Iron-catalyzed oxidative coupling of alkylamides with arenes through oxidation of alkylamides followed by Friedel-Crafts alkylation

Article abstract of DOI:10.1021/jo102217m

FeCl₃ in combination with t-BuOOt-Bu as an oxidant was found to be an efficient catalyst for oxidation of alkylamides to α-(tert-butoxy) alkylamides. FeCl₂ and CuCl showed, respectively, almost the same and slightly lower activities

Full text of DOI:10.1021/jo102217m

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Iron-Catalyzed Oxidative Coupling of Alkylamides with Arenes through
Oxidation of Alkylamides Followed by Friedel-Crafts Alkylation
Eiji Shirakawa,* Nanase Uchiyama, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto University, Kyoto 606-8502, Japan
shirakawa@kuchem.kyoto-u.ac.jp; thayashi@kuchem.kyoto-u.ac.jp
Received November 6, 2010
FeCl3 in combination with t-BuOOt-Bu as an oxidant was found to be an efficient catalyst for oxi-
dation of alkylamides to R-(tert-butoxy)alkylamides. FeCl2 and CuCl showed, respectively, almost
the same and slightly lower activities compared with FeCl3 in the tert-butoxylation of N-phenylpyr-
rolidone (1a), whereas no tert-butoxylated product was obtained by use of Fe(OTf)3, RuCl3, or
Zr(OTf)4. FeCl3 was found to be effective also as a catalyst for the Friedel-Crafts alkylation with
thus obtained R-(tert-butoxy)alkylamides. The Friedel-Crafts alkylation proceeded smoothly also
in the presence of a catalytic amount of Fe(OTf)3, RuCl3, or Zr(OTf)4. In contrast, FeCl2 and CuCl,
which showed certain activity toward the tert-butoxylation, failed to promote the Friedel-Crafts
alkylation. Among the transition metal complexes thus far examined, only FeCl3 showed high
catalytic activities for both the oxidation and the Friedel-Crafts alkylation. The bifunctionality of
FeCl3 was utilized for the oxidative coupling of alkylamides with arenes through a tandem reaction
consisting of oxidation of alkylamides to R-(tert-butoxy)alkylamides and the following Friedel-
Crafts alkylation. The FeCl3-catalyzed oxidative coupling is applicable to a wide variety of alkylamides
and arenes, though a combination of FeCl3 with Fe(OTf)3 was found to be effective for the reaction of
arenes with low nucleophilicity. A Fe(II)-Fe(III) catalytic cycle is concerned with the tert-butoxylation,
whereas a Fe(III) complex as a Lewis acid catalyzes the Friedel-Crafts alkylation.
Introduction
halogen-containing waste. R-Oxyalkylamides, which are
converted into acyliminium ions upon elimination of the
oxygen leaving group, are used for amidoalkylation of arenes
to give R-arylalkylamides.2 Amidoalkylations of arenes with
R-oxyalkylamides are often conducted in the presence of a
stoichiometric amount of a Brønsted or Lewis acid, but use
of a Lewis acid as a catalyst also is possible.3 Oxidation of
alkylamides is one of the most convenient methods to obtain
R-oxyalkylamides. In addition to anodic oxidation using an
alcohol as a solvent giving R-alkoxyalkylamides,4 combina-
tions of a transition metal catalyst with an oxygen-based
The Friedel-Crafts alkylation is one of the most versatile
methods for introduction of C(sp3) substituents into aro-
matic rings.1 The most frequently used electrophiles in this
electrophilic aromatic substitution (SEAr) are alkyl halides,
whereas oxy compounds such as alcohols and ethers also
act as efficient alkylating reagents, which do not give any
(1) For a review, see: Olah, G. A.; Krishnamurti, R.; Prakash, G. K. S. In
Comprehensive Organic Synthesis; Trost, B. M.; Fleming, I.; Pattenden, G.,
Eds.; Pergamon Press; Oxford, 1991; Vol. 3, Chapter 1.8; pp 293-339.
(2) For reviews on generation of acyliminium salts and reactions with
nucleophiles including arenes, see: (a) Speckamp, W. N.; Hiemstra, H.
Tetrahedron 1985, 41, 4367–4416. (b) Hiemstra, H.; Speckamp, W. N. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon Press: Oxford, 1991; Vol. 2; Chapter 4.5; pp
1047-1082. (c) Speckamp, W. N.; Moolenaar, M. J. Tetrahedron 2000, 56,
3817–3856. (d) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. Rev. 2004, 104, 1431–1628.
(3) Amidoalkylation of arenes has been extensively studied with simple
alkylation reagents such as N-(hydroxymethyl)-R-chloroacetamide and
N-(hydroxymethyl)phthalimide, which are used on the assumption that the
acyl groups are removed after amidoalkylation to give H2NCH2-substituted
arenes. For reviews, see: (a) Zaugg, H. E. Synthesis 1970, 49–73. (b) Zaugg,
H. E. Synthesis 1984, 85–110. (c) Zaugg, H. E. Synthesis 1984, 181–212. See
also refs 2 and 4.
DOI: 10.1021/jo102217m
r
Published on Web 12/15/2010
J. Org. Chem. 2011, 76, 25–34 25
2010 American Chemical Society

Shirakawa et al.
JOCFeatured Article
oxidant are useful for preparation of R-oxyalkylamides.
Among the combinations, Cu/t-BuOOCOPh5 and Ru/
t-BuOOH6 are particularly effective to give R-benzoyloxy-
amides and R-(tert-butyldioxy)amides, respectively.7
iron complexes fulfill the requirement. They are known to
catalyze oxidation11,12 of C(sp3)-H bonds to C(sp3)-O
bonds and have strong Lewis acidity13 to promote SEAr
with various electrophiles. Here we report that FeCl3 effec-
tively catalyzes the following three reactions: (1) oxidation
of alkylamides into R-alkoxyalkylamides, (2) SEAr with
the R-alkoxyalkylamides, and (3) oxidative coupling of alkyl-
amides with arenes as a sequence of these two reactions to
give a wide variety of R-arylalkylamides.14
As mentioned above, R-arylalkylamides can be obtained
from alkylamides and arenes through oxidation of alkyl-
amides followed by SEAr with the resulting R-oxyalkylamides,
but tandem reaction consisting of these two reactions is more
convenient because introduction of oxy substituents in ad-
vance is not required. In this context, we have previously
reported the Zr(OTf)4-catalyzed oxidative coupling of alkyl-
amides with arenes using O2 as an oxidant, but the scope is
severely limited to γ-lactams and electron-rich heteroarenes.8,9
This oxidative coupling is considered to be a tandem reaction
consisting of oxidation and SEAr both catalyzed by the
zirconium complex, though the existence of any intermedi-
ary R-oxygenated alkylamide is not confirmed. It is not so
easy to effectively operate this type of tandem catalysis, where
one catalyst sequentially promotes two mechanistically dis-
tinct reactions in a single reactor,10 because the catalyst is
required to show two different types of catalytic abilities. The
narrow scope in the zirconium-catalyzed reaction is likely to
be ascribed mainly to its low catalytic activity for oxidation.
Expansion of the substrate scope of the oxidative coupling
apparently requires a more effective transition metal cat-
alyst, which oxidizes a wide variety of alkylamides in com-
bination with a properly chosen oxidant and has strong
Lewis acidity to smoothly promote SEAr with the resulting
R-oxygenated alkylamides. We anticipated that high valent
Results and Discussion
Oxidation of Alkylamides to r-(tert-Butoxy)alkylamides.
We examined efficiency of FeCl3 as a catalyst for oxida-
tion of alkylamides using t-BuOOt-Bu as an oxidant in the
expectation that the oxidation gives relatively stable R-(tert-
butoxy)alkylamides. Thus, treatment of N-phenylpyrroli-
done (1a) with FeCl3 (1 mol %) and t-BuOOt-Bu (3 equiv)
in 1,2-dichloroethane (DCE) at 90 °C for 24 h gave 5-(tert-
butoxy)-1-phenyl-2-pyrrolidone (2a) in 53% yield with 89%
conversion (entry 1 of Table 1). The yield was increased by
use of 1,2-dichloroisobutane (DCB) as a solvent in combina-
tion with t-BuOH (TBA), which possibly stabilizes 2a (entry 2).
N-Methylpyrrolidone (1b) accepted tert-butoxylation prefer-
entially on the ring over at the methyl (entry 3), where a higher
conversion resulted in a lower efficiency with coproduction of a
considerable amount of di(tert-butoxy)amide 2b00 (entry 4).
The oxidation proceeded also with acyclic amides (entries 5
and 6), but again dibutoxylation is troublesome with N,N-
dimethylacetamide (DMA, 1d), which has two reaction
sites. Selective monobutoxylation of 1d and 1b was observed
by use of the amides in large excess as solvents (entries 7
and 8). The catalytic activity of FeCl2 was comparable to that
of FeCl3, whereas 2a was not obtained at all with Fe(OTf)3
(entries 9 and 10). Among transition metals that are known
to be effective for oxidation of alkylamides to R-oxylated
products,5,6 CuCl showed certain activity, but oxidation of
1a was not completed even after 48 h (entries 11 and 12). No
tert-butoxylation product was obtained with RuCl3 or
Zr(OTf)4, which is known to catalyze oxidative coupling of
five-membered lactams with indoles using oxygen as an
oxidant (entries 13 and 14).8 Only a small amount of 2a
was obtained in the absence of a metal catalyst (entry 15).
(4) For reviews on anodic oxidation of organic compounds including
alkylamides and synthetic applications of the oxidation products, see:
(a) Shono, T. Tetrahedron 1984, 40, 811–850. (b) Moeller, K. D. Tetrahedron
2000, 56, 9527–9554.
(5) For a review, see: Rawlinson, D. A.; Sosnovsky, G. Synthesis 1972,
1–28.
(6) (a) Murahashi, S.-I.; Naota, T.; Kuwabata, T.; Saito, T.; Kumobayashi,
H.; Akutagawa, S. J. Am. Chem. Soc. 1990, 112, 7820–7822. For reviews, see:
(b) Murahashi, S.-I. Angew. Chem., Int. Ed. 1995, 34, 2443–2465. (c) Murahashi,
S.-I.; Komiya, N. In Ruthenium in Organic Synthesis; Murahashi, S.-I., Ed.;
Wiley-VCH: Weinheim, 2004; Chapter 3.4.4; pp 79-81. (c) Murahashi, S.-I.;
Zhang, D. Chem. Soc. Rev. 2008, 37, 1490–1501.
(7) For examples of oxidation of alkylamides to R-oxyalkylamides, see:
(a) Mitani, M.; Watanabe, K.; Tachizawa, O.; Koyama, K. Chem. Lett. 1992,
21, 813–814. (b) Wang, D.-H.; Hao, X.-S.; Wu, D.-F.; Yu, J.-Q. Org. Lett.
2006, 8, 3387–3390.
