Silver-Catalyzed Decarboxylative Bromination of Aliphatic Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.7b00439

The silver-catalyzed Hunsdiecker bromination of aliphatic carboxylic acids is described. With Ag(Phen)₂OTf as the catalyst and dibromoisocyanuric acid as the brominating agent, various aliphatic carboxylic acids underwent decarboxylative bromination to provide the corresponding alkyl bromides under mild conditions. This method not only is efficient and general but also enjoys wide functional group compatibility. An oxidative radical mechanism involving Ag(II) intermediates is proposed.

Full text of DOI:10.1021/acs.orglett.7b00439

Letter
pubs.acs.org/OrgLett
Silver-Catalyzed Decarboxylative Bromination of Aliphatic Carboxylic
Acids
Xinqiang Tan,† Tao Song,† Zhentao Wang,† He Chen,† Lei Cui,† and Chaozhong Li*,†,‡
†Key Laboratory of Organofluorine Chemistry and Collaborative Innovation Center of Chemistry for Life Sciences, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
‡School of Chemical Engineering, Ningbo University of Technology, No. 89 Cuibai Road, Ningbo 315016, China
S
* Supporting Information
ABSTRACT: The silver-catalyzed Hunsdiecker bromination of
aliphatic carboxylic acids is described. With Ag(Phen)2OTf as the
catalyst and dibromoisocyanuric acid as the brominating agent,
various aliphatic carboxylic acids underwent decarboxylative
bromination to provide the corresponding alkyl bromides
under mild conditions. This method not only is efficient and
general but also enjoys wide functional group compatibility. An oxidative radical mechanism involving Ag(II) intermediates is
proposed.
while nonbridgehead tertiary alkyl bromides thus obtained
ecarboxylative bromination of carboxylic acids, the
DHunsdiecker reaction, is one of the fundamental suffered from the contamination of alkenes presumably due to
functional group transformations in organic chemistry.1 The
the instability of tertiary alkyl bromides under basic and
initial discovery by Borodine2 and Hunsdiecker3 required
photolytic conditions. Therefore, it is still highly desirable to
develop efficient and general methods for catalytic Hunsdiecker
bromination, especially with the use of cheaper metal catalysts.
We recently reported the Ag(I)-catalyzed decarboxylative
chlorination of aliphatic carboxylic acids.10 Since alkyl bromides
are generally of more synthetic value than alkyl chlorides, it is
certainly interesting to know whether or not this method could
be extended to catalytic Hunsdiecker bromination. As a
continuation of our interest in silver-catalyzed decarboxylative
functionalization reactions,11−13 we report herein the Ag(I)-
catalyzed Hunsdiecker bromination of aliphatic carboxylic acids
with dibromoisocyanuric acid. These reactions proceed at room
temperature and no base or visible light is required, which helps
to keep the product bromides safer (Figure 1b). Moreover, the
coproduct isocyanuric acid can be easily separated and recycled
as the precursor to dibromoisocyanuric acid (vide infra).
Thus, 2-ethyltetradecanoic acid (1a) was chosen as the
model substrate for the optimization of reaction conditions
(Table 1). We first screened the brominating agents with
Ag(Phen)2OTf as the catalyst (entries 1−4, Table 1). It turned
out that no reaction occurred when NBS (N-bromosuccini-
mide, 2a) was used. Switching NBS to 1,3-dibromo-5,5-
dimethylhydantoin (2b) yielded only a trace amount of
product. However, when the commercially available dibromoi-
socyanuric acid (2c) was used as the brominating agent, the
expected bromide 3a was achieved in 70% yield. Tribromoi-
socyanuric acid (2d) was also tested, but a lower product yield
(42%) was observed. Next, we compared the effects of different
silver complexes with 2c as the brominating agent (entries 3
strictly anhydrous silver carboxylates to react with bromine. To
avoid this disadvantage, a number of modifications were later
developed. For example, Hg(II) or Tl(I) carboxylates that are
more stable than Ag(I) carboxylates also undergo decarbox-
ylative bromination with Br2.3,4 Direct decarboxylative bromi-
nation of carboxylic acids can be implemented by reaction with
red HgO and Br2 (Cristol−Firth modification)5 or with
Pb(OAc)4 and LiBr (Kochi modification).6 The conversion of
carboxylic acids to thiohydroxamate esters followed by
treatment with BrCCl3 provides the decarboxylative bromina-
tion products in two steps under metal-free conditions (Barton
modification).7 In the meantime, the bromination reaction was
further extended to decarboxylative chlorination and iodina-
tion.6−8 However, none of the above methods is catalytic. Very
recently, Glorius et al. nicely developed the Ir(III)-catalyzed
decarboxylative bromination of carboxylic acids with diethyl
bromomalonate under photoredox conditions (Figure 1a).9
Nevertheless, yields were moderate for primary alkyl bromides,
Received: February 13, 2017
Figure 1. Catalytic Hunsdiecker bromination.
