Catalyst-and metal-free rapid functionalizations of alkynes using TsNBr2

Article abstract of DOI:10.1055/s-0033-1339194

A very rapid (3-12 min) and efficient method has been developed for a one-pot synthesis of α,α-dibromoalkanones and β-bromoenol alkanoates directly from alkynes using N,N-dibromo-p-toluenesulfonamide (TsNBr₂). The protocol is embellished with f

Full text of DOI:10.1055/s-0033-1339194

1558▌
LETTER
lCettaertalyst- and Metal-Free Rapid Functionalizations of Alkynes Using TsNBr2
Functionalizations of Alkynes Using TsNBr2
Ruchi Chawla, Atul K. Singh, Lal Dhar S. Yadav*
Green Synthesis Lab, Department of Chemistry, University of Allahabad, Allahabad 211 002, India
Fax +91(532)2460533; E-mail: ldsyadav@hotmail.com
Received: 02.05.2013; Accepted after revision: 20.05.2013
temperatures, and microwave induction in some cases and
Abstract: A very rapid (3–12 min) and efficient method has been
suffer from long reaction times and limited substrate
developed for a one-pot synthesis of α,α-dibromoalkanones and β-
scope. Also, only a very few methods are available for the
bromoenol alkanoates directly from alkynes using N,N-dibromo-p-
toluenesulfonamide (TsNBr2). The protocol is embellished with
highly regio- and stereoselective synthesis of β-haloenol
features like ambient temperature, high regioselectivity, operational acetates.13 Recent reports are from Jiang et al. for the syn-
simplicity, and metal- and catalyst-free conditions.
thesis of (Z)-β-haloenol acetates from terminal alkynes
catalyzed by expensive silver salts13b and from Zhu and
Key words: alkynes, TsNBr2, α,α-dibromoalkanones, β-bromoenol
alkanoates, catalyst-free conditions
co-workers who have developed a convenient and practi-
cal method for the regio- and stereoselective synthesis of
(Z)-β-haloenol acetates via the palladium-catalyzed cou-
pling of alkynyl halides with allyl acetate under mild con-
ditions.13c Thus, there is still scope for developing a metal-
free efficient synthesis of α,α-dibromoalkanones and β-
haloenol alkanoate molecular skeletons.
Functionalization of alkynes to provide highly efficient
access to complex frameworks has grasped the attention
of the synthetic community tremendously over the recent
years. Among these functionalizations, the transition-met-
al-catalyzed difunctionalization reactions of terminal al-
kynes have progressed rapidly during the last decade.1 But
these metal-based processes are generally not much pre-
ferred from a practical point of view, especially in the
pharmaceutical industry where the removal of undesired
metal contamination can be expensive.2 Moreover, certain
functional groups are incompatible with transition metals
due to competing cross-coupling processes. On the other
hand, the reactions involving the activation of alkynes us-
ing electrophilic halogen sources have emerged as power-
ful tools to achieve diverse functionalizations.3 Use of
stoichiometric amounts of simple electrophilic reagents
such as electrophilic halogen sources can serve as excel-
lent alternatives to the expensive transition-metal-cata-
lyzed transformations keeping in line with environmental
and economic issues.
N,N-Dibromo-p-toluenesulfonamide (TsNBr2) was first
utilized as a reagent by Kharasch for the synthesis of
1-phenyl-2-(p-toluenesulfonamido)-1-bromoethane
in
1939.14 Also, there are reports on the preparation of halo-
amines and aziridines using N,N-dihalosulfonamides.15
Recently, Phukan and co-workers have explicitly exploit-
ed the high reactivity of TsNBr2 to carry out various or-
ganic transformations establishing its versatility and
efficiency.16 However, to the best of our knowledge there
are no examples in the literature reporting the reaction of
TsNBr2 with simple alkynes; but highly functionalized al-
kynes have been reported to react with TsNBr2 furnishing
densely functionalized aziridine derivatives.17 Prompted
by the above points and in continuation of our work on
one-pot synthetic methodologies,18 we herein report the
first very rapid, catalyst- and metal-free efficient synthesis
of α,α-dibromoalkanones and β-bromoenol alkanoates
from alkynes using TsNBr2 as depicted in Scheme 1.
