Stereoselective synthesis of chiral 3-aryl-1-alkynes from bromoallenes and heterocuprates

Article abstract of DOI:10.1021/jo0522456

The synthesis of chiral 3-aryl-1-alkynes 3 via cross-coupling of 3-alkyl- and 3,3-dialkyl-1-bromo-1,2-dienes 1 and arylbromocuprates (RCuBr)MgBr-LiBr 2 was examined. With phenylcopper reagents and its para-substituted derivatives, as well as with 2-naphth

Full text of DOI:10.1021/jo0522456

Stereoselective Synthesis of Chiral 3-Aryl-1-alkynes from
Bromoallenes and Heterocuprates
Anna Maria Caporusso,*,† Alessia Zampieri,† Laura Antonella Aronica,† and
Donatella Banti‡
Dipartimento di Chimica e Chimica Industriale, UniVersita` degli Studi di Pisa, Via Risorgimento 35,
56126 Pisa, Italy, and School of Pharmaceutical and Chemical Sciences, Kingston UniVersity, Penrhyn
Road, Kingston upon Thames - Surrey, KT1 2EE, United Kingdom
capored@dcci.unipi.it
ReceiVed October 28, 2005
The synthesis of chiral 3-aryl-1-alkynes 3 via cross-coupling of 3-alkyl- and 3,3-dialkyl-1-bromo-1,2-
dienes 1 and arylbromocuprates (RCuBr)MgBr‚LiBr 2 was examined. With phenylcopper reagents and
its para-substituted derivatives, as well as with 2-naphthyl cuprates, the reaction gave compounds 3 with
high regioselectivity and good yields on the chemically pure product. On the contrary, when ortho-
substituted phenyl reagents and 1-naphthyl cuprates were used, the regioselectivity of the process was
very dependent upon the steric requirements of the alkyl substituents on the bromoallenic substrate. When
the steric bulk was increased, remarkable quantities of isomeric arylallenes 4 were also observed in the
reaction mixtures. The high 1,3-anti stereoselectivity of the coupling process allowed us to obtain
enantiomerically enriched 3-aryl-1-alkynes from optically active allenic substrates, thus indicating a simple
pathway toward the synthesis of quaternary stereogenic centers characterized by an aryl group. A possible
cross-coupling mechanism was also suggested to explain the regio- and stereochemical data. For the
preparation of ω-functionalized 3-phenyl-1-alkynes, the reaction of 1-bromo-3-phenylpropadiene with
Knochel reagents RCu(CN)ZnCl‚2LiCl was also studied; this reaction led to the acetylenic compounds
in high yields mainly when the R group (also ω-functionalized) on the copper reagent was primary.
Introduction
characterized by a tertiary or a quaternary stereogenic center R
to the triple bond.3
Simple terminal acetylenic compounds are increasingly used
as fundamental substrates in transition-metal chemistry for the
synthesis of high valued organic compounds (e.g., sp to sp2
couplings, oxidative dimerizations, aminoalkylations, silyl-
formylation, to name a few).1 It is worth noting the potentiality
of optically active 1-alkynes as key intermediates in the
preparation of a wide range of chiral molecules.2
The reaction proceeded in a highly 1,3-anti stereoselective
fashion. The regioselectivity of the process appeared to be
sensitive to steric interactions, the size of the R substituent in
the copper species being the dominant factor.3d Indeed, when
phenyl or n-alkyl bromocuprates 2 were used, the acetylenic
compounds 3 were obtained in good yields independently of
It was demonstrated that the cross-coupling reaction between
optically active allenic bromides 1 and bromocuprates (RCuBr)-
MgBr‚LiBr, 2, (Scheme 1) was the most simple and convenient
way to obtain enantiomerically enriched chiral acetylenes
(1) For review, see: (a) Modern Acetylenic Chemistry; Stang, P. J.,
Diederich, F., Eds.; VCH: Weinheim, 1995. (b) Brandsma, L.; Vasilevsky,
S. F.; Verkruijsse. H. D. In Application of Transition Metal Catalysts in
Organic Synthesis; Springer-Verlag: Berlin, 1998. (c) Metal-catalyzed
Cross-coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH:
Weinheim, 1998. (d) Marciniec, B. Appl. Organomet. Chem. 2000, 14, 527-
538. (e) Vizer, S. A.; Yerzhanov, K. B.; Al Quntar, A. A.; Dembitsky, V.
M. Tetrahedron 2004, 5499-5538.
† Universita` degli Studi di Pisa.
‡ Kingston University.
10.1021/jo0522456 CCC: $33.50 © 2006 American Chemical Society
Published on Web 02/09/2006
1902
J. Org. Chem. 2006, 71, 1902-1910

StereoselectiVe Synthesis of Chiral 3-Aryl-1-alkynes
SCHEME 1
outcome of the reactions as related to the structural features of
the aromatic bromocuprate reagents. An accurate investigation
on the stereochemistry of the coupling process was also carried
out with enantiomerically enriched bromoallenes.
Taking into account the high selectivity for compounds 3 we
obtained when reacting bromoallenes 1 with functionalized zinc-
based alkylcyanocuprates 5,4 we also explored the reaction of
these copper reagents with 3-phenyl-1-bromopropadiene as a
potential synthetic approach to functionalized 3-phenyl-1-
alkynes. Indeed, it is well-known that 3-phenyl-1-bromoallenes
react with the alkylbromocuprates 2 to afford mainly substantial
amounts of polymeric byproducts.3a
Results and Discussion
Coupling of Bromoallenes with Arylbromocuprates. A.
Regiochemical Results. The complex arylbromocuprates 2a-k
used as nucleophiles were prepared in situ in THF from LiCuBr2
and 1 equiv of the appropriate aryl Grignard reagent.3a The
racemic 1-bromo-1,2-dienes 1a-d were also obtained chemi-
cally pure and in high yields (70-90%) from the corresponding
propargylic alcohols through well-known procedures.6 Accord-
ing to the experimental conditions previously reported for
reactions between compounds 1 and the phenylbromocuprate
2a,3a all of the experiments were carried out adding a tetrahy-
drofuran solution of the bromoallenic substrate 1 to a stirred
suspension of 2 equiv of the arylcopper reagent 2, cooled at
-70 °C. The reaction mixture was then allowed to warm to
room temperature and carefully followed by GC analysis of
hydrolyzed samples; in general, a reaction time of 30 min at
room temperature was adequate for a complete conversion of
the substrate into a mixture of 3-aryl-1-alkyne 3 and the 1-aryl-
1,2-diene 4. The two products were separated by fractional
distillation or elution on silica gel column (n-pentane as eluent)
and identified by chromatographic and/or spectroscopic methods
(Table 1).
the structure of the allenic bromide. When tertiary, secondary,
or R-branched primary copper reagents were used, the competi-
tive formation of the allenic derivatives 4 was favored (Scheme
1).3a,d In a second stage of our study we introduced the use of
aliphatic zinc-based cuprates RCu(CN)ZnCl‚2LiCl 5 for the
same cross-coupling processes.4 These zinc cyanocuprates
(Knochel reagents)5 reacted with bromoallenes 1 with higher
regioselectivity than the corresponding magnesium bromocu-
prates 2, affording acetylenes 3 almost quantitatively even when
hindered allenic substrates and secondary or R-branched primary
copper compounds were used as starting materials. Only when
R was a tertiary group could the steric requirements of the
substrate have a determining effect on the product distribution.
