Iron-catalyzed regio- and stereoselective carbolithiation of Alkynes

Article abstract of DOI:10.1002/1521-3773(20010202)40:3<621::AID-ANIE621>3.0.CO;2-O

Butylation problems ironed out: 3-Pentynyl ethers react with butyllithium at - 20°C in toluene, upon addition of a catalytic amount of a cheap iron(III) salt, to afford (E)-4-methyl-3-octenyl ethers in high yields. Stereochmically defined tetrasubstituted alkenes were also obtained by the subsequent addition of electrophiles (E⁺, see scheme; acac = acetylacetonate, Bn = benzyl).

Full text of DOI:10.1002/1521-3773(20010202)40:3<621::AID-ANIE621>3.0.CO;2-O

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Ar
Ar
Ar
HN
HN
N
H
Ar
Ar
a
NH
NH
HN
N
Inversion
NH
Ar
NH
Ar
Ar
N
H
Ar
H
Ar
N
H
+
Ar
N
Ar
H
Ox
Cyclization
Ox
NH
NH
HN
HN
H
Ar
H
Ar-CHO
Ar
H
Ar
Ox
b
NFP5-R
NFP5-Y
Pentaphyrinogen
Red
Scheme 2. A possible reaction mechanism for the formation of NFP5.
for 2 h under nitrogen. After adding DDQ (2.27 g, 10 mmol), the solution
was stirred for 10 h, then passed through a short alumina column to remove
the tar. The reaction mixture was then separated by column chromatog-
raphy on silica gel with CH2Cl2:n-hexane (1:4). The red solution of 1-R was
eluted after the purple fraction of meso-pentafluorophenylhexaphyrin. The
solution of 1-R was evaporated, and the residue recrystallized from n-
hexane to give pure 1-R (146 mg, 15%).
[12] Supporting this facile interconversion, the two-electron redox proc-
esses between 1-Y and 1-R were recorded at low potential, 0.447 V
‡
and ‡0.067 V (versus the ferrocene/ferrocenium couple (Fc/Fc )) by
cyclic voltammetry.
[13] D. Dolphin, J. Heterocycl. Chem. 1971, 7, 275 ± 283.
1-Y: NaBH4 (22.7 mg, 0.6 mmol, 15 equiv) was added to a solution of 1-R
(50 mg, 0.04 mmol) in CH3OH (10 mL) and the solution was stirred for
10 min under nitrogen. After removing the solvent, the residues were
dissolved in CH2Cl2, and filtered through a short alumina column. After
evaporation, the residue was recrystallized from n-hexane to give 1-Y
(50 mg, 100%).
Iron-Catalyzed Regio- and Stereoselective
Carbolithiation of Alkynes**
Received: August 15, 2000 [Z15639]
Makoto Hojo, Yoshio Murakami, Hidenori Aihara,
Rie Sakuragi, Yu Baba, and Akira Hosomi*
[1] a) E. Vogel, J. Heterocycl. Chem. 1996, 33, 1461 ± 1487; b) A. Jasat, D.
Dolphin, Chem. Rev. 1997, 97, 2267 ± 2340; c) J. L. Sessler, A. Gebauer,
E. Vogel, The Porphyrin Handbook, Vol. 2 (Eds.: K. M. Kadish, K. M.
Smith, R. Guilard), Academic Press, San Diego, 1999, Chap. 8; d) D.
Lash, Angew. Chem. 2000, 112, 1833 ± 1837; Angew. Chem. Int. Ed.
2000, 39, 1763 ± 1767.
Organolithium compounds are one of the most popular
organometallics and have been used for organic synthesis as
nucleophiles in carbon ± carbon bond formation, and as
transmetalation agents onto other metals.[1] Carbometalation
of alkynes is recognized to be useful in the preparation of
stereochemically defined tri- and tetrasubstituted alkenes,
while in reactions of alkynes without a conjugated electron-
withdrawing group, the regioselectivity becomes the principal
problem.[2] The carbolithiation of alkynes has limited syn-
thetic use because only particular kinds of alkynes can be
used, and as for the stereochemistry, the vinyllithium inter-
mediates produced tend to isomerize with ease.[3] We report
herein a preliminary result on the regio- and stereoselective
carbolithiation of alkynes by a simple procedure that uses
cheap iron salts as a catalyst.
