Synthesis of benzoate-functionalized phosphanes as novel building blocks for the traceless staudinger ligation

Article abstract of DOI:10.1055/s-0029-1216947

A new synthetic pathway for the preparation of benzoate-functionalized phosphanes for microwave-mediated traceless Staudinger ligations is described. Novel phosphane derivatives based on 4-substituted iodophenyl benzoates were prepared via palladium(II)-catalyzed P-C cross-coupling reaction strategy in high yields. The application of microwave conditions for the ligation reactions reduced the reaction time considerably. An approach to fast and facile labeling strategies using this ligation was established.

Full text of DOI:10.1055/s-0029-1216947

PAPER
3311
Synthesis of Benzoate-Functionalized Phosphanes as Novel Building Blocks for
the Traceless Staudinger Ligation
Novel Building
B
o
locks for the
n
T
raceless
S
s
taudinge
r
t
Ligatio
a
n
ntin Mamat,*a Anke Flemming,b Martin Köckerling,b Jörg Steinbach,a Frank R. Wuestc
a
Institut für Radiopharmazie, Forschungszentrum Dresden-Rossendorf e. V., Postfach: 50 01 19, 01314 Dresden, Germany
Fax +49(351)2602915; E-mail: c.mamat@fzd.de
b
c
Institut für Chemie, Universität Rostock, Albert-Einstein-Straße 3a, 18059 Rostock, Germany
Department of Oncologic Imaging, Cross Cancer Institute, University of Alberta, Edmonton, AB, T6G 1Z2, Canada
Received 2 March 2009; revised 10 June 2009
nophenol leading to the corresponding phosphane-
functionalized esters.3 Recently Xian et al. demonstrated
a reductive ligation procedure involving S-nitrosothiols
based on a benzoate-functionalized phosphanes.8
Abstract: A new synthetic pathway for the preparation of ben-
zoate-functionalized phosphanes for microwave-mediated traceless
Staudinger ligations is described. Novel phosphane derivatives
based on 4-substituted iodophenyl benzoates were prepared via pal-
ladium(II)-catalyzed P–C cross-coupling reaction strategy in high
yields. The application of microwave conditions for the ligation re-
actions reduced the reaction time considerably. An approach to fast
and facile labeling strategies using this ligation was established.
Palladium-catalyzed carbon–carbon and carbon–heteroat-
om cross-coupling reactions are widely used in synthetic
organic chemistry for various arylation and acylation re-
actions involving a broad variety of organic substrates.9
However, only a few reports in the literature deal with the
synthesis of phosphanes using metal-catalyzed PIII–C
cross-coupling reactions, mainly through Stille-type reac-
tions.10 The synthetic application of P–C coupling reac-
tions was improved by the direct use of secondary
phosphanes as shown by the group of Stelzer and co-
workers in 1996.11 They described a direct route towards
tertiary phosphanes containing polar substituents via a
palladium(II)-catalyzed P–C cross-coupling reaction be-
tween aryl halides and HPPh2 or H2PPh. Further improve-
ments were implemented by the use of borane-protected
phosphanes in ionic liquids as reported by Valette et al.12
or by the use of triflates as more reactive leaving groups.13
The high hydrophilicity of these phosphanes is an advan-
tage for their application in reactions in polar or aqueous
solvents and in biological systems.
Key words: Staudinger ligation, traceless, click chemistry, P–C
cross-coupling, palladium-catalyzed
The Staudinger ligation1 is widely used in biochemistry
and medicinal chemistry for the interconnection of molec-
ular entities like carbohydrates, amino acids, and proteins
to give various hybrid-bioconjugates under mild condi-
tions.2–5 Moreover, the incorporation of molecular probes
into biomolecules, as frequently exemplified by fluores-
cence labels, has gained great interest over the last years
to study metabolic pathways in complex biological
systems6 as pointed out in Scheme 1. Despite the desirable
bioorthogonal character of the reaction partners through
chemoselective reaction between organic azides and
phosphanes, and the mild reaction conditions, the major
drawback of the Staudinger ligation lies in its very long
reaction time of up to 24 hours upon completion. Howev-
er, in 2008 Bernardi and co-workers demonstrated the
beneficial effect of microwave activation to reduce reac-
tion times to less than one hour by synthesizing glycosyl
amides via the Staudinger ligation.7
In this paper, we describe an easy access to novel ben-
zoate-functionalized phosphanes as versatile building
blocks for traceless Staudinger reaction and their applica-
tion in microwave-mediated Staudinger ligation. This ap-
proach represents an interesting synthesis route for
subsequent incorporation of various molecular probes
into bioactive molecules. Moreover, an efficient proce-
dure for the protection of phosphanes via borane-
phosphane adduct formation is described, which enables
subsequent functionalization reactions.
Acylated phosphanes are of great interest as versatile
building blocks for the traceless Staudinger ligation. Most
of these phosphanes were prepared by reacting aliphatic
carboxylic acid chlorides or anhydrides with phospha-
O
O
biomolecule
N3
O
DMF–H2O, MW, 20 min
biomolecule
N
PPh2
H
label
label
Scheme 1 Labeling strategy via the traceless Staudinger ligation
SYNTHESIS 2009, No. 19, pp 3311–3321
x
x.
x
x
.
2
0
0
9
Advanced online publication: 21.08.2009
DOI: 10.1055/s-0029-1216947; Art ID: T05009SS
© Georg Thieme Verlag Stuttgart · New York

3312
C. Mamat et al.
PAPER
The benzoate residue is an important motif for the incor-
poration of the short-lived positron emitter fluorine-18
(18F, t1/2 = 109.8 min) into biologically active molecules
due to the high in vivo stability of the 18F–C bond in 4-
[18F]fluorobenzoate groups.14 Incorporation of 18F into
benzoates is usually accomplished via nucleophilic aro-
matic substitution with [18F]fluoride on the activated aro-
matic system bearing 4-nitro, 4-trimethylammonium, or
4-iodo substituents as leaving group.
Table 1 2-Iodophenyl Benzoates 6a–h
Substrate
R
Method
Product
6a
Yield (%)
3a
3b
3c
5d
5e
5f
H
A
A
A
B
B
B
B
B
89
98
83
74
81
67
39
42
F
6b
NO2
6c
I
6d
Conventional esterification of phosphanol 2 with appro-
priate benzoyl chlorides 3a–c in the presence of a base
like Et3N or t-BuOK in THF, or via Steglich esterification
(for 4d) was envisaged for the synthesis of substituted
phosphanes 4a–d as shown in Scheme 2. However, appli-
cation of these reaction conditions sometimes led to low
chemical yields of the desired phosphanes and the forma-
tion of by-products, which made the purification steps dif-
ficult. Furthermore, the corresponding phosphane oxides
were also formed in small amount (approx. 0.5–0.9%).
OCH2CH2OH
OCH2CH2F
OH
6e
6f
5g
5h
6g
NMe2
6h
Pd(OAc)2 as the catalyst. The reaction proceeded smooth-
ly, and no protecting group manipulations for the OH
groups in compounds 6e and 6g were necessary under
these reaction conditions. The reactions were accom-
plished within 4 to 16 hours. After aqueous workup, puri-
fication of the crude product was carried out by column
chromatography to afford the desired products 4a,b,e–h
in moderate to high chemical yields of 58 to 89% without
the formation of by-products or oxidation products. Most
of the studied functions seem to be compatible with these
reaction conditions. However, no product formation was
observed when the nitro-containing compound 6c was
subjected to palladium-catalyzed cross-coupling reaction.
Scope and limitation of this formation are pointed out in
Scheme 4 and Table 2.
Therefore, we developed an alternative strategy based on
palladium-catalyzed P–C cross-coupling reactions11 be-
tween various 2-iodophenyl benzoates and diphenylphos-
phane. Two possibilities were applied for the preparation
of substrates 6a–h as intermediates for subsequent cross-
couplings (Scheme 3). In the first set of reactions (method
A) several 2-iodophenyl benzoates 6a–c were prepared in
excellent yields from 83 to 98% through the reaction of
benzoyl chlorides 3a–c with 2-iodophenol (1) in the pres-
ence of Et3N as the base. A second approach (method B)
was based on the reaction of benzoic acids 5d–h with 2-
iodophenol (1) and DCC/DMAP according to Steglich
esterification15 that delivers compounds 6d–h in good
yields of 39 to 81%. The results are summarized in
Table 1.
31P NMR investigations of phosphanes 4a–h showed sig-
nals in the range of d = –15 indicative of aromatic organ-
ophosphanes in the oxidation state +3 (compared to
d = 3016 for Ph3PO). The observed singlet indicates that
no oxidized species were formed during the reaction.
In the next step, synthesis of benzoylated phosphanes
4a,b,e–h was performed via palladium-catalyzed cross-
coupling reaction of 2-iodophenyl benzoates 6a,b,e–h
with diphenylphosphane in the presence of KOAc, and
It was possible to obtain crystals from compound 4a suit-
able for a single crystal X-ray structural analysis. Figure 1
3a–c, 5d
Et3N or t-BuOK
THF, r.t., 1.5 h
O
OH
OH
KOAc, DMA, HPPh2
Pd(OAc)2, 100 °C
PPh2
O
I
PPh2
R
1
2
4a–d
a: R = H, b: R = F, c: R = NO2, d: R = I
Scheme 2 Synthesis of substituted phosphanes 4a–d
method B
method A
1, Et3N, THF
0 °C to r.t., 1.5 h
Cl
O
1, DCC, DMAP
THF (DMF), r.t.
