Bronsted acid-promoted intramolecular carbocyclization of alkynals leading to cyclic enones

Article abstract of DOI:10.1021/ol900142r

TFA-promoted exo carbocyclizations of nonterminal 7-alkynals gave good to excellent yields of seven-membered cycloalkenones, a medium-sized functionalized ring present in natural products with relevant pharmacological properties. Nonterminal 5-and 6-alkyn

Full text of DOI:10.1021/ol900142r

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1531-1533
Brønsted Acid-Promoted Intramolecular
Carbocyclization of Alkynals Leading to
Cyclic Enones
Carlos Gonza´lez-Rodr´ıguez, Luz Escalante, Jesu´s A. Varela, Luis Castedo, and
Carlos Saa´*
Departamento de Qu´ımica Orga´nica, Facultad de Qu´ımica, UniVersidad de Santiago
de Compostela, 15782 Santiago de Compostela, Spain
carlos.saa@usc.es
Received January 22, 2009
ABSTRACT
TFA-promoted exo carbocyclizations of nonterminal 7-alkynals gave good to excellent yields of seven-membered cycloalkenones, a
medium-sized functionalized ring present in natural products with relevant pharmacological properties. Nonterminal 5- and 6-alkynals
also gave very good yields of the corresponding exo cyclopentenones and cyclohexenones. On the other hand, terminal 5-alkynals
gave endo carbocyclizations to cyclohexenones. These carbocyclizations can be considered as tandem alkyne hydration/aldol condensation
processes.
Transition-metal- and Lewis and Brønsted acid-catalyzed
or promoted cyclizations involving alkynes and carbonyl
groups have emerged as an important strategy for the
assembly of functionalized carbocyclic compounds. Tran-
sition-metal-catalyzed cyclizations of alkynals to give a
variety of cyclic structures have been described.1 Brønsted
and Lewis acid-catalyzed cyclizations of acetylenic ke-
tones to afford conjugated cycloalkenones are well-known
processes.2 More recently, Lewis acid-catalyzed cycloi-
somerizations of nonterminal alkynals and alkynones to
endo- or exocyclic R,ꢀ-unsaturated cyclopentenones and
cyclohexenones have been reported.3,4 We describe here
the first cycloisomerization of nonterminal alkynals promoted
by Brønsted acids (mainly trifluoroacetic acid) to give seven-
membered exo cycloalkenones, an important core in several
biologically important natural products,5 as well as new
cycloisomerizations of alkynals to give exo and endo five-
and six-membered cycloalkenones (Scheme 1 and Table 1).6
(1) For Rh, see: (a) Tanaka, K.; Fu, G. C. J. Am. Chem. Soc. 2001,
123, 11492. (b) Tanaka, K.; Sasaki, K.; Takeishi, K.; Sugishima, K. Chem.
Commun. 2005, 4711. (c) Shintani, R.; Okamoto, K.; Otomaru, Y.; Ueyama,
K.; Hayashi, T. J. Am. Chem. Soc. 2005, 127, 54. (d) Rhee, J. U.; Krische,
M. J. J. Am. Chem. Soc. 2006, 128, 10674. For Ru, see: (e) Chatani, N.;
Morimoto, T.; Fukumoto, Y.; Murai, S. J. Am. Chem. Soc. 1998, 120, 5335.
(f) Varela, J. A.; Gonza´lez-Rodr´ıguez, C.; Rub´ın, S. G.; Castedo, L.; Saa´,
C. J. Am. Chem. Soc. 2006, 128, 9576. For Ni, see: (g) Montgomery, J.
Angew. Chem., Int. Ed. 2004, 43, 3890. For Pd, see: (h) Asao, N.; Nogami,
T.; Takahashi, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124, 764. (i)
Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343. (j) Tsukamoto,
H.; Ueno, T.; Kondo, Y. J. Am. Chem. Soc. 2006, 128, 1406. (k) Kusama,
H.; Ishida, K.; Funami, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2008,
47, 1.
(3) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493.
(4) (a) Jin, T.; Yamamoto, Y. Org. Lett. 2007, 9, 5259. Enynones: (b)
Jin, T.; Yamamoto, Y. Org. Lett. 2008, 10, 3137. For related intermolecular
cyclizations of alkynes and aldehydes, see: (c) Saito, A.; Umakoshi, M.;
Yagyu, N.; Hanzawa, Y. Org. Lett. 2008, 10, 1783.
(5) (a) Brady, S. F.; Bondi, S. M.; Clardy, J. J. Am. Chem. Soc. 2001,
123, 9900. (b) Williams, M. J.; Deak, H. L.; Snapper, M. L. J. Am. Chem.
Soc. 2007, 129, 486.
(6) For carbocyclization of ynamide-aldehyde substrates to five- and six-
membered cycloalkenamides, see: (a) Kurtz, K. C. M.; Hsung, R. P.; Zhang,
Y. Org. Lett. 2006, 8, 231. (b) Formation of a seven-membered cycloalk-
enimide in low yield using a singular ynamide-aldehyde substrate has also
been described. (c) For carbocyclization of terminal alkynals to cyclopen-
tencarbaldehydes, see: Binder, J. T.; Crone, B.; Haug, T. T.; Menz, H.;
Kirsch, S. F. Org. Lett. 2008, 10, 1025.
(2) (a) Harding, C. E.; King, S. L. J. Org. Chem. 1992, 57, 883, and
references therein. (b) Balog, A.; Geib, S. J.; Curran, D. P. J. Org. Chem.
1995, 60, 345, and references therein. (c) Wempe, M. F.; Grunwell, J. R.
J. Org. Chem. 1995, 60, 2714, and references therein.
10.1021/ol900142r CCC: $40.75
Published on Web 02/26/2009
2009 American Chemical Society