[2] P. Rothemund, J. Am. Chem. Soc. 1939, 61, 2912 ± 2915.
[3] a) H. Furuta, T. Asano, T. Ogawa, J. Am. Chem. Soc. 1994, 116, 767 ±
Â
768; b) P. J. Chmielewski, L. Latos-GrazÇynski, K. Rachlewicz, T.
Gøowiak, Angew. Chem. 1994, 106, 805 ± 808; Angew. Chem. Int. Ed.
Engl. 1994, 33, 779 ± 781.
Â
[4] a) P. J. Chmielewski, L. Latos-GrazÇynski, K. Rachlewicz, Chem. Eur.
J. 1995, 1, 68 ± 72; b) G. R. Geier III, J. S. Lindsey, J. Org. Chem. 1999,
64, 1596 ± 1603.
[5] M. G. P. M. S. Neves, R. M. M. Martins, A. C. Tome, A. J. D. Silvestre,
A. M. S. Silva, M. G. B. Drew, J. A. S. Cavaleiro, Chem. Commun.
1999, 385 ± 386.
[6] H. Furuta, T. Ishizuka, A. Osuka, T. Ogawa, J. Am. Chem. Soc. 1999,
121, 2945 ± 2946; H. Furuta, T. Ishizuka, A. Osuka, T. Ogawa, J. Am.
Chem. Soc. 2000, 122, 5748 ± 5757.
[7] A variety of higher homologues, such as octaphyrins, nonaphyrins,
decaphyrins, undecaphyrins, and dodecaphyrins, are isolated from the
reaction mixture: J.-Y. Shin, H. Furuta, A. Osuka, unpublished results.
[8] Spectral data and the X-ray structure of 2-Y are shown in the
Supporting Information.
We found that 3-pentynyl 3-phenylpropyl ether (1a), upon
addition of a catalytic amount of FeCl3, reacted with
[*] Prof. Dr. A. Hosomi, Dr. M. Hojo, Y. Murakami, Dr. H. Aihara,
R. Sakuragi, Y. Baba
[9] Crystallographic data (excluding structure factors) for the structure
reported in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
no. CCDC-147880. Copies of the data can be obtained free of charge
on application to CCDC, 12 Union Road, Cambridge CB21EZ, UK
(fax: (‡44)1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).
[10] The Porphyrin Handbook, Vol. 10 (Eds.: K. M. Kadish, K. M. Smith,
R. Guilard), Academic Press, San Diego, 1999, pp. 1 ± 254.
[11] The absorption spectral changes of the redox reaction between 1-Y
and 1-R are shown in the Supporting Information.
Department of Chemistry
Graduate School of Pure and Applied Sciences
University of Tsukuba, Tsukuba, Ibaraki 305-8571 (Japan)
Fax : (‡81)298-53-6503
[**] This work was partly supported by Grants-in-Aid for Scientific
Research and Grants-in-Aid for Scientific Research on Priority Areas
from the Ministry of Education, Science, Sports, and Culture, Japan.
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
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butyllithium to yield (E)-4-methyl-3-octenyl 3-phenylpropyl
ether (2a) as a single isomer [Eq. (1)]. As shown in Table 1,
the choice of a solvent is crucial for this reaction. In benzene
butylation was not only successful with alkynyl ethers, even
the pentynylamine 1d gave a butylation product (2d) in 72%
yield [Eq. (3)]. Interestingly, a simple alkyne, 6-dodecyne did
not react at all under the conditions shown in Equations (2) ±
(4). o-Methoxy-1-pentynylbenzene (1e) also reacted with
10% FeIII
BuLi (3 equiv)
OR
Bu
(1)
OR
1a: R = CH2CH2CH2Ph
1b: R = CH2Ph
2a: R = CH2CH2CH2Ph
2b: R = CH2Ph
10% [Fe(acac)3]
BuLi (3 equiv)
OBn
Bu
Bu
OBn
2c 99%
(2)
(3)
toluene
−20 °C, 4 h
1c
Table 1. Reaction of 3-pentynyl ethers 1 with butyllithium in the presence
[a]
of FeIII
.
