Reactions of Carbonyl-Conjugated Alkynes with N-Bromosuccinimide and N-Iodosuccinimide in DMF/H2O and Methanol/Sulfuric Acid: Syntheses of Dihalo Diketones, Dihalo Ketoesters, and Dihalo Acetals

Article abstract of DOI:10.1021/jo980260n

The following terminal, carbonyl-conjugated alkynes were reacted with N- bromosuccinimide (NBS) and N-iodosuccinimide (NIS) in MeOH/H₂SO₄ to give dibromo and diiodo acetals in the indicated yields: 3-butyn-2-one, 1: NBS (75%), NIS (95%); 1-phenyl-1-propyn-l-one, 2: NBS (90%), NIS (40%); 1-hexyn-3-one, 3: NBS (90%), NIS (70%); methyl propiolate, 4: NBS (20%, not isolated), NIS (95%). 4,4-Dimethyl-l-pentyn-3-one (5) gave only a trace of dibromo acetal and no diiodo acetal; tribromide and tetrabromide were the major products. NBS and NIS reactions required, respectively, 20% and 33 wt % of H₂SO₄. The reaction was unsuccessful with internal alkynes 4-phenyl-3-butyn-2-one and 3-hexyn-2-one which gave only complex mixtures of products. Alkyne 2 gave a significant yield of acetal-ketal in addition to the dihalo acetals. Both the dibromo acetal- ketal and diiodo acetal-ketal were isolated, but only the former could be hydrolyzed to the dibromo acetal. Internal, carbonyl-conjugated alkynes reacted with NBS and NIS in H₂O/DMF (40:60) to give the following products in the indicated yields: 4-phenyl-3-butyn-2-one (6): 1-phenyl-3,3- dibromo-1,3-butanedione (17, 70%), 1-phenyl-3,3-diiodo-1,3-butanedione (21, 95%); 3-hexyn-2-one (7): 3,3-dibromo-2,4-hexanedione (18, 80%), 3,3-diiodo-2,4-hexanedione (22, 95%); methyl 3- phenyl-2-propynoate (8): methyl 2,2-dibromo-3-keto-3-phenylpropanoate (19, 43%), methyl 2,2- diiodo-3-keto-3-phenylpropanoate (23, 95%); methyl 2-pentynoate (9): methyl 2,2-dibromo-3- ketopentanoate (20, 80%), methyl 2,2-diiodo-3-ketopentanoate (24, 95%). All reactions, except for 6 and 8 with NBS, required H₂-SO₄. The terminal, carbonyl-conjugated alkyne, 3-butyn-2-one, did not give products, possibly because of oxidation of the intermediate aldehyde by NBS and NIS. Mechanisms involving electrophilic attack by halogen on the triple bond and an acid-catalyzed mechanism are discussed.

Full text of DOI:10.1021/jo980260n

J . Org. Chem. 1998, 63, 4433-4437
4433
Rea ction s of Ca r bon yl-Con ju ga ted Alk yn es w ith
N-Br om osu ccin im id e a n d N-Iod osu ccin im id e in DMF /H O a n d
2
Meth a n ol/Su lfu r ic Acid : Syn th eses of Dih a lo Dik eton es, Dih a lo
Ketoester s, a n d Dih a lo Aceta ls†
Victor L. Heasley,* Dale F. Shellhamer, Alfred E. Chappell, J ason M. Cox, David J . Hill,
Shanna L. McGovern, and Cyndi C. Eden
Department of Chemistry, Point Loma Nazarene College, San Diego, California 92106
Charles L. Kissel
CNC Development, Inc., Anaheim, California 92804
Received February 12, 1998
The following terminal, carbonyl-conjugated alkynes were reacted with N-bromosuccinimide (NBS)
and N-iodosuccinimide (NIS) in MeOH/H
2 4
SO to give dibromo and diiodo acetals in the indicated
yields: 3-butyn-2-one, 1: NBS (75%), NIS (95%); 1-phenyl-1-propyn-1-one, 2: NBS (90%), NIS (40%);
1
4
-hexyn-3-one, 3: NBS (90%), NIS (70%); methyl propiolate, 4: NBS (20%, not isolated), NIS (95%).
,4-Dimethyl-1-pentyn-3-one (5) gave only a trace of dibromo acetal and no diiodo acetal; tribromide
and tetrabromide were the major products. NBS and NIS reactions required, respectively, 20%
and 33 wt % of H SO . The reaction was unsuccessful with internal alkynes 4-phenyl-3-butyn-2-
2
4
one and 3-hexyn-2-one which gave only complex mixtures of products. Alkyne 2 gave a significant
yield of acetal-ketal in addition to the dihalo acetals. Both the dibromo acetal-ketal and diiodo
acetal-ketal were isolated, but only the former could be hydrolyzed to the dibromo acetal. Internal,
carbonyl-conjugated alkynes reacted with NBS and NIS in H
products in the indicated yields: 4-phenyl-3-butyn-2-one (6): 1-phenyl-3,3-dibromo-1,3-butanedione
17, 70%), 1-phenyl-3,3-diiodo-1,3-butanedione (21, 95%); 3-hexyn-2-one (7): 3,3-dibromo-2,4-
2
O/DMF (40:60) to give the following
(
hexanedione (18, 80%), 3,3-diiodo-2,4-hexanedione (22, 95%); methyl 3-phenyl-2-propynoate (8):
methyl 2,2-dibromo-3-keto-3-phenylpropanoate (19, 43%), methyl 2,2-diiodo-3-keto-3-phenylpro-
panoate (23, 95%); methyl 2-pentynoate (9): methyl 2,2-dibromo-3-ketopentanoate (20, 80%), methyl
2
,2-diiodo-3-ketopentanoate (24, 95%). All reactions, except for 6 and 8 with NBS, required H
2
-
SO . The terminal, carbonyl-conjugated alkyne, 3-butyn-2-one, did not give products, possibly
4
because of oxidation of the intermediate aldehyde by NBS and NIS. Mechanisms involving
electrophilic attack by halogen on the triple bond and an acid-catalyzed mechanism are discussed.
