Tetrabutylammonium dichlorobromide: An efficient and mild reagent for geminal bromochlorination of α-diazo carbonyl compounds

Article abstract of DOI:10.1016/j.tetlet.2014.12.117

An efficient and mild one-pot procedure for geminal bromochlorination of α-diazo carbonyl compounds has been developed for the first time using tetrabutylammonium dichlorobromide (TBADCB) via metal carbenoids. This protocol was found to be highly selectiv

Full text of DOI:10.1016/j.tetlet.2014.12.117

Accepted Manuscript
Tetrabutylammonium dichlorobromide: An efficient and mild reagent for gemi-
nal bromochlorination of α-diazo carbonyl compounds
Nusrathulla Shariff, Selvam Mathi, Chidambaram Rameshkumar, Lourdusamy
Emmanuvel
PII:
S0040-4039(14)02195-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.117
TETL 45642
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 November 2014
18 December 2014
21 December 2014
Please cite this article as: Shariff, N., Mathi, S., Rameshkumar, C., Emmanuvel, L., Tetrabutylammonium
dichlorobromide: An efficient and mild reagent for geminal bromochlorination of α-diazo carbonyl compounds,
Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.117
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Abstract
Tetrabutylammonium dichlorobromide: An efficient and mild reagent for geminal
bromochlorination of α - diazo carbonyl compounds
Nusrathulla Shariff ,a Selvam Mathi,a Chidambaram RameshKumar, b † Lourdusamy Emmanuvel *
X
O
X
O
-
n-Bu4N+BrCl2
R
R'
R
R'
Br
Cl
cat. Cu(OTf)2
CH2Cl2, 40 oC
N2
X = O, N-OMe
R = Alkyl, aryl
R' = alkyl, Oalkyl
2 h
yield up to 89%
An efficient and mild one-pot procedure for geminal bromochlorination of α-diazo carbonyl
compounds has been developed for the first time using tetrabutylammonium dichlorobromide
(TBADCB) via metal carbenoids. This protocol was found to be highly selective and does not
result in dichlorination or dibromination products. The reagent, TBADCB, is commercially
available, easy to prepare and handle.

Tetrabutylammonium dichlorobromide: An efficient and mild reagent for
geminal bromochlorination of α-diazo carbonyl compounds
Nusrathulla Shariff,a Selvam Mathi,a Chidambaram Rameshkumar,b Lourdusamy Emmanuvel a,٭
a
School of Science and Humanities, Department of Chemistry, Karunya University,
Karunya Nagar, Coimbatore, 641114, India
E-mail:emmanuvel@karunya.edu
Fax: 0422-2615615Ph:+919042678370
b School of Basic Sciences, Vel Tech University, Avadi, Chennai, 600062
Key words: Geminal bromochlorination, Diazo compounds, Dichlorobromide.
Introduction of halogens on aliphatic chain or aromatic nucleus had always been of great
interest due to their important biological activities.1 Several natural products such as
halomon, chloramphenical, nucleocidin, rogioloxepanes etc. have been found to possess
halogens in aliphatic chain while several drugs and pesticides are found to have halogens in
the aromatic nucleus.2 Further, halides are highly versatile intermediates in organic synthesis
due to its ability to act as leaving group.3 Even though, several methods and reagents are
available for vicinal dihalogenation, 4 geminal heterodihalogenation is rarely studied.
Geminal heterodihalogenation is generally achieved by a two-step process comprising
bromination followed by chlorination or vice versa.5 The major problems associated with this
route are dihalogenation which reduces the yield considerably and difficulties in separation.
Displacement of nitrogen from diazo compounds with halogens has also been understood as
the simplest alternate method to access gem dihalogenation.6This reaction was further
extended to interhalogen compounds such as ICl, IBr etc. to introduce two different halogen
atoms to the same carbon atom. This reaction was used to synthesize several β-lactam
derivatives such as penicillinates 1 and 2 (Fig. 1).7 Even though such reactions are known
with ICl and IBr, stable and commercially available mixed halides, no attempt has been made
to introduce Br and Cl since BrCl is a gas at room temperature and is not readily available.
Fig. 1

