Amination of aryl iodides using a fluorous-tagged ammonia equivalent

Article abstract of DOI:10.1002/ejoc.201000367

A fluorous-tagged ammonia equivalent for the Cu-catalyzed amination of aryl iodides is described in which N-Boc-protected anilines are produced in high overall yield and purity. All purification steps are performed using Fluorous SolidPhase Extraction (F-SPE) greatly simplifying and speeding up the isolation of the desired products.

Full text of DOI:10.1002/ejoc.201000367

FULL PAPER
DOI: 10.1002/ejoc.201000367
Amination of Aryl Iodides Using a Fluorous-Tagged Ammonia Equivalent
Simon Dalsgaard Nielsen,[a] Garrick Smith,[b] Mikael Begtrup,[a] and
Jesper Langgaard Kristensen*[a]
Keywords: Amination / Ammonia equivalent / Fluorous synthesis / N–O linker
A fluorous-tagged ammonia equivalent for the Cu-catalyzed
amination of aryl iodides is described in which N-Boc-pro-
tected anilines are produced in high overall yield and purity.
All purification steps are performed using Fluorous Solid-
Phase Extraction (F-SPE) greatly simplifying and speeding
up the isolation of the desired products.
By-products from the catalyst or homo-couplings are
often formed in transition metal catalyzed coupling reac-
tions, which complicates the purification of the desired
compounds. Trace amounts of residual catalyst is very un-
desirable in the products, especially within the pharmaceuti-
cal industry. Solid-phase organic synthesis alleviates many
of these purification problems, but also has some serious
drawbacks.[5]
Introduction
Anilines have numerous applications in many areas of or-
ganic chemistry. They are used for the production of dyes
and as intermediates in pharmaceutical and agrochemical
research.[1] Various methods for the synthesis of anilines
have been developed, but due to their importance new pro-
tocols are still being pursued. In particular transition-metal
catalyzed procedures in which an aryl halide or pseudo ha-
lide is coupled with an amine have been very actively devel-
oped in recent years.[2] One of the most challenging trans-
formation has been the coupling of the simplest of all
amines: NH3. This has led to the development of several
different ammonia surrogates that can be used to pre-
pareanilines indirectly, see Figure 1 for a list of different
reagents.[3] Procedures for direct coupling of ammonia with
aryl halides have been developed only recently.[4]
Fluorous linker-facilitated chemical synthesis is an
emerging technique in organic synthesis.[6] A fluorous tag is
attached to the substrate by using a linker. After the reac-
tion has been completed, very often with an excess of rea-
gents to ensure complete conversion, the crude mixture is
passed through a cartridge containing a perfluorinated
bonded silica phase. In a simple two-step procedure, termed
Fluorous Solid-Phase Extraction (F-SPE), fluorous com-
Figure 1. NH3 surrogates for the synthesis of anilines.[3]
pounds and non-fluorous compounds are split into two
separate fractions.[7]
[a] Department of Medicinal Chemistry, University of
Copenhagen, Pharma,
Universitetsparken 2, 2100 Copenhagen, Denmark
Fax: +45-35336040
Using a fluorophobic eluent (such as methanol/water or
acetonitrile/water), the non-fluorous material is washed off
the cartridge. The fluorous-tagged compound is then eluted
using a fluorophilic solvent (such as methanol, acetone or
THF).
E-mail: jekr@farma.ku.dk
[b] H. Lundbeck A/S,
Ottiliavej 9, 2650 Valby, Denmark
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000367.
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Amination of Aryl Iodides
Finally, the fluorous-tag is cleaved thereby releasing the
product.
Herein we wish to report that 2 can be coupled very ef-
fectively with aryl iodides, and that N-Boc-anilines are re-
The use of fluorous-tags has several advantages com- leased in high overall yield and purity upon chemoselective
pared to classic solid-phase organic synthesis; for example, cleavage of the N–O linker with Mo(CO)3(CH3CN)3.
favorable homogeneous solution phase reaction kinetics.
This means that protocols developed in solution very often
can be adapted to a fluorous procedure with very little opti-
mization effort. Furthermore, reactions can be monitored
by standard analytical methods (such as TLC, NMR and
HPLC), and conventional methods for purification can also hydroxylamine with aryl iodides by using 0.1 equiv. of CuI
be used in addition to F-SPE. in combination with 0.5 equiv. of 1,10-phenanthroline as
Results and Discussion
Jones et al.[9] reported the coupling of N-Boc-O-methyl-
The fluorous-tagged ammonia equivalents 1h and 1i have catalyst system. When these conditions were applied to the
been developed as direct analogs of 1a and 1g, thereby tak- coupling of 2 the desired products were obtained, but F-
ing advantage of the F-SPE purification technique, see Fig- SPE purification gave very dark-colored products, presum-
ure 1.[3] Subsequent removal of the fluorous tag under ably due to contamination from the catalyst, hence the se-
acidic conditions produced the anilines.
arch for an alternative protocol was initiated. After screen-
We recently described how 2 can be implemented in the ing a series of different conditions, it was found that the use
synthesis of N-alkylated amides, ureas and sulfonamides, of CuI in combination with N,NЈ-dimethylethylenediamine
using a novel fluorous strategy.[8] The key starting material was very efficient for the cross coupling of 2 with aryl io-
2 is readily prepared in 91% isolated yield on multigram dides.[10] Under these optimized conditions 2 was treated
scale via alkylation of N-Boc-hydroxylamine with with four equivalents of aryl iodides in the presence of
I(CH2)3C8F17.
10 mol-% CuI, 20 mol-% N,NЈ-dimethylethylenediamine
Table 1. Synthesis of anilines via Cu-catalyzed amination of aryl iodides using a fluorous-tagged ammonia equivalent.
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S. D. Nielsen, G. Smith, M. Begtrup, J. L. Kristensen
FULL PAPER
Scheme 1. Reagents and conditions: a) ethyl 4-iodobenzoate, CuI, N,NЈ-dimethylethanediamine, Cs2CO3, toluene, 110 °C, 16 h. b) i) HCl/
EtOH, ii) 4-ClC6H4–COCl, Et3N, MeCN. c[ (i] HCl/EtOH (ii) 4-MeC6H4–CH2Cl, Cs2CO3, MeCN. d) Mo(CH3CN)3(CO)3, MeOH, µW,
130 °C, 15 min.
and 1.5 equiv. Cs2CO3 in toluene at 110 °C for 16 hours, and if the reaction was left to run overnight substantial de-
which led to full conversion of 2, see Table 1.[11] Further- composition was observed.
more, F-SPE was not hampered by coloration of the prod-
However, at 50 °C deprotection was complete after two
ucts, as observed above. After aqueous workup the crude hours. The resulting hydrochloride salt slowly decomposed
mixtures were loaded onto F-SPE cartridges. Firstly, the upon storage, so it was used immediately after evaporation
non-fluorous material was eluted with methanol/water of the solvent. Acylation with 4-chlorobenzoyl chloride
(4:1), acetonitrile/water (4:1) and acetone/water (2:1). Sub- gave 6 in 82% yield and alkylation with 4-methylbenzyl bro-
sequently, the fluorous-tagged products were eluted with mide gave 8 in 77% yield after F-SPE. Subsequent cleavage
methanol and acetone. Evaporation of the fluorous frac- of the N–O linker produced 7 and 9 in 78 and 80% yield
tions gave the products 3a–p in high yield and purity, see after F-SPE.
