Preparation of functional benzofurans and indoles via chemoselective intramolecular Wittig reactions

Article abstract of DOI:10.1039/c2cc33972b

A general preparation of new types of benzofurans, benzothiophenes and indoles is realized via chemoselective intramolecular Wittig reactions with the corresponding ester, thioester and amide functionalities using in situ formed phosphorus ylides as key i

Full text of DOI:10.1039/c2cc33972b

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COMMUNICATION
Preparation of functional benzofurans and indoles via chemoselective
intramolecular Wittig reactionsw
Yu-Ting Lee,z Yeong-Jiunn Jang,z Siang-en Syu, Shu-Chi Chou, Chia-Jui Lee and
Wenwei Lin*
Received 3rd June 2012, Accepted 22nd June 2012
DOI: 10.1039/c2cc33972b
A general preparation of new types of benzofurans, benzothiophenes
and indoles is realized via chemoselective intramolecular Wittig
reactions with the corresponding ester, thioester and amide function-
alities using in situ formed phosphorus ylides as key intermediates.
The reaction conditions are very mild, and numerous Michael
acceptors and commercially available acid chlorides can be
applied very efficiently in a one-step procedure.
Scheme 1 Chemoselective intramolecular Wittig reactions of 3.
The exploration of chemoselectivity of reactions always attracts
scientists attention because of their importance in the synthesis of
Table 1 Formation of benzofuran derivatives via intramolecular
Wittig reactionsa
complex structures of molecules such as natural products.1
Accordingly, many synthetic chemists took great efforts to
develop novel protocols or even new reagents with good chemo-
selectivity for the synthesis of a molecule, which bears more than
one sensitive functional group.2 The Wittig reaction, which was
firstly reported by George Wittig, is one of the most powerful
reactions for carbon–carbon double bond formation and has
numerous important applications in organic synthesis.3,4 How-
ever, among all the literature concerning the studies of chemo-
selectivity for known reactions or reagents, few of them are
reported with intramolecular Wittig reactions. For our interest in
the study of chemoselective intramolecular Wittig reactions, we
therefore proposed the intermediates 3 with two possibly reacting
ester functions and a phosphorus ylide moiety, which can be
prepared from the corresponding Michael acceptors 1, Et3N, Bu3P,
and acid chlorides 2.5 The phosphorus ylides with two possibly
reactive functionalities such as an ester and an amide will also be
investigated. Herein, we wish to report the preparation of highly
functional benzofurans, indoles, and benzothiophenes via chemo-
selective intramolecular Wittig reactions from the corresponding
phosphorus ylides (Scheme 1 and Tables 1 and 2 and Scheme 4).6–8
Firstly, we started to investigate the chemoselectivity of
phosphorus ylide and two possibly reacting benzoate moieties
(FG = H, R1 = R2 = R3 = Ph) within one equal molecular
b,c,d
Entry FG, R1, R2, R3
Time/min Yield of 4 or 40
(%)
1
2
3
H, Ph, Ph, Ph
4-Cl, Ph, Ph, Ph
4-Br, Ph, Ph, Ph
40
20
20
10
60
60
40
70
60
40
90
90
7 h
10
4ae, 89
4b, 92
4c, 89
4d, 90
4e, 87
4f, 91
4g, 90
4h, 74
4i, 80
4j, 80
4k, 78
4l, 71
4m, 54; 40m, 29
4n, 83
4o, 73
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18f
4,6-Cl2, Ph, Ph, Ph
4-MeO, Ph, Ph, Ph
H, 4-BrC6H4, Ph, Ph
H, 3-ClC6H4, Ph, Ph
H, 4-MeOC6H4, Ph, Ph
H, 2-BrC6H4, Ph, Ph
H, CH3, Ph, Ph
H, i-Pr, Ph, Ph
H, c-Hexyl, Ph, Ph
H, t-Bu, Ph, Ph
4-Br, Ph, 2-BrC6H4, Ph
4-Br, Ph, 4-MeOC6H4, Ph 90
4-Br, Ph, c-Hexyl, Ph 2 h
H, t-Bu, Ph, 4-NO2C6H4 40
4p, 85
4q, 5; 40qe, 76
4r, 71
H, t-Bu, Ph, t-Bu
30 h
a
Reactions were performed with 1 (0.5 mmol), 2 (1.1 equiv.), Bu3P
(1.2 equiv.), and Et3N (1.3 equiv.) in dry THF (1 mL) under nitrogen.
