A simple synthesis of nitriles from aldoximes

Article abstract of DOI:10.1021/jo900100v

Easily synthesized aldoximes have been converted to the corresponding nitriles under very mild conditions by a simple reaction with lH-benzotriazol-l-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) and DBU in CH₂CI₂, THF, or DMF. As an alternative reagent that eliminates the formation of hexamethylphosphoramide as a byproduct, use of lH-benzotriazol-lyl-4-methylbenzenesulfonate (Bt-OTs) and DBU was investigated. Reactions with this reagent also proceeded smoothly and in good yields, although in one case N-sulfonylation was observed. An attempt to gain mechanistic insight into the BOP-mediated reaction has been made using ³¹P{ ¹H} NMR. However, no phosphorus-bearing intermediate could be readily observed. Finally, the method has been applied to the synthesis of an antiviral 4'-cyano adenosine analogue from a commercial precursor using a single saccharide protecting group.

Full text of DOI:10.1021/jo900100v

A Simple Synthesis of Nitriles from Aldoximes1
Manish K. Singh and Mahesh K. Lakshman*
Department of Chemistry, The City College and The City UniVersity of New York, 160 ConVent AVenue,
New York, New York 10031-9198
lakshman@sci.ccny.cuny.edu
ReceiVed January 15, 2009
Easily synthesized aldoximes have been converted to the corresponding nitriles under very mild
conditions by a simple reaction with 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (BOP) and DBU in CH2Cl2, THF, or DMF. As an alternative reagent that
eliminates the formation of hexamethylphosphoramide as a byproduct, use of 1H-benzotriazol-1-
yl-4-methylbenzenesulfonate (Bt-OTs) and DBU was investigated. Reactions with this reagent also
proceeded smoothly and in good yields, although in one case N-sulfonylation was observed. An
attempt to gain mechanistic insight into the BOP-mediated reaction has been made using 31P{1H}
NMR. However, no phosphorus-bearing intermediate could be readily observed. Finally, the method
has been applied to the synthesis of an antiviral 4′-cyano adenosine analogue from a commercial
precursor using a single saccharide protecting group.
Introduction
dehydration of aldoximes remains a convenient route.4 Some
recently reported methods for aldoxime dehydration involve
The cyano moiety is a highly important one not only due
to its synthetic value as precursor to other functionalities but
also due to its presence in a variety of natural products,
pharmaceuticals, and novel materials. Although a plethora
of methods are known for access to the cyano functionality,2,3
(3) Larock, R. C. ComprehensiVe Organic Transformations, 2nd ed.; Wiley:
New York, 1999.
(4) For some examples, see: (a) Sharghi, H.; Sarvari, M. H. Synthesis 2003,
243–246. (b) Lingaiah, N.; Narender, R. Synth. Commun. 2002, 32, 2391–2394.
(c) Yang, S. A.; Chang, S. Org. Lett. 2001, 3, 4209–4211. (d) Ghiaci, M.;
Bakhtiari, K. Synth. Commun. 2001, 31, 1803–1807. (e) Desai, D. G.; Swami,
S. S.; Mahale, G. D. Synth. Commun. 2000, 30, 1623–1625. (f) Jose, B.; Sulatha,
M. S.; Pillai, P. M.; Prathapan, S. Synth. Commun. 2000, 30, 1509–1514. (g)
Chaudhari, S. S.; Akamanchi, K. G. Synth. Commun. 1999, 29, 1741–1745. (h)
Wang, E. C.; Lin, G. J. Tetrahedron Lett. 1998, 39, 4047–4050. (i) Fukuzawa,
S.-i.; Yamaishi, Y.; Furuya, H.; Terao, K.; Iwasaki, F. Tetrahedron Lett. 1997,
38, 7203–7206. (j) Cho, B. R.; Jang, W. J.; Je, J. T.; Bartsch, R. A. J. Org.
Chem. 1993, 58, 3901–3904. (k) Hendrickson, J. B.; Hussoin, M. S. J. Org.
Chem. 1987, 52, 4137–4139. (l) Kim, S; Yi, K. Y. Tetrahedron Lett. 1986, 27,
1925–1928. (m) Arrieta, A.; Aizpurua, J. M.; Palomo, C. Tetrahedron Lett. 1984,
25, 3365–3368. (n) Jung, M. E.; Long-Mei, Z. Tetrahedron Lett. 1983, 24, 4533–
4534.
