Efficient synthetic method of multisubstituted allenes from the reactions of allylindium reagents with 3°-propargyl alcohols

Article abstract of DOI:10.1021/ol800719g

(Chemical Equation Presented) An efficient synthetic method of tri- and tetra-substituted allenes having an allyl and methallyl group was developed by the reactions of allylindium reagents generated in situ from indium and allyl bromides with 3°-propargyl

Full text of DOI:10.1021/ol800719g

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2441-2444
Efficient Synthetic Method of
Multisubstituted Allenes from the
Reactions of Allylindium Reagents with
3°-Propargyl Alcohols
Kooyeon Lee and Phil Ho Lee*
National Research Laboratory for Catalytic Organic Reaction, Department of
Chemistry and Institute for Molecular Science & Fusion Technology, Kangwon
National UniVersity, Chunchon 200-701, Republic of Korea
phlee@kangwon.ac.kr
Received March 31, 2008
ABSTRACT
An efficient synthetic method of tri- and tetra-substituted allenes having an allyl and methallyl group was developed by the reactions of
allylindium reagents generated in situ from indium and allyl bromides with 3°-propargyl alcohols.
Development of efficient and practical synthetic methods for
multisubstituted allenes is highly desirable because these
compounds are versatile building blocks for organic synthe-
sis.1 In general, allene compounds can be prepared by
alkylation of allenylmethyl halides with appropriate carban-
ionic species,1e an SN2′-type selective displacement of
propargyl alcohol derivatives with organocopper reagents,2
intramolecular regio- and stereoselective reduction of an
acetylenic substrate,3 1,4-addition to enynes,4and 1,6-addition
reactions to acceptor-substituted enynes.5 Synthesis of allenes
by means of metal-catalyzed cross-coupling reactions would
be an alternative method.6 Among these, allene preparation
through SN2′ nucleophilic substitutions of propargylic elec-
trophiles using organocopper reagents has developed into one
of the most versatile and popular protocols. In these cases,
propargyl acetates and benzoates,7 carbonates,8 sulfonates,9
ethers and acetals,10 halides,11 oxiranes,12 and even aziri-
(2) (a) Rona, P.; Crabbe, P. J. Am. Chem. Soc. 1968, 90, 4733. (b)
Fleming, I.; Terrett, N. K. J. Organomet. Chem. 1984, 264, 99. (c) Trost,
B. M.; Urabe, H. J. Am. Chem. Soc. 1990, 112, 4982. (d) Alexakis, A.;
Marek, I.; Mangeney, P.; Normant, J. F. J. Am. Chem. Soc. 1990, 112,
8042. (e) Borzilleri, R. M.; Weinreb, S. M.; Parvez, M. J. Am. Chem. Soc.
1995, 117, 10905. (f) Jansen, A.; Krause, N. Inorg. Chim. Acta 2006, 359,
1761.
(1) (a) Rossi, R.; Diversi, P. Synthesis 1973, 25. (b) The Chemistry of
Ketenes, Allenes, and Related Compounds; Patai, S., Ed.; Wiley: New York,
1980. (c) Brandsma, L.; Verkruijsse, H. D. Synthesis of Acetylenes, Allenes
and Cumulenes; Elsevier: Amsterdam, 1981. (d) The Chemistry of Allenes;
Landor, S. R., Ed.; Academic Press: London, 1982. (e) Coppola, G. M.;
Schuster, H. F. Allenes in Organic Synthesis; Wiley: New York, 1984. (f)
Modern Allene Chemistry; Krause, N.; Hashmi, A. S. K., Eds.; Wiley-VCH:
Weinheim, 2004. (g) Urabe, H.; Takeda, T.; Hideura, D.; Sato, F. J. Am.
Chem. Soc. 1997, 119, 11295. (h) Funami, H.; Kusama, H.; Iwasawa, N.
Angew. Chem., Int. Ed. 2007, 46, 909. (i) Lee, J. H.; Toste, F. D. Angew.
Chem., Int. Ed. 2007, 46, 912.
(3) (a) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. (b)
Shepard, M. S.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 2597.
(4) Krause, N.; Gerold, A. Angew. Chem., Int. Ed. 1997, 36, 186.
(5) Krause, N.; Thorand, S. Inorg. Chim. Acta 1999, 296, 1.
(6) Lee, K.; Seomoon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002, 41,
3901.
(7) (a) Keinan, E.; Bosch, E. J. Org. Chem. 1986, 51, 4006. (b) Corriu,
R. J. P.; Huyn, V.; Iqbal, J.; Moreau, J. J. E.; Vernhet, C. Tetrahedron
1992, 48, 6231. (c) Spino, C.; Thibault, C.; Gingras, S. J. Org. Chem. 1998,
63, 5283. (d) Riveiros, R.; Rodriguez, D.; Sestelo, J. P.; Sarandeses, L. A.
Org. Lett. 2006, 8, 1403.
10.1021/ol800719g CCC: $40.75
Published on Web 05/14/2008
2008 American Chemical Society

