General and chemoselective bisphosphonylation of secondary and tertiary amides

Article abstract of DOI:10.1021/acs.orglett.5b00004

With Tf₂O as the activation reagent, a mild and general method has been developed for the bisphosphonylation of both secondary and tertiary amides. The protocol is highly efficient and chemoselective, and it tolerates a number of sensitive functional groups such as cyano, ester, and aldehyde groups.

Full text of DOI:10.1021/acs.orglett.5b00004

Letter
pubs.acs.org/OrgLett
General and Chemoselective Bisphosphonylation of Secondary and
Tertiary Amides
Ai-E Wang,*,† Zong Chang,† Wei-Ting Sun,† and Pei-Qiang Huang*,†,‡
†Department of Chemistry, Fujian Provincial Key Laboratory of Chemical Biology, College of Chemistry and Chemical Engineering,
and Collaborative Innovation Centre of Chemistry for Energy Materials, Xiamen University, Xiamen, Fujian 361005, P. R. China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, P. R. China
S
* Supporting Information
ABSTRACT: With Tf2O as the activation reagent, a mild and general method
has been developed for the bisphosphonylation of both secondary and tertiary
amides. The protocol is highly efficient and chemoselective, and it tolerates a
number of sensitive functional groups such as cyano, ester, and aldehyde groups.
α-Amino bisphosphonates are an important class of biologically
active compounds that possess inhibitory activity on a variety of
biosynthesis pathway enzymes such as farnesyl pyrophosphate
synthase (FPPS),1 squalene synthetase,2 and 1-deoxyxylulose-5-
phosphate reductoisomerase3 and display antiparasitic,4 anti-
bacterial,5 and herbicidal6 activities. Several α-amino bi-
sphosphonate-based pharmaceuticals are currently in clinical
use to treat a variety of bone resorption diseases such as
osteoporosis, hypercalcemia, and Paget’s disease.7 Some of them
are also of interest in the context of cancer immunotherapy8 and
radiodiagonosis.9 Representative α-amino bisphosphonates of
biological importance are shown in Figure 1. In addition, α-
PCl3/H3PO4-,12 POCl3-,13 and triphosgene-mediated14 bi-
sphosphonylations of amides are the most straightforward
approaches. Another advantage of this kind of methods resides
in the use of highly stable and easily available amides as the
starting materials. However, using classical amide activating
reagents, these methods have some drawbacks, such as being
restricted to alkanecarboxylic amides, the need to perform the
reaction at high temperature, and low to moderate yields. In
addition, the issue of chemoselectivity has not been addressed. As
the substituents on the N-atom and the side chains attached to
the α carbon have a significant influence on the biological
activities,7d,19 the purposeful synthesis of functionalized α-amino
bisphosphonate derivatives is of paramount importance in the
search for compounds with a desirable biomedical profile. The
development of an efficient and general method for the
bisphosphonylation of amides is thus highly desirable.
In recent years, chemoselective addition of nucleophiles to the
inert amide carbonyls has attracted much attention.20 The direct
and highly chemoselective nucleophilic addition to active N-
alkoxyamides21 and reductive functionalization of amides by
Schwartz’s reagent22,23 have been extensively investigated by
Sato and Chida, Vincent and Kouklovsky, and Ganem,
respectively. In this context, Zhao has developed the first general
method for the reductive phosphonylation of amides by using
Schwartz’s reagent.23 However, the method cannot be used for
the synthesis of α-amino bisphosphonates. On the other hand,
trifluoromethanesulfonic anhydride (Tf2O)24,25 has proven to be
an advantageous reagent for the in situ activation of amides to
facilitate the nucleophilic addition of various N-, O-, S-, H-, and
C-nucleophiles. However, to the best our knowledge, the
bisphosphonylation of amides using Tf2O has never been
reported.
Figure 1. Representative α-amino bisphosphonates of medicinal
relevance.
amino bisphosphonates can serve as synthetic precursors of α-
amino vinylphosphonates, which are both important pharmaco-
phores and building blocks for the synthesis of biologically active
compounds.10
As a result of the exceptionally interesting biological properties
of α-amino bisphosphonates, several approaches have been
developed for the synthesis of these compounds,11 which include
bisphosphonylation of amides,12−14 nitriles,15 and α,β-unsatu-
rated imines,16 condensation of amines with triethyl orthofor-
mate and phosphites,17 and Beckman rearrangement of oximes
in the presence of phosphorus nucleophiles.18 Among them,
In connection with our efforts to develop new synthetic
methods based on the activation of amides with Tf2O, our group
has recently developed a variety of C−C bond formation
Received: January 2, 2015
Published: January 27, 2015
© 2015 American Chemical Society
732
DOI: 10.1021/acs.orglett.5b00004
Org. Lett. 2015, 17, 732−735

