Transition-metal-free electrophilic amination between aryl grignard reagents and N-chloroamines

Article abstract of DOI:10.1021/ol100235b

In the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) as an additive, easily prepared and handled N-chloroamines react with aryl Grignard reagents to give a variety of arylamines in good to excellent yields. Functional groups such as ester and nitrile are compatible under the reaction conditions (Figure Presented).

Full text of DOI:10.1021/ol100235b

ORGANIC
LETTERS
2010
Vol. 12, No. 7
1516-1519
Transition-Metal-Free Electrophilic
Amination between Aryl Grignard
Reagents and N-Chloroamines
Takuji Hatakeyama,† Yuya Yoshimoto,† Sujit K. Ghorai,† and
Masaharu Nakamura*,†
International Research Center for Elements Science, Institute for Chemical Research,
and Department of Energy and Hydrocarbon Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Uji, Kyoto, 611-0011, Japan
masaharu@scl.kyoto-u.ac.jp
Received January 29, 2010
ABSTRACT
In the presence of N,N,N′,N′-tetramethylethylenediamine (TMEDA) as an additive, easily prepared and handled N-chloroamines react with aryl
Grignard reagents to give a variety of arylamines in good to excellent yields. Functional groups such as ester and nitrile are compatible under
the reaction conditions.
Aromatic carbon-nitrogen bond formation is an important
class of synthetic organic transformation.1 In the past two
decades, the Buchwald-Hartwig coupling2 based on pal-
ladium,3 copper,4 or nickel5 catalysis has been intensively
developed into a wide-spread method for the synthesis of
functional arylamines, which are of particular interest in
organic electronics6 and bioactive compounds; for example,
neuroregulating N-arylpiperidines and piperazines.7 Electro-
philic amination of arylmetal reagents represents an alterna-
tive approach and thus has attracted considerable interest
from synthetic chemists for a long time.8,9 Although N-
chloroamines are among the most desirable amination
reagents in the alternative amination strategy because of
availability and scalability,10 the classical methods with
arylmetal reagents have suffered from severe limitation of
substrate scope caused by undesirable elimination reactions
and chlorination reactions.11 Recently, the scope of electro-
† International Research Center for Elements Science (IRCELS), Institute
for Chemical Research, Kyoto University.
(1) Recent reviews: (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int.
Ed. 2003, 42, 5400–5449. (b) Tasler, S.; Lipshutz, B. H. J. Org. Chem.
2003, 68, 1190–1199. (c) Schlummer, B.; Scholz, U. AdV. Synth. Catal.
2004, 346, 1599–1626. (d) Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 6338–6361.
(2) Reviews : (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852–860.
(b) Wolfe, J. P.; Wagaw, S.; Marcoux, J.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805–818. (c) Hartwig, J. F. Angew. Chem., Int. Ed. 1998,
37, 2046–2067. (d) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002,
219, 131–209.
(6) (a) Shirota, Y. J. Mater. Chem. 2000, 10, 1–25. (b) Mishra, A.;
Fischer, M. K. R.; Ba¨uerle, P. Angew. Chem., Int. Ed. 2009, 48, 2474–
2499.
(7) (a) Prisinzano, T. E.; Rice K. C. In Dopamine Transporters:
Chemistry, Biology, and Pharmacology; Trudell, M. L., Izenwasser, S., Eds.;
Wiley & Sons: Weinheim, 2008; pp 211-232. (b) Kharkar, P. S.; Dutta,
A. D.; Reith, M. E. A.; Dutta, A. K. In Dopamine Transporters: Chemistry,
Biology, and Pharmacology; Trudell, M. L., Izenwasser, S., Eds.; Wiley &
Sons: Weinheim, 2008; pp 233-264.
(3) (a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609–3612.
(b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed.
1995, 34, 1348–1350.
(4) (a) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc.
1998, 120, 12459–12467. (b) Klapars, A.; Antilla, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727–7729.
(5) (a) Brenner, E.; Schneider, R.; Fort, Y. Tetrahedron 1999, 55, 12829–
12842. (b) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002, 67,
3029–3036. (c) Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem.
2008, 73, 1429–1434.
(8) Reviews: (a) Chiba, S.; Narasaka, K. In Amino Group Chemistry.
From Synthesis to the Life Sciences; Ricci, A., Ed.; Wiley-VCH: Weinheim,
2008; pp 1-54. (b) Erdik, E.; Ay, M. Chem. ReV. 1989, 89, 1947–1980.
(c) Greck, C.; Geneˆt, J. P. Synlett 1997, 741–748. (d) Dembech, P.; Seconi,
G.; Ricci, A. Chem.sEur. J. 2000, 6, 1281–1286. (e) Watson, I. D. G.;
Yudin, A. K. Curr. Opin. Drug DiscoVery DeV. 2002, 5, 906–917
.
10.1021/ol100235b  2010 American Chemical Society
Published on Web 03/11/2010

