Aromatization of enamines promoted by a stoichiometric amount of palladium(II) salts: A novel method for the synthesis of aromatic amines

Article abstract of DOI:10.1021/jo001331x

Enamines (1a-r) prepared from cyclohexanones, cyclohexane-1,3-diones, or tetralones led to arylamines (2a-r) in one pot when treated with a stoichiometric amount of palladium salts [PdCl₂-(MeCN)₂] in acetonitrile in the presence of triethylamine at room temperature or at elevated temperature, in some cases for 5 min to 2 h. The initial electrophilic attack of palladium chloride on the β-carbon of the enamines led to a σ-palladium species (8) which triggered a series of reactions (→ 9 → 19 → 11 → 12) destined for aromatization to give 2a-r in good yields. The intervention of such a σ-palladium species has been attested by a trapping experiment. On the basis of this reaction mechanism, we have developed another new process capable of transforming acyclic compounds having 6-en-2-one frameworks (16, 23, 25) to arylamines (2s-u) when their enamines were treated under the similar conditions as above, featuring again the formation of σ-palladium species such as 8 as the initial key intermediate.

Full text of DOI:10.1021/jo001331x

186
J . Org. Chem. 2001, 66, 186-191
Ar om a tiza tion of En a m in es P r om oted by a Stoich iom etr ic Am ou n t
of P a lla d iu m (II) Sa lts: A Novel Meth od for th e Syn th esis of
Ar om a tic Am in es
Teruhiko Ishikawa,* Eiji Uedo, Rie Tani, and Seiki Saito*
Department of Bioscience and Biotechnology, Faculty of Engineering, Okayama University,
Tsushima, Okayama, J apan 700-8530
seisaito@biotech.okayama-u.ac.jp
Received September 6, 2000
Enamines (1a -r ) prepared from cyclohexanones, cyclohexane-1,3-diones, or tetralones led to
arylamines (2a -r ) in one pot when treated with a stoichiometric amount of palladium salts [PdCl2-
(MeCN)2] in acetonitrile in the presence of triethylamine at room temperature or at elevated
temperature, in some cases for 5 min to 2 h. The initial electrophilic attack of palladium chloride
on the â-carbon of the enamines led to a σ-palladium species (8) which triggered a series of reactions
(f 9 f 10 f 11 f 12) destined for aromatization to give 2a -r in good yields. The intervention of
such a σ-palladium species has been attested by a trapping experiment. On the basis of this reaction
mechanism, we have developed another new process capable of transforming acyclic compounds
having 6-en-2-one frameworks (16, 23, 25) to arylamines (2s-u ) when their enamines were treated
under the similar conditions as above, featuring again the formation of σ-palladium species such
as 8 as the initial key intermediate.
In tr od u ction
aromatic amine conversion in one pot (eq 4). Highly
promising results in this context will also be reported.
Heteroatom-substituted carbon-carbon double bonds
such as enamines or enol silyl ethers have played a
unique role in organic synthesis when reacted with
transition metal salts, and two cases have been reported
so far.1,2 First, when reacted with mercuric acetate,
enamines led to an iminium ion intermediate bearing a
covalent carbon-mercury bond which was highly ame-
nable to hydride reduction and hence served as a precur-
sor for tertiary amines (eq 1).1 Second, enol silyl ethers
led to R,â-unsaturated carbonyl compounds via palladium
enolate when reacted with palladium acetate (eq 2).2 As
the third representative reaction along similar lines, we
found for the first time that the reaction of palladium-
(II) salts with cyclohexanone-based enamines provided
a novel method for the synthesis of aromatic amines (eq
3).3 In this reaction the initial formation of a σ-palladium
species triggered a series of reactions destined for aro-
matization under very mild conditions (room tempera-
ture, <2h) to give aniline or naphthylamine derivatives
of significant diverse applications.4 We have also been
intrigued with the combination of the present elementary
process involving the formation of the σ-palladium species
with well-known palladium chemistry. Such an idea,
when applied to acyclic 6-en-2-one frameworks, was
expected to make sense in realizing the acyclic enone to
Resu lts a n d Discu ssion
Ar om a tiza tion of Cycloh exa n on e-Ba sed En a m -
in es. When treated with PdCl2‚(MeCN)2 (200 mol %) and
Et3N (500 mol %) in acetonitrile at room temperature for
2 h (standard conditions), for instance, commercially
available enamine (1a ) gave N-phenylmorpholine (2a ) in
86% yield after chromatographical purification by silica
gel column without any appreciable side product.5 The
results of enamine aromatization under such conditions
are listed in Table 1.
The use of a variety of both cycloalkanones (cyclohex-
anone derivatives and R- or â-tetralones) and amines
(morpholine, piperidine, pyrrolidine, N-methylaniline,
and amino acid esters such as proline methyl ester)
allowed us to obtain a variety of aniline and naphthyl-
amine derivatives (2a -l). It is worthy of note that, to
the best of our knowledge, the present aromatization is
the only method by which we can introduce a phenyl
group on a nitrogen atom of an amino acid (2i, entry 9).
A vitamin L1 (anthranilic acid) derivative (2k ) was
(4) Transition metal-catalyzed amination of aromatic halides or
sulfonates is one of the most prevalent ways to prepare this class of
compounds; for pioneering work in this area, see: (a) Kosugi, M.;
Kameyama, M.; Migita, T. Chem. Lett. 1983, 927-928. (b) Paul, F.;
Patt, J .; Hartwig, J . F. J . Am. Chem. Soc. 1994, 116, 5969-5970. See
also: (c) Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
6054-6058. (d) Hartwig, J . F. Angew. Chem., Int. Ed. Engl. 1998, 37,
2046-2067. (e) Wolfe, J . P.; Wagaw, S.; Marcoux, J .-F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805-818 and references therein. For
recent interesting work using molecular nitrogen in this area, see:
Hori, K.; Mori, M. J . Am. Chem. Soc. 1998, 120, 7651-7652.
