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DOI: 10.1039/C9OB01547G

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COMMUNICATION

A cascade process for direct converting nitriles (RCN) to

cyanamides (RNHCN) via SO2F2-activated Tiemann rearrangement
Received 00th January 20xx,
Accepted 00th January 20xx Guofu Zhang, Yiyong Zhao and Chengrong Ding*
DOI: 10.1039/x0xx00000x

A simple, mild and practical process for direct converting nitriles amines access to cyanamides (Scheme 1, a). As an alternative
to cyanamides was newly discovered feathering a wide substrate approach, Tiemann rearrangement of amidoximes attracted
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scope and great functional-tolerability (36 examples). In this our great interest for the synthesis of cyanamides.13,14
efficient strategy the situ generated amidoximes, obtained from Especially in 2014, Chien reported the benzenesulfonyl
the reaction of nitriles with hydroxylamine, subsequently chlorides (TsCl or o-NsCl) promoted Tiemann rearrangement of
underwent Tiemann rearragement giving corresponding amidoximes to generated corresponding cyanamides (Scheme
cyanamides in great isolated yields under SO2F2. Additionally, 1, c).14 However, it is highly dependent on the electronic effect
control experiments were reported to shed light the tentative of the substrates, requires rigorous reaction conditions and
mechanism involved formation and elimination of key redundant work-up.
intermediate, sulfonyl ester.
a) The direct cyanation of amine by using "CN" sources
As a reactive N−C−N building blocks, the cyanamide moiety has R1 R1
"CN" sources
been found in various bioactive molecules and functionalized N H N CN
materials.1 But it is more commonly used as a precursor in the R2 R2
synthesis of pharmaceutically important N-containing "CN" sources: XCN (X = halo)
heterocycles and N-alkyl or N-aryl imides.2 Despite their CuCN, AIBN, TMSCN, imidazolium thiocyanates
versatile applications, only a limited number of synthetic b) The direct alkylation of cyanamide
routes for cyanamides have been reported in the literature.3 R1
Ts t-AmONa, TBAI (cat)
The most frequently adopted method is the cyanation of R 1
OH N CN N CN
amine using cyanogen halides,4 which is overshadowed by its R 2 R2
actue toxicity, unfavorable physical properties and sensitivity c) TsCl or o-NsCl promoted Tiemann rearrangement of amidoxime
to moisture (Scheme 1, a).5 Another straightforward approach OH
N TsCl or o-NsCl H
is the direct alkylation of cyanamide, but N,N-dialkylated N
DIPEA, CH2Cl2 R
cyanamides are usually obtained due to the competing R NH2 N
alkylation of the monoalkylated cyanamides (Scheme 1, b).6
d) This work: one-pot process for converting nitriles to cyanamides
Other approaches include dehydrosulfurization of thiourea,7 via SO2F2-activated Tiemann rearrangement
dehydration of urea, and the conversions from isocyanides, N
OH
N H2NOH SO2F2 H
isocyanates, or isothiocyantes.8 These methods are mutually R base, r.t. R
N
R NH2 N
complementary since they are all originated from the
corresponding amines with multistep manipulations. And Scheme 1 Strategies for the synthesis of cyanamides.
some of the transformations require harsh conditions or
hazardous reagents. Recently, several new cyanide sources Sulfuryl fluoride (SO2F2),15 an inexpensive, abundant and
including CuCN,9 AIBN,10 TMSCN,11 and imidazolium relatively inert electrophile (stable up to 400 oC when dry) has
thiocyanates,12 were achieved to the direct N ‑ cyanation of recently attracted significant attention for Sulfur (VI) fluoride
exchange (SuFEx) click chemistry and other versatile
manipulations.16 A perusal of the literature revealed that the
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou
310014, P. R. China. E-mail: gfzhang@zjut.edu.cn, dingcr@zjut.edu.cn. proton of phenolic hydroxyl or oxime hydroxyl can activate the
† Footnotes relating to the title and/or authors should appear here. exchange of S-F bonds of SO2F2 for S-O bonds to make
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
functional products, and fluorosulfate functional group (-
DOI: 10.1039/x0xx00000x OSO2F) could be applied in a controllable and targeted manner

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for varied transformations.17 Most recently, prof Qin and our desired product, even though increasing the reaction time
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groups simultaneously reported a mild and robust method for (Table S1, entries 4-6). It is worth noting
DOI: that reducing the
10.1039/C9OB01547G
efficiently converting aldehydes or aldoximes into loading of Et3N to 1.5 equiv. cause obvious decreasing yield of
corresponding nitriles mediated by SO2F2/base in a green 3a (Table 1, entry 5, 66 % yield), while increasing Et3N to 3.0