Scheme 1
.
Cycloisomerization of Nonterminal Alkynals in TFA
Table 2. Cycloisomerization of 5-Alkynals 1a-h and
6-Alkynals 4a-c in TFA
Table 1. Cycloisomerization of 5-Alkynal 1a in Acidic
Conditions
entry
acid
TFA
TFA
TFA
TFA
HBF4
TfOH
AcOH
TMSOTf
TMSOTf
InCl3
temp (°C)
(%)
1a
2a
90
50
25
90
25
25
90
25
90
60
15
s
3a
4b
5b
55
49
s
6b
7a
8b
30
35
63
60
9b
-78f25
25
25
10b
11b
BF3OEt2
a 0.5 mmol of 1a in 3 mL of acid. b 0.5 mmol of 1a and 3 equiv of acid
in 3 mL of DCE.
In the search for optimized conditions for the cycloisomer-
ization of alkynals, we first examined the reaction of terminal
5-alkynal 1a with the Brønsted and Lewis acids depicted in
Table 1. Gratifyingly, heating a trifluoroacetic acid solution
of 1a (0.12 M) in a sealed tube at 90 °C for 1 h gave very
smoothly the cyclohexenone 2a in excellent yield (Table 1,
entry 1). Lower yields and longer reaction times were found
on using lower temperatures (entries 2 and 3). This is the
first time that a new mode of endo cyclization of terminal
5-alkynals has been observed. Other Brønsted acids such as
HBF4 and TfOH also promote the reaction with only 3 equiv
at rt, albeit in moderate yields (entries 5 and 6), but TFA
(3 equiv) and the weaker AcOH led only to recovery of
starting material (entries 4 and 7). The cyclization also occurs
with Lewis acids: TMSOTf gave rapid evolution at rt to 2a
with a low yield (entries 8 and 9); InCl3 or BF3OEt2 afforded
quite good yields of 2a (entries 10 and 11).
a Conditions A: Heating a solution of 0.5 mmol of alkynal in 3 mL of
TFA in a sealed tube at 90 °C for 1-2 h (conditions A). b Conditions B:
Heating a solution of 0.5 mmol of alkynal and 20 equiv of TFA in 3 mL
of DCE in a sealed tube at 90 °C for 1-2 h. c Conditions A but 5 h heating.
E ) CO2Me.
also was cycloisomerized to the pyrroline derivative 3d′ in
relatively good yield (entry 4).8
Even nonterminal alkynal 1h, which does not have a
favorable Thorpe-Ingold effect for cyclization,9 gave an
Under optimized conditions (Table 1, entry 1), other
terminal 5-alkynals (mono- and disubstituted at C4, 1b and
1c) also cyclized to give quite good yields of the corre-
sponding endo cyclohexenones 2b and 2c (Table 2, entries
2 and 3). Interestingly, when nonterminal 5-alkynals 1d-g
were subjected to acidic conditions, the corresponding exo
cyclopentenones 3d-g were obtained smoothly in quite good
yields (Table 2, entries 4-7).7 Nitrogen-tethered alkynal 1d′
(7) Pyrroline 3d′ and exo cyclopentenone 3g have been obtained by
AgSbF6-, HBF4-, and BF3·OEt2-catalyzed cycloisomerization of 1d′ and 1g
in 58-81% yields. This and other cyclizations of nonterminal 5- and
6-alkynals are described in ref 3.
(8) Pyrroline 3d′ also was obtained by cycloisomerization of the
precursor dimethyl acetal of aldehyde 1d′ in the same yield.
(9) Ingold, K. C.; Sako, S.; Thorpe, J. F. J. Chem. Soc. 1922, 1117. For
a recent paper, see: Kaneti, J.; Kirby, A. J.; Koedjikov, A. H.; Pojarlieff,
I. G. Org. Biomol. Chem. 2004, 2, 1098.
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Org. Lett., Vol. 11, No. 7, 2009

