Preparation of aryl-alkylamines via electrophilic amination of functionalized arylazo tosylates with alkylzinc reagents

Article abstract of DOI:10.1021/ol061303m

A new electrophilic amination reaction of functionalized arylazo tosylates with alkylzinc halides or dialkylzinc reagents in THF leads to the corresponding hydrazines. A facile cleavage of the N-N bond is achieved using Raney nickel in refluxing ethanol, leading to substituted secondary aryl-alkylamines in 45-79% yield.

Full text of DOI:10.1021/ol061303m

ORGANIC
LETTERS
2006
Vol. 8, No. 17
3741-3744
Preparation of Aryl−Alkylamines via
Electrophilic Amination of
Functionalized Arylazo Tosylates with
Alkylzinc Reagents
Pradipta Sinha, Christiane C. Kofink, and Paul Knochel*
Department Chemie und Biochemie, Ludwig-Maximilians-UniVersita¨t,
Butenandtstrasse 5-13, 81377 Mu¨nchen, Germany
paul.knochel@cup.uni-muenchen.de
Received May 29, 2006
ABSTRACT
A new electrophilic amination reaction of functionalized arylazo tosylates with alkylzinc halides or dialkylzinc reagents in THF leads to the
corresponding hydrazines. A facile cleavage of the N N bond is achieved using Raney nickel in refluxing ethanol, leading to substituted
secondary aryl alkylamines in 45 79% yield.
−
−
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Electrophilic amination is an attractive method for preparing
polyfunctional amines. Organometallic reagents, such as
Grignard, or organolithium reagents have been most fre-
quently used for performing these reactions.1 Only a few
examples have been reported so far in the literature using
organozinc reagents. These reagents have the advantage of
being compatible with a broad range of functional groups.2
Recently, Erdik has reported the electrophilic amination of
triarylzincates with benzenediazonium tetrafluoroborates.3
Johnson has shown that organozinc reagents can act as
potential nucleophiles in the presence of copper and nickel
catalysts with O-benzoyl hydroxylamines, leading to tertiary
amines.4 The use of functionalized organozinc reagents opens
a synthetic route for the preparation of highly functionalized
amines, being complementary to the palladium-catalyzed
nucleophilic amination reaction.5
Recently, we have reported the reactions of functionalized
Grignard reagents with nitroarenes and arylazo tosylates,
which allow the synthesis of polyfunctionalized diary-
lamines.6 Herein, we wish to report a new facile method for
(1) For general electrophilic amination, see: (a) Erdik, E.; Ay, M. Chem.
ReV. 1989, 89, 1947. (b) Boche, G. In Houben-Weyl, Methods of Organic
Chemistry; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schaumann, E.,
Eds.; Thieme: Stuttgart, 1995. (c) Mulzer, J.; Altenbach, H. J.; Brown,
M.; Krohn, K.; Reissig, H. U. Organic Synthesis Highlights; VCH:
Weinheim, Germany, 1991; pp 45-53. (d) Narasaka, K.; Kitamura, M. Eur.
J. Org. Chem. 2005, 4505. (e) Mitchell, H.; Leblanc, Y. J. Org. Chem.
1994, 59, 682. For stoichiometric addition of organometallic reagents, see:
(f) Skriven, E. F. V.; Turnbull, K. Chem. ReV. 1988, 88, 298. (g) Kitamura,
M.; Suga, T.; Chiba, S.; Narasaka, K. Org. Lett. 2004, 6, 4619. (h) Bernardi,
P.; Dembech, P.; Fabbri, G.; Ricci, A.; Seconi, G. J. Org. Chem. 1999, 64,
641. (i) An, D. K.; Hirakawa, K.; Okamoto, S.; Sato, F. Tetrahedron Lett.
1999, 40, 3737. (j) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994,
116, 7901. (k) Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato,
G.; Ricci, A.; Seconi, G. J. Org. Chem. 1993, 58, 5620. (l) Alberti, A.;
Cane`, F.; Dembech, P.; Lazzari, D.; Ricci, A.; Seconi, G. J. Org. Chem.
1996, 61, 1677. For the use of organozinc reagents, see: (m) Cane`, F.;
Brancaleoni, D.; Dembech, P.; Ricci, A.; Seconi, G. Synthesis 1997, 5, 545.
(n) Erdik, E.; Daskapan, T. J. Chem. Soc., Perkin Trans. 1 1999, 3139.
(2) For a review, see: Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93,
2117.
(3) Erdik, E.; Kocoglu, M. Main Group Met. Chem. 2002, 25, 621.
(4) (a) Berman, A. M.; Johnson, J. S. J. Org. Chem. 2006, 71, 219. (b)
Berman, A. M.; Johnson, J. S. J. Org. Chem. 2005, 70, 364. (c) Berman,
A. M.; Johnson, J. S. Synlett 2005, 11, 1799. (d) Berman, A. M.; Johnson,
J. S. J. Am. Chem. Soc. 2004, 126, 5680.
(5) (a) Jiang, L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling
Reactions; De Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vol. 2, pp 699-760. (b) Wolfe, J. P.; Wagaw, S.; Marcoux,
J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (c) Hartwig, J. F. In
Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim,
Germany, 2002; pp 107-168. (d) Hartwig, J. F. In Handbook of Organo-
palladium Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; John Wiley
& Sons: Hoboken, NJ, 2002; Vol. 1, pp 1051-1096.
(6) (a) Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124, 9390.
(b) Sapountzis, I.; Knochel, P. Angew. Chem., Int. Ed. 2004, 43, 897.
10.1021/ol061303m CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/21/2006

