Iron-mediated [3 + 2] or [3 + 3] annulation of 2-(2-(ethynyl)phenoxy)-1- arylethanones: Selective synthesis of indeno[1,2-c ]chromenes and 5 H-naphtho[1,2-c ]chromenes

Article abstract of DOI:10.1021/ol102761m

An iron-mediated tandem annulation strategy has been developed for the synthesis of numerous functional indeno[1,2-c]chromenes and 5H-naphtho[1,2-c] chromenes. This work is the first to disclose an iron-mediated method through sequential electrophilic add

Full text of DOI:10.1021/ol102761m

ORGANIC
LETTERS
2011
Vol. 13, No. 1
14-17
Iron-Mediated [3 + 2] or [3 + 3] Annulation
of 2-(2-(Ethynyl)phenoxy)-1-arylethanones:
Selective Synthesis of
Indeno[1,2-c]chromenes and
5H-Naphtho[1,2-c]chromenes
Zhi-Qiang Wang,† Yong Lei,† Ming-Bo Zhou,† Guo-Xiang Chen,† Ren-Jie Song,†
Ye-Xiang Xie,† and Jin-Heng Li*,†,‡
Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry
of Education), Hunan Normal UniVersity, Changsha 410081, China, and College of
Chemistry and Materials Science, Wenzhou UniVersity, Wenzhou 325035, China
jhli@hunnu.edu.cn
Received August 29, 2010
ABSTRACT
An iron-mediated tandem annulation strategy has been developed for the synthesis of numerous functional indeno[1,2-c]chromenes and
5H-naphtho[1,2-c]chromenes. This work is the first to disclose an iron-mediated method through sequential electrophilic addition of a ketone
to an alkyne and annulation tandem reaction. Importantly, a halide is introduced into the products by a ring-opening process among the
annulation of alkynylcyclopropanes, which makes the methodology more attractive for organic synthesis.
Transition metal-catalyzed annulation reactions provide at-
tractive and efficient routes to the construction of the
polycyclic carboaromatic and heteroaromatic skeletons.1-4
However, regio- and chemoselectivity are unsatisfactory, and
inaccessible substrates are necessary in many cases. For these
reasons, versatile and efficient methodologies to synthesize
these compounds with selective control of substitution
patterns using readily accessible building blocks are still
needed. Recently, transition metal-catalyzed [4 + 2] ben-
zannulations of alkynes with carbonyl groups have been
proven as a powerful tool to polycyclic aromatic compounds,
and most were realized by the metal activation of the alkyne
moiety under neutral conditions (Scheme 1).3,4 We have also
reported a novel protocol under basic conditions using FeCl3
catalyst and 2-(2-ethynyl)phenoxy)-1-arylethanone substrates
in MeCN that proceeds via a [4 + 2] cyclization/ring-opening
process to afford naphthalen-1-ol derivatives in good yields.5
In light of these results, we have decided to broaden this
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Katritzky, A. R.; Li, J.; Xie, L. Tetrahedron 1999, 55, 8263. (c) Modern
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ReV. 2000, 100, 2901. (i) Yamamoto, Y. Curr. Org. Chem. 2005, 9, 503.
(j) Kotha, S.; Brahmachary, E.; Lahiri, K. Eur. J. Org. Chem. 2005, 4741.
(k) Galan, B. R.; Rovis, T. Angew. Chem., Int. Ed. 2009, 48, 2830. (l)
Larock, R. C. Top. Organomet. Chem. 2005, 14, 147. (m) Zeni, G.; Larock,
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† Hunan Normal University.
‡ Wenzhou University.
10.1021/ol102761m  2011 American Chemical Society
Published on Web 12/01/2010