(8) Tsuchimoto, T.; Ozawa, Y.; Negoro, R.; Shirakawa, E.; Kawakami,
Y. Angew. Chem., Int. Ed. 2004, 43, 4231–4233.
(9) As a part of extensive work on homolytic aromatic substitution
(HAS), Minisci has reported the oxidative coupling of alkylamides with
N-heteroarenes such as pyridine in the use of a peroxy oxidant including
t-BuOOt-Bu, but the scope of arenes is limited to pyridine derivatives, which
as protonated forms accept addition of nucleophilic acylaminomethyl radical
intermediates. (a) Arnone, A.; Cecere, M.; Galli, R.; Minisci, F.; Perchinunno,
M.; Porta, O.; Gardini, G. Gazz. Chim. Ital. 1973, 103, 13–29. For a review on
HAS: (b) Minisci, F.; Vismara, E.; Fontana, F. Heterocycles 1989, 28, 489–519.
For an iron-catalyzed reaction: (c) Citterio, A.; Gentile, A.; Minisci, F.;
Serravalle, M.; Ventura, S. J. Chem. Soc., Chem. Commun. 1983, 916–917.
(10) Fogg and dos Santos call this, in their review, “auto-tandem cata-
lysis” with the definition “processes of this type involve two or more
mechanistically distinct catalyses promoted by a single catalyst precursor:
both cycles occur spontaneously by cooperative interaction of the various
species (catalyst, substrate, additional reagents if required) present at the
outset of reaction.” (a) Fogg, D. E.; dos Santos, E. N. Coord. Chem. Rev.
2004, 248, 2365–2379. For other recent reviews on tandem catalysis, see:
(b) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001–1020. (c) Shindoh, N.; Takemoto, Y.; Takasu, K. Chem.;Eur. J.
2009, 15, 12168–12179.
(12) Demethylation of N-methylamides through iron-catalyzed oxidation
has been reported as a side reaction of homolytic aromatic substitution.
(a) Citterio, A.; Gentile, A.; Minisci, F.; Serravalle, M.; Ventura, S. J. Org.
Chem. 1984, 49, 3364–3367. (b) Minisci, F.; Giordano, C.; Vismara, E.; Levi,
S.; Tortelli, V. J. Am. Chem. Soc. 1984, 106, 7146–7150.
(13) For reviews, see: (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem.
Rev. 2004, 104, 6217–6254. (b) Kischel, J.; Mertins, K.; Jovel, I.; Zapf, A.;
Beller, M. In Iron Catalysis in Organic Chemistry; Plietker, B., Ed.; Wiley-
VCH; Weinheim, 2008; Chapter 6.2.5; pp 183-188.
(14) Very recently, a report on iron-catalyzed oxdiative coupling of
N-acyl-1,2,3,4-tetrahydroisoquinolines with indoles or polymethoxyben-
zenes appeared. (a) Ghobrial, M.; Harhammer, K.; Mihovilovic, M. D.;
€
Schnurch, M. Chem. Commun. 2010, 46, 8836–8838. For iron-catalyzed
homo- and cross-coupling of alkylamines with arenes: (b) Murata, S.; Miura,
M.; Nomura, M. J. Chem. Soc., Chem. Commun. 1989, 116–118. (c) Ohta,
€
M.; Quick, M. P.; Yamaguchi, J.; Wunsch, B.; Itami, K. Chem. Asian J. 2009,
4, 1416–1419. (d) Liu, P.; Zhou, C.-Y.; Xiang, S.; Che, C.-M. Chem.
Commun. 2010, 46, 2739–2741. For oxidative couplings catalyzed by an
iron(II) or iron(0) complex: (e) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int.
Ed. 2007, 46, 6505–6507. (f) Zhang, Y.; Li, C.-J. Eur. J. Org. Chem. 2007,
4654–4657. (g) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497–
7500. (h) Volla, C. M. R.; Vogel, P. Org. Lett. 2009, 11, 1701–1704. (i) Li,
Y.-Z.; Li, B.-J.; Lu, X.-Y.; Lin, S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2009, 48,
ꢀ
(11) For reviews, see: (a) Dıaz, D. D.; Miranda, P. O.; Padron, J. I.;
Martın, V. S. Curr. Org. Chem. 2006, 10, 457–476. (b) Mayer, A. C.; Bolm, C.
In Iron Catalysis in Organic Chemistry; Plietker, B., Ed.; Wiley-VCH;
Weinheim, 2008; Chapter 3.1; pp 73-83. (c) Sarhan, A. A. O.; Bolm, C.
Chem. Soc. Rev. 2009, 38, 2730–2744.
~
3817–3820. (j) Richter, H.; Mancheno, O. G. Eur. J. Org. Chem. 2010, 4460–
4467.
26 J. Org. Chem. Vol. 76, No. 1, 2011

Shirakawa et al.
JOCFeatured Article
TABLE 2. SEAr with R-(tert-Butoxy)alkylamidesa
TABLE 1. Oxidation of Amides with t-BuOOt-Bua
entry
2
catalyst temp (°C) time (h) conv (%)b yield (%)c
temp time conv yield product(s)
solventb (°C) (h) (%)c (%)c,d (ratio)c
1
2
3
4
5
6
7
8
2a FeCl3
2a FeCl2
2a CuCl
2a Fe(OTf)3
2a RuCl3
2a Zr(OTf)4
2b FeCl3
2d FeCl3
40
40
40
40
40
40
70
70
2
2
2
0.8
2
2
2
2
>99
<2
<2
>99
>99
>99
>99
>99
94
<1
<1
96
99
98
entry
1
catalyst
1
2
3
1a FeCl3
1a FeCl3
1b FeCl3
DCE
DCB/TBA 100 21
DCE/TBA 90
90 24
89
88
55
53 2a
65e 2a
3
53 2b/2b0/2b00
(83/13/4)
65 2b/2b0/2b00
(75/9/16)
62 2c
4
1b FeCl3
DCE/TBA 90 24
88
96
96
aThe reaction was carried out in 1,2-dichloroethane (DCE, 1.0 mL)
under a nitrogen atmosphere using 3m (0.25 mmol) and 2 (0.30 mmol;
for entry 8, 0.38 mmol) in the presence of a metal complex (2.5 μmol).
bDetermined by 1H NMR. cYield based on 3m.
5
6
1c FeCl3
1d FeCl3
DCB
DCB
100 24
94
64
100
120
90
3
1
1
51 2d/2d00
(90/10)
84g 2d/2d00
(>99/1)
79g 2b/2b0/2b00
(86/14/<1)
66 2a
7
8
9
1d FeCl3
1b FeCl3
1a FeCl2
1df
1b/TBAh
examined, only FeCl3 showed high catalytic activities for
both oxidation of alkylamides and SEAr with the resulting
alkoxyalkylamides. Now the oxidative coupling of alkyl-
amides with arenes as a sequence of these two reactions
definitely is possible with FeCl3 as a catalyst. Thus, treat-
ment of N-phenylindole (3m, 1 equiv) and N-phenylpyrrolidone
(1a, 6 equiv) with FeCl3 (3 mol %) and t-BuOOt-Bu (3 equiv) in
DCE at 90 °C for 7 h gave 72% yield of coupling product
4am (entry 1 of Table 3).16 Other cyclic and acyclic amides
also underwent the coupling with 3m in DCE or DCB
(entries 2-5). The coupling is applicable to less nucleophilic
arenes (entries 6-8), though the reaction of arenes that have
multiple reaction points such as 2-methoxythiophene (3o)
and 1,3-dimethoxybenzene (3p) gave a mixture of regio-
isomers in addition to 1:2 coupling products. This is an
inherent drawback of the Friedel-Crafts alkylation. The
reaction of a naphthalene having an electron-withdrawing
ester group with DMA (1d) gave no coupling products even
with an increased amount (10 mol %) of FeCl3 (entry 9). To
facilitate the SEAr step by enhancing Lewis acidity, FeCl3 (7
mol %) was used in combination with Fe(OTf)3 (3 mol %),
which has Lewis acidity higher than that of FeCl3 and thus
is more efficient in SEAr (cf. entries 1 and 4 of Table 2) but
poorly catalyzes the oxidation (cf. entries 2 and 10 of Table 1),
to give coupling product 4dq in 84% yield (entry 10). This
protocol was applied to other arenes of low nucleophilicity
(entries 11-13).
DCB/TBA 100 23
91
92
53
68
39
65
32
10 1a Fe(OTf)3 DCB/TBA 100 21
<1 2a
44 2a
11 1a CuCl
12 1a CuCl
13 1a RuCl3
DCB/TBA 100 21
DCB/TBA 100 48
DCB/TBA 100 21
59 2a
<1 2a
14 1a Zr(OTf)4 DCB/TBA 100 21
15 1a DCB/TBA 100 24
<1 2a
4 2a
;
aThe reaction was carried out under a nitrogen atmosphere using
an amide (1, 1.5 mmol), t-BuOOt-Bu (4.5 mmol), and a metal complex
(15 μmol) in a solvent (1.0 mL) or a 1:1 mixture of solvents (1.0 mL).
bDCE = 1,2-dichloroethane, DCB = 1,2-dichloroisobutane, TBA =
tert-butyl alcohol. cDetermined by 1H NMR. dYield based on 1. eYield
after purification was 66%. f1d/FeCl3/t-BuOOt-Bu = 14/0.01/1. gYield
based on t-BuOOt-Bu. h1b/FeCl3/t-BuOOt-Bu/t-BuOH = 14/0.01/1/1.
Friedel-Crafts Alkylation with r-(tert-Butoxy)alkylamides.
FeCl3 was found to be an effective catalyst for SEAr with
thus obtained R-(tert-butoxy)alkylamides. The reaction of
N-phenylindole (3m, 1 equiv) with 5-(tert-butoxy)-1-phenyl-
2-pyrrolidone (2a, 1.2 equiv) in the presence of FeCl3
(1 mol %) in DCE at 40 °C for 2 h gave 1-phenyl-5-(1-phenyl-
3-indolyl)-2-pyrrolidone (4am) in 94% yield (entry 1 of Table 2).15
In contrast, the other complexes (FeCl2 and CuCl) that
showed activities toward the oxidation of alkylamides (cf.
entries 9, 11, and 12 of Table 1) did not catalyze the Friedel-
Crafts alkylation at all (entries 2 and 3). Fe(OTf)3, which has
Lewis acidity higher than that of FeCl3 but lacks the tert-
butoxylation ability (cf. entry 10 of Table 1), was effective
as a catalyst for the SEAr as same as RuCl3 and Zr(OTf)4
(entries 4-6). R-(tert-Butoxy)alkylamides 2b and 2d also
underwent efficient coupling with 3m in the presence of
FeCl3 as a catalyst (entries 7 and 8).