The cross-coupling reaction with the Knochel reagents could
also be performed, maintaining very high regio- and stereose-
lectivities, using aliphatic zinc reagents and catalytic amounts
of copper salts (10 mol %).4 Phenyl zinc-based cuprates such
as PhCu(CN)ZnCl‚2LiCl reacted with compounds 1, affording
instead complex mixtures of acetylenic and allenic products (3
and 4, respectively) in both the stoichiometric and the catalytic
reactions.4 As reported,3a,b other types of phenylcopper reagents,
such as Ph2CuLi, 6, and PhCu(CN)Li, 7, gave essentially
phenylallene derivatives 4. It appeared therefore evident that
chiral 3-phenyl-1-alkynes 3 could be obtained in high yields in
copper-mediated coupling processes only when the phenylbro-
mocuprate (PhCuBr)MgBr‚LiBr was used (Scheme 1). Conse-
quently, we extended the scope of our research by elucidating
the synthetic utility of the reaction between 1-bromo-1,2-dienes
1 and a series of arylbromocuprates in the preparation of chiral
3-aryl-1-alkynes 3 (R ) Ar). The present paper deals with the
1
The acetylene/allene ratio, determined by H NMR and GC
analyses on the crude reaction mixtures, was found to be mainly
influenced by the structure of the bromocuprate; the regio-
chemical results are summarized below:
(i) Phenylbromocuprate 2a (Table 1, entries 1-3)3a and para-
substituted arylcuprates (Table 1, entries 5, 6, 11-16) led
predominantly to the acetylenic products 3; independent of the
bulkiness of substituents R1 and R2 on the bromoallene 1,
product 3 was generally obtained chemically pure (62-86%
isolated yields). With ortho-substituted arylcuprates we observed
greater amounts of the allene derivative 4 which eventually
became the main product as the bulkiness of R1 and R2 increased
enough (Table 1, entries 4, 7-10).
(ii) The electronic nature of the substituent on the aromatic
ring of the cuprate (electron-donating or electron-withdrawing
group) did not significantly affect the regioselectivity of the
reaction. Indeed, the acetylenes were always the major products
in reactions with para-substituited cuprates (Table 1, entries 5,
6, 11-16).
Very similar results were obtained employing naphthylcu-
prates. Also in these cases we found that the structure of the
cuprate played a crucial role in the regioselectivity of the
(2) See as examples: (a) Giacomelli, G.; Rosini, C.; Caporusso, A. M.;
Palla, F. J. Org. Chem. 1983, 48, 4887-4891 and references therein. (b)
Kishimoto, Y.; Itou, M.; Miyatake, T.; Ikariya, T.; Noyori, R. Macromol-
ecules 1995, 28, 6662-6666. (c) Pertici, P.; Verrazzani, A.; Pitzalis, E.;
Caporusso, A. M.; Vitulli, G. J. Organomet. Chem. 2001, 621, 246-253.
(d) Aronica, L. A.; Terreni, S.; Caporusso, A. M.; Salvadori, P. Eur. J.
Org. Chem. 2001, 4321-4329.
(3) (a) Caporusso, A. M.; Polizzi, C.; Lardicci, L. J. Org. Chem. 1987,
52, 3920-3923. (b) Caporusso, A. M.; Polizzi, C.; Lardicci, L. Tetrahedron
Lett. 1987, 28, 6073-6076. (c) Caporusso, A. M.; Consoloni, C.; Lardicci,
L. Gazz. Chim. Ital. 1988, 118, 857-859. (d) Polizzi, C.; Consoloni, C.;
Lardicci, L.; Caporusso, A. M. J. Organomet. Chem. 1991, 417, 289-304.
(e) Caporusso, A. M.; Aronica, L. A.; Geri, R.; Gori, M. J. Organomet.
Chem. 2002, 648, 109-118.
(4) Caporusso, A. M.; Filippi, S.; Barontini, F.; Salvadori, P. Tetrahedron
Lett. 2000, 41, 1227-1230.
(5) Knochel, P.; Singer, R. D. Chem. ReV. 1993, 93, 2117-2188.
(6) (a) Landor, S. R.; Patel, A. N.; Wither, P. F. J. Chem. Soc. C 1966,
1223-1226. (b) Montury, M.; Gore´, J. Synth. Commun. 1980, 10, 873-
879. (c) Elsevier, C. J.; Vermeer, P.; Gedanken, A.; Runge, W. J. Org.
Chem. 1985, 50, 364-367. (d) Caporusso, A. M.; Zoppi, A.; Da Settimo,
F.; Lardicci, L. Gazz. Chim. Ital. 1985, 115, 293-295.
J. Org. Chem, Vol. 71, No. 5, 2006 1903

Caporusso et al.
TABLE 1. Coupling Reactions of Arylbromocuprates 2 with Bromoallenes 1a
a All reactions were performed on a 10-20 mmol scale by treating 1a-d with 2 equiv of the arylcuprate in THF at -70 °C and by allowing the reaction
b
mixture to warm to room temperature (30 min; 100% conversion of 1). The yields, based on starting 1, were determined by 1H NMR and GC analysis on
the crude reaction mixture after workup (isolated yields of >98% pure compounds are shown in parentheses).
1904 J. Org. Chem., Vol. 71, No. 5, 2006

StereoselectiVe Synthesis of Chiral 3-Aryl-1-alkynes
TABLE 2. Stereoselectivity in the Synthesis of 3-Aryl-1-alkynes 3 via Coupling Reactions of Arylbromocuprates 2 with Chiral Bromoallenes
(S)-1
(S)-1
(R)-3
yieldb (%)
correlation product
entry
eea (%)
[R]25D (heptane)
[R]25
ee (%)
stereoselectivity (%)
D
1
2
3
4
(S)-1a
(S)-1a
(S)-1b
(S)-1c
(S)-1c
(S)-1d
(S)-1d
(S)-1d
51
51
70
35
35
32
32
32
(R)-3ad
(R)-3aje
(R)-3ba
(R)-3caj
(R)-3ca
(R)-3da
(R)-3df
(R)-3dg
70
52
65
51
68
64
41
48
-3.95
-6.36
+0.68
-1.32
-1.22
-1.42
-4.17
-2.51
(S)-10adc
+25.6d
-12.7g
-58.4i
+10.6l
+10.3l
+10.8o
43
42
58
35
92
91
91
100
99
100
100
100
(R)-9ajf
(S)-8bah
(S)-10cak
(S)-10ca k
(S)-11da
(S)-11df
(S)-11dg
5
34m
32m
32m
32m
6n
7n
8n
a Determined by GC analyses on a Cydex-B chiral column or 1H NMR with heptakis(2,3,6-tri-O-methyl)-â-cyclodextrin as chiral solvating agent (see ref
8). b Isolated yields of pure compounds, obtained by silica gel column chromatography or preparative GC. c See ref 9. d EtOH (c 3.0). e A pure sample of
14% ee (S)-(+)-1-(2-naphthyl)-1,2-butadiene, (S)-4aj, was also obtained. f See ref 13. g Heptane (c 2.4). h See ref 11a. i Neat. j A pure sample of 22% ee
(R)-(-)-1-phenyl-3-methyl-1,2-pentadiene, (R)-4ca, was also obtained. k See ref 12. l Benzene (c 4.4). m Determined by 1H NMR of the corresponding
diastereomeric salts with optically pure (R)-1-(1-naphthyl)ethylamine. n In this case, the absolute configuration of the stereogenic center of compounds 3 and
11 was assigned on the basis of the 1,3-anti stereochemistry of the coupling process between heterocuprates and 1-bromo-1,2-dienes to afford alkynes, now
widely proved (see also refs 3 and 4). o CHCl3 (c 8.0).
