Allyl- And Benzylindium Reagents. Carboindation of Carbon-Carbon and Carbon-Nitrogen Triple Bonds

Article abstract of DOI:10.1021/jo990160x

The reaction of unactivated simple terminal alkynes 1 with allylindiums in THF proceeded smoothly to give the corresponding allylation products 2 in good to high yields. This result is in marked contrast to that of the reaction carried out in DMF, where the allylation of unactivated alkynes was very sluggish. The allylic group of the reagent was attached to the internal carbon of the triple bond, and indium was attached to the less substituted terminal carbon, except for the case of TMS substituted acetylenes 1j and 1k in which the allyl group went to the less substituted carbon of the triple bond. The reaction of unactivated simple terminal and certain internal acetylenes with benzylindium in THF proceeded smoothly to afford the corresponding benzylation products 18 in good to high yields. The benzyl group was attached to the less substituted unhindered carbon of the triple bond, and indium was attached to the more sterically congested carbon. The reaction of activated nitriles 3 with allylindiums in THF at 70°C gave the corresponding allylationenamination products 4 in high to excellent yields. This reaction provides a useful method for the synthesis of highly functionalized enamines, which are not easily available via conventional methods. The mechanisms on the above three indation reactions are discussed.

Full text of DOI:10.1021/jo990160x

J . Org. Chem. 1999, 64, 4095-4101
4095
Allyl- a n d Ben zylin d iu m Rea gen ts. Ca r boin d a tion of
Ca r bon -Ca r bon a n d Ca r bon -Nitr ogen Tr ip le Bon d s
Naoya Fujiwara and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, J apan
Received J anuary 28, 1999
The reaction of unactivated simple terminal alkynes 1 with allylindiums in THF proceeded smoothly
to give the corresponding allylation products 2 in good to high yields. This result is in marked
contrast to that of the reaction carried out in DMF, where the allylation of unactivated alkynes
was very sluggish. The allylic group of the reagent was attached to the internal carbon of the triple
bond, and indium was attached to the less substituted terminal carbon, except for the case of TMS
substituted acetylenes 1j and 1k in which the allyl group went to the less substituted carbon of
the triple bond. The reaction of unactivated simple terminal and certain internal acetylenes with
benzylindium in THF proceeded smoothly to afford the corresponding benzylation products 18 in
good to high yields. The benzyl group was attached to the less substituted unhindered carbon of
the triple bond, and indium was attached to the more sterically congested carbon. The reaction of
activated nitriles 3 with allylindiums in THF at 70 °C gave the corresponding allylation-
enamination products 4 in high to excellent yields. This reaction provides a useful method for the
synthesis of highly functionalized enamines, which are not easily available via conventional methods.
The mechanisms on the above three indation reactions are discussed.
In tr od u ction
allenols5b in DMF at 100-140 °C gave the corresponding
allylation products in good to high yields. However, the
presence of a hydroxy group was essential for facilitating
the addition and the allylation of simple unactivated
alkynes was sluggish even at higher temperatures (150-
180 °C), giving the allylation products in low yields (12-
28%).5a In the meantime, it is well-known that the
reaction of nitriles (carbon-nitrogen triple bond, R-Ct
N) with organometallics (R′-MLn, M ) Li, Mg, Zn, and
others) including allylic compounds gives the correspond-
ing metalated imines R(R′)CdNM, which produces ke-
tones R(R′)CdO after hydrolysis.6
We previously reported that allylindium reagents react
with simple unactivated alkynes 1 very readily in THF7
to give the corresponding allylation product 2 in good to
high yields (eq 1)8 and that those allylindium reagents
also react with certain activated nitriles 3 to afford in
good to high yields the allylation-enamination products
4 that are not easily available via the reaction of
conventional allylating reagents with nitriles (eq 2).9
Herein, we describe in detail the reaction of carbon-
carbon and carbon-nitrogen triple bonds with allyl- and
benzylindium reagents.
Since the first carbometalation discovered by Ziegler
and Ba¨hr in 1927,1 a number of additions of organome-
tallics to the carbon-carbon triple bond (-CtC-) have
been reported.2 Although the carbometalation of activated
alkynes, such as alkynyl ketones (Michael acceptor) and
alkynols (functional group substituted alkynes), and/or
the intramolecular carbometalation proceed smoothly
with various allylmetals,2 the carbometalation of simple
unactivated alkynes 1 is not so easy and only a limited
number of allylmetals are available for this purpose.3
More recently, Araki and co-workers reported that the
reaction of allylindium4 with terminal alkynols5a and
(1) Ziegler, K.; Ba¨hr, K. Chem. Ber. 1928, 61, 253.
(2) For reviews, see: (a) Normant, J . F.; Alexakis, A. Synthesis 1981,
841 (organo-Li, Mg, Zn, B, Al, and Cu compounds). (b) Oppolzer, W.