(100 °C), 16 h
O
O
O
OH
I
R
R
R
5d–h
6a–h
3a–c
a: R = H, b: R = F, c: R = NO2, d: R = I, e: R = OCH2CH2OH, f: R = OCH2CH2F,
g: R = OH, h: R = NMe2
Scheme 3 Synthesis of several 2-iodophenyl benzoates 6a–h as synthons for the palladium-catalyzed P–C cross-coupling
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

PAPER
Novel Building Blocks for the Traceless Staudinger Ligation
3313
thesis of chiral phoshanes20 and diphosphanes21 as well as
‘protecting group’ for the preparation of key intermedi-
ates for the Staudinger ligation.4 The main application of
phosphane-borane adducts is stabilization of phosphorus
at the oxidation state +3 to prevent side reactions. For fur-
ther reactions involving alkyl halides leading to phospho-
nium salts or under oxidative conditions leading to
phosphane oxides, the phosphorous is blocked with the
BH3 group. Two different synthesis pathways for borane-
phosphane adducts are described in the literature. McNulty
and co-workers reported a strategy based on the conver-
sion of alkylphosphanes with NaBH4 (or LiBH4) as the
borane source under acidic conditions.22 An alternative
approach is based on the transfer of the BH3 group from a
weaker THF·BH3 or Me2S·BH3 adduct to phosphorus.23
O
O
HPPh2, KOAc, DMA
Pd(OAc)2, 100 °C
O
O
I
PPh2
R
R
6a,b,e–h
4a,b,e–h
a: R = H, b: R = F, d: R = OCH2CH2OH,
f: R = OCH2CH2F, g: R = OH, h: R = NMe2
Scheme 4 Palladium-catalyzed cross-coupling of 6a,b,e–h with
HPPh2
Table 2 Substituted Phosphanes 4a–h
Substrate
3a
R
Product
4aa
Yield (%)
92
In a first experiment, HPPh2 (7) was protected with BH3
according to literature procedures24 resulting in the diphe-
nylphosphane-borane adduct 8 followed by reaction of
compound 8 with 2-iodophenol (1) under palladium(II)
catalysis. Borane-protected phosphane 9 could not be iso-
lated under these reaction conditions (Scheme 5).
H
6a
H
4ab
4ba
4bb
4ca
79
3b
F
57
6b
F
65
3c
NO2
38
6c
NO2
4cb
n.d.c
76
5d
I
4da
4eb
6e
OCH2CH2OH
OCH2CH2F
OH
89
6f
4fb
67
6g
4gb
4hb
58
6h
NMe2
75
a Preparation via esterification (Scheme 2).
b Preparation via Pd-catalyzed P–C cross-coupling (Scheme 4).
c No formation of the desired product was observed by this method.
depicts the molecular structure of 4a.17 The central phos-
phorus atom has a pyramidal configuration, the P–C dis-
tances with an average of 1.83 Å are within the range of
normal P–C single bonds (1.87 Å18).
Phosphane-borane adducts19 are frequently applied to or-
ganic chemistry and catalysis. They are used for the syn-
Figure 1 Molecular structure of compound 4a (ORTEP-Plot, 50%
probability level). Selected bond lengths (Å) and angles (°): P1–C1
1.8358(8), P1–C13 1.8339(8), P1–C7 1.8343(9), O2–C19
1.2060(10), O1–C19 1.3618(9), C19–O1–C14 116.01(6), O2–C19–
O1 122.88(7), C13–P1–C7 101.65(4), C13–P1–C1 101.11(3).
2-iodophenol (1)
Pd(OAc)2, DMA
100 °C, 6 h
OH
BH3
Ph
THF
–78 °C
H
P
H
PPh2
+
THF-BH3
P
Ph
Ph
Ph
2
8
7
THF⋅BH3
THF
–78 °C
16h
1, Pd(OAc)2
DMA, 100 °C, 6 h
3a,b
O
O
O
O
t-BuOK
THF, r.t.
16 h
BH3
BH3
PPh2
THF⋅BH3
OH
THF, –78 °C
PPh2
PPh2
R
R
9
4c,d,h
10a–d,h
a: R = H, b: R = F, c: R = NO2, d: R = I, h: R = NMe2
Scheme 5 Synthesis of phosphane-boranes 8, 9, and 10a–d,h
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

3314
C. Mamat et al.
PAPER
Direct conversion of 2-(diphenylphosphano)phenol (2)
into the phosphane borane adduct 9 was accomplished by
the reaction with a 1 M THF·BH3 solution at –78 °C.
Warming up the reaction mixture to room temperature
overnight, removal of the solvent, and subsequent purifi-
cation of the crude product via column chromatography
gave compound 9 as colorless crystals in 95% yield. Com-
pound 9 functions as key intermediate for the preparation
of all other substituted phosphane-borane compounds. For
this purpose, compound 9 was likewise reacted with the
benzoyl chloride derivatives 3a,b in the presence of t-
BuOK as the base. Products 10a,b were obtained in good
yields, respectively. Another possibility consists of the di-
rect treatment of the substituted phosphanophenols 4c,d,h
with THF·BH3 solution to give the corresponding phos-
phane-boranes 10c,d,h in 67 to 85% yields. Scheme 5 and
Table 3 summarize the synthesis and the obtained chemi-
cal yields.
Figure 2 Molecular structure of compound 10c (ORTEP-Plot, 50%
probability level). Selected bond lengths (Å) and angles (°): P1–B1
1.9324(15), N1–O4 1.2178(24), C1–O1 1.3680(15), C1–O2
1.2002(17), B1–P1–C8 115.27(6), O4–N1–O3 123.67(18), C25–O1–
C1 118.26(10), O1–C1–O2 123.97(13), O1–C1–C2 110.65(11).
in the range of the values typically found for Me3PBH3
(1.901 Å) or H3PBH3 (1.937 Å)25 and an average of 1.81
Å was found for the P–C bonds (1.819 Å for Me3PBH3).
Table 3 Synthesis of Borane Adducts 10a–d,h by Protection with
BH3
A special challenge for the application of Staudinger liga-
tion involving the short-lived positron emitter 18F is the
relatively long time required for the reaction. To over-
come this obstacle we have performed various attempts to
accelerate the ligation procedure. First, as a test reaction
phosphane 4a was reacted with benzyl azide (11) at ambi-
ent temperature and at 90 °C (Scheme 6). Increasing the
temperature was accompanied with a considerable reduc-
tion of reaction time from 6.5 hours to 1 hour to reach
comparable chemical yields of compound 14. In addition,
the application of microwave activation at 50 Watt further
reduced reaction time to 15 to 20 minutes (Table 4).
Substrate R
Product Yield (%) 31P NMR, d 31P NMR,a d
3a
3b
4c
4d
4h
H
10a
10b
10c
10d
10h
60
95
84
67
85
19.8
20.8
20.7
21.0
21.2
–14.8
–14.6
–14.7
–14.7
–14.8
F
NO2
I
NMe2
a The 31P NMR shifts belong to the unprotected phosphane com-
pounds 4a–d,h, respectively.
The azide functionalized galactose derivative 12 and
amide 13 as biologically relevant compounds were react-
ed successfully within the Staudinger ligation under mi-
crowave conditions to give the corresponding
fluorobenzoylated amides in 92 and 78% yields, respec-
tively. The results are summarized in Table 4.
The presence of the BH3 group was confirmed by the eval-
1
uation of H, 13C as well as 31P NMR analysis. A broad
multiplet originating from the borane protons was ob-
1
served as a new signal between d = 1–2 in the H NMR
spectra. Furthermore, a multiplet appears for the phospho-
rus atom that is shifted downfield from d = ca. –15 for
phosphanes to d = ca. +20 for the phosphane-borane ad-
ducts in the 31P NMR spectra. The multiplet results from
complex couplings of the central phosphorus with 10B,
11B, and the borane protons. In the 11B NMR spectrum a
signal in the range of d = –36 was observed, which is in-
dicative of the BH3 group.
In summary, we have developed a straightforward and
convenient synthetic route to substituted phosphanes 4a–
h by the palladium-catalyzed P–C cross-coupling reaction
of appropriate 2-iodophenyl esters 6a–h with HPPh2. The
synthesis represents an alternative approach to the com-
monly employed esterification of substituted phenol de-
rivatives. The starting material for the coupling reaction
was easily available through the reaction of 2-iodophenol
(1) with benzoic acids 5d–h under Steglich conditions, or
by the reaction with the appropriate benzoyl chlorides
3a–c. The benzoylated phosphane derivatives 4a,b,e–h
obtained by this method represent as key intermediates for
In addition, it was possible to obtain crystals from com-
pound 10c suitable for a single crystal X-ray analysis17
(Figure 2). The central phosphorus atom of this structure
adopts a tetracoordinated configuration with the BH3
group as fourth ligand. The P–B distance with 1.93 Å lies
O
O
O
N3
DMF, H2O
+
N
H
PPh2
F
F
11
14
4a
Scheme 6 Sample Staudinger ligation under different reaction conditions
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

PAPER
Novel Building Blocks for the Traceless Staudinger Ligation
3315
Table 4 Staudinger Conditions and Substrates
Substrate
Conditions
Time
Product
Yield
O
r.t.
90 °C
microwave (50 W)
6.5 h
1 h
15 min
81%
85%
83%
N3
11
14
N
H
F
O
N3
O
H
N
O
O
O
O
O
O
12
13
microwave (50 W)
microwave (50 W)
20 min
20 min
15
16
92%
78%
O
F
O
O
F
O
O
H
N3
N
N
H
N
H
O
placed on geometrically calculated positions and refined using a
riding model. The three H atoms of the BH3 group in 10c were re-
fined isotropically.
the traceless Staudinger ligation and can be used as start-
ing material for various radiolabeling purposes due to the
great variety of introduced functional groups. Treatment
of phosphanes with THF·BH3 solution gave the corre-
sponding phosphane-borane adducts 10a–d,h in excellent
yields. Protection of the phosphorous with the BH3 group
enabled further functionalizations of the carbon scaffold.
Moreover, a considerable reduction of reaction time from
6 hours to 20 minutes for the Staudinger ligation was
achieved through the application of microwave activation.
Substituted Phosphanes 4a–d; General Procedure A
t-BuOK or Et3N (1–1.2 equiv) was added to a solution of phospha-
nol 2 (1 equiv) in anhyd THF or CH2Cl2 at r.t. and the solution was
allowed to stir for 30 min. Afterwards the respective benzoyl chlo-
ride 3a–c (1.2–1.5 equiv) was added at r.t. and the solution was al-
lowed to stir overnight. H2O (10 mL) was added, the organic layer
separated, and the aqueous layer was extracted with Et2O (3 × 10
mL). The combined organic layers were dried (Na2SO4) and con-
centrated under reduced pressure. The crude product was purified
by column chromatography (PE–EtOAc, 20:1).
