Direct synthesis of benzofuro[2,3-b]pyrroles through a radical addition/[3,3]-sigmatropic rearrangement/cyclization/lactamization cascade

Article abstract of DOI:10.1002/chem.201402217

A straightforward synthetic method for the construction of benzofuro[2,3-b]pyrrol-2-ones by a novel domino reaction through a radical addition/[3,3]-sigmatropic rearrangement/cyclization/lactamization cascade has been developed. The domino reaction of O-phenyl-conjugated oxime ether with an alkyl radical allows the construction of two heterocycles with three stereogenic centers as a result of the formation of two C-C bonds, a C-O bond, and a C-N bond in a single operation, leading to pyrrolidine-fused dihydrobenzofurans, which are not easily accessible by existing synthetic methods. Furthermore, asymmetric synthesis of benzofuro[2,3-b]pyrrol-2-one derivatives through a diastereoselective radical addition reaction to a chiral oxime ether was also developed.

Full text of DOI:10.1002/chem.201402217

DOI: 10.1002/chem.201402217
Full Paper
&
Synthetic Methods
Direct Synthesis of Benzofuro[2,3-b]pyrroles through a Radical
Addition/[3,3]-Sigmatropic Rearrangement/Cyclization/
Lactamization Cascade
Masafumi Ueda, Yuta Ito, Yuki Ichii, Maiko Kakiuchi, Hiroko Shono, and Okiko Miyata*[a]
Abstract: A straightforward synthetic method for the con-
struction of benzofuro[2,3-b]pyrrol-2-ones by novel
of the formation of two CÀC bonds, a CÀO bond, and a CÀN
bond in a single operation, leading to pyrrolidine-fused dihy-
drobenzofurans, which are not easily accessible by existing
synthetic methods. Furthermore, asymmetric synthesis of
benzofuro[2,3-b]pyrrol-2-one derivatives through a diastereo-
selective radical addition reaction to a chiral oxime ether
was also developed.
a
domino reaction through a radical addition/[3,3]-sigmatropic
rearrangement/cyclization/lactamization cascade has been
developed. The domino reaction of O-phenyl-conjugated
oxime ether with an alkyl radical allows the construction of
two heterocycles with three stereogenic centers as a result
Introduction
lishing a conventional method for the synthesis of simplified
analogues is highly desirable. Recently, Vincent[4] and Bisai[5] in-
dependently reported the stepwise synthesis of tetracyclic
dihydrobenzofuro[2,3-b]indoles 1.[6] The methods relied on the
oxidative cyclization of 3-(2-hydroxyphenyl)indolines prepared
by Freidel–Crafts reaction of indoles or oxindoles with phenol,
and are similar to typical synthetic protocols for tricyclic
tetrahydrofuro[2,3-b]indoles 2.[7] Tetrahydrobenzofuro[2,3-b]pyr-
roles 3 are unique skeletons, but efficient routes for their syn-
thesis are relatively unknown. Current approaches to their syn-
thesis involve radical annulation of N-chlorosulfonamide with
benzofuran,[8] cycloaddition of dichloroketene with sulfili-
mine,[9] cyclization of nitrone,[10] and skeletal rearrangement of
benzoxazine[11] and chromen-2-one.[12] However, these strat-
egies are limited by the requirement for functionalized starting
materials, making it more difficult to achieve diversified struc-
tures. Development of straightforward, flexible, and general
synthetic methods of this structural moiety from a relatively
simple substrate is therefore highly desirable.
Indoline-fused dihydrobenzofurans are a core component of
biologically active natural products such as the antitumor com-
pound diazonamide A (Figure 1).[1] Accordingly, there is consid-
For the synthesis of the benzofuro[2,3-b]pyrrole skeleton, we
decided to employ a [3,3]-sigmatropic rearrangement of O-
aryl-N-vinyl hydroxylamine, which is a potential approach to
benzofurans from an O-aryl oxime ether developed by Sherad-
sky in 1966 and closely parallels the Fischer indole synthesis.[13]
Although the Sheradsky reaction has considerable value for its
operational simplicity, a significant drawback of the method is
that strongly acidic conditions at high temperature are gener-
ally required for the isomerization of oxime ether 4 to enami-
ne A and [3,3]-sigmatropic rearrangement (Scheme 1a).[14] Be-
cause of the acidic conditions, elimination of the ammonium
group usually occurs to give the aromatized benzofuran 5. For
purposes of synthesizing 2-aminobenzofuran and from the
perspective of atom economy, the loss of the amino group is
a serious disadvantage.[15] To address this problem, we rea-
soned that the generation of a highly reactive enamine under
Figure 1. Pyrrolidine-fused dihydrobenzofurans and tetrahydrofuran.
erable interest from the synthetic community to access these
molecules and evaluate their biological activities.[2,3] For pur-
poses of further biological studies and investigation of struc-
ture–activity relationships aimed at designing new drugs, the
pharmacophoric structural elements of diazonamide A and re-
lated structures need to be identified. For this purpose, estab-
[a] Dr. M. Ueda, Y. Ito, Y. Ichii, M. Kakiuchi, H. Shono, Prof. Dr. O. Miyata
Kobe Pharmaceutical University
Motoyamakita, Higashinada, Kobe 658-8558 (Japan)
Fax: (+81)78-441-7554
E-mail: miyata@kobepharma-u.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402217.
Chem. Eur. J. 2014, 20, 1 – 9
1
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Table 1. Optimization studies for the formation of benzofuro[2,3-b]pyrrol-
2-one 12.[a]
Substrate
Additive[b]
T
Yield [%]
1
2
3
4[c]
5
6
7
8
9
8 (R=Et)
8 (R=Et)
8 (R=Et)
8 (R=Et)
9 (R=Ph)
10 (R=C6Cl5)
11 (R=C6F5)
11 (R=C6F5)
11 (R=C6F5)
11 (R=C6F5)
–
RT
RT
n.d.[d]
50
64
49
73
67
88
75
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
Me3Al
–
reflux
reflux
reflux
reflux
reflux
RT
Scheme 1. Strategies for benzofuran synthesis.
reflux
RT
81
95
10
–
neutral and mild conditions would provide a dihydrobenzofur-
an bearing an aminal moiety. We focused our attention on N-
aryloxy-N-boryl enamine C as a reactive intermediate, which is
generated by triethylborane-mediated radical addition to a con-
jugated oxime ether (Scheme 1b).[16]
[a] Reaction conditions: 8–11 (0.2 mmol) and Et3B (1.0 mmol) for 1–2 h.
Ratio of stereoisomer: endo/exo=1:1. [b] With 2.4 equiv of Me3Al. [c] Tolu-
ene was used as a solvent. [d] n.d.=not detected.
We envisaged that the regioselective intermolecular alkyl
radical addition to the conjugated oxime ether 6 bearing an
ester gave N-boryl enamine C, which would spontaneously un-
dergo [3,3]-sigmatropic rearrangement and cyclization to gen-
the effect of the ester moiety on the reaction revealed that the
yield was improved by changing from an ethyl ester to phenyl
esters (9 and 10, entries 5 and 6). Furthermore, the pentafluor-
ophenyl ester 11 was found to be the most effective substrate
and gave 12 in 88% yield (entry 7). It is worth noting that the
domino reaction of 11 proceeded even in the absence of tri-
methylaluminum at room temperature to furnish the
benzofuro[2,3-b]pyrrol-2-one 12 in high yield (entry 10). The
pentafluorophenoxy group enhanced not only the lactamiza-
tion reaction but also the reactivity toward the nucleophilic
ethyl radical. To the best of our knowledge, this reaction repre-
sents the first reported example of [3,3]-sigmatropic rearrange-
ment of an N-aryloxy-N-borylenamine generated through a rad-
ical process.
erate 2-borylaminodihydrobenzofuran D. Because
D
has
a highly nucleophilic amine moiety, undesired elimination is in-
hibited and thus lactamization would proceed effectively to
produce
tetrahydrobenzofuro[2,3-b]pyrrol-2-one
7. The
domino-type sequential reaction involving radical, concerted,
and ionic reactions represents a novel cascade reaction.[17]
Domino reactions are transformations that allow for complex
molecules to be constructed from a simple substrate in one
operation in a straightforward, efficient, and elegant way with-
out isolation of intermediates.[18] Consequently, the develop-
ment of a new type of domino reaction is of great importance
to the field of synthetic chemistry. Herein, we report the direct
synthesis of benzofuro[2,3-b]pyrrol-2-ones from a conjugated
oxime ether by a domino reaction through the generation of
N-borylenamine as a reactive intermediate.