philic amination has been extended by using transition metal
catalysts: a copper-catalyzed amination of arylboronic acid
with N-aryl-N-chloroamides12 and a nickel-catalyzed ami-
nation of diarylzinc with N,N-dialkyl-N-chloroamines.13
Nonetheless, development of a simple and effective aromatic
amination without hazardous transition metals can contribute
to practical syntheses of the above-mentioned functional
arylamines. Herein, we report a transition-metal-free elec-
trophilic amination14 between aryl Grignard reagents and
N,N-dialkyl-N-chloroamines with the aid of N,N,N′,N′-
tetramethylethylenediamine (TMEDA) as a key additive.
proceeded sluggishly to give 1-(4-methoxyphenyl)piperidine
1 in 16% yield via substitution at the nitrogen atom and
1-chloro-4-methoxybenzene 2 in 46% yield via substitution
at the chlorine atom (entry 1). Addition of 1.5 equiv of
TMEDA considerably improved the yield of 1 (50%) and
suppressed the undesirable formation of 2 (24%, entry 2).
Further improvement has been achieved by using 3.0 and
5.0 equiv of TMEDA (65 and 76% yields, respectively,
entries 3 and 4). N,N,N′,N′-Tetramethylpropanediamine
(TMPDA) was not as effective as TMEDA (entry 5). Other
amines, diazabicyclo[2.2.2]octane (DABCO), hexamethyl-
enetetramine (HMTA), N,N,N′,N′′,N′′-pentamethyldiethyl-
enetriamine (PMDTA), and 1,2-dimethoxyethane (DME) did
not improve the product yield (entries 6-9). In the following
studies, we thus chose TMEDA as the additive.
Table 1. Effect of Coordinative Additives
Table 2. Scope of Arylmagnesium Reagents
entrya
additive (X equiv)
yield of 1b (%)
yield of 2b (%)
1
2
3
4
5
6
7
8
9
none (-)
16
50
65
76
30
14
1
46
24
15
7
31
15
21
8
TMEDAc (1.5)
TMEDA (3.0)
TMEDA (5.0)
TMPDAd (5.0)
DABCOe (5.0)
HMTAf (5.0)
PMDTAg (5.0)
DMEh (5.0)
4
17
31
a Reactions were carried out on a 0.5 mmol scale. b The yield was
determined by GC analysis by using undecane as an internal standard.
c N,N,N′,N′-Tetramethylethylenediamine. d N,N,N′,N′-Tetramethylpropane-
diamine. e Diazabicyclo[2.2.2]octane. f Hexamethylenetetramine. g N,N,N′,N′′,
N′′-Pentamethyldiethylenetriamine. h 1,2-Dimethoxyethane.
We conducted the reaction of 1-chloropiperidine and
p-methoxyphenylmagnesium bromide at -40 °C for screen-
ing of additives (Table 1). Without any additives, the reaction
a Reactions were carried out on a 0.5-25 mmol scale. b Isolated yield.
c 1.5 equiv of Grignard reagent was used. Grignard reagent was prepared
from the corresponding aryl bromide and i-PrMgCl·LiCl.
(9) Copper-mediated reaction: (a) Casarini, A.; Dembech, P.; Lazzari,
