Reaction of Alkynes with Iodine Monochloride Revisited

Article abstract of DOI:10.1021/jo035372f

6-Exo-dig and/or 7-endo-dig iodocyclization reactions of functionalized acetylenic derivatives with ICl are disfavored in comparison with the corresponding electrophilic addition reactions providing regioselectively (E)-1-chloro-2-iodoethene derivatives. On the contrary, 6-endo-dig and 5-exo-dig iodocyclizations of methyl ynoates with ICl seem to be favored in comparison with the corresponding electrophilic addition reactions.

Full text of DOI:10.1021/jo035372f

SCHEME 1. Rea ction of Iod in e Mon och lor id e
w ith Eth yl 3-Bu tyn oa te3
Rea ction of Alk yn es w ith Iod in e
Mon och lor id e Revisited
Fabio Bellina,*,† Francesca Colzi,† Luisa Mannina,‡,§
Renzo Rossi,† and Stephane Viel§
Dipartimento di Chimica e Chimica Industriale, University
of Pisa, via Risorgimento 35, I-56126 Pisa, Italy, Facolta` di
Scienze M.F.N., University of Molise, via Mazzini 8,
I-86170 Isernia, Italy, and Istituto di Metodologie Chimiche,
CNR, Area della Ricerca di Roma/ Montelibretti, via Salaria
Km 29.300, I-00016 Monterotondo Stazione, Roma, Italy
obtained in this last reaction even though a 5-endo-dig
ring closure might occur according to Baldwin’s rules15
(Scheme 1).
On the other hand, the reaction of 1 with propiolic acid
gave (E)-1-chloro-2-iodopropenoic acid,2 the regiochem-
istry different from that of the addition of 1 to ethyl
3-butynoate being explainable on the basis of the opposite
polarity of the C-C triple bond of these acetylenic
derivatives. More recently, it was shown that alkyny-
lamine hydrochlorides react with 1 in refluxing THF to
give regioisomeric mixtures of (E)-chloroiodoalkene de-
rivatives in which the major products were those con-
taining the chlorine atom attached to the olefinic carbon
atom more distant from the nitrogen-containing group.8
It was also reported that treatment of R,â-acetylenic
ketones with 1 in CH2Cl2, CH2Cl2/pyridine, or methanol
provides mixtures of (E)- and (Z)-chloroiodoenones as
major products in which the chlorine atom is linked to
the olefinic carbon atom more distant from the carbonyl
group.11 On the contrary, it was found that treatment of
1 with acetylenic derivatives such as acetylenic â-dike-
tones,7 5-substituted (Z)-2-methyl-2-en-4-ynoic acids,10,16
stereodefined methyl 2-en-4-ynoates,9 methyl 2-(aryl-
ethynyl)benzoates,9 and the corresponding carboxylic
acids9,12 in CHCl3 or CH2Cl2 solution provides products
derived from electrophilic ring closure according to Bald-
win’s rules,15 i.e., 3-iodo-4H-pyran-4-ones, 6-substituted
5-iodo-3-methyl-2H-pyran-2-ones, 5-iodo-2H-pyran-2-
ones, and 3-aryl-4-iodoisocoumarins, respectively, instead
of compounds derived from an electrophilic addition
reaction.
bellina@dcci.unipi.it
Received September 18, 2003
Abstr a ct: 6-Exo-dig and/or 7-endo-dig iodocyclization reac-
tions of functionalized acetylenic derivatives with ICl are
disfavored in comparison with the corresponding electro-
philic addition reactions providing regioselectively (E)-1-
chloro-2-iodoethene derivatives. On the contrary, 6-endo-dig
and 5-exo-dig iodocyclizations of methyl ynoates with ICl
seem to be favored in comparison with the corresponding
electrophilic addition reactions.
