Unlocking the potential of phenacyl protecting groups: CO2-based formation and photocatalytic release of caged amines

Article abstract of DOI:10.1021/acs.joc.8b00096

Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO₂ for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)₃](PF₆)₂-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.

Full text of DOI:10.1021/acs.joc.8b00096

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2
Unlocking the Potential of Phenacyl Protecting Groups – CO-
Based Formation and Photocatalytic Release of Caged Amines
Elisabeth Speckmeier, Michael Klimkait, and Kirsten Zeitler
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00096 • Publication Date (Web): 05 Mar 2018
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The Journal of Organic Chemistry
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Unlocking the Potential of Phenacyl Protecting Groups – CO2-Based
Formation and Photocatalytic Release of Caged Amines
Elisabeth Speckmeier, Michael Klimkait and Kirsten Zeitler*
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Institut für Organische Chemie, Universität Leipzig, Johannisallee 29, D-04103 Leipzig, Germany.
Supporting Information Placeholder
ABSTRACT: Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical
biology and material research applications. A robust, highly efficient and sustainable method for the formation of phenacyl based
carbamate esters has been developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly
applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary
amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection proto-
col using visible light. Key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a
neutral, buffered, two-phase acetonitrile/water mixture granting fast and highly selective deprotection for all presented examples.
movable protecting groups (PRPG)4b fulfil quite a number of the
INTRODUCTION
aforementioned requirements and additionally offer the precise
resolution for spatial and temporal control of deprotection by an
external trigger. As a consequence photocleavable protecting
groups are of crucial importance, but still limited to a small
number of possible structural motifs.4b
In recent years organic synthesis has witnessed an increasing
a
emphasis on efficiency, hence aiming at redox,1 atom,1b pot1c as
well as step economy.1d Although this ultimately implies to
minimize the use of protection/deprotection manipulations,
accessing control over reactivity within multifunctional complex
molecular systems is still a fundamental challenge in chemistry.
Hence, powerful synthetic tools, such as activating,2 directing3
as well as protecting groups,4 continue to be of essential impor-
tance and often play critical roles in multistep syntheses. More-
over, protecting groups (caging groups) are also widely applied
in biological studies, analytics and polymer material sciences,
whenever the controlled release of a certain molecular entity is
required, being triggered by an external event.
Scheme 1. Strategies for the formation of Phenacyl (Pac) urethanes.
From a practical point of view broadly applicable protecting
groups need to meet a number of prerequisites. Starting from
inexpensive and readily (preferably commercially) available
precursors their introduction should proceed easily in an effi-
cient and selective manner to provide stable protected products
in high yields, allowing for purification, storage and a wide
range of reaction conditions for further manipulations. For
complex settings, such as multistep syntheses, polyfunctional
molecules or late stage deprotections, orthogonality is of cru-
cial importance. Therefore cleavage should also occur under
mild, but highly selective conditions under which potentially
generated by-products are non-reactive5 and easy to separate.
Catalytic deprotections,6 but by far more significantly, photore-
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Especially phenacyl based (Pac) scaffolds have found wide-
Page 2 of 9
significance also would require mild conditions and chemose-
lective reagents without the production of excessive waste.
Among the comprehensive literature describing different
methods for the formation of urethanes in general (other than
Pac),4a especially sustainable, CO2-based methods have re-
cently gained great interest.13 Inspired by the procedures de-
scribed by Jung14 and following improved protocols by
Hooker15 and especially Das,16 we questioned whether this
strategy, employing solvents being saturated with CO2, could
be translated to the direct carbamate coupling of the challeng-
ing primary amines with phenacyl bromide (Scheme 2). Unfor-
tunately, initial experiments carried out using phenacyl bro-
mide instead of conventional alkyl halides referring to condi-
tions detailed by Das afforded the same undesired cyclization
product (3a) as observed by other groups before.10d,12
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spread application for the design of photocleavable protecting
groups, as, for example, their resulting Pac esters can be
cleaved effectively with either UV light,7 or, as recently
documented, in a photocatalytic approach with visible light.8
Besides the remarkable orthogonality of Pac protected carbox-
ylic acids to common protecting group cleavage protocols
(TFA, piperidine etc.) our photocatalytic cleavage mechanism
grants tolerance to a great variety of functional groups.8 But
despite the excellent suitability of Pac as an orthogonal pro-
tecting group motif, until now Pac has mainly been used for
the protection of carboxylic acids, while examples for amine
protection remain rather scare,9 not least due to the fact that
typical transfer reagents such as its chloroformate or bicarbon-
ate (Pac2O) derivatives are not stable. In addition to the hence
often required employment of harsh conditions and highly
toxic and cumbersome chemicals like phosgene (and equiva-
lents) for the formation of phenacyl urethanes,10 the strongly
limited substrate of all other reported protocols to secondary
amine substrates is particularly problematic (Scheme 1, top).11a
A general method to transfer the both photochemically and –
catalytically cleavable, promising Pac motif as Pac urethane to
amines (including amino acids) remains an unmet challenge.
Herein, we report an operationally simple, nontoxic and
broadly applicable method for the synthesis of Pac urethanes
from their corresponding amines with phenacyl bromide and
CO2 as phosgene replacing, abundant C1 building block. Addi-
tionally, we demonstrate the complete cleavage of all Pac car-
bamates by a convenient, mild and highly selective photocata-
lytic deprotection protocol mediated by visible light.8
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Scheme 2: Attempted formation of PacCO2-phenethylamine 2a
following a protocol of Das.16
All our optimization efforts to alternatively employ different
organic bases like DBU, DIPEA and Et3N instead of Cs2CO3, also
resulted in the formation of oxazolone 3a as main product. Nei-
ther could the cyclization to 3a be decreased by a solvent change
to dichloromethane (DCM) or acetonitrile. Interestingly, an
attempt to prepare the carbamic acid anion in DMSO with its
subsequent trapping by phenacyl bromide in DCM to access
Pac urethane 2a, significantly increased the yield of oxazolone
3a up to 100%.17 Triggered by this instructive result, we rea-
soned anion stabilization to be of crucial importance for the
RESULTS AND DISCUSSION
Pac carbamate protection of amines is often hampered by the
well-documented, concurrent formation of undesired cyclized
oxazolone byproducts (Scheme 2).10d,12 A reaction of practical
successful
transformation
to
the
Pac
urethane.
Scheme 3: Substrate scope for protection of various amines.a
a Conditions for protection: 1.0 mmol amine (1.0 equiv), Cs2CO3 (1.0 equiv for primary amines; 2.0 equiv for HCl salts and secondary. amines,
1.5 equiv for anilines), phenacyl bromide (1.1 equiv), CO2 in 5 mL DMSO; yield of isolated product. b large scale: 10 mmol. c Cs2CO3 (1.0 equiv).
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By contrast to DCM, DMSO, which is also a good H-bond accep-
tection method for Pac protected acids8 to these Pac urethanes.
a
tor solvent, has no ability to function as H-bond donor18 and
Despite facing the additional challenge that a possible
photoredox catalytic protocol would harbor the danger of an
oxidation of the just released amines and therefore undesirable
side reaction, we hoped to circumvent this problem based on
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hence we assumed this to be beneficial for suppressing the base
induced cyclization (starting with the deprotonation of Pac
urethane 2a and being strongly dependent on the stabilization
of the corresponding anion).18 As DMSO offers an outstanding
our knowledge of this catalytical bond breakage.8, We se-
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solubility of Cs2CO3 as well as CO2 and moreover Cs2CO3
has been used successfully for carbamate formations in previ-
ous literature,21 additionally providing increased nucleophilic-
ity of the corresponding deprotonated amines,22 we considered
the combination of Cs2CO3 in DMSO as most promising for
the development of a new synthetic protocol. Specifically, we
hypothesized that, instead of performing a screening focused
on additives, solvent and reagent changes, the direct optimiza-
tion of the reaction technique and conditions could be benefi-
cial to facilitate the challenging formation of Pac urethanes
from amines. We hence examined conditions to suppress the
cyclization via concentration and especially timing effects.
