A general animation method based on the addition of polyfunctional arylmagnesium reagents to functionalized arylazo tosylates

Article abstract of DOI:10.1002/anie.200353241

A one-pot reaction sequence consisting of a Grignard reaction, allylation, and reduction provides new functionalized diarylamines in good yields (see scheme, Ts = toluene-4-sulfonyl, NMP = N-methylpyrrolidine, TFA = trifluoroacetic acid). In the first ste

Full text of DOI:10.1002/anie.200353241

Angewandte
Chemie
Amination
A General Amination Method Based on the
Addition of Polyfunctional Arylmagnesium
Reagents to Functionalized Arylazo Tosylates**
Ioannis Sapountzis and Paul Knochel*
Dedicated to Professor Gernot Boche
The preparation of polyfunctional diarylamines of type 1 is an
important goal in synthesis since these building blocks are
present in many pharmaceuticals and various fine chemicals.
[
1]
There are two approaches to such target molecules involv-
ing either the generation of a nucleophilic amino synthon 2
which will react with an electrophilic aromatic reagent
+
À
(
Ar X 3,path a in Scheme 1). This retrosynthetic analysis
has been successfully demonstrated recently with palladium-
[
2]
[3]
and copper-catalyzed reactions between aryl halides 4 and
various amines 5.
Scheme 1. Retrosynthetic analysis for the preparation of diarylamines.
Alternatively,one may envision adding an organometallic
reagent 6 to a positively charged arylamine synthon 7 (path b
[
4]
in Scheme 1). We reported recently that nitroarenes of type
are excellent equivalents for electrophilic nitrogen synthons.
They react with arylmagnesium halides 9 and provide after
8
[*] Dipl.-Chem. I. Sapountzis, Prof. Dr. P. Knochel
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13, Haus F, 81377 München (Germany)
Fax: (+49)089-21-80-776-80
E-mail: paul.knochel@cup.uni-muenchen.de
[
**] We thank Aventis Pharma (Frankfurt a.M.) for a fellowship (I.S.) and
the Fonds der Chemischen Industrie for financial support. We also
thank K. Becker for the preparation of starting materials as well as
Chemetall GmbH (Frankfurt a.M.), Wacker Chemie GmbH (Mün-
chen), and BASF AG (Ludwigshafen) for generous gifts of
chemicals.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 897 –897
DOI: 10.1002/anie.200353241
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897

Communications
reductive workup diarylamines of type 1 in excellent overall
yields. A drawback of this method is requirement of two
Table 1: Polyfunctional diarylamines 1a–l obtained by the addition of
functionalized Grignard reagents 9a–f to functionalized arylazo tosylates
[
5]
11a–f followed by in situ allylation and reductive workup.
equivalents of the Grignard reagent 9,since one equivalent of
2
2
[a]
[b]
Ar MgX is consumed in the reduction of the nitroarene to an
Entry Diazo reagent Ar MgBr
Product
Yield [%]
[
5d]
intermediate arylnitroso species 10. We have examined the
direct use of the arylnitroso derivatives 10 as starting
[
6]
materials for the amination procedure since this would
preclude the use of an excess of the arylmagnesium reagent.
Although the reaction of nitrosoarenes of type 10 with
arylmagnesium species proceeds well,their stability is limited
and their synthesis is complicated by dimerization reactions
1
63
2
3
76
65
[
6]
which reduce the scope of this approach.
[
7]
We report herein that arylazo tosylates of type 11 are
powerful synthetic equivalents of the electrophilic arylamino
synthon 7 (Schemes 1 and 2). They are readily prepared from
4
5
6
7
8
9
70
80
83
69
86
81
83
71
64
Scheme 2. Preparation of arylazo tosylates and diarylamines.
aromatic amines of type 5 in a two step-sequence consisting of
[
8]
a diazotation (NaNO ,50% HBF in water,25 8C,1 h) and
2
4
subsequent reaction of the resulting diazonium tetrafluoro-
borates 12 with sodium p-toluenesulfinate (NaTs) in dichloro-
methane (CH Cl ,25 8C,overnight). Various functionalized
2
2
arylazo tosylates of type 11 result in overall yields of over
[
7]
8
0%.
