Direct acyl substitution of carboxylic acids: A chemoselective o- to N-acyl migration in the traceless staudinger ligation

Article abstract of DOI:10.1002/chem.201201773

A chlorophosphite-modified, Staudinger-like acylation of azides involving a highly chemoselective, direct nucleophilic acyl substitution of carboxylic acids is described. The reaction provides the corresponding amides with analytical purity in 32-97 % yield after a simple aqueous workup without the need for a pre-activation step. The use of chlorophosphites as dual carboxylic acid-azide activating agents enables the formation of acyl C-N bonds in the presence of a wide range of nucleophilic and electrophilic functional groups, including amines, alcohols, amides, aldehydes, and ketones. The coupling of carboxylic acids and azides for the formation of alkyl amides, sulfonyl amides, lactams, and dipeptides is described. Copyright

Full text of DOI:10.1002/chem.201201773

FULL PAPER
DOI: 10.1002/chem.201201773
Direct Acyl Substitution of Carboxylic Acids: A Chemoselective O- to N-
Acyl Migration in the Traceless Staudinger Ligation
Andrew D. Kosal, Erin E. Wilson, and Brandon L. Ashfeld*[a]
Abstract: A chlorophosphite-modified,
Staudinger-like acylation of azides in-
volving a highly chemoselective, direct
nucleophilic acyl substitution of car-
boxylic acids is described. The reaction
provides the corresponding amides
with analytical purity in 32–97% yield
after a simple aqueous workup without
the need for a pre-activation step. The
use of chlorophosphites as dual carbox-
ylic acid–azide activating agents ena-
cleophilic and electrophilic functional
groups, including amines, alcohols,
amides, aldehydes, and ketones. The
coupling of carboxylic acids and azides
for the formation of alkyl amides, sul-
fonyl amides, lactams, and dipeptides is
described.
À
bles the formation of acyl C N bonds
in the presence of a wide range of nu-
Keywords: acyl
substitution
·
amides · azides · carboxylic acids ·
Staudinger ligation
Introduction
The interconversion of carboxylic acid derivatives through
nucleophilic acyl substitution constitutes one of the most
fundamental transformations in chemical synthesis.[1] Wheth-
er in enzymatic reactions,[2] or the construction of biological-
ly active natural products by using macrocyclization and
fragment coupling reactions,[3] the functionalization of car-
boxylic acid derivatives is widespread. Although recent de-
velopments in transition-metal-catalyzed acyl substitution
reactions[4] have greatly expanded the number of accessible
carbonyl functional groups, the dehydration of carboxylic
acids 1 to form an activated acyl intermediate 2 en route to
derivative 3 is still one of the most widely utilized strategies
for carbonyl functionalization (Scheme 1).[5] However, sepa-
ration of the product from undesired byproducts, in combi-
nation with the often harshly acidic conditions associated
with many conventional methods, has led to recent efforts
to develop alternative protocols.[6] Although the ready avail-
ability of carboxylic acids makes them ideal substrates, a
direct dehydration protocol that proceeds with high chemo-
selectivity and requires minimal purification remains elusive.
Herein, we report the use of chlorophosphites as dual acti-
vating agents for the direct nucleophilic acyl substitution of
Scheme 1. Carboxylic acid functionalization. X=halide, DEAD=diethyl
azodicarboxylate, DIAD=diisopropyl azodicarboxylate, DCC=N,N’-di-
cyclohexylcarbodiimide, CDI=carbonyldiimidazole.
the presence of nucleophilic and electrophilic functional
groups (e.g., ROH, RNH2, and RCHO), while avoiding the
formation of undesirable byproducts (e.g., Ph3P=O and
ureas). We hypothesized that the desired chemoselectivity
could be achieved by designing a Staudinger-type ligation[7]
À
in which the key C N bond is formed through an acyl mi-
gration of a phosphite ylide 4 (X=N, Z =O) to provide the
desired amide upon hydrolysis of phosphonyl imide 5
(Scheme 2). Application of this concept in the construction
À
carboxylic acids in the context of C N bond formation.
To concurrently address the challenges of selectivity and
product isolation, we sought to develop a method for the
direct functionalization of carboxylic acids that proceeds in
[a] A. D. Kosal, E. E. Wilson, Prof. Dr. B. L. Ashfeld
Department of Chemistry and Biochemistry
University of Notre Dame, 251 Nieuwland Science Hall
Notre Dame, IN 46556 (USA)
Fax : (+1)574-631-6652
E-mail: bashfeld@nd.edu
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201773.
Scheme 2. Dual carboxylic acid–azide activation.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

of amides[6f] relies on the concomitant activation of carbox-
ylic acid 1 and azide 6 by using a bifunctional chlorophos-
phite to generate the intermediate ester azaylide 7, which
would lead to amide 8. The intramolecularity of the acyl
substitution allows for carbonyl functionalization in the
presence of more electrophilic and nucleophilic functional
groups. Additionally, the phosphate acid and basic byprod-
ucts are readily removed through an aqueous workup, there-
by greatly simplifying product purification.
lysis of intermediate 12 occurs to yield the desired amide.[14]
ACHTUNGTRENNUNG
Although the Rainesꢁ and Bertozziꢁs methods exhibit broad
reactivity profiles, the inherent instability of phosphine 9,[13b]
the inability to use widely available carboxylic acids directly,
and the stoichiometric phosphine oxide generated prompted
us to pursue an alternative ligation strategy.
