8-Bromocaffeine (8-BC): A new versatile reagent for conversion of aldoximes into nitriles

Article abstract of DOI:10.1055/s-0031-129036

A rapid and highly convenient synthesis of nitriles from the corresponding aldoximes using 8-bromocaffeine (8-BC) is described. In this protocol, aldoximes react with 8-BC in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-dimethylformamide (DMF) to furnish the corresponding nitriles under both microwave-assisted and/or conventional heating (reflux) conditions in short times and in good to excellent yields. This methodology is highly efficient for structurally diverse aldoximes including aliphatic, aromatic, and heteroaromatic oximes. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-129036

LETTER
▌1191
letter
8-Bromocaffeine (8-BC): A New Versatile Reagent for Conversion of
Aldoximes into Nitriles
Conversion of Aldoximes into Nitriles
Mohammad Navid Soltani Rad,* Somayeh Behrouz,* Abdo-Reza Nekoei
Department of Chemistry, Shiraz University of Technology, Shiraz 71555-313, Iran
Fax +98(711)7354520; E-mail: soltani@sutech.ac.ir; E-mail: behrouz@sutech.ac.ir
Received: 09.02.2012; Accepted after revision: 12.03.2012
pharmaceutical and cosmetic applications are ongoing.24a
8-Bromocaffeine (8-BC, CAS-No: 10381-82-5) is a com-
mercially available and stable compound that can easily
participate in nucleophilic aromatic substitution reactions.
Abstract: A rapid and highly convenient synthesis of nitriles from
the corresponding aldoximes using 8-bromocaffeine (8-BC) is de-
scribed. In this protocol, aldoximes react with 8-BC in the presence
of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and N,N-dimethyl-
formamide (DMF) to furnish the corresponding nitriles under both Additionally, 8-BC is an important precursor for many
drug syntheses. 24b However, to the best of our knowledge,
there have been no reports on the application of 8-BC as a
microwave-assisted and/or conventional heating (reflux) conditions
in short times and in good to excellent yields. This methodology is
highly efficient for structurally diverse aldoximes including aliphat-
reagent in organic chemistry. In attempts at the synthesis
ic, aromatic, and heteroaromatic oximes.
of the aldehyde O-1,3,7-trimethyl-2,6-dioxo-2,3,6,7-tet-
rahydro-1H-purin-8-yl oxime (i.e., adducts of aldoximes
Key words: nitriles, oximes, synthetic methods, dehydration
and 8-BC) in basic media for certain pharmaceutical stud-
ies (Figure 1), the formation of nitriles and 1,3,7-trimethyl
uric acid in remarkable yields were observed, instead of
the desired adducts. Therefore, we found that 8-BC could
be considered as an appropriate dehydrating agent for the
conversion of aldoximes into nitriles.
The nitrile moiety is a key constituent in numerous natural
products, and it also serves as an important synthetic in-
termediate for pharmaceuticals, agricultural chemicals,
dyes, and material sciences.1,2 There are numerous general
methods for the introduction of nitrile groups from vari-
ous organic functional groups.3,4 Among these, the con-
version of oximes1–4 and/or O-substituted aldoximes5,6
into nitriles has been shown to be a suitable and attractive
strategy for the preparation of both aliphatic and aromatic
nitriles because the very toxic cyanide ion is not used. To
date, many different reagents and conditions have been
established for the dehydration of aldoximes to give ni-
triles. For example, Pd(OAc)2/PPh3,7 N-(p-toluenesulfo-
nyl) imidazole (TsIm),8 [RuCl2(p-cymene)]2/molecular
sieves,9 2-chloro-1-methyl pyridinium iodide,10 triethyl
amine/SO2,11 PPh3/CCl4,12 acetic anhydride,13 Vilsmeier
reagent,14 Burgess reagent,15 cyanuric chloride,16 di-2-
pyridylsulfite,17 AlI3,18 TiCl3(OTf),19 AlCl3·6H2O/KI,20
chlorosulfonic acid,21 S,S-dimethyl dithiocarbonate,22 and
sulfonyl chlorides23 have been employed as dehydrating
agents for this transformation. Although many of these
methods possess synthetic value, their practical applica-
tion may encounter some drawbacks such as the use of ex-
pensive or less readily available reagents, harsh reaction
conditions, low yields, long reaction time, tedious work-
up, complex reaction procedures, or limited substrate
scope. Consequently, the search for a mild, rapid, and uni-
versally applicable method for the conversion of aldox-
imes into nitriles still continues.
