A novel naphthylmethyleneimino-type photocleavable protecting group for primary amines

Article abstract of DOI:10.1055/s-2007-980370

A novel naphthylmethyleneimino-type protecting group for aliphatic and aromatic primary amines including α-amino acids was devised and its introduction was accomplished in good to excellent yields. This type of protecting group was found to be cleanly removed photochemically to regenerate the primary amines in good to high yields, regardless of steric and electronic properties. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-980370

1436
LETTER
A Novel Naphthylmethyleneimino-Type Photocleavable Protecting Group for
Primary Amines
Photocleavable
eProtecting
t
G
roup
s
for Primar
u
y Amines taro Igarashi, Masaru Shimokawa, Miyuki Iwasaki, Kensaku Nagata, Masato Fujii, Tadamitsu Sakurai*
Department of Material and Life Chemistry, Faculty of Engineering, Kanagawa University, Kanagawa-ku, Yokohama 221-8686, Japan
Fax +81(45)4917915; E-mail: sakurt01@kanagawa-u.ac.jp
Received 18 December 2006
about 310 nm (molar absorption coefficient, emax = 1.2–
Abstract: A novel naphthylmethyleneimino-type protecting group
1.4·104 dm3 mol–1 cm–1 in acetonitrile) and becomes a
for aliphatic and aromatic primary amines including a-amino acids
powerful triplet-energy acceptor3 prompted us to design
was devised and its introduction was accomplished in good to ex-
this type of chromophore-introduced carbamate deriva-
cellent yields. This type of protecting group was found to be cleanly
removed photochemically to regenerate the primary amines in good tives 1a–r (Figure 1) and to develop a novel photolabile
to high yields, regardless of steric and electronic properties.
protecting group which is applicable to aliphatic and aro-
matic primary amines including a-amino acids.
Key words: amines, protecting groups, carbamates, photochemis-
try, deprotection
O
NHR
O
Much attention has recently been directed to the photo-
removable protecting group as one of the promising
photofunctional chromophores, because this group en-
ables the construction of complicated compounds and
natural products which are difficult to prepare by conven-
tional methods.1 Thus far, many protecting groups that
can be removed photochemically under neutral conditions
have been developed and applied to the synthesis of many
organic compounds.1,2
N
H
1a–r
R = Bn (1a)
CH2C6H4(4-OMe) (1b)
C6H4(4-COPh) (1j)
C6H4(4-SMe) (1k)
CH2C6H4(4-Me) (1c)
CH2(1-naphthyl) (1d)
CH2(CH2)3Ph (1e)
Ph (1f)
C6H4(2-t-Bu) (1l)
CH2C(=O)OBn (1m)
In the course of our systematic study on the nitrile-form-
ing radical elimination reaction of 1-naphthaldehyde O-
aroyloximes activated by triplet benzophenone, it was
found that simultaneous N–O and C(=O)–Ar bond cleav-
ages proceed in the triplet excited state to give the
corresponding benzene derivatives and 1-cyano-
naphthalene in high quantum yields.3 This finding led us
to predict that replacement of the aroyl substituent by the
N-aryl carbamoyl results in an efficient formation of aryl
amines in addition to 1-cyanonaphthalene and, hence, the
1-naphthylmethyleneimino group in a given carbamate
functions as a photoremovable protecting group for pri-
mary amines. A survey of the recently published literature
shows that there are many photocleavable protecting
groups for amines,4 such as nitrobenzyl-4b,f,l,m,p, di-
methoxybenzoin-4g,h,j and xanthenylmethyl-type4n func-
tional groups. These benzyl-type protecting groups have
some limitations, including the weak absorption in the
ultraviolet region, the formation of complicated byprod-