* To whom correspondence should be addressed. Tel: (212) 650-7835. Fax:
(212) 650-6107.
(1) Singh, M.; Lakshman, M. K. Abstracts of Papers. 236th National Meeting
of the American Chemical Society; August 2008, Philadelphia, PA; American
Chemical Society: Washington, DC, 2008; ORGN 649.
(2) (a) North, M. In ComprehensiVe Organic Functional Group Transforma-
tions; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Pattenden, G., Eds.;
Pergamon: Oxford, 1995; Volume 3, Chapter 18. (b) Friedrich, K.; Wallenfels,
K. In The Chemistry of the Cyano Group; Rappaport, Z., Ed.; Wiley-Interscience
Publishers: New York, 1970. (c) Miller, J. S.; Manson, J. L. Acc. Chem. Res.
2001, 34, 563–570.
(5) Telvekar, V. N.; Patel, K. N.; Kundiakar, H. S.; Chaudhari, H. K.
Tetrahedron Lett. 2008, 49, 2213–2215.
10.1021/jo900100v CCC: $40.75
Published on Web 03/20/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3079–3084 3079

Singh and Lakshman
NaICl2/aq NH3,5 N-chlorosuccinimide and pyridine,6 W-Sn
mixed hydroxide in o-xylene at 149 °C,7 thermal dehydra-
tion,8 reaction with ethyldichlorophosphate/DBU/3 Å MS,9
use of Silphos [PCl3-n(SiO2)n] in MeCN,10 ZnO/AcCl at 80
°C,11 reaction with chlorosulfonic acid in toluene at 90 °C,12
use of Ga(III)OAc/MeCN at 85-120 °C,13 and reaction with
dimethylacetylene dicarboxylate and Et3N.14
TABLE 1. Initial Experiments on the Dehydration of
2-Naphthaldoxime Using BOP
In connection with some on going studies on nucleoside
modification, we had reason to examine mild methods for the
conversion of aldoximes to nitriles. In this respect, use of PPh3/
I2 in CH2Cl2 has been reported to yield nitriles in high yield
and within short reaction times.15 However, in our hands, a test
reaction of 2-naphthaldoxime under these conditions showed
incomplete reaction in 5 h, and upon prolonging the reaction
time, formation of some 2-naphthaldehyde was also observed
entry
base, solvent
time (h) yielda (%)
1
2
3
4
5
6
7
8
2.3 molar equiv of DBU, THF
2.3 molar equiv of DBU, DMF
2.3 molar equiv of DBU, CH2Cl2
2.3 molar equiv of DBU, CHCl3
2.3 molar equiv (i-Pr)2NEt, DMF
2.3 molar equiv of (i-Pr)2NEt, CH2Cl2
no base, CH2Cl2
3.5
3.5
1
1
19
91
93
95
NAb
Incc
90
20
6 days
45
NRd
NRd
no base, DMF
1
(resonance at δ 10.17 ppm in the H NMR) in addition to the
a Yield where reported is of isolated and purified product. b Although
this reaction was complete within 1 h, the reaction was not clean, and
therefore, the product was not isolated. c The aldoxime was still present
although product formation was observed. d No product formation was
observed, and aldoxime was still present.
nitrile. Switching from PPh3 to hexamethylphosphorus triamide
[HMPT, (Me2N)3P] did not provide a significant improvement,
and aldehyde formation was again observed. This led us to
question whether the formation of aldehyde could become a
complicating problem in the dehydration of other oximes. On
the basis of the foregoing, as well as the procedural aspects of
several recently described methods and the belief that mild
methods would be necessary for relatively fragile substrates,
we decided to reinvestigate aldoxime dehydration. This paper
reports our results on the development of a new method for the
synthesis of nitriles from aldoximes.
From the results in Table 1 it is evident that use of BOP and
DBU in CH2Cl2 led to fast conversion of the aldoxime and in
good yield (entry 3). THF and DMF are also suitable solvents
(entries 1 and 2), whereas CHCl3 was inferior in which the
reaction did not proceed cleanly. The weaker base (i-Pr)NEt2
also appears to be suitable, although a much slower reaction
was observed (entry 6). With this base, DMF proved to be an
inferior solvent (entry 5). Presence of the base is important as
demonstrated by absence of reaction without added base (entries
7 and 8).