NMR spectra of the compounds were recorded on a Varian Inova-
400 and chemical shifts of the 1H, 13C, 19F, and 31P spectra were re-
ported in parts per million (ppm) using TMS as internal standard for
1H and 13C, CFCl3 for 19F, and H3PO4 for 31P spectra. 11B NMR
spectra were recorded on a Bruker ARX 300 with B(OMe)3 as ex-
ternal standard. Mass spectrometric data were obtained on a
Quattro/LC mass spectrometer (MICROMASS) by electron spray
ionization or on a Bruker autoflex II TOF/TOF mass spectrometer
(Matrix: DHB, reflector mode). Melting points were determined on
a Galen III (Cambridge Instruments) melting point apparatus
(Leica, Vienna, Austria) and are uncorrected. Microanalyses were
carried out with a LECO CHNS 932 elemental analyzer. Anhyd sol-
vents [THF, CH2Cl2, N,N-dimethylacetamide (DMA)] were pur-
chased from Fluka (anhyd, over molecular sieves, 99.7%) and other
chemicals used for the syntheses were purchased from Sigma-
Aldrich, Fluka, or ABCR and were used as received. Petroleum
ether (PE) used refers to the fraction boiling in the range 40–60 °C.
Chromatographic separations and TLC detections were carried out
with Merck Silica Gel 60 (63–200 mm) and Merck Silica Gel 60 F254
sheets, respectively. TLCs were developed by ninhydrin solution
(5% in EtOH) and heating (amine-containing compounds) or visu-
alized under UV light (l = 254 nm). All reactions concerning the
Pd-catalyzed coupling of HPPh2 and the borane-phosphane adduct
formation were carried out under argon using Schlenk techniques.
Phosphanol 2 was synthesized according to a method of Herd and
co-workers11 and carbohydrate 12 was synthesized by a method de-
scribed in the literature.26 Crystallographic data were collected with
a Bruker-Nonius Apex-X8 CCD-diffractometer with Mo-Ka radia-
tion (l = 0.71073 Å). The structures were solved by direct methods
using SHELXS-97 and refined against F2 on all data by full-matrix
least-squares with SHELXL-97.27 All non-hydrogen atoms were re-
fined anisotropically; all hydrogen atoms bonded to C atoms were
2-(Diphenylphosphano)phenyl Benzoate (4a)8
Following the general procedure A, phosphanol 2 (150 mg, 0.54
mmol), t-BuOK (61 mg, 0.54 mmol), and benzoyl chloride (3a; 114
mg, 0.81 mmol) yielded compound 4a as colorless crystals; yield:
190 mg (92%); mp 101 °C; Rf = 0.57 (PE–EtOAc, 10:1).
1H NMR (400 MHz, C6D6): d = 6.84 (t, 3J = 7.4 Hz, 1 H, Hp¢), 6.93
(t, 3J = 7.4 Hz, 2 H, Hp), 6.98–7.08 (m, 9 H, Hm, Hm¢, 4-H, 5-H, H-
6), 7.25 (dd, 3JH,P = 4.4 Hz, 3J = 8.2 Hz, 1 H, H-3), 7.34–7.40 (m, 4
H, Ho), 8.06 (d, 3J = 7.8 Hz, 2 H, Ho¢).
3
13C NMR (101 MHz, C6D6): d = 123.2 (d, JC,P = 1.6 Hz, C-6),
3
126.3 (C-4), 128.4 (Cm¢), 128.9 (d, JC,P = 7.1 Hz, Cm), 129.0 (Cp),
130.0 (Cipso¢), 130.1 (C-5), 130.4 (Co¢), 131.5 (d, 1JC,P = 16.0 Hz, C-
2), 133.2 (Cp¢), 134.0 (d, 2JC,P = 1.1 Hz, C-3), 134.4 (d, 2JC,P = 20.7
Hz, Co), 136.4 (d, 1JC,P = 11.4 Hz, Cipso), 148.7 (d, 1JC,P = 9.6 Hz, C-
1), 164.2 (C=O).
31P NMR (162 MHz, C6D6): d = –14.8.
MS (ESI+): m/z (%) = 405 (70, [M+ + Na]), 383 (100, [M+ + H]).
Anal. Calcd for C25H19O2P: C, 78.52; H, 5.01. Found: C, 78.44; H,
5.01.
2-(Diphenylphosphano)phenyl 4-Fluorobenzoate (4b)
Following the general procedure A, phosphanol 2 (200 mg, 0.93
mmol), Et3N (109 mg, 0.72 mmol), and 4-fluorobenzoyl chloride
(3b; 148 mg, 1.08 mmol) yielded compound 4b as colorless crys-
tals; yield: 255 mg (87%); mp 94 °C; Rf = 0.37 (PE–EtOAc, 5:1).
1H NMR (400 MHz, C6D6): d = 6.55 (t, 3Jo¢,m¢ = 3JH,F = 8.6 Hz, 2 H,
Hm¢), 6.84 (t, 3J4,5 = 7.8 Hz, 3J3,4 = 7.0 Hz, 1 H, H-4), 6.97–7.09 (m,
8 H, Hm, Hp, H-5, H-6), 7.27 (dd, 4JH,P = 3.9 Hz, 3J5,6 = 7.8 Hz, 1 H,
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3316
C. Mamat et al.
PAPER
3
H-3), 7.32–7.39 (m, 4 H, Ho), 7.84 (dd, Jo¢,m¢ = 8.6 Hz, 4JH,F = 5.4
Hz, 2 H, Ho¢).
equiv) was added dropwise and the solution was stirred for 30 min
at 0 °C and 1 h at r.t. Afterwards, the precipitate was filtered off and
the solvent was removed under reduced pressure. Aq 1 M NaOH (30
mL) was added and the aqueous solution was extracted with EtOAc
(3 × 10 mL), the combined organic layers dried (Na2SO4), and the
solvent removed under reduced pressure. Purification was done by
distillation under high vacuum (compounds 6a,b) or by column
chromatography.
13C NMR (101 MHz, C6D6): d = 115.6 (d, JC,F = 22.1 Hz, Cm¢),
2
123.2 (C-6), 126.1 (d, 4JC,F = 3.4 Hz, Cipso¢), 126.4 (C-4), 128.9 (d,
3JC,P = 7.4 Hz, Cm), 129.2 (Cp), 130.1 (C-5), 131.4 (d, JC,P = 14.3
1
2
Hz, C-2), 133.1 (d, JC,F = 8.8 Hz, Co¢), 134.0 (C-3), 134.4 (d,
2JC,P = 20.6 Hz, Co), 136.3 (d, JC,P = 11.8 Hz, Cipso), 153.6 (d,
1
2JC,P = 17.8 Hz, C-1), 163.2 (C=O), 166.2 (d, 1JC,F = 253.3 Hz, Cp¢).
19F NMR (376 MHz, C6D6): d = –105.6.
2-Iodophenyl Benzoate (6a)
31P NMR (162 MHz, C6D6): d = –14.6.
Following the general procedure B, 2-iodophenol (1; 1.00 g, 4.54
mmol), Et3N (0.95 mL, 6.82 mmol), and benzoyl chloride (3a; 0.7
mL, 5.91 mmol) in THF (30 mL) yielded compound 6a as a color-
less liquid after distillation under high vacuum; yield: 1.31 g (89%);
bp 155 °C/5·10–3 mbar.
MS (ESI+): m/z (%) = 423 (21, [M+ + Na]), 401 (19, [M+ + H]).
Anal. Calcd for C25H18FO2P: C, 75.00; H, 4.53. Found: C, 75.36; H,
5.08.
1H NMR (400 MHz, C6D6): d = 6.36 (t, Jm,p = 7.8 Hz, 1 H, Hp),
3
2-(Diphenylphosphano)phenyl 4-Nitrobenzoate (4c)
Following the general procedure A, phosphanol 2 (200 mg, 0.72
mmol), t-BuOK (100 mg, 0.89 mmol), and 4-nitrobenzoyl chloride
(3c; 200 mg, 1.08 mmol) in CH2Cl2 yielded compound 4c as color-
less crystals; yield: 175 mg (38%); mp 95 °C; Rf = 0.44 (PE–
EtOAc, 10:1).
6.79 (dt, 4J = 1.4 Hz, 3J3,4 = 7.8 Hz, 3J4,5 = 8.0 Hz, 1 H, H-4), 6.89
3
3
(dd, 4J = 1.3 Hz, J5,6 = 8.2 Hz, 1 H, H-6), 6.99 (t, Jm,p = 7.8 Hz,
3Jo,m = 8.0 Hz, 2 H, Hm), 7.07 (dt, 4J = 1.3 Hz, 3J5,6 = 8.2 Hz, 1 H, H-
5), 7.45 (dd, 4J = 1.2 Hz, J3,4 = 7.8 Hz, 1 H, H-3), 8.22 (d,
3
3Jo,m = 8.0 Hz, 2 H, Ho).
13C NMR (101 MHz, C6D6): d = 91.0 (C-2), 123.6 (C-6), 127.6 (C-
4), 128.8 (Cm), 129.4 (C-5), 129.9 (Cipso), 130.7 (Co), 133.7 (Cp),
139.6 (C-3), 152.0 (C-1), 164.1 (C=O).
1H NMR (400 MHz, C6D6): d = 6.83 (t, 3J = 7.0Hz, 3J = 7.8 Hz, 1
3
H, H-4), 6.96–7.02 (m, 7 H, Hm, Hp, H-3), 7.05 (dt, J = 7.8 Hz,
4J = 1.6 Hz, 1 H, H-5), 7.20 (dd, 3J = 8.6 Hz, 4J = 3.9 Hz, 1 H, H-6),
7.30–7.37 (m, 4 H, Ho), 7.58 (d, 3Jo,m = 8.6 Hz, 2 H, Ho¢), 7.68 (d,
3Jo,m = 8.6 Hz, 2 H, Hm¢).
MS (ESI+): m/z (%) = 347 (100, [M+ + Na]), 325 (10, [M+ + H]).
Anal. Calcd for C13H9IO2: C, 48.17; H, 2.80. Found: C, 48.33; H,
2.75.