Angew. Chem., Int. Ed. Engl. 1989, 28, 38 (stoichiometric organo-Li,
Mg, Zn and catalytic Ni, Pd, Pt compounds). (c) Negishi, E. Pure Appl.
Chem. 1981, 53, 2333 (organo-Al/Ti and Al/Zr system). (d) Knochel, P.
Comprehensive Organometallic Chemistry II; Able, E. W., Stone, F.
G. A., Wilkinson, G., Eds.; Pergamon Press: Oxford, 1995; Vol. 11, p
159 (organo-Li, Mg, Zn, B, Al, Cu, Hg/Pd, Ni, Mn compounds). (e)
Knochel, P. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, 1991; Vol. 4, p 865. (f) Yamamoto,
Y.; Asao, N. Chem. Rev. 1993, 93, 2207 (organo-Li, Mg, Zn, B, Al
compounds).
Resu lts a n d Discu ssion
(3) (a) Takai, K.; Yamada, M.; Odaka, H.; Utimoto, K.; Fujii, T.;
Furukawa, I. Chem. Lett. 1995, 315 (allyl-Ta). (b) Takahashi, T.;
Kotora, M.; Kasai, K.; Suzuki, N. Tetrahedron Lett. 1994, 35, 5685
(allyl-Zr). (c) Chatani, N.; Amishiro, N.; Morii, T.; Yamashita, T.; Murai,
S. J . Org. Chem. 1995, 60, 1834 (allyl-Zn). (d) Molander, G. A. J . Org.
Chem. 1983, 48, 5409 (allyl-Zn). (e) Miller, J . A.; Negishi, E. Tetrahe-
dron Lett. 1984, 25, 5863 (allyl-Al). (f) Negishi, E.; Miller, J . A. J . Am.
Chem. Soc. 1983, 105, 6761 (allyl-Zn). (g) Eisch, J . J .; Boleslawski, M.
P. J . Organomet. Chem. 1987, 334, C1 (allyl-Ti). (h) Yeon, S. H.; Han,
J . S.; Hong, E.; Do, Y.; J ung, I. N. J . Organomet. Chem. 1995, 499,
159 (Lewis acid-catalyzed allyl-Si). (i) Asao, N.; Matsukawa, Y.;
Yamamoto, Y. J . Chem. Soc., Chem. Commun. 1996, 1513 (Lewis acid-
catalyzed allyl-Sn). (j) Asao, N.; Yoshikawa, E.; Yamamoto, Y. J . Org.
Chem. 1996, 4874 (Lewis acid-catalyzed allyl-Si).
Allyla tion of Un a ctiva ted a n d /or F u n ction a lized
Alk yn es w ith Allylin d iu m s. Allylindium reagents were
(6) Courtois, G.; Miginiac, L. J . Organomet. Chem. 1974, 69, 1.
(7) The allylindium reagent was prepared originally in DMF (ref
4). Since then, the allylindation reactions of acetylenes have been
carried out in this solvent. Now, it is clear that the reagent can be
prepared in THF, and this finding expands the scope of this reagent
to the carboindation. The reactions of R- and/or â-oxy aldehydes with
allylindiums in H2O and aqueous/dry THF have been studied: (a)
Paquette, L. A.; Mitzel, T. M. Tetrahedron Lett. 1995, 36, 6863. (b)
Paquette, L. A.; Mitzel, T. M. J . Am. Chem. Soc. 1996, 118, 1931. (c)
Paquette, L. A.; Mitzel, T. M. J . Org. Chem. 1996, 61, 8799.
(8) Fujiwara, N.; Yamamoto, Y. J . Org. Chem. 1997, 62, 2318. See
also: Ranu, B. C.; Majee, A. J . Chem. Soc., Chem. Commun. 1997,
1225.
(4) Araki, S.; Ito, H.; Butsugan, Y. J . Org. Chem. 1988, 53, 1831.
(5) (a) Araki, S.; Imai, A.; Shimizu, K.; Yamada, M.; Mori, A.;
Butsugan, Y. J . Org. Chem. 1995, 60, 1841. (b) Araki, S.; Usui, H.;
Kato, M.; Butsugan, Y. J . Am. Chem. Soc. 1996, 118, 4699.
(9) Fujiwara, N.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 4729.