To investigate the molecular diversity of this transformation,
we next examined the reaction in the presence of a range of
alkyl iodides as carbon radical precursors (Table 2). When 11
was treated with ethyl iodoacetate and triethylborane in reflux-
Table 2. Domino reaction with various alkyl iodides.[a]
Results and Discussion
We initiated our investigation with the O-phenyl-conjugated
oxime ether 8 containing an ethoxycarbonyl group (Table 1).
Treatment of 8 with triethylborane as an ethyl radical source in
benzene at room temperature did not afford the desired prod-
uct and a complex mixture was obtained probably because of
unsuitable conditions for rearrangement and lactamization
(entry 1). In the presence of trimethylaluminum, the reaction
did afford the desired cis-fused tricyclic compound 12,
benzofuro[2,3-b]pyrrol-2-one, as a 1:1 mixture of diastereomers
at the C3-position, which were easily separated by preparative
TLC (entry 2). The reaction temperature played a significant
role in this process, thus, improvement of chemical yield was
observed in benzene at reflux (entries 3 and 4). Examination of
RI
Product
Yield
[%]
Selectivity
(exo:endo)
1
2
3
4
5[b]
EtO2CCH2I
iPrI
c-C5H9I
tBuI
13a
13b
13c
13d
13d
67
81
62
66
98
1:1
2:1
2:1
>10:1
>10:1
tBuI
[a] Reaction conditions: 11 (0.2 mmol), RI (12 mmol) and Et3B (1.0 mmol)
for 1 h. [b] With 3.5 equiv of Na2S2O3.
&
&
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
2
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
ing benzene,[19] the expected domino reaction proceeded to
give 13a, which has an ester functionality (entry 1). Interesting-
ly, employment of secondary alkyl radicals, such as isopropyl
and cycloalkyl, increased the stereoselectivity of the reaction
(entries 2 and 3). It should be noted that the reaction with the
tert-butyl radical proceeded stereoselectively to afford exo-13d
as a sole stereoisomer, albeit in relatively low yield because of
the instability of the product 13d under the reaction condi-
tions (entry 4). Indeed, treatment of the isolated 13d with tBuI
and Et3B in benzene at reflux led to decomposition by I2 gener-
ated from tBuI. Therefore, the reaction was carried out in the
presence of sodium thiosulfate as an iodine scavenger[20] and
as expected, an excellent chemical yield and stereoselectivity
was observed (entry 5).
under these radical reaction conditions, thereby facilitating fur-
ther transformation (15c). Although steric hindrance induced
to the substrate by substituents at the ortho-position slightly
affected the reaction, 7-substituted benzofuro[2,3-b]pyrrol-2-
ones 15d–f were obtained in moderate to good yields. To in-
vestigate the role of the substrate in the stereoselective syn-
thesis of benzofuro[2,3-b]pyrrol-2-ones, a tert-butyl radical was
employed for the domino reaction. As expected, 3-tert-
butylbenzofuro[2,3-b]pyrrol-2-ones 16a–e were obtained with
excellent stereoselectivities, whereas the substrate bearing the
trifluoromethyl group at the meta-position was converted to
16g and 16g’ as regioisomers.
To gain an understanding of the rearrangement process, we
investigated the reaction of the conjugated oxime ether 11
with a thiyl radical (Scheme 3). When 11 was treated with thio-
We then proceeded to investigate the substituent effect on
the phenyl group, first with respect to the domino reaction ini-
tiated by ethyl radical addition (Scheme 2). The substrate bear-
Scheme 3. Reaction of 11 with thiyl radical.
phenol and triethylborane under an air atmosphere, b-hydrox-
ysulfide 17 was formed as the sole product instead of the ex-
pected benzofuro[2,3-b]pyrrol-2-one 18. The hydroxysulfenyla-
tion proceeded via generation of the a-imino radical E, trap-
ping with molecular oxygen, and reduction.[21] The result indi-
cated that the a-imino radical E could not participate in the
rearrangement process for the benzofuran synthesis, thus the
[3.3]-sigmatropic rearrangement proceeded via N-borylena-
mine.
Scheme 2. Substituent effect. [a] Reaction conditions: 14a–f (0.2 mmol), Et3B
(1.0 mmol) and benzene at reflux for 1 h. Ratio of stereoisomer: 1:1. [b] In
the presence of Me3Al (0.48 mmol). [c] Reaction conditions: 14a–e, g
(0.2 mmol), tBuI (12 mmol), Na2S2O3 (0.7 mmol), Et3B (1.0 mmol) and benzene
at reflux for 0.5 h. Ratio of stereoisomer: >10:1.
A possible reaction pathway that could account for the for-
mation of 13d is illustrated in Scheme 4. It involves the regio-
selective addition of a tert-butyl radical, generated from an
ethyl radical and tBuI by means of an iodine-atom transfer, to
a CÀC double bond, generating an aminyl radical H, which is
trapped by Et3B to form N-borylenamine I (Scheme 4a). The N-
boryl-N-phenoxyenamine I undergoes [3,3]-sigmatropic rear-
rangement via a six-membered transition state that minimizes
the steric repulsion between the tert-butyl group and the
phenyl group to eventually lead to the stereoselective forma-
tion of syn-a-arylimine J (Scheme 4b). Since the subsequent
cyclization of J would be reversible, equilibrium exists between
ing a trifluoromethyl group at the para-position afforded 5-tri-
fluoromethylbenzofuropyrrole 15a in 89% yield. A slightly
lower yield was observed for product 15b with a methyl
group as an electron-donating substituent. Interestingly, run-
ning the reaction in the presence of Me3Al improved the
chemical yield (15b). Notably, a bromo group was tolerated
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
3
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
a CÀO bond, and a CÀN bond in a single operation, leading to
pyrrolidine-fused dihydrobenzofurans which are not easily ac-
cessible from existing synthetic methods. Furthermore, asym-
metric synthesis of benzofuro[2,3-b]pyrrol-2-ones by means of
a diastereoselective radical addition reaction to a chiral oxime
ether was also developed. Clarification of the reaction mecha-
nism, extension of this methodology to other heterocycles,
and further study of the asymmetric synthesis of benzofuro-
[2,3-b]pyrrol-2-ones are currently underway in our laboratory.
Experimental Section
General
NMR spectra were recorded at 300 MHz/75 MHz (1H NMR/13C NMR)
or 500 MHz/125 MHz (1H NMR/13C NMR) using Varian Gemini-300
(300 MHz), Varian MERCURY plus 300 (300 MHz), or Varian NMR
system AS 500 (500 MHz) spectrometers. Chemical shifts (d) are re-
ported as follows: chemical shift, multiplicity (s=singlet, d=dou-
blet, t=triplet, q=quartet, m=multiplet, br=broad), coupling
constants, and integration. IR spectra were obtained on a Perki-
nElmer SpectrumOne A spectrometer. High-resolution mass spectra
were obtained by ESI methods on Thermo Fisher Scientific Exactive
instrument. Melting points (uncorrected) were determined on
a BꢁCHI M-565 apparatus. Optical rotation was measured with
a JASCO DIP-370 digital polarimeter. Preparative TLC separations
(PTLC) were carried out on precoated silica gel plates (E. Merck
60F254). Medium-pressure column chromatography was performed
using Lobar grçße B (E. Merck 310–25, Lichroprep Si60). HPLC was
performed on a Hitachi L-7100 liquid chromatograph coupled with
a Hitachi l-7400 spectrophotometeric detector. tert-Butyl iodide
was purified by column chromatography on Al2O3 prior to use.