O
Me
Me
O
H
R
N
N
O
N
N
N
Me
R = aryl, alkyl
Figure 1 General structure of aldehyde O-1,3,7-trimethyl-2,6-di-
oxo-2,3,6,7-tetrahydro-1H-purin-8-yl oxime
In a continuation of our ongoing research on nitrile chem-
istry,8,25 we now report 8-BC as a new, highly efficient
and stable dehydrating reagent for the conversion of
aldoximes into nitriles using 1,8-diazabicyclo[5.4.0]un-
dec-7-ene (DBU) in DMF under conventional heating
and/or microwave-assisted conditions (Scheme 1).
R
8-BC, DBU, DMF
R
N
N
OH
method A or B
H
method A: 65–80%
method B: 80–96%
O
Me
N
N
Me
N
N
8-BC =
DBU =
Br
N
O
N
Me
Caffeine is a well-known natural product belonging to the
xanthine alkaloid family, and interest in its social con-
sumption in drinks and foods, as well as its significance in
Scheme 1 Conversion of aldoximes into nitriles using 8-BC under
conventional heating (A) and/or microwave-assisted (B) conditions
After several attempts, it was found that the combination
of 8-BC and DBU in DMF heated to reflux (Scheme 1,
conditions A) can be used for the synthesis of both aro-
SYNLETT 2012, 23, 1191–1198
Advanced online publication: 26.04.2012
DOI: 10.1055/s-0031-129036; Art ID: ST-2012-B0117-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

1192
M. N. Soltani Rad et al.
LETTER
matic and aliphatic nitriles through dehydration of aldox-
imes after 1–3 hours in reasonable yields (65–80%). To
promote the reaction and to attain more satisfactory re-
sults, we conducted the reaction under microwave irradi-
ation (Scheme 1, conditions B).
Table 2 Effect of Base on the Conversion of 4-Nitrobenzaldehyde
Oxime into 4-Nitrobenzonitrile
8-BC, base
O2N
C
NOH
O2N
C
N
H
DMF, MW
Yield (%)b
Entry
Base
Time (s)
To optimize the reaction conditions, we initially chose the
reaction of 4-nitrobenzaldehyde oxime with 8-BC (1.2
equiv) under microwave irradiation to afford 4-nitroben-
zonitrile as a model reaction. We screened a variety of sol-
vents and examined their effect on reaction times and
yield (Table 1). The reaction proceeded in the absence of
solvent, but low yields of the nitrile were attained. DMF
(entry 4) was found to be the most appropriate solvent and
was therefore used for all subsequent reactions. Use of
hexamethylphosphoramide (HMPA), N-methyl-2-pyrro-
lidinone (NMP) or dimethyl sulfoxide (DMSO; Table 1,
entries 2, 3, and 8) led to moderate yields of 4-nitrobenzo-
nitrile; whereas, other solvents were inefficient for the
conversion of 4-nitrobenzaldehyde oxime into 4-nitroben-
zonitrile.
n.r.c
87
1
2
3
4
5
6
none
300
90
Cs2CO3
K2CO3
MgO
120
120
180
70
70
30
Et3N
26
a
85
Al2O3
7
8
9
DBU
30
180
180
96
37
45
DABCO
DMAP
a Basic alumina.
b Isolated yield.
c No reaction.
Table 1 Effect of Solvent on the Conversion of 4-Nitrobenzalde-
hyde Oxime into 4-Nitrobenzonitrile
8-BC, DBU
O2N
C
NOH
O2N
C
N
H
solvent, MW
Table 3 Effect of Microwave Irradiation Power on the Conversion
of 4-Nitrobenzaldehyde Oxime into 4-Nitrobenzonitrile
Yield (%)a
Entry
Solvent
Time (s)
8-BC, DBU
O2N
C
NOH
O2N
C
N
1
2
3
4
5
6
7
8
none
300
120
80
25
DMF, MW power
H
HMPA
NMP
70
Yield (%)a
Entry
Irradiation power (W) Time (s)
83
1
100
200
300
400
500
600
240
90
30
30
60
60
25
58
96
90
75
60
DMF
30
96
2
MeCN
toluene
THF
120
300
210
70
38
3
n.r.b
trace
74
4
5
DMSO
6
a Isolated yield.
b No reaction.
a Isolated yield.