At this point, we wanted to assess the generality of this
transformation and subjected a variety of aldoximes (prepared
by conventional methods involving the use of NH2OH·HCl and
aqueous Na2CO3, K2CO3, or NaOH) to the optimized reaction
conditions. The results of these reactions are summarized in
Table 2. During the course of these experiments, we learned
that use of CH2Cl2 at elevated temperature led to the formation
of a product resulting from the reaction of hydroxybenzotriazole
with CH2Cl2.19 Thus, THF is a preferred solvent for reactions
at higher temperatures. Some of the nitrile syntheses were
therefore performed in THF to assess its general suitability
(entries 3, 4, and 7 in Table 2). In one case (entry 5), DMF was
used for solubility reasons.
Results and Discussion
It has been reported that amides can be converted to nitriles
via the use of PyBOP and (i-Pr)2NEt in CH2Cl2 at 40 °C.16
This led us to consider whether aldoximes, which are generally
more acidic than alcohols,17,18 could undergo dehydrative
reactions with commercially available BOP (which is somewhat
cheaper than PyBOP) and a base. Herein we report development
of a simple dehydration of aldoximes using BOP. During the
course of these studies, we have also evaluated the use of a
sulfonate ester of HOBt (Bt-OTs) for this oxime to cyanide
conversion. Finally, we have used this method as one of three
steps in a short and efficient synthesis of adeninyl ribofurano-
nitrile, a compound that has demonstrated useful antiviral
activity.
Our initial work commenced with screening of solvent and
base so as to obtain optimal reaction conditions. These early
reactions were performed using 2-naphthaldoxime as a repre-
sentative, electronically unbiased substrate, and 2 molar equiv
of BOP. The results are shown in Table 1.
As can be seen from Table 2, reactions with BOP proceeded
smoothly. However, we wanted to assess whether the formation
of hexamethylphosphoramide [HMPA, (Me2N)3PO] as byprod-
uct could be eliminated. This would make the reaction more
useful for development of biologically important materials. For
this we evaluated several options and settled on 1H-benzotriazol-
1-yl-4-methylbenzenesulfonate (Bt-OTs) as a potential reagent.
Bt-OTs is known in the literature20 and can be quite readily
synthesized20a (Scheme 1).
(6) Gucma, M.; Gołe¸biewski, W. M. Synthesis 2008, 1997–1999.
(7) Yamaguchi, K.; Fujiwara, H.; Ogasawara, Y.; Kotani, M.; Mizuno, N.
Angew. Chem., Int. Ed. 2007, 46, 3922–3925.
(8) Supsana, P.; Liaskopoulos, T.; Tsoungas, P. G.; Varvounis, G. Synlett
2007, 2671–2674.
(9) Zhu, J.-L.; Lee, F.-Y.; Wu, J.-D.; Kuo, C.-W.; Shia, K.-S. Synlett 2007,
1317–1319.
(10) Iranpoor, N.; Firouzabadi, H.; Jamalian, A.; Tamami, M. Lett. Org.
Chem. 2006, 3, 267–270.
(11) Sarvari, M. H. Synthesis 2005, 787–790.
(12) Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46, 671–674.
(13) Yan, P.; Batamack, P.; Prakash, G. K. S.; Olah, G. A. Catal. Lett. 2005,
101, 141–143.
(14) Cos¸kun, N. Synth. Commun. 2004, 34, 1625–1630.
(15) Narsaiah, A. V.; Sreenu, D.; Nagaiah, K. Synth. Commun. 2006, 36,
137–140.
Interestingly, Bt-OTs has not found much use in such
dehydrative reactions. Application of Bt-OTs in the present cases
(19) Ji, J.-g.; Zhang, D.-y.; Ye, Y.-h.; Xing, Q.-y. Tetrahedron Lett. 1998,
39, 6515–6516.
(20) (a) Carpino, L. A.; Xia, J.; Zhang, C.; El-Faham, A. J. Org. Chem.
2004, 69, 62–71. (b) Pelyv´as, I. F.; Lindhorst, T. K.; Streicher, H.; Thiem, J.
Synthesis 1991, 1015–1018. (c) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C.