10.1021/jo990160x CCC: $18.00 © 1999 American Chemical Society
Published on Web 05/01/1999

4096 J . Org. Chem., Vol. 64, No. 11, 1999
Fujiwara and Yamamoto
Ta ble 1. Allyla tion of Sim p le Ter m in a l Alk yn es 1 w ith
Allyl-, Cr otyl-, a n d Meth a llylin d iu m s
prepared by mixing In powder (1.2 equiv) with allyl iodide
(1.8 equiv) or crotyl- and methallyl bromides (1.8 equiv)
in dry THF at room temperature for 1 h. The results on
the reaction of the allylindiums with various acetylenes
are summarized in Table 1. The reaction of phenylacety-
lene 1a with 0.6 equiv of allylindium,10 generated in situ,
gave the allylation product 2a regioselectively in 94%
yield (entry 1). The reactions of various para-substituted
aryl alkynes 1b, 1c, and 1d and of benzylacetylene 1e
proceeded smoothly to give 2b-e, respectively, in high
to good yields (entries 2-5). The reactions shown in
entries 1-5 were complete within 2 h at 70 °C. The
reactions of 1-octyne 1f and 1-dodecyne 1g gave 2f and
2g, respectively, in good yields (entries 6 and 7). The
allylation of the enyne 1h also proceeded smoothly to give
the corresponding allylation product 2h in excellent yield
(entry 8). The allylations in entries 6-8 were complete
within 1 h at 70 °C. The amino-substituted alkyne 1i,
which was inert to the Lewis acid-catalyzed allylsilylation3j
due to the coordination of Lewis acid to the nitrogen
atom,11 reacted with allylindium at 70 °C for 2 h, giving
the corresponding allylation product 2i in 75% yield
(entry 9). It should be noted that the regioselectivity of
the allylation of 1i is opposite to that of propargyl alcohol
and related hydroxy-substituted alkynes;5a chelation-
promoted allylation5 is not involved in the allylation of
1i. In addition, the reaction of 1a with crotylindium,
prepared from In powder (1.2 equiv) and crotyl bromide
(1.8 equiv) in THF, gave the γ-adduct 5 in 88% yield
(entry 10); the straight-chain R-adduct was not detected.
The reaction of 1a with methallylindium, generated in
situ from In powder (1.2 equiv) and metallyl bromide (1.8
equiv) in THF, gave 6 in 90% yield (entry 11).
a
b
Isolated yield. Bromides were used as starting materials
instead of iodide for the preparation of allylindium reagents.
Interestingly, the use of silyl-substituted alkynes
brought a regioselectivity different from the cases shown
above. The allylation of trimethylsilylacetylene 1j oc-
curred on the terminal carbon,12 giving the (Z)-allylation
product 7 stereoselectively in 75% yield. The reaction of
silyl-substituted internal alkyne, 1-trimethylsilyl-1-pro-
pyne 1k , gave a mixture of trans- and cis-allylation
products 8 in 50% yield. In the case of the silyl-substitued
alkynes 1j and 1k , an exceptionally longer reaction time
(∼36 h) was necessary to complete the allylation reaction,
compared to the ordinary terminal acetylenes 1a -1i. The
usual internal alkynes, such as 1-phenyl-1-propyne and
4-octyne, did not react at all with allylindium reagents.
To help clarify the mechanism of the allylindation, the
reaction of 1a (1 equiv) with allylindium reagent (0.6
equiv) was quenched with DCl (20 wt % solution in D2O),
giving the d1-allylation product 2a -d1 (95% D content)
in 85% yield: the ratio of E to Z was 32:68 (eq 3). As
mentioned above, concerning the stoichiometry of the
allylindation, 0.5 equiv of (allyl)3In2I3 corresponds to 1
equiv of acetylenes. The reaction of 1j with 0.6 equiv of
allylindium reagent was quenched similarly, affording
7-d1 (89% D content) in 82% yield: only Z isomer was
obtained (eq 4). These two results clearly indicate that
(10) Two allyl (or PhCH2) groups of the indium reagents (allyl)3In2I3
[or (PhCH2)3In2I3] are used for the allylation (or benzylation) reaction,
and the third allyl (or PhCH2) group acts as a ligand of the In complex
(ref 4). Accordingly, if the addition of the indium reagents to acetylenes
proceeds in quantitative yield, 0.5 equiv of the reagents are needed
for 1 equiv of acetylenes. Normally, we used 0.6 equiv of the reagents
toward 1 equiv of acetylenes.
(11) Yamamoto, Y.; Yoshikawa, E. Unpublished result.
(12) The allylation of TMS-substituted alkynes with allylzinc bro-
mide gives the same regioselectivity as the present allylindation (ref
3d).

Carboindation of C-C and C-N Triple Bonds
J . Org. Chem., Vol. 64, No. 11, 1999 4097
Sch em e 1
terated product 2g-d1 (93% D content) in 81% yield; the
ratio of E to Z was 49:51 (eq 7). Accordingly, it is clear
that the formation of the dideuterated product takes
place only in the case of 1a . Actually, rather acidic
aromatic acetylenes 1b and 1d behaved similarly, but
no dideuteration occurred in the case of other aliphatic
acetylenes such as 1e and 1f.
two of the three allyl groups of the reagent (allyl)3In2I3
were transferred to the triple bond and indium metal was
bonded to the vinyl carbon to which deuterium was
attached. However, the observation became complicated
was made when an excess amount (1 equiv) of allylin-
dium reagent was used.