Table 4 A Comparative Study of Dehydrating Agents in the Model
Reaction
The effect of various organic and inorganic bases on the
model reaction was then investigated (Table 2). In the ab-
sence of base, no reaction was achieved, even when the re-
action time was prolonged. Among the examined bases,
DBU (entry 7) was the most appropriate base for the reac-
tion. Moderate yields of 4-nitrobenzonitrile were obtained
by using Cs2CO3, K2CO3 or Al2O3 (entries 2, 3 and 6)
whereas other bases were inefficient.
DA, DBU
O2N
C
NOH
O2N
C
N
H
DMF, MW
DA = dehydrating agent
Yield (%)a
Entry Dehydrating reagent
Time (s)
1
2
3
4
cyanuric chloride
8-BC
70
30
90
90
96
94
91
We also evaluated the effect of microwave power on the
progress of the model reaction (Table 3). The best result
was obtained when microwave irradiation was applied at
300 W; low yields of 4-nitrobenzonitrile were obtained at
100 and 200 W. Further increases in irradiation power
(>300 W) caused no distinguishable improvement in the
progress of the reaction.
Ac2O
2-chloro-1-methylpyridinium iodide 110
a Isolated yield.
Synlett 2012, 23, 1191–1198
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conversion of Aldoximes into Nitriles
1193
CN
O
O
Me
Me
O
Me
O
Me
O
N
N
DBU, DMF
N
N
H
Br
+
NHOH
+
+
NH2OH⋅HCl
MW (300 W)
N
N
N
N
O2N
NO2
Me
Me
47%
Scheme 2 The 3CRs of aldehyde, NH2OH·HCl and 8-BC under microwave irradiation
The optimized amount of 8-BC was found to be 1.2 equiv- interested in the direct conversion of aldehydes into ni-
alent per equivalent of oxime. To establish the dehydrat- triles through 3CRs of aldehyde, NH2OH·HCl, and 8-BC
ing potency of 8-BC, we performed the same experiment under microwave irradiation (Scheme 2). In this context,
with other dehydrating agents under the same conditions the microwave-assisted reaction of 4-nitrobenzaldehyde
applied to the model reaction. The comparative data are with NH2OH·HCl and 8-BC was achieved in the presence
shown in Table 4. A higher yield of nitrile was obtained in of DBU in DMF, however, the reaction led to the forma-
a shorter reaction time using 8-BC (entry 2). Although tion of 4-nitrobenzonitrile in low yields (47%). The low
other dehydrating reagents afforded satisfactory results, yield attained in this MCR approach was attributed to
the reactions required longer to reach completion.
scavenging of NH2OH by 8-BC and to the formation of
considerable amounts of 8-hydroxyamino-1,3,7-trimeth-
yl-3,7-dihydropurine-2,6-dione.
Because multicomponent reactions (MCRs) avoid time-
consuming and costly purification processes,26 we were
Table 5 Investigation of the Reaction Scope under Conventional Heating (Conditions A) and Microwave Irradiation (Conditions B)
R-CNa
IR (cm–1)b
2223
Entry
18
Conditions A
Yield (%)c
Conditions B
Yield (%)c
Time (h)
1
Time (s)
30
80
95
Cl
CN
Cl
28
38
48
2220
2230
2228
72
80
75
1.5
1
90
96
93
110
30
CN
O2N
O2N
CN
1.25
70
CN
NO2
58
2237
68
1.75
86
130
CN
68
78
MeO
N
CN
2224
2233
79
77
1
96
92
40
60
CN
1.25
MeO
827
O
CN
2239
2225
73
75
2
2
87
90
120
100
CN
O
O
928
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1191–1198