Organic & Biomolecular Chemistry Accepted Manuscript

manner.18 Subsequently, an efficient activation of the
Beckmann rearrangement of ketoximes for accessing amides
or lactams utilizing the SO2F2 was developed in our lab.19
Similarly to aldoxime or ketoxime, we speculated that the
proton of amidoxime could also activate the exchange of S-F
bond of SO2F2 for S-O bond to generate the corresponding
intermediate sulfonyl ester under alkalinous conditions, which
will subsequently fluorosulfonic ester elimination to promote
Tiemann rearrangement. Herein, we report a cascade process
for direct converting nitriles to cyanamides via SO2F2-activated
Tiemann rearrangement (Scheme 1, d).
Table 1 Optimization of the reaction conditions.a
OH
N H
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equiv., the yield is basically unchanged (Table 1, entry 6, 93 %
yield). Subsequently, the usage of other common solvents,
such as CH3CN, CH3OH, EtOAc, DMSO and THF, did not
improve the yield of this transformation (Table 1, entries 7-11).
Furthermore, reducing the concentration of substrate bring a
superior isolated yield of 3a in 96% (Table 1, entry 12).
Alternatively, considering of developing sustainable and cost-
effective methods from readily available and abundant starting
materials in a PASE (pot, atom and step-economical) manner
with the least requirements of isolation or purification of
intermediates,21 a series of continuous conversions,22 including
oximation of nitriles and cyanation of amidoximes, was tested
by using benzonitrile 1a as starting material. It’s exciting to
find that the final product 3a was still generated in 95 %
isolated yield (Table 1, entry 13).

N
SO2F2 (balloon)
NH2 base, solvent, r.t. N
Table 2 Substrate scope of the SO2F2-promoted Tiemann rearrangement.a,b
2.0 h
2a 3a OH SO2F2 (balloon)
N 50 wt% NH2OH (1.5 eq.) N H
Entry Base (equiv) Solvent Isolated yield (%) Et3N (2.0 eq.) N
R EtOH, reflux, 3.0 h CH2Cl2 (0.1 M), r.t., 2.0 h R
R NH2 N
1 Et3N (2.0) CH2Cl2 94 1
2 3
2 DBU (2.0) CH2Cl2 47
3 DIPEA (2.0) CH2Cl2 73
4 Pyridine (2.0) CH2Cl2 58 H H H
N R N N
CN H CN
5 Et3N (1.5) CH2Cl2 66 N CN
CN
R R
6 Et3N (3.0) CH2Cl2 93 3a, R = H, 95% FO2SO 3r, R = Me, 87% 3u, R = Me, 87%
7 Et3N (2.0) CH3CN 49 3b, R = Me, 86% 3s, R = Br, 89% 3v, R = Br, 90%
3c, R = OMe, 78% 3q, 75% 3t, R = CF3, 88% 3w, R = CF3, 78%
8 Et3N (2.0) CH3OH 15 3d, R = t-Bu, 85%
9 Et3N (2.0) EtOAc 85 3e, R = F, 87%
H H H
3f, R = Cl, 85% MeO N N N
10 Et3N (2.0) DMSO 62 CN CN O CN
3g, R = Br, 90%
11 Et3N (2.0) THF 30 3h, R = I, 84% MeO Cl Cl O
3i, R = COOMe, 82%
12b Et3N (2.0) CH2Cl2 96 3x, 83% 3y, 73% 3z, 91%
3j, R = Ph, 94%
3k, R = CF3, 87% H H
13c Et3N (2.0) CH2Cl2 95 H
N N
3l, R = OCF3, 90% N CN CN
a Reaction conditions: benzamidoxime 2a (0.5 mmol), base (1.0 mmol, 2.0 eq.), 3m, R = NO2, 67%c
CN
N
solvent (2.5 mL, 0.2 M), and SO2F2 balloon, room temperature, 2.0 h. b 5.0 mL of 3n, R = AcNH, 68%c N N
H
solvent (0.1 M). c Benzonitrile 1a (1.0 mmol), 50 wt% NH2OH (100 mg, 1.5 mmol, 1.5 3o, R = NMe2, 84% 3ac, 80%
3aa, 77% 3ab, 76%
eq.), and EtOH (10 mL, 0.1 M), reflux, 3.0 h; then the mixture was concentrated, 3p, R = NH2, 81%
CH2Cl2 (10 mL, 0.1 M) and Et3N (280 uL, 2.0 mmol, 2.0 eq.) was added, and SO2F2 H
H N
was introduced by slow bubbling through a SO2F2 balloon, room temperature, 2.0 S H N CN
NH N CN
h. CN
CN