Table 1.
It should be noted that the sequence shown in Scheme 1
A wide variety of functional groups were tolerated in the is limited to compounds containing an electron-with-
cross coupling, including bromine (entry 1), free alcohol drawing group on the aromatic ring. Attempted N-Boc de-
(entry 3), nitrile (entry 4), aldehyde (entry 5), ketone (entry protection of a 4-tolyl derivative led to decomposition, pre-
8) and a free phenol (entry 9). Bulky ortho substituents were sumably via a Bamberger-type rearrangement.[13]
also allowed (entries 15 and 16). Aryl iodides were ef-
ficiently coupled, whereas aryl bromides did not react. This
Conclusions
selectivity towards aryl iodides gives the option of having a
bromo substituent on the product, as in 3a, that sub-
sequently can be used for further transition-metal-catalyzed
transformations.
In conclusion, the application of a new fluorous-tagged
ammonia equivalent has been described, where substituted
iodoarenes are transformed into N-Boc-anilines in high
yields and purity after F-SPE. The procedure tolerates a
wide range of functional groups, thus providing easy access
to N-Boc-anilines suitably poised for further manipulations.
The results described herein supplements our previously
published application of 2[8] making it a very versatile start-
ing point fluorous linker-facilitated chemical synthesis of
wide array of compound classes.
The fluorous tag was released by reductive cleavage of
the N–O bond using Mo(CH3CN)3(CO)3. This reagent has
several advantages when compared to Mo(CO)6.[12] It is
more reactive and solvents other than CH3CN can be
used.[8] The substrates 3a–p were heated using microwave
irradiation at 130 °C for 15 min with 1.5 equiv. of
Mo(CH3CN)3(CO)3 in methanol. Prior to heating, the mo-
lybdenum complex was dissolved by ultrasonication of the
vial for 10 min. Aqueous workup and F-SPE gave the N-
Boc-protected anilines 4a–p in moderate to excellent yield
and high purity. The N–O cleavage procedure was very
chemoselective being compatible with all the indicated func-
tional groups present on the aromatic ring in the products.
It is also possible to remove the Boc group from some of
the coupling products and further functionalize the re-
sulting fluorous-tagged anilines. To demonstrate this, the se-
quence outlined in Scheme 1 was performed. Coupling of 2
with ethyl 4-iodobenzoate gave 5 in 90% yield after F-SPE.
Deprotection of the Boc group in 5 with HCl in EtOH gave
Experimental Section
General: Chemicals and solvents were obtained from commercial
suppliers and used as received unless otherwise noted. THF and
DMF were dried with molecular sieves (3 Å) prior to use. The mo-
lybdenum
complex tris(acetonitrile)(tricarbonyl)molybdenum
[CAS # 15038-48-9] used for reductive N–O cleavage in general
procedure B was purchased from AcrosOrganics and used as re-
ceived. The reagent appears as a dark brown powder, however if it
turns black over time it is not reliable. Flash column chromatog-
raphy was carried out using Scharlau 60 (230–400 mesh) silica gel
the best results. The reaction was slow at room temperature, (sorbil) and thin-layer chromatography (TLC) was performed on
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Amination of Aryl Iodides
1
1
Merck 60 F254 0.25-µm silica-gel plates. H-NMR and H-decou-
pled/13C-NMR spectra were recorded at 500.13 MHz and
125.67 MHz, respectively, on a Bruker Avance DRX 500 instru-
ment using deuterated chloroform (99.8%) unless otherwise noted.
Chemical shifts for 1H-NMR are reported in ppm with TMS as
internal reference. Chemical shifts for 13C-NMR are reported in
ppm relative to chemical shifts of CHCl3. Coupling constants (J
values) are in Hertz. The following abbreviations are used for multi-
plicity of NMR signals: s = singlet, d = doublet, t = triplet, q =
quartet, dd = double doublet, ddt = double doublet of triplets and
m = multiplet. Elemental analyses were performed at H. Lundbeck
A/S, with a Flash EA1112 from Thermo Fischer Scientific. HRMS
were performed on an Agilent/Bruker Daltonics LC-SPE-MS at H.
Lundbeck A/S. The vacuum centrifuges applied were either HT-4
or EZ2 from genevac®. Fluorous Solid Phase Extraction (F-SPE)
was carried out using cartridges from Fluorous Technologies Inc.
and a FlashVac-10 from Biotage designed to accommodate 10 col-
lection tubes with 25 mm diameter vessels.
light brown solid. Purity by LC-UV(ELS): 95% (100%). 1H and
13C NMR showed impurities after F-SPE so an analytical sample
was obtained by flash chromatography (heptane/ethyl acetate, 9:1),
1
TLC Rf = 0.66 (heptane/ethyl acetate, 3:1). H NMR: δ = 1.52 (s,
9 H), 1.92–1.99 (m, 2 H), 2.22–2.34 (m, 2 H), 3.95 (t, J = 5.9 Hz,
2 H), 7.30 (d, J = 8.8 Hz, 2 H), 7.46 (d, J = 8.8 Hz, 2 H) ppm. 13C
NMR: δ = 19.3, 28.0 (t, J = 22 Hz), 28.1, 73.1, 82.9, 118.6, 107–
121 (8 fluorinated C), 123.3, 131.6, 139.6, 153.2 ppm. HRMS calcd.
for C17H12BrF17NO+, 647.9825 (– Boc, + H+); found 647.9812.
tert-Butyl 4-Fluorophenyl(3-perfluorooctylpropoxy)carbamate (3b):
Prepared by general procedure A to give 279 mg (96%) of 3b as a
1
brown oil. Purity by LC-UV(ELS): 100% (100%). H NMR: δ =
1.51 (s, 9 H), 1.91–1.97 (m, 2 H), 2.19–2.32 (m, 2 H), 3.96 (t, J =
5.9 Hz, 2 H), 7.01–7.06 (m, 2 H), 7.33–7.38 (m, 2 H) ppm. 13C
NMR: δ = 19.3, 28.0 (t, J = 22 Hz), 28.2, 73.0, 82.6, 107–121 (8
fluorinated C), 115.4 (d, J = 22 Hz), 124.6 (d, J = 8 Hz), 136.6,
153.9, 160.6 (d,
J = 246 Hz) ppm. HRMS calcd. for
C17H12F18NO+, 588.0626 (+ H+); found 588.0622.
