Base-labile tert-butoxycarbonyl (Boc) group on phenols

Article abstract of DOI:10.1016/j.tetlet.2003.11.008

Phenols are deprotected with weak bases from their tert-butoxycarbonyl (Boc) derivatives. Boc deprotection with bases can avoid side reactions during the deprotection with acids. We note the lability of the Boc to bases and are able to utilize it as a new cleavage condition for synthetic studies.

Full text of DOI:10.1016/j.tetlet.2003.11.008

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 495–499
Base-labile tert-butoxycarbonyl (Boc) group on phenolsq
Kozo Nakamura,a,*,ꢀ Takero Nakajima,a Hiroshi Kayahara,a Eisaku Nomurab and
Hisaji Taniguchib
aGraduate School of Agriculture, Shinshu University, 8304 Minamiminowa, Kamiina, Nagano 399-4598, Japan
bIndustrial Technology Center of Wakayama Prefecture, 60 Ogura, Wakayama 649-6261, Japan
Received 12 August 2003; revised 4 November 2003; accepted 4 November 2003
Abstract—Phenols are deprotected with weak bases from their tert-butoxycarbonyl (Boc) derivatives. Boc deprotection with bases
can avoid side reactions during the deprotection with acids. We note the lability of the Boc to bases and are able to utilize it as a new
cleavage condition for synthetic studies.
Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
A variety of natural polyphenols have become of inter-
est to many scientists and synthetic research has been
vigorously carried out in recent years.1 The phenolic
hydroxyl group(s) on them often play an important role
in their biological activities.2 Protection of the hydroxyl
group(s) is necessary in order to maintain these activities
and avoid expected side reactions. Variety kinds of
protecting groups for phenols have been developed and
utilized in synthetic studies.3 Recent research has
reported the usefulness of the tert-butoxycarbonyl (Boc)
group for phenols.4 The Boc group is extensively used
for amino protection for chemically inertness to nucleo-
philic reagents including the base and deprotection using
acid reagents.5 Based on these properties, we could
employ the Boc as a protecting group for phenols. We
report herein our results that provide additional infor-
mation about the already known properties of the Boc
group on phenols.
An electron donating tert-butyl group and resonance in
the Boc deactivate the carbonyl carbon of the Boc
group. Therefore, the Boc group can resist nucleophilic
reagents. Actually, the Boc group on an amino group of
d,l-phenylalanine was inert to treatment with
75% piperidine in CH2Cl2 or 1 N NaOH in THF.6
However, the Boc group on phenol was labile to bases.
Table 1 shows the cleavage conditions for the Boc group
Table 1
O
O
O
OH
1
Base/solvent
0.5%a MeONa/CH2Cl2
Equivc
Time (h)
Yield (%)
1.2
10
1
8
88
75
1 N NaOH/MeOH (2/1)
15 N NH3 aq/MeOH (2/1)
25%b Piperidine/CH2Cl2
10%b DBU/CH2Cl2
10%b TEA/CH2Cl2
20%b Pyridine/CH2Cl2
150
30
5
94
86
6
Keywords: Phenols; tert-Butoxycarbonyl (Boc) group; Deprotection;
Base.
20
22
3
83
48
48
––d
––d
q Supplementary data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2003.11.008
* Corresponding author. Tel./fax: +81-265-77-1638; e-mail: knakamu@
gipmc.shinshu-u.ac.jp
33
a %, w/v.
b %, v/v.
ꢀ
Domestic Research Fellow of Japan Science and Technology
Corporation.
c Equivalent of base.
d The Boc group was not cleaved under these basic conditions.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.008

496
K. Nakamura et al. / Tetrahedron Letters 45 (2004) 495–499
on a phenol with bases.7;8 The Boc group was removed
by treatment in dilute solutions of MeONa in CH2Cl2
for 1 h and the phenol was recovered in good yield. Only
a catalytic amount of MeONa (1.2 equiv) was necessary
to complete this deprotection. MeOH containing a cat-
alytic amount of 1 N NaOH or excess amount of
ammonia was the reagent used to remove the Boc group.
