Synthesis and application of a new fluorous-tagged ammonia equivalent

Article abstract of DOI:10.1002/chem.200903178

A novel fluorous-tagged ammonia equivalent has been developed. It is based on a nitrogen-oxygen bond, which can be cleaved in a traceless manner by a molybdenum complex or samarium diiodide. The application in the synthesis of ureas, amides, sulfonamides, and carbamates is described. The scope of the fluo-rous N-O linker is exemplified by the synthesis of itopride, a drug used for the treatment of functional dyspepsia. Itopride was synthesized with the aid of fluorous purification methods and the product was isolated in good overall yield, with high purity.

Full text of DOI:10.1002/chem.200903178

FULL PAPER
DOI: 10.1002/chem.200903178
Synthesis and Application of a New Fluorous-Tagged Ammonia Equivalent
Simon D. Nielsen,[a] Garrick Smith,[b] Mikael Begtrup,[a] and Jesper L. Kristensen*[a]
Abstract: A novel fluorous-tagged ammonia equivalent has been developed. It is
based on a nitrogen–oxygen bond, which can be cleaved in a traceless manner by
a molybdenum complex or samarium diiodide. The application in the synthesis of
Keywords: ammonia equivalents ·
ureas, amides, sulfonamides, and carbamates is described. The scope of the fluo-
cleavage reactions · fluorous syn-
ꢁ
rous N O linker is exemplified by the synthesis of itopride, a drug used for the
thesis · itopride · molybdenum
treatment of functional dyspepsia. Itopride was synthesized with the aid of fluo-
rous purification methods and the product was isolated in good overall yield, with
high purity.
Introduction
used for purification, in addition to the fluorous purification
strategies.
Amides, ureas, and sulfonamides are ubiquitous structural
motifs within drug design and discovery. Thus, these classes
of compounds are very often targeted and can be synthe-
sized by using a solid-phase approach. In an attempt to ad-
dress this process in a more efficient way we wanted to de-
velop a fluorous-tagged ammonia equivalent. Fluorous link-
ers have several advantages over polymer linkers. Fluorous
linkers have well-defined structures and molecular weights.
In contrast, polymer linkers are functional materials with
batch dependent loading. In addition, fluorous linkers have
the following advantages over solid-phase linkers:[1] 1) Fa-
vorable homogeneous solution-phase reaction kinetics.
2) Amenable to quick adaptation of literature synthetic pro-
cedures. 3) Fluorous reactions can be monitored by conven-
tional analytical methods such as TLC, NMR spectroscopy,
HPLC, and IR spectroscopy. 4) Conventional methods such
as chromatography, distillation, and recrystallization can be
Herein, we describe a novel fluorous-phase strategy for
the synthesis of N-alkylated amides, ureas, and sulfon-
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
et al.[5] reported the use of fluorous tert-butyl carbamate. In
many cases, the ammonia surrogates are used in Buchwald–
Hartwig palladium-catalyzed cross-coupling reactions to pre-
pare aniline derivatives, however, other reaction types have
also utilized ammonia equivalents. Benzhydrylamine has
been used in a titanocene-catalyzed addition to alkynes to
give primary alkylamines.[6] tert-Butyl carbamate has been
used as an ammonia equivalent in Sharpless asymmetric
aminohydroxylations.[7] O-Methylhydroxylamine has been
used in the total synthesis of (ꢀ)-haouamine A.[8] Hydroxyl-
amine has been used in palladium-catalyzed aminocarbony-
lations.[9] All of these examples indicate the need for alter-
natives to ammonia in organic synthesis.
Fluorous methods for synthesis and separation are poised
to move from a relatively small, specialized field into the
mainstream of organic synthesis.[1] The adaptation of fluo-
rous methods into mainstream organic synthesis depends on
the availability of a diverse assortment of proven reagents
and tags, and we wanted to expand the toolbox in this re-
spect.
[a] Dr. S. D. Nielsen, Dr. M. Begtrup, Dr. J. L. Kristensen
Department of Medicinal Chemistry
University of Copenhagen, Faculty of Pharmaceutical Sciences
2100 Copenhagen (Denmark)
Fax : (+45)35336040
E-mail: jekr@farma.ku.dk
We selected a protected hydroxylamine derivative 1,
shown in Scheme 1, as a possible ammonia surrogate for the
use in alkylation, acylation, isocyanation, reductive amina-
tion, and sulfonation reactions, with the following rationale:
[b] Dr. G. Smith
H. Lundbeck A/S, Ottiliavej 9, 2500 Valby (Denmark)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200903178.
Chem. Eur. J. 2010, 16, 4557 – 4566
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4557

tively mild conditions by using Cs2CO3 in CH3CN at 458C.
Various alkyl halides were used including alkyl chlorides
(Table 1, entries 7, 14, 19–21), alkyl bromides (Table 1, en-
tries 1–6, 8–13, 15, 16, 18), and an alkyl iodide (Table 1,
entry 17).
Addition of the alkyl halide to a preheated mixture of 1
and Cs2CO3 in CH3CN gave the best results. In most cases,
TLC indicated full conversion of 1 after two hours at 458C.