tert-Butyl (3-Perfluorooctyl)propoxycarbamate (2):[8] A mixture of
tert-butyl N-hydroxycarbamate (17.0 g, 0.13 mol) and DBU
(13 mL, 80 mmol) in dry tetrahydrofuran (300 mL) was cooled to
0 °C. To it was added a solution of 3-(perfluorooctyl)propyl iodide
(25.0 g, 42.5 mmol) in 100 mL of dry tetrahydrofuran dropwise
over 1.5 h. After 1 h the mixture became milky-white, the ice bath
was removed and it was stirred at room temperature overnight. The
solvent was evaporated on a rotavapor and the crude was worked
up with saturated aqueous hydrogen carbonate (300 mL) and ethyl
acetate (3ϫ200 mL). The combined organic phases were dried with
magnesium sulfate, evaporated and purified by flash chromatog-
raphy (heptane/ethyl acetate, 9:1) to yield 22.9 g (91%) of 2 as a
colourless oil. The oil was dissolved in 100 mL of dioxane, cooled
to –78 °C and freeze dried in vacuo to give a white solid (mp 33–
tert-Butyl 4-(Hydroxymethyl)phenyl(3-perfluorooctylpropoxy)carb-
amate (3c): Prepared by general procedure A to give 270 mg (92%)
of 3c as a yellow solid. Purity by LC-UV(ELS): 80% (96%). 1H
NMR: δ = 1.52 (s, 9 H), 1.92–1.98 (m, 2 H), 2.21–2.34 (m, 2 H),
3.96 (t, J = 5.9 Hz, 2 H), 4.68 (s, 2 H), 7.35 (d, J = 8.5 Hz, 2 H),
7.39 (d, J = 8.5 Hz, 2 H) ppm. 13C NMR: δ = 19.3, 28.1 (t, J = Hz),
28.2, 64.8, 73.0, 82.5, 107–121 (8 fluorinated C), 122.3, 127.3,
+
138.3, 139.8, 153.6 ppm. HRMS calcd. for C19H15F17NO4
,
644.0724 (– tBu, + H+); found 644.0710.
tert-Butyl 4-Cyanophenyl(3-perfluorooctylpropoxy)carbamate (3d):
Prepared by general procedure A to give 245 mg (84%) of 3d as a
1
white solid. Purity by LC-UV(ELS): 99% (100%). H NMR: δ =
1.56 (s, 9 H), 1.96–2.03 (m, 2 H), 2.25–2.37 (m, 2 H), 3.98 (t, J =
6.0 Hz, 2 H), 7.58 (d, J = 6.9 Hz, 2 H), 7.63 (d, J = 6.9 Hz, 2 H)
ppm. 13C NMR: δ = 19.3, 28.0 (t, J = 23 Hz), 28.1, 73.4, 83.8, 107–
121 (8 fluorinated C), 107.7, 118.7, 119.9, 132.7, 144.1, 152.3 ppm.
HRMS calcd. for C18H12F17N2O+, 595.0673 (+ H+); found
595.0668.
1
34 °C). H NMR: δ = 1.49 (s, 9 H), 1.91–1.97 (m, 2 H), 2.20–2.33
(m, 2 H), 3.93 (t, J = 6.0 Hz, 2 H), 7.10 (br. soad, 1 H) ppm. 13C
NMR: δ = 19.3, 27.8 (t, J = 22.2 Hz), 28.1, 75.0, 82.0, 156.9 ppm.
HRMS calcd. for C12H9F17NO3+, 538.0305 (– tBu, + H+); found
538.0302. C16H16F17NO3 (593.28): calcd. C 32.39, H 2.72, N 2.36;
found C 32.50, H 2.70, N 2.31.
tert-Butyl 4-Formylphenyl(3-perfluorooctylpropoxy)carbamate (3e):
Prepared by general procedure A to give 262 mg (89%) of 3e as a
General Procedure for Fluorous Solid-Phase Extraction (F-SPE): A
5-g or 10-g F-SPE cartridge was charged with water corresponding
to the volume of about half of the dissolved crude product. This
was followed by addition of the crude oil or solid dissolved in a
water-miscible solvent. Using vacuum, the non-fluorous fraction
was eluted with approximately 15 mL of methanol/water (4:1),
15 mL of acetonitrile/water (4:1), and 15 mL of acetone/water (2:1).
The fluorous fraction was eluted with approximately 25 mL of
MeOH and 25 mL of acetone.
1
green solid. Purity by LC-UV(ELS): 99% (100%). H NMR: δ =
1.58 (s, 9 H), 1.98–2.04 (m, 2 H), 2.26–2.38 (m, 2 H), 4.00 (t, J =
5.9 Hz, 2 H), 7.63 (d, J = 8.7 Hz, 2 H), 7.86 (d, J = 8.7 Hz, 2 H),
9.95 (s, 1 H) ppm. 13C NMR: δ = 19.4, 28.0 (t, J = 22 Hz), 28.2,
73.4, 83.6, 107–121 (8 fluorinated C), 119.8, 130.5, 132.6, 145.5,
152.4, 191.0 ppm. HRMS calcd. for C18H13F17NO2+, 598.0669
(– Boc, + H+); found 598.0674.
tert-Butyl 4-(Trifluoromethyl)phenyl(3-perfluorooctylpropoxy)carb-
amate (3f): Prepared by general procedure A to give 290 mg (93%)
of 3f as a light brown oil. Purity by LC-UV(ELS): 100% (99%).
1H NMR: δ = 1.55 (s, 9 H), 1.95–2.02 (m, 2 H), 2.25–2.37 (m, 2
H), 3.99 (t, J = 5.9 Hz, 2 H), 7.57 (d, J = 9.0 Hz, 2 H), 7.60 (d, J
= 9.0 Hz, 2 H) ppm. 13C NMR: δ = 19.4, 28.05 (t, J = 22 Hz),
28.13, 73.3, 83.3, 107–121 (8 fluorinated C), 120.5, 124.8 (q, J =
272 Hz) 125.8 (q br, J = 4 Hz) 126.8 (q, J = 33 Hz), 143.4, 152.9
ppm. HRMS calcd. for C18H12F20NO+, 638.0594 (– Boc, + H+);
found 638.0578.
