Experimental and theoretical study of tunable 1,3-lithium shift of proparglie/allem lie species, transmetallation and Pd-catalyzed crosscoupling reactions

Article abstract of DOI:10.1002/chem.200900325

The highly selective tuning of the isomerization from 1-arylalka1,2-dien-l- yllithium to l-arylalka-1,2dien-3-yllithium has been realized in the deprotonation of 1-arylalk-l-yne (conditions A and B) and carbolithiation of l-arylbut-3-en-l-yne with alkyllithium (conditions C and D). Subsequent transmetallation and Pd-catalyzed Negishi coupling reactions afforded 1,1-diaryl or 1,3-diaryl alienes with high selectivity. Deuterium-labeling cross experiments indicated that an intermolecular lithiation process occurred in both 1,3-lithium shift conditions (conditions B and D). 1-Arylalka1,2-diene was confirmed experimentally to be the intermediate. A computational study at the B3LYP level for the isomerization indicated that the acidity of H at the 3-position is higher than that of the H at the 1-position of 1phenyl-l,2-butadiene. Under conditions B, (Pr₂NH acts as a proton carrier to finish the 1,3-lithium shift. The overall activation barrier for the rate-determining step in the solvated models is ≈ 21.0 kcal mol^-1, indicating that the isomerization is reasonable at room temperature. For the isomerization under conditions D, DFT calculations indicated that the addition of TMEDA (tetramethylethylenediamine) and HMPA (hexamethylphosphoramide) changes the global minimum of the system; among the possible mechanisms (P1-P5) considered, the mechanism catalyzed by dilithiated species (P5) is the most probable one. The overall activation barriers for isomerization in THF and TMEDA solvated models are 22.6 and 19.7 kcal mol^-1, respectively, proving that the isomerization may proceed at RT in THF or at -78°C with TMEDA, due to the fact that the solvation of the additives may increase the concentration of 1-phenyl1,2-butadienyllithium monomer by a deaggregation effect.

Full text of DOI:10.1002/chem.200900325

FULL PAPER
DOI: 10.1002/chem.200900325
Experimental and Theoretical Study of Tunable 1,3-Lithium Shift of
Propargylic/Allenylic Species, Transmetallation, and Pd-Catalyzed Cross-
Coupling Reactions
Jinbo Zhao,[a] Yu Liu,[b] Qiwen He,[a] Yuxue Li,*[a] and Shengming Ma*[a, b]
Abstract: The highly selective tuning
of the isomerization from 1-arylalka-
1,2-dien-1-yllithium to 1-arylalka-1,2-
dien-3-yllithium has been realized in
the deprotonation of 1-arylalk-1-yne
(conditions A and B) and carbolithia-
tion of 1-arylbut-3-en-1-yne with alkyl-
lithium (conditions C and D). Subse-
quent transmetallation and Pd-cata-
lyzed Negishi coupling reactions af-
forded 1,1-diaryl or 1,3-diaryl allenes
with high selectivity. Deuterium-label-
ing cross experiments indicated that an
intermolecular lithiation process oc-
curred in both 1,3-lithium shift condi-
tions (conditions B and D). 1-Arylalka-
1,2-diene was confirmed experimental-
ly to be the intermediate. A computa-
tional study at the B3LYP level for the
isomerization indicated that the acidity
of H at the 3-position is higher than
that of the H at the 1-position of 1-
phenyl-1,2-butadiene. Under condi-
tions B, iPr2NH acts as a proton carrier
to finish the 1,3-lithium shift. The over-
all activation barrier for the rate-deter-
mining step in the solvated models is
ꢀ21.0 kcalmolÀ1, indicating that the
isomerization is reasonable at room
temperature. For the isomerization
under conditions D, DFT calculations
indicated that the addition of TMEDA
(tetramethylethylenediamine) and
HMPA (hexamethylphosphoramide)
changes the global minimum of the
system; among the possible mecha-
nisms (P1–P5) considered, the mecha-
nism catalyzed by dilithiated species
(P5) is the most probable one. The
overall activation barriers for isomeri-
zation in THF and TMEDA solvated
models are 22.6 and 19.7 kcalmolÀ1, re-
spectively, proving that the isomeriza-
tion may proceed at RT in THF or at
À788C with TMEDA, due to the fact
that the solvation of the additives may
increase the concentration of 1-phenyl-
1,2-butadienyllithium monomer by a
deaggregation effect.
Keywords: allenes · cross-coupling ·
density functional calculations
·
lithiation · reaction mechanisms
Introduction
bond-forming reactions, in which there is usually no issue of
regioselectivity involved.[2]
Selectivity control in reactions of the same materials to
form different products has attracted much attention in or-
ganic synthesis.[1] Palladium-catalyzed coupling reactions be-
tween an organic halide or triflate and an organometallic re-
However, there will be such an issue if propargylic/al-
AHCTUNGTREGlNNNU enylic species are applied, since both allenes and alkynes
may be the products. In most cases, coupling reactions of
propargylic/allenylic halides with Grignard reagents,[3] orga-
nozinc reagents,[4] organoboron reagents,[5] and organotin re-
agents[6] favor the formation of allene products, whereas al-
kynic products are formed if the steric hindrance of sub-
strates or catalyst is appropriate.[7]
À
agent have become one of the most commonly used C C
[a] J. Zhao, Dr. Q. He, Prof. Dr. Y. Li, Prof. Dr. S. Ma
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
Recently, our group has reported that the propargylic/al-
AHCTUNGTREGlNNUN enylic lithium formed by the lithiation of 1-aryl-1-alkyne
would undergo sequential transmetallation and Pd-catalyzed
coupling with organic halides leading to alkynes or allenes
depending on the structures of the starting materials.[8] Fur-
thermore, we also observed a ligand effect in the coupling
reaction of propargyl/allenyl palladium species with organo-
zinc reagents.[9] During our ongoing investigation, we ob-
served the 1,3-lithium shift of 1-arylalka-1-yn-3-yl/1-aryl-
354 Fenglin Lu, Shanghai 200032 (P. R. China)
Fax : (+86)21-6260-9305
E-mail: masm@mail.sioc.ac.cn
[b] Y. Liu, Prof. Dr. S. Ma
Department of Chemistry, East China Normal University
3663 North Zhongshan Road, Shanghai, 200062 (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900325.
AHCTUNGERTGaNNUN lka-1,2-dien-1-yllithium forming 1-arylalka-1,2-dien-3-yl/1-
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arylalka-2-yn-1-yllithium (Scheme 1). This lithium shift can
be controlled and followed by transmetallation and Pd-cata-
lyzed coupling with halides to form 1,1-diaryl allenes or 1,3-
diaryl allenes with high selectivity.[10]
The deuterated compound [D]-1c was synthesized by a
three-step protocol in which the deuterium was introduced
by the reaction of methyl butyrate with LiAlD4
(Scheme 3).[16]
Scheme 3. Synthesis of [D]-1c.