In a continuation of our studies on the reactions of R,â-
unsaturated ketones and esters with halogens and N-
halosuccinimides in nucleophilic solvents,1 we decided
to investigate the reactions of carbonyl-conjugated alkynes
also require acid catalysis. No previous studies on the
less reactive carbonyl-conjugated alkynes with halogen
systems in nucleophilic solvents have been undertaken.
Several years ago, it was shown that three alkynes (not
-3
with NBS and NIS in H
MeOH), catalyzed by H SO
2
O/DMF and in methanol
, as potential syntheses of
2
carbonyl-conjugated) reacted with NBS in H O/DMF to
(
2
4
give dibromo ketones in good yield.4 Dichlorodimethyl
ketals (acetals were not reported) have been prepared by
the reaction of alkynes (not carbonyl-conjugated) with
N-chlorosuccinimide (NCS) in MeOH.5
dihalo diketones/dihalo ketoesters and dihalo acetals,
respectively. Previously, we showed that methoxy bro-
mides could be synthesized from the reaction of R,â-
unsaturated alkenic ketones and esters with NBS in
3
MeOH and H
2
SO
4
.
We suspected that the carbonyl-
Resu lts a n d Discu ssion
conjugated alkynes, because of lower reactivities, would
Reactants, conditions, products, and yields for the
reactions of several terminal carbonyl-conjugated alkynes
†
Presented in part at the Third International Conference on the
with NBS/NIS in MeOH/H
conjugated alkynes with NBS/NIS in H
SO in certain cases, are summarized in Tables 1 and 2,
respectively. All products were characterized with
2
SO
4
and internal carbonyl-
Chemistry and Applications of Bromine and Bromine-Containing
Products (OrgaBrom ‘97) on February 3, 1997, in Baton Rouge, LA
2
O/DMF, and H -
2
(
V.L.H.) and the 1997 Southern California Undergraduate Research
4
Conference in Chemistry and Biochemistry on April 26, 1997, in
Northridge, CA (S.L.M., J .M.C., D.J .H.).
1
H
NMR, 13C NMR, and IR. Furthermore, the structures of
all products were confirmed by one or more of the
following: high-resolution mass spectrometry, reduction
to known compounds with tributyltin hydride and, in the
case of 17, by literature data. Low resolution mass
(
1) Heasley, V. L.; Elliott, S. L.; Erdman, P. E.; Figueroa, D. E.;
Krosley, K. K.; Louie, T. J .; Moore, H. B.; Mudge, B. P.; Nogales, D.
F.; Nordeen, J .; Oakes, M. E.; Rosbrugh, J r., J . W.; Sauerbrey, A. M.;
Shibuya, T. Y.; Stanley, M. S.; Stewart, C. C.; Shellhamer, D. F.;
Heasley, G. E. J . Chem. Soc., Perkin Trans. 2 1991, 393.
(2) Heasley, V. L.; Louie, T. J .; Luttrull, D. K.; Millar, M. D.; Moore,
H. B.; Nogales, D. F.; Sauerbrey, A. M.; Shevel, A. B.; Shibuya, T. Y.;
Stanley, M. S.; Shellhamer, D. F.; Heasley, G. E. J . Org. Chem. 1988,
5
3, 2199.
3) Heasley, V. L.; Wade, K. E.; Aucoin, T. G.; Gipe, D. E.;
Shellhamer, D. F.; Heasley, G. E. J . Org. Chem. 1983, 48, 1377.
(4) Mitsev, I. D.; Panaiotova, B. D.; Iovchev, A. L.; Khristova, N. I.
Dokl. Bolg. Akad. Nauk. 1974, 27, 1403.
(5) Reed, J r., S. F. J . Org. Chem. 1965, 30, 2195.
(
S0022-3263(98)00260-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/02/1998

4
434 J . Org. Chem., Vol. 63, No. 13, 1998
Heasley et al.
Ta ble 1. Syn th eses of Dih a lo Aceta ls
purified by chromatography (hexane/ether, 1-2%). Di-
iodo acetals were isolated crude in high purity but could
not be purified because of decomposition during recrys-
tallization or chromatography over silica. Solutions of
the diiodo acetals rapidly turned purple. The purities of
the dibromo and diiodo acetals were confirmed by their
1
13
H and C NMR spectra; the purities (>90%) of the
dibromo acetals were also confirmed by reverse-phase
HPLC (acetonitrile/H O).
H2SO4 (%)a
NBS NIS
acetal, yield (%)
alkyne
R
NBS
NIS
2
Internal alkynes 4-phenyl-3-butyn-2-one (6) and 3-hex-
yn-2-one (7) were investigated with both NBS and NIS
in MeOH, with varying amounts of acid, but without
success. With NBS, low yields of dibromo ketal, vinyl
dibromoketones, and many other byproducts were ob-
served by GC and GC-MS. NIS yielded no identifiable
products. 1-Hexyne, a non-carbonyl-conjugated alkyne,
1
2
3
4
Me
Ph
Pr
20
20
20
b
33
33
33
33
10 (75)
11 (90)
12 (90)
b
13 (95)
14 (40)
15 (70)
16 (95)
OMe
a
H2SO4 is percent by weight of DMF, H2O, and H2SO4. b Yield
was low (20%); product was not isolated.