Table 1. Synthesis of Aryl-Alkylamines 3a-3m from the Reaction of Arylazo Tosylates 1a-1f with Alkylzinc Reagents 2a-2i
a Isolated yield of analytically pure product. b A 4:1 ratio of exo:endo isomers was obtained.
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Org. Lett., Vol. 8, No. 17, 2006

the preparation of secondary aryl-alkylamines via an elec-
trophilic amination reaction of organozinc reagents (RZnX
or R2Zn)7 with functionalized arylazo tosylates (ArN2Ts)8
(Scheme 1). This method is applicable to a wide range of
The electrophilic amination reaction also takes place in
the presence of an electron-withdrawing fluoride substituent
in the aromatic ring of the arylazo tosylate and affords the
corresponding amine 3e in 75% yield (entry 5). The reaction
is found equally efficient in the presence of electron-donating
substituents on the arylazo tosylate. Thus, the reaction of
4-methoxyphenylazo tosylate (1c) leads to amine 3f in 71%
yield, and 3,5-dimethylphenylazo tosylate (1d) provides
amine 3g in 76% yield (entries 6 and 7). Remarkably, this
method also offers an easy access to secondary amines
bearing a neophyl group, PhC(Me)2CH2, which is usually
difficult to introduce by nucleophilic substitution. The
reaction of neophylzinc bromide (2g), prepared via the
transmetalation of neophyllithium by zinc bromide, with
4-phenylazo tosylate (1a) leads to the formation of the
desired amine 3h in 79% yield (entry 8). This methodology
is successfully applied to bicyclic diorganozinc compounds,
such as di-2-norbornylzinc (2f) and dimyrtanylzinc (2h)
(entries 6 and 9-11). It is noteworthy that, di-2-norbornylz-
inc (2f), prepared by the described procedure,10 reacts with
4-methoxyphenylazo tosylate (1c) and provides the desired
secondary amine 3f in 71% yield with an exo:endo ratio of
80:20 (entry 6). Similarly, product 3i is obtained by the
reaction of di-2-norbornylzinc (2f) with the quinoline arylazo
tosylate 1e (62%, entry 9). Interestingly, the presence of an
ester group in the organozinc reagent 2i also furnishes the
expected secondary amine 3l in 45% yield (entry 12).
However, in the case of a highly electron-deficient arylazo
tosylate system bearing two CF3 groups 1f, the reductive
workup fails and only the intermediate addition product 3m
can be isolated in 41% yield (entry 13).
Scheme 1. General Reaction Sequence
polyfunctional substrates due to its excellent compatibility
and mild reaction conditions.
Preliminary studies showed that the reaction of a 4-phe-
nylazo tosylate ethyl ester (1a) with cyclopentylzinc iodide
(2a) in dry THF at -20 °C leads to the corresponding
hydrazine (Scheme 1). However, as reported earlier,6 the
reductive cleavage of the N-N bond using allyl iodide in
N-methylpyrrolidinone (NMP), followed by the treatment
with zinc dust in a mixture of trifluoroacetic acid/acetic acid
(1:5 v/v), affords the desired secondary amine 3a only in
40% yield. Searching for an efficient route to perform the
reductive cleavage of the N-N bond, we found that Raney
nickel in refluxing ethanol gave amine 3a in 71% isolated
yield within 3 h (Scheme 1, Table 1).
These optimized reaction conditions allow us to synthesize
a wide range of highly functionalized secondary aryl-
alkylamines (3a-3l) in good to excellent yields (Table 1).
Both alkylzinc iodides and dialkylzinc reagents can be used
in this addition reaction, which enables us to prepare
diastereoselective aryl-alkylamines. Thus, the reaction of
cyclopentylzinc iodide (2a) and dicyclohexylzinc (2b) with
the arylazo tosylate (1a) gives rise to the aryl-cycloalkyl-
amines 3a and 3b, respectively, in 71 and 62% yield (entries
1 and 2). The reaction of n-alkylzinc compounds, such as
n-pentylzinc iodide (2c) and n-octylzinc iodide (2d), with
4-phenylazo tosylate ethyl ester (1a) leads to the formation
of aryl-n-alkylamines 3c and 3d in 52-55% yield (entries 3
and 4).
Remarkably, this procedure can be further utilized for the
synthesis of chiral amines starting from chiral organozinc
compounds (Scheme 2).11 The chiral alkylzinc derivative 2j