Scheme 1. The observed 1,3-Li shift of propargyl/1,2-allenyllithium spe-
cies.
1,3-Lithium shift of propargylic/allenylic lithium in lithiation
of 1-aryl-1-alkynes: We have developed two sets of condi-
tions to control the 1,3-lithium shift of propargylic lithiums
A or 1,2-allenylic lithiums B formed by lithiation of 1-aryl-
1-alkynes[10] (the alkyl group is beyond CH3). By applying
conditions A (lithiation at À208C with nBuLi for 1 h fol-
lowed by transmetallation and coupling at RT), 1,1-diarylal-
lenes 2 can be formed highly selectively. By conducting the
reaction under conditions B (lithiation at RT with LDA for
1 h followed by transmetallation and coupling at RT), 1,3-di-
arylallenes 3 were produced exclusively (Scheme 4). The re-
sults summarized in Table 1 indicated that: 1) the reaction is
Although highly selective synthesis of allenes from prop-
argylic/allenylic metallic derivatives has been widely stud-
ied,[11] only very few examples on 1,3-lithium-shift-based se-
lective allene formation[12] have been reported. Most recent-
ly, E. Vrancken and co-workers reported their preliminary
studies on the mechanism of this LDA-mediated 1,3-Li shift
process of propargyl/1,2-allenyllithium species during the
preparation of this manuscript:[13] they excluded the possibil-
ity of intramolecular and stepwise shift pathways based on
DFT calculations (at the B3LYP/6-31+G** level), and pro-
posed that LDA/iPr2NH might act as a proton shuttle on the
basis of experimental proof.
This promoted us to present
our own study on this reaction:
the scope and mechanistic as-
pects of the 1,3-lithium shift
and related transmetallation/
cross-coupling reaction.
Results and Discussion
Preparation of the starting ma-
terials 1a–1h: The starting 1-
aryl-1-alkynes 1a–h were easily
prepared by the reaction of
arylethynyllithium with alkyl io-
dides[14] or the Sonogashira cou-
Scheme 4. A controlled 1,3-lithium shift reaction.
pling of terminal alkynes with
organic halides[15] (Scheme 2).
general for differently substitut-
ed aryl halides and the regiose-
lectivity for the formation of
1,1-diarylallenes 2 or 1,3-diary-
lallenes 3 is excellent; 2) the
more sterically bulky aryl hal-
ides such as a-naphthyl iodide
give the product in a lower
yield (Table 1, entry 4); 3) both
the aryl halides with an elec-
tron-donating group or an elec-
Scheme 2. Synthesis of starting materials 1a–h.
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1,3-Lithium Shift of Propargylic/Allenylic Species
FULL PAPER
Table 1. Sequential lithiation of 1-aryl-1-alkynes, transmetallation, and
the subsequent Pd-catalyzed coupling reactions with aryl halides under
conditions A and B.
Table 2. The effect of temperature on carbolithiation of 1-phenylbut-3-
en-1-yne with nBuLi, sequential transmetallation, and Pd0-catalyzed
cross-coupling with phenyl iodide.
1a–d
CH2R
Ar2
Ph
Conditions A Conditions B
Yield of 2[a] Yield of 3[a]
Ar1
T [8C]
4a/5a
Yield of
4a+5a [%][a]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
C2H5 (1a)
nC4H9 (1c) Ph
nC4H9 (1c) p-MeC6H4
nC4H9 (1c) a-naphthyl
nC4H9 (1c) p-MeOC6H4
55
G
84
89
99
56
83
71
ACHTUNGTRENNUNG
71[b]
ACHTUNGTRENNUNG
1
2
À78
À40
À20
À78
100:0
57:43
14:86
0:100
54
42
44
18
79[b]
ACHTUNGTRENNUNG
63
74[c]
(2 f)
(2g)
(2h)
(2i)
ACHTUNGTRENNUNG
3
4[b]
ACHTUNGTRENNUNG
nC4H9 (1c) p-MeO2CC6H4 93
nC3H7 (1b) Ph
ACHTUNGTRENNUNG
[a] The yields are based on 1-phenylbut-3-en-1-yne and determined by
300 MHz 1H NMR analysis with CH2Br2 as the internal standard.
[b] After carbolithiation at À788C for 1 h, the reaction was warmed up to
RT within a period of 2 h. Then, ZnBr2 was added at room temperature,
which was followed by Pd-catalyzed cross-coupling with phenyl iodide.
76
77
69
N
96[d]
ACHTUNGTRENNUNG
p-PhC6H4 nC3H7 (1d) Ph
p-PhC6H4 nC3H7 (1d) p-BrC6H4
72
71
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a] Isolated yield. [b] The ratio of 2/3=99:1 as determined by 300 MHz
1H NMR analysis. [c] The ratio of 2e/3e=98:2 as determined by
300 MHz 1H NMR analysis. [d] NMR yield determined with CH2Br2 as
the internal standard.
was treated with nBuLi at different temperatures, 1,1-diphe-
nylocta-1,2-diene (4a) and 1,3-diphenylocta-1,2-diene (5a)
were formed in different ratios. As shown in Table 2, a
lower carbolithiation temperature favors the formation of
4a, but a higher carbolithiation temperature favors the for-
mation of the migrated product 5a. When we raised the
temperature to RT within 2 h after carbolithiation at À788C
for 1 h, a complete 1,3-lithium shift occurred to afford 5a as
the only product, albeit in only 18% yield (Table 2, entry 4).
Some additives which may affect the 1,3-lithium shift re-
action were screened: 1) pyridine, nBu4NI, N,N-diisoprop-
tron-withdrawing group could give the products in good to
excellent yields (Table 1, entries 3, 5, and 6); 4) coupling
with 4-bromophenyl iodide afforded the products 2i and 3i
highly selectively, with the carbon–bromine bond untouched,
in good yields (Table 1, entry 9).