Scheme 1
.
Annulation of Alkynes with Carbonyl Groups
Table 1. FeCl3-Mediated Synthesis of Indeno[1,2-c]chromenesa
isolated yield (%)
entry
FeCl3 (mol %)
solvent
t (h)
2a
3a
1
2
3
4
5
20
20
40
60
100
MeCN
48
48
4
4
4
trace
18
48
45
42
0
trace
25
20
26
toluene
toluene
toluene
toluene
a Reaction conditions: 1a (0.3 mmol) and solvent (2 mL) at 120 °C.
desired product 2a was low (entry 2). The FeCl3 loading
was subsequently examined (entries 3-5). We were pleased
to find that at 40 mol % FeCl3 the yield of 2a was enhanced
to 48% together with another chloro-addition annulation product
3a in 25% yield (entry 3). However, identical results were obtained
even using 60 or 100 mol % FeCl3 (entries 4 and 5).
research under neutral conditions. Here, we report an
unprecedented iron-mediated intramolecular annulation of
2-(2-(ethynyl)phenoxy)-1-arylethanones under neutral condi-
tions through intramolecular [3 + 2] or [3 + 3] cyclization
of an alkyne with a carbonyl group to produce polycyclic
heteroarenes; indeno[1,2-c]chromenes and 5H-naphtho[1,2-
c]chromenes can be selectively accessed by judicious choice
of substituents at the terminal alkyne (Scheme 1).6,7
To shift the selectivity toward products 2, methyl-substituted
substrates were employed for the reaction (Scheme 2). As
Under neutral conditions, no reaction was observed from
1-phenyl-2-(2-(phenylethynyl)phenoxy)ethanone (1a) with 20
mol % FeCl3 in the reported effective MeCN solvent (entry 1,
Table 1).5,8 Interestingly, an expected [3 + 2] annnulation
reaction took place in toluene although the yield of the
Scheme 2.
FeCl3-Mediated [3 + 2] Annulationa
(2) For special reviews, see: (a) Joule, J. A.; Mills, K. Heterocyclic
Chemistry, 4th ed.; Blackwell: Oxford, 2000. (b) Eicher, T.; Hauptmann,
S. The Chemistry of Heterocycles; Wiley-VCH: Weinheim, 2003. (c)
Katrizky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry,
2nd ed.; Pergamon: Amsterdam, 2000.
(3) A review: (a) Yamamoto, Y.; Gridnev, I. D.; Patil, N. T.; Jin, T.
Chem. Commun. 2009, 5075. Au: (b) Asao, N.; Takahashi, K.; Lee, S.;
Kasahara, T.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 12650. (c)
Straub, B. F. Chem. Commun. 2004, 1726. Cu: (d) Asao, N.; Nogami, T.;
Lee, S.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 10921. Au or Cu: (e)
Asao, N.; Sato, K.; Menggenbateer, Yamamoto, Y. J. Org. Chem. 2005,
70, 3682.
(4) Ga: (a) Viswanathan, G. S.; Wang, M.; Li, C.-J. Angew. Chem., Int.
Ed. 2002, 41, 2138. (b) Viswanathan, G. S.; Li, C.-J. Synlett 2002, 1553.
TiCl4: (c) Kabalka, G. W.; Ju, Y.; Wu, Z. J. Org. Chem. 2003, 68, 7915.
Au/Ag: (d) Balamurugan, R.; Gudla, V. Org. Lett. 2009, 11, 3116.
(5) Wang, Z.-Q.; Liang, Y.; Lei, Y.; Zhou, M.-B.; Li, J.-H. Chem.
Commun. 2009, 5242.
(6) For selected reviews on iron chemistry, see: (a) Bolm, C.; Legros,
J.; Le Paih, J.; Zani, L. Chem. ReV. 2004, 104, 6217. (b) Iron Catalysis in
Organic Chemistry: Reactions and Applications; Plietker, B., Ed.; Wiley-
VCH: Weinheim, 2008. (c) Correa, A.; Manchen˜o, O. G.; Bolm, C. Chem.
Soc. ReV. 2008, 37, 1108
.
(7) For papers on iron-catalyzed activation of alkynes with nucleophiles
or π-bonds, see: (a) Xu, X.; Liu, J.; Liang, L.; Li, H.; Li, Y. AdV. Synth.
Catal. 2009, 351, 2599. (b) Cao, K.; Zhang, F.-M.; Tu, Y.-Q.; Zhuo, X.-
T.; Fan, C.-A. Chem.sEur. J. 2009, 15, 6332. (c) Fan, J.; Gao, L.; Wang,
Z. Chem. Commun. 2009, 5021. (d) Komeyama, K.; Igawa, R.; Takaki, K.
Chem. Commun. 2010, 1748. (e) Ren, K.; Wang, M.; Wang, L. Eur. J.
Org. Chem. 2010, 565. (f) Liu, Z.; Wang, J.; Zhao, Y.; Zhou, B. AdV. Synth.
Catal. 2009, 351, 371. (g) Kohno, K.; Nakagawa, K.; Yahagi, T.; Choi,
J.-C.; Yasuda, H.; Sakakura, T. J. Am. Chem. Soc. 2009, 131, 2784. (h)
Cantagrel, G.; de Carne´-Carnavalet, B.; Meyer, C.; Cossy, J. Org. Lett.
2009, 11, 4262. (i) Xu, T.; Yu, Z.; Wang, L. Org. Lett. 2009, 11, 2113. (j)
Xu, T.; Yang, Q.; Li, D.; Dong, J.; Yu, Z.; Li, Y. Chem.sEur. J. 2010, 16,
a Reaction conditions: 1 (0.3 mmol), FeCl3 (100 mol %), and toluene
(2 mL) at 120 °C for 4 h. b FeCl3 (40 mol %). A cyclization/hydrolysis
product 4b, (2-methyl-3-phenyl-2H-chromen-4-yl)(phenyl)methanone, was
isolated in 44% yield. c At 100 °C.
expected, product 2b was obtained in 40% yield and no
chloro-addition annulation product 3b was observed using
9264
.
Org. Lett., Vol. 13, No. 1, 2011
15

