Photochemical protection of amines with Cbz and Fmoc groups

Article abstract of DOI:10.1021/jo026581n

The photochemical conversion of amines into carbamates was achieved using N-Cbz-, N-Fmoc-, and N-Boc-5,7-dinitroindolines. This reaction allows the protection of amines in neutral medium. Primary and unhindered secondary amines were protected to yield their benzyloxycarbonyl- and 9-fluorenylmethoxycarbonyl derivatives efficiently, whereas bulky amines or anilines gave low yields or no product. On the other hand, the formation of N-Boc compounds, although possible, proceeded only with low yields.

Full text of DOI:10.1021/jo026581n

P h otoch em ica l P r otection of Am in es w ith
Cbz a n d F m oc Gr ou p s
C e´ line Helgen and Christian G. Bochet*
Department of Chemistry, University of Geneva,
0 quai Ernest Ansermet, CH-1211 Geneva 4, Switzerland
3
F IGURE 1. Commonly used carbamates.
christian.bochet@unifr.ch.
Received October 18, 2002
SCHEME 1. P h otoch em ica l Acyla tion of
Nu cleop h iles
Abstr a ct: The photochemical conversion of amines into
carbamates was achieved using N-Cbz-, N-Fmoc-, and
N-Boc-5,7-dinitroindolines. This reaction allows the protec-
tion of amines in neutral medium. Primary and unhindered
secondary amines were protected to yield their benzyloxy-
carbonyl- and 9-fluorenylmethoxycarbonyl derivatives ef-
ficiently, whereas bulky amines or anilines gave low yields
or no product. On the other hand, the formation of N-Boc
compounds, although possible, proceeded only with low
yields.
The three most common protecting groups for amines
1
are the benzyloxycarbonyl- (Z, Cbz, 1), the 9-fluorenyl-
2
methoxycarbonyl- (Fmoc, 2), and the tert-butoxycarbo-
later trigger the acylation by turning on the 350-nm light.
This external control of the timing of events represents
a great versatility for photoaffinity studies or in cascade
reactions.9
The irradiation with UV light converts the normally
inert species 4 into a highly reactive acyl-transfer inter-
mediate (of tentative structure 5), which is then trapped
by the nucleophile, releasing the neutral indoline deriva-
tive 6 (Scheme 1).10
3
nyl- (Boc, 3) derived carbamates. Various reagents have
been developed over the years that allow the introduction
of these groups under basic conditions. However, meth-
ods to protect amines in strictly neutral conditions are
4
5
still scarce, and we wish to disclose here a clean and
exceptionally mild method to convert them into these
useful carbamates. The work of Patchornik et al. has
shown that it is possible to photochemically acylate
amines to give amides under irradiation conditions at 360
P r ep a r a tion of th e Acyla tin g Agen ts. We antici-
pated that carbamates could be accessed by a similar
mechanism, but our initial experiments were unsuccess-
ful in both the preparation and photoacylation reaction.
A Lewis acid promoted acylation of 5,7-dinitroindoline 6
proved to be inappropriate for the formation of the
6
nm. This method was initially used by these authors as
a carboxyl protecting group and later to assemble two
peptidic units. We recently published an improved ver-
sion of this reaction that allows a clean, mild, and
practical preparation of amides.7,8 The advantage of such
an approach is, in addition to the perfectly neutral
conditions, that it is possible to premix the reagents and
7
carbamates 4a -c. Whereas the anionic route was inef-
7
fective for the preparation of the amides, it turned out
that the carbamate 4a was efficiently prepared by prior
deprotonation of 6 with sodium hydride (1.5 equiv, THF,
rt, 3 h), followed by the addition of benzyl chloroformate
(1.5 equiv, rt, 3 h) (Scheme 2). Similarly, the Fmoc-
derivative 4b was prepared using 9-fluorenylmethyl
chloroformate (1.2 equiv, 40 h) after deprotonation. On
the other hand, the Boc-derivative 4c was prepared by
*
Present address: Department of Chemistry, University of Fri-
bourg, Chemin du Mus e´ e 9, CH-1700 Fribourg, Switzerland.