The alkyl chlorides 2t and 2u required longer reaction
times, up to five hours. The workup of the reactions was
very simple. The reaction mixture was added directly on to
a fluorous solid-phase extraction (F-SPE) cartridge together
with water (2 mL). Excess of alkyl halide, Cs2CO3, and
other non-fluorous materials were then eluted with MeOH/
water (4:1) and the fluorous product was subsequently
eluted with neat MeOH. The fluorous fraction was evapo-
rated to give the product in high yield and with high purity.
The UV purity for the aromatic products ranged from 79–
100%. In the case of silyl-alkynyl ether 2u, the product was
not pure after F-SPE, probably because the silyl ether had
been partly hydrolyzed under the basic conditions. Subse-
quent flash chromatography gave pure 2u in 45% yield.
The Boc-group could be removed by using 10 equivalents
of HCl in absolute ethanol with microwave heating at 808C
for 15 min (Table 2). TLC of the reaction mixture showed
full conversion and evaporation of the reaction mixture
gave the pure hydrochloride salt. Deprotection with TFA in
CH2Cl2 at room temperature also worked well.
Scheme 1. Fluorous-tagged ammonia surrogate.
1) Hydroxylamines are more nucleophilic than amines due
to the alpha effect.[10] This should make it easier to ach-
ieve full conversion of the fluorous-tagged reagent.
ꢁ
2) The N O bond can be cleaved in several ways by using
mild reagents that leave other classic nitrogen protecting
groups like tert-butoxycarbonyl (Boc) and benzyloxycar-
bonyl (Cbz) intact.[11–14]
ꢁ
3) The N O bond is inert to a range of aggressive reagents,
which include Grignard and organolithium reagents,[15]
and to reducing reagents such as NaBH3CN and NaBH-
ACHTUNGTRENNUNG
(OAc)3.[16,17]
ꢁ
The N O bond and the C8F17 tag in 1 are separated by
three methylene groups to mitigate the electron-withdraw-
ing effect from the fluorine atoms. We speculated that this
tert-butyl-N-perfluoroalkoxycarbamate would serve as
a
The hydrochlorides of the perfluoroalkoxyamines were
treated with different electrophiles, which included isocya-
nates, sulfonyl chlorides, and acid chlorides. DMF was used
as the solvent for the isocyanate reaction, whereas THF was
used in the cases of acid chlorides and sulfonyl chlorides.
All of the reactions in Table 3 were performed at room tem-
perature with triethylamine as a base. At the end of the re-
action the mixture was transferred directly to a F-SPE car-
tridge and purified without aqueous workup or other purifi-
cation steps. The non-fluorous materials were eluted with
MeOH/water (4:1) and the fluorous product was eluted with
neat MeOH. In two cases (4d and 4h), the product had
poor solubility in MeOH. In these cases a second purifica-
tion with F-SPE were performed by using DMF as the fluo-
rophilic eluent. All products in Table 3 were obtained in
good to excellent yield (70–100%), with purity in the range
of 93–100%.
convenient surrogate for ammonia in the synthesis of N-
monoalkylated amides, ureas, and sulfonamides. The Boc
group blocks one of the free positions, which alleviates
problems of unwanted disubstitution on the alkoxyamine.
Others have used N-Boc-protected, O-substituted hydroxyl-
amines as nucleophiles following the same rationale. Mac-
Millan and co-workers used N-Boc-O-TBS (tert-butyldime-
thylsilyl) hydroxylamine as a nucleophile in asymmetric imi-
nium-ion-catalyzed conjugate addition to a,b-unsaturated al-
dehydes.[18] In a similar approach Vesley et al. used N-Boc-
protected methoxyamine.[19] The organocatalytic asymmetric
conjugate addition was further developed by Lu and Deng
to involve a,b-unsaturated ketones by the use of a chiral pri-
mary amine catalyst, instead of a chiral secondary amine.[10]
In the last case it is notable that N-Boc-protected benzy-
loxyamine was a superior nucleophile than N-Boc-protected
benzylamine.
ꢁ
We questioned whether the reductive N O cleavage
would allow the presence of various functional groups and
considered several different methods. A range of different
ꢁ
Results and Discussion
reagents have been used for reductive cleavage of N O
bonds,
which
included
Li/4,4’-di-tert-butylbiphenyl
Methods in the literature for N-alkylation of O-alkyl-N-
Boc-hydroxylamines include the use of Mitsunobu condi-
tions[20] and Finkelstein conditions with NaH as a base.[21]
Neither of these methods gave satisfactory results. Micro-
wave heating at temperatures up to 1208C did not push the
reaction to completion with any of the previously reported
methods. Instead we found that 1 was alkylated under rela-
(DTBB),[22,23] Na/Hg amalgam,[24,25] SmI2,[14,26–30] TiCl3,[31–34]
indium,[8,11] LiAlH4,[35,36] BH3,[37] [Mo(CO)6],[13,24,38–49]
[Co2(CO)8],[50]
[Fe(CO)5],[13,51]
Zn/H+,[43,52–55]
NiB2,[56]
Na2S2O4,[57] [Ti(iPrO)4]/EtMgBr,[58] NiH2,[59] trimethylsilyl
ACTHNUGTRNENUG
chloride/KI,[60] and several types of catalytic hydrogenation,
including Raney nickel.[61–83] Among the most popular and
selective methods are [Mo(CO)6]/CH3CN/H2O, SmI2/THF,
4558
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A Fluorous-Tagged Ammonia Equivalent
FULL PAPER
Table 1. Synthesis of fluorous-tagged ammonia equivalent 1 and subsequent alkylation.
