 8 h. Although we
are unable to explain the protecting-group-based differences
poxanthine nucleosides into adenosine derivatives, and is
particularly useful with cyclic secondary amines. However,
in reactivity, there appears to be a link between the protect-
the previously reported procedure[10–12] is overall more ver-
ing group on the saccharide and reactivity at the purine. A
satile in terms of the diversity of nucleophiles that can be
similar effect has previously been observed in direct dis-
used for the C-6 functionalization.
placement reactions at the C-6 position in a purine nucleo-
side.[21]
Finally, we wanted to assess whether a relatively hindered
HAPT such as (Et2N)3P and I2 could be used to activate
Experimental Section
the C-6 amide carbonyl group with a second nucleophilic
amine performing the displacement (Scheme 6). Thus, PCl3 (250 µm), and column chromatographic purifications were per-
General: Thin layer chromatography was performed on silica plates
formed on silica gel (200–300 mesh). PhMe was distilled from Na,
DCE, iPr2NEt, and CH2Cl2 were distilled from CaH2, and anhy-
drous DME was obtained from a commercial supplier. All other
reagents were obtained from commercial sources and used without
further purification. The conventional numbering system for purine
nucleosides is used. 1H NMR spectra were recorded at 500 MHz
and were referenced to the residual protonated solvent. 31P{1H}
NMR spectra were recorded at 202 MHz and were referenced to
85% H3PO4 as external standard. Chemical shifts (δ) are reported
in parts per million, and coupling constants (J) are in Hertz. Some
representative synthetic procedures are given below. HRMS data is
reported for new compounds.
(3.0 mol-equiv.) was exposed to Et2NH (9 mol-equiv.) and
I2 (2.2 mol-equiv.) in DCE. Addition of either 1a or 1b,
imidazole (30 mol-equiv.) and heating at 90 °C then led to
formation of the imidazol-1-yl derivative from both 1a and
1b (67% and 86% product yields, respectively). These re-
sults are particularly relevant, as 1b did not undergo suc-
cessful reaction when the imidazole/PCl3/I2 combination
was used for amide carbonyl activation.
9-[2-Deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-6-
(morpholin-4-yl)purine (2b)[10]
With iPr2NEt and Stoichiometric Morpholine: PCl3 (43.6 µL,
0.499 mmol) and dry toluene (10.7 mL) were placed under nitrogen
in a clean, dry, round-bottomed flask containing a stirring bar, and
the mixture was cooled in an ice/water bath to ca. 5 °C. After the
mixture had been kept at this temperature for 20 min, morpholine
(0.26 mL, 2.99 mmol) was added slowly and dropwise, while the
temperature was maintained below 10 °C. The mixture was brought
to room temperature and was stirred for 30 min. I2 (126.7 mg,
0.499 mmol) was added to the reaction mixture, and the stirring
was continued at room temperature for 10 min. Disilyl-2Ј-deoxy-
Scheme 6. Synthesis of 6-imidazolyl derivatives from disilyl-pro-
tected 2Ј-deoxyinosine and triacetyl-protected inosine through use
of PCl3/Et2NH/I2 for amide activation.
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N6,N6-Dialkyladenine Nucleosides
inosine 1a (80.0 mg, 0.166 mmol) and DIPEA (0.26 mL, 1.49
mmol) were added, and the mixture was stirred at room tempera-
ture for 21 h. The reaction mixture was diluted with EtOAc
(50 mL) and washed with water (2 ϫ15 mL), followed by brine
(15 mL). The organic layer was separated and dried with Na2SO4,
and the solvents were evaporated to dryness. Chromatographic pu-
rification on silica gel with 20% acetone in hexanes afforded the
a clean, dry, round-bottomed flask containing a stirring bar, and
the mixture was cooled in an ice/water bath to ca. 5 °C. After the
mixture had been kept at this temperature for 15 min, morpholine
(0.32 mL, 3.66 mmol) was added slowly and dropwise, while the
temperature was maintained below 10 °C. The mixture was brought
to room temperature and was stirred for 30 min. I2 (154.4 mg,
0.609 mmol) was added to the reaction mixture, and the stirring
was continued at room temperature for 10 min. Inosine triacetate
morpholinyl nucleoside 2b (64.5 mg, 71% yield) as a viscous, pale-
1
yellow oil. H NMR (CDCl3): δ = 8.34 (s, 1 H, Ar-H), 8.02 (s, 1 1b (80.0 mg, 0.203 mmol) and iPr2NEt (0.32 mL, 1.84 mmol) were
H, Ar-H), 6.46 (t, J = 6.8 Hz, 1 H, 1Ј-H), 4.59 (app. dt, J = 6.2, added, and the mixture was stirred at room temperature for 24 h.