General Procedure A: Cross Coupling of 2 with Aryl Iodides: A vial
was charged with 2 (0.4 mmol), cesium carbonate (0.6 mmol), cop-
per(I) iodide (0.04 mmol), dry toluene (2.5 mL), N1,N2-dimethyl-
ethane-1,2-diamine (1.6 mmol) aryl iodide (1.6 mmol), flushed with
argon and finally sealed with a septum. The mixture was stirred
for 16 h at 110 °C and analysed by TLC (heptane/ethyl acetate,
3:1). In most cases 2 was fully consumed after this time and the
reaction mixture was worked up with water (40 mL) and ethyl acet-
ate (3 ϫ20 mL). The organic fractions were evaporated and puri-
fied by F-SPE. The fluorous fraction was evaporated on a rotav-
apor and dried in a vacuum centrifuge. The average yield was 87%
ranging from 51–100%. The average purity by LC-UV was 96%
ranging from 73–100%.
tert-Butyl
4-Isopropylphenyl(3-perfluorooctylpropoxy)carbamate
(3g): Prepared by general procedure A to give 601 mg (100%) of
1
3g as a light brown oil. Purity by LC-UV(ELS): 99% (100)%. H
NMR: δ = 1.24 (d, J = 6.9 Hz, 6 H), 1.52 (s, 9 H), 1.91–1.97 (m,
2 H), 2.21–2.34 (m, 2 H), 2.90 (hept, J = 6.9 Hz, 1 H), 3.97 (t, J =
5.8 Hz, 2 H), 7.20 (d, J = 8.5 Hz, 2 H), 7.31 (d, J = 8.5 Hz, 2 H)
tert-Butyl 4-Bromophenyl(3-perfluorooctylpropoxy)carbamate (3a):
Prepared by general procedure A to give 312 mg (99%) of 3a as a
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S. D. Nielsen, G. Smith, M. Begtrup, J. L. Kristensen
FULL PAPER
ppm. 13C NMR: δ = 19.4, 24.0, 28.2 (t, J = 22 Hz), 28.3, 33.7, 73.0,
82.3, 107–121 (8 fluorinated C), 122.7, 126.6, 138.2, 146.7, 154.0
ppm. HRMS calcd. for C20H19F17NO+, 612.1190 (– Boc, + H+);
found 612.1196.
116.9, 117.1, 134.0, 142.0, 143.2, 154.1 ppm. HRMS calcd. for
C19H15F17NO3+, 628.0775 (– Boc, + H+); found 628.0770.
tert-Butyl 2-(Methylthio)phenyl(3-perfluorooctylpropoxy)carbamate
(3n): Prepared by general procedure A to give 204 mg (68%) of 3n
1
as a brown oil. Purity by LC-UV(ELS): 97% (99%). H NMR: δ
tert-Butyl 4-Acetylphenyl(3-perfluorooctylpropoxy)carbamate (3h):
Prepared by general procedure A to give 265 mg (89%) of 3h as a
light brown solid. Purity by LC-UV(ELS): 92% (100%). 1H NMR:
δ = 1.56 (s, 9 H), 1.96–2.03 (m, 2 H), 2.25–2.38 (m, 2 H), 2.58 (s,
3 H), 3.99 (t, J = 5.9 Hz, 2 H), 7.55 (d, J = 8.7 Hz, 2 H), 7.95 (d,
J = 8.7 Hz, 2 H) ppm. 13C NMR: δ = 19.4, 26.4, 28.0 (t, J = 22 Hz),
= 1.47 (s, 9 H), 1.91–1.98 (m, 2 H), 2.15–2.27 (m, 2 H), 2.44 (s, 3
H), 4.01 (t, J = 5.9 Hz, 2 H), 7.15–7.18 (m, 1 H), 7.24–7.27 (m, 1
H), 7.28–7.32 (m, 2 H) ppm. 13C NMR: δ = 15.4, 19.4, 28.0 (t, J
= 22 Hz), 28.1, 73.4, 82.2, 107–121 (8 fluorinated C), 125.2, 125.9,
127.5, 128.9, 138.47, 138.50, 154.5 ppm. HRMS calcd. for
C18H15F17NOS+, 616.0597 (– Boc, + H+); found 616.0582.
28.2, 73.3, 83.4, 107–121 (8 fluorinated C), 119.7, 129.7, 129.1,
+
133.4, 144.4, 152.6, 196.9 ppm. HRMS calcd. for C19H15F17NO2
,
tert-Butyl {2-[tert-Butoxycarbonyl(methyl)amino]methyl}phenyl(3-
perfluorooctylpropoxy)carbamate (3o): Prepared by general pro-
cedure A to give 256 mg (74%) of 3o as a brown oil. Purity by LC-
612.0826 (– Boc, + H+); found 612.0830.
tert-Butyl
3-Hydroxyphenyl(3-perfluorooctylpropoxy)carbamate
1
UV(ELS): 100% (100%). H NMR: δ = 1.43 & 1.50 (two [s br], 9
(3i): Prepared by general procedure A to give 251 mg (86%) of 3i
as a black oil. Purity by LC-UV(ELS): 73% (96%). 1H NMR
showed the presence of starting material 2 and other impurities
after F-SPE so an analytical sample was obtained by flash
chromatography (heptane/ethyla acetate, 9:1) TLC Rf = 0.39 (hept-
ane/ethyl acetate, 3:1). 1H NMR (600 MHz): δ = 1.52 (s, 9 H), 1.90–
1.96 (m, 2 H), 2.21–2.31 (m, 2 H), 3.94 (t, J = Hz, 2 H), 6.03 (br.
s, 1 H), 6.64–6.66 (m, 1 H), 6.92–6.96 (m, 2 H), 7.16–7.19 (m, 1 H)
ppm. 13C NMR (150 MHz): δ = 19.3, 28.0 (t, J = 22 Hz), 28.1,
H, E/Z isomers), 1.46 (s, 9 H), 1.86–1.93 (m, 2 H), 2.16–2.28 (m,
2 H), 2.77–2.84 (m, 3 H), 3.94 (t, J = 5.9 Hz, 2 H), 4.46 (br. s, 2
H), 7.20–7.34 (m, 4 H) ppm. 13C NMR: δ = 19.4, 27.9 (t, J =
22 Hz), 28.1, 28.4, 34.2, 47.6, 48.4, 72.8, 79.8, 82.3, 107–121 (8
fluorinated C), 126.8, 127.5, 128.6, 135.5, 138.4, 154.6, 156.0 ppm.
HRMS calcd. for C20H18F17N2O3+, 657.1040 (– Boc, – tBu, + H+);
found 657.1044.
tert-Butyl-4-{2-[tert-butoxycarbonyl(3-perfluorooctylpropoxy)amino]-
benzyl}piperi-dine-1-carboxylate (3p): Prepared by general pro-
cedure A to give 187 mg (51%) of 3p as a brown oil. Purity by LC-
UV(ELS): 100% (100%); TLC Rf = 0.46 (heptane/ethyl acetate,
3:1) 1H NMR & TLC showed the presence of starting material
after F-SPE. The product was used in the next step without
further purification. HRMS calcd. for C23H24F17N2O+, 667.1312
(– Bocϫ2, + H+); found 667.1600.
72.9, 82.9, 109.5, 113.0, 114.4, 107–121 (8 fluorinated C), 129.5,
+
141.2, 153.8, 156.2 ppm. HRMS calcd. for C17H13F17NO2
,
586.0669 (– Boc, + H+); found 586.0671.
tert-Butyl 3-(Ethoxycarbonyl)phenyl(3-perfluorooctylpropoxy)carb-
amate (3j): Prepared by general procedure A to give 277 mg (89%)
of 3j as a light brown oil. Purity by LC-UV(ELS): 100% (100%).