excellent yield of the exo cyclopentenone 3h (Table 2, entry
8). Note also that nonterminal 6-alkynals 4a-c gave the
corresponding exo cyclohexenones 5a-c in reasonably good
yields (Table 2, entries 9-11).10
Scheme 2
.
Proposed Mechanism for the TFA-Promoted
Carbocyclization of Alkynals
Gratifyingly, cycloisomerization of nonterminal 7-alkynals
9 occurred smoothly to give exclusively the new exo
cycloheptenones 10 in good to excellent yields (Table 3).
Table 3. Cycloisomerization of Nonterminal 7-Alkynals 9
reported by Harding2a and later by Krische3scannot be ruled
out. Addition of TFA to the terminal and nonterminal
alkynes11 could lead to the formation of vinyl trifluoroac-
etates A or B, respectively.12 These intermediates can
undergo aldol-type condensations to give the observed endo-
or exocyclic enones, respectively.13 These products could
be considered as being derived from a controlled tandem
alkyne hydration/aldol condensation process.
In summary, we report here the efficient TFA-promoted
exo carbocyclizations of nonterminal 5-, 6-, and 7-alkynals
and endo carbocyclizations of terminal 5-alkynals to give
cyclic enones in good to excellent yields. These carbocy-
clizations can be considered as tandem alkyne hydration/
aldol condensation processes. Work is in progress aimed at
highlighting further applications.
Acknowledgment. This work was supported by the
MICINN (CTQ2008-06557), Consolider Ingenio 2010
(CSD2007-00006), and by the Xunta de Galicia (2007/
XA084 and INCITE08PXIB209024PR). C.G.R. also thanks
the MEC (Spain) for a FPI fellowship, and L.E. thanks
Fundayacucho (Venezuela) for a predoctoral grant.
a Conditions A. b Conditions B. X ) C(CO2Me)2.
Thus, alkyl and aryl alkynals 9a-c gave the corresponding
cycloheptenones 10a-c in good to excellent yields (Table
3, entries 1-3). The 4,4- and 3,3-disubstituted 7-alkynals
9d and 9e also cyclized to the corresponding exo cyclohep-
tenones 10d and 10e in quite good yields (Table 3, entries
4 and 5). Even the parent hexadec-7-ynal 9f, which lacks a
favorable Thorpe-Ingold effect,9 cyclized smoothly to the
cycloheptenone 10f in very good yield (Table 3, entry 6).
A plausible cycloisomerization mechanism is shown in
Scheme 2, although alternative oxete intermediatessas
Supporting Information Available: A typical experi-
mental procedure and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900142R
(11) For Markovnikov and anti-Markovnikov hydration of alkynes, see:
Hintermann, L.; Labonne, A. Synthesis 2007, 1121.
(12) In careful cyclization experiments using CF3COOD, evidence was
found for some intermediates that contain vinyl groups (1H NMR) and
trifluoroacetate units (GCMS). See Supporting Information for details.
(13) Heating the 5,5-disubstituted 9-methyl-8-nonynal 11 in TFA gave
the corresponding 8-oxodecanal 12 in 40% yield, indicating that only
hydration of the alkyne (from the corresponding vinyl trifluoroacetate)
occurred. See Supporting Information for details.
(10) Unexpectedly, the corresponding terminal 6-alkynal 4d gave a
mixture of three cyclized products: cyclopentenal 6d (27%), cyclopentenone
7d (27%), and cyclohexenal 8d (10%). See Supporting Information for
details.
Org. Lett., Vol. 11, No. 7, 2009
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