Isolation and characterization of 2-alkylaminobenzo[b]furans. Evidence for competing O-arylation in Cu-catalyzed intramolecular amidation

Article abstract of DOI:10.1016/j.tetlet.2006.11.084

2-Alkylaminobenzo[b]furans were isolated and characterized by X-ray crystal structural analysis, for the first time, from the Cu-catalyzed intramolecular amidation of hindered secondary amides under controlled microwave heating. A mechanism was proposed t

Full text of DOI:10.1016/j.tetlet.2006.11.084

Tetrahedron Letters 48 (2007) 401–404
Isolation and characterization of 2-alkylaminobenzo[b]furans.
Evidence for competing O-arylation in Cu-catalyzed
intramolecular amidation
Gaofeng Feng,a Jinlong Wua and Wei-Min Daia,b,
*
aLaboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China
bDepartment of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong SAR, PR China
Received 8 September 2006; revised 9 November 2006; accepted 13 November 2006
Available online 1 December 2006
Abstract—2-Alkylaminobenzo[b]furans were isolated and characterized by X-ray crystal structural analysis, for the first time, from
the Cu-catalyzed intramolecular amidation of hindered secondary amides under controlled microwave heating. A mechanism was
proposed to account for competing Cu-catalyzed intramolecular N- and O-arylation pathways, which were controlled by the bulk-
iness of substituents on the nitrogen atom of secondary amides.
Ó 2006 Elsevier Ltd. All rights reserved.
The Cu-mediated CAr–heteroatom bond formation1 has
been known in the literature and practiced in synthetic
laboratories since the Ullmann era over 100 years ago.
The catalytic versions of these transformations, in par-
ticular, the Cu-catalyzed N-arylation of amines (Ull-
mann reaction)2 and amides (Goldberg reaction)3,
have been developed recently with the introduction of
various types of enabling ligands to Cu.1 For example,
amino acids,4 1,2-diamines,5 N,N-diethylsalicylamide,6
and 1,10-phenanthrolines7 have been reported for N-
arylation of amides at relatively lower temperatures
(80–120 °C for aryl halides). Despite significant advance
witnessed in Cu-catalyzed transformations, a survey on
the current literature reveals that the Cu-catalyzed ami-
dation of aryl or vinyl bromides and iodides has been
limited to primary amides, anilides, and lactams.1 Ex-
cept for N-cyclohexylformamide,5 there is no prior
report on the Cu-catalyzed N-arylation of sterically
hindered acyclic secondary amides such as N-cyclohexyl
and N-t-butyl carboxamides.8 As a matter of steric hin-
drance,9 the acyclic secondary amides possessing an N-
bulky substituent might be difficult in coordination with
the metal via the deprotonated amide nitrogen, render-
ing alternative reaction pathways such as O-arylation
of amides possible.10 We report here the isolation and
structural characterization of 2-alkylaminobenzo[b]fur-
ans and propose a competing O-arylation pathway for
Cu-catalyzed intramolecular N-arylation of bulky acy-
clic secondary amides.
We initiated our investigation with the N-benzyl (2-
bromophenyl)acetamides 1a–c (Scheme 1). The sub-
strates were easily prepared from 2-aminophenols,
2-bromobenzaldehyde, 2-bromoacetic acid, and benzyl
isocyanide through the microwave-assisted one-pot U-
4CR and intramolecular O-alkylation approach recently
reported in our laboratories.11 Upon treating 1a–c with
CuI and L-proline4 in the presence of a base in a protic
polar solvent, the 2-oxindoles 2a–c were produced
(Table 1). As compared to the conventional heating at
100 °C for 20 h in DMSO, microwave heating11,12 at
8
O
7
6
2
O
N
R
R
N
N
O
L
CuI, -proline
5
O
O
O
a: R = 7-Me
b: R = 6-Me
c: R = 6-Cl
Ph
NH
Br
Ph
Keywords: Amidation; Benzo[b]furan; Cu catalysis; 2-Oxindole.
1a-c
2a-c
*
Corresponding author. Tel.: +852 2358 7365; fax: +852 2358 1594;
e-mail addresses: chdai@ust.hk; chdai@zju.edu.cn
Scheme 1. Cu-catalyzed intramolecular amidation to 2-oxindoles.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.11.084