3.4 Hz, 1 H, 3Ј-H), 4.29 (br. s, 4 H, 2 OCH2), 4.00 (app. q, J =
The reaction mixture was diluted with EtOAc (50 mL) and washed
3.9 Hz, 1 H, 4Ј-H), 3.85–3.81 (m, 5 H, 2 NCH2 and 5Ј-H), 3.76 with water (2ϫ15 mL), followed by brine (15 mL). The organic
(dd, J = 11.2, 4.4 Hz, 1 H, 5Ј-H), 2.59 (app. dt, J = 13.6, 6.4 Hz, layer was separated and dried with Na2SO4, and the solvents were
1 H, 2Ј-H), 2.41 (ddd, J = 13.6, 5.8, 4.0 Hz, 1 H, 2Ј-H), 0.90 (s, 18 evaporated to dryness. Chromatographic purification on silica gel
H, tBu), 0.09, 0.07 (2 s, 12 H, SiCH3) ppm.
with 30% acetone in hexanes afforded the morpholinyl nucleoside
3b (60.9 mg, 65% yield) as a viscous, pale-yellow oil. 1H NMR
(CDCl3): δ = 8.34 (s, 1 H, Ar-H), 7.89 (s, 1 H, Ar-H), 6.21 (d, J =
5.5 Hz, 1 H, 1Ј-H), 5.89 (t, J = 5.4 Hz, 1 H, 2Ј-H), 5.64 (dd, J =
5.3, 4.6 Hz, 1 H, 3Ј-H), 4.43 (dd, J = 4.6, 2.0 Hz, 1 H, 4Ј-H), 4.42
(dd, J = 12.8, 3.2 Hz, 1 H, 5Ј-H), 4.36 (dd, J = 12.8, 5.2 Hz, 1 H,
5Ј-H), 4.29 (br. s, 4 H, 2 OCH2), 3.82 (t, J = 4.9 Hz, 4 H, 2 NCH2),
2.14, 2.13, 2.07 (3 s, 9 H, OCOCH3) ppm.
With Excess Morpholine: PCl3 (40.8 µL, 0.468 mmol) and dry tolu-
ene (4.0 mL) were placed under nitrogen in a clean, dry, round-
bottomed flask containing a stirring bar, and the mixture was co-
oled in an ice bath to 0 °C. After the mixture had been kept at
this temperature for 5 min, morpholine (0.41 mL, 4.68 mmol) was
added slowly and dropwise, and a white precipitate formed. The
mixture was brought to room temperature and was stirred for
30 min. I2 (87.1 mg, 0.343 mmol) was added, followed by the ad-
dition of disilyl-2Ј-deoxyinosine 1a (75.0 mg, 0.156 mmol). The
mixture was heated at 90 °C for 6 h. The orange-colored reaction
mixture was diluted with EtOAc and washed with water. The or-
ganic layer was separated and dried with Na2SO4, and the solvents
were evaporated to dryness. Chromatographic purification on silica
gel with 20% acetone in hexanes afforded the morpholinyl nucleo-
side 2b (59.2 mg, 69% yield).