© XXXX American Chemical Society
A
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Table 1. Optimization of Reaction Conditions
Scheme 1. Ag(I)-Catalyzed Decarboxylative Bromination of
Aliphatic Carboxylic Acids
a
b
entry
catalyst (mol %)
[Br] (equiv)
solvent
DCE
yield (%)
1
Ag(Phen)2OTf (10)
Ag(Phen)2OTf (10)
Ag(Phen)2OTf (10)
Ag(Phen)2OTf (10)
Ag(TMPhen)2OTf (10)
Ag(DPPhen)2OTf (10)
Ag(DMPhen)2OTf (10)
Ag(Phen)2OTf (10)
Ag(Phen)2OTf (5.0)
Ag(Phen)2OTf (2.5)
Ag(Phen)2OTf (1.0)
Ag(Phen)2OTf (2.5)
Ag(Phen)2OTf (2.5)
Ag(Phen)2OTf (2.5)
Ag(Phen)2OTf (2.5)
Ag(Phen)2OTf (2.5)
Ag(Phen)2OTf (2.5)
none
2a (1.0)
2b (1.0)
2c (1.0)
2d (1.0)
2c (1.0)
2c (1.0)
2c (1.0)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
2c (0.8)
0
trace
70
42
66
68
38
75
74
75
50
74
54
50
40
80
88
0
2
DCE
3
DCE
4
DCE
5
DCE
6
DCE
7
DCE
8
DCE
9
DCE
10
11
12
13
14
DCE
DCE
DCM
CH3CN
Me2CO
DCE/H2O
DCE
c
15
d
16
e
17
DCE
e
18
DCE
19
AgOTf (2.5)
DCE
0
a
Reaction conditions: 1a (0.2 mmol), [Br] reagent, catalyst, solvent (2
b
c
mL), rt, 24 h. Isolated yield based on 1a. DCE (1 mL) and H2O (1
mL) were used. DCE (4 mL) was used. DCE (8 mL) was used.
d
e
and 5−7, Table 1). Changing the ligand 1,10-phenanthroline
(Phen) to 3,4,7,8-tetramethyl-1,10-phenanthroline (TMPhen)
or 4,7-diphenyl-1,10-phenanthroline (DPPhen) did not show
much difference. On the other hand, the use of 2,9-dimethyl-
1,10-phenanthroline (DMPhen) resulted in a much lower yield
of 3a. Interestingly, when we lowered the amount of 2c to 0.8
equiv, the product yield was slightly improved to 75% (entry 8,
Table 1). The same result could also be achieved when the
amount of catalyst was also decreased to 2.5 mol % (entries 8−
11, Table 1). Our further examination on the solvent showed
that DCE was the best choice (entries 12−15, Table 1). Finally,
when we lowered the substrate concentration from 0.1 to 0.025
M, the product yield increased from 75% to 88% (entries 16
and 17, Table 1). The catalytic role of Ag(Phen)2OTf was
further confirmed by the control experiment (entry 18, Table
1). Also note that AgOTf failed to catalyze the reaction
presumably because of its insolubility in DCE (entry 19, Table
1).
