2
P. GAUR AND S. BANERJEE
to their strong mutagenic and carcinogenic properties, they have also been found to
possess vasorelaxant activity.[7] In addition, recently, N-nitroso functionality has
emerged as a traceless directing group for various metal catalyzed aryl C–H functionali-
zation reactions. N-nitrosamines were reported to exhibit captivating biological activ-
ities. For example, many N-nitrosamines have proven to be strong inhibitors of
cysteine-containing enzymes such as papain and caspase.[8] Few cyclic nitrosamines
exhibit properties of thrombus formation inhibition in arterioles and venules of rats. N-
methyl-N-nitrosourea and its derivatives are found to display anti-tumor properties.[9]
For example, Carmustine, Lomustine, and Semustine are widely used as an alkylating
agent in chemotherapy. Streptozocin (E) is a sugar derived N-methylnitrosourea used as
an antibiotic and antineoplastic agent.[10] 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. Under certain circumstances, N-nitrosamines could
release nitric oxide and, therefore, could have medical implications against hypertensive
conditions.[11] They are also utilized as synthetic blocks for different synthetic proce-
dures using nitroso aldol and cycloaddition reactions. They are useful for studying the
stereochemistry of compounds, NO-releasing activity relationship and also for N–NO
bond dissociation energy calculations.[12]
As per literature reports, a great amount of exploration on the synthetic procedures
towards the formation of nitrosamine has been done till date (Figure 1). Traditional and
classically nitrous acid, generated from sodium nitrite and mineral acids in water or in
mixed alcohol-water solvents is used for N-nitrosation reactions. Apart from these,
sodium nitrite with various combinations have been investigated in order to get the fast
and easy formation of nitrosamines including NaNO2-PhI(OAc)2, Tin(IV)
Chloride–Sodium Nitrite,[13] sodium nitrite with phase transfer conditions, NaNO2-p-
TSA,[14] NaNO2/HClO4-SiO2,[15] NaNO2-Alumina-methanesulfonic acid(AMA),[16]
NaNO2/PS-SNAP,[17] Poly(N,N0-dibromo-N-ethylene-benzene-1,3-disulfonamide) and
N,N,N,N-tetrabromobenzene1,3-disulfonamide/NaNO2,[18] NaNO2-Molybdatophosphoric
[20]
acid,[19] Nafion-H -NaNO2,
Silica Sulfuric Acid-NaNO2,[21] Trichloroisocyanuric
R
V
Acid-NaNO2,[22] Silica Chloride-NaNO2,[23] H5IO6 or HIO3/NaNO2,[24] NaNO2/Wet
SiO2(50% w/w)/Mg(HSO4)2 and NaHSO4.H2O,[25] NaNO2-C2H2O4.2H2O,[26] NaNO2-
Ac2O,[27] 1,3,5-Triazine-2,4,6-triyltrisulfamic acid (TTSA)-NaNO2,[28] Bismuth Chloride-
Sodium Nitrite,[29] and Trichloromelamine-NaNO2.[30] Other nitrosating agents, Fremy’s
salt[31] oxyhyponitrite and sodium nitrite have also been used. Besides, a few other
reagents such as nitrosonium tetrafluoroborate (NOBF4),[32] tert.butyl nitrite,[33]
[NOþ.Crown.H(NO3)2],[34] nitrogen oxides (N2O3),[35] N2O4/Charcoal),[36] PVP-N2O4,[37]
(E)-1-nitro-4-(2-nitrovinyl)-benzene,[38] NaNO2/Mukaiyama reagent/wet SiO2,[39] 1-Butyl-
3-methylimidazolium Nitrite,[40] and Ph3P/Br2/n-Bu4NNO2,[41] were also employed. The
major limitations of these reagents are the use of the strong acidic medium, reagents that
are difficult to handle and store, harsh reaction conditions, etc. For this reason, there is
still a curiosity in the development of further, mild methods for the N-nitrosation of
amines. Use of nitromethane towards N-nitrosation of secondary and tertiary amines in
the presence of oxidizing agents such as IBX/TBAF,[42] KI/TBHP,[43] Cu(OTf)2/DBU/
O2,[44] and K2S2O8/DBU[45] have been established. However, the use of expensive oxidants