dines13 have been successfully employed as substrates.
Although the synthetic utility of allylallenes is very useful
in thermal aromatization,14 radical cyclization,15 gold-
Scheme 1
.
Reactions of Allylindiums with 3°-Propargyl
Alcohols
mediated
cyclization,16
and
preparation
of
bicyclo[3.1.0]hexanone,17 (E)-vinyl azides, and polysubsti-
tuted pyrroles,18 synthesis of tri- and tetra-substituted ally-
lallenes is tedious. In addition, as far as we are aware, there
is no report that propargyl alcohol itself instead of propargyl
alcohol derivatives has been used as an electrophile in SN2′
nucleophilic substitution reactions. It is presumably due to
the basicity of a variety of organometallic reagents which
act as nucleophiles. Therefore, there is still a strong need
for a highly efficient synthesis of multisubstituted allenes
despite the recent progress of allene synthesis.19 Recently,
allylindiums and propargylindiums generated in situ from
the reactions of indium with allyl halides and propargyl
halides could participate as nucleophiles in Pd-catalyzed
substitution reactions of allyl carbonates to produce 1,5-
dienes and 1,5-enynes in good yields.20 In continuation of
our studies directed toward the development of efficient
indium-mediated reactions, we describe herein an efficient
synthetic method of multisubstituted allenes containing allyl
groups from the reactions of allylindiums with 3°-propargyl
alcohols (Scheme 1).
1). The use of indium (1.5 equiv) with allyl bromide (1.5
equiv) afforded the desired product in 50% yield (entry 2).
Of the reactions screened, the best results were obtained with
Table 1. Reaction Optimization of Allylindium with
3°-Propargyl Alcohola
temp time yield
entry
X
Met additive
solvent
THF
THF
THF
THF
THF
THF
THF
THF
DMF
H2O
Wet-THF
THF
THF-H2O
THF-NH4Cl 70
THF
THF
(°C)
(h)
(%)b
1c
2d
3e
4c
5c
6f
7
8
9
10
11
12
13
14
15
16
Br In
Br In
Br In
Br In
Br In
Br In
Br In
70
70
70
70
70
35
35
35
100
100
70
70
70
3
7
7
20
20
3
4
3
20
20
20
20
20
20
5
51
50
40
0
10
88
87
87
0
0
9
0
0
Our initial study focused on reaction of 2-phenyl-3-butyn-
2-ol (1a) with allylindium generated in situ from indium and
allyl halides. The results are summarized in Table 1.
Allylindium obtained from indium (1.0 equiv) and allyl
bromide (1.5 equiv) gave allylallene 2a in 51% yield (entry
LiI
LI
I
In
(8) (a) Darcel, C.; Bruneau, C.; Dixneuf, P. H. Chem. Commun. 1994,
1845. (b) Dixneuf, P. H.; Guyot, T.; Ness, M. D.; Robert, S. M. Chem.
Commun. 1997, 2083. (c) Ishikura, M.; Matsuzaki, Y.; Agata, I.; Katagiri,
N. Tetrahedron 1998, 54, 13929.
Br In
Br In
Br In
Cl In
Br In
Br In
Br Zn
Br Mg
(9) (a) Agami, C.; Couty, F.; Evano, G.; Mathieu, H. Tetrahedron 2000,
56, 367. (b) Ohno, H.; Anzai, M.; Toda, A.; Ohishi, S.; Fujii, N.; Tanaka,
T.; Takemoto, Y.; Ibuka, T. J. Org. Chem. 2001, 66, 4904.
(10) A1exakis, A.; Marek, I.; Mangeney, P.; Normant, J. F. J. Am. Chem.
Soc. 1990, 112, 8042.
0
0
0
70
70
5
(11) (a) Pasto, D. J.; Hennion, G. F.; Shults, R. H.; Waterhouse, A.;
Chou, S.-K. J. Org. Chem. 1976, 41, 3496. (b) Jeffery-Luong, T.;
Linstrumelle, G. Tetrahedron Lett. 1980, 21, 5019. (c) Yus, M.; Gomis, J.
Eur. J. Org. Chem. 2003, 2043.
a Reactions were carried out with 1a (1 equiv), indium (1.5 equiv) and
allyl halide (2.25 equiv) unless otherwise noted. b Isolated yield. c 1a:In:allyl
halide ) 1:1:1.5. d 1a:In:allyl halide ) 1:1.5:1.5. e 1a:In:allyl halide )
1:1.5:1. f 1a:In:allyl halide ) 1:2:3.
(12) (a) A1exakis, A. Pure Appl. Chem. 1992, 64, 387. (b) Marshall,
J. A.; Pinney, K. G. J. Org. Chem. 1993, 58, 7180. (c) Spino, C.; Frechette,
S. Tetrahedron Lett. 2000, 41, 8033.
(13) (a) Ohno, H.; Toda, A.; Miwa, Y.; Taga, T.; Fujii, N.; Ibuka, T.
Tetrahedron Lett. 1999, 40, 349. (b) Ohno, H.; Toda, A.; Fujii, N.;
Takemoto, Y.; Tanaka, T.; Ibuka, T. Tetrahedron 2000, 56, 2811.
(14) Huntsman, W. D.; Chen, J. P.; Yelekci, K.; Yin, T.-K.; Zhang,
L. J. J. Org. Chem. 1988, 53, 4357.
allylindium generated in situ from the reaction of indium
(1.5 equiv) with allyl bromide (2.25 equiv) in THF at 35 °C
for 4 h under a nitrogen atmosphere, producing allylallene
2a in 87% yield with complete regioselectivity (entry 7).
There is no propargylic substitution product (3) through SN-
reaction nor carboindation products (4 and 5) through
addition of allylindium to triple bond formed in this reaction
(see Figure 1). The present method worked equally well with
allyl iodide (entry 8). However, 1-phenyl-2-propyn-1-ol,
which is a 2°-propargyl alcohol, did not react with allylin-
dium reagent. Also, when 1a was used, 2-phenyl-1-buten-
3-yne was not obtained. These results indicate that the present
reactions proceeded through an SN1 like mechanism. The use
of indium in less than 1.5 equiv and allyl bromide in less
than 2.25 equiv resulted in sluggish reactions and gave lower
yields (entries 1-3). The use of indium (2.0 equiv) and allyl
(15) El Gueddari, F.; Grimaldi, J. R.; Hatem, J. M. Tetrahedron Lett.
1995, 36, 6685.
(16) Lemiere, G.; Gandon, V.; Cariou, K.; Fukuyama, T.; Dhimane, A.;
Fensterbank, L.; Malacria, M. Org. Lett. 2007, 9, 2207.
(17) Grimaldi, J.; Malacria, M.; Bertrand, M. Tetrahedron Lett. 1974,
275.
(18) Huang, X.; Shen, R.; Zhang, T. J. Org. Chem. 2007, 72, 1534.
(19) (a) Russel, C. E.; Hegedus, L. S. J. Am. Chem. Soc. 1983, 105,
943. (b) Keinan, E.; Peretz, M. J. Org. Chem. 1983, 48, 5302. (c) Tsuji, J.;
Sugiura, T.; Minami, I. Synthesis 1987, 603. (d) Mandai, T.; Kunitomi, H.;
Higashi, K.; Kawada, M.; Tsuji, J. Synlett 1991, 697. (e) Bouyssi, D.; Gore,
J.; Balme, G.; Louis, D.; Wallach, J. Tetrahedron Lett. 1993, 34, 3129. (f)
Aidhen, I. S.; Braslau, R. Synth. Commun. 1994, 24, 789. (g) Badone, D.;
Cardamone, R.; Guzzi, U. Tetrahedron Lett. 1994, 35, 5477. (h) Ma, S.;
Zhang, A. J. Org. Chem. 1998, 63, 9601. (i) Ma, S.; Zhang, A.; Yu, Y.;
Xia, W. J. Org. Chem. 2000, 65, 2287.
(20) (a) Lee, P. H.; Sung, S.-Y.; Lee, K.; Chang, S. Synlett 2002, 146.
(b) Lee, P. H.; Shim, E.; Lee, K.; Seomoon, D.; Kim, S. Bull. Korean Chem.
Soc. 2005, 26, 157.
2442
Org. Lett., Vol. 10, No. 12, 2008

