Nonafluorobutanesulfonyl azide as a shelf-stable highly reactive oxidant for the copper-catalyzed synthesis of 1,3-diynes from terminal alkynes

Article abstract of DOI:10.1021/jo5025909

Nonafluorobutanesulfonyl azide is a highly efficient reagent for the copper-catalyzed coupling of terminal alkynes to give symmetrical and unsymmetrical 1,3-diynes in good to excellent yields and with good functional group compatibility. The reaction is e

Full text of DOI:10.1021/jo5025909

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Article
Nonafluorobutanesulfonyl Azide as a Shelf-Stable Highly Reactive Oxidant
for the Copper-Catalyzed Synthesis of 1,3-Diynes from Terminal Alkynes
Jose Ramon Suárez, Daniel Collado-Sanz, Diego J. Cardenas, and Jose Luis Chiara
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5025909 • Publication Date (Web): 16 Dec 2014
Downloaded from http://pubs.acs.org on December 25, 2014
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Nonafluorobutanesulfonyl Azide as a Shelf-Stable
Highly Reactive Oxidant for the Copper-Catalyzed
Synthesis of 1,3-Diynes from Terminal Alkynes
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José Ramón Suárez,† Daniel ColladoꢀSanz,‡ Diego J. Cárdenas‡, and Jose
Luis Chiara*,†
† Instituto de Química Orgánica General (IQOGꢀCSIC), Juan de la Cierva 3,
28006 Madrid, Spain
‡ Departamento de Química Orgánica, Facultad de Ciencias, Universidad
Autónoma de Madrid, Campus de Cantoblanco, 28049 Madrid, Spain
jl.chiara@csic.es
Table of Contents/Abstract Graphic
Abstract
Nonafluorobutanesulfonyl azide is a highly efficient reagent for the copperꢀ
catalyzed coupling of terminal alkynes to give symmetrical and unsymmetrical
1,3ꢀdiynes in good to excellent yields and with good functional group
compatibility. The reaction is extremely fast (<10 min), even at low temperature
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(–78 ºC), and requires substoichiometric amounts of a simple copper(I) or
copper(II) salt (2ꢀ5 mol%) and an organic base (0.6 mol%). A possible
mechanistic pathway is briefly discussed on the basis of model DFT theoretical
calculations. The quantitative assessment of the safety of use and shelf stability
of nonafluorobutanesulfonyl azide has confirmed that this reagent is a superior
and safe alternative to other electrophilic azide reagents in use today.
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Introduction
The synthesis of conjugated diynes and polyynes has recently experienced a
renaissance due to their importance as building blocks for the preparation of
natural products, pharmaceuticals and advanced materials with interesting
optoelectronic properties.1 The oxidative coupling of terminal alkynes has
become the standard method for the preparation of these essential πꢀ
conjugated structural motifs. Alkyne homocoupling to give 1,3ꢀdiynes was first
discovered by Glaser2 in 1869 employing stoichiometric copper(I) salts in the
presence of a base under aerobic conditions, and was latter improved by Hay,3
and Campbell and Eglinton4 using catalytic amounts of copper salts or
complexes with appropriate nitrogen bases (as ligands or solvents) in the
presence of dioxygen, the soꢀcalled GlaserꢀHay coupling. More recent research
on the GlaserꢀHay coupling reaction has mainly focused on modifications of
Glaser’s original conditions to improve its efficiency,5 introducing other catalytic
systems based on Pd/Cu,6 Co,7 combination of Cu and Ag,8 Fe9 or Ni5d,k,10 salts,
and more recently, Au.11 The Pdꢀcatalyzed version has developed into a
powerful synthetic tool due to its mildness and efficiency, but palladium
reagents are expensive and require airꢀsensitive and expensive phosphine
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ligands and copper coꢀcatalysts. The copperꢀcatalyzed homocoupling remains
attractive because copper salts are economical, easy to handle and relatively
environmentally friendly, but this method has also drawbacks. The requirement
of stoichiometric amounts of copper salts to achieve acceptable rates and yields,
excess oxidants, high temperature, excess bases, coꢀcatalysts, relatively long
reaction times (2ꢀ48 h) and the low to moderate yields generally obtained for
coupling aliphatic alkynes are the major shortcomings.
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In our recent work on the copperꢀcatalyzed synthesis of N,N’ꢀ
disulfonylamidines from sulfonamides and terminal alkynes using the shelfꢀ
stable nonafluorobutanesulfonyl azide (NfN3),12 we observed the formation of
varying amounts of 1,3ꢀdiynes when attempting to perform the reaction in a
oneꢀpot fashion by mixing all the reagents together with the copper catalyst.
This formal oxidative homocoupling of the starting terminal alkyne was the
dominant process under some of the conditions tested in those studies.
Surprised by the high rate observed for this coupling, we decided to further
explore and optimize the reaction in order to obtain the 1,3ꢀdiynes in
synthetically useful yields. We describe below our experimental results on this
novel oxidative coupling of terminal alkynes promoted by NfN3, its application to
the preparation of symmetrical and nonꢀsymmetrical 1,3ꢀdiynes, a theoretical
investigation of the possible mechanistic pathway of this process, and a
quantitative assessment of the safety of use and shelf stability of NfN3.
Results and Discussion
We selected phenyl acetylene as model alkyne and studied its reaction with
NfN3 in an open flask under different experimental conditions (Table 1). No
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reaction took place by stirring both compounds together, with or without
catalytic CuI (5 mol%), in THF at room temperature for 12 h (entries 1 and 2).