Ta ble 2. Syn th eses of Dih a lo Dik eton es a n d Dih a lo
Ketoester s
2 4
reacted with NBS in MeOH/H SO to give the ketal, 1,1-
dibromo-2-hexanone, and vinyl dibromide, suggesting
that the carbonyl group is required for terminal acetal
formation.
2 4
Alkyne (2) reacted with NBS in MeOH/H SO to form
an acetal-ketal (25) in addition to dibromo acetal (11).
Acetal-ketal 25 was isolated and hydrolyzed to 11:
H
2
SO
4
dihalo diketone/
dihalo ketoester, yield (%)
a
(%)
alkyne
R
1
, R
2
NBS NIS
NBS
NIS
6
7
8
9
R
R
R
R
1
1
1
1
) Ph, R
2
) Me
0
8
0
12
12
20
20
17 (70)
18 (80)
19 (43)
20 (80)
21 (95)
22 (95)
23 (95)
24 (95)
) Et; R
) Ph, R
2
) Me
2
) OMe
) OMe
) Et, R
2
15
a
H2SO4 is percent by weight of DMF, H2O, and H2SO4.
2 4
NIS and 2 in MeOH/H SO also gave both diiodo acetal
spectra were obtained for many of the compounds.
Elemental analyses were not attempted on any of the
products because of their instabilities. Only one of the
products (17) from either synthetic procedure has been
reported previously. Yields were determined by NMR
14 and diiodo acetal-ketal 26, but 26 could not be
hydrolyzed to 14. Alkynes 1 and 3 and NBS also formed
small amounts of acetal-ketals which were identified by
their mass spectra.
The data in Table 2 show that internal alkynes
4-phenyl-3-butyn-2-one (6), 3-hexyn-2-one (7), methyl
3-phenyl-2-propynoate (8), and methyl 2-pentynoate (9)
gave dihalo ketones and dihalo ketoesters in good yield.
Vinyl dihaloketones and dihaloketoesters were formed
as minor byproducts and were identified by GC/MS but
not isolated. Dibromo diketones and ketoesters were
purified by chromatography (hexane/ether, 1-2%). The
diiodo ketones were isolated in high purity at the end of
the workup but, with the exceptions of 21 and 23, which
were recrystallized from hexane, could not be purified
further because of decomposition during distillation,
recrystallization, or chromatography, as indicated by the
extensive formation of iodine. The purities of the dihalo
diketones and dihalo ketoesters were confirmed by their
using internal standards. CH
9, 21, 22, 23, 24; C : 13, 15, 16, 18, 20. Preliminary
examination showed that NCS with terminal alkynes in
MeOH/H SO failed to give products. NCS reacted with
, an internal alkyne, in H O/DMF to give a product
2 2
Cl : 10, 11, 12, 14, 17,
1
6 6
H
2
4
6
2
suspected of being 1-phenyl-3,3-dichloro-1,2-butanedione,
but the reaction failed with 7.
As shown in Table 1, terminal alkynes 3-butyn-2-one
(1), 1-phenyl-2-propyn-1-one (2), and 1-hexyn-3-one (3)
gave acceptable yields of dibromo and diiodo acetals. The
regiochemistry of our products (acetals) is the opposite
of the products (ketals) in the earlier study with NCS
and terminal alkynes.5 High concentrations of sulfuric
acid were definitely required. In the presence of lower
1
13
amounts of acid (10-15% H
2
SO
4
), vinyl dihaloketones
H and C NMR spectra. All of the internal alkynes
were the major products with both NBS and NIS.
Apparently, with less acid, decomposition occurs to give
Br and I which add to the alkyne. Methyl propiolate
2 2
reacted slowly with NIS without acid catalysis, but
significant byproducts were formed in the absence of acid,
and the reactions did not go to completion. With acid in
high concentration, NIS and the alkynes reacted rapidly,
leading to very pure products (ca. 95%). NBS is appar-
ently less reactive than NIS since acid is required for a
reaction to occur with NBS and alkynes 7 and 9.
Reaction of terminal alkyne 3-butyn-2-one (1) with either
(
4) produced the dibromo acetal in low yield (∼20% by
GC) which was confirmed by GC-MS but could not be
isolated. Only a trace of dibromo acetal could be detected
in the reaction of 4,4-dimethyl-1-pentyn-3-one (5) with
NBS. The major products were tribromide and tetra-
bromide. We have no explanation for the fact that 5
failed to react like the other alkynes. NIS and 5 in
2
NBS or NIS in DMF/H O did not lead to products. We
suspect that a dihalo aldehyde may have formed initially
and then was oxidized further, perhaps to a carboxylic
acid. To test this hypothesis, we determined that an
aldehyde, pentanal, disappeared rapidly, probably by
oxidation with NBS.
2 4
MeOH/H SO gave a complex mixture which was not
resolved. Vinyl dihaloketones always accompanied the
dihalo acetals as minor byproducts. They were identified
by GC/MS but were not isolated. Dibromo acetals were

Reactions of Carbonyl-Conjugated Alkynes with NBS and NIS
J . Org. Chem., Vol. 63, No. 13, 1998 4435
Because of the requirement for strong acid, we specu-
late that an acid-catalyzed mechanism, as reported
previously1 for alkenes, is involved in the reaction of
the terminal alkynes with NBS and NIS. The following
reactions illustrate this mechanism using 3-butyn-2-one
localized on the â-carbon because of stabilization by the
phenyl ring or ethyl group. Positive charge would not
be anticipated on the R-carbon because of proximity to
the carbonyl group. On the other hand, in those reactions
involving acid, formation of only one regioisomer may be
a consequence of the acid-catalyzed mechanism described
above with the terminal alkynes.
