Iron(III) catalyzed halo-functionalization of alkynes

Article abstract of DOI:10.1016/j.tetlet.2015.05.039

Abstract Aromatic and aliphatic alkynes can be halo-functionalized to α,α-dihalodimethyl ketals catalyzed by FeCl₃ in excellent yields. MeOH is used as a nucleophilic solvent and N-halosuccinimide as the halogen source for this efficient transformation. The resulting α,α-dibromodimethyl ketals can be converted to the corresponding α,α-dibromoketones by treatment with 8% FeCl₃ in silica gel.

Full text of DOI:10.1016/j.tetlet.2015.05.039

Accepted Manuscript
Iron (III) catalyzed halo-functionalization of alkynes
Bryant Catano, John Lee, Claudia Kim, David Farrell, Jeffrey L. Petersen, Yalan
Xing
PII:
S0040-4039(15)00848-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.05.039
TETL 46311
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 April 2015
10 May 2015
11 May 2015
Please cite this article as: Catano, B., Lee, J., Kim, C., Farrell, D., Petersen, J.L., Xing, Y., Iron (III) catalyzed halo-
functionalization of alkynes, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.05.039
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Iron (III) catalyzed halo-functionalization of alkynes
Bryant Catano1, John Lee1, Claudia Kim1, David Farrell1, Jeffrey L. Petersen2 and Yalan Xing1*
1Department of Chemistry, William Paterson University, 300 Pompton Rd, Wayne, NJ 07470, US
2Bennett Department of Chemistry, West Virginia University, Morgantown, WV 26506, US
xingy@wpunj.edu
Graphic abstract
Keywords
Alkyne, halo-functionalization, one-pot, iron.
Abstract
Aromatic and aliphatic alkynes can be halo-functionalized to ꢀ,ꢀ-dihalodimethyl ketals catalyzed by FeCl3 in excellent
yields. MeOH is used as a nucleophilic solvent and N-halosuccinimide as the halogen source for this efficient transformation. The
resulting ꢀ,ꢀ-dibromodimethyl ketals can be converted to the corresponding ꢀ,ꢀ-dibromoketones by treatment with 8% FeCl3 in
silica gel.
Introduction
The transition metal catalyzed functionalization of carbon-carbon multiple bonds is of prime importance in synthetic
organic chemistry.1 Alkynes are readily available as synthetic starting materials and can be converted to a variety of different
functional groups. In the past few decades, the development of transition metal catalyzed functionalizations of alkynes has seen
an increased amount of research. Halo-functionalization of alkenes and alkynes is one of the most widely used strategies for the
synthesis of halogen containing compounds, which are versatile intermediates and substrates in organic synthesis.2
Herein we report our investigation of the iron (III) catalyzed formation of ꢀ,ꢀ-dihalodimethyl ketals from alkynes and
N-halosuccinimide in the presence of nucleophilic solvent MeOH, as well as the treatment of the crude ꢀ,ꢀ-dihalodimethyl ketals
with 8% FeCl3 in silica gel to generate ꢀ,ꢀ-dihaloketones according to known literature procedures.3 Only limited methods are
currently available in the literature for the preparation of these compounds. Phukan and coworkers have recently reported a facile
generation of ꢀ,ꢀ-dibromodimethyl ketals from terminal alkynes;4 however, this reaction requires the reagent N,N-dibromo-p-

