An efficient synthesis of: N -nitrosamines under solvent, metal and acid free conditions using tert -butyl nitrite

Article abstract of DOI:10.1039/c5gc02880a

Synthesis of various N-nitroso compounds from secondary amines is reported using tert-butyl nitrite (TBN) under solvent free conditions. Broad substrate scope, metal and acid free conditions, easy isolation procedure and excellent yields are few important features of this methodology. The acid labile protecting groups such as tert-butyldimethylsilyl (TBDMS) and tert-butyloxycarbonyl (Boc) as well as sensitive functional groups such as phenols, olefins and alkynes are found to be stable under the standard reaction conditions. Besides N-nitrosation, TBN is also found to be an efficient reagent in few other transformations including aryl hydrazines to aryl azides and primary amides to carboxylic acids under mild conditions.

Full text of DOI:10.1039/c5gc02880a

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DOI: 10.1039/C5GC02880A
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An efficient synthesis of N-nitrosamines under solvent, metal and
acid free conditions using tert-butyl nitrite
Priyanka Chaudhary,a# Surabhi Gupta,a# Nalluchamy Muniyappan,b Shahulhameed Sabiahb and
Jeyakumar Kandasamya*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
experimental antihypertensive agent that inhibits copper-
dependent dopamine β-hydroxylase effieciently.2a,6 Similarly, the N-
nitroso-N-cyclohexylhydroxylamine (G) is used as a synergistic agent
which increases the insecticidal activity of chlordane.2a
Synthesis of various N-nitroso compounds from secondary amines
is reported using tert-butyl nitrite (TBN) under solvent free
conditions. Broad substrate scope, metal and acid free conditions,
easy isolation procedure and excellent yields are the few
important features of this methodology. The acid labile protecting
groups such as tert-butyldimethylsilyl (TBDMS) and tert-
butyloxycarbonyl (Boc) as well as sensitive functional groups such
as phenols, olefins and alkynes are found to be stable under the
standard reaction conditions. Besides the N-nitrosation, TBN is
also found to be an efficient reagent in few other transformations
including aryl hydrazines to aryl azides and primary amides to
carboxylic acids under mild conditions.
N-Nitroso compounds present in a wide range of foods, cosmetics
and natural products.1 More attention is being paid to the
chemistry of N-nitroso compounds owing to their unique
carcinogenic and mutagenic properties.2 These compounds have
been used in various treatments including cancer, cardiovascular
diseases, central nervous disorders, and diseases related to
immunity and physiological disorders (Figure 1).1-2 For instance, a
derivative of N-nitrosoaniline, dephostatin (Figure 1, A) is known to
be a potential inhibitor of cysteine-containing enzymes such as
protein tyrosine phosphatases, papain and caspase.2a,3 The cyclic-
nitrosamines B and C have been found to inhibit thrombus
formation in arterioles and venules of rats.2a Although N-methyl-N-
nitrosourea is a cancer inducer, its derivatives were found to be
potent antitumor agents. For example, carmustine (Figure 1, D) and
related compounds (e.g. Lomustine and Semustine) are widely used
as an alkylating agent in chemotherapy.4 Streptozocin (E) is a sugar
derived N-methylnitrosourea used as an antibiotic and
antineoplastic agent.4b In addition, streptozocin is also a well-known
diabetogenic agent currently used in medical research to produce
animal models for hyperglycemia and Type 1 diabetes.5 The N-
nitrosohydroxylamine derivative dopastin (Figure 1, F) is used as an
Figure 1. Biologically important N-nitroso compounds.
Besides the biological importance, N-nitrosamine compounds have
become valuable intermediates in organic synthesis.7 Preparations
of biologically important α-disubstituted hydrazines8 and
mesoionic-heterocyclic compound sydnones9 are the traditional
applications of N-nitrosamines (Scheme 1). Aryl C-nitroso
compounds can be obtained in good yield from N-nitrosamines
through Fischer–Hepp rearrangement.10 Moreover, the electrophilic
substitutions at the α-carbon of the secondary amines have been
performed in a regio- and stereoselective manner by masking the
secondary amines as N-nitrosamines.11 Recently, N-nitrosamine
functional groups have emerged as a traceless directing group for
a.Department of chemistry, Indian Institute of Technology (BHU), Varanasi, Uttar
Pradesh-221005; Email: jeyakumar.chy@iitbhu.ac.in
b.Department of chemistry, Pondicherry University, Pondicherry-605014
Both authors contributed equally to this work
#
† Electronic Supplementary Informaꢀon (ESI) available: See
DOI: 10.1039/x0xx00000x. NMR Spectra is available for all the products. CIF file of
compound 2f with CCDC number 1444786 is available as supplementary information
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the activation of inert C-H bond in aryl rings by associating with environmental awareness with respect to green chemistry, there is
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transition metals.12 These C-H activation reactions provide a fruitful also a pressing need to develop eco-friendly approaches for the
DOI: 10.1039/C5GC02880A
way to construct various biologically important heterocyclic preparation of various fine chemicals.22
compounds.
