Dual functionalization of allene: facile construction of heteropolycycles mediated by Bronsted acid

Article abstract of DOI:10.1246/cl.2009.628

A facile construction of a heteropolycyclic framework is developed by exploiting the dual functionalization of allene. On treatment of phenethyl alcohol or amine bearing a terminal allene with the Bronsted acid, two consecutive reactions to allene, nucleophilic addition of heteroatom and the Friedel-Crafts reaction, occurred to give 2-oxa-or azabicyclo[2.2.2]octane skeleton. Copyright

Full text of DOI:10.1246/cl.2009.628

628
Chemistry Letters Vol.38, No.6 (2009)
Dual Functionalization of Allene: Facile Construction
of Heteropolycycles Mediated by Brønsted Acid
Keiji Mori, Shosaku Sueoka, and Takahiko Akiyamaꢀ
Department of Chemistry, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8558
(Received April 16, 2009; CL-090378; E-mail: takahiko.akiyama@gakushuin.ac.jp)
A facile construction of a heteropolycyclic framework is
Table 1. Examination of reaction conditions
O
developed by exploiting the dual functionalization of allene.
On treatment of phenethyl alcohol or amine bearing a terminal
allene with the Brønsted acid, two consecutive reactions to al-
lene, nucleophilic addition of heteroatom and the Friedel–Crafts
reaction, occurred to give 2-oxa- or azabicyclo[2.2.2]octane
skeleton.
OH
O
Acid (20 mol%)
Ph
+
+
Ph
conditions
Ph
·
Ph
Ph
Ph
2
3
4
5
Yield/%
Entry
Acid
Solvent Temp/ꢁC Time/h
3
4
5
1
2
3
4
5
6a
CSA
TFA
.
toluene
toluene
TsOH H2O toluene
reflux
reflux
reflux
60
reflux
reflux
4
9
5
3
5
4
— —
— —
— 39 14
— 56 trace
— 80 trace
— 64 trace
—
—
Tetrahydrofuran and pyrrolidine are ubiquitous skeletons
found in many naturally occurring and biologically active com-
pounds. Because of this, considerable effort has been directed to-
ward the construction of these structures.1 The intramolecular
addition of an X–H bond to a C=C bond, namely, hydroalk-
oxylation and hydroamination, is the most straightforward and
atom-economical method. Although scattered examples of the
transition metal-catalyzed hydroalkoxylation and hydroamina-
tion of alkene have been reported recently,2 the addition reaction
with unactivated alkene is difficult to accomplish due to the low
reactivity of the alkene. In contrast, allene is more reactive than
alkene due to the strained nature of the cumulated C=C bond.3
For this reason, the transition metal-catalyzed hydrofunctionali-
zation of allenes has been investigated as a means to circumvent
some of the difficulties associated with catalytic alkene function-
alization.4 The Brønsted acid-catalyzed version, however, re-
mains elusive.5 In this communication, we wish to report the
functionalization of allenes induced by a Brønsted acid. Interest-
ingly, in this process, hydrofunctionalization and the Friedel–
Crafts reaction occurred successively to afford heteropolycycles
(dual functionalization of allene).
TfOH
TfOH
TfOH
toluene
CH2Cl2
CH2Cl2
a10 mol % acid was employed.
Figure 1. X-ray structure of 4. Hydrogen atoms are omitted for
clarity.
OH
H+
·
Ph
O+
O
Ph
O
H+
2
Ph
Ph
Ph
+
H+
Ph
Phenethyl alcohol 2 was chosen as the substrate for cycliza-
tion for two reasons (eq 1): 1) easy preparation from commer-
cially available 1 in three steps4d and 2) high propensity for cyc-
lization due to the ‘‘Thorpe–Ingold Effect.’’6
B
D
C
OH
I
path I
+
·
4
Ph
path II
II
+
HO
HO
HO
H+
OH
A
CO2Me
ref. 4d
+
Ph
Ph
Ph
Ph
Ph
Ph
·
synthesized
in 3 steps
Ph
ð1Þ
1
2
E
F
G
geminal
disubstitution
OMe
MeO
TfOH (20 mol%)
recovery of 6
With the requisite substrate in hand, the cyclization was per-
formed: a solution of 2 in toluene was exposed to several strong
Brønsted acids (20 mol %, Table 1). On treatment with CSA, no
other products were obtained even in refluxing toluene (Entry 1).