-3
(1) and NBS:
Exp er im en ta l Section
Ma ter ia ls. 3-Butyn-2-one (1), methyl propiolate (4), and
4
2
3
3
-phenyl-3-butyn-2-one (6) were obtained from Aldrich; 3-hexyn-
-one (7) was purchased from Farchan Laboratories. Methyl
-phenyl-2-propynoate (8) was prepared by refluxing overnight
-phenylpropiolic acid (Aldrich, 1 g, 6.8 mmol) in 10 mL of
MeOH containing 0.5 mL of BF
of the MeOH with H O, saturation with salt, and extraction
with ether. The ether was washed with 5% NaHCO , dried,
and removed under vacuum. Distillation gave 8 whose boiling
point (70 °C at 1.5 Torr) compared favorably with that reported
in the literature.7 Methyl 2-pentynoate (9) was prepared from
2-pentynoic acid (Farchan Laboratories) as described for 8. Its
boiling point (83 °C at 0.1 Torr) also compared favorably with
the literature value.8 1-Phenyl-2-propyn-1-one (2), 1-hexyn-
3
etherate, followed by dilution
2
Apparently, NIS is sufficiently reactive to deliver “I+”
to the π-bond of the internal alkynes, as shown below
with 6, leading to an intermediate enol which reacts
3
rapidly with a second NIS, producing the diiodo dike-
tones:6
3
-one (3), and 4,4-dimethyl-1-pentyn-3-one (5) were obtained,
as described below, by oxidation of their respective alcohols:
-phenyl-2-propyn-1-ol (Aldrich), 1-hexyn-3-ol (Pfaltz and
1
Bauer), and 4,4-dimethyl-1-pentyn-3-ol, prepared as described
previously.9 General oxidation procedure: 15.0 g (50.0 mmol)
of sodium dichromate and 9.6 mL of concentrated H
2 4
SO were
dissolved in 15 mL of H O. A 5.0 mL volume of each alcohol
2
was added to 15 mL of glyme in a 50 mL flask with a condenser
and heated to reflux. The dichromate solution was added to
the alcohol/glyme mixture at the rate of 1 mL/min. After 2 h
of reflux, water was added, and the product was extracted with
CH
2 2 3 4
Cl , washed with 5% NaHCO , and dried over MgSO .
After removal of solvent under vacuum, 2 and 3 were distilled
Acid may increase the rate of the reaction by proto-
nating the oxygen in NIS, leading to a more reactive
iodinating agent:
10
(
2
bps: 60-70 °C/70 mm). Ketone 3 was confirmed by its bp;
10
crystallized in the condenser and was confirmed by its mp.
The solvent from the isolation of 5 was removed by fractional
distillation at atmospheric pressure. Ketone 5 was distilled
9
at 120 °C which compared favorably with the literature.
Further purification of 5, to remove glyme, was accomplished
by preparative GC: 2.6 m × 1 cm glass column packed with
DC550 on Chromosorb W at 75 °C and a He flowrate of 100
mL/min. Ketones 2, 3, and 5 were synthesized in high yield
(
>90%) and in 90-95% purity as determined by GC.
x
NBS is also able to deliver “Br ” to alkynes 6 and 8,
Chromatographic separations were performed with Prep Sep
probably because of the stabilities of the phenyl-substi-
tuted cation intermediates; a mechanism like that de-
scribed for 6 and NIS is likely involved. Protonated NBS,
as discussed with NIS, probably accounts for the increase
in reactivity of NBS with acid. Conceivably, the increase
in the rates of reaction of NIS and NBS in the presence
of acid occurs via the acid-catalyzed mechanism described
above for terminal alkynes.
Extraction Columns obtained from Fisher Scientific.
An a lysis Con d ition s. 300 MHz 1H NMR, 60 MHz 1H
NMR, and 75.4 MHz 13C NMR spectra are reported relative
to Me
4 3
Si in CDCl . Mass spectral analyses were obtained at
7
0 eV and are expressed as m/ z and as relative intensity (%).
Errors in exact masses do not exceed 3 ppm. GC and GC-MS
analyses were done with a 25 m column of internal diameter
0
.20 mm with a methyl silicone stationary phase of 0.33 µm
film thickness.
The fact that only one of the two possible isomers is
formed with the internal alkynes may be explained by
assuming that the charge in the intermediate cation is
Red u ction s w ith Tr ibu tyltin Hyd r id e. Reduction of the
dihalo acetals with tributyltin hydride was accomplished as
follows: the solvent was removed from a reaction mixture and
6
the product was dissolved in 400 µL of d -benzene in an NMR
tube. The tube was placed in ice and 400 µL (1.5 mmol) of
tributyltin hydride was added. After 1 h at room temperature,
the solution was analyzed by NMR and/or GC-MS. When the
latter procedure was used, the solution from the NMR tube
was washed through a chromatography column before analysis
by GC-MS.
(
6) A reviewer has pointed out that our data are consistent with an
enamide intermediate (see structure), perhaps accounting for the
regiochemistry and the difference in reactivity between NBS and NIS.
An enamide intermediate is also compatible with the acid-catalyzed
mechanism. We have no evidence to support the formation of this
intermediate.
Rea ction Con d ition s for Ter m in a l Alk yn es. Ketones
1
, 2, and 3 with NBS: the appropriate amount of concentrated
(
(
8) Priebe, H. Acta Scan. Ser. B 1987, 41, 640.