tert-Butyl nitrite (TBN) is a very useful synthetic reagent frequently
used for diazotization reactions.23 In addition, TBN is also explored
in a regiospecific C-nitration of phenols, azoarenes, arylboronic
acids, anilides, aromatic sulfonamides, olefins and alkynes.24
Recently, a regioselective C-nitrosation of imidazoheterocycles has
been accomplished by using tert-butyl nitrite under catalyst free
condition.25 As a metal-free reagent, tert-butyl nitrite has many
advantages like commercial availability, inexpensiveness, easy
handing, medium volatility, good solubility in common solvents, etc.
In this context, here we would like to report an important
application of tert-butyl nitrite i.e. N-nitrosation of secondary
amines under solvent free conditions.
Scheme 1. Some traditional applications of N-nitrosamines
Table 1. Nitrosation of N-methyl aniline using tert-butyl nitrite.a
Figure 2. Recent applications of N-nitrosamines as a directing group for
inert C-H bond activation.12
The chemical syntheses of N-nitrosamines are well-established
reaction in organic synthesis.7a The most common procedure
involves the use of nitrous acid generated (in situ) from sodium
nitrite and concentrated mineral acid (e.g. HCl, H2SO4). Besides this
traditional
reagent,
nitrosyl
chloride,13
nitrosonium
tetrafluoroborate,14 nitroso-crown ether adduct [NO+,Crown,
‾
H(NO3)2 ],15 Fremy’s salt16 and nitrogen oxides (e.g. N2O3, N2O4,
etc)17 were used to accomplish various N-nitroso compounds from
corresponding secondary amines. In addition, various
heterogeneous systems have been developed in the last decade
using a combination of sodium nitrite with solid acids18 or nitrogen
oxide with different solid supports.19 However, most of these
methods proceed through a strong acidic condition which limits
their use in a complex synthesis, particularly, when there is an acid-
labile group on the substrate. Moreover, preparation, handling and
storing of some of these reagents are very difficult which further
limit their extensive uses in organic synthesis. Dealkylative
nitrosation of tert-amines have been performed previously using
some alkyl nitrites.20 Very recently, nitromethane (CH3NO2) has
been employed as an alternative source for generating nitrosyl (NO)
moiety in the presence of various oxidizing systems (e.g. IBX or
KI/TBHP or [Cu]/O2).21 However, these methods are not practical on
a
Reaction conditions: Amine (1 mmol) and TBN was stirred in the respective solvents (2
b
d
mL) at room temperature. Isolated yields. cCrude yield (seen in 1H NMR). n-Butyl
e
nitrite was employed. Isoamyl nitrite was employed.
At the outset, commercially available N-methylaniline (1a) was used
as a model substrate for N-nitrosation reaction with tert-butyl
nitrite (TBN). The reactions were performed at room temperature
in various protic and aprotic solvents (Table 1). Dichloromethane
provides the desired product 2a in 81% with one equiv. of TBN after
40 minutes (Table 1, entry 1). Further, no improvement was
observed in the yield with increase in time. However, by increasing
TBN to 1.5 equiv. the reaction leads to completion (92%, Isolated
yield) in 25 minutes (Table 1, entry 2). Similarly, other aprotic
solvents such as chloroform, dichloroethane, diethyl ether,
a
parallel synthesis due to poor yields and harsh reaction
conditions. In this context, development of an acid free and metal
free nitrosating reagent which will work efficiently under mild
conditions remains an important goal. With the increase in
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tetrahydrofuran and acetonitrile took around 20-30 minutes and accomplished from corresponding secondary amineViienw Ahritgichle Oynielinlde
DOI: 10.1039/C5GC02880A
provide the desired product in good to excellent yields (Table 1, within 60 minutes (Table 2, 2j).
entries 3-7). However, the protic solvents such as methanol,
ethanol and H2O took slightly longer reaction time (45-90 mins) for
completion which may be due to the interaction of nucleophilic
solvents with TBN (Table 1, entries 8-10). Overall, TBN is found to
be an efficient nitrosating reagent in most of the commonly used
organic solvents.