13C NMR (101 MHz, C6D6): d = 122.9 (C-6), 123.4 (Cm¢), 126.8 (C-
4), 129.0 (d, 3JC,P = 7.3 Hz, Cm), 129.4 (Cp), 130.2 (C-5), 131.1 (Co¢),
131.2 (d, 1JC,P = 16.3 Hz, C-2), 134.2 (d, 2JC,P = 1.1 Hz, C-3), 134.4
(Cipso¢), 134.0 (d, 2JC,P = 1.1 Hz, C-3), 134.4 (d, 2JC,P = 20.7 Hz, Co),
2-Iodophenyl 4-Fluorobenzoate (6b)
Following the general procedure B, 2-iodophenol (1; 1.00 g, 4.54
mmol), Et3N (0.95 mL, 6.82 mmol), and 4-fluorobenzoyl chloride
(3b; 0.7 mL, 5.91 mmol) in THF (30 mL) yielded compound 6b as
a colorless liquid after distillation under high vacuum; yield: 1.53 g
(98%); bp 150 °C/1·10–3 mbar.
1
1
135.9 (d, JC,P = 10.8 Hz, Cipso), 153.2 (d, JC,P = 17.6 Hz, C-1),
162.6 (C=O).
31P NMR (162 MHz, C6D6): d = –14.7.
MS (ESI+): m/z (%) = 450 (27, [M+ + Na]), 428 (71, [M+ + H]).
3
3
1H NMR (400 MHz, C6D6): d = 6.46 (dt, J4,5 = 7.5 Hz, J3,4 = 7.9
Hz, 4J = 1.6 Hz, 1 H, H-4), 6.67 (t, 3Jo,m = 3JH,F = 8.9 Hz, 2 H, Hm),
6.89 (dt, 3J4,5 = 7.5 Hz, 3J5,6 = 8.2 Hz, 1 H, H-5), 6.97 (dd, 3J5,6 = 8.2
Hz, 4J = 1.6 Hz, 1 H, H-6), 7.53 (dd, 3J5,6 = 7.9 Hz, 4J = 1.5 Hz, 1 H,
H-3), 7.90 (dd, 3Jo,m = 8.9 Hz, 4JH,F = 5.5 Hz, 2 H, Ho).
Anal. Calcd for C25H18NO4P: C, 70.26; H, 4.25; N, 3.28. Found: C,
70.15; H, 4.60; N, 3.26.
2-(Diphenylphosphano)phenyl 4-Iodobenzoate (4d)
Phosphanol 2 (300 mg, 1.08 mmol), 4-iodobenzoic acid (5d; 267
mg, 1.08 mmol), and DMAP (50 mg) were dissolved in anhyd THF
(5 mL). DCC (334 mg, 1.62 mmol) was added slowly at r.t. and the
mixture was allowed to stir overnight. Afterwards, the precipitate
was filtered off, the solvent was removed under reduced pressure
and purification was done by column chromatography (PE–EtOAc,
10:1); yield: 414 mg (76%); mp 133 °C; Rf = 0.75 (PE–EtOAc, 4:1).
2
13C NMR (101 MHz, C6D6): d = 90.9 (C-2), 116.0 (d, JC,F = 22.1
4
Hz, Cm), 123.6 (C-6), 125.9 (d, JC,F = 3.0 Hz, Cipso), 127.7 (C-4),
129.5 (C-5), 133.3 (d, 3JC,F = 9.5 Hz, Co), 139.6 (C-3), 151.8 (C-1),
163.1 (C=O), 166.4 (d, 1JC,F = 254.6 Hz, Cp).
19F NMR (376 MHz, C6D6): d = –104.7.
MS (MALDI-TOF): m/z = 365 [M+ + Na], 342 [M+ + H], 341 [M+].
1H NMR (400 MHz, C6D6): d = 6.83 (t, 3J = 7.0 Hz, 3J = 7.8 Hz, 1
Anal. Calcd for C13H8FIO2: C, 45.64; H, 2.36. Found: C, 45.73; H,
2.41.
3
H, H-4), 6.95–7.09 (m, 8 H, H-5, H-6, Hm, Hp), 7.20 (dd, J = 7.8
4
Hz, J = 4,7 Hz, 1 H, H-3), 7.28–7.39 (m, 6 H, Hm¢, Ho), 7.50 (d,
3Jo,m = 8.4 Hz, 2 H, Ho¢).
2-Iodophenyl 4-Nitrobenzoate (6c)
13C NMR (101 MHz, C6D6): d = 101.5 (Cp¢), 123.1 (C-6), 126.5 (C-
4), 128.9 (d, 3JC,P = 7.4 Hz, Cm), 129.2 (Cp), 130.1 (C-5), 131.5 (d,
1JC,P = 23.5 Hz, C-2), 131.7 (Co¢), 134.0 (C-3), 134.4 (d, 2JC,P = 20.6
Following the general procedure B, 2-iodophenol (1; 1.00 g, 4.54
mmol), Et3N (0.95 mL, 6.82 mmol), and 4-nitrobenzoyl chloride
(3c; 0.7 mL, 5.91 mmol) in THF (30 mL) yielded compound 6c as
pale yellow crystals after column chromatography (PE–EtOAc,
20:1); yield: 1.40 g (83%); mp 132 °C; Rf = 0.86 (PE–EtOAc, 3:1).
1
Hz, Co), 136.2 (d, JC,P = 10.3 Hz, Cipso), 137.9 (Cm¢), 153.5 (d,
1JC,P = 16.3 Hz, C-1), 163.8 (C=O).
1H NMR (400 MHz, C6D6): d = 6.46 (dt, 4J = 1.6 Hz, 3J4,5 = 7.0 Hz,
1 H, H-4), 6.88 (dt, 4J = 1.6 Hz, 3J4,5 = 7.0 Hz, 1 H, H-5), 6.92 (dd,
4J = 2.3 Hz, 3J5,6 = 8.6 Hz, 1 H, H-6), 7.51 (d, 3J3,4 = 7.8 Hz, 1 H, H-
3), 7.68 (d, 3Jo,m = 8.6 Hz, 2 H, Ho), 7.88 (d, 3Jo,m = 8.6 Hz, 2 H, Hm).
13C NMR (101 MHz, C6D6): d = 90.5 (C-2), 123.2 (C-6), 123.8
(Cm), 129.6 (C-5), 131.3 (Co), 134.2 (Cipso),139.8 (C-3), 152.0 (C-
1), 151.5 (Cp), 162.4 (C=O).
31P NMR (162 MHz, C6D6): d = –14.7.
MS (MALDI-TOF): m/z = 531 [M+ + Na], 507 [M+ – H].
Anal. Calcd for C25H18IO2P: C, 59.07; H, 3.57. Found: C, 59.49; H,
3.72.
2-Iodophenyl Benzoates 6a–c; General Procedure B
2-Iodophenol (1; 1 equiv) and Et3N (1.5 equiv) were dissolved in
THF (30 mL). At 0 °C, the respective benzoyl chloride 3a–c (1.3
MS (MALDI-TOF): m/z = 369 [M+], 353 [M+ – O], 337 [M+ – 2 O].
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

PAPER
Novel Building Blocks for the Traceless Staudinger Ligation
3317
Anal. Calcd for C13H8INO4: C, 42.30; H, 2.18; N, 3.79. Found: C,
42.43; H, 2.08; N, 3.78.
5), 7.03 (dd, 4J = 1.5 Hz, 3J5,6 = 8.1 Hz, 1 H, H-6), 7.55 (dd, 4J = 1.5
Hz, 3J5,6 = 8.0 Hz, 1 H, H-3), 8.28 (d, 3Jo,m = 9.0 Hz, 2 H, Ho).
13C NMR (101 MHz, C6D6): d = 67.1 (d, JC,F = 20.8 Hz,
2
2-Iodophenyl Benzoates 6d–h; General Procedure C
CH2CH2F), 81.2 (d, 1JC,F = 170.9 Hz, CH2CH2F), 91.1 (C-2), 114.7
(Cm), 122.7 (Cipso), 123.8 (C-6), 127.5 (C-4), 129.4 (C-5), 132.9
(Co), 139.6 (C-3), 152.1 (C-1), 163.1 (Cp), 163.8 (C=O).
2-Iodophenol (1; 1.5 equiv), the respective benzoic acid 5d–h (1
equiv), and DMAP (100 mg) were dissolved in anhyd THF (or an-
hyd DMF for compound 6g) and DCC (1.2–2 equiv) was added
slowly at r.t. The mixture was allowed to stir overnight at r.t. (at
100 °C for compound 6g). Afterwards, the precipitate was filtered
off, the organic layer was diluted with Et2O (30 mL) and the com-
bined organic layers were washed with aq 1 M HCl (15 mL) and aq
1 M NaOH (15 mL), and dried (Na2SO4). The solvent was removed
under reduced pressure and purification of the crude product was
done by column chromatography.
19F NMR (376 MHz, C6D6): d = –223.7.
MS (MALDI-TOF): m/z = 385 [M+ – H].
Anal. Calcd for C15H12FIO3: C, 46.65; H, 3.13. Found: C, 46.40; H,
3.00.
2-Iodophenyl 4-Hydroxybenzoate (6g)
Following the general procedure C, 4-hydroxybenzoic acid (5g;
1.00 g, 7.24 mmol), 2-iodophenol (1; 2.33 g, 10.86 mmol), DCC
(1.6 g, 7.96 mmol), and DMAP (100 mg) in anhyd DMF (30 mL)
yielded compound 6g as colorless crystals after column chromatog-
raphy (PE–EtOAc, 10:1); yield: 985 mg (67%); mp 130–134 °C;
Rf = 0.54 (PE–EtOAc, 3:1).
2-Iodophenyl 4-Iodobenzoate (6d)
Following the general procedure C, 4-iodobenzoic acid (5d; 1.50 g,
6.05 mmol), 2-iodophenol (1; 2.00 g, 9.07 mmol), DCC (1.87 g,
9.07 mmol), and DMAP (100 mg) in anhyd THF (15 mL) and anhyd
DMF (3 mL) yielded compound 6d as colorless crystals after col-
umn chromatography (PE–EtOAc, 10:1); yield: 2.02 g (74%); mp
126 °C; Rf = 0.76 (PE–EtOAc, 4:1).