In the past years, several investigations have been
performed on the reaction of acetylenic compounds with
iodine monochloride 11-13 and the synthetic applications
of the resulting reaction products.7,10,12-14 As regards the
reactions of 1 with alkylethynes,4 phenylethyne,4 internal
acetylenic hydrocarbons,4,6 propiolic acid,2 and ethyl
3-butynoate,3 it was found that the only reaction products
isolated resulted from a regio- and stereoselective elec-
trophilic addition. In particular, the reaction of terminal
acetylenic hydrocarbons with 1 in acetonitrile was found
to provide (E)-2-chloro-1-iodo-1-alkenes having 95-99%
stereoisomeric purity,4 and similarly, ethyl (E)-2-chloro-
1-iodo-3-butenoate proved to be the only product of the
reaction of 1 with ethyl 3-butynoate3 (Scheme 1). Inter-
estingly, no five-membered iodolactonization product was
The variety of outcomes of the reactions involving the
above-mentioned acetylenic compounds prompted us to
investigate the reaction of a CH2Cl2 solution of 1 with
ClCH2CH2Cl solutions either of the alkyl-substituted
acetylenes 2a -d or of the phenyl-substituted acetylenes
3a -g, some of which might undergo electrophilic ring
closure reactions, e.g., 2b, 2c, 3b, and 3c. This study
included also propargyl alcohol 4. In fact, no data were
available in the literature on the regio- and stereochem-
ical outcomes of the reaction of 1 with all these com-
pounds in CH2Cl2 and ClCH2CH2Cl solution.We thought
it right to perform the investigation on the stereochem-
istry of the reactions leading to addition products by
NMR spectroscopy using NOESY experiments. In fact,
the stereochemistry of the products derived from an
electrophilic addition of 1 to alkynes has been established
† University of Pisa.
‡ University of Molise.
§ Istituto di Chimica Nucleare, CNR.
(1) Schmidt, G. H. The Chemistry of the Carbon Carbon Triple Bond;
Patai, S., Ed.; J ohn Wiley: New York, 1978; Part 1, p 330.
(2) Andersson, K. Chem. Scr. 1972, 2, 117.
(3) Tendil, J .; Verney, M.; Vessiere, R. Tetrahedron 1974, 30, 579.
(4) Uemura, S.; Okazaki, H.; Onoe, A.; Okano, M. J . Chem. Soc.,
Perkin Trans. 1 1977, 676.
(5) Moreau, P.; Commeyras, A. J . Chem. Soc., Chem. Commun. 1985,
817.
(6) Al-Hassan, M. I. J . Organomet. Chem. 1989, 372, 183.
(7) Marei, M. G.; Mishrikey, M. M.; El-Sayed El-Kholy, I. J .
Heterocycl. Chem. 1986, 23, 1849.
(8) Lambert, J .; Kabalka, G. W.; Knapp, F. F., J r.; Srivastava, P. C.
J . Org. Chem. 1991, 56, 3707.
(9) Biagetti, M.; Bellina, F.; Carpita, A.; Stabile, P.; Rossi, R.
Tetrahedron 2002, 58, 5023.
(10) Biagetti, M.; Bellina, F.; Carpita, A.; Viel, S.; Mannina, L.; Rossi,
R. Eur. J . Org. Chem. 2002, 1063.
(11) Heasley, V. L.; Buczala, D. M.; Chappell, A. E.; Hill, D. J .;
Whisenand, J . M.; Shellhamer, D. F. J . Org. Chem. 2002, 67, 2183.
(12) Rossi, R.; Carpita, A.; Bellina, F.; Stabile, P.; Mannina, L.
Tetrahedron 2003, 59, 2067.
(13) Yao, T.; Larock, R. C. J . Org. Chem. 2003, 68, 5936.
(14) Luo, F. T.; Lai, J . H.; Shae, J . C. Bull. Inst. Chem., Acad. Sin.
1987, 34, 17.
(15) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
(16) The reaction between 1 and 5-substituted (Z)-2-methyl-2-en-
4-ynoic acids provides a mixture of 6-substituted 5-iodo-3-methyl-2H-
pyran-2-ones and (E)-3-methyl-5-ylidene-5H-furan-2-ones in which
these last compounds are the minor components (see: ref 10).
