Intramolecular carbolithiation of heterosubstituted alkynes: An experimental and theoretical study

Article abstract of DOI:10.1002/chem.201500201

A series of heterosubstitued alkynes was successfully submitted to the intramolecular carbolithiation of their triple bond. We show that the addition is stereoselective because of the control exerted by the terminal substituent X on the geometry of the transition state. A complementary DFT study suggests that the addition is anti when a strong Li-X interaction occurs.

Full text of DOI:10.1002/chem.201500201

DOI: 10.1002/chem.201500201
Full Paper
&
Lithiations
Intramolecular Carbolithiation of Heterosubstituted Alkynes: An
Experimental and Theoretical Study
Rudy Lhermet, Maha Ahmad, Clꢀmence Hauduc, Catherine Fressignꢀ, Muriel Durandetti,*
and Jacques Maddaluno*[a]
Abstract: A series of heterosubstitued alkynes was success-
fully submitted to the intramolecular carbolithiation of their
triple bond. We show that the addition is stereoselective
because of the control exerted by the terminal substituent X
on the geometry of the transition state. A complementary
DFT study suggests that the addition is anti when a strong
Li–X interaction occurs.
Introduction
cases, the resulting gem-disubstituted vinyl entities can be
regarded as potential carbenoids because they juxtapose
a cation and a leaving group (Cl, OR or SR, Scheme 1).
However, no reaction typical of a carbene is reported in the
papers mentioned above, suggesting that, in these species,
a same sp2 carbon can exhibit both a nucleophilic and
electrophilic character.
The carbometallation of internal alkynes is a simple but power-
ful reaction that gives access to trisubstituted vinyl metals.[1]
Such species can, in turn, trap an electrophile and afford tetra-
substituted olefins, often in a stereocontrolled manner.[2] In the
case of the carbolithiation, the counterintuitive addition of
a nucleophilic organometallic onto an already electron-rich
triple bond works thanks to the Lewis acid character of the
metallic counterion.[2f–g] Thus, highly polarized organolithiums
provide simultaneously the triple bond activation and the
reactive nucleophile, in contrast to neutral nucleophiles,
which require an external activator such as the ynophile gold
or platinum cations.
Heterosubstituted alkynes have benefited from a renewed
interest lately, in particular ynamides, the chemistry of which
has overcome that of the fragile ynamines studied in the
1970s.[3] Until now, the carbolithiation of heterosubstituted
alkynes has been the subject of very little attention, except for
the trimethylsilylacetylenic derivatives, which have been stud-
ied in detail by Negishi[4a] and Coldham.[4b] Beyond silicon, only
a few examples dealing with CꢀCꢁX have been reported, and
these concern the carbolithiation of ynol ethers[5a,6] and thio-
ethers,[5] and our own recent publication on chloroalkynes.[7f]
Funk observed a competition between the 5-exo-dig and
6-endo-dig processes with the ynol ethers, whereas the thio-
ethers provided the 5-exo-dig product selectively.[5a] Almost ten
years later, Hoppe obtained the 5-exo-dig products exclusively
when working on ethynylcarbamates.[6a] Notably, in all these
Scheme 1. Intramolecular carbometallation of heterosubstituted alkynes.
This peculiarity implies that the stereochemical control of
the newly created double bond will be a key issue. It is known
that the carbolithiation of “regular” internal alkynes occurs
through a syn-pathway. This rule applies to the silicon and ger-
manium derivatives,[2j] but fails with compounds endowed
with oxygen and sulfur appendages, which afford products re-
sulting from either an anti (Funk[5a] and Hoppe[6a]) or a 1:1 syn-
anti (Coldham[4b]) carbolithiation. This deviation was explained
by Hoppe, who assumed that a second lithium cation may act
as an external Lewis acid.[6a] Our previous studies[7] suggested
that a single lithium cation could also steer the course of the
reaction through a proximal coordination by the alkyne
substituent.
This complex landscape led us to undertake a systematic
study of the influence of typical heteroatoms (X=N, O, P, S) on
the chemo- and stereo-selectivities of the carbolithiation of
heterosubstituted alkynes. In addition, substrates with X=Ge
and Se have been included to parallel with the X=Si and S
cases. Finally, this work has been conducted by using both
experimental and theoretical approaches, in an effort to
rationalize the influence of X on the course of the reaction.
[a] Dr. R. Lhermet, M. Ahmad, C. Hauduc, Dr. C. Fressignꢀ, Dr. M. Durandetti,
Dr. J. Maddaluno
Laboratoire COBRA, CNRS UMR 6014 & FR 3038
Univ. Rouen, INSA Rouen
76821 Mt St Aignan Cedex (France)
E-mail: muriel.durandetti@univ-rouen.fr
jmaddalu@crihan.fr
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500201.