α,α-Dibromoalkanones and β-haloenol alkanoates are im-
portant synthons in organic synthesis and pharmaceutical
industry, the former being used for the synthesis of a vari-
ety of biologically active heterocyclic compounds.4 The
vinyl moiety in the latter makes β-haloenol acetate molec-
ular skeletons versatile intermediates in organic
synthesis5,6 as they can be employed for transition-metal-
catalyzed cross-coupling and halogen–metal exchange
reactions.7 Haloenol acetates are also known to be effec-
tive precursors of α-keto dianions.6 Earlier, the syntheses
of α,α-dibromoalkanones have been accomplished using
reagents like benzyltrimethylammonium tribromide,8
MeCN–H2O
O
(10:1)
R2
R1
r.t., 3–10 min
Br
Br
Br
Br
3
N
Ts
R1
R2
+
Br
1
R3CO2H
2
R3
O
R2
4
R1
r.t., 3–12 min
O
5, 6
dioxane
dibromide,9
Selectfluor/KBr,10
PhI(OAc)2/NaX/CTAB11 and oxone/NaBr.12 These meth-
ods generally involve the use of expensive reagents, high
Scheme 1 Synthesis of α,α-dibromoalkanones and β-haloenol
alkanoates
We began our study using one equivalent of phenylacety-
lene (1a) as a model substrate and one equivalent of
TsNBr2 (2) as a reagent in acetonitrile with few drops of
SYNLETT 2013, 24, 1558–1562
Advanced online publication: 20.06.2013
DOI: 10.1055/s-0033-1339194; Art ID: ST-2013-D0409-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Functionalizations of Alkynes Using TsNBr2
1559
water at room temperature. A brisk reaction took place and 2.17 ppm). For each pair, the downfield signal pre-
with the conversion of phenylacetylene (1a) into α,α-di- dominated (in a ratio of 2.5:1). In the NMR spectrum,
bromoacetophenone (3a) as monitored by TLC. The reac- NOE enhancement was observed for the aromatic protons
tion proceeded with almost complete consumption of upon irradiation of the major vinyl singlet at δ = 6.55, es-
TsNBr2 but phenylacetylene still persisted in the reaction tablishing the Z-configuration for the major isomer. The
mixture. As a result, the substrate/reagent ratio was var- mixture could be separated by preparative chromatogra-
ied. When two equivalents of TsNBr2 were used with one phy.
equivalent of phenylacetylene, the yield of the reaction in-
creased from 45% to 87%. Encouraged by these results,
The results appeared interesting due to two reasons: (i) β-
bromoenol acetates 5a and 6a could be formed so easily
we next decided to try the reaction in different solvents.
and rapidly under metal-free conditions, and (ii) different
The results of the study are compiled in Table 1. For ob-
results compared to the previous methods using other
taining α,α-dibromoalkanones, MeCN–H2O (10:1) was
electrophilic halogen sources with alkynes were obtained.
Previously, when oxidative bromination of phenylacety-
lene was carried out using Selectfluor/KBr, α,α-dibromo-
acetophenone (3a) was formed under neutral conditions in
identified as the best solvent system (Table 1, entry 2).
Though a number of nucleophilic and non-nucleophilic
solvents were tried, different and interesting results were
obtained in glacial acetic acid (Table 1, entry 7). In this
30 minutes, whereas in the presence of acetic acid, a mix-
case, another product along with α,α-dibromoacetophe-
ture of cis- and trans-1,2-dibromostyrene instead of β-
none (3a) was formed instantaneously which on 1H NMR
bromoenol alkanoates was formed.10 After establishing
these results, the reaction was further optimized and ex-
analysis was found to be a diastereomeric mixture of E-
and Z-isomers of β-bromoenol acetates 5a and 6a, and
amined for the substrate scope for obtaining α,α-dibro-
could not be readily separated by column chromatogra-
moalkanones and β-haloenol acetates separately. In the
1
phy. The H NMR spectrum of the purified mixture
case of α,α-dibromoalkanones, the reaction worked well
showed two singlets for the vinylic H (at δ = 6.55 and 6.31
for terminal as well as nonterminal alkynes (Table 2).
