Rh2(esp)2: An Efficient Catalyst for O-H Insertion Reactions of Carboxylic Acids into Acceptor/Acceptor Diazo Compounds

Article abstract of DOI:10.1002/ejoc.201600064

Rh₂(esp)₂ has been identified as a highly efficient catalyst for O-H insertion of carboxylic acids into acceptor/acceptor diazo compounds. The insertion reaction proceeds in CH₂Cl₂ within minutes at room temperature in excellent yields and accommodates carboxylic acids having varying functionalities including amino acids, free alcoholic and phenolic O-H, indole N-H, alkenes, alkynes, and substituted aromatics. In addition, the reaction tolerates a broad range of stable diazo compounds carrying diverse functional groups. Diazo-Acid Insertion: A novel Rh₂(esp)₂-catalyzed O-H insertion reaction of carboxylic acids into acceptor/acceptor diazo compounds has been developed. The reaction is highly chemoselective and accommodates carboxylic acids having varying functionalities including amino acids, free alcoholic and phenolic O-H, indole N-H, alkenes, alkynes, and substituted aromatics.

Full text of DOI:10.1002/ejoc.201600064

DOI: 10.1002/ejoc.201600064
Communication
Diazo, O–H Insertion
Rh2(esp)2: An Efficient Catalyst for O–H Insertion Reactions of
Carboxylic Acids into Acceptor/Acceptor Diazo Compounds
Arianne C. Hunter,[a] Kiran Chinthapally,[a] and Indrajeet Sharma*[a]
Abstract: Rh2(esp)2 has been identified as a highly efficient ties including amino acids, free alcoholic and phenolic O–H,
catalyst for O–H insertion of carboxylic acids into acceptor/ indole N–H, alkenes, alkynes, and substituted aromatics. In addi-
acceptor diazo compounds. The insertion reaction proceeds in tion, the reaction tolerates a broad range of stable diazo com-
CH2Cl2 within minutes at room temperature in excellent yields pounds carrying diverse functional groups.
and accommodates carboxylic acids having varying functionali-
Introduction
Acceptor/acceptor (A/A) diazo compounds are important build-
ing blocks in organic synthesis capable of novel transformations
such as cyclopropanation, cyclopropenation, insertion reactions
(C–H, N–H, O–H, S–H, B–H), trifluoromethylation, dipolar addi-
tion, cascade, and rearrangement reactions.[1] However, A/A di-
azo compounds, particularly those derived from dicarbonyls,
are the most stable diazo reagents.[2] Because of their stability,
harsh reaction conditions are required for the extrusion of nitro-
gen to generate reactive carbene intermediates. These reaction
conditions limit the utility of A/A diazos in significant transfor-
mations that demand selectivity such as cascade reactions, and
access to the α-acyloxy carbonyl motif found in complex mol-
ecules and bioactive scaffolds.[3]
O–H insertion reactions of alcohols into diazo compounds
have been thoroughly investigated. However, only a few exam-
ples of O–H insertion reactions of carboxylic acids into A/A di-
azo compounds are reported in the literature with RhII, PdII,
and CuII salts (Scheme 1, a).[4] The reaction conditions for these
transformations require long reaction times, high temperature,
and use of carboxylic acids as a solvent.[5] Therefore, these con-
ditions are not suitable for the O–H insertion reaction of carb-
oxylic acids carrying reactive functional groups such as alkene,
alkyne, aliphatic- and phenolic-OH, and electron-rich aromatic
rings. In particular, there is no example known in the literature
for the insertion of amino acids into A/A diazo compounds such
as diazodicarbonyls.
Scheme 1. O–H insertion reactions of carboxylic acids into acceptor–acceptor
diazo compounds.
Herein, we report a novel Rh2(esp)2-catalyzed O–H insertion
reaction of carboxylic acids into A/A diazo compounds. The re-
action proceeds under mild conditions within minutes at room
temperature to provide the insertion product in excellent yield
(Scheme 1, b).