Piperidine (25%) or 10% DBU in CH2Cl2 (both are
reagents used to deprotect the base-labile Fmoc group9
in the peptide synthesis) was enough to cleave the Boc
group. However, the Boc group resisted 10% TEA or
20% pyridine in CH2Cl2. To examine the Boc depro-
tective conditions for several kinds of phenols with
bases, 2–9 in Table 2 were synthesized using (Boc)2O/
DMAP.4a;10;11 Though harder basic conditions than that
for phenol were required, the Boc on 2 and 3 possessing
an electron-releasing group were cleaved by treatment
with piperidine or NaOH. As the electron-releasing
effect by the substituted alkyl group(s) increased, more
drastic basic conditions were required to cleave it. Steric
hindrance is also one of the major factors making a
phenolic Boc group stable for bases. The Boc where it
locates between two methyl groups on 4 resisted 75%
piperidine, though cleaved with 28% MeONa or 10 N
NaOH, which are relatively harder basic conditions.
Higher steric hindered Boc where it locates between two
isopropyl groups on 5 was cleaved with 28% MeONa,
but not with 10 N NaOH. It took longer to remove the
Boc on 5 with 28% NaOMe completely than to remove
it on 4. The Boc on 6 possessing highest steric hindrance
and electron-releasing properties among phenols in this
paper was not cleaved under basic conditions showing in
the table anymore. The Boc on 7 possessing a methoxy
group, which had a relative electron-releasing property,
Table 2
Boc–phenols
Base/solvent
Equivc
Time (h)
Yield (%)
Boc
1 N NaOH/MeOH (2/1)
25%a Piperidine/CH2Cl2
10
75
12
9
81
84
2
3
O
Boc
O
1 N NaOH/MeOH (2/1)
50%a Piperidine/CH2Cl2
10
150
24
10
87
93
28%b MeONa/MeOH
12
30
3
12
48
98
90
––d
Boc
O
10 N NaOH/MeOH (3/20)
75%a Piperidine/CH2Cl2
4
5
450
Boc
O
28%b MeONa/MeOH
12
30
9
48
48
96
10 N NaOH/MeOH (3/20)
75%a Piperidine/CH2Cl2
––d
––d
450
28%b MeONa/MeOH
12
30
48
48
48
––d
––d
––d
Boc
O
6
10 N NaOH/MeOH (3/20)
75%a Piperidine/CH2Cl2
450
O
1 N NaOH/MeOH (2/1)
25%a Piperidine/CH2Cl2
10
75
10
6
94
97
Boc
O
7
8
10%a DIPEA/CH2Cl2
1%a Piperidine/CH2Cl2
10%a Piperidine/CH2Cl2
17
48
20
4
––d
89
Boc
O
O
O
1.3
1.3
92
O
1 N NaOH/MeOH (2/1)
1%a Piperidine/CH2Cl2
10%a Piperidine/CH2Cl2
20%a Pyridine/CH2Cl2
10
3
36
6
92
92
90
––d
Boc
O
1.3
1.3
33
O
O
9
48
a %, v/v.
b %, w/v.
c Equivalent of base.
d The Boc group was not cleaved under these basic conditions.

K. Nakamura et al. / Tetrahedron Letters 45 (2004) 495–499
497
was cleaved under similar conditions as 2. The electron-
withdrawing group substituted on the benzene ring
made the Boc much more sensitive to base. The Boc on
methyl 4-tert-butoxycarbonyloxy-benzoate (8) and tert-
butyl 4-tert-butoxycarbonyloxy-3-methoxy-cinnamate
(9) were cleaved even with 1% piperidine in CH2Cl2. The
methyl ester on 8 was completely safe during the
deprotection using 10% or 1% piperidine, and methyl
4-hydroxylbenzoate was obtained in good yield as a
deprotected product. Of course, the tert-butyl ester on 9
was stable under basic conditions and the selective
cleavage of the Boc was achieved. These base-sensitive
Boc, however, resisted DIPEA or pyridine.
Scheme 1 shows a utilization of the Boc deprotection
with base for a synthesis of tyrosine derivative 13, which
is one of available reactants of angiotensin-converting
enzyme inhibitor.12;13 11 was prepared from commer-
cially available Boc-Tyr-OH in ordinary method. Then
the carbonyl group was esterified with isopropanol in
good yield. Without Boc protection of phenol group,
esterification among Tyr derivatives was imperative. The
Boc on phenol worked as a protecting group in the
esterification. In order to form 13, the Boc on phenol
ring was selectively removed from the Boc on amino
group with piperidine. As a result of these successful
reactions, 13 could be synthesized in one pot reaction
in good yield (route iv in Scheme 1).