(
1) Bergmann, M.; Zervas, L. Ber. Dtsch. Chem. Ges. 1932, 65, 1192-
1
5
201.
(
2) Carpino, L. A.; Han, G. Y. J . Am. Chem. Soc. 1970, 92, 5748-
749.
(3) (a) McKay, F. C.; Albertson, N. F. J . Am. Chem. Soc. 1957, 79,
4
1
9
686-4690. (b) Anderson, G. W.; McGregor, A. C. J . Am. Chem. Soc.
957, 79, 6180-6183. (c) Carpino, L. A. J . Am. Chem. Soc. 1957, 79,
8-101.
the reaction of 6 with Boc
2
O (1.2 equiv, THF) in the
1
1
presence of DMAP (0.1 equiv) at 60 °C for 3 h.
(4) (a) Kocienski, P. J . Protecting Groups; Georg Thieme Verlag:
Stuttgart, New York, 1994; pp 192-205. (b) Greene, T. W.; Wuts, P.
G. M. Protective Groups in Organic Synthesis, 2nd. ed.; J ohn Wiley:
New York, 1991; pp 315-348.
P h otoa cyla tion Rea ction s. The protection of amines
as N-Cbz derivatives proceeded smoothly upon irradia-
(
5) For an interesting example, see: Kita, Y.; Haruta, J .; Yasuda,
H.; Fukunaga, K.; Shirouchi, Y.; Tamura, Y. J . Org. Chem. 1982, 47,
(9) (a) For an example of external control in organic synthesis, see:
Bochet, C. G. Angew. Chem., Int. Ed. 2001, 41, 6341-6346. (b) Blanc,
A.; Bochet, C. G. J . Org. Chem. 2002, 67, 5567-5577.
(10) (a) Goissis, G.; Erickson, B. W.; Merrifield, R. B. Peptides:
Proceedings of the 5th American Peptide Symposium; Halsted Press:
New York, 1977; pp 559-561. (b) Papageorgiou, G.; Ogden, D. C.;
Barth, A.; Corrie, J . E. T. J . Am. Chem. Soc. 1999, 121, 6503-6504.
(11) Darnbrough, S.; Mervic, M.; Condon, S. M.; Burns, C. J . Synth.
Commun. 2001, 31, 3273-3280.
2
697-2700.
6) (a) Amit, B.; Patchornik, A. Tetrahedron Lett. 1973, 24, 2205-
208. (b) Amit, B.; Ben-Efraim, D. A.; Patchornik, A. J . Am. Chem.
(
2
Soc. 1976, 98, 843-844. (c) Pass, S.; Amit, B.; Patchornik, A. J . Am.
Chem. Soc. 1981, 103, 7674-7675.
(
7) Helgen, C.; Bochet, C. G. Synlett 2001, 1968-1970.
(8) For independent parallel work, see: Nicolaou, K. C.; Safina, B.
S.; Winssinger, N. Synlett 2001, 900-903.
1
0.1021/jo026581n CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/28/2003
J . Org. Chem. 2003, 68, 2483-2486
2483

SCHEME 2. P r ep a r a tion of P h otoa ctiva ble
Ca r ba m a tes
SCHEME 4. P r otection of a m in es w ith th e Boc
gr ou p
TABLE 2. P r otection of Am in es w ith th e Boc Gr ou p
1
R , R2
yielda
entry
amine
1
2
3
4
5
6
9a
9b
9c
9d
9e
9j
n-C12H25, H
c-Hex, H
PhCH(Me), H
n-C5H11, n-C5H11
-(CH2)5-
27
29
26
0
0
24
(CH3)2CHCH2CH(COOR), H
a
Isolated yields (chromatography).