1,3-Lithium shift of propargylic/allenylic lithiums formed by
conjugate addition of 1-arylbut-3-en-1-ynes with organolithi-
ums: It has been reported that propargylic/allenylic lithium
intermediates can also be formed by the conjugate addition
of 1-arylbut-3-en-1-ynes 1 f–h with organolithium spe-
cies.[17,18] Thus, we tried to extend this chemistry to the orga-
nolithiums formed by this conjugated addition reaction
(Scheme 5).[19]
AHCTUNGTREGyNNNU lethylamine, or DMAP (4-dimethylaminopyridine) have a
limited effect on the 1,3-lithium shift (Table 3, entries 1–4);
2) although TMEDA (tetramethylethylenediamine) has
Table 3. The effect of additives on carbolithiation of 1-phenylbut-3-en-1-
yne with nBuLi, and sequential transmetallation, Pd0-catalyzed cross-cou-
pling with phenyl iodide.
We initially tested the effect of temperature on the se-
quential reaction (Table 2). When 1-phenylbut-3-en-1-yne
Additive (1.2 equiv)
4a/5a[a]
Combined yield[b] [%]
1
2
3
4
5
6
7
pyridine
nBu4NI
N,N-diisopropylethylamine
DMAP
TMEDA
100:0
100:0
98:2
95:5
34
92
98
98
0:100
ꢀ50/ꢀ70[c]
quantitative
83[f]
HMPA
100:0–0:100[d]
0:100
HMPA[e]
[a] The ratios of 4a and 5a are determined by 300 MHz 1H NMR analy-
sis. [b] The yields are based on aryl halides and determined by 300 MHz
1H NMR analysis with CH2Br2 as the internal standard. [c] The isolated
product was contaminated with an impurity. [d] The ratios changed con-
stantly. [e] Two equivalents of HMPA were used (conditions D). [f] Isolat-
ed yield.
Scheme 5. 1,3-Lithium shift of propargylic/1,2-allenylic lithiums formed
by conjugate addition of 1-arylbut-3-en-1-ynes 1 f–h with organolithiums.
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S. Ma, Y. Li et al.
Table 4. Carbolithiation of 1-arylbut-3-en-1-yne with organolithiums, and
sequential transmetallation-Pd0-catalyzed cross-coupling with aryl halides
under conditions C and D.
been proven to effect a clean 1,3-Li shift, the reaction was
not easily reproducible with respect to chemical yields
(Table 3, entry 5); 3) HMPA (hexamethylphosphoramide)
has a similar effect to TMEDA on the 1,3-lithium shift
(Table 3, entry 6). However, these reactions were surprising-
ly not easily reproducible even by the same chemist refer-
ring to the ratio of 4a/5a. However, if the amount of
HMPA was increased to two equivalents, reproducible re-
sults were obtained.
Through trial and error, we established a set of reproduci-
ble conditions to realize a clean 1,3-lithium shift in this pro-
tocol: after 1-phenylbut-3-en-1-yne was carbolithiated with
nBuLi at À788C for 1 h, HMPA (2 equiv) was added at
À788C, which was followed by warming up naturally to
room temperature; subsequent transmetallation and Pd0-cat-
alyzed cross-coupling afforded 5a exclusively, in 83% yield
(Table 3, entry 7), indicating a complete 1,3-lithium shift.
Thus, different conditions were established for the highly
selective formation of 1,1-diarylallenes 4 or 1,3-diarylallenes
5 from the carbolithiation of 1 f–h. Conditions C afforded
1,1-diarylallenes 4: 1-phenylbut-3-en-1-yne was carbolithiat-
ed with nBuLi at À788C for 1 h followed by transmetalla-
tion and coupling at RT. Conditions D afforded 5: 1-phenyl-
but-3-en-1-yne was carbolithiated with nBuLi at À788C for
1 h, followed by addition of HMPA (2 equiv) at À788C; the
solution was then warmed up naturally to room tempera-
ture, followed by transmetallation and coupling at room
temperature.
1 f–h
RLi Ar2I
Ar2
Conditions C Conditions D
Ar1
R
Yield of 4[a]
Yield of 5[a]
1
2
3
4
5
Ph (1 f)
Ph (1 f)
Ph (1 f)
Ph (1 f)
Ph (1 f)
nBu Ph
81 (4a)
78 (4b)
92 (4c)
97 (4d)
96 (4e)
83 (5a)
75 (5b)
91 (5c)
98[b] (5d)
93 (5e)
nBu o-CH3C6H4
nBu a-naphthyl
nBu p-MeOC6H4
nBu p-
MeO2CC6H4
nBu p-CNC6H4
sBu Ph
6
7
8
9
Ph (1 f)
Ph (1 f)
Ph (1 f)
Ph (1 f)
95 (4 f)
84 (4g)
92 (4h)
95 (4i)
99 (4j)
97 (4k)
76 (4l)
89 (4m)
61 (4d)
95 (5 f)
76 (5g)
85 (5h)
79 (5i)
62 (5j)
69[c] (5k)
69[c] (5l)
59 (5m)
–
tBu Ph
tBu o-CH3C6H4
tBu a-naphthyl
tBu p-MeOC6H4
tBu p-NCC6H4
nBu Ph
10 Ph (1 f)
11 Ph (1 f)
12 Ph (1 f)
13 p-MeC6H4 (1g)
14 p-MeOC6H4
(1h)
nBu Ph
[a] Isolated yields. [b] The ratio 5d/4d=97:3. [c] Three equivalents of
HMPA were used.
Some typical results are summarized in Table 4, which in-
dicate that: 1) primary, secondary and tertiary organolithium
reagents may all be used; 2) the reaction is general for dif-
ferently substituted 1-arylbut-3-en-1-ynes and aryl halides;
3) the switch is neat; and 4) the reactions all give good to
excellent yields.
and 1-phenyl-1,2-diene E, followed by lithiation of E with F
to finish the 1,3-shift. As described in detail in the computa-
tional parts in the following paragraphs, the iPr2NH induced
pathway was found to be in operation in the LDA-mediated
isomerization process.