Although analogous to these phosphorus-based amidation
methods, it was not clear at the outset whether an inter-
mediate ester phosphite would tolerate the presence of nu-
cleophilic functionality, react with a range of azides to gen-
erate the putative ester azaylide intermediate, or undergo
The Staudinger-type ligation[8] of carboxylic acid deriva-
tives with azides has seen a recent resurgence since its initial
discovery in 1968, primarily due to its utility in the installa-
tion of bioactive probes for the study of metabolic function
and the synthesis of peptide frameworks.[9] The addition of
in situ generated azaylides to carboxylic acid derivatives, in-
cluding acid chlorides, anhydrides, and thioesters, has
proven to be an effective strategy for amide bond construc-
tion. The Vilarrassa group and others have demonstrated
the utility of these nucleophilic nitrogen species in the acyl
substitution of carboxylic acid derivatives.[10] In 2000, the
groups of Raines[11] and Bertozzi[12] independently reported
alternative Staudinger-like ligation reactions for the conver-
sion of thioesters and esters, respectively, into their corre-
sponding amides. Raines and co-workers demonstrated the
utility of phosphinothiol 9 in the ligation of thioesters and
azides to yield dipeptides through an intramolecular acyla-
tion involving iminophosphorane 10 [Eq. (1); Bn=
benzyl].[13] In contrast, Bertozzi and co-workers have devel-
oped a highly effective, rapid screening ligation protocol for
the synthesis of glycoproteins from phosphine-containing
esters and glycosidic azides to study glycosyltransferase ac-
tivity [Eq. (2)].[9b] Mechanistic studies indicate that a five-
exo-trig cyclization involving azaylide 11 followed by hydro-
À
the desired acyl migration to give the C N bond. However,
we pursued the strategy outlined in Scheme 2 because it
would provide a powerful method for the direct, chemose-
lective functionalization of carboxylic acids without the
need for exotic reagents or additional purification other
than a simple aqueous workup. To evaluate our hypothesis,
we initially focused on the coupling of anisic acid (1a) with
benzyl azide (6a) by using readily available diethyl chloro-
phosphite [Eq. (3)]. Formation of the phosphite ester by
treatment of acid 1a with Et3N and ClPACHTNUGTRNEUNG(OEt)2 at 08C in 1,4-
dioxane was followed by addition of azide 6a and warming
to 808C for 2 h to facilitate azaylide formation.[7a] Heating
the reaction at reflux for an additional 12 h led to the for-
mation of benzyl amide 8a in 35% yield. Also formed
under these conditions were anhydride 2a and acyl phos-
phonate 2b in 31 and 10% yield, respectively, indicating ef-
ficient phosphite ester formation, but sluggish O-to-N-acyl
migration.[15]
Emboldened by this result, we directed our efforts toward
the detailed analysis of this modified Staudinger ligation
protocol. Herein, we report our findings on the use of inex-
pensive and readily available chlorophosphites for the liga-
tion of carboxylic acids with azides to generate amides and
lactams, as well as peptide bonds. This work reveals a highly
chemoselective method for the direct functionalization of
carboxylic acids that will find broad applicability to the as-
sembly of a wide array of amide-containing synthetic tar-
gets.
Results and Discussion
Optimization of base and solvent: We began our initial opti-
mization studies by varying the amine base and reaction
&
2
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Direct Acyl Substitution of Carboxylic Acids
FULL PAPER
Table 2. Chlorophosphite ligation.[a]
conditions for the conversion of acid 1a into amide 8a
(Table 1). In an effort to access higher reaction tempera-
tures, we initially examined the use of high-boiling-point sol-
Table 1. Identification of the best base and solvent for the reaction.[a]
Entry
R
Base
Solvent
Yield
[%][b]
Entry
R1
ClP
G
1a/6
AHCTUNGTRENGN[UN equiv]
Yield
[%][b]
1
2
3
4
5
6
7
8
9
Bn (6a)
Bn (6a)
Bn (6a)
Ts (6b)
Bn (6a)
Bn (6a)
Bn (6a)
Bn (6a)
Bn (6a)
Bn (6a)
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
DBU
DABCO
iPr2NH
DMAP
PhMe
xylenes
PhCl
16 (8a)
38 (8a)
40 (8a)
41 (13a)
21 (8a)
23 (8a)
31 (8a)
<5 (8a)
17 (8a)
10 (8a)
1
2
3
4
5
6
7
Ts (6b)
Ts (6b)
Ts (6b)
Ts (6b)
Bn (6a)
Bn (6a)
Bn (6a)
ClP
ClP
ClP
ClP
ClP
ClP
ClP
1.3:1.0
1.3:1.0
1.3:1.0
1.3:1.0
1.3:1.0
1.3:1.0
1.0:3.0
69 (13a)
96 (13a)
89 (13a)
20 (13a)
48 (8a)
63 (8a)
59 (8a)
PhCl
PhCl (0.5m)
PhCl (2.0m)
PhCl
PhCl
PhCl
[a] Reactions conducted on a 0.3 mmol scale at 0.2m by using the stoichi-
ometry of 1a and 6 indicated, with ClP(OR)2 and Et3N in equimolar
amounts to 1a (see the Supporting Information for details). [b] Isolated
yield.
10
PhCl
[a] Reactions conducted by using azide 6 (0.3 mmol), 1a (0.39 mmol),
ClP(OEt)2 (0.39 mmol), and a base (0.39 mmol) in the solvent indicated
(see the Supporting Information for details). DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene, DABCO=1,4-diazabicyclo[2.2.2]octane, DMAP=4-
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
dimethylaminopyridine, Ts=para-toluenesulfonyl. [b] Isolated yield.
trend was observed in the formation of amide 8a from acid
1a and azide 6a by using ClPACTHNUGRTENNUG(cat) and ClPACHTUNGTNER(NUGN pin) (Table 2,
entries 5 and 6). The relative stoichiometry of acid 1a and
azide 6a proved important to the efficiency of the coupling
event. When an excess of azide 6a relative to acid 1a was
used, the yield of 8a dropped slightly to 59% (Table 2,
entry 7). Based on these findings, we used the optimized
vents.[16] However, treatment of acid 1a with azide 6a, ClP-
ACHTUNGTRENNUNG(OEt)2, and Et3N in PhMe led to a reduced yield of 8a
(Table 1, entry 1), whereas running the reaction in xylenes
increased the yield to 38% (Table 1, entry 2). We quickly
discovered that performing the reaction in PhCl provided
the best yield of benzyl amide 8a after 16 h at 1308C
(Table 1, entry 3). Employing TsN3 (6b) under the same
conditions gave results comparable to those for azide 6a
(Table 1, entry 4). Not surprisingly, the reaction concentra-
tion proved crucial, as illustrated by the lower yields of 8a
obtained for reactions at 0.5m and 2.0m (Table 1, entries 5
and 6). Substituting Et3N for DBU, DABCO, iPr2NH, and
DMAP provided inferior results (Table 1, entries 7–10).
With these findings in hand, we next sought to determine
the optimal chlorophosphite reagent.
conditions of ClPACTHUNTRGNE(UNG pin) and Et3N with a 1.3:1.0 ratio of acid
to azide in PhCl to complete our study.