Unless otherwise stated, all the reagents and solvents were used
as received from the manufacturer.
Scheme 4. Reaction pathway.
Scheme 5. Asymmetric synthesis of benzofuro[2,3-b]pyrrol-2-one.
cis- and trans-K. The irreversible lactamization pushes the equi-
librium toward the formation of the sterically favored cis-fused
tricyclic compound 13d.[22]
Finally, we demonstrated the asymmetric synthesis of
benzofuro[2,3-b]pyrrol-2-ones involving traceless cleavage of
a chiral auxiliary (Scheme 5). The auxiliary of choice was Op-
polzer’s camphorsultam, because it had shown excellent ste-
reoselectivity in our previous work on radical reactions.[16,23,24]
Triethylborane was added to the solution of chiral conjugated
oxime ether 19 and trimethylaluminum in acetonitrile at
À408C and then the reaction mixture was warmed to reflux. In
contrast to the reaction with pentafluorophenyl ester 11, the
endo-isomer 20 was predominately obtained in 57% yield with
93% ee, which confirmed the [3,3]-sigmatropic rearrangement
would proceed thereby avoiding the steric interaction of the
camphorsultam moiety with the phenyl group in a six-mem-
bered transition state.[25] Although the removal of a chiral auxil-
iary is generally tedious in a diastereoselective reaction, use of
the domino reaction allows release of the chiral auxiliary.
General procedure for domino reaction of conjugated oxime
ether with ethyl radical
Et3B (1.0m in hexane, 1.0 mmol) was added to a solution of 11
(0.2 mmol) in benzene (5 mL) under an N2 atmosphere at reflux.
After being stirred for 1 h, the reaction mixture was diluted with
H2O and extracted with CHCl3. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The crude prod-
uct was purified by PTLC (hexane/AcOEt=1:2) to afford the corre-
sponding benzofuro[2,3-b]pyrrol-2-one 12 and 15a–f.
Data for exo-3-ethyl-1,3,3a,8a-tetrahydro-2H-benzofuro[2,3-
b]pyrrol-2-one (exo-12): White solid; m.p. 126–1288C; 1H NMR
(300 MHz, CDCl3): d=7.20–7.14 (m, 3H), 6.93 (dd, J=8.0, 7.5 Hz,
1H), 6.80 (d, J=8.0 Hz, 1H), 6.10 (d, J=7.5 Hz, 1H), 3.83 (dd, J=
7.5, 3.0 Hz, 1H), 2.55–2.50 (m, 1H), 2.05–1.91 (m, 1H), 1.74–1.59 (m,
1H), 1.14 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
178.7, 157.6, 129.2, 128.5, 124.6, 121.7, 110.4, 90.7, 50.0, 47.3, 25.4,
11.5 ppm; IR (CHCl3): n˜ =3430, 1712 cmÀ1; ESI-HRMS: m/z calcd for
C12H14O2N [M+H]+: 204.1019; found: 204.1021.
Conclusion
We have established a straightforward synthetic method for
the construction of benzofuro[2,3-b]pyrrol-2-ones by a novel
domino reaction through a radical addition/[3,3]-sigmatropic
rearrangement/cyclization/lactamization cascade. This domino
reaction employs readily accessible starting material and
allows the construction of two heterocycles with three stereo-
genic centers as a result of the formation of two CÀC bonds,
Data for endo-3-ethyl-1,3,3a,8a-tetrahydro-2H-benzofuro[2,3-
b]pyrrol-2-one (endo-12): White solid; m.p. 152–1538C; 1H NMR
(300 MHz, CDCl3): d=7.24–7.17 (m, 3H), 6.91 (dd, J=8.0, 7.5 Hz,
1H), 6.82 (d, J=8.0 Hz, 1H), 6.10 (d, J=7.0 Hz, 1H), 4.26 (dd, J=
9.0, 7.0 Hz, 1H), 2.72 (td, J=9.0, 5.0 Hz, 1H), 1.91–1.77 (m, 1H),
1.73–1.58 (m, 1H), 1.12 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=178.0, 158.3, 129.3, 126.5, 124.4, 121.1, 110.5, 90.0, 45.4,
&
&
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
4
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
45.2, 20.1, 12.8 ppm; IR (CHCl3): n˜ =3431, 1713 cmÀ1; ESI-HRMS: m/
z calcd for C12H14O2N [M+H]+: 204.1019; found: 204.1013.
Data for exo-3-ethyl-7-trifluoromethyl-1,3,3a,8a-tetrahydro-2H-
benzofuro[2,3-b]pyrrol-2-one (exo-15d): White solid; m.p. 186–
1878C; H NMR (300 MHz, CDCl3): d=7.42 (d, J=8.0 Hz, 1H), 7.33
1
Data for exo-3-ethyl-5-trifluoromethyl-1,3,3a,8a-tetrahydro-2H-
benzofuro[2,3-b]pyrrol-2-one (exo-15a): White solid; m.p. 157–
1588C; 1H NMR (300 MHz, CDCl3): d=7.75 (brs, 1H), 7.45 (d, J=
8.5 Hz, 1H), 7.39 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.20 (d, J=7.5 Hz,
1H), 3.86 (dd, J=7.5, 3.0 Hz, 1H), 2.57–2.51 (m, 1H), 2.06–1.93 (m,
1H), 1.76–1.61 (m, 1H), 1.15 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=179.1, 160.4 (d, J=1.0 Hz), 129.5, 127.1 (q, J=
4.0 Hz), 124.2 (q, J=270.0 Hz), 124.1 (q, J=32.0 Hz), 122.0 (q, J=
4.0 Hz), 110.5, 92.0, 50.0, 46.6, 25.2, 11.4 ppm; IR (CHCl3): n˜ =330,
(d, J=7.5 Hz, 1H), 7.01 (dd, J=8.0, 7.5 Hz, 1H), 6.65 (brs, 1H), 6.25
(dd, J=7.5, 1.5 Hz, 1H), 3.87 (dd, J=7.5, 3.0 Hz, 1H), 2.52 (m, 1H),
2.07–1.93 (m, 1H), 1.76–1.63 (m, 1H), 1.15 ppm (t, J=7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=178.4, 155.0 (d, J=2.5 Hz), 130.8,
128.2, 126.1 (q, J=4.5 Hz), 123.1 (q, J=270.5 Hz), 121.5, 113.6 (q,
J=33.0 Hz), 92.2, 50.0, 46.6, 25.3, 11.4 ppm; IR (CHCl3): n˜ =3427,
1718 cmÀ1
;
ESI-HRMS: m/z calcd for C13H13O2NF3 [M+H]+:
272.0893; found: 272.0884.
1719 cmÀ1
;
ESI-HRMS: m/z calcd for C13H13O2NF3 [M+H]+:
Data for endo-3-ethyl-7-trifluoromethyl-1,3,3a,8a-tetrahydro-2H-
benzofuro[2,3-b]pyrrol-2-one (endo-15d): White powder; m.p.
203–2048C; 1H NMR (300 MHz, CDCl3): d=7.45 (d, J=8.0 Hz, 1H),
7.40 (d, J=7.5 Hz, 1H), 7.01 (dd, J=8.0, 7.5 Hz, 1H), 6.48 (brs, 1H),
6.25 (d, J=7.0 Hz, 1H), 4.31 (dd, J=9.0, 7.0 Hz, 1H), 2.75 (td, J=
9.0, 5.0 Hz, 1H), 1.87–1.76 (m, 1H), 1.69–1.54 (m, 1H), 1.13 ppm (t,
J=7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=177.1, 155.6, 130.1,
126.8, 126.3 (q, J=4.5 Hz), 123.1 (q, J=270.0 Hz), 121.0, 113.8 (q,
J=33.0 Hz), 91.2, 45.0, 44.7, 20.3, 12.7 ppm; IR (CHCl3): n˜ =3431,
272.0893; found: 272.0888.