Thus, we designed the coupling reaction initiated by lith-
iation of 1-phenylocta-1,2-diene (7; an example of inter-
Mechanistic study of the 1,3-lithium shift: In order to study
the real nature of the reaction,
we first carried out a cross ex-
periment for lithiation of a 1:1
mixture of [D]-1c and 1e under
conditions B. After sequential
transmetallation and coupling
with phenyl iodide catalyzed by
Pd0, a mixture of 3b, [D]-3b , 6,
and [D]-6 was produced. The
lithiation by nBuLi and addi-
tion of HMPA also gave similar
results, implying the possibility
of an intermolecular mecha-
nism (Scheme 6).
Based on these results, two
pathways were proposed for the
1,3-lithium shift (Scheme 7):
a) the iPr2NH induced pathway;
b) the bimolecular mechanism:
intermolecular lithiation form-
Scheme 6. Cross experiment reactions initiated with the lithiation of a 1:1 mixture of [D]-1c and 1e. Lithiation
conditions 1): LDA (2 equiv; prepared by mixing diisopropylamine and nBuLi with a molar ratio of 1:1.5);
yield of 3b+[D]-3b: 57%; ratio 3b/[D]-3b: 80:20; Yield of 6+[D]-6: 78%; ratio 6/[D]-6: 71:29. The cross ex-
periment was carried out under conditions B. Lithiation conditions 2): A mixture of [D]-1c and 1e was lithiat-
ed with nBuLi at À208C for 1 h followed by addition of HMPA at À208C and warming up to room tempera-
ture over a period of 1 h. Subsequent transmetallation and Pd0-catalyzed coupling reaction afforded the prod-
ing 1,3-dilithium intermediate F ucts. Yield of 3b+[D]-3b: 36%; ratio 3b/[D]-3b: 58:42; Yield of 6+[D]-6: 52%; ratio 6/[D]-6: 62:38.
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1,3-Lithium Shift of Propargylic/Allenylic Species
FULL PAPER
Scheme 10. Lithiation of 1-phenylocta-1,2-diene 7 and the subsequent
quenching with D2O.
Scheme 7. Proposed pathways for the 1,3-lithium shift.
Theoretical calculations: We used the simplest model inter-
mediate B-1 to study the mechanism of this 1,3-Li shift reac-
tion by density functional (DFT) calculations with the Gaus-
mediate allene E)—prepared by conjugate addition of 1-
phenylbut-3-en-1-yne (1 f) with nBuLi followed by protona-
tion (Scheme 8)[16]—to study the possibility of path a. Com-
Scheme 11. Isomerization of 1-phenyl-1,2-butadienyllithium.
sian 03 program[20] and the B3LYP[21] methods (Scheme 11).
For each structure in the text, a harmonic vibration frequen-
cy calculation was conducted and thermal corrections were
made. All structures were shown to be minima (having no
imaginary frequencies) or first-order saddle points (transi-
tion states, having one imaginary frequency).
Scheme 8. Synthesis of 1-phenylocta-1,2-diene 7.
pound 7 was then lithiated by commercially available LDA
(from Aldrich) or LDA prepared by mixing N,N-diisopro-
pylamine with nBuLi for 1 h, followed by transmetallatation
and Pd0-catalyzed cross-coupling with phenyl iodide. As a
result, 1,3-diphenylocta-1,2-diene 5a was isolated in moder-
ate yields (Scheme 9). These facts indicated that the 1,3-lith-
ium shift may proceed via the 7-type allene intermediate in
The mechanism under conditions B (deprotonation with
LDA): In solution, there may be several solvated organo-
lithium species: monomers, dimers, and higher oligomers.
NMR studies indicate that LDA exits mostly in the form of
dimers in THF.[22] However, monomers are usually more re-
active than the dimer towards deprotonation,[23] which was
also indicated in test calculations of these two pathways (see
the Supporting Information). Therefore, in this study, the
calculations of the deprotonation and isomerization reac-
tions are all based on the monomeric organolithium model.
Gas-phase models: The reactants, intermediates, and transi-
tion states of deprotonation and isomerization were opti-
mized at the B3LYP/6-31G** level[24a] and are shown in
Figure 1.[25] Our test calculations show that the 6-31G**
basis set is appropriate for this calculation (see the Support-
Scheme 9. Lithiation of 1-phenylocta-1,2-diene 7, subsequent transmetal-
lation, and Pd0-catalyzed cross-coupling with phenyl iodide.
ing Information). To obtain more accurate energies, DGACHTUNGTRENNUNG(6-
the presence of a base (Scheme 9). Furthermore, when D2O
was added after the treatment of 1-phenylocta-1,2-diene 7
with LDA, 1-phenyl-3-d-octa-1,2-diene [D]-7 was formed,
311G**) was obtained by adding the thermal free energy
corrections at the B3LYP/6-31G** level to the single point
energy at the B3LYP/6-311G** level. The calculated relative
indicating the intermediacy of allenylic lithium
(Scheme 10).
8
free energies, DG
step of the deprotonation and isomerization process are
ACHUTGTNREN(UNG 6-31G**) and DGAHCTUNGTREN(NUGN 6-311G**), for each
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11365

S. Ma, Y. Li et al.
Figure 1. The optimized structures with selected bond lengths (ꢁ) of the gas phase models shown in Scheme 12 (optimized at the B3LYP/6-31G** level).
TS represents transition states. Hydrogen atoms not involved in the reactions are omitted for clarity.
shown in Scheme 12. B1/B2 and C1/C2 are conformational
isomers of B-1 and C-1, respectively, with the amine ligand.
LDA forms a complex with 1-phenyl-1-butyne, that is, R,
and then the nitrogen atom of LDA abstracts Ha via transi-
tion state TS-R-B1 yielding B1, which has a curved carbon
skeleton.[26,27] Rotating the diisopropylamine moiety in B1
À
1808 around the N Li bond leads to conformer B2, in which
Ha of the diisopropylamine is pointing to the left.
In step 2, Ca abstracts Ha connected to the nitrogen atom,
producing the 1-phenylbuta-1,2-diene-LDA complex E1
with an activation energy of 19.9 kcalmolÀ1. By the end of
this step, Ha has been transferred from Cc to Ca. Complex
E2 is a regioisomeric coordination complex of E1. In the
third step N abstracts Hb from Cc, affording the isomerized
product C1 with a much lower activation energy (6.8 kcal
molÀ1). Compound C1 may isomerize to the more stable
conformational isomer C2, which is 4.0 kcalmolÀ1 more
stable than B1. A comparison between the activation ener-
gies of the three steps indicates that step 2 is the rate-deter-
mining step. The existence of the proposed transient inter-
mediate 1-phenylbuta-1,2-diene and the validity of step 3
are supported by the experimental results presented in
Schemes 9 and 10.