Highly nucleophilic arenes such as N-methylindole (3u)
did not undergo efficient oxidative coupling under the stand-
ard conditions of Table 3. For example, the coupling of 3u
(1 equiv) with DMA (1d, 6 equiv) in DCB using FeCl3
(3 mol %) and t-BuOOt-Bu (3 equiv) at 110 °C for 9 h gave
only 28% yield of 4du with full conversion of 3u (Scheme 1).
Oxidative Coupling of Alkylamides with Arenes through
Tandem Reaction Consisting of Oxidation and the Friedel-
Crafts Alkylation. Among the transition metal complexes
(16) The reaction of 3m with 1a by use of FeCl2 instead of FeCl3 as a
catalyst under the same conditions gave 73% yield of 4am. However, the
FeCl2-catalyzed coupling of 1d with 3n, which is less nucleophilic than 3m,
scored a lower yield (46%) under the same conditions as entry 6 of Table 3.
(15) The reaction of 3m with 2a in the presence of HCl (1 mol %) under
the same conditions (40 °C, 2 h, DCE) gave 4am in 2% yield (5% conv).
J. Org. Chem. Vol. 76, No. 1, 2011 27

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TABLE 3. Oxidative Coupling of Alkylamides with Arenesa
SCHEME 1. Oxidative Coupling Using a Highly Nucleophilic
Arene
electron-rich indole nucleus. Reduction of the amount
(2 equiv) of t-BuOOt-Bu was partially effective, whereas the
yield was considerably improved by use of an increased
amount (18 equiv) of 1d. Use of 1d in much excess as a solvent
further increased the yield to 86%, though a higher tempera-
ture and a higher catalyst loading are required to compensate
deceleration of the SEAr step by an increased amount of the
Lewis basic amide. This protocol was applied to the oxida-
tive coupling of highly nucleophilic heteroarenes and arenes
with liquid amides (Table 4). Amide 1d, used as a solvent,
underwent coupling with indoles, 2-pentylfuran, and 1,3,5-
trimethoxybenzene (entries 1-4). The oxidative coupling is
applicable to an N-monoalkylamide (entries 5 and 6). The
methyl group on nitrogen was preferred over the ethyl as a
coupling partner (entry 7). Arylation took place predomi-
nantly on the ring in the oxidative coupling of cyclic amides
(entries 8-11). An arene of moderate nucleophilicity also
underwent the coupling in a high yield under these condi-
tions (entry 12, cf. entry 3 of Table 3).
The tandem oxidative coupling is valuable not only in its
operational simplicity but also in efficient utilization of reac-
tive intermediates, especially in the reaction of amides that
gives unstable tert-butoxylated amides upon oxidation. For
example, N-[1-(tert-butoxy)ethyl]acetamide was obtained
only in e20% yield by oxidation of N-ethylacetamide (1g)
under the conditions (entry 6 or 7 in Table 1) suitable for tert-
butoxylation of DMA (1d). Despite the instability, the tandem
reaction of 1g with 3u for 2 h under the conditions of Table 4
gave 4gu in 69% yield (Scheme 2). In contrast, a reaction with
sequential additions, where arene 3u was added after full
consumption of t-BuOOt-Bu, under conditions similar to the
tandem reaction gave only 26% yield of 4gu, clearly showing
the advantage of the tandem reaction.
Application of the Oxidative Coupling to Synthesis of
Isoquinoline Alkaloids. The present oxidative coupling gives
R-arylalkylamides, which are often observed as substruc-
tures in natural products. We synthesized isoquinoline alka-
loids utilizing an intramolecular oxidative coupling as a key
carbon-carbon bond-forming step (Scheme 3). Although
the oxidative cyclization of 1-[2-(3,4-dimethoxyphenyl)ethyl]-
pyrrolidone (5) under the standard conditions of Table 3 using
t-BuOOt-Bu (3 equiv) scored a low yield probably because of
overoxidation of the amide moiety, the yield/conversion ratio
was greatly improved by reduction of the amount of t-BuOOt-Bu
at the cost of a lower conversion. Cyclization product 6
was transformed to (()-crispine A17 or (()-trolline18 by
reduction with LiAlH4 or demethylation of ethers with BBr3,
respectively.
aThe reaction was carried out at 110 °C under a nitrogen atmosphere
using an arene (3, 0.50 mmol), an amide (1, 3.0 mmol), and t-BuOOt-Bu
(1.5 mmol) in the presence of FeCl3 (15 μmol) in 1,2-dichloroisobutane
(DCB, 2 mL). bYield based on 3. cDetermined by GC, GC-MS, and 1H
NMR. dConducted in 1,2-dichloroethane (DCE) at 90 °C. eAt 100 °C.
fFeCl3 (0.050 mmol). gFeCl3 (0.035 mmol)/Fe(OTf)3 (0.015 mmol).
The low efficiency is ascribed, at least in part, to loss of
coupling product 4du by oxidation at the methylene carbon
adjacent to the amide nitrogen because the carbon atom
becomes more electron-rich upon substitution by the highly
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TABLE 4. Oxidative Coupling of Alkylamides with Arenes Using the
Amides as Solventsa
SCHEME 2. Tandem versus Sequential Additions
SCHEME 3. Application to Synthesis of Isoquinoline Alkaloids
as Cycle A, whereas Cycle B shows the mechanism of the
Friedel-Crafts alkylation. Cycle A starts with abstraction of
H• from 1d by t-BuO•, which is generated in a small amount
•
by thermal homolysis of t-BuOOt-Bu, giving AcN(Me)CH2
(7d). The reaction of 1d with t-BuOOt-Bu is reported to give
AcN(Me)CH2CH2N(Me)Ac through hydrogen radical ab-
straction from 1d by t-BuO• followed by dimerization of
resulting 7d.19 Iron(III) complexes are known to oxidize acyl-
aminomethyl radicals to acyliminium salts.12 Thus, FeCl3
oxidizes 7d to 8d, which readily reacts with t-BuOH to
give tert-butoxyamide 2d and HCl. FeCl2, produced during
transformation of 7d to 8d, reacts with t-BuOOt-Bu, giving
t-BuO• and (t-BuO)FeCl2. The combination of an iron(II)
complex with a peroxy compound is often used in homolytic
aromatic substitution to generate an oxy radical, which
abstracts a hydrogen radical from an organic compound to
give a nucleophilic carbon radical attacking a protonated
N-heteroarene.20 Acid-base reaction between HCl and
(t-BuO)FeCl2 gives FeCl3 and t-BuOH to complete Cycle A.
(17) Zhang, Q.; Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795–
6798.
(18) Wang, R. F.; Yang, X. W.; Ma, C. M.; Cai, S. Q.; Li, J. N.; Shoyama,
Y. Heterocycles 2004, 63, 1443–1448.
aThe reaction was carried out at 120 °C under a nitrogen atmosphere
using an arene (3, 0.25 mmol), an amide (1, 1.0 mL), and t-BuOOt-Bu
(0.75 mmol) in the presence of FeCl3 (25 μmol). bYield based on 3.
cDetermined by GC, GC-MS, and 1H NMR. dFeCl3 (50 μmol) was
used. eAt 100 °C.
(19) The reaction of DMA (1d, 12 equiv) with t-BuOOt-Bu (1 equiv) at
140 °C for 22 h gave AcN(Me)CH2CH2N(Me)Ac (85% yield) through
dimerization of radical 7d. Friedman, L.; Shechter, H. Tetrahedron Lett.
1961, 2, 238–243. The reaction of 1d with 3u using t-BuOOt-Bu (0.75 mmol)
under the same conditions as entry 1 of Table 4 but in the absence of an iron
catalyst gave AcN(Me)CH2CH2N(Me)Ac (0.22 mmol) in addition to 4du
(2% yield) and the corresponding 2-indolyl isomer (5% yield).
(20) (a) Minisci, F.; Citterio, A.; Vismara, E.; Giordano, C. Tetrahedron
1985, 41, 4157–4170. (b) Giordano, C.; Minisci, F.; Vismara, E.; Levi, S.
J. Org. Chem. 1986, 51, 536–537. (c) Minisci, F.; Vismara, E.; Fontana, F.;
Redaelli, D. Gazz. Chim. Ital. 1987, 117, 363–367. See also ref 9b.
Reaction Mechanism. A plausible mechanism of the tan-
dem reaction is shown in Scheme 4. The catalytic cycle of oxi-
dation of alkylamides, exemplified by DMA (1d), is described
J. Org. Chem. Vol. 76, No. 1, 2011 29

Shirakawa et al.
JOCFeatured Article
SCHEME 4. A Plausible Reaction Mechanism
The FeCl3-catalyzed Friedel-Crafts alkylation of arenes
with R-(tert-butoxy)alkylamides (Table 2) should follow the
generally accepted catalytic cycle of Lewis acid-catalyzed
amidoalkylation as shown in Cycle B.2 FeCl3 promotes elim-
ination of the tert-butoxy group to give acyliminium ion
8d,21 which adds to arene 3. Elimination of a proton from
adduct 9 gives 4 with regeneration of FeCl3.
In the tandem reaction consisting of the oxidation and the
Friedel-Crafts alkylation, R-(tert-butoxy)alkylamide 2d
produced through Cycle A is likely to get into Cycle B.
R-(tert-Butoxy)alkylamide 2d is relatively stable and always
observed in the reaction of DMA (1d), and arene 3 is usually
converted to R-arylalkylamide 4 even after full conversion of
t-BuOOt-Bu, showing that 2d is an intermediate. However,
in the reaction of arenes having nucleophilicity higher than
that of t-BuOH, acyliminium salt 8d generated by oxidation
possibly reacts directly with the arene without being trapped
by t-BuOH as shown in the dotted square.
of less than 3, were ineffective as catalysts, whereas FeCl3,
Fe(OTf)3, RuCl3, and Zr(OTf)4 effectively catalyzed the
Friedel-Crafts alkylation. Among the examined transition
metal complexes, only FeCl3 showed high catalytic activities
for both the oxidation and the Friedel-Crafts alkylation. As
a natural consequence, FeCl3 effectively catalyzed the oxi-
dative coupling consisting of these two reactions. The oxi-
dative coupling was found to be applicable to a wide variety
of alkylamides and arenes, including an intramolecular one
that was utilized for synthesis of simple alkaloids. For the
reaction of arenes not having sufficient nucleophilicity, a com-
bination of FeCl3 with Fe(OTf)3, which has higher activity
than FeCl3 in SEAr but poorly catalyzes the oxidation, is
effective. In the reaction of alkylamides that give unstable
R-(tert-butoxy)alkylamides, an advantage of the tandem
reaction in efficient utilization of reactive intermediates
was disclosed in comparison with a common sequential
reaction. Thus, the tandem coupling of N-ethylacetamide with
N-methylindole scored a much higher yield than a reaction
with sequential additions, where the arene was added after
oxidation of the amide was completed.
