An organic molecule modulated chemoselective cyclization of alkynyl nitriles tethered to 2-alkyl substituted chromones with multireactive sites

Article abstract of DOI:10.1021/ol302964x

A small organic molecule phenylacetonitrile promoted chemoselective cyclization of (chromen-3-yl)alkynylnitriles to generate a novel tetracyclic or tricyclic chromone scaffold has been discovered. Importantly, the phenylacetonitrile serves as an anion transfer reagent changing the normal reaction of the substrate.

Full text of DOI:10.1021/ol302964x

ORGANIC
LETTERS
2012
Vol. 14, No. 24
6122–6125
An Organic Molecule Modulated
Chemoselective Cyclization of Alkynyl
Nitriles Tethered to 2‑Alkyl Substituted
Chromones with Multireactive Sites
Liping Huang, Yang Liu, Fuchun Xie, and Youhong Hu*
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 ZuChongZhi Road, China
yhhu@mail.shcnc.ac.cn
Received August 21, 2012
ABSTRACT
A small organic molecule phenylacetonitrile promoted chemoselective cyclization of (chromen-3-yl)alkynylnitriles to generate a novel tetracyclic
or tricyclic chromone scaffold has been discovered. Importantly, the phenylacetonitrile serves as an anion transfer reagent changing the normal
reaction of the substrate.
Intramolecular carbocyclizations of alkynes serve as
direct and efficient methods for the preparation of five-
or six-membered cyclic compounds.1 A number of transi-
tion metal (Pd,2 Au,3 or other transition metal4) catalyzed,
electrophile induced5 or base promoted6 cyclizations of
alkynes and stabilized carbanions derived from malonate
derivatives or enolates have been explored. These cycliza-
tions usually proceed via a 5- or 6-exo-dig mode; however,
5- or 6-endo-dig cyclizations of nonterminal alkynes are
relatively rare,2n,3a,3c,4d,5a and few examples exist of an
6-endo-dig cyclization of a stabilized lithio carbanion with
an alkoxyacetylene under basic conditions.7 In the investi-
gation described below, we have developed chemoselective
(1) For reviews of intramolecular carbocyclizations of alkynes, see: (a)
ꢀ ꢁ
ꢀ
Denes, F.; Perez-Luna, A.; Chemla, F. Chem. Rev. 2010, 110, 2366. (b)
Guo, L.-N.; Duan, X.-H.; Liang, Y.-M. Acc. Chem. Res. 2010, 44, 111.
(2) For papers of Pd-catalyzed intramolecular cyclizations of al-
kynes, see: (a) Bouyssi, D.; Balme, G.; Fournet, G.; Monteiro, N.;
Gore, J. Tetrahedron Lett. 1991, 32, 1641. (b) Monteiro, N.; Balme, G.;
Gore, J. Tetrahedron Lett. 1991, 32, 1645. (c) Monteiro, N.; Gore, J.;
Balme, G. Tetrahedron 1992, 48, 10103. (d) Tsukada, N.; Yamamoto, Y.
Angew. Chem., Int. Ed. 1997, 36, 2477. (e) Duan, X.-H.; Guo, L. N.; Bi,
H.-P.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2006, 8, 3053. (f) Duan, X.-H.;
Guo, L.-N.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2006, 8, 5777.
(g) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu, X.-Y.; Liang, Y.-M. J. Org.
Chem. 2006, 71, 3325. (h) Zhang, D.; Liu, Z.; Yum, E. K.; Larock, R. C.
J. Org. Chem. 2006, 72, 251. (i) Guo, L.-N.; Duan, X.-H.; Bi, H.-P.; Liu,
X.-Y.; Liang, Y.-M. J. Org. Chem. 2007, 72, 1538. (j) Guo, L.-N.; Duan,
X.-H.; Liu, X.-Y.; Hu, J.; Bi, H.-P.; Liang, Y.-M. Org. Lett. 2007, 9,
5425. (k) Guan, Z.-H.; Ren, Z.-H.; Zhao, L.-B.; Liang, Y.-M. Org.
Biomol. Chem. 2008, 6, 1040. (l) Hess, W.; Burton, J. W. Chem.;Eur. J.
2010, 16, 12303. (m) Chernyak, N.; Gorelsky, S. I.; Gevorgyan, V.
Angew. Chem., Int. Ed. 2011, 50, 2342. (n) Fujino, D.; Yorimitsu, H.;
Osuka, A. Org. Lett. 2012, 134, 2914.
(4) For papers of other transition-metal-catalyzed intramolecular
cyclizations of alkynes, see: (a) Gou, F.-R.; Bi, H.-P.; Guo, L.-N.;
Guan, Z.-H.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2008, 73, 3837. (b)
Montaignac, B.; Vitale, M. R.; Ratovelomanana-Vidal, V.; Michelet,
V. R. J. Org. Chem. 2010, 75, 8322. (c) Tang, B.-X.; Song, R.-J.; Wu,
C.-Y.; Wang, Z.-Q.;Liu, Y.;Huang, X.-C.;Xie, Y.-X.;Li, J.-H.Chem. Sci.
2011, 2, 2131. (d) Suzuki, S.; Tokunaga, E.; Reddy, D. S.; Matsumoto, T.;
Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2012, 51, 4131.
(5) For papers of electrophile induced cyclizations of alkynes, see: (a)
ꢀ
Barluenga, J.; Palomas, D.; Rubio, E.; Gonzalez, J. M. Org. Lett. 2007,
9, 2823. (b) Bi, H.-P.; Guo, L.-N.; Duan, X.-H.; Gou, F.-R.; Huang,
S.-H.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2007, 9, 397. (c) Khan, Z. A.;
Wirth, T. Org. Lett. 2009, 11, 229.
(6) For papers of base promoted cyclizations of alkynes, see: (a)
Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P. Synlett 1998,
1998, 446. (b) Koradin, C.; Rodriguez, A.; Knochel, P. Synlett 2000,
2000, 1452. (c) Arcadi, A.; Marinelli, F.; Rossi, L.; Verdecchia, M.
Synthesis 2006, 2006, 2019.
(7) For a related example of a 6-endo-dig carbocyclization process of
a stabilized lithio carbanion with an alkoxyacetylene, see: Funk, R. L.;
Bolton, G. L.; Brummond, K. M.; Ellestad, K. E.; Stallman, J. B. J. Am.
Chem. Soc. 1993, 115, 7023.
(3) For papers of Au-catalyzed intramolecular cyclizations of al-
kynes, see: (a) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F. D. Angew
Chem. Int. Ed. 2004, 43, 5350. (b) Pan, J.-H.; Yang, M.; Gao, Q.; Zhu,
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N.-Y.; Yang, D. Synthesis 2007, 2007, 2539. (c) Barabe, F.; Levesque, P.;
Korobkov, I.; Barriault, L. Org. Lett. 2011, 13, 5580.
r
10.1021/ol302964x
Published on Web 12/04/2012
2012 American Chemical Society