SCHEME 2. Correlation of 3-Aryl-1-alkynes to
reaction. The 2-naphthylcuprates 2j and 2k always afforded the
corresponding acetylenic products with good yields (Table 1,
Stereochemically Defined Compoundsa
entries 20-25). When using the 1-naphthylcuprate 2i instead,
we observed that an increase in the size of the substituents on
the bromoallene 1 disfavored the alkyne product (Table 1, entries
17-19).
B. Stereochemical Results. In a previous paper,3a we reported
that (R)-(-)-1-bromo-1,2-butadiene, (R)-1a, reacted with the
phenylbromocuprate 2a affording as main product (S)-(+)-3-
phenyl-1-butyne, (S)-3aa, with 83% 1,3-anti stereoselectivity.
In light of this result and taking into account that analogous
cross-coupling reactions performed with aliphatic bromocuprates
proceeded with almost complete anti stereochemistry,3d we
considered it useful to evaluate in general the stereochemical
outcome of the coupling reaction between enantiomerically
enriched bromoallenes 1 and arylbromocuprates 2. Chiral
1-alkynes 3, having a tertiary or a quaternary stereogenic center
characterized by an aryl group in the R-position to the triple
bond, are generally difficult to prepare enantiomerically enriched
via conventional procedures7 and the cross-coupling reaction
proposed could then be regarded as a straightforward stereo-
selective method for their synthesis.
This stereochemical study required the synthesis of the chiral
bromoallenes (S)-1a-d. These were achieved by reacting the
methanesulfonate esters of the corresponding optically active
(R)-carbinols with LiCuBr2 or Li2CuBr3.6c,d The enantiomeric
purities of compounds (S)-1a-d were determined by GC
analyses on a Cydex-B chiral column and/or 1H NMR in CD3-
OD as solvent and heptakis(2,3,6-tri-O-methyl)-â-cyclodextrin
as chiral solvating agent (Table 2).8 The stereochemical outcome
of the coupling reaction was studied for those cases in Table 1
where the alkynes 3 were the major products. The optically
active acetylenic compounds were isolated in chemically pure
form (41-70% yields) and correlated to compounds of known
or determinable stereochemistry (Table 2 and Scheme 2).
Thus, a sample of levorotatory 3-[4-(2-methylpropyl)phenyl]-
1-butyne, (-)-3ad, obtained from (S)-1a (51% ee), was treated
with diisobutylaluminum hydride (DIBAH) to yield the corre-
a Key: (a) see Table 1; (b) i-Bu2AlH, n-pentane, rt, 40-80 h; (c)
i-Bu2AlH, n-pentane, 40 °C, 48 h; (d) KMnO4-NaIO4/K2CO3, t-BuOH/
H2O, 0 °C, 70-90 h, then diluted H2SO4 (5%); (e) n-BuLi (1 equiv), hexane,
rt, 10-20 h, reflux, 3-5 h, then solid CO2, 60 h.
sponding 1-alkene 8ad. Compound 8ad was related to dex-
trorotatory 2-[4-(2-methylpropyl)phenyl]propanoic acid, (+)-
10ad, of known S stereochemistry [(S)-ibuprophen, 43% ee]9
(7) Caporusso, A. M.; Lardicci, L. J. Chem. Soc., Perkin Trans. 1 1983,
949-953.
(8) (a) Uccello-Barretta, G.; Balzano, F.; Caporusso, A. M.; Salvadori,
P. J. Org. Chem. 1994, 59, 836-839. (b) Uccello-Barretta, G.; Balzano,
F.; Caporusso, A. M.; Iodice, A.; Salvadori, P. J. Org. Chem. 1995, 60,
2227-2231.
10
by reaction with KMnO4-NaIO4 (Scheme 2; Table 2, entry
(9) Kaiser, D. G.; Vangiessen, G. J.; Reische, R. J.; Wechter, W. J. J.
Pharm. Sci. 1976, 65, 269-273.
J. Org. Chem, Vol. 71, No. 5, 2006 1905

Caporusso et al.
1). Both the hydroalumination7 and the oxidative demolition11
processes were known to proceed in a completely stereospecific
manner. Analogously, samples of (-)-3-phenyl-3-methyl-1-
pentyne, (-)-3ca, obtained from (S)-1c were transformed into
the corresponding (+)-2-phenyl-2-methyl-butanoic acid, (+)-
10ca, of known S stereochemistry12 (Scheme 2; Table 2, entries
4 and 5). The value of the maximum rotatory power for the
acid (S)-10ca was evaluated by Cram via maximum resolution
criteria.12 However, the relation between the enantiomeric
composition and the optical rotation of (+)-10ca was confirmed
by 300 MHz 1H NMR analysis of the diastereomeric salts
obtained by reacting the acid, in CDCl3, with an equimolar
amount of optically pure (R)-1-(1-naphthyl)ethylamine. The
obtained results perfectly agreed (Table 2, entries 4-5) despite
the experimental error connected with the NMR measurements.
The R configuration and the enantiomeric composition of the
alkynes (-)-3aj and (+)-3ba (obtained from (S)-1a and (S)-
1b, respectively) were evaluated by correlation to the corre-
sponding hydroalumination products, the (R)-2-(2-naphthyl)-
butane, (R)-9aj,13 and (S)-3-phenyl-4,4-dimethyl-1-pentene, (S)-
8ba,11a of known stereochemistry (Scheme 2; Table 2, entries
2 and 3).
SCHEME 3
between (R/S)-1d and the phenylbromocuprate 2a (Table 1, entry
3), was treated with equimolar amounts of n-buthyllithium and
then with carbon dioxide to yield the racemic 4-phenyl-4,4,5-
trimethyl-2-hexynoic acid, (R/S)-11da (75%). The acid was
reacted in diethyl ether with (+)-dehydroabietylamine, and the
resulting diastereomeric salts were recrystallized three times
from 95% ethanol to yield a salt fraction having [R]25D +15.45
(CHCl3). Alkaline hydrolysis followed by acidification gave the
acid (R)-11da, [R]25D -32.70 (CHCl3), which was found to be
All of these data (Table 2, entries 1-5) indicated that the
coupling reaction occurred with high stereoselectivity (90-
100%) and confirmed the 1,3-anti mechanism. It is noteworthy
that the alkyne (R)-3ca, characterized by a quaternary center at
the R-position to the triple bond, was formed with complete
stereoselectivity. The stereochemical results were found to be
highly reproducible (Table 2, entries 4 and 5).