Table 2. Reactions of Allylindium with 3°-Propargyl Alcoholsa
a Alcohol:In:allyl halide ) 1:1.5:2.25. Reactions proceeded at 35 °C. b Isolated yield. c Reactions proceeded at 70 °C. d Alcohol:In:allyl halide ) 1:2:3.
bromide (3.0 equiv) provided a similar result to entry 7 (entry
6). THF was the best solvent among several reaction media
(DMF, THF, H2O, DMF-H2O, and THF-H2O) that were
examined (entries 7-14). The use of LiI and KI as an
additive did not give the desired product at 70 °C for 20 h
(entries 4 and 5). Treatment of 1a with allylzinc bromide
and allylmagnesium bromide (1 or 2 equiv) in THF did not
give trisubstituted allene 2a (entries 15 and 16), indicating
that allylindium is essential to produce multisubstituted
allylallenes.
To demonstrate the efficiency and scope of the present
method, we applied the above reaction system to a variety
of propargyl alcohols and allyl halides. The results are
summarized in Table 2. Compound 1a was treated with
methallylindium obtained from indium and methallyl bro-
mide to afford 2b in 75% yield (entry 1). 3°-Propargyl
alcohols possessing an internal triple bond turned out to be
compatible with the reaction conditions (entries 2-7 and
16-19). Reaction of 2-phenyl-3-pentyn-2-ol (1b) with meth-
allylindium provided tetrasubstituted allene (2d) in 85% yield
(entry 3). Allylindium reacted with 2-phenyl-3-octyn-2-ol
(1c) and 2,4-diphenyl-3-butyn-2-ol (1d) to give tetrasubsti-
tuted allenes 2e and 2g in 75% and 80% yields, respectively
(entries 4 and 6). The presence of various substituents such
as bromide, hydroxyl, and methyl group on the aromatic ring
in propargyl alcohol showed minor effects on the efficiency
of reactions (entries 8-13). It is noteworthy that protection
of hydroxyl groups on the substrates is not necessary as
demonstrated by reaction of 2-(3-hydroxyphenyl)-3-butyn-
2-ol (1f) with allylindiums (entries 10 and 11). Subjecting
1,1-diphenyl-2-propyn-1-ol (1h) to allylindium and methal-
lylindium produced trisubstituted allenes 2o and 2p in 85%
and 83% yields, respectively (entries 14-15). 3°-Propargyl
alcohols possessing alkyl groups instead of phenyl group at
the propargylic position worked equally well with the present
conditions. Exposure of compound 1i, having dimethyl
groups, to allylindium and methallylindium gave tetra-
substituted allene 2q and 2r in good yields (entries
16-17). Treatment of compound 1j obtained from cyclo-
hexanone and 5-phenyl-1-pentyne with indium reagents
afforded allenes 2s and 2t possessing four substituents
(entries 18-19). No propargylic substitution products
through SN-type selective displacement and carboindation
products through addition of allylindiums to triple bonds
are formed in any reactions. Failure of reactions of 1a
with a variety of allylindiums obtained from cinnamyl
bromide, crotyl bromide, cyclohexenyl bromide, and
prenyl bromide is presumably due to solvent incompat-
ibility for formation of allylindium in THF and steric
Org. Lett., Vol. 10, No. 12, 2008
2443