9) Barrelle, M.; Gilenat, R. Bull. Soc. Chem. 1967, 453.
(
7) Moriarity, R. M.; Vaid, R. K.; Farid, P. J . Chem. Soc., Chem.
(10) Bowden, K.; Heilbron, I. M.; J ones, E. R. H.; Weedon, B. C. L.
J . Chem. Soc. 1946, 39.
Commun. 1987, 711.

4
436 J . Org. Chem., Vol. 63, No. 13, 1998
SO (Table 1) was added with stirring to 1 mL of MeOH in
Heasley et al.
H
2
4
133.2, 133.3, 188.9. MS m/z (EI): 218, 216, 214 (CBr
105 (C CO, 100), 77 (C ), 75 (CH(OCH ). IR (cm ):
OCH , 2850; CO, 1700. GC analysis conditions: programmed
2
CHO),
-
1
an ice bath. The ice bath was removed as soon as the solution
reached room temperature. To this solution were added 1
mmol of alkyne and 4 mmols of NBS. After 1.5 h, 3 mL of
CCl
filtrate was washed with H
CCl layer was separated, dried, and removed under vacuum.
The crude product was added to 1 mL of THF and 1 mL of 9
M H SO and stirred for 2 h to hydrolyze ketal-acetal to acetal
and to remove a byproduct from the reaction of succinimide
and acid (probably MeO C(CH CONH , based on GC-MS)
which interfered with chromatography. (Ketal-acetals are
minor products except with 2 where the product composition
is 11, 21%, and 25, 79%). The hydrolysis product was
extracted with 3 mL of CCl
NaHCO , and dried over MgSO
6
H
5
6
H
5
3 2
)
3
from 75 to 220 °C at 20 °C/min; retention time (min), 11.7.
2,2-Dibr om o-1,1,3,3-tetr am eth oxy-1-ph en ylpr opan e (25).
Acetal-ketal 25 was isolated from the reaction of alkyne 2 with
4
was added, and NBS and succinimide were filtered. The
2
O and saturated NaHCO , and the
3
4
NBS/MeOH/H
2
SO
phy. H NMR (60 MHz): δ 3.32 (s, 1H), 3.41 (s, 6H), 3.54 (s,
6H), 7.28-7.59 (m, 5H). GC/MS m/z (EI): 151 (C C(OCH
). IR (cm ): OCH , 2846.
4
prior to hydrolysis to 11 by chromatogra-
1
2
4
6
H
5
3 2
) ,
-
1
100), 105 (C
6
H
5
CO), 75 (CH(OCH
3
)
2
3
2
2
)
2
2
GC analysis conditions: programmed from 75 to 220 °C at 20
°C/min; retention time (min), 14.3.
2,2-Dibr om o-1,1-dim eth oxyh exan -3-on e (12). The struc-
ture of 12 was confirmed by its high-resolution mass spec-
+
4
, washed with a saturated
After solvent removal,
trum: HRMS (CI): MNH
4
, calcd for C
8
H
14
O
3
Br
2
NH
4
, 333.9664;
1
3
4
.
found, 333.9653. H NMR (300 MHz): δ 0.96 (t, 3H, J ) 7.2
dibromo acetals 10-12 were purified by chromatography with
hexane/ether (1-2%).
Hz), 1.69 (sextet, 2H, J ) 7.2 Hz), 3.00 (t, 2H, J ) 7.2 Hz),
1
3
3.65 (s, 6H), 4.69 (s, 1H). C NMR: 13.3, 17.9, 39.3, 59.0,
Ketones 1, 3, and 4 with NIS: to 2 mmol of NIS in 0.5 mL
69.0, 106.6, 197.8. GC/MS m/z (EI): 289, 287, 285 (M -
of MeOH was added 0.5 mmol of alkyne. The appropriate
OCH
3
), 218, 216, 214 (CHBr
CHO), 75 (CH(OCH
2
COCH
3 2
), 203, 201, 199 (CBr -
-
1
amount of concentrated H
stirred solution. After 1 h, the reaction product was extracted
with 1.5 mL of CCl , washed with saturated NaHCO , and
dried over MgSO . The diiodo acetals 13-16 were not purified
further because of decomposition. Ketone 2 with NIS: syn-
thesis of 14 required a special approach since the reaction of
2
SO
4
(Table 1) was dropped into this
3
)
2
, 100), 43 (CH CO). IR (cm ): OCH ,
3
3
2844; CO, 1728. GC analysis conditions: programmed from
55 to 220 °C at 20 °C/min; retention time (min), 8.7.
4
3
Rea ction of Meth yl P r op iola te (4) w ith NBS/CH
SO
Only a low yield (∼20% by GC) of dibromo acetal
(methyl 2,2-dibromo-3,3-dimethoxypropanoate) was obtained
in the reaction of 4 with NBS/CH OH/H SO . The product
3
OH/
4
H
2
4
.
2
with NIS/MeOH/H
2
SO
4
as described for 1, 3, and 4 led to a
3
2
4
mixture of 14 and the diiodo acetal-ketal 26 (67% 14, 33% 26)
which could not be hydrolyzed to 14. Furthermore, 14 could
not be separated cleanly from 26 by chromatography. Syn-
thesis of 14: to a stirred solution of 0.35 mL of MeOH and
could not be isolated from the complex mixture by preparative
GC or chromatography, but its structure was confirmed by GC-
MS m/z (EI): 277, 275, 273 (M - OCH
OCH - CO CH ), 75 ((CH O) CH, 100), 59 (CO
Rea ction of 4,4-Dim eth yl-1-p en tyn -3-on e (5). Com-
pound 5 and NBS/CH OH/H SO under all reaction conditions
gave only a trace of desired acetal, 1,1-dimethoxy-2,2-dibromo-
,4-dimethylpentan-3-one, which was identified by its mass
spectrum, GC-MS m/z (EI): 218, 216, 214 (CBr CHOCH ), 85
(CH CCO), 75 (CH(OCH , 100), 57 ((CH C). The major
3
); 218, 216, 214 (m -
3
2
3
3
2
2
CH ).