In this communication, we wish to report, for the first time, the use of tetrabutylammonium
-
dichlorobromide, n-Bu4N+BrCl2 (TBADCB) as a selective and efficient reagent to achieve
geminal bromochlorination of diazo carbonyls and imines in good yields at mild condition.
In continuation of our research on diazo compounds,8 we found that diazo compound 3a,
prepared from ethyl acetoacetate via diazo transfer reaction, reacts with TBADCB in the
presence of Cu(OTf)2 (5 mol%) at 40 oC in CH2Cl2 to give gem bromochlorinated compound
4a in good yield (Scheme 1).9
O
O
O
O
-
nBu4N+BrCl2
OEt
OEt
Br
Cl
cat. Cu(OTf)2
CH2Cl2, 40 oC
2 h
N2
3a
4a
89%
Scheme 1: Geminal bromochlorination
In order to standardize the reaction condition we screened several catalysts such as Pd(PPh3)4,
Rh2(OAc)4, Cu(hfacac)2, CuI, Pd(dppf)Cl2, Pd(OAc)2, etc.10 that are known to form
carbenoids with diazo compounds and the results are tabulated (Table 1). A control
experiment was also carried out without catalyst and the reaction failed. It is noteworthy to
observe that this gem bromochlorination required catalyst while Br2, ICl, etc. reacts with
diazo compounds in the absence of catalyst. Cu(hfacac)2 and Cu(OTf)2 gave comparable
yields while CuI even at 20 mol% catalyst loading gave poor yield. Palladium catalysts were
found to be not as effective as copper catalysts. To our surprise, Cu and Pd promote this
reaction at different degree of oxidation. We presume that TBADCB might have oxidized
Cu(Ι) and Pd(0) to result in Cu(ΙΙ) and Pd(ΙΙ) which promotes geminal bromochlorination.
Rh2(OAc)4 was found to be highly reactive at higher temperature and gave several spots but
o
proceeded smoothly to complete bromochlorination at 10 C to furnish 4 in excellent yield
(91%). Among the solvents, CH2Cl2 and CHCl3 gave better yields while ethers gave
moderate yields. When the reaction was carried out in toluene, a mixture of 4a and 4-bromo
toluene (36%) was obtained along with 4 (25%).

Table 1: Geminal Bromochlorination of Diazo compounds
O
O
O
O
-
nBu4N+BrCl2
OEt
OEt
Br
Cl
cat., Solvent, 2 h
N2
Sl. No
Catalyst
Solventb
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
CCl4
Yieldc
1
2
No catalyst
Cu(hfacac)2
Cu(OTf)2
CuId
No reaction
85
89
3
4
22
5
Pd(PPh3)4
Pd(dppf)Cl2
Pd(OAc)2
Rh2(OAc)4
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
59
6
55
7
42
8e
91
9
85
10
11
12
13
45
THF
49
Dioxane
Toluene
trace
25f,g
aDiazo compound (2 mmol), TBADCB (2.4 mmol), catalyst (5 mol%),
o
b
solvent (6 ml), 40 C, 2 h. All the solvents were properly dried and used.
cYield refers to isolated yield. d20mol% CuI was used. eReaction was carried
o
f
out at 10 C with 2 mol% catalyst. 36% Bromo toluene was also obtained.
gyield of bromo toluene was calculated based on TBADCB.
Encouraged with this result, to study the scope of this gem bromochlorination reaction, we
screened several diazocompounds and the yields are presented in table 2. Both diazo
carbonyls and diazo imines underwent bromochlorination smoothly under the reaction
condition to give the products in good to excellent yields. Diazo compounds derived from 1,3
-diketones, β-ketoesters and 1,3-diesters all gave the gem-bromochlorination. Meldrum’s acid
derived diazo compound was found to be unstable under the reaction condition and failed to
give the desired product. The bromochlorinated product from ethyl diazoacetate was purified
using pentane and CH2Cl2. All the products were characterized properly by spectroscopic
techniques such as 1H, 13C NMR, IR and Mass spectra.
Since tetrabutylammonium dichlorobromide is well known to brominate anisole,11
reactivity study was carried out under the same condition. Accordingly, when TBADCB was
a

