Oxidative intramolecular coupling of amidocuprates as a novel route to amines and hydrazines

Article abstract of DOI:10.1021/jo9512315

Amidocuprates, derived from organocopper reagents and lithium amides upon exposure to oxygen at low temperature, provide new amine derivatives in satisfactory yields. Details of this flexible and simple methodology are given. The reaction mechanism is analyzed in terms of an oxidative intramolecular coupling of aminyl radicals with the ligands on Cu in the intermediate amidocuprate. This reaction is a mild and efficient method for N-alkylation, -vinylation, and -arylation by which a number of amines, not easily accessible by normal routes, can be synthesized. Once applied to lithium hydrazides, it also provides a new and straightforward entry to N-substituted hydrazines.

Full text of DOI:10.1021/jo9512315

J . Org. Chem. 1996, 61, 1677-1681
1677
Oxid a tive In tr a m olecu la r Cou p lin g of Am id ocu p r a tes a s a Novel
Rou te to Am in es a n d Hyd r a zin es
†
‡
,†
†,§
,‡
Angelo Alberti, Francesco Can e` , Pasquale Dembech,* Dario Lazzari, Alfredo Ricci,* and
†
Giancarlo Seconi
Dipartimento di Chimica Organica “A. Mangini”, Facolt a` di Chimica Industriale, Via Risorgimento 4,
I-40136 Bologna, Italy, and Istituto dei Composti del Carbonio Contenenti Eteroatomi del CNR,
Area di Ricerca di Bologna, Via P. Gobetti 101, I-40129 Bologna, Italy
Received J uly 10, 1995X
Amidocuprates, derived from organocopper reagents and lithium amides upon exposure to oxygen
at low temperature, provide new amine derivatives in satisfactory yields. Details of this flexible
and simple methodology are given. The reaction mechanism is analyzed in terms of an oxidative
intramolecular coupling of aminyl radicals with the ligands on Cu in the intermediate amidocuprate.
This reaction is a mild and efficient method for N-alkylation, -vinylation, and -arylation by which
a number of amines, not easily accessible by normal routes, can be synthesized. Once applied to
lithium hydrazides, it also provides a new and straightforward entry to N-substituted hydrazines.
In tr od u ction
Sch em e 1
The delivery of an amino group to a nucleophilic site
constitutes a useful transformation in organic chemistry,
and for this purpose a practical electrophilic amination
1
protocol has been developed. Several reagents for elec-
trophilic amination have been reported in which the
nitrogen atom is bonded to a leaving group2 whose
leaving ability can be enhanced by interaction with a
suitable metal center. Indications are that the formation
of the new C-N bond is a S
We reported in an earlier paper that the electrophilic
amination of higher order (H.O.) cyanocuprates by bis-
N
2-type reaction.3
4
5
(trimethylsilyl)hydroxylamine provides a suitable entry
into otherwise inaccessible amine derivatives. The present
paper expands upon this investigation by showing that
new amine derivatives can be obtained by an even
simpler procedure, i.e., by reaction of organocuprates with
amines lacking good leaving groups, followed by quench-
ing with molecular oxygen.
The reaction took place in an analogous manner and
with comparable yields whether amines were combined
(procedure B) with bis anionic (H.O.) cuprates with
deprotonation and in situ generation of lithium amides
in the first step or by adding (procedure C) cuproamides
obtained by transmetalation of lithium amides with CuI,
CuBr‚Me
2
S, or CuCN to a suitable organolithium deriva-
Resu lts a n d Discu ssion
tive. Since procedure C is the usual method for the
6
generation of amidocuprates, the existence of these
We found that reaction of lithium amides, obtained by
species throughout the range of reactions so far reported
is inferred.
metalation of amines with n-BuLi, with an equimolar
5
amount of monoanionic (L.O.) cuprate (procedure A in
Even though a Cu-mediated Ullmann condensation
leading to C-N bond formation has been the subject of
a mechanistic study,7 to our knowledge only two ex-
amples of a synthetically useful N-alkylation of an amine,
based on an oxidative coupling of lithium alkyl copper
amides, have been previously reported.8 These proce-
dures utilize 3- or 5-fold excesses of cuprate with respect
to the amine used. Furthermore, no description of the
mechanism of this reaction has been given. It is noted
that the use of organocuprates is crucial for the efficient
introduction of nitrogen at donor sites since neither the
use of simple organolithium derivatives nor that of
Grignard reagents afforded the amine derivatives I upon
reaction with lithium amides.
Scheme 1) affords a clear, fairly stable solution which at
low temperature in the presence of oxygen decomposes
into a heterogeneous dark mixture. From this mixture
a newly formed amine derivative could be recovered (see
the Experimental Section).
†
Istituto dei Composti del Carbonio Contenenti Eteroatomi del CNR.
Dipartimento di Chimica Organica “A. Mangini”.
Recipient of a Fellowship of the Progetto Finalizzato Chimica Fine
‡
§
II (CNR-Italy). Present address: Ciba-Geigy Divisione Additivi, Via
Pila 6/3°, 4044 Pontecchio Marconi Bologna, Italy.