1194
M. N. Soltani Rad et al.
LETTER
Table 5 Investigation of the Reaction Scope under Conventional Heating (Conditions A) and Microwave Irradiation (Conditions B)
(continued)
R-CNa
IR (cm–1)b
Entry
1029
Conditions A
Yield (%)c
Conditions B
Yield (%)c
Time (h)
1.75
Time (s)
90
O
2230
75
92
CN
MeO
CN
CN
118
N
2202
2228
72
73
1.5
1.5
88
90
70
60
Me
1230
O
O
138
148
2221
2223
70
73
2.15
1.75
87
89
110
50
O
CN
O
O
O
CN
O
158
168
N
2215
2222
65
67
2.75
2.75
81
83
170
160
O
CN
O
N
O
O2N
CN
N
Me
O
H
N
NHEt
N
H
O
1729
N
2223
2220
65
69
3
80
84
180
70
CN
H
1831
CH2CN
1.5
N
Me
CN
CN
198
208
2227
2232
76
74
1
1
90
88
40
40
CN
2135
2214
78
1.25
90
70
a All products were characterized by 1H and 13C NMR, IR, CHN and MS analysis.38
b IR signal of nitrile.
c Isolated yield.
To explore the scope of this method, the optimized reac- useful for aromatic (Table 5, entries 1–6, 8–10, 13, and
tion conditions were applied to a range of aldoximes (Ta- 14), heteroaromatic (entries 7, 11, and 12), aliphatic (en-
ble 5). It is clear that this method is highly efficient and tries 19 and 20), and conjugated (entry 21) aldoximes as
Synlett 2012, 23, 1191–1198
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conversion of Aldoximes into Nitriles
1195
well as other aldoximes containing N-heterocycles (en- nonplanar Z-isomer. Furthermore, two different E-iso-
tries 15–18). This protocol is favorably chemoselective mers can also be assigned for this intermediate by 180° ro-
for compounds with multiple functional groups. Addition- tation about the N–O single bond (see Figure 2).
ally, excellent results were obtained for aryl aldoximes According to the conformational analysis, E-isomer (2) is
with different substituents at the meta and/or para posi- about 6.0 kcal/mol more stable than E-isomer (1). Upon
tions; lower yields of nitriles were obtained for ortho-sub- linkage of the 8-caffeinyl moiety to O(24) of aldoxime,
stituted aromatic aldoximes. By using this procedure, both and due to the electron-withdrawing character of 8-caffei-
E- and Z-isomers of oximes could be converted into the nyl, the charge density of O(24) atom is transferred to
corresponding nitriles; in most cases, the oxime used in N(7) and, especially, to N(9) (because of the conjugated
these experiments were mixtures of Z- and E-isomers. resonance form), in such a way that the charge densities of
Furthermore, by using this method, the configuration of these nitrogen atoms in both (1) and (2) isomers are en-
asymmetric carbons remains intact {Table 5, entry 18; hanced. The calculations also show that, upon formation
[α]D24 –69.5° (c = 1.0, MeOH)}. The data presented in Ta- of the mentioned linkage, the positive charge on C(8) is
ble 5 clearly show that the microwave-assisted reaction is enhanced. Therefore, O(24) adjacent to the 8-caffeinyl
superior to the conventional heating procedure because fragment becomes a good leaving group and, in the pres-
higher yields and shorter reaction time were obtained ence of DBU, the aldoxime is dehydrated to its corre-
when the former technique was employed (method B).
sponding nitrile.
To rationalize the dehydrating ability of 8-BC and to un- These results are confirmed by analyzing the orbitals’ do-
derstand the mechanism of the reaction, quantum mechan- nor–acceptor interactions. The second order perturbation
ical calculations on Gaussian 03W32 and NBO 5.0 theory analysis of Fock matrix in NBO basis show that
programs,33 employing the DFT method at the B3 LYP/6- there is an interaction of the type nO(24)→π*
N(25)–C(26)
31G** level, have been applied to the reactants and reac- [where n is the second lone pair of O(24)] with the energy
tion intermediates. Some of the calculated results are sum- of 17.88 kcal/mol in isomer (2) of the studied (E)-benzal-
marized in Table 6.
dehyde oxime. Similar analysis for the intermediate 8-caf-
feinyl O-benzaldehyde oxime ether shows that the
mentioned interaction is reduced (12.68 kcal/mol), which
means that the tendency of the lone pair of the oxygen to
transfer toward the oxime part of the molecule is de-
creased. Instead, another strong interaction of the kind
nO(24)→π*C(8)–N(9) with an energy of 37.11 kcal/mol is cal-
culated for the 8-caffeinyl O-benzaldehyde oxime ether
intermediate, which shows that the oxygen charge has a
high tendency to transfer toward the 8-caffeinyl part of
this molecule. These changes in the mentioned interac-
tions also cause the O(24)–N(25) bond in the studied in-
termediate (bond length 1.421 Å) to be weaker than that
in (E)-benzaldehyde oxime (bond length 1.401 Å).
