Photorelease of primary aliphatic and aromatic amines by visible-light-induced electron transfer

Article abstract of DOI:10.1021/ol202456d

Visible-light-absorbing tris(bipyridyl)ruthenium(II) has been used to mediate electron transfer to N-methylpicolinium carbamates that undergo C-O bond fragmentation followed by spontaneous carbon dioxide release to give free amines. Release of several aliphatic and aromatic primary amines has been demonstrated under mild conditions using visible light.

Full text of DOI:10.1021/ol202456d

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6156–6159
Photorelease of Primary Aliphatic and
Aromatic Amines by Visible-Light-Induced
Electron Transfer
Joseph B. Edson, Liam P. Spencer, and James M. Boncella*
Materials, Physics and Applications Division, Los Alamos National Laboratory,
Los Alamos, New Mexico 87545, United States
boncella@lanl.gov
Received September 12, 2011
ABSTRACT
Visible-light-absorbing tris(bipyridyl)ruthenium(II) has been used to mediate electron transfer to N-methylpicolinium carbamates that undergo
CꢀO bond fragmentation followed by spontaneous carbon dioxide release to give free amines. Release of several aliphatic and aromatic primary
amines has been demonstrated under mild conditions using visible light.
Protecting groups (PGs) that are attached to substrates
quickly and with readily separated byproducts in addition
to clean removal under mild conditions and in high yields
are in ever-increasing demand for a variety of applications.
The use of photoremovable protecting groups (PRPGs)
has attracted much attention as its release step is triggered
by exposure to light, rather than a chemical reagent, which
allows deprotection in the presence of other protecting
groups insensitive to light.1 Examples of such PRPGs
include o-nitrobenzyl ethers and esters,2 phenacyl esters,3
3,5-dimethoxybenzoin,4 and coumarin5 derivatives. How-
ever, some limitations of these groups are that ultraviolet
(UV) and near-UV light is required for deprotection,
which can cause further photochemical side reactions in
the system (especially in the case of using high energy UV
light). Some advances have been made in modifying
PRPGs to red-shift their absorption profiles; however, this
can come at the cost of altering efficiencies and rates of the
release reactions.6
Recently, Falvey and co-workers haveintroduced a class
of PRPGs that relies on photoinduced electron transfer
(PET) to drive deprotection of N-alkylpicolinium (NAP)
protected carboxylic acids and other substrates with the
appropriate choice of a photosensitizer.7 The NAP group
(1) (a) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125.
(b) Pelliccioli, A. P.; Wirz, J. Photochem. Photobiol. 2002, 1, 441. (c) Givens,
R. S.; Conrad, P. G., II; Yousef, A. L. Lee, J. Photoremovable Protect-
ing Groups. In CRC Handbook of Organic Photochemistry and Photobiol-
ogy, 2nd ed.; Horspool, W., Lenci, F., Eds.; CRC Press LLC: Boca Raton, FL,
2004.
(2) (a) Patchorn, A.; Amit, B.; Woodward, R. B. J. Am. Chem. Soc.
1970, 92, 6333. (b) Kaplan, J. H.; Forbush, B.; Hoffman, J. F. Biochem-
istry 1978, 17, 1929. (c) Dunkin, I. R.; Gebicki, J.; Kiszka, M.; Sanin-
Leira, D. J. Chem. Soc., Perkin Trans. 2 2001, 1414. (d) Dussy, A.;
Meyer, C.; Quennet, E.; Bickle, T. A.; Giese, B.; Marx, A. ChemBio-
Chem 2002, 3, 54.
(3) (a) Sheehan, J. C.; Umezawa, K. J. Org. Chem. 1973, 38, 3771.
(b) Givens, R. S.; Athey, P. S.; Matuszewski, B.; Kueper, L. W.; Xue, J. Y.;
Fister, T. J. Am. Chem. Soc. 1993, 115, 6001. (c) Banerjee, A.; Falvey, D. E.
J. Org. Chem. 1997, 62, 6245. (d) Banerjee, A.; Lee, K.; Falvey, D. E.
Tetrahedron 1999, 55, 12699.
(4) (a) Sheehan, J. C.; Wilson, R. M. J. Am. Chem. Soc. 1964, 86,
5277. (b) Baldwin, J. E.; McConnaughie, A. W.; Moloney, M. G.; Pratt,
A. J.; Shims, S. B. Tetrahedron 1990, 46, 6879. (c) Corrie, J. E. T.;
Trentham, D. R. J. Chem. Soc., Perkin Trans. 1 1992, 2409. (d) Cameron,
J. F.; Willson, C. G.; Frechet, J. M. J. J. Chem. Soc., Perkin Trans. 1 1997,
2429. (e) Rajesh, C. S.; Givens, R. S.; Wirz, J. J. Am. Chem. Soc. 2000,
122, 611.
(5) (a) Furata, T.; Torigai, H.; Sugimoto, M.; Iwamura, M. J. Org.
Chem. 1995, 60, 3953. (b) Suzuki, A. Z.; Watanabe, T.; Kawamoto, M.;
Nishiyama, K.; Yamashita, H.; Ishii, M.; Iwamura, M.; Furuta, T. Org.
Lett. 2003, 5, 4867. (c) Shembekar, V. R.; Chen, Y.; Carpenter, B. K.;
Hess, G. P. Biochemistry 2007, 46, 5479.
(6) (a) Bochet, C. G. Tetrahedron Lett. 2000, 41, 6341. (b) Conrad,
P. G.; Givens, R. S.; Weber, J. F. W.; Kandler, K. Org. Lett. 2000, 2,
1545. (c) Aujard, I.; Benbrahim, C.; Gouget, M.; Ruel, O.; Baudin, J.-B.;
Neveu, P.; Jullien, L. Chem.;Eur. J. 2006, 12, 6865. (d) Stensrud, K. F.;
Heger, D.; Sebej, P.; Wirz, J.; Givens, R. S. Photochem. Photobiol. 2008,
7, 614. (e) San Miguel, V.; Bochet, C. G.; del Campo, A. J. Am. Chem.
Soc. 2011, 133, 5380.
(7) (a) Sundararajan, C.; Falvey, D. E. J. Org. Chem. 2004, 69, 5547.
(b) Sundararajan, C.; Falvey, D. E. Org. Lett. 2005, 7, 2631. (c) Sundararajan,
C.;Falvey, D. E. J. Am. Chem. Soc. 2005, 127, 8000. (d) Sundararajan,
C.; Falvey, D. E. Photochem. Photobiol. Sci. 2006, 5, 116. (e) Borak,
J. B.; Lopez-Sola, S.; Falvey, D. E. Org. Lett. 2008, 10, 457. (f) Borak,
J. B.; Falvey, D. E. J. Org. Chem. 2009, 74, 3894.
r
10.1021/ol202456d
Published on Web 11/02/2011
2011 American Chemical Society