ucts and the low ability to undergo a sensitized photolysis,
though a coumarin-4-ylmethyl-type protecting group with
intense UV absorption has recently been developed.4o,5
Thus, the fact that the 1-naphthylmethyleneimino chro-
mophore displays a rather intense UV absorption band at
(S)-CH(Me)C(=O)OBn (1n)
(S)-CH(i-Pr)C(=O)OMe (1o)
(S)-CH(Bn)C(=O)OBn (1p)
(S)-CH[CH2C6H4(4-OBn)]C(=O)OMe (1q)
(S)-CH(CH2CH2SMe)C(=O)OMe (1r)
C6H4(4-OMe) (1g)
C6H4(4-Me) (1h)
C6H4(4-COMe) (1i)
Figure 1
In order to introduce the 1-naphthylmethyleneimino pro-
tecting group into a given primary amine, it was allowed
to react with 4-nitrophenyl chloroformate in dichlo-
romethane containing pyridine (Scheme 1). The 4-nitro-
phenylcarbamate derivative, obtained quantitatively, was
purified either by reprecipitation or by using column chro-
matography over silica gel. Nucleophilic substitution
reaction at the carbonyl carbon between N-substituted 4-
nitrophenylcarbamate and 1-naphthaldehyde oxime acti-
vated by triethylamine in dichloromethane accomplished
the introduction of the photolabile protecting group into
the amine, as shown in Scheme 1. Short column chroma-
tography over silica gel or reprecipitation afforded analyt-
ical-grade carbamate derivative 1 in a yield ranging from
73% to 95%. The structure of the protected primary amine
was elucidated by melting point, elemental analysis, as
well as IR and NMR spectroscopy.6 The 1H NMR spectral
behavior of 1 was consistent with the existence of a single
geometrical isomer and, hence, the previous configura-
tional analysis led us to assign this isomer to anti-1.3
SYNLETT 2007, No. 9, pp 1436–1440
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1.
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6.
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Advanced online publication: 23.05.2007
DOI: 10.1055/s-2007-980370; Art ID: U15306ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Photocleavable Protecting Group for Primary Amines
1437
N
OH
O
O
Cl
O
O2N
NHR
RNH2
O2N
O
1a–r
pyridine, CH2Cl2
Et3N, CH2Cl2
Scheme 1
After an argon-saturated acetonitrile solution of 1h As already described,3 the 1-naphthylmethyleneimino
(3.2·10–3 mol dm–3, 50 mL) was irradiated with Pyrex fil- group is one of the excellent triplet energy acceptors for
tered light (l > 280 nm) from a 450 watt high-pressure benzophenone. If the presence of benzophenone could in-
mercury lamp for two hours at room temperature, a five- duce highly efficient photodeprotection of 1, it is possible
fold molar excess of trifluoroacetic acid was added to pre- to expand the scope of our photoremovable protecting
vent loss of volatile amine upon concentration, and the group. For this end 1h was chosen as the typical starting
resulting solution was concentrated to dryness in vacuo.7 carbamate derivative and its argon-saturated acetonitrile
Column chromatography over silica gel allowed us to iso- solution (3.2·10–3 mol dm–3) containing benzophenone
late 4-methylanilinium trifluoroacetate and 1-cyanonaph- (9.6·10–2 mol dm–3) was irradiated with light (of wave-
thalene in 78% and 82% yields, respectively. A 1H NMR lengths longer than 340 nm) from a 450 watt high-pres-
spectral analysis of the vacuum-dried reaction mixture in sure mercury lamp for two hours at room temperature.
DMSO-d6 containing acetanilide (3.2·10–3 mol dm–3) as Without benzophenone under this irradiation conditions,
an internal standard revealed that there exists 1-naphth- the photofragmentation proceeded to only a slight extent.