The reaction of 1a with 1 equiv of allylindium was
quenched with DCl (20 wt % solution in D2O), giving the
d2-allylation product 2a -d2 (>95% D content) in which
two deuteriums were incorporated at the C-1 position (eq
3). The reaction of phenylacetylene-d 1a -d with 1 equiv
of allylindium followed by the usual workup using HCl/
H2O afforded 2a , in which no deuterium was incorpor-
ated, in 91% yield (eq 5). However, as mentioned above,
the use of 0.6 equiv of allylindium toward 1a -d gave 2a -
d1 in 85% yield (eq 5). Furthermore, the allylation of 1a
with 1.0 equiv of allylindium followed by treatment with
LiI or I2 (5.0 equiv) at room temperature gave the
diiodinated product 9 in 65-74% yield (eq 6). These
results indicate that the allylation of 1a with excess
amounts of allylindium gave the geminal diindation
product,13 which produced 2a -d2 upon deuteriolysis or
produced diiodinated 9 upon treatment with I2. The
deuterium loss in the case of 1a -d (eq 5) also indicates
that the C-D bond was cleaved in a certain stage of the
allylindation with excess amounts of the indium reagent,
but not cleaved with 0.6 equiv amount of the reagent (eq
5). The acetylenic hydrogen of aromatic acetylenes is
more acidic than that of aliphatic acetylenes. We exam-
ined the deuteriolysis of the products from allylindation
of 1g. The reaction of 1g with 1.0 equiv of allylindium
followed by treatment with D2O/DCl gave the monodeu-
When 0.6 equiv of allylindium (which is approximately
stoichiometric amount toward 1 equiv of an acetylene)
was used, the allylindation would occur as shown in
Scheme 1; the coordination of Lewis acidic indium to an
electron-rich triple bond followed by allylindation would
give the vinylindium 10, which would undergo E-Z
isomerization under the reaction conditions to give an
E/Z mixture of 11; the isomerization would occur via the
intermediate 12. Since the structure of the allylindium
reagent is assumed to be a sesquidimeric 13,4 X in 10-
12 is either I or allyl. In the case of aromatic acetylenes,
the vinylindium intermediate would coordinate to the
indium metal of the reagent once more (14), producing
the diindated compound 16 through a cationic intermedi-
ate 15. Perhaps the cation stabilization of aliphatic
derivatives is weaker in comparison with that of aromatic
cases (15), and therefore, no double indation takes place
in the case of aliphatic acetylenes although the further
coordination of allylindium reagent to aliphatic vinylin-
dium may take place. Actually, the dideuteration took
place in the reaction of 1h with 1.0 equiv of allylindium;
an allylic cation is involved in the intermediate derived
from the reaction of 1h , and thus, the cation intermediate
would be stabilized. When 2,4-hexadiene (5 equiv) was
added, to detect HI, at the beginning of the reaction of
1a with 1 equiv of the allylindium, 2-iodo-3-hexene was
(13) A double-zincation intermediate was proposed in the allylzin-
cation of terminal alkynes: Frangin, Y.; Gaudemar, M. J . Organomet.
Chem. 1977, 142, 9. See also: Knochel, P. In Comprehensive Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, p 883.

4098 J . Org. Chem., Vol. 64, No. 11, 1999
Fujiwara and Yamamoto
Sch em e 2
Ta ble 2. Ben zyla tion of Sim p le Alk yn es w ith
Ben zylin d iu m s
benzylindium,10 generated in situ by mixing In powder
(1.2 equiv) with benzyl iodide (1.8 equiv) in THF, gave
the benzylation product 18a regio- and Z-stereoselec-
tively14 in 91% yield (entry 1). The reactions of p-
tolylacetylene 1b and the enyne 1h proceeded smoothly
to give 18b and 18c, respectively, in high yields (entries
2 and 3). The Z configurations of 18a -c were determined
by the coupling constants between the vinylic protons
2
(J HandR ) 11.0-11.5 Hz). The benzylation of the internal
alkyne 1l proceeded significantly slowly, compared to the
reaction of terminal alkynes, to give the corresponding
benzylation product 18d regio- and Z-stereoselectively in
64% yield along with small amounts of the recovered 1l
(entry 4). No regio- and stereoisomers were detected by
a
Isolated yield. Yields in parentheses are the recovery yields
b
of 1. Benzylation products are given as mixtures of E/Z isomers,
and the ratio of E/Z isomers are given in parentheses.
1
the H NMR and GC-MS analysis of the crude reaction
obtained, strongly supporting the reaction course shown
in Scheme 1. One may think that an acidic acetylenic
hydrogen reacts with allylindium reagent prior to the
allylindation to liberate either HI or 1-propene and to
produce the acetylenic indium reagent 17, which under-
goes the allylindation in the presence of excess allylin-
dium reagent. If this mechanism is involved for the
reaction of aromatic acetylenes, the reaction of 1a with
0.6 equiv of allylindium reagent followed by quenching
with D2O should produce the dideuterated allylation
product 2a -d2 (see eq 3): only monodeuterated 2a -d1 was
obtained. Therefore, the mechanism through acetylenic
indium intermediate 17 is not operative.