Data for endo-3-ethyl-5-trifluoromethyl-1,3,3a,8a-tetrahydro-2H-
benzofuro[2,3-b]pyrrol-2-one (endo-15a): White solid; m.p. 192–
1
1938C; H NMR (300 MHz, CDCl3): d=7.49 (d, J=8.5 Hz, 1H), 7.46
(s, 1H), 7.10 (brs, 1H), 6.89 (d, J=8.5 Hz, 1H), 6.20 (d, J=7.0 Hz,
1H), 4.30 (dd, J=9.0, 7.0 Hz, 1H), 2.75 (td, J=9.0, 5.5 Hz, 1H), 1.88–
1.74 (m, 1H), 1.69–1.54 (m, 1H), 1.12 ppm (t, J=7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=177.6, 161.1, 127.3 (q, J=4.0 Hz),
125.5, 124.2 (q, J=270.0 Hz), 123.7 (q, J=32.0 Hz), 123.7 (q, J=
3.5 Hz), 110.6, 91.0, 45.0, 44.9, 20.4, 12.6 ppm; IR (CHCl3): <GÇ=
3431, 1720 cmÀ1; ESI-HRMS: m/z calcd for C13H13O2NF3 [M+H]+:
272.0893; found: 272.0889.
1717 cmÀ1
;
ESI-HRMS: m/z calcd for C13H13O2NF3 [M+H]+:
272.0893; found: 272.0888.
Data for exo-3-ethyl-1,3,3a,8a-tetrahydro-7-methyl-2H-
benzofuro[2,3-b]pyrrol-2-one (exo-15e): White powder; m.p. 170–
1
1728C; H NMR (300 MHz, CDCl3): d=7.01–6.98 (m, 2H), 6.87 (brs,
Data
for
exo-3-ethyl-1,3,3a,8a-tetrahydro-5-methyl-2H-
1H), 6.84 (dd, J=8.0, 7.0 Hz, 1H), 6.10 (d, J=7.0 Hz, 1H), 3.84 (dd,
J=7.0, 3.0 Hz, 1H), 2.54–2.49 (m, 1H), 2.20 (s, 3H), 2.05–1.91 (m,
1H), 1.73–1.58 (m, 1H), 1.14 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=178.9, 156.1, 130.3, 127.8, 121.8, 121.6, 120.6,
90.4, 50.2, 47.6, 25.3, 15.2, 11.5 ppm; IR (CHCl3): n˜ =3431,
1712 cmÀ1; ESI-HRMS: m/z calcd for C13H16O2N [M+H]+: 218.1176;
found: 218.1170.
benzofuro[2,3-b]pyrrol-2-one (exo-15b): White solid; m.p. 161–
1
1638C; H NMR (300 MHz, CDCl3): d=6.98–6.95 (m, 3H), 6.69 (d, J=
8.5 Hz, 1H), 6.08 (d, J=7.5 Hz, 1H), 3.79 (dd, J=7.5, 3.0 Hz, 1H),
2.54–2.49 (m, 1H), 2.29 (s, 3H), 2.02–1.90 (m, 1H), 1.73–1.58 (m,
1H), 1.14 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=
178.9, 155.5, 131.1, 129.6, 128.5, 125.0, 109.9, 90.9, 50.1, 47.3, 25.3,
20.8, 11.5 ppm; IR (CHCl3): n˜ =3430, 1713 cmÀ1; ESI-HRMS: m/z
calcd for C13H16O2N [M+H]+: 218.1176; found: 218.1171.
Data
for
endo-3-ethyl-1,3,3a,8a-tetrahydro-7-methyl-2H-
benzofuro[2,3-b]pyrrol-2-one (endo-15e): White solid; m.p. 193–
1
Data
for
endo-3-ethyl-1,3,3a,8a-tetrahydro-5-methyl-2H-
1948C; H NMR (300 MHz, CDCl3): d=7.05 (d, J=7.5 Hz, 1H), 7.02
benzofuro[2,3-b]pyrrol-2-one (endo-15b): White solid; m.p. 171–
(d, J=8.0 Hz, 1H), 6.82 (dd, J=8.0, 7.5 Hz, 1H), 6.74 (brs, 1H), 6.10
(d, J=7.0 Hz, 1H), 4.27 (dd, J=9.0, 7.0 Hz, 1H), 2.70 (td, J=9.0,
5.0 Hz, 1H), 2.19 (s, 3H), 1.90–1.58 (m, 2H), 1.12 ppm (t, J=7.5 Hz,
3H); 13C NMR (75 MHz, CDCl3): d=177.7, 156.7, 130.5, 123.8, 123.6,
121.0, 120.7, 89.5, 45.6, 45.4, 20.1, 15.2, 12.9 ppm; IR (CHCl3): n˜ =
3431, 1712 cmÀ1; ESI-HRMS: m/z calcd for C13H16O2N [M+H]+:
218.1176; found: 218.1178.
1
1728C; H NMR (300 MHz, CDCl3): d=7.01–6.97 (m, 3H), 6.70 (d, J=
8.0 Hz, 1H), 6.07 (d, J=7.0 Hz, 1H), 4.21 (dd, J=9.0, 7.0 Hz, 1H),
2.69 (td, J=9.0, 5.0 Hz, 1H), 2.29 (s, 3H), 1.90–1.76 (m, 1H), 1.74–
1.59 (m, 1H), 1.13 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=177.9, 156.2, 130.4, 129.7, 126.9, 124.4, 110.0, 90.0, 45.4, 45.3,
20.9, 20.1, 12.8 ppm; IR (CHCl3):n˜ =3432, 1714 cmÀ1; ESI-HRMS: m/z
calcd for C13H16O2N [M+H]+: 218.1176; found: 218.1171.
Data
for
exo-7-bromo-3-ethyl-1,3,3a,8a-tetrahydro-2H-
Data
for
exo-5-bromo-3-ethyl-1,3,3a,8a-tetrahydro-2H-
benzofuro[2,3-b]pyrrol-2-one (exo-15 f): White solid; m.p. 170–
1728C; H NMR (300 MHz, CDCl3): d=7.34 (d, J=8.0 Hz, 1H), 7.09
1
benzofuro[2,3-b]pyrrol-2-one (exo-15c): White solid; m.p. 157–
1588C; H NMR (300 MHz, CDCl3): d=7.28 (d, J=8.5 Hz, 1H), 7.26
1
(d, J=7.5 Hz, 1H), 7.00 (brs, 1H), 6.82 (dd, J=8.0, 7.5 Hz, 1H), 6.20
(d, J=7.5 Hz, 1H), 3.92 (dd, J=7.5, 2.5 Hz, 1H), 2.54–2.49 (m, 1H),
2.05–1.91 (m, 1H), 1.74–1.59 (m, 1H), 1.14 ppm (t, J=7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=178.9, 155.6, 132.7, 130.4, 124.0,
123.5, 103.8, 91.5, 50.4, 48.5, 25.7, 11.9 ppm; IR (CHCl3): n˜ =3431,
(s, 1H), 6.70 (d, J=8.5 Hz, 1H), 6.42 (brs, 1H), 6.12 (d, J=7.5 Hz,
1H), 3.84 (dd, J=7.5, 3.0 Hz, 1H), 2.53–2.48 (m, 1H), 2.04–1.90 (m,
1H), 1.73–1.57 (m, 1H), 1.14 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=178.5, 156.9, 132.1, 131.0, 127.6, 113.4, 112.0,
91.4, 49.9, 47.1, 25.3, 11.4 ppm; IR (CHCl3): n˜ =3431, 1717 cmÀ1; ESI-
HRMS: m/z calcd for C12H13O2N79Br [M+H]+: 282.0124; found:
282.0119.
