Transition-metal-free synthesis of aromatic amines via the reaction of benzynes with isocyanates

Article abstract of DOI:10.1016/j.tetlet.2018.01.022

An unexpected reaction between benzynes and isocyanates to generate aromatic amines has been developed under transition-metal-free conditions. The in situ prepared anions formed through cleavage of the N–C bond in isocyanates, reacted with aryne precursor

Full text of DOI:10.1016/j.tetlet.2018.01.022

Accepted Manuscript
Transition-metal-free synthesis of aromatic amines via the reaction of benzynes
with isocyanates
Jeong Hoon Seo, Haye Min Ko
PII:
S0040-4039(18)30035-2
https://doi.org/10.1016/j.tetlet.2018.01.022
TETL 49609
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
13 November 2017
28 December 2017
5 January 2018
Please cite this article as: Seo, J.H., Ko, H.M., Transition-metal-free synthesis of aromatic amines via the reaction
of benzynes with isocyanates, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.01.022
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Tetrahedron Letters
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Transition-metal-free synthesis of aromatic amines via the reaction of benzynes with
isocyanates
Jeong Hoon Seo, Haye Min Ko ∗
Department of Bio-Nano Chemistry, Wonkwang University, 460 Iksandae-ro, Iksan, Jeonbuk, 54538, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
An unexpected reaction between benzynes and isocyanates to generate aromatic amines has been
developed under transition-metal-free conditions. The in situ prepared anions formed through
cleavage of the N-C bond in isocyanates, reacted with aryne precursors to afford various aniline
derivatives in moderate to excellent yield and tolerated various substituents on the o-silyl aryl
triflate and the isocyanate.
Received in revised form
Accepted
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Aniline derivatives
Transition-metal-free
Benzynes
Isocyanates
Fluoride
Introduction
in detail.
Aromatic amines are important motifs in natural products,
materials, pharmaceuticals and dyes.1 Therefore, efficient and
concise synthetic strategies towards this class of compounds is of
significant interest. Traditional methods to access these useful
building blocks typically proceed via the formation of carbon-
nitrogen bonds. In particular, the palladium-catalyzed carbon-
nitrogen bond formation reaction (Buchwald-Hartwig amination),
Ullmann reaction, and Chan-Lam coupling reaction in the
presence of Cu are well represented in the literature.2 An
amination reaction using carbon-hydrogen activation has been
reported as an alternative methodology to construct Caryl-N
bonds.3 Despite several advantages, the requirement for
expensive transition metals and directing groups is an obstacle
for the utility of these reactions.
Over the past decades, benzyne chemistry has been extremely
well developed. The reactivity of benzyne intermediates is
attributed to a lowered LUMO arising from a strained π-bond,
which facilitates several coupling reactions with neutral
nucleophiles such as ureas4 and imines.5 The in situ generated
benzyne intermediates formed from o-silyl aryl triflates under the
action of fluoride reported by Kobayashi and co-workers6 have
allowed functionalization at the 1- and 2-positions of benzene.
Figure 1. Synthetic Methods for Constructing Caryl-N Bonds
utilizing benzyne
A representative mono N-arylation reaction utilizing primary
or secondary amines has been demonstrated by Larock and co-
workers.7d Due to the difficulty in reacting tertiary amines with
arynes according to the formation of an ammonium salt, only one
successful reaction has been reported by Biju and co-workers.7a
To the best of our knowledge, the use of substituted isocyanates
Such mild reaction conditions help overcome the limitations
of transition metal catalyzed cross-coupling amination reactions,
such as the use of strong bases or high temperature. Interestingly,
with respect to benzynes, mono N-arylation7 has not been studied
———
∗ Corresponding author. e-mail: hayeminko@wku.ac.kr; Tel.:+82 63 850 6229