With Excess Morpholine: PCl3 (42.7 µL, 0.489 mmol) and dry tolu-
ene (6 mL) were placed under nitrogen in a clean, dry, round-bot-
tomed flask containing a stirring bar, and the mixture was cooled
in an ice bath to 0 °C. After the mixture had been kept at this
temperature for 5 min, morpholine (0.33 mL, 3.77 mmol) was
added slowly and dropwise, and a white precipitate formed. The
mixture was brought to room temperature and was stirred for
30 min. I2 (0.106 mg, 0.418 mmol) was added, followed by the ad-
dition of inosine triacetate 1b (75.0 mg, 0.19 mmol). The mixture
was heated at 90 °C for 2 h 10 min. The reaction mixture was di-
luted with EtOAc and washed with water. The organic layer was
separated and dried with Na2SO4, and the solvents were evaporated
to dryness. Chromatographic purification on silica gel with 5%
MeOH in CH2Cl2 gave a slightly impure product that was rechro-
matographed with 20% acetone in CH2Cl2 to yield the morpholinyl
nucleoside 3b (62.7 mg, 71% yield).
9-[2-Deoxy-3,5-bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-6-
(imidazol-1-yl)purine (2e)[10]
With Et2NH and Imidazole: PCl3 (40.8 µL, 0.468 mmol) and dry
DCE (4.0 mL) were placed under nitrogen in a clean, dry, round-
bottomed flask containing a stirring bar, and the mixture was co-
oled in an ice bath to 0 °C. After the mixture had been kept at this
temperature for 10 min, Et2NH (0.144 mL, 1.404 mmol) was added
slowly and dropwise, while the temperature was maintained at 0 °C,
during which a white precipitate formed. The mixture was brought
to room temperature and was stirred for 30 min, during which time
the precipitate appeared to dissolve. I2 (87.1 mg, 0.343 mmol) was
added to the reaction mixture, and the stirring was continued at
room temperature for 10 min. Disilyl-2Ј-deoxyinosine 1a (75.0 mg,
0.156 mmol) and imidazole (318.6 mg, 4.68 mmol) were added, and
the mixture was stirred at 90 °C for 2 h. The reaction mixture was
diluted with CH2Cl2 (30 mL) and washed with water (2ϫ15 mL),
followed by brine (15 mL). The organic layer was separated and
dried with Na2SO4, and the solvents were evaporated to dryness.
Chromatographic purification on silica gel with 60% EtOAc in hex-
anes afforded the imizadolyl nucleoside 2e (56.0 mg, 67% yield) as
a colorless oil. 1H NMR (CDCl3): δ = 9.20 (s, 1 H, Ar-H), 8.80 (s,
1 H, Ar-H), 8.46 (s, 1 H, Ar-H), 8.40 (s, 1 H, Ar-H), 7.27 (s, 1 H,
Ar-H), 6.55 (t, J = 6.0 Hz, 1 H, 1Ј-H), 4.59 (app. dt, J = 5.6, 4.2 Hz,
1 H, 3Ј-H), 4.06 (app. q, J = 4.2 Hz, 1 H, 4Ј-H), 3.91 (dd, J = 11.4,
3.9 Hz, 1 H, 5Ј-H), 3.80 (dd, J = 11.4, 2.9 Hz, 1 H, 5Ј-H), 2.65
(app. dt, J = 12.7, 6.0 Hz, 1 H, 2Ј-H), 2.51 (ddd, J = 12.7, 5.9,
2.3 Hz, 1 H, 2Ј-H), 0.92, 0.91 (2 s, 18 H, tBu), 0.11, 0.10 (2 s, 12
H, SiCH3) ppm.