J. Chem. Res., Synop. 1977, 182. (d) Itoh, M.; Nojima, H.; Notani, J.; Hagiwara,
D.; Takai, K. Tetrahedron Lett. 1974, 15, 3089–3092. (e) Fujii, T.; Sakakibara,
S. Bull. Chem. Soc. Jpn. 1974, 47, 3146–3151.
(16) Bose, D. S.; Narsaiah, A. V. Synthesis 2001, 373–375.
(17) Bordwell, F. G.; Ji, G.-Z. J. Org. Chem. 1992, 57, 3019–3025.
(18) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org. Chem. 1980,
45, 3295–3299.
3080 J. Org. Chem. Vol. 74, No. 8, 2009

A Simple Synthesis of Nitriles from Aldoximes
TABLE 2. Generality of the Dehydration Methodology Using BOP or Bt-OTs and DBUa
a Reactions were conducted on a 1 mmol scale except in the case of the pyrene oxime (entry 5) where reaction with Bt-OTs was conducted on a 0.75
mmol scale. b Yield of isolated and purified products. c Reaction was performed in THF. d Reaction was performed in DMF. e In this reaction with
Bt-OTs, in addition to indole-3-carbonitrile 7, the 1-(p-toluenesulfonyl)indole-3-carbonitrile 8 was also isolated in 50% yield.
SCHEME 1. Synthesis of 1H-Benzotriazol-1-yl-4-methylbenzene sulfonate (Bt-OTs)
also resulted in satisfactory conversions to the nitriles, and these
results are shown in Table 2 as well. Reaction of the unprotected
indole with BOP and DBU produced a very satisfactory return
of the nitrile 7 (entry 7). However, reaction of this oxime with
Bt-OTs and DBU produced an easily separable product mixture
consisting of the carbonitrile 7 (42%) as well as the correspond-
ing N-tosyl derivative21 8 (50%). Such N-sulfonylation has been
observed during amide formation.20d Interestingly, the aldoxime
derived from 3-phenyl-1-propanal also underwent conversion
in good yield to the nitrile 9 (entry 8) despite the generally lower
acidity of alkyl aldoximes.17 From the standpoint of functional
group compatibility, reactions with BOP are tolerant of the nitro,
organometallic, and free amino entities (entries 2, 4, and 7) as
well as ortho substituents on an aryl ring. Additionally, it can
be reasoned that in cases such as indole carboxaldehyde,
protection and dehydration can be effectuated in one step under
appropriate conditions using Bt-OTs.
From a mechanistic consideration, we wanted to evaluate the
course of the dehydration reaction of aldoximes with BOP and
DBU. As shown in Scheme 2, there are two mechanistic
possibilities. In pathway 1, upon oxime deprotonation by DBU,
initial reaction could occur at the phosphorus atom of BOP with
the formation of a new phosphonium species. In the alternative
pathway 2, an SN2′-like reaction at the nitrogen atom could result
in a direct expulsion of HMPA. Since each pathway involves
formation of new phosphorus-containing species, we felt that
31P{1H} NMR may prove useful in this assessment.
(21) Iida, S.; Togo, H. Tetrahedron 2007, 63, 8274–8281.
J. Org. Chem. Vol. 74, No. 8, 2009 3081

Singh and Lakshman
FIGURE 1. Monitoring the course of the reaction between 2-naphthaldoxime, 2 molar equiv of BOP, and 2.3 molar equiv of DBU in CD2Cl2 using
31P{1H} NMR: (A) naphthaldoxime (0.2 M in CD2Cl2) + BOP; (B) 5 min after addition of DBU; (C) 45 min after addition of DBU; (D) 100 min
after addition of DBU; and (E) reaction mixture spiked with HMPA (1.0 molar equiv).