+
Ph
·
Ph
CH2Cl2
reflux, 21 h
61%
Ph
6
24%
7
Scheme 1. Plausible mechanism.
.
TFA was also ineffective (Entry 2). In the case of TsOH H2O,
the starting material was almost completely consumed. Surpris-
ingly, the resulting product was not tetrahydrofuran 3 but unex-
pected polycyclic product 4 (39%, Entry 3), whose structure was
confirmed by single-crystal X-ray analysis (Figure 1).7 In this
case, a small amount of naphthalene 5 was also obtained
(14%). After several experiments, we found that TfOH was the
most effective, giving 4 exclusively (56%). Gratifyingly, when
CH2Cl2 was used instead of toluene, the chemical yield of 3
was dramatically improved (80%). Decreasing the catalyst load
to 10 mol % lowered the chemical yield (64%, Entry 6).
Scheme 1 illustrates a plausible mechanism of this reaction.
At first, the nucleophilic addition of oxygen atom to vinyl cation
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.6 (2009)
629
Table 2. Examination of reaction conditions using phenethyl-
amine derivative as starting material
Ts
N
NHTs
TfOH (150 mol%)
Ar
Ts
N
CH2Cl2, 0 °C
·
Ar
Ar
TsNH
Ph
NHTs
R
TfOH (x mol%)
+
8b: Ar = p-CH3-C6H4
8c: Ar = p-Cl-C6H4
9b: R = CH3, 61%, 0.25 h
9c: R = Cl, 26%, 3 h
Ph
CH2Cl2
conditions
·
Ph
Ph
8a
9a
10
Ts
N+
Friedel-Crafts
H+
reaction
Yield/%
Entry x/mol % Temp/ꢁC Time/h
8c
9c
slow
Ar
C6H4-p-Cl
9a
10
8a
by-products
H
1
2
3
4
20
50
150
150
reflux
reflux
reflux
0 ꢁC
18
3
2
17
30
58
68
52
35
5
23
—
—
6
Scheme 2. Substituent effect of internal phenyl group.
nitrogen-containing heterocycles. Further study on related reac-
tions is underway.
3
8
References and Notes
A,8 generated by the protonation of terminal allene, occurred to
give vinyl ether B. The generation of oxonium cation C and the
subsequent the Friedel–Crafts reaction of the internal phenyl
group furnished polycycle 4 (path I). Thus, two reactions (nucle-
ophilic addition of heteroatom and the Friedel–Crafts reaction)
to allene occurred successively in one reaction vessel (dual func-
tionalization of allene). Another reaction pathway, the Friedel–
Crafts reaction followed by nucleophilic addition of heteroatom
sequence (path II), may be operative.
To confirm the actual reaction pathway, we conducted the
following reaction: a solution of corresponding methyl ether 6
in CH2Cl2 was exposed to TfOH (20 mol %). The Friedel–Crafts
product (dihydronaphthalene) 7 was obtained in 24% yield.
However, starting material 6 was not consumed completely
(61% recovery) even over prolonged reaction time (21 h, cf.
5 h, Entry 5, Table 1). These data suggest that both pathways
(I and II) are operative in this reaction, with path I being predom-
inant.9
Next, we examined the formation of isoquinoline polycycle
9 from phenethylamine 8 (Table 2), which was prepared in a
manner similar to that using alcohol 2.4e First, the reaction was
conducted with the above optimized conditions (20 mol % TfOH
in refluxing CH2Cl2). Desired product 9a was obtained in a low
yield (17%), accompanied by a substantial amount of by-product
(the Friedel–Crafts product) 10 (52%, Entry 1). The large cata-
lyst load was crucial to this reaction, i.e., the employment of
50 mol % catalyst afforded 9a in 30% yield (Entry 2). In the case
of 150 mol % catalyst load, the chemical yield was raised to 58%
(Entry 3). Gratifyingly, when the reaction was conducted at 0 ꢁC,
9a was obtained in good yield (68%, Entry 4).