The alkyne also remained unreacted after addition of Et3N (1.2 equivalents) to
an equimolar mixture of alkyne and NfN3 under the same experimental
conditions, but in the absence of the metal catalyst (entry 3). In these
experiments, most of NfN3 apparently remained unreacted as readily evidenced
by the characteristic pungent odour of this reagent. In contrast, when the alkyne
(1.0 equiv), NfN3 (1.2 equiv), CuI (5 mol%), and Et3N (1.2 equiv) were all mixed
together in THF (the order of addition of reagents is of no consequence,
although for practical reasons the final dropwise addition of NfN3 is
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recommended), a fast (<5 min.) and exothermic reaction occurred accompanied
by strong gas evolution (N2) to afford 1,4ꢀdiphenylbutaꢀ1,3ꢀdiyne (1) in very high
yield along with nonafluorobutanesulfonamide (2) (entry 4). Other organic
solvents (entries 5ꢀ7), including hydroxylic ones (entry 6), were successfully
employed in this reaction with variable yields. The use of CHCl3 (entry 7) was
particularly appealing since it facilitated purification of the product diyne by
allowing a simple removal of insoluble 2 by filtration through a small pad of silica,
which also removed most of the inorganic catalyst. The reaction was also very
tolerant to changes in the nature of the base and the copper catalyst. Thus,
aromatic bases (2,6ꢀlutidine: entries 8 and 9), or amidines (DBU: entries 11ꢀ20),
and copper(I) salts such as CuCl (entry 9) and CuBr (entries 10 and 11), or
copper(II) salts such as Cu(OTf)2 (entry 13), could be used with similarly good
yields. The amount of added copper catalyst (entries 14ꢀ16) and base (entries
17ꢀ19) could be significantly reduced at the expense of the product yield,
although even under the most economical conditions (entry 16: 1 mol% CuI;
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entry 19: 0.2 equiv DBU) moderately good yields were still obtained (72% or
69%, respectively). The amount of NfN3 could be reduced to 0.6 equivalents
with no significant change in yield (entry 17), but further reduction of the
equivalents of base (entries 18, 19) or oxidant (data not shown) significantly
lowered the yield as could be anticipated from the atom balance of the reaction
shown in the scheme of Table 1. Remarkably, the reaction could be performed
at very low temperatures (entry 20: –78 ºC) with almost equal rate and
efficiency.
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Table 1. Development of the oxidative coupling of terminal alkynes
a
promoted by NfN3
Entry Cat. (mol%) Base
(equiv)
Solvent Temp Yieldb (%)
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10
–
–
THF
THF
THF
THF
r.t.
r.t.
r.t.
r.t.
n.r.c
n.r.
n.r.d
93
CuI (5)
–
–
Et3N
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuI (5)
CuCl (5)
CuBr (5)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
Et3N (1.2)
MeCN r.t.
MeOH r.t.
CHCl3 r.t.
64
62
88
2,6ꢀlutidine (1.2) CHCl3 r.t.
2,6ꢀlutidine (1.2) CHCl3 r.t.
92
90
Et3N (1.2)
THF
r.t.
82
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17e
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20e
CuBr (5)
Cul (5)
DBU (1.2)
DBU (1.2)
CHCl3 r.t.
CHCl3 r.t.
CHCl3 r.t.
CHCl3 r.t.
CHCl3 r.t.
CHCl3 r.t.
CHCl3 r.t.
CHCl3 r.t.
CHCl3 r.t.
85
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Cu(OTf)2 (5) DBU (1.2)
Cul (3)
Cul (2)
Cul (1)
Cul (2)
Cul (2)
Cul (2)
Cul (2)
DBU (1.2)
DBU (1.2)
DBU (1.2)
DBU (0.6)
DBU (0.3)
DBU (0.2)
DBU (0.6)
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CHCl3 –78 ºC 80
a Unless otherwise stated, 1.2 equiv. of NfN3 were used. b Isolated yield after
purification by column chromatography. c No reaction. d The alkyne remained
unreacted under these conditions and NfN3 reacted with the tertiary amine to
give N,NꢀdiethylꢀN'ꢀ((perfluorobutyl)sulfonyl)formimidamide together with other
unidentified minor products.13 e Only 0.6 equivalents of NfN3 were used.
Under the optimized reaction conditions, to a mixture of alkyne (1.0
equiv), catalytic CuI (5 mol%), and DBU (0.6 equiv) in CHCl3 was added NfN3
(0.6 equiv) dropwise at room temperature in an open flask (strong gas
evolution!). As indicated above, the process is rather exothermic and we
recommend cooling the reaction to 0ꢀ4 ºC when ≥2.0 mmol of alkyne is
employed. Using this procedure, a series of differently substituted terminal
alkynes were efficiently transformed into the corresponding 1,4ꢀdisubstitutedꢀ
1,3ꢀdiynes in good to excellent yields (78ꢀ93%) and in short reaction times (<10
min) (Scheme 1).
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Scheme 1. Synthesis of symmetrical 1,3-diynes
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Aromatic, aliphatic and silylꢀsubstituted alkynes were all smoothly
homocoupled in good to very high yields. The procedure was readily extended
to the preparation of unsymmetrical diynes by heterocoupling of a terminal
alkyne A with an excess (4 equiv) of a different terminal alkyne B using the
same optimized conditions (Scheme 2). In this case, separation of the target
heterodiyne (AB) from the major homodiyne product (BB), which is
concomitantly formed under these conditions, can be readily performed by
column chromatography when the less polar alkyne is selected as B (see
Experimental Section). The reaction was compatible with the presence of ether
groups (4, 7), tertiary amines (5), aryl halides (6, 15, 16, 18, 20), free hydroxyl
groups (9, 10, 15ꢀ21, 23), and imides (14) in the substrate.
