Iron-catalyzed oxidative monoarylation of primary amines with organozinc reagents

Article abstract of DOI:10.1021/ol2024357

The reaction of a primary zinc amide with a diorganozinc reagent gives a secondary amine in the presence of Fe(acac)₃ as a catalyst and 1,2-dichloroisobutane (DCIB) as an oxidant. Halogen groups such as F, Cl, Br, and I are tolerated well. The dichloride oxidant and heat are essential to achieve the C-N bond formation presumably from a catalytic iron intermediate species bearing aryl and amido groups.

Full text of DOI:10.1021/ol2024357

ORGANIC
LETTERS
2
011
Vol. 13, No. 22
998–6001
Iron-Catalyzed Oxidative Monoarylation of
Primary Amines with Organozinc
Reagents
5
Yuki Nakamura, Laurean Ilies, and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033
nakamura@chem.s.u-tokyo.ac.jp
Received September 8, 2011
ABSTRACT
3
The reaction of a primary zinc amide with a diorganozinc reagent gives a secondary amine in the presence of Fe(acac) as a catalyst and 1,2-
dichloroisobutane (DCIB) as an oxidant. Halogen groups such as F, Cl, Br, and I are tolerated well. The dichloride oxidant and heat are essential to
achieve the CꢀN bond formation presumably from a catalytic iron intermediate species bearing aryl and amido groups.
Intensiveresearchcontinuestoexplorenewpropertiesof
iron, motivated by the interest in pure science as well as in
with an arylzinc reagent to selectively obtain a secondary
amine (Scheme 1, right). Our design of the catalytic system
was inspired by the pioneering work of Yamamoto on the
copper-mediated oxidative coupling of an organolithium
1
finding solutions to the issues related to the environment
ꢀ4
2
and the scarcity of chemical elements.
catalysis is no exception. Various new types of iron catalysis
Research on
8
compound and an amine (Scheme 1, top left), which
has not received proper attention until Knochel’s recent
5
have received recent interest, including an attempted cross-
coupling-type synthesis of aromatic amine derivatives. We
report here a new reactivity of an iron amide intermediate
that enables the oxidative coupling of a primary aryl amine
6,7
9
revisit to this stoichiometric chemistry. The reaction is
retrosynthetically complementary to the much explored
1
0
11
cross-coupling synthesis under palladium, nickel, or
1
2
copper catalysis and possesses some attractive fea-
tures: the use of nontoxic and ubiquitous metal salt
(
(
(
1) Bolm, C. Nat. Chem. 2009, 1, 420.
2) Nakamura, E.; Sato, K. Nat. Mater. 2011, 10, 158–161.
3) http://www.rsc.org/ScienceAndTechnology/roadmap/sustaina-
[
Fe(acac) ] and a simple ligand (TMEDA), and the
3
tolerance of aryl chloride, bromide, and iodide groups.
This last feature makes the present amine synthesis
complementary to the cross-coupling approaches using
ble_global_society/CS3_download.asp.
4) Kamihara, Y.; Hiramatsu, H.; Hirano, M.; Kawamura, R.;
Yanagi, H.; Kamiya, T.; Hosono, H. J. Am. Chem. Soc. 2006, 128,
(
1
0012–10013.
5) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
04, 6217–6254. (b) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem.,
(
1
(8) Yamamoto, H.; Maruoka, K. J. Org. Chem. 1980, 45, 2739–2740.
(9) (a) del Amo, V.; Dubbaka, S. R.; Krasovskiy, A.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 7838–7842. (b) Kienle, M.; Dubbaka,
S. R.; del Amo, V.; Knochel, P. Synthesis 2007, 8, 1272–1278. (c) Kienle,
M.; Dunst, C.; Knochel, P. Org. Lett. 2009, 11, 5158–5161.
(10) (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. 1998,
31, 852–860. (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544.
(d) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–
6361. (e) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27–50.
(11) (a) Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem.
2008, 73, 1429–1434. (b) Gao, C.-Y.; Yang, L.-M. J. Org. Chem. 2008,
73, 1624–1627.
