Tandem cyclization of α-cyano α-alkynyl aryl ketones induced by tert -butyl hydroperoxide and tetrabutylammonium iodide

Article abstract of DOI:10.1021/ol3028972

The radical cascade protocol of the α-cyano α-TMS/aryl-capped alkynyl aryl ketones promoted by tert-butyl hydroperoxide under catalysis with tetrabutylammonium iodide in refluxing benzene has been developed, leading to the construction of a variety of highly functionalized [6,6,5] tricyclic frameworks in an efficient manner.

Full text of DOI:10.1021/ol3028972

ORGANIC
LETTERS
2012
Vol. 14, No. 23
6024–6027
Tandem Cyclization of r‑Cyano r‑Alkynyl
Aryl Ketones Induced by tert-Butyl
Hydroperoxide and Tetrabutylammonium
Iodide
Ying-Chieh Wong, Chen-Tso Tseng, Tzu-Ting Kao, Yu-Cheng Yeh, and
Kak-Shan Shia*
Institute of Biotechnology and Pharmaceutical Research, National Health Research
Institutes, Miaoli County 35053, Taiwan, R. O. C.
ksshia@nhri.org.tw
Received October 23, 2012
ABSTRACT
The radical cascade protocol of the R-cyano R-TMS/aryl-capped alkynyl aryl ketones promoted by tert-butyl hydroperoxide under catalysis with
tetrabutylammonium iodide in refluxing benzene has been developed, leading to the construction of a variety of highly functionalized [6,6,5]
tricyclic frameworks in an efficient manner.
During the past decade, a variety of annulation pro-
cesses based on R-activated cross-conjugated cycloalke-
none systems have been developed in our laboratories.1
As indicated below, R-cyano ketone 2 thus obtained from
1 via 1,4-addition was found to undergo autoxidative
In continuation of our studies on this unexpected aero-
bic oxidation, as depicted in Scheme 1, an acyclic benzoy-
lacetonitrile 4 was then synthesized and subjected to the
standard reaction conditions previously optimized for R-
cyano cycloalkanone substrates.2 To our surprise, instead
of forming the expected acysilane product, compounds 5
and 6 were provided, respectively, in 18% and 30% yields,
structures of which were fully characterized by spectro-
scopic methods, and tricyclic compound 5 was further
unambiguously confirmed by the X-ray crystallographic
analysis.4 Mechanistically, the former might be potentially
formed via a tandem radical cyclization process and the
latter via a direct oxidative cleavage pathway.
cyclization under air to afford product 3 in a significant
amount.2,3
(1) (a) Fleming, F. F.; Huang, A.; Sharief, V. A.; Pu, Y. J. Org. Chem.
1997, 62, 3036. (b) Fleming, F. F.; Huang, A.; Sharief, V. A.; Pu, Y. J.
Org. Chem. 1999, 64, 2830. (c) Fleming, F. F.; Shook, B. C. Org. Synth.
2002, 78, 254. (d) Chou, H. H.; Wu, H. M.; Wu, J. D.; Ly, T. W.; Jan,
N. W.; Shia, K. S.; Liu, H. J. Org. Lett. 2008, 10, 121. (e) Hsieh, M. T.;
Chou, H. H.; Liu, H. J.; Wu, H. M.; Shia, K. S. Org. Lett. 2009, 11, 1673.
(f) Zhu, J. L.; Shia, K. S.; Liu, H. J. Chem. Commun. 2000, 1599. (g)
Kung, L. R.; Tu, C. H.; Shia, K. S.; Liu, H. J. Chem. Commun. 2003,
2490. (h) Wu, Y. K.; Ly, T. W.; Shia, K. S. Curr. Org. Synth. 2010, 7, 78.
(i) Hsieh, M. T.; Shia, K. S.; Liu, H. J.; Kuo, S. C. Org. Biomol. Chem.
2012, 10, 4609. (j) Wu, Y. K.; Ly, T. W.; Shia, K. S. Adv. Org. Synth.
2012, 5, 216.
(2) Wong, Y. C.; Hsieh, M. T.; Amancha, P. K.; Chin, C. L.; Liao,
C. F.; Kuo, C. W.; Shia, K. S. Org. Lett. 2011, 13, 896.
(3) (a) Chin, C. L.; Liao, C. F.; Liu, H. J.; Wong, Y. C.; Hsieh, M. T.;
Amancha, P. K.; Chang, C. P.; Shia, K. S. Org. Biomol. Chem. 2011, 9,
4778. (b) Chang, S. Y.; Jiaang, W. T.; Cherng, C. D.; Tang, K. H.;
Huang, C. H.; Tsai, Y. M. J. Org. Chem. 1997, 62, 9089. (c) Jiaang,
W. T.; Lin, H. C.; Tang, K. H.; Chang, L. B.; Tsai, Y. M. J. Org. Chem.
1999, 64, 618.
(4) Crystallographic data for CCDC-892910 (5): C17H18ClNOSi,
˚
MW = 315.86, monoclinic, a = 17.1290(12) A, b = 10.1809(6) A,
˚
3
˚
˚
c = 19.7805(10) A, V = 3344.8(3) A , space group P21/c, Z = 8, a total
of 18471 reflections were collected in the range 2.12 < 2θ < 25.04o. Of
these, 5875 were independent; for the observed data, wR2 = 0.2132,
R = 0.0763.
r
10.1021/ol3028972
Published on Web 11/28/2012
2012 American Chemical Society