2
as a coupling partner for mono N-arylation employing benzyne
precursors has not been reported. Herein, we report an efficient
transition-metal free mono N-arylation reaction between
benzynes and various isocyanates.
products (3c, 3g, 3i, 3k). Polyaromatic 3g and compounds 3h,
3i, 3j were obtained in moderate yields.
Scheme 1. Substrate Scope of Various Benzyne Precursors
Results and Discussion
CH3
Initially, we investigated the reaction employing the model
substrate 1a and the commercially available tosyl isocyanate 2a
(1.2 equiv.) in presence of CsF in acetonitrile at room
temperature (Table 1). Unexpectedly, the tosyl protected aniline
3a was obtained in 28% yield (Entry 1). Encouraged by this
H3C
O
O
OTf
a,b
S
conditions
CH3
O
R1
+
O
NH
S
C
N
R1
TMS
O
3a
1
2a
o
CH3
CH3
result, the temperature was increased to 100 C, which improved
O
the yield to 48% (Entry 2). Interestingly, when the amount of
tosyl isocyanate 2a (2.4 equiv.) was increased, product 3a was
isolated in excellent yield 94% (Entry 3). Decreasing the fluoride
source amount or using THF instead of acetonitrile, resulted in a
diminished yield for 3a (Entry 4). To examine the effect of
additives, 18-crown-6, methanol and isopropyl alcohol were
examined (Entries 5-7). Unfortunately, the crown ether or alcohol
provided lower yield. Additionally, the use of TBAF failed to
give product 3a (Entries 8-9). Upon using KF/18-crown-6 or
K2CO3/18-crown-6 as the benzyne triggering reagent, 3a was
observed in 28% or trace amounts, respectively (Entries 10-12).
Finally, the use of tosyl isocyanate 2a (2.4 equiv.) in presence of
O
O
O
O
S
S
S
O
NH
NH
H3CO
NH
, 71%
3c
3a, 94%
3b, 89%
(1 : 0.5)d
CH3
CH3
CH3
O
O
O
O
S
S
S
O
O
NH
H3CO
H3CO
NH
H3C
NH
3e, 63%c
(1 : 0.75)d
3f, 54%
(1 : 0.5)d
3d, 72%
CH3
H3C
H3C
CH3
CH3
O
O
O
S
S
S
O
O
o
O
NH
NH
NH
CsF (3.0 equiv.) in acetonitrile at 100 C was selected as the best
reaction conditions.
3g, 55%
3h, 55%
(1 : 0.4)d
3i, 53%
F
Cl
Table 1. Optimization studiesa
CH3
CH3
O
O
S
S
O
O
H3C
NH
F
F
NH
3k, 42%b
, 51%
3j
Br
aReagents and conditions: o-silyl aryl triflate (0.1 mmol), tosyl isocyanate
(0.24 mmol), CsF (0.3 mmol), acetonitrile (0.1 M), 100 oC, 14 h. bTosyl
isocyanate (0.12 mmol), CsF (0.2 mmol). cTosyl isocyanate (0.5 mmol), CsF
(0.6 mmol). d Ratio of isomers was determined by 1H-NMR spectroscopy.
In order to further expand the reaction scope, different
substituted isocyanates were also explored (Scheme 2). For the
benzenesulfonyl isocyanates, para hydrogen as
a neutral
substituent or a para electron-withdrawing substituent such as F
on the aryl group influenced the product yields (Scheme 2, 3aa-
3ab). However, a variety of phenyl isocyanates bearing an aryl
group instead of benzenesulfonyl group gave the desired products
in 23-75% yield (Scheme 2, 3ac-3al). Introducing para methyl,
methoxy and tertiary butyl groups onto the phenyl group did not
hamper the N-arylation reaction, affording 3ac, 3ad, 3ae in 77%,
75%, 51% yield, respectively. Additionally, electron-poor phenyl
isocyanates with para-NO2, Cl, F, CF3 substituents reacted with
benzyne 1a in moderate yields compared with benzenesulfonyl
isocyanates.
aReagents and conditions: o-silyl aryl triflate (0.1 mmol), tosyl isocyanate
(0.24 mmol), fluoride source (0.3 mmol), solvent (0.1 M), 100 oC, 14 h.
bIsolated yield. cTosyl isocyanate (0.12 mmol). dFluoride source (0.12 mmol).
eRoom Temperature. fAdditive (3 equiv.). gPotassium carbonate (0.24 mmol).
Interestingly,
when 4-(6-methyl-2-benzothiazolyl)phenyl
isocyanate was used, 3aj was afforded in 56% yield. Isocyanates
with naphthyl and dimethylphenyl groups gave the corresponding
products 3ak and 3al in 36%, 30% yields, respectively.
Unfortunately, when alkyl isocyanates were utilized instead of
phenyl isocyanate, the reaction proceeded sluggishly and the
desired product was not observed (3am, Scheme 2).
With the optimized conditions in hand, the scope of benzyne
precursors was examined (Scheme 1). Both electron-donating
and electron-withdrawing functional groups on the benzyne
precursors were tolerated in this reaction. Alkyl groups such as
tert-butyl, methyl, and dimethyl afforded the products (3b, 3d,
3e) in good to high yield, whereas methoxy groups gave 3c and
3f in 71% and 54% yields, respectively. In some cases involving
tert-butyl, methoxy, dimethoxy groups, a regioisomeric mixture
was observed (approximately 1:2 for 3b, 3f and 4:3 for 3e).
However, only one regioisomer was detected for the desired
During the investigation of several substrates, we observed the
unexpected product 3e’ which had a biphenyl backbone with a
tosyl amine in 45% yield (Scheme 3). This structure was
confirmed by 1H-NMR, 13C-NMR, and high-resolution mass
spectroscopy. The biphenyl scaffold is useful to develop new