Ben zyla tion of Sim p le Alk yn es w ith Ben zylin -
d iu m . We investigated the addition of other organoin-
dium reagents, such as benzyl-, propargyl-, methyl-, and
ethylindium reagents, to alkynes. However, among these
reagents only benzylindium underwent the addition to
alkynes. Benzylindium sesquiiodide [(PhCH2)3In2I3] was
prepared in situ by mixing In powder (1.2 equiv) with
benzyl iodide (1.8 equiv) in THF at room temperature.
Simple terminal and internal alkynes 1 readily reacted
with benzylindium to give the corresponding benzylation
products 18 in good to high yields (eq 8). This is the first
example of the direct carbometalation of organometallics
to both simple terminal and internal alkynes.3 Allylin-
diums did not react with the ordinary internal alkynes
(see above), but benzylindium reacts with them.
mixture. The Z-configuration of 18d was confirmed by a
400 MHz NOE experiment where signal enhancement
(6.0%) of the vinylic proton was observed when the
methyl protons were irradiated. The reactions shown in
entries 1-4 were carried out at 100 °C in sealed reaction
vials for 2-3 days, and the reaction progress was
monitored by TLC analysis of the reaction mixture.
In addition, we also tried the reaction with some
aliphatic and silyl-substituted alkynes. The benzylation
of 1-dodecyne 1g gave the corresponding benzylation
product 18e in 48% along with the recovered 1g (39%)
(entry 5). The reaction of dodeca-5,7-diyne 1m , where
there are two possible sites of alkynyl moieties, gave only
monobenzylation product 18f exclusively, and no diben-
zylation product was obtained (entry 6). The reaction of
trimethylsilylacetylene 1j gave the benzylation product
18g (entry 7). Since the reactions shown in entries 5-7
were rather sluggish, longer reaction times (4-6 d) were
needed to consume the benzylindium reagent and even
at the stage when the reagent was consumed completely
significant amounts of the starting acetylenes remained
unreacted. Another point different from the case of
aromatic and conjugated acetylenes, the products 18e-g
were obtained as a mixture of E,Z-isomers (entries 5-7).
To help clarify the mechanism of the benzylindation,
the reaction of 1a with 0.6 equiv of benzylindium was
quenched with DCl (20 wt % solution in D2O), giving the
d-benzylation product 18a -d (91% D content) in which a
deuterium was incorporated at the C-1 position (Scheme
2); in this case, no dideuteration occurred when even 1
equiv of benzylindium was used. Furthermore, the ben-
zylation of 1a with 0.6 equiv of the reagent, followed by
treatment with excess lithium iodide, gave the benzyla-
tion-iodination product 19 in 80% yield as a mixture of
E,Z stereoisomers (E/Z ) 57:43). These results clearly
indicate that the benzylation of simple alkynes 1 gives
the vinyl indium intermediate 20 via the benzylindation
of alkynes (Scheme 3). In the case of aromatic and
conjugated alkynes, the benzylindium proceeds in a
(14) The stereoselectivity of the addition of aluminum hydride to
alkynes was precisely studied. According to the study, the trans-
carbometalation product is favored thermodynamically under high-
temperature reaction conditions: Eisch, J . J .; Rhee, S.-G. J . Am. Chem.
Soc. 1975, 97, 4673. See also ref 2d, p 280.
The results are summarized in Table 2. The reaction
of phenylacetylene 1a (1.0 equiv) with 0.6 equiv of

Carboindation of C-C and C-N Triple Bonds
J . Org. Chem., Vol. 64, No. 11, 1999 4099
Ta ble 3. Allyla tion -En a m in a tion Rea ction of Nitr iles
Sch em e 3
w ith Allylin d iu m s
trans-addition manner, while that of aliphatic alkynes
proceeds in a nonstereoselective fashion. Also, the treat-
ment with LiI of the vinylindium intermediate derived
from 1a gave a trans and cis mixture of 19. Perhaps the
isomerization would take place in the presence of LiI.
It occurred to us that 20 would undergo the palladium-
catalyzed cross coupling with organic halides.15 If this is
the case, a “one-shot” three-component coupling reaction
between phenylacetylene 1a , benzylindium, and iodo-
benzene would become possible. Actually, the three
component coupling reaction took place in the presence
of 10 mol % of Pd(PPh3)4, giving 21 in low yield (eq 9).16
The reaction of 1a with 0.6 equiv of (PhCH2)In2I3 followed
by the addition of 2.0 equiv of benzyl iodide and 10 mol
% of Pd(PPh3)4 gave the three-component coupling prod-
uct 22 in 49% yield (eq 9).17,18
a
b
Isolated yield. Bromides were used as starting materials
instead of iodide for the preparation of allylindium reagents.
reactions shown in entries 1-4 were completed within 2
h at 70 °C. The reaction of 3a with crotylindium, prepared
from In powder and crotyl bromide in THF, gave the
γ-adduct 23 in 93% yield (entry 5); the regioisomeric
R-adduct was not detected. The reactions of 3a with
methallyl-, prenyl-, and cinnamylindium gave 24-26,
respectively, in high to good yields (entries 6-8). Here
also, the branched γ-adducts 25 and 26 were obtained
exclusively in the reactions of prenyl- and cinnamylin-
diums, respectively. The reactions shown in entries 5-8
were completed in longer reaction time depending upon
the substituents in the allyl group (2-36 h).