ppm) and two singlets for the methyl protons (at δ = 2.34
Table 1 Optimization of Solvents20
O
solvent
Br
Br
Ph
r.t., 5–45 min
Br
Br
Br
3a
Ph
H
+
N
Ts
1a
MeCO2H
2
O
O
4a
Br
+
r.t., 5 min
O
Ph
O
Ph
5a
6a
Entry
Solventa
Time (min)
Yield (%)b
1
2
MeCN
MeCN
EtOAc
dioxane
CH2Cl2
DMF
5
5
45c
87
82
80
83
85
10e
34
62
64
12
3
8
4
7
5
5
6
5
7
glacial AcOHd
DMSO
5
8
15
45
30
15
9
EtOH
10
11
MeOH
MeCNd
a Conditions: 0.2 mL of H2O were added to 2 mL of solvent.
b Isolated yield of purified product 3a.
c Reaction conditions: phenylacetylene (1a, 1.0 mmol) and TsNBr2 (2, 1.0 mmol) in 2 mL solvent with 0.2 mL H2O.
d No H2O was added.
e A mixture of products 5a and 6a was formed in 62% yield.
© Georg Thieme Verlag Stuttgart · New York
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R. Chawla et al.
LETTER
Table 2 Synthesis of α,α-Dibromoalkanones20
Table 3 Synthesis of β-Bromoenol Alkanoates21
Br
O
MeCN–H2O
(10:1)
Br
R3
O
R2
Br
R1
R2
+
R2
R1
N
Ts
R3CO2H
r.t., 3–10 min
5
Br
O
O
R1
Br
Br
Br
Z-isomer
4
R1
R2
1
2
3
N
Ts
+
+
r.t., 3–12 min
R3
R2
Entry
R1
R2
Product Time
(min)
Yield
(%)a,b
1
2
O
Br
R1
6
1
2
Ph
H
3a
3b
3c
3d
3e
3f
5
87
82
76
72
74
85
61
78
70
68
E-isomer
4-MeC6H4
3-MeC6H4
4-MeOC6H4
4-O2NC6H4
Ph
H
4
Entry R1
R2
R3
Product Time Yield Ratioc of
(min) (%)a,b 5a/6a
3
H
5
4
H
4
1
2
Ph
H
H
H
H
H
H
H
H
H
H
H
Me 5a, 6a
Me 5b, 6b
Me 5c, 6c
Me 5d, 6d
Me 5e, 6e
Me 5f, 6f
Me 5g, 6g
5
3
85
81
78
75
76
74
71
63
82
70
68
2.5:1
2.2:1
2.4:1
2.6:1
2.7:1
1:5.0
1:4.8
2.2:1
2.3:1
2.2:1
2.1:1
5
H
3
4-MeC6H4
6
Ph
6
3
3-MeC6H4
3
7
Ph
4-ClC6H4
3g
3h
3i
5
4
4-MeOC6H4
5
8
Pr
Pr
H
H
7
5
4-O2NC6H4
4
9
Bu
8
6
Bu
t-Bu
Ph
7
10
t-Bu
3j
10
7
8
a Isolated yield of purified product 3.
8
H
5h, 6h
5i, 6i
5
b All compounds gave C, H, and N analyses within ±0.36%, and sat-
isfactory spectral (IR, 1H NMR, 13C NMR, and EIMS) data.
9
Ph
Et
Pr
8
10
11
Ph
5j, 6j
10
12
In view of the prime significance of haloenol acetates as
intermediates in organic synthesis and pharmaceutical in-
dustry, we first optimized the reaction conditions for their
synthesis and also explored the substrate scope of the re-
action. In order to obtain a better yield of β-bromoenol ac-
etates, the substrate/reagent ratio was varied. When 1.0
equivalent of phenylacetylene was treated with 0.5 equiv-
alents of TsNBr2, the yield of β-bromoenol acetate in-
creased from 62% to 85%. With the optimized reaction
conditions in hand, we extended our synthetic protocol to
a number of alkynes and carboxylic acids. The reaction
worked well with different alkynes using glacial acetic ac-
id, and the results are presented in Table 3 (entries1–7). In
the case of aryl-substituted terminal alkynes, the Z-iso-
mers 5 were obtained as the major product (Table 3, en-
tries 1–5) which indicates that the electrophilic addition of
Br+ ion (generated from TsNBr2) to alkynes formed the
classical vinyl bromonium cation intermediate 7 suscepti-
ble to both syn and anti addition (Scheme 2). Also, the re-
action displayed high regioselectivity which can be
explained by considering the fact that the vinyl carboca-
tion was stabilized by the aromatic ring. However, in the
case of alkyl-substituted terminal alkynes, the bromoenol
acetates were formed predominantly with E-configuration
(Table 3, entries 6 and 7) suggesting that the reaction took
place via a cyclic bromonium ion intermediate 8 (Scheme
2). The proposed mechanism is in accordance with earlier
observations.19 The reaction also proceeded if other car-
boxylic acids were used. When we used the optimized
conditions for the reaction of phenylacetylene, TsNBr2
Ph
Bu 5k,6k
a Isolated yield of purified products 5 and 6.