aldehyde (7% yield) as well as small amounts of uniden- The irradiation of 1h was made with Pyrex-filtered light
tified products, in addition to 4-methylanilinium under the same conditions in order to compare conversion
trifluoroacetate (92%) and 1-cyanonaphthalene (93%, and product distribution for the direct and triplet-sensi-
Table 1). Gaseous product was identified as carbon diox- tized photolyses. As illustrated in Scheme 3, both the di-
ide by comparing its GLC behavior with that of an authen- rect and triplet-sensitized photolyses produced 4-
tic sample. Because the starting carbamate derivative 1h methylanilinium trifluoroacetate and 1-cyanonaphthalene
was stable in the presence of trifluoroacetic acid or trieth- in nearly the same composition ratio, though the conver-
ylamine,8 we examined the dependence of these product sion of 1h in the latter photolysis (61%) was lower than
yields on irradiation time and found the photoreaction to that (100%) in the former. This finding strongly suggests
be complete within two hours. On the other hand, the that the former photolysis takes place preferentially from
three-hour irradiation of an acetonitrile solution of 1a the triplet excited state. Taking the negligible formation of
under the same conditions gave benzaldehyde (13% yield) N-(4-tolyl)carbamic acid into account, we propose that the
and 1-naphthaldehyde (8%), along with benzylammoni- starting carbamate derivative 1 undergoes simultaneous
um trifluoroacetate (87%) and 1-cyanonaphthalene (92%, N–O and C(=O)–NH bond cleavages in its triplet excited
1H NMR yield, Table 1). This finding provides evidence state to form a caged triplet radical-pair intermediate I
in support of the mechanism depicted in Scheme 2 where shown in Scheme 4. As already discussed in a previous
hydrogen abstraction from the benzylaminyl radical by paper,3 rapid intersystem crossing to the corresponding
the naphthylmethyleneiminyl radical takes place in com- singlet radical pair II followed by efficient hydrogen ab-
petition with the predicted nitrile-forming radical elimina- straction of the caged radicals may eventually yield depro-
tion reaction that affords the major products.
tected primary amine and 1-cyanonaphthalene as major
products, as well as 1-naphthaldehyde and aminyl radical-
derived byproduct(s) as minor ones.
CO2
O
NHC6H4(4-Me)
hν
N
ArCH=N• + RNH• + CO2
1h
ArCN + RNH2 + ArCHO + unidentified product(s)
O
H
Ar
O
NHR
N
1i (Ar = 1-naphthyl)
93%
92%
7%
O
H
Ar
hν (λ >280 nm)
CO2
ArCHO
7%
ArCN
93%
MeC6H4(4-NH2)
92%
Ar = 1-naphthyl
hν
ArCH=N• + PhCH2NH• + CO2
2 h (conversion, 100%)
1a
ArCN + PhCH2NH2 + ArCH=NH + PhCH=NH
92% 87%
ArCH=NH + PhCH=NH
hν (λ >340 nm), PhCOPh
MeC6H4(4-NH2)
58%
O
ArCN
61%
ArCH
ArCHO + PhCHO + (NH3)
8% 13%
H2O
<1%
2 h (conversion, 61%)
Scheme 3
Scheme 2
Synlett 2007, No. 9, 1436–1440 © Thieme Stuttgart · New York

1438
T. Igarashi et al.
LETTER
Table 1 Protection Yields and Substituent Effects on the Conversion of 1a–r and the Yields of Primary Amines (RNH2), 1-Cyanonaphthalene
(ArCN), 1-Naphthaldehyde (ArCHO) and 4-Substituted Benzaldehydes (Ar¢CHO)a
Compound
Protection yield (%) Time (h)
Conversion (%)
Yield (%)b
c
RNH2
ArCN
92
ArCHO
Ar¢CHO
1a
1b
1c
1d
1e
1f
78
81
82
75
83
78
81
80
95
88
83
81
82
81
73
93
82
87
3
4
3
2
5
2
2
2
3
1
3
5
3
3
4
2
2
3
100
100
98
87
74
64
51
80
83
96
92
82
81
85
85
81
86
92
88
91
82
8
29
12
62
4
13
26
34
–
71
86
100
100
100
100
100
100
100
100
100
99
87
96
–
100
95
0
–
1g
1h
1i
5
–
93
7
–
95
5
–
1jd
1k
1l
95
5
–
97
3
–
94
6
–
1m
1n
1oe
1p
1q
1r
86
13
25
6
–
100
100
100
99
75
–
94
–
79
21
6
–
93
–
100
89
11
–
a Obtained upon the irradiation of argon-saturated MeCN solutions of 1 for 1–5 h at r.t.
b 1H NMR yield.
c Estimated as the corresponding trifluoroacetate salt.
d [1j] = 6.4·10–4 mol dm–3.
e Specific rotations of (S)-valine methyl ester measured as its trifluoroacetate salt before the protection of this methyl ester and after the photo-
deprotection of 1o were +52.7° and +55.0° (c 0.10, MeOH) at 25 °C, respectively.