1H NMR: δ = 1.38 (t, J = 7.1 Hz, 3 H), 1.53 (s, 9 H), 1.93–2.00
(m, 2 H), 2.23–2.35 (m, 2 H), 3.98 (t, J = 5.9 Hz, 2 H), 4.37 (q, J
= 7.1 Hz, 2 H), 7.39–7.43 (m, 1 H), 7.60–7.63 (m, 1 H), 7.84–7.86
(m, 1 H), 8.08 (s, 1 H) ppm. 13C NMR: δ = 14.2, 19.3, 28.0 (t, J =
22 Hz), 28.1, 61.1, 73.2, 82.9, 107–121 (8 fluorinated C), 122.8,
126.0, 126.5, 128.6, 131.1, 140.8, 153.3, 166.0 ppm. HRMS calcd.
for C20H17F17NO3+, 642.0931 (– Boc, + H+); found 642.0933.
General Procedure B: Release of the Fluorous Tag by Reductive
Cleavage of the N–O Bond: A microwave vial was charged with the
N–O substrate (1.0 equiv., 0.15 mmol), tris(acetonitrile)molyb-
denumtricarbonyl (1.5 equiv., 67 mg, 0.22 mmol), methanol
(2.5 mL), flushed with argon and sealed with a cap. The mixture
was sonicated with ultrasound for 15 min and then heated in a
Biotage Initiator sixty microwave for 15 min at 130 °C. The mixture
was then added 3 mL of sat. aq. hydrogen carbonate, 3 mL of
water, 6 mL of ethyl acetate and stirred overnight with no lid on
the tube (in a few instances the dark brown colour had not disap-
peared and the remaining molybdenum was oxidized by adding
2 equiv. KIO3). It was then worked up with ethyl acetate
(3ϫ20 mL) and water (20 mL). The combined organic phases were
evaporated and purified by F-SPE. The non-fluorous fraction was
rotavaped and dried in a vacuum centrifuge. The average yield was
74% ranging from 20 to Ͼ99%. The average purity by LC-UV was
94% ranging from 61–100%.
tert-Butyl
3-Methoxyphenyl(3-perfluorooctylpropoxy)carbamate
(3k): Prepared by general procedure A to give 284 mg (96%) of 3k
as a light brown oil. Purity by LC-UV(ELS): 97% (100%). 1H
NMR: δ = 1.53 (s, 9 H), 1.92–1.99 (m, 2 H), 2.23–2.35 (m, 2 H),
3.80 (s, 3 H), 3.97 (t, J = 5.9 Hz, 2 H), 6.71–6.74 (m, 1 H), 6.99–
7.01 (m, 2 H), 7.22–7.27 (m, 1 H) ppm. 13C NMR: δ = 19.3, 28.1
(t, J = 22 Hz), 28.2, 55.3, 73.0, 82.5, 107.8, 107–121 (8 fluorinated
C), 111.2, 114.4, 129.2, 142.6, 153.5, 159.9 ppm. HRMS calcd. for
C18H15F17NO2+, 600.0826 (– Boc, + H+); found 600.0830.
tert-Butyl 3-Chlorophenyl(3-perfluorooctylpropoxy)carbamate (3l):
Prepared by general procedure A to give 279 mg (94%) of 3l as an
tert-Butyl (4-Bromophenyl)carbamate (4a): Prepared by general
procedure B to give 26 mg (71%) of 4a as a white solid. Purity by
1
orange oil. Purity by LC-UV(ELS): 100% (100%). H NMR: δ =
1
LC-UV(ELS): 99% (n.d.). H NMR: δ = 1.51 (s, 9 H), 6.50 (s, 1
1.54 (s, 9 H), 1.94–2.00 (m, 2 H), 2.24–2.36 (m, 2 H), 3.97 (t, J =
5.9 Hz, 2 H), 7.12–7.15 (m, 1 H), 7.25–7.29 (m, 1 H), 7.31–7.34 (m,
1 H), 7.46–7.48 (m, 1 H) ppm. 13C NMR: δ = 19.3, 28.0 (t, J =
22 Hz), 28.1, 73.2, 83.0, 105–121 (8 fluorinated C) 119.4, 121.5,
125.3, 129.5, 134.3, 141.6, 153.1 ppm. HRMS calcd. for
C18H12ClF17NO3+, 648.0229 (– tBu, + H+); found 648.0223.
H), 7.25 (d, J = 8.6 Hz, 2 H), 7.38 (d, J = 8.6 Hz, 2 H) ppm. 13C
NMR: δ = 28.3, 80.9, 115.4, 120.0, 131.8, 137.4, 152.5 ppm. HRMS
calcd. for C7H7BrNO2+, 215.9655 (– tBu, + H+); found 215.9661.
tert-Butyl (4-Fluorophenyl)carbamate (4b): Prepared by general pro-
cedure B to give 16 mg (49%) of 4b as a grey solid. Purity by LC-
1
UV(ELS): 100% (n.d.). H NMR: δ = 1.51 (s, 9 H), 6.46 (s, 1 H),
tert-Butyl 2,3-Dihydrobenzo[b][1,4]dioxin-6-yl(3-perfluorooctylprop-
oxy)carbamate (3m): Prepared by general procedure A to give
295 mg (96%) of 3m as a white solid. Purity by LC-UV(ELS): 98%
6.96–7.00 (m, 2 H), 7.29–7.33 (m, 2 H) ppm. 13C NMR: δ = 28.3,
80.6, 115.4, 115.6, 120.3 (broad), 134.3, 152.9, 158.8, 159.7 ppm.
HRMS calcd. for C7H7FNO2+, 156.0455 (– tBu, + H+); found
156.0463.
1
(99%). H NMR: δ = 1.50 (s, 9 H), 1.89–1.95 (m, 2 H), 2.20–2.32
(m, 2 H), 3.94 (t, J = 5.9 Hz, 2 H), 4.24 (br. s, 4 H), 6.81–6.87 (m,
2 H), 6.90–6.92 (m, 1 H) ppm. 13C NMR: δ = 19.3, 28.1 (t, J =
22 Hz), 28.2, 64.3, 72.8, 82.2, 107–121 (8 fluorinated C), 112.9,
tert-Butyl (4-Hydroxyphenyl)carbamate (4c): Using general pro-
cedure B this compound was obtained as a black oil, 27 mg (98%),
3708
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3704–3710

Amination of Aryl Iodides
purity by LC-UV(ELS): 74% (91%). An analytically pure sample
80.5, 104.0, 108.9, 110.6, 129.6, 139.6, 152.6, 160.2 ppm. HRMS
was obtained by FC (heptane/ethyl acetate, 6:1) TLC Rf = 0.39
calcd. for C8H10NO3+, 168.0655 (– tBu, + H+); found 168.0654.