D.; Marini, E.; Reginato, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1993, 58,
5620–5623. (b) Greck, C.; Bischoff, L.; Ferreira, F.; Genet, J. P. J. Org.
Chem. 1995, 60, 7010–7012. (c) Zhang, Z.; Yu, Y.; Liebeskind, L. S. Org.
Lett. 2008, 10, 3005–3008. Copper-catalyzed reactions: (d) Berman, A. M.;
Johnson, J. S. J. Am. Chem. Soc. 2004, 126, 5680–5681. (e) Berman, A. M.;
Johnson, J. S. J. Org. Chem. 2005, 70, 364–366. (f) Berman, A. M.; Johnson,
J. S. J. Org. Chem. 2006, 71, 219–224. (g) Campbell, M. J.; Johnson, J. S.
Org. Lett. 2007, 9, 1521–1524. Nickel-catalyzed reaction: (h) Berman,
A. M.; Johnson, J. S. Synlett 2005, 1799–1801.
Table 2 illustrates the scope of arylmagnesium reagents
in the reaction with 1-chloropiperidine at -40 °C. The
reaction of p-methoxyphenylmagnesium bromide gave the
desired amination product in 76% yield (entry 1). p-Tolyl-,
3,5-dimethylphenyl-, and 2-naphthylmagnesium bromides
showed higher selectivity even with reduced amounts of
TMEDA to give the corresponding arylpiperidines in 91, 89,
and 93% yields, respectively (entries 2-4). The reaction can
also be conducted at 0 °C, although slightly lower yield and
selectivity were observed (see the Supporting Information).
(10) N-Chloroamines can be prepared by treating the corresponding
amines with NaClO or NCS. See: (a) Zhong, Y.; Zhou, H.; Gauthier, D. R.,
Jr.; Lee, J.; Askin, D.; Dolling, U. H.; Volante, R. P. Tetrahedron Lett.
2005, 46, 1099–1101. (b) Broka, C. A.; Eng, K. K. J. Org. Chem. 1986,
51, 5043–5045.
(11) (a) Coleman, G. H. J. Am. Chem. Soc. 1933, 55, 3001–3005. (b)
Coleman, G. H.; Yager, C. B.; Soroos, H. J. Am. Chem. Soc. 1934, 56,
965–966. (c) Coleman, G. H.; Hermanson, J. L.; Johnson, H. L. J. Am.
Chem. Soc. 1937, 59, 1896–1897. (d) Coleman, G. H.; Blomquist, R. F.
J. Am. Chem. Soc. 1941, 63, 1692–1694. (e) Yamada, S.; Oguri, T.; Shioiri,
T. J. Chem. Soc., Chem. Commun. 1972, 623a. (f) Oguri, T.; Shioiri, T.;
Yamada, S. Chem. Pharm. Bull. 1975, 23, 167–172. (g) Sinha, P.; Knochel,
P. Synlett 2006, 3304–3308.
(13) Barker, T. J.; Jarvo, E. R. J. Am. Chem. Soc. 2009, 131, 15598–
15599.
(14) Transition-metal-free nucleophilic aminations: (a) Shi, L.; Wang,
M.; Fan, C.-A.; Zhang, F.-M.; Tu, Y.-Q. Org. Lett. 2003, 5, 3515–3517.
(b) Xu, G.; Wang, Y.-G. Org. Lett. 2004, 6, 985–987. (c) Bolliger, J. L.;
Frech, C. M. Tetrahedron 2009, 65, 1180–1187.
(12) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A. Angew.
Chem., Int. Ed. 2008, 47, 6414–6417.
Org. Lett., Vol. 12, No. 7, 2010
1517