A New En a m in e Syn th esis: Allyla tion -En a m i-
n a tion Rea ction of Nitr iles w ith Allylin d iu m s. Al-
lylindium reagents were prepared as described above.
The results on the reaction of the allylindiums with
various activated nitriles are summarized in Table 3.19
The reaction of methyl cyanoacetate 3a with 0.6 equiv
of allylindium10 gave the allylation-enamination product
4a regio- and (Z)-stereoselectively in essentially quanti-
tative yield (entry 1). The Z configuration was confirmed
by a 400 MHz NOE experiment where signal enhance-
ment (6.1%) of the olefinic proton next to the ester group
was observed when the methylene protons of the allyl
group were irradiated. The reactions of malononitrile 3b
and cyanoacetylpiperidine 3c proceeded smoothly to give
4b and 4c, respectively, in high to good yields (entries 2
and 3). The reaction of ethyl phenylcyanoacetate 3d ,
which has a bulky phenyl group at the position R to the
cyano group, also proceeded smoothly to give the corre-
sponding enamine product 4d in good yield (entry 4). The
(15) Negishi et al. reported the palladium-catalyzed coupling reac-
tion of vinylic bromides and alkenylalane, which was prepared in situ
from alkynes and alkylaluminum hydride (ref 2c).
(16) In the three-component coupling reaction, a fair amount of
byproducts (mono- and dibenzylation products 18a and 22, respec-
tively) were formed along with 21.
(17) The stereochemistry of the dibenzylation product 22 was not
determined clearly because no apparent signal enhancement between
the two benzyl protons was observed by 400 MHz NOE. Analysis with
1H NMR and GC-MS showed that 22 was obtained as a single
stereoisomer. The Z-conformation were assigned by the analogy from
the result of 18a -d (Scheme 2).
(18) The three-component coupling reaction would proceed as fol-
lows: oxidative insertion of Pd(0) into R3-X′ would produce R2-Pd-
(II)X′ species, which would undergo the transmetalation reaction with
the vinylindium 20 to give the vinylpalladium intermediate. Reductive
elimination would give the three-component coupling product along
with the Pd(0) catalyst.
A plausible mechanism of this allylation-enamination
reaction is shown in Scheme 4. The nitrile may coordinate
to the Lewis acidic indium of allylindium reagent, making
the protons next to the coordinated nitrile more acidic
and facilitating the formation of the intermediate 27. The
allyl transfer to the carbon of the CdN double bond would
produce 28, which upon hydrolysis20 would give the
(19) Araki and co-workers reported that allylindiums are inert to
nitriles in DMF.4

4100 J . Org. Chem., Vol. 64, No. 11, 1999
Fujiwara and Yamamoto
Sch em e 4
that even (Me)2C(CO2Me) of 30 is sterically demanding.
Enamines are important synthetic intermediates in
organic synthesis since the discovery of the Stork reac-
tion.22 Nevertheless, fewer reactions are available for
their preparation.23,24 The present procedure with al-
lylindiums may be useful for the synthesis of certain
functionalized enamines since such enamines are not
easily available via conventional methods.
Con clu sion
Although further study is needed to settle the mech-
anism of allylation and benzylation, we are now in a
position to carry out the allyl- and benzylindation of
simple unactivated alkynes in good to high yields and to
synthesize various 2-substituted 1,4-pentadiene and
1-substituted 3-phenyl-1-propene derivatives in regio-
and stereocontrolled manner. In addition, nitriles having
another electron-withdrawing group at the R-position can
be converted to allylated enamines with allylindiums,
providing a new procedure for the synthesis of highly
functionalized enamines.
Exp er im en ta l Section
The following materials were commercially available and
used as such: phenylacetylene (1a ), p-tolylacetylene (1b),
p-chlorophenylacetylene (1d ), 3-phenyl-1-propyne (1e), 1-oc-
tyne (1f), 1-dodecyne (1g), 1-ethynyl-1-cyclohexene (1h ), 3-di-
ethylamino-1-propyne (1i), trimethylsilylacetylene (1j), 1-tri-
methylsilyl-1-propyne (1k ), 1-phenyl-1-propyne (1l), dodeca-
5,7-diyne (1m ), methyl cyanoacetate (3a ), malononitrile (3b),
cyanoacetylpiperidine (3c), ethyl phenylcyanoacetate (3d ),
indium powder, allyl iodide, crotyl bromide, methallyl bromide,
prenyl bromide, cinnamyl bromide, iodine, hydrochloric acid,
and deuterium chloride (as 20 wt % solution in D2O). Benzyl
iodide was prepared according to the known procedures.25
P r ep a r a tion of Allylin d iu m Sesqu iiod id e. In powder (69
mg, 0.60 mmol) was placed in a reaction vial under Ar, followed
by the addition of THF (1.0 mL) and allyl iodide (82 µL, 0.9
mmol) at room temperature. After being stirred for 1 h, the
THF suspension of In powder turned into a white solution of
allylindium sesquiiodide. The allylindium reagent was used
without any further purification. The crotyl(or metallyl)indium
sesquibromide was prepared with the same procedure from
In powder and crotyl(or metallyl) bromide.