First, we minimized the amount of Cs2CO3 to 1.0 equiv in
view of the base-promoted cyclization. Additionally, we dra-
matically shortened the indicated reaction time for the initial
formation of the carbamic anion to 1 h using a balloon of CO2
for bubbling through the solution for its saturation. After the
subsequent addition of phenacyl bromide the formation of
urethane 2a in DMSO is very fast, so the reaction must be
stopped after 5 minutes to avoid the detrimental cyclization to
begin and the reaction to result in an inseparable mixture of
oxazolone 3a and Pac urethane 2a.
With these optimized conditions in hand we next investi-
gated the scope of our protocol for selective formation of Pac
urethanes for a variety of different amines, including primary
amines (1a-c), amino acids (1d-j), anilines (1k-r) and secon-
dary amines (1s-x). We found the amount of Cs2CO3 to be
strongly dependent on the respective substrate. While primary
amines, that are the most susceptible substrates to the unde-
sired cyclization, 1.0 equiv Cs2CO3 must not be exceeded,
except for the direct usage of HCl salts (such as amino acid
esters 1d-j), where an extra of 1.0 equiv base is required for
additional neutralization. Anilines (except for the electron rich
anisidine (1n)) as well as secondary amines can be treated
with 1.5 equiv respectively 2.0 equiv of Cs2CO3 to guarantee
fast and full conversion to the intermediate carbamic anion.
Application of this revised protocol allows for reproducible
protection of all different types of amines as their correspond-
ing Pac urethanes in short reaction times and good to excellent
yields. As showcased for anilines our novel protection proto-
col tolerates electron donating effects (1l, 1n) and electron
withdrawing effects (1m, o, p) and hence less nucleophilic
amines as well as heavily sterically hindered amines (1r).
Notably, the efficient protection of amines was not impeded
by the presence of free alcohols (1g, x) or rather sensitive amino
acids such as tryptophan (1j) and biogenic amines (1a-c). Fur-
thermore, a series of piperazines bearing common protecting
groups (Boc: 1s, Cbz: 1t, Alloc: 1u) showed an unlimited stabil-
ity under these conditions. With only three examples out of 24
resulting in yields below 80%, the broad substrate scope high-
lights the general applicability of our synthetic protocol for the
Pac based protection of amines as urethanes.
lected [Ru(bpy)3](PF6)2 as a photocatalyst in combination with
ascorbic acid as a reductive quencher in a neutral buffered
two-phase acetonitrile/water mixture. Fortunately, this proto-
col proved to be efficient and concurrently mild enough to
deprotect all examples showing full conversion and quantita-
tive yields of acetophenone 4 (as determined by GC-FID,
Table 1). Due to their volatility Boc protection served to facili-
tate the isolation of Pac urethane deprotected amino acid me-
thylesters 5d-j by adding Boc2O and NaOH directly to the
reaction mixture after irradiation. Using this formal re-
protection we could successfully isolate all amino acids, with
the exception of proline 5f (71%) and serine 5g (55%), in
excellent yields (up to 98%). However, simple primary amines
turned out to be most challenging: usage of the same re-
protection strategy for isolation only afforded the correspond-
ing amine derivative in poor yields (6b). Direct isolation as
HCl salt could slightly increase the amount of isolated product
to moderate yields (6a, 6c).
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Table 1. Photocatalytic Deprotection of Pac urethanes.a
protected entity
amino acids
urethane
isolated as
yield
Boc-Ala-OMe (5d)
Boc-Val-OMe (5e)
Boc-Pro-OMe (5f)
Boc-Ser-OMe (5g)
Boc-Met-OMe (5h)
Boc-Phe-OMe (5i)
Boc-Trp-OMe (5j)
86%
88%
71%
55%
86%
98%
95%
2d
2e
2f
2g
2h
2i
2j
HCl-amine (6a)
Boc-amine (6b)
HCl-amine (6c)
49%
29%
58%
2a
2b
2c
primary amines
83%
quantb
quant
81%
2k
2l
2m
2n
2o
2p
2q
2r
anilines
aniline (1k-1r)
quant
0%
93%
quantb
90%
92%
85%
78%
87%
32%
2s
2t
2u
2v
2w
2x
secondary amines
amine (1s-1x)
With regard to the previous investigation of only single ex-
amples of Pac urethanes and their photochemical cleavage in
literature10,11a,12 that furthermore suffer from the typical inher-
ent drawbacks of using UV light,23 we decided to extend our
recently reported, visible light mediated, photocatalytic depro-
aConditions: 0.5 mmol Pac-protected amine (1.0 equiv), 1 mol %
[Ru(bpy)3](PF6)2, ascorbic acid (1.5 equiv), K3PO4, (1.0 equiv) in 3 mL
MeCN/H2O 4:1, irradiated with blue LEDs, rt, 4 h; yield of isolated prod-
uct. byield determined by GC-FID with mesitylene as internal standard.
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For the deprotection and direct isolation of anilines and sec-
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DMSO (0.2 M). The tube was sealed with a septum and, while
stirring for 1 h at room temperature, a balloon filled with CO2
was bubbled through the reaction mixture. Then 2-bromo
acetophenone (1.1 equiv) was added in one portion. After
stirring of the reaction mixture for approx. 5 min (consump-
tion of bromo acetophenone monitored by TLC) the reaction
was quenched by the addition of water. The mixture was then
extracted with DCM (3×) and the combined organic phases
were washed with brine. After drying over Na2SO4 the solvent
was removed in vacuo and the crude product was purified by
flash chromatography to afford the corresponding urethane.
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ondary amines our protocol affords excellent yields for nearly
all examples, except of pseudoephedrine (1x) and nitroaniline
1p, being in good agreement with our recently published
work8 and the limitation of easily reducible aryl nitro groups
for these conditions. Pseudoephedrine (1x) most probably
suffers from isolation problems from the two-phase system
due the free alcohol, as also observed for Boc-Ser-OMe (5g).
To further showcase the mildness and orthogonality of this
protocol we successfully carried out a broad screening with a
great variety of different additives to assess the functional
group tolerance for Pac as a simulation of more complex sys-
tems (different functional groups, heterocycles etc.).17 We also
could assure that no oxidation problem occurs during this mild
photoredox catalysis (e. g. dimethylaniline), and no additional
limitations could be found within this screening.17
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General Procedure B – Deprotection. [Ru(bpy)3](PF6)2
(1.0 mol%), ascorbic acid (1.5 equiv), potassium triphosphate
K3PO4 (1.0 equiv) and the protected aniline or amine
(1.0 equiv) were added in a screw-capped reaction tube and
dissolved in an acetonitrile/water mixture (4:1 v/v; 0.17 M).
The mixture was irradiated with blue LEDs at room tempera-
ture under vigorous stirring for the time indicated.
CONCLUSION
For the isolation as amine×HCl: The reaction mixture was
poured into a saturated solution of Na2CO3 and extracted with
DCM (3×). The combined organic phases were extracted with
HCl (1 M) (3×) and the aqueous phase was then basified with
NaOH (3 M) (~ pH 13) and extracted again with DCM (3×).
