Zinc catalyzed Guanylation reaction of Amines with Carbodiimides/ Isocyanate leading to Guanidines/Urea derivatives formation

Article abstract of DOI:10.1007/s12039-016-1096-y

We report the highly chemo-selective catalytic addition of N–H bonds from various aromatic amines to carbodiimides and isocyanates using (Ar-BIAO)ZnCl₂ complexes [Ar-BIAO = N-(aryl)imino-acenapthenone, Ar = 2,6-Me₂C₆H₃ (1), 2,4,6 Me₃C₆H₂ (2), 2,6-ⁱPr₂C₆H₃ (3)] as the pre-catalyst to prepare guanidine and urea derivatives in 55-90% yield. The complex 3 showed higher catalytic activity than analogous complexes 1 and 2 under similar reaction conditions. The catalytic guanylation of N–H bonds with heterocumulenes displays a broad substrate scope. The amines having electron donating groups underwent higher conversion than the amines having electron withdrawing groups to afford corresponding guanidine or urea derivatives. A possible mechanism involving penta-coordinated zinc transition state for the catalytic reaction is presented. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-016-1096-y

c
J. Chem. Sci. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-016-1096-y
Zinc catalyzed Guanylation reaction of Amines with Carbodiimides/
Isocyanate leading to Guanidines/Urea derivatives formation
JAYEETA BHATTACHARJEE, MITALI SACHDEVA, INDRANI BANERJEE and
TARUN K PANDA∗
Department of Chemistry, Indian Institute of Technology Hyderabad, Kandi 502 285, Sangareddy,
Telangana, India
e-mail: tpanda@iith.ac.in
MS received 29 February 2016; revised 16 April 2016; accepted 20 April 2016
Abstract. We report the highly chemo-selective catalytic addition of N–H bonds from various aromatic
amines to carbodiimides and isocyanates using (Ar-BIAO)ZnCl2 complexes [Ar-BIAO = N-(aryl)imino-
acenapthenone, Ar = 2,6-Me2C6H3 (1), 2,4,6 Me3C6H2 (2), 2,6-iPr2C6H3 (3)] as the pre-catalyst to prepare
guanidine and urea derivatives in 55-90% yield. The complex 3 showed higher catalytic activity than analogous
complexes 1 and 2 under similar reaction conditions. The catalytic guanylation of N–H bonds with heterocumu-
lenes displays a broad substrate scope. The amines having electron donating groups underwent higher conver-
sion than the amines having electron withdrawing groups to afford corresponding guanidine or urea derivatives.
A possible mechanism involving penta-coordinated zinc transition state for the catalytic reaction is presented.
Keywords. Carbodiimide; isocyanate; guanidine; urea; Zn catalyst; guanylation.
1. Introduction
The un-catalyzed guanylation of amines with carbod-
imides is not a viable process due to requirement of
harsh conditions.6d Thus, analyzing various metal cata-
lysts for guanylation reactions has received much inter-
est. Metal complexes such as LiN(SiMe3)2,8 lanthanide
Guanidine, and the substituted guanidine derivatives are
an important class of compounds present in biologi-
cally and pharmaceutically active molecules. They have
received considerable attention due to their electronic amides and triflets,9 titanacarborane amides,10 metal
and variable static effects.1 Today, Guanidine deriva- alkyls such as half sandwich lanthanide alkyl complex11
tives are utilized for many purposes as they can serve as have been utilized for the synthesis of guanidines.
building blocks in various pharmaceutical and natural In addition, commercially available alkyl metal com-
products.2 Guanidine derivatives have found extensive plexes ZnEt2, MgBu2, n-BuLi, and AlR3 have also been
applications in medicinal chemistry due to their ability explored to be efficient catalysts for this reaction.12
to interact with functional groups present in enzymes
Recently, we have reported the synthesis and struc-
or receptors through hydrogen bonds and electrostatic tural details of various zinc complexes with bi-dentate
N-(aryl)imino-acenapthenone (Ar-BIAO) ligand, where
Ar-BIAO ligand contains conjugated exocyclic car-
bonyl and imine groups (scheme 1 and figure 1).13
We have observed from their molecular structures that
a bidentate ligation from the Ar-BIAO ligands occur
in each case through lone pairs of nitrogen and oxy-
gen atoms and, by changing the steric crowding on the
Ar-BIAO ligand, the nuclearity of the zinc complexes
can be changed. In continuation with this project, we
found that these zinc complexes are extremely active as
pre-catalyst for the guanylation reaction between car-
bodiimides and amines. Herein we report the reactivity
of zinc complexes as pre-catalyst for the reaction of
a number of amines with different carbodiimides and
isocyanates to synthesize various guanidine and urea
derivatives.
interactions. They are extensively used in medicine as
therapeutic agents suitable for the treatment of various
diseases and are also involved in antidiabetic, antibac-
terial, antihistaminic, anti-inflammatory and cardiovas-
cular activity. These molecules can also act as organic
bases, and catalyze various organic transformations.3
Guanidines are also used as ancillary ligands in the pre-
paration of a variety of metal complexes including those
of main group, transition and lanthanide metals.4 Many
synthetic procedures have been explored for the prepa-
ration of guanidines. The most convenient and relevant
route is the catalytic addition of amine N-H bonds to
carbodiimides, also known as guanylation reaction.5–7
∗For correspondence