Conclusion
The oxidative coupling of alkylamides with arenes to give
R-arylalkylamides through a tandem reaction consisting of
oxidation of alkylamides and the Friedel-Crafts alkylation
with the resulting oxidized alkylamides is possible when a
catalyst can promote both reactions. We expected high
valent iron complexes to fulfill the requirement. FeCl3 was
found to be active as a catalyst for oxidation of alkylamides
with t-BuOOt-Bu to give R-(tert-butoxy)alkylamides. FeCl2
and CuCl also showed activities for the oxidation, whereas
Fe(OTf)3, RuCl3, and Zr(OTf)4 failed to catalyze the
tert-butoxylation. On the other hand, for the Friedel-
Crafts alkylation of arenes with R-(tert-butoxy)alkylamides,
metal complexes showed activities according to their Lewis
acidities. FeCl2 and CuCl, both of which have formal charges
Considering the mechanism in homolytic aromatic sub-
stitution, a Fe(II)-Fe(III) catalytic cycle is likely to be opera-
tive in the oxidation. Fe(III) oxidizes an amidomethyl radical,
which is generated by the reaction of an alkylamide and
t-BuO•, to the acyliminium salt, whereas the resulting Fe(II)
is oxidized by t-BuOOt-Bu to give Fe(III) and t-BuO•. The
acyliminium salt is readily converted to R-(tert-butoxy)-
alkylamides. The Friedel-Crafts alkylation is considered
to be catalyzed by a Lewis acidic iron complex, probably in
the Fe(III) state.
Experimental Section
General Remarks. All manipulations of oxygen- and moisture-
sensitive materials were conducted with a standard Schlenk
technique under a nitrogen atmosphere. Nuclear magnetic
resonance spectra (1H, 500 MHz; 13C, 125 MHz) were taken
using tetramethylsilane as an internal standard. Preparative re-
cycling gel permeation chromatography (GPC) was performed
(21) (a) Sasamoto, N.; Dubs, C.; Hamashima, Y.; Sodeoka, M. J. Am.
Chem. Soc. 2006, 128, 14010–14011. (b) Dubs, C.; Hamashima, Y.; Sasamoto,
N.; Seidel, T. M.; Suzuki, S.; Hashizume, D.; Sodeoka, M. J. Org. Chem. 2008,
73, 5859–5871.
30 J. Org. Chem. Vol. 76, No. 1, 2011

Shirakawa et al.
JOCFeatured Article
using chloroform as an eluent. Unless otherwise noted, reagents
were commercially available and used without further purifica-
tion. 1-Phenylindole and 1-(4-ethoxycarbonylphenyl)indole were
prepared according to the literature procedure.22 2-Methoxy-
6-(methoxycarbonyl)naphthalene was prepared by esterification
of the corresponding carboxylic acid with methanol in the presence
of a catalytic amount of H2SO4. N-Ethyl-N-methylacetamide
was prepared by the reaction of acetyl chloride with ethyl-
(methyl)amine in an aqueous solution.
Oxidation of Alkylamides with t-BuOOt-Bu (Table 1). To a
solution of an iron complex (15 μmol) in a solvent specified
in Table 1 (1.0 mL) in a 20 mL Schlenk tube were added
successively an amide (1, 1.5 mmol) and t-BuOOt-Bu (850 μL,
4.5 mmol). After stirring at the temperature for the time both
specified in Table 1, the reaction mixture was diluted with
EtOAc-Et3N (95:5, 100 mL) and passed through a pad of SiO2,
and the solvent was evaporated. The NMR yield was determined
using MeNO2 as an internal standard. For entry 2, purification
with SiO2 column chromatography (hexane/EtOAc/Et3N =
75:20:5) gave 2a.
Electrophilic Aromatic Substitution with r-(tert-Butoxy)alkyl-
amides (Table 2). To a solution of an iron complex (2.5 μmol) in
1,2-dichloroethane (DCE, 1.0 mL) in a 20 mL Schlenk tube were
added successively 1-phenylindole (3m, 0.25 mmol) and an R-(tert-
butoxy)alkylamide (2, 0.30 mmol; for entry 8, 0.38 mmol). After
stirring at the temperature for the time both specified in Table 2, the
reaction mixture was diluted with CHCl3-MeOH (9:1, 100 mL)
and passed through a pad of SiO2. Evaporation of the solvent
followed by purification with PTLC (SiO2) gave the corresponding
product (4).
1-Phenyl-5-(1-phenyl-3-indolyl)-2-pyrrolidone (4am). A white
solid. 1H NMR (500 MHz, CDCl3) δ 2.31-2.36 (m, 1 H),
2.63-2.71 (m, 2 H), 2.81-2.90 (m, 1 H), 5.64-5.66 (m, 1 H),
7.06 (t, J = 7.3 Hz, 1 H), 7.11 (s, 1 H), 7.21 (t, J = 7.8 Hz, 1 H),
7.24-7.27 (m, 3 H), 7.32 (t, J = 7.3 Hz, 1 H), 7.37 (d, J = 7.7 Hz,
2 H), 7.47 (t, J = 7.7 Hz, 2 H), 7.53-7.57 (m, 3 H), 7.68 (d, J =
7.8 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 27.4, 31.5, 57.6,
111.0, 116.8, 119.0, 120.5, 121.9, 122.9, 124.2, 124.8, 125.6,
126.4, 126.6, 128.6, 129.6, 136.7, 138.5, 139.2, 174.6. HRMS
(ESI) calcd for C24H20N2O: [M þ Na]þ, 375.1473. Found:
m/z 375.1467.
5-(tert-Butoxy)-1-phenyl-2-pyrrolidone (2a). A white solid. 1H
NMR (500 MHz, CDCl3) δ 1.02 (s, 9 H), 2.00-2.06 (m, 1 H),
2.37-2.49 (m, 2 H), 2.73-2.82 (m, 1 H), 5.40 (dd, J = 5.9,
1.6 Hz, 1 H), 7.28 (t, J = 7.3 Hz, 1 H), 7.28 (d, J = 7.7 Hz, 2
H), 7.38 (t, J = 7.7 Hz, 2 H). 13C NMR (125 MHz, CDCl3) δ 28.4,
29.3, 29.4, 73.9, 85.9, 127.2, 127.3, 128.8, 137.1, 174.6. HRMS (ESI)
calcd for C14H19NO2: [M þ Na]þ, 256.1313. Found: m/z 256.1307.
5-(tert-Butoxy)-1-methyl-2-pyrrolidone (2b). A colorless liquid.
1H NMR (500 MHz, CDCl3) δ 1.26 (s, 9 H), 1.83-1.90 (m, 1 H),
2.20-2.29 (m, 2 H), 2.49-2.57 (m, 1 H), 2.80 (s, 3 H), 5.01 (dd,
J = 5.9, 2.0 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 26.9, 28.5,
28.7, 28.8, 73.8, 84.8, 174.6. HRMS (ESI) calcd for C9H17NO2:
[M þ Na]þ, 194.1157. Found: m/z 194.1154.
1-Methyl-5-(1-phenyl-3-indolyl)-2-pyrrolidone (4bm).8 A pale
yellow oil. 1H NMR (500 MHz, CDCl3) δ 2.22-2.30 (m, 1 H),
2.47-2.57 (m, 2 H), 2.63-2.70 (m, 1 H), 2.78 (s, 3 H), 4.92 (t, J =
7.0 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 7.26 (s, 1 H), 7.26 (t, J =
8.2 Hz, 1 H), 7.38 (t, J = 7.2 Hz, 1 H), 7.49 (d, J = 8.6 Hz, 2 H),
7.53 (d, J = 8.3 Hz, 2 H), 7.57 (d, J = 7.2 Hz, 1 H), 7.59, (d, J =
6.9 Hz, 1 H).
N-Methyl-N-[(1-phenyl-3-indolyl)methyl]acetamide (4dm). A
colorless liquid. Observed as two rotamers of 68/32 ratio in 1H
NMR. 1H NMR (500 MHz, CDCl3) δ 2.14/2.30 (s, 3 H), 2.97/
3.05 (s, 3 H), 4.82/4.75 (s, 2 H), 7.18-7.37 (m, 4 H), 7.48-7.80
(m, 5 H). For aromatic region, only two peaks were defined.
δ 7.34 (s, 1 H, major isomer), 7.79 (d, J=7.5, 1 H, major isomer).
13C NMR (125 MHz, CDCl3) δ 21.5, 22.0, 33.4, 35.0, 41.4, 46.6,
110.4, 110.8, 112.8, 113.3, 118.7, 119.9, 120.4, 120.5, 122.7,
123.0, 124.1, 124.2, 125.6, 126.4, 126.6, 127.37, 127.44, 128.3,
129.5, 129.6, 136.2, 136.4, 139.3, 139.5, 170.3, 170.7. HRMS
(ESI) calcd for C18H18N2O: [M þ Na]þ, 301.1317. Found: m/z
301.1321.
Iron-Catalyzed Oxidative Coupling of Alkylamides with Arenes
in a Chlorinated Hydrocarbon (Table 3). To a solution of (an) iron
complex(es) in 2.0 mL of 1,2-dichloroethane (DCE) or 1,2-
dichloroisobutane (DCB, 1,2-dichloro-2-methylpropane) in a 20 mL
Schlenk tube were added successively an arene (3, 0.50 mmol), an
amide (1, 3.0 mmol), and t-BuOOt-Bu (280 μL, 1.5 mmol). After
stirring at the temperature for the time both specified in Table 3,
the reaction mixture was diluted with CHCl3/MeOH (9:1,
100 mL) and passed through a pad of SiO2. Evaporation of the
solvent followed by purification with PTLC (SiO2) gave the
corresponding coupling products (4). The product was further
purified with GPC if necessary.
1-(tert-Butoxymethyl)-2-pyrrolidone (2b0).23 A colorless liq-
uid. 1H NMR (500 MHz, CDCl3) δ 1.23 (s, 9 H), 2.01 (quint., J =
7.7 Hz, 2 H), 2.37 (t, J = 8.0 Hz, 2 H), 3.49 (t, J = 7.1 Hz,
2 H), 4.75 (s, 2 H).
5-(tert-Butoxy)-1-(tert-butoxymethyl)-2-pyrrolidone (2b00). A
colorless liquid. 1H NMR (500 MHz, CDCl3) δ 1.23 (s,
9 H), 1.26 (s, 9 H), 1.84-1.90 (m, 1 H), 2.18-2.29 (m, 2 H),
2.50-2.58 (m, 1 H), 4.30 (d, J = 9.7 Hz, 1 H), 5.14 (d, J = 9.7
Hz, 1 H), 5.28 (dd, J = 6.0, 2.0 Hz, 1 H). 13C NMR (125 MHz,
CDCl3) δ 28.0, 28.5, 28.6, 29.3, 63.2, 73.6, 73.8, 80.9, 174.2.
HRMS (ESI) calcd for C13H25NO3: [M þ Na]þ, 266.1732.
Found: m/z 266.1727.