Organic Letters
Letter
methods starting from tertiary26 and secondary amides.27 As an
extension of this methodology, herein we report an efficient and
general method for the synthesis of α-amino bisphosphonates
from secondary and tertiary amides (Scheme 1).
a
Table 2. Bisphosphonylation of Secondary Amides
b
R1
R2
product yield (%)
Scheme 1. Bisphosphonylation of Amides by Tf2O Activation
entry
1
2
3
4
5
6
7
8
9
Ph
p-ClC6H4
m-BrC6H4
p-CF3C6H4
p-NCC6H4
p-NO2C6H4
p-MeO2CC6H4
p-HC(O)C6H4
p-Et2NC(O)C6H4
p-MeOC6H4
3,4,5-(MeO)3C6H2
o-MeC6H4
1-naphthyl
2-thienyl
Ph
i-Pr
i-Pr
2a
2b
2c
2d
2e
2f
93
88
83
82
76
76
82
64
62
72
79
d
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
2g
2h
2i
i-Pr
i-Pr
The bisphosphonylation of secondary amides was investigated
at first. N-Isopropylbenzamide 1a was chosen as the model
substrate. Initial screening of various base additives showed that
the incorporation of sterically hindered, weakly nucleophilic
bases, such as 2,6-lutidine, 2,6-di-tert-butyl-4-methylpyridine
(DTBMP), 2-chloropyridine, and 2-fluoropyridine, was crucial
to achieve an appreciable level of efficiency (Table 1). Among the
c
10
i-Pr
2j
c
11
i-Pr
2k
2l
12
13
i-Pr
i-Pr
2m
2n
2o
2p
2q
2r
d
c
14
i-Pr
80
83
76
80
85
57
71
63
55
d
15
16
17
18
19
20
21
22
23
24
c-pentyl
Bn
Ph
Ph
CH2CH2Cl
CH2CH2CO2Me
i-Pr
Table 1. Reaction Optimization for the Bisphosphonylation of
a
Ph
Secondary Amides
n-C10H21
n-C10H21
MeO2C(CH2)3
Me
2s
c-hexyl
n-butyl
n-butyl
Ph
2t
2u
2v
2w
2x
Me
b
HP(O)(OEt)2
(equiv)
yield
(%)
Me
2,6-Me2C6H3
d
entry
base
base (equiv)
a
Reaction conditions: Tf2O (1.2 equiv), 2,6-lutidine (1.2 equiv), DCM
(0.2 M), 0 °C, 30 min then HP(O)(OEt)2 (3.0 equiv), rt, 3 h.
Isolated yield. 9.0 equiv of HP(O)(OEt)2 was used. No desired
product was detected.
1
none
Et3N
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
2.0
2.5
4.0
40
2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.5
2.0
1.2
1.2
1.2
55
73
87
b
c
d
3
i-Pr2NEt
4
pyridine
c
5
2,6-lutidine
DTBMP
98 (93 )
96
6
7
2-chloropyridine
2-fluoropyridine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
2,6-lutidine
90
groups but also ester and aldehyde groups, which are sensitive
and labile under Tf2O activation, are largely compatible with the
current process to furnish the desired α-amino bisphosphonates
in good yields (entries 2−3 and 5−8). Significantly, the reactions
took place chemoselectively even in the presence of a tertiary
amide group (entry 9) to give the corresponding α-amino
bisphosphonate 2i. The bisphosphonylation of sterically
hindered 2-methylbenzamide 1l and 1-naphthamide 1m failed
to give the desired product (entries 12 and 13). Thiophene-2-
carboxamide 1n could also react chemoselectively to produce the
corresponding α-amino bisphosphonate 2n in 80% (entry 14). In
addition, the N-substituents on the secondary aroyl amides could
vary from isopropyl to other alkyl substituents and some
functional groups such as halogen and ester groups are tolerated
(entries 15−18).
The reaction also proceeded smoothly with alkanamides
(entries 19−22). High chemoselectivity was observed when the
reaction was carried out with ester functionalized amides 1u,
producing the corresponding α-amino bisphosphonate 2u in an
isolated yield of 63%. The N-substituents can be primary or
secondary alkyl groups, and they do not have much influence on
the reactivity. However, introduction of an N-aryl group to a
secondary amide completely abolished product formation
(entries 23 and 24).
8
91
9
99
10
11
12
13
72
65
91
97
a
Reaction conditions: Tf2O (1.2 equiv), base, DCM (0.2 M), 0 °C, 30
b
c
min then HP(O)(OEt)2, rt, 3 h. Determined by 31P NMR. Isolated
yield.
base additives screened, 2,6-lutidine was the optimal choice for
its high efficiency and low price. Further optimization on the
amount of 2,6-lutidine and diethyl phosphite showed that
treatment of amide 1a with 3.0 equiv of diethyl phosphite in the
presence of 1.2 equiv of 2,6-lutidine and 1.2 equiv of Tf2O
produced α-amino bisphosphonate 2a in an optimal isolated
yield of 93%.
Under the optimized conditions, a wide array of secondary
aroyl amides could be converted into the corresponding α-amino
bisphosphonates in good to modest yields (entries 1−18, Table
2). In general, benzamide derivatives bearing electron-with-
drawing groups on the phenyl ring (entries 2−9) show higher
reactivities than those having electron-donating groups (entries
10 and 11). The reaction is widely functional group tolerant and
highly chemoselective. Not only halogen, nitro, and cyano
Interestingly, when the reaction was performed with 4-bromo-
N-isopropylbutanamide 1y, the tandem bisphosphonylation and
733
DOI: 10.1021/acs.orglett.5b00004
Org. Lett. 2015, 17, 732−735