Benzaldehyde oxime was selected as the sample aldoxime
(R = Ph in Scheme 1) for theoretical investigations. As
shown in Figure 2, there are two possible conformations
for the E-isomer (which is more stable than the Z-isomer)
of this molecule. Between these, E-isomer (2) is 4.55
kcal/mol more stable than the E-isomer (1).
In accordance with the theoretical calculations, the link-
age of the Br atom to the caffeine causes an enhancement
in positive charge on C(8), which, in turn, make this atom
susceptible to attack by an aldoxime molecule such as (E)-
benzaldehyde oxime in a SNAr type reaction. The gener-
ated intermediate 8-caffeinyl O-oxime ether can also exist
as E- and/or Z-isomers. The calculations show that the for-
mer is quite planar and 2.80 kcal/mol more stable than the
Table 6 Conformations, Absolute Energies and Partial Atomic Charges Calculated at the B3 LYP/6-31G** Level of DFT Theory
H
Me
24
Me
24
O
O
7 Me
N
7 Me
25
N
O
O
7 N
7 N
O
O
Me
O
Me
O
N
8
N
8
24
25
N
N
8
8
Br
N
N
H
9
N
Me
9
N
Parameter
Me
N
N
N
N
9
9
N
N
Me
Me
Me
Me
O
O
Caffeine
–680.39019
8-BC
E-isomer (1)
E-isomer (2)
E (hartrees)
–3251.48924
–1080.06453
6.01
–1080.07411
0.00
ΔE (kcal/mol)
Mulliken charge
N(7)
C(8)
–0.513
–0.533
0.446
–0.593
0.814
–0.595
0.807
0.285
N(9)
Br(24)
–0.521
–0.521
–0.054
–0.617
–0.558
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1191–1198

1196
M. N. Soltani Rad et al.
LETTER
Table 6 Conformations, Absolute Energies and Partial Atomic Charges Calculated at the B3 LYP/6-31G** Level of DFT Theory (continued)
H
Me
24
Me
24
O
O
7 Me
N
7 Me
25
N
O
O
7 N
7 N
O
O
Me
O
Me
O
N
8
N
8
24
25
N
N
8
8
Br
N
N
H
9
N
Me
9
N
Parameter
Me
N
N
N
N
9
9
N
N
Me
Me
Me
Me
O
O
Caffeine
8-BC
E-isomer (1)
E-isomer (2)
O(24)
N(25)
NBO charge
N(7)
–0.461
–0.176
–0.457
–0.154
–0.362
0.226
–0.374
0.306
–0.383
0.736
–0.390
0.748
C(8)
N(9)
–0.523
–0.520
0.124
–0.606
–0.557
Br(24)
O(24)
N(25)
–0.378
–0.118
–0.395
–0.116
olism (oxidation) of caffeine in living organs.34 The
generation of 4 through the course of reaction was easily
followed by TLC analysis.
pathway A:
O
Me
O
Me
O
Me
N
N
Me
O
R
H
O
N
DBU
N
N
Br + HO
N
N
R
N
– DBUH+
••
N
H
N
Me
2
1
Me
O
Me
Me
N
N
O
+
R
N
Figure 2 The optimized geometries for the different E-isomers of
benzaldehyde oxime (right) and the intermediate 8-caffeinyl O-oxime
ether (left) at the B3 LYP/6-31G** level of theory
3
N
H
O
N
Me
4
pathway B:
O
These results confirm that O(24) adjacent to the 8-caffei-
nyl fragment becomes a good leaving group in the reac-
tion intermediate, to produce nitriles from their
corresponding aldoximes, in the presence of DBU.