b All compounds are gave C, H, and N analyses within ±0.36%, and
satisfactory spectral (IR, 1H NMR, 13C NMR and EIMS) data.
c As determined by 1H NMR integration of the two stereoisomers 5
and 6 in the crude product.
and different acids as the solvent (2 mL), the correspond-
ing β-bromoenol alkanoates were obtained in good yields
(Table 3, entries 8–11).
In summary, a metal-free method for the synthesis of α,α-
dibromoalkanones and β-bromoenol alkanoates from
readily available alkynes using TsNBr2 has been devel-
oped. The procedure is rapid, catalyst-free, and easy to
perform at room temperature, and in the case of bro-
moenol alkanoates, it gives high regioselectivity and mod-
est stereoselectivity. Further work to exploit this synthetic
protocol using other nucleophiles is under way in our lab-
oratory.
Acknowledgment
We sincerely thank SAIF, Punjab University, Chandigarh, for pro-
viding microanalyses and spectra. R. Chawla is grateful to the De-
partment of the Science and Technology, New Delhi, for the award
of Senior Research Fellowship (Reference No. SR/S1/OC-
22/2010).
Synlett 2013, 24, 1558–1562
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionalizations of Alkynes Using TsNBr2
1561
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5, 6
6
mixture of Z- and E-isomers
E-isomer
Scheme 2 Plausible mechanism for the formation of β-bromoenol
alkanoates
References and Notes
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Chromatogr. Relat. Technol. 2007, 30, 877.
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(c) Duggan, P. J.; Liepa, A. J.; O’Dea, L. K.; Tranberg, C. E.
Org. Biomol. Chem. 2007, 5, 472.
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(20) General Procedure for the Synthesis of α,α-
Dibromoalkanones 3
A mixture of alkyne 1 (1.0 mmol) and TsNBr2 (2, 2.0 mmol)
in MeCN (2 mL) with H2O (0.2 mL) was stirred at r.t. for 3–
10 min (Table 2). After completion of the reaction
(monitored by TLC), H2O was added and the mixture was
extracted with EtOAc (3 × 5 mL). The combined organic
phases were dried over anhyd Na2SO4, filtered, and
concentrated under reduced pressure. The resulting crude
product was purified by silica gel column chromatography
using a mixture of EtOAc–n-hexane (1:99) as eluent to
afford an analytically pure sample of α,α-dibromoalkanones
3 (Table 2).
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Characterization Data of Representative Compounds
Compound 3a: viscous liquid; yield 87%. IR (neat):
© Georg Thieme Verlag Stuttgart · New York
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R. Chawla et al.
LETTER
νmax = 3448, 2926, 1600, 1475, 1092 cm–1. 1H NMR (400
MHz, CDCl3): δ = 6.71 (s, 1 H), 7.49–7.57 (m, 2 H), 7.63–
7.67 (m, 1 H), 8.08–8.10 (m, 2 H). 13C NMR (100 MHz,
CDCl3): δ = 39.7, 128.9, 129.8, 130.3, 134.7, 185.7. MS
(EI): m/z = 276 [M+], 278 [M+ + 2]. Anal. Calcd for
C8H6Br2O: C, 34.57; H, 2.18. Found: C, 34.33; H, 2.26.