3
0
.15 mL of H
2
O was added 450 mg of NIS and 65 mg of 2 and
SO . After 5 h, the reaction was
the appropriate amount of H
worked up as described above to give 14 in high purity.
2
4
3
2
4
4
Gen er a l R ea ct ion Con d it ion s for In t er n a l Alk yn es
2
3
6
-9. All reactions were done by placing the appropriate
amounts of alkyne and N-halosuccinimide in 0.6 mL of DMF/
.4 mL of H O/acid (concentrated H SO ), if needed, in a small
flask equipped with a magnetic stirrer. After appropriate
reaction times, 2 mL of CCl were added to the reaction
(
3
)
3
3
)
2
3 3
)
products were the vinyl dibromo ketone, the tribromide (1,2,2-
tribromo-4,4-dimethylpentan-3-one), and the tetrabromide
1,1,2,2,-tetrabromo-4,4-dimethylpentan-3-one); the structures
of the tribromide and tetrabromide were confirmed by GC-
3 2 4
MS, H NMR, and C NMR. NIS with 5 in CH OH/H SO
did not give the diiodo acetal but yielded a complex mixture
whose components were not confirmed.
,3-Diod o-4,4-d im eth oxybu ta n -2-on e (13). The struc-
ture of 13 was confirmed (GC-MS and H NMR) by reduction
0
2
2
4
(
4
mixtures. With NBS, the mixture was filtered. (Filtration was
unnecessary with NIS). The organic layer was removed and
washed with 5% NaHCO and dried over MgSO .
3 4
Specific conditions that gave the best yields with NBS: 6
and 8: 1 mmol of NBS, 0.334 mmol of alkyne, and react for 2
h. Then add a second mmol of NBS and react for another 2 h.
1
13
3
1
with tributyltin hydride to the known 4,4-dimethoxybutan-2-
7
and 9: 1 mmol of NBS, 0.25 mmol of alkyne, appropriate
1
one (Aldrich). H NMR (300 MHz): δ 2.63 (s, 3H), 3.65 (s,
percent of H SO (Table 2) by weight in DMF/H O, and react
for 1 h. Specific conditions that gave the best yields with
NIS: 1.55 mmol of NIS, 0.5 mmol alkyne, appropriate percent
2
4
2
1
3
6
H), 4.67 (s, 1H). C NMR: δ 18.9, 25.5, 58.8, 107.5, 196.8.
+
GC-MS m/z (EI): 384 (M ), 353 (M - OCH
CHOCH ), 75 (CH(OCH , 100), 43 (CH CO). IR (cm ):
OCH , 2842; CO, 1714. GC analysis conditions: programmed
from 55 to 220 °C at 10 °C/min; retention time (min), 14.3.
,2-Diiod o-3,3-d im eth oxy-1-p h en ylp r op a n -1-on e (14).
3 2
), 310 (CI -
-
1
3
3
)
2
3
2 4 2
of H SO (Table 2) by weight in DMF/H O, and react for 1 h.
3
P r oof for th e Str u ctu r es of th e P r od u cts fr om th e
Ter m in a l Alk yn es. 3,3-Dibr om o-4,4-d im eth oxybu ta n -2-
on e (10). The structure of 10 was confirmed (GC-MS) by
reduction with tributyltin hydride to the known 4,4-dimethoxy-
butan-2-one (Aldrich) and by its high-resolution mass spec-
trum: HRMS (CI): MNH
2
1
The structure of 14 was confirmed (GC-MS and H NMR) by
1
0
reduction with tributyltin hydride to the known 3,3-dimethoxy-
1
(
1
1
-phenyl-1-propane. 1H NMR (300 MHz): δ 3.69 (s, 6H), 4.07
13
+
4
, calcd for C
6
H
10
O
3
Br
2
NH
4
, 305.9340;
s, 1H), 7.41-8.30 (m, 5H).
C NMR: δ 18.2, 59.0, 107.8,
1
1
found, 305.9348. H NMR (300 MHz): δ 2.63 (s, 3H), 3.66 (s,
-
28.4, 131.1, 132.7, 134.3, 182.7. IR (cm ): OCH
740.
3
, 2842; CO,
1
3
6
H), 4.68 (s, 1H). C NMR: δ 25.4, 59.0, 68.6, 106.6, 195.4.
MS m/z (EI): 261, 259, 257 (m-OCH ), 218, 216, 214 (CH
COCHBr ), 203 201, 199 (CBr CHO), 75 (CH(OCH , 100), 43
CH CO). IR (cm ): OCH , 2844; CO, 1731. GC analysis
3
3
-
2
,2-Diiod o-1,1,3,3-tetr a m eth oxy-1-p h en ylp r op a n e (26).
Acetal-ketal 26 was separated from 14 by chromatography.
2
2
3 2
)
-
1
(
3
3
1
H NMR (300 MHz): δ 3.44 (s, 6H), 3.84 (s, 6H), 3.70 (s, 1H),
conditions: programmed from 55 to 220 °C at 10 °C/min;
retention time (min), 11.2.