X
Abstract published in Advance ACS Abstracts, February 1, 1996.
(1) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 298. Erdik,
E.; Ay, M. Chem. Rev. 1989, 89, 1947. Mitchell, H.; Leblanc, Y. J . Org.
Chem. 1994, 59, 682 and references cited therein.
(
2) Genet, J .-P.; Mallart, S.; Greck, C.; Piveteau, E. Tetrahedron Lett.
991, 32, 2359. Greck, C.; Bischoff, L.; Ferreira, F.; Pinel, C.; Piveteau,
E.; Genet, J .-P. Synlett, 1993, 475.
3) Beak, P.; Kokko, B. J . Org. Chem. 1982, 47, 2822. Beak, P.;
Basha, A.; Kokko, B.; Loo, D. K. J . Am. Chem. Soc. 1986, 108, 6016.
4) Casarini, A.; Dembech, P.; Lazzari, D.; Marini, E.; Reginato, G.;
Ricci, A.; Seconi, G. J . Org. Chem. 1993, 58, 5620.
5) The terms “higher order” (H.O.) and “lower order” (L.O.) refer
to the RLi/Cu(I) ratios employed in the cuprate preparation.
1
The relevant results of the N-alkylation and N-aryla-
tion of primary and secondary amines with organocopper
(
(
(6) Rossiter, B. E.; Eguchi, M. Tetrahedron Lett. 1990, 31, 965.
(7) Paine, J . A. J . Am. Chem. Soc. 1987, 109, 1496.
(8) Yamamoto, H.; Maruoka, K J . Org. Chem. 1980, 45, 2739. Iwao,
M.; Reed, J . N.; Snieckus, V. J . Am. Chem. Soc. 1982, 104, 5531.
(
0
022-3263/96/1961-1677$12.00/0 © 1996 American Chemical Society

1
678 J . Org. Chem., Vol. 61, No. 5, 1996
Ta ble 1. Oxygen -P r om oted Electr op h ilic Am in a tion of Cya n ocu p r a tes w ith Lith iu m Am id es
Alberti et al.
reagents are reported in Table 1. Along with the desired
amines isolated in satisfactory yields, variable amounts
of C-C homocoupling byproducts were also present in
the reaction mixtures.
Substitution at the nitrogen played an important role,
and secondary amines bearing aliphatic substituents
were the most suitable starting materials for the title
reaction. Finally, a sizeable reduction of yield was
observed upon replacing molecular oxygen with other
(Ii-l) of (R)-(+)-1-(1-naphthyl)ethylamine reported in
Table 1 (entries 9-12). Apart from the N-alkylation (Ii)
and N-arylation (Ij) products, the chiral N-(2-methoxy-
phenyl)-(R)-(-)-1-(1-naphthyl)ethylamine (Ik ) and the
N-[2-(benzyloxy)phenyl]-(R)-(-)-1-(1-naphthyl)ethyl-
amine (Il), valuable chiral auxiliaries in asymmetric
catalytic reactions,10 although not readily accessible,
could be synthesized in fairly good yields. No racemiza-
tion could be detected during these reactions.11
oxidizing reagents such as CuCl
2
, copper(II) 2-ethylhex-
When applied to hydrazines, this reaction proved to
be a mild method for the delivery of the hydrazido group
to nucleophilic sites, thus opening a new and viable route
to functionalized hydrazines (IIa -c) from commercially
available starting materials. A few representative ex-
amples of this latter reaction are reported in Table 2.
anoate, VOCl , Me SiOOSiMe , or RuO .
3
3
3
2
In addition to providing a method for monoalkylation
at the nitrogen atom (Table 1, entries 1, 2, 4, and 5), this
oxidative coupling reaction allows for the N-vinylation
(Table 1, entry 8) and -heteroarylation (Table 1, entries
6
and 7) of amines of synthetic interest. These reactions
Interestingly, N-alkylation with groups bearing hy-
drogens at the carbon of the newly formed C-N bond (as
in entry 14) led to formation of the corresponding
hydrazone as the major product, presumably by hydrogen
elimination from the expected hydrazine. The use in-
stead of the usual lithium-hydrazidocuprate of a more
stable lithium-zinc-hydrazidocuprate whose stoichio-
metric composition (see the Experimental Section) can
do not have simple or straightforward counterparts in
the literature. Regarding N-arylation (Table 1, entry 3),
arylamines are structural components in a variety of
synthetic and natural biologically active compounds, and
many synthetic methods for the construction of an
9
aryl-N bond have been reported, most of which, how-
ever, suffer from a need for severe reaction conditions or
activated substrates. These difficulties can be overcome
by using the oxidative coupling methodology reported
herein. For instance, this method was well-suited for use
in the convenient synthesis of N-substituted derivatives
be described as [n-Bu(Ph
2
N-NR)CuZnCl/LiCl,LiCN], pre-
vented this side reaction.
(10) J ansen, J . F. G. A.; Feringa, B. L. J . Org. Chem. 1990, 55, 4168.