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action during the TS, a phenomenon already pointed out, in
particular by Hilmersson and colleagues.[9]
Results and Discussion
Moving from sulfur to selenium proved troublesome. Carbo-
lithiation of the selenated analogue of 3a (X=SePh in
Scheme 1) under the conditions described above led to a com-
plex mixture of products containing less than 25% cyclization
derivatives (mainly 6-endo plus a E and Z mixture of 5-exo
products in an approximate 55:37:8 ratio). With the main
products being terminal alkynes, it seems that the formation
of a selenate complex competes with the lithium–iodide
exchange in this case, which interferes with the course of the
reaction.[10]
Experimental Studies
We started with the intramolecular carbolithiation of ynol
ethers, which has been studied in a few cases.[5a,6] We chose to
retain the model depicted in Scheme 1 to prepare diether 1 by
condensation of 1-methoxy-propyn-3-ol[8] and 2-iodophenol.
This substrate underwent an easy carbolithiation promoted by
phenyllithium, and afforded the sole 5-exo-dig product 2 in
a regio- and stereoselective fashion, isolated in 51% yield
(Scheme 2), which is a reasonable result considering the
sensitivity of the exocyclic enol ether function in 2.
Moving to the next column of the periodic table, we tried to
extend the scope of this carbolithiation to various ynamides.
Much more stable than ynamines, ynamides have been shown
to undergo carbo-cuprations[11a,c–e] and -lithiation.[11b] The sub-
strates were prepared by following a convenient procedure de-
veloped by Hsung, based on a CuI- or CuII-catalyzed coupling
between a secondary “amide” and bromoalkyne 5, which was
itself obtained by bromination of the silver acetylide by N-bro-
mosuccinimide (NBS).[3d] Five compounds were thus prepared
and submitted, as described above, to iodine–lithium ex-
change (Table 1). The addition on the triple bond occurred
smoothly at ꢁ788C. After hydrolysis, conversion was complete
but the products were generally recovered in modest yields
because the resulting enamides were relatively sensitive.
Interestingly, tosylamide 6a and carbamate 6b led exclusive-
ly, as described above, to the sole 5-exo-dig products 7a,b in
a fully anti fashion (Table 1, entries 1–2). In contrast, phos-
phorylynamide 6c afforded 4-amino-chromene 8c selectively,
which was likely derived from a 6-endo-dig addition (Table 1,
entries 3–4), irrespective of the organolithium species used to
trigger the Li–I exchange. This result, which was established on
the bases of unambiguous NMR data, was examined by DFT
calculations, the results of which are presented below.
Scheme 2. Intramolecular carbometallation of ynol ether 1.
This 5-exo-dig selectivity is worth highlighting with respect
to the results obtained by Funk,[5a] who observed both 5-exo-
and 6-endo-dig cyclizations (75:25) with an sp3 carbanion. The
results of a NOESY study indicated that an anti-carbolithiation
occurred, in agreement with Funk’s observations on cyclo-
pentanic products.[5a] We hypothesized that this selectivity
could be related to a MeO–Li interaction during the transition
state, and this conclusion was subsequently supported by the
computational results (see below).
We then considered the thiophenyl ether 3a. As mentioned
in a previous paper,[7d] the I–Li exchange elicits an efficient car-
bolithiation, but in this case, the isomerized product 4’a is ob-
tained, which provides no information on the stereoselectivity
of the addition. Providentially, we discovered that replacing
the thiophenyl by a thiomethyl group leads to the original cyc-
lization product, without isomerization. Indeed, reacting com-
pound 3b with PhLi (1.1 equiv) afforded 4b isolated in 56%
yield (Scheme 3). The substituent carried by the sulfur thus
seems to influence the stability of the exocyclic double bond.
Compound 4b, being the kinetic product, converts quickly
into benzofuran 4’b during purification on silica gel, explaining
the moderate chemical yield for isolated 4b. Its (E)-double
bond (established by NOESY analysis) suggests that an anti
addition occurs, probably triggered by an attractive Li–S inter-
We then studied the application of oxazolidinone and imida-
zolidinone 6d and 6e, respectively, in this reaction because
these substituents are expected to enlarge the methodological
potential of our approach through the introduction of a source
of asymmetry. Both derivatives were easily obtained as de-
scribed above from commercially available 2-oxazolidinone for
6d and from the (4R,5S)-1,5-dimethyl-4-phenylimidazolidin-2-
one [resulting from the fusion of urea and (ꢁ)-ephedrinium
chloride][12] for 6e. Addition of nBuLi upon ynamide 6d led to
degradation of the starting material, probably because of
direct addition on the carbamate moiety. Replacing nBuLi by
PhLi (1 equiv) led to the 5-exo-dig addition product 7d, mixed
with 9d, the likely product of oxazolidinone opening by PhLi
after cyclization. The ratio 7d/9d was 36:63 (total yield 55%;
Table 1, entries 5–6). Replacing the oxazolidinone by an imida-
zolidinone led, upon reaction with PhLi (1 equiv), to the sole 5-
exo-dig product 7e, without opening of the imidazolidinone
core, in a selective anti fashion.