Isolated yield. c All the structures of 4 and 40 were also confirmed by
b
d
deacylation (see ESI). In the case of 4a–l, 4n–p, and 4r, there is no
Department of Chemistry, National Taiwan Normal University, 88,
Sec. 4, Tingchow Road, Taipei 11677, Taiwan, R.O.C.
E-mail: wenweilin@ntnu.edu.tw; Fax: +886 229324249
w Electronic supplementary information (ESI) available. CCDC
865909–865911 (4a, 8, 40q), 866846 (20a), 866847 (20b), 869630
(19a), 874692 (18d), 874693 (17e), 876151 (22b). For ESI and crystal-
lographic data in CIF or other electronic format see DOI: 10.1039/
c2cc33972b
observation of formation of 40. e The structures of 4a (CCDC 865909) and
40q (CCDC 865911) were determined by X-ray analysis. f Bu3P (3.0 equiv.),
pivaloyl chloride (1.3 equiv.), and Et3N (1.5 equiv.) were used.
structure 3a. After the treatment of 1a with benzoyl chloride
(2a, 1.1 equiv.), Bu3P (1.2 equiv.) and Et3N (1.3 equiv.) at
room temperature, the corresponding functional benzofuran 4a
z These authors have contributed equally to this work.
c
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Chem. Commun., 2012, 48, 8135–8137 8135

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Table 2 Formation of indole derivatives via intramolecular Wittig
reactionsa
Scheme 2 Synthesis of functional benzofuran 7 via twice chemoselective
Entry
R1
R2
Time/h
Yield of 17–20b,c,d (%)
intramolecular Wittig reactions.
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Boc
Cbz
Ts
1.5
2
8
1.5
3
3
5
2
2
1.5
1.5
3
3
4
17a, 80
18a, 82
(83%, 10 min), 4o (73%, 90 min) or 4p (85%, 2.0 h) accompanying
the same chemoselectivity as that of 1c (entries 3 and 14–16). In
the case of 3q with two possibly reacting ester functionalities
(R1 = t-Bu, R3 = 4-NO2C6H4), the intramolecular Wittig
reaction of the R3CO2 group and the phosphorus ylide function-
ality favored to yield the furan 40q as the major product (76%,
40 min) (entry 17 vs. entry 13). Remarkably, when the t-butyl
group was employed as the R1 group as well as the R3 group, the
expected intramolecular Wittig reaction of 3r proceeded chemo-
selectively to provide the benzofuran 4r in 71% yield, albeit a
longer reaction time (30 h, entry 18). It is also worth mentioning
that the stereochemistry of all adducts 4a–r is Z-configuration.
Our developed protocol can be even employed nicely with a
complex structure such as the substrate 5 (Scheme 2). After
treatment of 5 (0.5 mmol) with 2a (1.1 mmol), Bu3P (1.2 mmol)
and Et3N (1.3 mmol), the resulting presumable intermediate 6
with two phosphorus ylides and four ester functionalities
underwent chemoselective intramolecular Wittig reactions
smoothly (RT, 1 h) to give the highly functional benzofuran
7 in 78% yield.