Carboxylic acid and azide substrate scope: Satisfied that we
had identified the optimal reaction conditions to promote
À
C N bond construction while suppressing anhydride forma-
tion, we turned our attention to determining the structural
variability tolerated within the carboxylic acid component 1
with sulfonyl azide 6b (Table 3). In general, good to excel-
lent yields were obtained by using an assortment of aromat-
ic and aliphatic carboxylic acids, regardless of stereoelec-
tronic factors. Benzoic acid (1b) gave an excellent yield of
amide 13b (Table 3, entry 1). Electron-deficient benzoic
acid derivatives underwent smooth conversion to the corre-
sponding amides in 81–96% yield (Table 3, entries 2–5). Ni-
triles were well tolerated (Table 3, entry 3), and the pres-
ence of aryl halides in 1e and 1 f did not adversely affect
the formation of amides 13e and 13 f (Table 3, entries 4 and
5). Notably, conversion of pyrrole 1g into amide 13g occur-
red in 81% yield, highlighting the viability of unprotected
N-heterocyclic substrates (Table 3, entry 6). Treatment of
Effect of phosphite ligation in the Staudinger-like ligation:
To determine what effect varying the alkoxy ligands on the
phosphite coupling reagent would have on amide bond for-
mation, we began by examining a series of bidentate ligand
scaffolds, including chlorophosphites derived from catechol
[ClP
[ClP
C
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ment of acid 1a and azide 6b with ClPACTHUNGTRENNNUG
ACHTUNGTRENNUNG
A
R
cinnamic acid (1h) with 6b and ClPACTHNGUTERNNU(G pin) provided amide
yield of 13a dramatically improved to 96 and 89%, respec-
tively (Table 2, entries 2 and 3). Interestingly, by employing
13h in excellent yield without formation of the 1,4-adduct
that would result from a [3,3]-rearrangement of the inter-
mediate ester azaylide (Table 3, entry 7).[18] Phenyl acetic
the seven-membered-ring phosphite ClP
ACHTUNGTREN(NGNU bin), 13a was ob-
À
tained in a mere 20% yield (Table 2, entry 4). A similar
acid (1i) and octanoic acid (1j) underwent C N coupling to
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

B. L. Ashfeld et al.
Table 3. Carboxylic acid substrates.[a]
With the reaction scope towards substituted carboxylic
acids established, we focused our attention on the variability
of the azide component (Table 4). Consistent with our earli-
Entry
1
Carboxylic acid
Product
Yield
[%][b]
Table 4. Azide substrates.[a]
93
81
96
91
83
81
Entry
Azide
Acid
1c
Product
Yield
[%][b]
2
3
4
5
6
1
2
85
76
1h
3[c]
1h
1a
77
89
4
[a] Reactions conducted by using azide 6 (0.3 mmol), 1 (0.39 mmol), ClP-
(pin) (0.39 mmol), and Et3N (0.39 mmol) in PhCl (0.2m; see the Support-
AHCTUNGTRENNUNG
ing Information for details). Ms=methanesulfonyl. [b] Isolated yield.
[c] This reaction employed NaH in place of Et3N and was run at 808C.
7
8
9
93
94
91
er observations by using anisic acid 1a, BnN3 (6a) reacted
smoothly with electron-deficient benzoic acid derivative 1c
and ClPACHTNUTRGNE(UNG pin) to provide amide 8b in 85% yield (Table 4,
entry 1). The more reactive MsN3 (6c) compared favorably
with TsN3 (6a), as demonstrated by the formation of amide
14 in 76% yield upon treatment with cinnamic acid 1h
(Table 4, entry 2). Given the notable instability of acyl
azides,[20] we were pleased to discover that treatment of ben-
zoyl azide 6d with acid 1h provided imide 15 in 77% yield
(Table 4, entry 3). In addition, phenyl azide (6e) reacted
10[c]
11
80
56[c]
[a] Reactions conducted by using TsN3 (6b; 0.3 mmol), 1 (0.39 mmol),
ClP(pin) (0.39 mmol), and Et3N (0.39 mmol) in PhCl (0.2m; see the Sup-
smoothly with acid 1a and ClPACHTNUTRGNE(UNG pin) to yield acylated aniline
ACHTUNGTRENNUNG
16 in 89% yield (Table 4, entry 4). This result highlights the
utility of this approach as a complementary method for the
synthesis of protected anilines, which are a prevalent struc-
tural motif in biologically active natural products and phar-
maceutical targets.[21] The results presented in Tables 3 and 4
highlight the versatility of this carboxylic acid ligation strat-
egy in the context of a diversity-oriented approach to the
construction of amide derivatives by using widely available
carboxylic acids and functionally diverse azides.
To evaluate the utility of our modified Staudinger ligation
in the synthesis of chemotherapeutic agents, we targeted the
sulfonamide linkage in the antitumor agent LY573636 (18;
Scheme 3).[22] Synthesis of azide 6 f was achieved in 45%
yield over two steps by sulfonylation of bromothiophene
17[23] followed by addition of NaN3. Treatment of carboxylic
porting Information for details). [b] Isolated yield. [c] This reaction em-
ployed NaH in place of Et3N.
give amides 13i and 13j in 94 and 91% yield, respectively
(Table 3, entries 8 and 9). The amidation reaction also
proved tolerant of sterically encumbered a-substituted ali-
phatic acids. The presence of cyclohexyl and tert-butyl sub-
stitution in acids 1k and 1l did not hinder acyl substitution,
providing amides 13k and 13l in 80 and 56% yield, respec-
tively (Table 3, entries 10 and 11). Additionally, the efficient
conversion of pivalic acid 1l into amide 13l indicates that
the reaction does not proceed through a ketene intermedi-
ate.[19]
&
4
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Direct Acyl Substitution of Carboxylic Acids
FULL PAPER
pleased to see that the formation of such strained heterocy-
cles occurred with ease by employing this method.
Peptide bond formation reactions: Recently, the Staudinger
ligation has arisen as a powerful alternative to the “native
chemical ligation” approach to peptide fragments[28] that ad-
dresses the inherent limitations associated with the need for
a cysteine residue at the site of elaboration.[29] To evaluate
our method for the derivatization of amino acids and the
construction of optically active dipeptides, we assembled a
collection of N-protected amino acids 23 and examined their
ligation with functionalized azides 6 (Table 5). In general,
we discovered that the desired dipeptides were obtained in
slightly better yields by employing ClPPh2 than with ClP-
Scheme 3. Synthesis of antitumor agent LY573636. pyr.=pyridine,
IPAc=isopropyl acetate.