From the environmental perspective, green chemistry gets an
Scheme 2. Conversion of N-benzylaniline to corresponding N-nitrosoaniline
immense appreciation in recent years. According to one of the
using NaNO2-HCl and TBN.
principles of green chemistry, toxic solvents in organic synthesis
should be replaced with greener alternatives (e.g. water, ionic
liquids, supercritical CO2, bio-based green solvents, etc.) or
chemical reaction should be favored under solvent free
conditions.22 Development of solvent free protocols appears to be
an ideal case, because, solvent free reactions not only reduce the
environmental pollution but also high yielding and cost effective.26
However, to best of our knowledge so far there is no convenient
solvent free protocol has been described for the preparation of N-
nitrosamines. Hence, the N-nitrosation of methylaniline (1a) was
attempted under solvent free condition using one equiv. of tert-
Scheme 3. Nitrosation reaction with N-(4-Hydroxybenzyl) 4-
bromoaniline (1m).
butyl nitrite at room temperature (Table 1, entry 11). We were
pleased to see
a quantitative formation of N-nitroso-N-
Functional group and protecting group tolerance is one of the most
important aspects in multistep organic synthesis. In order to test
the compatibility of commonly used acid labile protecting groups
such as tert-butyldimethylsilyl (TBDMS) and tert-butyloxycarbonyl
(Boc), compounds 1k and 1l have been synthesized and subjected
for N-nitrosation reactions under optimized condition. It was found
that both TBDMS and Boc protecting groups remain stable during
the reaction and desired products (2k and 2l) were obtained in
good yields. By considering the previous reports on C-nitration of
phenols, olefins and alkynes with tert-butyl nitrite,24d, 24m, 24n N-(4-
Hydroxybenzyl)4-bromoaniline (1m), N-allyl aniline (1n) and N-
propargyl aniline (1o) (i.e. substrates containing secondary amine
with phenol, olefin and alkyne functionalities) were subjected for
nitrosation reaction under optimized conditions. Remarkably, in all
three cases the desired N-nitroso products (2m, 2n and 2o) were
obtained in high yields which show the broad scope of this
methodology. Moreover, with an excess amount of TBN (≈4 equiv.)
alkene and alkyne functionalities remained intact while
interestingly, ortho-nitrated N-nitroso phenol (2m') was obtained
from the phenolic substrate 1m in 84% yield (Scheme 3).
methylaniline (2a) within 5 minutes. Although, the other frequently
used alkyl nitrites such as n-butyl nitrite and isoamyl nitrite provide
the desired product in comparable yield (Table 1, entries 12 and
13), tert-butyl nitrite offers some important advantages over
others. For example, tert-butanol i.e. the resulted byproduct of tert-
butyl nitrite during the N-nitrosation, is less susceptible to further
reactions (e.g. oxidation, nucleophilic substitution, etc.) when
compared with primary alcohols which is resulted from n-butyl
nitrite and isoamyl nitrite. In addition, tert- butanol is completely
miscible with water while n-butanol and isoamyl alcohol has limited
water solubility (e.g. water solubility of isoamyl alcohol: 28 g/L and
n-butanol: 73 g/L) which increases the difficulty in isolation of pure
products through simple aqueous work up procedures. In the case
of tert-butyl nitrite, the product was obtained in high purity by
aqueous work-up or filtering the crude product through a short
silica pad without any work-up procedures. To some extent, this
solvent-free and easy isolation procedure minimizes the exposures
of chemists to the carcinogenic N-nitroso compounds.