With the optimized conditions in hand (entry 17, Table 1),
we set out to examine the scope and limitation of this method,
and the results are summarized in Scheme 1. Similar to acid 1a,
a number of secondary alkyl acids underwent smooth
decarboxylative bromination leading to secondary alkyl
bromides 3b−h in satisfactory yields. The reactions of tertiary
alkyl acids also proceeded nicely, furnishing the expected
tertiary alkyl bromides 3i−l in high yields. The time required
for the completion of reaction was typically shorter for tertiary
alkyl acids than for secondary alkyl acids. Benzylic carboxylic
a
Reaction conditions: 1 (0.2 mmol), Ag(Phen)2OTf (0.005 mmol), 2c
b
(0.16 mmol), DCE (8 mL), rt. Isolated yield based on 1.
c
d
Ag(Phen)2OTf (10 mol %) and 2c (3 equiv) were used. 2c (1.5
e
equiv) was used. cis/trans = 1:1. The reaction was carried out at 40
°C.
acids were also ideal substrates for the decarboxylative
bromination, and the corresponding benzyl bromides 3m−w
were achieved in excellent yields. This method was also
applicable to allylic carboxylic acids, as exemplified by the
synthesis of allyl bromide 3x. On the other hand, the reactions
of primary alkyl acids under the above conditions were much
slower. However, when the reactions were carried out at 40 °C
for a longer period of time, the bromination products could be
obtained in good yields, as evidenced by the synthesis of
primary alkyl bromides 3y and 3z. A number of functional
groups were well tolerated in the decarboxylative bromination,
including ketone, ester, amide, sulfonamide, nitro, alkyl
bromide, aryl halides (Cl, Br, and I), alkyne, and alkene. In
all cases, no alkenes (via HBr elimination of alkyl bromides)
could be observed, indicating the mildness of reaction
conditions. It is worth mentioning that, after the completion
of reaction, the coproduct isocyanuric acid precipitated out of
the solution. Simply by filtration, it was obtained in over 90%
B
DOI: 10.1021/acs.orglett.7b00439
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
yield (based on the amount of 2c used). Since isocyanuric acid
serves as the starting material for the preparation of 2c (by
reaction with Br2), this catalytic decarboxylative bromination
method is thus highly sustainable. Nevertheless, the method
was not applicable to aromatic acids such as 4-chlorobenzoic
acid, which remained unchanged under the above reaction
conditions.
On the basis of the above results, a catalytic radical
mechanism similar to that of silver-catalyzed chlorodecarbox-
ylation is proposed (Figure 2).10 First, the interaction of Ag(I)
The above results clearly demonstrate the broad substrate
scope and wide functional group compatibility of silver-
catalyzed decarboxylative bromination, thus allowing the late-
stage modification of more complex molecules. For example,
the reaction of dehydrolithocholic acid (4) under the above-
optimized conditions provided the expected bromide 5 in 85%
yield (eq 1). The results in Scheme 1 also show that the
Figure 2. Proposed mechanism.
with dibromoisocyanuric acid 2c generates Ag(II) intermedi-
ates such as A. Complex A then undergoes ligand exchange
with carboxylate to give intermediate B. The subsequent single-
electron transfer between Ag(II) and carboxylate in B leads to
the generation of carboxyl radical, which undergoes fast
decarboxylation to give the corresponding alkyl radical. Finally,
the bromine atom transfer from the Ag(II)Br to alkyl radical
gives rise to alkyl bromide and regenerates Ag(I). Thus,
dibromoisocyanuric acid serves as both the bromine source and
the oxidant. The failure of NBS and dibromohydantoin 2b in
decarboxylative bromination can be rationalized by their weaker
oxidizing ability. Indeed, the reduction potential was estimated
to be −0.07 V in water or 0.17 V in acetonitrile for NBS15 and
1.03 V in water (pH = 2) for 2c.16 The oxidation potential of
Ag(Phen)2 was measured to be about 1.39 V.17 These data
+
support the oxidation of Ag(Phen)2+ by 2c but not by NBS. An
alternative mechanism involves the oxidation of Ag(I) by one
N−Br bond in 2c, and the alkyl radical generated after
decarboxylation abstracts a bromine atom from the other N−Br
moiety in 2c. However, this mechanism is unlikely because at
least 1 equiv of 2c is required on the basis of this mechanism,
while in many cases of our experiments the use of 0.8 equiv of
2c leads to the product bromide in over 90% yield. Thus, both
bromine atoms in 2c may well be incorporated into the
products.