The combined organic phases were dried over Na2SO4, filtered
and HCl in diethyl ether (conc.) was added until no further
precipitation was formed. The solvent was then removed un-
der reduced pressure.
In summary, for the first time we have developed a high
yielding synthetic strategy for the selective, mild and sustainable
protection of primary amines, amino acids, anilines and secon-
dary amines as Pac urethanes using CO2 as phosgene replacing
C1 building block. The utility of our Pac protection group strat-
egy is completed by a broadly applicable, visible light photo-
catalytic protocol for the mild and selective deprotection.
EXPERIMENTAL SECTION
For the isolation as Boc-protected amine: Di-tert-butyl di-
carbonate (1.5 equiv) and sodium hydroxide (0.1 M, 1.5 equiv)
were added to the reaction mixture. After stirring for 30 min
the mixture was poured into water and extracted with DCM
(3×). The organic layers were combined and dried over
Na2SO4. Following filtration, the solvent was removed under
reduced pressure and the residue was purified by column
chromatography.
For the isolation as free amine by extraction: The reaction
mixture was poured into a saturated solution of Na2CO3 and
extracted with DCM (3×). The combined organic phases were
extracted with HCl (1 M) (3×) and the aqueous phase was then
basified with NaOH (3 M) (~ pH 13) and extracted again with
DCM (3×). The combined organic phases were dried over
Na2SO4, filtered and the solvent was removed under reduced
pressure.
For the isolation as free amine by column chromatography:
The reaction mixture was poured into water and extracted with
DCM (3×). The water layer was basified with NaHCO3 (aq.)
and extracted again with DCM (1×). The organic layers were
combined and dried over Na2SO4. Following filtration, the
solvent was removed under reduced pressure and the residue
was purified by column chromatography.
General Information. Unless otherwise noted, all commer-
cially available compounds were used as received without
further purification. NMR spectra were recorded on a Varian
Mercury plus 300 (300.08 MHz) and Varian Mercury plus 400
(400.00 MHz) using the solvent peak as internal reference
(CDCl3: δ H 7.26; δ C 77.0 and DMSO-d6: δ H 2.51; δ C
39.5). Multiplicities are indicated, s (singlet), d (doublet), t
(triplet), q (quartet), quint (quintet), sept (septet), m (multi-
plet)); coupling constants (J ) are in Hertz (Hz). Asterisks (*)
indicate signal doubling due to formation of diastereomers or
rotamers within the protection step. Mass spectra (MS ESI)
were recorded using a Bruker APEX II FT-ICR. All reactions
were monitored by thin-layer chromatography using Merck
silica gel plates 60 F254; visualization was accomplished with
UV light and/or staining with appropriate stains. Flash chro-
matography procedures were performed on a Biotage® Isolera
One using 10 g or 50 g Biotage® SNAP cartridge KP-Sil col-
umns filled with Kieselgel 60 silica (size 40−63 µm). GC-FID
spectra were recorded on a Thermo Scientific Trace 1310 gas
chromatograph equipped with a Thermo Scientific TG-5MS
column (5% diphenyl- and 95% dimethylpolysiloxane,
0.25 mm ID, 0.25 µm film thickness, length 30 m) using hy-
drogen as carrier gas and nitrogen as make-up gas. Melting
points were recorded on a Büchi Melting point M-565 instru-
ment. Absorption spectra were measured on a Shimadzu UV-
1280 UV/VIS spectrometer. Irradiation was performed with
eight OSLON LD H9GP deep blue (OSRAM®, λ = 455 nm)
attached to a heat sink. The LEDs were operated at 700 mA. All
reactions were carried out under a protective atmosphere of dry
nitrogen using oven-dried glassware unless otherwise stated.
3-Phenethyl-4-phenyloxazol-2(3H)-one (3a). 121 mg
phenethylamine (1.0 mmol, 1.0 equiv) and 658 mg Cs2CO3
(2.0 mmol, 2.0 equiv) were added in a Schlenk tube and dis-
solved in 5 mL DMSO. The tube was sealed with a septum
and while stirring for 1 h at room temperature a balloon filled
with CO2 was bubbled through the reaction mixture. After that
the reaction mixture was slowly added dropwise (syringe) to a
stirred solution of 219 mg 2-bromo acetophenone (1.1 mmol,
1.1 equiv) in 5 mL DCM (round bottom flask). After stirring
for 30 min the reaction mixture was poured into water and
extracted with DCM (3×). The combined organic phases were
washed with brine (1×) and dried over Na2SO4. After filtration
the solvent was removed under reduced pressure and the resi-
Experimental Details.
General Procedure A – Protection. The corresponding amine
(1.0 equiv) and Cs2CO3 (1.0 equiv for primary amines; 2.0
equiv for ×HCl salts and secondary amines; 1.5 equiv for
anilines) were added in a Schlenk tube and dissolved in dry
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due was purified by column chromatography (25 g silica gel,
Methyl ((2-oxo-2-phenylethoxy)carbonyl)alaninate (2d).
According to general procedure A using 140 mg L-alanine
methyl ester hydrochloride (1.0 mmol, 1.0 equiv); yield after
column chromatography (25 g silica gel, hexanes/acetone 3-
30%): 229 mg (0.86 mmol, 86%) white solid; mp: 84-88 °C.
1H NMR (400 MHz, CDCl3) δ 7.98 – 7.89 (m, 2H), 7.66 –
7.60 (m, 1H), 7.54 – 7.47 (m, 2H), 5.69 – 5.57 (m, 1H), 5.50 –
5.23 (m, 2H), 4.56 – 4.37 (m, 1H), 3.80 (s, 3H), 1.49 (d, J =
7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 193.2, 173.3,
155.0, 134.4, 134.0, 129.0, 127.9, 66.7, 52.6, 49.9, 18.7.
HRMS (ESI) m/z: [M + Na]+: Calcd for C13H15NO5Na
288.0842; Found: 288.0841.
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hexanes/acetone 3-30%) to afford 270 mg 3a as a colorless
solid (1.0 mmol, 100%); mp: 146 °C. H NMR (400 MHz,
1
CDCl3) δ 7.50 – 7.38 (m, 3H), 7.27 – 7.20 (m, 3H), 7.19 –
7.08 (m, 2H), 7.02 – 6.98 (m, 2H), 6.77 (s, 1H), 3.93 – 3.81
(m, 2H), 2.94 – 2.85 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
155.9, 137.4, 129.7, 129.5, 128.9, 128.8, 128.6, 128.5, 126.7,
126.4, 123.8, 43.6, 34.5. HRMS (ESI) m/z: [M + Na]+: Calcd
for C17H15NO2Na 288.0995; Found: 288.0969.
2-Oxo-2-phenylethyl phenethylcarbamate (2a). According
to general procedure A using 121 mg phenethylamine
(1.0 mmol, 1.0 equiv); yield after column chromatography
(25 g silica gel, hexanes/acetone 3-30%): 212 mg (0.75 mmol,
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Methyl (tert-butoxycarbonyl)alanate (5d). According to
general procedure B using 133 mg 1d (0.50 mmol, 1.0 equiv)
and irradiation for 3 h; yield after isolation as Boc-protected
amine (10 g silica gel, hexanes/acetone 3-30%) 87 mg
1
75%) white solid; mp: 105 °C. H NMR (400 MHz, CDCl3)
δ 8.02 – 7.87 (m, 2H), 7.67 – 7.58 (m, 1H), 7.57 – 7.42 (m,
2H), 7.38 – 7.18 (m, 5H), 5.33 (s, 2H), 5.23 – 5.08 (m, 1H),
3.62 – 3.44 (m, 2H), 2.94 – 2.79 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 193.6, 155.7, 138.8, 134.4, 133.9, 128.9 (2C),
128.8, 127.9, 126.6, 66.4, 42.5, 36.1. HRMS (ESI) m/z: [M +
Na]+: Calcd for C17H17NO3Na 306.1101; Found: 306.1099.