Int. Ed. 2008, 47, 3317–3321. (c) Iron Catalysis in Organic Chemistry;
Plietker, B., Ed.; Wiley-VCH: Weinheim, Germany, 2008. (d) Sherry, B. D.;
F €u rstner, A. Acc. Chem. Res. 2008, 41, 1500–1511. (e) Czaplik, W. M.;
Mayer, M.; Cvengros, J.; Jacobi von Wangelin, A. ChemSusChem 2009,
2, 396–417. (f) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75,
6061–6067. (g) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111,
1293–1314.
(
6) (a) Correa, A.; Manche n~ o, O. G.; Bolm, C. Chem. Soc. Rev. 2008,
7, 1108–1117, and references therein. (b) Buchwald, S. L.; Bolm, C.
3
Angew. Chem., Int. Ed. 2009, 48, 5586–5587. (c) Taillefer, M.; Xia, N.;
Ouali, A. Angew. Chem., Int. Ed. 2007, 46, 934–936. (d) Wu, X.-F.;
Darcel, C. Eur. J. Org. Chem. 2009, 4753–4756.
(
7) Lef ꢀe vre, G.; Taillefer, M.; Adamo, C.; Ciofini, I.; Jutand, A. Eur.
J. Org. Chem. 2011, 3768–3780.
(12) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400–5449, and references therein.
1
0.1021/ol2024357 r 2011 American Chemical Society
Published on Web 10/18/2011

1
3
aryl halides as the coupling partner. Aryl amines have
been key players in pharmaceutical research and have
become increasingly popular also in organic electronics
stoichiometric experiments, we can speculate the fol-
lowing. (1) Two amide molecules act as a ligand for
iron, in which more than one aryl moiety coordinates to
iron, and (2) the oxidant is crucial for CꢀN bond
formation.
1
4
research, which is our current concern.
Scheme 1. Oxidant-Promoted Reductive Elimination from an
Organoiron Amide To Form a CꢀN or CꢀC Bond
Table 1. Oxidative Phenylation of p-Toluidine (1) with Diphe-
nylzinc Using 1.0 Equiv of Fe(acac)3
a
b
1
2
“Ph Zn”
DCIB
temp
3
4
1
entry (equiv)
(equiv)
(equiv)
(°C)
(%) (%) (%)
1
2
3
4
5
6
1.0
1.0
1.0
2.0
2.0
2.0
1.0
1.0
2.0
1.0
2.0
2.0
0
80
80
80
80
80
rt
0
8
86
2.0
2.0
2.0
2.0
2.0
33 47 62
42 114 53
33 19 158
93 61 98
22 69 176
To probe the stoichiometry necessary for the iron-
mediated CꢀN coupling, we first studied the stoichio-
a
Reaction conditions: zinc amide 2 was generated from the corre-
sponding amine (1.0 or 2.0 equiv), n-BuLi in hexane (1.0 or 2.0 equiv),
and ZnCl TMEDA (1.0 or 2.0 equiv), and then it was allowed to react
metric coupling reaction using Fe(acac) (Table 1). The
3
reaction between 1.0 equiv of in situ generated primary
zincamide from p-toluidine 1 and 1.0 equivofdiphenylzinc
reagent (prepared from PhMgBr and ZnCl TMEDA) in
2
3
with an organozinc reagent generated from PhMgBr in Et
4
2
O (2.0 or
.0 equiv) and ZnCl TMEDA (1.0 or 2.0 equiv) in the presence of
2
3
2
3
Fe(acac) (0.30 mmol) and DCIB (2.0 equiv) in chlorobenzene at 80 °C
3
chlorobenzene at 80 °C after 15 h afforded none of
the desired product 3 with recovery of starting material
for 15 h. Yields were determined by gas chromatography (GC) using n-
b
tridecane as an internal standard. “Ph
2
Zn” was prepared from
PhMgBr and ZnCl TMEDA in chlorobenzene.