Soai, K.; Yokoyama, S.; Hayasaka, T. Ibid. 1991, 56, 4264. Brown, J .
M.; Lloyd-J ones, G. C. J . Am. Chem. Soc. 1994, 116, 866.
(
9) March, J . Advanced Organic Chemistry, 4th ed.; Wiley: New
York, 1992. For recent reports on substitution reactions of N-nucleo-
philes with aromatic substrates bearing activating groups, see also:
Semmelhack, M. F.; Rhee, H. Tetrahedron Lett. 1993, 34, 1395. Hattori,
T.; Sakamoto, J .; Hayashizaka N.; Miyano, S. Synthesis 1994, 199.
(11) Treatment of (R)-(+)-1-(1-naphthyl)ethylamine in THF at -78
°C with 1 equiv of n-BuLi followed by aqueous quenching gave a
1
13
D
compound with spectral data ( H-, C-NMR) and [R] +60 (c ) 5,
MeOH) identical with those of the starting material.

Oxidative Intramolecular Coupling of Amidocuprates
J . Org. Chem., Vol. 61, No. 5, 1996 1679
Ta ble 2. Oxygen -P r om oted Electr op h ilic Am in a tion
of Cya n ocu p r a tes w ith Lith iu m Hyd r a zid es
by treating lithiated amines with molecular oxygen is to
our knowledge unprecedented.
On the other hand, the rate constants of the reactions
between aminyls and oxygen must be very fast, possibly
close to the diffusion-controlled limit. The direct EPR
detection of aminyls in oxygenated media is therefore
unlikely, especially when taking into consideration the
fact that metal-complexed aminyls are much more reac-
tive16 than neutral aminyls. Even if no direct spectro-
scopic evidence of the participation of aminyl radicals in
these reactions could be obtained, we infer that these
species, possibly generated in situ via an electron transfer
process, may be considered to be the precursors of the
observed aminoxyls as outlined in Scheme 2.17
Sch em e 2
-
+
R′R′′NH + n-BuLi f R′R′′N Li
a
O2
9
O2
9
A darkened bond in the formula indicates the bond created
-
+
•
•-
•
b
R′R′′N Li
8 R′R′′N + O
8 R′R′′NOO
by the carbon-nitrogen bond-forming reactions. Isolated yields;
average of three or more runs. Gc yields. Only trace amounts
2% ca.) of the expected product were isolated according to the
standard procedure. A significant increase of yields (18% of
isolated product) was achieved by using n-BuCu(CN)ZnCl/LiCl
instead of n-BuCu(CN)Li.
2
c
d
(
•
2
R′R′′NOO f [R′R′′NOOOONR′R′′] f
•
1
2
R′R′′NO + O
2
Similar results were obtained with the amidocuprates
The reaction under study competes with a common side
process associated with the inadvertent oxidation by
from the same amines. When solutions of these amido-
cuprates were put inside the cavity of the EPR spectrom-
eter prior to oxygen quenching, in no case did they exhibit
any EPR signal, even at low temperature (T e -80 °C).
On the other hand, purging the solutions with oxygen
resulted again in the observation of intense EPR signals
due to diisopropyl, diethyl, or diphenyl nitroxide, thus
suggesting that the oxygen-induced decomposition of the
amidocuprates might involve the formation of aminyl
radicals in a preliminary step.
Finally, an experiment in which interaction of lithium
anilide PhHNLi with the cuproamide PhNHCu(CN)Li
was followed by quenching with oxygen under the usual
conditions led to the isolation of 70% PhNdNPh from
dehydrogenation of the corresponding 1,2-diphenylhy-
drazine. We believe that the formation of a new N-N
bond provides further support for the presence of aminyl
radicals in the oxidative coupling reaction.
1
2
dioxygen of lithioorganocuprates which leads to cou-
pling between the ligands on copper.13 Rationalization
of the new C-N bond formation might suggest, in
principle, the intervention of long-lived free radicals as
reaction intermediates. Experiments were therefore
carried out inside the cavity of an EPR spectrometer
under a variety of experimental conditions in order to
detect the formation in the present reaction of species
such as aminyl radicals, which are known1
4,15
to be easily
generated by thermolysis of a tetrazene species or by
photolysis of di-tert-butyl peroxide in the presence of
amines.