1
(0.43 mmol, 86%) colorless oil. H NMR (400 MHz, CDCl3)
δ 5.04 (bs, 1H), 4.38 – 4.25 (m, 1H), 3.74 (s, 3H), 1.44 (s,
9H), 1.38 (d, J = 7.2 Hz, 3H).
Methyl ((2-oxo-2-phenylethoxy)carbonyl)valinate (2e). Ac-
cording to general procedure A using 168 mg L-valine
methyl ester hydrochloride (1.0 mmol, 1.0 equiv); yield after
column chromatography (25 g silica gel, hexanes/acetone 3-
30%): 252 mg (0.86 mmol, 86%) white solid; mp: 65 °C.
1H NMR (400 MHz, CDCl3) δ 7.99 – 7.88 (m, 2H), 7.68 –
7.55 (m, 1H), 7.53 – 7.42 (m, 2H), 5.61 – 5.49 (m, 1H), 5.46 –
5.20 (m, 2H), 4.37 – 4.26 (m, 1H), 3.76 (s, 3H), 2.27 – 2.08
(m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.9 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 193.2, 172.3, 155.7, 134.4, 133.9,
129.0, 127.9, 66.8, 59.4, 52.3, 31.6, 19.0, 17.7. HRMS (ESI)
m/z: [M + Na]+: Calcd for C15H19NO5Na 316.1155; Found:
316.1155.
Phenethylamine hydrochloride (6a). According to general
procedure B using 142 mg 2a (0.50 mmol, 1.0 equiv) and
irradiation for 3 h; yield after isolation as amine×HCl:
1
48.5 mg (0.24 mmol, 49%) white solid. H NMR (300 MHz,
D2O) δ 7.53 – 7.32 (m, 5H), 3.31 (t, J = 7.3 Hz, 2H), 3.03 (t,
J = 7.3 Hz, 2H).25
2-Oxo-2-phenylethyl benzylcarbamate (2b). According to
general procedure A using 107 mg benzylamine (1.0 mmol,
1.0 equiv); yield after column chromatography (25 g silica gel,
hexanes/acetone 3-30%): 172 mg (0.64 mmol, 64%) white
solid; mp: 109 °C. 1H NMR (400 MHz, CDCl3) δ 7.97 – 7.90
(m, 2H), 7.65 – 7.56 (m, 1H), 7.52 – 7.44 (m, 2H), 7.39 – 7.26
(m, 5H), 5.36 (s, 2H), 5.32 (bs, 1H), 4.48 – 4.41 (m, 2H). 13C
NMR (101 MHz, CDCl3) δ 193.5, 155.8, 138.2, 134.3, 133.8,
128.8, 128.7, 127.8, 127.6, 127.5, 66.5, 45.3. HRMS (ESI) m/z:
[M + Na]+: Calcd for C16H15NO3Na 292.0944; Found:
292.0941.
Methyl (tert-butoxycarbonyl)valinate (5e). According to
general procedure B using 147 mg 1e (0.50 mmol, 1.0 equiv)
and irradiation for 3 h; yield after isolation as Boc-protected
amine (10 g silica gel, hexanes/acetone 3-30%) 102 mg
1
(0.44 mmol, 88%) colorless oil. H NMR (400 MHz, CDCl3)
δ 5.01 (d, J = 8.7 Hz, 1H), 4.26 – 4.16 (m, 1H), 3.73 (s, 3H),
2.17 – 2.06 (m, 1H), 1.44 (s, 9H), 0.95 (d, J = 6.9 Hz, 3H),
0.89 (d, J = 6.8 Hz, 3H).
tert-Butyl benzylcarbamate (6b). According to general pro-
cedure B using 135 mg 2b (0.50 mmol, 1.0 equiv) and irradia-
tion for 3 h; yield after isolation as Boc-protected amine (10 g
silica gel, hexanes/acetone 3-30%) 29 mg (0.14 mmol, 29%)
2-Methyl 1-(2-oxo-2-phenylethyl) pyrrolidine-1,2-dicarb-
oxylate (2f). According to general procedure A using 166 mg
L-proline methyl ester hydrochloride (1.0 mmol, 1.0 equiv);
yield after column chromatography (25 g silica gel, hex-
anes/acetone 3-30%): 250 mg (0.86 mmol, 86%) colorless
gum. 1H NMR (400 MHz, CDCl3): δ 7.96 – 7.82 (m, 2H), 7.64
– 7.55 (m, 1H), 7.53 – 7.41 (m, 2H), 5.57 – 5.14 (m, 2H), 4.57
– 4.36 (m, 1H), 3.75 (2 s, Ʃ 3H), 3.72 – 3.52 (m, 2H), 2.39 –
2.18 (m, 1H), 2.12 – 1.89 (m, 3H). 13C NMR (101 MHz,
CDCl3) δ 193.2*, 173.1*, 154.2*, 134.4, 133.7, 128.8, 127.7,
66.8, 59.3*, 52.3*, 47.0*, 30.9*, 24.3*. HRMS (ESI) m/z: [M +
Na]+: Calcd for C15H17NO5Na 314.0999; Found: 314.0993.
1
colorless oil.: H NMR (300 MHz, CDCl3) 7.47 – 7.20 (m,
5H), 4.88 (bs, 1H), 4.49 – 4.20 (m, 2H), 1.49 (s, 9H).
2-Oxo-2-phenylethyl
carbamate (2c) According to general procedure A using
202 mg 3,4-methylenedioxyphenethylamine hydrochloride
(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-
(1.0 mmol, 1.0 equiv); yield after column chromatography (25 g
silica gel, hexanes/acetone 3-30%): 265 mg (0.81 mmol, 81%)
white solid; mp: 108 °C. 1H NMR (400 MHz, CDCl3) δ 8.00 –
7.85 (m, 2H), 7.65 – 7.55 (m, 1H), 7.55 – 7.44 (m, 2H), 6.83 –
6.63 (m, 3H), 6.00 – 5.86 (m, 2H), 5.31 (s, 2H), 5.01 (bs, 1H),
3.51 – 3.36 (m, 2H), 2.77 (t, J = 6.9 Hz, 2H). 13C NMR (101
MHz, CDCl3) δ 193.6, 155.7, 148.0, 146.4, 134.4, 133.9,
132.5, 129.0, 127.9, 121.9, 109.3, 108.5, 101.0, 66.5, 42.7,
35.8. HRMS (ESI) m/z: [M + Na]+: Calcd for C18H17NO5Na
350.0999; Found: 350.0993.
1-(tert-Butyl) 2-methyl pyrrolidine-1,2-dicarboxylate (5f).
According to general procedure B using 146 mg 2f
(0.50 mmol, 1.0 equiv) and irradiation for 3 h; yield after
isolation as Boc-protected amine (10 g silica gel, hex-
anes/ethyl acetate 3-30%) 80.8 mg (0.35 mmol, 71%) color-
3,4-Methylenedioxyphenethylamine hydrochloride (6c). Ac-
cording to general procedure B using 164 mg 1c (0.50 mmol,
1.0 equiv) and irradiation for 3 h; yield after isolation as
1
less oil. H NMR (400 MHz, CDCl3) δ 4.34 – 4.12 (m, 1H),
3.72 (2 s, Ʃ 3H), 3.59 – 3.33 (m, 2H), 2.28 – 2.08 (m, 1H),
1.99 – 1.80 (m, 3H), 1.43 (2 s, Ʃ 9H).