402
G. Feng et al. / Tetrahedron Letters 48 (2007) 401–404
Table 1. Cu-catalyzed intramolecular amidation with microwave heatinga
Entry
Substrate
Solvent
Basec
T (°C)
t (min)
Isolated yield (%)
1b
2
3
4
5
6
1a
1a
1a
1a
1b
1c
DMSO
DMSO
MeCN
MeCN
MeCN
MeCN
K2CO3
K2CO3
K2CO3
K3PO4Æ3H2O
K3PO4Æ3H2O
K3PO4Æ3H2O
100
150
150
150
150
150
1200
30
35
35
50
2a: 71
2a: 90
2a: 88
2a: 90
2b: 85
2c: 59
50
a Except for entry 1, all reactions were carried out in closed pressurized vials with the reaction temperature measured by an IR sensor. CuI (10 mol %)
and L-proline (20 mol %) were used as the catalyst.
b Entry 1 was performed in an oil bath with 23 mol % CuI and 37 mol % L-proline.
c 2 equiv of the base was used.
150 °C for 30 min afforded an improved yield of 90% for
product 2a (Table 1, entries 1 and 2). Similar efficiency
of the microwave-heated amidation in MeCN was ob-
tained (Table 1, entry 3). We also found that a mild
base, K3PO4Æ3H2O, could be used to furnish 2a–c in
59–90% yields (Table 1, entries 4–6). By using DMF
as the solvent, the same Cu-catalyzed intramolecular
amidation of 1a–c could occur in the absence of
L-proline.11
formed by oxidative cleavage of the C2–C3 double bond
upon exposure to air.15,16 Formation of 9b could be sup-
pressed by recrystallization of 3e under an inert atmo-
sphere. On the other hand, 9a could be obtained by
bubbling a stream of oxygen gas into a solution of 3d
in EtOAc–hexane at room temperature. In order to opti-
mize the amidation conditions, we varied the catalyst
loading and base for the reaction of 1d and no better re-
sults were obtained (Table 2, entries 3–5). Extension of
the reaction time of 1e to 120 min with 15 mol % CuI
and 30 mol % L-proline led to formation of a decom-
posed byproduct 10 (10%, Table 2, entry 7). Change
of MeCN to DMF as the solvent gave only 2e (13%, Ta-
ble 2, entry 8), while replacement of the base K3PO4Æ
3H2O by K2CO3 furnished similar product distribution
(Table 2, entry 9). When a stoichiometric CuI or N,N0-
dimethyl-1,2-ethylenediamine5 was used, almost no
reaction took place (Table 2, entries 10 and 11). We also
examined amidation of iodide 1f and obtained both 2-
oxindole 2e and benzo[b]furan 3e but in favor of the
N-arylation product 2e (Table 2, entries 12 and 13). A
deiodination byproduct 11 was isolated in the reaction
of 1f even at 130 °C and it became the major component
(45%) when heating 1f in an oil bath in MeCN at 80 °C
for 48 h (Table 2, entry 14). Byproduct 10 was produced
at 80 °C in 35% yield as well. In contrast to the Cu-cat-
Scheme 2 and Table 2 summarize our results on the
microwave-assisted Cu-catalyzed intramolecular amida-
tion of 1d–f. We carried out the amidation of 1d at 150
and 180 °C for 80 min, the desired 2-oxindole 2d was
isolated in up to 40% yield along with 2-(cyclohexyl-
amino)benzo[b]furan 3d (Table 2, entries 1 and 2).13
The structures of 2d and 3d were assigned spectroscopi-
cally and 2d was further confirmed by X-ray crystallo-
graphic analysis (Fig. 1).14 As expected, reaction of the
N-t-Bu-substituted 1e by using 10 mol % CuI and
20 mol % L-proline at 180 °C for 60 min afforded only
3% of 2e and 17% of 3e along with 60% recovery of 1e
(Table 2, entry 6). During recrystallization of 3e, a
new compound 9b was obtained. The structures of both
3e and 9b were proved by X-ray crystal structural anal-
ysis as shown in Figures 2 and 3.14 Clearly, 9b was
Me
O
N
Me
base, L2CuI
O
N
Me
R
O
N
Me
O
N
Me
O
N
O
O
O
O
O
O
O
R
N
N
R
N
NH
R N
L2CuI
O
O
R
O
CuIII
L
7
X
X
X
L2CuI
X
1a: R = Bn, X = Br
1d: R = Cy, X = Br
1e: R = t-Bu, X = Br
1f: R = t-Bu, X = I
11: R = t-Bu, X = H
5
4
8
Me
O
N
Me
O
Me
O
N
Me
O
N
O
air
N
O
O
Me
O
O
O
O
O
3
H
N
from 3d,e
O
N
O
O
2
N
R
N
H
CuIII
L
6
R
O
R
N
R
10
X
H
2a: R = Bn
2d: R = Cy
2e: R = t-Bu
3a: R = Bn
3d: R = Cy
3e: R = t-Bu
9a: R = Cy
9b: R = t-Bu
Scheme 2. Competitive reaction pathways for Cu-catalyzed intramolecular O- and N-arylation of secondary amides.