Not surprisingly, the reaction between diisopropyl,
diethyl, or diphenylamine with butyllithium under an
inert atmosphere did not lead to the observation of any
EPR signals; however, after the reaction mixture was
purged with oxygen, intense and broad signals of the
Reliable information is available on the structures of
7
1
18
corresponding diisopropyl (a2H ) 4.45 G, a
2.0059 ), diethyl (a4H ) 10.30 G, a ) 15.20 G, g )
.0059 ), and diphenyl (a6H ) 1.80 G, a4H ) 0.80 G, a
.68 G, g ) 2.0056 ) nitroxides were observed, whose
N
) 14.72 G, g
the amidocuprates by Li and H NMR spectroscopy and
by analogy with reported X-ray studies for organocopper
compounds.19 Taking into consideration the Li:Cu and
the amide:C-ligand ratios used in this work, the forma-
)
2
9
6
N
9
N
)
8
resolution drastically improved upon removing the excess
oxygen with argon. On the other hand, no EPR spectra
were observed upon saturating solutions of the amines
with oxygen. Although it is known15 that the reaction of
secondary amines with singlet oxygen affords the corre-
sponding nitroxides, the observation of aminoxyl radicals
2 2 2 2
tion of discrete dimers [(R′R′′N) Cu R′′′ ]Li ‚2LiCN can
be hypothesized. For these species, a roughly planar
structure (III) with staggered organo and amido ligands,
each bound to two metals by a three-center two-electron
bond and occupying the corner positions, can be proposed
in accordance with the literature reports.6
,18,20
These
observations together with previously reported evidence
for the formation of radical species upon oxygen-induced
(
12) Whitesides, G. M.; San Filippo, J . J r.; Casey, C. P.; Panek, E.
J . J . Am. Chem. Soc. 1967, 89, 5302.
13) This synthetically unattractive reaction from which statistical
(
(16) Maeda, Y.; Ingold, K. U. J . Am. Chem. Soc. 1980, 102, 328.
(17) At this stage the formation of the tetraoxide is only speculative
and is based on the behavior of peroxy radicals, but no efforts have
been made to detect singlet oxygen. As an alternative, it is possible to
envisage the coupling of the amino peroxy radicals with aminyl radicals
to afford RRNOONRR whose fragmentation would lead to two mol-
ratios of three products are generated, when performed on products
with mixed-ligand reagents, has been very recently reevaluated by
Lipshutz through the generation of “kinetic” bis anionic cuprates.
Extremely high levels of unsymmetrical ligand coupling have been
achieved which allow for a novel straightforward synthesis of biaryls
through inter- or intramolecular coupling: Lipshutz, B. H.; Kayser,
F.; Maullin, N. Tetrahedron Lett. 1994, 35, 815. Lipshutz, B. H.; Kayser,
F.; Liu, Z.-P. L. Angew. Chem., Int. Ed. Engl. 1994, 33, 1842 and
references therein.
•
ecules of the RRNO nitroxide.
(18) Dieter, R. K.; Hanks, T. W.; Lagu, B. Organometallics, 1992,
11, 3549.
(19) Olmstead, M. M.; Power, P. P. J . Am. Chem. Soc. 1990, 112,
8008.
(20) Dieter, R. K.; Tokles, M. J . Am. Chem. Soc. 1987, 109, 2040.
(
(
14) J ones, P. W.; Gesser, H. D. J . Chem. Soc. B 1971, 1873.
15) Roberts, J . R.; Ingold, K. U. J . Am. Chem. Soc. 1973, 95, 3228.

1
680 J . Org. Chem., Vol. 61, No. 5, 1996
Alberti et al.
Sch em e 3
column. High-resolution mass spectra (HRMS, EI/DP) were
obtained at 70 eV. Elemental analyses are within (0.3%.
N-Bu tyla n ilin e (Ia ): Typ ica l P r oced u r e. To a brown
clear solution of n-BuCuCNLi (2.00 mmol), cooled to -40 °C,
was added a THF solution of N-lithium anilide (2.00 mmol).
The mixture was allowed to react at this temperature for 15
min. In the reaction mixture cooled to -78 °C was introduced
a vigorous stream of oxygen for an additional 20 min. A dark
precipitate was formed during this time. The reaction mixture
was allowed to rise to rt, filtered through a Celite pad, and
concentrated, and the crude material was purified by flash
chromatography on silica gel with pentane-ether (8:2) to give
0
6
.185 g (62%) of (Ia ) as a pale yellow liquid: 1H NMR δ 7.3-
.5 (m, 5H), 2.41 (t, 2H), 1.66-1.20 (m, 4H), 0.95 (t, 3H); MS
+
m/ z (relative intensity) 149 (M , 64), 106 (100), 77 (40), 51
(21). Spectroscopic data are in agreement with those of a
commercial sample.
N-Bu tyld iisop r op yla m in e (Ib). The typical procedure
was followed employing n-BuCuCNLi (2.00 mmol) and LDA
(2.00 mmol). The crude material was distilled by Kugelrohr
(
pot temperature, 75 °C/20 mmHg) to give 0.157 g (50%) of a
1
decomposition of amidocuprates allow us to visualize the
overall process as depicted in Scheme 3.
pale yellow liquid: H NMR δ 3.8 (m, 2H), 2.39 (t, 2H, J ) 6.6
Hz), 1.68-1.20 (m, 4H), 1.24 (d, 12H, J ) 6.3 Hz), 0.95 (t, 3H,
+
No attempts were made to establish the fate of the
copper upon decomposition of the organocuprates, but
when oxygen-quenched solutions where allowed to warm
to room temperature inside the cavity of the EPR
J ) 6.6 Hz); MS m/ z (relative intensity) 157 (M , 30), 142
(89), 114 (100), 100 (94), 72 (96), 58 (48). Anal. Calcd for
10
C H23N: C, 76.34; H, 14.75; N, 8.91. Found: C, 76.23; H,
1
4.80; N, 8.95.