toluenesulfonamide (TsNBr2), which is not readily available.5 Bromine6 and tetrabutylammonium tribromide7 have been reported
as halogen sources in reaction with alkynes, leading to only moderate yields of ꢀ,ꢀ-dibromodimethyl ketals with a significant
amount of the E-ꢀ,ꢁ-dibromoalkene byproduct being generated. The preparation of ꢀ,ꢀ-dihalodialkoxyl ketals using N-
halosuccinimide as the halogen source has been reported using catalytic amount of acids, such as p-toluenesulfonic acid8 and
H2SO4,9 which give relatively harsh conditions. As part of our investigations into novel methods of the transition metal catalyzed
functionalizations of alkynes, we developed a highly efficient iron (III) catalyzed halo-functionalization reaction under mild and
simple conditions.
Results and discussion
The optimal reaction conditions were first screened for with phenyl acetylene chosen as a model substrate. Initially, the
reaction was conducted with four different transition metal catalysts in the presence of N-bromosuccinimide (NBS) and the
nucleophilic solvent methanol at room temperature (Table 1). The reaction process was monitored using TLC and GC-MS and
the structure of the products determined by NMR. The use of AgNTf2 produced only trace amounts of the ꢀ,ꢀ-dibromodimethyl
ketal product 2a10 with the major product being bromoacetylene 2c (Entry 3). A 56% yield of 2a was observed when AuCl3 was
used as the catalyst; however, a significant amount of the methyl ketone hydration product 2b was detected (Entry 4). Iron (III)
chloride and ruthenium (III) chloride both gave similar yields of the desired product 2a at room temperature (Entries 5 and 6)
with similar reaction times. Due to the abundance and lower cost of iron catalysts,11 the use of FeCl3 as a catalyst was
investigated further. The conversion of the starting material under FeCl3 catalyzed condition at rt was only 65% (Entry 6). As
expected, increasing the reaction temperature to 50 °C while using FeCl3 gave 100% GC conversion and 98% isolated yield of the
desired product 2a for the same 5 h reaction time (Entry 7). When performed without any transition metal catalyst, either at rt or
elevated temperature and longer reaction times, this reaction gave very low yield of 2a (Entries 1 and 2). Instead, a significant
amount of the (1,2-dibromovinyl)benzene product 2d, generated by a radical reaction mechanism,12 was observed.

a
Table 1. Optimization of reaction conditions for the synthesis of α,α-dibromodimethyl ketals
With the optimal conditions in hand, we then explored the substrate scope and limitations of this reaction by
investigating a variety of alkynes, as shown in Table 2. The ꢀ,ꢀ-dibromodimethyl ketals and ꢀ,ꢀ-diiododimethyl ketals were both
synthesized in good yields using NBS and N-iodosuccinimide under the standard conditions. When N-chlorosuccinimide was
used, none of the corresponding ꢀ,ꢀ-dichlorodimethyl ketals were detected. In addition, aromatic alkynes underwent the halo-
functionalization in good yields with both electron-donating and electron-withdrawing groups on the benzene ring. In particular,
substrates with a halogen group at any position on the benzene ring gave excellent yields of over 90%. The aliphatic alkynes 1-
nonyne and 1-hexyne afforded the products 2d and 2t, respectively, in good yields while maintaining the high regioselectivity.
The phenyl-substituted internal alkynes 5-phenyl-1-pentyne, prop-1-yn-1-ylbenzene, and 1,2-diphenylethyne also afforded the
products 2p, 2u, and 2v, respectively, in good yields. A single crystal of 2h was obtained and the X-ray crystallographic analysis
confirmed the structure and stereochemistry of the ꢀ,ꢀ-dibromodimethyl ketal (Figure 1).13

Table 2. Substrate scope
Figure 1. X-ray structure of 2h
A plausible mechanism for this transformation is proposed in Scheme 1. The iron (III) catalyst first activates the triple
bond. Nucleophilic methanol then adds to the benzylic position to give the vinyl iron intermediate 3, which reacts with the
electrophilic halogen Br+ to generate a vinyl bromide 4. The nucleophilic methanol and electrophilic Br+ again regioselectively
add to the resulting double bond to give the ꢀ,ꢀ-dibromodimethyl ketal.

Scheme 1. Proposed mechanism I
A second possible mechanism is also proposed in Scheme 2. The iron (III) catalyst may coordinate with one of the
carbonyl oxygen atoms of NBS to give complex II, in which the Br is more electrophilic. Treatment of phenyl acetylene with this
more electrophilic bromination reagent generates intermediate III, which reacts with methanol to provide intermediate 4. Similar
to the proposed mechanism I, intermediate 4 further reacts with methanol and Br+ to give the ꢀ,ꢀ-dibromodimethyl ketal.
Scheme 2. Proposed mechanism II
Both of these proposed mechanisms involve the generation of intermediate 4. A test reaction was performed to confirm
the formation of this intermediate. In the test reaction, one equivalent of NBS was used to react with phenyl acetylene under the
standard condition. Intermediate 4 was not detected by GC-MS while the isolated yield of 2a dropped to 45%. We believe that
intermediate 4 is very reactive with too short of a life time to be detected; once formed it would react immediately with methanol
and NBS to give the ketal.
It was found that when the acetal 2a was treated with a preprepared reagent of 8% FeCl3 by mass in chromatographic
silica gel, the dimethyl acetal was cleaved to give the ꢀ,ꢀ-dibromoketone 5a14 (Scheme 3).3 Using this mild and convenient acetal
deprotection procedure, we developed a one-pot strategy to directly prepare ꢀ,ꢀ-dibromoketones from alkyne starting materials.15
First, the alkyne is treated with our optimal conditions to yield the ꢀ,ꢀ-dibromodimethyl ketal. Next, without isolation of the ketal
product, 8% FeCl3 in silica gel is added directly to the reaction flask after removal of the methanol solvent. The ꢀ,ꢀ-
dibromoketone is obtained in comparable yield (96%) to the two-step reaction after 12 h of stirring. As shown in Scheme 2, a