We have now found that these highly electrophilic diazo
derivatives react under mild conditions (À208C,1 h) with a
broad range of polyfunctional arylmagnesium halides pre-
[
9]
pared by an iodine–magnesium exchange reaction. The
intermediate addition products were allylated in situ by
addition of first N-methylpyrrolidinone (NMP) and then allyl
iodide. The resulting hydrazine derivatives 13 were treated,
after evaporation of the solvents,with zinc in a 5:1 mixture of
acetic acid and trifluoroacetic acid (TFA; 758C,1–8 h). This
one-pot procedure furnishes polyfunctionalized diarylamines
1
0
1
a–k in overall yields of 63–86% (Scheme 2 and Table 1).
Various functionalized arylazo tosylates 11a–f undergo
11
addition reactions with magnesium compounds. Thus,the
presence of electron-withdrawing groups such as an ester
(
entries 1 and 2),a halogen substituent (entries 3–8 and 11),
and a nitrile function (entry 12) or an electron-donating group
like a methoxy substituent (entries 9 and 10) is compatible
with the reaction of a range of functionalized Grignard
reagents. Remarkably,both the Grignard reagent as well as
the arylazo tosylates of type 11 can bear a bromine (entries 3–
1
2
[a] The dotted lines indicate the new carbon–nitrogen bond. [b] Overall
yields of analytically pure product from the one-pot procedure including
the allylation with allyl iodide and subsequent zinc reduction in AcOH/
TFA (5:1).
8
) or an iodine substituent (entries 1 and 11). A highly
electrophilic functionality like a triflate (entries 2,4,and 9) is
898
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Chemie
also tolerated under the mild reaction conditions. In this
respect our amination method differs from the Pd-,Cu-,and
heterocyclic magnesium compounds providing a range of new
polyfunctional amines,some of which are difficult to prepare
by standard methods. The extension of this method to other
organometallic reagents is currently being investigated in our
laboratories.
[
2,3]
Ni-catalyzed amination reactions of aromatic halides,
and
our method is thus complementary to the Buchwald–Hartwig
amination procedure. Steric hindrance is also not problem-
atic,since in both the arylazo tosylate as well as in the
Grignard reagent the presence of an ortho substituent does
not reduce the amination yields (entries 3,7,and 10). Our
procedure can also be applied successfully to heterocyclic
systems. Thus,the functionalized 3-indolylmagnesium reagent
Experimental Section
General procedure for the synthesis of arylazo tosylates: 11c:
4
-Bromoaniline (1.72 g,10 mmol) was dissolved in 15 mL aq HBF 4
solution (50% in water) and cooled to 08C before a solution of
NaNO2 (760 mg,11 mmol) in water (5 mL) was added dropwise.
After 30 min of stirring,the reaction mixture was allowed to warm to
room temperature and was stirred for an additional hour. The white
precipitate was filtered off and washed subsequently with aq HBF4
solution (10 mL),ethanol (10 mL),and diethyl ether (20 mL). The
white crystalline powder was dissolved in
1
4 prepared from the corresponding heterocyclic iodide 15 by
iodine–magnesium exchange reacts with the arylazo tosylates
1a and 11c under the usual reaction conditions,providing
1
the new 3-arylaminated indole derivatives 16a–b in 58–71%
yield (Scheme 3).
dichloromethane without further purification
or drying. NaTs (2.14 g,12 mmol) was added,
and the reaction mixture was stirred over-
night. The salts were removed by filtration,
and the crude reaction mixture was concen-
trated in vacuo. Recrystallization from etha-
nol yielded 11c (2.71 g,80%) as an orange
solid.
General procedure for the amination:
1
f: A dry and argon-flushed 25-mL round-
Scheme 3. Preparation of (3-arylamino)indole derivatives.