SCHEME 3. P r otection of Am in es w ith th e Cbz
Gr ou p
SCHEME 5. P r otection of Am in es w ith th e F m oc
Gr ou p
TABLE 1. P r otection of Am in es w ith th e Cbz Gr ou p
R1, R2
yielda
TABLE 3. P r otection of Am in es w ith th e F m oc Gr ou p
entry
amine
R , R2
1
yielda
entry
amine
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9e
9f
9g
9h
9i
n-C12H25, H
c-Hex, H
PhCH(Me), H
n-C5H11, n-C5H11
-(CH2)5-
c-Hex, c-Hex
PhCH(OH)CH(Me), Me
4-MeO(C6H4), H
99
84
86
82
92
24
43
0
85
1
2
3
4
5
6
9a
9b
9d
9e
9f
9j
n-C12H25, H
76
65
76
72
19
65
c-Hex, H
n-C5H11, n-C5H11
-(CH2)5-
b
c-Hex, c-Hex
b
(CH3)2CHCH2CH(COOR), H
a
CH2dCHCH2, H
Isolated yields (chromatography).
b
1
1
1
0
1
2
9j
9k
9l
(CH3)2CHCH2CH(COOR), H
4-OH-C6H4-CH2CH(COOR), H
PhCH2CH(COOR), H
66
33
82
b
In this case, mixed results were obtained (Table 2).
Indeed, as a result of the lower stability of 4c, only
primary amines reacted, albeit in low yields (24-29%,
entries 1-3 and 6). Secondary amines were also unsuc-
cessful (entries 4 and 5). Again, no noticeable background
reaction was observed in the absence of light (18 h, 40
C).
Finally, we attempted to introduce the Fmoc group
Scheme 5). The typical reactivity pattern observed with
a
b
Isolated yields (trituration). Isolated yields (chromatogra-
t
phy). R ) allyl or Bu.
tion for 3 h in a Rayonet apparatus using RPR-3500
lamps. We used a 1:1 mixture of amine and acylating
agent 4a in 1,2-dichloroethane at room temperature
°
(
Scheme 3). Most of the aliphatic (primary and secondary)
(
unhindered amines we checked gave high yields of
carbamate and no purification other than trituration with
cyclohexane was necessary (Table 1). On the other hand,
very bulky amines or poorly nucleophilic arylamines gave
low yields or no reaction at all. In these cases, chroma-
tography was necessary to purify the carbamates. Esters
of amino acids gave satisfactory yields, except for the
unprotected tyrosine ester 9k (entries 10-12). No back-
ground reaction was observed in the absence of light (18
h, 40 °C).
the Cbz group was restored, albeit with slightly lower
yields (Table 3). However, the poor solubility of 4b
required a higher temperature (65 °C, 3 h). Under these
conditions, a slow background reaction was observed in
the absence of light (ca. 30% decomposition of 4b at 70
°
C for 22 h).
It is interesting to note that with all three indolines
4
a -c, the photochemical reaction released the deacylated
dinitroindoline 6, which could be recycled. In contrast to
the formation of amides, variable amounts of the corre-
7
The same reaction was also attempted to introduce the
Boc group, by using the dinitroindoline derivative 4c
Scheme 4), under slightly different conditions (1.5 equiv
of 4c, 9 h).
sponding 7-nitrosoindoline 8 were also detected (identi-
fied by isolation and high-resolution MS). The amount
of side-product seems proportional to the decrease in
carbamate yield. This suggests a second, unproductive
(
2
484 J . Org. Chem., Vol. 68, No. 6, 2003

reaction pathway. Nitroso-containing side-products have
50.5 (CH
697.7, 1609.0, 1548.1, 1534.6, 1461.8, 1438.1, 1385.4, 1344.1,
1302.3. UV (46 µM soln in MeCN) λmax (ꢀ) 202 (0.90), 224 (0.68),
49 (0.52). MS m/z (%) 251 (2, M ), 209 (100), 163 (11), 117 (13),
9 (10). HR-MS 251.0553 (C10 calcd 251.0542).
,7-Din itr oin d olin e 6. A mixture of 1-acetyl-5,7-dinitroin-
doline (1.07 g, 4.3 mmol), methanol, THF, and saturated K CO
was stirred at room temperature for 3 h. The precipitate was
then filtered, washed with water, and dried in vacuo. More
material was obtained by extracting the water layer with AcOEt.