N-(tert-Butoxymethyl)-N-(tert-butyl)acetamide (2c). A color-
less liquid. 1H NMR (500 MHz, CDCl3) δ 1.24 (s, 9 H), 1.44 (s, 9
H), 2.16 (s, 3 H), 4.64 (s, 2 H). 13C NMR (125 MHz, CDCl3)
δ 24.4, 27.7, 28.8, 57.0, 70.3, 72.2, 172.8. HRMS (ESI) calcd for
C11H23NO2: [M þ Na]þ, 224.1627. Found: m/z 224.1619.
N-(tert-Butoxymethyl)-N-methylacetamide (2d). A colorless
liquid. Observed as two rotamers of 57/43 ratio in 1H NMR. 1H
NMR (500 MHz, CDCl3) δ 1.24/1.22 (s, 9 H), 2.14/2.06 (s, 3 H),
2.95/3.00 (s, 3 H), 4.65/4.85 (s, 2 H). 13C NMR (125 MHz,
CDCl3) δ 20.8, 22.0, 27.5, 27.7, 33.0, 33.8, 69.9, 72.6, 73.6, 74.3,
170.6, 171.3. HRMS (ESI) calcd for C8H17NO2: [M þ Na]þ,
182.1151. Found: m/z 182.1145.
1-[(1-Phenyl-3-indolyl)methyl]-2-pyrrolidone (4bm0).8 A pale
yellow oil. 1H NMR (500 MHz, CDCl3) δ 1.95 (quint, J =
7.6 Hz, 1 H), 2.43 (t, J = 8.2 Hz, 2 H), 3.33 (t, J = 7.1 Hz, 1 H),
4.69 (s, 2 H), 7.19 (t, J = 7.0 Hz, 1 H), 7.25 (t, J = 7.1 Hz, 1 H),
7.32 (s, 1 H), 7.36 (t, J = 6.9 Hz, 1 H), 7.48-7.53 (m, 4 H), 7.55
(d, J = 8.2 Hz, 1 H), 7.75 (d, J = 7.8 Hz, 1 H).
N-[Phenyl(1-phenyl-3-indolyl)methyl]acetamide (4em). A yel-
lowish solid. 1H NMR (500 MHz, CDCl3) δ 2.08 (s, 3 H), 6.16
(bs, 1 H), 6.61 (d, J = 8.2 Hz, 1 H), 6.92 (s, 1 H), 7.16 (t, J =
8.0 Hz, 1 H), 7.23-7.37 (m, 3 H), 7.37 (t, J = 7.3 Hz, 2 H),
7.41-7.45 (m, 4 H), 7.48 (d, J = 7.3 Hz, 1 H), 7.48 (t, J = 8.3 Hz,
1 H), 7.54 (d, J = 8.8 Hz, 2 H). 13C NMR (125 MHz, CDCl3)
δ 23.2, 50.1, 110.7, 118.4, 119.7, 120.5, 122.9, 124.2, 126.5, 126.9,
127.0, 127.3, 128.4, 129.5, 136.6, 139.3, 141.1, 169.1. HRMS (ESI)
calcd for C23H20N2O: [M þ Na]þ, 363.1473. Found: m/z 363.1474.
N,N-Di(tert-butoxymethyl)acetamide (2d00). A colorless liquid.
1H NMR (500 MHz, CDCl3) δ 1.23 (s, 9 H), 1.26 (s, 9 H), 2.16 (s, 3
H), 4.72 (s, 2 H), 4.89 (s, 2 H). 13C NMR (125 MHz, CDCl3)
δ 21.5, 27.7, 27.9, 67.7, 70.2, 72.8, 73.7, 171.6. HRMS (ESI) calcd
for C12H25NO3: [M þ Na]þ, 254.1732. Found: m/z 254.1717.
(22) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727–7729. (b) Klapars, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421–7428.
(23) Zezza, C. A.; Kwon, T. W.; Sheu, J.; Smith, M. B. Heterocycles 1992,
34, 1325–1342.
J. Org. Chem. Vol. 76, No. 1, 2011 31

Shirakawa et al.
JOCFeatured Article
N-[Phenyl(1-phenyl-3-indolyl)methyl]benzamide (4fm). A white
solid. 1H NMR (500 MHz, CDCl3) δ 6.79 (bs, 2 H), 6.94 (s, 1 H),
7.17 (t, J = 7.5 Hz, 1 H), 7.26 (t, J = 7.7 Hz, 1 H), 7.30-7.53 (m,
13 H), 7.56 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 8.1 Hz, 1 H), 7.84
(d, J = 7.4 Hz, 2 H). 13C NMR (125 MHz, CDCl3) δ 50.8, 110.8,
118.3, 119.7, 120.7, 123.0, 124.4, 126.7, 127.0, 127.1, 127.3, 127.36,
127.44, 128.59, 128.60, 129.6, 131.6, 134.4, 136.7, 139.3, 141.1,
166.5. HRMS (ESI) calcd for C28H22N2O: [M þ Na]þ, 425.1630.
Found: m/z 425.1612.
FIGURE 1. NOE analysis (irradiation to the major rotamers).
N-{[1-(4-Ethoxycarbonylphenyl)-3-indolyl]methyl}-N-methyl-
acetamide (4dn). A yellow oil. Observed as two rotamers of 65/35
ratio in 1H NMR. 1H NMR (500 MHz, CDCl3) δ 1.43/1.43 (t,
J = 7.1/7.1 Hz, 3 H), 2.14/2.28 (s, 3 H), 2.98/3.04 (s, 3 H), 4.42/
4.43 (q, J = 7.1/7.1 Hz, 2 H), 4.80/4.75 (s, 2 H), 7.37/7.23 (s,
1 H), 7.21/7.23 (t, J = 7.6/7.6 Hz, 1 H), 7.27/7.31 (t, J = 7.7/7.7
Hz, 1 H), 7.58/7.56 (d, J = 8.6/8.1 Hz, 2 H), 7.62/7.58 (d, J =
8.3/8.3 Hz, 1 H), 7.78/7.64 (d, J = 7.8/8.4 Hz, 1 H), 8.19/8.21
(d, J = 8.6/8.1 Hz, 2 H). 13C NMR (125 MHz, CDCl3) δ 14.3, 21.5,
21.9, 33.4, 35.1, 41.4, 46.6, 61.07, 61.12, 110.5, 110.9, 114.1, 114.5,
119.0, 120.1, 121.0, 121.1, 123.0, 123.1, 123.2, 123.5, 124.9, 126.8,
127.8, 127.9, 128.2, 128.7, 131.1, 131.2, 135.7, 136.0, 143.0, 143.2,
165.7, 165.8, 170.3, 170.7. HRMS (ESI) calcd for C21H22N2O3: [M
þ Na]þ, 373.1523. Found: m/z 373.1520.
2.24 (s, 3 H), 2.46 (q, J = 7.2 Hz, 2 H), 3.57 (s, 2 H), 3.86 (s, 3 H),
6.00 (d, J = 3.7 Hz, 1 H), 6.49 (d, J = 3.7 Hz, 1 H). 13C NMR
(125 MHz, CDCl3) δ 12.3, 41.3, 50.4, 56.6, 60.1, 102.7, 123.1,
128.4, 165.8. GC-MS m/z: 185, 127.
3,5-Bis(N-acetyl-N-methylaminomethyl)-2-methoxythiophene
(4do00). A pale yellow oil. Each component was observed as a set
1
1
of 4-7 peaks in H NMR due to existence of 4 rotamers. H
NMR (500 MHz, CDCl3) δ 2.09/2.10/2.11/2.19 (s, 6 H), 2.89/
2.91/2.92/2.93/2.95/2.97 (s, 6 H), 3.87/3.888/3.892 (s, 3 H), 4.27/
4.28/4.37/4.44/4.48/4.49/4.51 (s, 4 H), 6.48/6.50/6.62/6.63 (s, 1
H). 13C NMR (125 MHz, CDCl3) δ 21.6, 21.8, 21.9, 29.7, 33.0,
33.1, 33.2, 35.3, 35.4, 35.56, 35.63, 41.6, 41.7, 46.0, 46.5, 50.19,
50.22, 61.6, 61.8, 62.1, 67.1, 114.9, 116.0, 117.1, 124.0, 124.8,
125.4, 125.6, 125.8, 126.0, 126.5, 161.5, 162.2, 170.2, 170.49,
170.54, 170.56, 170.58, 170.59. HRMS (ESI) calcd for C13H20-
N2O3S: [M þ Na]þ, 307.1087. Found: m/z 307.1099.
N-[(5-Methoxy-2-thienyl)methyl]-N-methylacetamide (4do).
A colorless oil. Observed as two rotamers of 65/35 ratio in
1
1H NMR. H NMR (500 MHz, CDCl3) δ 2.10/2.19 (s, 3 H),
2.96/2.93 (s, 3 H), 3.84/3.86 (s, 3 H), 4.53/4.47 (s, 2 H), 6.00/6.03
(d, J = 3.8/3.8 Hz, 1 H), 6.57/6.53 (d, J = 3.8/3.8 Hz, 1 H). 13
C
N-[(2,4-Dimethoxylphenyl)methyl]-N-methylacetamide (4dp).
A pale brown oil. Observed as two rotamers of 63/37 ratio in
NMR (125 MHz, CDCl3) δ 21.5, 21.8, 33.0, 35.2, 46.3, 50.2,
60.2, 60.3, 102.8, 103.1, 123.2, 124.2, 125.4, 125.9, 166.0, 166.3,
170.3, 170.4. HRMS (ESI) calcd for C9H13NO2S: [M þ Na]þ,
222.0559. Found: m/z 222.0553.
1
1H NMR. H NMR (500 MHz, CDCl3) δ 2.15/2.11 (s, 3 H),
2.88/2.93 (s, 3 H), 3.80/3.79 (s, 3 H), 3.805/3.797 (s, 3 H), 4.41/
4.53 (s, 2 H), 6.45/6.44 (d/dd, J = 8.5/8.8, 2.3 Hz, 1 H), 6.46/6.44
(s/d, J = 2.3 Hz, 1 H), 6.95/7.14 (d, J = 8.5/8.8 Hz, 1 H). 13
N-[(2-Methoxy-3-thienyl)methyl]-N-methylacetamide (4do0).
This product could not be isolated in a pure form. The fol-
lowing data were obtained from spectra of a mixture with 4do
(4do:4do0 = 53:47). 4do0 was observed as two rotamers of 55/45
ratio in 1H NMR. 1H NMR (400 MHz, CDCl3) δ 2.08/2.19 (s,
3 H), 2.91/2.89 (s, 3 H), 3.91/3.92 (s, 3 H), 4.44/4.33 (s, 2 H), 6.55/
6.59 (d, J = 5.9/5.9 Hz, 1 H), 6.75/6.65 (d, J = 5.8/5.9 Hz, 1 H).
GC-MS m/z: 199, 184, 156, 142, 127, 99. These ions were
observed also in the GC-MS of 4do, which appears later than
4do0 on GC.