1716 cmÀ1
;
ESI-HRMS: m/z calcd for C12H13O2N79Br [M+H]+:
282.0124; found: 282.0119.
Data for endo-7-bromo-3-ethyl-1,3,3a,8a-tetrahydro-2H-
Data
for
endo-5-bromo-3-ethyl-1,3,3a,8a-tetrahydro-2H-
benzofuro[2,3-b]pyrrol-2-one (endo-15 f): White powder; m.p.
187–1888C; 1H NMR (300 MHz, CDCl3): d=7.37 (d, J=8.0 Hz, 1H),
7.16 (d, J=8.0 Hz, 1H), 6.82 (t, J=8.0 Hz, 1H), 6.45 (brs, 1H), 6.21
(d, J=7.0 Hz, 1H), 4.37 (dd, J=9.0, 7.0 Hz, 1H), 2.73 (td, J=9.0,
5.5 Hz, 1H), 1.89–1.75 (m, 1H), 1.70–1.55 (m, 1H), 1.12 ppm (t, J=
7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=177.1, 155.7, 132.5, 125.9,
125.4, 122.5, 103.6, 90.2, 46.2, 45.1, 20.2, 12.8 ppm; IR (CHCl3): n˜ =
3431, 1718 cmÀ1; ESI-HRMS: m/z calcd for C12H13O2N79Br [M+H]+:
282.0124; found: 282.0120.
benzofuro[2,3-b]pyrrol-2-one (endo-15c): White solid; m.p. 197–
1988C; H NMR (300 MHz, CDCl3): d=7.32–7.29 (m, 2H), 6.96 (brs,
1
1H), 6.71 (dd, J=9.0 Hz, 1H), 6.12 (d, J=7.5 Hz, 1H), 4.25 (dd, J=
9.0, 7.5 Hz, 1H), 2.71 (td, J=9.0, 5.0 Hz, 1H), 1.90–1.56 (m, 2H),
1.12 ppm (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=177.4,
157.6, 132.3, 129.3, 126.9, 113.0, 112.1, 90.5, 45.3, 45.1, 20.3,
12.8 ppm; IR (CHCl3): n˜ =3431, 1718 cmÀ1; ESI-HRMS: m/z calcd for
C12H13O2N79Br [M+H]+: 282.0124; found: 282.0120.
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
Data for endo-3-cyclopentyl-1,3,3a,8a-tetrahydro-2H-benzofuro-
[2,3-b]pyrrol-2-one (endo-13c): White solid; m.p. 150–1528C;
1H NMR (300 MHz, CDCl3): d=7.26 (d, J=7.5 Hz, 1H), 7.20 (dd, J=
8.0, 7.5 Hz, 1H), 6.91 (dd, J=8.0, 7.5 Hz, 1H), 6.81 (d, J=8.0 Hz,
1H), 6.55 (brs, 1H), 6.06 (d, J=7.5 Hz, 1H), 4.22 (dd, J=9.0, 7.5 Hz,
1H), 2.81 (dd, J=9.0, 7.0 Hz, 1H), 2.20–2.09 (m, 1H), 1.99–1.89 (m,
1H), 1.83–1.22 ppm (m, 7H); 13C NMR (75 MHz, CDCl3): d=177.3,
158.7, 129.4, 126.5, 125.1, 121.1, 110.3, 89.7, 47.2, 46.2, 38.1, 32.7,
29.1, 25.7, 24.8 ppm; IR (CHCl3): n˜ =3431, 1713 cmÀ1; ESI-HRMS: m/
z calcd for C15H18O2N [M+H]+: 244.1332; found: 244.1329.
General procedure for domino reaction of conjugated oxime
ether with RI
RI (12.0 mmol) and Et3B (1.0m in hexane, 1.0 mmol) were added to
a solution of 11 (0.2 mmol) in benzene (5 mL) under an N2 atmos-
phere at reflux. After being stirred for 1 h, the reaction mixture
was diluted with H2O extracted with CHCl3. The organic phase was
dried over MgSO4 and concentrated under reduced pressure. The
crude product was purified by PTLC (hexane/AcOEt=1:2) to afford
the corresponding benzofuro[2,3-b]pyrrol-2-one 13a–c.
Data for exo-1,2,3a,8a-tetrahydro-2-oxo-3H-benzofuro[2,3-b]pyr-
role-3-acetic acid ethyl ester (exo-13a): Colorless crystals; m.p.
151–1538C; 1H NMR (300 MHz, CDCl3): d=7.35 (d, J=7.0 Hz, 1H),
7.19 (t, J=7.5 Hz, 1H), 7.10 (brs, 1H), 6.94 (t, J=7.5 Hz, 1H), 6.81
(d, J=7.5 Hz, 1H), 6.15 (d, J=7.0 Hz, 1H), 4.23 (q, J=7.0 Hz, 2H),
3.96 (dd, J=7.0, 3.0 Hz, 1H), 3.00–2.90 (m, 2H), 2.76–2.66 (m, 1H),
1.31 ppm (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=177.5,
171.4, 157.6, 129.4, 128.1, 125.0, 121.8, 110.3, 90.8, 61.1, 47.6, 45.0,
36.0, 14.2 ppm; IR (CHCl3): n˜ =3430, 1725 cmÀ1; ESI-HRMS: m/z
calcd for C14H16O4N [M+H]+: 262.1074; found: 262.1081.
General procedure for domino reaction of conjugated oxime
ether with tBuI
tBuI (12.0 mmol) and Et3B (1.0m in hexane, 1.0 mmol) were added
to a solution of 11 (0.2 mmol) and Na2S2O3 (0.7 mmol) in benzene
(5 mL) under an N2 atmosphere at reflux. After being stirred for
30 min, the reaction mixture was diluted with 10% Na2S2O3 solu-
tion and extracted with CHCl3. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The crude prod-
uct was purified by PTLC (hexane/AcOEt=1:2) to afford the corre-
sponding benzofuro[2,3-b]pyrrol-2-one 13d and 16a–g.
Data for endo-1,2,3a,8a-tetrahydro-2-oxo-3H-benzofuro[2,3-
b]pyrrole-3-acetic acid ethyl ester (endo-13a): Colorless crystals;
m.p. 151–1538C; 1H NMR (300 MHz, CDCl3): d=7.20 (t, J=8.0 Hz,
1H), 7.04 (d, J=7.5 Hz, 1H), 6.89 (t, J=7.5 Hz, 1H), 6.82 (d, J=
8.0 Hz, 1H), 6.79 (brs, 1H), 6.17 (d, J=7.0 Hz, 1H), 4.43 (dd, J=9.5,
7.0 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 3.34 (ddd, J=10.5, 9.5, 3.5 Hz,
1H), 2.92 (dd, J=18.0, 3.5 Hz, 1H), 2.48 (dd, J=18.0, 10.5 Hz, 1H),
1.29 ppm (t, J=7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=176.9,
172.2, 158.3, 129.5, 126.1, 123.9, 121.1, 110.5, 90.3, 61.0, 44.9, 40.3,
32.3, 14.1 ppm; IR (CHCl3): n˜ =3432, 1721 cmÀ1; ESI-HRMS: m/z
calcd for C14H16O4N [M+H]+: 262.1074; found: 262.1069.
Data
for
exo-1,3,3a,8a-tetrahydro-3-(1,1-dimethylethyl)-2H-
benzofuro[2,3-b]pyrrol-2-one (exo-13d): White solid; m.p. 181–
1
1828C; H NMR (500 MHz, CDCl3): d=7.17 (dd, J=8.0, 7.5 Hz, 1H),
7.13 (d, J=7.5 Hz, 1H), 6.94 (dd, J=8.0, 7.5 Hz, 1H), 6.80 (d, J=
8.0 Hz, 1H), 6.52 (brs, 1H), 6.03 (d, J=7.0 Hz, 1H), 3.97 (dd, J=7.0,
2.5 Hz, 1H), 2.36 (d, J=2.5 Hz, 1H), 1.15 ppm (s, 9H); 13C NMR
(125 MHz, CDCl3): d=177.2, 157.5, 129.2, 128.9, 124.6, 121.8, 110.4,
90.3, 58.9, 45.3, 33.4, 27.6 ppm (3C); IR (CHCl3): n˜ =3431,
1712 cmÀ1; ESI-HRMS: m/z calcd for C14H18O2N [M+H]+: 232.1332;
found: 232.1324.