19ae, 81
17b, 77
17c, 67
4-MeOC6H4
2-BrC6H4
CH3
Boc
Boc
Boc
Boc
Boc
Cbz
Cbz
Cbz
Cbz
Bn
17d, 75
i-Pr
17ee, 80
17f, 70
18b, 73
CO2Et
4-MeOC6H4
4-BrC6H4
3-ClC6H4
i-Pr
9
10
11
12
13
14
15
16
18c, 80
18de, 79
18e, 75; 180e, 3
20ae, 88
20be, 82
20c, 89
Ph
4-MeOC6H4
4-ClC6H4
i-Pr
Bn
Bn
Bn
2
24
20d, 12; 200d, 50
a
Reactions were performed with 9–12 (0.5 mmol), 2 (1.1 equiv.), Bu3P
(1.2 equiv.), and Et3N (1.3 equiv.) in dry THF (1 mL) under nitrogen.
b
c
Isolated yield. All the structures of 17–20 were determined by
1H NMR in comparison with 19a and 20a–c. In the case of 17a–f,
d
18a–d, 19a, and 20a–c, there is no observation of formation of 170–200.
e
The structures of 19a (CCDC 869630), 17e (CCDC 874693), 18d
(CCDC 874692), 20a (CCDC 866846), and 20b (CCDC 866847) were
determined by X-ray analysis.
A two-step, controlled experiment was carried out to demon-
strate the existence of the intermediate 8 as the precursor of the
corresponding phosphorus ylide in our preliminary studies
(Scheme 3).9 In the absence of Et3N, the phosphonium chloride
8, which was formed via the 1,4-addition of Bu3P toward 1a
followed by acylation of 2a, can be observed in the crude
1H NMR study. There is no formation of the desired benzofuran
4a until Et3N was added, and then 8 was transformed into 4a in
88% yield. Interestingly, the intermediate 8 can be purified simply
by washing the crude reaction mixture with pentane and its
structure was confirmed by X-ray analysis (CCDC 865910).
We then turned our attention to the chemoselectivity of
intramolecular Wittig reactions in the designed systems 13–16
with the phosphorus ylide, an amide, and an ester fuctionality
inside the same molecule (Table 2). The amide functionality
was supposed to be less reactive than the ester group. To our
surprise, chemoselective intramolecular Wittig reactions of the
phosphorus ylides 13–15 with two possibly reacting groups
such as (PhCO)NR2 (R2 = Boc, Cbz or Ts) and (PhCO)O
proceeded smoothly within 1.5 to 8 h at room temperture, giving
the corresponding indoles 17a, 18a and 19a in 80%, 82% and 81%
was provided efficiently within 40 min in 89% yield (Table 1,
entry 1). The presumable intermediates 3b–d with an electron-
withdrawing group (FG = 4-Cl, 4-Br or 4,6-Cl2) or 3e with an
electron-donating group (FG = 4-MeO) were all generated
successfully from 1b–e according to our protocol, and the
highly chemoselective intramolecular Wittig reactions of 3b–e
underwent smoothly to give the corresponding benzofurans
4b–e within 10–60 min in excellent yields (entries 2–5). In order
to understand the origin of chemoselectivity of 3, different
R1, R2 as well as R3 of 3 were proposed and investigated
(entries 6–18). When the intermediates 3f–i (R2 = R3 = Ph)
have an electron-withdrawing group (4-Br, 3-Cl or 2-Br) or an
electron-donating group (4-MeO) on the phenyl ring of R1, the
phosphorus ylide moiety of 3 chemoselectively reacted with
the R1CO2 group instead of the R3CO2 group to afford the
corresponding benzofurans 4f–i in 74–91% yields within
40–70 min (entries 6–9). Even the phosphorus ylides 3j–l with
a primary or secondary alkyl group as the R1 group underwent
chemoselective Wittig reactions within 40–90 min to furnish the
benzofuran derivatives 4j–l in 71–80% yields (entries 10–12).
Interestingly, when the t-butyl group was employed as the
R1 group of 1m, the competitively intramolecular Wittig reac-
tions of the R1CO2 group and the R3CO2 group (R3 = Ph) with
the phosphorus ylide moiety took place, leading to the adducts
4m (54%) and 40m (29%) in a prolonged time (7 h) (entry 13).