SCHEME 2. Two Possible Pathways for the Formation of Nitriles by Dehydration of Aldoximes Using BOP
SCHEME 3. Independent Reactions of E- and Z-Cinnamaldoximes
Therefore, a series of experiments was undertaken. First, a
reaction of 2-naphthaldoxime and DBU was conducted in
CH2Cl2 in the absence of BOP. Consistent with our expectations,
no reaction was observed over a 2-h period and only starting
material was present, clearly indicating that BOP is necessary
for the reaction (which is complete within 1 h in the presence
of BOP). Next, a reaction between 2-naphthaldoxime and BOP
was conducted in CD2Cl2 using DBU, and the reaction was
monitored by 31P{1H} NMR (Figure 1). In CD2Cl2, the phos-
phonium resonance of BOP appears at δ 44.1 ppm relative to
was observed at δ 25.8 ppm (pure HMPA appears at δ 25.4
ppm in CD2Cl2). Finally, after 100 min, the reaction mixture
was spiked with 1 molar equiv of HMPA. An increase in the
signal intensity δ 25.8 ppm was observed, confirming the HMPA
resonance.
A second 31P{1H} NMR experiment was conducted with
o-bromobenzaldoxime (see Figure 1 in the Supporting Informa-
tion). The result was identical to that obtained with 2-naph-
thaldoxime. Thus, if a phosphonium salt was indeed an
intermediate in this reaction as in pathway 1 shown in Scheme
2, it was perhaps a fleeting species and not easily observed via
31P{1H} NMR. Carboxylic acids20c and amide functionalities
of nucleosides22 have been shown to react with BOP via a
phosphonium derivative. On the other hand, the NMR experi-
-
85% H3PO4 as external standard (the PF6 septet appears at δ
-143.9 ppm). As the reaction progressed, no new discernible
signal for a second phosphonium species was observed even at
a short reaction time of 5 min, but only formation of HMPA
3082 J. Org. Chem. Vol. 74, No. 8, 2009

A Simple Synthesis of Nitriles from Aldoximes
SCHEME 4. Short Synthesis of Adeninyl Ribofuranonitrile
Using a Single Protecting Group
ment raises the question of the alternate mechanism that causes
rapid formation of HMPA without intermediacy of a new
phosphonium species, such as pathway 2 in Scheme 2. However,
at the present time we have not been able to identify any other
reactive intermediate, and the question of the mechanism
remains open.
In order to assess whether there is a substantial difference in
the relative ease with which E- and Z-oximes undergo dehydra-
tion under the conditions described, we separated the isomeric
oximes of cinnamaldehyde (silica gel eluted with 10% EtOAc
in hexanes) and characterized each by NMR.23 Reaction of
E-isomer with BOP and DBU under the optimized conditions
(Scheme 3) led to complete reaction within 30 min and an 83%
isolated yield of nitrile 10. Similar reaction of the Z-isomer was
also complete within 30 min with a 90% isolated yield of 10.
Thus, it appears that oxime stereochemistry may not have a
major influence on the ease of this conversion.
As a final stage in the development of this method, we were
interested in assessing its utility for the transformation of
relatively sensitive molecules. Thus, we chose to synthesize
adeninyl ribofuranonitrile from the commercially available 2′,3′-
acetonide of adenosine using minimal protecting groups. Adenyl
ribofuranonitrile has shown promising acvitity agains vesicular
stomatitis virus (VSV, EC50 1.2 µg/mL) and human cytome-
galovirus (HCMV, EC50 1.4 µg/mL).24
smoothly, and in the case of the nucleoside no N-sulfonylation
was observed with Bt-OTs. Compound 14 has previously been
synthesized from the adeninyl methyl ribofuranuronate via the
amide in 46% yield.28
Although the E/Z 5′-carbaldoximes derived from adenosine
are known compounds,25 their synthesis posed some challenges.