Data
for
exo-1,3,3a,8a-tetrahydro-3-(1-methylethyl)-2H-
Data for exo-5-trifluoromethyl-1,3,3a,8a-tetrahydro-3-(1,1-dime-
thylethyl)-2H-benzofuro[2,3-b]pyrrol-2-one (exo-16a): White
solid; m.p. 224–2258C; 1H NMR (300 MHz, CDCl3): d=7.46 (d, J=
8.5 Hz, 1H), 7.35 (s, 1H), 6.88 (brs, 1H), 6.87 (d, J=8.5 Hz, 1H), 6.12
(d, J=7.0 Hz, 1H), 3.99 (dd, J=7.0, 2.5 Hz, 1H), 2.36 (d, J=2.5 Hz,
1H), 1.16 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=177.0, 160.3,
129.9, 127.1 (q, J=4.0 Hz), 124.3 (q, J=32.5 Hz), 124.2 (q, J=
270.0 Hz), 122.0 (q, J=4.0 Hz), 110.5, 91.4, 58.7, 44.7, 33.5,
27.5 ppm (3C); IR (CHCl3): n˜ =3431, 1712 cmÀ1; ESI-HRMS: m/z
calcd for C15H17O2NF3 [M+H]+: 300.1206; found: 300.1206.
benzofuro[2,3-b]pyrrol-2-one (exo-13b): White solid; m.p. 155–
1568C; H NMR (300 MHz, CDCl3): d=7.17 (dd, J=8.0, 7.5 Hz, 1H),
1
7.12 (d, J=7.5 Hz, 1H), 7.00 (brs, 1H), 6.93 (dd, J=8.0, 7.5 Hz, 1H),
6.80 (d, J=8.0 Hz, 1H), 6.06 (d, J=7.5 Hz, 1H), 3.87 (dd, J=7.5,
3.0 Hz, 1H), 2.56 (dd, J=4.0, 3.0 Hz, 1H), 2.39–2.28 (m, 1H), 1.18 (d,
J=7.0 Hz, 3H), 0.97 ppm (d, J=7.0 Hz, 3H); 13C NMR (75 MHz,
CDCl3): d=178.3, 157.6, 129.1, 128.8, 124.5, 121.7, 110.4, 90.9, 55.1,
43.6, 29.1, 20.7, 17.6 ppm; IR (CHCl3): n˜ =3430, 1712 cmÀ1; ESI-
HRMS: m/z calcd for C13H16O2N [M+H]+: 218.1176; found:
218.1167.
Data for exo-1,3,3a,8a-tetrahydro-5-methyl-3-(1,1-dimethyleth-
yl)-2H-benzofuro[2,3-b]pyrrol-2-one (exo-16b): White solid; m.p.
186–1878C; 1H NMR (300 MHz, CDCl3): d=6.95 (d, J=8.0 Hz, 1H),
6.91 (s, 1H), 6.86 (brs, 1H), 6.68 (d, J=8.0 Hz, 1H), 6.00 (d, J=
7.0 Hz, 1H), 3.91 (dd, J=7.0, 2.5 Hz, 1H), 2.35 (d, J=2.5 Hz, 1H),
2.29 (s, 3H), 1.15 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=177.4,
155.3, 131.1, 129.5, 128.8, 125.0, 109.9, 90.5, 58.9, 45.2, 33.4, 27.6
(3C), 20.8 ppm; IR (CHCl3): n˜ =3431, 1705 cmÀ1; ESI-HRMS: m/z
calcd for C15H20O2N [M+H]+: 246.1489; found: 246.1492.
Data
for
endo-1,3,3a,8a-tetrahydro-3-(1-methylethyl)-2H-
benzofuro[2,3-b]pyrrol-2-one (endo-13b): White solid; m.p. 194–
1958C; H NMR (500 MHz, CDCl3): d=7.25 (d, J=7.5 Hz, 1H), 7.20
1
(dd, J=8.0, 7.5 Hz, 1H), 6.92 (dd, J=8.0, 7.5 Hz, 1H), 6.80 (d, J=
8.0 Hz, 1H), 6.34 (brs, 1H), 6.07 (dd, J=7.5, 1.5 Hz, 1H), 4.25 (dd,
J=10.0, 7.5 Hz, 1H), 2.66 (dd, J=10.0, 5.0 Hz, 1H), 2.11–2.05 (m,
1H), 1.22 (d, J=6.5 Hz, 3H), 0.71 ppm (d, J=6.5 Hz, 3H); 13C NMR
(125 MHz, CDCl3): d=177.2, 158.9, 129.4, 126.4, 124.8, 121.1, 110.1,
89.9, 48.2, 45.5, 27.0, 23.2, 17.9 ppm; IR (CHCl3): n˜ =3432,
1713 cmÀ1; ESI-HRMS: m/z calcd for C13H16O2N [M+H]+: 218.1176;
found: 218.1168.
Data for exo-5-bromo-1,3,3a,8a-tetrahydro-3-(1,1-dimethyleth-
yl)-2H-benzofuro[2,3-b]pyrrol-2-one (exo-16c): White solid; m.p.
1
215–2178C; H NMR (300 MHz, CDCl3): d=7.26 (dd, J=8.5, 2.0 Hz,
Data for exo-3-cyclopentyl-1,3,3a,8a-tetrahydro-2H-benzofuro-
[2,3-b]pyrrol-2-one (exo-13c): White solid; m.p. 138–1408C;
1H NMR (300 MHz, CDCl3): d=7.19–7.12 (m, 3H), 6.92 (t, J=7.5 Hz,
1H), 6.80 (d, J=8.0 Hz, 1H), 6.08 (d, J=7.5 Hz, 1H), 3.85 (dd, J=
7.5, 2.5 Hz, 1H), 2.63 (dd, J=6.5, 2.5 Hz, 1H), 2.37–2.24 (m, 1H),
2.03–1.43 (m, 7H), 1.34–1.22 ppm (m, 1H); 13C NMR (75 MHz,
CDCl3): d=178.4, 157.6, 129.2, 128.6, 124.6, 121.7, 110.4, 90.8, 52.2,
45.8, 41.9, 30.5, 29.3, 25.2, 25.0 ppm; IR (CHCl3): n˜ =3430,
1713 cmÀ1; ESI-HRMS: m/z calcd for C15H18O2N [M+H]+: 244.1332;
found: 244.1328.
1H), 7.21 (s, 1H), 7.12 (brs, 1H), 6.67 (d, J=8.5 Hz, 1H), 6.04 (d, J=
7.5 Hz, 1H), 3.93 (dd, J=7.5, 2.5 Hz, 1H), 2.33 (d, J=2.5 Hz, 1H),
1.14 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=177.2, 156.8, 132.0,
131.4, 127.5, 113.4, 112.0, 91.1, 58.7, 45.0, 33.4, 27.5 ppm (3C); IR
(CHCl3): n˜ =3431, 1710 cmÀ1; ESI-HRMS: m/z calcd for C14H17O2N79Br
[M+H]+: 310.0437; found: 310.0444.