During the deprotection of Boc on 9 in benzyl alcohol,
O-Boc-benzyl alcohol was isolated in 76% yield besides
the deprotected product, and the piperidine treatments
of 8 and 9 quantitatively yielded N-Boc-piperidine.
These products indicated that the main reactions for
cleavage of the Boc with bases is the transesterification
of the Boc to benzyl alcohol in the presence of bases and
the transition of the Boc to an amino group on piperi-
dine. It is suggested that the following particularity of
phenol makes these reactions possible. More than a pair
of electrons on the oxygen atom adjacent to the benzene
ring can be shared with the ring and delocalized. This
resonance could render the carbonyl carbon active
enough to be attacked by a nucleophile including the
amino or hydroxyl groups, even though the carbonyl
carbon of the Boc is deactivated by an electron donating
tert-butyl group and the effect of resonance in the Boc.
However, hindered nucleophiles like tertiary amines or
pyridine with a much weaker nucleophilicity could not
attack the carbonyl carbon, even on 8 and 9. The effects
of the substituents on the benzene ring support this
reaction mechanism. Electron-attracting substituents
tend to induce the resonance described above and could
make the Boc sensitive to base, whereas the electron-
releasing substituents could make the Boc insensitive
to base by maintaining the resonance.
We confirmed that all Boc-phenols in this study could be
cleaved with acids, such as 100% TFA and 4 N HCl/
dioxane.14 During the deprotection of the Boc group
with acids, by-products substituted by the liberated tert-
butyl cations on the aromatic ring were observed.
During the deprotection of 3 with 30% TFA–CH2Cl2,
10% of a by-product was presented in the crude prod-
ucts.15 Removal of the Boc with bases effectively avoids
these side reactions. The data described in this paper
display a unique property of the Boc on phenols. Thus,
we should note the lability of the Boc to nucleophilic
reagents including bases and be able to utilize it as a new
cleavage condition for the Boc in synthetic studies.
References and Notes
1. (a) Konieczny, M. T.; Horowska, B.; Kunikowski, A.;
Konopa, J.; Wierzba, K.; Yamada, Y.; Asao, T. J. Org.
Chem. 1999, 64, 359–364; (b) Keck, G. E.; Wager, T. T.;
Rodriquez, J. F. D. J. Am. Chem. Soc. 1999, 121, 5176–
5190; (c) Al-Maharik, N. I.; Kaltia, S. A. A.; Mutikainen,
€ € €
I.; Wahala, K. J. Org. Chem. 2000, 65, 2305–2308; (d)
€
Kozikowski, A.; Tuckmantel, W.; George, C. J. Org.
Chem. 2000, 65, 5371–5381; (e) Speranza, G.; Morelli, C.
F.; Manitto, P. Synthesis 2000, 123–126; (f) Al-Maharik,
€ € €
N. I.; Mutikainen, I.; Wahala, K. Synthesis 2000, 411–416;
(g) Taniguchi, H.; Hosoda, A.; Tuno, T.; Maruta, Y.;
Nomura, E. Anticancer Res. 1999, 19, 3557–3562; (h)
Horiuchi, H.; Shirase, H.; Okutsu, T.; Matsushima, R.;
Hiratsuka, H. Chem. Lett. 2000, 96–97.
OH
O
ii
Boc
2. (a) Onyeneho, S. N.; Hettiarachchy, N. S. J. Agric. Food
Chem. 1992, 40, 1496–1500; (b) Shahidi, F.; Wanasundara,
P. K. J. P. D. Crit. Rev. Food Sci. Nutr. 1992, 32, 67–103;
(c) Bravo, L. Nutr. Rev. 1998, 56, 317–333.
3. Green, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis. 3rd ed.; Wiley-Interscience: New York,
1999; pp 249–287.
i
Boc
Boc
OH
OH
N
N
H
H
O
O
iv
11
10
OH
O
Boc
4. (a) Hansen, M. M.; Riggis, J. R. Tetrahedron Lett. 1998,
39, 2705–2706; (b) Jarowicki, K.; Kociꢁnski, P. L. J. Chem.
Soc., Perkin Trans. 1 1999, 1589–1615; (c) Water, R. W. V.
D.; Magdzisk, D. J.; Chau, J. N.; Pettus, T. R. R. J. Am.