(5) We can quickly recognize how mild the reaction conditions were
by remembering those for the aromatization of 4,5,6,7-tetrahydroin-
dazole to indazole (heating a solution of Decaline under reflux (>190
°C) for 24 h in the presence of Pd-charcoal). See: Ainsworth, C.
Organic Syntheses; Wiley: New York, 1963; Vol. IV, pp 536-539.
(1) Bach, R. D.; Mitra, D. K. J . Chem. Soc., Chem. Commun. 1971,
1433-1434.
(2) (a) Ito, Y.; Hirao, T.; Saegusa, T. J . Org. Chem. 1978, 43, 1011-
1013. (b) Baba, T.; Nakano, K.; Nishiyama, S.; Tsuruya, S.; Masai, M.
J . Chem. Soc., Chem. Commun. 1989, 1697-1699. See also: Theissen,
R. J . J . Org. Chem. 1971, 36, 752-757.
(3) Only one fragmentary description is available that an enamine
prepared from cyclohexanone and 2-(methoxymethyl)pyrrolidine can
be oxidized to lead to an aromatic amine on treatment with Pd(OAc)2
in the presence of iodobenzene, Et3N, and Ph3P in DMF at 80 °C, while
the Heck coupling of iodobenzene proceeded to give a biphenyl. See:
de Meijere, A.; Bra¨se, S. J . Organomet. Chem. 1999, 576, 88-110.
10.1021/jo001331x CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/15/2000

Synthesis of Aromatic Amines
Sch em e 1
J . Org. Chem., Vol. 66, No. 1, 2001 187
Ta ble 1. Su m m a r y of th e Ar om a tiza tion of En a m in esa
obtained from a ketoester-based enamine (1k ) (entry 11)
though it required elevated temperature.
In addition, the present method can be applied to the
synthesis of m-aminophenols from 1,3-cyclohexanediones
(Scheme 2). For instance, on treatment of the aminoenone
(1m ), prepared from 2-methylcyclohexane-1,3-dione in
quantitative yield, with TBSOTf in THF in the presence
of Et3N (5 equiv) at 0 °C for 1 h followed by the addition
of PdCl2(CH3CN)2 (1 eq) and heating the mixture at 50
°C for 1 h led to N-[o-methyl-m-(tert-butyldimethylsily-
loxy)phenyl]pyrrolidine (2m ) in 42% overall yield through
a three-step process as indicated in Scheme 2: 2n was
also obtained likewise in 33% overall yield from 1,3-
cyclohexanedione.
We attempted to introduce other amino-substituents
along this scheme using aliphatic secondary amines such
as dimethylamine, diethylamine, dibenzylamine, or ben-
zylmethylamine. To the marked contrast to the case of
pyrrolidine, the direct formation of the desired ami-
noenones from 1,3-cyclohexanediones resulted in complex
mixture. However, an indirect method via the acetoxy
enone (4) as shown in Scheme 3 gave the temporary
answer to this problem. Thus, the reactions of 4 with the
secondary aliphatic amines (1.2 equiv) in THF were
carried out under the conditions indicated in Scheme 3
followed by the addition of excess TBSOTf and Et3N at
-78 °C and stirring the resulting mixture at -78 °C to
0 °C for 1 h. Further stirring of the mixture at 0 °C for
0.5 h and at 70 °C for 5 min in the presence of PdCl2(CH3-
CN)2 furnished the desired aminophenol derivatives
(2o-r ) probably via the intermediate 5 albeit in low yield
but pure state after chromatographical purification al-
though accompanied by the side product (6: 10%).
Mech a n ism of th e Ar om a tiza tion of Cycloh ex-
a n on e-Ba sed En a m in es. The plausible mechanism of
this aromatization is outlined in Scheme 4. Electrophilic
attack of a palladium salt on the â-carbon of enamines
(1) produces a palladium substituted iminium ion inter-
a
200 mol % PdCl2(MeCN)2/500 mol % Et3N/CH3CN/rt for 2 h.
b
For chromatographically pure products; yields in parentheses for
Pd(OAc)2/THF. c A mixture of enamine regioisomers (7:3).
A
d
mixture of enamine regioisomers (1:1). e 100 mol % of PdCl2(MeCN)2/
300 mol % Et3N. f 1% of 2c as byproduct. At elevated tempera-
g
h
ture (80 °C) for 0.5 h. Enamine, not purified.
mediate (8), in which â-hydride elimination smoothly
takes place to give an R,â-unsaturated iminium ion (9).
The reversible reaction between palladium salts and 1
might result in complexation at nitrogen to give 7, but
this species has no chance to undergo further reactions
except for the reverse reaction under standard conditions.
In order for 9 to be converted into an aniline framework,
the iminium ion 9 must generate the second enamine
intermediate (10) through deprotonation followed by the
same sequence of reactions as 1 f 8 f 9, leading to 12
successively via 10 and 11. The final deprotonation from
12 terminates this aromatization process to give 2.6 In
support of this mechanism, 200 mol % of palladium salt
was required (1 f 3 and 6 f 7 conversions) for the

188 J . Org. Chem., Vol. 66, No. 1, 2001
Ishikawa et al.