acid 1m and azide 6 f with ClPACHTNUGRTENUNG(pin) and Et3N in PhCl pro-
vided LY573636 (18) in 97% yield. Our three-step protocol
compares favorably to the four-step synthesis of 18 reported
by Yates and co-workers in which the crucial amide linkage
was constructed by using either CDI or via the acid chloride
of 1m. This efficient and chemoselective route for the syn-
thesis of heterocyclic sulfonamides is ideal for the rapid syn-
thesis and screening of sulfonamide-containing biologically
active molecules.[24]
AHCTUNGTREG(NNNU pin). It is important to note that the diphenylphosphinic
acid generated is easily removed through an aqueous
workup. Treatment of Cbz- and Fmoc-protected alanine
(23a and 23b) with BnN3 (6a) and the azido ester derivative
of glycine 6g provided amide 24a and dipeptide 24b in 60
À
and 88% yields, respectively. Importantly, C N bond forma-
tion proceeded without loss of optical purity, as determined
by comparing the optical rotations of 24a and 24b to litera-
ture values.[30]
Application to lactam formation: Given the pervasiveness
of the lactam motif in chemotherapeutics,[25] and the critical
role lactamization reactions play in the construction of bio-
logically active natural products,[26] we chose to assess our
method in the context of direct intramolecular coupling of
carboxylic acids and azides. Thus, treatment of carboxylic
Additional substitution on the amino acid side chain did
not adversely affect the amidation reaction, as illustrated by
the coupling of Fmoc-protected isoleucine 23c with azido
glycine 6g to yield dipeptide 24c in 51% yield. N-Protected
phenylalanine 23d underwent coupling with azides 6b and
6g to provide amides 24d and 24e in excellent yields. Treat-
ment of 23d with azido phenylalanine ethyl ester 6h provid-
ed dipeptide 24 f in 71% yield as a single diastereomer and
without loss of optical purity. Interestingly, the trityl sulfide
in Fmoc-cysteine 23e did not hinder the formation of dipep-
tide 24g, which proceeded in 73% yield.[31] Furthermore,
coupling of Fmoc-protected proline 23 f with azido glycine
6g and phenylalanine 6h proceeded in excellent yields to
give dipeptides 24h and 24i in 90 and 83% yield, respective-
ly. As in the formation of dipeptide 24 f, 24i was obtained as
a single, optically active diastereomer. Treatment of the
N,N-diprotected tryptophan with azido glycine 6g provided
dipeptide 24j in 78% yield. Employing the azido ester de-
rivative of phenylalanine (6h) led to a modest decrease in
yield of the fully protected Trp-Phe dipeptide 24k, which
acid 21a, containing a pendant benzyl azide, with ClPACHTUNTRGNEUNG(pin)
and Et3N led to an excellent yield (87%) of lactam 22a
[Eq. (4)]. Likewise, the acyclic azido acid 21b also under-
went intramolecular amidation to give lactam 22b in 64%
yield [Eq. (5)]. The use of NaH in lieu of Et3N led to a
slightly cleaner conversion of acid 21b into amide 22b in
this instance. Shortening the carbon chain to access b-lac-
tams did not hinder the cyclization, as illustrated by the con-
version of 21c into b-lactam 22c in 86% yield [Eq. (6)].[27]
Again, NaH proved superior to Et3N for the conversion of
azide 21c into lactam 22c. Considering the role b-lactams
play in the design of new antibiotic treatments, we were
À
was formed as a single diastereomer. In each case, C N
bond formation gave the optically active amide, providing
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

B. L. Ashfeld et al.
Table 5. Synthesis of peptide bonds.[a]
gation involving azide 6g, was obtained in a 5:1 ratio with
amide 24l, arising from an acyl substitution of the phosphite
ester with amine 25a. The preference for azide ligation is
comparable to that observed by Raines in the competitive li-
gation of thioeseters (azide/amine=3:1).[13d] Based on the
chemoselectivity for azide 6g over amine 25a in the ligation
of acid 23 f, we speculated that this phosphite-mediated acyl
substitution strategy would enable the peptide coupling of
N-unprotected amino acids. Thus, treatment of proline
(23h) with NaH, ClPPh2, and azido glycine ester 6g led to
formation of the crucial peptide bond en route to the ob-
served cyclic dipeptide 26, which was formed in 62% yield
[Eq. (8)]. The opportunity to avoid additional protection
and deprotection steps in peptide synthesis, which is stand-
ard in conventional amino acid coupling strategies,[33] consti-
tutes a significant advance in amide construction.
23a+6a
23b+6g
23c+6g
23d+6b
23d+6g
23d+6h
23e+6g
23 f+6g
23 f+6h
23g+6g
23g+6h
Azide chemoselectivity for sulfonyl azides was evaluated
in
sulfon
with 1 equivalent each of TsN3, ClPAHCTNUGTRENNNUG
tosyl amide 13a in 74% yield [Eq. (9)]. When the reaction
was performed in the presence of benzene sulfonamide 25b
(1 equiv), amide 13a was produced in 79% yield, while 25b
was recovered quantitatively [Eq. (10)].
a
head-to-head competition experiment involving
amide additive. Treatment of 1 equivalent of acid 1a
(pin), and NaH provided
a
[a] Reactions conducted by using azide 6 (0.3 mmol), 23 (0.39 mmol), ClPPh2
(0.39 mmol), and NaH (0.39 mmol) in PhCl (0.2m; see the Supporting Informa-
tion for details). Cbz=carbobenzyloxy, Fmoc=9-fluoromethyloxycarbonyl.
AHCTUNGTRENNUNG
additional evidence that the reaction does not proceed
through a ketene intermediate.[19]
Chemoselectivity for azides: The chemoselectivity in nucleo-
philic acyl substitution reactions is an important considera-
tion in the synthesis of complex targets.[13a,32] The acyl migra-
tion from a putative ester azaylide intermediate outlined
herein was designed to tolerate the presence of unprotected
electrophilic and nucleophilic functionality, while chemose-
lectively unmasking the latent nucleophilicity of the azide
and electrophilicity of the carboxylic acid. To evaluate azide
chemoselectivity, we treated Fmoc-Pro 23 f with azido gly-
cine 6g, NaH, ClPPh2, and 1 equivalent of methyl glycine
25a [Eq. (7)]. Amide 24h, resulting from intramolecular li-
&
6
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Direct Acyl Substitution of Carboxylic Acids
FULL PAPER
Table 6. Carboxylic acid chemoselectivity.[a]
Chemoselectivity for carboxylic acids: The presence of other
electrophilic carbonyl derivatives and nucleophilic hetero-
ACHTUNGTRENNUNGatoms presents additional challenges to Staudinger ligations
involving an activated carboxylic acid and nucleophilic
azide. However, the unprotected hydroxyl group in benzoic
acid 1n did not hinder formation of amide 13n, which pro-
ceeded in 64% yield without competitive intermolecular es-
terification or anhydride formation from the intermediate
ester phosphite [Eq. (11)].[5b] More electrophilic carbonyl
Entry
18
Yield of 13a
Recovered 23
[%][b]
[%][b]
1
2
3
93
93
92
94
>99
93
À
derivatives also survived the C N coupling event, as illus-
trated by the conversion of para-formyl benzoic acid 1o into
amide 13o in 60% yield and acetophenone-substituted acid
1p into amide 13p in 82% yield [Eqs. (12) and (13)]. Inter-
estingly, neither the Schmidt rearrangement products, result-
ing from addition of azide to the electrophilic ketone and al-
dehyde,[34] nor imines, due to competitive aza-Wittig reac-
tions involving the intermediate azaylide, were observed.[35]
In contrast, the addition of BnN3 (6a) and chlorophosphite
to benzoic acid derivative 1q, containing a benzophenone at
the ortho-position, proved problematic, leading to a low
yield of the corresponding amide 8d [Eq. (14)]. The ligation
of 1q resulted in a mixture of unidentifiable side products,
likely resulting from side reactions involving attack of the
neighboring carbonyl on the intermediate ester phosphite.