In Table 1 are summarized the protection yields, irradia- increasing hydrogen-donating ability of the aminyl radi-
tion times, conversions of the starting carbamates 1a–r cal for the naphthylmethyleneiminyl radical. This sugges-
and yields for the regenerated primary amines, 1-cyano- tion implies that the relative rate for hydrogen abstraction
naphthalene, 1-naphthaldehyde and 4-substituted benz- of the iminyl and aminyl radicals within the singlet radi-
aldehydes. Various types of primary amines, including cal-pair intermediate II is one of the major factors deter-
a-amino acids, could be protected by the photoremovable mining the deprotection yield for a given primary amine.
1-naphthylmethyleneimino group in good to excellent In addition, the observation of a relatively large difference
yields according to simple procedures.6 Optimum irradia- in the 1H NMR yields of the amine and 1-cyanonaphtha-
tion time for the complete deprotection of 1 was in the lene, particularly, for 1c and 1d makes it very likely that
range of 2–5 hours and longer irradiation resulted in a there is some contribution from the ‘out-of-cage’ reaction
secondary photoreaction to only a negligible extent. As to the product yields, as depicted in Scheme 4.
Table 1 clearly shows, the naphthylmethyleneimino
In conclusion, the 1-naphthylmethyleneimino protecting
protective group was readily removed photochemically to
group could be introduced into various types of primary
regenerate the primary amines in good to high yields, re-
amines in good to excellent yields and also both direct and
gardless of steric and electronic properties of substituents
triplet-sensitized photolyses of the protected amines
in these amine molecules. Closer inspection of these
proceeded efficiently and chemoselectively to regenerate
substituent effects strongly suggested that the yield for the
the primary amines. In addition to these observations, the
regenerated amine has a clear tendency to decrease with
Synlett 2007, No. 9, 1436–1440 © Thieme Stuttgart · New York

LETTER
Photocleavable Protecting Group for Primary Amines
1439
J.; Rakotoarisoa, H. Tetrahedron Lett. 2000, 41, 2097.
(l) Bochet, C. G. Tetrahedron Lett. 2000, 41, 6341.
hν
1
11*
31*
(m) Stutz, A.; Hobartner, C.; Pitsch, S. Helv. Chim. Acta
2000, 83, 2477. (n) Du, H.; Boyd, M. K. Tetrahedron Lett.
2001, 42, 6645. (o) Schoenleber, R. O.; Giese, B. Synlett
2003, 501. (p) Bhushan, K. R.; DeLisi, C.; Laursen, R. A.
Tetrahedron Lett. 2003, 44, 8585.
3
31*
ArCH=N•
ArCH=N•
ArCN
CO2
•HNR
•HNR
cage
cage
I
1
I
CO2
II
(5) (a) Montgomery, H. J.; Perdicakis, B.; Fishlock, D.; Lajoie,
G. A.; Jervis, E.; Guillemette, J. G. Bioorg. Med. Chem.
2002, 10, 1919. (b) Perdicakis, B.; Montgomery, H. J.;
Abbott, G. L.; Fishlock, D.; Lajoie, G. A.; Guillemette, J. G.;
Jervis, E. Bioorg. Med. Chem. 2005, 13, 47.
major path
+
II
II
RNH2
+
CO2
minor path
ArCHO (via ArCH=NH)
+
(6) Typical Experimental Procedures for the Synthesis of
Compounds 1, and Physical Data of Selected Compounds
O-(4-Nitrophenyl)-N-(4-tolyl)carbamate and O-(1-
naphthylmethyleneimino)-N-(4-tolyl)carbamate (1h),
chosen as typical carbamate derivatives, were prepared
according to the following procedures.