Sch em e 2
Sch em e 4
Sch em e 5
Sch em e 3
intervention. Thus, when an acyclic ketoester-based
enamine (17) without isolation and purification was
treated with PdCl2‚(MeCN)2 (200 mol %) and Et3N (500
mol %) in acetonitrile at 80 °C for 1 h, a methyl-
substituted anthranilic acid derivative (2s) was obtained
in 37% overall yield from 16. As shown in Scheme 6, a
combination of elementary reactions appeared in Scheme
4, corresponding to 17 f 18 f 19 f 20 in this case, with
the well-known organopalladium reaction (20 f 21)
playing an important role in this transformation.
Another acyclic ketoester 23 was also a successful
substrate for the similar transformation as 16 f 2s. In
this case the rather stable enamine 24 was purified by
bulb-to-bulb distillation and was treated with palladium-
(II) species to give the desired 2t in 45% yield from 24.
Furthermore, this basic strategy turned out to be ap-
plicable to a more simple 6-en-2-one framework such as
25,9 which was available through titanium tetrachloride-
mediated Michael addition of allyl silane to 1-acetylcy-
clopentene which was provided through Rupe rearrange-
ment of a 1,2-adduct of cyclopentanone and ethynylmag-
nesium bromide. An Indan derivative (2u ) was the
product of transformation of this class and was obtained
more efficiently (57% yield from 25) probably via 26.
Although exhaustive examinations for the above-
mentioned conversion have not been conducted yet, these
results suggest that this novel route to aromatic amines
from acyclic precursors with the 6-en-2-one framework
would be of high synthetic potential and open a general
method for efficient access to tailored aromatic amines.
Attem p ted Con str u ction of a Ca ta lytic System .
When 1c was treated with 10 mol % PdCl2(MeCN)2
complex in the presence of an oxidant such as CuCl2 (300
mol %) and Et3N (400 mol %) in acetonitrile at room
reaction to be completed except for entries 7 and 8 in
which 100 mol % was enough.
To attest to the intervention of the σ-palladium inter-
mediates, we took up an acetophenone-based enamine
(13). This enamine can also lead to the corresponding
intermediate (14), which would be trapped through an
oxidative carbonylation reaction7 because there is no
opportunity for 14 to undergo â-hydride elimination. In
fact, the reaction of 13 with the palladium salt followed
by CO treatment in methanol gave 15 (Scheme 5).
Although the yield of 15 was low,8 its formation revealed
by itself the intervention of the σ-palladium interme-
diate 14.
Str a tegy for th e Con ver sion of Acyclic En on e to
Ar om a tic Am in es. A novel idea by which, if realized,
we can transform acyclic enones to arylamines in one pot
is based on the recognition of the σ-palladium species
(6) Enamine prepared from 3,3,5,5-tetramethylcyclohexanone was
recovered unchanged under standard conditions, which also supports
the proposed mechanism (3 f 5 conversion to be prohibited).
(7) Heck, R. F. Acc. Chem. Res. 1979, 12, 146-151.
(8) Because of the reducing ability of CO, the palladium(II) salt was
quickly reduced to metallic state under the reaction conditions. This
is probably the reason 15 was isolated only in very low yield (16%).
(9) House, H. O.; Gaa, P. C.; VanDerveer, D. J . Org. Chem. 1983,
48, 1661-1670.

Synthesis of Aromatic Amines
Sch em e 6
J . Org. Chem., Vol. 66, No. 1, 2001 189
that several enamines 1a -c in place of 1-[1-(2-methoxy-
methyl)pyrrolidinyl]cyclohexene did not act as the re-
ductant for this process (eq 5). This result clearly
indicated that the haloarenes such as p-methoxyiodo-
benzene did not serve as oxidant in our case and only
the specific enamine used by Meijere and Bra¨se can
function as reductant in eq 5.
Con clu d in g Rem a r k . From a chronological point of
view, electrophilic aromatic substitution (SE1 mechanism
involving nitration followed by reduction10 or direct
amination11) is the first generation of aromatic amine
synthesis followed by nucleophilic aromatic substitution
(SNAr,12 benzyne,13 or SRN114 mechanism) and transition
metal-catalyzed amination of aromatic halides4 as the
second and third generation, respectively. The third
generation method has now become the most prevalent
one, the original reaction of which was reported in 1983
by Kosugi,4a and the elementary processes involved
therein were rationalized in 1994 by Hartwig,4b triggering
off modern activity in this area. The present reaction may
be a first step toward a potentially useful reaction to
make aromatic amines featuring aliphatic-to-aromatic
transformation.15 We could make use of this novel
transformation in synthetic objectives which are difficult
to achieve relying on the previous methods. In any event,
the most important task remaining is to reduce the
stoichiometric use of palladium salts to a catalytic
amount, and this is now under active investigation with
regard to oxidants, ligands, and solvents.
Exp er im en ta l Section
Gen er a l. Melting points are not corrected. 1H NMR spectra
were recorded at 300 MHz and 13C NMR at 75 MHz using
CDCl3 as a solvent. The chemical shifts (δ) are given in parts
per million relative to internal CHCl3 (7.26 ppm for 1H) or
CDCl3 (77 ppm for 13C). 1H-H COSY experiments were
obtained at 300 MHz. FR-IR spectra were recorded using
NaCl cells or mixtures of compound/KBr. Analytical thin-layer
chromatography was performed on Merck, precoated silica gel
60 F-254 (0.25 mm thickness). Column chromatography was
performed on a Merck silica gel 60 7734 using an appropriate
ratio of ethyl acetate-hexane mixed solvent and is abbreviated
as CC. Elemental analyses were carried out by Dr. Miyoko
Izawa of this laboratory. All reactions, unless otherwise noted,
were conducted under a nitrogen or an argon atmosphere.