5- or 6-endocarbocyclization of biscarbanions arising from
alkynyl nitriles tethered to chromones. These processes,
which utilize 4-N,N-diethylaminophenylacetonitrile as an
anion transfer reagent along with n-Bu4NCl as a phase-
transfer reagent, take place under transition-metal-free
conditions to form polycyclic chromones.
We envisioned that the novel transformation of 1a to 3a
might occur involving double cyclizations as depicted in
Scheme 2. Initially, the anion was selectively transferred
from compound 2 to the R-carbon of the cyano in 1a
(Scheme 1, site c). The triple bond of A was attacked by the
R-cyano anion to give the first cyclized product B via a
5-endo-dig mode. Subsequently, the intermediate B was
isomerized to the conjugate C. Under the basic conditions,
the resulting methyl anion of C could further add to the
cyano group by intramolecular 1,2-addition to provide the
second cyclized product D, which upon aromatization
gave product 3a.
To gain support for this mechanistic proposal, the reac-
tion was performed at 90 °C instead of 150 °C. Under these
conditions, intermediate C was isolated, which was com-
pletely converted to 3a in excellent yields in either the pres-
ence or absence of 2a (Scheme 3). When the methyl of 1a
was replaced with nondeprotonatable phenyl (1a0), the
anticipated product C0 could be obtained only in the
presence of 2a. When the methyl was replaced by hydro-
gen, only amino-substituted xanthone8c was isolated.
In our earlier studies with 3-(1-alkynyl)chromones, we
have devised routes for the preparation of functionalized
xanthones.8 When (chromen-3-yl)alkynylnitrile 1a was
treated with 2-(3-bromophenyl)acetonitrile 2a in the pres-
ence of t-BuOK at 150 °C under microwave irradiation
(MW), a surprising new product 3a was isolated rather
than the anticipated product 4a8c (Scheme 1). The struc-
ture of 3a was unambiguously established by X-ray crystal
structure analysis (Figure 1). Significantly, the control
experiments showed that a reaction without 2a was com-
plicated and only a trace of 3a (<5%) was obtained.
There are three potential reactive sites of 1a under basic
conditions (Scheme 1). The methyl group (site a) of 1a can
be deprotonated by a strong base to form a carbanion that
then undergoes the cascade dimeric reaction involving
double Michael additions and cyclizations to afford 5a.8d
Alternatively, 1a could serve as a Michael acceptor (site b),
which is attacked by the nucleophile 2a to eventually
generate amino-substituted xanthone 4a.8c
Scheme 2. Plausible Mechanism for the Formation of 1a
Scheme 1. Regio- and Chemoselective Reactions of 1a under
Basic Conditions
To further investigate the particular role of 2a played in
the conversion of 1a to B, we first carried out the reactions
without 2a in the presence of common bases (t-BuOK,
NaH, LDA, or NaHDMS). The reactions were compli-
cated, and only a trace of 3a was obtained (Table 1,
entry 1). These strong bases could deprotonate both the
methyl8d (site a) and R-methylene of cyano1a (site c) of 1a
and rendered the reaction less selective and more compli-
cated. Other carbanion transferring reagents similar to 2a
were then screened (Table 1, entries 2ꢀ11). The results
showed that when ortho- and para-position substituted
electron-donating groups were used for R1, the formation
of 3awas favored (Table 1, entries 2ꢀ11). Phenylacetate 2k
and phenylacetamide 2l resulted in inferior efficiency, and
only 5a was afforded (Table 1, entries 12ꢀ13). Notably,
when2m9H-fluorene was empolyed, 3awas alsoformedin
45% yield (Table1, entry 14), which further confirmedthat
these small molecules acted as anion donors. Finally, the
effect of the strength of anion donors was investigated. The
reaction gave complicated products when the weak anion
donor MeCN was used (Table 1, entry 15). Surprisingly,
when the strong anion donor ethyl 2-cyanoacetate 2o or
Figure 1. X-ray structure of 3a.9
(8) (a) Zhao, L.; Xie, F.; Cheng, G.; Hu, Y. Angew. Chem., Int. Ed.
2009, 48, 6520. (b) Gong, J.; Xie, F.; Chen, H.; Hu, Y. Org. Lett. 2010,
12, 3848. (c) Liu, Y.; Huang, L.; Xie, F.; Hu, Y. J. Org. Chem. 2010, 75,
6304. (d) Xie, F.; Chen, H.; Hu, Y. Org. Lett. 2010, 12, 3086. (e) Xie, F.;
Pan, X.; Lin, S.; Hu, Y. Org. Biomol. Chem. 2010, 8, 1378. (f) Liu, Y.;
Huang, L.; Xie, F.; Chen, X.; Hu, Y. Org. Biomol. Chem. 2011, 9, 2680.
Org. Lett., Vol. 14, No. 24, 2012
6123