Theoretical studies. In an attempt to understand the exceptional
efficiency of NfN3 in promoting the copperꢀcatalyzed coupling of terminal
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alkynes as compared to common oxidants generally employed in this
transformations, we have calculated the reaction enthalpies of a series of model
simplified processes (Table 2). For this, we have selected the DFT
B3LYP/dgdzvp method that has been shown14 to give good agreement with
experimental bond lengths and reaction enthalpies of iodine compounds, which
are involved in some of the model reactions included in Table 2.
Scheme 2. Synthesis of unsymmetrical 1,3-diynes
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Table 2. Theoretical reaction enthalpies (ꢀHº, 298 K) calculated at the DFT
B3LYP/dgdzvp level for the homocoupling of acetylene promoted by a
series of common oxidants, including trifluoromethanesulfonyl azide
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a
(TfN3) and NfN3
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ꢀHº (kcal mol–1)
Entry X (oxidant) Y (reduced products)
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—
H2
–6.18
I2
2 HI
–7.68
BQ
NIS
HQ
–27.28
–33.74
–60.88
–66.43
–68.32
–78.38
–77.92
NHS + HI
PhI(OAc)2 PhI + 2 AcOH
MeOOH
½ O2
MeOH + H2O
H2O
TfN3
TfNH2 + N2
NfNH2 + N2
NfN3
a NIS: Nꢀiodosuccinimide; NHS: succinimide; BQ: benzoquinone; HQ:
hydroquinone.
The theoretical results clearly show that i) acetylene homocoupling in the
absence of an oxidant, with formation of dihydrogen, is an exoergic process
(entry 1); and ii) perfluoroalkanesulfonyl azides provide the strongest enthalpic
driving force (ca. ≥10 kcal mol–1 more exothermic than the next best oxidant:
O2) for this coupling when compared to other oxidants used (cf. entries 2ꢀ7 and
8ꢀ9), thus explaining the strong exothermic behavior experimentally observed.
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Scheme 3. Calculated reaction profile for the initial steps of the alkyne
activation and the role of NfN3 at B3LYP/6-31G(d) (C,H,N,O,S,F) LANL2DZ
(Cu) level. ꢀ(E+ZPE) values in kcal mol–1 (ꢀG values in brackets)
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The generally accepted mechanism of the Glaser reaction was proposed
by Bohlmann and coꢀworkers in 1964.15 Thus, the coordination of Cu(I) ions to
the alkyne triple bond activates it to deprotonation giving a dinuclear Cu(II)ꢀ
acetylide complex in the presence of an oxidant that then collapses to the
oxidatively coupled product. However, the strong exothermicity and high rate of
the NfN3ꢀpromoted coupling as compared to a typical GlaserꢀHay reaction
reveal that both processes should be mechanistically distinct. We have carried
out additional DFT calculations (B3LYP/6ꢀ31G(d)/LANL2DZ), in order to get
insight into the possible reaction mechanism of this alkyne dimerization.
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Trifluoromethanesulfonyl azide (I), propyne and Me3N were used as simplified
model reagents. We considered alkynylꢀCu(I) complex II (Scheme 3) as the
starting point, since these intermediates are readily formed by reaction of Cu(I)
salts and alkynes in the presence of base. Initially, coordination of the sulfonyl
azide and Me3N to intermediate II was considered. Extrusion of N2 from
coordinated azide was calculated to have a relatively high activation energy
(18.8 kcal mol–1), which is hardly compatible with the observed fast reaction rate
at low temperature (see Supporting Information for details). For this reason, this
pathway can be disregarded. Alternatively, 1,3ꢀcycloaddition of azide I with
alkynylꢀCu complex II is a faster process (ꢀGa = 10.1 kcal mol–1, Scheme 3).
This elementary step has been previously proposed for the formation of
triazoles and imidines involving methylsulfonyl azide.16 In contrast to this
previously reported computational result, the activation energy is significantly
lower in our case. Although transition state TSII-III suggests the occurrence of a
[3+3] cycloaddition involving the alkyne carbons and Cu, intrinsic reaction
coordinate (IRC) studies lead to the formation of the five membered ring
complex III in a strongly exoergic process (–55.0 kcal mol–1). This is also in
contrast to the result obtained for methylsulfonyl azide and pyridine as ligand,
which affords a six membered cupracycle previous to ring contraction to a
similar triazol derivative.16 Triazolyl complex III subsequently experiences a
slightly endoergic ring opening process (+2.4 kcal mol–1) with a relatively low
activation barrier (8.9 kcal mol–1) leading to complex IV. Elimination of N2 from
this intermediate takes place through TSIV-V, which lies 11.5 kcal mol–1 above
the reagent. Interestingly, after a partial IRC calculation, minimization led to
intermediate V, in which 1,2ꢀmigration of Cu has taken place along the reaction
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coordinate. This type of complex has been proposed as intermediate in the Cuꢀ
catalyzed formation of amidines from sulfonyl azides and alkynes in the
presence of secondary amines.16 We searched for several possible pathways
that could explain the formation of diynes from V, since formation of this
intermediate is highly probable following the above mentioned pathway, which
is very favorable thermodynamically and involves low activation barriers. After a
high number of trials, we were able to locate a transition state involving CꢀC
coupling for which association of V and an alkynylꢀCu(I) have to previously
occur. This transition state is only 16.3 kcal mol–1 above the reagents. Partial
IRC calculation leads to the structure shown in Scheme 4, which is not a
stationary point. This complex is 26.3 kcal mol–1 more stable than the transition
state, and shows complete C—C bond formation. Therefore, this transition state
(TSC-C) actually corresponds to a productive reaction. Dissociation of the final
diyne from Cu will be probably assisted by coordination of amine and
protonation of the N ligand, an overall process that has been calculated to be
strongly favorable, as shown in Scheme 5.