Compound 3h: viscous liquid; yield 78%. IR (neat):
(s, 3 H), 6.55 (s, 1 H), 7.33–7.35 (m, 3 H), 7.37–7.41 (m, 2
H). 13C NMR (100 MHz, CDCl3): δ = 20.5, 96.6, 124.3,
126.1, 128.5, 133.0, 150.2, 166.6. MS (EI): m/z = 240 [M+],
242 [M+ + 2]. Anal. Calcd for C10H9BrO2: C, 49.82; H, 3.76.
Found: C, 49.46; H, 3.82.
Compound 6a: yellow oil; yield 24%. IR (KBr): νmax = 3096,
2929, 2855, 1762, 1624, 1438, 1370, 1185, 1036, 740, 690,
625, 567, 489 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.17
(s, 3 H), 6.31 (s, 1 H), 7.34–7.43 (m, 4 H), 7.61–7.64 (m, 1
H). 13C NMR (100 MHz, CDCl3): δ = 20.3, 94.6, 124.8,
128.5, 129.3, 133.2, 148.7, 167.3. MS (EI): m/z = 240 [M+],
242 [M+ + 2]. Anal. Calcd for C10H9BrO2: C, 49.82; H, 3.76.
Found: C, 49.55; H, 3.78.
Compound 5d: yellow oil; yield 54%. IR (KBr): νmax = 3094,
2938, 1765, 1609, 1510, 1458, 1370, 1035, 896, 835, 770,
658, 597, 512 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.31
(s, 3 H), 3.76 (s, 3 H), 6.37 (s, 1 H), 6.85 (d, J = 8.8 Hz, 2 H),
7.33 (d, J = 8.8 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
δ = 20.8, 55.2, 96.4, 113.5, 125.3, 126.3, 150.2, 160.1,
167.3. MS (EI): m/z = 270 [M+], 272 [M+ + 2]. Anal. Calcd
for C11H11BrO3: C, 48.73; H, 4.09. Found: C, 48.44; H, 4.12.
Compound 6d: yellow oil; yield 20%. IR (KBr): νmax = 3092,
2940, 1763, 1606, 1514, 1457, 1370, 1035, 898, 835, 770,
657, 595, 511 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.13
(s, 3 H), 3.80 (s, 3 H), 6.22 (s, 1 H), 6.87 (d, J = 9.2 Hz, 2 H),
7.56 (d, J = 8.0 Hz, 2 H).13C NMR (100 MHz, CDCl3):
δ = 20.5, 55.3, 94.4, 114.1, 125.8, 129.7, 148.5, 160.4,
168.6. MS (EI): m/z = 270 [M+], 272 [M+ + 2]. Anal. Calcd
for C11H11BrO3: C, 48.73; H, 4.09. Found: C, 48.40; H, 4.19.
ν
max = 2960, 2938, 2871, 1720, 1461, 1380, 1243, 1147,
1105, 627 cm–1. 1H NMR (400 MHz, CDCl3): δ = 0.99 (m, 6
H), 1.70 (m, 4 H), 2.43 (m, 2 H), 3.09 (t, J = 7.2 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 13.1, 13.6, 18.6, 20.7,
38.3, 46.8, 71.5, 198.0. MS (EI): m/z = 284 [M+], 286 [M+ +
2]. Anal. Calcd for C8H14Br2O: C, 33.60; H, 4.93. Found: C,
33.52; H, 5.02.
(21) General Procedure for the Synthesis of Bromoenol
Alkanoates 5 and 6
A mixture of alkyne 1 (2.0 mmol) and TsNBr2 (2, 1.0 mmol)
in carboxylic acid 4 (2 mL) was stirred at r.t. for 3–12 min
(Table 3). After completion of the reaction (monitored by
TLC), H2O was added, and the mixture was extracted with
EtOAc (3 × 5 mL). The combined organic phases were dried
over anhyd Na2SO4, filtered, and concentrated under
reduced pressure. The resulting crude product was purified
by preparative chromatography using a mixture of EtOAc–
n-hexane (1:99) as eluent to afford an analytically pure
sample of bromoenol alkanoates 5 and 6 (Table 3).
Characterization Data of Representative Compounds
Compound 5a: yellow oil; yield 60%. IR (KBr): νmax = 3095,
2928, 2852, 1765, 1625, 1436, 1370, 1180, 1036, 740, 694,
627, 569, 488 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.34
Synlett 2013, 24, 1558–1562
© Georg Thieme Verlag Stuttgart · New York

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