An efficient protocol for the amidation of carboxylic acids promoted by trimethyl phosphite and iodine

Article abstract of DOI:10.1002/ejoc.201101030

A practical, one-pot protocol is described for the conversion of carboxylic acids into amides through carboxyl activation by the reagent combination of trimethyl phosphite and iodine. This method integrates several advantages: (1) it allows amines to be chemoselectively acylated with excellent results in the presence of sulfur and oxygen nucleophiles; (2) the method shows wide generality in respect of solvent, base, and substrate; (3) the reagents used are widely available and much less expensive than common coupling reagents, and (4) the process is remarkably convenient, permitting extraction, recrystallization, and column chromatography as optional work-up procedures. The chemoselectivity and generality of the method, the low cost, and wide availability of reagents combined with the ease of use make it a very favorable process.

Full text of DOI:10.1002/ejoc.201101030

FULL PAPER
DOI: 10.1002/ejoc.201101030
An Efficient Protocol for the Amidation of Carboxylic Acids Promoted by
Trimethyl Phosphite and Iodine
[a]
[a]
[a]
[a]
[a]
[b]
Qun-Li Luo,* Lina Lv, Yu Li, Jian-Ping Tan, Wenhui Nan, and Qun Hui*
Keywords: Synthetic methods / Amides / Carboxylic acids / Peptides
A practical, one-pot protocol is described for the conversion
of carboxylic acids into amides through carboxyl activation
by the reagent combination of trimethyl phosphite and io-
dine. This method integrates several advantages: (1) it allows
amines to be chemoselectively acylated with excellent re-
sults in the presence of sulfur and oxygen nucleophiles; (2)
the method shows wide generality in respect of solvent, base,
and substrate; (3) the reagents used are widely available and
much less expensive than common coupling reagents, and
(4) the process is remarkably convenient, permitting extrac-
tion, recrystallization, and column chromatography as op-
tional work-up procedures. The chemoselectivity and gener-
ality of the method, the low cost, and wide availability of rea-
gents combined with the ease of use make it a very favorable
process.
Introduction
(TPP) or polymer-supported triphenylphosphane (Pol-TPP)
[10]
with an additive, such as TPP or Pol-TPP with CCl ,
4
Amide bond formation is still an active research topic
and is a fundamentally important reaction in organic syn-
[11]
[12]
[13]
BrCCl3,
Br ,
N-halosuccinimide,
dithiodipyridine
2
[14]
[15]
trihalomethyl derivative,[16] I2,[17]
or its dioxide,
and others.
SO3,
[
1–4]
thesis.
The most straightforward route to form an amide
[18]
is through direct reaction of a carboxylic acid with an
amine. However, this method is limited due to the require-
ment for high reaction temperature. Thus, pre-activation of
the carboxyl group has become the standard strategy for
amide formation. A carboxylic acid can be transformed in
advance into an activated derivative, such as acid halide or
anhydride, or activated in situ by activating reagents. Such
a reagent for amidation, often named a coupling reagent, is
an additive or additive combination. Many coupling rea-
Trimethyl phosphite, which is a widely available and inex-
pensive chemical, is an important material in industry that
is used as an intermediate in the synthesis of pesticides and
flame retardants, as a polymerization catalyst, and as a
coating additive. It shows low potential safety risk accord-
[19]
ing to the safety data.
To the best of our knowledge,
[
5]
trimethyl phosphite has not been investigated as an activa-
ting reagent to promote amide formation, in spite of the
[2c,7,10–18]
fact that various organophosphorous reagents
have
[
6]
gents are commercially available, such as carbodiimides,
been universally applied as activating reagents for carbox-
ylic acids and as peptide coupling reagents. We found that
the combination of P(OMe)3 and I2 had the ability to
mildly activate a range of carboxylic acids, and the active
intermediates could be used to acetylate amines selectively
over thiols and alcohols. This finding provides a practical
method with which to acylate amines chemoselectively in
the presence of sulfur and oxygen nucleophiles.
phosphonium salts,[ and uronium salts. Although these
reagents have been universally used, they suffer to a greater
or lesser extent from a number of drawbacks: (1) relatively
high cost of the reagent; (2) poor stability of the reagent
toward moisture; (3) difficulties associated with removing
the reagent-derived byproduct during purification, and (4)
generation of carcinogenic reagent-derived byproducts. For
7]
[8]
these reasons, there have been a number of reports concern-
ing alternative coupling reagents.[
9–18]
Particular attention
has focused on the combination of triphenylphosphane Results and Discussion
To check the feasibility of this process, the acylation of
aniline with benzoic acid was chosen as a model reaction.