variety of terminal and internal aromatic alkynes were smoothly converted to ꢀ,ꢀ-dibromoketones using this one-pot strategy in
greater than 90% overall yield. However, a benzene ring-bearing methoxy group (5c) was observed to give a slightly lower yield
of 80%. When ꢀ,ꢀ-diiododimethyl ketal 2q was treated with this acetal deprotection procedure, a mixture of the corresponding ꢀ-
iodoketone and ꢀ,ꢀ-diiodoketone was observed.
Scheme 3. Ketone formation
Conclusion
In summary, we have developed a convenient and efficient synthesis of ꢀ,ꢀ-dihalodimethyl ketals and ꢀ,ꢀ-
dibromoketones from readily available alkynes. The first row transition metal iron is an excellent choice of catalyst for this
transformation due to its low cost, high abundance, and minimal toxicity. This transformation has a broad substrate scope, able to
be performed with a variety of aromatic and aliphatic alkynes, both terminal and internal. This reaction opens a new bridge
between alkyne and carbonyl chemistry where the alkynes can be selectively converted to ꢀ-halogenated ketones or the protected
ketone acetals based on need by changing the conditions. The resulting products are versatile substrates for many SN2, carbonyl,
and Reformatsky reactions16. The direct synthesis of ꢀ-halogenated ketones from corresponding ketones using electrophilic
halogen sources suffers poor regioselectivity; this alkyne functionalization strategy provides an alternative preparation to avoid
this regioselectivity issue.
Acknowledgements
The authors are grateful to the William Paterson University College of Science and Health and Chemistry Department,
as well as the Garden State Louis Stokes Alliance for Minority Participation. J. L. P. acknowledges the support provided by the
Major Research Instrumentation Program of the National Science Foundation (CHE-1336071) for the acquisition of a Bruker
AXS D8 Venture X-ray diffractometer by the Bennett Department of Chemistry at West Virginia University.

References and notes
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March 2015).
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10. The general procedure for synthesis of 2: To a 0.2 M methanol solution of alkyne 1 (1.0 mmol), NBS (2.0 mmol) and FeCl3
( 5 mol %) were added at rt. The reaction solution was stirring for 5 h at 50 oC. The solvent was removed and the crude
mixture was purified by flash column chromatography on silica gel to give pure product 2.
11. Bauer, I.; Knolker, H., Chem Rev. 10.1021/cr500425u.
12 A radical mechanism for formation of 2d using NBS was proposed: Liu, J.; Li, W.; Wang, C.; Li, Yao; Li, Z,
Tetrahedron Lett. 2011, 52, 4320.
13. CCDC 1057702 contains the supplementary crystallographic data for compound 2h. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
14. The general procedure for synthesis of 5: To a 0.2 M methanol solution of alkyne 1 (1.0 mmol), NBS (2.0 mmol) and FeCl3
(5 mol %) were added at rt. The reaction solution was stirring for 5 h at 50 oC. The solvent was removed and the preprepared
reagent FeCl3 in silica gel (2 g) was added, the reaction mixture was stirring for 12 h and then directly loaded on a silica
column. Purification by flash chromatography gave pure product 5.
15. A procedure for synthesis of ꢀ,ꢀ-dihaloketones from alkynes using FeCl3 was reported: Liu, J.; Li, W.; Wang, C.; Li, Yao;
Li, Z, Tetrahedron Lett. 2011, 52, 4320. In this procedure, THF/H2O was used as solvent, ꢀ,ꢀ-dihalodimethyl ketals were
not involved.
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