can undergo a one-electron reduction through PET from a
photoexciteddonor. While theNAP groupcanberemoved
in many of these systems using high wavelength UV light,
recent results have demonstratedthat judicious selection of
the photosensitizer allows PET deprotection using visible
light (>400 nm).7e,f
Scheme 1. Reduction of N-Methylpicolinium Group
Our group has recently applied this approach for the
generation of fatty acid molecules leading to spontaneous
vesicle formation, which is a process driven only by an
external energy source (visible light).8 Thecoreofthesystem
relies on the use of an 8-oxo-guanine modified [tris(2,20-
bipyridine)Ru(II)] photosensitizer. Interested in extending
this protection chemistry toward other functional groups
and for other applications, we began to explore use of the
NAP group for the protection of aliphatic and aromatic
primary amines. While photolabile protecting groups have
been developed for amines and anilines,9 each system dis-
plays some limitations. The o-nitrobenzyl group has been
extensively studied for aliphatic amine protection and de-
protection under UV light (254 nm).9eꢀh One limitation of
this reaction is that the product amine can react with the
aldehydic group of the photoproduct to form an imine,
which is not entirely avoidable. One application of this
system was in the successful UV-induced cross-linking of
protected polymeric amines with formulations containing
epoxy groups.9h In 1995, Pirrung and Huang extended the
use of 3,5-dimethoxybenzoin photoprotecting groups for
amines. Protection and deprotection proceeded in good
yields; however the reaction was limited to secondary
amines, as primary amines were found to undergo intra-
molecular cyclization leading to byproducts inert to
photolysis.9i Arylsulfonamides have also been studied as
photoremovable protecting groups for amines but suffer
from poor deprotection yields.9j In all cases UV or near-UV
light is required for the photolysis reaction.
transfer. PET to N-methylpicolinium carbamates results
in CꢀO bond fragmentation via one-electron reduction
followed by spontaneous carbon dioxide (CO2) release
to give the free amines (Scheme 1). The modest reduction
potentialof the N-methylpicolinium group (Ered = ꢀ1.1 V
vs SCE) ensures a thermodynamically feasible electron
transfer from many excited photosensitizers. [tris(2,20-
bipyridine) ruthenium(II)] ([Ru(bpy)3]2þ) was chosen for
the photosensitizer because of its moderate reduction
potentials and its absorbance across a wide range of the
UVꢀvis spectrum. Because [Ru(bpy)3]2þ requires an
external electron donor to proceed down the reductive
quenching pathway, ascorbic acid (H2Asc) was chosen
as it is a known reductant to the Ru metal-to-ligand
charge transfer (MLCT) state,10 and it can also serve as
an H-atom donor to trap the N-methylpicolinium
(NMP) methylene radicals. To understand the thermo-
dynamics of this catalytic reaction, the photoredox
properties of [Ru(bpy)3]2þ must be considered and are
summarized in Figure 1.11 The cycle involves in its initial
stage the absorption of light by [Ru(bpy)3]2þ and sub-
sequent reductive quenching of its excited state by
ascorbate (HAscꢀ, kq = 2 ꢁ 107 Mꢀ1
s
ꢀ1).12 Because
the one-electron reduction potential for the [Ru(bpy)3]2þ/þ
couple is ꢀ1.3 V,13 the [Ru(bpy)3]þ ion is thermodyna-
mically capable of reducing the NMP carbamate to the
corresponding NMP methylene radical with CꢀO bond
cleavage to yield the carbamates. The NMP methylene
radical will react with the ascorbate radical formed while
the carbamate can undergo spontaneous CO2 release
giving the free amine upon abstraction of a proton from
the solvent or ascorbic acid.
The demand for synthesis of complex organic molecules
and biomolecules containing amino functionality with
increasing complexity requires the need to develop novel
protecting groups that are readily cleaved under funda-
mentally different and mild conditions to ensure selective
modifications of specific functional groups. Development
of new photoremovable protecting groups that are cleaved
under visible light irradiation is one avenue toward in-
creasing viable deprotection pathways of amines under
mild conditions.
Herein we report the photorelease of aliphatic and
aromatic primary amines by visible-light-induced electron
(8) DeClue, M. S.; Monnard, P.; Bailey, J. A.; Maurer, S. E.; Collis,
G. E.; Ziock, H.; Rasmussen, S.; Boncella, J. M. J. Am. Chem. Soc. 2009,
131, 931.
(9) (a) Barnett, B. K.; Roberts, T. D. J. Chem. Soc., Chem Commun.
1972, 758. (b) Pincock, J. A.; Jurgens, A. Tetrahedron Lett. 1979, 1029.
(c) Hamada, T.; Nishida, A.; Yonemitsu, O. J. Am. Chem. Soc. 1986,
108, 140. (d) Hamada, T.; Nishida, A.; Yonemitsu, O. Tetrahedron Lett.
1989, 30, 4241. (e) Cameron, J. F.; Frechet, J. M. J. J. Org. Chem. 1990,
55, 5919. (f) Cameron, J. F.; Frechet, J. M. J. J. Am. Chem. Soc. 1991,
113, 4303. (g) Cameron, J. F.; Frechet, J. M. J. J. Photochem. Photobiol.
A: Chem. 1991, 59, 105. (h) Beecher, J. E.; Cameron, J. F.; Frechet,
J. M. J. J. Mater. Chem. 1992, 2, 811. (i) Pirrung, M. C.; Huang, C.-Y.
Tetrahedron Lett. 1995, 36, 5883. (j) Corrie, J. E. T.; Papageorgiou, G.
J. Chem. Soc., Perkin Trans. 1 1996, 1583. (k) Cossy, J.; Rakotoarisoa,
H. Tetrahedron Lett. 2000, 41, 2097.
Figure 1. [Ru(bpy)3]2þ photochemistry with respect to ascorbate
(HAscꢀ) electron donor and N-methylpicolinium carbamate
(NMPC). HAscꢀ reduces the MLCT state of Ru, and the
NMPC is then reduced to NMP methylene radical.
Org. Lett., Vol. 13, No. 23, 2011
6157