When the reaction was performed with an organic base in
dichloromethane (CH Cl ), anilide was obtained in excel-
lent yield (Table 1). Encouraged by this result, we tested
several common bases. The results clearly demonstrated
that common organic bases were suitable for the model re-
action, and that these were superior to inorganic bases
(Table 1, entry 1–4 vs. 5 and 6). This was partially attributed
[
[
a] College of Chemistry and Chemical Engineering, Southwest
University,
Chongqing, 400715, China
Fax: +86-23-6825-4000
E-mail: qlluo@swu.edu.cn
2
2
b] College of Material Science and Engineering, Southwest
University,
Chongqing, 400715, China
E-mail: qhui01@swu.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101030.
6916
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6916–6922

Efficient Amidation of Carboxylic Acids
to the solubility of bases; organic bases are more soluble in ability to dissolve common organic chemicals it was se-
organic solvent, leading to the rapid formation of the mixed lected as the solvent of choice for subsequent investigations.
carboxylic-phosphoric anhydride (see below).
Interestingly, a very recent method of activating carbox-
[
17b]
ylic acids with Ph P/I reported by Robles et al.
showed
3
2
Table 1. Base screening experiments.
that solvent and base strongly affected the extent of esterifi-
cation and amidation. When the authors replaced Ph3P
with P(OEt) , no product was obtained.
3
To assess the scope of the present protocol, various aro-
matic and aliphatic substrates were examined. The results,
summarized in Table 3, showed that both aromatic and ali-
phatic carboxylic acids quickly reacted with aromatic and
aliphatic primary amines as well as aliphatic secondary
amines, giving the expected amide product in good to excel-
lent yields. Simple carboxylic acids, for example, benzoic
acid, propionic acid, and heptanoic acid, produced amides
in excellent yields (Table 3, entries 1–13). Even with the
Entry[a]
Base
(iPr)
Et
pyridine
DMAP
Time [h]
Yield [%][b]
1
2
3
4
5
6
2
N
NEt
3
3
3
3
3
3
96
98
93
95
54
67
3
K
2
CO
3
NaOH
[a] Reagents and conditions: benzoic acid (3 mmol), aniline
(
(
2 mmol), trimethyl phosphite (3 mmol), iodine (3 mmol), base sterically hindered pivalic acid, good yields were obtained
5 mmol), CH Cl
2
2
(15 mL). [b] Yield of the isolated product after (Table 3, entries 14 and 15). Notably, this protocol also gave
chromatographic purification on silica column.
high yields with less nucleophilic amines (Table 3, entries
–12) and less active conjugated carboxylic acids (Table 3,
8
The role of the solvent is crucial in many organic reac-
tions. To investigate possible solvent effects in our process,
several aprotic solvents were screened by taking the model
reaction with triethylamine as base (Table 2). The reaction,
when conducted in common solvents such as halohydrocar-
bon, ether, ester, or nitrile, was found to be extraordinarily
effective. All gave clean anilide in excellent yield, demon-
strating the viability of this method for amide formation.
These results suggested that it was possible to perform the
reaction in a broad-spectrum of solvents, and that the amid-
ation can proceed smoothly without significant fluctuations
in yield. However, N,N-dimethylformamide (DMF) was not
suitable for this reaction (Table 2, entry 7). A possible ex-
planation is that DMF readily reacts with the active or-
ganophosphorous intermediate (see below). In contrast,
good yield was obtained when the reaction was performed
in N-methyl-2-pyrrolidone (NMP), which is a more stable
dipolar solvent than DMF (Table 2, entry 8).
entries 16–19). Generally, for acylating less nucleophilic
amines or amidating less active conjugated carboxylic acids,
it is preferable to use more active acyl halides instead of
acids that are activated in situ, to obtain good yields. The
present method provides an efficient alternative for the for-
mation of amides directly from sluggish substrates that avo-
ids the use of acyl halides by in situ activation of carboxylic
acids. Furthermore, α,β-unsaturated carboxylic acids and
heterocyclic substituted carboxylic acids produced satisfac-
tory results (Table 3, entries 20–24). These results confirm
that the present protocol is of wide generality with respect
to solvent, base, and substrate.
It should be noted that the pure products were obtained
in high yields directly through simple extraction (Table 3,
entries 6, 7, and 13) or by recrystallizing the concentrated
extract of the reaction mixture (Table 3, entries 18, 21, and
22); this was possible because the reactions were very clean
and the byproducts were soluble in the aqueous layer. Prob-
lems associated with purification is one of the major disad-
vantages for some amidation methods, for example, with
N,NЈ-dicyclohexylcarbodiimide (DCC) mediated condensa-
Table 2. Solvent screening experiments.
[
5b]
tion. Fortunately, our method completely overcomes this
drawback.