[a] Reactions conducted by using azide 4b (0.3 mmol), 1a (0.30 mmol),
27 (0.30 mmol), ClP(pin) (0.30 mmol), and Et3N (0.30 mmol) in PhCl
(0.2m; see the Supporting Information for details). [b] Isolated yield.
AHCTUNGTRENNUNG
hyde 27a was recovered (Table 6, entry 1). Although a
Schmidt rearrangement of aldehyde 27a with azide 6b in-
volving hydrogen migration to bolster the yield of 13a
cannot be ruled out, this appears unlikely in light of the
findings by Aubꢂ and co-workers, which indicate a migrato-
ry preference of carbon over hydrogen in the absence of a
Lewis acid, and the efficient amidation of acid 1n
[Eq. (11)].[36] The addition of acetophenone (27b) or methyl
benzoate (27c) to the reaction of acid 1a with azide 6b did
not adversely affect the yield of amide 13a, which was ob-
tained in 93 and 92% yield, respectively, with excellent re-
covery of 27b and 27c (Table 6, entries 2 and 3).
Mechanism of the chlorophosphite and chlorophosphine-
mediated Staudinger ligation: A distinct advantage of the
amidation protocol described herein is the ability to conduct
the acyl substitution of carboxylic acids directly without the
product-isolation complications common to conventional de-
hydration methods. Specifically, the chloride anion (e.g.,
Et3N·HCl or NaCl) and phosphoric acid byproducts, as well
as any unreacted carboxylic acid, are readily removed from
the crude reaction mixture through a simple aqueous
workup.[30] Unlike other Staudinger ligation methods involv-
ing phosphines, the pre-ligation of carboxylic acids directly
to phosphorus results in some intriguing mechanistic ques-
À
tions, as well as enhancing the utility of this versatile C N
bond-forming strategy. Although a more complete mecha-
nistic study of the chlorophosphite-facilitated Staudinger li-
gation is the focus of our current research efforts, our find-
ings thus far allow us to draw some preliminary mechanistic
conclusions.
Intermolecular carboxylic acid chemoselectivity in the
phosphite-mediated ligation was examined by using a series
of competition experiments between carboxylic acid 1a and
a carbonyl additive (Table 6). Treatment of 1a and 6b with
Based on the findings by the groups of Bertozzi and Berg-
man,[14] and independently by the Raines group,[13d] involv-
ing esters and thioesters, respectively, our working hypothe-
sis involves initial addition of carboxylic acid 1 to the chlor-
ophosphite (Scheme 4). The formation of ester phosphite 28
is key to the observed reactivity and high levels of chemose-
ClP
ACHTUNGTRENNUNG(pin) and Et3N in the presence of aldehyde 27a led to
the formation of amide 13a in 93% yield and 94% of alde-
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
7
&
ÞÞ
These are not the final page numbers!

B. L. Ashfeld et al.
Effect of solvent and phosphite ligation: Drawing compari-
sons to the aforementioned mechanistic studies on the Stau-
dinger ligation by the groups of Bertozzi/Bergman,[14] and
Raines,[13d] a number of empirical observations that support
our mechanistic hypothesis are worth noting. During our ini-
tial optimization of the phosphite-mediated Staudinger liga-
tion, we speculated that the yield of amide 8a would im-
prove if intermediates 29 and 7 were stabilized by the use of
more polar solvents. Our finding that PhCl (40% yield)
proved superior to PhMe (16% yield) in the formation of
amide 8a supports the involvement of a polar intermediate,
and is consistent with Bertozziꢁs and Rainesꢁ findings
(Table 1). However, the boiling point of the solvent also
proved crucial, with more polar solvents, such as THF,
MeCN, DMF, DMSO, and 1,4-dioxane, failing to provide
amide 8a in greater than 26% yield.[13d] This is likely due to
the inability of these solvents to reach the elevated tempera-
tures necessary to effect a [1,3]-acyl migration.[38]
Scheme 4. Possible mechanistic pathways.
A previously under-explored aspect of the Staudinger li-
gation pertains to the geometry around phosphorus, as influ-
enced by the monodentate or bidentate ligand scaffolds.[17–18]
Employing a series of different phosphites in the ligation of
acid 1a and azide 6b reveals an intriguing correlation be-
tween the bite angle at phosphorus and the yield of amide
13a (Table 2). Superior yields were obtained with chloro-
phosphites containing diol ligands that form five- and six-
membered-ring chelates. The improved reaction efficiency
lectivity in the direct nucleophilic acyl substitution of acid 1,
and is consistent with the observed precipitation of either
Et3N·HCl or NaCl in the presence of Et3N or NaH, respec-
tively. Additionally, it is important to note that the omission
of chlorophosphite led to quantitative recovery of carboxylic
acid 1a and azide 6a. Upon addition of the electron-defi-
cient phosphite to azide 6, the generation of phosphazide 29
concomitantly activates both the carboxylic acid and the
azide motifs for the incipient acyl substitution event. One
possible acyl substitution pathway involves N2 evolution to
provide ester azaylide 7, which then undergoes [1,3]-acyl mi-
gration to the basic ylide nitrogen (path a).[37] The elevated
in going from ClP
that the decreased bite angle at phosphorus promotes aza-
ylide formation through improved lone-pair accessibility.[40]
ACHTUNGRTEN(UNGN OEt)2 and ClPAHCTUNRTGEGUNN(N bin) to ClPACHTNUGRTEN(NUGN pin) indicates
AHCTUNGTRENNUNG
À
temperatures required for C N bond formation would indi-
Conclusion
cate a high-energy transition state consistent with the 4-exo-
trig cyclization for the formation of phosphorimide 31, in
spite of being driven by formation of a strong P=O bond.[38]
Alternatively, one can envisage a reaction pathway in which
azaylide formation is slow relative to cyclization (path b);
thus a six-membered transition state would provide the acyl
phosphoryl triazene 30 without N2 evolution, leading to
31.[39] Dephosphorylation under the reaction conditions
yields the observed amide 8. Although it is unclear at pres-
ent whether acyl substitution is occurring via the ester aza-
ACHTUNGTRENNUNGylide 7 or directly from phosphazide 29, it is conceivable
that both pathways operate under the reaction conditions,
and this is the subject of current investigations.