10.1021/jo035372f CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/22/2003
J . Org. Chem. 2003, 68, 10175-10177
10175

SCHEME 3. Rea ction betw een Iod in e
Mon och lor id e a n d P r op a r gyl Alcoh ol
SCHEME 4. Rea ction betw een Iod in e
Mon och lor id e a n d P h en yl-Su bstitu ted Alk yn es 3
F IGURE 1. Chemical structures of alkynes 2a -d , 3a -g, and
4.
SCHEME 2. Rea ction betw een Alk yn es 2a -d a n d
Iod in e Mon och lor id e
peaks between the protons of the CH3 or CH2 groups
adjacent to the C-Cl bond and the protons of the CH2 or
CH groups adjacent to the C-I bond.22
Similarly, a NOESY experiment allowed us to establish
the E-configuration of 6, which was obtained stereoiso-
merically pure in 46% yield by reaction of 4 with 1
(Scheme 3).23
so far on the basis of a comparison between the 13C
chemical shifts calculated from substituent parameters
for vinyl derivatives17 and the corresponding 13C chemical
shifts observed4 or taking into account the relative
stability of the stereoisomeric addition products obtained
in this addition reaction.11
Our studies began with the reaction of ClCH2CH2Cl
solutions of alkynes 2a -d with 1 equiv of 1 in CH2Cl2
solution at room temperature, and we found that the
addition proceeded until completion in 1.5-23 h to give
the corresponding chloroiodoalkenes 5a -d in 41-75%
isolated yields (Scheme 2).18 Stereoisomerically pure
compounds (E)-5b-d were found to be the only reaction
products, but (E)-5a had ca. 90% stereoisomeric purity
(Scheme 2).18,19
The regiochemical outcome of these addition reactions
was established taking into account the different effects
exerted by chlorine and iodine atoms on the chemical
shift of the carbon to which they were directly bonded.
In fact, a chlorine atom induces a downfield shift of the
carbon resonance due to its high electronegativity, whereas
an iodine atom leads to an upfield shift of the carbon
resonance due to the “heavy atom effect”.20
This regiochemical outcome corresponded to that pre-
dicted by the Markovnikov rule.8,21 On the other hand,
the E-configuration of compounds 5a -d was established
by NOESY experiments that showed the absence of cross-
We next investigated the reaction of 1 with alkynes
3a -e,g and found that the reaction was completed in 1-7
h at room temperature. Stereoisomerically pure com-
pounds (E)-7a -f, which were obtained in 70-93% iso-
lated yields, were found to be the only reaction products
(Scheme 4).18
The regiochemical outcome of these reactions was
established in a way similar to that used for the addition
reactions involving 2a -d . On the other hand, for the
configurational assignment to compounds 7, initially we
used NOESY experiments and, unlike what was observed
for compound 5, we noticed the presence of cross-peaks
between the aromatic protons in the o- and o′-positions
of the phenyl group of these compounds and the protons
of the CH2 or CH groups in the R-position to the C-C
double bond of these substances. However, these cross-
peaks had weak intensity and their presence could be
justified by the E-configuration of compounds 7.
In fact, molecular models24 showed that the distance
between the allylic protons of these compounds and the
aromatic protons in the o- and o′-positions of their phenyl
goup was about 5 Å, i.e., in agreement with that expected
on the basis of the intensity of the observed cross-peaks.25
This configurational assignment was confirmed by
determination of the dipolar moment of compounds (E)-
(17) Stothers, J . B. Carbon-13 NMR Spectroscopy; Academic Press:
New York, 1972; pp 71 and 184.
(22) This assignment supports the formation of a cyclic iodonium
intermediate similar to that previously proposed for the electrophilic
addition of I-X species to dialkyl acetylenes [Bassi, P.; Tonellato, U.