Liquid reagents are transferred via a dry hypodermic syringe
and added through a rubber septa wired onto a reaction flask
from which a steady stream of inert gas was flowing. Aceto-
nitrile (CH3CN), triethylamine (Et3N), dichloromethane
(CH2Cl2), and benzene were freshly distilled from CaH2 prior
to use. Methanol was distilled from magnesium turnings under
argon. Tetrahydrofuran (THF) was distilled from benzophe-
temperature for 30 min, 2c was obtained in 20% yield.
This result means that the Pd(II) species effected dehy-
drogenation catalytically with a turnover number of 4.
Except for this hopeful result, however, we have exam-
ined in vain other oxidants such as benzoquinone or alkyl
nitrites.
Recently, Meijere and Bra¨se have reported that an
enamine can be employed as a reducing agent in pal-
ladium-catalyzed homo coupling of haloarenes leading to
biaryls (eq 5).3
(10) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration: Methods
and Mechanisms; VCH: New York, 1989.
(11) (a) Kovacic, P.; Russell, R. L.; Bennett, R. P. J . Am. Chem. Soc.
1964, 86, 1588-1592 and references therein. (b) Olah, G. A.; Ernst,
T. D. J . Org. Chem. 1989, 54, 1203-1204.
(12) (a) Ibata, T.; Isogami, Y.; Toyoda, J . Chem. Lett. 1987, 1187-
1190. (b) Chiacchiera, S. M.; Singh, J . O.; Anunziata, J . D.; Silber, J .
J . J . Chem. Soc., Perkin Trans. 2 1987, 987-993. (c) Pardisi, C. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, Chapter 2.1.
(13) Kessar, S. V. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 2.3.
(14) Norris, R. K. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, Chapter 2.2.
See also: Kim, J . K.; Bunnett, J . F. J . Am. Chem. Soc. 1970, 92, 7463-
7464.
(15) Formation of aromatic rings through enamine annulation
reported recently gains entry to this category: Wang, C.; Kohn, H.
Org. Lett. 2000, 2, 1773-1775.
This reaction suggests that the haloarenes might serve
as oxidant in the present case. It turned out, however,

190 J . Org. Chem., Vol. 66, No. 1, 2001
Ishikawa et al.
none-ketyl prior to use. Pd(OAc)2 and PdCl2 were commercial
reagents.
N-P h en yl-L-p r olin e Meth yl Ester (2i). Method A: color-
less crystals (99 mg, 71%); mp 72.0-74.0 °C; [R]32D ) -13.9 (c
1.0, CHCl3); 1H NMR δ 2.05-2.43 (m, 4H), 3.36-3.48 (m, 1H),
3.60-3.69 (m, 1H), 3.78 (s, 3H), 4.30-4.36 (m, 1H), 6.58-6.65
(m, 2H), 6.75-6.82 (m, 1H), 7.25-7.34 (m, 2H); 13C NMR δ
23.8, 30.9, 48.2, 52.1, 60.7, 111.8, 116. 6, 129.2, 146.5, 174.9;
IR (KBr) 2950, 1750, 1598, 1506, 1370, 747 cm-1. Anal. Calcd
for C12H15O2N: C, 70.22; H, 7.37. Found: C, 70.50; H, 7.51.
N-(4-Meth oxyp h en yl)m or p h olin e (2j). Method C: color-
less crystals (40 mg, 36%); mp 71.0-73.3 °C (lit.1 mp 71 °C,
Palladium chloride-acetonitrile complex [PdCl2(CH3CN)2]
was prepared by heating a suspension of PdCl2 in acetonitrile
under reflux and by cooling the thus-obtained solution to room
temperature: the desired crystalline complex precipitated and
was collected by filtration. Enamines were prepared after the
reported procedure (Hu¨nig, S.; Lu¨cke, E.; Brenninger, W.
Organic Syntheses; Wiley: New York, 1973; Coll. Vol. V, pp
808-809).
Gen er a l P r oced u r e for Ar om a tiza tion of En a m in es.
Meth od A. To a stirred suspension of PdCl2(CH3CN)2 (309 mg,
1.19 mmol) in acetonitrile (3 mL) were added Et3N (0.41 mL,
3.0 mmol) and then enamine (0.59 mmol) dissolved in aceto-
nitrile or dichloromethane (1 mL) at room temperature. The
mixture was stirred at room temperature for 2 h. After
filtration through a short Florisil pad, the filtrate was con-
centrated by a rotary evaporator. The residue was purified
by CC.
1
lit.18 mp 73.3 °C); H NMR δ 3.03-3.08 (m, 4H), 3.77 (s, 3H),
3.84-3.88 (m, 4H), 6.82-6.92 (m, 4H); 13C NMR δ 50.8, 55.5,
67.0, 114.4, 117.8, 145.6, 153.9; IR (KBr) 2970, 2853, 1513,
1266, 818 cm-1
.
N-[(2-Meth oxycar bon yl)ph en yl]pyr r olidin e (2k). Method
1
C: colorless oil (56 mg, 57%); H NMR δ 1.90-1.99 (m, 4H),
3.20-3.29 (m, 4H), 3.88 (s, 3H), 6.67-6.81 (m, 2H), 7.27-7.34
(m, 1H), 7.55-7.59 (m, 1H); 13C NMR δ 25.8, 50.8, 51.9, 113.9,
115.6, 117.0, 131.0, 131.7, 147.9, 169.5; IR (film) 2948, 1713,
1599, 1362, 1225, 747 cm-1. Anal. Calcd for C12H15O2N: C,
70.22; H, 7.37. Found: C, 70.09; H, 7.20.