Although a mechanism involving intermolecular azaylide
addition to ester phosphite 27 or a ketene cannot be ruled
out completely, this pathway appears unlikely based on the
lack of crossover carbonyl byproducts observed from the re-
actions of substrates containing nucleophilic functional
groups. The exceptional chemoselectivity for carboxylic acid
and azide functional groups observed in our study is likely a
The present method allows for ready access to a diverse as-
sortment of amides through the direct functionalization of
carboxylic acids and azides by using a chlorophosphite as a
dual activating agent. This procedure complements current
amide-bond-forming technology by virtue of the highly che-
moselective intramolecular acyl-migration event, and simpli-
fied product isolation due to the aqueous solubility of the
byproducts generated. The bimodal reactivity of phosphite
to unmask the latent electrophilicity of carboxylic acids and
nucleophilicity of azides in a controlled fashion is directly
applicable to the assembly of biologically active natural
products and synthetic targets containing amides, lactams,
and peptide linkages. The use of this reaction in total syn-
thesis is currently being pursued, and will be reported in
due course.
Experimental Section
À
direct result of the initial O P bond formation in ester phos-
Representative procedure for the phosphite-mediated Staudinger-like li-
gation: Et3N (0.39 mmol, 1.3 equiv) was added to a solution of carboxylic
acid 1 (0.39 mmol, 1.3 equiv) in chlorobenzene (1 mL) at room tempera-
phite 28 that precedes acyl migration, resulting in an overall
dual activation of the targeted functional groups by phos-
phorus.
ture. This mixture was then cooled to 08C and ClPACTHUNRTGNEUNG(pin) (0.39 mmol,
&
8
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Direct Acyl Substitution of Carboxylic Acids
FULL PAPER
1.3 equiv) was added in one portion with rapid stirring. The resulting
slurry was allowed to warm slowly to room temperature. This was fol-
lowed by addition of a solution of the azide (0.30 mmol, 1 equiv) in chlo-
[8] M. Kçhn, R. Breinbauer, Angew. Chem. 2004, 116, 3168–3178;
Angew. Chem. Int. Ed. 2004, 43, 3106–3116.
[9] a) M. Fernꢅndez-Suꢅrez, H. Baruah, L. Martinez-Hernandez, K. T.
Xie, J. M. Baskin, C. R. Bertozzi, A. Y. Ting, Nat. Biotechnol. 2007,
25, 1483–1487; b) H. C. Hang, C. Yu, M. R. Pratt, C. R. Bertozzi, J.
Am. Chem. Soc. 2004, 126, 6–7; c) K. L. Kiick, E. Saxon, D. A. Tir-
rell, C. R. Bertozzi, Proc. Natl. Acad. Sci. USA 2002, 99, 19–24;
d) G. A. Lemieux, C. L. de Graffenried, C. R. Bertozzi, J. Am.
Chem. Soc. 2003, 125, 4708–4709.
[10] a) I. Bosch, P. Romea, F. Urpi, J. Vilarrasa, Tetrahedron Lett. 1993,
34, 4671–4674; b) J. Burꢂs, M. Martꢆn, F. L. Urpꢆ, J. Vilarrasa, J.
Org. Chem. 2009, 74, 2203–2206; c) J. Garcia, F. Urpꢆ, J. Vilarrasa,
Tetrahedron Lett. 1984, 25, 4841–4844; d) F. Urpꢆ, J. Vilarrasa, Tetra-
hedron Lett. 1986, 27, 4623–4624.
ACHTUNGTRENNUNGrobenzene (0.3 mL). The mixture was stirred for 1 h, heated to 808C and
stirred for an additional 2 h, heated to 1308C and stirred until complete
consumption of the starting materials was observed by TLC (ca. 10 h).
The solution was diluted with EtOAc (5 mL) and saturated aqueous
NaHCO3 (10 mL), extracted with EtOAc (3ꢃ10 mL), dried (MgSO4),
and concentrated under reduced pressure to provide the corresponding
amide in >90% purity.
[11] B. L. Nilsson, L. L. Kiessling, R. T. Raines, Org. Lett. 2000, 2, 1939–
1941.
Acknowledgements
[12] a) E. Saxon, J. I. Armstrong, C. R. Bertozzi, Org. Lett. 2000, 2,
2141–2143; b) E. Saxon, C. R. Bertozzi, Science 2000, 287, 2007–
2010.
The authors thank the NSF (CHE-1056242) and the University of Notre
Dame for financial support of this research. We also thank Professor
Richard E. Taylor (University of Notre Dame), whose helpful discussions
were instrumental in the development of this work.
[13] a) N. A. McGrath, R. T. Raines, Acc. Chem. Res. 2011, 44, 752–761;
b) B. L. Nilsson, L. L. Kiessling, R. T. Raines, Org. Lett. 2001, 3, 9–
12; c) M. B. Soellner, B. L. Nilsson, R. T. Raines, J. Org. Chem.
2002, 67, 4993–4996; d) M. B. Soellner, B. L. Nilsson, R. T. Raines,
J. Am. Chem. Soc. 2006, 128, 8820–8828; e) A. Tam, M. B. Soellner,
R. T. Raines, J. Am. Chem. Soc. 2007, 129, 11421–11430.
[14] F. L. Lin, H. M. Hoyt, H. van Halbeek, R. G. Bergman, C. R. Ber-
tozzi, J. Am. Chem. Soc. 2005, 127, 2686–2695.
[15] B. Chen, A. K. Mapp, J. Am. Chem. Soc. 2004, 126, 5364–5365.
[16] a) B. C. Challis, J. A. Challis, J. N. Iley, J. Chem. Soc. Perkin Trans. 2
1978, 813–818; b) B. C. Challis, A. D. Frenkel, J. Chem. Soc. Chem.
Commun. 1972, 303–304.
[17] B. Chen, A. K. Mapp, J. Am. Chem. Soc. 2005, 127, 6712–6718.
[18] a) E. E. Lee, R. A. Batey, Angew. Chem. 2004, 116, 1901–1904;
Angew. Chem. Int. Ed. 2004, 43, 1865–1868; b) R. P. Lutz, Chem.
Rev. 1984, 84, 205–247; c) F. Vçgtle, E. Goldschmitt, Chem. Ber.
1976, 109, 1–40.
[19] A. O.-Y. Chan, C.-M. Ho, H.-C. Chong, Y.-C. Leung, J.-S. Huang,
M.-K. Wong, C.-M. Che, J. Am. Chem. Soc. 2012, 134, 2589–2598.
[20] J. Suh, B. H. Lee, J. Org. Chem. 1980, 45, 3103–3107.
[21] a) K. Foo, T. Newhouse, I. Mori, H. Takayama, P. S. Baran, Angew.
Chem. 2011, 123, 2768–2771; Angew. Chem. Int. Ed. 2011, 50, 2716–
2719; b) J. Krauss, V. Knorr, V. Manhardt, S. Scheffels, F. Bracher,
Arch. Pharm. 2008, 341, 386–392; c) C. E. Masse, M. Yang, J. Solo-
mon, J. S. Panek, J. Am. Chem. Soc. 1998, 120, 4123–4134.
[22] M. H. Yates, N. J. Kallman, C. P. Ley, J. N. Wei, Org. Process Res.