J . Chem. Soc., Perkin Trans. 2 1973, 669].
(23) The regiochemistry of 6, which was assigned on the basis of a
principle similar to that used to establish the structures of 5a -d ,
proved to be in agreement with that of the products of the reaction of
1 either with alkylethynes in acetonitrile (see ref 4) or with ethyl
3-butynoate in CCl4, AcOEt, AcOH, or EtCOOH solution (see ref 3).
(24) We used MOPAC 97 software for Chem3D v. 5 (MNDO method)
by Cambridgesoft.
(18) All new compounds were characterized by elemental analysis,
EI-MS spectrometry, and IR, 1H and 13C NMR spectroscopy. The
structures of compounds (E)-5a -d , (E)-6, and (Z)-7a -e were assigned
on the basis of their 1H and 13C NMR spectra and by a combination of
two-dimensional NMR techniques, which included 1H-1H COSY, 1H-
13C COSY, 1H-13C HSQC (heteronuclear single quantum coherence)
and 1H-13C HMBC (heteronuclear multiple-bond correlation).
(19) GLC analysis showed that (E)-5a was contaminated by less
than 10% of (Z)-5a .
(20) Friebolin, H. Basic One- and Two-Dimensional NMR Spectros-
copy; VCH Publisher: New York, 1991; p 56.
(21) Reference 1, p 278.
(25) Claridge, T. D. W. High-Resolution NMR Techniques in Organic
Chemistry; Pergamon-Elsevier Science Ltd.: Oxford, 1999; p 303.
10176 J . Org. Chem., Vol. 68, No. 26, 2003

TABLE 1. Com p a r ison betw een th e Mea su r ed Va lu es
µ(ga s)exp of th e Dip ola r Mom en t of Com p ou n d s 7d a n d 7f
a n d th e Th eor etic Va lu es µ(ga s)th eor of th e Dip ola r
Mom en ts of Th ese Com p ou n d s Ha vin g E- a n d
Z-Con figu r a tion
SCHEME 7. Iod ola cton iza tion of 3f
dipolar moment (in Debye)
µ(gas)theor
A first conclusion that can be drawn from the above-
reported results is that 6-exo-dig and/or 7-endo-dig elec-
trophilic ring closures do not occur when functionalized
acetylenes, containing a nucleophilic site at the δ position
from their C-C triple bond (e.g., compounds 2b, 2c, 3b,
and 3c), are reacted with 1 in CH2Cl2 and/or ClCH2CH2-
Cl solution. In fact, these ring closures proved to be
disfavored in comparison with the corresponding elec-
trophilic addition reaction. On the contrary, as shown
either from the result illustrated in Scheme 7 or from
those concerning the reaction between 1 and 5-substi-
tuted (Z)-2-methyl-2-en-4-ynoic acids,10 stereodefined
methyl 2-en-4-ynoates,9 and methyl 2-(arylethynyl)ben-
zoates9 or the corresponding carboxylic acids,9,12 6-endo-
dig and 5-exo-dig ring closures seem to be favored in
comparison with the electrophilic addition reaction.
µ(gas)exp
compound
(E)-7
(Z)-7
7d
7f
0.74a
0.96b
0.97
1.08
2.68
2.63
The corresponding value of µ(sol)exp was 0.67. b The correspond-
a
ing value of µ(sol)exp was 0.87.
SCHEME 5. Rea ction betw een 7f a n d Activa ted
Zin c Meta l
SCHEME 6. P ostu la ted In ter m ed ia tes of th e
Rea ction betw een 1 a n d Alk yn es 3
This study also allowed us to establish that the
electrophilic addition of 1 to alkyl- and phenyl-substituted
acetylenes in CH2Cl2 and ClCH2CH2Cl solution provides
regio- and stereoselectively (E)-chloroiodoalkenes con-
taining the iodine atom linked to the olefinic carbon atom
more distant from the alkyl or the phenyl group.