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In summary, although other possible pathways cannot be discarded, we
have found a plausible mechanism that accounts for the observed reactivity.
The formation of the C—C bond would be the rate limiting step, and the
activation energy we have found constitutes an upper limit for the process.
Scheme 4. Plausible mechanism for the formation of the C—C bond by
reaction of V and an alkynyl-Cu intermediate. B3LYP/6-31G(d)
(C,H,N,O,S,F) LANL2DZ (Cu) level. ꢀ(E+ZPE) value in kcal mol–1 (grey: C;
white: H; dark blue: N; pink: Cu; yellow: S; red: O; light blue: F)
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Scheme 5. Overall transformation of V and an alkynyl-Cu intermediate into
the final products. B3LYP/6-31G(d) (C,H,N,O,S,F) LANL2DZ (Cu) level.
ꢀ(E+ZPE) value in kcal mol–1
Assessment of the safety of use and shelf-stability of NfN3. The
growing number of applications of NfN3 in synthetic organic chemistry (as a
diazoꢀtransfer reagent, 1,3ꢀdipole in cycloadditionꢀstarted multicomponent
reactions, or as a nitrenenoid precursor in CH amination reactions),12,17 outꢀ
performing its more costly and hazardous lower homologue triflyl azide (TfN3),
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calls for a rational assessment of its safety of use and shelf stability. To this end,
the sensitivity of neat NfN3 toward heat, impact, and electrostatic discharge
(ESD) has been quantified (Table 3 and Supporting Information).18
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Table 3. Sensitivity and thermal stability data for sulfonyl azide reagents
Sensitivity
Friction
DSC
Compd.
NfN3
Impact
(J)
ESD (J)
>3.4
Teo (ºC)a Tp (ºC)b
ꢀH
(N)
(kcal/g)
c
>25.5
140.82d,e 163.66d,e 0.100d,e
152.02d,f 174.00d,f 0.107d,f
g
h
h
h
h
h
h
h
h
h
h
BtSO2N3
>95
ADMPi
>25
>360
240
>200j
102
ImSO2N3— 6
HClk
0.50
0.30
0.50
h
h
h
h
ImSO2N3— 40
240
240
131
146
k
H2SO4
ImSO2N3— 40
k
HBF4
a Extrapolated onset temperature. b Peak temperature. c Not applicable because
the compound is a liquid under standard conditions. d In hermetic sealed
aluminium pan. At atmospheric pressure (in aluminium pan with pierced lid), the
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compound evaporates at 100 ºC without decomposition. e At 10 ºC/min. f At 20
ºC/min. g Ref. 19. h Not reported. i Ref. 20. j In open aluminium pan. k Ref. 21.
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The thermal stability was assessed by differential scanning calorimetry
(DSC) using two different heating rates (10.0 or 20.0 ºC min–1) in hermetic
aluminium pans with either sealed or pierced lids. The DSC curve (see
Supporting Information) at 10 ºC min–1 in pierced lid pan (atmospheric pressure)
showed that NfN3 melts at –22 ºC and boils at 100 ºC without decomposition. In
hermetic sealed pan, a small exotherm of only 0.100 kcal g–1 was observed with
an extrapolated onset temperature of 140.8 ºC. The exotherm was 0.107 kcal g–
1 with an onset temperature of 152.0 ºC when the heating rate was 20.0 ºC min–
1. Both energy values are well below those of conventional energetic materials
(>0.24 kcal g–1). An ignition temperature assay was also carried out by heating
two 0.5 g samples in open glass tubes at a 5 ºC min–1 heating rate from room
temperature to 450 ºC. Boiling of the samples was observed at 100 ºC, with
formation of white fumes above 144 ºC. An energetic decomposition with gas
evolution (N2), but without detonation, was seen at 152 ºC, with deposition of an
unidentified white solid residue at the walls of the tube, which remained to the
end of the experiment. Thus, no potential thermal hazards were detected for
NfN3 at or below its boiling point. The shock sensitiveness was determined with
a BAM drophammer following a 30ꢀtrial Bruceton method, which gave a
minimum impact energy of at least 25.5 J, which is comparable to that of TNT
(30 J) considered as not sensitive to impact. The compound proved to be also
insensitive toward electrostatic discharge (tested at up to 30000 V, i.e. 3.4 J, for
10 repetitions). Regarding its shelf stability, we have safely stored 40 g batches
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of the neat reagent in closed vials at –25 ºC for 12 months without any
observed decomposition. These stability and safety parameters compare very
favorably with those recently described for related azide reagents (Table 3).
Contrary to NfN3, these reagents have been reported to be hygroscopic and
sensitive to moisture, which poses an explosion hazard due to inadvertent
formation of hydrazoic acid. The nonꢀhazardous nature of NfN3, its high shelf
stability, low sensitivity to hydrolysis, good reaction yields and easyꢀtoꢀpurify
reaction mixtures, makes it a clearly superior alternative to other electrophilic
azide reagents in use today.