This organic layer was then washed with brine, dried over
2 2 3 3
), 28.0 (CH ), 23.3 (CH ). IR (CHCl ) 3099.5, 3035.7,
1
already been detected in related reactions, but no definite
explanation is currently available.10b,12 We are currently
+•
3
8
examining the mechanism of both productive and un-
productive pathways.
9 3 5
H N O
5
In conclusion, we have shown that N-Cbz- and N-Fmoc-
derived carbamates could easily and smoothly be pre-
pared by photochemical acylation of amines. This should
be useful to protect sensitive amines, for example, in the
synthesis of peptides from unnatural amino acids. The
N-Boc amines, on the other hand, could only be prepared
in mediocre yields. It is interesting to note that while
photo-deprotection of functional groups has been known
for some time,13 this is the first example of photo-
protection of amines. A combined protection-deprotection
approach is under development and will be reported in
due course.
2
3
MgSO
4
, and evaporated. The combined brown solid (mp 250-
53 °C) yielded 883 mg (99%). 1H NMR (d
-DMSO) δ 9.05 (s,
H), 8.55 (m, 1H), 7.97 (m, 1H), 3.89 (t, J ) 8.5 Hz, 2H), 3.18 (t,
2
1
6
J ) 8.0 Hz, 2H). 13C NMR (d -DMSO) δ 151.7 (C), 137.5 (C),
6
135.6 (C), 125.3 (C), 122.6 (CH), 121.2 (CH), 47.8 (CH
CH ). IR (CHCl ) 3442.5, 3015.9, 1630.7, 1525.6, 1433.1, 1318.0.
UV (53 µM soln in MeCN) λmax (ꢀ) 193 (6.00), 211 (0.63), 264
2
), 26.6
(
2
3
+
•
(
8
0.58), 364 (0.80). MS m/z (%) 209 (100, M ), 163 (18), 117 (40),
9 (18), 63 (13). HR-MS 209.0444 (C calcd 209.0437).
N-Cbz-5,7-d in itr oin d olin e 4a . A mixture of 5,7-dinitroin-
8 7 3 4
H N O
Exp er im en ta l Section
doline (200 mg, 0.96 mmol) and NaH (∼60%, 57.4 mg, 1.43
mmol) in 5 mL of dry THF was stirred at room temperature
under Ar for 3 h. Benzyl chloroformate (200 µL, 1.43 mmol) was
then added dropwise, and the resulting mixture was stirred at
room temperature for 3 h. AcOEt was added, and the organic
Gen er a l Meth od s. H and 13C NMR spectra were recorded
1
on a 500 or 400 MHz spectrometer with solvent used as a
1
3
reference. For C NMR, the number of hydrogen was deter-
mined by a DEPT sequence. Absorption bands of IR spectra are
layer was washed with water and brine, dried over MgSO
evaporated. Purification by FC (TLC R 0.49, cyclohexane/AcOEt
:1) gave 237 mg (72%) of pure product as a brown solid (mp
32-135 °C). 1H NMR (CDCl
) δ 8.54 (m, 1H), 8.21 (m, 1H),
.39 (5H), 5.24 (s, 2H), 4.36 (t, J ) 8.6 Hz, 2H), 3.29 (t, J ) 8.6
4
, and
-1
in cm . Absorption bands of UV spectra are in nm. Mass spectra
were recorded with EI (70 eV). All melting points are uncor-
rected. Photochemical irradiations were made in a Rayonet-RPR-
f
1
1
7
3
1
00 photoreactor, in a quartz vessel, with 16 RPR-3500 lamps
(at 350 nm). Purification by flash column chromatography (FC)
13
Hz, 2H). C NMR (CDCl
3
) δ 152.4 (C), 142.9 (C), 140.4 (C), 138.2
C), 138.0 (C), 135.0 (C), 128.8 (C), 128.75 (CH), 128.7 (CH), 123.1
CH), 120.1 (CH), 69.0 (CH ), 50.5 (CH ), 27.8 (CH ). IR (CHCl
030.4, 1727.0, 1616.4, 1547.1, 1468.8, 1391.6, 1343.6, 1302.1.
was done on silica gel, with cyclohexane/AcOEt. Unless other-
wise indicated, all commercial reagents were used without
further purification.