The electronic effect of the R2 group (R2 = 2-BrC6H4,
4-MeOC6H4 or c-Hexyl) of 1n–p (FG = 4-Br; R1 = R3 = Ph)
had significant influence on the reactivity for the formation of 4n
Scheme 3 Formation of the phosphonium chloride 8.
c
8136 Chem. Commun., 2012, 48, 8135–8137
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Surprisingly, the phosphorus ylide 25a or 25b underwent a
chemoselective intramolecular Wittig reaction smoothly to
provide the corresponding furan 26a or 26b in high yield.11
In conclusion, a general procedure for novel syntheses of highly
functional benzofurans and indoles is developed. The reaction
conditions are very mild, and numerous Michael acceptors and
acid chlorides can be applied efficiently in one step to provide
benzofurans or indoles in high yields. The reaction mechanism
is proposed to undergo chemoselective intramolecular Wittig
reactions of presumable phosphorus ylides as the key step. Our
study also demonstrates that a chemoselective Wittig reaction in
the presence of two reactive functionalities is possible, which may
also be utilized in other interesting and complex systems. Further
studies and the extensions of this concept in the preparation of
other heterocycles are currently underway.
Scheme 4 Formation of benzothiophene derivatives via intramolecular
Wittig reactions.
Scheme 5 Chemoselective intramolecular Wittig reactions of 25.
We thank the National Science Council of the Republic of
China (NSC 99-2113-M-003-004-MY2) and National Taiwan
Normal University (NTNU100-D-06) for financial support.
yield, respectively (Table 2, entries 1–3). The protecting group
R2 of the amide function, such as Boc, Cbz or Ts, also works
as an electron-withdrawing group, and it therefore increases
the electrophilicity of the amide functionality that lead to
chemoselective formation of indoles 17–19. A wide variety of
R1 (4-MeOC6H4, 2-BrC6H4, CH3, i-Pr, and CO2Et) of 9b–f
(R2 = Boc) can be tolerated in our protocol, and the corres-
ponding indoles 17b–f were afforded chemoselectively in
67–80% yields within 1.5–5 h (entries 4–8). The substrates
10b–d (R2 = Cbz; R1 = 4-MeOC6H4, 4-BrC6H4 or 3-ClC6H4)
reacted with 2a, Bu3P and Et3N efficiently within 1.5–2 h at room
temperature, furnishing the corresponding indoles 18b, 18c and 18d
in 73%, 80% and 79% yield, respectively (entries 9–11). When i-Pr
was employed as R1 of 10e (R2 = Cbz), the corresponding indole
18e was provided in 75% yield along with a trace amount of 180e
(3% yield) within 3 h. Interestingly, even the amide with an
electron-donating group (16a–c) such as the benzyl group as the
protecting group can undergo a chemoselective intramolecular
Wittig reaction with the phosphorus ylide moiety in the prensence
of the ester functionality to provide the corresponding indoles 20a–c
in 82–89% yields (entries 13–15). The electron-withdrawing group
on the R1 group has an influence on the electrophilicity of the
amide function of 16a–c (entries 13–15; 20a, 3 h; 20b, 4 h; 20c, 2 h).
However, the chemoselectivity of the intramolecular Wittig reaction
of 16d was worse than that of 13e and 14e when the i-Pr group was
utilized as the R1 group (entry 16 vs. 7 and 12). In addition, only the
adducts 17–20 with Z-configuration were observed.
Notes and references
1 (a) R. A. Shenvi, D. P. O’Malley and P. S. Baran, Acc. Chem. Res.,
2009, 42, 530; (b) N. A. Afagh and A. K. Yudin, Angew. Chem.,
Int. Ed., 2010, 49, 262.
2 (a) X.-L. Sun and Y. Tang, Acc. Chem. Res., 2008, 41, 937;
(b) S. P. Nolan and H. Clavier, Chem. Soc. Rev., 2010, 39, 3305.
