Direct Amidation of N-Boc- and N-Cbz-Protected Amines via Rhodium-Catalyzed Coupling of Arylboroxines and Carbamates

Article abstract of DOI:10.1021/acs.orglett.5b03061

N-Boc- and N-Cbz-protected amines are directly converted into amides by a novel rhodium-catalyzed coupling of arylboroxines and carbamates, replacing the traditional two-step deprotection-condensation sequence. Both protected anilines and aliphatic amines are efficiently transformed into a wide variety of secondary benzamides, including sterically hindered and electron-deficient amides, as well as in the presence of acid-labile and reducible functional groups.

Full text of DOI:10.1021/acs.orglett.5b03061

Letter
pubs.acs.org/OrgLett
Direct Amidation of N‑Boc- and N‑Cbz-Protected Amines via
Rhodium-Catalyzed Coupling of Arylboroxines and Carbamates
Diane S. W. Lim, Tedrick T. S. Lew, and Yugen Zhang*
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, Singapore 138669, Singapore
S
* Supporting Information
ABSTRACT: N-Boc- and N-Cbz-protected amines are
directly converted into amides by a novel rhodium-catalyzed
coupling of arylboroxines and carbamates, replacing the
traditional two-step deprotection−condensation sequence.
Both protected anilines and aliphatic amines are efficiently
transformed into a wide variety of secondary benzamides,
including sterically hindered and electron-deficient amides, as
well as in the presence of acid-labile and reducible functional
groups.
mide bond formation ranks as one of the most utilized
A
chemical reactions in drug discovery.1 While traditional
amide synthesis by dehydrative condensation of a carboxylic
acid and an amine has proven suitable for the majority of
amides, this approach relies on stoichiometric amounts of
coupling reagents, raising economic and environmental
concerns.2 Added to the limited success this disconnection
has achieved in constructing sterically hindered and electron-
deficient amides,3 the search for new catalytic modes of amide
bond formation remains an ongoing challenge.
Figure 1. One-step conversion of N-Boc-protected amines to amides.
In recent years, extensive work in the field of three-
component carbonylations of halides, amines, and carbonyl
source has produced notable advances in metal-catalyzed
amidations.4 However, practical applications are hampered by
the risks of handling of gaseous CO, while the alternative
pathway of carbon nucleophile addition to carbamoyl-based
electrophiles requires added steps of converting amines into
reactive carbamoyl chlorides5 or isocyanates6 utilizing toxic
phosgene-based reagents. In contrast, no metal-catalyzed
amidation has been developed for carbamates despite the
prevalence of this compound class as a protecting group in
multistep syntheses, possibly owing to the poor electrophilicity
of the sp2-hybridized carbon center.7,8 In particular, carbamates
with tert-butyl and benzyl O-substitution, better known as Boc
and Cbz groups, are widely employed as amine protecting
groups in medicinal and process chemistry,1 and a direct
catalytic amidation of such carbamates would be of interest to
the synthetic community, achieving in a single step the same
overall transformation as a deprotection−condensation se-
quence traditionally applied to protected amines (Figure 1).
During the course of developing a copper(I)-catalyzed
amidation of isocyanates with boronic esters activated by
alkoxides, we observed carbamate intermediate 1 (Table 1). On
extended reaction times, consumption of this intermediate
corresponded to increased amide yields.6d Encouragingly, when
we submitted carbamate 1 to identical reaction conditions with
boronic ester 2a, a low yield of amide 3a was obtained along
with significant amounts of amidine 4 and 3,5-dimethylaniline
(entry 1). A survey of different combinations of boronic acid
derivatives and transition-metal complexes revealed that both
amidine formation and carbamate deprotection could be
suppressed by employing arylboroxine 2c in conjunction with
dimeric rhodium(I) complexes when the reaction was
conducted in 1,4-dioxane (entries 2−5). Surprisingly, none of
the boronic esters included in our study were reactive under
these conditions and were recovered as biphenyl homocoupled
side products (entry 3). Exchanging sodium tert-butoxide for
potassium hydroxide resulted in carbamate hydrolysis, yielding
3,5-dimethylaniline (entry 6), while potassium fluoride
returned an excellent yield of amide 3a (entry 7). Interestingly,
employing cesium fluoride, the more commonly employed
albeit costly and moisture-sensitive base, resulted in no product
formation, and carbamate 1 was recovered unchanged (entry
8). Reducing the amount of organoboron nucleophile to 1.2
equiv resulted in minimal loss of isolated amide product (entry
9).