Product 2
X
Yield [%]
Product 2
X
Yield [%]
1
2
3
2a
2b
2c
R=4-Br
R=4-NO2
R=4-CN
Br
Br
Br
99
99
97
15
16
17
2o
2p
2q
R=CH2CH2Ph
Br
Br
I
94
97
100
ꢁ
R= CCH
ꢁ
R= CH2CH2CH3
4
2d
R=4-Me
Br
100
18
2r
Br
96
79
5
2e
R=4-CO2Et
Br
99
19
2s
Cl
6
7
2 f
R=4-NHAc
R=4-C=CH2
Br
Cl
98
94
20[a]
2t
Cl
Cl
97
45
2g
21[a,b]
2u
8
9
10
11
12
2h
2i
2j
2k
2l
R=3-OMe
R=3-F
R=3-Br
R=3-I
Br
Br
Br
Br
Br
98
99
100
98
R=2-F
97
13
14
2m
Br
Cl
97
96
2n
[a] Compounds 2t and 2u required 5 h of reaction time. [b] Compound 2u was additionally purified by flash chromatography.
+
+
and In/EtOH/NH4 . We tested these three reagents on sub-
(NH4 and AcOH), and sonication did not change the
result. [Mo(CO)6] and SmI2 were both efficient, however,
SmI2 is less convenient to work with due to the high air sen-
sitivity, so we proceeded with [Mo(CO)6]. The latter reagent
strate 2o in an initial study carried out to find the optimal
cleavage conditions. Indium was clearly the least efficient.
Addition of a large excess of the metal, different acids
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J. L. Kristensen et al.
Table 2. N-Boc deprotection of compounds 2d, 2q, and 2t.
Table 3. Reaction of 3 with different electrophiles.[a]
Substrate 2
Product 3
Yield [%]
100
Electrophile
Isolated
product 4
Yield [%]
1
2
1[b]
2[b]
3[b]
4[b]
5[c]
98
97
99
4a
100
100
85
3
4b
4c
is traditionally used in CH3CN/H2O (15:1) at reflux for 2–
3 h.[84] Under these conditions it is believed that [Mo(CO)6]
is converted to the more reactive complex [Mo-
ACHTUNGTRENNUNG ACHTUNTGREN(NUNG CH3CN)3(CO)3] is commercially
(CH3CN)3(CO)3].[13] [Mo
available and we decided to compare this with [Mo(CO)6] in
different solvents under microwave heating. The optimal
conditions for reductive cleavage of the N O bond in 2o
were heating the substrate by microwave irradiation at
1308C for 15 min, with 1.5 equivalents of [Mo-
ꢁ
4d
4e
ACHTUNGTRENNUNG(CH3CN)3(CO)3] in MeOH. Before the sample was heated
98
in the microwave, the Mo complex was dissolved with the
aid of sonication of the reaction vessel for 10 min. The
workup procedure was also changed from the traditional
molybdenum procedure. Molybdenum is believed to form a
ꢁ
stable complex with the amino alcohol once the N O bond
6[c]
96
is cleaved and the stability of this complex is believed to
cause a lower yield in some cases.[84] Decomplexation has
previously been carried out by stirring the crude mixture
with silica and triethylamine,[46] however, we did not find
this procedure sufficient. Instead, we found that stirring the
crude mixture overnight in air, in a two-phase system of
aqueous sodium bicarbonate and ethyl acetate, was accom-
panied by a color change from brown to colorless and gave
slightly higher yield and purity of 2o. A plausible explana-
tion is that molybdenum is oxidized by air and is thereby li-
berated from the product. This was supported by observing
the change in color after only one hour when adding the
mild oxidant potassium iodate. These optimized conditions
4 f
4g
4h
7[c]
70
79
8[c]
ꢁ
for cleaving N O bonds are highly chemoselective, compati-
ble with numerous functional groups (Table 4), amongst
them an internal allylic double bond (5a); terminal double
bond (5j); acetanilide (5l), aryl iodide, bromide, and chlo-
ride (5c, 5d, 5n); nitrile (5 f); ester (5h); and sulfonamide
4560
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A Fluorous-Tagged Ammonia Equivalent
Table 3. (Continued)
FULL PAPER
Electrophile
Isolated
Yield [%]
product 4
9[c]
90
ꢁ
Scheme 2. Substrates in which the N O bond could not be cleaved with
Mo complexes.
4i
rous tag in substrates containing a triple bond, SmI2 was
[a] EWG=electron-withdrawing group. [b] Reaction conditions:
(1 equiv, 0.3 mmol), triethylamine (1.1 equiv), DMF (2.5 mL), and isocya-
nate (1.5 equiv), 238C, 16 h. [c] Reaction conditions: (1 equiv,
0.3 mmol), triethylamine (5 equiv), THF (2.5 mL), and acid chloride or
sulfonyl chloride (3 equiv), 238C, 16 h.
3
ꢁ
used to cleave the N O bond in substrate 4i. The terminal
3
triple bond in 4i was unaffected after treatment with SmI2
for 15 min in THF/MeOH at room temperature and the re-
action yielded 96% of 6 with a UV purity of 100%
(Scheme 3).
groups (5w). The products were obtained in moderate to ex-
cellent yield (20–100%) and with a UV purity ranging from
65–100%.