1H NMR (400 MHz, C6D6): d = 5.10 (br s, 1 H, OH), 6.42 (dt,
3
3
4J = 1.5 Hz, J3,4 = 7.8 Hz, 1 H, H-4), 6.47 (d, Jo,m = 8.5 Hz, 2 H,
Hm), 6.85 (dt, 4J = 1.5 Hz, J5,6 = 8.0 Hz, 1 H, H-5), 6.98 (dd,
3
3
3
1H NMR (400 MHz, C6D6): d = 6.43 (t, J3,4 = 7.03 Hz, J4,5 = 7.8
4J = 1.5 Hz, J5,6 = 8.0 Hz, 1 H, H-6), 7.53 (dd, 4J = 1.5 Hz,
3
3
Hz, 1 H, H-4), 6.85 (t, J5,6 = 3J4,5 = 7.8 Hz, 1 H, H-5), 6.92 (d,
3J5,6 = 7.8 Hz, 1 H, H-3), 8.22 (d, 3Jo,m = 8.5 Hz, 2 H, Ho).
3J5,6 = 7.8 Hz, 1 H, H-6), 7.39 (d, 3Jo,m = 8.8 Hz, 2 H, Hm), 7.51 (d,
3J3,4 = 7.03 Hz, 1 H, H-3), 7.73 (d, 3Jo,m = 8.8 Hz, 2 H, Ho).
13C NMR (101 MHz, C6D6): d = 91.2 (C-2), 115.7 (Cm), 122.0
(Cipso), 123.8 (C-6), 127.5 (C-4), 129.4 (C-5), 133.2 (Co), 139.6 (C-
3), 152.1 (C-1), 161.3 (Cp), 164.0 (C=O).
13C NMR (101 MHz, C6D6): d = 91.2 (C-2), 123.5 (C-6), 127.7 (C-
4), 129.1 (Cipso), 129.5 (C-5), 131.9 (Co), 138.2 (Cm), 139.6 (C-3),
151.8 (C-1), 163.7 (C=O).
MS (ESI–): m/z (%) = 339 (100, [M+ + H]), 212 (9, [M+ – HI]).
MS (MALDI-TOF): m/z = 450 [M+].
Anal. Calcd for C13H9IO3: C, 45.91; H, 2.67. Found: C, 46.00; H,
2.66.
Anal. Calcd for C13H8I2O2: C, 34.70; H, 1.79. Found: C, 35.27; H,
1.82.
2-Iodophenyl 4-(Dimethylamino)benzoate (6h)
Following the general procedure C, 4-(dimethylamino)benzoic acid
(5h; 1.50 g, 9.08 mmol), 2-iodophenol (1; 3.00 g, 13.62 mmol),
DCC (2.25 g, 10.9 mmol), and DMAP (100 mg) in anhyd THF (30
mL) yielded compound 6h as colorless crystals after column chro-
matography (PE–EtOAc, 20:1 → 10:1); yield: 1.39 g (42%); mp
126 °C; Rf = 0.54 (PE–EtOAc, 3:1).
1H NMR (400 MHz, C6D6): d = 2.31 [s, 6 H, N(CH3)2], 6.36 (d,
3Jo,m = 9.0 Hz, 2 H, Hm), 6.45 (t, 3J3,4 = 3J4,5 7.8 Hz, 1 H, H-4), 6.89
(t, 3J4,5 = 3J5,6 = 7.8 Hz, 1 H, H-5), 7.12 (d, 3J5,6 = 7.8 Hz, 1 H, H-6),
7.58 (d, 3J3,4 = 7.8 Hz, 1 H, H-3), 8.41 (d, 3Jo,m = 9.0 Hz, 2 H, Ho).
2-Iodophenyl 4-(2-Hydroxyethoxy)benzoate (6e)
Following the general procedure C, 4-(2-hydroxyethoxy)benzoic
acid (5e;28 500 mg, 2.72 mmol), 2-iodophenol (1; 896 mg, 4.07
mmol), DCC (672 mg, 3.26 mmol), and DMAP (50 mg) in anhyd
THF (30 mL) yielded compound 6e as colorless crystals after col-
umn chromatography (PE–EtOAc, 20:1 → 10:1); yield: 840 mg
(81%); mp 103–104 °C; Rf = 0.49 (PE–EtOAc, 1:2).
1H NMR (400 MHz, C6D6): d = 3.39–3.46 (m, 5 H, CH2CH2OH),
6.45 (t, 3J4,5 = 7.7 Hz, 1 H, H-4), 6.65 (d, 3Jo,m = 8.8 Hz, 2 H, Hm),
6.89 (t, 3J4,5 = 7.8 Hz, 1 H, H-5), 7.04 (d, 3J5,6 = 8.6 Hz, 1 H, H-6),
7.55 (d, 3J5,6 = 8.9 Hz, 1 H, H-3), 8.31 (d, 3Jo,m = 8.8 Hz, 2 H, Ho).
13C NMR (101 MHz, C6D6): d = 61.0 (CH2CH2OH), 69.6
(CH2CH2OH), 91.2 (C-2), 114.8 (Cm), 122.4 (Cipso), 123.8 (C-6),
127.5 (C-4), 129.5 (C-5), 133.0 (Co), 139.6 (C-3), 152.1 (C-1),
163.6 (Cp), 163.9 (C=O).
13C NMR (101 MHz, C6D6): d = 39.4 [N(CH3)2], 91.5 (C-2), 111.3
(Cm), 116.6 (Cipso), 124.1 (C-6), 127.1 (C-4), 129.3 (Co), 132.7 (C-
5), 139.5 (C-3), 152.6 (C-1), 153.9 (Cp), 164.4 (C=O).
MS (ESI+): m/z (%) = 390 (93, [M+ + Na]), 368 (11, [M+ + H]), 148
(100, [M+ – C6H4IO]).
MS (ESI–): m/z (%) 383 [M+ – H], 339 [M+ – CH2CH2OH].
Anal. Calcd for C15H14INO2: C, 49.07; H, 3.84; N, 3.81. Found: C,
49.35; H, 3.86; N, 3.78.
Anal. Calcd for C15H13IO4: C, 46.90; H, 3.41. Found: C, 46.56; H,
3.52.
Substituted Phosphanes 4a,b,e–h; General Procedure D
KOAc (1.2 equiv), HPPh2 (1 equiv), and Pd(OAc)2 in catalytical
amount were added to a solution of 2-iodophenyl benzoate 6a–h (1
equiv) in anhyd DMA (5 mL) at r.t. under argon. The mixture was
allowed to stir for 5–8 h at 100 °C (or at 70 °C overnight). After-
wards, H2O (10 mL) and CH2Cl2 (20 mL) were added, the organic
layer was separated and the aqueous layer was extracted with
CH2Cl2 (3 × 10 mL). The combined organic layers were dried
(Na2SO4) and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (PE–EtOAc, 20:1 →
10:1).
2-Iodophenyl 4-(2-Fluoroethoxy)benzoate (6f)
Following the general procedure C, 4-(2-fluoroethoxy)benzoic acid
(5f;29 700 mg, 3.80 mmol), 2-iodophenol (1; 1.25 g, 5.70 mmol),
DCC (1.57 g, 7.60 mmol), and DMAP (50 mg) in anhyd THF (30
mL) yielded compound 6f as colorless crystals after column chro-
matography (PE–EtOAc, 20:1 → 10:1); yield: 985 mg (67%); mp
128 °C; Rf = 0.5 (PE–EtOAc, 1:2).
3
3
1H NMR (400 MHz, C6D6): d = 3.35 (dt, J = 8.2 Hz, JH,F = 27.6
2
3
Hz, 2 H, CH2CH2F), 4.05 (dt, JH,F = 47.6 Hz, J = 8.2 Hz, 2 H,
CH2CH2F), 6.44 (dt, 4J = 1.5 Hz, 3J3,4 = 8.0 Hz, 1 H, H-4), 6.61 (d,
3Jo,m = 9.0 Hz, 2 H, Hm), 6.88 (dt, 4J = 1.5 Hz, 3J5,6 = 8.1 Hz, 1 H, H-
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

3318
C. Mamat et al.
PAPER
2-(Diphenylphosphano)phenyl 4-Hydroxybenzoate (4g)
2-(Diphenylphosphano)phenyl Benzoate (4a)
Following the general procedure D, 2-iodophenyl benzoate (6a; 534
mg, 1.65 mmol), KOAc (194 mg, 1.98 mmol), HPPh2 (0.29 mL,
1.65 mmol), and Pd(OAc)2 (5 mg) yielded compound 4a as color-
less crystals (496 mg, 79%). Analytical and spectral data were in ac-
cordance with those shown above (vide supra).
Following the general procedure D, 2-iodophenyl 4-hydroxyben-
zoate (6g; 830 mg, 2.16 mmol), KOAc (254 mg, 2.59 mmol), HPPh2
(402 mg, 2.16 mmol), and Pd(OAc)2 (5 mg) yielded compound 4g
as colorless syrup; yield: 340 mg (58%); Rf = 0.41 (PE–EtOAc,
3:1).
1H NMR (400 MHz, C6D6): d = 6.27 (d, Jo,m = 8.6 Hz, 2 H, Hm¢),
3
2-(Diphenylphosphano)phenyl 4-Fluorobenzoate (4b)
6.78 (t, 3J = 7.8 Hz, 1 H, H-4), 6.91–7.03 (m, 8 H, Hm, Hp, H-5, H-
6), 7.17–7.24 (m, 4 H, H-3), 7.28–7.37 (m, 4 H, Ho), 7.89 (d,
3Jo,m = 8.6 Hz, 2 H, Ho¢).
Following the general procedure D, 2-iodophenyl 4-fluorobenzoate
(6b; 521 mg, 1.53 mmol), KOAc (180 mg, 1.83 mmol), HPPh2 (0.26
mL, 1.53 mmol), and Pd(OAc)2 (5 mg) yielded compound 4b as col-
orless crystals (396 mg, 65%). Analytical and spectral data were in
accordance with those shown above (vide supra).