The scope of the reaction was investigated with a variety of
arylboroxines and N-Boc-anilines with the results summarized
in Figure 2. Arylboroxines with electron-rich substituents in the
para position underwent smooth coupling with carbamate 1 to
Received: October 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03061
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Letter
a
Table 1. Optimization of Reaction Conditions
b
c
entry
PhB(OR)2
catalyst
base
solvent (temp, °C)
yield (%)
d
1
2
3
4
5
6
7
8
2a
IPrCuCl
NaOt-Bu
NaO-t-Bu
NaOt-Bu
NaOt-Bu
NaOt-Bu
KOH
DMF (140)
16
e
f
2b
2a/2b
2c
SIPrCuCl
DMF (140)
30
[Cl(cod)Rh]2
[Cl(cod)Rh]2
[Cl(nbd)Rh]2
[Cl(cod)Rh]2
[Cl(cod)Rh]2
[Cl(cod)Rh]2
[Cl(cod)Rh]2
dioxane (110)
dioxane (110)
dioxane (110)
dioxane (100)
dioxane (100)
dioxane (100)
dioxane (100)
0
37
25
0
2c
2c
2c
KF
89
0
2c
CsF
g
9
2c
KF
86
a
b
Standard reaction conditions: 1 (0.25 mmol), 2 (2a/2b: 0.50 mmol, 2c: 0.17 mmol), base (0.25 mmol), solvent (0.5 mL), 16 h. 5 mol % of Cu or
c
d
e
f
g
Rh. Yield of isolated product. 9% of 4. 0.13 mmol. 20% of 4. 0.10 mmol of 2c. IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. SIPr =
1,3-bis(2,6-diisopropylphenyl) imidazolidene. nbd = norbornadiene. cod = 1,5-cyclooctadiene.
partners bearing electron-withdrawing trifluoromethyl, ester,
and nitro groups in the para or meta positions.6b,9 The
amidation conditions tolerate both an ortho substitution and
extended aromatic system on the boroxine partner (3i,j), while
successful coupling of a heteroarylboroxine with carbamate 1
for the synthesis of thiophenecarboxamide 3k was achieved
with a three-fold excess of the organoboron coupling partner.
A similar pattern of reactivity was observed when substitution
on the N-Boc-aniline was varied: electron-rich and halide-
substituted arenes underwent efficient conversion to amides 3l,
3m, and 3o, while an electron-withdrawing nitro substituent
resulted in a modest yield of amide 3n even after an extended
reaction time. Coumarin-based amide 3p was prepared in a
moderate yield and notably contains a Michael acceptor as a
competing site for the organoboron nucleophile to undergo
1,4-addition.10 Despite the use of fluoride base, suitably bulky
silyl ethers were not degraded, as evinced by the isolation of
silyl-protected phenol 3q. Carbamates in sterically congested
environments also proved to be competent substrates, allowing
the bulky amides 3r and 3s to be prepared using this method.
In addition to tert-butyl carbamates, benzyl carbamates (Cbz)
were transformed into benzamides under identical reaction
conditions (Figure 3). The reaction profiles of N-Cbz-amines
were generally cleaner than that of their N-Boc counterparts
and corresponded to improved yields of amide products from
Figure 2. Coupling of N-Boc-protected anilines and arylboroxines.
Reaction conditions: N-Boc-aniline (0.50 mmol), arylboroxine (0.20
mmol), [Cl(cod)Rh]2 (13 μmol), KF (0.50 mmol), 1,4-dioxane (1
boroxine and carbamate substrates that had proved challenging
(3h, 3n, and 3o).