Chem. Soc. 2000, 122, 6502–6503.
iii
Boc
Boc
O
O
N
N
H
H
O
O
13
12
5. (a) Yajima, H.; Fujii, N. In The Peptides: Analysis,
Synthesis, Biology; Gross, E., Meienhofer, J., Eds.; Aca-
demic: NY, 1983, Vol. 5, pp 65–109; (b) Bodanszky, M. In
Principles of Peptide Chemistry; Springer: New York,
1984, p 99; (c) Green, T. W.; Wuts, P. G. M. In Protective
Groups in Synthesis. 3rd ed.; Wiley-Interscience: New
York, 1998; pp 518–525.
Scheme 1. Reagents and conditions: (i) (Boc)2O, DMAP (1 mol %),
CH2Cl2, TEA, 3 h, rt, 89%; (ii) isopropanol, EDCÆHCl, DMAP
(10 mol %), CH2Cl2, 3 h, rt, 88%; (iii) 50% piperidine (150 equiv),
CH2Cl2, 3 h, rt, 85%; (iv) (Boc)2O, DMAP (1 mol %), CH2Cl2, TEA,
3 h; isopropanol, EDCÆHCl, DMAP (20 mol %), 3 h; piperidine
(75 equiv), 2 h, rt, 81%.

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K. Nakamura et al. / Tetrahedron Letters 45 (2004) 495–499
D,L-Phe-OH with 30 equiv of each 7-undecene in CH2Cl2 at room temperature. After stirring
6. After treatment of Boc-
base at room temperature for 24 h, it was recovered in over
90% yield.
for 3 h, to the reaction mixture was added 30 mL of
ethylacetate and 30 mL of 4% KHSO4 aq solution. The
organic layer was washed with 4% KHSO4 aq solution
(30 mL), water (30 mL), and saturated NaCl aq solution
(30 mL), dried over MgSO4, then evaporated under
reduced pressure. The residue was purified by passage
through a silica gel column (hexane/ethyl acetate ¼ 1/0 to
10/1) to afford 7.8 mg (83 lmol, 83%) of a colorless solid.
9. Fmoc is 9-fluorenylmethoxycarbonyl group for a-N-
protection on amino acid. Fmoc is employed as another
major strategy for automatic peptide synthesis as well as Boc.
10. Synthesis of Boc-phenols: 2–9 were synthesized in a similar
fashion as 1. Analytical data for 2–9 are as follows.
7. Synthesis of 1-tert-butoxycarbonyloxybenzene (1): To a
solution of 0.47 g (5.0 mmol) of phenol and 61 mg
(0.5 mmol) of 4-dimethylaminopyridine (DMAP) in 5 mL
CH2Cl2, 1.1 g (5.0 mmol) of di-tert-butyl dicarbonate
((Boc)2O) was added at room temperature. After stirring
for 1 h, the reaction mixture was evaporated under
reduced pressure, then the residue was purified through
a silica gel column (hexane/ethyl acetate ¼ 1/0 to 10/1).
The product was obtained as a colorless oil, 0.91 g
(4.7 mmol), 94% yield; Rf ¼ 0:52 (hexane/ethyl ace-
tate ¼ 5/1); IR (neat) 3045, 2982, 2936, 1759, 1497, 1371,
1
1275, 1259, 1217, 1150 cmꢀ1; 400 MHz H NMR (CDCl3)
1-tert-Butoxycarbonyloxy-4-methylbenzene (2): 90% yield;
Rf ¼ 0:44 (hexane/ethyl acetate ¼ 5/1); IR (neat) 3045,
d 7.38–7.32 (2H, m, ArH), 7.23–7.18 (1H, tt, J ¼ 7:4,
1.2 Hz, ArH), 7.17–7.14 (2H, m, ArH), 1.55 (9H, s, CH3);
100 MHz 13C NMR (CDCl3) d 151.9 (C), 151.1 (C), 129.3
(CH), 125.7 (CH), 121.2 (CH), 83.4 (C), 27.7 (CH3).
8. Cleavage of the Boc on phenol with bases: Boc cleavage
with MeONa on 1: To a solution of 19 mg (100 lmol) of 1
in 1 mL CH2Cl2, 23 mg (120 lmol) of 28% sodium
methoxide in methanol was added at room temperature.
After stirring for 1 h, to the reaction mixture was added
30 mL of ethylacetate and 30 mL of 4% KHSO4 aq
solution. The organic layer was washed with 4% KHSO4
aq solution (30 mL), water (30 mL), and saturated NaCl
aq solution (30 mL), dried over MgSO4, then evaporated
under reduced pressure. The residue was purified by
passage through a silica gel column (hexane/ethyl ace-
tate ¼ 1/0 to 10/1) to afford 8.3 mg (88 lmol, 88%) of a
colorless solid. Analytical data for the product by mp, IR,
1H, and 13C NMR are identical with commercially
available phenol.