Dev. 2009, 13, 255–262.
[1] Comprehensive Organic Synthesis, Vol. 6 (Eds.: B. M. Trost, I. Flem-
ing), Pergamon, New York, 1991, pp. 301–460.
[2] a) F. Bordusa, Chem. Rev. 2002, 102, 4817–4868; b) K. Krishna-
moorthy, T. P. Begley, J. Am. Chem. Soc. 2011, 133, 379–386;
c) B. L. Nilsson, R. J. Hondal, M. B. Soellner, R. T. Raines, J. Am.
Chem. Soc. 2003, 125, 5268–5269.
[3] For representative examples, see: a) S.-i. Yamada, Y. Takeuchi, Tet-
rahedron Lett. 1971, 12, 3595–3598; b) X. Cheng, C. M. Duhaime,
S. P. Waters, J. Org. Chem. 2010, 75, 7026–7028; c) J. Zheng, X. Xie,
C. Zhao, Y. He, H. Zheng, Z. Yang, X. She, Org. Lett. 2011, 13,
173–175.
[4] For selected examples, see: a) H. Lundberg, F. Tinnis, H. Adolfsson,
Chem. Eur. J. 2012, 18, 3822–3826; b) N. C. Ganguly, S. Roy, P.
Mondal, Tetrahedron Lett. 2012, 53, 1413–1416; c) C. L. Allen,
J. M. J. Williams, Chem. Soc. Rev. 2011, 40, 3405–3405; d) A. C.
Shekhar, A. R. Kumar, G. Sathaiah, V. L. Paul, M. Sridhar, P. S.
Rao, Tetrahedron Lett. 2009, 50, 7099–7101; e) C. Gunanathan, Y.
Ben-David, D. Milstein, Science 2007, 317, 790–792; f) J. Coste, M.-
N. Dufour, A. Pantaloni, B. Castro, Tetrahedron Lett. 1990, 31, 669–
672.
[5] a) X. Wu, L. Hu, J. Org. Chem. 2007, 72, 765–774; b) J. R. Dunetz,
Y. Xiang, A. Baldwin, J. Ringling, Org. Lett. 2011, 13, 5048–5051;
c) E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606–631; d) T.
Niu, W. Zhang, D. Huang, C. Xu, H. Wang, Y. Hu, Org. Lett. 2009,
11, 4474–4477; e) O. David, W. J. N. Meester, H. Bierꢄugel, H. E.
Schoemaker, H. Hiemstra, J. H. van Maarseveen, Angew. Chem.
2003, 115, 4509–4511; Angew. Chem. Int. Ed. 2003, 42, 4373–4375;
f) P. Li, J.-C. Xu, Tetrahedron 2000, 56, 8119–8131; g) F. S. Gibson,
M. S. Park, H. Rapoport, J. Org. Chem. 1994, 59, 7503–7507;
h) L. A. Carpino, B. J. Cohen, K. E. Stephens, S. Y. Sadat-Aalaee,
J. H. Tien, D. C. Langridge, J. Org. Chem. 1986, 51, 3732–3734; i) R.
Appel, Angew. Chem. 1975, 87, 863–874; Angew. Chem. Int. Ed.
Engl. 1975, 14, 801–811; j) O. Mitsunobu, M. Yamada, Bull. Chem.
Soc. Jpn. 1967, 40, 2380–2382; k) J. C. Sheehan, J. J. Hlavka, J. Org.
Chem. 1956, 21, 439–441.
[6] a) A. M. Dumas, G. A. Molander, J. W. Bode, Angew. Chem. 2012,
124, 5781–5784; Angew. Chem. Int. Ed. 2012, 51, 5683–5686;
b) D. J. Hardee, L. Kovalchuke, T. H. Lambert, J. Am. Chem. Soc.
2010, 132, 5002–5003; c) S. T. Heller, T. Fu, R. Sarpong, Org. Lett.
2012, 14, 1970–1973; d) K. Ishihara, S. Ohara, H. Yamamoto, J.
Org. Chem. 1996, 61, 4196–4197; e) Q. L. Luo, L. Lv, Y. Li, J. P.
Tan, W. Nan, Q. Hui, Eur. J. Org. Chem. 2011, 6916–6922; f) V. R.
Pattabiraman, J. W. Bode, Nature 2011, 480, 471–479; g) P. Tang,
Org. Synth. 2005, 81, 262–272.
[23] T. Sone, Y. Abe, N. Sato, M. Ebina, Bull. Chem. Soc. Jpn. 1985, 58,
1063–1064.
[24] a) A. Scozzafava, T. Owa, A. Mastrolorenzo, C. T. Supuran, Curr.
Med. Chem. 2003, 10, 925–953; b) T. Owa, H. Yoshino, T. Okauchi,
K. Yoshimatsu, Y. Ozawa, N. H. Sugi, T. Nagasu, N. Koyanagi, K.
Kitoh, J. Med. Chem. 1999, 42, 3789–3799; c) S. R. Turner, J. W.
Strohbach, R. A. Tommasi, P. A. Aristoff, P. D. Johnson, H. I. Skul-
nick, L. A. Dolak, E. P. Seest, P. K. Tomich, M. J. Bohanon, M.-M.
Horng, J. C. Lynn, K.-T. Chong, R. R. Hinshaw, K. D. Watenpaugh,
M. N. Janakiraman, S. Thaisrivongs, J. Med. Chem. 1998, 41, 3467–
3476; d) Y. Tamura, F. Watanabe, T. Nakatani, K. Yasui, M. Fuji, T.
Komurasaki, H. Tsuzuki, R. Maekawa, T. Yoshioka, K. Kawada, K.
Sugita, M. Ohtani, J. Med. Chem. 1998, 41, 640–649.
[25] a) W. Dꢇrckheimer, J. Blumbach, R. Lattrell, K. H. Scheunemann,
Angew. Chem. 1985, 97, 183–205; Angew. Chem. Int. Ed. Engl.
1985, 24, 180–202; b) Chemistry and Biology of b-Lactam Antibiot-
ics, Vols. 1–3 (Eds.: R. B. Morin, M. Gorman), Academic Press,
New York, 1982; c) The Chemistry of b-Lactams (Ed.: M. I. Page),
Chapman and Hall, London, 1992; d) J. R. Struble, J. W. Bode, Tet-
rahedron 2009, 65, 4957–4967; e) X. K. Wee, W. K. Yeo, B. Zhang,
V. B. C. Tan, K. M. Lim, T. E. Tay, M.-L. Go, Bioorg. Med. Chem.
2009, 17, 7562–7571.
[7] a) Y. G. Gololobov, I. N. Zhmurova, L. F. Kasukhin, Tetrahedron
1981, 37, 437–472; b) H. Staudinger, J. Meyer, Helv. Chim. Acta
1919, 2, 635–646.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
9
&
ÞÞ
These are not the final page numbers!