To establish the mechanism of the current process, we
Entry[a]
Solvent
CHCl
Time [h]
Yield [%][b]
31
used P NMR spectroscopy to monitor the progress of the
1
2
3
4
5
6
7
8
3
3
3
3
3
3
3
3
3
97
98
96
93
93
94
0
31
reaction. As shown in Scheme 1, the P NMR signal of
CH
CH
2
Cl
CN
2
P(OMe)3 appeared at δ = 141.7 ppm as an octet in
3
[
20]
CDCl3. When an equimolar amount of solid iodine was
dissolved in the reaction mixture, cooled with an ice bath,
dioxane
AcOEt
THF
DMF
NMP
the signal of P(OMe) disappeared immediately and a single
3
3
signal appeared at δ = –35.3 ppm as a septet ( J
=
P–O–CH
81
[
21a]
[21b]
1
5.0 Hz, ref.
J = 14.9 Hz). Skowronska et al.
investi-
[
(
a] Reagents and conditions: benzoic acid (3 mmol), aniline
2 mmol), trimethyl phosphite (3 mmol), iodine (3 mmol), triethyl-
gated the reaction of P(OEt) with I in detail at low tem-
3
2
perature in CD Cl solution; they disclosed that triethoxy-
2
2
amine (5 mmol), solvent (15 mL). [b] Yield of the isolated product
after chromatographic purification on silica column.
iodophosphonium iodide (A in Scheme 1, δ = 15 ppm) was
P
formed in quantitative yield almost instantaneously at
Among the tested solvents, CH Cl proved to be slightly –100 °C and rapidly transformed at –85 °C into diethyl
2
2
better than the others, and because this solvent has a good iodophosphate (B) with the simultaneous appearance of a
Eur. J. Org. Chem. 2011, 6916–6922
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6917

Q.-L. Luo, Q. Hui et al.
FULL PAPER
3 2
Table 3. Substrate generality of the amidation reactions promoted by P(OMe) /I .
[
a] Reagents and conditions: acid (3 mmol), amine (2 mmol), P(OMe)
noted otherwise. The product was isolated by chromatographic purification on silica column if not noted otherwise. [b] CHCl
iPr) NEt as base; the reaction was performed at –15 °C. [c] The reaction was performed in AcOEt (15 mL) at –10 °C. [d] CHCl
solvent, (iPr) NEt as base, the reaction mixture was gradually warmed to 35 °C. [e] AcOEt as solvent. [f] NMP as solvent. [g] The
reactions were performed with N-protected amino acid (1.5 mmol), HCl·H-Gly-OEt (1 mmol), P(OMe) (1.5 mmol), I (1.5 mmol), and
iPr) NEt (3.5 mmol) in AcOEt (10 mL). [h] The pure product was directly obtained through simple extraction with AcOEt from the
reaction mixture. [i] The pure product was obtained through recrystallization from AcOEt of the extract of the reaction mixture.
3
(3 mmol), I
2
(3 mmol), Et
3
N (5 mmol), CH
2
Cl
2
(15 mL) unless
as solvent,
as
3
(
2
3
2
3
2
(
2
3
1
P NMR signal at δ = –41.0 ppm. Our observations were was consistent with the consumption of aniline, which was
consistent with these data.[
21]
Thus, the signal at δ = monitored by thin layer chromatography (TLC). Therefore,
–35.3 ppm arose from dimethyl iodophosphate (C). When our observation suggested that the key step of the protocol
benzoic acid was introduced into the reaction mixture, no was the formation of the mixed anhydride from the phos-
new signal appeared in the spectrum. After triethylamine phoryl iodide produced in situ. The phosphoryl iodide is an
[
24]
was added, the signal at δ = –35.3 ppm quickly disappeared active intermediate that can react with DMF, therefore it
and a new signal appeared simultaneously at δ = –5.1 ppm is understandable that a negative result was obtained when
3
(
septet, J
= 11.6 Hz). This signal was confirmed to the present method was conducted in DMF (Table 2, entry
P–O–CH
[22]
arise from BzOP(O)(OMe) (D). The addition of aniline 7).
2
gradually weakened the signal at δ = –5.1 ppm and simulta-
To elucidate the chemoselectivity of this method, several
neously intensified the signal at δ = 0.95 ppm, which was competitive experiments were conducted (Scheme 2[ ).
25]
[
23]
presumed to arise from dimethyl phosphate ion (E). Af- When a mixture of aniline and methanol (1:10) was used
ter three hours at room temperature, no perceptible change in this procedure [Scheme 2, Equation (1)], the amine was
3
1
was observed in the P NMR spectrum. This observation predominantly acylated in 94% yield, and no ester was
6918
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6916–6922

Efficient Amidation of Carboxylic Acids
nucleophiles against sulfur and oxygen nucleophiles. Thus,
by taking advantage of the differential reactivity between
nucleophiles, it is possible to carry out the acetylation of
amines chemoselectively in the presence of thiol and alcohol
moieties.
Scheme 2. Chemoselective acylation of amines.
Scheme 1. Reaction pathway of the trimethyl phosphite-mediated
amidation process.
To expand the application scope of this method, the con-
densation reactions of amino acid derivatives were tested.