13C NMR (101 MHz, C6D6): d = 115.5 (Cm¢), 123.4 (C-6), 126.2 (C-
4), 128.8 (d, 3JC,P = 7.1 Hz, Cm), 129.0 (Cp), 130.1 (C-5), 132.9 (Co¢),
133.9 (C-3), 134.5 (d, 2JC,P = 20.6 Hz, Co), 136.6 (d, 1JC,P = 11.7 Hz,
Cipso),154.0 (d, 2JC,P = 17.8 Hz, C-1), 161.3 (Cp¢), 164.1 (C=O).
31P NMR (162 MHz, C6D6): d = –14.7.
MS (ESI+): m/z (%) = 421 (94, [M+ + Na]), 399 (52, [M+ + H]).
2-(Diphenylphosphano)phenyl 4-Nitrobenzoate (4c)
It was not possible to synthesize compound 4c. TLC monitoring
showed only decomposition of products.
Anal. Calcd for C25H19O3P: C, 75.37; H, 4.81. Found: C, 75.25; H,
5.15.
2-(Diphenylphosphano)phenyl 4-(2-Hydroxyethoxy)benzoate
(4e)
Following the general procedure D, 2-iodophenyl 4-(2-hydroxy-
ethoxy)benzoate (6e; 830 mg, 2.16 mmol), KOAc (254 mg, 2.59
mmol), HPPh2 (402 mg, 2.16 mmol), and Pd(OAc)2 (5 mg) yielded
compound 4e as a colorless syrup; yield: 850 mg (89%); Rf = 0.5
(PE–EtOAc, 1:1).
1H NMR (400 MHz, C6D6): d = 2.39 (br s, 1 H, OH), 3.45–3.56 (m,
4 H, CH2CH2OH), 6.58 (d, 3Jo,m = 8.4 Hz, 2 H, Hm¢), 6.85 (t, 3J = 7.8
Hz, 1 H, H-4), 6.97–7.15 (m, 9 H, Hm, Hp, H-3, H-5, H-6), 7.36–7.42
(m, 4 H, Ho), 8.02 (d, 3Jo,m = 8.4 Hz, 2 H, Ho¢).
2-(Diphenylphosphano)phenyl 4-(Dimethylamino)benzoate
(4h)
Following the general procedure D, 2-iodophenyl 4-(dimethylami-
no)benzoate (6h; 924 mg, 2.52 mmol), KOAc (296 mg, 3.02 mmol),
HPPh2 (469 mg, 2.52 mmol), and Pd(OAc)2 (5 mg) yielded com-
pound 4h as colorless crystals; yield: 807 mg (75%); mp 145 °C;
Rf = 0.5 (PE–EtOAc, 4:1).
1H NMR (400 MHz, C6D6): d = 2.25 [s, 6 H, N(CH3)2], 6.25 (d,
3Jo,m = 8.4 Hz, 2 H, Hm¢), 6.85 (t, 3J = 7.4 Hz, 1 H, H-6), 7.01–7.11
(m, 8 H, Hm, Hp, H-4, H-5), 7.37 (m, 5 H, Ho, H-3), 8.17 (d,
3Jo,m = 8.4 Hz, 2H, Ho¢).
13C NMR (101 MHz, C6D6): d = 61.0 (CH2CH2OH), 69.6
(CH2CH2OH), 114.5 (Cm¢), 122.4 (Cipso¢), 123.4 (C-6), 126.3 (C-4),
3
128.9 (d, JC,P = 7.3 Hz, Cm), 129.1 (Cp), 130.2 (C-5), 132.2 (d,
13C NMR (101 MHz, C6D6): d = 111.1 (Cm¢), 116.9 (Cipso¢), 123.7
1JC,P = 16.2 Hz, C-2), 132.7 (Co¢), 134.0 (C-3), 134.4 (d, 2JC,P = 20.6
Hz, Co), 136.5 (d, 1JC,P = 11.8 Hz, Cipso),153.9 (d, 2JC,P = 17.6 Hz, C-
1), 163.3 (Cp¢), 164.1 (C=O).
(C-6), 125.9 (C-4), 128.8 (d, 3JC,P = 6.1 Hz, Cm), 128.9 (Cp), 130.0
1
(C-5), 131.4 (d, JC,P = 16.4 Hz, C-2), 132.3 (Co¢), 133.9 (C-3),
134.5 (d, 2JC,P = 19.2 Hz, Co), 137.0 (d, 1JC,P = 11.7 Hz, Cipso), 153.6
31P NMR (162 MHz, C6D6): d = –14.8.
MS (ESI+): m/z (%) = 426 (58, [M+ + H]).
(Cp¢), 154.5 (d, 2JC,P = 17.7 Hz, C-1), 164.6 (C=O).
31P NMR (162 MHz, C6D6): d = –14.8.
MS (ESI+): m/z (%) = 426 (58, [M+ + H]).
Anal. Calcd for C27H24NO2P: C, 73.30; H, 5.24. Found: C, 73.32; H,
5.51.
Anal. Calcd for C27H24NO2P: C, 76.22; H, 5.69. Found: C, 76.12; H,
6.11.
2-(Diphenylphosphano)phenyl 4-(2-Fluoroethoxy)benzoate (4f)
Following the general procedure D, 2-iodophenyl 4-(2-fluoroeth-
oxy)benzoate (6f; 437 mg, 1.13 mmol), KOAc (133 mg, 1.36
mmol), HPPh2 (211 mg, 1.13 mmol), and Pd(OAc)2 (5 mg) yielded
compound 4f as a colorless syrup; yield: 337 mg (67%); Rf = 0.24
(PE–EtOAc, 3:1).
2-(Diphenylphosphano)phenol-Borane Complex (9)
2-(Diphenylphosphano)phenol (2; 1.00 g, 3.60 mmol) was dis-
solved in anhyd THF (7 mL) under argon. The solution was cooled
down to –78 °C and a 1 M THF·BH3 complex solution (4.0 mL,
3.96 mmol) was added slowly. The temperature of the reaction mix-
ture was allowed to raise to r.t. overnight. Afterwards, the solvent
was removed under reduced pressure and the crude product was pu-
rified via column chromatography (PE–EtOAc, 10:1) to yield col-
orless crystals; yield: 1.0 g (95%); mp 155 °C; Rf = 0.37 (PE–
EtOAc, 5:1).
3
3
1H NMR (400 MHz, C6D6): d = 3.29 (dt, J = 8.4 Hz, JH,F = 27.2
2
3
Hz, 2 H, CH2CH2F), 4.02 (dt, JH,F = 47.4 Hz, J = 8.4 Hz, 2H,
3
3
CH2CH2F), 6.50 (dt, Jo¢,m¢ = 9.2 Hz, 1 H, Hm¢), 6.85 (t, J3,4 = 7.8
Hz, 1 H, H-4), 7.01–7.10 (m, 8 H, H-5, H-6, Hp, Hm), 7.31 (dd,
4J = 1.5 Hz, 3J3,4 = 7.8 Hz, 1 H, H-3), 7.38–7.44 (m, 4 H, Ho), 8.03
(d, 3Jo¢,m¢ = 9.2 Hz, 2 H, Ho¢).
1H NMR (400 MHz, C6D6): d = 1.80–2.70 (m, 3 H, BH3), 6.52 (t,
3J = 6.9 Hz, 1 H, H-4), 6.87–7.01 (m, 9 H, Hm, Hp, H-3, H-5, H-6),
7.49–7.56 (m, 4 H, Ho), 8.10 (s, 1 H, OH).
2
13C NMR (101 MHz, C6D6): d = 67.0 (d, JC,F = 20.6 Hz,
CH2CH2F), 81.2 (d, 1JC,F = 172.1 Hz, CH2CH2F), 114.7 (Cm¢), 122.7
(Cipso¢), 123.4 (C-6), 126.3 (C-4), 128.8 (Cp), 129.0 (d, 3JC,P = 20.6
Hz, Cm), 130.1 (C-5), 132.7 (Co), 134.0 (C-3), 134.5 (d, 2JC,P = 20.6
Hz, Co), 136.6 (d, 1JC,P = 11.8 Hz, Cipso), 154.0 (d, 2JC,P = 17.5 Hz,
C-1), 163.9 (C=O).
3
13C NMR (101 MHz, C6D6): d = 118.9 (d, JC,P = 6.1 Hz, C-6),
120.6 (d, 3JC,P = 7.7 Hz, C-4), 128.5 (Cp), 129.1 (d, 2JC,P = 10.4 Hz,
1
Co), 131.4 (C-5), 131.5 (d, JC,P = 10.3 Hz, C-2), 133.3 (d,
1
3JC,P = 10.3 Hz, Cm), 134.2 (C-3), 134.7 (d, JC,P = 4.5 Hz, Cipso),
19F NMR (376 MHz, C6D6): d = –223.9.
31P NMR (162 MHz, C6D6): d = –14.6.
MS (MALDI–TOF): m/z = 443 [M+ – H], 428 [M+ – CH4].
161.6 (d, 2JC,P = 10.2 Hz, C-1).
31P NMR (162 MHz, C6D6): d = 14.8 (m).
11B NMR (96 MHz, C6D6): d = –35.5 (m).
MS (ESI–): m/z = 291 (100%, [M+ – H]).
Anal. Calcd for C27H22FO3P: C, 72.97; H, 4.99. Found: C, 72.89; H,
5.50.
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

PAPER
Novel Building Blocks for the Traceless Staudinger Ligation
3319
Anal. Calcd for C18H18BO2P: C, 74.01; H, 6.21. Found: C, 74.24; H,
6.46.
M THF·BH3 complex solution (0.79 mL, 0.80 mmol) was added
slowly. The temperature of the reaction mixture was allowed to
raise to r.t. overnight. Afterwards, the solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (PE–EtOAc, 20:1 → 5:1) to yield pale yellow
crystals; yield: 520 mg (84%); mp 175 °C; Rf = 0.22 (PE–EtOAc,
5:1).
1H NMR (400 MHz, C6D6): d = 1.53–2.57 (m, 3 H, BH3), 6.71 (dt,
3J = 7.8 Hz, 4J = 1.5 Hz, 1 H, H-4), 6.83–6.91 (m, 6 H, Hm, Hp), 7.03
(dt, 3J = 8.4 Hz, 4J = 1.6 Hz, 1 H, H-5), 7.09–7.16 (m, 2 H, H-3, H-
6), 7.59 (‘t’, 3Jo¢,m¢ = 8.8 Hz, 3 H, Ho¢, Hm¢), 7.62–7.70 (m, 4 H, Ho).