Me
Me
N
N
••
O
R
H
N
3 + 4
+
N
N
O
N
N
Me
2
A plausible mechanism for 8-BC/DBU mediated conver-
sion of aldoximes into nitriles is proposed (Scheme 3). In
this mechanism, we suggest that a preliminary SNAr type
reaction of 8-BC with oxime (1) in the presence of DBU
occurs to afford compound 2 as the key intermediate. In
pathway (A), the conversion proceeds in a concerted-type
1,4-elemination of compound 2, which undergoes thermal
elimination to afford nitrile 3, followed by the liberation
of 1,3,7-trimethyluric acid (1,3,7-trimethyl-7,9-dihydro-
3H-purine-2,6,8-trione; 4), whereas in pathway (B), in the
presence of base, the conversion proceeds through 1,2-el-
emination of 2. 1,3,7-Trimethyluric acid 4 (CAS-No:
5415-44-1; Mp >300 °C) is a nontoxic, naturally occur-
ring compound that is normally produced from the metab-
Scheme 3 A plausible mechanism for conversion of aldoximes into
nitriles using 8-BC. Path A: 1,4-elimination; Path B: 1,2-elimination.
In summary, a convenient and facile method has been
established for the conversion of aliphatic and aromatic
aldoximes into nitriles using 8-bromocaffeine36 in the
presence of DBU and DMF under microwave or conven-
tional heating conditions. The simple experimental proce-
dure, mild reaction conditions, short reaction time,
relatively high yields of products, generality, and versatil-
ity are advantages of the current method.37
Synlett 2012, 23, 1191–1198
© Georg Thieme Verlag Stuttgart · New York

LETTER
Conversion of Aldoximes into Nitriles
1197
(28) Kokel, B.; Menichi, G.; Hubert-Habart, M. Synthesis 1985,
201.
(29) Lai, G.; Bhamare, N. K.; Anderson, W. K. Synlett 2001, 230.
(30) Meshram, H. M. Synthesis 1992, 943.
Acknowledgment
The authors wish to thank Pars Industrial Pioneer Engineering
Company and also the Shiraz University of Technology research
council for financial support of this work.
(31) Mizuno, A.; Hamada, Y.; Shioiri, T. Synthesis 1980, 1007.
(32) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A. Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.;
Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi,
M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.;
Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.;
Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.;
Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.;
Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman,
J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.;
Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith,
T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.;
Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03,
Revision B.05; Gaussian Inc: Pittsburgh, 2003.
References and Notes
(1) Friedrich, K.; Wallenfels, K. In The Chemistry of the Cyano
Group; Rappaport, Z., Ed.; Wiley: New York, 1970.
(2) Fatiadi, A. J. In Preparation and Synthetic Applications of
Cyano Compounds; Patai, S.; Rappaport, Z., Eds.; Wiley:
New York, 1983.
(3) March, J. Advanced Organic Chemistry, 4th ed.; John Wiley
& Sons (Asia) Ltd: Singapore, 2005.
(4) Larock, R. C. Comprehensive Organic Transformations,
2nd ed.; Wiley: New York, 1999.
(5) Anand, N.; Owston, N. A.; Parker, A. J.; Slatford, P. A.;
Williams, J. M. J. Tetrahedron Lett. 2007, 48, 7761.
(6) Hegarty, A. F.; Tuohey, P. J. J. Chem. Soc., Perkin Trans. 2
1980, 1313.
(7) Kim, H. S.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2009,
50, 1717.
(8) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.;
Amini, Z.; Behrouz, M. Synth. Commun. 2010, 40, 2429.
(9) Yang, S. H.; Chang, S. Org. Lett. 2001, 3, 4209.
(10) Lee, K.; Han, S. B.; Yoo, E. M.; Chung, S. R.; Oh, H.; Hong,
S. Synth. Commun. 2004, 34, 1775.
(11) Olah, G. A.; Vankar, Y. D. Synthesis 1978, 702.
(12) Kim, J. N.; Chung, K. H.; Ryu, E. K. Synth. Commun. 1990,
20, 2785.
(13) Gabriel, S.; Meyer, R. Ber. Dtsch. Chem. Ges. 1881, 14,
2332.
(14) Dulcere, J.-P. Tetrahedron Lett. 1981, 22, 1599.
(15) Miller, C. P.; Kaufman, D. H. Synlett 2000, 1169.
(16) Chakrabarti, J. K.; Hotten, T. M. J. Chem. Soc., Chem.
Commun. 1972, 1226.
(17) Kim, S.; Yi, K. Y. Tetrahedron Lett. 1986, 27, 1925.
(18) Konwar, D.; Boruah, R. C.; Sandhu, J. S. Tetrahedron Lett.