Low yield was observed in the cases with a fluoro-substi-
tuted benzyl group. In both 5l and 5o, unreacted starting
material was found in the fluorous fraction. Increasing the
reaction temperature to 1508C did not improve the yield.
ꢁ
ꢁ
N O cleavage in substrate 2b resulted in a complex mix-
ture, probably due to competing reduction of the nitro
group.
Scheme 3. SmI2-mediated reduction of the N O bond in substrate 4i.
ꢁ
Attempts to cleave the N O bond with [Mo-
(CH3CN)3(CO)3] in substrates with a triple bond (Scheme 2)
To demonstrate the scope of our fluorous-tagged ammo-
nia equivalent we decided to employ this strategy for the
synthesis of itopride, a drug used for the treatment of func-
tional dyspepsia.[86] Itopride was synthesized as shown in
Scheme 4. N-Boc deprotection of 1 in ethanol/HCl gave al-
koxyamine 7 quantitatively. Treatment of 7 with 4-hydroxy-
benzaldehyde in methanol gave 8 in 90% yield after fluo-
G
failed and gave complex mixtures. This can presumably be
explained by the fact that molybdenum complexes, similar
to the one used, are able to catalyze alkyne metathesis[85a]
and other reactions involving carbon–carbon triple
bonds.[85b] To circumvent the problem of removing the fluo-
Scheme 4. Fluorous synthesis of itopride.
Chem. Eur. J. 2010, 16, 4557 – 4566
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J. L. Kristensen et al.
Table 4. Removal of the fluorous tag through N O cleavage with [MoACHTNUTGRNEUNG
(CH3CN)3(CO)3].[a]
ꢁ
Isolated
Yield [%]
Isolated
Yield [%]
product 5
product 5
1
2
92
17
18
87
5a
5q
95
99
5b
5c
5r
3
100
19
20
93
94
5s
5t
4
5
R=4-Br (5d)
90
0
R=4-NO2 (5e)
21
22
23
88
97
90
6
7
8
R=4-CN (5 f)
87
81
94
5u
5v
R=4-CH3 (5g)
R=4-CO2Et (5h)
9
R=4-NHAc (5i)
52
64
10
R=4-CH=CH2 (5j)
5w
11
R=3-OMe (5k)
92
24
25
93
85
12
13
R=3-F (5l)
20
70
5x
5y
R=3-Br (5m)
14
15
R=3-I (5n)
R=2-F (5o)
100
10
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A Fluorous-Tagged Ammonia Equivalent
Table 4. (Continued)
FULL PAPER
Isolated
Yield [%]
Isolated
Yield [%]
product 5
product 5
16
60
5p
[a] Reaction conditions: 4 (1 equiv, 0.2 mmol), [MoACTHNUTRGNE(UNG CH3CN)3(CO)3] (1.5 equiv), MeOH (2.5 mL), ultrasound 15 min, microwave irradiation at 1308C for
15 min. See the Experimental Section for a detailed workup procedure.
Experimental Section
rous liquid extraction (FL-E). Phenol 8 was treated with 2-
chloro-N,N-dimethylethanamine (4 equiv) in DMF/Cs2CO3.
Aqueous workup and F-SPE yielded 85% of 9. Oxime 9
was reduced to perfluoroalkoxyamine 10 by using borane
trimethylamine complex and Et2O/HCl in toluene. Aqueous
workup and F-SPE yielded 10 in 93% yield. Other reducing
General: Chemicals and solvents were obtained from commercial suppli-
ers and used as received unless otherwise noted. THF and DMF were
dried over 3 ꢁ molecular sieves prior to use. Flash column chromatogra-
phy was carried out using Scharlau 60 (230–400 mesh) silica gel (sorbil)
and TLC was performed on Merck 60 F254 0.25 mm silica gel plates.
1H NMR and 1H-decoupled 13C NMR spectra were recorded at 500 and
125 MHz, respectively, on a Bruker Avance DRX 500 instrument in deu-
terated chloroform (99.8%) unless otherwise noted. Chemical shifts for
1H NMR spectra are reported in ppm with TMS as the internal reference.
Chemical shifts for 13C NMR spectra are reported in ppm relative to the
chemical shift of CHCl3. Coupling constants (J values) are in Hertz. The
following abbreviations are used for the multiplicity of NMR signals: s=
singlet, d=doublet, t=triplet, q=quartet, dd=double doublet, ddt=
double doublet of triplets, m=multiplet, and br=broad. Elemental anal-
yses 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 ap-
plied were either HT-4 or EZ2 from Genevac. Fluorous solid-phase ex-
traction (F-SPE) was carried out using cartridges from Fluorous Technol-
ogies and a FlashVac-10 from Biotage designed to accommodate 10 col-
lection tubes with 25 mm diameter vessels. The solution of SmI2 in THF
(0.09m) was prepared by a known procedure.[87]
agents such as NaBH3CN and NaBHACHTNUTRGNE(NUG OAc)3 did not give
satisfactory results. The perfluoroalkoxyamine 10 was treat-
ed with 3,4-dimethoxybenzoyl chloride (1.5 equiv) in THF/
Et3N at room temperature. Subsequent aqueous workup and
F-SPE yielded 89% of amide 11. Finally the fluorous tag
ꢁ
was removed by reductive N O cleavage under the opti-
mized conditions: [Mo
A
workup and F-SPE gave 78% of itopride with a UV purity
of 99%. This fluorous approach is ideal for parallel synthe-
sis of itopride analogues and the mild conditions should
permit structural variations in most parts of the molecule.