Prompted, N-nitrosation of various secondary amines was studied
using TBN under solvent free conditions and the results are
summarized in Table 2. Similar to N-methyl aniline (1a), N-ethyl,
phenyl and benzyl anilines underwent nitrosation smoothly at room
temperature in a chemo-selective manner (Table 2, 2b-2i). In all the
cases quantitative conversion (>94%) was observed irrespective of
substituents on the substrate. In this context, the traditional
procedure (i.e. NaNO2/HCl) was found to be inferior, particularly
observed in the case of conversion of N-benzylanilines to
corresponding nitrosamines.12c For example, N-benzyl N-
nitrosoaniline (2d) was obtained only in 66% from corresponding
secondary amine using the traditional procedure while the current
method (i.e. TBN) provides 96%, which clearly distinguish the
efficiency of TBN over NaNO2/HCl (Scheme 2). On the other hand,
TBN is also found to be very efficient in nitrosating sterically
hindered anilines where N-nitroso N-isopropylaniline was
Further to extend the scope of this methodology, N-nitrosation of
various dibenzyl, benzyl alkyl, dialkyl and cyclic secondary amines
were carried out under optimized conditions (1p-1y). During the
nitrosation of dibenzyl amine (1p), a slower rate of conversion was
observed at room temperature, thus, the reaction was performed
at 45 °C with 1.5 equiv. of tert-butyl nitrite. Under this elevated
temperature, dibenzyl and benzyl alkyl amines underwent
nitrosation in high yields (>91%) within the period of one hour (2p-
2s). On the other hand, dialkyl and cyclic secondary amines (1t-1y)
undergo N-nitrosation within the period of 4-5 hrs to provide
desired products (2t-2y) in good yields (>80%), however with 2.0
equivalents of tert-butyl nitrite. Overall, the reactivities of different
types of secondary amines were found in the following order: aryl
amines>benzyl amines>alkyl amines.
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DOI: 10.1039/C5GC02880A
Table 2. Nitrosation of secondary amines using tert-butyl nitrite under solvent free conditions.a,b
aReaction conditions: Amine (1 mmol) and t-BuONO (1.0 equiv.) was stirred at room temperature or 45 °C. bIsolated yields. c Reaction was started at 0°C and
allowed to stir at RT. dReactions were carried out at 45 °C with 1.5 equiv. TBN. eReactions were carried out at 45 °C with 2 equiv. TBN.
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DOI: 10.1039/C5GC02880A
Scheme 5. One-pot synthesis of 1-methyl-1-phenylhydrazine directly from N-methylaniline.
The scope of this methodology was further investigated by
attempting the synthesis of biologically important N-nitroso-N-
cyclohexylhydroxylamine (Figure 1, G). The synthesis of compound
G was accomplished from cyclohexanone in three steps as shown in
Scheme 4. The reaction of cyclohexanone with hydroxylamine
hydrochloride followed by sodium cyanoborohydride reduction
provides the N-cyclohexylhydroxylamine in 24% yield27 which was
subjected for the N-nitrosation under solvent free condition using
tert-butyl nitrite. The N-nitrosation reaction underwent smoothly at
room temperature to provide the desired product in 83% yield.
(e.g. 2j) and unsymmetrical benzyl amines (e.g. 2q-2s) gave two
rotamers approximately in 1:1 ratio (Figure 3, IV and V, see ESI).
Figure 4. ORTEP (at 50% ellipsoid) diagram of 2f. 28
α-Disubstituted hydrazines and their derivatives exhibit a wide
range of biological properties.29 In addition, they are also used as
building blocks for the construction of various biologically
important heterocyclic compounds.29 One-pot syntheses of α-
disubstituted hydrazines directly from secondary amines (via N-
nitrosamine intermediate) is not well-established reaction in
organic synthesis. Nevertheless, it is expected that the
development of such protocol will reduce the time and labor as well
as prevent the exposure of chemists to N-nitrosoamines. In a
representative reaction, we have attempted one-pot synthesis of 1-
methyl-1-phenylhydrazine directly from N-methylaniline, i.e.
nitrosation followed by reduction using TBN and zinc-acetic acid,
respectively (Scheme 5). The reaction provides 46% (under non-
optimized conditions) of the desired product while the usual two
step protocol provides 53% (overall yield) which basically require
workup procedures, isolation of intermediates, etc. (Scheme 5).8c
Scheme 4. A synthetic route for the preparation of compound G.
Aryl azides have found growing applications in organic synthesis
especially for the assembly of heterocyclic compounds and
dendrimers.30 Aryl azides are usually prepared by the nucleophilic
displacement of aryl halides with sodium azide. Alternatively,
mono-substituted aryl hydrazines can be converted to
corresponding aryl azides using a nitrosating reagent under mild
conditions. Basically, this transformation proceeds through
a
Figure 3. Different orientations of N-nitrosamines.
formation of terminal N-nitroso intermediate (Table 3) from which
a water molecule is removed to yield the corresponding azide. This
transformation was previously explored with NaNO2/HCl,31 N2O4,32
nitrosyl tetrafluoroborate33 and Ph3P/Br2/n-Bu4NNO234 where these
reactions proceed through an acidic medium. The efficiency of TBN
in this transformation was studied using 4-bromophenyl hydrazine
(3a) as a model substrate with 2.0 equiv. of TBN in acetonitrile
(Table 3). We were glad to see a clean reaction that provides 91% of
4-bromophenyl azide (4a) within 60 minutes at room temperature.