N,N-Diisop r op yla n ilin e (Ic). The typical procedure was
2
+
spectrometer, a four-line signal attributable to a Cu
complex [a( Cu) ) 82 G, g ) 2.116 ] was observed.
8
followed, employing PhCuCNLi (2.00 mmol) and LDA (2.00
mmol). After the usual workup, 0.210 g (60%) of a yellow oil
was obtained by Kugelrohr distillation (pot temperature 100
6
3
Nothwithstanding the question it raises concerning the
nature of the intermediate(s) and the mechanism, we
have demonstrated that, through oxidative intramolecu-
lar coupling, a range of amido- and hydrazidocuprates
easily generated in situ from readily available starting
materials can be converted into the corresponding amines
and hydrazines, respectively. Overall, the amidocuprate/
oxidative decomposition sequence provides a fairly gen-
eral and attractive entry to C-N bond formation. Gen-
erality, flexibility, and the possibility of performing
selective functionalization at the nitrogen are important
characteristics of this reaction which favorably compares
to a very recent, elegant N-arylation procedure based on
a transamination reaction coupled with Pd catalysis.21
Efforts to modify the reaction conditions, broaden the
scope, and develop synthetic applications of these and
related reactions are currently in progress.
1
°C/20 mmHg): H NMR δ 7.69-7.33 (m, 5H), 3.80 (m, 2H),
+
1
5
8
.24 (d, 12H, J ) 6.3 Hz); MS m/ z (relative intensity) 177 (M ,
8), 162 (60), 120 (100), 77 (59). Anal. Calcd for C12H19N: C,
1.29; H, 10.81; N, 7.90. Found: C, 82.00; H, 10.40; N, 7.92.
N-Meth yl-N-p h en ylben zyla m in e (Id ). The typical pro-
cedure was followed by adding lithium N-benzylanilide (2.00
mmol) to MeCuCNLi (2.00 mmol). After the usual workup,
0.197 g (50%) of Id was recovered by Kugelrohr distillation
(pot temperature, 130 °C/20 mmHg) as a pale yellow viscous
oil: 1H NMR δ 7.51-7.10 (m, 10H), 3.51 (s, 2H), 2.91 (s, 3H);
MS m/ z (relative intensity) 197 (M , 84), 120 (84), 91 (100),
7
Found: C, 85.71; H, 7.70; N, 7.18.
N-Bu tyl-N-m eth ylben zyla m in e (Ie). The typical proce-
dure was followed starting from lithium N-benzylmethylamide
+
7 (73). Anal. Calcd for C14H15N: C, 85.23; H, 7.67; N, 7.10.
(2.00 mmol) and n-BuCuCNLi (2.00 mmol). After the usual
workup, 0.160 g (45%) of a pale yellow viscous oil was
recovered by Kugelrohr distillation (pot temperature, 100 °C/
2
0 mmHg): 1H NMR δ 7.31-7.29 (m, 5H), 3.51 (s, 2H), 2.39
(t, 2H, J ) 6.6 Hz), 2.21 (s, 3H), 1.68-1.6 (m, 4H) 0.95 (t, 3H,
Exp er im en ta l Section
+
J ) 6.6 Hz); MS m/ z (relative intensity) 177 (M , 13), 134
85), 91 (100), 65 (25). Anal. Calcd for C12 19N: C, 81.29; H,
0.81; N, 7.90. Found: C, 81.00; H, 10.79; N, 7.95.
Meth ylp h en ylth iop h en e-2-yla m in e (If). Lithium N-
phenylmethylamide (2.00 mmol) was added to the bis-anionic
(H.O.) cyanocuprate (C S) CuCNLi made by reacting 4
(
1
H
Gen er a l Meth od s. THF was freshly distilled under a
nitrogen atmosphere from sodium and benzophenone ketyl.
Thiophene, benzofuran, n-butyllithium, tert-butyllithium, phe-
nyllithium, methyllithium, and CuCN were commercially
available and were used without any further purification. The
purity of commercially available lithium derivatives was
4
H
3
2
2
mmol of 2-thienyllithium with 2 mmol (179 mg) of CuCN.
According to the typical procedure, the reaction mixture was
allowed to warm to rt, filtered through a Celite pad, and
concentrated, and the crude material was purified by flash
chromatography on silica gel with pentane-ether (8:2) to give
0.197 g (52%) of If as a yellow viscous oil: 1H NMR δ 7.35-
2
2
checked according to Gilman. All the air-sensitive reactions
were run under a nitrogen atmosphere, and reagents were
added through septa using oven-dried syringes. Unless oth-
erwise stated, the LO lithium cyanocuprates were prepared
according to the following general procedure: the lithium
compound (2.00 mmol) was added to 10 mL of THF at -40
1
3
7.16 (m, 3H), 7.1-6.8 (m, 4H), 6.68 (m, 1H), 3.34 (s, 3H);
C
°
C. CuCN (2 mmol) was introduced quickly under a nitrogen
NMR (50.3 MHz; CDCl ) δ 128.9, 127.8, 125.8, 124.4, 123.8,
3
+
flow, and the reaction mixture was stirred with dissolution of
119.9, 119.5, 116.3, 42.0; MS m/ z (relative intensity) 189 (M ,
1
100), 174 (31), 173 (36), 130 (10), 104 (4), 77 (19), 51 (16). Anal.