diethyl malonate 2p was employed (Table 1, entries 16ꢀ17),
5a and 6a (X-ray structure in Supporting Information) was
isolated instead of 3a. The corresponding anion of 2o or 2p
selectively transferred to the methyl to form the dimeric
product 5a,8d which gave 6a by further cyclization, isomer-
ization, and desalicyloylation (Scheme 4).
Scheme 4. Formation of 5a and 6a Modulated by 2p and the
Plausible Mechanism of 6a
Scheme 3. Support for the Proposed Mechanism
Table 2. Optimization of Reaction Conditionsa
With 2h as the best anion transfer reagent, the examina-
tion of the effect of temperature and base to the reaction
was carried out (Table 2). When the temperature was
decreased from 150 to 110 °C, the yield increased to 62%
(Table 2, entries 1ꢀ2). Among a variety of bases tested,
t-BuOK was found to be superior to MeONa, EtONa
(Table 2, entries 2ꢀ4). In addition, this process did not
entry
base
additive (equiv)
temp, time
yield(%)b
1
t-BuOK
t-BuOK
MeONa
EtONa
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
t-BuOK
none
150 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 10 min
110 °C, 20 min
110 °C, 20 min
110 °C, 20 min
110 °C, 20 min
110 °C, 20 min
110 °C, 20 min
110 °C, 20 min
110 °C, 20 min
110 °C, 20 min
55
62
52
27
34
31
20
33
30
60
80
70
64
60
71
74
65
67
70
2
none
3
none
4
none
5c
Ag2SO4
Table 1. Screening of Anion Transfer Reagentsa
6c
CuCl
7c
CuCl2
8c
PdCl2(PPh3)2
Pd(PPh3)4
PtCl2
9c
10c
11
12
13
14
15d
16e
17
18
19
n-Bu4NCl (2)
n-Bu4NF (2)
n-Bu4NBr (2)
n-Bu4NI (2)
n-Bu4NCl (2)
n-Bu4NCl (2)
n-Bu4NCl (0.2)
n-Bu4NCl (0.5)
n-Bu4NCl (1)
entry
anion transfer reagent
3a (%)b
4 (%)b
1c
2
ꢀ
<5
35
35
40
42
37
50
42
55
52
48
<5
<5
45
<5
0
ꢀ
27
30
20
15
20
8
2a R1 = 3-Br
3
2b R1 = 4-Br
2c R1 = H
2d R1 = 2-OMe
2e R1 = 3-OMe
2f R1 = 4-OMe
2g R1 = 3,4,5-OMe
2h R1 = 4-NEt2
2i R1 = 4-N(CH2)4
2j R1 = 2-N(CH2)4
2k ethyl 2-phenylacetate
2l 2-phenylacetamide
2m 9H-fluorene
2n MeCN
4
5
6
a General conditions: 1a (0.4 mmol), base (0.8 mmol), and 2h
(0.4 mmol) in DMF (2 mL). b Isolated yield. c 5 mol % of metal was
added. d 0.2 equiv of 2h was added. e 0.5 equiv of 2h was added.
7
8
18
0
9
10
11
12
13
14
15
16d
17d
0
5
occur efficiently when common solvents, such as THF,
DMSO, MeCN, and toluene, were used. Moreover, the
addition of transition metals to the reaction mixture did
not lead to improved yields but gave 4a and intermediate C
as byproducts, confirming that this unique process would
not be promoted by metal impurities (Table 2, entries 5ꢀ10).
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2o EtOOCꢀCH2CN
2p CH2(COOEt)2
0
a General conditions: 1a (0.4 mmol), t-BuOK (0.8 mmol), and 2
(0.4 mmol) in DMF (2 mL). b Isolated yield. c The reaction was carried
out in the presence of bases (t-BuOK, NaH, LDA, or NaHDMS)
without 2. d 3a was not isolated (see Scheme 4).
(9) CCDC 883517 (3a) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
6124
Org. Lett., Vol. 14, No. 24, 2012

