MgBr 2 · OEt 2: A Lewis Acid Catalyst for the O - And N -Boc Protection of Phenols and Amines

Article abstract of DOI:10.1080/00397911.2014.976348

MgBr₂ · OEt₂ efficiently catalyzes the O- and N-tert-butoxycarbonylation of functionalized phenols and amines. The presented procedure is operationally simple and done under solvent-free conditions. GRAPHICAL ABSTRACT.

Full text of DOI:10.1080/00397911.2014.976348

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MgBr · OEt : A Lewis Acid Catalyst for
2
2
the O- and N-Boc Protection of Phenols
and Amines
a
a
b
Aaron Schechter , David Goldrich , Jessica R. Chapman , Beatrix M.
b
a
Uberheide & Daniel Lim
a
Department of Chemistry, Yeshiva University, New York, New York,
USA
b
Click for updates
Proteomics Resource Center, New York University School of
Medicine, New York, New York, USA
Accepted author version posted online: 01 Dec 2014.Published
online: 12 Jan 2015.
To cite this article: Aaron Schechter, David Goldrich, Jessica R. Chapman, Beatrix M. Uberheide &
Daniel Lim (2015) MgBr · OEt : A Lewis Acid Catalyst for the O- and N-Boc Protection of Phenols and
2
2
Amines, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 45:5, 653-660, DOI: 10.1080/00397911.2014.976348
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Synthetic Communications , 45: 653–660, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2014.976348
MgBr · OEt : A LEWIS ACID CATALYST FOR
2
2
THE O- AND N-Boc PROTECTION OF PHENOLS
AND AMINES
1
1
2
Aaron Schechter, David Goldrich, Jessica R. Chapman,
2
1
Beatrix M. Uberheide, and Daniel Lim
Department of Chemistry, Yeshiva University, New York, New York, USA
Proteomics Resource Center, New York University School of Medicine,
1
2
New York, New York, USA
GRAPHICAL ABSTRACT
2 2
Abstract MgBr · OEt efficiently catalyzes the O- and N-tert-butoxycarbonylation of
functionalized phenols and amines. The presented procedure is operationally simple and
done under solvent-free conditions.
Keywords: Amines; Boc; di-tert-butyl dicarbonate; Lewis acid; phenols; protecting group
INTRODUCTION
An important aspect of the total synthesis of molecules is the development and
implementation of functional-group protection strategies. It has become imperative
to develop protecting group strategies for commonly encountered functional groups
[
1,2]
in organic synthesis, such as alcohols and amines.
The tert-butoxycarbonyl (Boc)
group is one of the most important protecting groups available for organic synthesis.
Among carbonic acid derivatives used as protecting groups, tert-butyl carbonates
Received September 28, 2014.
Address correspondence to Daniel Lim, Department of Chemistry, Yeshiva University, 500 W.
185th St., New York, NY 10033, USA. E-mail: dlim@yu.edu
6
53