In conclusion, we have successfully developed the silver-
catalyzed decarboxylative bromination of aliphatic carboxylic
acids with dibromoisocyanuric acid under mild conditions. This
method not only is efficient and general but also enjoys wide
functional group tolerance. In view of the versatility of alkyl
bromides in organic chemistry and easy availability of carboxylic
acids and dibromoisocyanuric acid, this catalytic Hunsdiecker
bromination should find important applications in organic
synthesis.
reactivities of carboxylic acids follow the order of benzyl ≈
tertiary > secondary > primary ≫ aromatic. This reactivity
pattern not only indicates that an oxidative decarboxylation
mechanism is involved but also suggests that chemoselective
decarboxylation can be implemented. As an example, the
treatment of diacid 6 with Ag(Phen)2OTf and 2c at 30 °C for
12 h led to the exclusive formation of γ-lactone 7 in 80% yield
(eq 2). Apparently, the carboxyl group at the quaternary carbon
in 6 underwent decarboxylative bromination chemoselectively
to give 5-bromo-5-methylpentanoic acid, which then cyclized to
afford 7 via intramolecular nucleophilic substitution.
A catalytic radical mechanism14 can be inferred from the
above results. To provide further evidence, the following
experiments were designed. Both cis- and trans-2-benzoylcyclo-
hexane-1-carboxylic acid 8 gave rise to the same decarboxylative
bromination product 9 in almost the same yield (eq 3). N-Allyl-
substituted β-amino acid 10 as a radical probe underwent a
decarboxylation−cyclization−bromination sequence, yielding
pyrrolidine 11 as a mixture of four diastereoisomers in a
51:26:13:10 ratio determined by crude 1H NMR (eq 4). These
two experiments support the formation of alkyl radicals after
decarboxylation.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b00439.
Full experimental details, characterizations of products,
1
and H and 13C NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.7b00439
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Letter
(14) For a comprehensive review on catalytic radical processes, see:
Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58.
(15) (a) Lind, J.; Jonsson, M.; Eriksen, T. E.; Merenyi, G.; Eberson,
L. J. Phys. Chem. 1993, 97, 1610. (b) Eberson, L.; Barry, J. E.;
Finkelstein, M.; Moore, W. M.; Ross, S. D. Acta Chem. Scand. 1986,
40, 283.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: clig@mail.sioc.ac.cn.
ORCID
Chaozhong Li: 0000-0002-5135-9115
Notes
(16) Gottardi, W. Monatsh. Chem. 1977, 108, 1067.
(17) Po, H. N. Coord. Chem. Rev. 1976, 20, 171.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was supported by the National Basic Research
Program of China (973 Program) (Grant No. 2015CB931900),
the National Natural Science Foundation of China (Grant Nos.
21421002, 21472220, and 21532008), and the Strategic Priority
Research Program of the Chinese Academy of Sciences (Grant
No. XDB20020000).
REFERENCES
■
(1) For reviews, see: (a) Johnson, R. G.; Ingham, R. K. Chem. Rev.
1956, 56, 219. (b) Wilson, C. V. Org. React. 1957, 332. (c) Sheldon, R.
A.; Kochi, J. K. Org. React. 1972, 19, 279. (d) Crich, D. Comp. Org.
Synth. 1991, 7, 717.
(2) Borodine, A. Ann. 1861, 119, 121.
(3) (a) Hunsdiecker, H.; Hunsdiecker, C. Ber. Dtsch. Chem. Ges. B
1942, 75, 291. (b) Hunsdiecker, H.; Hunsdiecker, C.; Vogt, E. U.S.
Patent 2176181, 1939; Chem. Abstr. 1940, 34, 1685.
(4) McKillop, A.; Bromley, D.; Taylor, E. C. J. Org. Chem. 1969, 34,
1172.
(5) Cristol, S. J.; Firth, W. C., Jr. J. Org. Chem. 1961, 26, 280.