We pursued our investigations in the pnictogen series with
alkynyl phosphane 10, which was obtained by addition of the
above lithium acetylide onto diphenylchlorophosphane. The
I–Li exchange performed with PhLi again led to the 5-exo-dig
Scheme 3. Intramolecular carbometallation of thioethers 3.
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ments run on 11-BH3 revealed that the double bond
had (Z)-configuration,[13] which is a result that was
confirmed by X-ray crystallographic analysis of this
stable solid (Scheme 4). The (Z)-selectivity suggests
that, on the contrary, a low X–Li interaction in the in-
termediates, such as the P–Li interaction,[14] leads to
syn-carbolithiation.
Table 1. Intramolecular carbometallation of ynamides 6a–e.
We concluded the experimental part of this work
with germanylated substrate 13 (Scheme 5), in an
effort to extend our previous work on the trimethyl-
silyl analogue. Similar to the TMS case, the addition
occurred under the standard conditions to afford
the expected vinyl germane 14 in 53% yield and as
a single (Z)-isomer.[15] The similarity between the
sizes of the Si and Ge nuclei and the absence of
Ge–Li interaction can explain this selectivity. Note
that 14 is much less prone to isomerization than its
silylated analogue.
Entry Substrate
Method[a] Product
Yield [%][b]
1
6a
6b
B
7a
7b
46
2
3
B
42
6c
6c
6d
A
8c
8c
77[c]
Theoretical Study
To analyze the phenomena driving the stereoselec-
tivities, a series of computations was run in parallel
with the experimental work. We used the B3P86
functional with the 6-31G** basis set, as implement-
ed in the Jaguar 7.6 software, in line with our previ-
ous studies in the field.[7b–f] The models considered
were the lithio-aryl intermediates derived from 1,
3b, 6a, 10, and 13, and these were solvated by two
THF.[7e,16]
4
5
B
72
A
B
degradation
As before, the full optimization of all these
Ar-Li·2THF led to a “folded” conformer in which the
triple bond faces the lithium cation.[7c] From there,
the TS was localized by a potential energy scan
(PES) that was undertaken by decreasing the dis-
tance between the two connecting carbon atoms. A
reoptimization of this “primary” TS led to a transition
state that was properly characterized; the cases of 1-
Li and 10-Li are illustrated in Figure 1. In all cases,
a 5-exo-dig cyclization occurred through a TS that
was reached after a low-lying activation barrier (less
than 10 kcalmolꢁ1; see Figure 1 and the Supporting
Information). In accord with our previous results, the
TS exhibits a pro-E or pro-Z bending of the triple
bond, depending on the coordinating ability of the
heteroatom borne by the triple bond (measured by
the XꢁLi distance: 2.32 ꢂ for 1-Li!anti addition, and
3.40 ꢂ for 10-Li!syn-addition).
6
7
6d
7d/9d 20:35
6e
B
7e
58
[a] Method A: reaction was conducted with nBuLi (1 equiv). Method B: reaction was
conducted with PhLi (1 equiv); [b] yield of isolated product; [c] NMR yield with respect
to mesitylene as internal standard: typical procedure: aryl iodide 6c (0.5 mmol),
mesitylene (0.25 mmol), nBuLi (0.55 mmol), THF (5 mL) under argon at ꢁ788C.
addition product, vinylphosphane 11, exclusively . However, its
We then tried to understand the 6-endo-dig preference ex-
configuration could not be determined because it rapidly ar-
omatized into benzofuran 12 (Scheme 4). Complexing 10 with
BH3 before the carbolithiation did not improve the situation,
with 12-BH3 being obtained in modest yield.
Fortunately, 11 could be trapped as a phosphane–borane
complex by adding BH3·THF (2 equiv) at ꢁ788C, directly after
protonolysis of the vinyllithium intermediate. The reason why
BH3 prevents isomerization of 11 is not clear. NMR NOE experi-
hibited by N-phosphorylynamide 6c. We thought that an alter-
ation of the triple bond polarity induced by the N-phosphoryl
group could be at the origin of this unexpected regioselectivi-
ty. We thus ran a NBO analysis on a model of 6c and com-
pared the data with those obtained with derivatives affording
the “regular” 5-exo-dig addition (Table 2). The data show that
the triple bond of the N-phosphorylynamide indeed undergoes
an inversion of polarization with respect to internal alkynes
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Table 2. NBO charges computed for
a
series of model acetylenic
derivatives.