Low yields of tricyclic product 5 (entries 1ꢀ3) in dif-
ferent solvents again confirmed that molecular oxygen was
a poor reagent to trigger the observed tandem radical
process. Triethylborane (Et3B) was then attempted.7 It
was found that when Et3B was incrementally increased up
to 3 equiv, the best yield of 5 was obtained in 45% (entry 4)
and 30% (entry 5), respectively. Unfortunately, an intro-
duction of oxygen or hydrogen peroxide was necessary for
Et3B to initiate the ethyl radical formation. Consequently,
besides 6, an additional side product 7 (ca. 20%) was
detected. Mechanistically, both are assumed to be derived
from a common R-carbonyl peroxide radical, which could
undergo either a direct oxidative cleavage to give 6 or
further reduction with Et3B followed by excluding the
cyano moiety to furnish diketone 7.7a
Scheme 1
Facilitating efficient construction of polycyclic rings
through [m þ n] annulations, involving vinyl, imidoyl
and/or iminyl radical, remains an important topic in
organic synthesis.5 An intramolecular radical cascade fol-
lowing [4 þ 1] and [4 þ 2] annulations found in the current
case is quite unique and worth further development.6
It is conceivable that as oxygen is replaced with other
free-radical initiators topromote the reaction, side product
6 should be substantially suppressed and reaction might be
exclusively directed toward the desired product 5. To this
end, screening reaction conditions through combination
with various radical initiators, solvent systems and reac-
tion concentrations was then extensively carried out, and
results are compiled in Table 1.
Given that upon exposure to air or oxygen reactant 4
would suffer a significant loss in forming undesired pro-
ducts, attention was then paid to radical initiators which
could work under inert gas atmosphere. A conventional
radical initiator azobisisobutyronitrile (AIBN) under N2
was first attempted (entry 6), but results were rather
disappointing because a low conversion rate (32%) was
observed even after reaction time was prolonged over 96 h.
Reaction with tert-butyl hydroperoxide (TBHP) was then
performed (entry 7), but the desired product, again, was
obtained in low yield along with most of the starting
material recovered intact.8 However, to our delight, when
the same reaction was conducted under catalysis with
tetrabutylammonium iodide (TBAI, 20 mol %),9 the yield
was substantially improved up to 86% in 1 h though
another side product 8 was detected in ca. 10% yield
(entry 8).10 On the basis of these encouraging results, an
in-depth investigation on the above catalytic system was
then carried out. Finally, we found that lowering both
oxidant TBHP and reaction concentration to 1.1 equiv
and 0.03 M, respectively, allowed for clean preparation of
product 5 in 95% yield. As such, TBHP (1.1 equiv)/TBAI
(20 mol %)/PhH (0.03 M) was considered the reaction
system of choice and thus applied to an array of substrates
Table 1. Screening of Reaction Conditions
conc
(M)
temp
time
(h)
yieldb
(%)
entry
initiator
solvent
(°C)
1
2
3
4
5
6
7
8
9
O2
O2
DMF
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.1
0.03
rt
72
72
72
24
24
96
8
5
<5
9
toluene
DCM
DMF
rt
O2 or air
Et3Bc/air
Et3Bc/H2O2
AIBNd
rt
rt
45
30
32
10
86
95
c
DMF
rt
toluene
PhH
100
80
80
80
TBHPd
TBHPd/TBAIe PhH
1
TBHPf/TBAIe PhH
1
a All reactions were performed using reactant 4 (100 mg, 0.32 mmol)
and a free radical initiator in an amount as indicated below in the selected
solvent. b Isolated yield. c 3.0 equiv was used under N2. d 1.5 equiv was
used under N2. e 20 mol % was used. f 1.1 equiv was used under N2.
(7) (a) Ueda, M.; Miyabe, H.; Kimura, T.; Kondoh, E.; Naito, T.;
Miyata, O. Org. Lett. 2009, 11, 4632. (b) Yorimitsu, H.; Shinokubo, H.;
Matsubara, S.; Oshima, K. J. Org. Chem. 2001, 66, 7776. (c) Valpuesta,
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M.; Munoz, C.; Dıaz, A.; Torres, G.; Suau, R. Eur. J. Org. Chem. 2010,
1934. (d) Yorimitsu, H.; Nakamura, T.; Shinokubo, H.; Oshima, K.;
Omoto, K.; Fujimoto, H. J. Am. Soc. Chem 2000, 122, 11041. (e)
Brucelle, F.; Renaud, P. Org. Lett. 2012, 14, 3048.
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Green Chem. 2009, 11, 1973. (b) Reddy, K. R.; Venkateshwar, M.;
Maheswari, U.; Kumar, P. S. Tetrahedron Lett. 2010, 51, 2170.
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Org. Lett. 2012, 14, 3384. (b) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.;
Wan, X. Angew. Chem., Int. Ed. 2012, 51, 3231. (c) Chen, L.; Shi, E.; Liu,
Z.; Chen, S.; Wei, W.; Li, H.; Xu, K.; Wan, X. Chem.;Eur. J 2011, 17,
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15958.
Org. Lett., Vol. 14, No. 23, 2012
6025