allylation-enamination product 4. Here again, two of the
three allyl groups of allylindium reagent (allyl)3In2I3 were
used for the allylation-enamination reaction and the
third allyl group must remain in the resulting monoal-
lylindium reagent; it is assumed from the stoichiometry
of the reaction that (allyl)InI2 is produced, as a byproduct,
along with InI. Actually, when the allylation-enamina-
tion reaction using 0.6 equiv of cinnamylindium was
quenched with DCl/D2O, allylbenzene-d (PhCHDCHd
CH2, 96% D content) was obtained, strongly suggesting
that the third cinnamyl group remained as a cinnamylin-
dium species.
The reaction of 1.2 equiv of allylmagnesium chloride
with 3a resulted in recovery of 3a and the allylation-
enamination product was not obtained,21 showing that
the present allylation-enamination reaction takes place
only with less basic allylindium reagents, and failure of
the Grignard reagent to react with 3a is presumably due
to deprotonation from the activated methylene position.22
The reactions of 29 and 30 with allylindium and allyl-
P r ep a r a tion of Ben zylin d iu m Sesqu iiod id e. In powder
(69 mg, 0.60 mmol) was placed in a reaction vial under Ar,
followed by the addition of THF (1.0 mL) and benzyl iodide
(0.20 g, 0.90 mmol) at room temperature. After being stirred
for 1 h, the THF suspension of In powder turned into white
(20) The protonation would take place at the workup stage: nor-
mally, an acidic silica gel column was used (see Experimental Section).
On the other hand, when the reaction was quenched with diluted HCl,
the desired allylation-enamination product was not obtained.
(21) Only abstraction of activated methylene hydrogen due to the
basicity of allylmagnesium chloride was observed in this case (pKa of
the methylene hydrogen of 3a ≈ 9; see: Peason, R. G.; Dillon, R. L. J .
Am. Chem. Soc. 1953, 75, 2439).
(22) Stork, G.; Terrell, R.; Szmuszkovicz, J . J . Am. Chem. Soc. 1954,
76, 2029.
(23) Hickmott, P. W. Tetrahedron 1982, 38, 1975.
(24) (a) Leonard, N. J .; Hay, A. S.; Fulmer, R. W.; Gash, V. W. J .
Am. Chem. Soc. 1955, 77, 439. (b) Katritzky, A. R.; Long, Q.-H.; Lue,
P.; J ozwiak, A. Tetrahedron 1990, 46, 8153. (c) Broekhof, N. L. J . M.;
J onkers, F. L.; van der Gen, A. Tetrahedron Lett. 1979, 2433. (d)
Broekhof, N. L. J . M.; J onkers, F. L.; van der Gen, A. Tetrahedron
Lett. 1980, 21, 2671. (e) Bekker, B. H.; A-Lim, D. S. T.; van der Gen,
A. Tetrahedron Lett. 1984, 25, 4259. (f) Comi, R.; Franck, R. W.;
Reitano, M.; Weinreb, S. M. Tetrahedron Lett. 1973, 3107. (g) White,
W. A.; Weingarten, H. J . Org. Chem. 1967, 32, 213. (h) Kuo, S. C.;
Daly, W. H. J . Org. Chem. 1970, 35, 1861.
magnesium reagents were carried out. However, both
substrates were recovered after a prolonged reaction
time, irrespective of the reagent type. No reactions with
allylindium are reasonable since there is no activated
methyne proton in both substrates. No reactions with
allylmagnesium chloride are presumably due to the steric
bulkiness at the R-position of nitriles 29 and 30; it seems
(25) Aizpurua, J . M.; Palomo, C. Tetrahedron Lett. 1984, 25, 1103.