Scheme 5. Formation of the Tetracyclic Chromone Derivatives 3a,b
Scheme 6. Cyclization of 1l and 1m To Form 7a and 7b
of 1i took place exclusively via a 6-endo-dig rather than
5-exo-dig mode. When the nitrile was replaced by the ester
or amide, the desired product was not observed and only
amino-substituted xanthone8c was obtained. Finally, this
process occurred in a reasonable yield when the R3 sub-
stituent was methyl (e.g., 3jꢀ3k).
Remarkably, this cascade reaction displayed a different
chemoselectivity when the 2-substituent of chromone was
either benzyl or isopropyl (1lꢀ1m). The respective sub-
stituted cyclopenta[b]chromen-9(3H)-ones 7a and 7b were
produced in high yields by chemoselective cyclization
through deprotonation at the R-hydrogen of the 2-sub-
stituent (Scheme 6). The benzyl group in 1l might be more
acidic than the R-methylene of the cyano, and the bulky
isopropyl group in 1m might sterically hinder the 5-endo-
dig cyclization.
In the study described above, we discovered a novel,
small organic molecule-modulated, intramolecular carbo-
cyclization of alkynyl nitriles tethered to chromones that
chemoselectively affordanew classof polycyclicchromone
derivatives. The cascade process, which does not require
transition metal catalysts, involves multiple reactions in-
cluding an endo-dig cyclization, an isomerization, and a
1,2-addition. Importantly, the results of this effort show
that a small organic molecule can serve asananion transfer
reagent and changethe course of thenormalreaction of the
substrate with three reactive sites.
a Unless otherwise noted, reactions were carried out under the
optimized reaction conditions. b Isolated yields given. c 0.5 equiv of 2h
was employed. d Reactions were carried out for 30 min. e Reactions were
carried out at 150 οC.
Importantly, when n- Bu4NCl (2.0 equiv) was used as a
phase transfer reagent, the yield increased to 80%. Other
additives such as n-Bu4NF, n-Bu4NBr, and n-Bu4NI re-
sulted in inferior efficiency (Table 2, entries 11ꢀ14).
Finally, the reaction of 1a to generate 3a also took place
smoothly in a slightly lower yield when a a catalytic
amount of 2h or n-Bu4NCl was employed (Table 2, entries
15ꢀ19). The observations described above showed that
the optimized coditions for the production of 3a involve
t-BuOK (2.0 equiv), n-Bu4NCl (2.0 equiv), and 2h (1.0
equiv) in DMF at 110 °C for 20 min under microwave
irradiation.
The scope of this process, utilizing the optimized condi-
tions, was explored (Scheme 5). The results showed that
electron-donating groups in contrast to electron-with-
drawing groups on the arene ring of chromone 1 (R2)
facilitate the cascade reaction (e.g., 3bꢀ3d and 3eꢀ3g).
When the central atom X in 1a was replaced by nitro-
gen,the fused pyrrolidine product 3h was generated in
71% yield. When a four carbon tether was present in the
reactant, the reaction occurred at the higher temperature
150 °C to form the fused cyclohexane product 3i. It should
benotedthat thefirstcyclization stepinthe transformation
Acknowledgment. This work was supported by a grant
from the National Natural Science Foundation of China
(21172232) and Ministry of Science and Technology of
China (2009CB940903).
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This information is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 24, 2012
6125