Entry
1[a]
Compound
Charge C1
Charge C2
+0.03
ꢁ0.13
2[a]
ꢁ0.03
ꢁ0.09
ꢁ0.09
+0.09
Scheme 4. Carbolithiation of alkynylphosphane 10 and single-crystal XRD
characterization of 11-BH3.
3
4
ꢁ0.11
+0.13
Scheme 5. Intramolecular carbometallation of alkynyl germane 13.
5
6
ꢁ0.12
ꢁ0.21
+0.13
+0.27
[a] These compounds lead to 5-exo-dig cyclization. See Ref. [7a], [7b], and
[7c] for entry 1, and Ref. [7d] and [7e] for entry 2.
the CO2tBu, SO2Tol, and PO(OEt)2 substituents is known to vary
significantly,[17] and this could play a role here through the dif-
ferent mesomeric forms that these groups involve. With re-
spect to energy, our preliminary computations, which are still
in progress, indicate that the 5-exo-dig route should be the
lowest energy pathway (by ca. 6 kcalmolꢁ1).
We finally extended this investigation to the case of halo-
genated substrates 15–18 (Table 3). Experimentally, chlorinated
16 has been shown to cyclize stereoselectively into 19,[7f]
whereas 15 could not be prepared and 17–18 underwent
competitive halogen–lithium exchange.
The DFT computations run as described above on 15-Li/18-
Li led to an interesting set of results. The data indeed show
that both fluorine and chlorine interact strongly with the lithi-
um[18] during the cyclization (as indicated by the LiꢁX distances
of less than 2.8 ꢂ in the TS, Table 3) and should afford the anti
products after passing a low-lying activation barrier (less than
8 kcalmolꢁ1), in good accord with the results obtained for 19.
In contrast, the bromine and iodine atoms are computed to
remain at relatively long distance from the lithium (more than
3.6 ꢂ, Table 3), and yield the syn-products. The difference of be-
havior between these two groups of halogens toward lithium,
which is probably related to the electronegativity and/or the
size of the nuclei, is puzzling and deserves further investiga-
tion. It is unfortunate that the biased reactivity of 17 and 18
Figure 1. Energy profile along the carbolithiation of 1-Li and 10-Li.
(compare entry 5 with entries 1 and 2[7e]). However, the tosyl-
amide and carbamate derivatives, which react in a 5-exo-dig
mode, exhibit similar characteristics (entries 3 and 4). The same
is true for the methoxy derivative 1, which gives unambigu-
ously the 5-exo-dig addition. Thus, the regiochemical derailing
observed for 6c cannot be explained on purely electronic
grounds. The conjugation between the nitrogen lone pair and
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The DFT computations run in parallel give a good account
for the efficiency and selectivity of the reactions involving all
substrates considered except 6c, for which the preference for
a 6-endo-dig route remains baffling. The case of the halogenat-
ed alkynes has also been examined by theoretical means. The
results suggest that two classes of compounds can be de-
lineated on the basis of the X–Li affinity: F and Cl, on one
hand, should afford the anti-carbolithiation, and Br and I, on
the other hand, should give the syn-products. Starting from
different substrates, this dichotomy could be an attractive
method to generate stereocontrolled carbenoids.
Table 3. Computed cyclization parameters for halogenated derivatives
15–18.
Entry
Substrate
TS[a]
Product
1
15-Li
E° = +6.5, dLiꢁF =2.54 ꢂ
Experimental Section
2
General: All the reactions were carried out in an argon atmos-
phere. All reagents were purchased from commercial sources and
were used as obtained. Titration of organolithium was performed
twice to establish their exact concentration prior to use. GC analy-
sis was carried out by using a 24 m HP-methyl silicon capillary
column. Mass spectra were recorded with a quadrupolar MS instru-
ment coupled to a gas chromatograph. Elemental analyses were
performed by the Laboratoire de Microanalyse Organique (C.N.R.S.,
IRCOF, Rouen). Column chromatographies were performed with
16-Li
E° = +7.8, dLiꢁCl =2.76 ꢂ
19
3
1
standard silica gel (230–400 mesh). H NMR spectra were recorded
in CDCl3 at 300 MHz, and 13C NMR spectra were recorded at
75 MHz; chemical shifts (d) are given in parts per million (ppm)
and the coupling constants (J) in hertz. IR spectra were recorded
by transmission with an FTIR spectrometer. DMF was stored under
argon. THF, Et2O, and toluene were distilled from sodium/benzo-
phenone. CH2Cl2 was dried over CaH2 and acetone over K2CO3.
Yields refer to isolated products estimated to be ꢂ 95% pure as
determined by 1H NMR spectroscopic analysis, unless otherwise
noted.