From our earlier reports it is known that, after being lithi-
ated with BuLi or LDA, 1-phenyl-1-propyne can undergo a
double 1, 3-hydrogen shift to form acetylide.[28] For C2, if
the diisopropylamine molecule continues to transfer hydro-
gen to Ca, the final product will be an alkyne, that is, 1-
phenyl-2-butyne. However, with a methyl here, the barrier
for the second proton transfer (step 4 in Scheme 12) is
higher (25.9 kcalmolÀ1), and the alkyne product
G is
16.9 kcalmolÀ1 less stable than C2. Therefore C-1 is the final
product of the isomerization. The corresponding activation
barriers of step 2 in Scheme 12 with tBuLi and nBuLi are
Scheme 12. Reaction pathways and relative free energies DG
(in bold) and DG(6-311G**) (in italic) for gas phase models (in kcal
molÀ1, 298 K), optimized at the B3LYP/6-31G** level.
ACHTUNGTRENNUNG(6-31G**)
AHCTUNGTRENNUNG
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1,3-Lithium Shift of Propargylic/Allenylic Species
FULL PAPER
36.1 and 33.2 kcalmolÀ1,[24b] respectively, indicating that it is
impossible for tBuLi and nBuLi to transfer protons as LDA
does at RT.
that in the solvated models the relative free energies are
within 2.4 kcalmolÀ1 for all the isomers of B-1 and C-1. It is
noted that minor changes in the relative position of the sol-
vent molecules and the steric effect would lead to dramatic
changes in the optimized structures of the intermediates,
which are consistent with Reichꢂs conclusion.[31] Compared
with the gas phase models, the solvated models have some
features (Figure 2): in addition to the bridged allenyl struc-
ture (b) (THF-B1-b and THF-B2-b), the linear allenyl (a)
(THF-B1-a)- and propargyl (p) (THF-B2-p)-type isomers
have also been located for B-1 and THF-B1-a is the most
stable; the p-type isomer is located for C-1 (THF-C1-p) in
addition to the b type isomer (THF-C2-b), which is the most
stable.
The nature of the isomerization: It should be noted that the
relative free energies of TS-B2-E1 and TS-E2-C1 are 15.3
and 11.7 kcalmolÀ1, respectively (Scheme 12). A comparison
of the energy of B1 and C2 (the most stable conformational
isomers of B-1 and C-1, respectively) suggests that C-1 is
4.0 kcalmolÀ1 more stable than B-1 in the gas phase, indicat-
ing a stronger acidity for Hb over Ha in E1 and E2. There-
fore, the nature of this isomerization is a series of acid-base
equilibrium reactions.[29]
À
Solvated models: For the reaction in THF, the THF mole-
cule and the Li ion have strong short-range effects, therefore
the “mixed solvation model (explicit solvation model +
continuum solvation model)” was used. For each structure
the lithium atom was solvated with a THF molecule, and
then the IEFPCM[30] (UAHF atomic radii) method was used
to estimate the long-range effects in THF (e=7.58). Based
on the gas-phase models, the solvated models for the inter-
mediates and transition states included in steps 1–3 in
Scheme 12 were constructed and optimized at the B3LYP/6-
31G** level (Figure 2).[25] Then single-point energies and the
long-range solvation effects were calculated at the B3LYP/6-
311G** level. DGsol was obtained by adding the thermal free
energy corrections at the B3LYP/6-31G** level to the
single-point energy and solvation corrections at the B3LYP/
6-311G** level.
A relaxed potential energy surface scan along the N Li
bond in B1 in the gas phase shows that no transition state
exists in the dissociation of B1 to free iPr2NH and proparg-
yl/1,2-allenyllithium species and the binding energy of the
diisopropylamine to the lithium atom in B1 is only 10.1 kcal
molÀ1 (step 1 in Scheme 12).[24b] For solvated models, the dis-
sociation free energy of the coordinated diisopropylamine
molecule from the lithium atom of THF-B1-a decreased fur-
ther to 3.9 kcalmolÀ1 (at the B3LYP/6-31G** level), indicat-
ing that it is very easy for the diisopropylamine molecules to
be exchanged intermolecularly. This accounts for the inter-
molecular proton transfer observed in the isotopic labeling
cross experiments (Scheme 6).
As depicted in Figure 2, the three transition states of the
solvated model, THF-TS-R-B1, THF-TS-B2-E1, and THF-
TS-E2-C1, have the shortest Li O bond lengths among all
the structures listed in Figure 2. Thus, they are stabilized
better than the other structures by THF. Consequently, com-
pared with their gas phase counterparts, these three transi-
tion states have lower relative free energies (decreased by
ꢀ4–7 kcalmolÀ1). In conclusion, all the deprotonation and
À
For the gas-phase models of B1/B2 and C1/C2, an exten-
sive conformational search was carried out to locate the
linear allenyl or propargyl type structures, but the models
all converged to bridged allenyl structures (Figure 1), which
is consistent with previous calculations.[26] It should be noted
Figure 2. The optimized solvated species with selected bond lengths (ꢁ) and relative free energies in solution DGsol (in kcalmolÀ1, 298 K). TS represents
transition states. For allenyllithium intermediates: a represents linear allenyl structure, b represents bridged allenyl structure, p represents propargyl
structure. Hydrogen atoms not involved in the reactions are omitted for clarity.
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S. Ma, Y. Li et al.
isomerization steps (steps 1–3) in Scheme 12 are accelerated
by the solvation of THF.