2Ј,3Ј,5Ј-Tri-O-acetyl-N6,N6-diethyladenosine (3e):[21,25] PCl3
(40.8 µL, 0.468 mmol) and dry toluene (4.0 mL) were placed under
nitrogen in a clean, dry, round-bottomed flask containing a stirring
bar, and the mixture was cooled in an ice/water bath to 10 °C. After
the mixture had been kept at this temperature for 10 min, Et2NH
(0.59 mL, 5.70 mmol) was added dropwise, while the temperature
was maintained at 10 °C. A very viscous mixture was formed, and
the stirring was continued at room temperature for 30 min. I2
(106.1 mg, 0.418 mmol) was added to the reaction mixture, and the
stirring was continued for 10 min. Inosine triacetate 1b (75.0 mg,
0.190 mmol) was added, and the mixture was stirred at room tem-
perature for 4 h. The reaction mixture was diluted with CH2Cl2
(30 mL) and washed with water (2 ϫ15 mL), followed by brine
(15 mL). The organic layer was separated and dried with Na2SO4,
and the solvents were evaporated to dryness. Chromatographic pu-
rification on silica gel with 70% EtOAc in hexanes afforded 3e
(69.7 mg, 81% yield) as a light yellow, viscous liquid. 1H NMR
(CDCl3): δ = 8.32 (s, 1 H, Ar-H), 7.87 (s, 1 H, Ar-H), 6.21 (d, J =
5.7 Hz, 1 H, 1Ј-H), 5.90 (t, J = 5.6 Hz, 1 H, 2Ј-H), 5.65 (dd, J =
5.5, 4.2 Hz, 1 H, 3Ј-H), 4.43 (dd, J = 4.2, 2.0 Hz, 1 H, 4Ј-H), 4.41
(dd, J = 12.7, 3.3 Hz, 1 H, 5Ј-H), 4.36 (dd, J = 12.7, 5.4 Hz, 1 H,
5Ј-H), 4.17–3.72 (br. s, 4 H, CH2), 2.13 (s, 6 H, OCOCH3), 2.06 (s,
3 H, OCOCH3), 1.28 (t, J = 6.9 Hz, 6 H, CH3) ppm.
9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-6-(morpholin-4-yl)purine
(3b)[8b,21]
With iPr2NEt and Stoichiometric Morpholine: PCl3 (53.1 µL,
0.61 mmol) and dry toluene (10 mL) were placed under nitrogen in
Eur. J. Org. Chem. 2009, 152–159
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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157

M. K. Lakshman et al.
FULL PAPER
9-(2,3,5-Tri-O-acetyl-β-
D
-ribofuranosyl)-6-(imidazol-1-yl)purine NMR (CDCl3): δ = 8.29 (s, 1 H, Ar-H), 7.94 (s, 1 H, Ar-H), 6.00
(d, J = 5.5 Hz, 1 H, 1Ј-H), 4.79 (app. t, J = 5.0 Hz, 1 H, 2Ј-H),
(3f)[8b,21]
4.33 (app. t, J = 3.7 Hz, 1 H, 3Ј-H), 4.10 (app. q, J = 4.5, 3.5 Hz,
With Et2NH and Imidazole: PCl3 (42.7 µL, 0.571 mmol) and dry
DCE (6.0 mL) were placed under nitrogen in a clean, dry, round-
bottomed flask containing a stirring bar, and the mixture was co-
oled in an ice bath to 0 °C. After the mixture had been kept at this
temperature for 10 min, Et2NH (0.18 mL, 1.74 mmol) was added
slowly and dropwise, while the temperature was maintained at 0 °C,
and a white precipitate formed. The mixture was brought to room
temperature and was stirred for 30 min, during which time the pre-
cipitate appeared to dissolve. I2 (106.2 mg, 0.418 mmol) was added
to the reaction mixture, and the stirring was continued at room
temperature for 10 min. Inosine triacetate 1b (75.0 mg,
0.190 mmol) and imidazole (388.4 mg, 5.71 mmol) were added, and
the mixture was stirred at 90 °C for 5 h. The reaction mixture was
diluted with CH2Cl2 (30 mL) and washed with water (2ϫ15 mL),
followed by brine (15 mL). The organic layer was separated and
dried with Na2SO4, and the solvents were evaporated to dryness.
Chromatographic purification on silica gel with EtOAc afforded 3f
1 H, 4Ј-H), 4.02 (dd, J = 11.5, 5.0 Hz, 1 H, 5Ј-H), 4.02–3.92 (br. s,
4 H, CH2), 3.76 (dd, J = 11.5, 3.5 Hz, 1 H, 5Ј-H), 1.27 (t, J =
7.0 Hz, 6 H, CH3), 0.93, 0.78 (2 s, 27 H, tBu), 0.10, –0.05, –0.02
(3 s, 18 H, SiCH3) ppm. HRMS: calcd. for C32H63N5O4Si3 [M]+
665.4188; found 665.4201.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H NMR spectra of compounds 2a–e, 3a–f, 4b, and
3Ј,5Ј-bis-O-(tert-butyldimethylsilyl)-N6,N6-diethyl-2Ј-deoxyadenos-
ine.