Conclusion
General procedure for fluorous solid-phase extraction (F-SPE): Water
(2 mL) was added to a 5 g F-SPE cartridge, followed by the reaction mix-
ture. The non-fluorous fraction was eluted with methanol/water, 4:1
(60 mL). The fluorous fraction was eluted with MeOH (50 mL).
The increased nucleophilicity of hydroxylamines compared
to amines, combined with the orthogonal cleavage condi-
tions, has led to the development of a very versatile fluo-
rous-tagged ammonia equivalent.
Tert-butyl-(3-perfluorooctyl)propoxycarbamate (1): A mixture of tert-
butyl-N-hydroxycarbamate (17.0 g, 0.13 mol) and 1,8-diazabicyclo-
AHCTUNGTREG[NNUN 5.4.0]undec-7-ene (DBU) (13 mL, 80 mmol) in dry THF (300 mL) was
cooled to 08C . A solution of 3-(perfluorooctyl)propyl iodide (25.0 g,
42.5 mmol) in dry THF (100 mL) was added dropwise over 1.5 h. After
1 h the mixture became milky-white, the ice bath was removed, and the
reaction mixture was stirred at room temperature overnight. The solvent
was evaporated under vacuum, the residue was taken up in saturated
aqueous sodium bicarbonate (300 mL), and extracted with ethyl acetate
(3ꢂ200 mL). The combined organic phases were dried over anhydrous
magnesium sulfate, evaporated, and purified by flash chromatography
(heptane/ethyl acetate, 9:1) to yield 1 as a colorless oil (22.9 g, 91%).
The oil was dissolved in dioxane (100 mL), cooled to ꢁ788C, and freeze
dried in vacuo to give a white solid. M.p. 33–348C; 1H NMR (500 MHz,
CDCl3): d=1.49 (s, 9H), 1.91–1.97 (m, 2H), 2.20–2.33 (m, 2H), 3.93 (t,
J=6.0 Hz, 2H), 7.10 ppm (brs, 1H); 13C NMR (125 MHz, CDCl3): d=
19.3, 27.8 (t, J=22 Hz), 28.1, 75.0, 82.0, 156.9 ppm; HRMS: m/z calcd for
C12H9F17NOþ3 : 538.0305 (dealkylated); found: 538.0302; elemental analy-
sis calcd (%) for C12H9F17NO3: C 32.39, H 2.72, N 2.36; found: C 32.50,
H 2.70, N 2.31.
This was demonstrated by the synthesis of a wide selec-
tion of N-monoalkylated amides, ureas, and sulfonamides.
The release of the fluorous tag was achieved by using an im-
proved and highly chemoselective reductive cleavage of the
ꢁ
N O bond; treatment with [MoACTHUNTRGNE(UNG CH3CN)3(CO)3] under mi-
crowave irradiation. Furthermore, the effectiveness of this
new approach was illustrated by an efficient and flexible
synthesis of itopride.
General procedure A: Alkylation of 1: Compound
1 (200 mg,
0.34 mmol), cesium carbonate (274 mg, 0.84 mmol), and acetonitrile
(2.5 mL) were added to a vial, which was then sealed with a septum. The
mixture was heated to 458C and alkyl halide (2 equiv, 0.67 mmol) was
added slowly through the septum by using a needle and syringe. In cases
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J. L. Kristensen et al.
when the alkyl halide was a solid, it was dissolved in DMF (500 mL) prior
to addition. The reaction was stirred for 2 h at 458C and analyzed by
TLC (heptane/ethyl acetate, 3:1). In most cases, starting material 1 was
fully consumed after this time and the reaction mixture was purified di-
rectly by F-SPE. The fluorous fraction was concentrated in vacuo and
dried in a vacuum centrifuge. The purity by LC-UV ranged from 79–
100%. (the products are shown in Table 1).
for 15 min at 1308C. Saturated aqueous sodium bicarbonate (3 mL),
water (3 mL), and ethyl acetate (6 mL) were added and the reaction mix-
ture was stirred overnight with no cap (if the dark-brown color had not
disappeared, the remaining molybdenum was oxidized with KIO3
(2 equiv)). Water (20 mL) was added and the product was extracted with
ethyl acetate (3ꢂ20 mL). The combined organic phases were evaporated
and purified by F-SPE. The non-fluorous fraction was concentrated in
vacuo and dried in a vacuum centrifuge. The purity by LC-UV ranged
from 65–100%. (The products are shown in Table 4).
Compound 2d: This compound was obtained by following general proce-
dure A, as a white solid (585 mg, 100%, 100% purity by LC-UV).