+
(heptane/ethyl acetate, 1:1). HRMS calcd. for C8H10NO3
,
tert-Butyl (3-Chlorophenyl)carbamate (4l): Prepared by general pro-
cedure B to give 27 mg (73%) of 4l as a brown solid. Purity by LC-
168.0655 (– tBu, + H+); found 168.0651. Spectral data (1H NMR)
matched those previously reported in the literature.[14]
1
UV(ELS): 99% (n.d.). H NMR: δ = 1.52 (s, 9 H), 6.49 (s, 1 H),
6.99–7.01 (m, 1 H), 7.13–7.21 (m, 2 H), 7.52 (s, 1 H) ppm. 13C
NMR: δ = 28.3, 81.0, 116.3, 118.5, 123.0, 129.9, 134.7, 134.7, 139.5,
152.4 ppm. HRMS calcd. for C7H7ClNO2+, 172.0160 (– tBu, +
H+); found 172.0156.
tert-Butyl (4-Cyanophenyl)carbamate (4d): Prepared by general pro-
cedure B to give 31 mg (92%) of 4d as a grey solid. Purity by LC-
1
UV(ELS): 91% (100%). H NMR: δ = 1.52 (s, 9 H), 6.76 (s, 1 H),
7.48 (d, J = 8.6 Hz, 2 H), 7.57 (d, J = 8.6 Hz, 2 H) ppm. 13C NMR:
δ = 28.2, 81.7, 105.7, 118.1, 119.0, 133.3, 142.6, 151.9 ppm. HRMS
calcd. for C8H7N2O2+, 163.0502 (– tBu, + H+); found 163.0503.
tert-Butyl 2,3-Dihydrobenzo[b][1,4]dioxin-6-ylcarbamate (4m): Pre-
pared by general procedure B to give 36 mg (91%) of 4m as a light
1
brown solid. Purity by LC-UV(ELS): 97% (100%). H NMR: δ =
tert-Butyl (4-Formylphenyl)carbamate (4e): Prepared by general
procedure B to give 32 mg (92%) of 4e as a brown solid. Purity by
1.49 (s, 9 H), 4.20 (d, J = 5.3 Hz, 1 H), 4.22 (d, J = 5.3 Hz, 1 H),
6.37 (s, 1 H), 6.76 (s, 2 H), 6.95 (s, 1 H) ppm. 13C NMR: δ = 28.3,
64.2, 64.4, 80.2, 108.5, 112.3, 117.1, 132.1, 139.5, 143.5, 152.9 ppm.
HRMS calcd. for C9H10NO4+, 196.0604 (– tBu, + H+); found
196.0603.
1
LC-UV(ELS): 81% (81%). H NMR: δ = 1.54 (s, 9 H), 6.92 (s, 1
H), 7.55 (d, J = 8.4 Hz, 2 H), 7.83 (d, J = 8.4 Hz, 2 H), 9.90 (s, 1
H) ppm. 13C NMR: δ = 28.2, 81.5, 117.8, 131.2 (both para- and
meta-carbons), 144.2, 152.0, 191.0 ppm. HRMS calcd. for
C7H8NO+, 122.0600 (– Boc, + H+); found 122.0595.
tert-Butyl [2-(Methylthio)phenyl]carbamate (4n): Prepared by gene-
ral procedure B to give 17 mg (44%) of 4n as a brown oil. Purity
tert-Butyl 4-(Trifluoromethyl)phenylcarbamate (4f): Prepared by ge-
neral procedure B to give 8 mg (20%) of 4f as a brown solid. Purity
1
by LC-UV(ELS): 97% (n.d.). H NMR: δ = 1.54 (s, 9 H), 2.36 (s,
1
3 H), 6.97 (m, 1 H), 7.25–7.29 (m, 1 H), 7.44–7.47 (m, 1 H), 7.60
(br. s, 1 H), 8.08–8.12 (m, 1 H) ppm. 13C NMR: δ = 19.0, 28.3,
80.6, 118.8, 123.0, 124.1, 128.9, 133.2, 139.0, 152.8 ppm. HRMS
calcd. for C7H10NS+, 140.0528 (– Boc, + H+); found 140.0527.
by LC-UV(ELS): 100% (n.d.). H NMR: δ = 1.53 (s, 9 H), 6.63 (s,
1 H), 7.47 (d, J = 8.5 Hz, 2 H), 7.54 (d, J = 8.5 Hz, 2 H) ppm. 13C
NMR: δ = 28.2, 117.8, 124.3 (q, J = 271 Hz), 124.8 (q, J = 33 Hz),
126.3 (q, J = 4 Hz), 141.5, 152.2 ppm. HRMS calcd. for
C8H7F3NO2+, 206.0423 (– tBu, + H+); found 206.0420.
tert-Butyl 2-(tert-Butoxycarbonylamino)benzyl(methyl)carbamate
(4o): Prepared by general procedure B to give 47 mg (92%) of 4o
tert-Butyl (4-Isopropylphenyl)carbamate (4g): Prepared by general
procedure B to give 30 mg (70%) of 4g as a yellow solid. Purity by
1
as a brown oil. Purity by LC-UV(ELS): 100% (100%). H NMR:
1
δ = 1.50 (s, 9 H), 1.52 (s, 9 H), 2.74 (s, 3 H), 4.36 (s, 2 H), 6.92–
6.96 (m, 1 H), 7.08–7.11 (m, 1 H), 7.26–7.30 (m, 1 H), 8.24 (br. s,
1 H), 8.67 (br. s, 1 H) ppm. 13C NMR: δ = 28.30, 28.34, 32.9, 49.6,
79.7, 80.6, 119.3, 121.7, 124.3, 129.0, 131.2, 138.3, 153.5, 156.5
ppm. HRMS calcd. for C18H29N2O4+, 337.2122 (+ H+); found
337.2115.
LC-UV(ELS): 100% (100%). H NMR: δ = 1.22 (d, J = 6.9 Hz, 6
H), 1.51 (s, 9 H), 2.85 (hept, J = 6.9 Hz, 1 H), 6.42 (s, 1 H), 7.14
(d, J = 8.3 Hz, 2 H), 7.26 (d, J = 8.3 Hz, 2 H) ppm. 13C NMR: δ
= 24.0, 28.3, 33.5, 80.3, 118.8, 126.8, 135.9, 143.7, 152.9 ppm.
HRMS calcd. for C10H14NO2+, 180.1019 (– tBu, + H+); found
180.1020.
tert-Butyl 4-[2-(tert-Butoxycarbonylamino)benzyl]piperidine-1-carb-
oxylate (4p): Prepared by general procedure B to give 23 mg (57%)
of 4p as a light brown oil. Purity by LC-UV(ELS): 100% (100%).
1H NMR: δ = 1.11–1.22 (m, 2 H), 1.44 (s, 9 H), 1.51 (s, 9 H), 1.57–
1.66 (m, 2 H), 2.15–2.17 (m, 2 H), 2.49 (d, J = 6.8 Hz, 2 H), 2.57–
2.67 (m, 2 H), 4.07 (br. s, 2 H), 6.22 (s, 1 H), 7.01–7.06 (m, 1 H),
7.07–7.10 (m, 1 H), 7.17–7.21 (m, 1 H), 7.64–7.69 (m, 1 H) ppm.