1
optically pure by H NMR analysis of its diastereomeric salt
The significant racemization phenomema (ca. 16-17%) we
observed in the coupling reactions yielding alkynes 3 with
tertiary propargylic centers (Table 2, entries 1-3) can be thus
related to the mobility of the hydrogen atoms to the stereogenic
carbon atoms (propargylic and also benzylic) in the reaction
conditions. To confirm this hypothesis, compounds 3da, 3df,
and 3dg, with quaternary stereogenic centers, were synthesized
by reacting (S)-1d with phenyl-, p-methoxyphenyl-, and p-
fluorophenylbromocuprates, 2a, 2f, and 2g, respectively. The
R absolute configuration to the obtained chemically pure
levorotatory compounds was assigned on the basis of the 1,3-
anti stereochemistry now widely proved for the coupling process.
The enantiomeric composition of the alkynes was determined
by transforming them into the R,â-acetylenic acids 11 and by
300 MHz 1H NMR analysis of the corresponding diastereomeric
salts with optically pure (R)-1-(1-naphthyl)ethylamine.
The obtained results (Scheme 2; Table 2, entries 6-8)
indicated for these cases a complete absence of racemization
phenomena (100% stereoselectivity).
with (R)-1-(1-naphthyl)ethylamine. As chiral R,â-acetylenic
acids could be easily decarboxylated to the corresponding
1-alkynes without significant racemization phenomena [copper-
(I) chloride in acetonitrile at room temperature],7 the resolution/
decarboxylation procedure was confirmed to be, at least in some
cases, an attractive route to obtain optically active 3-aryl-1-
alkynes.
C. Mechanistic Aspects. Given the undefined structure of
the involved organocopper species, every mechanistic interpre-
tation of the data at this stage has to be speculative. However,
both the dynamic and stereochemical results (Tables 1 and 2)
are consistent with syn addition-anti elimination steps, involv-
ing alternatively the C1-C2 or the C2-C3 double bond of the
allenic substrate (Scheme 3; for simplicity, the complex bromo-
cuprate 2 is presented as the monomeric discrete species
“ArCuBr”) as previously proposed also for reactions of bromo-
allenes 1 with aliphatic bromo- and cyanocuprates.3d The syn
attack of the copper reagent on the C2-C3 double bond backside
of the bromine atom followed by an anti elimination would ac-
count for the 1,3-anti stereoselectivity observed in the formation
of 1-alkynes 3 (Table 2). By increasing the steric bulkiness of
Ar, R1, and R2 groups on the reagents, the preference for
addition of the copper species to the C1-C2 bond increased
affording the arylallenes 4 (Table 1) with retention of config-
uration (Scheme 3) by a successive anti-elimination step.
In this context, it was also verified that racemic R,â-acetylenic
acids 11 could be easily resolved into optically pure enantio-
meric forms with (+)-dehydroabietylamine as resolving agent,
as reported for (R/S)-4-phenyl-2-pentynoic acid.7 Thus, a sample
of chemically pure (R/S)-3-phenyl-3,4,4-trimethyl-1-pentyne,
(R/S)-3da, obtained in 84% yield from the coupling reaction
(10) Gil-Av, E.; Shabtai, J. J. Org. Chem. 1964, 29, 257-262.
(11) (a) Lardicci, L.; Menicagli, R. J. Org. Chem. 1972, 37, 1060-1062.
(b) Lardicci, L.; Salvadori, P.; Caporusso, A. M.; Menicagli, R.; Belgodere,
E. Gazz. Chim. Ital. 1972, 102, 64-84.
From the reaction between (S)-1a and 2-naphthylbromocu-
prate, 2j, we obtained the 1-alkyne (R)-3aj as the main product
as well as small amounts of chemically pure (S)-1-(2-naphthyl)-
1,2-butadiene, (S)-4aj, with retention of configuration and
extensive racemization, [R]25D +32.4 (c 3.3, n-heptane), (Table
2, entry 2).14-16 Almost completely racemized (R)-1-phenyl-
(12) (a) Cram, D. J.; Allinger, J. J. Am. Chem. Soc. 1954, 76, 4516-
4522. (b) Cram, D. J.; Knight, J. D. J. Am. Chem. Soc. 1952, 74, 5835-
5838.
(13) Menicagli, R.; Piccolo, O.; Lardicci, L.; Wis, M. L. Tetrahedron
1979, 35, 1301-1306.
1,2-butadiene, (R)-4aa, [R]25 -1.20 (c 3.0, ethanol) (<1%
D
1906 J. Org. Chem., Vol. 71, No. 5, 2006

StereoselectiVe Synthesis of Chiral 3-Aryl-1-alkynes
SCHEME 4
products was attributed to the higher stability of the σ-allenyl
complex. As an example, chiral allenic bromides and 2-propynyl
esters in palladium-catalyzed reactions with organozinc reagents
gave only allenic products18 as well as 2-propynyl esters with
organocopper(I) derivatives of different natures;8b,17,21 in all
cases, a high anti stereochemistry was observed.
D. Coupling of 1-Bromo-3-Phenylpropadiene with Zinc
Alkylcyanocuprates. Zinc alkylcynocuprates RCu(CN)ZnCl‚
2LiCl 5a-f (Knochel reagents)5 were generated in THF at -10
°C from alkylzinc chlorides and the soluble copper salt CuCN‚
2LiCl; the necessary organozinc derivatives were obtained from
the corresponding Grignard reagents by transmetalation with
ZnCl2. In particular, the starting Grignard reagents of 5d and
5f were prepared in THF from 3-chloro-1-propanol and 4-bromo-
1-trimethylsilyl-1-butyne according to procedures previously
reported by Normant22 and Rossi.23 When the cyanocuprates
5a-f were reacted with 1-bromo-3-phenylpropadiene 1e (molar
ratio 2:1), the desired 3-phenyl-1-alkynes 3 were selectively
obtained (Table 3), contrary to what we previously observed
with alkylbromocuprates 2 which afforded essentially polymeric
byproducts.3a However, once again, the structure of the alkyl
in the organocopper species significantly affected the selectivity
of the reaction. In general with primary cuprates the reaction
proceeded to completion within 1-2 h at -70 °C yielding
exclusively the acetylenic products 3 (Table 3, entries 1, 4, and
6). With secondary and tertiary copper reagents a decrease in
the reaction rate as well as in the chemo- and regioselectivity
was observed instead. Therefore, the isopropylzinc cuprate 5b
afforded the alkyne 3eb together with minor amounts of the
allenic regioisomer 4eb (Table 3, entry 2). The tert-butyl
derivative 5c provided substantial amounts of phenylallene 14,
probably via metal-halogen exchange processes, along with
the expected coupling products 3ec and 4ec (Table 3, entry 3).