1H NMR (500 MHz, CDCl3): d=1.50 (s, 9H), 1.74–1.80 (m, 2H), 2.01–
2.13 (m, 2H), 2.33 (s, 3H), 3.76 (t, J=5.8 Hz, 2H), 4.55 (s, 2H), 7.14 (d,
J=7.7 Hz, 2H), 7.22 ppm (d, J=7.7 Hz, 2H); 13C NMR (125 MHz,
CDCl3): d=19.3, 21.0, 27.9 (t, J=22 Hz), 28.2, 53.5, 73.4, 81.7, 107–121 (8
fluorinated C), 128.6, 129.1, 133.6, 137.4, 156.7 ppm; HRMS: m/z calcd
for C20H17F17NOþ3 , 642.0931 (dealkylated); found: 642.0946.
Compound 5t: This compound was obtained by following general proce-
1
dure E, as a white solid (23 mg, 94%, 100% purity by LC-UV). H NMR
(500 MHz, CDCl3): d=1.08 (t, J=7.2 Hz, 3H), 2.31 (s, 3H), 3.16 (q, J=
7.2 Hz, 2H), 4.59 (brs, 1H), 4.88 (brs, 1H), 7.11 (d, J=7.8 Hz, 2H),
7.15 ppm (d, J=7.8 Hz, 2H); 13C NMR (125 MHz, CDCl3): d=15.4, 21.0,
35.3, 44.2, 127.4, 129.2, 136.2, 136.9, 158.2 ppm; HRMS: m/z calcd for
C11H17N2O+: 193.1335 [M+H+]; found: 193.1337.
General procedure B: Removal of the Boc group: Absolute ethanol
(2.2 mL) and acetyl chloride (260 mL, 3.7 mmol) were added to a micro-
wave vial. After stirring for 5 min under an argon atmosphere, Boc-pro-
tected amine (0.73 mmol) was added. The mixture was subjected to mi-
crowave irradiation for 15 min at 808C and then dried in a vacuum cen-
trifuge at 408C to give the product as a hydrochloride salt. (The products
are shown in Table 2).
ꢁ
N
O cleavage by samarium diiodide (6): A solution of SmI2 in THF
(3.1 mL 0.092m) was slowly added to a solution of 4i in dry THF
(0.5 mL) under argon. The color of the SmI2 changed from blue to green
as it was added. The reaction mixture was stirred for 5 min and TLC
showed full consumption of the starting material. The reaction mixture
was quenched with aqueous Na2S2O3, saturated aqueous sodium bicar-
bonate was added, and the aqueous layer was extracted with ethyl ace-
Compound 3b: This compound was obtained by following general proce-
dure B, as a white solid (437 mg, 97%, >90% purity by NMR spectros-
copy). 1H NMR (500 MHz, CDCl3): d=1.97–2.03 (m, 2H), 2.21–2.33 (m,
2H), 2.37 (s, 3H), 4.20 (t, J=6.3 Hz, 2H), 4.47 (s, 2H), 7.29 (d, J=
7.8 Hz, 2H), 7.40 ppm (d, J=7.8 Hz, 2H); 13C NMR (125 MHz, CDCl3):
d=20.3, 21.2, 28.2 (t, J=22 Hz), 54.4, 73.8, 126.7, 130.8, 131.8, 141.5 ppm;
HRMS: m/z calcd for C19H17F17NO+: 598.1033 [M+H+]; found:
598.1029.
tate (3ꢂ20 mL). Purification by F-SPE yielded
6 as a yellow solid
(25 mg, 96%, 100% purity by LC-UV). An analytical sample was ob-
tained by flash chromatography (heptane/ethyl acetate, 5:1). 1H NMR
(500 MHz, CDCl3): d=1.58–1.65 (m, 2H), 1.71–1.79 (m, 2H), 1.96 (t, J=
2.4 Hz, 1H) 2.25 (dt, J=6.9, 2.4 Hz) 3.45–3.50 (m, 2H), 6.29 (brs, 1H),
7.39–7.44 (m, 2H), 7.46–7.50 (m, 1H), 7.74–7.78 ppm (m, 2H); 13C NMR
(125 MHz, CDCl3): d=18.1, 25.7, 28.7, 39.4, 68.7, 84.0, 126.8, 128.5, 131.3,
134.7, 167.5 ppm, HRMS: m/z calcd for C13H16NO+: 202.1226 [M+H+];
found: 202.1221.
General procedure C: Isocyanations: Isocyanate (1.5 equiv, 1 mmol) was
added to
a mixture of 3 (1 equiv, 0.32 mmol) and triethylamine
Compound 7: Absolute ethanol (50 mL, 800 mmol) was added to a dry,
argon-purged Schlenk flask. Acetyl chloride (4.8 mL, 67 mmol) was
slowly added under argon backflow. The reaction mixture was stirred for
5 min, then 1 (7.60 g, 13 mmol) was added and the stirring was continued
at 508C for 1 h. The reaction mixture was evaporated to give 7 as a white
solid (6.76 g, 100%, >95% purity by GC–MS). 1H NMR (500 MHz,
[D4]MeOH): d=1.98–2.05 (m, 2H), 2.28–2.41 (m, 2H), 4.20 ppm (brt,
2H); 13C NMR (125 MHz, [D4]MeOH): d=20.3, 28.3 (t, J=22 Hz) 74.8,
107–122 ppm (8 fluorinated C): HRMS: m/z calcd for C11H9F17NO+:
494.0407 [M+H+]; found: 494.0401.