Jayeeta Bhattacharjee et al.
toluene, and subsequently, the amine (1 mmol, 1 equiv)
followed by the carbodiimides (1 mmol, 1 equiv)
were added to the Schlenk tube. The mixture was stirred
in an oil bath at the desired temperature (90◦C). After
12 h, the solvent was evaporated under vacuum and the
residue was dissolved in hexane and kept under stirring
for 6 h. The solvent was evaporated to get the white
solid product. The yield was calculated from the weight
of the compound obtained.
Scheme 1. Synthesis of zinc catalysts 1–3.13
2.1b Characterization of the products A-O (see table 2):
The data for A is already described in the literature.14
The 1H and 13C NMR spectral data for guanidine (B-K)
and urea derivatives (M-O) are given in the Supporting
Information. The 1H and 13C NMR spectra for guanidine
and urea derivatives B-O are given in the Supporting
Information.
3. Results and Discussion
In this study, we describe the catalytic addition of
N–H bonds from various amines to N,N’- dicyclohexyl-
carbodiimides and isocyanates with zinc complexes
1-3 as the pre-catalyst. Catalytic experiments were car-
ried out using 10 mol% of zinc complex and equimo-
lar amounts of either carbodiimides or isocyanate and
amines which were added to a solution of the catalyst
with suitable solvent under an inert atmosphere. Ini-
tially we employed mesitylamine (2,4,6-Me3C5H2NH2)
and N,N’-dicyclohexylcarbodiimide (DCC) as model
substrates to explore and optimize their catalytic reac-
tion. When 10 mol% of zinc catalyst 1 was employed
as Lewis acid catalyst at 90◦C, we were pleased to find
that the desired guanidine product A was obtained in
good yield (table 1, entry 1). Then, other zinc cata-
lysts were examined as Lewis acids in the reaction. The
experimental results indicated among these three zinc
complexes 1-3, complex 3 exhibited best catalytic activ-
ity to the desired guanidine A in 81% yield (table 1,
compare entry 3 with entries 1-2). When a zinc bro-
mide complex 2* (MesBIAOZnBr2)13 was used as pre-
catalyst, only 76% yield was isolated (table 1, entry 7).
We also examined the solvent effect into the reaction
and observed that toluene could be the better combina-
tion than tetrahydrofuran and dichloromethane (table 1,
entries 3-5). It should be noted when only zinc dichlo-
ride was used as catalyst, no product was detected
Figure 1. The molecular structure of zinc catalyst 3.13
2. Experimental
2.1 General Information
All manipulations of air-sensitive materials were per-
formed under inert atmosphere and in flame-dried
Schlenk-type glassware, either on a dual manifold
Schlenk line interfaced with a high vacuum (10−4 Torr)
line, or in an argon-filled MBRAUN glove box. Hydro-
carbon solvents (toluene and n-hexane) were distilled
under nitrogen from LiAlH4 and stored in the glove box.
1H NMR (400 MHz) and 13C{1H}(100 MHz), spectra
were recorded on a BRUKER AVANCE III-400 spec-
trometer. All amines, N, N’-di-cyclohexylcarbodiimide,
N, N’-di-tert-butylcarbodiimide and phenylisocyanate
werepurchasedfromeitherSigmaAldrichorAlfaAesar.
Amineswere distilled over CaH2 prior to use. Zinc com-
plexes 1-3 were synthesized according to the published
procedure.13 NMR solvent (CDCl3) was purchased
from Alfa Aesar and distilled over molecular sieves.
2.1a Typical procedure for guanylation reactions: (table 1, entry 6). Further raising the temperature from
Zinc complex catalyzed guanylation reactions were 90◦C to 110◦C was not beneficial to the reaction as
carried out by using the standard protocol mentioned no increase in yield was observed (table 1, entry 8).
hereunder. In the glove-box, the chosen pre-catalyst The aliphatic amines were not suitable for this catalytic
(0.1 mmol) was loaded into a Schlenk tube in 5 mL reaction due to their lower boiling points.