(
(
3
2
2
2
3
)
1
-Acetylin d olin e. A solution of indoline (4.00 g, 33.6 mmol)
UV (52 µM soln in MeCN) λ
max
(ꢀ) 203 (1.30), 342 (0.58). MS
in acetic acid (56 mL) and acetyl chloride (14 mL) was stirred
at 90 °C for 3 h. Evaporation of the volatiles gave 5.42 g
m/z (%) 343 (7, M+•), 282 (64), 252 (14), 209 (5), 193 (56), 91
(100), 65 (70). HR-MS 343.0780 (C16H13N O calcd 343.0804).
3
6
(
quantitative) of the pure product as a pale pink solid (mp 103-
N-F m oc-5,7-d in itr oin d olin e 4b. A mixture of 5,7-dinitroin-
doline (1.20 g, 5.74 mmol) and NaH (∼60%, 344 mg, 8.60 mmol)
in 30 mL of dry THF was stirred at room temperature under Ar
for 3 h. 9-Fluorenylmethyl chloroformate (1.77 g, 6.84 mmol) was
then added dropwise, as a solution in 10 mL dry THF, and the
resulting mixture was stirred at room temperature for about 40
h. AcOEt and water were then added, and the precipitate was
filtered and washed with water and AcOEt. Drying gave 1.02 g
1
1
06 °C, lit. 102-104 °C). H NMR (CDCl
δ 8.23 (d, J ) 8.1 Hz, 1H), 7.21 (m, 2H), 7.03 (t, J ) 7.3 Hz, 1H),
.07 (t, J ) 8.5 Hz, 2H), 3.22 (t, J ) 8.5 Hz, 2H), 2.25 (s, 3H);
minor rotamer (16%) δ 8.23 (d, J ) 8.1 Hz, 1H), 7.21 (m, 2H),
.03 (t, J ) 7.3 Hz, 1H), 4.16 (t, J ) 8.3 Hz, 2H), 3.09 (t, J ) 8.1
3
) major rotamer (84%)
4
7
1
3
Hz, 2H), 2.46 (s, 3H). C NMR (CDCl
3
) major rotamer δ 168.7
(C), 142.8 (C), 131.1 (C), 127.4 (CH), 124.5 (CH), 123.5 (CH),
1
1
16.9 (CH), 48.7 (CH
68.3 (C), 141.7 (C), 133.8 (C), 127.2 (CH), 125.8 (CH), 123.1
), 26.8 (CH ), 24.6 (CH ). IR (CHCl
005.4, 1731.4, 1651.9, 1599.0, 1483.6, 1409.4. MS m/z (%) 161
2 2 3
), 27.9 (CH ), 24.2 (CH ); minor rotamer δ
(
°
7
7
41%) of the pure product as a yellow solid (decomp 270-275
1
C). H NMR (CDCl
3
) δ 8.57 (m, 1H), 8.23 (m, 1H), 7.77 (d, J )
(CH), 114.0 (CH), 47.9 (CH
2
2
3
3
)
.7 Hz, 2H), 7.57 (d, J ) 7.2 Hz, 2H), 7.44 (t, J ) 7.4 Hz, 2H),
3
.35 (t, J ) 7.0 Hz, 2H), 4.67 (d, J ) 6.2 Hz, 2H), 4.30 (t, J ) 6.2
13
+
•
(44, M ), 119 (91), 118 (100), 91 (17). HR-MS 161.0847 (C10
11
H -
Hz, 1H), 4.16 (t, J ) 8.4 Hz, 2H), 3.23 (t, J ) 8.5 Hz, 2H).
NMR (CDCl ) δ 152.6 (C), 143.2 (C), 143.1 (C), 141.4 (C), 140.4
3
C
NO calcd 161.0841).