Similarly, 3-nitrophenyl azide (4b) and 4-cyanophenyl azide (4c) was
obtained in high yield (>85%) under the same conditions. Moreover,
heterocyclic azide i.e. 2-pyridyl azide (4d) was obtained in a
It is well known that N-nitrosamines exhibit two orientations (i.e.
syn and anti) due to restricted rotation of the N–N bond resulting
from nitrogen lone-pair delocalization (Figure 3, I and II).7a During
the N-nitrosation with TBN, the α-unsubstituted and mono-
substituted N-alkyl anilines gave predominantly one isomer
(observed in NMR for the products 2a, 2b, 2d-2i, 2k-2m). The
orientation of N-nitroso group in these compounds is expected to
be less hindered side (i.e. alkyl side, Figure 3, III) and this was
further confirmed by single crystal XRD analysis of the product 2f
(Figure 4).28 On the other hand, α-di-substituted N-alkyl anilines
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under strong acidic or basic conditions. Hydrolysis of primary
quantitative yield (94%) from 2-hydrazinopyridine which shows the
broad synthetic utility of this methodology.
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amides via diazotization is another simple approach, but less
DOI: 10.1039/C5GC02880A
explored in organic synthesis.35 The efficiency of TBN in this
Table 3. Conversion of aryl hydrazines into corresponding azides.a,b
transformation was examined using benzamide as
a model
substrate. The reaction was performed using three equiv. of TBN in
acetic acid at 75°C. The reaction provides benzoic acid (6a) as a
single product in quantitative yield within 60 minutes. Likewise, 4-
methoxy and 4-nitrobenzamides (electron-rich and poor amides)
were converted to corresponding benzoic acids (6b and 6c,
respectively) in quantitative yield within a short time. Interestingly,
this protocol is also compatible with heterocyclic amides where
nicotinamide is successfully converted to nicotinic acid (6d) in an
excellent yield. As a matter of fact, TBN is found to be a superior
diazotizing reagent when compared with iso-amyl nitrite which
requires not only longer reaction time but also provides lower
yields.35c For example, conversion of 4-methoxybenzamide to
corresponding acid was achieved within 30 mins using TBN while 12
hrs required with iso-amyl nitrite, although the yields of both
reactions are approximately same (>94%). On the other hand, 4-
nitrobenzoic acid was obtained only in 57% using iso-amyl nitrite
after 6hrs while TBN provides quantitative yield in one hour. It is
also worthy to mention that this transformation basically doesn’t
need any work-up procedures or column chromatography. Simple
evaporation of acetic acid provides the desired products in enough
purity. Overall, the tert-butyl nitrite is found to be a versatile
reagent in organic synthesis.
aReaction conditions: Hydrazine (2 mmol) and TBN (2.0 equiv.) was stirred in
acetonitrile ( 3mL) at room temperature bIsolated yield. C 5.0 equiv. of TBN is
used.
In conclusion, we have demonstrated here an efficient and greener
method for the N-nitrosation of secondary amines using tert-butyl
nitrite under solvent free, metal free and acid free conditions. A
number of aryl, benzyl and alkyl secondary amines were nitrosated
in excellent yields under mild conditions. Remarkably, the acid
labile protecting groups such as tert-butyldimethylsilyl (TBDMS) and
tert-butyloxycarbonyl (Boc) as well as sensitive functional groups
such as phenols, olefin and alkyne were found to be remain intact
under the standard reaction conditions. One-pot synthesis of α-
disubstituted hydrazine from secondary amine was successfully
demonstrated using TBN as nitrosating reagent. Besides the N-
nitrosation, TBN is also found to be an efficient reagent in the
transformation of aryl hydrazines to aryl azides and primary amides
into carboxylic acids under mild conditions. The scope and
limitations of these preliminary reports will be explored in due
course.
Table 4. Conversion of benzamides into benzoic acids. a,b
Acknowledgements
J. K gratefully acknowledges IIT (BHU) for the start-up research
grant and DST for young scientist start-up research grant
(YSS/2014/000236). P. C and S. G acknowledge IIT (BHU) for a
research fellowship. J. K thanks to Dr K. Murugan (Yung Shin,
Taiwan) for a helpful discussion during the manuscript preparation.