1
amine×HCl: 58 mg (0.29 mmol, 58%) white solid. H NMR
(300 MHz, D2O) δ 6.95 – 6.79 (m, 3H), 6.03 – 5.93 (m, 2H),
Methyl ((2-oxo-2-phenylethoxy)carbonyl)serinate (2g). Ac-
cording to general procedure A using 156 mg L-serine
3.25 (t, J = 7.2 Hz, 2H), 2.94 (t, J = 7.2 Hz, 2H).25
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The Journal of Organic Chemistry
Page 6 of 9
methyl ester hydrochloride (1.0 mmol, 1.0 equiv); yield after
column chromatography (25 g silica gel, hexanes/acetone 3-
30%): 244 mg (0.87 mmol, 87%) white solid; mp: 99-102 °C.
1H NMR (400 MHz, CDCl3) δ 7.96 – 7.84 (m, 2H), 7.65 –
7.55 (m, 1H), 7.55 – 7.43 (m, 2H), 6.20 – 6.09 (m, 1H), 5.51 –
5.20 (m, 2H), 4.55 – 4.41 (m, 1H), 4.12 – 3.96 (m, 2H), 3.80
(s, 3H), 2.59 (bs, 1H). 13C NMR (101 MHz, CDCl3) δ 193.2,
173.3, 155.0, 134.4, 134.0, 129.0, 127.9, 66.7, 52.6, 49.9,
18.7. HRMS (ESI) m/z: [M + Na]+: Calcd for C13H15NO6Na
304.0792; Found: 304.0777.
hexanes/acetone 3-30%): 347 mg (0.91 mmol, 91%) white
solid; mp: 64-70 °C. H NMR (400 MHz, CDCl3): δ 8.22 (bs,
1
1
2
3
4
5
6
7
8
1H), 7.95 – 7.85 (m, 2H), 7.65 – 7.55 (m, 2H), 7.52 – 7.44 (m,
2H), 7.38 – 7.32 (m, 1H), 7.22 – 7.08 (m, 3H), 5.68 – 5.59 (m,
1H), 5.46 – 5.16 (m, 2H), 4.82 – 4.64 (m, 1H), 3.68 (s, 3H),
3.35 (d, J = 5.3 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 193.2,
172.1, 155.0, 136.1, 134.2, 133.8, 128.8, 127.7, 127.5, 123.3,
122.1, 119.6, 118.6, 111.2, 109.6, 66.5, 54.5, 52.4, 27.8.
HRMS (ESI) m/z: [M + Na]+: Calcd for C21H20N2O5Na
403.1264; Found: 403.1261.
9
Methyl (tert-butoxycarbonyl)serinate (5g). According to
general procedure B using 141 mg 2g (0.50 mmol, 1.0 equiv)
and irradiation for 3 h; yield after isolation as Boc-protected
amine (silica gel, hexanes/acetone 3-30%) 60 mg (0.27 mmol,
55%) colorless liquid. 1H NMR (400 MHz, CDCl3) δ 5.46 (bs,
1H), 4.38 (bs, 1H), 4.01 – 3.85 (m, 2H), 3.78 (s, 3H), 2.50 –
2.16 (m, 1H), 1.45 (s, 9H).
Methyl (tert-butoxycarbonyl)tryptophanate (5j). According
to general procedure B using 191 mg 2j (0.50 mmol,
1.0 equiv) and irradiation for 3 h; yield after isolation as Boc-
protected amine (10 g silica gel, hexanes/acetone 3-30%)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
152 mg (0.48 mmol, 95%) colorless oil. H NMR (400 MHz,
CDCl3) δ 8.29 (s, 1H), 7.59 – 7.53 (m, 1H), 7.37 – 7.32 (m,
1H), 7.22 – 7.16 (m, 1H), 7.16 – 7.09 (m, 1H), 7.00 – 6.94 (m,
1H), 5.15 – 5.05 (m, 1H), 4.71 – 4.60 (m, 1H), 3.67 (s, 3H),
3.35 – 3.23 (m, 2H), 1.36 (s, 9H).
Methyl ((2-oxo-2-phenylethoxy)carbonyl)methioninate (2h).
According to general procedure
A
using 150 mg
L-methionine methyl ester hydrochloride (0.75 mmol,
1.0 equiv); yield after column chromatography (25 g silica gel,
hexanes/acetone 3-30%): 225 mg (0.69 mmol, 92%) white
2-Oxo-2-phenylethyl phenylcarbamate (2k). According to
general procedure A using 931 mg aniline (10.0 mmol,
1.0 equiv); yield after column chromatography (100 g silica gel,
hexanes/acetone 3-30%): 2.36 g (9.2 mmol, 92%) white solid;
mp: 152 °C. 1H NMR (400 MHz, CDCl3): δ 7.98 – 7.91 (m, 2H),
7.67 – 7.58 (m, 1H), 7.56 – 7.46 (m, 2H), 7.45 – 7.37 (m, 2H),
7.34 – 7.27 (m, 2H), 7.12 – 6.96 (m, 2H), 5.42 (s, 2H). 13C NMR
(101 MHz, CDCl3) δ 193.0, 152.7, 137.5, 134.2, 134.0, 129.1,
128.9, 127.8, 123.8, 118.8, 66.5. HRMS (ESI) m/z: [M + Na]+:
Calcd for C15H13NO3Na 278.0788; Found: 278.0786.
1
solid; mp: 60-63 °C. H NMR (400 MHz, CDCl3): δ 8.03 – 7.86
(m, 2H), 7.71 – 7.57 (m, 1H), 7.57 – 7.41 (m, 2H), 5.90 – 5.76 (m,
1H), 5.54 – 5.20 (m, 2H), 4.66 – 4.48 (m, 1H), 3.79 (s, 3H), 2.60 (t,
J = 7.3 Hz, 2H), 2.25 – 1.99 (m, 5H). 13C NMR (101 MHz, CDCl3)
δ 193.2, 172.3, 155.3, 134.3, 134.0, 129.0, 127.9, 66.8, 53.4, 52.7,
32.0, 29.9, 15.6. HRMS (ESI) m/z: [M + Na]+: Calcd for
C15H19NO5SNa 348.0876; Found: 348.0884.
Methyl (tert-butoxycarbonyl)methioninate (5h). According
to general procedure B using 163 mg 2h (0.50 mmol,
1.0 equiv) and irradiation for 3 h; yield after isolation as Boc-
protected amine (10 g silica gel, hexanes/acetone 3-30%)
Aniline (1k). According to general procedure B using
128 mg 2k (0.50 mmol, 1.0 equiv) and irradiation for 3 h;
yield after isolation as amine by column chromatography
(10 g silica gel, hexanes/acetone 9:1) 38.4 mg (0.41 mmol,
83%) pale yellow liquid. 1H NMR (400 MHz, CDCl3) δ 7.23 –
7.10 (m, 2H), 6.83 – 6.65 (m, 3H), 3.49 (bs, 2H).
1
113 mg (0.43 mmol, 86%) colorless oil. H NMR (400 MHz,
CDCl3) δ 5.20 – 5.09 (m, 1H), 4.51 – 4.39 (m, 1H), 3.78 (s,
3H), 2.56 (t, J = 7.4 Hz, 2H), 2.22 – 2.08 (m, 1H), 2.12 (s,
3H), 2.02 – 1.91 (m, 1H), 1.47 (s, 9H).