with greater structural diversity. As listed in Table 2, not
only the generality of the methodology was attested but
also a series of complex tricyclic compounds 20ꢀ30 be-
came accessible. All substrates were readily prepared via
the modified Knoevenagel condensation of commercially
available arylacetonitrile with 5-(trimethylsilyl)-4-pentan-
1-al in the presence of Hantzsch ester as a mild reducing
agent and L-proline as a base in excellent yields,11 with the
exception that substrates 10, 15, and 19 were synthesized in
a two-step sequence, involving Knoevenagel condensation
and 1,4-conjugate addition, in good yields. The above
synthetic procedures are detailed in the Supporting Infor-
mation. In the current cases examined, the corresponding
tricyclic products were obtained in high to excellent yields
(85ꢀ98%) under optimized reaction conditions; however,
while a strong electron-donating methoxy substituent at
the para position was introduced (i.e., 14), the cyclization
product 25 was produced in moderate yield (72%)
(Table 2, entry 6). An explanation could be that during
the second [4 þ 2] annulation, ring closure might be
somewhat hampered, presumably due to a high delocaliz-
ing electron density bestowed with the methoxy group,
thus rendering the formation of product slightly unfavor-
able. Nevertheless, as a gem-dimethyl group was installed
at the β position to the ketone carbonyl, compound 15 thus
formedcould facilitate thecyclization processdramatically
under similar reaction conditions, giving desired product
26 in excellent yield (94%) in less than 30 min (entry 7).
These remarkable phenomena, enhancing reaction rate
and/or yield by a gem-dimethyl group, were also observed
with β-dimethyl substrates 10 (96%, 30 min vs 9 (85%,
1 h)) and 19 (95%, 30 min vs 4 (95%, 1 h)), suggesting that
the ThorpeꢀIngold effect12 might play an important role
in the current radical cascade by forcing an initial R-keto
radical species to adopt a correct puckered conformation,
ready for the subsequent [4 þ 1] annulation, resulting in
acceleration of the reaction rate; however, whether this
process is a rate-limiting step remains to be determined in
that mechanistically, four activation-energy barriers might
exist along the reaction course.
Table 2. Tandem Annulation of Various R-Cyano R-TMS-
Capped Alkynyl Aryl Ketones
The mechanistic rationale for the titled system is de-
picted in Scheme 2 using substrate 4 as a typical example.
The cascade process is proposed to be initiated with
abstracting H-atom, R to both cyano and carbonyl groups,
by the free radical species t-BuO• or t-BuOO• generated
by a catalytic cycle of oxidants TBHP and I2. The initial
R-keto radical intermediate A thus formed might undergo
the first intramolecular 5-exo-dig cyclization to produce
the vinyl radical intermediate B, by which the ensuing
6-endo-trig addition, giving rise to a cyclic pentadienyl
(11) (a) Ramachary, D. B.; Kishor, M.; Babul Reddy, G. Org.
Biomol. Chem. 2006, 4, 1641. (b) Ramachary, D. B.; Kishor, M.;
Ramakumar, K. Tetrahedron Lett. 2006, 47, 651. (c) Mukhopadhyay,
C.; Tapaswi, P. K.; Butcher, R. J. Tetrahedron Lett. 2010, 51, 1797. (d)
Ramachary, D. B.; Chowdari, N. S.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2003, 42, 4233. (e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.;
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T. W.; Shia, K. S. Eur. J. Org. Chem. 2010, 3473.
a Isolated yield. b Reaction completed in 1 h. c Reaction completed in
30 min.
(12) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. Trans
1915, 107, 1080.
6026
Org. Lett., Vol. 14, No. 23, 2012