The global minimum of the system: To understand the role
of TMEDA and HMPA in the current reaction, identifica-
tion of the global minimum of the system is necessary.[32]
The alteration of the monomer/dimer equilibrium by addi-
tives may lead to a change in the global minimum of the
system, which in turn could affect the overall activation bar-
rier. Seven monomers (including bridged allenyl, linear al-
lenyl, and propargyl structures) and three dimers with differ-
ent numbers of explicit solvated THF molecules of 1-phe-
nylbuta-1,2-dien-1-yllithium were used to find out the most
stable species in THF (see the Supporting Information). The
results show that in THF the most stable monomer
(THF2Mb, Figure 3) has a bridged allenyl structure, with
the lithium atom being solvated by two THF molecules; the
most stable dimer (THF2D, Figure 3) has a four-centered
cyclic structure, solvated with a THF on each lithium atom,
which is consistent with the NMR study.[22] The solvation
numbers of the THF and HMPA dimers are all one solvent/
lithium, as reported in the X-ray diffraction studies,[27,33]
thus, the initial structures of Py (pyridine)-, TMEDA-, and
HMPA-solvated monomers and dimers are constructed
based on the THF-solvated structures. Two TMEDA-solvat-
ed dimers have been located: the bidentate model
The activation energy for the rate-determining step
(step 2, Scheme 12) is 16.4 kcalmolÀ1 in the solvated models
(compare the energies of THF-B1-a and THF-TS-B2-E1,
Figure 2). As an approximation, the overall activation
energy could be viewed as the sum of the energies for
dimer/monomer isomerization and the monomer-based acti-
vation barriers. After taking the energy difference between
the dimer and monomer into account (approximately ob-
tained by comparing the energy difference between
THF2Mb and THF2D in Figure 3), the overall activation
barriers for the isomerization with LDA in solvated models
is ꢀ21.0 kcalmolÀ1, indicating that the isomerization is rea-
sonable at room temperature in THF (Table 1).
The mechanism under conditions D (facilitated by the addi-
tion of TMEDA and HMPA): The models in this section
were all optimized at the B3LYP/6-31G* level. DGACHTUNTRGNEUNG(6-
311G**) was obtained by adding the thermal free energy
corrections at the B3LYP/6-31G* level to the single point
energy at the B3LYP/6-311G** level.
(6-311G**) (in italic) (scaled to monomer, in kcalmolÀ1
Figure 3. The optimized structures and relative free energies DGACTHNUTRGENN(GU 6-31G*) (in bold) and DGAHCTUNGTRENNUGN ,
298 K) of monomers (M) and dimers (D) solvated by THF, Py, TMEDA, and HMPA. These structures are named in this way (take THF solvated model
for an example): THF2Mb represents monomeric bridged allenyl structure solvated by two THF molecules; THF2D represents dimeric structure solvat-
ed by two THF molecules). The Py-, TMEDA-, and HMPA-solvated structures are named similarly. The energy of THF2D is set to zero energy. The rel-
ative energies are obtained by calculating the change of free energies of model reactions. Hydrogen atoms not involved in the reactions are not shown
for clarity.
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1,3-Lithium Shift of Propargylic/Allenylic Species
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(TMEDA2D) has a slightly lower free energy (0.2 kcal
molÀ1) than the monodentate structure (TMEDA2D’,
Figure 3). Generally, the solvation energies of monomers
are higher than for dimers, but there is usually strong elec-
trostatic stabilization in the latter.[34] The relative stabilities
of monomers and dimers in solution depend on the structure
of the carbanions and the solvents. The optimized dimer and
trations of dilithium species instead of allene, therefore, the
allene catalyzed pathway (P4) is not considered here (see
the Supporting Information).
In the pathway P5, 1-phenylbuta-1,2-dien-1,3-yl dilithium
may abstract the proton from 1-phenylbuta-1,2-dien-1-yl-
lithium to finish the isomerization process and regenerate
this dilithium intermediate. The optimized intermediates
and transition structures of THF-, Py-, and TMEDA-solvat-
ed models for the pathway P5 shown in Scheme 14 are listed
monomer models with relative free energies DG
ACHTUNGTRENN(UNG 6-31G*)
and DG
ACHTUNGTRENNUNG
Py, dimeric 1-phenylbuta-1,2-dien-1-yllithium structures
(THF2D and Py2D) are the global minima as their energies
are lower relative to the corresponding monomeric struc-
tures, whereas with TMEDA and HMPA, monomeric struc-
tures (TMEDA1Mb and HMPA2Mb) are the global
minima.
The catalytic dilithiated species mechanism: We again took
the monomeric 1-phenylbuta-1,2-dien-1-yllithium as the re-
active species in the calculation. There are several possible
mechanisms for the isomerization under conditions D
(Scheme 13): the calculation results show that the transition
Scheme 14. Representative sketch of the reaction pathway. The relative
free energies DG
ACHTUNGTREN(NGNU 6-311G**) for THF- (bold), Py- (italic), and TMEDA-
(underlined) solvated models are in kcalmolÀ1
.
in Figure 4.[25] HMPA models are too large and thus not cal-
culated due to the limitation of the computer. In the transi-
tion state 3Li-TS-S (S=solvent), while the proton Hb trans-
fers from Cc of the 1-phenylbuta-1,2-dien-1-yllithium moiety
to Cd of the dilithiated species, Lib shifts from the dilithiated
species to the 1-phenylbuta-1,2-dien-1-yllithium; the struc-
tures for the transition state 3Li-TS’-S solvated by THF and
TMEDA are less stable due to the repulsion between Lia
and Lib (see the Supporting Information).
Scheme 13. Possible mechanisms for the isomerization.
As shown in Figure 4, the energy differences between the
three transition states of 3Li-TS-solvent, that is, 3Li-TS-
THF, 3Li-TS-Py, and 3Li-TS-TMEDA, are within
1.7 kcalmolÀ1. Similarly, if the energy difference between
the dimer and monomer is taken into account (Figure 3),
the overall activation barriers for the isomerization in THF-
and TMEDA-solvated models are approximately 22.6 and
19.7 kcalmolÀ1, respectively (Scheme 15), indicating that the
isomerization is reasonable at room temperature in THF
(entry 4, Table 2), and at a lower temperature (À788C,
state for concerted double-hydrogen transfer[32] (P1) cannot
be located; the overall activation energies for the first step
of the stepwise pathway (P2) and the separated ion-pair-
based mechanism[33] (P3) are over 30 kcalmolÀ1, which is too
high for an isomerization that proceeds at room temperature
(entry 4, Table 2). In the presence of excessive BuLi under
the experimental conditions, there should be higher concen-
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11369

S. Ma, Y. Li et al.
Figure 4. The optimized intermediates 3Li-R-solvent and transition states 3Li-TS-solvent (solvent=THF, Py, and TMEDA). The relative energies DGACHTUNGTRENNUNG(6-
31G*) (in bold) and DGACHTUNGTRENNUNG
(6-311G**) (in italic) are in kcalmolÀ1. Hydrogen atoms not involved in the reactions are not shown for clarity.