For instance, the exocyclic amino group needed protection and
oxidation of the 5′-hydroxyl group had to be performed via a
N,N′-diphenylethylenediamino derivative that yielded the alde-
hyde hydrate upon hydrolysis. This aldehyde hydrate had to be
azeotroped with benzene prior to synthesis of the oxime
mixture.26
On the basis of these considerations, we opted for a
completely different route shown in Scheme 4. Relying on the
recently reported O-(tert-butyldimethylsilyl)-N-tosylhydroxy-
lamine as a convenient reagent for synthesis of oximes,23 the
5′-hydroxyl group of commercially available 11 was converted
to the N-tosyl-O-silylhydroxylamine via a Mitsunobu reaction,
to give 12 in 81% yield. This step can be readily accomplished
without protection of the exocyclic amino group.27
Next, fluoride-mediated desilylation of 12 led to the E/Z
mixture of oximes 13 (80% yield), via the anticipated expulsion
of p-toluenesulfinate and tautomerization of the incipient nitroso
nucleoside. Comparison of the NMR data of this product mixture
to reported data25 confirmed the formation of 13. Finally,
exposure of 13 to 2 molar equiv of BOP and 2.3 molar equiv
of DBU in CH2Cl2 at room temperature led to the formation of
the ribofuranonitrile 14 in 95% yield within 45 min. Alterna-
tively, the use of 2.0 molar equiv of Bt-OTs and 2.3 molar equiv
of DBU in CH2Cl2 also led to the formation of 14 in 93% yield,
within 35 min at room temperature. Both reactions proceeded
Conclusions
In summary, we have developed a mild and efficient
conversion of aldoximes to nitriles via the use of BOP or Bt-
OTs as dehydrating agent in the presence of a base such as
DBU. These reactions proceed in CH2Cl2 at room temperature
in almost all cases tested. THF and DMF are also suitable
solvents when elevated temperature is necessary or for solubility
reasons. Using this dehydration reaction as one step in a three-
step sequence, we have developed a new approach to adeninyl
ribofuranonitrile (as its 2′,3′-acetonide) requiring a minimal
protecting group strategy. In principle, simple cleavage of the
acetonide should yield the fully deprotected compound. The
approach described should prove useful for modification of other
nucleoside derivatives as well. Finally, we believe that the
strategy utilizing the Mitsunobu reaction for oxime synthesis23
in combination with this new dehydration method will prove
to be of use in the synthesis of a wide range of organic nitriles.
Experimental Section
Most of the cyano compounds listed in Table 2 are commercially
available. Characterization of cyanoferrocene29 and 1-cyanopyrene30
have been reported in the literature.
General Procedure for Nitrile Synthesis Using BOP. In an
oven-dried, two-necked, 50 mL round-bottomed flask, equipped
with a stirring bar was placed a solution of the oxime (1.0 mmol)
and BOP (2.0 mmol) in anhydrous CH2Cl2 (5.0 mL). The mixture
was stirred at room temperature for 5 min, and then DBU (2.3
mmol) was added dropwise to the stirring mixture over 2 min. The
reaction mixture became a clear homogeneous solution after
addition of DBU. The reaction was monitored by TLC, and upon
complete consumption of the starting material the mixture was
diluted with EtOAc and washed with water (2×) followed by brine.
(22) (a) Bae, S.; Lakshman, M. K. Org. Lett. 2008, 10, 2203–2206. (b) Bae,
S.; Lakshman, M. K. J. Am. Chem. Soc. 2007, 129, 782–789.
(23) Kitahara, K.; Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2008,
10, 2259–2261.
(24) Matsuda, A.; Kosaki, H.; Yoshimura, Y.; Shuto, S.; Ashida, N.; Konno,
K.; Shigeta, S. Bioorg. Med. Chem. Lett. 1995, 5, 1685–1688.
(25) Wnuk, S. F.; Yuan, C.-S.; Borchardt, R. T.; Balzarini, J.; De Clercq,
E.; Robins, M. J. J. Med. Chem. 1997, 40, 1608–1618.
(26) Ranganathan, R. S.; Jones, G. H.; Moffatt, J. G. J. Org. Chem. 1974,
39, 290–298.
(28) Baker, J. J.; Mian, A. M.; Tittensor, J. R. Tetrahedron 1974, 30, 2939–
2942.
(29) Kivrak, A.; Zora, M. J. Organomet. Chem. 2007, 692, 2346–2349.
(30) (a) Laali, K. K.; Okazaki, T.; Mitchell, R. H.; Ayub, K.; Zhang, R.;
Robinson, S. G. J. Org. Chem. 2008, 73, 457–466. (b) Kitagawa, F.; Murase,
M.; Kitamura, N. J. Org. Chem. 2002, 67, 2524–2531.
(27) (a) Comstock, L. R.; Rajski, S. R. J. Org. Chem. 2004, 69, 1425–1428.
(b) Kolb, M.; Danzin, C.; Barth, J.; Claverie, N. J. Med. Chem. 1982, 25, 550–
556.