The results show that dipeptides were obtained in satisfac-
tory yields, albeit slightly inferior to those of simple amides
obtained. With an equimolar mixture of aniline and (Table 3, entries 25–27). Both Boc- and Cbz-protected
benzenethiol [Scheme 2, Equation (2)], 93% anilide was iso- amino acids were tolerated under the condensation condi-
lated, leaving the thiol unaffected (reaction monitored by tions. Compared with simple acid and amine substrates,
TLC). On the other hand, competitive experiments with the amino acid derivatives are more sterically hindered because
acid component [Scheme 2, Equations (3) and (4)] showed of their α-substituent, and their reactivity is consequently
that (i) an aliphatic carboxylic acid is superior to its aro- lowered to some extent. Nevertheless, the results were
matic counterpart to some extent (selectivity ratio of propi- equivalent to, or even better than, those obtained using
[
4b,4c]
onic acid to benzoic acid, 2.7:1), suggesting that the elec- many of the recently developed methods
tronic effect of the substituents on the carboxylic acid affec- perior to results obtained using conventional coupling
ted the reactivity slightly, and (ii) the steric effects of the methods.
and were su-
[
4a,5–17]
4-Nitroaniline could be introduced into the
substituents on the carboxylic acid had more impact on the specific peptide substrate of an enzyme as a fluorogenic tag
[
26]
reactivity than the electronic effect. In comparison, the to enable an assay for the enzyme, but its nucleophilicity
selectivity ratio of the reaction towards propionic acid com- is reactively low for some coupling methods. Gratifyingly,
pared to pivalic acid reached as high as 21:1. To further our method was sufficiently efficient to couple a Boc-pro-
confirm the reactivity of the activated acid with an oxygen tected amino acid with an amine of such low nucleophilicity
nucleophile, another experiment was carried out [Scheme 2, in 70% yield (Table 3, entry 27).
Equation (5)]. Consistently, under these conditions, no es-
Although methods involving the mixed carboxylic-phos-
phoric anhydride derived from phosphoryl chlorides and
ters were isolated even at elevated reaction temperature. 31
P
[
27]
NMR spectroscopic monitoring of the reaction (see above) bromides are known for amidation reactions, to our best
demonstrated that the actual active species of carboxylic knowledge, methods involving phosphoryl iodide or phos-
acid was the mixed carboxylic-phosphoric anhydride. The phorus acid tri-ester have not been reported. In essence, the
good chemoselectivity of this method was deductively at- success of our protocol was attributed to carboxyl acti-
tributed to the fact that the relatively low reactivity of the vation by phosphoryl iodide formed in situ (Scheme 1).
mixed anhydride allowed discrimination between the subtly Comparing the present results with the methods mentioned
[
27]
different nucleophilicities of the nucleophiles. In other above, it was found that the method described herein was
words, for highly activated carboxyl forms, for example, superior in a number of respects. Phosphoryl iodides were
acyl halides, the selectivity tends to be low.[ These obser- more active than phosphoryl chlorides and bromides. Nev-
vations implied that our protocol had the remarkable ad- ertheless, dimethyl iodophosphate (C) in solution at –15 °C
vantage that it can be used to exclusively select nitrogen to room temperature was found to be moderately active.
25]
Eur. J. Org. Chem. 2011, 6916–6922
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6919

Q.-L. Luo, Q. Hui et al.
FULL PAPER
As the 31P NMR spectroscopic monitoring of the reaction Experimental Section
revealed (see above), no reaction between C and benzoic
General: Commercially available reagents were used as received.
Solvents for reactions were dried using standard procedures and
acid took place before the addition of TEA. As soon as
TEA was added, the mixed anhydride (D) was formed in-
stantaneously. In our protocol, the phosphoryl iodide was
quantitatively generated from phosphorus acid tri-ester, and
stored in Schlenk flasks over molecular sieves under N
otherwise. All solvents for chromatographic separations were dis-
tilled before use. All reactions were performed in N -balloon-pro-
2
if not noted
2
it was easier to exclusively form the mixed anhydride than tected round-bottomed flasks and were monitored by TLC with
the corresponding chloride and bromide counterparts be- Huanghai HSGF254 silica gel coated plates (Yantai, China). Col-
cause of its better activity. The mild anhydride selectively umn chromatography was carried out with Haiyang 200–300 mesh
silica gel (Qingdao, China). Melting points were recorded with an
reacted with nitrogen nucleophiles to yield the desired prod-
X-6 microscope melting point detector (Beijing Focus Instrument
uct. The method involving mixed carboxylic-phosphoric
1
13
31
Co., Ltd.). H, C, and P NMR spectra were recorded with a
anhydride usually gave higher regioselectivity toward nucleo-
philic attack than did the method involving mixed carbonic
anhydride. The main reason was that a second acylation of
the nucleophile could take place at the carbonyl carbon of
the activating reagent in the case of the mixed carbonic an-
1
Bruker AV 300 spectrometer at ambient temperature. The H NMR
experiments are reported in δ units, parts per million (ppm) down-
field from tetramethylsilane (internal standard) and were measured
relative to the signals for residual chloroform (δ = 7.26 ppm) or
dimethyl sulfoxide (δ = 2.50 ppm) in the deuterated solvents. The
[
2c]
1
3
hydride.