7
1
.26-8.14 (m, 5H). 13C NMR: δ 28.9, 51.2, 57.3, 104.2, 106.8,
1
-
27.9, 130.3, 132.5, 136.6. IR (cm ): 2842 (OCH
,2-Diiod o-1,1-d im eth oxyh exa n -3-on e (15). The struc-
ture of 15 was confirmed by its high-resolution mass spec-
3
).
2
,2-Dibr om o-3,3-dim eth oxy-1-ph en ylpr opan -1-on e (11).
2
The structure of 11 was confirmed (GC-MS) by reduction with
tributyltin hydride to the known 3,3-dimethoxy-1-phenyl-
propan-1-one and by its high-resolution mass spectrum: HRMS
1
1
+
trum: HRMS (CI): MNH , calcd for C H O I NH , 429.9388;
4 8 14 3 2 4
1
found 429.9376. H NMR (300 MHz): δ 0.99 (t, 3H, J ) 7.2
+
(CI): MNH
4
, calcd for C11
H
2
O
3
Br
2
NH
4
, 367.9497; found,
Hz), 1.70 (sextet, 2H, J ) 7.2), 3.22 (t, 2H, J ) 7.2), 3.67 (s,
1
3
7
67.9484. H NMR (300 MHz): δ 3.72 (s, 6H), 4.86 (s, 1H),
13
6
1
H), 3.95 (s, 1H).
C NMR: δ 13.3, 18.9, 19.1, 39.5, 58.9,
1
3
.51-8.14 (m, 5H). C NMR: δ 59.2, 65.3, 106.8, 127.9, 130.5,
07.5, 199.0. GC-MS m/z (EI): 412, 381 (m - OCH
), 75 (CH(OCH , 100), 43 (CH
CO). IR (cm 1):
, 2842; CO, 1712. Purity (70%) was determined using
benzene as an internal standard and integrating the methine
3 2
), 310 (CI -
-
CHOCH
OCH
3
3
)
2
3
(11) DeKempe, N.; Verhe, R.; DeBuyck, L.; Tukiman, S.; Schamp,
3
N. Tetrahedron 1979, 35, 789.

Reactions of Carbonyl-Conjugated Alkynes with NBS and NIS
J . Org. Chem., Vol. 63, No. 13, 1998 4437
1
hydrogen. The impurities (30%) were suggested by H NMR
1-P h en yl-3,3-d iiod o-1,3-bu ta n ed ion e (21). The structure
of 21 was confirmed ( H NMR) by reduction with tributyltin
1
(integration of CH
3
O groups) and could not be removed. GC
analysis conditions: programmed for 45-200 °C at 10 °C/min;
retention time (min), 16.3.
hydride to known 1-phenyl-1,3-butanedione (Aldrich) and by
its high-resolution mass spectrum: HRMS (CI): MH , calcd
+
for C10
8 2 2
H I O H, 414.8692; found, 414.8688. Comparison of the
Meth yl 2,2-Diiod o-3,3-d im eth oxyp r op a n oa te (16). The
structure of 16 was confirmed (GC-MS and H NMR) by
1
1
compounds was made by NMR and GC-MS. H NMR (60
MHz): δ 2.60 (s, 3H), 7.40-8.03 (m, 5H). C NMR: δ 22.3,
1
3
reduction with tributyltin hydride to the known methyl 3,3-
-
1
1
24.6, 128.7, 130.3, 130.9, 134.0, 186.5, 193.5. IR (cm ): CO,
1700. Diiodide 9 is a solid and was recrystallized from
hexane: mp 56-57 °C.
dimethoxypropanoate (Aldrich). H NMR (300 MHz): δ 3.69
1
3
(
1
3
(
1
1
s, 6H), 3.86 (s, 3H), 3.93 (s, 1H). C NMR: δ 0.4, 54.9, 59.5,
+
08.5, 167.7. GC-MS m/z (EI): 400 (M ), 369 (M - OCH
3
),
), 75
, 2842; CO,
3
,3-Diiod o-2,4-h exa n ed ion e (22). The structure of 22 was
41 (M - CH
3
CO
2
), 294 (CI
2
CHO), 242 (M - I, -OCH
3
1
-
1
confirmed ( H NMR and GC-MS) by reduction with tributyltin
hydride to the known 2,4-hexanedione.13 H NMR (300
MHz): δ 1.23 (t, 3H, J ) 7.2 Hz), 2.81 (s, 3H), 3.17 (q, 2H, J
CH(OCH
3
)) , 100), 59 (CH
2
3
CO
2
). IR (cm ): OCH
3
1
739. GC analysis conditions: programmed for 45-200 °C at
0 °C/min; retention time (min), 16.3.
P r oof for th e Str u ctu r es of th e P r od u cts fr om th e
1
3
)
7.2 Hz). C NMR: δ 10.6, 22.7, 23.3, 29.6, 195.1, 198.5.
+
GC-MS m/ z (EI): 366 (m ), 323 (C
2 5 2 3
H COCI ), 309, (CH -
In ter n a l Alk yn es. 1-P h en yl-3,3-d ibr om o-1,3-bu ta n ed ion e
-
1
1
2
COCI ), 57 (C CO), 43 (CH CO, 100). IR (cm ): CO, 1713.
2
2
H
5
3
(
17). This compound was reported previously, and its
GC analysis conditions: programmed from 60 to 200 °C at 10°/
min; retention time (min), 15.3.