bottom flask equipped with a magnetic stirrer
and a septum was charged with ethyl 4-
iodobenzoate (306 mg,1.1 mmol) dissolved
Finally,the new amination reaction has a broad scope and
can be extended to other classes of organomagnesium
reagents. Thus,the preparation of elusive ferrocenyl aryl
in dry THF (5 mL) and cooled to À208C. iPrMgCl (1.15 mL,
1.1 mmol,0.95 m in THF) was added dropwise and the I/Mg exchange
was monitored by GC analysis until completion (30 min). 4-Bromo-
phenylazo tosylate (11c) (339 mg,1 mmol) was dissolved in THF
[
10]
amines can be readily achieved by treating ferrocenylmag-
(
3 mL) and added dropwise to the Grignard reagent. After 1 h of
stirring at À208C,the reaction mixture was treated with allyl iodide
510 mg,3 mmol) and NMP (2 mL),and stirred for additional 2 h at
nesium bromide (17),which is prepared from tributylstan-
[
11]
nylferrocene, with the arylazo tosylate 11c followed by the
usual reductive workup. Under these conditions,the new
aminated ferrocenyl derivative 18 is obtained in 58% yield
(
room temperature. The solvents were removed in vacuo and the
residue taken up in glacial acetic acid (10 mL). Zinc powder
(10 mmol) and TFA (2 mL) were added,and the reaction mixture
(
Scheme 4).
was heated to 758C until no starting material was evident by TLC
analysis (2 h). The reaction mixture was allowed to cool to room
temperature and was poured on crushed ice (ca. 30 g) and 20 mL of
Aliphatic magnesium compounds undergo the amination
reaction as well. Thus cyclopropylmagnesium bromide 19
reacts with the arylazo tosylates 11a and 11c to afford the
expected N-arylcyclopropylamines 20a and 20b,respec-
2
3
m NaOH. The aqueous phase was extracted with diethyl ether (3 ”
0 mL),and the combined organic phases were washed successively
[
12]
tively, in 62–67% yields (Scheme 4).
with sat. NaHCO solution and brine. The organic phases were dried
3
In summary,we have shown that arylazo tosylates of type
1,which are easily prepared from arylamines,are excellent
amination reagents. They react with various aromatic and
over Na
raphy on silica gel (pentane/diethyl ether 9:1) furnished 1 f (265 mg,
3%) as a colorless solid.
2 4
SO ,filtered,and concentrated in vacuo. Flash chromatog-
1
8
Received: November 3,2003 [Z53241]
Keywords: amination · Grignard reaction · halogen–
.
magnesium exchange · heterocycle synthesis ·
synthetic methods
[
1] a) A. Ricci, Modern Amination Methods,Wiley-
VCH,Weinheim, 2000; b) P. Dembech,G. Seconi,A.
Ricci, Chem. Eur. J. 2000, 6,1281; c) E. Erdik,M. Ay,
Chem. Rev. 1989, 89,1947; d) G. Boche, Houben-
Weyl, Methods of Organic Chemistry (Eds.: G.
Helmchen,R. W. Hoffmann,J. Mulzer,E. Schau-
mann),Thieme,Stuttgart, 1995.
Scheme 4. Preparation of ferrocenyl aryl amine 18 and N-arylcyclopropylamines
0a and 20b.
2
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Communications
[
2] a) J. P. Wolfe,S. Wagaw,J.-F. Marcoux,S. L. Buchwald,
Acc.
Chem. Res. 1998, 31,805; b) J. F. Hartwig, Angew. Chem. 1998,
110,2155; Angew. Chem. Int. Ed. 1998, 37,2046; c) L. M.
Alcazar-Roman,J. F. Hartwig,A. L. Rheingold,L. M. Liable-
Sands,I. A. Guzei, J. Am. Chem. Soc. 2000, 122,4618; d) U. K.
Singh,E. R. Strieter,D. G. Blackmond,S. L. Buchwald, J. Am.
Chem. Soc. 2002, 124,14104; d) T. E. Mueller,M. Beller, Chem.
Rev. 1998, 98,675; e) For a nickel-catalyzed amination,see:
B. H. Lipshutz,H. Ueda, Angew. Chem. 2000, 112,4666; Angew.
Chem. Int. Ed. 2000, 39,4492.
[
3] a) J. C. Antilla,S. L. Buchwald, Org. Lett. 2001, 3,2077; b) J. P.
Collman,M. Zhong, Org. Lett. 2000, 2,1233; c) P. Y. S. Lam,G.
Vincent,D. Bonne,C. G. Clark, Tetrahedron Lett. 2003, 44,4927;
d) P. Y. S. Lam,S. Deudon,K. M. Averill,R. Li,M. Y. He,P.
DeShong,C. G. Clark, J. Am. Chem. Soc. 2000, 122,7600; e) J.
Zanon,A. Klapars,S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
2890; f) F. Y. Kwong,S. L. Buchwald, Org. Lett. 2003, 5,793;
g) D. Zim,S. L. Buchwald, Org. Lett. 2003, 5,2413.