2-Oxo-2-phenylethyl p-tolylcarbamate (2l). According to
general procedure A using 214 mg p-toluidine (2.0 mmol,
1.0 equiv); yield after column chromatography (25 g silica gel,
hexanes/acetone 3-30%): 484 mg (1.8 mmol, 90%) white
Methyl ((2-oxo-2-phenylethoxy)carbonyl)phenylalaninate
(2i). According to general procedure A using 216 mg
L-phenylalanine methyl ester hydrochloride (1.0 mmol,
1.0 equiv); yield after column chromatography (25 g silica gel,
hexanes/acetone 3-30%): 307 mg (0.90 mmol, 90%) white
1
solid; mp: 154 °C. H NMR (400 MHz, CDCl3) δ 7.97 – 7.91
(m, 2H), 7.66 – 7.57 (m, 1H), 7.53 – 7.46 (m, 2H), 7.33 – 7.26
(m, 2H), 7.17 – 7.08 (m, 2H), 7.03 – 6.95 (m, 1H), 5.41 (s,
2H), 2.30 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 193.1,
152.8, 138.0, 133.9, 129.5, 128.9, 127.8, 124.6, 119.0, 66.4,
20.8. HRMS (ESI) m/z: [M + Na]+: Calcd for C16H15NO3Na
292.0944; Found: 292.0942.
1
solid; mp: 70-78 °C. H NMR (400 MHz, CDCl3) δ 7.96 –
7.87 (m, 2H), 7.65 – 7.57 (m, 1H), 7.55 – 7.43 (m, 2H), 7.35 –
7.26 (m, 3H), 7.20 – 7.15 (m, 2H), 5.57 – 5.43 (m, 1H), 5.40 –
5.22 (m, 2H), 4.75 – 4.63 (m, 1H), 3.73 (s, 3H), 3.24 – 3.10
(m, 2H). 13C NMR (101 MHz, CDCl3) δ 193.0, 171.6, 154.9,
135.5, 134.3, 133.8, 129.4, 128.8, 128.6, 127.8, 127.2, 66.6,
55.0, 52.4, 38.1. HRMS (ESI) m/z: [M + Na]+: Calcd for
C19H19NO5Na 364.1155; Found: 364.1152.
p-Toluidine (1l). According to general procedure B using 135
mg 2l (0.50 mmol, 1.0 equiv) and irradiation for 3 h; yield (> 99%)
determined by GC-FID with mesitylene as internal standard.
Methyl 4-(((2-oxo-2-phenylethoxy)carbonyl)amino)benzoate
(2m). According to general procedure A using 151 mg
methyl 4-aminobenzoate (1.0 mmol, 1.0 equiv); yield after
column chromatography (25 g silica gel, hexanes/acetone 3-
30%): 254 mg (0.83 mmol, 83%) white solid; mp: 150 °C.
1H NMR (400 MHz, CDCl3) δ 8.06 – 7.90 (m, 4H), 7.69 –
7.59 (m, 1H), 7.56 – 7.44 (m, 4H), 7.22 (s, 1H), 5.44 (s, 2H),
3.90 (s, 3H). 13C NMR (101 MHz, CDCl3) δ192.9, 166.7, 152.4,
141.9, 134.2, 134.0, 130.9, 129.0, 127.8, 125.1, 117.8, 66.6, 52.0.
HRMS (ESI) m/z: [M + Na]+: Calcd for C17H15NO5Na
336.0842; Found: 336.0835.
Methyl (tert-butoxycarbonyl)phenylalaninate (5i). Accord-
ing to general procedure B using 171 mg 2i (0.50 mmol,
1.0 equiv) and irradiation for 3 h; yield after isolation as Boc-
protected amine (10 g silica gel, hexanes/ethyl acetate 3-30%)
1
137 mg (0.49 mmol, 98%) colorless oil. H NMR (400 MHz,
CDCl3) δ 7.33 – 7.23 (m, 3H), 7.18 – 7.07 (m, 2H), 4.96 (d,
J = 8.3 Hz, 1H), 4.64 – 4.51 (m, 1H), 3.71 (s, 3H), 3.16 – 2.99
(m, 2H), 1.41 (s, 9H).
Methyl ((2-oxo-2-phenylethoxy)carbonyl)tryptophanate (2j).
According to general procedure
A
using 255 mg
D-tryptophan methyl ester hydrochloride (1.0 mmol,
1.0 equiv); yield after column chromatography (25 g silica gel,
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The Journal of Organic Chemistry
Methyl 4-aminobenzoate (1m). According to general pro-
4-Iodoaniline (1q). According to general procedure B using
191 mg 2q (0.50 mmol, 1.0 equiv) and irradiation for 2.5 h; yield
after isolation as amine by column chromatography (10 g silica
gel, hexanes/acetone 3-30%) 101 mg (0.46 mmol, 93%) colorless
solid. 1H NMR (400 MHz, CDCl3) δ 7.52 – 7.31 (m, 2H), 6.62 –
6.33 (m, 2H), 3.68 (bs, 2H).
1
2
3
4
5
6
7
8
cedure B using 157 mg 2m (0.50 mmol, 1.0 equiv) and irra-
diation for 2.5 h; yield after isolation as amine by column
chromatography (10 g silica gel, hexanes/acetone 3-30%)
76 mg (0.50 mmol, quantitative) colorless solid. 1H NMR
(400 MHz, CDCl3) δ 7.92 – 7.80 (m, 2H), 6.69 – 6.58 (m, 2H),
4.03 (bs, 2H), 3.85 (s, 3H).
2-Oxo-2-phenylethyl
(2,6-diisopropylphenyl)carbamate
2-Oxo-2-phenylethyl (4-methoxyphenyl)carbamate (2n).
According to general procedure A using 123 mg methyl
p-anisidine (1.0 mmol, 1.0 equiv); yield after column chroma-
tography (25 g silica gel, hexanes/acetone 3-30%): 191 mg
(0.67 mmol, 67%) white solid; mp: 162 °C. 1H NMR
(400 MHz, CDCl3) δ 8.07 – 7.89 (m, 2H), 7.69 – 7.60 (m, 1H),
7.55 – 7.48 (m, 2H), 7.41 – 7.22 (m, 2H), 6.93 – 6.77 (m, 3H),
5.43 (s, 2H), 3.88 – 3.78 (m, 3H). 13C NMR (101 MHz, CDCl3)
193.2, 159.1, 134.2, 133.9, 128.9, 128.7, 127.8, 120.8, 114.5,
114.3, 66.4, 55.5. HRMS (ESI) m/z: [M + Na]+: Calcd for
C16H15NO4Na 308.0893; Found: 308.0890.