can be prepared from 1-(2-methoxyphenyl)cyclopentene (4)
via hydroboration with (-)-IpcBH2, followed by a boron-
zinc exchange with i-Pr2Zn. The chiral organozinc reagent
2j subsequently reacts with arylazo tosylate (1a) leading to
the chiral secondary amine 3n in 40% isolated yield with an
enantiomeric excess of 85% and a diastereoselectivity of 98%
(Scheme 2).
Ethyl esters of (alkylamino)benzoic acids, such as 3c and
3d, have a serum sterol and triglyceride lowering activity
(in vivo). Furthermore, such compounds decrease the activity
of the enzyme fatty acyl CoA:cholesterol acyltransferase
(ACAT) (in vitro) and therefore decrease the accumulation
of cholesteryl esters in the arterial wall.9
(10) Jensen, A. E.; Knochel, P. J. Org. Chem. 2002, 67, 79.
(11) (a) Hupe, E.; Calaza, M. I.; Knochel, P. J. Organomet. Chem. 2003,
136. (b) Hupe, E.; Calaza, M. I.; Knochel, P. Chem.sEur. J. 2003, 9, 2789.
(c) Harrington-Frost, N.; Leuser, H.; Calaza, M. I.; Kneisel, F. F.; Knochel,
P. Org. Lett. 2003, 5, 2111. (d) Hupe, E.; Knochel, P. Org. Lett. 2001, 3,
127. (e) Boudier, A.; Knochel, P. Tetrahedron Lett. 1999, 40, 687.
(12) Typical procedure: preparation of cyclopentyl-(3,5-dimethylphenyl)-
amine 3g. In a flame-dried argon-flushed 25 mL two-neck round-bottom
flask equipped with a magnetic stirrer and septum, cyclopentylzinc iodide
2a (0.92 mL, 1.2 mmol, 1.31 M in THF) was dissolved in dry THF (1 mL)
and cooled to -20 °C. 3,5-Dimethylphenylazo tosylate 1d (288 mg, 1.0
mmol) was dissolved in dry THF (2 mL) and added dropwise to the
organozinc reagent. The reaction mixture was stirred at -20 °C for 30 min
to form the intermediate zinc hydrazide. The solvent was removed, and the
residue was dissolved in ethanol (5 mL). Raney nickel (activated catalyst
50%, in water; Acros Chemical) (2.5 g) was added, and the reaction mixture
was refluxed for 1.5 h. The reaction mixture was allowed to cool to room
temperature, and the Raney nickel residue was separated by filtration.
Ethanol was removed in vacuo and the residue extracted with diethyl ether
(2 × 10 mL), washed with brine (2 × 10 mL), and dried over sodium
sulfate. Purification by flash chromatography (n-pentane/diethyl ether 99:
1) yielded 144 mg (76% isolated yield) of 3g as a light-yellow viscous
liquid.
(7) (a) Knochel, P.; Calaza, M. I.; Hupe, E. In Metal-Catalyzed Cross-
Coupling Reactions; De Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; Vol. 2, pp 619-670. (b) Boudier, A.; Bromm,
L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 4414. (c)
Knochel, P.; Jones, P.; Langer, F. In Organozinc Reagents; Knochel, P.,
Jones, P., Eds.; Oxford University Press: Oxford, UK, 1999; pp 179-212.
(d) Knochel, P.; Millot, N.; Rodrriguez, A. L.; Tucker, C. In Organic
Reactions; Overman, E. L., Ed.; John Wiley & Sons: New York, 2001;
Vol. 58.
(8) For the preparation of arylazo tosylate, see: Karzeniowski, S. H.;
Gokel, G. W. Tetrahedron Lett. 1977, 3519, and see ref 6b.
(9) Albright, J. D.; DeVries, V. G.; Largis, E. E.; Miner, T. G.; Reich,
M. F.; Schaffer, S. A.; Shepherd, R. G.; Upeslacis, J. J. Med. Chem. 1983,
26, 1378 and references therein.
Org. Lett., Vol. 8, No. 17, 2006
3743

Scheme 2. Synthesis of the Chiral Amine 3n
In summary, we have reported a mild procedure for the
dation for a fellowship. We also thank Boehringer Ingelheim
(Vienna, Austria) and Chemetall GmbH (Frankfurt, Ger-
many) for the generous gift of chemicals.
synthesis of various secondary aryl-alkylamines bearing a
broad variety of functional groups attached at the aromatic
ring.12 This method can also be used for the preparation of
chiral aryl-alkylamines (Scheme 2). Further work is un-
derway to explore the reactivity of organometallic reagents
toward other electrophilic amino synthons.
Supporting Information Available: Experimental pro-
cedures and full characterization of all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Fonds der Chemischen
Industrie for financial support. C.K. thanks the DFG for a
fellowship. P.S. thanks the Alexander von Humboldt Foun-
OL061303M
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