Nickel-catalyzed amination of aryl sulfamates

Article abstract of DOI:10.1002/anie.201007325

Broad in scope: The first amination of aryl sulfamates, which are attractive cross-coupling partners, particularly for multistep syntheses, was achieved by using a nickel catalyst. The method provides a versatile means to use simple derivatives of phenol as precursors to polysubstituted aryl amines, as exemplified by a concise synthesis of the antibacterial drug linezolid (see scheme).

Full text of DOI:10.1002/anie.201007325

DOI: 10.1002/anie.201007325
Amination Reactions
Nickel-Catalyzed Amination of Aryl Sulfamates**
Stephen D. Ramgren, Amanda L. Silberstein, Yang Yang, and Neil K. Garg*
Carbon–nitrogen bonds are ubiquitous in medicinal agents
and natural products.[1] Transition metal-catalyzed amination
reactions, pioneered by Buchwald and Hartwig, are amongst
the most powerful methods available for accessing these
motifs.[1] Copper- and palladium-mediated aminations of aryl
halides and triflates are now well-established,[1] and examples
of mesylate[2] and tosylate[3] aminations have been reported.
Most recent efforts have focused on the amination of
classically “inert” phenolic derivatives (i.e., arylmethyl
ethers[4] and aryl pivalate esters[5]), which could potentially
be used in multistep synthesis.[6,7] With the aim of assembling
polysubstituted aryl amines, motifs commonly encountered in
drug scaffolds, naturally occurring small molecules, pesticides,
ligands for catalysis, and materials chemistry, we sought to
uncover a versatile class of phenol-derived substrates that
could undergo transition metal-catalyzed amination.
toward Pd0.[9,10] Moreover, the sulfamate moiety can be used
to functionalize an arene at both the ortho or para posi-
tions,[9a,10,11] prior to carrying out a cross-coupling event.
Despite that aryl O-sulfamates have been employed in
carbon–carbon bond forming reactions,[9,10] their use in
carbon–nitrogen bond construction has remained undiscov-
ered.[12] Herein, we report the first amination of aryl O-
sulfamates (1!2) and the application of this methodology to
a concise synthesis of the antibacterial drug linezolid (4).[13]
Initial studies were aimed at promoting the amination of
dimethylsulfamate derivatives of phenol and 1-naphthol.
Although catalytic systems based on nickel and PCy3 have
been the cornerstone of several recent nickel-catalyzed cross-
coupling reactions involving carbon–oxygen bonds,[14] includ-
ing the Suzuki–Miyaura coupling of aryl O-sulfamates,[10] this
metal/ligand combination was ineffective in our amination
studies.[12] After conducting an extensive survey of reaction
parameters (e.g., nickel catalysts, ligands, solvents, bases,
temperature, etc.) it was observed that N-heterocyclic car-
bene (NHC) ligands uniquely facilitated the desired amina-
tion. Under optimal conditions, treatment of sulfamate 3 with
morpholine in the presence of catalytic [Ni(cod)2] (cod =
cyclooctadiene), SIPr·HCl (5), and NaOtBu, in dioxane at
808C for 3 h afforded the aminated product in 95% yield
(Table 1, entry 1).[15]
Although relatively unexplored, N,N-dialkylaryl O-sulfa-
mates (e.g., 1, Scheme 1) are highly attractive electrophiles
for cross-coupling reactions. They are easy to prepare,[8] stable
to a variety of reaction conditions, and exhibit low reactivity
A variety of sulfamate substrates were examined in the
nickel-catalyzed amination process (Table 1). Methyl sub-
stituents at the para and meta positions were tolerated
(entries 2 and 3), in addition to the electron-withdrawing
trifluoromethyl group and the electron-donating methoxy
group (entries 4 and 5, respectively). Given the utility of the
sulfamate in directed metalation chemistry,[9a,10] we examined
the amination of several ortho-substituted substrates bearing
a methyl, trimethylsilyl (TMS), phenyl, or methoxy substitu-
ent. In all cases, amination proceeded smoothly (entries 6–9).
Naphthyl-based substrates were found to be excellent ami-
nation substrates (entries 10 and 11). Furthermore, hetero-
cycles, such as indole and pyridine, were tolerated in this
methodology (entries 12 and 13).
Scheme 1. Amination of aryl sulfamates and linezolid (4).
[*] S. D. Ramgren, A. L. Silberstein, Y. Yang, Prof. N. K. Garg
Department of Chemistry and Biochemistry
University of California, Los Angeles
Los Angeles, CA 90095 (USA)
As shown in Table 2, the scope of aryl O-sulfamate
amination is also broad with respect to the amine coupling
partner. Both cyclic and acyclic secondary amines were found
to be suitable substrates (entries 1–3). In addition, anilines
could be employed (entries 4–6), including 2,6-dimethylani-
line (entry 6). The methodology also allows for the coupling
of amines with appended heterocycles, as demonstrated by
the coupling of pyridine- and carbazole-containing substrates
(entries 7 and 8).
To further probe the scope and utility of the sulfamate
amination methodology, a concise synthesis of the antibacte-
rial drug linezolid (4) was performed (Scheme 2).[13] Begin-
ning from phenol (6), fluorosulfamate 7 was readily prepared
Fax: (+1)310-206-1843
E-mail: neilgarg@chem.ucla.edu
Homepage: http://www.chem.ucla.edu/dept/Faculty/garg/
Garg_Group/Home.html
[**] The authors are grateful to the NIH-NIGMS (R00 GM079922),
Boehringer Ingelheim, DuPont, Eli Lilly, the University of California,
Los Angeles, the Chemistry–Biology Interface training program
(A.L.S., USPHS National Research Service Award GM08496), and
the UCLA CSST Program (Y.Y.) for financial support. We thank the
Garcia–Garibay laboratory (UCLA) for access to instrumentation,
Dr. John Greaves (UC Irvine) for mass spectra, and Materia Inc. for
chemicals.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007325.
Angew. Chem. Int. Ed. 2011, 50, 2171 –2173
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Table 1: Cross-coupling of aryl sulfamates with morpholine.[a]
Table 2: Cross-coupling of aryl sulfamates with amines.[a]
Entry
Amine
Product
Yield
[%][b]
Entry
Ar-OSO2NMe2
Product
Yield
[%][b]
1c]
2
88
93
1
2
95
76
3
84
77
3
77
4[d]
4
91
80
5[c]
5[d]
64
6[d]
7[e]
8[f]
9[f]
80
50
64
74
6[e]
91
90
7[c]
8[c]
92
10
11
96
86
[a] Conditions unless otherwise stated: [Ni(cod)2] (5 mol%), 5 (10
mol%), sulfamate substrate (1 equiv), amine (1.2 equiv), NaOtBu
(1.4 equiv), dioxane (0.2m), 808C for 3 h. [b] Yields of isolated product.
[c] [Ni(cod)2] (10 mol%), 5 (20 mol%), NaOtBu (1.5 equiv). [d] [Ni-
(cod)2] (15 mol%), 5 (30 mol%), amine (1.8 equiv), NaOtBu (2.2 equiv).
[e] [Ni(cod)2] (15 mol%), 5 (30 mol%), amine (2.4 equiv), NaOtBu
(2.2 equiv).
12[d]
13
72
86
[a] Conditions unless otherwise stated: [Ni(cod)2] (5 mol%), 5 (10
mol%), sulfamate substrate (1 equiv), morpholine (1.2 equiv), NaOtBu
(1.4 equiv), dioxane (0.2m), 808C for 3 h. [b] Yields of isolated product.
[c] [Ni(cod)2] (10 mol%), 5 (20 mol%), NaOtBu (1.5 equiv). [d] [Ni-
(cod)2] (15 mol%), 5 (30 mol%), morpholine (1.8 equiv), NaOtBu
(2.2 equiv). [e] [Ni(cod)2] (20 mol%), 5 (40 mol%), NaOtBu (1.7 equiv),
608C. [f] [Ni(cod)2] (15 mol%), 5 (30 mol%), NaOtBu (1.6 equiv).
using our previously reported sequence.[10] This conversion
proceeds by sulfamylation, followed by ortho-fluorination
(two steps), and showcases the sulfamateꢀs directing ability.
Nickel-catalyzed sulfamate amination proceeded smoothly to
deliver intermediate 8, without interference from the fluoro
substituent.[16] Subsequent iodination furnished trisubstituted
arene 9, which in turn, underwent copper-catalyzed coupling
with oxazolidinone 10 to afford arylated oxazolidinone 11 in
good yield. In the final step, reductive acetylation of azide 11
furnished linezolid (4). Overall, our synthesis illustrates the
merits of sulfamate-directed arene functionalization and
coupling methodology in a complex setting.
Scheme 2. Synthesis of linezolid (4) using Ni-catalyzed amination.
SIPr·HCl=1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride, [Ni-
(cod)2]=bis(1,5-cycloactadiene)nickel(0), NIS=N-iodosuccinimide,
TFA=trifluoroacetic acid.
In summary, we have discovered the first amination
reactions of aryl O-sulfamates, which are attractive cross-
coupling partners, particularly for use in multistep synthesis.
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Angew. Chem. Int. Ed. 2011, 50, 2171 –2173