(2r). According to general procedure A using 177 mg
2,6-diisopropylaniline (1.0 mmol, 1.0 equiv); yield after col-
umn chromatography (25 g silica gel, hexanes/acetone 3-
9
1
30%): 318 mg (0.94 mmol, 94%) white solid; mp: 116 °C. H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
NMR (400 MHz, CDCl3) δ 8.00 – 7.83 (m, 2H), 7.65 – 7.56
(m, 1H), 7.53 – 7.41 (m, 2H), 7.34 – 7.28 (m, 1H), 7.23 – 7.15
(m, 2H), 6.28, 5.96 (2 bs, Ʃ 1H), 5.42, 5.26 (2 s, Ʃ 2H), 3.50 –
3.37, 3.33 – 3.18 (2 m, Ʃ 2H), 1.33 – 1.19 (m, 12H). 13C NMR
(101 MHz, CDCl3) δ 193.3, 154.6, 147.0*, 134.4, 133.8*,
130.3, 128.8, 128.5, 127.8*, 123.6, 66.8, 28.6*, 23.7*. HRMS
(ESI) m/z: [M + Na]+: Calcd for C21H25NO3Na 362.1727;
Found: 362.1722.
p-Anisidine (1n). According to general procedure B using
143 mg 2n (0.50 mmol, 1.0 equiv) and irradiation for 4 h;
yield after isolation as amine by column chromatography
(10 g silica gel, hexanes/acetone 3-30%) 50 mg (0.40 mmol,
2,6-Diisopropylaniline (1r). According to general proce-
dure B using 170 mg 2r (0.50 mmol, 1.0 equiv) and irradia-
tion for 2 h; yield ((> 99%) determined by GC-FID with me-
sitylene as internal standard.
1
81%) pale yellow solid. H NMR (400 MHz, CDCl3) δ 6.81 –
6.73 (m, 2H), 6.73 – 6.61 (m, 2H), 3.77 (s, 3H), 3.47 (s, 2H).
2-Oxo-2-phenylethyl 4-(3,3-dimethylbutanoyl)piperazine-1-
carboxylate (2s). According to general procedure A using
186 mg 1-Boc-piperazine (1.0 mmol, 1.0 equiv); yield after
column chromatography (silica gel, hexanes/acetone 3-30%):
2-Oxo-2-phenylethyl (4-cyanophenyl)carbamate (2o). Ac-
cording to general procedure
A
using 118 mg
4-aminobenzonitrile (1.0 mmol, 1.0 equiv); yield after column
chromatography (25 g silica gel, hexanes/acetone 3-30%):
237 mg (0.85 mmol, 85%) white solid; mp: 156-171 °C.
1H NMR (400 MHz, CDCl3) δ 7.98 – 7.92 (m, 2H), 7.68 –
7.59 (m, 3H), 7.57 – 7.49 (m, 4H), 7.17 (s, 1H), 5.45 (s, 2H).
13C NMR (101 MHz, CDCl3) δ 192.9, 152.4, 141.9, 134.5, 134.0,
133.5, 129.2, 127.9, 119.0, 118.7, 106.7, 66.8. HRMS (ESI) m/z:
[M + Na]+: Calcd for C16H12N2O3Na 303.0740; Found: 303.0731.
1
323 mg (0.93 mmol, 93%) white solid; mp: 123 °C. H NMR
(400 MHz, CDCl3) δ 7.97 – 7.89 (m, 2H), 7.67 – 7.57 (m, 1H),
7.56 – 7.44 (m, 2H), 5.36 (s, 2H), 3.66 – 3.42 (m, 8H), 1.48 (s,
9H). 13C NMR (101 MHz, CDCl3) δ 193.2, 154.7, 154.6,
134.3, 133.8, 128.9, 127.7, 80.2, 66.9, 43.9, 28.4. HRMS
(ESI) m/z: [M + Na]+: Calcd for C18H24N2O5Na 371.1577;
Found: 371.1570.
4-Aminobenzonitrile (1o). According to general proce-
dure B using 140 mg 2o (0.50 mmol, 1.0 equiv) and irradia-
tion for 2 h; yield after isolation as amine by column chroma-
tography (10 g silica gel, hexanes/acetone 3-30%) 59 mg
1-Boc-piperazine (1s). According to general procedure B
using 174 mg 2s (0.50 mmol, 1.0 equiv) and irradiation for
2 h; yield after isolation as amine by extraction: 84 mg
(0.45 mmol, 90%) colorless solid. 1H NMR (400 MHz,
CDCl3) δ 3.48 – 3.37 (m, 4H), 2.89 – 2.76 (m, 4H), 2.02 (bs,
1H), 1.46 (s, 9H).
1
(0.50 mmol, quantitative) colorless solid. H NMR (400 MHz,
CDCl3) δ 7.46 – 7.37 (m, 2H), 6.69 – 6.61 (m, 2H), 4.14 (s, 2H).
2-Oxo-2-phenylethyl (4-nitrophenyl)carbamate (2p). Ac-
cording to general procedure A using 138 mg 4-nitroaniline
(1.0 mmol, 1.0 equiv); yield after column chromatography (25 g
silica gel, hexanes/acetone 3-30%): 254 mg (0.85 mmol, 85%)
1-Benzyl 4-(2-oxo-2-phenylethyl) piperazine-1,4-dicarboxy-
late (2t). According to general procedure A using 220 mg
benzyl piperazine-1-carboxylate (1.0 mmol, 1.0 equiv); yield
after column chromatography (25 g silica gel, hexanes/acetone
3-30%): 295 mg (0.81 mmol, 81%) white solid; mp: 90 °C. 1H
NMR (400 MHz, CDCl3) δ 7.97 – 7.87 (m, 2H), 7.65 – 7.56
(m, 1H), 7.53 – 7.45 (m, 2H), 7.41 – 7.30 (m, 5H), 5.36 (s,
2H), 5.16 (s, 2H), 3.66 – 3.45 (m, 8H). 13C NMR (101 MHz,
CDCl3) δ 193.3, 155.3, 154.8, 136.6, 134.4, 134.0, 129.0,
128.7, 128.3, 128.1, 127.9, 67.6, 67.1, 43.7. HRMS (ESI) m/z:
[M + Na]+: Calcd for C21H22N2O5Na 405.1421; Found:
405.1419.
1
pale yellow solid; mp: 155 °C. H NMR (400 MHz, CDCl3) δ
8.28 – 8.21 (m, 2H), 8.02 – 7.94 (m, 2H), 7.71 – 7.64 (m, 1H), 7.63
– 7.59 (m, 2H), 7.58 – 7.52 (m, 2H), 5.50 (s, 2H).26 13C NMR (101
MHz, CDCl3) δ 191.4, 164.4, 150.9, 135.0, 134.3, 134.1,
131.2, 129.1, 127.9, 123.7, 67.2. HRMS (ESI) m/z: [M + Na]+:
Calcd for C15H12N2O5Na 323.0638; Found: 323.0605.
2-Oxo-2-phenylethyl (4-iodophenyl)carbamate (2q). Ac-
cording to general procedure A using 219 mg 4-iodoaniline
(1.0 mmol, 1.0 equiv); yield after column chromatography
(25 g silica gel, hexanes/acetone 3-30%): 326 mg (0.87 mmol,
87%) white solid; mp: 173-186 °C. 1H NMR (400 MHz,
CDCl3) δ 7.99 – 7.89 (m, 2H), 7.68 – 7.58 (m, 3H), 7.56 –
7.46 (m, 2H), 7.23 – 7.15 (m, 2H), 6.92 (s, 1H), 5.42 (s, 2H).
13C NMR (101 MHz, CDCl3) δ 192.8, 152.5, 137.9, 137.4,
134.1, 128.9, 127.8, 120.7, 110.0, 86.7, 66.5. HRMS (ESI)
m/z: [M + Na]+: Calcd for C15H12N2O5Na 403.9754; Found:
403.9753.
Benzyl piperazine-1-carboxylate (1t). According to general
procedure B using 191 mg 2t (0.50 mmol, 1.0 equiv) and
irradiation for 2 h; yield after isolation as amine by extraction:
101 mg (0.46 mmol, 92%) colorless liquid. 1H NMR
(400 MHz, CDCl3): δ 7.41 – 7.28 (m, 5H), 5.13 (s, 2H), 3.58 –
3.45 (m, 4H), 2.95 – 2.79 (m, 4H), 2.47 (bs, 1H).