Meth yl 2,2-Diiodo-3-keto-3-ph en ylpr opan oate (23). The
structure of 23 was confirmed by its high-resolution mass
spectrum: HRMS (CI): MNH
structure was established by comparison to the reported NMR
1
spectrum. H NMR (300 MHz): δ 2.51 (s, 3H), 7.35-8.15 (m,
1
3
5
1
°
H). C NMR: δ 24.7, 68.7, 128.6, 130.7, 130.8, 134.2, 185.2,
91.5. GC analysis conditions: programmed from 75 to 200
+
4
, calcd for C10
H
8
O
3
I
2
NH
4
,
C at 20 °C/min; retention time (min), 10.0.
1
4
3
1
47.8910; found, 447.8907. H NMR (300 MHz): δ 3.77 (s,
3
,3-Dibr om o-2,4-h exa n ed ion e (18). The structure of 18
13
H), 7.40-8.02 (m, 5H). C NMR: δ 2.15, 55.3, 128.1, 128.6,
1
was confirmed ( H NMR and GC-MS) by reduction with
-
1
3
30.4, 133.6, 167.3, 184.6. IR (cm ): CH O, 2842; CO, 1747
tributyltin hydride to the known 2,4-hexanedione.13 H NMR
1
and 1684. Diiodide 11 is a solid and was recrystallized from
hexane: mp 74-76 °C.
Meth yl 2,2-Diiod o-3-k etop en ta n oa te (24). The structure
of 24 was confirmed ( H NMR) by reduction with tributyltin
hydride to the known methyl 3-ketopropanoate (Aldrich) and
(
300 MHz): δ 1.24 (t, 3H, J ) 7.36), 2.62 (s, 3H), 3.00 (q, 2H,
13
J ) 7.36). C NMR: 9.24, 24.5, 30.5, 68.1, 193.2, 196.9. GC-
MS m/ z (EI) 232, 230, 228 (C Br O), 57 (C CO, 100), 43
CO). IR (cm ): CO, 1730. GC analysis conditions:
programmed from 60 to 200 °C at 6 °C/min; retention time
4
H
6
2
2 5
H
1
-
1
(
CH
3
+
by its high-resolution mass spectrum: HRMS (CI): MNH
calcd for C10
4
,
(
min), 13.1.
1
8 3 2 4
H O I NH , 447.8910; found, 447.8907. H NMR
Meth yl 2,2-Dibr om o-3-k eto-3-p h en ylp r op a n oa te (19).
The structure of 19 was confirmed by its high-resolution mass
(
300 MHz): δ 1.25 (t, 3H, J ) 7.2 Hz), 3.07 (q, 2H, J ) 7.2
13
Hz), 3.98 (s, 3H). C NMR: δ 3.70, 10.6, 27.6, 55.2, 166.5,
1
+
spectrum: HRMS (CI): MNH
4
, calcd for C10
H
8
Br
2
O
3
NH
4
,
+
95.9. GC-MS m/z (EI): 382 (M ), 326 (CH
3
OCOCHI
2
), 294
O,
1
3
3
1
51.9184; found, 351.9173. H NMR (300 MHz): δ 3.84 (s,
-1
(COCI ), 59 (CH CO), 57 (C CO, 100). IR (cm ): CH
2
3
2
H
5
3
1
3
H), 7.46-8.02 (m, 5H). C NMR: δ 55.1, 58.7, 128.6, 130.2,
30.4, 134.0, 165.1, 182.9. GC-MS m/ z (EI): 258, 256 (M -
2
4
842; CO, 1739. GC analysis conditions: programmed from
5 to 200 °C at 10 °C/min; retention time (min), 15.1.
Br), 202, 200, 198 (COCBr
2
), 105 (C
6 5 6 5
H CO, 100), 77 (C H ).
-
1
IR (cm ): CH
3
O, 2847; CO, 1776 and 1722. GC analysis
Ack n ow led gm en t. With pleasure we recognize sup-
conditions: programmed from 75 to 200 °C at 20 °C/min;
retention time (min), 12.2.
port from the following sources: Petroleum Research
Fund (V.L.H.), administered by the American Chemical
Society, 29546-B1; NSF-RUI (V.L.H.), CHE-9528446;
NSF-RUI (D.F.S.), CHE-9321094 and CHE-9616442;
Howard Hughes Medical Institute Award, 71196-
Meth yl 2,2-Dibr om o-3-k etop en ta n oa te (20). The struc-
1
ture of 20 was confirmed ( H NMR) by reduction with tribu-
tyltin hydride to the known methyl 3-ketopropanoate (Aldrich).
1
Comparison of the compounds was made with H NMR and
5
52001; the Wesleyan Center for 21st Century Study;
1
GC-MS. H NMR (300 MHz): δ 1.22 (t, 3H, J ) 7.3 Hz), 2.96
1
3
Research Associates of Point Loma Nazarene College;
and Dr. Mary K. Young, Mass Spectrometry Facility,
University of California, Riverside.
(
5
q, 2H, J ) 7.3 Hz), 3.92 (s, 3H). C NMR: 9.36, 29.5, 55.1,
9.0, 164.4, 194.7. GC-MS m/ z (EI): 234, 232, 230 (C
3 4
H -
Br ), 59 (CH OCO), 57 (C CO, 100). GC analysis condi-
2
O
2
3
2 5
H
tions: programmed from 45 to 200 °C at 10 °C/min; retention
time (min), 12.2.
Su p p or tin g In for m a tion Ava ila ble: NMR spectra of new
compounds (33 pages). This material is contained in libraries
on microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
(
12) Yoshida, J .; Yano, S.; Ozawa, T.; Kawabata, N. J . Org. Chem.
985, 50, 3470.
13) Hampton, K. R.; Harris, T. M.; Hauser, C. R. J . Org. Chem.
965, 30, 61.
1
1
(
J O980260N