13C NMR: δ = 28.3, 28.4, 32.1, 37.0, 38.4, 43.8, 79.3, 80.4, 123.2,
124.3, 127.0, 130.4, 130.9, 135.8, 153.4, 154.8 ppm. HRMS calcd.
for C22H35N2O4+, 391.2591 (– Boc, – tBu, +H+); found 391.2608.
tert-Butyl (4-Acetylphenyl)carbamate (4h): Prepared by general pro-
cedure B to give 36 mg (100%) of 4h as a white solid. Purity by
LC-UV(ELS): 100% (100%). H NMR: δ = 1.52 (s, 9 H), 2.56 (s,
3 H), 6.77 (br. s, 1 H), 7.45 (d, J = 8.5 Hz, 2 H), 7.91 (d, J = 8.5 Hz,
2 H) ppm. 13C NMR: δ = 26.3, 28.2, 81.3, 117.4, 129.8, 131.8,
142.9, 152.1, 196.9 ppm. HRMS calcd. for C13H18NO3+, 236.1281
(+H+); found 236.1279.
1
tert-Butyl (3-Hydroxyphenyl)carbamate (4i): Prepared by general
procedure B to give 24 mg (86%) of 4i as a brown oil. Purity by
+
LC-UV(ELS): 61% (86%). HRMS calcd. for C11H15NNaO3
,
tert-Butyl 4-(Ethoxycarbonyl)phenyl(3-perfluorooctylpropoxy)carb-
amate (5): Prepared by general procedure A to give 553 mg (90%)
of 5 as a white solid. Purity by LC-UV(ELS): 100% (99%). 1H
NMR: δ = 1.37 (t, J = 7.1 Hz, 3 H), 1.55 (s, 9 H), 1.95–2.01 (m, 2
H), 2.25–2.36 (m, 2 H) 3.98 (t, J = 5.9 Hz, 2 H), 4.37 (q, J = 7.1 Hz,
2 H), 7.51 (d, J = 8.8 Hz, 2 H), 8.02 (d, J = 8.8 Hz, 2 H) ppm. 13C
NMR δ = 14.3, 19.4, 28.0 (t, J = 22 Hz), 28.2, 60.9, 73.2, 83.2,
107–121 (8 fluorinated C), 119.8, 126.6, 130.2, 144.2, 152.7, 166.0
ppm. HRMS calcd. for C21H17F17NO5+, 686.0830 (– tBu, + H+);
found 686.0827.
232.0944 (+Na+); found 232.0948, An analytical sample was ob-
tained by flash chromatography (heptane/ethyla acetate, 8:1) TLC
Rf = 0.29 (heptane/ethyl acetate, 3:1). Spectral data (1H NMR) was
identical to an authentic sample.
tert-Butyl [3-(Ethoxycarbonyl)phenyl]carbamate (4j): Prepared by
general procedure B to give 38 mg (88%) of 4j as a white solid.
1
Purity by LC-UV(ELS): 100% (100%). H NMR: δ = 1.38 (t, J =
7.1 Hz, 3 H), 1.52 (s, 9 H), 4.37 (q, J = 7.1 Hz, 2 H), 6.61 (s, 1 H),
7.36 (m, 1 H), 7.71 (m, 1 H), 7.90 (s, 1 H) ppm. 13C NMR: δ =
14.3, 28.3, 61.1, 80.9, 119.4, 122.8, 124.1, 129.0, 131.2, 138.6, 152.6,
166.3 ppm. HRMS calcd. for C10H12NO4+, 210.0761 (– tBu, + H+);
found 210.0769.
Ethyl 4-[4-Chloro-N-(3-perfluorooctyl)propoxybenzamido]benzoate
(6): Water-free ethanol (3 mL) was slowly added acetyl chloride
(720 µL, 10.1 mmol) and stirred for 5 min. To it was added 5
(250 mg, 0.34 mmol) and the mixture was heated on an oil bath for
two hours at 50 °C under argon. TLC (heptane/ethyl acetate, 3:1)
showed completion of the reaction. The solvent and excess HCl
was removed in vacuo and the remaining solid was dissolved in dry
acetonitrile (5 mL) and cooled to 0 °C in an ice bath under argon.
tert-Butyl (3-Methoxyphenyl)carbamate (4k): Prepared by general
procedure B to give 29 mg (74%) of 4k as a light brown oil. Purity
1
by LC-UV(ELS): 100% (n.d.). H NMR: δ = 1.52 (s, 9 H) 3.79 (s,
3 H), 6.55 (br. s, 1 H), 6.57–6.60 (m, 1 H), 6.82–6.86 (m, 1 H), 7.10
(br. s, 1 H), 7.14–7.19 (m, 1 H) ppm. 13C NMR: δ = 28.3, 55.2,
Eur. J. Org. Chem. 2010, 3704–3710
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3709

S. D. Nielsen, G. Smith, M. Begtrup, J. L. Kristensen
FULL PAPER
versity Press: Cambridge, 2004; c) S. Suwanprasop, T. Nhujak,
S. Roengsumran, A. Petsom, Ind. Eng. Chem. Res. 2004, 43,
4973–4978.
To it was added triethylamine (140 µL, 1.0 mmol) and 4-chloro-
benzoyl chloride (86 µL, 0.67 mmol). The mixture was stirred over-
night at room temperature and purified by F-SPE to give 248 mg
(94%) of 6 as a white solid. Purity by LC-UV(ELS): 98% (100%).
1H NMR: δ = 1.38 (t, J = 7.1 Hz, 3 H), 1.81–1.88 (m, 2 H), 1.90–
2.03 (m, 2 H), 3.91 (t, J = 5.9 Hz, 2 H), 4.39 (q, J = 7.1 Hz, 2 H),
7.34 (d, J = 8.4 Hz, 2 H), 7.57–7.60 (m, 4 H), 8.07 (d, J = 8.7 Hz,
2 H) ppm. 13C NMR: δ = 14.3, 19.1, 27.5 (t, J = 22 Hz), 61.2, 73.3,
[2] a) S. D. Surry, S. L. Buchwald, Angew. Chem. Int. Ed. 2008, 47,
6338–6361; b) J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534–
1544.
[3] 1a: i) J. P. Wolfe, J. Åhman, J. P. Sadighi, R. A. Singer, S. L.
Buchwald, Tetrahedron Lett. 1997, 38, 6367–6370; ii) S. Bhag-
wanth, G. M. Adjabeng, K. R. Hornberger, Tetrahedron Lett.
2009, 50, 1582–1585. 1b: S. Jaime-Figueroa, Y. Liu, J. M. Mu-
chowski, D. G. Putman, Tetrahedron Lett. 1998, 39, 1313–1316.