1
-Acetyl-5,7-d in itr oin d olin e (4, R ) Me).14 1-Acetylindoline
(
1
(
1
C), 138.1 (C), 138.05 (C), 128.0 (CH), 127.3 (CH), 124.9 (CH),
23.1 (CH), 120.2 (CH), 120.1 (CH), 68.8 (CH ), 50.3 (CH ), 47.0
CH), 28.0 (CH ). IR (KBr) 3088.9, 2955.6, 2900.0, 1723.7, 1611.1,
550.0, 1522.2, 1394.4, 1336.1, 1293.9, 1192.6, 1039.0. UV (52
(
(
2.58 g, 16 mmol) was dissolved in a solution of sodium nitrate
4.08 g, 48 mmol) in trifluoroacetic acid (75 mL), and the mixture
2
2
2
was stirred at room temperature for 20 h. It was then poured
into ice-cold water. A yellow solid precipitated, which was
filtered, washed with water, and dried. The filtrate was extracted
with AcOEt; this organic layer was washed with saturated
NaHCO (until basic pH) and with brine, dried over MgSO , and
3 4
evaporated. Both solids were purified by recrystallization in
µM soln in MeCN) λmax (ꢀ) 208 (2.15), 265 (0.98), 289 (0.417),
+•
3
(
00 (0.49), 342 (0.47). MS m/z (%) 431 (<1, M ), 209 (8), 178
100), 165 (9), 89 (7). HR-MS 209.0434 (C
N-Boc-5,7-d in itr oin d olin e 4c. A mixture of 5,7-dinitroin-
doline (200 mg, 0.96 mmol), Boc O (250 mg, 1.15 mmol), and
8 7 3 4
H N O calcd 209.0437).
2
toluene/EtOH 1:1, to give 2.33 g (58%) of pure product as yellow
1
DMAP (11.7 mg, 0.10 mmol) in 10 mL of dry THF was stirred
at 60 °C for 3 h. The reaction mixture was evaporated and
extracted with AcOEt. This organic layer was washed with 10%
crystals (mp 214-219 °C, lit. 216-217 °C). H NMR (d
6
-DMSO)
δ 8.48 (m, 1H), 8.46 (m, 1H), 4.40 (t, J ) 8.3 Hz, 2H), 3.37 (t, J
1
3
)
8.2 Hz, 2H), 2.30 (s, 3H). C NMR (d
42.6 (C), 139.9 (C), 139.2 (C), 138.2 (C), 123.6 (CH), 119.2 (CH),
6
-DMSO) δ 169.3 (C),
HCl (twice) and brine, dried over Na
2 4
SO , and evaporated, to
1
give 280 mg (95%) of the pure product as a brown solid (mp 110-
1
1
15 °C). H NMR (CDCl
J ) 8.5 Hz, 2H), 3.28 (t, J ) 8.5 Hz, 2H), 1.51 (s, 9 H). C NMR
CDCl ) δ 151.2 (C), 142.4 (C), 140.9 (C), 138.3 (C), 137.6 (C),
23.2 (CH), 120.3 (CH), 84.4 (C), 50.7 (CH ), 28.0 (CH ), 27.7
CH ). IR (CHCl ) 3033.3, 2983.1, 1718.5, 1616.7, 1545.7, 1371.8,
1335.7, 1311.5, 1152.9. UV (50 µM soln in MeCN) λmax (ꢀ) 200
3
) δ 8.58 (m, 1H), 8.20 (m, 1H), 4.31 (t,
(
12) Loudwig, S.; Goeldner, M. Tetrahedron Lett. 2001, 42, 7957-
13
7
959.
(
1
(
3
(
13) (a) Pillai, V. N. R. Synthesis 1980, 1-26. (b) Pillai, V. N. R.
2
3
Org. Photochem. 1987, 9, 225-321. (c) Bochet, C. G. J . Chem. Soc.,
2
3
Perkin Trans. 1 2002, 125-142.
(14) Mortensen, M. B.; Kamounah, F. S.; Christensen, J . B. Org.
+
•
Prep. Proc. Int. 1996, 28, 123-125.