17-Li
E° = +7.6, dLiꢁBr =3.65 ꢂ
4
18-Li
E° = +8.3, dLiꢁI =3.81 ꢂ
[a] E° (in kcalmolꢁ1) is computed as the difference between the energy of
the
Carbolithiation: typical procedure for (E)-3-(methoxymethylene)-
2,3-dihydrobenzofuran (2): PhLi (2m in Bu2O, 383 mL, 0.77 mmol)
was added to a solution of iodoaryl 1 (147 mg, 0.51 mmol) in anhy-
drous THF (5 mL) under an argon atmosphere at ꢁ788C. The mix-
ture was stirred for 15 min at ꢁ788C, then hydrolyzed with EtOH
(2 mL) and diluted with water (5 mL). The aqueous layer was ex-
tracted with Et2O (2ꢃ10 mL) and the combined organic layers
were washed with brine (10 mL), dried over anhydrous MgSO4, and
transition state and that of the starting substrate.
prevents checking these theoretical conclusions, and also for-
bids the preparation, at will, of the (E)- or the (Z)-isomers of
these halovinyl dihydrobenzofurans.
concentrated to afford the crude material. Pure
2 (42 mg,
0.26 mmol, 51%) was isolated by flash chromatography on silica
1
(Et2O/n-pentane, 0.5%) as a colorless oil. H NMR (300 MHz, CDCl3):
Conclusion
d=3.73 (s, 3H), 5.07 (d, J=2.2 Hz, 1H), 6.11 (t, J=2.2 Hz, 1H), 6.75
(d, J=7.9 Hz, 1H), 6.84 (t, J=7.6 Hz, 1H), 7.05 (t, J=7.9 Hz, 1H),
7.61 ppm (d, J=7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=60.7,
72.4, 109.3, 114.2, 120.8, 124.7, 125.6, 128.5, 138.7, 162.2 ppm; NMR
2D NOESY: correlation between d=3.73 and 7.61 ppm; IR (neat):
n=3067, 2932, 2839, 1679, 1456, 1136 cmꢁ1; MS (EI, 70 eV): m/z
(%): 162 (100) [M]+, 146, 131 [MꢁOMe], 119.
3-[(Phenylthio)methyl]benzofuran (4’a): The general procedure
was employed for the coupling of iodoaryl 3a (183 mg, 0.5 mmol).
Yield: 95 mg (78%); colorless oil; 1H NMR (300 MHz, CDCl3): d=
4.19 (d, J=1.0 Hz, 2H), 7.16–7.35 (m, 7H), 7.42 (t, J=1.0 Hz, 1H),
7.46 (dd, J=7.5, 1.6 Hz, 1H), 7.65 ppm (dd, J=6.8, 1.7 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=28.4, 111.7, 116.8, 120.1, 122.7, 124.7,
126.8, 127.2, 129.1 (2C), 130.5 (2C), 136.0, 142.9, 155.6 ppm; IR
(neat): n=3058, 2923, 1583, 1452, 1232, 1182, 1098 cmꢁ1; MS (EI,
70 eV): m/z (%): 240 [M]+, 131 (100) [MꢁSPh]; HRMS (EI): m/z calcd
for C15H12OS: 240.0609 [M]+; found: 240.0598.
This series of results demonstrate that the carbolithiation of
heterosubstituted alkynes can be regarded as a new and versa-
tile source of vinyl carbenoids. The results confirm that:
1) these substrates are generally well adapted to the addition
on the triple bond and provide the expected cyclization prod-
ucts in average to good yields; 2) the ability of the terminal
group to coordinate lithium is a key factor that controls the
syn or anti character of this reaction. Thus, the MeO, MeS and
various ynamides susceptible of coordinating Li+ led to the
anti isomer whereas the PPh2 and GeMe3 derivatives, which
have no affinity for Li+, afforded the syn-isomer. In addition, N-
phosphorylynamide 6c gives access to a 6-endo-dig cyclization
and affords the 4-amino-chromene 8c. This route had not
been observed before in this series.
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(E)-3-[(Methylthio)methylene]-2,3-dihydrobenzofuran (4b): The
general procedure was employed for the coupling of iodoaryl 3b
(152 mg, 0.5 mmol). Yield: 50 mg (56%); colorless oil; 1H NMR
(300 MHz, CDCl3): d=2.41 (s, 3H), 5.10 (d, J=2.4 Hz, 1H), 5.93 (t,
J=2.4 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.92 (t, J=7.5 Hz, 1H), 7.15
(t, J=7.7 Hz, 1H), 7.73 ppm (d, J=7.7 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d=18.6, 75.7, 110.0, 115.5, 120.8, 125.2, 126.0, 129.8, 132.4,
164.4 ppm; NMR 2D NOESY: correlation between d=2.41 and
7.73 ppm; IR (neat): n=3072, 2971, 1683, 1478 cmꢁ1; MS (EI, 70 eV):
m/z (%):177 (100) [MꢁH], 161, 131 [MꢁSMe], 119; HRMS (EI): m/z
calcd for C10H10OS: 178.0452; found: 178.0458.