1-Allyl 4-(2-oxo-2-phenylethyl) piperazine-1,4-dicarboxy-
late (2u). According to general procedure A using 170 mg
allyl piperazine-1-carboxylate (1.0 mmol, 1.0 equiv); yield
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The Journal of Organic Chemistry
Page 8 of 9
after column chromatography (25 g silica gel, hexanes/acetone
CDCl3) δ 194.5*, 156.2, 142.0*, 134.1*, 128.8, 128.5, 127.9,
127.8, 127.0, 126.9, 76.0, 66.8*, 59.1*, 30.6*, 15.0*. HRMS
(ESI) m/z: [M + H]+: Calcd for C19H21NO4H 328.1543; Found:
328.1539.
3-30%): 305 mg (0.92 mmol, 92%) white solid; mp: 98 °C. 1H
NMR (400 MHz, CDCl3) δ 7.96 – 7.86 (m, 2H), 7.65 – 7.56
(m, 1H), 7.54 – 7.45 (m, 2H), 5.94 (ddt, J = 17.3, 10.8, 5.6 Hz,
1H), 5.36 (s, 2H), 5.34 – 5.20 (m, 2H), 4.62 (dt, J = 5.6, 1.5
Hz, 2H), 3.70 – 3.41 (m, 8H). 13C NMR (101 MHz, CDCl3)
δ 193.2, 155.1, 154.8, 134.3, 134.0, 132.9, 129.0, 127.8, 117.9,
67.1, 66.4, 43.7. HRMS (ESI) m/z: [M + Na]+: Calcd for
C17H20N2O5Na 355.1264; Found: 355.1256.
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3
4
5
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7
8
Pseudoephedrine (1x). According to general procedure B
using 149 mg 2x (0.46 mmol, 1.0 equiv) and irradiation for
3 h; yield after isolation as amine by extraction: 25 mg
1
(0.15 mmol, 32%) white solid. H NMR (300 MHz, CDCl3)
δ 7.39 – 7.25 (m, 5H), 4.19 (d, J = 8.2 Hz, 1H), 2.80 – 2.49
(m, 3H), 2.45 (s, 3H), 0.95 (d, J = 6.4 Hz, 3H).
Allyl piperazine-1-carboxylate (1u).27 According to general
procedure B using 166 mg 2u (0.50 mmol, 1.0 equiv) and
irradiation for 2 h; yield after isolation as amine by extraction
72 mg (0.42 mmol, 85%) colorless liquid. 1H NMR (400 MHz,
CDCl3): δ 6.03 – 5.86 (m, 1H), 5.37 – 5.12 (m, 2H), 4.68 –
4.50 (m, 2H), 3.60 – 3.35 (m, 4H), 2.95 – 2.74 (m, 4H), 2.17
(bs, 1H).
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ASSOCIATED CONTENT
Supporting Information
Additional data for a functional group tolerance survey and copies
of 1H NMR and 13C NMR spectra for all new compounds (PDF).
This material is available free of charge via the Internet at
http://pubs.acs.org.
2-Oxo-2-phenylethyl 3,4-dihydroquinoline-1(2H)-carboxy-
late (2v). According to general procedure A using 136 mg
1,2,3,4-tetrahydroquinoline (1.0 mmol, 1.0 equiv); yield after
column chromatography (silica gel, hexanes/acetone 3-30%):
AUTHOR INFORMATION
Corresponding Author
1
283 mg (0.96 mmol, 96%) pale yellow solid; mp: 69 °C. H
* E-mail: kzeitler@uni-leipzig.de
NMR (400 MHz, CDCl3) δ 7.97 – 7.91 (m, 2H), 7.85 – 7.80
(m, 1H), 7.65 – 7.58 (m, 1H), 7.53 – 7.46 (m, 2H), 7.20 – 7.14
(m, 1H), 7.13 – 7.08 (m, 1H), 7.06 – 7.00 (m, 1H), 5.44 (s,
ORCID
Kirsten Zeitler: 0000-0003-1549-5002
2H), 3.88 (t,
J = 6.1 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.01 (p,
Notes
J = 6.4 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 193.3, 154.4,
138.1, 134.4, 133.9, 130.4, 129.0, 128.7, 127.9, 126.2, 124.4,
124.1, 67.2, 45.2, 27.4, 23.6. HRMS (ESI) m/z: [M + H]+:
Calcd for C18H17NO3H 296.1281; Found: : 296.1282.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the generous funding by the Deutsche
Forschungsgemeinschaft (DFG, GRK 1626).
1,2,3,4-Tetrahydroquinoline (1v). According to general
procedure B using 148 mg 2v (0.50 mmol, 1.0 equiv) and
irradiation for 16 h; yield yield after isolation as amine by
extraction: 52 mg (0.39 mmol, 78%) pale yellow liquid.
1H NMR (400 MHz, CDCl3) δ 7.02 – 6.91 (m, 2H), 6.65 –
6.57 (m, 1H), 6.51 – 6.45 (m, 1H), 3.48 (bs, 1H), 3.34 – 3.27
(m, 2H), 2.77 (t, J = 6.4 Hz, 2H), 2.00 – 1.90 (m, 2H).
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2-oxo-2-phenylethyl methyl(phenethyl)carbamate (2w). Ac-
cording to general procedure A using 219 mg N-methyl-
phenethylamine (1.0 mmol, 1.0 equiv); yield after column chroma-
tography (silica gel, hexanes/acetone 3-30%): 290 mg (0.98 mmol,
98%) pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.99 – 7.88
(m, 2H), 7.66 – 7.56 (m, 1H), 7.56 – 7.44 (m, 2H), 7.38 – 7.18
(m, 5H), 5.39 – 5.27 (m, 2H), 3.68 – 3.47 (m, 2H), 3.04 – 2.81
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134.6, 133.8, 129.0, 128.9, 128.6, 127.9, 126.5, 66.9, 51.6*,
35.6*, 34.7*. HRMS (ESI) m/z: [M + Na]+: Calcd for
C18H19NO3Na 320.1257; Found: 320.1252.
N-Methyl-phenethylamine (1w). According to general pro-
cedure B using 149 mg 2w (0.50 mmol, 1.0 equiv) and irra-
diation for 16 h; yield after isolation as amine by extraction:
59 mg (0.44 mmol, 87%) pale yellow liquid. 1H NMR
(400 MHz, CDCl3) δ 7.36 – 7.23 (m, 5H), 2.93 – 2.83 (m, 4H),
2.48 (s, 3H), 1.76 (bs, 1H).
2-Oxo-2-phenylethyl (1-hydroxy-1-phenylpropan-2-yl)(me-
thyl)carbamate (2x). According to general procedure A using
165 mg pseudoephedrine (1.0 mmol, 1.0 equiv); yield after col-
umn chromatography (25 g silica gel, hexanes/acetone 3-30%):
306 mg (0.94 mmol, 94%) pale yellow resin. 1H NMR
(400 MHz, CDCl3) δ 8.02 – 7.87 (m, 2H), 7.67 – 7.56 (m, 1H),
7.54 – 7.43 (m, 2H), 7.43 – 7.27 (m, 5H), 5.72 – 5.25 (m, 2H),
4.70 – 4.53 (m, 1H), 4.50 – 4.16 (m, 1H), 3.75, 3.20 (2 bs, Ʃ
1H) 2.97 (s, 3H), 1.10 – 1.00 (m, 3H). 13C NMR (101 MHz,
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