3007, 2976, 2932, 1749, 1510, 1277, 1221, 1151 cmꢀ1
;
400 MHz 1H NMR (CDCl3) d 7.16–7.13 (2H, m, ArH),
7.05–7.02 (2H, m, ArH), 2.32 (3H, s, CH3), 1.54 (9H, s,
CH3); 100 MHz 13C NMR (CDCl3) d 152.1 (C), 148.8 (C),
135.3 (C), 129.8 (CH), 120.9 (CH), 83.2 (C), 27.6 (CH3),
20.8 (CH3).
1-tert-Butoxycarbonyloxy-4-tert-butylbenzene (3): 88%
yield; Rf ¼ 0:43 (hexane/ethyl acetate ¼ 5/1); IR (neat)
3045, 2966, 1755, 1512, 1369, 1275, 1258, 1223, 1151,
1
1111 cmꢀ1; 400 MHz H NMR (CDCl3) d 7.39–7.34 (2H,
m, ArH), 7.10–7.05 (2H, m, ArH), 1.55 (9H, s, CH3), 1.30
(9H, s, CH3); 100 MHz 13C NMR (CDCl3) d 152.2 (C),
148.8 (C), 148.5 (C), 126.2 (CH), 120.6 (CH), 83.2 (C),
34.4 (C), 31.4 (CH3), 27.7 (CH3).
1-tert-Butoxycarbonyloxy-2,6-dimethylbenzene (4): 99%
1
yield; Rf ¼ 0:44 (hexane/ethyl acetate ¼ 9/1); 500 MHz H
NMR (CDCl3) d 7.04–7.02 (3H, m, ArH), 2.20 (6H, s,
CH3), 1.55 (9H, s, CH3); 125 MHz 13C NMR (CDCl3) d
151.3 (C), 148.4 (C), 130.3 (C), 128.6 (CH), 125.8 (CH),
83.1 (C), 27.7 (CH3), 16.1 (CH3).
Boc cleavage with NaOH aq on 1: To a solution of 19 mg
(100 lmol) of 1 in 0.5 mL MeOH, 1 mL of 1 N NaOH aq
was added at room temperature. After stirring for 8 h, to
the reaction mixture was added 30 mL of ethylacetate and
30 mL of 4% KHSO4 aq solution. The organic layer was
washed with 4% KHSO4 aq solution (30 mL), water
(30 mL), and saturated NaCl aq solution (30 mL), dried
over MgSO4, then evaporated under reduced pressure.
The residue was purified by passage through a silica gel
column (hexane/ethyl acetate ¼ 1/0 to 10/1) to afford
7.1 mg (75 lmol, 75%) of a colorless solid.
Boc cleavage with NH3 aq on 1: To a solution of 19 mg
(100 lmol) of 1 in 0.5 mL MeOH, 0.1 mL of 15 N NH3 aq
was added at room temperature. After stirring for 5 h, to
the reaction mixture was added 30 mL of ethylacetate and
30 mL of 4% KHSO4 aq solution. The organic layer was
washed with 4% KHSO4 aq solution (30 mL), water
(30 mL), and saturated NaCl aq solution (30 mL), dried
over MgSO4, then evaporated under reduced pressure.
The residue was purified by passage through a silica gel
column (hexane/ethyl acetate ¼ 1/0 to 10/1) to afford
8.8 mg (94 lmol, 94%) of a colorless solid.
1-tert-Butoxycarbonyloxy-2,6-diisopropylbenzene (5): 99%
yield; Rf ¼ 0:50 (hexane/ethyl acetate ¼ 9/1); 500 MHz
1H NMR (CDCl3) d 7.26–7.13 (3H, m, ArH), 3.08–3.02
(2H, sep, J ¼ 6:9 Hz, CH), 1.55 (9H, s, CH3), 1.21 (12H, d,
J ¼ 6:9 Hz, CH3); 125 MHz 13C NMR (CDCl3) d 152.2
(C), 145.7 (C), 140.6 (C), 126.5 (CH), 124.0 (CH), 83.0 (C),
27.7 (CH), 27.3 (CH3), 23.3 (CH3).