Acknowledgments
This work was partially supported by the National Science Founda-
tion (grant CHE-0640417) and a Professional Staff Congress
CUNY-39 award. E. R. was supported through Research Experi-
ence for Undergraduates supplements from the National Science
Foundation (grant CHE-0314326). Acquisition of a mass spec-
trometer was funded by the National Science Foundation (grant
CHE-0520963). Infrastructural support was provided by the
National Institutes of Health Research Centers in Minority Insti-
tutions (grant G12 RR03060).
1
(76.0 mg, 86% yield) as a light-brown syrup. H NMR (CDCl3): δ
= 9.17 (s, 1 H, Ar-H), 8.79 (s, 1 H, Ar-H), 8.39 (s, 1 H, Ar-H), 8.27
(s, 1 H, Ar-H), 7.25 (s, 1 H, Ar-H), 6.27 (d, J = 5.3 Hz, 1 H, 1Ј-
H), 5.97 (t, J = 5.4 Hz, 1 H, 2Ј-H), 5.67 (t, J = 5.3 Hz, 1 H, 3Ј-H),
4.49 (app. q, J = 4.1 Hz, 1 H, 4Ј-H), 4.47 (dd, J = 12.7, 3.1 Hz, 1
H, 5Ј-H), 4.40 (dd, J = 12.7, 4.3 Hz, 1 H, 5Ј-H), 2.17, 2.14, 2.09 (3
s, 9 H, OCOCH3) ppm.
[1] For some examples, see: a) T. D. Ashton, S. P. Baker, S. A.
Hutchinson, P. J. Scammells, Bioorg. Med. Chem. 2008, 16,
1861–1873; b) L. Cappellacci, P. Franchetti, P. Vita, R. Petrelli,
A. Lavecchia, B. Costa, F. Spinetti, C. Martini, K.-N. Klotz,
M. Grifantini, Bioorg. Med. Chem. 2008, 16, 336–353; c) T. D.
Ashton, K. M. Aumann, S. P. Baker, C. H. Schiesser, P. J.
Scammells, Bioorg. Med. Chem. Lett. 2007, 17, 6779–6784; d)
L. K. Jeong, S. A. Choe, P. Gunaga, H. O. Kim, H. W. Lee,
S. K. Lee, D. K. Tosh, A. Patel, K. K. Palaniappan, Z.-G. Gao,
K. A. Jacobson, H. R. Moon, J. Med. Chem. 2007, 50, 3159–
3162; e) H. Adachi, K. K. Palaniappan, A. A. Ivanov, N.
Bergman, Z.-G. Gao, K. A. Jacobson, J. Med. Chem. 2007, 50,
1810–1827; f) R. Volpini, D. Dal Ben, C. Lambertucci, S. Taffi,
S. Vittori, K.-N. Klotz, G. Cristalli, J. Med. Chem. 2007, 50,
1222–1230; g) M. P. Gonzalez, C. Teran, M. Teijeira, A. M.
Helguera, Curr. Med. Chem. 2006, 13, 2253–2266.
[2] For some examples, see: a) M. A. Peterson, P. Ke, H. Shi, C.
Jones, B. R. McDougall, W. E. Robinson Jr, Nucleosides Nu-
cleotides Nucleic Acids 2007, 26, 499–519; b) S. Zhou, J. Zem-
licka, E. R. Kern, J. C. Drach, Nucleosides Nucleotides Nucleic
Acids 2007, 26, 231–243; c) S. Zhou, E. R. Kern, E. Gullen, Y.-
C. Cheng, J. C. Drach, S. Tamiya, H. Mitsuya, J. Zemlicka, J.
Med. Chem. 2006, 49, 6120–6128; d) Y.-h. Koh, J. H. Shim,
J. Z. Wu, W. Zhong, Z. Hong, J.-L. Girardet, J. Med. Chem.
2005, 48, 2867–2875; e) S. F. Wnuk, E. Lewandowska, P. R.