40 mol % FeCl3. However, the other cyclization/hydrolysis
product 4b, (2-methyl-3-phenyl-2H-chromen-4-yl)(phenyl)-
methanone, was isolated in 44% yield. Gratifyingly, product
2b was obtained alone in 81% yield when 100 mol % FeCl3
was added. The reaction temperature has a fundamental
influence on the reaction: the yield of 2b was reduced to
47% at 100 °C. We were delighted to disclose that both
electron-rich and electron-deficient arylalkynes were suc-
cessfully annulated with 100 mol % FeCl3 at 120 °C to afford
indeno[1,2-c]chromenes 2c-2h in moderate yields, although
the steric hindrance and electron-deficient aryl groups
lowered the substrate activity (2d and 2g). Notably, the
introduction of an olefin or a heterocycle into this system
makes this methodology more useful for the preparation of
pharmaceuticals and nature products (2i-2j). The same
conditions were also consistent with substrate bearing a p-Me
group on the aryl ring of the arylethanone moiety (2k). For
substrates with a methyl, a fluoro or dichloro groups on the
aromatic ring of the phenoxy moiety, the corresponding
indeno[1,2-c]chromenes 2l-2o were also obtained in good
yields at 100 mol % FeCl3.
Scheme 4
.
Sequential [3 + 3] Annulation and Friedel-Crafts
Reaction
at 100 °C afforded the desired 12-(2-chloroethyl)-5H-
naphtho[1,2-c]chromene (5p) in 37% yield. After a series
of trials, we found that TMSCl could promote the reaction;
the yield of 5p was enhanced to 50% in the presence of 1
equiv of TMSCl. Subsequently, substituents on the aromatic
ring of the arylethanone moiety were examined in the
presence of FeCl3 and TMSCl (5q, 5r and 5v). Substrates
bearing a p- or m-methyl group afforded the corresponding
products 5q, 5r and 5v in moderate yields; two regioselective
5r were isolated from m-methyl-substituted substrate with
1.6:1 ratio, and substrate with another methyl group at the
R-position of ketone provided the best yield (5v). Therefore,
a variety of R-methyl-substituted substrates were tested
(5t-5ac, Scheme 3). Gratifyingly, the furan ring was suitable
to construct an interesting benzofuro[7,6-c]chromene skeleton
(5u). Substituents, such as cyano and halo groups, on the
aromatic ring of the phenoxy moiety were uniformly well
tolerated (5w-5ab, Scheme 3). Chloro-substituted substrate,
for instance, successfully underwent the reaction with FeCl3
and TMSCl in 66% yield (5x). Interestingly, this chloro-
substituted substrate could react with FeBr3 and TMSBr,
producing the corresponding bromo-addition product 6x in
50% yield. Another substrate with dichloro groups also
reacted smoothly with either FeCl3 or FeBr3 in satisfactory
yields (5y and 6y). Notably, substrate having both a formyl
and a methoxy groups was compatible (5ac).
For alkynylcycloalkanes,9 to our surprise, the ring-opening
and cyclization tandem reactions took place leading to 5H-
naphtho[1,2-c]chromenes (Schemes 3 and 4). As summarized
Scheme 3.
FeX3-Mediated [3 + 3] Annulationa
Alkynylcyclobutanes are also viable substrates for the ring-
opening and annulation reaction (Scheme 4). Surprisingly,
the reaction of substrate 1ad (0.3 mmol) with FeCl3 (100
mol %) and TMSCl (1 equiv) provided a Friedel-Crafts
alkylation product 7ad, not the chloro-addition product.
(8) See the Supporting Information for details, including Tables
S1-S2.
(9) For papers on inactive alkynylcycloalkanes in organic synthesis, see
the following. Au: (a) Zhang, J.; Schmalz, H.-G. Angew. Chem., Int. Ed.
2006, 45, 6704. (b) Xiao, H.-Q.; Shu, X.-Z.; Ji, K.-G.; Qi, C.-Z.; Liang,
Y.-M. New J. Chem. 2007, 31, 2041. (c) Zhang, G.; Huang, X.; Li, G.;
Zhang, L. J. Am. Chem. Soc. 2008, 130, 1814. (d) Li, G.; Huang, X.; Zhang,
L. J. Am. Chem. Soc. 2008, 130, 6944. (e) Liu, L.; Zhang, J. Angew. Chem.,
Int. Ed. 2009, 48, 6093. Au/Ag: (f) Markham, J. P.; Staben, S. T.; Toste,
F. D. J. Am. Chem. Soc. 2005, 127, 9708. (g) Ye, S.; Yu, Z.-X. Org. Lett.
2010, 12, 804. Au or Ag: (h) Zhang, X.-M.; Tu, Y.-Q.; Jiang, Y.-J.; Zhang,
Y.-Q.; Fan, C.-A.; Zhang, F.-M. Chem. Commun. 2009, 4726. Rh: (i)
Yamauchi, Y.; Onodera, G.; Sakata, K.; Yuki, M.; Miyake, Y.; Uemura,
S.; Nishibayashi, Y. J. Am. Chem. Soc. 2007, 129, 5175. Pd: (j) Liebeskind,
L. S.; Mitchell, D.; Foster, B. S. J. Am. Chem. Soc. 1987, 109, 7908. (k)
Larock, R. C.; Reddy, C. K. Org. Lett. 2000, 2, 3325. Co: (l) Iwasawa, N.;
Matsuo, T.; Iwamoto, M.; Ikeno, T. J. Am. Chem. Soc. 1998, 120, 3903.
Electrophilic cyclization (I2): (m) Huang, X.; Fu, W.; Miao, M. Tetrahedron
Lett. 2008, 49, 2359. SN2′ addition: (n) Ce´rat, P.; Gritsch, P. J.; Goudreau,
S. R.; Charette, A. B. Org. Lett. 2010, 12, 564.
a Reaction conditions: 1 (0.3 mmol), FeCl3 (100 mol %), TMSX (1
equiv) and toluene (2 mL) at 100 °C for 4 h. b Without TMSCl.
in Scheme 3,8 treatment of 2-(2-(cyclopropylethynyl)phe-
noxy)-1-phenylethanone with 100 mol % FeCl3 in toluene
16
Org. Lett., Vol. 13, No. 1, 2011