2
3
1
biphenyl 4 in 8% yield (entry 1). The same reaction
in 86% yield (based on iron) and gave only the
1
5
in the presence of 2.0 equiv of 1,2-dichloroisobutane
(
yields, respectively (entry 2). Further investigation on
1
DCIB) as an oxidant produced 3 and 4 in 33 and 47%
5
Having learned the essential role of DCIB and heat, we
next explored the catalytic conditions and achieved the
desired CꢀN coupling in isolated yield as high as 94%
the amount of 1 and “Ph Zn” (entries 3ꢀ5) showed that
2
(eq 1). A typical example for the iron-catalyzed oxidative
the use of 2.0 equiv each of 1 and diphenylzinc in the
presence of 2.0 equiv of DCIB yielded 3 and 4 in 93 and
monoarylation is as follows: the reaction of zinc amide 2
generated from p-toluidine (32.1 mg, 0.30 mmol), n-BuLi,
and ZnCl TMEDA with diphenylzinc (2.0 equiv) gener-
6
1% yields, respectively (entry 5). When the reaction
2
3
temperature was lowered to 25 °C, the reaction gave
the products 3 and 4 in 22 and 69% yields, respectively
ated from PhMgBr and ZnCl TMEDA in the presence of
2
3
2
0 mol % of Fe(acac) as a catalyst and 2.0 equiv of DCIB as
3
(
requires high temperature. We obtained essentially
entry 6), indicating that the CꢀN bond formation
1
6
an oxidant in chlorobenzene at 80 °C for 15 h gave the
desired N-phenyl-p-toluidine 3 in 94% isolated yield after
chromatographic purification on silica gel. The catalyst
loading could be reduced to 5 mol % at the expense of
reduced reaction rate. The use of pure diphenylzinc resulted
in complete recovery of the starting amine. This observation
suggests the necessary presence of the magnesium(II) ion,
whereas aryl Grignard reagents only took part in the CꢀN
bond formation in low yield and gave largely biphenyl. The
same reaction performed on a 1 g scale (9.3 mmol) afforded
3 in 85% yield. The side product 4 (109%; 0.33 mmol)
the same result when using Fe(acac) . From these
2
(
13) Lawrence, S. A. Amines: Synthesis Properties and Application;
Cambridge University: Cambridge, UK, 2004.
14) (a) Tsuji, H.; Mitsui, C.; Sato, Y.; Nakamura, E. Adv. Mater.
009, 21, 3776–3779. (b) Matsuo, Y.; Sato, Y.; Niinomi, T.; Soga, I.;
Tanaka, H.; Nakamura, E. J. Am. Chem. Soc. 2009, 131, 16048–16050.
15) (a) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E.
(
2
(
J. Am. Chem. Soc. 2008, 130, 5858–5859. (b) Yoshikai, N.; Matsumoto,
A.; Norinder, J.; Nakamura, E. Synlett 2010, 313–316. (c) Yoshikai, N.;
Mieczkowski, A.Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem.
Soc. 2011, 133, 428–429. (d) Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am.
Chem. Soc. 2011, 133, 6557–6559. (e) Ilies, L.; Asako, S.; Nakamura, E. J.
Am. Chem. Soc. 2011, 133, 7672–7675. (f) Yoshikai, N.; Asako, S.;
Yamakawa, T.; Ilies, L.; Nakamura, E. Chem.;Asian J. 2011, DOI:
1
7
formed by the iron-catalyzed homocoupling of the zinc
reagent could be removed readily by column chromatogra-
phy. The reaction selectively afforded the secondary amine
and did not produce the diarylated product (N,N-diphenyl-
p-toluidine).
10.1002/asia.201100470.
(
16) While monitoring of the reation system by NMR was difficult,
cyclic voltammetric measurements indicated that the heat is necessary to
drive the reaction probably through promotion of the ligand exchange
on iron. The reversible reduction wave of Fe(II) at ꢀ1.44 V (vs ferrocene)
2
observed for a solution of Fe(acac) in chlorobenzene at ambient
temperature became irreversible upon addition of the zinc amide, which
shifted the oxidation peak to around ꢀ0.70 V. This indicates that no
reaction takes place by the addition of zinc amide, and the ligand
7
exchange only takes place by the reaction with reduced iron species.
Upon addition of diphenylzinc, no change was observed by CV. After
heating this mixture at 60 °C, two new reversible reduction waves at
ꢀ
0.58 and ꢀ0.99 V were observed, which suggests the formation of iron
species that can be reduced more easily than Fe(acac)
2
.