Data for exo-7-trifluoromethyl-1,3,3a,8a-tetrahydro-3-(1,1-dime-
thylethyl)-2H-benzofuro[2,3-b]pyrrol-2-one (exo-16d): White
solid; m.p. 178–1808C; 1H NMR (300 MHz, CDCl3): d=7.41 (d, J=
&
&
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
8.0 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.01 (dd, J=8.0, 7.5 Hz, 1H),
6.66 (brs, 1H), 6.17 (d, J=7.0 Hz, 1H), 3.99 (dd, J=7.0, 3.0 Hz, 1H),
2.35 (d, J=3.0 Hz, 1H), 1.16 ppm (s, 9H); 13C NMR (75 MHz, CDCl3):
d=176.7, 154.8, 131.2, 128.2, 126.0 (q, J=4.5 Hz), 123.1 (q, J=
270.0 Hz), 121.5, 113.6 (q, J=33.0 Hz), 91.7, 58.7, 44.5, 33.5,
27.5 ppm (3C); IR (CHCl3): n˜ =3427, 1710 cmÀ1; ESI-HRMS: m/z
calcd for C15H17O2NF3 [M+H]+: 300.1206; found: 300.1204.
warmed up to reflux. After being stirred for 2 h, the reaction mix-
ture was diluted with Rochelle salt aqueous solution (1.0m, 15 mL)
and extracted with CHCl3. The organic phase was dried over
MgSO4 and concentrated under reduced pressure. The crude prod-
uct was purified by PTLC (hexane/AcOEt=1:2) to afford benzofuro-
[2,3-b]pyrrol-2-one 20 (23 mg, 57%).
Data for (3S,3aS,8aR)-3-ethyl-1,3,3a,8a-tetrahydro-2H-benzofuro-
[2,3-b]pyrrol-2-one (20): [a]2D5 =À114.0 (c=1.00 in CHCl3, 93% ee);
the enantiomeric purity was determined by HPLC analysis (Daicel
CHIRALCEL OD-H, hexane/iPrOH=80:20, flow rate=1.0 mLminÀ1
,
Data for exo-1,3,3a,8a-tetrahydro-7-methyl-3-(1,1-dimethyleth-
yl)-2H-benzofuro[2,3-b]pyrrol-2-one (exo-16e): White solid; m.p.
1
206–2078C; H NMR (300 MHz, CDCl3): d=6.99–6.94 (m, 3H), 6.83
(t, J=7.5 Hz, 1H), 6.01 (d, J=7.0 Hz, 1H), 3.94 (dd, J=7.0, 2.5 Hz,
1H), 2.34 (d, J=2.5 Hz, 1H), 2.19 (s, 3H), 1.14 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=177.6, 155.9, 130.2, 128.1, 121.8, 121.6, 120.5,
90.1, 59.0, 45.4, 33.3, 27.6 (3C), 15.1 ppm; IR (CHCl3): n˜ =3431,
1705 cmÀ1; ESI-HRMS: m/z calcd for C15H20O2N [M+H]+: 246.1489;
found: 246.1490.
l=254 nm, retention times: 9.77 min [minor] and 12.86 min
[major]).
Acknowledgements
Data for exo-4-(trifluoromethyl)-1,3,3a,8a-tetrahydro-3-(1,1-di-
methylethyl)-2H-benzofuro[2,3-b]pyrrol-2-one (exo-16g): White
solid; m.p. 169–1718C; H NMR (300 MHz, CDCl3): d=7.31 (dd, J=
8.0, 7.5 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.66
(brs, 1H), 6.09 (d, J=6.5 Hz, 1H), 4.18 (d, J=6.5 Hz, 1H), 2.71 (s,
1H), 1.13 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=176.8, 158.6,
129.8, 127.8 (q, J=32.5 Hz), 125.7, 123.6 (q, J=271.0 Hz), 119.3 (q,
J=5.0 Hz), 114.6, 90.9, 56.9, 46.4, 33.7, 27.7 ppm (3C); IR (CHCl3):
n˜ =3431, 1710 cmÀ1; ESI-HRMS: m/z calcd forC15H17O2NF3 [M+H]+:
300.1206; found: 300.1199.
This work was supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
(MEXT), the MEXT-Supported Program for the Strategic Re-
search Foundation at Private Universities, and Takeda Science
Foundation. M.U. is grateful to the Mitsubishi Chemical Award
in Synthetic Organic Chemistry of Japan.
1
Keywords: domino reaction · heterocycles · radical reactions ·
rearrangement · synthetic methods
Data for exo-6-(trifluoromethyl)-1,3,3a,8a-tetrahydro-3-(1,1-di-
methylethyl)-2H-benzofuro[2,3-b]pyrrol-2-one (exo-16g’): White
[1] N. Lindquist, W. Fenical, G. D. V. Duyne, J. Clardy, J. Am. Chem. Soc.
1991, 113, 2303–2304.
1
solid; m.p. 172–1748C; H NMR (300 MHz, CDCl3): d=7.21 (m, 2H),
7.08 (brs, 1H), 7.03 (s, 1H), 6.11 (d, J=7.0 Hz, 1H), 3.99 (dd, J=7.0,
3.0 Hz, 1H), 2.35 (d, J=3.0 Hz, 1H), 1.16 ppm (s, 9H); 13C NMR
(75 MHz, CDCl3): d=177.1, 157.9, 133.1 (d, J=1.0 Hz), 131.7 (q, J=
32.0 Hz), 124.9, 123.8 (q, J=271.0 Hz), 118.8 (q, J=4.0 Hz), 107.6 (q,
J=4.0 Hz), 91.2, 58.7, 44.9, 33.5, 27.5 ppm (3C); IR (CHCl3): n˜ =
3431, 1710 cmÀ1; ESI-HRMS: m/z calcd for C15H17O2NF3 [M+H]+:
300.1206; found: 300.1200.
[2] a) R. R. Knowles, J. Carpenter, S. B. Blakey, A. Kayano, I. K. Mangion, C. J.
Sinz, D. W. C. MacMillan, Chem. Sci. 2011, 2, 308–311; b) K. C. Nicolaou,
D. Y.-K. Chen, X. Huang, T. Ling, M. Bella, S. A. Snyder, J. Am. Chem. Soc.
2004, 126, 12888–12896; c) A. W. G. Burgett, Q. Li, Q. Wei, P. G. Harran,
Angew. Chem. 2003, 115, 5111–5116; Angew. Chem. Int. Ed. 2003, 42,
4961–4966.
[3] a) Z. Cruz-Monserrate, H. C. Vervoort, R. Bai, D. J. Newman, S. B. Howell,
G. Los, J. T. Mullaney, M. D. Williams, G. R. Pettit, W. Fenical, E. Hamel,
Mol. Pharmacol. 2003, 63, 1273–1280; b) G. Wang, L. Shang, A. W. G.
Burgett, P. G. Harran, X. Wang, Proc. Natl. Acad. Sci. USA 2007, 104,
2068–2073.
[4] R. Beaud, R. Guillot, C. Kouklovsky, G. Vincent, Angew. Chem. 2012, 124,
12714–12718; Angew. Chem. Int. Ed. 2012, 51, 12546–12550.
[5] S. Ghosh, L. K. Kinthada, S. Bhunia, A. Bisai, Chem. Commun. 2012, 48,
10132–10134.
[6] a) C. Poriel, M. Lachia, C. Wilson, J. R. Davies, C. J. Moody, J. Org. Chem.
2007, 72, 2978–2987; b) P. Magnus, R. Turnbull, Tetrahedron Lett. 2006,
47, 6461–6464; c) M. A. Zajac, E. Vedejs, Org. Lett. 2004, 6, 237–240.
[7] For recent report for the synthesis of furo[2,3-b]indolines, see: a) G.
Cera, P. Crispino, M. Monari, M. Bandini, Chem. Commun. 2011, 47,
7803–7805; b) M. B. Calvert, J. Sperry, Tetrahedron Lett. 2012, 53, 5426–
5429.
3-Hydroxy-4-(phenoxyimino)-2-(phenylthio)butanoic acid
2,3,4,5,6-pentafluorophenyl ester (17)
Thiophenol (77 mg, 0.7 mmol) and Et3B (1.0m in hexane, 0.1 mL,
0.1 mmol) were added to a solution of 11 (71 mg, 0.2 mmol) in
benzene (5 mL) under an air atmosphere at room temperature.