J. K also acknowledges Prof. V. Srivastava and Prof. M. A. Quraishi
(IIT BHU) for a helpful discussion during the course of experiments.
J. K thanks Central Instrumentation Facility Center (CIFC)-IIT BHU
and Prof. Rajeev Prakash (Head, CIFC) for the NMR facilities. J.K
gratefully acknowledges Dr. Babu Varghese, SAIF, IIT Madras for
single crystal XRD data analysis. S.S and N.M acknowledge
Pondicherry University for NMR and MASS facilities.
aReaction conditions: Amide (1 mmol) and TBN (3.0 equiv.) was stirred in
acetic acid (3mL) at 75 C. bIsolated yield. CReactions with iso-amyl nitrite
°
(ref. 35c). d5.0 equiv. of TBN is used.
Similarly, the conversion of primary amides into corresponding
carboxylic acids is an important transformation typically achieved
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16. L. Castedo, R. Riguera and M. P. Vazquez, J. Chem. Soc., Chem.
References and notes
View Article Online
Commun., 1983, 301-302.
DOI: 10.1039/C5GC02880A
17. (a) E. H. White, J. Am. Chem. Soc., 1955, 77 6008–6010; (b) B.
C. Challis and S. A. Kyrtopoulos, J. Chem. Soc., Perkin Trans. 1 ,
1979, 299-304.
18. (a) M. A. Zolfigol, D. Habibi, B. F. Mirjalili and A. Bamoniri,
Tetrahedron Lett., 2003, 44, 3345-3349; (b) M. A. Zolfigol and
A. Bamoniri, Synlett, 2002, 1621-1624; (c) M. A. Zolfigol, A. G.
Choghamarani and H. Hazarkhani, Synlett, 2002, 1002-1004.
(d) M. A. K. Zarchi and J. Noei, J. Appl. Polym. Sci. 2009, 114,
2134–2138.
19. (a) D. Roche, C. Lardy, L. Tournier, M. Prunier and E. Valeur,
Tetrahedron Lett., 2010, 51, 2277-2280; (b) N. Iranpoor, H.
Firouzabadi and A. R. Pourali, Synth. Commun., 2005, 35, 1517-
1526; (c) N. Iranpoor, H. Firouzabadi and A. R. Pourali,
Synthesis, 2003, 1591-1597.
20. (a) G. Verardo, A. G. Giumanini and P. Strazzolini, Tetrahedron,
1991, 47, 7845-7852; (b) G. Verardo, A. G. Giumanini and P.
Strazzolini, Tetrahedron, 1990, 46, 4303-4332.
1. (a) R. N. Loeppky and J. R. Outram, N-Nitroso Compounds:
Occurrence and Biological Effects, IARC Scientific Publishers,
Lyon, 1982; (b) R. N. Loeppky and C. J. Michejda, Nitrosamines
and Related N-Nitroso Compounds: Chemistry and
Biochemistry, ACS Symposium Series, American Chemical
Society, Washington, DC, 1994.
2. (a) P. G. Wang, T. B. Cai and N. Taniguchi, Nitric Oxide Donor:,
For Pharmaceutical and Biological Applications, WILEY-VCH
Verlag GmbH & Co. KGaA, Weinheim, 2005; (b) P. G. Wang, M.
Xian, X. Tang, X. Wu, Z. Wen, T. Cai and A. J. Janczuk, Chem.
Rev., 2002, 102, 1091-1134.
3. (a) H. Kakeya, M. Imoto, Y. Takahashi, H. Naganawa, T.
Takeuchi and K. Umezawa, J. Antibiot., 1993, 46, 1716-1719;
(b) M. Li, S. M. Shandilya, M. A. Carpenter, A. Rathore, W. L.
Brown, A. L. Perkins, D. A. Harki, J. Solberg, D. J. Hook, K. K.
Pandey, M. A. Parniak, J. R. Johnson, N. J. Krogan, M.
Somasundaran, A. Ali, C. A. Schiffer and R. S. Harris, ACS Chem.
Biol., 2012, 7, 506-517.
4. (a) R. Sen, Principles and Management of Cancer, B I
Publications Pvt Ltd, New Delhi, 2004; (b) C. T. Gnewuch and G.