Meth od B. Pd(OAc)2 (267 mg, 1.19 mmol) and THF were
employed in place of PdCl2(CH3CN)2 and acetonitrile, respec-
tively.
Meth od C. The same mixture as that of method A was
heated at 80 °C under stirring for 0.5 h.
Dip h en yleth yla m in e (2l). Method A: pale yellow oil (35
1
mg, 48%); H NMR δ 3.34 (s, 3H), 6.94-7.08 (m, 6H), 7.23-
7.33 (m, 4H); 13C NMR δ 40.2, 120.4, 121.2, 129.2, 149.0; IR
(film) 2930, 1591, 1496, 749 cm-1
.
4-P h en ylm or p h olin e (2a ). Method A: colorless crystals
(84 mg, 86%) (method B, 90%); mp 48-50 °C (lit.16 mp 51-54
3-(1-P yr r olid in yl)-2-m eth yl-2-cycloh exen on e (1m ). To
a solution of 2-methylcyclohexane-1,3-dione (0.5 g, 3.96 mmol)
in benzene (10 mL) was added pyrrolidine (2.0 mL), and the
mixture was heated and liberated water was removed by
percolating the azeotropic mixture down through a MS-3A pad
over 0.5 h. The mixture was evaporated to give an oil, which
was dried under high vacuum to give 1.05 g of 1m as a pale
brown gum (quant): 1H NMR δ 1.89 (s, 3H), 1.75-1.90 (m,
6H), 2.26-2.33 (m, 2H), 2.21-2.28 (m, 2H), 2.46-2.53 (m, 2H),
3.46-3.54 (m, 4H); 13C NMR δ 12.8, 20.5, 25.5, 30.3, 36.4, 51.2,
1
°C); H NMR δ 3.15-3.20 (m, 4H), 3.85-3.90 (m, 4H), 6.84-
6.96 (m, 3H), 7.24-7.34 (m, 2H); 13C NMR δ 49.4, 66.9, 115.7,
120.0, 129.1, 151.3; IR (KBr) 2855, 1598, 1376, 1120, 772 cm-1
.
1-P h en ylp ip er id in e (2b).1 Method A: colorless oil (35 mg,
74%); 1H NMR δ 1.61-1.71 (m, 2H), 1.75-1.86 (m, 4H), 3.21-
3.28 (m, 4H), 6.75-6.89 (m, 1H), 7.01-7.06 (m, 2H), 7.30-
7.38 (m, 2H); 13C NMR δ 24.3, 25.8, 50.6, 116.5, 119.1, 128.9,
152.2; IR (film) 2933, 1597, 1383,1237, 756 cm-1
.
1-P h en ylp yr r olid in e (2c). Method A: colorless oil (81 mg,
89%); 1H NMR δ 2.01-2.11 (m, 4H), 3.30-3.39 (m, 4H), 6.60-
6.76 (m, 3H), 7.25-7.33 (m, 2H); 13C NMR δ 25.4, 47.5, 111.6,
115.3, 129.1, 147.9; IR (film) 2962, 1595, 1370, 1260, 1025,
105.7, 162.8, 197.0; IR (film) 2949, 2871, 1611, 1544, 729 cm-1
.
N-(3-ter t-Bu tyld im eth ylsiloxy-2-m eth ylp h en yl)p yr r o-
lid in e (2m ). To a solution of 1m (87 mg, 0.49 mmol) in THF
was added 0.34 mL (1.5 mmol) of Et3N, and the mixture was
cooled to -78 °C followed by the addition of 0.22 mL (0.60
mmol) of TBSOTf and continued stirring at -78 °C to room
temperature for 2 h, followed by the addition of PdCl2(CH3-
CN)2. The reaction was stirred at 50 °C for 1 h, filtered through
a short Florisil pad, and mixed with saturated aqueous
NaHCO3 solution. This mixture was extracted with AcOEt,
and the combined organic solutions were dried (Na2SO4),
filtered, and concentrated by a rotary evaporator. The residue
was purified by CC to give 2m (36 mg, 43%) as a colorless oil:
1H NMR δ 0.22 (s, 6H), 1.03 (s, 9H), 1.86-1.96 (m, 4H), 2.16
(s, 3H), 3.09-3.17 (m, 4H), 6.42-6.47 (m, 1H), 6.55-6.61 (m,
1H), 6.93-7.00 (m, 1H); 13C NMR δ -4.19, 13.3, 18.3, 24.8,
25.7, 25.8, 51.3, 109.2, 111.7, 120.2, 125.6, 151.1, 154.7; IR
798 cm-1
.
N-(2-Meth ylp h en yl)p yr r olid in e (2d ). Method A: colorless
1
oil (33 mg, 70%); H NMR δ 1.94-2.06 (m, 4H), 2.37 (s, 3H),
3.18-3.30 (m, 4H), 6.83-6.96 (m, 2H), 7.15-7.21(m, 2H); 13
C
NMR δ 20.5, 24.9, 51.0, 115.7, 120.2, 126.2, 126.6, 128.6, 131.6,
149.3; IR (KBr) 2965, 1493, 753, 716 cm-1. Anal. Calcd for
C
11H15N: C, 81.94; H, 9.38. Found: C, 81.71; H, 9.22.