654
A. SCHECHTER ET AL.
(
O-Boc alcohols) and tert-butyl carbamates (N-Boc amines) are of great importance
[
3]
in organic chemistry.
Although there are a number of protecting groups for the alcohol functional
group, organic tert-butyl carbonates, or O-Boc, derivatives have gained increas-
ing use and importance in the past few years both in industry and in academic
[
4]
research. This is due to their increased stability in comparison to the corre-
[
5]
sponding esters under basic conditions. Likewise, tert-butyl carbamates, or
N-Boc, derivatives are extensively used for protecting amino groups, because of
their stability in basic environments and ability to assist in developing orthogonal
[
6]
functional-group protection strategies. A majority of the O- and N-Boc meth-
[
7,8]
odologies work in basic media or in the presence of a Lewis base.
cases, preparation of organic carbonates and carbamates have required the use
In some
[
9]
of toxic reagents, such as phosgene, pyridine, and carbon monoxide. Thus
much effort has been devoted to developing more environmentally friendly pro-
[
10]
cedures for their synthesis.
Although there are a variety of base-mediated reaction conditions available for
O- and N-Boc protection in the literature, a number of novel modes of catalyzing the
[11]
Boc protection of phenols and amines have been reported. For example, the use of
Lewis acids to catalyze the Boc protection of alcohols and amines has shown great
[
12]
promise.
However, it is important to note that one of the more interesting limita-
tions in the Lewis acid–catalyzed Boc protection is that O-Boc formation does not
become feasible as phenols form the tert-butyl ethers with Boc O in the presence
2
of a strong Lewis acid. In contrast, O-Boc formation occurs with the use of a mild
[
13,14]
Lewis acid, which may require heating.
Because of the very attractive nature of the N-Boc group, apart from the classi-
cal base-induced procedures, only a handful of Lewis acids have been used as cata-
[
12]
lysts for the N-Boc protection of amines.
have been a few examples of organocatalytic O- and N-tert-butoxycarbonylation
In contrast to Lewis acid catalysis, there
[15]
protocols that have been reported using reagents such as CBr , PPh , and I .
4
3
2
Herein we report MgBr · OEt as a novel Lewis acid catalyst for the O- and N-
2
2
tert-butoxycarbonylation of phenols and amines under neat and neutral conditions
at room temperature. We deliberately chose these reagents because they are compat-
ible with the capacity to retain their activity even in the presence of oxygen- and
nitrogen-containing compounds. MgBr · OEt is commercially available, inexpen-
2
2
sive, and generates no toxic by-products on aqueous workup, which would allow
us to conduct the reactions open to the atmosphere using untreated, reagent-grade
solvent if necessary.
DISCUSSION
To explore the use of MgBr · OEt toward the preparation of O-Boc-protected
2
2
phenols we chose 4-nitrophenol as a test substrate and treated it with equimolar
amounts of Boc O and MgBr · OEt in CH Cl (Table 1, entry 1). The O-Boc-
2
2
2
2
2
protected phenol product was obtained in good yield, 72%, after column chromato-
graphy. After exploring the effects of catalyst loading we discovered an optimum
catalytic amount of 10 mol% of MgBr · OEt was sufficient to afford the desired
2
2
product in excellent yield at room temperature (88% yield after column

MgBr
2
·OEt
2
-CATALYZED O- AND N-Boc PROTECTION
· OEt -catalyzed O-Boc protection
655
Table 1. MgBr
2
2
b
Entry
% Catalyst
Solvent
Time (h)
% Yield
1
2
3
4
100
25
10
CH
CH
CH
2
2
2
Cl
Cl
Cl
2
2
2
0.5
1
16
16
72
80
88
88
10
None
a
Reactions were run with 1.0 mmol of alcohol and 1.0 mmol of Boc
Isolated yield after coloumn chromatography.
2
O.
b
chromatography). We were also pleased to discover that the same results could be
obtained when the reaction was repeated without solvent. Typically, shortly after
the introduction of a catalytic amount of MgBr · OEt into the reaction mixture
2
2
there is evolution of gas that took place, which was followed by the formation of
the corresponding O-Boc derivative. All products were characterized by instrumental
1
13
techniques such as infrared (IR), H NMR, C NMR, and mass spectrometry.
Having found suitable reaction conditions with MgBr · OEt as a Lewis acid
2
2
catalyst, we decided to explore the ease at which the alcohol group of various phenols
can be manipulated in the presence of other functional groups. We planned to test
the compatibility of the reaction conditions with various functional/protecting
groups such as nitro, carboalkoxy, bromo, methoxy, acetyl, formyl, acetamido,
and nitrile (Table 2, entries 1–10). The desired O-Boc compounds were formed in
good to excellent isolated yields (80–95%) with excellent chemoselectivity and no
competitive side reactions. These conditions were also applied to a benzyl alcohol
derivative, along with an Fmoc-protected tyrosine methyl ester (Table 2, entries 11
and 12). Unfortunately, for both cases heating was necessary to obtain moderate
to good yields of the respective O-Boc products.
With the optimized reaction conditions for O-Boc protection of phenols in
hand, we then evaluated the scope of the reaction using a variety of structurally
divergent amines and Boc O (Table 3), ranging from aromatic, aliphatic, and hetero-
2
cyclic to amino acid methyl esters. All substrates reacted to give the corresponding
N-Boc adducts within 3 h in moderate to excellent isolated yields.
Thus, the following mechanism can be proposed for the reaction. Both car-
bonyl oxygen atoms of Boc O are activated by MgBr · OEt (Scheme 1, 21) initially,
2
2
2
making the carbonyl group more susceptible to nucleophilic attack by a phenol or
amine. This facilitates extrusion of tert-butanol and carbon dioxide as leaving