[9] For Kumada couplings, see: a) T. K. Macklin, V. Snieckus, Org.
Lett. 2005, 7, 2519 – 2522; b) P. M. Wehn, J. Du Bois, Org. Lett.
2005, 7, 4685 – 4688.
The amination is broad in scope with respect to both the
sulfamate and amine coupling partners. The methodology
presented herein provides an effective means for accessing
polysubstituted aryl amines, as demonstrated by a concise
synthesis of the antibacterial drug linezolid.
[10] For the use of aryl sulfamates in directed metalation, electro-
philic aromatic substitution, multistep synthesis, and Suzuki–
Miyaura couplings, see: K. W. Quasdorf, M. Riener, K. V.
Petrova, N. K. Garg, J. Am. Chem. Soc. 2009, 131, 17748 – 17749.
[11] Other phenol-based amination partners cannot be used effec-
tively for directed metalation/functionalization. Specifically, aryl
sulfonates and pivalates are not suitable substrates, whereas aryl
methyl ethers are poor metalation substrates. For reviews see:
a) V. Snieckus, Chem. Rev. 1990, 90, 879 – 933; b) C. G. Hartung,
V. Snieckus in Modern Arene Chemistry (Ed.: D. Astruc), Wiley-
VCH, New York, 2002, pp. 330 – 367; c) T. Macklin, V. Snieckus
in Handbook of C-H Transformations (Ed.: G. Dyker), Wiley-
VCH, New York, 2005, pp. 106 – 119.
Received: November 11, 2010
Published online: January 20, 2011
Keywords: amination · aryl sulfamates · cross-coupling ·
.
homogeneous catalysis · nickel
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ꢀ
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