C
NMR (125 MHz, CDCl3) δ 21.3, 21.9, 33.3, 35.8, 44.7, 49.5,
55.2, 55.31, 55.34, 55.4, 98.3, 98.6, 103.9, 104.2, 116.9, 118.0,
128.1, 130.4, 158.2, 158.5, 160.1, 160.5, 170.7, 171.2. HRMS
(ESI) calcd for C12H17NO3: [M þ Na]þ, 246.1101. Found: m/z
246.1103.
N-[(2,6-Dimethoxylphenyl)methyl]-N-methylacetamide (4dp0).
A pale brown solid. This product could not be isolated in a
pure form, being contaminated with 4dp (4dp0:4dp = 93:7). 4dp0
was observed as two rotamers of 80/20 ratio in 1H NMR.
1H NMR (500 MHz, CDCl3) δ 2.30/2.08 (s, 3 H), 2.73/2.73
(s, 3 H), 3.82/3.81 (s, 6 H), 4.54/4.72 (s, 2 H), 6.56/6.55 (d, J =
8.4/8.3 Hz, 2 H), 7.24/7.23 (t, J = 8.4/8.3 Hz, 1 H). 13C NMR
(125 MHz, CDCl3) δ 21.5, 29.7, 31.4, 38.4, 42.4, 55.6, 55.8,
103.60, 103.63, 112.3, 112.8, 129.0, 129.5, 159.0, 159.4. HRMS
(ESI) calcd for C12H17NO3: [M þ Na]þ, 246.1101. Found: m/z
246.1089.
The above two compounds (4do and 4do0) were characterized
as follows. The aromatic methyne protons of 2-methoxythio-
phene appear in 1H NMR at 6.19 ppm (dd, J = 3.8, 1.5 Hz, C-3),
6.52 ppm (dd, J = 5.8, 1.5 Hz, C-5), and 6.70 ppm (dd, J = 5.8,
3.8 Hz, C-4),24 which are reported not to change largely upon
introduction of aminomethyl25,14c or alkyl26,27 groups into the
thiophene ring. NOE analysis (Figure 1) of 4do and 4do0 shows
that both of these have two adjacent methyne protons on the
thiophene ring and that the methyne proton at 6.00 ppm and the
methoxy group in 4do are located next to each other. These
observations imply that 4do and 4do0 have an acylaminomethyl
group at C-5 and C-3, respectively. In addition, 1H NMR of the
reduction product (LiAlH4, Et2O, 40 °C, 4.5 h, 74% yield) of 4do
is similar to that of 2-(N-benzyl-N-methylaminomethyl)-5-
methoxythiophene [δ 2.22 (s, 3 H), 3.53 (s, 2 H), 3.59 (s, 2 H),
3.87 (s, 3 H), 6.00 (d, J = 3.2 Hz, 1 H), 6.51 (d, J = 3.2 Hz, 1 H),
7.20-7.40 (m, 5 H)],26 being consistent with the above deter-
mined structure of 4do.
1,5-Bis(N-acetyl-N-methylaminomethyl)-2,4-dimethoxybenzene
(4dp00). A white solid. Each component was observed as a set
1
1
of 2-4 peaks in H NMR due to existence of 3 rotamers. H
NMR (500 MHz, CDCl3) δ 2.11/2.17/2.18 (s, 6 H), 2.82/2.91/
2.92 (s, 6 H), 3.82/3.83/3.84/3.85 (s, 6 H), 4.38/4.40/4.52 (s, 4 H),
6.42/6.44/6.46 (s, 1 H), 6.77/6.88/6.94 (s, 1 H). 13C NMR (125
MHz, CDCl3) δ 21.3, 21.8, 21.9, 29.6, 32.8, 32.9, 35.8, 35.9,
44.92, 44.94, 49.50, 49.52, 55.37, 55.44, 55.57, 55.58, 94.78,
94.81, 95.0, 116.0, 116.1, 117.0, 128.6, 129.7, 130.2, 157.6,
157.8, 158.1, 158.2, 170.7 (broad), 171.0 (broad). HRMS (ESI)
calcd for C16H24N2O4: [M þ Na]þ, 331.1628. Found: m/z
331.1614.
2-(N-Ethyl-N-methylaminomethyl)-5-methoxythiophene. A col-
orless oil. 1H NMR (500 MHz, CDCl3) δ 1.08 (t, J = 7.2 Hz, 3 H),
N-[(2-Methoxy-6-methoxycarbonyl-1-naphthyl)methyl]-N-
methylacetamide (4dq). A white solid. Observed as two
rotamers of 84/16 ratio in 1HNMR. 1H NMR(500MHz, CDCl3)
δ 2.10/2.41 (s, 3 H), 2.72/2.62 (s, 3 H), 3.95/3.97 (s, 3 H), 4.00/
4.00 (s, 3 H), 5.16/4.96 (s, 2 H), 7.34/7.36 (d, J = 9.1/9.0 Hz,
1 H), 7.94/7.96 (d, J = 9.1/9.0 Hz, 1 H), 8.05/7.99 (d, J = 8.9/
9.1 Hz, 1 H), 8.15/8.09 (d, J = 9.1/8.8 Hz, 1 H), 8.53/8.58
(24) Satonaka, H. Bull. Chem. Soc. Jpn. 1983, 56, 2463–2468.
(25) Heaney, H.; Papageorgiou, G.; Wilkins, R. F. Tetrahedron 1997, 53,
2941–2958.
(26) Pedersen, E. B.; Lawesson, S.-O. Tetrahedron 1971, 27, 3861–3868.
(27) Chunchatprasert, L.; Shannon, P. V. R. J. Chem. Res. (M) 1999,
1542–1560.
32 J. Org. Chem. Vol. 76, No. 1, 2011

Shirakawa et al.
JOCFeatured Article
(s, 1 H). 13C NMR (125 MHz, CDCl3) δ 21.8, 21.9, 30.7, 33.7,
39.0, 43.7, 52.0, 52.1, 56.1, 56.3, 113.2, 113.3, 116.2, 117.8,
122.1, 124.3, 125.1, 125.3, 126.5, 126.6, 127.8, 128.0, 131.4,
131.5, 131.98, 132.01, 135.67, 135.72, 157.4, 157.9, 166.9,
167.2, 170.3, 170.8. HRMS (ESI) calcd for C17H19NO4:
[M þ Na]þ, 324.1212. Found: m/z 324.1194.
4.76/4.69 (s, 2 H), 7.18/7.06 (d, J = 2.4/2.3 Hz, 1 H), 7.13/7.15
(t, J = 7.5/7.5 Hz, 1 H), 7.21/7.24 (t, J = 7.6/7.6 Hz, 1 H), 7.37/
7.41 (d, J = 8.1/8.2 Hz, 1 H), 7.72/7.53 (d, J = 7.9/7.9 Hz, 1 H),
8.18/8.29 (bs, 1 H).
N-Methyl-N-[(5-pentyl-2-furyl)methyl]acetamide (4dw). A pale
yellow oil. Observed as two rotamers of 52/48 ratio in 1H
NMR. 1H NMR (500 MHz, CDCl3) δ 0.85-0.94 (m, 3 H),
1.27-1.38 (m, 4 H), 1.61/1.61 (quint, J = 7.3/7.3 Hz, 2 H), 2.22/
2.10 (s, 3 H), 2.57/2.57 (t, J = 7.6/7.6 Hz, 2 H), 2.98/2.93 (s, 3 H),
4.36/4.51 (s, 2 H), 5.90/5.89 (d, J = 3.1/2.9 Hz, 1 H), 6.08/6.11 (d,
J = 3.1/2.9 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 13.92,
13.94, 21.5, 21.8, 22.30, 22.33, 27.5, 27.6, 27.9, 28.0, 31.29, 31.30,
33.2, 35.4, 43.3, 47.6, 105.18, 105.24, 108.4, 108.8, 148.0, 149.0,
156.4, 156.9, 170.3, 170.7. HRMS (ESI) calcd for C13H21NO2:
[M þ Na]þ, 246.1465. Found: m/z 246.1475.
N-[(6-Bromo-2-methoxy-1-naphthyl)methyl]-N-methylacetamide
(4dr). A brownish solid. Observed as two rotamers of 87/13 ratio
in 1H NMR. 1H NMR (500 MHz, CDCl3) δ 2.09/2.39 (s, 3 H),
2.72/2.60 (s, 3 H), 3.96/3.95 (s, 3 H), 5.12/4.91 (s, 2 H), 7.29/7.31
(d, J= 9.1/8.7 Hz, 1 H), 7.53/7.56 (d, J= 9.2/9.2 Hz, 1 H), 7.72/7.76
(d, J = 9.1/8.7 Hz, 1 H), 7.91/7.96 (s, 1 H), 8.02/7.79 (d, J = 9.2/9.3
Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 21.8, 21.9, 30.7, 33.8, 39.0,
43.7, 56.2, 56.5, 113.7, 113.8, 116.4, 117.2, 117.6, 118.1, 123.8, 126.2,
127.9, 129.0, 129.5, 130.0, 130.2, 130.4, 130.5, 130.7, 131.9, 132.0,
156.17, 156.23, 170.3, 170.7. HRMS (ESI) calcd for C15H16BrNO2:
[M þ Na]þ, 344.0262. Found: m/z 344.0250.
N-Methyl-N-[(2,4,6-trimethoxyphenyl)methyl]acetamide (4dx).
A white solid. Observed as two rotamers of 80/20 ratio in
1
1H NMR. H NMR (500 MHz, CDCl3) δ 2.26/2.05 (s, 3 H),
N-[(2-Methoxy-1-naphthyl)methyl]-N-methylacetamide (4ds).
A white solid. Observed as two rotamers of 82/18 ratio in
2.70/2.70 (s, 3 H), 3.78/3.77 (s, 6 H), 3.803/3.799 (s, 3 H), 4.43/
4.61 (s, 2 H), 6.11/6.11 (s, 2 H). 13C NMR (125 MHz, CDCl3) δ
21.4, 22.1, 31.1, 33.7, 38.0, 42.1, 55.2, 55.3, 55.5, 55.7, 90.2, 90.3,
104.9, 105.4, 159.7, 160.0, 160.9, 161.1, 170.0, 170.7. HRMS
(ESI) calcd for C13H19NO4: [M þ Na]þ, 276.1206. Found: m/z
276.1203.
1
1H NMR. H NMR (500 MHz, CDCl3) δ 2.11/2.42 (s, 3 H),
2.73/2.63 (s, 3 H), 3.966/3.959 (s, 3 H), 5.17/4.96 (s, 2 H), 7.29/
7.30 (d, J = 8.4/8.4 Hz, 1 H), 7.35/7.37 (t, J = 7.6/7.6 Hz,
1 H), 7.50/7.52 (t, J = 7.4/7.4 Hz, 1 H), 7.78/7.82 (d, J =
8.2/8.2 Hz, 1 H), 7.83/7.87 (d, J = 9.0/9.0 Hz, 1 H), 8.11/7.92
(d, J = 8.7/8.7 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 21.9,
22.0, 30.6, 33.6, 39.0, 43.7, 56.1, 56.4, 112.7, 112.8, 115.9, 117.6,
121.9, 123.5, 123.7, 124.0, 127.1, 127.2, 128.1, 128.75, 128.82,
129.0, 129.9, 130.3, 133.3, 133.4, 155.9, 156.0, 170.4 (broad).