2-(Diphenylphosphano)phenyl Benzoate-Borane Complex
(10a)
t-BuOK (74 mg, 0.66 mmol) was added to a solution of 2-(diphe-
nylphosphano)phenol-borane complex (9; 160 mg, 0.55 mmol) in
anhyd THF (10 mL) and the mixture was stirred for 30 min. Subse-
quently, benzoyl chloride (3a; 115 mg, 0.82 mmol) was added slow-
ly and the mixture was stirred overnight. The precipitate was
filtered off, the solvent removed under reduced pressure, and the re-
sulting crude product was purified by column chromatography (PE–
EtOAc, 20:1 → 10:1) to yield colorless crystals; yield: 130 mg
(60%); mp 137 °C; Rf = 0.25 (PE–EtOAc, 5:1).
13C NMR (101 MHz, C6D6): d = 123.2 (Cipso¢), 124.4 (d, 3JC,P = 6.0
3
3
Hz, C-6), 126.4 (d, JC,P = 8.8 Hz, C-4), 129.0 (d, JC,P = 10.3 Hz,
Cm), 129.1 (Cp), 131.3 (Co¢), 131.4 (C-5), 132.6 (C-3), 133.5 (d,
1H NMR (400 MHz, CDCl3): d = 0.79–1.73 (m, 3H, BH3), 7.23–
7.70 (m, 19 H, Harom).
1
2JC,P = 10.3 Hz, Co), 133.8 (Cipso¢), 134.7 (d, JC,P = 5.9 Hz, Cipso),
150.8 (Cp¢), 152.6 (d, 2JC,P = 3.8 Hz, C-1), 162.1 (C=O).
31P NMR (162 MHz, C6D6): d = 20.7 (m).
3
13C NMR (101 MHz, CDCl3): d = 124.3 (d, JC,P = 5.9 Hz, C-6),
3
126.1 (d, JC,P = 8.9 Hz, C-4), 128.1 (Cp), 128.5 (Cipso¢), 128.9 (d,
11B NMR (96 MHz, C6D6): d = –36.4 (m).
MS (MALDI–TOF): m/z = 440 [M+], 426 [M+ – BH3].
3JC,P = 10.3 Hz, Cm), 130.4 (Cm¢), 131.3, 131.4 (Co¢, C-5), 131.6 (d,
2
1JC,P = 20.3 Hz, C-2), 132.9 (C-3), 133.2 (d, JC,P = 10.3 Hz, Co),
1
133.6 (Cp¢), 134.9 (d, JC,P = 7.1 Hz, Cipso), 152.7 (C-1), 163.9
Anal. Calcd for C25H21BFO4P: C, 68.05; H, 4.80; N, 3.17. Found:
C, 68.00; H, 4.86; N, 3.10.
(C=O).
31P NMR (162 MHz, CDCl3): d = 19.8 (m).
11B NMR (96 MHz, C6D6): d = –36.7 (m).
MS (MALDI–TOF): m/z = 396 [M+], 382 [M+ – BH3].
2-(Diphenylphosphano)phenyl 4-Iodobenzoate-Borane Com-
plex (10d)
Phosphane 4d (355 mg, 0.66 mmol) was dissolved in anhyd THF (6
mL) under argon. The solution was cooled down to –78 °C and a 1
M THF·BH3 complex solution (0.66 mL, 0.66 mmol) was added
slowly. The temperature of the reaction mixture was allowed to
raise to r.t. overnight. Afterwards, the solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (PE–EtOAc, 10:1) to yield colorless crystals;
yield: 244 mg (67%); mp 186 °C; Rf = 0.72 (PE–EtOAc 3:1).
Anal. Calcd for C25H22BO2P: C, 75.78; H, 5.60. Found: C, 75.85; H,
5.69.
2-(Diphenylphosphano)phenyl 4-Fluorobenzoate-Borane Com-
plex (10b)
t-BuOK (192 mg, 1.72 mmol) was added to a solution of 2-(diphe-
nylphosphano)phenol-borane complex (9; 334 mg, 1.14 mmol) in
anhyd THF (15 mL) and the mixture was stirred for 30 min. Subse-
quently, 4-fluorobenzoyl chloride (3b; 272 mg, 1.72 mmol) was
added slowly and the mixture was stirred overnight. The precipitate
was filtered off, the solvent removed under reduced pressure and the
resulting crude product was purified by column chromatography
(PE–EtOAc, 20:1 → 10:1) to yield colorless crystals; yield: 450 mg
(95%); mp 130 °C; Rf = 0.53 (PE–EtOAc, 5:1).
1H NMR (400 MHz, C6D6): d = 1.47–2.63 (m, 3 H, BH3), 6.73 (t,
3J3,4 = 7.0 Hz, 3J4,5 = 7.8 Hz, 1 H, H-4), 6.83–6.93 (m, 6 H, Hm, Hp),
3
3
4
7.02 (t, J4,5 = 7.8 Hz, 1 H, H-5), 7.12 (dd, J5,6 = 7.8 Hz, J = 4.0
3
Hz, 1 H, H-6), 7.25 (dd, J3,4 = 7.0 Hz, 1 H, H-3), 7.27 (d,
3Jo¢,m¢ = 8.6 Hz, 1 H, Hm¢), 7.37 (d, 3Jo¢,m¢ = 8.6 Hz, 2 H, Ho¢), 7.64–
7.73 (m, 4 H, Ho).
3
13C NMR (101 MHz, C6D6): d = 101.7 (Cp¢), 124.6 (d, JC,P = 5.8
1H NMR (400 MHz, C6D6): d = 1.39–2.55 (m, 3 H, BH3), 6.51 (‘t’,
3JH,F = 3Jo,m = 8.6 Hz, 2 H, Hm¢), 6.73 (‘t’, 3J3,4 = 7.0 Hz, 3J4,5 = 7.8
Hz, 1 H, H-4), 6.84–6.93 (m, 6 H, Hm, Hp), 7.03 (‘t’, 3J4,5 = 7.8 Hz,
3
Hz, C-6), 126.1 (d, JC,P = 8.9 Hz, C-4), 128.8 (Cipso¢),128.9 (d,
3JC,P = 10.3 Hz, Cm), 129.1 (C-5),131.2 (Co¢), 131.9 (Cp), 132.6 (C-
2
1
3), 133.5 (d, JC,P = 10.3 Hz, Co), 134.8 (d, JC,P = 5.8 Hz, Cipso),
3
3
1 H, H-5), 7.15 (m, 1 H, H-6), 7.25 (ddd, JH,P = 11.7 Hz, J = 7.8
137.7 (Cm¢), 152.9 (C-1), 163.3 (C=O).
Hz, 4J = 1.4 Hz, 1 H, H-3), 7.67–7.75 (m, 6 H, Ho, Ho¢).
31P NMR (162 MHz, C6D6): d = 21.0 (m).
11B NMR (96 MHz, C6D6): d = –37.1 (m).
MS (MALDI–TOF): m/z = 521 [M+ – H].
3
13C NMR (101 MHz, C6D6): d = 115.4 (d, JC,F = 22.1 Hz, Cm¢),
124.7 (d, 3JC,P = 4.4 Hz, C-6), 125.3 (d, 4JC,F = 2.9 Hz, Cipso¢), 126.0
(d, 3JC,P = 8.9 Hz, C-4), 128.8 (Cp), 128.9 (d, 3JC,P = 10.3 Hz, Cm),
129.4 (C-5), 131.6 (d, 1JC,P = 10.3 Hz, C-2), 133.3 (d, 2JC,F = 8.8 Hz,
Co¢), 132.6 (C-3), 133.5 (d, 2JC,P = 8.8 Hz, Co), 134.8 (d, 1JC,P = 7.3
Anal. Calcd for C25H21BIO2P: C, 57.51; H, 4.05. Found: C, 57.54;
H, 4.21.
2
Hz, Cipso), 153.0 (d, JC,P = 3.1 Hz, C-1), 162.7 (C=O), 166.2 (d,
1JC,F = 254.4 Hz, Cp¢).
2-(Diphenylphosphano)phenyl 4-(Dimethylamino)benzoate-
Borane Complex (10h)
19F NMR (376 MHz, C6D6): d = –105.2.
31P NMR (162 MHz, C6D6): d = 20.8 (m).
11B NMR (96 MHz, C6D6): d = –36.9 (m).
MS (MALDI–TOF): m/z = 415 [M+ + H], 414 [M+].
Phosphane 4h (250 mg, 0.59 mmol) was dissolved in anhyd THF (5
mL) under argon. The solution was cooled down to –78 °C and a 1
M THF·BH3 complex solution (0.59 mL, 0.59 mmol) was added
slowly. The temperature of the reaction mixture was allowed to
raise to r.t. during 14 h. Afterwards, the solvent was removed under
reduced pressure and the crude product was purified by column
chromatography (PE–EtOAc 5:1) to yield colorless crystals; yield:
220 mg (85%); mp 173 °C; Rf = 0.33 (PE–EtOAc, 3:1).
1H NMR (400 MHz, C6D6): d = 6.22 (d, 3Jo¢,m¢ = 8.6 Hz, 2 H, Hm¢),
6.77 (t, 3J3,4 = 7.7 Hz, 1 H, H-3), 6.88–7.01 (m, 6 H, Hm, Hp), 7.05
(t, 3J5,6 = 8.6 Hz, 1 H, H-5), 7.28 (dd, 4J = 4.1 Hz, 3J3,4 = 7.7 Hz, 1
Anal. Calcd for C25H21BFO2P: C, 72.49; H, 5.11. Found: C, 72.69;
H, 5.37.
2-(Diphenylphosphano)phenyl 4-Nitrobenzoate-Borane Com-
plex (10c)
Phosphane 4c (340 mg, 0.80 mmol) was dissolved in anhyd THF (5
mL) under argon. The solution was cooled down to –78 °C and a 1
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

3320
C. Mamat et al.
PAPER
H, H-4), 7.45 (dd, 3J5,6 = 8.6 Hz, 1 H, H-6), 7.77–7.88 (m, 4 H, Ho),
7.99 (d, 3Jo¢,m¢ = 8.6 Hz, 1 H, Ho¢).