ee),17 was generated by reaction of (R)-1a (27% ee) with
phenylbromocuprate, 2a, along with (S)-3-phenyl-1-butyne, (S)-
3aa, (18% ee) as the major product.3a The racemization
phenomena can be attributed to the contact, during the reaction,
of the allenic products with the cuprate or the Cu(0) which might
arise from decomposition of the cuprate itself.18 However, this
process should not be very fast under our experimental condi-
tions. A different explanation could be related to the possible
presence of multiple mechanisms acting simultaneously. On the
other hand, from the reaction between (S)-1c and the phenyl-
cuprate 2a, which afforded (R)-3-phenyl-3-methyl-1-pentyne,
(R)-3ca, as the main product, we obtained the phenylallene (R)-
4ca, [R]25 -25.1 (c 9.0, n.heptane), racemized and with
D
inversion of configuration (Table 2, entry 4).3b As proposed by
Corey and Boaz,19 the anti selectivity for both the acetylenic
and the allenic products, as well as the regiochemical results
(Table 1), could be rationalized through the mechanism reported
in Scheme 4. Initially, the nucleophilic copper attacks anti to
the bromine yielding the σ-propargylic CuIII intermediate 12
(oxidative addition) which equilibrates to the σ-allenyl derivative
13 via a suprafacial 1,3-shift (Scheme 4). The CuIII transient
species readily collapse by reductive eliminations to give the
alkyne 3 and/or the allene 4 with the observed anti stereose-
lectivity. Formation of 4 should be favored as it increases the
steric bulkiness of both the substrate and the copper reagent.
It is nevertheless more likely that 1-alkynes 3 originated
essentially from addition-elimination steps as shown in Scheme
3,3d while competitive routes with different stereochemistry
(such those depicted in Schemes 3 and 4) should account for
the formation of arylallenes 4. In all cases which started from
allenyl or propargyl substrates, an equilibrium between σ-allenyl
and σ-propargylmetalcomplexes was postulated (Scheme 4), and
the formation, with anti stereselectivity, of allenes as the only
These data completely agreed with the results previously
obtained by reacting alkylcyanocuprates 5 with aliphatic 1-bro-
moallenes 1a-d.4 They also suggested that an appropriate
selection of the structure of the Knochel reagent (primary or
secondary) in the cross-coupling with 1e could yield a large
variety of functionalized 3-phenyl-1-alkynes, such as R,ω-
acetylenic carbinols, R,ω-enynes, and R,ω-diynes, useful syn-
thetic intermediates not easily available via simple alternative
methods.24 In this context, it is worth noting that the coupling
reaction could be performed with primary alkylzinc chlorides
in the presence of catalytic amounts (10%) of CuCN‚2LiCl,
affording quantitatively the 1-alkynes 3 isolated in high yields
(Table 3, entries 5 and 7).4 The reaction rate of the catalytic
process was generally slower than that of the stoichiometric
one, but an increase in the reaction temperature (-70 °C to rt)
overcame this inconvenience (Table 3, entries 5 and 7 v/s entries
4 and 6).
(20) (a) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1985, 50, 3042-
3045. (b) Elsevier, C. J.; Kleijn, H.; Boersma, J.; Vermeer, P. Organome-
tallics 1986, 5, 716-780.
(14) The absolute (S)-configuration of (+)-4aj was deduced from the
Lowe’s extension of Brewster’s rules (see ref 15) and confirmed by the
Runge “chirality functions approach” (see ref 16); the enantiomeric purity
was evaluated by GC analysis on a Cydex-B chiral column.
(15) (a) Lowe, G. Chem Commun. 1965, 411-413. (b) Brewster, J. H.
J. Am. Chem. Soc. 1959, 81, 5475-5483.
(21) (a) Dollat, J. M.; Luche, J. L.; Crabbe´, P. J. Chem. Soc., Chem.
Commun. 1977, 761-762. (b) Vermeer, P.; Meijer, J.; Brandsma, L. Recl.
TraV. Chim. Pays-Bas 1975, 94, 112-114.
(22) Cahiez, G.; Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1978,
19, 3013-3014.
(23) Rossi, R.; Carpita, A.; Ciofalo, M.; Lippolis, V. Tetrahedron 1991,
47, 8443-8460.
(24) (a) Feldman, K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt,
A. C. J. Org. Chem. 1996, 61, 5440-5452. (b) Yan, J.; Zhu, J.; Matasi, J.
J. J. Org. Chem. 1999, 64, 1291-1301. (c) Cadierno, V.; Conejero, S.;
Gamasa, M. P.; Gimeno, J. Organometallics 2002, 21, 3837-3940.
(16) Elsevier, C. J.; Vermeer, P.; Runge, W. Isr. J. Chem. 1985, 26,
174-180.
(17) Elsevier, C. J.; Vermeer, P. J. Org. Chem. 1989, 54, 3726-3730.
(18) (a) Claesson, A.; Olsson, L. I. J. Chem. Soc., Chem. Commun. 1979,
524-525. (b) Chenier, J. H. B.; Howard, J. A.; Mile, B. J. Am. Chem. Soc.
1985, 107, 4190-4191.
(19) Corey, E. J.; Boaz, N. W. Tetrahedron Lett. 1984, 25, 3059-3062.
J. Org. Chem, Vol. 71, No. 5, 2006 1907

Caporusso et al.
TABLE 3. Coupling Reactions of Zinc Alkylcyanocuprates 5 with 1-Bromo-3-phenylpropadiene, 1e a
cyanocuprate, 5
products
yieldb (%)
entry
R
T (°C)
-70
-70 f rt
-70 f rt
-70
-70 f rt
-70
-70 f rt
-70 f rt
t (h)
3, 4
3
4
14
1
2
3
5a
5b
5c
5d
5d
5e
5e
5f
Et
i-Pr
t-Bu
1
2
3
2
1
1
1
2
ea
eb
ecc
ed
ed
ee
ee
ef
100 (73)
94
6
12
50
38
4
ClMgO(CH2)3
ClMgO(CH2)3
CH2dCH(CH2)2
CH2dCH(CH2)2
Me3SiCtC(CH2)2
100 (77)d
100 (80)d
100 (69)
100 (82)
100 (68)
5e
6
7e
8
a Except as noted all reactions were run in 10-20 mmol scale by treating 1e with 2 equiv of zinc cyanocuprate 5 in THF at -70 °C and by allowing the
reaction mixture to warm to room temperature. b The yields, based on starting 1e, were determined by 1H NMR and GC analysis on the crude reaction
mixture after workup (isolated yields of >98% pure compounds are shown in parentheses). c Compounds 3ec and 4ec are identical to 3ba and 4ba, respectively.
d As acetylenic carbinol. e The reaction was performed by treating 1e with 2 equiv of the desired organozinc reagent (RZnCl) in the presence of 10 mol %
of CuCN‚2LiCl.
ether (3 × 100 mL), and the combined extracts were washed with
Conclusions
water, dried (Na2SO4), and analyzed by GC and GC-MS. The
The 1,3-substitution on the allenic bromides 1 with arylbro-
mocuprates 2 was found to be a very useful method of obtaining
a large variety of 3-aryl-1-alkynes 3 with good yields. The
chemoselectivity of the process depended on several factors,
with the structure of the aryl group of the copper reagent playing
a key role. Indeed, considerable amounts of allenic byproducts
4, deriving from a direct substitution, were detected as the size
of this group increased.