[
4] a) G. Boche,H. U. Wagner, J. Chem. Soc. Chem. Commun. 1984,
1
591; b) G. Boche,C. Boie,F. Bosold,K. Harms,M. Marsch,
Angew. Chem. 1994, 106,90; Angew. Chem. Int. Ed. Engl. 1994,
3,115; c) A. Casarini,P. Dembech,D. Lazzari,E. Marini,G.
Reginato,A. Ricci,G. Seconi, J. Org. Chem. 1993, 58,5620;
d) J. P. GenÞt,S. Mallart,C. Greck,E. Piveteau, Tetrahedron
3
Lett. 1991, 32,2359; e) C. Greck,J. P. GenÞt, Synlett 1997,741;
f) P. Beak,A. Basha,B. Kokko, J. Am. Chem. Soc. 1984, 106,
1
2
511; g) B. M. Trost,W. H. Pearson, J. Am. Chem. Soc. 1981, 103,
483; h) H. Tsutsui,T. Ichikawa,K. Narasaka, Bull. Chem. Soc.
Jpn. 1999, 72,1869.
[
[
[
5] a) I. Sapountzis,P. Knochel, J. Am. Chem. Soc. 2002, 124,9390;
b) H. Wieland, Ber. Dtsch. Chem. Ges. 1903, 36,2315; c) H.
Gilman,R. McCracken, J. Am. Chem. Soc. 1927, 49,1052; d) G.
Koebrich,P. Buck, Chem. Ber. 1970, 103,1412.
6] a) F. Kopp,I. Sapountzis,P. Knochel, Synlett 2003,885; b) N.
Momoyama,H. Yamamoto, Angew. Chem. 2002, 114,3112;
Angew. Chem. Int. Ed. 2002, 41,2986; c) N. Momoyama,H.
Yamamoto, Org. Lett. 2002, 4,3579.
7] a) M. J. Evers,L. E. Christiaens,M. R. Guillaume,M. J. Renson,
J. Org. Chem. 1985, 50,1779; b) M. J. Evers,L. E. Christiaens,
M. J. Renson, J. Org. Chem. 1986, 51,5196; c) N. Kimigata,A.
Satoh,T. Kondoh,M. Mameyama, Bull. Chem. Soc. Jpn. 1988,
61,3575; d) C. Dell'Erba,M. Novi,G. Petrillo,C. Tafani,
Tetrahedron 1995, 51,3905; e) C. Dell'Erba,M. Novi,G. Petrillo,
C. Tafani, Tetrahedron 1997, 53,2125.
[
[
8] S. H. Karzeniowski,G. W. Gokel, Tetrahedron Lett. 1977,3519.
9] a) P. Knochel,W. Dohle,N. Gommermann,F. Kneisel,F. Kopp,
T. Korn,I. Sapountzis,V. A. Vu, Angew. Chem. 2003, 115,4438;
Angew. Chem. Int. Ed. 2003, 42,4302; b) A. Staubitz,W. Dohle,
P. Knochel, Synthesis 2003,233; c) F. F. Kneisel,P. Knochel,
Synlett 2002,1799; d) N. Gommermann,C. Koradin,P. Knochel,
Synthesis 2002,2143; e) A. E. Jensen,W. Dohle,I. Sapountzis,
D. M. Lindsay,V. A. Vu,P. Knochel, Synthesis 2002,565.
[
10] a) G. R. Knox,P. L. Pauson,D. Willison,E. Solcaniova,S. Toma,
Organometallics 1990, 9,301; b) F. S. Arimoto,A. C. Haven, J.
Am. Chem. Soc. 1955, 77,6295; c) D. W. Hall,J. H. Richards, J.
Org. Chem. 1963, 28,1549; d) E. M. Acton,R. M. Silverstein, J.
Org. Chem. 1959, 24,1487.
[
[
11] D. Giullaneux,H. B. Kagan, J. Org. Chem. 1995, 60,2502.
12] a) A. de Meijere,S. I. Kozhushkov,A. I. Savchenko in Titanium
and Zirconium in Organic Synthesis (Ed.: I. Marek),Wiley-
VCH,Weinheim, 2002; b) W. Cui,R. N. Loeppky, Tetrahedron
2001, 57,2953.
9
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