Entry Substrate Fe salt
Solvent Conditions Yield (2) [%][b]
NEt2
as above
as above
NEt2
2d 72%
1
2
3
4[e]
5[e]
6
1a
1a
1b
1a
1a
1b
1b
1b
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
THF
408C, 4 h
0[c]
1d
Et2O
Et2O
benzene
toluene
408C, 3 h 79 (2a)
408C, 3 h 79 (2b)[d]
208C, 2 h 86 (2a)
208C, 2 h 97 (2a)
208C, 2 h 97 (2b)
208C, 2 h 85 (2b)
208C, 2 h 13 (2b)[g]
MeO
MeO
[Fe(acac)3][f] toluene
(4)
7
8
[Fe(dbm)3][f] toluene
FeCl3
toluene
Bu
1e
2e 55% (82/18)
[a] All reactions were carried out using 3.0 equivalents of butyllithium and
10 mol% of FeIII, unless otherwise noted. Reactions were quenched with
1n HCl solution. [b] Isolated Yield. [c] 1a (18%) was recovered. 3-Phenyl-
propanol (80%) and nona-2,3-diene[7] (20%) were found in the reaction
mixture. [d] Benzyl alcohol (13%) was produced. [e] Suspension of FeCl3
in the respective solvent was used. [f] The amount of FeIII was reduced to
5 mol%. [g] 1b (45%) was recovered and benzyl alcohol (34%) was
produced. DBM ˆ 1,3-diphenyl 1,3-propanedione (dibenzoylmethane).
butyllithium to give a mixture of two stereoisomeric products
2e in moderate yield [Eq. (4)]. In these reactions, a Lewis-
basic moiety in a substrate alkyne not only activates the triple
bond toward butylation, but possibly also controls stereo-
selectivity. Recently, Nakamura et al. reported iron-catalyzed
olefin carbometalation, where organomagnesium and zinc
reagents were employed.[8] As for the present reaction, when
BuMgBr[9] was used for the reaction of 1b, the yield of 2b was
low; 56% ( 208C, 4 h), 60% (RT, 4 h),[10] and further
synthetic use seems to be difficult, as indicated by the low
D-content of the product 2b in a deuteration experiment.
When a reaction of 1b was quenched with DCl/D2O,
deuterated 2b (94%-D) was obtained in 96% yield
[Eq. (5)].[11] The postulated vinyllithium intermediate further
or toluene, a butylated product 2a was obtained in high yield
(entries 4 and 5). In diethyl ether or THF, the cleavage of the
C O bond to yield the corresponding alkynyl alcohol or the b-
elimination of ROH, such as 3-phenylpropanol or benzyl
alcohol, takes place in preference to the desired butylation.
As for an iron catalyst,[4] when an FeIII salt was employed, 2
was produced in high yield, while with FeCl2, only a poor yield
of 2 was obtained. The actual catalyst for the present
carbometalation has not been clearly determined. Previously,
cross-coupling reactions with catalytic amounts of FeIII species
were reported and in those reactions, an FeI center generated
by the reduction of the FeIII species with a Grignard reagent
was proposed as a catalyst.[5] In our system, a low-valent iron
species may possibly catalyze the reactions. To determine the
stoichiometry of butyllithium to Fe, we attempted the reaction
with an equimolar amount of [Fe(acac)3] and the substrate 1b
(acac ˆ 2,4-pentanedione (acetylacetone)). When 8 equiva-
lents of butyllithium were introduced, the yield of 2b was
63%, and using 12 equivalents of the lithium reagent 89% of
2b was obtained.[6] These experiments suggest that the present
iron catalysis may be based on an iron ± ate complex.