hindrance related to attack of the γ-position of allylindium
in the substitution reaction of propargyl alcohol.
In summary, we have developed an efficient synthetic
method to prepare tri- and tetra-substituted allenes having
an allyl and methallyl group from the reactions of allylin-
diums generated in situ from indium and allyl halides with
3°-propargyl alcohols. It is worth noting because propargyl
alcohols possessing surplus hydroxyl groups can react with
allylindiums without protection. The present method comple-
ments the existing synthetic methods due to direct substitu-
tion of 3°-propargyl alcohols without activation and some
advantageous properties of allylindiums over organometallics
such as availability, ease of preparation and handling, high
reactivity and selectivity, and operational simplicity.
Figure 1. Propargylic Substitution and Carboindation Products.
Ministry of Science and Technology (No. M10600000203-
06J0000-20310) and by KOSEF (R01-2006-000-11283-0).
The NMR data were obtained from the central instrumental
facility in Kangwon National University. Dr. Sung Hong Kim
at the KBSI (Daegu) is thanked for obtaining the MS data.
Supporting Information Available: Experimental pro-
cedure and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was supported by the Korea
Science and Engineering Foundation (KOSEF) through the
National Research Laboratory Program funded by the
OL800719G
2444
Org. Lett., Vol. 10, No. 12, 2008