N-(3-Meth ylp h en yl)p yr r olid in e (2e). Method A: colorless
1
oil (44 mg, 94%); H NMR δ 1.96-2.06 (m, 4H), 2.35 (s, 3H),
3.25-3.35 (m, 4H), 6.32-6.43 (m, 2H), 6.46-6.48 (m, 1H),
7.12-7.19 (m, 1H); 13C NMR δ 21.8, 25.4, 47.6, 108.9, 112.3,
116.3, 129.0, 138.8, 148.0; IR (film) 2965, 1499, 803, 763 cm-1
.
N-(p-ter t-Bu tylp h en yl)p yr r olid in e (2f). Method A: color-
less crystals (42 mg, 79%); mp 41.0-42.0 °C (lit.17 mp 38-39
°C); 1H NMR δ 1.29 (s, 9H), 1.90-2.03 (m, 4H), 3.25-3.31 (m,
4H), 6.54 (d, J ) 8.8 Hz, 2H), 7.26 (d, J ) 8.8 Hz, 2H); 13C
NMR δ 25.5, 31.6, 33.8, 47.7, 111.3, 125.9, 137.9, 145.9; IR
(film) 2957, 2929, 2858, 1591, 1471, 837 cm-1
.
3-(1-P yr r olid in yl)-2-cycloh exen -1-on e (1n ). To a solution
of cyclohexane-1,3-dione (1.5 g, 13.4 mmol) in benzene (20 mL)
was added pyrrolidine (3.0 mL), and the mixture was heated
under reflux while liberated water was removed by percolating
the azeotropic mixture down through a MS-3A pad for 0.5 h.
The mixture was concentrated by a rotary evaporator, and the
residue was further dried under a high vacuum to give 1n (2.19
g, 99%) as a brown gum: 1H NMR δ 1.92-2.04 (m, 6H), 2.26-
2.33 (m, 2H), 2.42-2.49 (m, 2H), 3.15-3.26 (m, 2H), 3.38-
3.49 (m, 2H), 5.06 (s, 1H); 13C NMR δ 22.1, 24.7, 25.3, 27.9,
35.8, 47.9, 98.4, 163.5, 196.2; IR (KBr) 2945, 2870, 1553,
(KBr) 2961, 1524, 1364, 810 cm-1
.
N-(2-Na p h th yl)m or p h olin e (2g). Method A: pale yellow
crystals (101 mg, 99%); mp 91.0-91.5 °C; 1H NMR δ 2.01-
2.21 (m, 4H), 3.37-3.45 (m, 4H), 6.85 (m, 1H), 6.97-7.02 (m,
1H), 7.11-7.18 (m, 1H), 7.31-7.37 (m, 1H), 7.60-7.71 (m, 2H);
13C NMR δ 25.5, 47.8, 104.6, 115.7, 121.1, 125.7, 126.1, 126.2,
127.6, 128.7, 135.2, 145.9; IR (KBr) 2962, 1513, 824, 739 cm-1
.
Anal. Calcd for C14H15N: C, 85.24; H, 7.66. Found: C, 85.11;
H, 7.70.
N-(1-Na p h th yl)p yr r olid in e (2h ). Method A: colorless oil
(95 mg, 95%); 1H NMR δ 2.03-2.21 (m, 4H), 3.38-3.59 (m,
4H), 7.14 (d, J ) 7.4 Hz, 1H), 7.45-7.66 (m, 4H), 7.89-7.98
(m, 1H), 8.32-8.39 (m, 1H); 13C NMR δ 24.7, 52.6, 111.3, 121.1,
124.2, 124.7, 125.4, 125.8, 128.0, 128.2, 134.9, 147.6; IR (KBr)
799 cm-1
.
N-[(3-ter t-Bu tyldim eth ylsiloxy)ph en yl]pyr r olidin e (2n ).
To a solution of 1n (50 mg, 0.30 mmol) in THF was added
Et3N (0.20 mL, 1.5 mmol), and the mixture was cooled to
-78 °C. To this cold mixture was added TBSOTf (0.07 mL,
0.30 mmol) and the solution was stirred at -78 °C to
room temperature for 2 h followed by the addition of PdCl2-
2966, 1574,1399, 796, 769 cm-1
.
(16) Tsuji, Y.; Huh, K. T.; Ohsugi, Y.; Watanabe, Y. J . Org. Chem.
1985, 50, 1365-1370.
(17) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1997, 62, 1264-
(18) Wolfe, J . P.; Buchwald, S. L. J . Org. Chem. 1996, 61, 1133-
1135.
1267.

Synthesis of Aromatic Amines
J . Org. Chem., Vol. 66, No. 1, 2001 191
(CH3CN)2. The resulting solution was stirred at 50 °C for 1 h,
filtered through a short Florisil pad, mixed with saturated
NaHCO3 aqueous solution, and extracted several times with
AcOEt. The combined organic solutions were dried (Na2SO4),
filtered, and concentrated by a rotary evaporator to give an
oily residue, which was purified by CC to give 2n (26 mg, 33%)
as a colorless oil: 1H NMR δ 0.26 (s, 6H), 0.99 (s, 9H), 1.94-
2.03 (m, 4H), 3.21-3.29 (m, 4H), 6.05-6.08 (m, 1H), 6.14-
6.22 (m, 2H), 7.06 (t, 1H, J ) 8.0 Hz); 13C NMR δ -4.32, 18.2,
25.4, 25.7, 25.8, 47.6, 103.6, 105.1, 107.3, 129.6, 149.2, 156.6;
1H), 7.21-7.37 (m, 5H); 13C NMR δ -4.4, 18.2, 25.7, 38.7, 56.6,
104.5, 105.8, 108.4, 126.7, 126.8, 128.5, 129.6, 139.0, 151.0,
156.6; IR (film) 2956, 2930, 2858, 1605 cm-1
.