The stereochemical results indicated that the acetylenic
compounds were formed in an unambiguous anti fashion with
very high optical yields. In particular, starting from optically
active 3,3-dialkyl-1-bromoallenes, the 1,3-substitution process
appeared as a stereospecific synthetic pathway for the construc-
tion of enantiomerically enriched quaternary stereogenic centers,
characterized by an aryl and an ethynyl group. Since a triple
bond represents a very useful synthetic moiety, the reported
method can be applied to the preparation of a large variety of
optically active organic molecules.
solvents were removed at reduced pressure (10-20 mmHg), and a
1H NMR spectrum of the crude product was determined. Successive
fractional distillation (Fischer-Spaltrohr column) and/or column
silica gel chromatography (pentane as eluent) afforded pure samples
of alkynes 3 and, in most cases, arylallenes 4, which were identified
and characterized by spectroscopic and analytical data; when
necessary, larger scale reactions or preparative GC were used for
these separations. Most of the products were also identified by
spectroscopic or chromatographic comparison with authentic
samples.3a,8,25
General Procedure for the Hydroalumination of (R)-3-Aryl-
1-alkynes (R)-3: Optically Active 3-Aryl-1-alkenes 8 (Scheme
2, Table 2). In a typical experiment, 10-20 mmol of the alkyne
(R)-3 was added, at 0 °C, to a solution of diisobutylaluminum
hydride (DIBAH) (15-40 mmol) in anhydrous n-pentane (30-60
mL). The reaction mixture was stirred at room temperature for the
desired time (40-80 h; the progress of the reaction was monitored
by GC) and was then cautiously hydrolyzed with water and dilute
sulfuric acid. The organic materials were extracted with n-pentane;
the combined extracts were washed with water, dried (Na2SO4) and
evaporated to dryness. Optically active products 8 were obtained
chemically pure by fractional distillation.
From the stereochemical results, we proposed also that the
coupling reaction which afforded the 1-alkynes 3 proceeded via
an addition-elimination mechanism rather than through a CuIII
intermediate.
(R)-3-[4-(2-Methylpropyl)phenyl]-1-butene [(R)-8ad]: 99%
1
yield; H NMR δ 0.90 (d, J ) 6.6 Hz, 6H), 1.35 (d, J ) 7.1 Hz,
From a synthetic point of view, it is noteworthy that the cross-
coupling reaction of primary functionalized Knochel reagents
with 1-bromo-3-phenylpropadiene 1e afforded selectively ω-func-
tionalized 3-phenyl-1-alkynes in high yields.
3H), 1.85 (m, 1H), 2.44 (d, J ) 7.2 Hz, 2H), 3.45 (m, 1H), 5.01
(m, 1H), 5.06 (m, 1H), 6.02 (ddd, J ) 16.9, 10.4, 6.5 Hz, 1H),
7.10 (m, 4H); 13C NMR δ 20.6, 22.2, 30.1, 42.7, 44.9, 112.9, 127.0,
129.3, 139.6, 142.9, 143.7. Anal. Calcd for C14H20: C, 89.29; H,
10.71. Found: C, 89.31; H, 10.69.
(S)-4,4-Dimethyl-3-phenyl-1-pentene [(S)-8ba] (entry 3, Table
Experimental Section
2): 90% yield; bp 84 °C (7 mmHg); [R]25 -58.4 (neat, d25
D
4
1
0.8808); H NMR δ 0.89 (s, 9H), 3.01 (d, J ) 9.6 Hz, 1H), 5.03
(dd, J ) 2.0, 16.6 Hz, 1H), 5.07 (dd, J ) 2.0, 10.0 Hz, 1H), 6.26
(dt, J ) 9.6, 16.6 Hz, 1H), 7.22 (m, 5H). [Optically pure (S)-8ba
General Procedure for Coupling Reactions of Arylbromocu-
prates 2a-k with Bromoallenes 1a-d: Synthesis of 3-Aryl-1-
alkynes 3 (Tables 1 and 2). All reactions were carried out at least
in duplicate. The required arylbromocuprate 2 (40 mmol) in THF
(120 mL) was cooled at -70 °C, and a solution of the 1-bromo-
1,2-diene 1 (20 mmol) in THF (20 mL) was added over a period
of 5 min. After stirring was continued at -70 °C for 10 min, the
cooling bath was removed and the mixture was allowed to warm
to room temperature (30 min). Generally, the reaction mixture was
quenched with saturated ammonium chloride solution (100 mL),
while dilute sodium hydroxide was used in the reactions carried
out with the p-N,N-dimethylaminophenyl-cuprate 2h (entries 15 and
16 in Table 1). The organic materials were extracted with diethyl
is reported to have [R]25 -101 (neat).]11a
D
(R)-3-Methyl-3-phenyl-1-pentene [(R)-8ca]: 95% yield; bp 89
°C (17 mmHg); 1H NMR δ 0.76 (t, J ) 7.4 Hz, 3H), 1.34 (s, 3H),
1.79 (m, 2H), 5.03 (dd, J ) 1.4, 17.5 Hz, 1H), 5.10 (dd, J ) 21.4,
10.8 Hz, 1H), 6.00 (dd, J ) 10.8, 17.5 Hz, 1H), 7.10-7.40 (m,
5H); 13C NMR δ 8.7, 24.2, 33.3, 44.4, 111.9, 125.8, 126.9, 128.1,
147.1, 147.6; GC-MS(EI) m/z (rel int) 160 (M+, 10), 145 (6), 131
(25) Uccello-Barretta, G.; Bernardini, R.; Balzano, F.; Caporusso, A. M.;
Salvadori, P. Org. Lett. 2001, 3, 205-207.
1908 J. Org. Chem., Vol. 71, No. 5, 2006

StereoselectiVe Synthesis of Chiral 3-Aryl-1-alkynes
(100), 115 (18), 103 (8), 91 (54), 77 (11), 65 (6), 51 (9). Anal.
Calcd for C12H16: C, 89.94; H, 10.06. Found: C, 90.03; H, 9.97.