3
ligands, or synthesize materials, pharmaceuticals, and natural
products.
also described and a detailed examination regarding the scope
of biphenyl formation is currently ongoing.
Scheme 2. Substrate Scope of Different Isocyanates
R2
Acknowledgements
OTf
NH
O
conditions a
R2
C
+
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Science, ICT & Future Planning (NRF-
2015R1C1A2A01051829).
N
TMS
1a
3aa
2
F
CH3
O
O
O
O
O
O
S
S
S
NH
NH
NH
, 94%
, 43%c
3a
3aa
24%b
3ab,
Supplementary data
OCH3
tBu
CH3
Supplementary data associated with this article can be found,
in the online version, at
NH
NH
NH
3ac
NO2
, 51%
3ae
, 77%
, 75%
3ad
F
Cl
References
NH
NH
NH
1. (a) Amines: Synthesis Properties and Applications; Lawrence, S.
A., Ed.; Cambridge University Press: Cambridge, 2004. (b)
Rappoport, Z., Ed. The Chemistry of Anilines; Wiley
VCH:Weinheim, 2007. (c) Amino Group Chemistry: From
Synthesis to the Life Sciences; Ricci, A., Ed.; Wiley-VCH:
Weinheim, 2008.
, 65%
, 53%
3ah
3af
, 68%
3ag
H3C
CF3
2. (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805-818. (b) Hartwig, J. F. Acc. Chem. Res.
2008, 41, 1534-1544. See also for Chan-Evans-Lam coupling: (c)
Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829-856.
N
S
NH
NH
, 36%c
CH3
3ak
, 59%
CH3
3ai
3. (a) Barker, T. J.; Jarvo, E. R. Synthesis 2011, 3954-3964. (b) Cho,
S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40,
5068-5083. (c) Zhang, M.; Zhang, A. Synthesis 2012, 1-14. (d)
Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.
Angew. Chem. Int. Ed. 2012, 51, 10236-10254.
NH
H3C
, 56%
3aj
H3C
NH
NH
3al
4. (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247-3249. (b) Biswas, K.; Greaney, M.
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C.; Horng, J.-C.; Hwu, J. R. Angew. Chem. Int. Ed. 2015, 54,
9926-9930.
, 30%c
, nr
3am
aReagents and conditions: o-silyl aryl triflate (0.1 mmol), tosyl isocyanate
(0.24 mmol), CsF (0.3 mmol), acetonitrile (0.1 M), 100 oC, 14 h. bTosyl
isocyanate (0.12 mmol), CsF (0.2 mmol). cTosyl isocyanate (0.3 mmol), CsF
(0.4 mmol).
Scheme 3. Discovery of Unexpected Product 3e’
6. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
1211-1214.
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Reagents and conditions: o-silyl aryl triflate (0.1 mmol), tosyl isocyanate
(0.24 mmol), CsF (0.3 mmol), acetonitrile (0.1 M), 100 oC, 14 h
Conclusion
An efficient transition-metal-free method for the preparation
of aromatic amines using benzynes and isocyanates has been
developed. The reaction tolerates various functional groups such
as alkyl, alkoxy, halogens, and polyaromatic groups. These mild
reaction conditions display good yields and represent a novel
synthetic strategy for the synthesis of substituted aniline
compounds. A preliminary outcome to obtain diphenyl moiety is

4
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Transition-metal-free synthesis of aromatic
amines via the reaction of benzynes with
isocyanates
Jeong Hoon Seo, Haye Min Ko*
Transition-metal-free
Ligand free
24 examples, 24-94% yield

5
Transition-metal-free and ligand-free reaction
Facile approach to construct carbon-nitrogen bond
utilizing aryne precursors and isocyanates
Unexpected cleavage of N-C bond in isocyanates to
afford anions