Meth yl 2-(1-P yr r olidin yl)-4-m eth ylben zoate (2s). Method
C (enamine 17 was not isolated): colorless oil (36 mg, 37%
1
from 16); H NMR δ 1.89-1.98 (m, 4H), 2.32 (s, 3H), 3.19-
3.28 (m, 4H), 3.86 (s, 3H), 6.51-6.56 (dd, J ) 8.0, 0.8 Hz, 1H),
6.60 (s, 1H), 7.45 (d, J ) 8.0 Hz, 1H); 13C NMR δ 21.9, 25.8,
50.9, 51.8, 114.4, 114.5, 116.9, 131.2, 142.2, 148.2, 169.4; IR
(film) 2948, 1716, 1606, 1500, 1229 cm-1
.
IR (film) 2959, 2856, 1607, 1499, 829 cm-1
.
Meth yl 2-Meth yl-6-(1-p yr r olid in yl)ben zoa te (2t). To a
solution of methyl 3-oxo-7-octenoate (23; 2.9 g, 17.0 mmol) in
benzene (15 mL) was added pyrrolidine (2.1 mL, 25.5 mmol)
and the mixture was heated under reflux while liberated water
was removed by percolating the azeotropical mixture down
3-Acetoxy-2-cycloh exen -1-on e (4). To a solution of cyclo-
hexane-1,3-dione (2 g, 17.8 mmol) in CH2Cl2 (40 mL) was
added pyridine (2.9 mL, 35.7 mmol), and the mixture was
cooled to 0 °C. To this solution was added acetyl chloride (1.9
mL, 26.8 mmol) in a dropwise manner. The reaction was
quenched by the addition of water and extracted with CH2-
Cl2. The combined organic phases were dried (Na2SO4), filtered,
and concentrated by a rotary evaporator to give an oil, which
was purified by CC to give 4 (2.32 g, 85%) as a colorless oil:
1H NMR δ 1.98-2.11 (m, 2H), 2.21 (s, 3H), 2.37-2.43 (m, 2H),
2.53 (dt, J ) 1.3, 6.1 Hz), 5.78-5.82 (m, 1H); 13C NMR δ 21.0,
21.0, 28.1, 36.5, 117.2, 167.1, 169.6, 199.5; IR (film) 1770, 1672,
through
a MS-3A pad. The resulting dark solution was
concentrated by a rotary evaporator to give a tar, which was
purified by bulb-to-bulb distillation (Kugelrohr, 0.1 mm Hg,
130-140 °C) to give 24 (2.5 g, 67%) as a pale yellow oil. A
part of this oil (0.1 g, 0.45 mmol) was dissolved in CH3CN (3
mL), and to the mixture were added Et3N (0.31 mL, 2.24 mmol)
and PdCl2(CH3CN)2 (232 mg, 0.9 mmol). The obtained suspen-
sion was heated at 90 °C and stirred at that temperature for
1 h. The mixture was filtered through a short Florisil pad and
the filtrate was concentrated by a rotary evaporator followed
by the addition of saturated aqueous NaHCO3 solution. The
mixture was extracted with AcOEt, and the combined organic
solutions were dried (Na2SO4), filtered, and concentrated by a
rotary evaporator to give an oil, which was purified by CC to
give 2t (44 mg, 45%) as a colorless oil: 1H NMR δ 1.88-1.98
(m, 4H), 2.27 (s, 3H), 3.22-3.29 (m, 4H), 3.89 (s, 3H), 6.51-
6.60 (m, 2H), 7.13 (dd, J ) 8.5, 7.4 Hz, 1H); 13C NMR δ 20.2,
25.8, 49.6, 50.8, 51.8, 111.5, 118.4, 129.8, 136.3, 146.2, 171.5;
922, 879 cm-1
.
1,3-O-Bis(ter t-bu tyldim eth ylsilyl)r esor cin ol (6). 1H NMR
δ 0.20 (s, 12H), 0.99 (s, 18H), 6.36 (t, J ) 2.3 Hz, 1H), 6.47 (m,
2H), 7.07 (t, J ) 8.0 Hz, 1H); 13C NMR δ -4.39, 18.2, 25.7,
112.3, 113.4, 129.5, 156.6; IR (film) 2956, 2931, 2860, 1587,
831 cm-1
.
[O-(ter t-Bu tyldim eth ylsilyl)-3-N,N-dim eth ylam in o]ph e-
n ol (2o). To a solution of 4 (0.1 g, 0.65 mmol) in THF (1 mL)
was added a solution of dimethylamine in THF (2 N, 0.65 mL,
1.3 mmol) at 0 °C. The mixture was stirred at the same
temperature for 2 h, concentrated, and dried under high
vacuum to give a pale yellow gum. The gum was dissolved in
THF (1 mL), and the obtained THF solution was cooled to -78
°C. To this cold solution were slowly added Et3N (0.45 mL,
3.25 mmol) and TBSOTf (0.3 mL, 1.3 mmol). The mixture was
stirred at -78 to 0 °C for 1 h, and PdCl2(CH3CN)2 (168 mg)
was added to the mixture and the obtained mixture was stirred
at 0 °C for 0.5 h and heated at 70 °C for 5 min. The mixture
was filtered through a short Florisil pad, and the pad was
rinsed with AcOEt. The combined organic solutions were
concentrated by a rotary evaporator to give an oil, which was
purified by CC to give 2o (48 mg, 29%) as a colorless oil: 1H
NMR δ 0.22 (s, 6H), 1.00 (s, 9H), 2.93 (s, 6H), 6.21-6.27 (m,
2H), 6.37 (dd, J ) 2.2, 8.2 Hz, 1H), 7.08 (m, 1H); 13C NMR δ
-4.3, 18.2, 25.8, 40.6, 104.7, 106.0, 108.4, 129.5, 152.0, 156.6;
IR (film) 2966, 2871, 1720, 1589 cm-1
.