Synthesis of the N-methylpicolinium carbamate pro-
tecting group precursor is outlined in Scheme 2. Reac-
tion of pyridine-4-methanol with methyliodide in metha-
nol furnishes 4-(hydroxymethyl)-N-methylpyridinium
iodide, 1. Subsequent reaction with carbonyldiimida-
zole in acetonitrile (CH3CN) precipitates 2 cleanly with no
double addition product observed. Counterion exchange
with AgOTf in CH3CN affords 3 in quantitative yield.
This three-step overall synthesis of the protecting group
precursor proceeds in high yield with no purification steps
required.
conditions at 60 °C (2ꢀ3 drops of CH3CN for the
reaction scale investigated, see Supporting Information)
facilitated formation of the protected aromatic amines,
which could similarly be purified by washing with THF.
Examples of protected aromatic amines that contain
electron-withdrawing groups include 4-acetylphenyl
(12), 4-ethylbenzoate (13), and 4-cyanophenyl (14). Aro-
matic amines containing para-nitro or carboxylic acid
functionalities proved to be unreactive under all condi-
tions investigated.
Photolysis solutions containing the protected amines
(4ꢀ14, 0.05 mmol), ascorbic acid (1 equiv), and Ru(bpy)3
Cl2 (10 mol %) were prepared in CD3OD (0.7 mL). The
solutions were degassed by two freezeꢀpumpꢀthaw
cycles with argon and irradiated with a 150 W broad-
band tungsten-filament lamp for a predetermined
amount of time. The product mixtures were then ana-
lyzed by 1H NMR spectroscopy to determine free amine
yields. Nearly quantitative deprotection was observed in
all cases after 2ꢀ4 h of irradiation (within error of
Scheme 2. Synthesis of Protecting Group Precursor
Table 1. Synthesis of Protected Amines
With 3 in hand, its reactivity toward a number of
aliphatic and aromatic primary amines was investi-
gated (Table 1). Reaction of 3 with a number of
aliphatic amines containing various functional groups
in CH3CN at room temperature gave the N-methylpi-
colinium carbamates. Examples of functional group
tolerance include allyl (4), aldehyde protected acetal
(5), hydroxyl (6), ether (7), and an aminonucleoside (8).
All the reactions proceed cleanly with purification of
the products involving simple washing with tetrahy-
drofuran (THF) or 1,4-dioxane of the unreacted start-
ing materials and imidazole byproduct from the
reaction mixture (see Supporting Information). Of
note is the selective reaction of the amine in the pre-
sence of hydroxy (6) and other more highly functiona-
lized groups (8), which is due to the more nucleophilic
nature of the primary amine. Aromatic amines con-
taining electron-donating groups react in solution as
well. Examples of these include phenyl (9), 4-methoxy-
phenyl (10), and 4-hydroxyphenyl (11) amines. Puri-
fication again involved washing with THF, though
higher yields could be obtained from recrystallization
(10, 11). Initial attempts to react aromatic amines
containing electron-withdrawing groups in CH3CN
at room temperature or reflux resulted in no pro-
duct formation. However, reaction under pseudoneat
(10) Binstead, R. A.; McGuire, M. E.; Dovletoglou, A.; Seok, W. K.;
Roecker, L. E.; Meyer, T. J. J. Am. Chem. Soc. 1992, 114, 173.
(11) Vlcek, A. A.; Dodsworsth, E. S.; Pietro, W. J.; Lever, A. B. P.
Inorg. Chem. 1995, 34, 1906.
(12) Creutz, C.; Sutin, N.; Brunschwig, B. J. Am. Chem. Soc. 1979,
101, 1297.
(13) Balzani, V.; Bolletta, F.; Gandolfi, M. T.; Maestri, M. Top. Curr.
Chem. 1978, 75, 31.
a Isolated yield for reactions carried out on ∼1.0 mmol scale.
b Reaction heated at 60 °C under pseudoneat conditions.
6158
Org. Lett., Vol. 13, No. 23, 2011