(1.1 equiv, 0.35 mmol, 50 mL) in DMF (2.5 mL). The mixture was stirred
overnight at room temperature and purified by F-SPE. The fluorous frac-
tion was concentrated in vacuo and dried in a vacuum centrifuge to give
the products 4a, 4b, 4c, and 4d. The purity by LC-UV ranged from 93–
100%. (The products are shown in Table 3).
Compound 4c: This compound was obtained by following general proce-
dure C, as a yellow oil (218 mg, 100%, 100% purity by LC-UV).
1H NMR (500 MHz, CDCl3): d=1.15 (t, J=7.2 Hz, 3H), 1.78–1.84 (m,
2H), 1.94–2.05 (m, 2H), 2.32 (s, 3H), 3.27–3.33 (m, 2H), 3.72 (t, J=
6.2 Hz, 2H), 4.59 (s, 2H), 5.73 (t, J=5.3 Hz, 1H), 7.12 (d, J=7.8 Hz,
2H), 7.22 ppm (d, J=7.8 Hz, 2H); 13C NMR (125 MHz, CDCl3): d=15.2,
19.5, 21.0, 27.7 (t, J=22 Hz), 35.1, 53.6, 73.1, 129.0, 129.1, 133.5, 137.4,
160.2 ppm; HRMS: m/z calcd for C22H22F17N2Oþ2 : 669.1404 [M+H+];
found: 669.1420.
Compound 8: A mixture of O-(3-perfluorooctyl)-propylhydroxylamine
hydrochloride (2.09 g, 3.95 mmol), 4-hydroxybenzaldehyde (578 mg,
4.74 mmol), sodium acetate (650 mg, 7.90 mmol), and absolute ethanol
(80 mL) was stirred overnight at room temperature. TLC showed the re-
action had gone to completion. The product was purified by fluorous
liquid extraction (FL-E) using HFE-7100 (80 mL) as the fluorous phase
and methanol/water, 4:1 (3ꢂ100 mL) as the aqueous phase. Compound 8
was obtained as a white solid (2.11 g, 90%, 99% purity by LC-UV).
1H NMR (500 MHz, CDCl3): d=1.99–2.07 (m, 2H), 2.17–2.30 (m, 2H),
4.18–4.24 (m, 2H), 5.10 (brs, 1H), 6.83 (d, J=7.5 Hz, 2H), 7.50 (d, J=
7.5 Hz, 2H), 8.03 ppm (s, 1H); 13C NMR (125 MHz, CDCl3): d=20.3,
27.8 (t, J=22 Hz), 72.3, 115.7, 124.9, 128.8, 148.6, 157.1 ppm; HRMS: m/z
calcd for C18H13F17NOþ2 : 598.0669 [M+H+]; found: 598.0668.
General procedure D: Acylations and sulfonylations: Acid chloride or
sulfonyl chloride (3 equiv, 1 mmol) was added to a mixture of 3 (1 equiv,
0.34 mmol) and triethylamine (5 equiv, 1.7 mmol, 233 mL) in THF
(2.5 mL). The mixture was stirred overnight at room temperature and pu-
rified by F-SPE. The fluorous fraction was concentrated in vacuo and
dried in a vacuum centrifuge to give the products 4e, 4 f, 4g, 4h, and 4i.
The purity by LC-UV ranged from 99–100%. (The products are shown
in Table 3).
Compound 4h: This compound was obtained by following general proce-
dure D, as a white solid (197 mg, 79%, 100% purity by LC-UV).
1H NMR (500 MHz, CDCl3): d=1.60–1.84 (m, 4H), 2.35 (s, 3H), 3.65 (t,
J=5.6 Hz, 2H), 4.87 (m, 2H), 7.17 (d, J=7.8 Hz, 2H), 7.26 (d, J=7.8 Hz,
2H), 7.38 (d, J=8.3 Hz, 2H), 7.61 ppm (d, J=8.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d=19.1, 21.1, 27.5 (t, J=22 Hz), 50.8, 73.1, 128.4 (2
C), 129.4, 129.6, 132.5, 132.7, 136.9, 137.9, 169.0 ppm; HRMS: m/z calcd
for C26H20ClF17NOþ2 : 736.0906 [M+H+]; found: 736.0923.
Compound 9: A mixture of 8 (1.06 g, 1.77 mmol), cesium carbonate
(3.4 g, 10.6 mmol), and b-dimethylaminoethyl chloride hydrochloride
(660 mg, 4.6 mmol) in DMF (10 mL) was stirred overnight at room tem-
perature. The reaction mixture was purified by F-SPE to give 9 as white
greasy crystals (1.004 g, 85%, 90% purity by LC-UV). 1H NMR
(500 MHz, CDCl3): d=1.99–2.06 (m, 2H), 2.17–2.29 (m, 2H), 2.34 (s,
6H), 2.73 (t, J=5.7 Hz, 2H), 4.08 (t, J=5.8 Hz, 2H), 4.20 (t, J=6.0 Hz,
2H), 6.91 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.8 Hz, 2H), 8.03 ppm (s, 1H);
13C NMR (125 MHz, CDCl3): d=20.3, 27.8 (t, J=22 Hz), 45.9, 58.2, 66.1,
72.3, 114.8, 124.70, 128.5, 148.6, 160.3 ppm; HRMS: m/z calcd for
C22H22F17N2Oþ2 : 669.1404 [M+H+]; found: 669.1401.