Scheme 2. Proposed Mechanism for the Intramolecular Tandem
Cyclization Process
Scheme 3
demonstrating that in addition to TMS, coupling with the
other appropriatefunctionality atthe terminalalkynylunit
to stabilize the vinyl radical species is feasible, thus broad-
ening the synthetic utility of this newly developed method.
In summary, an intramolecular radical cascade of the R-
cyano-TMS/aryl-capped alkynyl aryl alkyl ketones, pro-
moted by oxidant TBHP under catalysis with TBAI, has
been developed, culminating in the construction of a
variety of [6,6,5] tricyclic frameworks containing a high
level of functionalization efficiently. The methodology is
currently under active investigation to expand its scope
and is also extended to the synthesis of naturally occurring
products, such as stealthins and kinamycins, bearing the
tetracyclic benzo[b]fluorine skeletons with a broad spec-
trum of antibiotic properties.14
radical C, followed by aromatic homolytic substitution
could occur to afford rearomatization product 5.13
To clarify the role of the TMS group, substrate 31
(Scheme 3), a TMS-free counterpart of 9 (Table 2, entry
1), was synthesized for comparison. Upon treatment with
the standard reaction conditions, the corresponding pro-
duct 35 was merely obtained in 35% yield. As compared to
product 20 formed in 85% yield from 9, the results strongly
suggested that the vinyl radical intermediate resulting from
5-exo-dig cyclization should be sufficiently stabilized by
the TMS group to promote the ensuing [4 þ 2] cycloaddi-
tion. Along this line, compounds 32ꢀ34, replacing the
TMS moiety with the phenyl group or its para-substituted
analogues intended to provide the similar stabilizing force,
were further prepared. As a result, irrespective of the
stereoelectronicnatureof the parasubstituent, all reactions
proceeded in a predictable manner to afford the corre-
sponding products 36ꢀ38 in high yields (84ꢀ87%) in 1 h,
Acknowledgment. We are grateful to the National
Health Research Institutes and National Science Council
of Taiwan (NSC-100-2113-M-400-002; NSC-101-2113-M-
400-003-MY2) for financial support.
(13) (a) Bowman, W. R.; Storey, J. M. D. Chem. Soc. Rev. 2007, 36,
1803. (b) Vaillard, S. E.; Schulte, B. In Modern Arylation Methdods;
Ackermann, L., Eds.; Wiley-VCH: Weinheim, 2009; Chapter 13. (c) Vaillard,
S. E.; Studer, A. In Encyclopedia of Radicals in Chemistry, Biology and
Materials; Chatgilialoglu, C., Studer, A., Eds.; John Wiley&Sons: New
York, 2012; Chapter 37.
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, and copies
of NMR and X-ray spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
ꢀ
(14) (a) Barluenga, J.; Fernandez-Rodrıguez, M. A.; Aguilar, E. Org.
Lett. 2002, 4, 3659. (b) Gould, S. J. Chem. Rev. 1997, 97, 2499.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 23, 2012
6027