Org. Lett., Vol. 13, No. 22, 2011
5999

Table 2. Reaction Conditions for Iron-Catalyzed Oxidative
Phenylation of p-Toluidine (1)
Table 3. Iron-Catalyzed Oxidative Arylation of Various Pri-
mary Amines with Diorganozinc Reagents
a
a
b
b
b
entry
catalyst
oxidant
3 (%) 4 (%) 1 (%)
1
2
none
DCIB
DCIB
DCIB
DCIB
0
0
92
4
Fe(acac)
Fe(acac)
Fe(acac)
3
3
3
95
32
84
116
28
93
c
3
57
10
4
(
g94.2%)
FeCl
Fe(acac)
5
6
7
8
3
DCIB
DCIB
DCIB
86
82
96
13
12
2
88
CuI (Cu
Fe(acac)
2
O)
0(0)
64(66) 92(92)
3
þ dppp DCIB
82(75) 93(92) 8(10)
(phen)
9
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
Fe(acac)
3
3
3
3
3
3
none
0
17
44
51
13
46
50
88
58
5
1
0
t-BuCl
26
11
1,2-dibromoethane 44
dibenzoyl peroxide 29
1
1
1
2
3
4
0
dioxygen
air
55
39
0
0
a
Reaction conditions: the zinc amide 2 was generated from p-
TME-
toluidine (1, 0.30 mmol), n-BuLi in hexane (1.0 equiv), and ZnCl
2
3
DA (1.0 equiv), and then it was allowed to react with a diphenylzinc
reagent generated from PhMgBr in Et O (4.0 equiv) and ZnCl TME-
DA (2.0 equiv) in the presence of 20 mol % of Fe(acac)
2
2
3
3
(g99.9% purity
unless otherwise noted) and DCIB (2.0 equiv) in chlorobenzene at 80 °C
for 15 h; dppp = 1,3-bis(diphenylphosphino)propane; phen = 1,10-
b
phenanthroline. Yields were determined GC using n-tridecane as an
c
internal standard. 1.0 equiv of DCIB was used.
Various conditions were examined to optimize the cat-
alyticreaction(Table 2). No product formedin the absence
of the iron catalyst (entry 1). Several iron sources of
different purities catalyzed the reaction with equal ease
(
reaction (entry 7). These results suggest that contaminants in
entries 2 and 4ꢀ6), and copper salts did not catalyze the
6
b
the iron source do not play any significant role. Phosphine-
and pyridine-type ligands did not affect the catalytic activity,
which implies that the anionic amine binds more strongly to
18
the iron center than these neutral ligands (entry 8).
Both the choice and the amount of the oxidant were
crucial for the reaction. As can be seen by the comparison
among the entries 2 and 10ꢀ14, DCIB was found to serve
as the best oxidant for the CꢀN coupling to give 3 (entry
a
Reaction conditions: the zinc amide 2 was generated from the
corresponding amine (0.30ꢀ1.0 mmol), n-BuLi in hexane (1.0 equiv), and
ZnCl TMEDA (1.0 equiv), and then it was allowed to react with an
2
3
2
), which was the same with our previously reported CꢀC
organozinc reagent generated from RMgBr in Et
ZnCl2 3
2
O (4.0 equiv) and
3
TMEDA (2.0 equiv) in the presence of Fe(acac) (20 mol %) and
1
5a,dꢀf
bond formation reaction.
Reducing the amount of
DCIB (2.0 equiv) in chlorobenzene at 80 °C for 15 h. See the Supporting
Information for details. Isolated yield after purification on silica gel. In low-
DCIB to 1.0 equiv led to a significant decrease in the yields
of both CꢀN and CꢀC bond formation (entry 3). Without
DCIB, the CꢀN bond formation did not take place at all
b
c
yielding reactions, the starting amine was recovered. GC yield obtained
d
using n-tridecane as an internal standard. The monophenylzinc reagent was
prepared from an equimolar amount of PhMgBr and ZnCl
2
3 TMEDA.
(
entry 9). Other oxidants such as organic halides (entries 10
and 11), dibenzoyl peroxide (entry 12), dioxygen (entry
3), or air (entry 14) performed less satisfactorily. When
dioxygen or air was employed as an oxidant, homocou-
pling of the amine partner proceeded to form a small
0
19
amount (4ꢀ7%) of 4,4 -dimethylazobenzene in addition
to biphenyl (4). Addition of TEMPO did not significantly
affect the reaction. The reaction proceeded the best in
electron-deficient aromatic solvents such as chlorobenzene
or trifluoromethylbenzene (see Supporting Information)
1
(
17) (a) Cahiez, G.; Chaboche, C.; Mahuteau-Betzer, F.; Ahr, M.