G. Feng et al. / Tetrahedron Letters 48 (2007) 401–404
Table 2. Cu-catalyzed intramolecular O- and N-arylation of amides 1d–f a
403
Entry
Substrate
Catalyst (mol %)
Baseb
T (°C)
t (min)
Isolated yields (%)
1
2
3
4
5
6
7
8c
9
10
11
12
13
14e
1d
1d
1d
1d
1d
1e
1e
1e
1e
1e
1e
1f
CuI (10), L-prolin (20)
CuI (10), L-prolin (20)
CuI (20), L-prolin (40)
CuI (20), L-prolin (40)
CuI (10), L-prolin (20)
CuI (10), L-prolin (20)
CuI (15), L-prolin (30)
CuI (10), L-prolin (20)
CuI (10), L-prolin (20)
CuI (100), L-prolin (200)
CuI (10), DAd (20)
K3PO4Æ3H2O
K3PO4Æ3H2O
K3PO4Æ3H2O
Cs2CO3
150
180
180
180
180
180
180
180
180
180
180
180
130
80
80
80
80
50
50
60
120
60
60
60
2d: 19; 3d: 5
2d: 40; 3d: 11
2d: 40; 3d: 11
2d: 27
NaOt-Bu
2d + 3d: Trace
K3PO4Æ3H2O
K3PO4Æ3H2O
K3PO4Æ3H2O
K2CO3
K3PO4Æ3H2O
K3PO4Æ3H2O
K3PO4Æ3H2O
K3PO4Æ3H2O
K3PO4Æ3H2O
1e: 60; 2e: 3; 3e: 17
1e: 52; 2e: 2; 3e: 17; 10: 10
2e: 13; 3e: 0
2e: 5; 3e: 14
1e: 80; No other products
2e + 3e: Trace
2e: 25; 3e: 15; 11: 22
2e: 18; 3e: 12; 11: 23
2e: 9; 3e: Trace; 10: 35; 11: 45
60
60
120
2880
CuI (10), L-prolin (20)
CuI (10), L-prolin (20)
CuI (10), L-prolin (20)
1f
1f
a Except for entries 8 and 14, all reactions were carried out in MeCN in closed pressurized vials with the reaction temperature measured by an IR
sensor.
b 2 equiv of the base were used.
c In DMF.
d DA = N,N0-dimethyl-1,2-ethylenediamine.
e In MeCN using an oil bath.
alyzed amidation described above, the 2-oxindoles 2d
and 2e could be synthesized from 1d,e in 88–90% yields
by using 5 mol% Pd(OAc)2, 5 mol% BINAP and 2 equiv
of K2CO3 with microwave heating in PhMe at 150 °C
for 40–45 min.8b
The Cu-catalyzed intramolecular amidation of hindered
substrates as disclosed above has not reached the stage
for efficient synthetic application but the results are of
interest in elaborating the reaction mechanism. As out-
lined in Scheme 2, coordination of CuI with the depro-
tonated amide could give two equilibrating species 4
and 5. With a less bulky R, the N-ligated 4 should be
Figure 2. X-ray crystal structure of 2-(tert-butylamino)benzo[b]furan
3e.
favored, leading to formation of the N-arylation prod-
ucts 2 via the CuIII species 6. On the other hand, with
a bulky R at the nitrogen atom, the O-complexed CuI
Figure 1. X-ray crystal structure of 2-oxindole 2d.
Figure 3. X-ray crystal structure of O-protected salicylamide 9b.