ꢁ
ꢁ
General procedure E: N O cleavage with [Mo
ACHTNUGTNER(NUGN CH3CN)3(CO)3]: N O
substrate (1.0 equiv, 0.15 mmol), [Mo(CH3CN)3(CO)3] (1.5 equiv, 67 mg,
AHCTUNGTRENNUNG
0.22 mmol), and methanol (2.5 mL) were added to a microwave vial,
which was then flushed with argon and sealed with a cap. The mixture
was sonicated with ultrasound for 15 min and then heated in a microwave
Compound 10: Compound
9 (820 mg, 1.2 mmol), toluene (40 mL),
borane trimethylamine complex (179 mg, 2.45 mmol), and 2m HCl in di-
4564
www.chemeurj.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 4557 – 4566

A Fluorous-Tagged Ammonia Equivalent
FULL PAPER
ethyl ether (5 mL) were added to a Schlenk flask, under argon. The reac-
tion mixture was stirred overnight at room temperature and then
quenched with 1m aqueous sodium hydroxide. The product was extracted
into ethyl acetate (3ꢂ50 mL) and then purified by F-SPE to give 10 as a
brown solid (762 mg, 93%, 90% purity by LC-UV). 1H NMR (500 MHz,
CDCl3): d=1.78–1.85 (m, 2H), 2.00–2.12 (m, 2H), 2.33 (s, 6H), 2.72 (t,
J=5.7 Hz, 2H), 3.67 (t, J=6.0 Hz, 2H), 3.96 (brd, J=4.3 Hz, 2H), 4.05
(t, J=5.7 Hz, 2H), 5.60 (brt, 1H), 6.88 (d, J=8.5 Hz, 2H), 7.24 ppm (d,
J=8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): d=19.7, 27.1 (t, J=22 Hz),
45.8, 56.0, 58.3, 66.0, 72.3, 114.5, 129.5, 130.2, 158.4 ppm; HRMS: m/z
calcd for C22H22F17N2Oþ2 : 671.1561 [M+H+]; found: 671.1550.
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Compound 11: A mixture of 10 (672 mg, 1.00 mmol), THF (40 mL), tri-
ACHTUNGTRENNUNGethylamine (420 mL, 3.0 mmol), and 3,4 dimethoxybenzoyl chloride
P. Blaney, R. Grigg, Z. Rankovic, M. Thoroughgood, Tetrahedron
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(302 mg, 1.50 mmol) was stirred for 2 h at room temperature. Aqueous
sodium bicarbonate (100 mL) was added and the product was extracted
into ethyl acetate (3ꢂ50 mL). Purification by F-SPE gave 11 as a light
yellow oil (747 mg, 89%, 91% purity by LC-UV). 1H NMR (500 MHz,
CDCl3): d=1.65–1.72 (m, 2H), 1.83–1.95 (m, 2H), 2.33 (s, 6H), 2.73 (t,
J=5.8 Hz, 2H), 3.67 (t, J=5.8 Hz, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 4.06 (t,
J=5.8 Hz, 2H), 4.84 (s, 2H), 6.84 (d, J=8.3 Hz, 1H), 6.91 (d, J=8.6 Hz,
2H), 7.25 (d, J=1.8 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.34 ppm (dd, J=
8.3, 1.9 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=19.2, 27.6 (t, J=
22 Hz), 45.9, 51.4, 55.8, 55.9, 58.3, 66.0, 73.0, 110.0, 111.7, 114.7,
121.8,.126.2, 128.4, 129.7, 148.5, 151.2, 158.6, 169.5 ppm; HRMS: m/z
calcd for C20H17F17NOþ4 : 658.0881 (debenzylated); found: 658.0874.
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(27 mg, 0.88 mmol), and methanol (2 mL) was sonicated with ultrasound
for 15 min and then microwaved for 15 min at 1308C. Saturated aqueous
sodium bicarbonate (3 mL), water (3 mL), and ethyl acetate (6 mL) were
added and the reaction mixture was stirred overnight with no cap on the
vial. The product was extracted into ethyl acetate (3ꢂ20 mL) and the
combined organic phases were evaporated and purified by F-SPE to give
12 (16.5 mg, 78%, 99% purity by LC-UV). 1H NMR (500 MHz, CDCl3):
d=2.33 (s, 6H), 2.72 (t, J=5.7 Hz, 2H), 3.90 (s, 3H), 3.92 (s, 3H), 4.05
(t, J=5.7 Hz, 2H), 4.56 (d, J=5.5 Hz, 2H), 6.40 (brt, 1H), 6.83 (d, J=
8.2 Hz, 1H), 6.90 (d, J=8.4 Hz, 2H), 7.25–7.29 (m, 3H), 7.45 ppm (d, J=
1.9 Hz, 1H); 13C NMR (125 MHz, CDCl3): d=43.6, 45.9, 55.9, 56.0, 58.2,
66.0, 110.2, 110.6, 114.7, 119.2, 127.0, 129.2, 130.5, 148.9, 151.7, 158.3,
166.8 ppm; HRMS: m/z calcd for C20H27N2Oþ4 : 359.1965 [M+H+]; found:
359.1967.
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Received: November 19, 2009
Published online: March 23, 2010
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