Results and Discussion
We initiated our work toward identifying an efficient catalyst
that would allow the O–H insertion of carboxylic acids into
A/A diazo compounds under mild conditions. For the initial op-
timization, diethyl diazomalonate (1a), and Boc- -Phe-OH (2a)
L
[a] Department of Chemistry and Biochemistry, University of Oklahoma,
101 Stephenson Parkway, Norman, OK 73071, USA
E-mail: isharma@ou.edu
were selected as model substrates and exposed to the most
efficient conditions known in literature (Table 1, entries 1–5). To
our delight, insertion product 3a was obtained with all the
metal(II) salts (Rh/Pd/Cu).[6] Among all insertion reactions,
Rh2(OAc)4 proceeded under mildest conditions in moderate
http://www.indrajeetsharma.com/
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600064.
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yield (entry 1). Notably, diethyl 2-hydroxymalonate was ob-
tained as the major side product under all these conditions
presumably because of competing O–H insertion reaction of
water with carboxylic acid.
Table 1. O–H insertion reactions of Boc-L-Phe-OH into diethyl diazomalonate.
[a]
Entry Reagent
Solvent, T [°C], t
3, yield [%][b]
1
2
3
4
5
6
7
8
9
Rh2(OAc)4
Pd(OAc)2
Cu(acac)2
Cu(OAc)2
CH2Cl2, room temp., 12 h
CH2Cl2, reflux, 8 h
DCE, reflux, 5 h
DCE, reflux, 5 h
DCE, reflux, 12 h
CH2Cl2, r.t., 6 h
64
58
62
43
55
46
67
94
n.r.
40
Cu(OAc)2/CNCH2CO2Et
[c]
Rh2(TFA)4
[d]
Rh2(HFB)4
CH2Cl2, r.t., 6 h
Rh2(esp)2
–
CH2Cl2, r.t., 10 min
TFE,[e] reflux, 12 h
10
Hoveyda–Grubbs2nd gen. CH2Cl2, reflux, 10 h
[a] All optimization reactions were performed with 1a (1.50 equiv.), 2a
(1 equiv.) and catalyst (1 mol-%). [b] Isolated yields after column chromato-
graphy; n.r.: no reaction. [c] TFA = trifluoroacetate. [d] HFB = heptafluoro-
butyrate. [e] TFE = trifluoroethanol.
Encouraged by these findings, we then screened other RhII
salts that could reduce reaction time and avoid the byproduct
resulting from competing O–H insertion of water (entries 6–8).
To our surprise, Rh2(esp)2 developed by the Du Bois group for
C–H amination,[7] and also known for O–H insertion reactions
of alcohols into diazo compounds,[8] initiated the acid insertion
reaction at room temperature within minutes in excellent yield
(entry 8).
Figure 1. Scope of Rh2(esp)2-catalyzed room temperature O–H insertion reac-
[b]
tions of carboxylic acids. [a] 1a (1.5 equiv.), 2b–m (1 equiv.). Syringe pump
addition of diethyl diazomalonate 1a over a period of 2–4 h.
We also screened other known conditions for decomposition
of A/A diazo compounds such as trifluoroethanol (TFE) as a
solvent[9] (entry 9) and the Hoveyda–Grubbs (2nd generation)
catalyst recently reported by the Hussaini group[10] (entry 10).
However, these conditions were met with limited success as
evident with no reaction under TFE conditions even under re-
fluxing conditions.
With optimized conditions in hand, we then investigated
scope of the Rh2(esp)2-catalyzed O–H insertion reaction with
diethyl diazomalonate and its applicability to a range of amino
acids (Figure 1). Sterically hindered amino acids such as Boc-
Pro-OH were inserted with high efficiency into diethyl diazoma-
lonate (Figure 1, 3b). The reaction also proceeded in good yield
with Boc-Ser-OH having a free hydroxyl side chain (Figure 1,
our delight, carboxylic acids containing alkyne and alkene func-
tionality afforded the corresponding insertion product (Fig-
ure 1, 3g–i) in high yields without any evidence of cyclopropen-
ation or cyclopropanation.