(0.92), 222 (0.69), 345 (0.60). MS m/z (%) 309 (<1, M ), 236 (2),
J . Org. Chem, Vol. 68, No. 6, 2003 2485

2
09 (31), 163 (3), 117 (6), 57 (100). HR-MS 236.0303, 209.0434
, C calcd 236.0308, 209.0437).
Typ ica l P r oced u r e for P h otop r otection w ith Cbz. A
solution of N-Cbz-5,7-dinitroindoline 4a (0.07 mmol) and amine
0.07 mmol) in 7.5 mL of 1,2-dichloroethane was flushed with
) 6.8 Hz, 3H). 13C NMR (CDCl
31.9 (CH ), 30.1 (CH ), 29.63 (CH
29.33 (CH ), 29.29 (CH ), 28.4 (CH
(CH
1245.0, 1167.2. MS m/z (%) 230 (10), 185 (4), 184 (4), 74 (6), 59
(18), 57 (100).
Typ ica l P r oced u r e for P h otop r otection w ith F m oc. A
solution of N-Fmoc-5,7-dinitroindoline 4b (0.10 mmol) and amine
(0.07 mmol) in 7.5 mL of 1,2-dichloroethane was flushed with
argon for 5 min. It was then irradiated at 350 nm for 3 h, under
argon, with stirring but no cooling (ca. 65 °C). The volatiles were
then evaporated, and the solid was triturated with warm
cyclohexane; the evaporation of cyclohexane gave the impure
carbamate, which was purified by FC (on silica gel, cyclohexane/
AcOEt). The remaining brown solid was a mixture of 5,7-
dinitroindoline and 5-nitro-7-nitrosoindoline.
3
) δ 156.0 (C), 79.0 (C), 40.7 (CH
2
2
),
),
(C
9
H
6
N
3
O
5
8
H
7
N
3
O
4
2
2
2
), 29.61 (CH
2
), 29.57 (CH
2
2
3
), 26.8 (CH
2
2
), 22.7 (CH ), 14.1
3
). IR (neat) 3375.6, 2918.7, 2849.2, 1686.3, 1513.5, 1466.6,
(
argon for 5 min. It was then irradiated at 350 nm for 3 h, under
argon, with stirring and cooling by water. The volatiles were
then evaporated, and the solid was triturated with warm
cyclohexane; the evaporation of cyclohexane gave the carbamate,
and the remaining brown solid was mostly 5,7-dinitroindoline.
Some 5-nitro-7-nitrosoindoline was also formed.
N-Cbz-d od ecyla m in e 1a . Brown solid (mp 46-48 °C). 1
NMR (CDCl ) δ 7.39-7.30 (5H), 5.10 (s, 2H), 4.74 (br s, 1H),
.19 (q, J ) 6.6 Hz, 2H), 1.50 (2H), 1.26 (18 H), 0.89 (t, J ) 6.8
H
3
3
1
3
3
Hz, 3H). C NMR (CDCl ) δ 156.3 (C), 136.6 (C), 128.5 (CH),
1
2
2
28.09 (CH), 128.05 (CH), 66.5 (CH
2
), 41.1 (CH
2
), 31.9 (CH
), 29.52 (CH
2
),
),
9.9 (CH
9.3 (CH
2
), 29.61 (CH
), 29.2 (CH
2
), 29.60 (CH
2
), 29.55 (CH
2
2
N-F m oc-d od ecyla m in e 2a . Pale brown solid (mp 100-103
2
2
), 26.7 (CH ), 22.7 (CH
2
2
), 14.1 (CH
3
). IR
f 3
°C). TLC R ) δ
0.59 (cyclohexane/AcOEt 2:1). 1H NMR (CDCl
(
1
(
neat) 3349.9, 2921.8, 2848.0, 1688.2, 1527.4, 1462.8, 1247.0,
019.7, 726.8. MS m/z (%) 319 (1, M+•), 184 (3), 108 (100), 99
16), 91 (84), 55 (13). HR-MS 319.2500 (C20 calcd
7.78 (d, J ) 7.6 Hz, 2H), 7.61 (d, J ) 7.5 Hz, 2H), 7.41 (t, J )
7.2 Hz, 2H), 7.32 (td, J ) 7.5, 1.3 Hz, 2H), 4.73 (br s, 1H), 4.42
(d, J ) 6.8 Hz, 2H), 4.23 (t, J ) 6.7 Hz, 1H), 3.20 (q, J ) 6.1 Hz,
H33NO
2
1
3
3
19.2511).