B. L. Ashfeld et al.
[26] a) K. Ishihara, Y. Kuroki, N. Hanaki, S. Ohara, H. Yamamoto, J.
Am. Chem. Soc. 1996, 118, 1569–1570; b) Z. Luo, K. Peplowski,
G. A. Sulikowski, Org. Lett. 2007, 9, 5051–5054; c) R. G. Vaswani,
J. J. Day, J. L. Wood, Org. Lett. 2009, 11, 4532–4535.
1727; c) J. W. Bode, R. M. Fox, K. D. Baucom, Angew. Chem. 2006,
118, 1270–1274; Angew. Chem. Int. Ed. 2006, 45, 1248–1252; d) R.
Merkx, D. T. S. Rijkers, J. Kemmink, R. M. J. Liskamp, Tetrahedron
Lett. 2003, 44, 4515–4518.
[27] a) J. D. Buynak, B. Geng, B. Bachmann, L. Hua, Bioorg. Med.
Chem. Lett. 1995, 5, 1513–1518; b) J. D. Buynak, A. S. Rao, V. Ram-
ana Doppalapudi, G. Adam, P. J. Petersen, S. D. Nidamarthy,
Bioorg. Med. Chem. Lett. 1999, 9, 1997–2002; c) P. Pattanaik, C. R.
Bethel, A. M. Hujer, K. M. Hujer, A. M. Distler, M. Taracila, V. E.
Anderson, T. R. Fritsche, R. N. Jones, S. R. R. Pagadala, F. van de-
n Akker, J. D. Buynak, R. A. Bonomo, J. Biol. Chem. 2008, 284,
945–953.
[28] a) T. Wieland, E. Bokelmann, L. Bauer, H. U. Lang, H. Lau, Justus
Liebigs Ann. Chem. 1953, 583, 129–149; b) T. Wieland, H. Deter-
mann, Angew. Chem. 1963, 75, 539–551; Angew. Chem. Int. Ed.
Engl. 1963, 2, 358–370.
[29] a) D. Bang, G. I. Makhatadze, V. Tereshko, A. A. Kossiakoff, S. B.
Kent, Angew. Chem. 2005, 117, 3920–3924; Angew. Chem. Int. Ed.
2005, 44, 3852–3856; b) P. E. Dawson, T. W. Muir, I. Clark-Lewis,
S. B. Kent, Science 1994, 266, 776–779; c) S.-Y. Han, Y.-A. Kim, Tet-
rahedron 2004, 60, 2447–2467; d) C. A. G. N. Montalbetti, V. Falque,
Tetrahedron 2005, 61, 10827–10852; e) J. P. Tam, Q. Yu, Biopoly-
mers 1998, 46, 319–327; f) F. I. Valiyaveetil, M. Sekedat, T. W. Muir,
R. MacKinnon, Angew. Chem. 2004, 116, 2558–2561; Angew. Chem.
Int. Ed. 2004, 43, 2504–2507.
[33] a) I. Coin, M. Beyermann, M. Bienert, Nat. Protoc. 2007, 2, 3247–
3256; b) R. B. Merrifield, J. Am. Chem. Soc. 1963, 85, 2149–2154;
c) L. P. Miranda, P. F. Alewood, Biopolymers 2000, 55, 217–226.
[34] a) K. F. Schmidt, Angew. Chem. 1923, 36, 511; b) K. F. Schmidt, Ber.
Dtsch. Chem. Ges. 1924, 57, 704–706.
[35] F. Palacios, C. Alonso, D. Aparicio, G. Rubiales, J. M. de Los Santos,
Tetrahedron 2007, 63, 523–575.
[36] J. Aube, G. L. Milligan, J. Am. Chem. Soc. 1991, 113, 8965–8966.
[37] a) D. Y. Curtin, J. D. Druliner, J. Org. Chem. 1967, 32, 1552–1557;
b) X. Li, S. J. Danishefsky, J. Am. Chem. Soc. 2008, 130, 5446–5448;
c) D. G. McCarthy, A. F. Hegarty, J. Chem. Soc. Perkin Trans. 2
1977, 1085–1094; d) O. Mumm, H. Hesse, H. Volquartz, Ber. Dtsch.
Chem. Ges. 1915, 48, 379–391; e) F. Weygand, D. Hoffmann, E. Z.
Wꢇnsch, Z. Naturforsch B 1966, 21, 426.
[38] a) A. J. Clark, J. L. Peacock, Tetrahedron Lett. 1998, 39, 1265–1268;
b) A. DAnnibale, D. Nanni, C. Trogolo, F. Umani, Org. Lett. 2000, 2,
401–402; c) M. Rofoo, M.-C. Roux, G. Rousseau, Tetrahedron Lett.
2001, 42, 2481–2484.
[39] E. L. Myers, R. T. Raines, Angew. Chem. 2009, 121, 2280–2280;
Angew. Chem. Int. Ed. 2009, 48, 2246–2246.
[40] a) Z. Freixa, P. W. N. M. van Leeuwen, Dalton Trans. 2003, 1890–
1901; b) C. P. Casey, G. T. Whiteker, Isr. J. Chem. 1990, 30, 299–304.
[30] See the Supporting Information for details.
[31] a) K. Akaji, N. Kuriyama, T. Kimura, Y. Fujiwara, Y. Kiso, Tetrahe-
dron Lett. 1992, 33, 3177–3180; b) A. Saha, H. Rapoport, P. Schultz,
J. Am. Chem. Soc. 1989, 111, 4856–4859.
[32] a) T. Narumi, J. W. Bode, Heterocycles 2011, 82, 1515–1525; b) X.
Li, H. Y. Lam, Y. Zhang, C. K. Chan, Org. Lett. 2010, 12, 1724–
Received: May 20, 2012
Published online: && &&, 0000
&
10
&
www.chemeurj.org
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Direct Acyl Substitution of Carboxylic Acids
FULL PAPER
Acyl Substitution
A. D. Kosal, E. E. Wilson,
B. L. Ashfeld* ................ &&&& — &&&&
Direct Acyl Substitution of Carboxylic
Acids: A Chemoselective O- to N-
Acyl Migration in the Traceless Stau-
dinger Ligation
Turning the peptide with azides: A
modified Staudinger-like acylation of
azides involving a highly chemoselec-
tive, direct acyl substitution of carbox-
ylic acids is described. Structurally
diverse amides are obtained after a
simple aqueous workup (see scheme).
The use of chlorophosphites as dual
carboxylic acid–azide activating agents
À
enables the formation of acyl C N
bonds in the presence of a wide range
of nucleophilic and electrophilic func-
tional groups.
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
11
&
ÞÞ
These are not the final page numbers!