Calcd for C11H11NS: C, 69.80; H, 5.86; N, 7.40; S, 16.94.
Found: C, 69.84; H, 5.93; N, 7.39; S, 16.85.
Ben zofu r a n -2-yl-m eth ylp h en yla m in e (Ig). The lithium
N-phenylmethylamide was added to the L.O. benzofuryl cy-
anocuprate. After the usual workup, the reaction mixture at
rt was filtered through a Celite pad and concentrated, and the
crude material was purified by flash chromatography on
alumina with pentane-ethyl ether (8:2) to give 0.112 g (25%)
of Ig as a viscous yellow oil: 1H NMR δ 7.50-7.00 (m, 10H),
the salt, which was complete generally after about 20 min. H
NMR spectra unless otherwise stated were recorded at rt in
CDCl
3
at an operating frequency of 200 MHz and were
1
3
referenced to TMS. C NMR spectra were recorded at 50.3
MHz. Capillary GC analyses were performed using a 25 m ×
0
7
.25 mm, cross-linked 5% methylphenylsilicone capillary
(
21) Guram, A. S.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116,
901.
22) Gilman, H.; Haubein, A. H. J . Am. Chem. Soc. 1944, 66, 1515.
(

Oxidative Intramolecular Coupling of Amidocuprates
J . Org. Chem., Vol. 61, No. 5, 1996 1681
3
1
.45 (s, 3H); 13C NMR (50.3 MHz; CDCl
30.2, 129.2, 122.7, 121.3, 120.4, 118.7, 112.5, 110.1, 85.7, 38.6.
3
) δ 158.0, 150.8, 154.9,
synthesis of Ii. After filtration through a Celite pad, the crude
material was purified by flash chromatography (SiO , pen-
2
+
MS m/ z (relative intensity) 223 (M , 100), 208 (25), 180 (22),
1 (10), 77 (26), 51 (19). Anal. Calcd for C15 13NO: C, 80.68;
tane-ether (8:2)) to give 0.325 g (46%) of a white solid: mp
1
9
H
70-71°C (cyclohexane); [R]D -212 (c ) 0.6, MeOH); H NMR
H, 5.87; N, 6.28. Found: C, 80.50; H, 5.73; N, 6.42.
δ 8.22 (d, 1H, J ) 8.6 Hz), 7.95 (d, 1H, J ) 8.6 Hz), 7.78 (d,
1H, J ) 8.6 Hz), 7.70-7.30 (m, 9H), 6.92 (d, 1H, J ) 8.6 Hz),
6.65 (m, 2H), 6.30 (d, 1H), 5.33 (q, 1H, J ) 6.7Hz), 5.20 (s,
2H), 4.90 (br s, 1H), 1.71 (d, 3H, J ) 6.7 Hz); 13C NMR (50.3
Diisop r op ylstyr yla m in e (Ih ). The lithium derivative
PhCHdCHLi was obtained in situ by transmetalation of
PhCHdCHSnBu
3
2
(2 mmol) with n-BuLi (2 mmol) at -60 °C
0
in THF (10 mL). Then CuCN (2 mmol) was added at -30
MHz; CDCl ) δ 145.6, 140.2, 137.5, 137.4, 134.1, 130.8, 129.2,
3
°
C, and LDA (2.00 mmol) was injected dropwise following the
128.7, 128.3, 128.1, 127.7, 127.4, 126.0, 125.4, 122.6, 122.3,
general procedure previously employed. The crude material
was distilled by Kugelrohr (pot temperature, 155 °C/20 mmHg)
to give 0.183 g (45%) of Ih as a pale yellow liquid: H NMR δ
7
1
1
21.8, 116.3, 111.4, 111.3, 70.8, 49.5, 23.9. Anal. Calcd for
23NO: C, 84.95; H, 6.56; N, 3.96. Found: C, 85.69; H,
25
C H
1
6
.55; N, 3.94.
.30-7.10 (m, 5H), 6.91 (d, 1H, J ) 14 Hz), 5.24 (d, 1H, J )
4 Hz), 3.70 (m, 2H), 1.21 (d, 12H, J ) 6.6 Hz); 13C NMR (50.3
1,1-Dip h en yl-2-ter t-bu tylh yd r a zin e (IIa ). 1,1-Diphenyl-
hydrazine (2 mmol) was metalated by n-BuLi (2 mmol) at -60
°C in THF (8 mL) and then was added to t-BuCuCNLi (2 mmol)
at -40 °C. After 30 min, the clear solution was treated with
MHz; CDCl ) δ 140.9, 133.0, 128.5, 123.0, 122.5, 95.2, 46.3,
3
+
2
(
1.8; MS m/ z (relative intensity) 203 (M , 92), 188 (67), 160
100), 146 (59), 118 (34), 91 (53), 51 (15). Anal. Calcd for
21N: C, 82.70; H, 10.41; N, 6.89. Found: C, 81.90; H,
a stream of O
for 30 min at -78 °C. The reaction mixture
2
14
C H
was filtered through a Celite pad, the solvent was evaporated,
and the crude material was purified by flash chromatography
1
0.31; N, 6.93.