Sosnovsky, Chem. Rev., 1997, 97, 829-1013.
21. (a) N. Sakai, M. Sasaki and Y. Ogiwara, Chem. Commun., 2015,
51, 11638-11641; (b) J. Zhang, J. Jiang, Y. Li and X. Wan, J. Org.
Chem., 2013, 78, 11366-11372; (c) H. K. Potturi, R. K. Gurung
and Y. Q. Hou, J. Org. Chem., 2012, 77, 626-631.
22. (a) R. A. Sheldon, Green. Chem., 2005, 7, 267-278; (b) P. T.
Anastas and J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, New York, 1998. (c) S. Gupta,
P. Chaudhary, L. Seva, S. Sabiah and J. Kandasamy RSC Adv.,
2015, 5, 89133-89138
23. (a) K. Barral, A. D. Moorhouse and J. E. Moses, Org. Lett., 2007,
9, 1809-1811. (b) L. Marinescu, J. Thinggaard, I. B. Thomsen
and M. Bols, J. Org. Chem., 2003, 68, 9453-9455.
5. A. A. Rossini, A. A. Like, W. L. Chick, M. C. Appel and G. F.
Cahill, Jr., Proc. Natl. Acad. Sci. U. S .A., 1977, 74, 2485-2489.
6. H. Iimura, T. Takeuchi, S. Kondo, M. Matsuzaki and H.
Umezawa, J. Antibiot., 1972, 25, 497-500.
7. (a) J.-P. Anselme, N-Nitrosamines, ACS Symposium Series,
American Chemical Society, 1979; (b) J. E. Saavedra, Org. Prep.
Proced. Int., 1987, 19, 85-159.
8. (a) I. D. Entwistle, R. A. W. Johnstone and A. H. Wilby,
Tetrahedron, 1982, 38, 419-423; (b) F. W. Schueler and C.
Hanna, J. Am. Chem. Soc., 1951, 73, 4996–4996; (c)W. W.
Hartman and L. J. Roll, Org. Synth., 1933, 13, 66-67; (d) R. L.
Hinmap and K. L. Hamm, J. Org. Chem., 1958, 23 529–531.
9. (a) D. L. Browne and J. P. A. Harrity, Tetrahedron, 2010, 66,
553-568; (b) F. H. C. Stewart, Chem. Rev., 1964, 64 129–147.
10. (a) D. L. H. Williams, Tetrahedron, 1975, 31, 1343-1349; (b) I.
Cikotiene, M. Jonusis and V. Jakubkiene, Beilstein J. Org.
Chem, 2013, 9, 1819-1825.
24. (a) T. Taniguchi, A. Yajima and H. Ishibashi, Adv. Synth. Catal.,
2011, 353, 2643-2647; (b) X. F. Wu, J. Schranck, H. Neumann
and M. Beller, Chem. Commun., 2011, 47, 12462-12463; (c) B.
Kilpatrick, M. Heller and S. Arns, Chem. Commun., 2013, 49,
514-516; (d) S. Maity, T. Naveen, U. Sharma and D. Maiti, Org.
Lett., 2013, 15, 3384-3387; (e) S. Manna, S. Jana, T. Saboo, A.
Maji and D. Maiti, Chem. Commun., 2013, 49, 5286-5288; (f) Y.
Liu, J. L. Zhang, R. J. Song, P. C. Qian and J. H. Li, Angew. Chem.
Int. Ed. Engl., 2014, 53, 9017-9020; (g) B. Majhi, D. Kundu, S.
Ahammed and B. C. Ranu, Chem-Eur. J., 2014, 20, 9862-9866;
(h) T. Shen, Y. Z. Yuan and N. Jiao, Chem. Commun., 2014, 50,
554-556; (i) G. B. Deng, J. L. Zhang, Y. Y. Liu, B. Liu, X. H. Yang
and J. H. Li, Chem. Commun., 2015, 51, 1886-1888; (j) X. H.
Hao, P. Gao, X. R. Song, Y. F. Qiu, D. P. Jin, X. Y. Liu and Y. M.
Liang, Chem. Commun., 2015, 51, 6839-6842; (k) Y. F. Ji, H. Yan
and Q. B. Jiang, Eur. J. Org. Chem., 2015, 2051-2060; (l) X. H.
Yang, X. H. Ouyang, W. T. Wei, R. J. Song and J. H. Li, Adv.