Carboindation of C-C and C-N Triple Bonds
J . Org. Chem., Vol. 64, No. 11, 1999 4101
solution of benzylindium sesquiiodide. The benzylindium
reagent was used without any further purification.
stirred for 2 d at 100 °C. The reaction was quenched with
diluted aqueous hydrochloric acid solution (15 v/v %, 2.0 mL)
at room temperature. The reaction product was extracted with
ether, washed with brine, dried with anhyd Mg2SO4, concen-
trated under reduced pressure, and separated with silica gel
column chromatography (eluent: hexane/ethyl acetate ) 30/
1), giving the benzylation product 18a in 91% yield (88 mg)
as a pale yellow oil: 1H NMR (CDCl3, 300 MHz) δ 7.46-7.17
(m, 10H), 6.60 (dt, J ) 2.0, 11.5 Hz, 1H), 5.86 (dt, J ) 7.0,
11.5 Hz, 1H), 3.68 (dt, J ) 2.0, 7.0 Hz, 2H). Anal. Calcd for
P r ep a r a tion of (4-Meth oxyp h en yl)a cetylen e (1c). n-
BuLi (1.48 mL of 1.56 N in n-hexane, 2.3 mmol) was added to
a mixture of ether (1.5 mL) and THF (1.5 mL) at -40 °C under
Ar. 1,1-Dichloro-2-(4-methoxyphenyl)ethene (214 mg, 1.1 mmol)
was introduced at -78 °C, and the reaction mixture was
allowed to warm to room temperature. The reaction mixture
was quenched with aqueous 2 N sulfuric acid. The organic
layer was extracted with pentane, washed with water, dried
with anhyd Mg2SO4, and concentrated under reduced pressure.
The crude mixture was separated with column chromatogra-
phy on silica gel (hexane/ethyl acetate ) 10/1), giving the
alkyne 1c (60%, 83 mg).
P r ep a r a tion of 2a fr om 1a . Allylindium was prepared by
mixing In powder (69 mg, 0.60 mmol) with allyl iodide (82 µL,
0.90 mmol) in THF (1.0 mL) at room temperature for 1 h. To
a THF solution of allylindium was added phenylacetylene 1a
(55 µL, 0.50 mmol) at room temperature. The reaction mixture
was heated to 70 °C and stirred for 2 h. The reaction was
quenched with diluted aqueous hydrochloric acid solution (15
v/v %, 2.0 mL) at room temperature. The reaction product was
extracted with ether, washed with brine, dried with anhyd
Mg2SO4, concentrated under reduced pressure, and separated
with silica gel column chromatography using hexane as an
eluent, giving the allylation product 2a in 94% yield (68 mg)
as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.50-7.20 (m,
5H), 5.91 (ddt, J ) 6.5, 10.0, 16.6 Hz, 1H), 5.39 (d, J ) 1.1 Hz,
1H), 5.11 (ddt, J ) 1.6, 1.6, 16.6 Hz, 1H), 5.10 (dt, J ) 1.1, 1.4
Hz, 1H), 5.07 (ddt, J ) 1.6, 1.6, 10.0 Hz, 1H), 3.25 (ddt, J )
1.4, 1.6, 6.5 Hz, 2H). Anal. Calcd for C11H12: C, 91.61; H, 8.39.
Found: C, 91.72; H, 8.28.
C
15H14: C, 92.74; H, 7.26. Found: C, 92.97; H, 7.03.
P r ep a r a tion of 4a fr om 3a . Allylindium was prepared by
mixing In powder (69 mg, 0.60 mmol) with allyl iodide (82 µL,
0.90 mmol) in THF (1.0 mL) at room temperature for 1 h. To
a THF solution of allylindium was added methyl cyanoacetate
3a (44 µL, 0.50 mmol) at room temperature. The reaction
mixture was heated to 70 °C, stirred for 2 h, and then cooled
to room temperature. THF was removed under vacuo, and the
reaction product was separated with column chromatography
on silica gel (hexane/ethyl acetate ) 8/1), giving the allylation-
enamination product 4a in 100% yield (70 mg) as a pale yellow
oil: 1H NMR (CDCl3, 300 MHz) δ 7.86 (br s, 2H), 5.81 (ddt, J
) 7.0, 10.0, 17.5 Hz, 1H), 5.22 (ddt, J ) 1.5, 1.5, 17.5 Hz, 1H),
5.21 (ddt, J ) 1.5, 1.5, 10.0 Hz, 1H), 4.58 (br s, 1H), 3.65 (s,
3H), 2.90 (br d, J ) 7.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz)
δ 170.61, 160.82, 132.90, 119.32, 83.70, 50.18, 40.51; IR (neat)
3450, 3340, 2950, 1670, 1620, 1560, 1270, 1170, 1040, 790
cm-1; HRMS calcd for C7H11NO2 (m/z, M+) 141.0790, found
141.0782. Anal. Calcd for C7H11NO2: C, 59.56; H, 7.85; N, 9.92.
Found: C, 59.72; H, 8.00; N, 9.87.
P r ep a r a tion of 18a fr om 1a . Benzylindium was prepared
by mixing In powder (69 mg, 0.60 mmol) with benzyl iodide
(0.20 g, 0.90 mmol) in THF (1.0 mL) at room temperature for
1 h. To a THF solution of benzylindium was added phenyl-
acetylene 1a (55 µL, 0.50 mmol) at room temperature. The
reaction vial containing the reaction mixture was sealed and
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of 2b-i, 5-8, 18b-g, 22, 4b-d , and 23-26 and copies
of 1H and 13C NMR spectra for reaction products. This material
is available free of charge via the Internet at http://pubs.acs.org.
J O990160X