N-Bu tyl-(R)-(+)-1-(1-n a p h th yl)eth yla m in e (Ii). To a
on alumina with pentane-ether (1:1) to give 0.144 g (30%) of
brown clear solution of n-BuCuCNLi (2.00 mmol), cooled to
1
IIa as a red solid: mp 62-64 °C; H NMR (C
6
D
6
) δ 7.35-7.10
-
40 °C, was added a THF solution of lithium (R)-(+)-1-(1-
naphthyl)ethylamide (2.00 mmol) prepared by adding n-BuLi
1.6 M in hexanes, 1.25 mL, 2 mmol) to a solution of (R)-(+)-
-(1-naphthyl)ethylamine (342 mg, 2 mmol) in THF (3 mL)
(
m, 10H), 3.50 (br s, 1H), 1.40 (s, 9H); 13C NMR (50.3 MHz;
C
6
D
6
) δ 152.4, 129.8, 123.2, 122.2, 55.9, 29.6; MS m/ z (relative
(
1
+
intensity) 240 (M , 36), 184 (100), 168 (47), 77 (57), 65 (4), 51
cooled at -40 °C. After the usual treatment according to the
typical procedure, the crude material was purified by flash
chromatography on silica gel with pentane-ether (3:7) to give
(19); HRMS (EI) m/ z calcd for C16
240.1627. Anal. Calcd for C16
11.66. Found: C, 80.10; H, 8.37; N, 11.83.
,1-Diph en yl-2-n -bu tylh ydr azin e (IIb). Commercial ZnCl
300 mg, 2.2 mmol) was melted under reduced pressure (0.02
H
20
N
2
240.1626, found
H N : C, 79.95; H, 8.39; N,
20 2
0
.272 g (60%) of Ii as a pale yellow oil: [R] +40 (c ) 1.7,
D
1
2
1
MeCOMe); H NMR δ 8.23-7.47 (m, 7H), 4.66 (q, 1H, J ) 6.6
Hz), 2.59 (m, 2H), 2.04 (br s, 1H), 1.52 (d, 3H, J ) 6.6 Hz),
1
CDCl
1
intensity) 227 (M , 4), 155 (100), 129 (18), 100 (11), 57 (9).
Anal. Calcd for C16 21N: C, 84.53; H, 9.31; N, 6.16. Found:
C, 83.98; H, 9.20; N, 6.12.
(
mmHg) and cooled under argon several times. The anhydrous
salt was dissolved in dry THF (5 mL) and added to a solution
of n-BuLi (1.6 M in hexanes, 1.25 mL, 2 mmol) in THF (2mL)
at -78 °C. After 10 min, the temperature of the solution of
n-BuZnCl/LiCl was raised to -30 °C and CuCN (179 mg, 2
mmol) was added. After dissolution of the copper salt to the
resulting clear green-yellow solution, 1,1-diphenyllithium hy-
drazide (2 mmol) previously obtained from metalation at -60
.37 (m, 4H), 0.88 (t, 3H, J ) 7.2 Hz); 13C NMR (50.3 MHz;
3
) δ 141.1, 134.0, 131.3, 129.0, 127.2, 125.8, 125.7, 125.3,
22.9, 122.7, 53.6, 47.7, 32.4, 25.3, 20.5, 14.0; MS m/ z (relative
+
H
N-P h en yl-(R)-(-)-1-(1-n aph th yl)eth ylam in e (Ij) was pre-
pared as for Ii starting from lithium (R)-(+)-1-(1-naphthyl)-
ethylamide (2.00 mmol) and PhCu(CN)Li (2.00 mmol). The
crude material was purified by flash chromatography on silica
gel with pentane-ethyl ether (8:2) to give 0.237 g (48%) of Ij
as a viscous oil: [R]
°
C of 1,1-diphenylhydrazine by n-BuLi in THF (5 mL) was
added. After 30 min, the clear reaction mixture was treated
as usual with a stream of oxygen for 45 min at -78 °C.