carried out on a preparative scale. The product, p-ani-
1
side, was isolated in pure form (82% yield), and its H
NMR spectrum was found to be indistinguishable from
an authentic sample.
Table 2. Photorelease of NMP Carbamates
In summary, we have demonstrated that the N-methyl-
picolinium PRPG is easily installed on primary aliphatic
and aromatic amines. Deprotection proceeds under mild
conditions using visible-light-induced electron transfer to
drive the photorelease. The most attractive aspects of this
system include the development of a protecting group
precursor that can be used directly for protection of amines
rather than multistep amine protection chemistry, synth-
esis of the protected amines without the use of column
chromatography for purification, and the use of visible
light as a mild deprotection route in the presence of multi-
ple functional groups. Current efforts are focused on
employing this protection chemistry for biological applica-
tions focusing on aminonucleoside protection, which is
currently ongoing.
N-methylpicolinium
irradiation
amine
entrya
carbamate
time (h)b
formed (%)c
1
4
5
4
4
4
4
2
4
2
4
4
8
4
99
2
99
3
6
98
4
7
98
5
8
97
6
9
95
7
10
11
12
13
14
98 (82)d
94
8
9
93
10
11
96
99
Acknowledgment. We thank the NASA exobiology
program, Grant Number NNH08AI88I, for funding. We
also wish to thank the LANL LDRD program for partial
support of this work.
a Photolysis solution was 0.7 mL of CD3OD, (1.0:1.0:0.1) (NMPC/
ascorbic acid/[Ru(bpy)3Cl2]). b 150 W broad-band tungsten filament
lamp. c Determined by integration of the 1H NMR spectrum. d Isolated
yield on a preparative scale.
integration, Table 2). Control photolysis experiments
that lacked either Ru(bpy)3Cl2 or ascorbic acid or both
resulted in no detectable amount of released amine. To
confirm the identity of the products, photolysis of 11 was
Supporting Information Available. Experimental pro-
cedures, syntheses, 1H and 13C NMR spectral data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 23, 2011
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