13C NMR (50 MHz, CDCl3): d=51.3, 61.8, 73.3, 110.6, 118.2, 121.3,
122.4, 124.5, 127.7 (2C), 128.0 (2C), 130.7, 131.5, 135.5, 135.9, 164.3,
172.9 ppm; NMR 2D NOESY: correlation between d=4.95 and
6.12 ppm; IR (neat): n=2923, 2489, 1741.9, 1605, 1467, 1304, 1056,
980, 714 cmꢁ1; HRMS (ESI+): m/z calcd for C18H18NO3: 296.1282
[M+H]; found: 296.1287.
(4S,5R)-1-[(E)-Benzofuran-3(2H)-ylidenemethyl]-3,4-dimethyl-5-
phenylimidazolidin-2-one (7e): The general procedure was em-
ployed for the coupling of iodoaryl 6e (150 mg, 0.34 mmol). Yield:
63 mg (58%); off-white solid; [a]2D0 =ꢁ51.1 (10 gLꢁ1
; CHCl3);
1H NMR (300 MHz, CDCl3): d=0.83 (d, J=6.5, 3H), 2.88 (s, 3H), 3.95
(dq J=12.3 6.5 Hz, 1H), 4.92 (d, J=12.3 Hz, 1H), 4.97 (dd, J=13.8,
2.4 Hz, 1H), 5.07 (dd, J=13.8, 2.4 Hz, 1H), 5.78 (t, J=2.4 Hz, 1H),
6.80 (d, J=8.1 Hz, 1H), 6.93 (t, J=7.5 Hz, 1H), 7.06–7.10 (m, 2H),
7.17 (td, J=7.5, 0.8 Hz, 1H), 7.25–7.31 (m, 3H), 7.44 ppm (dd, J=
7.5, 0.8, 1H); 13C NMR (50 MHz, CDCl3): d=14.6, 28.9, 55.6, 63.8,
74.0, 110.1, 114.1, 120.8, 124.2, 125.1, 127.8 (2C), 128.2, 128.5 (2C),
130.0, 132.1, 136.0, 159.4, 164.3 ppm; NMR 2D NOESY: correlation
between d=5.07 and 5.78 ppm; IR (neat): n=2923, 1695, 1425,
1401, 1381, 1284, 1209, 986, 742, 699 cmꢁ1; MS (EI, 70 eV): m/z (%):
320 (100) [M]+, 305 [MꢁMe], 189, 146, 131, 118, 77; HRMS (EI): m/z
calcd for C20H21N2O2: 321.1592; found: 321.1603.
(E)-N-(Benzofuran-3(2H)-ylidenemethyl)-N-benzyl-4-methylben-
zenesulfonamide (7a): The general procedure was employed for
the coupling of iodoaryl 6a (517 mg, 1 mmol). Yield: 181 mg
(46%); pale-yellow solid; m.p. 141–1428C; 1H NMR (300 MHz,
CDCl3): d=2.43 (s, 3H), 4.34 (s, 2H), 4.99 (d, J=2.2 Hz, 2H), 5.23 (t,
J=2.2 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.86 (t, J=8.0 Hz, 1H), 7.16–
7.26 (m, 6H), 7.32 (d, J=8.1 Hz, 2H), 7.74 (d, J=8.1 Hz, 2H),
7.89 ppm (d, J=8.0 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=21.5,
55.0, 73.4, 110.1, 113.5, 120.8, 122.9, 126.4, 127.6 (2C), 127.8, 128.3
(2C), 128.6 (2C), 129.7 (2C), 131.4, 134.6, 135.5, 142.2, 143.8,
164.5 ppm; NMR 2D NOESY: correlation between d=5.00 and
5.24 ppm and between d=7.18–7.26 and 7.88 ppm; IR (neat): n=
3062, 3040, 2926, 2872, 1462, 1342, 1159 cmꢁ1; HRMS (ESI+): m/z
calcd. for C23H22NO3S: 392.1308 [M+H]; found: 392.1320.