Typ ica l P r oced u r e for P h otop r otection w ith Boc. A
solution of N-Boc-5,7-dinitroindoline 4c (0.10 mmol) and amine
0.07 mmol) in 7.5 mL of 1,2-dichloroethane was flushed with
2H), 1.51 (2H), 1.28 (18H), 0.90 (t, J ) 6.8 Hz, 3H). C NMR
(CDCl ) δ 156.4 (C), 144.1 (C), 141.4 (C), 127.6 (CH), 127.0 (CH),
125.0 (CH), 119.9 (CH), 66.5 (CH ), 47.4 (CH), 41.1 (CH ), 31.9
), 29.61 (CH ), 29.58 (CH ), 29.55
), 29.29 (CH ), 26.8 (CH ), 22.7 (CH ), 14.1
). IR (neat) 3333.1, 2920.0, 2851.8, 1688.2, 1537.1, 1451.9,
3
2
2
(
(CH
(CH
(CH
2
2
3
), 30.0 (CH
), 29.33 (CH
2
), 29.64 (CH
2
2
2
2
argon for 5 min. It was then irradiated at 350 nm for 9 h, under
argon, with stirring and cooling by water. The volatiles were
then evaporated, and the solid was triturated with warm
cyclohexane; the evaporation of cyclohexane gave the impure
carbamate, which was purified by FC (on silica gel, cyclohexane/
AcOEt). The remaining brown solid was a mixture of 5,7-
dinitroindoline and 5-nitro-7-nitrosoindoline 8, which was pu-
2
2
2
1265.1, 1154.7, 1028.2. MS m/z (%) 178 (100), 165 (7), 99 (2), 57
(3). HR-MS 407.2869 (C27 calcd 407.2824).
H
37NO
2
Ack n ow led gm en t. This work was supported by the
Swiss National Science Foundation grant 20-65047.01
and by the Fonds Fr e´ d e´ ric Firmenich et Philippe Chuit.
The generous support to C.H. by the J anggen-P o¨ hn
Stiftung is gratefully acknowledged.
rified by FC (TLC R
solid (mp 170-174 °C). H NMR (d
br s, 1H), 7.91 (s, 1H), 3.82 (t, J ) 7.7 Hz, 2H), 3.05 (t, J ) 7.9
f
0.14, cyclohexane/AcOEt 2:1) to get a brown
1
6
-DMSO) δ 10.50 (s, 1H), 9.33
(
1
3
Hz, 2H). C NMR (d
6
-DMSO) δ 151.9 (C), 138.8 (C), 136.3 (C),
), 25.4 (CH ). IR (KBr) 3291.7, 2927.4,
1
2
1
22.4 (CH), 47.7 (CH
2
2
Su p p or t in g In for m a t ion Ava ila b le: 1H NMR and 13C
851.6, 1621.0, 1587.8, 1543.1, 1499.0, 1421.0, 1328.0, 1296.2,
NMR spectra for all compounds and characterization data for
all compounds not described in the Experimental Section. This
material is available free of charge via the Internet at
http://pubs.acs.org.
154.5, 1067.0, 731.0. MS m/z (%) 193 (100, M+•), 163 (65), 117
(72), 89 (27). HR-MS 193.0479 (C
8
H
7
N
3
O
3
calcd 193.0487).
N-Boc-d od ecyla m in e 3a . Brown solid (mp 38-40 °C). TLC
1
R
1
f 3
0.61 (cyclohexane/AcOEt 2:1). H NMR (CDCl ) δ 4.49 (br s,
H), 3.11 (q, J ) 6.3 Hz, 2H), 1.45 (11H), 1.27 (18H), 0.89 (t, J
J O026581N
2
486 J . Org. Chem., Vol. 68, No. 6, 2003