Moreover, product 7ae was likewise obtained in 57% yield
from another cyclobutane 1ae.
Scheme 5. Working Mechanisms
The products 5 and 6 with a halo group provide an
attractive and useful route to introduce new groups into these
systems; dehydrohalogenation of product 5ab by t-BuOK
furnished alkene 8ab in quantitative yield (eq 1).10
A controlled experiment showed that product 3a could not
be converted to product 2a under the standard conditions
(eq 2).
In summary, we have demonstrated that by application of
an iron-mediated tandem annulation strategy numerous
functional indeno[1,2-c]chromenes and 5H-naphtho[1,2-
c]chromenes could be readily synthesized from 2-(2-(ethy-
nyl)phenoxy)-1-arylethanones. This work is the first to
disclose an iron-mediated method through sequential elec-
trophilic addition of a ketone to an alkyne and annulation
tandem reaction. Importantly, a halide is introduced into the
products by a ring-opening process among the [3 + 3]
annulation reactions of alkynylcyclopropanes, which makes
the methodology more attractive for organic synthesis. Work
to extend the reaction and study the detailed mechanism is
currently underway.
We envisioned a possible mechanism as outlined in
Scheme 5 on the basis of the present results.3,4,6-9 Initially,
coordination of FeCl3 to substrate 1 activates the alkyne
moiety (intermediate A), followed by sequential electrophilic
addition of a ketone and FeCl3 to an alkyne affords
intermediate B.3 Electrophilic addition to an aromatic ring
and ring-opening afford intermediate C.4 Nucleophilic ad-
dition among intermediate C yields intermediate D. Dehy-
droxylation and rearrangement of intermediate D results in
product 5. Notablely, the Friedel-Crafts alkylation of
products 5 and 6 can not take place because the construction
of a highly strained four-membered ring is not favored in
this system.
Acknowledgment. We thank the Scientific Research Fund
of Hunan Provincial Education Department (No. 08A037)
and NSFC (No. 20872112) for financial support.
For aryl or vinyl alkynes (Scheme 2), the electrophilic
addition among intermediate B′ provides intermediate C′,3
followed by dehydroxylation and rearrangement furnishes
product 2. Product 3a is generated from dehydroxylation/
chloro-addition of intermediates C′.
Supporting Information Available: Analytical data and
spectra (1H and 13C NMR) for all the products; typical
procedure. This material is available free of charge via the
Internet at http://pubs.acs.org.
(10) Hanekamp, C.; Klusener, P. A. A. Synth. Commun. 1989, 19, 2677.
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