After being stirred for 18 h, the reaction mixture was concentrated
under reduced pressure. Purification of the residue by medium-
pressure column chromatography (hexane/AcOEt=10:1) afforded
17 (72 mg, 74%) as a 1:2:5:10 mixture of stereoisomers. Yellow oil;
1H NMR (300 MHz, CDCl3): d=8.00 (d, J=5.0 Hz, 10/18H), 8.00 (d,
J=4.0 Hz, 5/18H), 7.63–7.58 (m, 2H), 7.38–7.25 (m, 5H), 7.17–7.01
(m, 3H + 3/18H), 4.94–4.85 (m, 1H), 4.49 (d, J=3.5 Hz, 1/18H),
4.36 (d, J=7.0 Hz, 2/18H), 4.27 (d, J=7.0 Hz, 5/18H), 4.18 (d, J=
8.0 Hz, 10/18H), 3.28 ppm (m, 1H); 13C NMR (75 MHz, CDCl3): d=
166.6, 158.8, 150.9, 150.7, 134.1, 134.0, 131.2, 130.9, 129.6, 129.5,
129.4 (2C), 129.3, 122.9, 122.8, 114.8, 114.5, 69.4, 68.5, 55.4,
54.3 ppm; IR (neat): n˜ =3446, 1780 cmÀ1; ESI-HRMS: m/z calcd for
C22H15O4NF5S [M+H]+: 484.0636; found: 484.0638.
[8] T. Tsuritani, H. Shinokubo, K. Oshima, J. Org. Chem. 2003, 68, 3246–
3250.
[9] A. Padwa, S. Nara, Q. Wang, J. Org. Chem. 2005, 70, 8538–8549.
[10] J.-L. Avril, B. Marcot, M. Coquillay, C. D. Rango, H. Moskowitz, J. Mayrar-
gue, New J. Chem. 1999, 23, 743–748.
[11] K. Harada, E. Kaji, K. Takahashi, S. Zen, Chem. Pharm. Bull. 1994, 42,
1562–1566.
[12] a) S. S. Soman, T. H. Thaker, J. Chem. Res. 2010, 34, 502–505; b) D. T.
Connor, M. V. Strandtmann, J. Org. Chem. 1973, 38, 3874–3877.
[13] T. Sheradsky, Tetrahedron Lett. 1966, 7, 5225–5227.
[14] For selected example, see: a) T. J. Maimone, S. L. Buchwald, J. Am.
Chem. Soc. 2010, 132, 9990–9991; b) Y. Liu, J. Qian, S. Lou, Z. Xu, J. Org.
Chem. 2010, 75, 6300–6303; c) F. Contiero, K. M. Jones, E. A. Matts, A.
Porzelle, N. C. O. Tomkinson, Synlett 2009, 3003–3006; d) A. Alemagna,
C. Baldoli, P. Del Buttero, E. Licandro, S. Maiorana, Synthesis 1987, 192–
196.
Asymmetric synthesis of benzofuro[2,3-b]pyrrol-2-one 20
Et3B (1.0m in hexane, 0.4 mL, 0.4 mmol) was added to a solution of
19 (78 mg, 0.2 mmol) in MeCN (5 mL) under an N2 atmosphere at
À408C. After being stirred for 1 h, Me3Al (1.1m in hexane, 0.65 mL,
0.72 mmol) was added dropwise and the resulting solution was
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Full Paper
[15] For the synthesis of 2-aminodihydrobenzofuran, see: a) N. Takeda, M.
Ueda, S. Kagehira, H. Komei, N. Tohnai, M. Miyata, T. Naito, O. Miyata,
Org. Lett. 2013, 15, 4382–4385; b) N. Takeda, O. Miyata, T. Naito, Eur. J.
Org. Chem. 2007, 1491–1509; c) J.-Y. Laronze, R. E. Boukili, D. Cartier, J.
Laronze, J. Lꢂvy, Tetrahedron Lett. 1989, 30, 2229–2232.
[16] a) M. Ueda, H. Miyabe, H. Sugino, O. Miyata, T. Naito, Angew. Chem.
2005, 117, 6346–6349; Angew. Chem. Int. Ed. 2005, 44, 6190–6193;
b) M. Ueda, H. Matsubara, K. Yoshida, A. Sato, T. Naito, O. Miyata, Chem.
Eur. J. 2011, 17, 1789–1792.
[17] Reported examples of the combination of radical reaction and sigma-
tropic rearrangement, see: a) J. W. Tucker, C. R. J. Stephenson, Org. Lett.
2011, 13, 5468–5471; b) D. P. Curran, Y. Nishii, J. Am. Chem. Soc. 1999,
121, 8955–8956; c) E. J. Enholm, K. M. Moran, P. E. Whitley, M. A. Battiste,
J. Am. Chem. Soc. 1998, 120, 3807–3808; d) B. F. Strick, D. A. Mundal,
R. J. Thomson, J. Am. Chem. Soc. 2011, 133, 14252–14255; e) H. Naga-
shima, H. Wakamatsu, N. Ozaki, T. Ishii, M. Watanabe, T. Tajima, K. Itoh, J.
Org. Chem. 1992, 57, 1682–1689.
[18] a) L. F. Tietze, G. Brasche, K. M. Gericke in Domino Reactions in Organic
Synthesis Wiley-VCH, Weinheim, 2006; b) Z. Xu, F. De Moliner, A. P. Cap-
pelli, C. Hulme, Angew. Chem. 2012, 124, 8161–8164; Angew. Chem. Int.
Ed. 2012, 51, 8037–8040.
[19] For the efficient generation of an alkyl radical from an ethyl radical,
higher temperature was required, see: H. Miyabe, M. Ueda, N. Yoshioka,
K. Yamakawa, T. Naito, Tetrahedron 2000, 56, 2413–2420.
[20] T. Yajima, H. Nagano, Org. Lett. 2007, 9, 2513–2515.
[21] M. Ueda, H. Miyabe, H. Shimizu, H. Sugino, O. Miyata, T. Naito, Angew.
Chem. 2008, 120, 5682–5686; Angew. Chem. Int. Ed. 2008, 47, 5600–
5604.
[22] a) O. Miyata, S. Takahashi, A. Tamura, M. Ueda, T. Naito, Tetrahedron
2008, 64, 1270–1284; b) E. Godineau, K. Schenk, Y. Landais, J. Org.
Chem. 2008, 73, 6983–6993.
[23] a) M. Ueda, A. Ono, D. Nakao, K. Matsuno, T. Naito, O. Miyata, Tetrahe-
dron 2013, 69, 6866–6874; b) M. Ueda, H. Miyabe, H. Sugino, T. Naito,
Org. Biomol. Chem. 2005, 3, 1124–1128.
[24] a) J. G. Stack, D. P. Curran, S. V. Geib, J. Rebek, Jr., P. Ballester, J. Am.
Chem. Soc. 1992, 114, 7007–7018; b) B. H. Kim, D. P. Curran, Tetrahedron
1993, 49, 293–318.
[25] The absolute configurations at the newly formed stereocenters were
deduced by our previous results and NMR studies (see reference [17a]).
Received: February 17, 2014
Published online on && &&, 0000
&
&
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
8
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Synthetic Methods
M. Ueda, Y. Ito, Y. Ichii, M. Kakiuchi,
H. Shono, O. Miyata*
&& – &&
Straightforward, efficient, and elegant:
Synthesis of benzofuro[2,3-b]pyrrol-2-
ones from a conjugated oxime ether by
a novel domino reaction through a radi-
cal addition/[3,3]-sigmatropic rearrange-
ment/cyclization/lactamization cascade
was developed. This domino reaction
employing readily accessible starting
material allows the construction of two
heterocycles and three stereogenic cen-
ters as a result of the formation of two
CÀC bonds, a CÀO bond and a CÀN
bond in a single operation.
Direct Synthesis of Benzofuro[2,3-
b]pyrroles through a Radical
Addition/[3,3]-Sigmatropic
Rearrangement/Cyclization/
Lactamization Cascade
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
9
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