[Fe(acac)3] is soluble in toluene, thus, we could carry out
most of the reactions simply using a stock solution of
[Fe(acac)3] in toluene.
1) 5% [Fe(acac)3]
BuLi (3 equiv)
D
toluene
OBn
Bu
−20 °C, 30 min
OBn
(5)
2) DCl/ D2O, −20 °C
1b
2b 96 % (94%-D)
‡
reacted with electrophiles (E ) such as chlorosilane to afford
stereochemically defined vinylsilane 3a in 73% yield
[Eq. (6)]. Both aromatic and aliphatic aldehydes also reacted
to give the corresponding allylic alcohols 3b and 3c,
respectively, in high yields. Even a ketone could be used as
an electrophile, and a tetrasubstituted alkene 3d was isolated
in 69%, as a single isomer.
4-Hexynyl ether 1c, a one-carbon homologue, also reacted
with butyllithium in toluene to afford the corresponding
addition product 2c as the sole product in quantitative yield
[Eq. (2)], while in diethyl ether the reaction resulted only in
the recovery of 1c, showing a clear solvent effect. The
It was found that cheap iron salts catalyze carbometala-
tion[12] of alkynes bearing an alkoxy or amino group. The
simple protocol presented here allows us to access tetrasub-
stituted alkenes in a stereoselective manner. Further synthetic
applications of this process are now under investigation.
622
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[10] Only allylmagnesium bromide successfully added to 1b (in Et2O at RT
for 7 h using 20 mol% of [Fe(acac)3]) and the corresponding allylated
product was obtained in quantitative yield.
[11] The produced vinyl anion seems to be unstable at room temperature.
Yield of 2b and its deuterium content were decreased to 90% and
82%-D, respectively when the reaction mixture was kept at ambient
temperature for 3 h before quenching with DCl/D2O, the reaction was
conducted under the same conditions as in Equation (5).
1) 5% [Fe(acac)3]
BuLi (3 equiv)
toluene
E
OBn
Bu
−20 °C, 4 h
OBn
OBn
(6)
2) E+
−20 °C - RT, 2 h
1b
3
HO
Bu
Ph
SiMe2H
[12] Ethyllithium and hexyllithium were also added to 1b to afford alkenes
in high yields (Et: 96%, Hex: 92%).
Bu
OBn
3a 73%
3b 83%
Et
Ph
HO
Bu
Et
HO
Bu
OBn
3c 80%
OBn
3d 69%
Radical Azidonation of Benzylic Positions with
Iodonium Azide**
Experimental Section
Christel Viuf and Mikael Bols*
Full experimental details are in the Supporting Information. A represen-
tative procedure is as follows: to a flask purged with argon, a solution of
[Fe(acac)3] in toluene (0.025m, 0.025 mmol, 1 mL), toluene (4 mL), and a
substrate 1b (0.5 mmol) were introduced. The flask was cooled to 408C
and a solution of butyllithium in hexane (1.5m, 1.5 mmol) was added to the
mixture. Reaction temperature was immediately raised to 208C and the
mixture was stirred at 208C for 2 h. The reaction was quenched with 1n
HCl. After the conventional workup and purification by chromatography
on silica gel, a pure product 2b was obtained in 97% yield.
We recently reported a procedure for the conversion of
benzyloxy alcohols like 1 into benzylidene derivatives like 2
with N-iodosuccinimide (NIS) and light (Scheme 1).[1] During
Received: September 15, 2000 [Z15812]
Scheme 1. The NIS-promoted transformation of benzyloxy alcohols into
[1] B. J. Wakefield in Organolithium Methods (Eds.: A. R. Katritzky, O.
Meth-Cohn, C. W. Rees), Academic Press, London, 1988.
[2] Zr: a) E. Negishi, T. Takahashi, Synthesis 1988, 1 ± 19; Ti: b) D. C.