RNH• –derived product(s)
CO2
+
I
CO2
+
•HNR
ArCH=N•
+
II
O-(4-Nitrophenyl)-N-(4-tolyl)carbamate: 4-Toluidine (1.1
g, 10 mmol) and pyridine (0.80 g, 10 mmol) were dissolved
in 10 mL CH2Cl2 at r.t.. 4-Nitrophenyl chloroformate (2.1 g,
10 mmol) was dissolved in 5 mL CH2Cl2 and added
dropwise to the 4-toluidine solution with stirring at r.t. After
30 min, the reaction mixture was concentrated to dryness in
vacuo and the remaining crystalline solid was reprecipitated
with CHCl3–hexane to give quantitatively O-(4-
+
ArCN
RNH2
+
•HNR
+
ArCH=N•
ArCHO
RNH• –derived product(s)
Scheme 4
nitrophenyl)-N-(4-tolyl)carbamate as a precursor of 1h; mp
137.0–138.0 °C. IR (KBr): nmax = 3337, 1709, 1537, 1346
cm–1. 1H NMR (500 MHz, DMSO-d6): d = 2.26 (3 H, s), 7.15
(2 H, d, J = 8.3 Hz), 7.40 (2 H, d, J = 8.3 Hz), 7.53 (2 H, d,
findings [that bulky (1l) and photoreactive (1i and 1j)
substituents exert only minor effects on the photode-
protection efficiency, and epimerization occurs during the
photolysis to only a very little extent (1o), if at all] render
the naphthylmethyleneimino chromophore a promising
photoremovable protecting group for primary amines.
J = 9.2 Hz), 8.30 (2 H, d, J = 9.2 Hz), 10.35 (1 H, s). 13
C
NMR (125 MHz, DMSO-d6): d = 20.4, 118.7 (2 C), 122.9 (2
C), 125.2 (2 C), 129.3 (2 C), 132.3, 135.5, 144.5, 150.5,
155.6. Anal. Calcd for C14H12N2O4: C, 61.76; H, 4.44; N,
10.29. Found: C, 61.91; H, 4.49; N, 10.24.
Acknowledgment
Compound 1h: 1-Naphthaldehyde oxime (0.86 g, 5.0 mmol)
and Et3N (0.50 g, 5.0 mmol) were dissolved in 20 mL
CH2Cl2 at r.t. To the 1-naphthaldehyde oxime solution was
added slowly O-(4-nitrophenyl)-N-(4-tolyl)carbamate (1.4
g, 5.0 mmol) dissolved in 5 mL CH2Cl2 and the resulting
reaction mixture was allowed to stand for 60 min at r.t. After
50 mL CHCl3 was added, the solution was washed with 1 M
NaHCO3 solution (2 × 100 mL), H2O (2 × 100 mL) and then
sat. NaCl solution (2 × 100 mL). The organic layer was
separated, dried over MgSO4, filtered and the solvent was
removed in vacuo. The residual solid obtained was
This research was partially supported by a ‘Scientific Frontier
Research Project’ from the Ministry of Education, Sports, Culture,
Science and Technology, Japan.
References and Notes
(1) (a) Binkley, R. W.; Flechtner, T. W. In Synthetic Organic
Photochemistry; Horspool, W. M., Ed.; Plenum: New York,
1984, 375. (b) Organic Photochemistry, Vol. 9; Pillai, V. N.
R.; Padwa, A., Eds.; Marcel Dekker: New York, 1987, 225.
(2) Bochet, C. G. J. Chem. Soc., Perkin Trans. 1 2002, 125.
(3) Yamada, K.; Sato, M.; Tanaka, K.; Wakabayashi, A.;
Igarashi, T.; Sakurai, T. J. Photochem. Photobiol., A 2006,
183, 205.
(4) (a) Abad, A.; Mellier, D.; Pete, J. P.; Portella, C.