(Benzofuran-3(2H)-ylidenemethyl)diphenylphosphane (11): The
general procedure was employed for the coupling of iodoaryl 10
(221 mg, 0.5 mmol). Yield: 75 mg (48%); colorless oil; 1H NMR
(300 MHz, CDCl3): d=5.18 (d, J=3.2 Hz, 2H), 6.45 (t, J=3.2 Hz, 1H),
6.88 (d, J=8.1 Hz, 1H), 6.92 (t, J=7.5 Hz, 1H), 7.25 (ddd, J=8.1,
7.5, 1.3 Hz, 1H), 7.32–7.38 (m, 6H), 7.41–7.49 ppm (m, 5H);
13C NMR (50 MHz, CDCl3): d=74.9 (d, J=21.2 Hz), 111.1, 111.4 (d,
J=10.8 Hz), 120.9, 121.4, 126.0 (d, J=9.5 Hz), 128.7 (d, J=6.9 Hz,
4C), 128.9 (2C), 131.5, 132.7 (d, J=18.9 Hz, 4C), 138.1 (d, J=
8.2 Hz,), 151.2 (d, J=25.7 Hz,), 164.3 ppm; 31P NMR (121 MHz,
CDCl3): d=ꢁ22.9 ppm; IR (neat): n=3056, 2910, 1571, 1468, 1220,
691 cmꢁ1; MS (EI, 70 eV) m/z (%): 316 [M]+, 183, 152, 131 (100)
[MꢁPPh2]; HRMS (EI): m/z calcd for C21H18O2P: 333.1044 [M+OHꢁ];
found: 333.1039.
(E)-tert-Butyl
(benzofuran-3(2H)-ylidenemethyl)(benzyl)carba-
mate (7b): The general procedure was employed for the coupling
of iodoaryl 6b (66 mg, 0.14 mmol). Yield: 20 mg (42%); brown oil;
1H NMR (300 MHz, CDCl3): d=1.42 (s, 9H), 4.66 (s, 2H), 5.12 (d, J=
1.8 Hz, 2H), 5.99 (brs, 1H), 6.83–6.95 (m, 2H), 7.17–7.31 (m, 6H),
7.38 ppm (d, J=7.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=28.2 (3C),
58.7, 73.7, 80.9, 110.3 (2C), 120.8, 123.4, 125.0, 127.3, 127.6, 128.4;
128.5 (2C), 130.5 (2C), 138.0, 154.6, 164.2 ppm; NMR 2D NOESY:
correlation between d=4.66 and 7.38 ppm; IR(neat): n=2973,
1695, 1453, 1366, 1154, 837, 745, 697 cmꢁ1; HRMS (ESI+): m/z
calcd for C21H24NO3: 338.1739 [M+H]; found: 338.1756.
Diethyl benzyl(2H-chromen-4-yl)phosphoramidite (8c): The gen-
eral procedure was employed for the coupling of iodoaryl 6c
(250 mg, 0.5 mmol). Yield: 135 mg (72%); yellow oil; 1H NMR
(300 MHz, CDCl3): d=1.33 (td, J=7.1, 1.4 Hz, 6H), 3.95–4.20 (m,
6H), 5.42 (d, J=4.4 Hz, 2H), 6.87–6.97 (m, 2H), 7.19–7.43 (m, 7H),
7.86 ppm (d, J=7.7 Hz, 1H); 13C NMR (50 MHz, CDCl3): d=16.5 (d,
J=6.0 Hz, 2C), 51.9, 62.1 (d, J=5.3 Hz, 2C), 74.9, 110.4, 121.1, 122.9,
125.4, 126.6, 127.6, 128.0 (3C), 128.9 (2C), 131.4, 139.7, 164.7 ppm;
31P NMR (121 MHz, CDCl3): d=15.3 ppm; IR (neat): n=2982, 1598,
(Z)-(Benzofuran-3(2H)-ylidenemethyl)diphenylphosphane-BH3
complex (11-BH3): The general procedure was employed for the
coupling of iodoaryl 10 (221 mg, 0.5 mmol), follow by BH3·THF ad-
1
dition. Yield: 81 mg (49%); white solid; H NMR (300 MHz, CDCl3):
d=0.94 (br. s, 3H), 5.17 (t, J=3.4 Hz, 2H), 6.24 (dt, J=6.0, 3.4 Hz,
1H), 6.93 (d, J=8.2 Hz, 1H), 6.96 (t, J=7.4 Hz, 1H), 7.33 (ddd, J=
8.2, 7.4, 1.2 Hz, 1H), 7.43–7.52 (m, 7H), 7.70–7.76 ppm (m, 5H);
13C NMR (75 MHz, CDCl3): d=74.5 (d, J=4.3 Hz), 100.6 (d, J=
61.3 Hz), 111.4 (d, J=0.9 Hz), 121.0, 121.6 (d, J=1.1 Hz), 125.5 (d,
J=14.7 Hz), 128.9 (d, J=10.2 Hz, 4C), 130.2 (d, J=59.5 Hz), 131.2
(d, J=2.4 Hz, 2C), 132.2 (d, J=9.7 Hz, 4C), 133.0, 156.4 (d, J=
7.7 Hz), 164.4 ppm; 31P NMR (121 MHz, CDCl3): d=11.0 ppm; NMR
2D NOESY: correlation between d=5.17 and 0.94 ppm and be-
tween d=6.24 and 7.43–7.52 ppm.