656
A. SCHECHTER ET AL.
a
Table 2. MgBr
2
· OEt
2
-catalyzed O-Boc protection of phenols
b
Entry
1
Substrate
Product
% Yield
2
88
2
3
3
4
95
85
4
5
95
92
5
6
6
7
7
8
90
85
8
9
82
(
Continued)

MgBr
2
·OEt
2
-CATALYZED O- AND N-Boc PROTECTION
657
Table 2. Continued
b
Entry
Substrate
Product
% Yield
c
9
10
80
1
0
1
11
80
c
1
72
68
1
2
c
12
13
a
b
c
Reactions were run with 1.0 mmol of alcohol and 1.0 mmol of Boc
Isolated yield after column chromatography.
Heated at 60 °C.
2
O for 16 hours.
entities, eventually leading to formation of O- or N-Boc-protected product 24
Scheme 1).
MgBr · OEt shows promising results for the protection of various electroni-
(
2
2
cally and structurally diverse phenols and amines, as O- and N-Boc derivatives in
moderate to excellent isolated yields. In contrast to the existing methods, this new
method offers the following advantages: (i) it is mild and operationally simple; (ii)
it is inexpensive, has lower catalyst loading, and uses a readily available and envir-
onmentally benign catalyst under solvent-free conditions; (iii) it displays chemoselec-
tivity; (iv) it has wide substrate scope; and (v) it has no side reactions.
In conclusion, we have described a simple procedure for the O- and N-Boc pro-
tection of phenols and amines using MgBr · OEt under solvent-free conditions.
2
2
Further work is in progress to explore this novel catalyst for use in other organic
transformations. We believe that our protocol will be a valuable contribution for
the O- and N-Boc protection of phenols and amines both in academia and industries.
EXPERIMENTAL
Boc O (1.0 mmol) was added to a mixture of phenol or amine (1.0 mmol) and
2
MgBr · OEt (0.1 mmol) in a round-bottom flask, at which point an evolution of gas
2
2

658
A. SCHECHTER ET AL.
a
Table 3. MgBr
2
· OEt
2
-catalyzed O-Boc protection of amines
b
Entry
1
Substrate
Product
% Yield
14
90
2
3
15
16
85
74
4
5
6
80
82
68
1
7
18
1
9
occurs, and the reaction mixture was stirred magnetically at room temperature (if
necessary, reactions was heated to ∼ 60 °C). After complete consumption of the phe-
nol or amine (by thin-layer chromatography, TLC; 3–16 h), the reaction mixture was
diluted with water and extracted with EtOAc (3 × 20 mL), and the combined EtOAc
extracts were dried with Na SO and concentrated under vacuum rotary evapor-
2
4
ation. The residue was isolated by column chromatography through a bed of silica
gel and eluted with 5–30% ethyl acetate in hexane to afford the desired Boc-
protected product.

MgBr
2
·OEt
2
-CATALYZED O- AND N-Boc PROTECTION
659
Scheme 1. Proposed mechanism for O- and N-Boc protection.
FUNDING
This work was supported by the Yeshiva University.
SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher's website.
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