Next, we investigated the electronic effects of aryl substitu-
ents on the reactivity of carboxylic acids (Figure 1, 3j–3l). Nota-
bly, 4-nitrobenzoic acid (Figure 1, 3k) was less reactive and re-
quired slow addition of diethyl diazomalonate via a syringe
pump to avoid decomposition of the A/A diazo without inser-
tion. Conversely, 4-methoxybenzoic acid was highly reactive
and provided the insertion product in excellent yield (Figure 1,
3l).
It is important to note that in the presence of the phenolic
3c) producing only a minimum amount (18 %) of the double –OH found in salicylic acid, the desired carboxylic acid –OH
insertion product (S1a, see Supporting Information for details). insertion product is obtained in excellent yield, with no produc-
The varying electron rich reactive sites of the indole moiety in tion of a bis-inserted side product (Figure 1, 3m). This finding
tryptophan exhibited some challenges, providing the desired demonstrates the compatibility of the phenolic O–H side chain
product (Figure 1, 3d) in a relatively lower yield.[11]
in this transformation.[12]
To further explore the generality of this transformation, a
Next, we examined the electronic effects of various electron-
wide range of carboxylic acids carrying reactive functional withdrawing groups on the reactivity of A/A diazos. All of the
groups such as alkene, alkyne, phenolic –OH, and electron-rich/ diazo substrates carrying varying functionalities were synthe-
-deficient aromatic rings were examined (Figure 1, 3e–m). To sized using literature procedures except compounds 1c and 1j.
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These compounds were prepared from the corresponding ac- the first example of an amino acid insertion into A/A diazos. An
tive methylene compounds using 4-acetamidobenzenesulfonyl important feature of this transformation is the chemoselectivity
azide as our diazo-transfer reagent (see Supporting Information toward carboxylic acid O–H insertion when molecules possess
for details).
diazo-reactive functionalities such as alkenes, alkynes, hydroxyl
and phenolic O–H, and electron-rich aromatics including indole
N–H. This methodology also offers the possibility to perform
enantioselective transformations when required given the mild
reaction conditions. Applications of this chemoselective O–H
insertion reaction to cascade transformations are on going and
will be reported in due course.
For the substrate scope, the reaction accommodates a broad
range of stable diazo compounds having diverse electron-with-
drawing functionalities such as esters, amides, and aliphatic
carbonyl compounds (Figure 2, 3n–q). We were delighted to
find that the highly stabilized 1,3-indandione derived diazo also
proceeds smoothly at room temperature to provide the inser-
tion product (Figure 2, 3r), albeit at a longer reaction time of 3
hours. The developed conditions were also conducive to vary-
ing sites of reactivity found within oxindoles, including free NH
(Figure 2, 3s, 3t). These reaction conditions are not only limited
to A/A diazos but also work efficiently with acceptor diazo com-
pounds (Figure 2, 3u). Lastly, it is important to note the applica-
bility of this transformation to biologically important molecules
as evident from the sole carboxylic acid O–H insertion product
obtained with diazo-containing phenylalanine (Figure 2, 3v).
Acknowledgments
The authors thank Dr. Susan Nimmo and Dr. Steven Foster for
expert NMR and mass spectral support, and the University of
Oklahoma start-up funds and the Office of the Vice President
for Research for generous financial support. We would also like
to thank the University of Oklahoma, College of Arts & Sciences
for monetary support through the Junior Faculty Fellowship
Award to I. S. and the Robberson Research Fellowship to A. H.
Keywords: Homogeneous catalysis · Diazo compounds ·
Rhodium · O–H Insertion · Chemoselective
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Received: January 17, 2016
Published Online: March 9, 2016
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