1451, 1206, 1039, 748 cmꢁ1
; HRMS (ESI+): m/z calcd for
C20H25NO4P: 374.1526 [M+H]; found: 374.1521.
(E)-3-(Benzofuran-3(2H)-ylidenemethyl)oxazolidin-2-one
(7d):
The general procedure was employed for the coupling of iodoaryl
6d (172 mg, 0.5 mmol). Yield: 22 mg (20%); yellow oil; 1H NMR
(300 MHz, CDCl3): d=3.83 (dd, J=8.5, 7.0 Hz, 2H), 4.50 (dd, J=8.5,
7.0 Hz, 2H), 5.17 (d, J=2.5 Hz, 2H), 6.05 (t, J=2.5 Hz, 1H), 6.83–
6.98 (m, 2H), 7.17–7.35 ppm (m, 2H); 13C NMR (50 MHz, CDCl3): d=
46.1, 62.7, 74.0, 110.7, 112.5, 121.1, 122.9, 124.9, 131.0, 133.6, 157.3,
164.6 ppm; NMR 2D NOESY: correlation between d=5.17 and
6.05 ppm; IR (neat): n=2908, 1739, 1679, 1406, 1222, 1029,
(Z)-(Benzofuran-3(2H)-ylidenemethyl)trimethylgermane (14): The
general procedure was employed for the coupling of iodoaryl 13
(374 mg, 1 mmol). Yield: 167 mg of an inseparable mixture of 14
(53.5%) and the allene 14’ (13.5%). Compound 14: 1H NMR
(300 MHz, CDCl3): d=0.32 (s, 9H), 5.09 (d, J=3 Hz, 2H), 6.11 (t, J=
3 Hz, 1H), 6.87 (d, J=7.7 Hz, 1H), 6.90 (t, J=7.7 Hz, 1H), 7.19 (t, J=
7.7 Hz, 1H), 7.37 ppm (d, J=7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=ꢁ1.3 (3C), 74.7, 110.7, 115.0, 120.6, 120.7, 126.9, 130.3, 149.6,
163.4 ppm; HRMS (EI): m/z: calcd for C12H16GeO: 250.0412 [M]+;
found: 250.0405.
748 cmꢁ1
(E)-2-[(Benzofuran-3(2H)-ylidenemethyl)amino]ethyl
.
benzoate
(9d): The general procedure was employed for the coupling of io-
doaryl 6d (172 mg, 0.5 mmol). Yield: 52.1 mg (35%); yellow oil;
1H NMR (300 MHz, CDCl3): d=3.35 (s, 1H), 3.88–3.93 (m, 4H), 4.94
(s, 2H), 6.12 (s, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H),
7.18–7.29 (m, 3H), 7.34 (t, J=7.3, 1H); 7.49–7.53 ppm (m, 3H);
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Full Paper
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Acknowledgements
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R.L. and M.A. are grateful to the Rꢀgion Haute-Normandie,
CNRS and the CRUNCh interregional research network for PhD
fellowships. We acknowledge the LabexSynOrg (ANR-11-LABX-
0029) for its financial contribution to our research projects. All
computations were run at CRIHAN (St Etienne-du-Rouvray). We
also wish to thank Professor S. Saito (Tokyo University of Scien-
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for her kind help in preparing the cover picture (cover photo
credits: Shutterstock)
Keywords: alkynes
· carbenoids · cyclization · density
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Received: January 16, 2015
Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 8
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7
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FULL PAPER
&
Lithiations
R. Lhermet, M. Ahmad, C. Hauduc,
C. Fressignꢀ, M. Durandetti,*
J. Maddaluno*
&& – &&
Triple effect: The carbolithiation of
heterosubstituted alkynes constitutes
a new, versatile, and stereocontrolled
source of vinyl carbenoids (see scheme).
Systematic experimental and DFT
investigations on the regio- and stereo-
selectivity of this reaction reveal the
origin of the control of the double
bond configuration during the cycliza-
tion step.
Intramolecular Carbolithiation of
Heterosubstituted Alkynes: An
Experimental and Theoretical Study
The regio- and stereoselectivity…
…of the carbolithiation of heterosubstituted alkynes
depends on the heteroelement borne by the triple
bond. If the heteroelement coordinates Li+, a 5-exo-dig
anti addition is observed, and the product has an E
configuration. The opposite pathway is followed if the
lithium has no affinity for the substituent—the addition
is syn and the product Z. Another deviance is observed
with N-phosphoryl ynamide of which cyclization
evolves with a 6-endo-dig route. These competitive itin-
eraries depend on the LiꢁX affinity that acts as the
primary driving force. The entangled bifurcations
symbolized on the picture illustrate this point. For
more information, see the Full Paper by M. Durandetti,
J. Maddaluno and co-workers on page&& ff.
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Chem. Eur. J. 2015, 21, 1 – 8
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ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!