Brown, S. A. Nichols, A. B. Gilpin, D. W. Thompson, J. Org. Chem.
1979, 44, 3457 ± 3461; Cu: c) J. F. Normant, A. Alexakis, Synthesis
1981, 841 ± 870; Zn: d) F. Bernadou, L. Miginiac, Tetrahedron Lett.
1976, 3083 ± 3086; e) M. Bellassoued, Y. Frangin, Synthesis 1978, 838 ±
840; Ni: f) B. B. Snider, R. S. E. Conn, M. Karras, Tetrahedron Lett.
1979, 1679 ± 1682; See also: g) P. Knochel in Comprehensive Organic
Synthesis, Vol. 4 (Eds.: B. M. Trost, I. Fleming, M. F. Semmelhack),
Pergamon, Oxford, 1991, pp. 865 ± 911.
[3] a) J. E. Mulvaney, Z. G. Gardlund, S. L. Gardlund, J. Am. Chem. Soc.
1963, 85, 3897; b) J. E. Mulvaney, D. J. Newton, J. Org. Chem. 1969, 34,
1936 ± 1939; c) W. Bauer, M. Feigel, G. Müller, P. von R. Schleyer, J.
Am. Chem. Soc. 1988, 110, 6033 ± 6046; d) L.-I. Olsson, A. Claesson,
Tetrahedron Lett. 1974, 2161 ± 2162.
benzylidene derivatives and the effect of NaN3 addition. Bn ˆ benzyl.
the investigation of this reaction we noticed that 1 was
transformed with excess NaN3 very rapidly into a variety of
products of which many had, according to mass spectrometry,
one to three hydrogen atoms replaced with azido groups.
When the analogous reaction was carried out on benzyl ethyl
ether 3 [Eq. (1), light substituted with heat to avoid decom-
position of azides] the monoazido derivative 4 was isolated in
65% yield together with small amounts of the by-products 5
and 6.[2]
[4] In the absence of a catalyst, a complex mixture without a normal
product 2b was produced.
[5] a) M. Tamura, J. K. Kochi, J. Am. Chem. Soc. 1971, 93, 1487 ± 1489;
b) S. M. Neumann, J. K. Kochi, J. Org. Chem. 1975, 40, 599 ± 606;
c) R. S. Smith, J. K. Kochi, J. Org. Chem. 1976, 41, 502 ± 509.
[6] Conditions for all reactions reported here are not fully optimized. A
sufficient amount of butyllithium per iron catalyst (5 mol%) seems to
be required during the reaction for the successful carbolithiation.
Therefore, 3 equivalents used in reactions are a large enough amount
for the present carbolithiation, and, indeed, a reaction of 1b with
2 equivalents of butyllithium gave essentially the same result (95% of
2b, cf. Table 1, entry 6).
[7] This product was possibly obtained by the addition of butyllithium to
pent-1-en-3-yne, produced by the b-elimination of phenylpropanol
from 1a. a) A. A. Petrov, V. A. Kormer, T. V. Yakovleva, Zh. Obshch.
Khim. 1960, 30, 2238; b) A. A. Petrov, Yu. I. Porfirꢁeva, V. A. Kormer,
Zh. Obshch. Khim. 1961, 31, 1518.
Since this azidonation reaction appeared faster than the
benzylidene derivative formation promoted by NIS alone and
since the red color of the reaction mixture indicated that IN3
was present, it was suggested that iodine azide was the reagent
[*] Dr. M. Bols, C. Viuf
University of Aarhus
Department of Chemistry
Langelandsgade 140, 8000 Aarhus C (Denmark)
Fax (‡45)86196199
[8] M. Nakamura, A. Hirai, E. Nakamura, J. Am. Chem. Soc. 2000, 122,
978 ± 979.
[9] BuMgBr was prepared in diethyl ether, and most of the solvent was
replaced with toluene before use.
E-mail: mb@kemi.aau.dk
[**] We thank the Danish National Research Council for financial support.
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