6-Meth yl-4-(1-p yr r olid in yl)in d a n (2u ). Method C (enam-
ine 26 was not isolated), colorless oil (57 mg, 57% from 25):
1H NMR δ 1.89-1.96 (m, 4H), 1.95-2.06 (m, 2H), 2.29 (s, 3H),
2.82 (tt, J ) 7.42, 7.41 Hz, 2H), 3.02 (t, 3H, J ) 7.41 Hz, 2H),
3.32-3.38 (m, 4H), 6.31 (s, 1H), 6.55 (s, 1H); 13C NMR δ 21.5,
25.3, 25.7, 33.1, 33.3, 49.9, 112.0, 115.2, 126.9, 136.7, 146.3,
146.4; IR (film) 2950, 2844, 1580, 1483, 1360, 821 cm-1
.
Meth yl 2-(1-P yr r olid in yl)cin n a m a te (15). To a suspen-
sion of PdCl2(CH3CN)2 (150 mg, 0.58 mmol) in CH3CN (5 mL)
was added R-(1-pyrrolidinyl)styrene (0.1 g, 0.58 mmol), and
the mixture was heated at 80 °C for 0.5 h, cooled to 0 °C, and
allowed to stand under a carbon monoxide atmosphere (1 atm)
for 1 h. To this mixture was added MeOH, and the resulting
mixture was stirred at room temperature for 1 h followed by
the addition of Et3N. After filtration through a short Florisil
pad, the filtrate was concentrated to give an oil, to which was
added water. The mixture was extracted three times with
AcOEt, and the combined organic solutions were dried (Na2-
SO4) and concentrated by a rotary evaporator to give an oil,
which was purified by CC and finally recrystallization (ether-
hexane) to give 15 (22 mg, 16%) as colorless crystals: mp 103
°C (dec); 1H NMR δ 1.65-2.12 (br, 4H), 2.88-3.40 (br, 4H),
3.46 (s, 3H), 4.69 (s, 1H), 7.18-7.24 (m, 2H), 7.33-7.43 (m,
3H); 13C NMR δ 25.2, 45.7 (br), 49.9, 84.3, 127.3, 128.0, 128.2,
IR (film) 1606, 835 cm-1
.
[O-(ter t-Bu tyld im eth ylsilyl)-3-N,N-d ieth yla m in o]p h e-
n ol (2p ). This compound was obtained by the same procedure
as that for the synthesis of 2o using diethylamine in place of
dimethylamine, 2p (27%) as a colorless oil: 1H NMR δ 0.23
(s, 6H), 1.11 (s, 9H), 1.17 (t, J ) 7.0 Hz, 6H), 3.33 (q, J ) 7.0
Hz, 4H), 6.13-6.21 (m, 2H), 6.32 (m, 1H), 7.05 (m, 1H); 13C
NMR δ -4.3, 12.6, 18.2, 25.7, 44.4, 103.84, 105.3, 107.2, 129.6,
149.2, 156.8; IR (film) 2956, 2930, 2858, 1606 cm-1
.
[O-(ter t-Bu tyldim eth ylsilyl)-3-N,N-diben zylam in o]ph e-
n ol (2q). This compound was obtained by the same procedure
as that for the synthesis of 2o using dibenzylamine in place
of dimethylamine, 30% yield, colorless oil: 1H NMR δ 0.08 (s,
6H), 0.94 (s, 9H), 4.67 (s, 4H), 6.22-6.29 (m, 2H), 6.40-6.45
(m, 1H), 7.05 (t, J ) 8.0 Hz, 1H), 7.25-7.41 (m, 10H); 13C NMR
δ -4.6, 18.2, 25.7, 54.5, 104.8, 105.9, 108.7, 126.8, 128.6, 129.8,
137.6, 161.1, 168.2; IR (KBr) 2938, 1697, 1556, 962, 788 cm-1
.
Anal. Calcd for C14H17O2N: C, 72.70; H, 7.41. Found: C, 72.47;
H, 7.66.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research from the Ministry
of Education, Science, Sports, and Culture, J apan.
138.6, 150.4, 156.6; IR (film) 2956, 2930, 2858, 1606, cm-1
.
[O-(ter t-Bu tyldim eth ylsilyl)-3-(N-ben zyl-N-m eth yl)am i-
n o]p h en ol (2r ). This compound was obtained by the same
procedure as that for the synthesis of 2o using benzylmethy-
lamine in place of dimethylamine: 30% yield, colorless oil; 1H
NMR δ 0.15 (s, 6H), 0.97 (s, 9H), 3.01 (s, 3H), 4.52 (s, 2H),
6.22-6.27 (m, 2H), 6.39 (dd, J ) 2.3, 8.2 Hz, 1H), 7.07 (m,
Su p p or tin g In for m a tion Ava ila ble: Copies of NMR
spectra (1H and 13C) for the arylamines (2a -u ). This material
is available free of charge via the Internet at http://pubs.acs.org.
J O001331X