We next investigated N-Boc-protected aliphatic amines as
mL), 100 °C, 16 h: (a) 12 h reaction time; (b) 24 h reaction time; (c)
coupling partners and were delighted to find that this could be
0.60 mmol of tris(thiophene-3-yl)boroxine; (d) recovered 26% N-Boc-
accomplished by exchanging dimeric rhodium(I) complex
[Cl(cod)Rh]2 for monomeric catalyst (cod)2Rh(OTf) (Figure
4). Under these conditions, Boc-protected benzylic amines with
primary and secondary substitution and amines appended to
(poly)cyclic scaffolds were efficiently coupled with trisphenyl-
boroxine to form benzamides 3t−x in excellent yields. The
conversion of primary aliphatic carbamates to amides 3y and 3z
required slightly elevated temperatures, which resulted in partial
lactamization of amide 3y. For the design of synthetic routes,
aniline; (e) recovered 12% N-Boc-aniline; (f) 120 °C. Boc = tert-
butyloxycarbonyl. TBS = tert-butyldimethylsilyl.
afford benzamides 3b and 3c in excellent yields, as did halide-
substituted arylboroxines to yield chloro- and bromoarenes 3d
and 3e. Although electron-deficient boronic acids have been
reported to undergo homocoupling and protodeboronation
under similar conditions, we were pleased to achieve good to
satisfactory yields of amides 3f−h with boroxine coupling
B
DOI: 10.1021/acs.orglett.5b03061
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Figure 3. Coupling of N-Cbz-protected anilines and arylboroxines.
Reaction conditions: N-Cbz-aniline (0.50 mmol), arylboroxine (0.20
mmol), [Cl(cod)Rh]2 (13 μmol), KF (0.50 mmol), 1,4-dioxane (1
mL), 100 °C, 16 h; (a) 24 h reaction time; (b) recovered 9% N-Cbz-
aniline. Cbz = benzyloxycarbonyl.
Figure 5. Possible mechanism for boroxine−carbamate coupling.
of hydrogen-bonding interactions between borate A and
1
carbamate 1 by an upfield shift of the N−H signal in the H
NMR spectrum of the mixture compared to that of the isolated
carbamate.11
In conclusion, we have reported a novel rhodium(I)-
catalyzed coupling of boroxines and tert-butyl or benzylcarba-
mates in the presence of fluoride to afford benzamides in good
yield. This method provides a direct route for converting N-
Boc- and N-Cbz-protected amines to amides and is tolerant of
acid-sensitive and reducible functional groups, thereby offering
an attractive alternative to the two-step deprotection−
condensation sequence traditionally employed for these amines.
Finally, evidence for carbamate activation by a borate
intermediate suggests the coupling may be extended to other
classes of carbon nucleophiles. Studies in this area are ongoing
in our laboratory.
Figure 4. Coupling of N-Boc-protected alkylamines and arylboroxines.
Reaction conditions: N-Boc-amine (0.50 mmol), arylboroxine (0.20
mmol), (cod)2Rh(OTf) (25 μmol), KF (0.50 mmol), 1,4-dioxane (1
mL), 100 °C, 16 h; (a) 120 °C; (b) 8:1, amide/lactam. Tr = trityl.
this method tolerates the conversion of N-Boc-protected
amines to amides in the presence of an acid-labile O-trityl
functional group (3z), which is incompatible with the strong
acid conditions required for Boc deprotection.
ASSOCIATED CONTENT
■
S
* Supporting Information
Initially, the coupling was thought to proceed via addition of
a boroxine-derived organorhodium species to the isocyanate
generated by elimination of tert-butyl alcohol from tert-butyl
carbamate. However, it was ruled out by the absence of
isocyanate intermediate by 1H NMR spectroscopy.11 With that,
the following mechanism is proposed for the reaction (Figure
5): fluoride-induced ring opening of trisarylboroxine 2c releases
mixed boronate A,12 which upon transmetalation with rhodium
complex generates arylrhodium(I) species B. Addition (or
carborhodation) of nucleophilic B at the sp2-hybridized carbon
of carbamate−borate complex C affords alkoxyrhodium(I)
complex D.13 Subsequent β-alkoxy elimination14 and borate
dissociation yields the amide product and returns rhodium(I)
alkoxide for the next catalytic turnover. This pathway is
supported by the following observations: (i) the unique
reactivity of boroxines over boronic esters and acids,
implicating mixed borate of type E as a critical intermediate,
(ii) secondary and cyclic carbamate systems are unreactive,
suggesting complexation is required to enhance the electro-
philicity of the carbamate coupling partner, and (iii) detection
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03061.
Experimental procedures, extended optimization experi-
ments, characterization, 1H and 13C NMR spectra of new
substrates and products, and mechanistic studies (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ygzhang@ibn.a-star.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Institute of Bioengineering and
Nanotechnology (Biomedical Research Council, Agency for
Science, Technology and Research (A*STAR), Singapore).
C
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Letter
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