Zinc catalyzed guanylation reaction
Table 1. Optimization of catalytic reaction between DCC and mesityl amine.
Entry
Amine
Carbodiimide Catalyst Solvent Time (h) T (◦C) Yield (%)a
1
2
3
4
5
6
7
8
9
Mesityl amine
Mesityl amine
Mesityl amine
Mesityl amine
Mesityl amine
Mesityl amine
Mesityl amine
Mesityl amine
Mesityl amine
DCC
DCC
DCC
DCC
DCC
DCC
DCC
DCC
DCC
1
2
3
3
3
Toluene
Toluene
Toluene
THF
12
12
12
12
12
12
12
12
24
90
90
90
60
25
90
90
110
90
75
78
81
70
65
0
76
81
0
CH2Cl2
ZnCl2 Toluene
2∗
3
–
Toluene
Toluene
Toluene
aIsolated yields.
After screening the reaction conditions, it can be con- hindrance of DippNH2 which restricted the approach
cluded that the optimized reaction should be performed of the bulky carbodiimide (DCC) towards itself (table 2,
using the catalyst of 10 mol% complex 3 at 90◦C using entry 11). When we reacted N,N’-di-tert-butylcarbodi-
toluene as the solvent. The reaction mixture in each imide with aniline, we obtained corresponding guani-
case was kept under stirring condition at elevated tem- dine in good yield 75% (entry 12). To extend the
perature for 12 h for carbodiimides and at room tem- scope of the reaction, we treated phenyl isocyanate with
perature for 1 h in case of isocyanates and the respec- tert-butylamine and pyrrolidine under room temperature
tive guanidine or urea products were isolated. The iso- using the zinc pre-catalyst 3. Recently, we have utilized
lated products were analysed through 1H and 13C NMR a titanium complex imidazolin-2-iminato titanium amido
spectroscopy and yields were calculated after isolation complexes [(ImDippN)Ti(NMe2)3] for the catalytic addi-
of pure products (table 2). Under optimized reaction tion of amines with carbodiimide or phenyl isocyanate.15
condition we found that a series of amines had under- In both the cases, we obtained excellent yield of the corres-
gone the N-H addition reaction smoothly with two dif- ponding urea derivatives (table 2, entry 13 and 14).
ferent carbodiimides to give corresponding guanidine However, the DippNH2 gave slightly reduced yield of
derivatives in moderate yield. The reaction of unsub- the respective urea due to bulky size of the aniline moi-
stituted aniline with DCC gave 95% yield (table 2, ety (table 2, entry 15). Thus we observed that, zinc
entry 1). The anilines having nitro group in ortho-, pre-catalyst 3 can smoothly catalyse the guanylation
or in para- position were tested for the N-H addition reaction of a number of anilines with DCC at a slightly
reaction and the yield of 85% and 75% of the respec- elevated temperature; however the reaction with phenyl
tive guanidines were observed (table 2, entries 2 and isocyanate with amines required room temperature only.
3); however substantial decrease in the yield (53%)
A possible mechanism for zinc complex 3 catalyzed
was noticed when m-nitroaniline was used as the sub- guanylation of amines to carbodiimides is proposed in
strate due to greater extent of deactivating nature of the scheme 2. In the first step, carbodiimido nitrogen should
nitro group at m-position of the aniline. However, the react with zinc complex 3 which is a Lewis acid cata-
aniline moieties were further deactivated when a halide lyst through the lone pair of nitrogen to generate penta-
group (F, Cl, I) was attached to the phenyl ring as 55– coordinated zinc intermediate I where zinc can bear the
57% yield of respective urea derivative were obtained negative charge and the second nitrogen of the carbod-
(table 2, entries 5-8). The mesityl and 2,6-dimethyl ani- imido moiety bears positive charge. The nucleophilic
line having electron donating effect from the methyl addition of an amine to I would afford another penta-
groups were observed to show no significant increase coordinated zinc intermediate II. Finally, intramolec-
in the yield (table 2, entries 9-10). However, no guany- ular proton transfer of II readily led to regenerate
lation product was observed when DippNH2 was used pre-catalyst 3 and release the free guanidine. Similar
as the amine substrate probably due to enhanced steric mechanistic cycles are known in literature.16

Jayeeta Bhattacharjee et al.
Table 2. Catalytic formation of guanidine and urea derivatives using 3 as pre-catalysta.
Entry
Amine
Carbodiimide/Isocyanate
Product
Yield (%)b
(B)
1
CyN=C=NCy
95
(C)
(D)
2
3
CyN=C=NCy
CyN=C=NCy
85
75
(E)
4
5
6
CyN=C=NCy
CyN=C=NCy
CyN=C=NCy
53
57
53
(F)
(G)
(H)
7
CyN=C=NCy
57

Zinc catalyzed guanylation reaction
Table 2. Continue.
Entry Amine
Carbodiimide/Isocyanate
Product
Yield (%)b
(I)
8
CyN=C=NCy
55
(A)
(J)
9
CyN=C=NCy
CyN=C=NCy
CyN=C=NCy
81
52
0
10
11
(K)
(L)
12
13
tBuN=C=NtBu
PhN=C=Oc
75
88
(M)
PhN=C=Oc
PhN=C=Oc
95
79
(N)
14
15
(O)
aAll compounds were characterized by 1H and 13C NMR spectroscopy using CDCl3 as NMR solvent. bYields
were calculated from isolated pure products. cRoom temperature.

Jayeeta Bhattacharjee et al.
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guanylation reaction with carbodiimides at elevated
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potent catalyst for the conversion of isocyanate to cor-
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Acknowledgements
This work was supported by Science and Engineer-
ing Research Board (SERB), Department of Sci-
ence and Technology (DST), India under project no.
(SB/S1/IC/045/2013). The instrumental facilities were
provided by the Indian Institute of Technology Hyder-
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