The dimethylamino group did not interfere with the reaction
(entry 5). Mesitylmagnesium bromide did not give the desired
product under the reaction conditions, suggesting that the
nucleophile substitution reaction is inherently sensitive to
steric demands.
The mild reaction conditions allow the participation of
functionalized Grignard reagents:15 4-cyano- and 3-cyano-
phenylmagnesium chlorides gave the corresponding aniline
derivatives in 80 and 92% yields, respectively (entries 6
and 7). A variety of pyridinylmagnesium chlorides also
took part in the reaction (entries 8-10). It is noteworthy
that a simple acid-base treatment of the reaction mixture
can give analytically pure products (see the Supporting
Information).
Table 3. Scope of N-Chloroamines
Figure 1. Postulated role of TMEDA.
Figure 1 shows the postulated role of TMEDA in the
present reaction. In the absence of TMEDA, arylmagnesium
bromide and N-chloroamine can form nitrogen-coordinated
complex A and chloride-coordinated complex B, which
would give rise to both electrophilic chlorination and
amination of Grignard reagent via TSA and TSB, respec-
tively. DFT calculations16 suggest that complex A is 8.5 kcal/
mol more stable than B (∆E), which can account for the
dominant formation of the aryl chloride in entry 1, Table 1.
In the presence of TMEDA, arylmagnesium bromide forms
complex C, which has no vacant coordination site for
N-chloroamine. The amination, thus, can take place
predominantly via TSC, which can be stabilized by
electrostatic interaction between the negatively charged
chloride atom of N-chloroamine and the magnesium atom
(entries 2-4, Table 1).
In summary, we have developed an efficient aromatic
carbon-nitrogen bond-forming reaction between aryl Grig-
nard reagents and N-chloroamines with the aid of TMEDA.
The features of the present method are as follows: high-
yielding, chemoselective, and free from transition metals.
The simple and scalable procedure is suitable for large-scale
production of N-arylpiperidines and piperazines as well as
various aniline derivatives as drug and agrochemical inter-
mediates.
a Reactions were carried out on a 0.5 or 1.0 mmol scale. b Isolated yield.
c 2.5 equiv of Grignard reagent was used. d 1.5 equiv of Grignard reagent
was used. Grignard reagent was prepared from the corresponding aryl
bromide and i-PrMgCl·LiCl.
The present amination reaction is applicable to a variety
of N-chloroamines (Table 3). 4-Chloromorpholine and
1-Boc-4-chloropiperazine smoothly reacted with p-tolyl-
magnesium bromide at -40 °C to give the corresponding
arylamines in 88 and 84% yields, respectively (entries 1
and 2). Double arylation of 1,4-dichloropiperazine took
place by using 2.5 equiv of phenylmagnesium bromide
to give 1,4-diphenylpiperazine in 78% yield (entry 3). An
ethoxycarbonyl group remained intact under the reaction
conditions (entry 4). The reaction of acyclic dibutylchlo-
roamine and pyridin-4-ylmagnesium chloride gave the
desired product in 78% yield (entry 5). Dibenzylchloro-
(15) Preparation of Grignard reagents from aryl bromides with
i-PrMgCl·LiCl: Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. 2004,
43, 3333–3336.
(16) Phenylmagnesium bromide, N-chloropiperidine, and tetrahydrofuran
(THF) were chosen as a chemical model. The DFT method was employed
using the B3LYP hybrid functional and the 6-31G* basis set. (a) Becke,
A. D. J. Chem. Phys. 1993, 98, 5648–5652. (b) Lee, C.; Yang, W.; Parr,
R. G. Phys. ReV. B 1988, 37, 785–789. (c) Hehre, W. J.; Radom, L.;
Schleyer, P. v. R.; Pople, J. A. Ab Initio Molecular Orbital Theory; John
Wiley & Sons: New York, 1986 and references cited therein. Details are
described in the Supporting Information.
+
amine, a synthetic equivalent of NH2 , can also participate
in the reaction (entry 6).
1518
Org. Lett., Vol. 12, No. 7, 2010

Acknowledgment. This work was partially supported by
Grant-in-Aids for Scientific Research on Priority Areas
“Synergistic Effects for Creation of Functional Molecules”
(M.N., 18064006) and “Chemistry of Concerto Catalysis”
(T.H., 20037033) and Grant-in-Aids for Young Scientists
(S, M.N., 2075003; B, T.H., 2175098), and Global COE
Program “International Center for Integrated Research and
Advanced Education in Materials Science” from JSPS and
MEXT. Financial support from the Uehara Memorial Foun-
dation and Tosoh Organic Chemical and Finechem Corps.
is gratefully acknowledged. We also thank Mr. Y. Hanasaki
(Tosoh Organic Chemical Co.) for bringing the industrial
importance of N-arylation to our attention.
Supporting Information Available: Experimental pro-
cedures and physical properties of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL100235B
Org. Lett., Vol. 12, No. 7, 2010
1519