1-tert-Butoxycarbonyloxy-2,4,6-tri-tert-butylbenzene (6):
94% yield; Rf ¼ 0:41 (hexane/ethyl acetate ¼ 25/1); IR
(KBr) 3088, 2984, 2872, 1759, 1269, 1258, 1157, 1111 cmꢀ1
;
400 MHz 1H NMR (CDCl3) d 7.29 (2H, s, ArH), 1.52 (9H,
s, CH3), 1.36 (18H, s, CH3), 1.29 (9H, s, CH3); 100 MHz
13C NMR (CDCl3) d 153.1 (C), 147.2 (C), 145.9 (C), 141.5
(C), 123.3 (CH), 82.8 (C), 35.6 (C), 34.8 (C), 31.5 (CH3),
31.5 (CH3), 27.8 (CH3).
1-tert-Butoxycarbonyloxy-2-methoxybenzene (7): 94%
yield; Rf ¼ 0:16 (hexane/ethyl acetate ¼ 5/1); IR (KBr)
3108, 2984, 1755, 1614, 1487, 1308, 1263, 1150, 1117 cmꢀ1
;
400 MHz 1H NMR (CDCl3) d 7.09 (1H, t, J ¼ 8:4 Hz,
ArH), 6.58 (2H, d, J ¼ 8:4 Hz, ArH), 3.81 (6H, s, CH3),
1.53 (9H, s, CH3); 100 MHz 13C NMR (CDCl3) d 152.4 (C),
151.3 (C), 129.2 (C), 126.0 (CH), 104.8 (CH), 83.1 (C), 56.1
(CH3), 27.5 (CH3).
Boc cleavage with 25% piperidine on 1:
A 19 mg
(100 lmol) sample of 1 was dissolved in 3 mL of 25%
piperidine in CH2Cl2 at room temperature. After stirring
for 3 h, to the reaction mixture was added 30 mL of
ethylacetate and 30 mL of 4% KHSO4 aq solution. The
organic layer was washed with 4% KHSO4 aq solution
(30 mL), water (30 mL), and saturated NaCl aq solution
(30 mL), dried over MgSO4, then evaporated under
reduced pressure. The residue was purified by passage
through a silica gel column (hexane/ethyl acetate ¼ 1/0 to
10/1) to afford 8.1 mg (86 lmol, 86%) of a colorless solid.
Boc cleavage with DBU on 1: A 19 mg (100 lmol) sample
of 1 was dissolved in 3 mL of 10% 1,8-diazabicyclo[5.4.0]-
Methyl 4-tert-Butoxycarbonyloxybenzoate (8): 91% yield;
IR (KBr) 3007, 2987, 1750, 1749, 1719, 1605, 1279,
1
1151 cmꢀ1; 400 MHz H NMR (CDCl3) d 8.06–8.02 (2H,
m, ArH), 7.25–7.20 (2H, m, ArH), 3.89 (3H, s, CH3), 1.54
(9H, s, CH3); 100 MHz 13C NMR (CDCl3) d 166.3 (C),
154.6 (C), 151.1 (C), 131.1 (CH), 127.5 (C), 121.1 (CH),
84.1 (C), 52.2 (CH3), 27.6 (CH3).
tert-Butyl 4-tert-butoxycarbonyloxy-3-methoxycinnamate
(9): 95% yield; Rf ¼ 0:41 (hexane/ethyl acetate ¼ 2/1); IR
(neat) 3062, 2980, 1763, 1709, 1638, 1510, 1256, 1144,

K. Nakamura et al. / Tetrahedron Letters 45 (2004) 495–499
499
1124 cmꢀ1; 400 MHz 1H NMR (CDCl3) d 7.50 (1H, d,
J ¼ 16:0 Hz, ArCH@), 7.11–7.04 (3H, m, ArH), 6.28 (1H,
d, J ¼ 15:6 Hz, @CH–), 3.85 (3H, s, OCH3), 1.53 (9H, s,
CH3), 1.51 (9H, s, CH3); 100 MHz 13C NMR (CDCl3) d
166.1 (C),151.5 (C), 151.2 (C), 142.8 (CH), 141.6 (C), 133.5
(C), 122.8 (CH), 121.1 (CH), 120.4 (CH), 111.2 (CH), 83.6
(C), 80.6 (C), 55.9 (CH3), 28.2 (CH3), 27.6 (CH3).