(S)-4-Phenyl-4,5,5-trimethyl-2-hexynoic acid [(S)-11da] (entry
25
6, Table 2): 80% yield; bp 145 °C (0.01 mmHg); [R]D +10.80
1
(c 8.0, CHCl3); the H and 13C NMR spectra were identical with
Hydroalumination of (R)-3-(2-Naphthyl)-1-butyne [(R)-3aj]
to (R)-2-(2-Naphthyl)butane [(R)-9aj] (Entry 2, Table 2). A
those of the racemic compound (R/S)-11da (see above). The
enantiomeric excess (ee) of the sample was determined to be 32%
by 1H NMR analysis of the diastereomeric salts obtained by reacting
the product, in CDCl3, with an equimolar amount of optically pure
(R)-1-(1-naphthyl)ethylamine: 1H NMR δ 0.76 [s, 5.94H, (S,R)-
t-BuC(Ph)] 0.77 [s, 3.06H, (R,R)-t-BuC(Ph)].
solution of (R)-3aj [1.0 g, 5.56 mmol, [R]25 -6.36 (heptane)] in
D
n-pentane (5 mL) was added, at 0 °C, to 30 mmol of DIBAH. The
reaction mixture was stirred for 72 h at room temperature, and then
a further amount of DIBAH (10 mmol) was added. After stirring
was continued at 40 °C for 48 h, the mixture was hydrolyzed as
above. Usual workup and successive fractional distillation gave
chemically pure (R)-9aj (0.52 g, 51% yield): bp 93 °C (0.9 mmHg);
[R]25D -12.7 (c 4.7, heptane); 1H NMR δ 0.84 (t, J ) 7.3 Hz, 3H),
1.31 (d, J ) 6.9 Hz, 3H), 1.68 (dq, J ) 6.9, 7.3 Hz, 2H), 2.75 (m,
1H), 7.37-7.81 (m, 7H). [Optically pure (R)-9aj is reported to have
(S)-4-(4-Methoxyphenyl)-4,5,5-trimethyl-2-hexynoic acid [(S)-
1
11df] (entry 7, Table 2): 74% yield; H NMR δ 0.98 (s, 9H),
1.68 (s, 3H), 3.81 (s, 3H), 6.85 (m, 2H), 7.37 (m, 2H); 13C NMR
δ 22.6, 26.3, 37.7, 47.3, 55.2, 75.3, 97.7, 112.7, 129.4, 132.8, 157.9,
158.4. Anal. Calcd for C16H20O3: C, 73.82; H, 7.74. Found: C,
73.90; H, 7.69. The enantiomeric excess (ee) of the sample was
[R]25 -30.2 (heptane).]13
D
1
determined to be 32% by H NMR analysis of the diastereomeric
KMnO4/NaIO4 Oxidative Demolition of (R)-2-[4-(2-Methyl-
propyl)phenyl]-1-butene [(R)-8ad]: (S)-2-[4-(2-Methylpropyl)-
phenyl]propanoic Acid [(S)-10ad] (Entry 1, Table 2). An aqueous
solution (1250 mL) containing 26.3 g (123 mmol) of NaIO4, 0.33
g (2.1 mmol) of KMnO4, and 2.26 g (16.4 mmol) of K2CO3 was
added to a well-stirred ice-cooled solution of 2.65 g (14 mmol) of
(R)-8ad in 60% aqueous tert-butyl alcohol (1420 mL). The reaction
mixture was stirred at 0 °C for 65 h and then treated with NaHSO3
and alkalinized with solid NaOH. The MnO2 precipitate was
eliminated by filtration, and the clarified mixture was concentrated
in a vacuum (17 mmHg), extracted with diethyl ether, and acidified
with diluted H2SO4 (5%). The acid aqueous phase was extracted
with ether, and the combined extracts were dried (Na2SO4) and
concentrated into a vacuo. Fractional distillation gave chemically
salts obtained by reacting the product, in CDCl3, with an equimolar
amount of optically pure (R)-1-(1-naphthyl)ethylamine: 1H NMR
δ 3.624 [s, 1.02H, (R,R)-OMe], 3.651 [s, 1.98H, (S,R)-OMe].
(S)-4-(4-Fluorophenyl)-4,5,5-trimethyl-2-hexynoic acid [(S)-
1
11dg] (entry 8, Table 2): 88% yield; H NMR δ 0.91 (s, 9H),
1.62 (s, 3H), 6.93 (m, 2H), 7.36 (m, 2H), 8.29 (s, 1H); 13C NMR
δ 22.5, 26.0, 37.6, 47.4, 75.7, 96.8, 114.3 (d, JCF ) 21.2 Hz), 130.1
(d, JCF ) 7.9 Hz), 136.6 (d, JCF ) 3.4 Hz), 158.1, 162.0 (d, JCF
)
247 Hz). Anal. Calcd for C15H17FO2: C, 72.56; H, 6.90. Found:
C, 72.64; H, 6.93. The enantiomeric excess (ee) of the sample was
1
determined to be 32% by H NMR analysis of the diastereomeric
salts obtained by reacting the product, in CDCl3, with an equimolar
amount of optically pure (R)-1-(1-naphthyl)ethylamine: 1H NMR
δ 1.321 [s, 1.02H, (R,R)-MeC(Ar)], 1.327 [s, 1.98H, (S,R)-MeC-
(Ar)].
pure (S)-10ad (2.10 g, 73% yield): bp 110 °C (0.1 mmHg); [R]25
D
+25.6 (c 3.0, EtOH); 1H NMR δ 0.89 (d, J ) 6.6 Hz, 6H) 1.50(d,
J ) 7.1 Hz, 3H), 1.84 (m, 1H), 2.45 (d, J ) 7.0 Hz, 2H), 3.71 (q,
J ) 7.1 Hz, 1H), 7.17 (m, 4H); 13C NMR: δ 17.9, 22.2, 30.0,
44.8, 127.4, 129.6, 137.2, 141.1, 181.0. [Optically pure (S)-10ad
Resolution of (R/S)-4-Phenyl-4,5,5-trimethyl-2-hexynoic Acid
(R/S)-11da. A solution of the racemic R,â-acetylenic acid 11da
(13.7 g, 60 mmol) in diethyl ether (50 mL) was added to a stirred
solution of (+)-dehydroabietylamine (17.2 g, 60 mmol) in ether
(200 mL) at 0 °C. The mixture was stirred at room temperature,
and the insoluble salt was filtered off, washed with diethyl ether,
dried into a vacuo [29.0 g, 94% yield; mp 80 °C; [R]25D +24.32 (c
5.0, CHCl3)], and then recrystallized three times from 95% ethanol
is reported to have [R]25 +60.0 (EtOH).]9
D
(S)-2-Phenyl-2-methylbutanoic Acid [(S)-10ca] (Entry 4,
Table 2). According to the above procedure, 2.7 g (17 mmol) of
(R)-3-phenyl-3-methyl-1-pentene (R)-8ca was treated, at 0 °C for
94 h, with the KMnO4/NaIO4 oxidation system. Usual workup and
successive fractional distillation gave chemically pure (S)-10ca (2.7
g, 87% yield): bp 124 °C (1.5 mmHg); mp 64-69 °C; [R]25D +10.6
(c 4.4, benzene); 1H NMR δ 0.85 (t, J ) 7.4 Hz, 3H), 1.55 (s, 3H),
2.05 (m, 2H), 7.20-7.50 (m, 5H). [Optically pure (S)-10ca is
to yield a fraction (6.5 g, 22%) having mp 196 °C and [R]25
D
+15.45 (c 5.0, CHCl3). This salt fraction was treated, at 0 °C, with
aqueous NaOH (20%) and the dehydroabietylamine extracted with
ether. The aqueous solution was acidified with 5% HCl and
extracted with ether (200 mL). The combined extracts were washed
with water, dried (Na2SO4), and distilled to give the pure acid (R)-
reported to have [R]25 +30.2 (benzene).]12
D
The enantiomeric excess (ee) of a sample of (S)-10ca having
11da (2.58 g, 89%): bp 145 °C (0.01 mmHg); [R]25 -32.70 (c
D
[R]25 +10.3 (c 4.4, benzene) (see entry 5 in Table 2) was
D
8.3, CHCl3). The spectral and analytical data were identical with
those of the racemic mixture. The enantiomeric excess (ee) of the
sample was determined to be 100% as the 1H NMR analysis of the
diastereomeric salt obtained with optically pure (R)-1-(1-naphthyl)-
ethylamine showed only a signal for the t-Bu moiety of the
product: 1H NMR δ 0.77 [s, 9H, (R,R)-t-BuC(Ph)] (see above).