The electron density of the internal phenyl group had a re-
markable influence on the chemical yield of 9 (Scheme 2).10,11
Tolyl-substituted 8b gave 9b in moderate yield (61%). On the
other hand, 7-chloro-substituted isoquinoline 9c was obtained
in only 26% yield. Due to the poor nucleophilicity of the chloro-
substituted phenyl group, active iminium species H, generated
by the nucleophilic addition of nitrogen atom to allene followed
by protonation, presumably reacted with some other nucleophile
(the most likely one was H2O in CH2Cl2), giving several by-
products.11
1
2
For recent reviews, see: a) E. D. Cox, J. M. Cook, Chem. Rev. 1995,
95, 1797. b) F. Alonso, I. P. Beletsaya, M. Yus, Chem. Rev. 2004,
104, 3079. c) S. Bur, A. Padwa, Adv. Heterocycl. Chem. 2007, 94, 1.
a) M. R. Crimmin, I. J. Casely, M. S. Hill, J. Am. Chem. Soc.
2005, 127, 2042. b) D. Riegert, J. Collin, A. Meddour, E. Schulz,
A. Trifonov, J. Org. Chem. 2006, 71, 2514. c) X. Han, R. A.
Widenhoefer, Angew. Chem., Int. Ed. 2006, 45, 1747. d) J. Zhang,
C.-G. Yang, C. He, J. Am. Chem. Soc. 2006, 128, 1798. e) D. V.
Gribkov, K. C. Hultzsch, F. Hampel, J. Am. Chem. Soc. 2006,
128, 3748. f) F. E. Michael, B. M. Cochran, J. Am. Chem. Soc.
2006, 128, 4246.
3
4
a) H. F. Schuster, G. M. Coppola, Allenes in Organic Synthesis,
Wiley-Interscience, New York, 1984. b) A. Padwa, M. A.
Filipkowski, M. Meske, S. S. Murphree, S. H. Watterson, Z. Ni,
J. Org. Chem. 1994, 59, 588.
For hydrofunctionalization of allene, see: a) S. Ma, W. Gao, Org.
Lett. 2002, 4, 2989. b) R. W. Bates, V. Satcharoen, Chem. Soc.
Rev. 2002, 31, 12. c) S. Ma, Chem. Rev. 2005, 105, 2829. d) Z.
Zhang, C. Liu, R. E. Kinder, X. Han, H. Qian, R. A. Widenhoefer,
J. Am. Chem. Soc. 2006, 128, 9066. e) Z. Zhang, R. A. Widenhoefer,
Angew. Chem., Int. Ed. 2007, 46, 283. f) Z. Zhang, C. F. Bender,
R. A. Widenhoefer, Org. Lett. 2007, 9, 2887. g) R. A. Widenhoefer,
Chem.—Eur. J. 2008, 14, 5382.
5
6
For a review, see: T. Akiyama, Chem. Rev. 2007, 107, 5744.
a) R. M. Beesley, C. K. Ingold, J. F. Thorpe, J. Chem. Soc., Trans.
1915, 107, 1080. b) C. K. Ingold, J. Chem. Soc., Trans. 1921, 119,
305. c) P. von R. Schleyer, J. Am. Chem. Soc. 1961, 83, 1368. d) S.
McIntyre, F. H. Sansbury, S. Warren, Tetrahedron Lett. 1991, 32,
5409. e) M. E. Jung, J. Gervay, J. Am. Chem. Soc. 1991, 113, 224.
Crystallographic data reported in this manuscript have been depos-
ited with the Cambridge Crystallographic Data Centre as supple-
mentary publication no. CCDC-726048.
In a formal sense, the formation of allylic carbocation intermediate
by protonation of the center carbon overwhelms that of vinyl cation.
However, kinetically favored protonation furnishes the vinyl cation
intermediate. This result could be explained by stereoelectronic fac-
tors. Because the allene structure is nonplanar, an initial protonation
of the center carbon leads to a twisted structure that avoids allylic
conjugation. See: a) K. B. Wiberg, C. M. Breneman, T. J. LePage,
J. Am. Chem. Soc. 1990, 112, 61. b) A. Gobbi, G. Frenking,
J. Am. Chem. Soc. 1994, 116, 9275.
7
8
9
Naphthalene 5 was formed by olefin isomerization from intermedi-
ate F followed by dehydrative 1,2-phenyl migration.
10 The preparation of corresponding starting materials (8b and 8c) is
described in Supporting Information.
11 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
In summary, we have developed a new method for the con-
struction of a polycyclic framework via the dual functionaliza-
tion of allene. This method is applicable to both oxygen- and
Published on the web (Advance View) May 23, 2009; doi:10.1246/cl.2009.628