1c: D. Y. Lee, J. F. Hartwig, Org. Lett. 2005, 7, 1169–1172. 1d:
C. Z. Tao, J. Li, Y. Fu, L. Liu, Q. X. Guo, Tetrahedron Lett.
2008, 49, 70–75. 1e: P. Anjanappa, D. Mullick, K. Selvakumar,
M. Sivakumar, Tetrahedron Lett. 2008, 49, 4585–4587. 1f: X.
Gao, H. Fu, R. Qiao, Y. Jiang, Y. Zhao, J. Org. Chem. 2008,
73, 6864–6866. 1g: S. Bhagwanth, A. G. Waterson, G. M. Adja-
beng, K. R. Hornberger, J. Org. Chem. 2009, 74, 4634–4637.
1h: C. L. Cioffi, M. L. Berlin, R. J. Herr, Synlett 2004, 5, 841–
845. 1i: A. Andrés, A. A. Trabanco, J. A. Vega, M. A.
Fernández, J. Org. Chem. 2007, 72, 8146–8148.
[4] a) N. Xia, M. Taillefer, Angew. Chem. Int. Ed. 2009, 48, 337–
339; b) H. Xu, C. Wolf, Chem. Commun. 2009, 3035–3037.
[5] F. Z. Dörwald, Organic Synthesis on Solid Phase, 2002, Wiley.
[6] W. Zhang, Chem. Rev. 2009, 109, 749–795.
[7] W. Zhang, D. P. Curran, Tetrahedron 2006, 62, 11837–11865.
[8] S. D. Nielsen, G. Smith, M. Begtrup, J. L. Kristensen, Chem.
Eur. J. 2010, ##in press. DOI: 10.1002/chem.200903178.
[9] K. L. Jones, A. Porzelle, A. Hall, M. D. Woodrow, N. C. O.
Tomkinson, Org. Lett. 2008, 10, 797–800.
107–121 (8 fluorinated C), 121.9, 128.5, 129.9, 130.6, 132.5, 137.5,
+
142.9, 165.7, 167.3 ppm. HRMS calcd. for C27H20F17NO4
,
780.0804 (+H+); found 780.0819.
Ethyl 4-(4-Chlorobenzamido)benzoate (7): Prepared by general pro-
cedure B to give 29 mg (78%) of 7 as a white solid. Purity by LC-
1
UV(ELS): 100% (100%). H NMR: δ = 1.39 (t, J = 7.1 Hz, 3 H),
4.36 (q, J = 7.1 Hz, 2 H), 7.45 (d, J = 8.6 Hz, 2 H), 7.72 (d, J =
8.6 Hz, 2 H), 7.81 (d, J = 8.6 Hz, 2 H), 8.04 (d, J = 8.6 Hz, 2 H),
8.08 (br. s, 1 H) ppm. 13C NMR: δ = 14.3, 61.0, 119.3, 126.4, 128.5,
129.2, 130.8, 132.9, 138.5, 141.8, 164.8, 166.1 ppm. HRMS calcd.
for C16H14ClNO3+, 304.0735 (+H+); found 304.0729.
Ethyl 4-[(4-Methylbenzyl)(3-perfluorooctylpropoxy)amino]benzoate
(8): Water-free ethanol (3 mL) was slowly added acetyl chloride
(650 µL, 9.1 mmol) and stirred for 5 min. To it was added 5
(225 mg, 0.3 mmol) and the mix was heated on an oil bath for two
hours at 50 °C under argon. TLC (heptane/ethyl acetate, 3:1)
showed completion of the reaction. The solvent and excess HCl
was removed in vacou and the remaining solid was dissolved in dry
acetonitrile (5 mL) and cooled to 0 °C in an ice bath under argon.
To it was added cesium carbonate (346 mg, 1.06 mmol) and 1-(bro-
momethyl)-4-methylbenzene (116 mg, 0.61 mmol). The mix was
stirred overnight at room temperature and purified by F-SPE to
give 175 mg (77%) of 8 as a light brown solid. Purity by LC-
[10] This catalyst system was reported for the coupling of amines
with vinyl bromides, see: L. Jiang, G. E. Job, A. Klapars, S. L.
Buchwald, Org. Lett. 2003, 5, 3667–3669.
[11] Subsequent to the initiation of the present study, the Pd-cata-
lyzed coupling of N-Boc-hydroxylamine derivatives with aryl
halides was published, see: A. Porzelle, M. D. Woodrow,
N. C. O. Tomkinson, Org. Lett. 2009, 11, 233–236.
1
UV(ELS): 90 (100). H NMR: δ = 1.38 (t, J = 7.1 Hz, 3 H), 1.74–
1.80 (m, 2 H), 1.87–1.98 (m, 2 H), 2.33 (s, 3 H), 3.68 (t, J = 5.9 Hz,
2 H), 4.35 (q, J = 7.1 Hz, 2 H), 4.44 (s, 2 H), 7.08 (d, J = 8.8 Hz,
2 H), 7.13 (d, J = 7.8 Hz, 2 H), 7.25 (d, J = 7.8 Hz, 2 H), 7.98 (d,
J = 8.8 Hz, 2 H) ppm. 13C NMR: δ = 14.4, 19.4, 21.0, 27.9 (t, J =
22 Hz), 60.6, 62.0, 72.0, 115.3, 107–121 (8 fluorinated C), 123.9,
129.0, 130.8, 133.4, 137.5, 155.1, 166.4 ppm. HRMS calcd. for
C28H25F17NO3+, 746.1557 (+H+); found 746.1552.
[12] a) P. G. Baraldi, A. Barco, S. Benetti, S. Manfredini, D. Simoni,
Synthesis-Stuttgart 1987, 276–278; b) S. Cicchi, A. Goti, A.
Brandi, A. Guarna, F. Desarlo, Tetrahedron Lett. 1990, 31,
3351–3354; c) R. Zimmer, M. Collas, M. Roth, H. U. Reissig,
Liebigs Ann. Chem. 1992, 7, 709–714; d) S. Hanessian, R. Y.
Yang, Tetrahedron Lett. 1996, 37, 8997–9000; e) M. J. Mulvih-
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Ethyl 4-[(4-Methylbenzyl)amino]benzoate (9): Prepared by general
procedure B to give 28 mg (80%) of 9 as a yellow solid. Purity by
1
LC-UV(ELS): 96% (100%). H NMR: δ = 1.35 (t, J = 7.2 Hz, 3
H), 2.35 (s, 3 H), 4.31 (q, J = 7.2 Hz, 2 H), 4.34 (s, 2 H), 4.43 (br.
s, 1 H), 6.58 (d, J = 8.7 Hz, 2 H), 7.16 (d, J = 7.8 Hz, 2 H), 7.23
(d, J = 7.8 Hz, 2 H), 7.87 (d, J = 8.7 Hz, 2 H) ppm. 13C NMR: δ
= 14.4, 21.1, 47.5, 60.2, 111.6, 119.0, 127.4, 129.4, 131.5, 135.3,
137.2, 151.7, 166.8 ppm. HRMS calcd. for C17H20NO2+, 270.1489
(+H+); found 270.1481.
Supporting Information (see also the footnote on the first page of
this article): Copies of NMR spectra.
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Received: March 17, 2010
Published Online: May 14, 2010
3710
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Eur. J. Org. Chem. 2010, 3704–3710