To minimize the side reaction, lower tempera-
C NMR spectra are reported in ppm relative to deuteriochloro-
tures and/or exotic reagents are often required. In contrast, form (δ = 77.0 ppm) or deuterated dimethyl sulfoxide (δ =
1
31
the mixed carboxylic-phosphoric anhydride method avoids 39.5 ppm) and all were obtained with H decoupling. The
such side reactions.
Compared with the existent methods, the present proto-
col is distinguished by its practicality and integrates several
advantages. Firstly, the reagents were widely available and
much less expensive than common coupling reagents. The
P
3 4
NMR spectra are reported in ppm relative to H PO (δ = 0 ppm).
The identities of all the products were confirmed by comparison of
their spectroscopic data with those of authentic samples (see the
Supporting Information). The yields in Tables 1, 2, and 3 refer to
isolated yields of compounds (average of two runs).
Typical Procedure for the Amidation of Simple Substrates. Reaction
of Benzoic Acid with Aniline: A solution of P(OMe)
.0 mmol) in dichloromethane (15 mL) was cooled with an ice bath,
2
then I (760 mg, 3.0 mmol) was added. After the solid iodine was
completely dissolved, benzoic acid (366 mg, 3.0 mmol) and Et
0.70 mL, 5.0 mmol) were added in sequential order, and the solu-
tion was stirred for 10 min in a cooling bath. Aniline (182 μL,
2.0 mmol) was added and the mixture was stirred for 10 min. After
key reagents are trimethyl phosphite and I . The combined
2
3
(0.35 mL,
cost of the reagents is 1–3% that of common coupling rea-
gents such as EDCI, PyBOP, and HBTU, and 10% that of
diethyl chlorophosphite,[ whereas the coupling efficiency
of the approach was equivalent or even better. Secondly,
unlike many common coupling reagents, trimethyl phos-
3
28]
3
N
(
phite and I are stable toward moisture. This permits the
2
operations to be managed under less restrictive conditions. removing the cooling bath, the reaction mixture was stirred for 3 h
Neither reagent storage and transfer nor the reaction instal- at room temperature (reaction monitored by TLC), then diluted
lation required strictly water-free techniques. Thirdly, the with saturated aqueous NaHCO and extracted with dichlorometh-
3
ane (3ϫ 30 mL). The combined organic layer was sequentially
washed with water, 1 m HCl, water, and brine, dried with anhydrous
purification process was extremely simple. The by-products
were water-soluble and could be removed easily through ex-
traction, recrystallization, or column chromatography. Fi-
nally, the method showed good chemoselectivity towards
the acylation of amines in the presence of sulfur and oxygen
nucleophiles.
Na
2 4
SO , and then purified by silica column chromatography (hex-
anes/EtOAc) to afford N-phenylbenzamide (1; 387 mg, 98% yield)
1
as a white solid; m.p. 64–66 °C. H NMR (300 MHz, CDCl
3
): δ =
.88 (s, 1 H), 7.87 (d, J = 7.2 Hz, 2 H), 7.64 (d, J = 7.8 Hz, 2 H),
.55 (t, J = 7.8 Hz, 1 H), 7.48 (t, J = 7.2 Hz, 2 H), 7.37 (t, J =
7
7
7
1
3
.8 Hz, 2 H), 7.15 (t, J = 7.3 Hz, 1 H) ppm. C NMR (300 MHz,
): δ = 165.8 (C), 137.9 (C), 135.0 (C), 131.8 (CH), 129.1
2ϫ CH), 128.8 (2ϫ CH), 127.0 (2ϫ CH), 124.6 (CH), 120.2 (2ϫ
CDCl
3
(
Conclusions
CH) ppm.
We have developed a mild, safe, convenient, and econ-
omic one-pot protocol for the conversion of carboxylic ac-
ids into amides through carboxyl activation by the reagent (10 mL) was cooled in an ice bath, then I (381 mg, 1.5 mmol) was
Typical Procedure for Peptide Synthesis. Synthesis of Boc-Phe-Gly-
OEt (25): A solution of P(OMe) (180 μL, 1.5 mmol) in EtOAc
3
2
combination of trimethyl phosphite and iodine. The ap- added. After the solid iodine was completely dissolved, Boc-Phe-
proach is general with respect to solvent, base, and sub- OH (398 mg, 1.5 mmol) and (iPr) NEt (610 μL, 3.5 mmol) were
2
added in sequential order, and the solution was stirred for 10 min in
a cooling bath. To the mixture was added HCl·H-Gly-OEt (139 mg,
strate. Extraction, recrystallization, and column chromatog-
raphy are optional in the work-up. This method provides
an excellent alternative to the known amidation procedures,
allowing the acylation of amines to proceed selectively in
the presence of sulfur and oxygen nucleophiles. It is also
suitable for peptide synthesis and involves extraordinarily
inexpensive reagents. The chemoselectivity and generality
1
mmol) and the reaction was stirred for 10 min. After removing
the cooling bath, the reaction mixture was continually stirred at
room temperature until the consumption of ethyl glycinate was
complete (reaction monitored by TLC), then diluted with saturated
3
aqueous NaHCO and extracted with EtOAc (3ϫ 30 mL). The
combined organic layer was sequentially washed with water, 1 m
of the method, the low cost, wide availability of reagents, HCl, water, and brine, dried with anhydrous Na SO , and then
2
4
and ease of use make it a very favorable process.