Sacasa, L. N. Crain, J. Zhang, R. T. Borchardt, E. De Clercq,
J. Med. Chem. 2004, 47, 5251–5257; f) D. F. Smee, R. W.
Sidwell, Nucleosides Nucleotides Nucleic Acids 2004, 23, 375–
383; g) M. I. Nieto, O. Caamano, F. Fernandez, M. Gomez, J.
Balzarini, E. De Clercq, Nucleosides Nucleotides Nucleic Acids
2002, 21, 243–255.
6-(Imidazol-1-yl)-9-[2,3,5-tri-O-(tert-butyldimethylsilyl)-β-D-ribofu-
ranosyl]purine (4a)
With Excess Imidazole: PCl3 (33.0 µL, 0.368 mmol) and dry DCE
(4.0 mL) were placed under nitrogen in a clean, dry, round-bot-
tomed flask containing a stirring bar, and the mixture was cooled
in an ice bath to 0 °C. After the mixture had been kept at this
temperature for 10 min, imidazole (249 mg, 3.66 mmol) was added,
and a white precipitate formed. The mixture was brought to room
temperature and was stirred for 30 min. I2 (68.1 mg, 0.268 mmol)
was added to the reaction mixture, and the stirring was continued
at room temperature for 10 min. Trisilylinosine 1c (75.0 mg,
0.122 mmol) was added, and the mixture was stirred at 90 °C for
36 h. The reaction mixture was diluted with CH2Cl2 (30 mL) and
washed with water (2ϫ15 mL), followed by brine (15 mL). The
organic layer was separated and dried with Na2SO4, and the sol-
vents were evaporated to dryness. Chromatographic purification on
silica gel with 25% EtOAc in hexanes afforded 4a (38.0 mg, 47%
yield) as a white solid. Characterization of this product has been
reported previously.[26]
2Ј,3Ј,5Ј-Tri-O-(tert-butyldimethylsilyl)-N6,N6-diethyl-2Ј-deoxyaden-
osine (4b): PCl3 (33.0 µL, 0.368 mmol) and dry toluene (4.0 mL)
were placed under nitrogen in a clean, dry, round-bottomed flask
containing a stirring bar, and the mixture was cooled in an ice/
water bath to 10 °C. After the mixture had been kept at this tem-
perature for 10 min, Et2NH (0.38 mL, 3.67 mmol) was added drop-
wise, while the temperature was maintained at 10 °C. A very vis-
cous mixture was formed, and the stirring was continued at room
temperature for 30 min. I2 (68.1 mg, 0.268 mmol) was added to the
reaction mixture, and the stirring was continued for 10 min. Trisil-
ylinosine 1c (75.0 mg, 0.123 mmol) was added, and the mixture was
stirred at 90 °C for 8 h. The reaction mixture was diluted with
CH2Cl2 (30 mL) and washed with water (2ϫ15 mL), followed by
brine (15 mL). The organic layer was separated and dried with
Na2SO4, and the solvents were evaporated to dryness. Chromato-
graphic purification on silica gel with 20% EtOAc in hexanes af-
forded 4b (67.0 mg, 81% yield) as a light-yellow, viscous oil. 1H
[3] For some examples, see: a) S. Sinha, R. Srivastava, B. Prusty,
B. C. Das, R. K. Singh, Nucleosides Nucleotides Nucleic Acids
2007, 26, 773–777; b) E.-J. Lee, H.-Y. Min, H.-J. Chung, E.-J.
Park, D.-H. Shin, L. S. Jeong, S. K. Lee, Biochem. Pharmacol.
2005, 70, 918–924; c) M. Panjehpour, F. Karami-Tehrani, Int.