N-(2-(Benzamino)-2-oxoethyl)-4-fluorobenzamide (16)
2-Azido-N-benzylacetamide (13;32 67 mg, 0.35 mmol) and phos-
phane 4b (118 mg, 0.29 mmol) were dissolved in a DMF–H2O mix-
ture (0.5 mL:0.05 mL) and heated under microwave conditions (50
Watt) for 20 min. After removal of the solvent under reduced pres-
sure, the crude product was purified by column chromatography
(PE–EtOAc, 20:1); yield: 66 mg (78%); colorless crystals; mp
194 °C; Rf = 0.13 (PE–EtOAc, 1:1).
13C NMR (101 MHz, C6D6): d = 39.3 (NMe2), 110.8 (Cm¢), 116.0
3
(Cipso¢), 125.0 (d, 3JC,P = 4.4 Hz, C-6), 125.4 (d, JC,P = 10.3 Hz, C-
3
4), 128.8 (d, JC,P = 10.3 Hz, Cm), 129.4 (C-5), 129.9 (C-3), 131.0
(Cp), 132.6 (Co¢), 133.8 (d, 2JC,P = 10.3 Hz, Co), 135.0 (d, 1JC,P = 8.8
Hz, Cipso), 153.6 (Cp¢), 154.2 (C-1), 164.0 (C=O).
31P NMR (162 MHz, C6D6): d = 21.2 (m).
11B NMR (96 MHz, C6D6): d = –36.3 (m).
MS (MALDI–TOF): m/z = 439 [M+], 438 [M+ – H].
1H NMR (400 MHz, CD3OD): d = 4.06 (s, 2 H, CH2CO), 4.42 (s, 2
3
H, PhCH2), 7.20 (‘t’, Jo,m = 3JH,F = 8.6 Hz, 2 H, H-3/H-5), 7.26–
7.35 (m, 5 H, C6H5), 7.83 (dd, 3Jo,m = 8.6 Hz, 4JH,F = 4.7 Hz, H-2/H-
6).
Anal. Calcd for C27H27BNO2P: C, 73.82; H, 6.20; N, 3.19. Found:
C, 73.80; H, 6.15; N, 3.26.
13C NMR (101 MHz, CD3OD): d = 44.0, 44.1 (2 × CH2N), 116.4 (d,
2JC,F = 22.1 Hz, C-3/C-5), 128.1 (Cp), 128.5 (Co), 129.5 (Cm), 131.1
(d, 3JC,F = 9.1 Hz, C-2/C-6), 139.8 (Cipso), 166.3 (d, 1JC,F = 250.4 Hz,
C-4), 169.4, 171.7 (2 × C=O).
CAUTION! Hazard warning for organic azides: risk of explosion
by shock, friction, fire upon heating. Store azides in a cool location.
19F NMR (376 MHz, CD3OD): d = –110.8.
MS (MALDI-TOF): m/z = 287 [M+ + H].
N-Benzyl-4-fluorobenzamide (14)30
Benzyl azide (11;31 60 mg, 0.45 mmol) and phosphane 4b (150 mg,
0.37 mmol) were dissolved in a DMF–H2O mixture (0.5 mL:0.05
mL) and heated under microwave conditions (50 Watt) for 20 min.
After removal of the solvent under reduced pressure, the crude
product was purified by column chromatography (PE–EtOAc,
20:1); yield: 71 mg (83%); colorless crystals; mp 143–144 °C;
Rf = 0.41 (PE–EtOAc, 1:1).
Anal. Calcd for C16H15FN2O2: C, 67.12; H, 5.28; N, 9.78. Found: C,
67.01; H, 5.23; N, 9.70.
References
(1) (a) Köhn, M.; Breinbauer, R. Angew. Chem. Int. Ed. 2004,
43, 3106; Angew. Chem. 2004, 116, 3168. (b) Gololobov,
Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353.
(2) (a) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R. G.;
Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686.
(b) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Am.
Chem. Soc. 2006, 128, 8820.
(3) (a) Bianchi, A.; Russo, A.; Bernardi, A. Tetrahedron:
Asymmetry 2005, 16, 381. (b) Bianchi, A.; Bernardi, A.
J. Org. Chem. 2006, 71, 4565. (c) Saxon, E.; Luchansky, S.
J.; Hang, H. C.; Yu, C.; Lee, S. C.; Bertozzi, C. R. J. Am.
Chem. Soc. 2002, 124, 14893.
(4) Grandjean, C.; Boutonnier, A.; Guerreiro, C.; Fournier,
J.-M.; Mulard, L. A. J. Org. Chem. 2005, 70, 7123.
(5) (a) Kleineweischede, R.; Hackenberger, C. P. R. Angew.
Chem. Int. Ed. 2008, 47, 5984; Angew. Chem. 2008, 120,
6073. (b) David, O.; Meester, W. J. N.; Bieräugel, H.;
Schoemaker, H. E.; Hiemstra, H.; van Maarseveen, J. H.
Angew. Chem. Int. Ed. 2003, 42, 4373; Angew. Chem. 2003,
115, 4509. (c) Merkx, R.; Rijkers, D. T. S.; Kemmink, J.;
Liskamp, R. M. J. Tetrahedron Lett. 2003, 44, 4515.
(d) Tam, A.; Soellner, M. B.; Raines, R. T. Org. Biomol.
Chem. 2008, 1173. (e) Masson, G.; den Hartog, T.;
Schoemaker, H. E.; Hiemstra, H.; van Maarseveen, J. H.
Synlett 2006, 865.
(6) (a) Wang, C. C.; Seo, T. S.; Li, Z.; Ruparel, H.; Ju, J.
Bioconjugate Chem. 2003, 14, 697. (b) Chang, P. V.;
Prescher, J. A.; Hangauer, M. J.; Bertozzi, C. R. J. Am.
Chem. Soc. 2007, 129, 8400. (c) Hangauer, M. J.; Bertozzi,
C. R. Angew. Chem. Int. Ed. 2008, 47, 2394; Angew. Chem.
2008, 120, 2428.
1H NMR (400 MHz, C6D6): d = 4.40 (d, 2J = 5.6 Hz, 2 H, CH2), 5.71
(br s, 1 H, NH), 6.64 (t, 3Jo,m = 3JH,F = 8.6 Hz, 1 H, Hm), 7.02–7.13
(m, 5 H, C6H5), 7.37 (dd, 3Jo,m = 8.6 Hz, 4JH,F = 5.5 Hz, 1 H, Ho).
13C NMR (101 MHz, C6D6): d = 44.0 (CH2N), 115.4 (d, 2JC,F = 22.1
Hz, C-3/C-5), 127.6 (Cp), 128.1 (Cm), 128.8 (C-1), 129.7 (d,
3JC,F = 8.8 Hz, C-2/C-6), 139.2 (Cipso), 165.5 (C=O), 167.4 (d,
1JC,F = 250.5 Hz, C-4).
19F NMR (376 MHz, C6D6): d = –109.5.
MS (ESI+): m/z (%) = 230 (12, [M+ + H]), 252 (100, [M+ + Na]).
Anal. Calcd for C14H12FNO: C, 73.35; H, 5.28; N, 6.11. Found: C,
73.61; H, 5.45; N, 6.14.
6-(4-Fluoro)benzamino-6-deoxy-1,2:3,4-di-O-isopropylidene-a-
D-galactopyranose (15)
6-Azido-6-deoxy-1,2:3,4-di-O-isopropylidene-a-D-galactopyranose
(12;26 100 mg, 0.35 mmol) and phosphane 4b (117 mg, 0.29 mmol)
were dissolved in a DMF–H2O mixture (0.5 mL:0.05 mL) and heat-
ed under microwave conditions (50 Watt) for 20 min. After removal
of the solvent under reduced pressure, the crude product was puri-
fied by column chromatography (PE–EtOAc, 20:1); yield: 190 mg
(92%); colorless syrup; Rf = 0.57 (PE–EtOAc, 4:1).
1H NMR (400 MHz, C6D6): d = 1.01, 1.13, 1.39, 1.46 [4 s, 3 H each,
2 × C(CH3)2], 3.44–3.52 (m, 1 H, H-6a), 3.81 (dd, 3J3,4 = 7.8 Hz, 1
3
H, H-4), 4.02–4.07 (m, 1 H, H-6b), 4.15 (dd, J1,2 = 4.7 Hz,
3J2,3 = 2.3 Hz, 1 H, H-2), 4.12–4.16 (m, 1 H, H-5), 4.42 (dd,
3J2,3 = 2.3 Hz, 3J3.4 = 7.8 Hz, 1 H, H-3), 5.45 (d, 3J1,2 = 4.7 Hz, 1 H,
H-1), 6.33 (br s, 1 H, NH), 6.64 (‘t’, 3Jo,m = 3JH,F = 8.6 Hz, 2 H, Hm),
7.55 (dd, 3Jo,m = 8.6 Hz, 4JH,F = 5.5 Hz, 2 H, Ho).
13C NMR (101 MHz, C6D6): d = 24.3, 25.0, 26.1, 26.3 [4 × CH3 of
C(CH3)2)], 41.2 (C-6), 66.9 (C-5), 71.2 (C-2), 71.4 (C-3), 72.0 (C-
4), 96.8 (C-1), 108.8, 109.3 [2 × C of C(CH3)2], 115.3 (d,
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3
2JC,F = 22.1 Hz, Cm), 128.7 (Cipso), 129.7 (d, JC,F = 8.8 Hz, Co),
164.8 (d, 1JC,F = 250.4 Hz, Cp), 166.2 (C=O).
19F NMR (376 MHz, C6D6): d = –109.5.
MS (MALDI–TOF): m/z = 380 [M+ – H].
Anal. Calcd for C19H24FNO6: C, 59.83; H, 6.34; N, 3.67. Found: C,
59.78; H, 6.30; N, 3.78.
Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York

PAPER
Novel Building Blocks for the Traceless Staudinger Ligation
3321
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Synthesis 2009, No. 19, 3311–3321 © Thieme Stuttgart · New York