Conclusions
In conclusion, we have developed four protocols to control
the 1,3-lithium shift. With the application of different reac-
tion conditions, highly selective formation of 1,1-diaryl al-
lenes or 1,3-diaryl allenes can be realized. Due to the easy
availability and structural diversities of both starting com-
pounds, this methodology will show its utility in organic syn-
thesis. Experimental studies and DFT calculations suggested
that LDA acts as a carrier to transfer the proton intra/inter-
molecularly with 1-phenylbuta-1,2-diene as the intermediate,
and that the isomerization step is accelerated by THF solva-
tion. Under conditions D, the reaction may be catalyzed by
the 1-aryl-1,2-akadien-1,3-yl dilithium species. TMEDA and
HMPA may increase the concentration of reactive mono-
mers, accelerating the isomerization reaction through the
deaggregation effect. Further studies in this area are being
pursued in our laboratory.
Scheme 15. The overall activation barriers of THF-, Py-, and TMEDA-
solvated models.
entry 5, Table 3) with TMEDA. The barrier for Py-solvated
models (21.4 kcalmolÀ1) is also consistent with the experi-
mental observation that Py could not facilitate the isomeri-
zation at À788C (entry 1, Table 3). Therefore, it could be
concluded that the isomerization under conditions D may be
catalyzed by dilithiated species and accelerated by additives
such as TMEDA and HMPA due to their deaggregation
effect: with the stabilization effect of TMEDA (or HMPA),
the monomeric species of 1-phenyl-1,2-butadienyl-1-lithium
is dominant or has a remarkable concentration in the reac-
tion solution. Consequently, the overall energy barrier for
the H/Li shift reaction is reduced.
Experimental Section
Syntheses of 1-(p-phenylphenyl)-1-(4’-bromophenyl)penta-1,2-diene (2i)
and 1-(p-phenylphenyl)-3-(4’-bromophenyl)penta-1,2-diene (3i)
Conditions A: nBuLi (0.23 mL, 1.6m in hexanes, 0.37 mmol) was added
to a solution of 1-(p-phenylphenyl)pent-1-yne (68 mg, 0.31 mmol) in
THF (3 mL) in a dry Schlenk tube at À208C under N2. After being
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1,3-Lithium Shift of Propargylic/Allenylic Species
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stirred at À208C for 1 h, a solution of dry ZnBr2 (140 mg, 0.62 mmol) in
THF (4 mL) was added at this temperature. After 5 min at this tempera-
ture the reaction mixture was warmed up to RT within 13 min, [Pd-
(m, 5H), 7.23–7.16 (m, 4H), 6.25 (t, J=3.0 Hz, 1H), 2.50–2.41 (m, 2H),
2.37 (s, 3H), 1.60–1.48 (m, 2H), 1.43–1.24 (m, 4H), 0.87 ppm (t, J=
7.1 Hz, 3H); 13C NMR (CDCl3, 75.4 MHz): d=203.9, 137.4, 135.9, 135.1,
130.5, 128.5, 128.0, 126.9, 126.8, 126.7, 125.8, 108.9, 95.1, 34.1, 31.6, 27.5,
22.5, 20.6, 14.1 ppm; MS (EI, 70 eV): m/z (%): 276 (5.70) [M+], 205
(100); IR (neat): n˜ =1943, 1598, 1456 cmÀ1; HRMS calcd for C21H24 [M+]:
276.1878; found: 276.1903.
ACHTUNGTRENNUNG(PPh3)4] (18 mg, 5 mol%) and 4-bromoiodobenzene (105 mg, 0.37 mmol)
were added subsequently at RT, and the resulting mixture was stirred at
this temperature. After the reaction was complete, as monitored by TLC
(eluent: petroleum ether (60–908C)), it was quenched with saturated
NH4Cl and extracted with diethyl ether. Drying over MgSO4, filtration,
rotary evaporation, and flash chromatography on silica gel (petroleum
1
ether) afforded 2i (80 mg, 69%) as a liquid. H NMR (300 MHz, CDCl3):
d=7.65–7.20 (m, 13H), 5.79 (t, J=6.6 Hz, 1H), 2.22 (quint, J=7.5 Hz,
2H), 1.13 ppm (t, J=7.5 Hz, 3H); 13C NMR (75.4 MHz, CDCl3): d=
205.1, 140.7, 140.0, 136.3, 135.8, 131.4, 130.0, 128.8, 128.6, 127.3, 127.1,
127.0, 120.9, 109.2, 96.6, 22.2, 13.5 ppm; MS (EI, 70 eV): m/z (%): 376
Acknowledgements
We thank Professor Yun-dong Wu of HKUST for his helpful discussion
with us. We are grateful to the Major State Basic Research Development
Program (Grant No. 2006CB806105), the National Natural Science Foun-
dation of China (Grant No. 20732005 and 20702059), and Shanghai Mu-
nicipal Committee of Science and Technology for financial support.
(96.17) [M CHTUNGTRENNUNG CHTUGNTRENNUGN
+A(81Br)], 374 (95.03) [M+A(79Br)], 347 (95.18), 345 (100); IR
(neat): n˜ =1937, 1485 cmÀ1; HRMS calcd for C23H19Br [M+]: 374.0670;
found: 374.0654.
Conditions B: LDA (0.37 mL, 2.0m in THF/ethyl benzene/pentane, com-
mercial product from Aldrich, 0.73 mmol) was added to a solution of 1-
(p-phenylphenyl)pent-1-yne (80 mg, 0.37 mmol) in THF (3 mL) in a dry
Schlenk tube at À788C under N2. The reaction was then warmed up to
RT over a period of 1 h and then a solution of dry ZnBr2 (407 mg,
1.81 mmol) in THF (4 mL) was added. After 25 min at this temperature,
[1] For some of the recent excellent results in this area, see: a) P. Wipf,
C. Kendall, C. R. J. Stephenson, J. Am. Chem. Soc. 2003, 125, 761;
b) J. Barluenga, J. Alonso, F. J. FaÇanꢃs, J. Am. Chem. Soc. 2003,
125, 2610; c) M. P. Doyle, M. Yan, W. Hu, L. S. Gronenberg, J. Am.