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Conclusion
We have shown that nonafluorobutanesulfonyl azide (NfN3) promotes the
copperꢀcatalyzed coupling of terminal alkynes in the presence of an organic
base to give symmetrical and unsymmetrical 1,3ꢀdiynes in high yields and with
good functional group compatibility. The very fast coupling rates observed, even
at low temperature, and the high exothermic character of the reaction point to a
distinct mechanism as compared with typical GlaserꢀHay couplings. A possible
mechanistic pathway via an intermediate ketenimine has been discussed on the
basis of model DFT calculations. Given the increasing importance of NfN3 as an
efficient and versatile reagent in organic synthesis, a quantitative assessment of
its safety of use and shelf stability has confirmed it to be a superior and safe
alternative to other electrophilic azide reagents in use today. The novel
procedure for the oxidative coupling of terminal alkynes here described could
prove of wide interest for the efficient synthesis of molecules and materials
based on the 1,3ꢀdiyne motif.
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Experimental Section
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General Methods. All melting points were measured with a microꢀ
melting apparatus. Analytical thin layer chromatography (TLC) was performed
on precoated silica gel 60 F254 plates. The chromatograms were viewed under
UV light and/or by treatment with a solution of ammonium molybdate (50 g) and
cerium(IV) sulphate (1 g) in 5 % aqueous H2SO4 (1 L) (Hanessian stain),
followed by charring on a hot plate. Flash column chromatography was
performed with silica gel, grade 60, 230–400 mesh. 1H and 13C NMR spectra
were recorded at 300 or 400 MHz and 75 or 100 MHz, respectively, using
CDCl3 or CD3COCD3 as solvents. Chemical shifts are expressed in parts per
million (δ scale) downfield from tetramethylsilane and are referenced to residual
peaks of the deuterated NMR solvent used. Accurate mass values were
determined on a mass spectrometer equipped with an electrospray or APCI ion
source and a TOF detector. All reactions were carried out with magnetic stirring
in loosely capped 15 mL reaction vials or open 25 mL round bottom flasks. All
solvents were of HPLC grade and were used as provided. All starting materials
and reagents are commercially available and were used as received, with the
exception of nonafluorobutanesulfonyl azide (NfN3), which was prepared from
nonafluorobutanesulfonyl fluoride and sodium azide following literature
procedures.22
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Typical Experimental Procedure for the Synthesis of Symmetrical
1,3-Diynes. To a solution of the corresponding alkyne (1.0 mmol) in CHCl3 (4
mL) was added CuI (9.5 mg, 0.05 mmol), DBU (0.045 mL, 0.3 mmol), and,
finally, perfluorobutanesulfonyl azide dropwise (195 mg, 0.6 mmol) (CAUTION!
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exotermic reaction with strong gas evolution). After stirring the mixture at room
temperature for 10 min, the reaction was quenched with a saturated aqueous
solution of NaHCO3 (5 mL) and extracted with CH2Cl2 (3 × 10 mL). The organic
layers were separated, dried over Na2SO4, and concentrated at reduced
pressure, and the crude product was purified by column chromatography on
silica gel (using a hexane/EtOAc mixture as eluent) to afford the corresponding
1,3ꢀdiyne. Alternatively, the reaction mixture was filtered through a small pad of
silica gel eluting with CHCl3 to remove the metal catalyst and most of
sulfonamide 2. Evaporation of the filtrate at reduced pressure removed residual
2 by sublimation to afford the crude product that could be further purified by
column chromatography as above.
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Typical Experimental Procedure for the Synthesis of Unsymmetrical
1,3-Diynes. To a solution of alkyne A (0.3 mmol, 1 equiv) and alkyne B (1.2
mmol, 4 equiv) in CHCl3 (4 mL) was added CuI (14 mg, 0.075 mmol), DBU
(0.276 mL, 1.8 mmol), and, finally, perfluorobutanesulfonyl azide dropwise (586
mg, 1.8 mmol) (CAUTION! exotermic reaction with strong gas evolution). After
stirring the mixture at room temperature for 10 min, the reaction was quenched
with a saturated aqueous solution of NaHCO3 (5 mL) and extracted with CH2Cl2
(3 × 10 mL). The organic layers were separated, dried over Na2SO4, and
concentrated at reduced pressure, and the crude product was purified by
column chromatography over silica gel. In all cases described in Scheme 2, the
less polar symmetrical alkyne (BB) was eluted first from the column with
hexane/EtOAc 9:1 (v/v) and then the corresponding unsymmetrical 1,3ꢀdiyne
(AB) using hexane/EtOAc 4:1 (v/v). Alternatively, the simplified workꢀup
procedure indicated for the symmetrical diynes could be followed.
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1,4-Diphenylbuta-1,3-diyne (1): Yield: 90% (91 mg); colorless solid; Rf =
0.35 (hexane). 1H NMR and 13C NMR were agreement with those reported in
the literature.5l 1H NMR (300 MHz, CDCl3) δ 7.31ꢀ7.38 (m, 6 H), 7.52ꢀ7.55 (m, 4
H); 13C NMR (75 MHz, CDCl3) δ 74.0, 81.7, 121.9, 128.6, 129.4, 132.6.
1,4-Di-p-tolylbuta-1,3-diyne (3): Yield: 90% (104 mg); colorless solid; Rf
= 0.41 (hexane); 1H NMR and 13C NMR were agreement with those reported in
the literature.5l 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 6 H), 7.15 (d, J = 8.0 Hz, 4
H), 7.42 (d, J = 8.0 Hz, 4 H); 13C NMR (75 MHz, CDCl3) δ 21.8, 73.6, 81.7,
118.9, 129.4, 132.5, 139.6.
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1,4-Bis(4-methoxyphenyl)buta-1,3-diyne (4): Yield: 86% (113 mg);
yellow solid; Rf = 0.33 (hexane/EtOAc 9:1). 1H NMR and 13C NMR were
agreement with those reported in the literature.5l 1H NMR (300 MHz, CDCl3) δ
3.82 (s, 6 H), 6.85 (d, J = 8.8 Hz, 4 H), 7.46 (d, J = 8.8 Hz, 4 H); 13C NMR (75
MHz, CDCl3) δ 55.5, 73.1, 81.4, 114.1, 114.3, 134.2, 160.4.