Tetrahedron Lett. 1971, 4555. (b) Amit, B.; Zehavi, U.;
Patchornik, A. J. Org. Chem. 1974, 39, 192. (c) Hanessian,
S.; Masse, R. Carbohydr. Res. 1977, 54, 142. (d) Pincock,
J. A.; Jurgens, A. Tetrahedron Lett. 1979, 1029. (e) Yuan,
W.; Fearon, K.; Gelb, M. H. J. Org. Chem. 1989, 54, 906.
(f) Sundberg, S. A.; Barrett, R. W.; Pirrung, M.; Lu, A. L.;
Kiangsoontra, B.; Holmes, C. P. J. Am. Chem. Soc. 1995,
117, 12050. (g) Cameron, J. F.; Willson, C. G.; Frechet, J.
M. J. J. Chem. Soc., Chem. Commun. 1995, 923.
reprecipitated with CHCl3–hexane to afford analytical grade
1h in a 80% yield; mp 135.0–136.0 °C. IR (KBr):
n
max = 3292, 1726, 1603 cm–1. 1H NMR (500 MHz, DMSO-
d6): d = 2.27 (3 H, s), 7.15 (2 H, d, J = 8.2 Hz), 7.45 (2 H, d,
J = 8.2 Hz), 7.63–7.67 (2 H, m), 7.70 (1 H, dd, J = 6.9, 7.9
Hz), 8.04 (1 H, d, J = 6.9 Hz), 8.06 (1 H, d, J = 8.6 Hz), 8.14
(1 H, d, J = 7.9 Hz), 8.81 (1 H, d, J = 8.6 Hz), 9.20 (1 H, s),
9.89 (1 H, s). 13C NMR (125 MHz, DMSO-d6): d = 20.4,
119.2 (2 C), 125.0, 125.5, 126.4, 126.6, 127.8, 128.8, 129.3
(2 C), 130.0, 130.1, 132.0, 132.1, 133.4, 135.8, 151.9, 155.2.
Anal. Calcd for C19H16N2O2: C, 74.98; H, 5.30; N, 9.20.
Found: C, 74.96; H, 5.42; N, 9.32.
(7) Typical Experimental Procedure for the Photo-
deprotection of Compounds 1
Analytical grade 1h (49 mg, 0.16 mmol) was dissolved in 50
mL MeCN at r.t. and the resulting solution was transferred
into a Pyrex glass vessel. External irradiation was made at
r.t. (25–30 °C) under an Ar atmosphere with Pyrex filtered
light (l > 280 nm) from a 450 W high-pressure Hg lamp
mounted in a home-made lamp house. After the 2 h
irradiation, TFA (91 mg, 0.80 mmol) was added to the
(h) Pirrung, M. C.; Huang, C.-Y. Tetrahedron Lett. 1995, 36,
5883. (i) Cameron, J. F.; Willson, C. G.; Frechet, J. M. J. J.
Chem. Soc., Perkin Trans. 1 1997, 2429. (j) Papageorgiou,
G.; Corrie, J. E. T. Tetrahedron 1997, 53, 3917. (k) Cossy,
Synlett 2007, No. 9, 1436–1440 © Thieme Stuttgart · New York

1440
T. Igarashi et al.
LETTER
irradiated solution and the resulting mixture was
(8) Control Experiments
concentrated to dryness in vacuo. The residue obtained was
dissolved in EtOAc and then subjected to column
chromatography over silica gel (230 mesh) with an EtOAc
eluent, which enabled the isolation of 4-methylanilinium
trifluoroacetate (78%) and 1-cyanonaphthalene (82%).
Analytical-grade 1h (49 mg, 0.16 mmol) and TFA (91 mg,
0.80 mmol) were dissolved in 50 mL MeCN and the
resulting solution was allowed to stand for 5 h at r.t. After the
solution was concentrated to dryness in vacuo, the remaining
crystalline solid was dissolved in 1 mL DMSO-d6 and
subjected to 1H NMR analysis. This analysis showed the
negligible decomposition of 1h. The same result was
obtained also in the presence of a fivefold molar excess of
Et3N (81 mg, 0.80 mmol).
Synlett 2007, No. 9, 1436–1440 © Thieme Stuttgart · New York