J. Biochem. Cell Biol. 2004, 36, 1502–1509; d) D. A. Carson,
D. B. Wasson, E. Beutler, Proc. Natl. Acad. Sci. USA 1984, 81,
2232–2236; e) L. F. Christensen, A. D. Broom, M. J. Robins,
A. Bloch, J. Med. Chem. 1972, 15, 735–739.
[4] For some examples, see: a) C. Herforth, J. Wiesner, P. Heidler,
S. Sanderbrand, S. Van Calenbergh, H. Jomaa, A. Link, Bio-
158
www.eurjoc.org
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 152–159

N6,N6-Dialkyladenine Nucleosides
org. Med. Chem. 2004, 12, 755–762; b) P. H. Heidler, C. Her-
forth, A. Link, Nucleosides Nucleotides Nucleic Acids 2003, 22,
977–979; c) C. Herforth, J. Wiesner, S. Franke, A. Golisade, H.
Jomaa, A. Link, J. Comb. Chem. 2002, 4, 302–314.
[5] For some representative examples on the use of SNAr chemis-
try, see: a) L. S. Jeong, D. Z. Jin, H. O. Kim, D. H. Shin, H. R.
Moon, P. Gunaga, M. W. Chun, Y.-C. Kim, N. Melman, Z.-G.
Gao, K. A. Jacobson, J. Med. Chem. 2003, 46, 3775–3777; b)
Y. Choi, C. George, P. Strazewski, V. E. Marquez, Org. Lett.
2002, 4, 589–592; c) S. Chaturvedi, M. K. Lakshman, Carcino-
genesis 1996, 17, 2747–2752; d) S. J. Kim, H. K. Jajoo, H.-Y.
Kim, L. Zhou, P. Horton, C. M. Harris, T. M. Harris, Bioorg.
Med. Chem. 1995, 3, 811–822; e) V. Samano, R. W. Miles, M. J.
Robins, J. Am. Chem. Soc. 1994, 116, 9331–9332; f) M. Laksh-
man, R. E. Lehr, Tetrahedron Lett. 1990, 31, 1547–1550; g) R.
Cosstick, M. E. Douglas, J. Chem. Soc. Perkin Trans. 1 1991,
1035–1040; h) J. F. Gerster, R. K. Robins, J. Am. Chem. Soc.
1965, 87, 3752–3759; i) Nucleosides and Nucleotides (Ed.: L. B.
Townsend), Plenum Press, New York, 1988, vol. 2, chapter 2,
pp. 113–281.
Frech, Angew. Chem. 2007, 119, 6634–6637; c) D. J. Dellinger,
D. M. Sheehan, N. K. Christensen, J. G. Lindberg, M. H. Ca-
ruthers, J. Am. Chem. Soc. 2003, 125, 940–950; d) L. A. Hus-
sain, A. J. Elias, M. N. S. Rao, Tetrahedron Lett. 1988, 29,
5983–5986.
a) I. D. Cunningham, M. Woodfall, J. Org. Chem. 2005, 70,
9248–9256; b) T. Rodima, V. Mäemets, I. Koppel, J. Chem. Soc.
Perkin Trans. 1 2000, 2637–2644.
[18]
[19]
[20]
a) R. Schwesinger, R. Link, P. Wenzl, S. Kossek, Chem. Eur. J.
2006, 12, 438–445; b) R. Schwesinger, R. Link, P. Wenzl, S.
Kossek, M. Keller, Chem. Eur. J. 2006, 12, 429–437.
6
6
3Ј,5Ј-Bis-O-(tert-butyldimethylsilyl)-N ,N -diethyl-2Ј-deoxyad-
enosine: O6-(Benzotriazol-1-yl)-2Ј,3Ј-bis-O-(tert-butyldimethyl-
silyl)-2Ј-deoxyinosine (59.8 mg, 0.100 mmol) and Et2NH
(41.4 µL, 0.400 mmol) in dry DME (1.0 mL) were placed in a
clean, dry reaction vial containing a stirring bar. The reaction
mixture was flushed with nitrogen and was stirred at room tem-
perature for 23 h. The reaction mixture was directly loaded
onto a bed of SiO2, and the product was eluted with EtOAc.