1,4-bis(p-N,N-dimethylaminophenylethynyl)buta-1,3-diyne (5): Yield:
90% (130 mg); dark powder; Rf = 0.32 (hexane/EtOAc 5:1). 1H NMR and 13C
NMR were agreement with those reported in the literature.6d 1H NMR (300 MHz,
CDCl3) δ 2.99 (s, 12 H), 6.61 (d, J = 8.7 Hz, 4 H), 7.39 (d, J = 8.7 Hz, 4 H); 13C
NMR (75 MHz, CDCl3) δ 40.3, 72.8, 82.5, 108.8, 111.8, 133.8, 150.5; HRMS
(ESI) calcd for C20H21N2 ([M + H+]) 289.1705, found m/z 289.1703.
1,4-Bis(4-fluorophenyl)buta-1,3-diyne (6): Yield: 85% (101 mg); white
solid; Rf = 0.52 (hexane/EtOAc 9:1). 1H NMR and 13C NMR were agreement
with those reported in the literature.5l 1H NMR (300 MHz, CDCl3) δ 7.04 (t, J =
8.7 Hz, 4 H), 7.51 (dd, J = 8.9, 5.4 Hz, 4 H); 13C NMR (75 MHz, CDCl3) δ 73.7,
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80.6, 116.1 (d, J = 22.3 Hz), 118.1 (d, J = 3.5 Hz), 134.71 (d, J = 8.6 Hz), 163.2
(d, J = 251.6 Hz).
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1,6-bis(benzyloxy)hexa-2,4-diyne (7): Yield: 92% (134 mg); orange oil;
Rf = 0.49 (hexane/EtOAc 9:1). 1H NMR and 13C NMR were agreement with
those reported in the literature.10d 1H NMR (300 MHz, CDCl3) δ 4.19 (s, 4 H),
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4.54 (s, 4 H), 7.23ꢀ7.30 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 57.7, 70.7, 71.9,
75.5, 128.1, 128.3, 128.6, 137.2.
Hexadeca-7,9-diyne (8): Yield: 83% (91 mg); yellow oil; Rf = 0.41
(hexane). 1H NMR and 13C NMR were agreement with those reported in the
literature.5l 1H NMR (300 MHz, CDCl3): δ 0.88 (t, J = 6.8 Hz, 6 H), 1.23ꢀ1.42 (m,
8 H), 1.46ꢀ1.55 (m, 4 H), 2.23 (t, J = 7.0 Hz, 4 H); 13C NMR (75 MHz, CDCl3) δ
14.2, 19.3, 22.7, 28.5, 28.7, 31.56, 65.4, 77.6.
1,1'-(Buta-1,3-diyne-1,4-diyl)bis(cyclopentan-1-ol) (9): Yield: 89% (97
mg); colorless solid; Rf = 0.42 (hexane/EtOAc 5:1). 1H NMR and 13C NMR were
agreement with those reported in the literature.5l 1H NMR (300 MHz,
CD3COCD3) δ 1.69ꢀ1.90 (m, 16 H); 13C NMR (75 MHz, CD3COCD3) δ 24.0, 42.9,
67.2, 74.4, 84.8.
1,1'-(Buta-1,3-diyne-1,4-diyl)bis(cyclohexan-1-ol) (10): Yield: 78% (96
mg); colorless solid; Rf = 0.39 (hexane/EtOAc 5:1).1H NMR and 13C NMR were
agreement with those reported in the literature.5l 1H NMR (300 MHz,
(CD3COCD3) δ 1.25ꢀ1.34 (m, 4 H), 1.46ꢀ1.72 (m, 120 H), 1.81ꢀ1.87 (m, 4 H);
13C NMR (75 MHz, CD3COCD3) δ 23.6, 26.0, 40.4, 68.2, 68.5, 84.8.
1,4-Bis(trimethylsilyl)buta-1,3-diyne (11): Yield: 93% (90 mg);
colorless solid; Rf = 0.58 (hexane). 1H NMR and 13C NMR were agreement with
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those reported in the literature.23 1H NMR (300 MHz, CD3COCD3) δ 0.18 (s, 18
H); 13C NMR (75 MHz, CD3COCD3) δ ꢀ0.36, 86.1, 88.1.
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N,N-Dimethyl-4-(phenylbuta-1,3-diyn-1-yl)aniline (12): Yield: 65% (48
mg); brown solid; mp 112ꢀ114 ºC (lit.24 113 ºC); Rf = 0.32 (hexane/EtOAc 15:1).
1H NMR and 13C NMR were agreement with those reported in the literature.24
1H NMR (300 MHz, CDCl3) δ 2.93 (s, 6 H), 6.55 (d, J = 8.8 Hz, 2 H), 7.26ꢀ7.28
(m, 3 H), 7.35 (d, J = 8.8 Hz, 2 H), 7.44ꢀ7.47 (m, 2 H); 13C NMR (75 MHz,
CDCl3): δ 40.2, 72.2, 74.9, 80.9, 83.6, 108.0, 111.8, 122.6, 128.5, 128.9, 132.5,
134.0, 150.7; HRMS (ESI) calcd for C18H16N ([M + H+]) 246.1286, found
246.1295.