404
G. Feng et al. / Tetrahedron Letters 48 (2007) 401–404
3. Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691–1692.
4. (a) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809–1812;
(b) Deng, W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X.
Tetrahedron Lett. 2004, 45, 2311–2315; (c) Yang, T.; Lin,
C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7, 4781–
4784.
5. (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, and references cited therein.
6. Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653–
6655.
7. (a) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett.
2001, 3, 3803–3805; (b) Han, C.; Shen, R.; Su, S.; Porco,
J. A., Jr. Org. Lett. 2004, 6, 27–30.
species 5 might take part in the subsequent oxidative
addition to form 7, which transforms into the O-aryl-
ation products 8 via reductive elimination. A base-
promoted rearrangement of
8 should afford 2-
alkylaminobenzo[b]furans 3. The determinant factor
among the competing N- and O-arylation pathways is
the size of the R group. For 1a possessing an N-benzyl
group, only lactam 2a was formed. The selectivity is
consistent with the intrinsic higher reactivity of 4 toward
oxidative addition to form CuIII species 6 as compared
to that of 5. At high reaction temperatures, CuI complex
5 becomes activated toward oxidative addition, eventu-
ally resulting in the formation of O-arylation products.
In summary, we have investigated the microwave-as-
sisted Cu-catalyzed intramolecular amidation and found
that the amide N-substituent played a determinant role
in selectivity among N- and O-arylation. As reported
in the literature, N-arylation is normally favored for
Cu-catalyzed arylation of primary amides, anilides,
and lactams.1 At the temperatures below 130 °C, hin-
dered secondary amides usually fail to react efficiently
with Cu catalysts. For example, on the completion of
this work, Zhu and co-workers8d reported that a combi-
nation of CuI and 1,2-diamines5 failed to promote the
formation of a 2-oxindole from the corresponding aryl
iodide in refluxing PhMe. In our study using controlled
microwave heating at high temperatures, the Cu-cata-
lyzed O-arylation of hindered secondary amides took
place, leading to the formation of 2-alkylaminobenzo[b]-
furans. The O-arylation of amides is unique to Cu cata-
lysts because exclusive formation of N-arylation
products was observed for Pd-catalyzed reactions of
similar hindered secondary amides.8b Finally, in order
to render synthetic application possible, much more
reactive Cu catalysts are needed for efficient O-arylation
of hindered secondary amides.
8. For successful examples of Pd-catalyzed intramolecular
amidation of N-cyclcohexyl carboxamides, see: (a) van den
Hoogenband, A.; den Hartog, J. A. J.; Lange, J. H. M.;
Terpstra, J. W. Tetrahedron Lett. 2004, 45, 8535–8537; (b)
Xing, X.; Wu, J.; Dai, W.-M. Synlett 2006, 2099–2103; (c)
Poondra, R. R.; Turner, N. J. Org. Lett. 2005, 7, 863–866;
(d) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J. Org. Lett.
2006, 8, 4351–4354; For a failed example of Pd-catalyzed
intramolecular amidation of N–t-butyl carboxamide, see:
(e) Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.;
Burdack, C.; Hiller, W. Tetrahedron Lett. 2006, 47, 3423–
3426.
9. Yin, J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101–1104.
10. For an example of Cu-catalyzed intramolecular O-aryl-
ation of ortho-halobenzanilides, see: Evindar, G.; Batey,
R. A. J. Org. Chem. 2006, 71, 1802–1808.
11. Xinglong, X.; Wu, J.; Feng, G.; Dai, W.-M. Tetrahedron
2006, 62, 6774–6781.
12. (a) Lang, J. H. M.; Hofmeyer, L. J. F.; Hout, F. A. S.;
Osnabrug, S. J. M.; Verver, P. C.; Kruse, C. G.; Feenstra,
R. W. Tetrahedron Lett. 2002, 43, 1101–1104; (b) Wann-
berg, J.; Dallinger, D.; Kappe, C. O.; Larhed, M. J. Comb.
Chem. 2005, 7, 574–583.
13. 2-Alkylaminobenzo[b]furans were synthesized from ammo-
nium formate, 2-hydroxybenzaldehyde, and alkylisocya-
nides, see: Bossio, R.; Marcaccini, S.; Paoli, P.; Pepino, R.;
Polo, C. Synthesis 1991, 999–1000.
14. The crystallographic data (excluding structure factors) of
2d, 3e and 9b have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion nos. CCDC 612701, CCDC 612702, and CCDC
612703, respectively. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44 1223 336033 or
e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements
This work is supported by a research grant provided by
Zhejiang University. Mr. Jianming Gu of the X-ray
crystallography facility of Zhejiang University is
acknowledged for the assistance on crystal structural
analysis. W.-M. Dai is the recipient of Cheung Kong
Scholars Award of The Ministry of Education of China.
15. Oxidative cleavage of an electron-rich benzo[b]furan by
singlet oxygen is known, see: Adam, W.; Kades, E.; Wang,
X. Tetrahedron Lett. 1990, 31, 2259–2262.
16. A mechanism for the formation of 9a,b from 3d,e, in the
absence of a photosensitizer, is proposed below, where
3d,e may act as photosensitizers for their own
photooxygenation.15
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.11.084.
O2
Me
O
N
References and notes
3d,e
1O2
1. For selected recent reviews, see: (a) Ley, S. V.; Thomas, A.
W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449; (b) Kunz,
K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428–2439; (c)
Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337–2364.
O
O
3d,e
9a,b
O
O
HN
R
2. Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–2384.