7d and (E)-7f.26,27 In fact, as shown in Table 1, the
measured values of µ(gas)exp for 7d and 7f, which were
higher than about 10% of the corresponding values
obtained at infinite dilution, were found to be similar to
Finally, it is worth mentioning that, whereas the
values of the 13C chemical shifts of the acetylenic carbon
atoms of alkynes 2 and propargyl alcohol 4 could allow
us to predict correctly that the iodine and chlorine
moieties of 1 will add to the more shielded and deshielded
acetylenic carbon atoms of these compounds, respec-
tively,30,31 the values of the 13C chemical shifts of the
acetylenic carbon atoms of alkynes 3 could not be used
for predicting the regioisomeric outcome of the electro-
philic addition of 1 to these alkynes.
24
the theoretic values of µ(gas)theor for the same E-configu-
rated substances in the form of a gas and very different
from the theoretic values for (Z)-7d and (Z)-7f in the form
of a gas.
A further confirmation of the E-configuration of com-
pounds 7 was obtained from the results of the reaction
of 7f with activated zinc metal28 in THF at room tem-
perature. As expected, this reaction did not provide the
organometallic reagent derived from insertion of zinc into
the C-I bond of 7f, but gave via an anti-elimination pro-
cess alkyne 3g as the only reaction product (Scheme 5).29
Thus, the regio- and stereochemical results of the
reaction of 1 with compounds 3 could be rationalized
assuming that this electrophilic addition reaction in-
volves an anti-attack of the chloride anion onto the
iodonium ion 8 (Scheme 6).
Ack n ow led gm en t. This work was supported by the
Ministero dell’Istruzione, dell’Universita` e della Ricerca
(MIUR), and the University of Pisa. We thank Professor
Annalaura Segre for the use of NMR facilities of the
Servizio NMR dell’Area della Ricerca di Roma (CNR)
and Professor Cinzia Chiappe (University of Pisa) for
helpful discussions.
Finally, we completed our investigations by examining
the reaction of 1 with the phenyl-substituted acetylene
3f, and we found that, when this reaction was carried
out under experimental conditions similar to those
employed for the preparation of (Z)-7a -e, no addition
product was obtained. In fact, this reaction provided only
compound 9, which was derived from an electrophilic
iodolactonization reaction (Scheme 7).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data for 2a -d , 3a -f, (E)-5a -d , (E)-
6, (Z)-7a -f, and 9, and lists of the 13C chemical shifts of the
acetylenic carbon atoms of alkynes 2 and 3 and of the olefinic
carbon atoms of (E)-5a -d and (Z)-7a -e (Tables 1-3). This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O035372F
(26) Shoemaker, G. Experiments in Physical Chemistry; McGraw-
Hill: New York, 1967; Chapter XII.
(27) Debou, A.; Masson, S.; Thuiller, A. Bull. Soc. Chim. Fr. 1975,
11-12, 2493.
(30) The chemical shifts of acetylenic carbon atoms have already
been used as an appoximative measure of the zonal charge density
[Meier, H.; Stavidrou, E.; Storek, C. Angew. Chem., Int. Ed. Engl. 1986,
25, 809. Rosenberg, D.; Drenth, W. Tetrahedron 1971, 27, 3893].
(31) Two tables containing either the chemical shift values of the
acetylenic carbon atoms of compounds 2, 3, and 4 or the resulting
chemical shift differences ∆δ are reported in the Supporting Informa-
tion.
(28) Knochel, P.; Rao, C. J . Tetrahedron 1993, 49, 29.
(29) An elimination process leading to alkynes has also been recently
observed when (E)-1,2-dibromoethene derivatives were reacted with
THF solutions of arylmagnesium bromides lacking ortho substituents
in the presence of a catalytic amount of PdCl2(PPh3)2 [Rathore, R.;
Deselnicu, M. I.; Burns, C. L. J . Am. Chem. Soc. 2002, 124, 14832].
J . Org. Chem, Vol. 68, No. 26, 2003 10177