Organic Letters
Letter
cyclization occurred to afford the cyclic α-amino bisphosphonate
2y (Scheme 2).
Furthermore, the bisphosphonylation reactions also pro-
ceeded smoothly with tertiary formamides. The N-substituents
of formamides could vary from alkyl to benzyl and cyclic
substituents. Even the highly sterically hindered N,N-diisopropyl
fomamide12f reacted smoothly to give the desired α-amino
bisphosphonate 4l in an isolated yield of 81%. The bi-
sphosphonylation of N-benzyl-N-c-heptylformamide gave α-
amino bisphosphonate 4k in 92% yield, which after debenzyla-
tion, hydrolysis, and neutralization would produce disodium
cycloheptylaminomethylene bisphosphonate, a representative of
the latest generation of antiosteoporotic drug commercialized as
incadronate.7c,28
In summary, we report the first bisphosphonylation of amides
using Tf2O as the activation reagent. Under mild conditions,
both secondary and tertiary amides could be converted into α-
amino bisphosphonates in good to excellent yields. Compared
with previously reported methods, this protocol is highly efficient
and chemoselective and tolerant of a number of functional
groups such as cyano, ester, and aldehyde groups.
Scheme 2. Tandem Bisphosphonylation-Cyclization of N-
Isopropyl-4-bromobutanamide
Having established an efficient method for the bisphospho-
nylation of secondary amides, the application of this method to
tertiary amides was envisaged. Using N-benzoylpyrrolidine 3a as
the model substrate, the effects of base additives were screened
(see the Supporting Information for details). Among them,
DTBMP was shown to give the best results. In the event,
treatment of tertiary amide 3a with 1.2 equiv of Tf2O, 4.0 equiv of
DTBMP, and 3.0 equiv of diethyl phosphite, the corresponding
α-amino bisphosphonate 4a was obtained in an isolated yield of
92%. The expensive DTBMP could be recovered from the
reaction mixture by column chromatography in high yield and
reused in the subsequent bisphosphonylation without any
influence on the outcome of the reaction.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedure and characterization data of the
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
With the optimal reaction conditions defined, the scope of the
reaction was then explored by varying both the acyl group and N-
substituents of the tertiary amides. As can be seen from Scheme
3, both aroyl and alkanoyl amides could be converted to the
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: aiewang@xmu.edu.cn.
*E-mail: pqhuang@xmu.edu.cn.
a
Scheme 3. Bisphosphonylation of Tertiary Amides/Lactams
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the Natural
Science Foundation (NSF) of China (21332007), the Program
for Changjiang Scholars and Innovative Research Team in
University (PCSIRT) of Ministry of Education, and the Natural
Science Foundation of Fujian Province of China (2014J01062).
DEDICATION
Dedicated to Professor Dr. Yu-Fen Zhao.
■
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