J. Org. Chem. Vol. 74, No. 8, 2009 3083

Singh and Lakshman
The organic layer was dried over MgSO4 and concentrated under
reduced pressure. The crude mixture was purified by column
chromatography. [DeViation from this procedure: (a) THF or DMF
was appropriately substituted as reaction solvent when needed, e.g.,
in the reactions with o-bromobenzaldoxime, ferrocene carbaldoxime,
and pyrene-1-carbaldoxime.]
material was loaded onto a dry-packed silica gel column and eluted
using 30% acetone in hexanes. Compound 13 (E/Z mixture) was
obtained as white powder (0.569 g, 80% yield). Rf (4% MeOH in
CH2Cl2) ) 0.03. HRMS calcd for C13H17N6O4 [M + H]+ 321.1311,
found 321.1311. The NMR data for this E/Z mixture has been
reported.25 The H NMR spectrum of this mixture is furnished in
1
General Procedure for Nitrile Synthesis Using Bt-OTs. Into
an oven-dried, two-necked, 50 mL round-bottomed flask equipped
with a stirring bar was placed a solution of the oxime (1.0 mmol)
and Bt-OTs (2.0 mmol) in anhydrous CH2Cl2 (5.0 mL). The mixture
was stirred at room temperature for 5 min, and then DBU (2.3
mmol) was added dropwise to the stirring mixture over 2 min. The
reaction was monitored by TLC, and upon complete consumption
of the starting material the reaction mixture was diluted with EtOAc
and washed with water (2×) followed by brine. The organic layer
was dried over MgSO4 and concentrated under reduced pressure.
The crude mixture was purified by column chromatography.
[DeViation from this procedure: (a) the reaction was conducted with
0.75 mmol of pyrene-1-carbaldoxime, (b) THF or DMF was
appropriately substituted as reaction solvent when needed, e.g., in
the reactions with o-bromobenzaldoxime, ferrocene carbaldoxime,
and pyrene-1-carbaldoxime.]
the Supporting Information.
Step 2 Using BOP. In an oven-dried, 50 mL, two-necked, round-
bottomed flask equipped with a stirring bar was placed a solution
of 13 (0.320 g, 1.0 mmol) and BOP (0.885 g, 2.0 mmol) in
anhydrous CH2Cl2 (5.0 mL). The mixture was stirred at room
temperature for 5 min, and then DBU (344 µL, 2.30 mmol) was
added dropwise over 2-3 min to the stirring solution. The reaction
mixture became clear after addition of DBU. After 45 min TLC
showed complete consumption of the starting material. The reaction
mixture was diluted with EtOAc and washed with water (2×)
followed by brine. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The crude product was
chromatographed on a silica gel column using 2% EtOH in CH2Cl2
as eluting solvent (the chromatography was repeated a second time).
Compound 14 obtained as white solid (0.288 g, 95% yield).
Step 2 Using Bt-OTs. In an oven-dried, 50 mL, two-necked,
round-bottomed flask equipped with a stirring bar was placed a
solution of 13 (0.277 g, 0.864 mmol) and Bt-OTs (0.500 g, 1.73
mmol) in anhydrous CH2Cl2 (5.0 mL). The mixture was stirred at
room temperature for 5 min, and then DBU (297 µL, 1.99 mmol)
was added dropwise over 2 min to the stirring solution. The reaction
mixture became clear after addition of DBU. After 35 min, TLC
showed complete consumption of the starting material. The reaction
mixture was diluted with EtOAc and washed with water (2×)
followed by brine. The organic layer was dried over MgSO4 and
concentrated under reduced pressure. The crude product was
chromatographed on a silica gel column using 2% EtOH in CH2Cl2
as eluting solvent (the chromatography was repeated a second time).
Compound 14 was obtained as a white solid (0.246 g, 93% yield).
5′-Deoxy-5′-[N-(tert-butyldimethylsilyloxy)-N-(p-toluenesulfonyl)]-
amino-2′,3′-O-(isopropylidene)adenosine (12). In a 100 mL oven-
dried, round-bottomed flask equipped with a stirring bar were placed
2′,3′-O-(isopropylidene)adenosine 11 (0.75 g, 2.44 mmol), O-(tert-
butyldimethylsilyl)-N-tosylhydroxylamine (TsNHOTBDMS, 1.10 g,
3.65 mmol), and PPh3 (1.28 g, 4.88 mmol). Anhydrous toluene
(12 mL) and THF (4 mL) were added, and the reaction mixture
was cooled to 0 °C with stirring. DEAD (576 µL, 3.66 mmol) was
added dropwise. The reaction mixture was stirred at 0 °C for 1 h
and then allowed to warm to room temperature. After 5 h, TLC
showed complete consumption of the starting material. The reaction
mixture was diluted with EtOAc and washed with saturated aq
NaHCO3 followed by water and brine. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The product
was loaded onto a silica gel column using CH2Cl2 and eluted with
15% EtOAc in CH2Cl2 followed by 40% EtOAc in CH2Cl2.