(6) (a) Kochi, J. K. J. Am. Chem. Soc. 1965, 87, 2500. (b) Kochi, J. K.
J. Org. Chem. 1965, 30, 3265. (c) Kochi, J. K. Science 1967, 155, 415.
(7) (a) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron
Lett. 1983, 24, 4979. (b) Barton, D. H. R.; Crich, D.; Motherwell, W.
B. Tetrahedron 1985, 41, 3901. (c) Barton, D. H. R.; Lacher, B.; Zard,
S. Z. Tetrahedron Lett. 1985, 26, 5939. (d) Barton, D. H. R.; Lacher,
B.; Zard, S. Z. Tetrahedron 1987, 43, 4321.
(8) (a) Barton, D. H. R.; Faro, H. P.; Serebryakov, E. P.; Woolsey, N.
F. J. Chem. Soc. 1965, 2438. (b) Concepcion
Freire, R.; Hernandez, R.; Salazar, J. A.; Suarez, E. J. Org. Chem. 1986,
51, 402. (c) Camps, P.; Lukach, A. E.; Pujol, X.; Vazquez, S.
́
, J. I.; Francisco, C. G.;
́
́
́
Tetrahedron 2000, 56, 2703. (d) Kulbitski, K.; Nisnevich, G.;
Gandelman, M. Adv. Synth. Catal. 2011, 353, 1438. (e) Nakai, Y.;
Moriyama, K.; Togo, H. Eur. J. Org. Chem. 2016, 2016, 768.
(9) Candish, L.; Standley, E. A.; Gom
́ ́
ez-Suarez, A.; Mukherjee, S.;
Glorius, F. Chem. - Eur. J. 2016, 22, 9971.
(10) Wang, Z.; Zhu, L.; Yin, F.; Su, Z.; Li, Z.; Li, C. J. Am. Chem. Soc.
2012, 134, 4258.
(11) (a) Yin, F.; Wang, Z.; Li, Z.; Li, C. J. Am. Chem. Soc. 2012, 134,
10401. (b) Liu, X.; Wang, Z.; Cheng, X.; Li, C. J. Am. Chem. Soc. 2012,
134, 14330. (c) Liu, C.; Wang, X.; Li, Z.; Cui, L.; Li, C. J. Am. Chem.
Soc. 2015, 137, 9820. (d) Cui, L.; Chen, H.; Liu, C.; Li, C. Org. Lett.
2016, 18, 2188.
(12) (a) Zhu, Y.; Wen, X.; Song, S.; Jiao, N. ACS Catal. 2016, 6,
6465. (b) Zhu, Y.; Li, X.; Wang, X.; Huang, X.; Shen, T.; Zhang, Y.;
Sun, X.; Zou, M.; Song, S.; Jiao, N. Org. Lett. 2015, 17, 4702. (c) Kan,
J.; Huang, S.; Lin, J.; Zhang, M.; Su, W. Angew. Chem., Int. Ed. 2015,
54, 2199. (d) Hu, F.; Shao, X.; Zhu, D.; Lu, L.; Shen, Q. Angew. Chem.,
Int. Ed. 2014, 53, 6105. (e) Wang, P.-F.; Wang, X.-Q.; Dai, J. J.; Feng,
Y.-S.; Xu, H.-J. Org. Lett. 2014, 16, 4586. (f) Feng, Y.-S.; Xu, Z. Q.;
Mao, L.; Zhang, F.-F.; Xu, H.-J. Org. Lett. 2013, 15, 1472.
(13) For reviews on decarboxylative functionalization reactions, see:
(a) Gooβen, L. J.; Rodriguez, N.; Gooβen, K. Angew. Chem., Int. Ed.
2008, 47, 3100. (b) Park, K.; Lee, S. RSC Adv. 2013, 3, 14165.
(c) Shen, C.; Zhang, P.; Sun, Q.; Bai, S.; Hor, T. S. A.; Liu, X. Chem.
Soc. Rev. 2015, 44, 291. (d) Xuan, J.; Zhang, Z.-G.; Xiao, W.-J. Angew.
Chem., Int. Ed. 2015, 54, 15632.
D
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