Org. Lett. 2005, 7, 1943–1946. (b) Nagano, T.; Hayashi, T. Org. Lett.
2
3
1
005, 7, 491–493.
18) Olmstead, M. M.; Power, P. P.; Shoner, S. C. Inorg. Chem. 1991,
0, 2547–2551.
19) Grirrane, A.; Corma, A.; Garcı
664.
(
(20) (a) Bart, S. C.; Hawrelak, E. J.; Labkovsky, E.; Chirik, P. J.
Organometallics 2005, 24, 5518–5527. (b) Radonovich, L. J.; Eyring,
M. W.; Groshens, T. J.; Klabunde, K. J. J. Am. Chem. Soc. 1982, 104,
2816–2819.
(
´
a, H. Science 2008, 322, 1661–
6
000
Org. Lett., Vol. 13, No. 22, 2011

1
5e,f
as was found in an iron-catalyzed CꢀC bond formation,
withasmall amount ofa dimethylated product. Heteroaryl
or alkenyl reagents did not react under these conditions, as
previously observed for iron-catalyzed CꢀH functionali-
suggesting a certain role in the catalysis, for example, by
2
0
stabilizing a low-valent iron species. The reaction tem-
perature of 80 °C was necessary to promote the CꢀN bond
formation, and the reaction at room temperature gave
only biphenyl due to CꢀC homocoupling. Notably, in all
cases, the formation of diarylated tertiary amine was not
observed.
1
5a,b,e,f
zation reactions.
In conclusion, we have developed an iron-catalyzed
oxidative reaction of a primary amine with an organozinc
reagent that selectively produces the corresponding sec-
ondary aryl amine. This new type of reaction is a new entry
to the rapidly expanding repertoire of iron catalysis. The
results of the stoichiometric reactions suggest that the
crucial iron intermediate species contains more than 1
equiv of aryl and amide ligands and, upon heating and
oxidation by DCIB, gives a mixture of aryl amine and
diaryl products. Driving the reaction selectively into the
desired CꢀN bond forming manifold apparently needs
further mechanistic information, which serves as an inter-
esting subject for future studies.
With the optimized conditions in hand, we investigated
the scope of this reaction (Table 3). While p-toluidine (1)
gave N-phenyl-p-toluidine (3) in 94% yield (entry 1), the
reaction of a secondary amine (entry 2) gave none of the
desired product. Aniline derivatives possessing an elec-
tron-donating or an electron-withdrawing group (entries 1
and 3ꢀ7) were smoothly monoarylated in good to excel-
lent yields. The reaction tolerated the presence of aromatic
halides such as F, Cl, Br, and I (entries 5ꢀ8), which marks
the difference between this reaction and the popular cross-
coupling routes to aryl amines. An ortho-substituted ani-
line reacted poorly (16% yield; entry 9), suggesting steric
effects. A primary alkylamine also took part in the reac-
tion, albeit with low yield (13%) and no recovery of
starting material (entry 10). Entries 11ꢀ14 illustrate the
scope of the organozinc reagent. Both electron-rich or
electron-deficient diarylzinc reagents (entries 11 and 12)
underwent the coupling reaction in good yields. The reac-
tion with a monophenylzinc reagent resulted in low yield
Acknowledgment. We thank MEXT for financial sup-
port of the research (KAKENHI Specially Promoted
Research 22000008 to E.N., 23750100 to L.I.); the Global
COE Program for Chemistry Innovation. Y.N. thanks the
Japan Society for the Promotion of Science for the Rese-
sarch Fellowship for Young Scientists (21•8591).
Supporting Information Available. Experimental pro-
cedures and physical properties of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(entry 13). The reaction with dimethylzinc gave the desired
monomethylated product in 12% yield (entry 14) together
Org. Lett., Vol. 13, No. 22, 2011
6001