The silylated N6,N6-diethyl-2Ј-deoxyadenosine derivative was
obtained as a clear gum (54.7 mg, quantitative yield). Rf (20%
[6] C. R. Allerson, S. L. Chen, G. L. Verdine, J. Am. Chem. Soc.
1997, 119, 7423–7433.
[7] a) P. Francom, M. J. Robins, J. Org. Chem. 2003, 68, 666–669;
b) P. Francom, Z. Janeba, S. Shibuya, M. J. Robins, J. Org.
Chem. 2002, 67, 6788–6796.
1
EtOAc in hexanes) = 0.40. H NMR (500 MHz, CDCl3): δ =
8.32 (s, 1 H, Ar-H), 7.96 (s, 1 H, Ar-H), 6.44 (t, J = 6.6 Hz, 1
H, 1Ј-H), 4.60 (m, 1 H, 3Ј-H), 4.00 (m, 1 H, 4Ј-H), 3.98 (br.
signal, 4 H, CH2), 3.81 (dd, J = 11.1, 4.8 Hz, 1 H, 5Ј-H), 3.75
(dd, J = 11.1, 3.5 Hz, 1 H, 5Ј-H), 2.63 (m, 1 H, 2Ј-H), 2.40
(ddd, J = 13.1, 6.0, 3.6 Hz, 1 H, 2Ј-H), 1.28 (t, J = 7.0 Hz, 6
H, CH3), 0.91, 0.90 (2 s, 18 H, tBu), 0.10, 0.07, 0.06 (3 s, 12 H,
SiCH3) ppm. HRMS: calcd. for C26H49N5O3Si2 [M]+ 535.3374;
found 535.3378.
E. A. Véliz, P. A. Beal, J. Org. Chem. 2001, 66, 8592–8598.
For a review, see: M. K. Lakshman, Curr. Org. Synth. 2005, 2,
83–112.
[8] a) J. Zlatko, X. Lin, M. J. Robins, Nucleosides Nucleotides Nu-
cleic Acids 2004, 23, 137–147; b) X. Lin, M. J. Robins, Org.
Lett. 2000, 2, 3497–3499.
[9] Z.-K. Wan, E. Binnun, D. P. Wilson, J. Lee, Org. Lett. 2005, 7,
5877–5880.
[10] S. Bae, M. K. Lakshman, J. Am. Chem. Soc. 2007, 129, 782–
789.
[11] S. Bae, M. K. Lakshman, J. Org. Chem. 2008, 73, 1311–1319.
[12] S. Bae, M. K. Lakshman, J. Org. Chem. 2008, 73, 3707–3713.
[13] Polymer-supported phosphanes from Lancaster and Strem
were tested.
[21]
[22]
[23] F. Brotzel, Y. C. Chu, H. Mayr, J. Org. Chem. 2007, 72, 3679–
3688.
[14] a) J. G. Verkade, P. B. Kisanga, Aldrichim. Acta 2004, 37, 3–14;
b) J. G. Verkade, P. B. Kisanga, Tetrahedron 2003, 59, 7819–
7858.
[15] E. A. Véliz, P. A. Beal, Tetrahedron Lett. 2000, 41, 1695–1697.
[16] J. J. Hans, R. W. Driver, S. D. Burke, J. Org. Chem. 1999, 64,
1430–1431.
[24] I. M. Lagoja, P. Herdewijn, Chem. Biodiv. 2005, 2, 923–927.
[25] T. Endo, J. Zemlicka, J. Org. Chem. 1979, 44, 3652–3656.
[26] a) P. Lagisetty, L. M. Russon, M. K. Lakshman, Angew. Chem.
Int. Ed. 2006, 45, 3660–3663; b) P. Lagisetty, L. M. Russon,
M. K. Lakshman, Angew. Chem. 2006, 118, 3742–3745.
Received: July 30, 2008
[17] a) J. L. Bolliger, O. Blacque, C. M. Frech, Angew. Chem. Int.
Ed. 2007, 46, 6514–6517; b) J. L. Bolliger, O. Blacque, C. M.
Published Online: November 25, 2008
Eur. J. Org. Chem. 2009, 152–159
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