HRMS (ESI) calcd for C15H17NO2: [M þ Na]þ, 266.1151.
Found: m/z 266.1138.
2,4-Bis(N-acetyl-N-methylaminomethyl)-1,3,5-trimethoxyben-
zene (4dx00). A white solid. Each component was observed as a
set of 2-4 peaks in 1H NMR due to existence of 3 rotamers. 1H
NMR (500 MHz, CDCl3) δ2.06/2.07/2.27/2.28 (s, 6 H), 2.68/2.69/
2.70 (s, 6 H), 3.64/3.66 (s, 3 H), 3.817/3.824/3.830 (s, 6 H), 4.45/
4.46/4.65/4.66 (s, 4 H), 6.28/6.29 (s, 1 H). 13C NMR (125 MHz,
CDCl3) δ 21.5, 22.0, 22.1, 31.15, 31.17, 33.68, 33.71, 38.5, 38.6,
43.0, 55.5, 55.6, 55.71, 55.74, 62.2, 62.6, 63.1, 91.29, 91.31,
91.5, 109.9, 110.1, 110.3, 110.5, 159.4, 159.6, 159.7, 159.86,
159.90, 160.3, 160.7, 170.2, 170.3, 170.7, 170.8. HRMS (ESI) calcd
for C17H26N2O5: [M þ Na]þ, 361.1734. Found: m/z 361.1727.
N-[1-(1-Methyl-3-indolyl)ethyl]acetamide (4gu). A brownish
solid. 1H NMR (500 MHz, CDCl3) δ 1.63 (d, J = 6.8 Hz, 3 H),
1.96 (s, 3 H), 3.76 (s, 3 H), 5.46 (quint, J = 6.8 Hz, 1 H), 5.68 (bs,
1 H), 6.99 (s, 1 H), 7.13 (t, J = 7.4 Hz, 1 H), 7.26 (t, J = 7.6 Hz,
1 H), 7.31 (d, J = 8.2 Hz, 1 H), 7.65 (d, J = 7.9 Hz, 1 H).
13C NMR (125 MHz, CDCl3) δ 20.5, 23.5, 32.7, 41.9, 109.4,
116.7, 119.3, 119.5, 122.1, 126.0, 126.3, 137.3, 169.0. HRMS (ESI)
calcd for C13H16N2O: [M þ Na]þ, 239.1155. Found: m/z 239.1165.
N-[1-(2,4,6-Trimethoxyphenyl)ethyl]acetamide (4gx). A col-
orless oil. Observed as two rotamers of 94/6 ratio in 1H NMR.
1H NMR (500 MHz, CDCl3) δ 1.34/1.45 (d, J = 6.8/6.8 Hz, 3
H), 1.93/2.04 (s, 3 H), 3.79/3.79 (s, 3 H), 3.84/3.83 (s, 6 H), 5.76/
5.18 (dq, J = 9.5, 6.8/10.3, 6.8 Hz, 1 H), 6.13/6.12 (s, 2 H), 6.83/
6.83 (d, J=8.8/8.8 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ
20.9, 21.2, 23.6, 28.5, 29.6, 40.2, 44.2, 55.2, 55.6, 55.7, 90.7, 91.0,
111.2, 111.6, 157.9, 158.3, 160.1, 160.3, 168.5 (broad). HRMS
(ESI) calcd for C13H19NO4: [M þ Na]þ, 276.1206. Found: m/z
276.1203.
N-[(2-Methoxy-5-methylphenyl)methyl]-N-methylacetamide
(4dt). A pale yellow oil. Observed as two rotamers of 62/38
ratio in 1H NMR. 1H NMR (500 MHz, CDCl3) δ 2.13/2.15 (s,
3 H), 2.28/2.26 (s, 3 H), 2.93/2.95 (s, 3 H), 3.81/3.79 (s, 3 H),
4.46/4.59 (s, 2 H), 6.78/6.76 (d, J = 8.4/8.2 Hz, 1 H), 6.85/6.99
(s, 1 H), 7.06/7.02 (d, J = 8.4/8.2 Hz, 1 H). 13C NMR (125
MHz, CDCl3) δ 20.47, 20.52, 21.3, 21.8, 33.6, 35.9, 45.0, 49.7,
55.2, 55.4, 110.1, 110.3, 124.2, 125.1, 127.6, 128.6, 128.8, 129.8, 129.86,
129.89, 155.0, 155.5, 170.7, 171.3. HRMS (ESI) calcd for C12H17NO2:
[M þ Na]þ, 230.1157. Found: m/z 230.1143.
Iron-Catalyzed Oxidative Coupling of Alkylamides with Arenes
Using the Amides as Solvents (Table 4). To a solution of FeCl3
(4.1 mg, 25 μmol) in an amide (1, 1.0 mL) in a 20 mL Schlenk
tube were added successively an arene (3, 0.25 mmol) and
t-BuOOt-Bu (140 μL, 0.75 mmol). After stirring at 120 °C for the
time specified in Table 4, the reaction mixture was diluted with
CHCl3-MeOH (9:1, 100 mL) and passed through a pad of SiO2.
Evaporation of the solvent and the amide followed by purification
with PTLC (SiO2) gave the corresponding coupling products (4). The
products were further purified with GPC if necessary.
N-Methyl-N-[(1-methyl-3-indolyl)methyl]acetamide (4du).28
1
A yellow oil. Observed as two rotamers of 65/35 ratio in H
NMR. 1H NMR (500 MHz, CDCl3) δ 2.11/2.26 (s, 3 H), 2.91/
2.98 (s, 3 H), 3.76/3.78 (s, 3 H), 4.73/4.67 (s, 2 H), 7.04/6.91 (s,
1 H), 7.12/7.14 (t, J = 7.3/7.5 Hz, 1 H), 7.24/7.25 (t, J = 7.9/8.3
Hz, 1 H), 7.30/7.33 (d, J = 8.3/8.2 Hz, 1 H), 7.70/7.52
(d, J = 7.9/8.1 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 21.5,
21.9, 32.6, 32.7, 33.2, 34.9, 41.4, 46.6, 109.1, 109.5, 110.0, 110.6,
118.5, 119.2, 119.4, 119.5, 121.7, 122.0, 126.5, 126.6, 127.3,
128.5, 137.0, 137.2, 170.1, 173.9. HRMS (ESI) calcd for
C13H16N2O: [M þ Na]þ, 239.1155. Found: m/z 239.1154.
N-(3-Indolylmethyl)-N-methylacetamide (4dv).29 A pale yel-
low oil. Observed as two rotamers of 65/35 ratio in 1H NMR. 1H
NMR (500 MHz, CDCl3) δ 2.12/2.26 (s, 3 H), 2.91/2.99 (s, 3 H),
N-Ethyl-N-[(1-methyl-3-indolyl)methyl]acetamide (4hu).Abrown-
1
1
ish oil. Observed as two rotamers of 64/36 ratio in H NMR. H
NMR (500 MHz, CDCl3) δ 1.15/1.12 (t, J = 7.1/7.1 Hz, 3 H), 2.13/
2.21 (s, 3 H), 3.27/3.47 (q, J = 7.1/7.1 Hz, 2 H), 3.76/3.77 (s, 3 H),
4.73/4.66 (s, 2 H), 7.05/6.89 (s, 1 H), 7.12/7.14 (t, J= 7.4/7.4 Hz, 1 H),
7.23/7.27 (t, J = 7.6/7.6 Hz, 1 H), 7.29/7.33 (d, J = 8.3/
8.2 Hz, 1 H), 7.68/7.52 (d, J = 7.8/8.0 Hz, 1 H). 13C NMR (125
MHz, CDCl3) δ 12.8, 13.5, 21.5, 21.8, 32.6, 32.8, 38.4, 40.2, 41.5,
44.1, 109.1, 109.5, 110.6, 111.0, 118.5, 119.26, 119.33, 119.4, 121.7,
122.1, 126.6, 127.0, 127.4, 128.6, 136.9, 137.3, 169.8, 170.3. HRMS
(ESI) calcd for C14H18N2O: [M þ Na]þ, 253.1311. Found: m/z
253.1302.
N-Methyl-N-[1-(1-methyl-3-indolyl)ethyl]acetamide (4hu0).
This product could not be isolated in a pure form. The fol-
lowing data were obtained from spectra of a mixture with 4hu
(28) Ikeda, K.; Morimoto, T.; Sekiya, M. Chem. Pharm. Bull. 1980, 28,
1178–1182.
(29) Pedras, M. S. C.; Minic, Z.; Jha, M. FEBS J. 2008, 275, 3691–3705.
J. Org. Chem. Vol. 76, No. 1, 2011 33

Shirakawa et al.
JOCFeatured Article
1
(4hu:4hu0 = 91:9). In H NMR, several peaks of the aromatic
3-[(2,4,6-Trimethoxyphenyl)methyl]-1,3-oxazolidin-2-one (4ix0).
A white solid. 1H NMR (500 MHz, CDCl3) δ 3.32 (t, J = 8.1 Hz,
2 H), 3.80 (s, 6 H), 3.82 (s, 3 H), 4.18 (t, J = 8.1 Hz, 2 H), 4.47
(s, 2 H), 6.12 (s, 2 H). 13C NMR (125 MHz, CDCl3) δ 36.2,
43.8, 55.3, 55.7, 61.6, 90.3, 104.0, 158.1, 159.9, 161.3. HRMS (ESI)
calcd for C13H17NO5: [M þ Na]þ, 290.0999. Found: m/z 290.0990.
Synthesis of (()-Crispine and (()-Trolline (Scheme 3). To a
solution of FeCl3 (1.2 mg, 7.4 μmol) in 1,2-dichloroisobutane
(DCB, 1,2-dichloro-2-methylpropane, 0.50 mL) and t-BuOH
(0.50 mL) in a 20 mL Schlenk tube were added N-[2-(3,4-
dimethoxyphenyl)ethyl]-2-pyrrolidone31 (5, 187 mg, 0.750 mmol)
and t-BuOOt-Bu (the amount specified in Scheme 3). After
stirring at 110 °C for the time specified in Scheme 3, the reaction
mixture was diluted with CHCl3-MeOH (9:1, 100 mL) and
passed through a pad of SiO2. Evaporation of the solvent
followed by purification with PTLC (SiO2, CHCl3/MeOH =
95/5) and GPC gave 8,9-dimethoxy-1,5,6,10b-tetrahydro-2H-
pyrrolo[2,1-a]isoquinolin-3-one (6) as a pale brown solid.32,33
MP: 108-109 °C (Et2O). 1H NMR (500 MHz, CDCl3) δ 1.75-
1.88 (m, 1 H), 2.40-2.48 (m, 1 H), 2.51-2.72 (m, 3 H),
2.82-2.93 (m, 1 H), 3.00 (td, J = 12.2, 4.4 Hz, 1 H), 3.847
(s, 3 H), 3.854 (s, 3 H), 4.29 (ddd, J = 12.9, 6.1, 2.0 Hz, 1 H), 4.71
(t, J = 7.9 Hz, 1 H), 6.56 (s, 1 H), 6.61 (s, 1 H).