Compound 12 was obtained as white, foamy solid (1.163 g, 81%
1
Rf (4% MeOH in CH2Cl2) ) 0.27. H NMR (CDCl3): δ 8.39 (s,
1H, Ar-H), 7.89 (s, 1H, Ar-H), 6.20 (s, 1H, H-1′), 5.83 (d, 1H,
H-2′, J ) 5.7), 5.79 (dd, 1H, H-3′, J ) 5.7, 1.4), 5.64 (br s, 2H,
NH2), 4.98 (d, 1H, H-4′, J ) 1.4), 1.58 and 1.43 (2s, 6H,
isopropylidine CH3). 13C NMR (CDCl3): δ 155.8, 153.5, 149.7,
140.1, 120.2, 116.2, 115.0, 92.0, 84.9, 84.1, 75.5, 26.7, 25.2. HRMS
(ESI): calcd for C13H15N6O3 [M + H]+ 303.1206, found 303.1207.
1
yield). Rf (50% EtOAc in CH2Cl2) ) 0.16. H NMR (CDCl3): δ
8.37 (s, 1H, Ar-H), 7.86 (s, 1H, Ar-H), 7.58 (d, 2H, Ar-H, J )
8.2), 7.27 (d, 2H, Ar-H, J ) 8.2), 6.03 (d, 1H, H-1′, J ) 1.7), 5.94
(br s, 2H, NH2), 5.56 (dd, 1H, H-2′, J ) 6.3, 1.7), 5.15 (dd, 1H,
H-3′, J ) 6.3, 2.7), 4.50 (dt, 1H, H-4′, J ) 6.9, 2.7), 3.43 (m, 1H,
H-5′), 2.91 (m, 1H, H-5′), 2.41 (s, 3H, p-toluyl CH3), 1.58 and
1.38 (2s, 6H, isopropylidine CH3), 0.89 (s, 9H, t-Bu), 0.34, 0.24
(2s, 6H, SiCH3). 13C NMR (CDCl3): δ 155.8, 153.1, 149.3, 145.0,
140.5, 129.9, 129.5, 120.5, 114.3, 91.8, 84.3, 84.1, 83.6, 58.0, 27.2,
26.2, 25.6, 21.8, 18.5, -4.1, -4.3. HRMS (ESI) calcd for
C26H39N6O6SSi [M + H]+ 591.2421, found 591.2427.
Acknowledgment. We are grateful to Dr. Natalya Gutner
(CCNY) for help in obtaining IR data for the products and to
Dr. Cliff Soll (Hunter College) for the high-resolution mass
spectral data for the new compounds described. Partial support
via PSC-CUNY awards is acknowledged, and M.K.S. was
supported via NSF Grant No. CHE-0640417. Infrastructural
support at CCNY was provided by NIH RCMI Grant No. G12
RR03060.
1′-Adenin-9-yl-2′,3′-O-(isopropylidene)-ꢀ-D-ribofuranurononi-
trile (14). Step 1. Compound 12 (1.32 g, 2.22 mmol) was dissolved
in anhydrous CH3CN (22 mL), and CsF (0.674 g, 4.44 mmol) was
added. The reaction mixture was stirred at 60 °C for 1.5 h, at which
time TLC showed complete consumption of the starting material.
Saturated aq NH4Cl was added to the cooled reaction mixture, and
the mixture was extracted with EtOAc. The organic layer was
washed with water followed by brine. The organic layer was dried
over Na2SO4 and concentrated under reduced pressure. The crude
1
Supporting Information Available: H NMR spectra of
carbonitriles 1-10 shown in Table 2 as well as those of 12-14
and COSY spectra of 12 and 14. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO900100V
3084 J. Org. Chem. Vol. 74, No. 8, 2009