Initially, we conducted our investigation by examining the 3ad, 52% 3af, 84% 3ag, 73%c
3ae, 63%
representativesubstrate benzamidoxime 2a to test the
H
feasibility of the proposed Tiemann rearrangement. N
CN N H
N
CN CN
H
Accordingly, after screening a large variety of conditions as
shown in Table 1. We are pleased to observe that the desired
3ah, 64%c 3ai, 61%c 3aj, 84%c
Tiemann product, N-phenylcyanamide 3a, was isolated in great
yield of 94% under SO2F2 atmosphere at room temperature a Reaction conditions: nitrile substrate 1 (1.0 mmol), 50 wt% NH2OH (100 mg, 1.5 mmol,
when 2.0 equiv. of triethylamine (Et3N) was employed in 1.5 eq.), and EtOH (10 mL, 0.1 M), reflux, 3.0 h; then the mixture was concentrated,
CH2Cl2 (10 mL, 0.1 M) and Et3N (280 uL, 2.0 mmol, 2.0 eq.) was added, and SO2F2 was
CH2Cl2 (Table 1, entry 1). Inspiringly, various bases, including introduced by slow bubbling through a SO2F2 balloon, room temperature, 2.0 h. b
organic bases (Table 1, entries 2-4) and inorganic bases were Isolated yields based on 1. c 5.0 h.
further screened (see ESI† for a more detailed account of
Having the optimization reaction conditions in our hand, we
optimization conditions). Although inorganic bases have
further pursued the scope and generality of this process with
significant advantages over their organic counterparts,20 we
respect to the other substrates (Table 2). Gratifyingly, a broad
were disappointed to find that using inorganic bases, such as t-
range of aromatic and aliphatic substituted amidoximes, which
BuONa, Na2CO3 and K2CO3 provided only a trace amount of the
were obtained (mostly in up to nearly quantitative yield) from

2 | J. Name., 2012, 00, 1-3 This journal is © The Royal Society of Chemistry 20xx

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corresponding nitriles without purification, was found to be dehydration process. Then amidoxime 2 was deprotonated
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rearranged smoothly by this protocol to afford the with SO2F2 under the promotion of Et 3N to form the key
DOI: 10.1039/C9OB01547G
corresponding cyanamides in good to excellent yields and a intermediate, sulfonyl ester A. Subsequently, the N−O bond
functional group-tolerant fashion. Irrespective of strongly cleavage occurred with concomitantly R group migration over

Organic & Biomolecular Chemistry Accepted Manuscript

activating (3b-d and 3i, 3x, 3z), weakly deactivating (3e-h and C−N bond to furnish the N-substituted cyanamides 3.
3y), moderately deactivating (3j) and strongly deactivating (3k-
n), the nature of substituents attached to the phenyl ring is N
OH R1
NH
N NH2OH SO2F2-promoted
equally effective. Especially the transformative moiety, iodic R EtOH, reflux Tiemann rearrangement O R2
R NH2
substituent was well tolerated (3h). Surprisingly, the 1 2 3
derivatives bearing oxidation-sensitive groups (NMe2 and NH2) SO2F2
also reacted efficiently, providing moderate yields of the Et3N, CH2Cl2 -HF