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2-Methoxy-6-(p-tolylbuta-1,3-diyn-1-yl)naphthalene (13): Yield: 71%
(63 mg); brown solid; mp 113ꢀ115 ºC (lit.25 92ꢀ95 ºC); Rf = 0.52 (hexane/EtOAc
9:1). 1H NMR and 13C NMR were agreement with those reported in the
literature.25 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3 H), 3.93 (s, 3 H), 7.10ꢀ7.19
(m, 4 H), 7.43 (t, J = 7.3 Hz, 2 H), 7.51 (dd, J = 8.5, 1.5 Hz, 1 H), 7.69 (t, J = 7.3
Hz, 2 H), 7.99 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 21.8, 55.5, 73.2, 73.9, 81.9,
82.2, 106.0, 116.8, 119.0, 119.8, 127.1, 128.5, 129.3, 129.4, 129.6, 132.6,
132.9, 134.7, 139.7, 158.9; HRMS (ESI) calcd for C22H17O ([M + H+]) 297.1274,
found 297.1284.
2-(5-(p-Tolyl)penta-2,4-diyn-1-yl)isoindoline-1,3-dione (14): Yield:
82% (74 mg); brown solid; mp 126ꢀ128 ºC; Rf = 0.28 (hexane/EtOAc 9:1; 1H
NMR (400 MHz, CDCl3) δ 2.34 (s, 3 H), 4.61 (s, 2 H), 7.10 (d, J = 8.4 Hz, 2 H),
7.35 (d, J = 8.4 Hz, 2 H), 7.75 (dd, J = 5.5, 3.0 Hz, 2 H), 7.90 (dd, J = 5.5, 3.0
Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 21.8, 28.1, 68.3, 72.9, 75.8, 78.0, 118.3,
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123.8, 129.3, 132.1, 132.7, 134.4, 139.9, 167.0; HRMS (ESI) calcd for
C20H14NO2 ([M + H+]) 300.1019, found 300.1029.
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8-(4-Fluorophenyl)octa-5,7-diyn-1-ol (15): Yield: 78% (51 mg); white
solid; mp 69ꢀ71 ºC; Rf = 0.22 (hexane/EtOAc 9:1). 1H NMR and 13C NMR were
agreement with those reported in the literature.26 1H NMR (300 MHz, CDCl3)
δ 1.49 (br s, 1 H), 1.65ꢀ1.76 (m, 4 H), 2.41 (t, J = 6.5 Hz, 2 H), 3.69 (t, J = 6.1
Hz, 2 H), 6.99 (t, J = 8.8 Hz, 2 H), 7.45 (dd, J = 8.9, 5.4 Hz, 2 H); 13C NMR (75
MHz, CDCl3) δ 19.5, 24.7, 31.9, 62.4, 65.5, 74.0, 74.2, 84.4, 115.9 (d, J = 22.3
Hz), 118.3 (d, J = 3.5 Hz), 134.6 (d, J = 8.5 Hz), 163.0 (d, J = 250.8 Hz); HRMS
(ESI) calcd for C14H12F ([M + H+]) 199.0918, found 199.0911.
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8-(4-Bromophenyl)octa-5,7-diyn-1-ol (16): Yield: 69% (57 mg); pale
yellow oil; Rf = 0.26 (hexane/EtOAc 4:1); 1H NMR (300 MHz, CDCl3) δ 1.41 (br s,
1 H), 1.62ꢀ1.74 (m, 4 H), 2.41 (t, J = 6.6 Hz, 2 H), 3.69 (t, J = 6.0 Hz, 2 H), 7.32
(d, J = 8.4 Hz, 2 H), 7.44 (t, J = 8.4 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 19.6,
24.7, 31.9, 62.4, 65.5, 73.9, 75.6, 85.1, 121.2, 123.4, 131.8, 134.0. HRMS (ESI)
calcd for C14H12Br ([M + H+]) 277.0223, found 277.0230.
1-(Phenylbuta-1,3-diyn-1-yl)cyclopentanol (17): Yield: 74% (47 mg);
orange solid; mp 88ꢀ90 ºC; Rf = 0.22 (hexane/EtOAc 9:1); 1H NMR (300 MHz,
CDCl3) δ 1.74ꢀ2.07 (m, 8 H), 7.29ꢀ7.33 (m, 3 H), 7.47ꢀ7.50 (m, 2 H); 13C NMR
(75 MHz, CDCl3) δ 23.7, 42.6, 68.1, 73.4, 75.1, 79.0, 86.1, 121.82, 128.6, 129.3,
132.6; HRMS (ESI) calcd for C15H13 ([M + Na+]) 233.0937, found 233.0933.
1-((4-Fluorophenyl)buta-1,3-diyn-1-yl)cyclopentanol (18): Yield: 74%
(51 mg); white solid; mp 90ꢀ92 ºC; Rf = 0.25 (hexane/EtOAc 9:1); 1H NMR (300
MHz, CDCl3) δ 1.71ꢀ2.09 (m, 8 H), 7.04 (t, J = 8.8 Hz, 2 H), 7.51 (dd, J = 8.8,
5.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 23.6, 42.5, 67.5, 73.7, 74.9, 80.6,
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83.4, 116.1 (d, J = 22.3 Hz), 118.0 (d, J = 3.4 Hz), 134.7 (d, J = 8.5 Hz), 163.2
(d, J = 251.6 Hz); HRMS (ESI, negative mode) calcd for C15H12FO ([M – H+])
227.0878, found 227.0882.