1990, 31, 1063.
(19) Iranpoor, N.; Zeynizadeh, B. Synth. Commun. 1999, 29,
2747.
(20) Boruah, M.; Konwar, D. J. Org. Chem. 2002, 67, 7138.
(21) Li, D.; Shi, F.; Guo, S.; Deng, Y. Tetrahedron Lett. 2005, 46,
671.
(22) Khan, T. A.; Peruncheralathan, S.; Ila, H.; junjappa, H.
Synlett 2004, 2019.
(33) Glendening, E. D.; Badenhoop, J. K.; Reed, A. E.;
Carpenter, J. E.; Bohmann, J. A.; Morales, C. M.; Weinhold,
F. NBO 5.0; Theoretical Chemistry Institute (University of
Wisconsin–Madison): Madison, 2001.
(34) Yu, C. L.; Kale, Y.; Gopishetty, S.; Louie, T. M.;
Subramanian, M. J. Bacteriol. 2008, 190, 772.
(35) Ghiaci, M.; Nasr Esfahani, R.; Aghaei, H. Catal. Commun.
2009, 10, 777.
(36) 8-BC [CAS Number: 10381-82-5] is commercially
available; however, using freshly prepared 8-BC affords
more favorable results. Fresh 8-BC can be easily prepared by
using the following procedure: To a round-bottom flask (500
mL) containing freshly distilled CH2Cl2 (300 mL) was added
caffeine (19.4 g, 0.1 mol) and NBS (35.2 g, 0.2 mol). When
the solids had dissolved in solvent, water (100 mL) was
added and the container was closed and stirred for 5 d. The
solution was transferred into a separator funnel and solution
of cold NaOH (100 mL, 2 M) was added the mixture was
shaken to decolorize the mixture. The organic layer was
separated, washed with water (2 × 200 mL), dried over
Na2SO4 (30 g), filtered, and evaporated to provide pure 8-
BC (26 g, ca. 100%).
(37) General procedure for microwave-assisted conversion of
aldoximes into nitriles by using 8-BC: Into a laboratory
microwave oven equipped with a condenser, was inserted a
round-bottom flask (50 mL) containing a solution of
aldoxime (5 mmol), DBU (5 mmol), and 8-BC (6 mmol) in
DMF (6 mL). The mixture was then irradiated at 300 W for
the indicated time (Table 5). When TLC monitoring
indicated no further improvement in the reaction, the crude
products were suspended in CH2Cl2 (30 mL) and washed
with H2O (2 × 100 mL). The organic layer was dried over
Na2SO4 (10 g) and concentrated to afford the crude product,
which was purified by column chromatography on silica gel
(n-hexane–EtOAc). All products were characterized by 1H
NMR, 13C NMR, IR, CHN and MS analysis.
(23) Bentley, T. J.; McGhié, J. F.; Barton, D. H. R. Tetrahedron
Lett. 1965, 2497.
(24) (a) Block, J.; Beal, J. M. Wilson & Gisvold’s Textbook of
Organic Medicinal and Pharmaceutical Chemistry, 11th
ed.; Lippincott, Williams & Wilkins: Baltimore, 2003.
(b) Kleeman, A.; Engel, J.; Kutscher, B.; Reichert, D.
Pharmaceutical Substances, 3rd ed.; Thieme: Stuttgart,
1999.
(25) Soltani Rad, M. N.; Khalafi-Nezhad, A.; Behrouz, S.;
Faghihi, M. A. Tetrahedron Lett. 2007, 48, 6779.
(26) (a) Zhu, J.; Bienaymé, H. Multicomponent Reactions;
Wiley-VCH: Weinheim, 2005. (b) Khalafi-Nezhad, A.;
Soltani Rad, M. N.; Hakimelahi, G. H.; Mokhtari, B.
Tetrahedron 2002, 58, 10341. (c) Soltani Rad, M. N.;
Khalafi-Nezhad, A.; Babamohammadi, S.; Behrouz, S.
Helv. Chim. Acta 2010, 93, 2454. (d) Soltani Rad, M. N.;
Behrouz, S.; Nekoei, A. R.; Faghih, Z.; Khalafi-Nezhad, A.
Synthesis 2011, 4068.