Chem. Soc. 2003, 125, 4692; d) S. E. Denmark, W. Pan, Org. Lett.
2003, 5, 1119; e) Y. Zhang, A. J. Raines, R. A. Flowers, II Org. Lett.
2003, 5, 2363; for our own results, see: f) S. Ma, J. Zhang, Angew.
Chem. 2003, 115, 193; Angew. Chem. Int. Ed. 2003, 42, 183; g) L.
Zhang, S. A. Kozmin, J. Am. Chem. Soc. 2005, 127, 6962.
[2] a) Transition Metal Reagents and Catalysts: Innovations in Organic
Synthesis (Ed.: J. Tsuji), Wiley, New York, 2003; b) Metal-catalyzed
Cross-coupling Reactions (Eds.: F. Diederich, P. J. Stang), Wiley-
VCH, Weinheim, 1998; c) for a recent monograph on the prepara-
tion and cross-coupling involving propargyl/allenyl zinc species, see:
E. Negishi, Q. Hu, Z. Huang, G. Wang, N. Yin, The Chemistry of
Organozinc Compounds (Eds.: Z. Rappoport, I. Marek), Wiley,
New York, 2006, Chapter 11.
[PdACHTUNGTRENNUNG(PPh3)4] (21 mg, 5 mol%) and 4-bromoiodobenzene (207 mg,
0.73 mmol) were added, and the resulting mixture was stirred at RT.
After the reaction was complete, as monitored by TLC, it was quenched
with saturated NH4Cl and extracted with ether. Drying over MgSO4, fil-
tration, rotary evaporation, and flash chromatography on silica gel (pe-
troleum ether) afforded 3i (97 mg, 71%) as a solid. M.p. 107–1088C
(hexane); 1H NMR (300 MHz, CDCl3): d=7.67–7.61 (m, 4H), 7.52–7.36
(m, 9H), 6.68 (t, J=3.3 Hz, 1H), 2.72–2.51 (m, 2H), 1.28 ppm (t, J=
7.5 Hz, 3H); 13C NMR (75.4 MHz, CDCl3): d=206.6, 140.8, 140.1, 135.2,
133.3, 131.6, 128.8, 127.7, 127.6, 127.3, 127.2, 127.0, 120.9, 111.1, 98.8,
23.2, 12.5 ppm; MS (EI, 70 eV): m/z (%): 376 (34.60) [M
(34.46) [M
+A(79Br)], 45 (100); IR (neat): n˜ =1930, 1488 cmÀ1; elemental
+A(81Br)], 374
CHTUNGTRENNUNG
CHTUNGTRENNUNG
analysis calcd (%) for C23H19Br: C 73.61, H 5.10; found: C 73.58, H 5.15.
[3] T. Jeffery-Luong, G. Linstrumelle, Tetrahedron Lett. 1980, 21, 5019.
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Synthesis of 1-phenyl-1-(2’-methylphenyl)octa-1,2-diene (4b) and 1-
phenyl-3-(2’-methylphenyl)octa-1,2-diene (5b):
Conditions C: 1-Phenylbut-3-en-1-yne (52 mg, 0.41 mmol) in THF (4 mL)
was added to a solution of nBuLi (0.30 mL, 1.6m in hexanes, 0.49 mmol)
in THF (2 mL) at À788C under N2. After being stirred at À788C for 1 h,
a solution of dry ZnBr2 (186 mg, 0.82 mmol) in THF (4 mL) was added.
After being stirred at À788C for 10 min, the reaction was allowed to
warm up to RT over a period of 25 min; this was then followed by the ad-
dition of [PdACHTUNGTRENNUNG(PPh3)4] (16 mg, 5 mol%) and 2-methylphenyliodide (34 mL,
0.27 mmol) at RT with stirring. After the reaction was complete, as moni-
tored by TLC, it was quenched with saturated NH4Cl and extracted with
diethyl ether. Drying over MgSO4, filtration, rotary evaporation, and
flash chromatography on silica gel (petroleum ether) afforded 4b (58 mg,
78%) as a liquid. 1H NMR (CDCl3, 300 MHz): d=7.35–7.13 (m, 9H),
5.61 (t, J=6.9 Hz, 1H), 2.23–2.10 (m, 5H), 1.59–1.43 (m, 2H), 1.38–1.22
(m, 4H), 0.87 ppm (t, J=6.8 Hz, 3H); 13C NMR (CDCl3, 75.4 MHz): d=
203.8, 137.3, 136.8, 136.5, 130.3, 130.2, 128.3, 127.4, 126.5, 126.4, 125.9,
107.6, 94.0, 31.4, 28.9, 28.8, 22.5, 20.1, 14.0 ppm; MS (EI, 70 eV): m/z
(%): 276 (0.55) [M+], 205 (100); IR (neat): n˜ =1946, 1597, 1492,
1451 cmÀ1; HRMS calcd for C21H24 [M+]: 276.1878; found: 276.1907.
[5] T. Moriya, N. Miyaura, A. Suzuki, Synlett 1994, 149.
[6] S. Rousset, M. Abarbri, J. Thibonnet, A. DuchÞne, J.-L. Parrain,
Chem. Commun. 2000, 1987.
[7] a) M. Ishikura, I. Agata, Heterocycles 1996, 43, 1591; b) K. Tsutsumi,
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[8] a) S. Ma, L. Wang, J. Org. Chem. 1998, 63, 3497; b) S. Ma, L. Wang,
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[9] S. Ma, G. Wang, Angew. Chem. 2003, 115, 4347; Angew. Chem. Int.
Ed. 2003, 42, 4215.
Conditions D: 1-Phenylbut-3-en-1-yne (52 mg, 0.41 mmol) in THF (4 mL)
was added to a solution of nBuLi (0.31 mL, 1.6m in hexanes, 0.49 mmol)
in THF (2 mL) at À788C under N2. After being stirred at À788C for 1 h,
HMPA (0.14 mL, 0.82 mmol) was added and the reaction mixture was al-
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dry ZnBr2 (185 mg, 0.82 mmol) in THF (4 mL) was added. After 25 min,
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Chem. Eur. J. 2009, 15, 11361 – 11372
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Received: February 6, 2009
Published online: September 16, 2009
11372
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Chem. Eur. J. 2009, 15, 11361 – 11372