treated with diazo compound 3a and anisole, 1 equivalent each, in the presence of catalyst
o
Cu(OTf)2 at 40 C 4-bromoanisole was obtained as the major product (67%) while
bromochlorination was obtained in 27% yield (Scheme 2).
A similar experiment was carried out with styrene and obtained the vicinal bromochlorination
of styrene exclusively.12 Geminal bromochlorination and cyclopropenation was not at all
observed (Scheme 3), which clearly shows that the vicinal bromochlorination is extremely
faster than geminal bromochlorination.
Table 2:
Geminal Bromochlorination of diazo compounds: Substrate Scopea
Sl. No
a
Diazo compound 3
Product 4
Yieldb
89
b
c
d
e
f
76
89
O
O
90
EtO
OEt
N2
75c, d
87
g
e
80
85

f
Not
observed
aDiazo compound (2 mmol), TBADCB (2.4 mmol), Cu(OTf)2 (5mol%),
o
b
c
CH2Cl2 (6 ml), 40 C, 2 h. Yield refers to isolated yield. purified using
pentane. dReaction at 25 oC.
Scheme 2: Reactivity study
OMe
Br
O
O
OMe
O
O
-
nBu4N+BrCl2
+
OEt
OEt
+
Br
Cl
cat. Cu(OTf)2
CH2Cl2, 40 oC
2 h
N2
4a, 27%
62%
Scheme 3: Reactivity Study
Br
Cl
O
O
O
O
O
O
-
n Bu4N+BrCl2
+
+
OEt
OEt
OEt
+
Br Cl
cat. Cu(OTf)2
CH2Cl2, 40 oC
2 h
N2
Ph
Not observed
92%
Mechanistically, the reaction is expected to proceed through metal carbenoids A formed by
-
the reaction of Cu(OTf)2 with diazo compounds. Since the bromine atom in BrCl2 is
eletrophilic, proven by aromatic electrophilic substitution reactions of TBADCB, chlorine
atom is expected to be nucleophilic and attack the carbenoid to form anionic intermediate B
which adds to the electrophilic bromine atom to give the product 4 (Fig. 2) . Alternatively, it
may also be expected to go through halogen insertion. Since halogen insertion takes place
without catalyst and the present protocol for geminal bromochlorination failed in the absence
of catalyst, we believe that this reaction proceeds through nucleophilic attack on carbenoids.
O
O
O
O
Cu(OTf)2
OEt
OEt
M
-
N2
Cl Br Cl
A
O
O
O
O
OEt
+BrCl
+
OEt
Br
Cl
-M
Cl
4
B
Fig. 2: Proposed Mechanism for gem bromochlorination

In conclusion we have developed a novel protocol for the geminal bromochlorination of
diazo carbonyl compounds using a cheap, readily available and less toxic reagent
tetrabutylammonium dichlorobromide. The reaction condition was mild and the product was
formed with greater selectivity. Further, this methodology could be extended for gem
iodobromination, gem iodochlorination, etc. by employing suitable ammonium mixed
halides. The synthetic applications of gem α, α'-bromochlorinated carbonyl compounds are
under investigation.
Acknowledgement
The authors thank DST/ SERB, New Delhi, India and Karunya University, Coimbatore, for
Fast Track financial support and the Seed Money Research Grant respectively to carry out
this research work. The authors also thank Dr. Daphy Inbasekar, Director, School of Science
and Humanities and Dr. S. VasanthaKumar, Head of the Department, Department of
Chemistry for their constant support and encouragement.

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To a solution of diazo compound and tetrabutylammonium dichlorobromide in CH2Cl2 at 40 C was
9
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12

X
O
X
O
-
n-Bu4N+BrCl2
R
R'
R
R'
Br
Cl
cat. Cu(OTf)2
CH2Cl2, 40 oC
N2
X = O, N-OMe
R = Alkyl, aryl
R' = alkyl, Oalkyl
2 h
yield up to 89%