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1-(p-Tolylbuta-1,3-diyn-1-yl)cyclohexanol (19): Yield: 68% (49 mg);
white solid; mp 58ꢀ60 ºC; Rf = 0.41 (hexane/EtOAc 5:1). 1H NMR and 13C NMR
were agreement with those reported in the literature.27 1H NMR (300 MHz,
CDCl3) δ 1.26ꢀ1.32 (m, 1 H), 1.56ꢀ1.74 (m, 7 H), 1.91ꢀ1.99 (m, 2 H), 2.07 (br s,
1 H), 2.35 (s, 3 H), 7.12 (d, J = 7.9 Hz, 2 H), 7.38 (d, J = 7.9 Hz, 2 H); 13C NMR
(75 MHz, CDCl3) δ 21.7, 23.3, 25.2, 40.0, 69.2, 69.5, 72.9, 78.9, 85.6, 118.6,
129.3, 132.6, 139.7; HRMS (ESI) calcd for C17H17 ([M + Na+]) 261.1250, found
261.1243.
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1-((4-Bromophenyl)buta-1,3-diyn-1-yl)cyclohexanol (20): Yield: 85%
(77 mg); white solid; mp 97ꢀ99 ºC; Rf = 0.25 (hexane/EtOAc 9:1); 1H NMR (300
MHz, CDCl3) δ 1.25ꢀ2.10 (m, 11 H), 7.33 (d, J = 7.8 Hz, 2 H), 7.45 (d, J = 7.8 Hz,
2 H); 13C NMR (75 MHz, CDCl3) δ 23.3, 25.2, 39.8, 68.9, 69.5, 70.6, 74.7, 87.0,
120.7, 123.8, 131.9, 134.0; HRMS (APCI, negative mode) calcd for C16H14BrO
([M – H+]) 301.0223, found 301.0216.
Tetradeca-5,7-diyn-1-ol (21): Yield: 77% (48 mg); yellow oil; Rf = 0.36
(hexane/EtOAc 3:1). 1H NMR and 13C NMR were agreement with those
reported in the literature.26,28 1H NMR (300 MHz, CDCl3) δ 0.86 (t, J = 6.7 Hz, 3
H), 1.25ꢀ1.68 (m, 12 H), 1.86 (br s, 1 H), 2.20ꢀ2.30 (m, 4 H), 3.64 (t, J = 6.1 Hz,
2 H); 13C NMR (75 MHz, CDCl3) δ 14.4, 19.4, 19.6, 22.9, 25.0, 28.7, 28.9, 31.7,
32.0, 62.7, 65.5, 66.1, 77.3, 78.2; HRMS (APCI) calcd for C14H23O ([M + H+])
207.1743, found 207.1749.
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2-(Deca-1,3-diyn-1-yl)-6-methoxynaphthalene (22): Yield: 88% (77
mg); yellow oil; Rf = 0.56 (hexane/EtOAc 9:1); 1H NMR (300 MHz, CDCl3) δ 0.91
(t, J = 6.9 Hz, 3 H), 1.26ꢀ1.50 (m, 6 H), 1.54ꢀ1.64 (m, 2 H), 3.91 (s, 3 H), 7.09 (d,
J = 2.4 Hz, 1 H), 7.15 (dd, J = 9.2, 2.5 Hz, 1 H), 7.45ꢀ7.48 (m, 1 H), 7.66 (t, J =
8.6 Hz, 2 H), 7.93 (s, 1 H); 13C NMR (75 MHz, CDCl3) δ 14.2, 19.8, 22.7, 28.4,
28.7, 31.5, 55.5, 65.4, 74.2, 75.5, 84.9, 105.9, 116.9, 119.7, 127.0, 128.4, 129.5,
132.7, 134.5, 158.7; HRMS (APCI) calcd for C21H23O ([M + H+]) 291.1743,
found 291.1749.
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1-((Trimethylsilyl)buta-1,3-diyn-1-yl)cyclohexanol (23): Yield: 73% (48
mg); white solid; mp 107ꢀ109 ºC (lit.29 108ꢀ109 ºC); Rf = 0.44 (hexane/EtOAc
9:1); 1H NMR (300 MHz, CDCl3) δ 0.18 (s, 9 H), 1.21ꢀ1.62 (m, 8 H), 1.88ꢀ1.93
(m, 2 H), 2.17 (br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 0.32, 23.2, 25.1, 39.7,
69.3, 81.5, 87.4, 87.5.
Computational methods. Calculations were performed with Gaussian
03 at DFT level.30 The geometries of all complexes here reported were
optimized using the B3LYP hybrid functional.31 Optimizations were carried out
using the standard 6ꢀ31G(d) basis set for C, H, N, O, S, and F, or the dgdzvp
basis set for the case of the model compounds in Table 2. The LANL2DZ basis
set, which includes the relativistic effective core potential (ECP) of Hay and
Wadt and employs a splitꢀvalence (doubleꢀ ) basis set, was used for Cu and
I.32 Harmonic frequencies were calculated at the same level to characterize the
stationary points and to determine the zeroꢀpoint energies (ZPE). The starting
approximate geometries for the transition states (TS) were graphically located.
Intrinsic reaction coordinate (IRC) studies were performed to confirm the
relation of the transition states with the corresponding minima.
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Acknowledgments
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We gratefully acknowledge financial support by the Spanish Ministerio de
Ciencia e Innovación (projects MAT2010ꢀ20646ꢀC04ꢀ03, and CTQ2010ꢀ15927),
and the European Social Fund and Comunidad de Madrid (project S2009/PPQꢀ
1634 “AVANCAT”). We also thank CSIC for a JAEDOC contract to J.R.S.,
Ministerio de Educación, Cultura y Deportes for a FPU fellowship to D. C.ꢀS.,
and the Centro de Computación Científica UAM for computation time.
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Supporting Information
DFT calculation results, stability and safety assay of NfN3, and images of 1H
and 13C NMR spectra of the isolated reaction products. This material is
available free of charge via the Internet at http://pubs.acs.org.
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