General Procedure for Coupling Reactions of Zinc Cyano-
cuprates 5a-f with 1-Bromo-3-phenylpropadiene 1e: Synthesis
of 3-Phenyl-1-alkynes (3ea-ef) (Table 3). All reactions were
carried out at least in duplicate. A solution of the required
alkylmagnesium halide (20 mmol) in THF (20 mL) was added, at
0 °C, to a stirred THF solution of ZnCl2 (20 mmol, 10 mL). The
mixture was stirred for 30 min at room temperature and then treated,
at -10 °C, with a solution of 18 mmol of CuCN‚2LiCl prepared
in THF (50 mL) [Some reactions were performed in the presence
of a catalytic amount of the cuprous salt (1.8 mmol, 10 mol %
relative to the organozinc reagent; entries 5 and 7 in Table 3).]
Stirring was continued at 0 °C during 30 min, then the reaction
mixture was cooled at -70 °C and the 1-bromo-3-phenylpropadiene
1e (1.80 g, 9 mmol) in THF (10 mL) was added over a period of
5 min. Stirring was continued at -70 °C, and the mixture was
monitored for completion by GC. When necessary, the cooling bath
was removed and the mixture was allowed to warm to room
1
determined to be 34% by H NMR analysis of the diastereomeric
salts obtained by reacting the product, in CDCl3, with an equimolar
amount of optically pure (R)-1-(1-naphthyl)ethylamine: 1H NMR
δ 1.17 [s, 0.99H, (R,R)-MeC(Ph)COO-], 1.19 [s, 2.01H, (S,R)-MeC-
(Ph)COO-]).
General Procedure for the Synthesis of 4-Aryl-4,5,5-trimeth-
yl-2-hexynoic Acids 11 starting from 3-Aryl-1-alkynes 3 (Scheme
2, Table 2). A solution of the appropriate, racemic or optically
active, alkyne 3 (10-15 mmol) in hexane (10-15 mL) was added
dropwise, at 0 °C, to an equimolar amount of n-butyllithium 1.6 N
in hexane. The resulting mixture was stirred at room temperature
for 10-15 h, heated under reflux for 3-5 h, and treated with solid
carbon dioxide for 60 h. After the mixture was quenched with ice
and diluted H2SO4 (5%), the organic materials were extracted with
ether, and the R,â-acetylenic acid 11 was purified through his
sodium salt. Distillation gave the pure acid.
(R/S)-4-Phenyl-4,5,5-trimethyl-2-hexynoic acid [(R/S)-11da]:
1
75% yield; bp 145 °C (0.01 mmHg); H NMR δ 0.99 (s, 9H),
1.71 (s, 3H), 7.30 (m, 3H), 7.47 (m, 2H), 10.62 (s, 1H); 13C NMR
δ 22.5, 26.4, 37.8, 48.1, 75.9, 97.7, 127.2, 127.8, 128.8, 141.0,
158.5. Anal. Calcd for C15H18O2: C, 78.23; H, 7.88. Found: C,
78.38; H, 7.86.
J. Org. Chem, Vol. 71, No. 5, 2006 1909

Caporusso et al.
temperature. Standard workup and successive fractional distillation
(Fischer-Spaltrohr column) and/or column silica gel chromatog-
raphy (pentane as eluent) afforded pure samples of alkynes 3
characterized by spectral and analytical data. Some products were
identified by spectroscopic or chromatographic comparison with
authentic samples.3a
(rel int) 170 (M+, 3), 169 (2), 155 (28), 142 (20), 141 (15), 129
(16), 128 (36), 127 (11), 115 (100), 91 (15), 89 (17), 79 (8). Anal.
Calcd for C13H14: C, 91.71; H, 8.29. Found: C, 91.68; H, 8.32.
1-Trimethylsilyl-5-phenyl-1,6-heptadiyne (3ef): 1H NMR δ
0.16 (s, 9H), 1.90-2.02 (m, 2H), 2.20-2.45 (m, 2H), 2.28 (d, J )
2.4 Hz, 1H), 3.79 (m, 1H), 7.20-7.40 (m, 5H); 13C NMR δ 0.1,
17.8, 36.4, 37.1, 71.4 (tCH), 85.1 (-Ct), 85.4 (-Ct), 106.1
(tC-Si), 127.0, 127.4, 128.6, 140.5; GC-MS(EI) m/z (rel int)
240 (M+, 2), 239 (3), 225 (61), 209 (21), 197 (17), 195 (25), 181
(26), 167 (20), 166 (19), 165 (20), 128 (23), 115 (49), 73 (100).
Anal. Calcd for C16H20Si: C, 79.93; H, 8.38. Found: C, 79.85; H,
8.40.
New products 3ed-ef were as follows:
1
3-Phenyl-1-hexyn-6-ol (3ed): H NMR δ 1.60-1.90 (m, 4H),
2.03 (s, 1H), 2.28 (d, J ) 2.5 Hz, 1H), 3.62 (t, J ) 6.2 Hz, 2H),
3.66 (m, 1H), 7.30 (m, 5H); 13C NMR δ 30.2, 34.4, 37.3, 62.4,
71.2 (tCH), 85.7 (-Ct), 126.8, 127.3, 128.5, 141.2; GC-MS-
(EI) m/z (rel int) 174 (M+), 156 (4), 130 (26), 129 (30), 128 (18),
115 (100), 91 (4), 89 (25), 77 (7), 65 (10), 63 (12), 51 (11). Anal.
Calcd for C12H14O: C, 82.72; H, 8.10. Found: C, 82.68; H, 8.06.
3-Phenyl-6-hepten-1-yne (3ee): 1H NMR δ 1.78-1.91 (m, 2H),
2.14-2.27 (m, 2H), 2.27 (d, J ) 2.5 Hz, 1H), 3.65 (m, 1H), 4.99
(m, 1H), 5.05 (m, 1H), 5.81 (ddt, J ) 6.6, 10.3, 17.0 Hz, 1H),
7.18-7.40 (m, 5H); 13C NMR δ 31.3, 36.9, 37.4, 71.1 (tCH), 85.7
(-Ct), 115.3, 126.8, 127.4, 128.5, 137.7, 141.4; GC-MS(EI) m/z
Supporting Information Available: General remarks and
spectral and analytical data for all new acetylenic 3 and allenic 4
cross-coupling products. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO0522456
1910 J. Org. Chem., Vol. 71, No. 5, 2006