desired cyanamides without the generation of other side

OSO2F
products (3o, 3p). Remarkably, the 4-hydroxybenzonitrile 1q N H OSO2F R
N
N
derived amidoxime containing both SuFEx-sensitive aromatic R N
H -HOSO2F C
H R NH NH
hydroxy group and Tiemann-active oxime hydroxy group was A B
smoothly achieved to form 4-cyanamidophenyl Figure 1 A plausible mechanism for the SO2F2-promoted Tiemann rearrangement.
sulfurofluoridate 3q in 75% yield. Notably, the satisfactory
results showed the position of substituents on thearyl rings To demonstrate the synthetic utility of this one-pot strategy
exhibited insignificant influence on the efficiency (3b, 3r, 3u, for direct converting nitriles to cyanamides, a gram-scale (10
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and 3g, 3s, 3v, and 3k, 3t, 3w). Moreover, this transformation mmol, 1.03 g) reaction was performed under the standard
of aromatic nitriles featuring a heterocyclic aromatic ring (3aa- conditions (Scheme 3). The desired N-phenylcyanamide 3a was
ad) and an aromatic fused ring (3ae, 3af) was furnished their obtained in 88% isolated yield. Due to the resulting product N-
corresponding cyanamides in gratifying yields. Besides, the phenylcyanamide 3a have been widely applied in direct and
phenylethynyl nitriles (3ag) were also achieved to give final efficient synthesis of many bioactive molecules as estimable
products in 73% isolated yield. As regards aliphatic moiety, building blocks, this protocol is particularly useful. For instance,
representative nitriles (3ah-aj) were also successfully tetrazolamine 4,23 urea 5,24 amide 6,25 guanidine 7,26 2-
transformed into their corresponding cyanamides in good aminoquinazolin-4-one 8,27 and aminobenzonitrile 9.28 These
yields. representative transformations clearly demonstrate the
versatilities of cyanamides in organic chemistry.
a) no SO2F2
Et3N (2.0 eq.)
3a H
CH2Cl2, r.t., 2.0 h CN 50 wt% NH2OH (1.5 eq.) N
OH < 1% EtOH, reflux, 3.0 h CN
N b) SO2F2 (balloon) H
N N then SO2F2 (balloon)
NH2OH (1.5 eq) NH2 no Et3N CN
CH2Cl2, r.t., 2.0 h
3a Et3N (2.0 eq.), CH2Cl2
EtOH, reflux 1a (10 mmol, 1.03 g)
< 1% r.t., 3.0 h 3a, 88% isolated yield
3.0 h
1a 2a c) SO2F2 (balloon) 3a
CH2Cl2, r.t., 2.0 h H
3a H
then degass, Et3N Ph N N N N
N Ref. 23 Ref. 28 Ph
2.0 h 2%
N N
Ph N CN
Scheme 2 Control experiments for mechanism investigation. H 3a
Re aminobenzonitrile, 9
tetrazolamine, 4 4 f.
.2 27
Ref
Ref.
5

O
As illustrated in Scheme 2, a series of control experiments
2
Ref.

Ph
26

were conducted to gain further insight into the mechanism of H

N
H
N Ph
N
Ph
this SO2F2-promoted Tiemann rearrangement. Mixing the O Bn
N NH2
O HN 2-aminoquinazolin-4-one, 8
benzamidoxime 2a, which was generated from benzonitrile 1a urea, 5 Ph Ph
Ph N N NH2
without any by-product, just with Et3N without the presence of H
amide, 6 guanidine, 7
SO2F2, the desired N-phenylcyanamide 3a was not generated
(Scheme 2, a). Coincidentally, only a trace amount of 3a was Scheme 3 A gram-scale preparation and further transformations of N-phenylcyanamide
observed while mixing 2a just with SO2F2 without 2.0 equiv. of 3a.
Et3N (Scheme 2, b). Moreover, pre-mixing the 2a with SO2F2,
then deaerating SO2F2 and adding 2.0 equiv. of Et3N, the N- In summary, we have developed a novel, mild, practical and
phenylcyanamide was formed in negligible yield (Scheme 2, c), robust method for direct converting nitriles into cyanamides
which demonstrating the generation and elimination of promoted by SO2F2 with the presence of Et3N in a PASE
sulfonyl ester were crucial for this Tiemann rearrangement. manner. More than 36 structurally diverse cyanamides were
Based on the results of the control experiments and our synthesized with moderate to great isolated yields,
previous works about SO2F2-activated transformations of demonstrating that the high efficiency, broad scope and
oximes,18,19 a plausible mechanism for this Tiemann functional-group compatibility of this new protocol. A gram-
rearrangement process was proposed (Figure 1). Initially, the scale reaction was performed to demonstrate the applicability of
nitrile 1 reacted with NH2OH in polar solvent (EtOH) to cyanamides, which can be efficiently converted to various
generate amidoxime 2 through a nucleophilic addition and

This journal is © The Royal Society of Chemistry 20xx J. Name., 2013, 00, 1-3 | 3

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structures. In addition, a SO2F2-activated Tiemann
rearrangement mechanism was also proposed.
Conflicts of interest
There are no conflicts to declare.
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 Page 5 of 5 Organic & Biomolecular Chemistry

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DOI: 10.1039/C9OB01547G

Graphical Abstract

Organic & Biomolecular Chemistry Accepted Manuscript

N NH2OH, EtOH, reflux H
N
R then SO2F2, Et3N, CH2Cl2, r.t. R
N
R = (hetero)aryl, 36 examples
alkyl, alkynyl moderated to great isolated yields

one-pot methology using readily available materials

transition-metal free, easy work-up
wide substrate scope, great functional-tolerability
up to gram-scale
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