purified by silica column chromatography (hexanes/EtOAc) to af-
6920
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6916–6922

Efficient Amidation of Carboxylic Acids
ford Boc-Phe-Gly-OEt (25; 311 mg, 89% yield) as a white solid;
[8] a) V. Dourtoglou, B. Gross, V. Lambropoulou, C. Zioudrou,
Synthesis 1984, 572–574; b) R. Knorr, A. Trzeciak, W.
Bannwarth, D. Gillessen, Tetrahedron Lett. 1989, 30, 1927–
1
m.p. 88–92 °C. H NMR (300 MHz, CDCl
3
): δ = 7.34–7.18 (m, 5
H), 6.60 (d, J = 5.2 Hz, 1 H), 5.13 (d, J = 7.5 Hz, 1 H), 4.43 (br.
s, 1 H), 4.19 (q, J = 7.1 Hz, 2 H), 4.01 (dd, J = 5.2, 18.2 Hz, 1 H),
1
930.
9] a) K. Venkataraman, D. R. Wagle, Tetrahedron Lett. 1979, 20,
037–3040; b) Z. J. Kami n´ ski, P. Paneth, J. Rudzi n´ ski, J. Org.
[
[
[
3
3
3
1
8
.93 (dd, J = 4.8, 18.3 Hz, 1 H), 3.13 (dd, J = 6.3, 13.8 Hz, 1 H),
.04 (dd, J = 6.3, 13.8 Hz, 1 H), 1.38 (s, 9 H), 1.27 (t, J = 7.0 Hz,
3
Chem. 1998, 63, 4248–4255; c) H. L. Rayle, L. Fellmeth, Org.
Process Res. Dev. 1999, 3, 172–176; d) L. De Luca, G. Giaco-
melli, A. Porcheddu, M. Salaris, Synlett 2004, 2570–2572; e)
A. Rolfe, D. A. Probst, K. A. Volp, I. Omar, D. L. Flynn, P. R.
Hanson, J. Org. Chem. 2008, 73, 8785–8790.
H) ppm. 13C NMR (300 MHz, CDCl
): δ = 171.5 (C), 169.4 (C),
55.4 (C), 136.6 (C), 129.2 (2ϫ CH), 128.5 (2ϫ CH), 126.8 (CH),
0.1 (C), 61.4 (CH ), 55.6 (CH), 41.2 (CH ), 38.3 (CH ), 28.2 (3ϫ
), 14.1 (CH ) ppm.
3
2
2
2
CH
3
3
10] a) S. Yamada, Y. Takeuchi, Tetrahedron Lett. 1971, 12, 3595–
Supporting Information (see footnote on the first page of this arti-
cle): Compound characterization data and copies of the NMR
spectra of compounds 1–27.
3
598; b) R. Appel, G. Biiumer, W. Striiver, Chem. Ber. 1975,
108, 2680–2692; c) R. Appel, G. Biiumer, W. Striiver, Chem.
Ber. 1976, 109, 801–804; d) R. Appel, W. Struves, L. Willms,
Tetrahedron Lett. 1976, 17, 905–906; e) R. Appel, L. Willms,
Chem. Ber. 1981, 114, 858–866; f) J. J. Landi Jr., H. R. Brink-
man, Synthesis 1992, 1093–1095.
Acknowledgments
11] L. E. Barstow, V. J. Hruby, J. Org. Chem. 1971, 36, 1305–1306.
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (NSFC) (grant number
[12] J. Garcia, F. Urpi, J. Vilarrasa, Tetrahedron Lett. 1984, 25,
4841–4844.
20971105), the Scientific Research Foundation for the Returned
[13] a) P. Frøyen, Tetrahedron Lett. 1997, 38, 5359–5362; b) B. P.
Bandgar, S. V. Bettigeri, Synth. Commun. 2004, 34, 2917–2924;
c) P. Frøyen, Synth. Commun. 1995, 25, 959–968.
Overseas Chinese Scholars, State Education Ministry (grant
number [2007]1108), the Natural Science Foundation of Chongqing
[
[
[
14] a) R. Matsueda, H. Takahagi, T. Mukaiyama, Chem. Lett.