(38) Selected spectral data:
4-(Allyloxy)-3-methoxy benzonitrile (Table 5, Entry 8):
White solid; Rf = 0.47 (EtOAc–n-hexane, 1:5); mp 59–
60 °C; 1H NMR (250 MHz, CDCl3): δ = 3.93 (s, 3 H, CH3),
4.60 (dd, J = 1.3, 5.1 Hz, 2 H, OCH2), 5.48 (dd, J = 1.5,
(27) Wang, E.-C.; Lin, G.-J. Tetrahedron Lett. 1998, 39, 4047.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1191–1198

1198
M. N. Soltani Rad et al.
LETTER
11.2 Hz, 2 H, =CH2), 6.11–6.14 (m, 1 H, =CH), 7.01 (d, J =
8.1 Hz, 1 H, ArH), 7.13 (s, 1 H, ArH), 7.25 (d, J = 8.1 Hz,
1 H, ArH); 13C NMR (250 MHz, CDCl3): δ = 54.17, 68.43,
104.51, 114.03, 115.94, 119.70, 119.93, 128.21, 134.58,
157.04, 161.37; MS: m/z (%) = 189.08 (30); Anal. Calcd for
C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.74; H,
5.94; N, 7.52.
3-(4-Methoxybenzyloxy) benzonitrile (Table 5, Entry
10): White solid; Rf = 0.31 (EtOAc–n-hexane, 1:9); mp 94–
95 °C; 1H NMR (250 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3),
5.30 (s, 2 H, OCH2), 7.11 (d, J = 8.2 Hz, 2 H, ArH), 7.25–
7.30 (m, 3 H, ArH), 7.39–7.46 (m, 3 H, ArH); 13C NMR (250
MHz, CDCl3): δ = 51.16, 69.45, 112.86, 115.37, 118.70,
121.57, 123.97, 127.05, 128.14, 130.91, 132.28, 158.76,
162.29; MS: m/z (%) = 239.09 (36); Anal. Calcd for
C15H13NO2: C, 75.30; H, 5.48; N, 5.85. Found: C, 75.42; H,
5.60; N, 5.80.
δ = 4.03 (t, J = 5.9 Hz, 2 H, NCH2), 4.22 (t, J = 5.9 Hz, 2 H,
OCH2), 6.88–6.91 (m, 2 H, aryl), 7.36–7.42 (m, 2 H, aryl),
7.58–7.63 (m, 2 H, aryl), 7.68–7.73 (m, 2 H, aryl); 13C NMR
(250 MHz, CDCl3): δ = 36.52, 65.19, 102.29, 112.29,
115.88, 121.31, 123.34, 131.86, 133.59, 133.76, 134.11,
159.66, 167.89; MS: m/z (%) = 292.08 (52); Anal. Calcd for
C17H12N2O3: C, 69.86; H, 4.14; N, 9.58. Found: C, 69.82; H,
4.17; N, 9.63.
2-[5-(2-Methyl-4-nitro-1H-imidazol-1-yl)pentyloxy]-
benzonitrile (Table 5, Entry 16): Bright yellow oil; Rf =
0.45 (EtOAc); 1H NMR (250 MHz, CDCl3): δ = 0.73–0.75
(m, 2 H, CH2), 1.05 (m, 4 H, 2 × CH2), 1.59 (s, 3 H, CH3),
3.20 (m, 4 H, NCH2, OCH2), 6.16–6.19 (m, 2 H, ArH), 6.67–
6.68 (m, 2 H, ArH), 7.13 (s, 1 H, C(5)-H, imidazole); 13
C
NMR (250 MHz, CDCl3): δ = 12.42, 22.37, 27.68, 29.28,
46.51, 68.12, 100.81, 111.99, 116.02, 120.23, 132.97,
134.15, 144.42, 145.57, 159.94, 161.84; MS: m/z (%) =
314.10 (48); Anal. Calcd for C16H18N4O3: C, 61.13; H, 5.77;
N, 17.82. Found: C, 61.15; H, 5.81; N, 17.79.
2-[2-(1,3-Dioxoisoindolin-2-yl)ethoxy]benzonitrile
(Table 5, Entry 15): White solid; Rf = 0.48 (EtOAc–n-
hexane, 1:1); mp 148–149 °C; 1H NMR (250 MHz, CDCl3):
Synlett 2012, 23, 1191–1198
© Georg Thieme Verlag Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.