Filtration through a Celite pad, evaporation of the solvent, and
Kugelrohr distillation of the crude material (pot temperature
1
D
-249 (c ) 1.9, MeOH); H NMR δ 8.18
(
2
d, 1H), 7.92 (d, 1H), 7.76 (d, 1H), 7.70-7.34 (m, 4H), 7.08 (t,
1
50 °C/0.02 mmHg) gave 0.086 g (18%) of IIb as a yellow-red
H, J ) 7.4 Hz), 6.64 (t, 1H, J ) 7.8 Hz), 6.48 (d, 2H, J ) 8.6
1
13
oil: H NMR δ 7.40-6.90 (m, 10H), 3.90 (br s, 1H), 2.84 (t,
2
MS m/ z (relative intensity) 240 (M , 48), 183 (100), 168 (87),
Hz), 5.28 (q, 1H, J ) 6.7 Hz), 4.22 (br s, 1H), 1.67 (d, 3H);
NMR (50.3 MHz; CDCl ) δ 147.1, 139.9, 134.1, 130.7, 129.5,
1
4
1
C
H, J ) 6.0 Hz), 1.6-1.35 (m, 4H), 0.90 (t, 3H, J ) 7.5 Hz);
3
+
29.1, 127.5, 126.1, 125.9, 125.4, 122.8, 122.3, 117.3, 113.2,
+
16 2
115 (7), 77 (67), 51 (23); HRMS (EI) m/ z calcd for C H20N
9.5, 23.6; MS m/ z (relative intensity) 247 (M , 21), 232 (18),
55 (100), 127 (10), 77 (18), 51 (7). Anal. Calcd for C18
H
17N:
240.1626, found 240.1619. Anal. Calcd for C16
20 2
H N : C, 79.95;
C, 87.41; H, 6.93; N, 5.66. Found: C, 87.90; H, 6.85; N, 5.56.
H, 8.39; N, 11.66. Found: C, 79.81; H, 8.28; N, 11.87.
N -(2-Me t h oxyp h e n yl)-(R )-(-)-1-(1-n a p h t h yl)e t h yl-
a m in e (Ik ) was prepared as for Ii starting from lithium (R)-
1,1-Dim eth yl-2-p h en ylh yd r a zin e (IIc). 1,1-Dimethyl-
hydrazine (2mmol) was metalated by n-BuLi (2 mmol) at -50
°C in THF (8 mL) and then was added to PhCuCNLi (2 mmol)
at -40 °C. After 40 min, the clear solution was treated by a
6 4
(+)-1-(1-naphthyl)ethylamide (2.00 mmol) and o-MeO-C H -
CuCNLi (2.00 mmol) prepared by metalation of 2-bromoanisole
with n-BuLi in THF at -78 °C followed by addition of CuCN.
After the usual workup, the crude material was purified by
flash chromatography on silica gel with pentane-ether (8:2)
stream of O for 30 min at -78 °C. The reaction mixture was
2
filtered through a Celite pad, the solvent was evaporated, and
the crude material was distilled by Kugelrohr (pot temperature
to give 0.305 g (55%) of Ik as a white solid: mp 81-82 °C
9
0 °C/20 mmHg) and then purified by flash chromatography
1
(
(
8
(
1
1
1
ether-ethanol); [R]
D
-246 (c ) 0.3, MeOH); H NMR δ 8.20
on alumina with pentane-ether (6:4) to give 0.109 g (40%) of
d, 1H, J ) 8.6 Hz), 7.92 (d, 1H, J ) 8.6 Hz), 7.76 (d, 1H, J )
.6 Hz), 7.70-7.32 (m, 4H), 6.82 (m, 1H), 6.60 (m, 2H), 6.25
m, 1H), 5.28 (q, 1H, J ) 6.7 Hz), 4.84 (br s, 1H), 3.92 (s, 3H),
.70 (d, 3H); C NMR (50.3 MHz; CDCl ) δ 146.2, 140.1, 136.9,
3
34.1, 130.7, 129.1, 127.3, 126.0, 125.9, 125.3, 122.6, 122.3,
1
IIc as a dark oil: H NMR (C
(
6
D
6
) δ 6.90-6.20 (m, 5H), 3.40
+
br s, 1H), 1.85 (s, 6H); MS m/ z (relative intensity) 136 (M ,
7
1), 183 (60), 121 (49), 92 (100), 77 (23), 65 (50), 51 (16), 42
136.1000, found
8 12 2
36.0997. Anal. Calcd for C H N : C, 70.55; H, 8.88; N,
1
3
8 12 2
(24); HRMS (EI) m/ z calcd for C H N
1
21.2, 116.4, 111.0, 109.3, 55.5, 49.4, 23.7; MS m/ z (relative
intensity) 277 (M , 34), 262 (27), 155 (100), 123 (34), 77 (13),
+
20.57. Found: C, 71.00; H, 8.74; N, 20.80.
5
1 (9). Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05.
Found: C, 82.00; H, 6.85; N, 5.00.
Ack n ow led gm en t. Financial support by the Italian
Progetto Finalizzato Chimica Fine II” (CNR, Rome) is
gratefully acknowledged.
N-[2-(Ben zyloxy)p h en yl]-(R)-(-)-1-(1-n a p h t h yl)et h y-
la m in e (Il). The experimental procedure starting from
“
lithium (R)-(+)-1-(1-naphthyl)ethylamide (2 mmol) and PhOCH
2
-
o-C CuCNLi (2 mmol) was the same as that used for the
6
H
4
J O9512315