977, 719; b) K. Horiki, Tetrahedron Lett. 1976, 17, 4103–4106.
15] I. J. Galpin, G. W. Kenner, A. Marston, Bioorg. Chem. 1979, 8,
23–332.
16] a) J. J. Hans, R. W. Driver, S. D. Burke, J. Org. Chem. 2000, 65,
114–2121; b) H.-P. Buchstaller, H. M. Ebert, U. Anlauf,
Science
& Technology Commission (CSTC) (grant number
1
2006BB4026), the Fundamental Research Funds for the Central
Universities (grant number XDJK2009C093), and the Science and
Technology Foundation of Southwest University (grant number
SWUB2006001).
3
2
Synth. Commun. 2001, 31, 1001–1005; c) D. H. Kang, T. Y. Joo,
W. H. Lee, S. Chaysripongkul, W. Chavasiri, D. O. Jang, Tetra-
hedron Lett. 2006, 47, 5693–5696.
[
[
[
1] a) R. C. Larock, Comprehensive Organic Transformations, A
Guide to Functional Group Preparations, 2nd ed., Wiley-VCH,
New York, 1999; b) T. W. Greene, P. G. M. Wuts, Protective
Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New
York, 1999.
2] For selected recent reviews, see: a) H. Charville, D. Jackson, G.
Hodges, A. Whiting, Chem. Commun. 2010, 46, 1813–1823; b)
I. Georgiou, G. Ilyashenko, A. Whiting, Acc. Chem. Res. 2009,
[
17] a) A. Kumar, H. K. Akula, M. K. Lakshman, Eur. J. Org.
Chem. 2010, 2709–2715; b) S. P. Morcillo, L. A. de Cienfuegos,
A. J. Mota, J. Justicia, R. Robles, J. Org. Chem. 2011, 76, 2277–
2
281; c) R. Caputo, E. Cassano, L. Longobardo, D. Mastro-
ianni, G. Palumbo, Synthesis 1995, 141–143.
[
18] a) K. E. Fairfull-Smith (née Elson), I. D. Jenkins, W. A. Lough-
lin, Org. Biomol. Chem. 2004, 2, 1979–1986; b) K. E. Elson,
I. D. Jenkins, W. A. Loughlin, Tetrahedron Lett. 2004, 45,
4
2, 756–768; c) S.-Y. Han, Y.-A. Kim, Tetrahedron 2004, 60,
2447–2467.
2
491–2493; c) R. C. Rodrigues, I. M. A. Barros, E. L. S. Lima,
3] For selected examples, see: a) C. Gunanathan, Y. Ben-David,
D. Milstein, Science 2007, 317, 790–792; b) L. U. Nordstrøm,
H. Vogt, R. Madsen, J. Am. Chem. Soc. 2008, 130, 17672–
Tetrahedron Lett. 2005, 46, 5945–5947; d) S.-B. Kang, H.-S.
Yim, J.-E. Won, M.-J. Kim, J.-J. Kim, H.-K. Kim, S.-G. Lee,
Y.-J. Yoon, Bull. Korean Chem. Soc. 2008, 29, 1025–1032; e) Y.
Saito, H. Ouchi, H. Takahata, Tetrahedron 2008, 64, 11129–
1
7673; c) K. Arnold, B. Davies, D. Herault, A. Whiting, Angew.
Chem. 2008, 120, 2713; Angew. Chem. Int. Ed. 2008, 47, 2673–
1
1135; f) X. Lin, M. J. Robins, Org. Lett. 2000, 2, 3497–3499;
2
1
2
676; d) X. Yang, V. B. Birman, Org. Lett. 2009, 11, 1499–
502; e) J. W. Bode, R. M. Fox, K. D. Baucom, Angew. Chem.
006, 118, 1270; Angew. Chem. Int. Ed. 2006, 45, 1248–1252;
g) A. V. Narsaiah, D. Sreenu, K. Nagaiah, Synth. Commun.
2
006, 36, 137–140; h) S. Bae, M. K. Lakshman, J. Org. Chem.
008, 73, 1311–1319.
2
f) A. Latorre, S. Rodríguez, J. Izquierdo, F. V. González, Tetra-
hedron Lett. 2009, 50, 2653–2655.
–
1
[
[
19] Its toxicity data are as follows: ORL-RAT LD50 1600 mg kg ,
IHL-RAT LC50 Ͼ 10000 ppm per 4 h, IPR-RAT LD50
[
[
4] For selected recent examples, see: a) M. C. Bröhmer, S. Mund-
inger, S. Brse, W. Bannwarth, Angew. Chem. Int. Ed. 2011, 50,
–
1
–1
4
180 mg kg , SKN-RBT LD50 2600 mg kg . Its UN Hazard
Code is Class 3.0, and its packing group is III (minor danger).