To a suspension of LiAlH4 (10.4 mg, 0.274 mmol) in THF
(0.50 mL) in a 20 mL Schlenk tube was added dropwise a
solution of 6 (61.8 mg, 0.250 mmol) in THF (1.0 mL) at 0 °C.
After stirring at 40 °C for 4 h, the reaction mixture was quenched
with H2O (20 mL) and extracted with EtOAc (30 mL ꢀ 3). The
combined organic layer was dried over MgSO4. Evaporation of
the solvent followed by purification with PTLC (SiO2, EtOAc/
Et3N = 95/5) gave (()-crispine A (55.4 mg, 95% yield) as a pale
yellow solid.17 MP: 90-91 °C (Et2O). 1H NMR (500 MHz,
CDCl3) δ 1.67-1.78 (m, 1 H), 1.80-2.00 (m, 2 H), 2.27-
2.37 (m, 1 H), 2.54-2.62 (m, 1 H), 2.62-2.69 (m, 1 H), 2.69-
2.77 (m, 1 H), 2.96-3.09 (m, 2 H), 3.13-3.19 (m, 1 H), 3.45
(t, J = 8.2 Hz, 1 H), 3.83 (s, 3 H), 3.84 (s, 3 H), 6.56 (s, 1 H), 6.60
(s, 1 H).
region (3 protons of the benzene ring of the indole) of 4hu0,
which was observed as two rotamers of 70/30 in 1H NMR, could
not be read because they are not sufficiently separated from
those of 4hu. In 13C NMR, many peaks could not be detected.
1H NMR (500 MHz, CDCl3) δ 1.49/1.61 (d, J = 6.8/6.8 Hz,
3 H), 1.94/2.35 (s, 3 H), 2.61/2.63 (s, 3 H), 3.76/3.75 (s, 3 H), 6.29/
5.30 (q, J = 6.8/6.8 Hz, 1 H), 6.95/6.91 (s, 1 H), 7.54/7.41 (d, J =
7.9/7.8 Hz, 1 H). 13C NMR (125 MHz, CDCl3) δ 14.8, 16.4,
22.4, 23.3, 29.6, 44.2, 109.0, 109.4, 119.8, 122.0, 122.1, 126.5.
GC-MS gave no information as 4hu and 4hu0 have the same
retention time on GC.
1-Methyl-5-(1-methyl-3-indolyl)-2-pyrrolidone (4bu).8 A white
solid. 1H NMR (500 MHz, CDCl3) δ 2.14-2.23 (m, 1 H),
2.40-2.56 (m, 2 H), 2.60-2.68 (m, 1 H), 2.71 (s, 3 H), 3.78 (s,
3 H), 4.84 (t, J = 7.2 Hz, 1 H), 6.97 (s, 1 H), 7.12 (t, J = 7.5 Hz,
1 H), 7.27 (t, J=7.6 Hz, 1 H), 7.34 (d, J=8.3 Hz, 1 H), 7.52 (d, J =
8.0 Hz, 1 H).
1-[(1-Methyl-3-indolyl)methyl]-2-pyrrolidone (4bu0).8 A pale
1
yellow oil. H NMR (500 MHz, CDCl3) δ 1.91 (quint, J =
7.4 Hz, 2 H), 2.41 (t, J = 8.0 Hz, 2 H), 3.27 (t, J = 7.1 Hz, 2 H),
3.77 (s, 3 H), 4.62 (s, 2 H), 7.03 (s, 1 H), 7.13 (t, J = 7.4 Hz, 1 H),
7.24 (t, J = 7.6 Hz, 1 H), 7.30 (d, J = 8.2 Hz, 1 H), 7.67 (d, J =
7.9 Hz, 1 H).
1-Methyl-5-(2,4,6-trimethoxyphenyl)-2-pyrrolidinone (4bx).30
1
A white solid. H NMR (500 MHz, CDCl3) δ 1.97-2.07 (m,
1 H), 2.25-2.36 (m, 1 H), 2.38-2.47 (m, 1 H), 2.53 (s, 3 H),
2.53-2.63 (m, 1 H), 3.77 (bs, 3 H), 3.81 (s, 6 H), 5.23 (dd, J =
9.6, 4.6 Hz, 1 H), 6.12 (s, 2 H). 13C NMR (125 MHz, CDCl3)
δ 23.7, 27.4, 31.2, 54.0, 55.3, 55.8, 90.6 (broad), 108.5, 159.8
(broad), 160.9, 175.4. HRMS (ESI) calcd for C14H19NO4: [M þ
Na]þ, 288.1206. Found: m/z 288.1201.
1-[(2,4,6-Trimethoxyphenyl)methyl]-2-pyrrolidinone (4bx0).
A white solid. 1H NMR (500 MHz, CDCl3) δ 1.87 (quint, J =
7.5 Hz, 2 H), 2.36 (t, J = 8.1 Hz, 2 H), 3.12 (t, J = 7.0 Hz, 2 H),
3.79 (s, 6 H), 3.82 (s, 3 H), 4.48 (s, 2 H), 6.12 (s, 2 H). 13C NMR
(125 MHz, CDCl3) δ 17.7, 31.4, 34.6, 46.1, 55.3, 55.7, 90.3,
104.7, 159.9, 161.0, 174.2. HRMS (ESI) calcd for C14H19NO4:
[M þ Na]þ, 288.1206. Found: m/z 288.1202.
To a solution of 6 (49.5 mg, 0.200 mmol) in CH2Cl2 (0.20 mL)
was added BBr3 (1.0 M in CH2Cl2, 1.0 mL, 1.0 mmol) at -20 °C.
After stirring for 18 h at -20 °C, the reaction mixture was quenched
with MeOH (5.0 mL), and the solvent was evaporated under the
reduced pressure. The MeOH addition/evaporation process was
repeated 5 times. The residue was washed with a small amount
(0.50 mL) of MeOH to give (()-trolline (42.0 mg, 96% yield) as a
3-Methyl-4-(1-methyl-3-indolyl)-1,3-oxazolidin-2-one (4iu).
1
A pale yellow solid. H NMR (500 MHz, CDCl3) δ 2.71 (s,
3 H), 3.80 (s, 3 H), 4.36 (dd, J = 8.8, 7.7 Hz, 1 H), 4.60 (t, J =
8.8 Hz, 1 H), 4.97 (dd, J = 8.8, 7.7 Hz, 1 H), 7.09 (s, 1 H), 7.15
(t, J = 7.4 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.36 (d, J = 8.3 Hz,
1 H), 7.60 (d, J = 7.9 Hz, 1 H). 13C NMR (125 MHz, CDCl3)
δ 28.9, 32.9, 55.4, 68.4, 109.8, 110.3, 118.9, 120.0, 122.5, 125.3,
128.3, 137.7, 158.4. HRMS (ESI) calcd for C13H14N2O2: [M þ
Na]þ, 253.0947. Found: m/z 253.0938.
white solid.18,34 MP: 252 °C dec (MeOH). H NMR (500 MHz,
1
DMSO-d6) δ 1.49-1.65 (m, 1 H), 2.18-2.26 (m, 1 H), 2.35-2.45
(m, 1 H), 2.50-2.64 (m, 3 H), 2.84-2.96 (m, 1 H), 3.93-3.99 (m,
1 H), 4.57 (t, J = 7.8 Hz, 1 H), 6.49 (s, 1 H), 6.51 (s, 1 H).
3-[(1-Methyl-3-indolyl)methyl]-1,3-oxazolidin-2-one (4iu0). An
orange oil. 1H NMR (500 MHz, CDCl3) δ 3.42 (t, J = 8.0 Hz,
2 H), 3.78 (s, 3 H), 4.22 (t, J = 8.0 Hz, 2 H), 4.61 (s, 2 H), 7.06 (s, 1
H), 7.15 (t, J = 7.5 Hz, 1 H), 7.26 (t, J = 7.5 Hz, 1 H), 7.32 (d, J =
8.2 Hz, 1 H), 7.69 (d, J = 7.9 Hz, 1 H). 13C NMR (125 MHz,
CDCl3) δ 32.8, 39.3, 43.9, 61.6, 109.0, 109.4, 119.1, 119.7, 122.1,
127.3, 128.5, 137.1, 158.3. HRMS (ESI) calcd for C13H14N2O2:
[M þ Na]þ, 253.0947. Found: m/z 253.0955.
Acknowledgment. This work has been supported finan-
cially in part by a Grant-in-Aid for Scientific Research (the
Global COE Program “Integrated Materials Science” on
Kyoto University) from Ministry of Education, Culture,
Sports, Science and Technology, Japan. N.U. thanks the
JSPS for a Research Fellowship for Young Scientists.
3-Methyl-4-(2,4,6-trimethoxyphenyl)-1,3-oxazolidin-2-one (4ix).
A white solid. 1H NMR (500 MHz, CDCl3) δ 2.57 (s, 3 H), 3.80
(s, 6 H), 3.82 (s, 3 H), 4.22 (dd, J = 8.2, 5.5 Hz, 1 H), 4.47 (dd,
J = 9.9, 8.2 Hz, 1 H), 5.38 (dd, J = 9.9, 5.5 Hz, 1 H), 6.13
(s, 2 H). 13C NMR (125 MHz, CDCl3) δ 28.3, 51.0, 55.3, 55.8,
66.9, 90.6 (broad), 105.1, 159.0, 160.1 (broad), 161.7. HRMS
(ESI) calcd for C13H17NO5: [M þ Na]þ, 290.0999. Found: m/z
290.0993.
Supporting Information Available: Characterization data
for all products. This material is available free of charge via the
Internet at http://pubs.acs.org.
(31) El-Subbagh, H.;Wittig, T.; Decker, M.; Elz, S.; Nieger, M.; Lehmann, J.
Arch. Pharm. Pharm. Med. Chem. 2002, 335, 443–448.
(32) Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235–244.
(33) Fontaine, H.; Baussanne, I.; Royer, J. Synth. Commun. 1997, 27,
2817–2824.
(30) Malmberg, M.; Nyberg, K. Acta Chem. Scand., B 1979, 33, 69–72.
(34) He, Q. Q.; Liu, C. M.; Li, K. Chin. Chem. Lett. 2007, 18, 651–652.
34 J. Org. Chem. Vol. 76, No. 1, 2011