3 For selected reviews of Wittig reactions, see: (a) D. Edmonds and
A. Abell, in Modern Carbonyl Olefinations, ed. T. Takeda, Wiley-VCH,
Weinheim, 2004, pp. 1–17; (b) A. Abell and D. M. K. Edmonds,
Organophosphorus Reagents, ed. P. J. Murphy, Oxford University
Press, Oxford, 2004, pp. 99–127; (c) R. W. Hoffmann, Angew. Chem.,
Int. Ed., 2001, 40, 1411; please also see: (d) G. Wittig and G. Geissler,
Justus Liebigs Ann. Chem., 1953, 580, 44; (e) G. Wittig and
U. Schollkopf, Chem. Ber., 1954, 87, 1318.
4 For recent examples, see: (a) C. J. O’Brien, J. L. Tellez, Z. S. Nixon,
L. J. Kang, A. L. Carter, S. R. Kunkel, K. C. Przeworski and G. A.
Chass, Angew. Chem., Int. Ed., 2009, 48, 6836; (b) D. M. Hodgson and
T. Arif, Org. Lett., 2010, 12, 4204; (c) N. Okamoto, K. Takeda and
R. Yanada, J. Org. Chem., 2010, 75, 7615.
5 For selected examples of an intramolecular Wittig reaction of
phosphorus ylide and an ester functionality, see: (a) T.-T. Kao,
S. Syu and W. Lin, Org. Lett., 2010, 12, 3066; (b) K.-W. Chen,
S. Syu, Y.-J. Jang and W. Lin, Org. Biomol. Chem., 2011, 9, 2098;
also see: (c) S. Syu, Y.-T. Lee, Y.-J. Jang and W. Lin, Org. Lett.,
2011, 13, 2970.
6 For recent examples of benzofuran synthesis, see: (a) X. Guo,
R. Yu, H. Li and Z. Li, J. Am. Chem. Soc., 2009, 131, 17387;
(b) Z. Shen and V. M. Dong, Angew. Chem., Int. Ed., 2009, 48, 784;
(c) T. J. Maimone and S. L. Buchwald, J. Am. Chem. Soc., 2010,
132, 9990.
In our preliminary study, we found that our protocol can also
be applied successfully for the synthesis of functional benzothio-
phenes 22a (94%, 1.5 h) and 22b (81%, 1.5 h)10 starting from
the Michael acceptor 21 and the corresponding acid chloride 2d
(4-ClC6H4COCl) and 2b (4-NO2C6H4COCl) (Scheme 4).
The formation of 22 is proposed to be via a chemoselective
intramolecular Wittig reaction of the phosphorus ylide and the
thioester functionality of the intermediate 23 in the presence of the
competitive ester functionality.
7 For recent examples of indole synthesis, see: (a) B. A. Haag,
Z.-G. Zhang, J.-S. Li and P. Knochel, Angew. Chem., Int. Ed.,
2010, 49, 9513; (b) J. Barluenga, A. Jime
C. Valdes, J. Am. Chem. Soc., 2009, 131, 4031; (c) P.
Kothandaraman, W. Rao, S. J. Foo and P. W. H. Chan, Angew.
´
nez-Aquino, F. Aznar and
´
Chem., Int. Ed., 2010, 49, 4619; (d) S. Kirchberg, R. Frohlich and
A. Studer, Angew. Chem., Int. Ed., 2009, 48, 4235.
¨
8 For recent examples of benzothiophene synthesis, see: (a) P. Gopinath,
S. Nilaya, T. R. Debi, V. Ramkumar and K. M. Muraleedharan,
Chem. Commun., 2009, 7131; (b) R. Sanz, V. Guilarte, E. Hernando
and A. M. Sanjuan, J. Org. Chem., 2010, 75, 7443; (c) C. S. Bryan,
J. A. Braunger and M. Lautens, Angew. Chem., Int. Ed., 2009, 48, 7064.
According to the observed results of chemoselective Wittig
reactions for the formation of benzofurans, benzothiophenes,
and indoles, we wonder if there is any extra effect coming from
the aromatic ring directly attached to the benzoate group
(–OCOAr). In order to understand the originality of chemo-
selectivity, the presumable intermediates 25a–b resulted from Bu3P,
Et3N, 2a or 2d, and the substrate 24 were proposed (Scheme 5).
1
9 More detailed information about mechanism studies by H NMR
analysis is provided inthe ESIw.
10 The structure of 22b was determined by X-ray analysis (CCDC
876151).
11 All the structures of 4, 40 and 26 were also confirmed by deacylation
(see ESIw).
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 8135–8137 8137