Nevertheless, the chemical is potentially carcinogenic and mu-
tagenic. These data are referenced from Chemical and Other
Safety Information at The Physical and Theoretical Chemistry
Laboratory, Oxford University, see: http://msds.chem.ox.ac.uk/
TR/trimethyl_phosphite.html.
6
175–6177; b) J. Pan, N. O. Devarie-Baez, M. Xian, Org. Lett.
2011, 13, 1092–1094; c) D. J. Hardee, L. Kovalchuke, T. H.
Lambert, J. Am. Chem. Soc. 2010, 132, 5002–5003; d) H. Jiang,
B. Liu, Y. Li, A. Wang, H. Huang, Org. Lett. 2011, 13, 1028–
1031.
5] a) F. A. Carey, R. J. Sundberg, Advanced Organic Chemistry,
Part B: Reactions, Synthesis, 4th ed.), Kluwer Academic, New
York, 2001; b) A. I. Pearson, W. R. Roush, Handbook of Rea-
gents for Organic Synthesis Activating Agents and Protecting
Groups, John Wiley & Sons, Chichester, UK, 1999.
3
1
20] The coupled P NMR signal of P(OMe) in principle should
3
appear as ten-line multiplet, but was observed as an octet.
[21] a) M. Kainosho, J. Phys. Chem. 1970, 74, 2853–2855; b) A.
Skowronska, M. Pakulski, J. Michalski, D. Cooper, S. Trippett,
Tetrahedron Lett. 1980, 21, 321–322.
[6] a) J. C. Sheehan, G. P. Hess, J. Am. Chem. Soc. 1955, 77, 1067–
1
068; b) W. Koenig, R. Geiger, Chem. Ber. 1970, 103, 788–798;
(D) was isolated in 78% yield. The 1H and
[22] BzOP(O)(OMe)
2
1
3
c) L. A. Carpino, A. El-Faham, Tetrahedron 1999, 55, 6813–
6
C NMR spectra were in agreement with its structure. The
3
1
830.
signal of P NMR was at δ = –4.7 ppm relative to H
CDCl (septet, JP–O–CH = 11.3 Hz), which appeared at δ =
3
4
PO in
3
[
7] a) J. Coste, M.-N. Dufour, A. Pantaloni, B. Castro, Tetrahedron
Lett. 1990, 31, 669–672; b) C. van der Auwera, S. van Damme,
M. J. O. Anteunis, Int. J. Pept. Res. 1987, 29, 464–471.
3
–5.1 ppm after it was added into the reaction mixture. Litera-
3
ture value was at δ = –4.5 ppm ( JP–O–CH = 11.7 Hz), see: R.
Eur. J. Org. Chem. 2011, 6916–6922
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6921

Q.-L. Luo, Q. Hui et al.
FULL PAPER
Kluger, L. L. Cameron, J. Am. Chem. Soc. 2002, 124, 3303–
Y. B. Kim, L. M. Kopcho, M. S. Kirby, L. G. Hamann, C. A.
Weigelt, W. J. Metzler, J. Marcinkeviciene, Arch. Biochem. Bio-
phys. 2006, 445, 9–18.
3308.
[
23] L. D. Quin, A Guide to Organophosphorus Chemistry, John
Wiley & Sons, Toronto, 2000.
24] The well-known Vilsmeier reaction demonstrates that DMF
can react with phosphoryl trichloride. Hence, we presumed
phosphoryl iodide could be deactivated by DMF. This aspect,
mechanistically and synthetically, is under further investiga-
tion.
[27] a) B. Gaede, Org. Process Res. Dev. 1999, 3, 92–93; b) A. Go-
recka, M. Leplawy, J. Zabrockl, A. Zwiersak, Synthesis 1978,
474–476.
[
[28] Price ratios were based on the specification of 25–500 g amount
from the current Alfa Aesar Chemicals Catalog in China, cal-
culated from the price per mole of each reagent. Price ratios
calculated from other commercial chemicals catalogs were sim-
ilar. EDCI: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride. PyBOP: [(benzotriazol-1-yl)oxy]tri(pyrrolidino)-
phosphonium hexafluorophosphate. HBTU: O-(1H-benzo-
triazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium hexafluorophos-
phate.
[
25] The percentage refers to the isolated yield after silica gel col-
umn chromatography. The reactions were performed with
2
.4 mmol carboxylic acid. For an example of the low chemose-
lectivity of acyl chloride, see: G. Xu, Q. Luo, S. Eibauer, A. F.
Rausch, S. Stempfhuber, M. Zabel, H. Yersin, O. Reiser, Dalton
Trans. 2011, 40, 8800–8806.
[
26] For examples of spectrophotometric assays using 4-nitroanilide
as the fluorogenic tag, see: a) A. Stockel-Maschek, B. Stiebitz,
R. Koelsch, K. Neubert, Anal. Biochem. 2003, 322, 60–67; b)
Received: July 15, 2011
Published Online: October 10, 2011
6922
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 6916–6922