Synth. Catal., 2015, 357, 1161-1166; (m) D. Koley, O. C. Colon
and S. N. Savinov, Org. Lett., 2009, 11, 4172-4175; (n) U. Dutta,
S. Maity, R. Kancherla and D. Maiti, Org. Lett., 2014, 16, 6302-
6305.
25. K. Monir, M. Ghosh, S. Jana, P. Mondal, A. Majee and A. Hajra,
Org. Biomol. Chem., 2015, 13, 8717-8722.
26. K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025-1074.
27. P. Li, C. Wu, J. Zhao, Y. Li, W. Xue, and F. Shi, Can. J. Chem.,
2013, 91, 43–50.
28. CCDC number 1444786. The compound 2f was crystallised
suitable for single crystal XRD analysis in DCM-EtOH at room
temperature. The X-Ray crystallographic studies were carried
out on Bruker Kappa APEXII Diffractometer with Mo-Kα
radiation (λ = 0.71073 Å). Structure solution and refinement
11. D. Seebach and D. Enders, Angew. Chem. Int. Ed. Engl., 1975,
14, 15-32.
12. (a) B. Liu, Y. Fan, Y. Gao, C. Sun, C. Xu and J. Zhu, J. Am. Chem.
Soc., 2013, 135, 468-473; (b) B. Q. Liu, C. Song, C. Sun, S. G.
Zhou and J. Zhu, J. Am. Chem. Soc., 2013, 135, 16625-16631;
(c) C. Wang and Y. Huang, Org. Lett., 2013, 15, 5294-5297; (d)
J. Chen, P. Chen, C. Song and J. Zhu, Chem-Eur. J., 2014, 20,
14245-14249; (e) T. Gao and P. Sun, J. Org. Chem., 2014, 79,
9888-9893; (f) Y. Wu, L. J. Feng, X. Lu, F. Y. Kwong and H. B.
Luo, Chem. Commun., 2014, 50, 15352-15354; (g) F. Xie, Z. S.
Qi, S. J. Yu and X. W. Li, J. Am. Chem. Soc., 2014, 136, 4780-
4787; (h) S. Yu and X. Li, Org. Lett., 2014, 16, 1200-1203; (i) D.
D. Li, Y. X. Cao and G. W. Wang, Org. Biomol. Chem., 2015, 13,
6958-6964. (j) J. Dong, Z. Wu, Z. Liu, P. Liu and P. Sun J. Org.
Chem., 2015, 80, 12588–12593.
13. M. A. Zolfigol, F. Shirini, A. G. Choghamarani, A. Taqian-Nasab,
H. Keypour and S. Salehzadeh, J. Chem. Res-S, 2000, 420-422.
14. G. Olah, L. Noszkwo, S. Kuhn and M. Szelke, Chem. Ber., 1956,
89, 2374–2377.
15. M. A. Zolfigol, M. H. Zebarjadian, G. Chehardoli, H. Keypour, S.
Salehzadeh and M. Shamsipur, J. Org. Chem., 2001, 66, 3619-
3620.
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were performed with SHELX-97. All non-hydrogen atoms were
refined anisotropically. Hydrogen atoms were generated
according to stereochemistry and refined using riding model in
SHELX-97. A. Altomare, G. Cascarano, C. Giacovazzo and A.
Guagliardi, J. Appl. Crystallogr., 1993, 26, 343–350.
29. U. Ragnarsson, Chem. Soc. Rev., 2001, 30, 205-213.
30. E. F. V. Scriven and K. Turnbull, Chem. Rev., 1988, 88 297–368.
31. R. O. Lindsay and C. F. H. Allen, Org. Synth., 1942, 22, 96.
32. Y. H. Kim, K. Kim and S. B. Shim, Tetrahedron Lett., 1986, 27
4749-4752.
View Article Online
DOI: 10.1039/C5GC02880A
33. V. Pozsgay and H. J. Jennings, Tetrahedron Lett., 1987, 28,
5091-5092.
34. N. Iranpoor, H. Firouzabadi and N. Nowrouzi, Tetrahedron
Lett., 2008, 49, 4242-4244.
35. (a) Y. H. Kim, K. Kim and Y. J. Park, Tetrahedron Lett., 1990, 31
3893–3894; (b) K. Kim and Y. H. Kim, B. Kor. Chem. Soc., 1994,
15, 100-101; (c) G. T. Potter, G. C. Jayson, G. J. Miller and J. M.
Gardiner, Tetrahedron Lett., 2015, 56, 5153-5156.
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