tate ¼ 3/1). The product was obtained as a colorless solid:
0.37 g (0.88 mmol), 88% yield; Rf ¼ 0:51 (hexane/ethyl
acetate ¼ 3/1); 500 MHz 1H NMR (CDCl3) d 7.16–7.08
(4H, m, ArH), 5.01–4.97 (2H, m, NH, CH), 4.52–4.49 (1H,
m, a-CH), 3.08–3.05 (2H, m, CH2), 1.55 (9H, s, CH3), 1.42
(9H, s, CH3), 1.20 (6H, dd, J ¼ 13, 6.3 Hz, CH3); 125 MHz
13C NMR (CDCl3) d 171.2 (C), 151.8 (C), 150.1 (C), 133.7
(C), 130.4 (CH), 125.9 (C), 121.2 (CH), 83.5 (C), 79.9 (C),
69.2 (CH), 54.5 (CH), 37.7 (CH2), 28.3 (CH3), 27.7 (CH3),
21.8 (CH3).
11. Cleavage of the Boc on phenol with bases: Boc on 2–9
were cleaved with bases in a similar fashion as 1.
12. (a) Fink, Cynthia A.; Carlson, J. Eric; McTaggart,
Patricia A.; Qiao, Ying; Webb, Randy; Chatelain,
Ricardo; Jeng, Arco Y.; Trapani, Angelo J. J. Med.
Chem. 1996, 39(16), 3158–3168; (b) Kayahara, H.; Kawa-
kami, A.; Tanji, Y.; Tadasa, K. In Chemistry of Novel
Foods; Spanier, Arthur M., Ed.; Allured Publishing Corp.:
Illinois, 1997; pp 355–366.
BocTyrOiPr (13): A 42 mg (100 lmol) sample of 12 was
dissolved in 3 mL of 50% piperidine in CH2Cl2 at room
temperature. After stirring for 3 h, to the reaction mixture
was added 30 mL of ethylacetate and 30 mL of 4% KHSO4
aq solution. The organic layer was washed with 4%
KHSO4 aq solution (30 mL), water (30 mL), and saturated
NaCl aq solution (30 mL), dried over Na2SO4, then
evaporated under reduced pressure. The residue was
purified through a silica gel column (hexane/ethyl ace-
tate ¼ 3/1). The product was obtained as a white solid:
28 mg (85 lmol), 85% yield; Rf ¼ 0:21 (hexane/ethyl ace-
13. Synthesis of Tyr derivatives: BocTyr(OBoc)OH (11): To a
solution of 1.4 g (5.0 mmol) of BocTyrOH (10), 6.1 mg
(0.05 mmol) of DMAP and 0.69 mL (5.0 mmol) of trieth-
ylamine (TEA) in 5 mL CH2Cl2, 1.4 g (6.5 mmol) of
(Boc)2O was added at room temperature. After stirring
for 3 h, to the reaction mixture was added 80 mL of
ethylacetate and 80 mL of 4% KHSO4 aq solution. The
organic layer was washed with 4% KHSO4 aq solution
(80 mL), water (80 mL), and saturated NaCl aq solution
(80 mL), dried over Na2SO4, then evaporated under
reduced pressure. The residue was purified through a
silica gel column (hexane/ethyl acetate ¼ 3/1 to 1/1). The
product was obtained as a colorless solid: 1.7 g (4.4 mmol),
89% yield; Rf ¼ 0:58 (chloroform/methanol ¼ 5/1);
500 MHz 1H NMR (CDCl3) d 7.20–7.09 (4H, m, ArH),
5.00–4.94 (1H, m, NH), 4.63–4.57 (1H, m,
a-CH), 3.23–3.04 (2H, m, CH2), 1.55 (9H, s, CH3), 1.42
(9H, s, CH3); 125 MHz 13C NMR (CDCl3) d 175.2 (C),
151.9 (C), 150.2 (C), 133.5 (C), 130.4 (CH), 125.9 (C),
121.4 (CH), 83.6 (C), 80.6 (C), 54.2 (CH), 37.1 (CH2), 28.3
(CH3), 27.7 (CH3).
1
tate ¼ 3/1); 500 MHz H NMR (CDCl3) d 7.01–6.72 (4H,
m, ArH), 5.04–4.96 (2H, m, NH, CH), 4.50–4.44 (1H, m,
a-CH), 3.06–2.96 (2H, m, CH2), 1.42 (9H, s, CH3), 1.20
(6H, dd, J ¼ 10, 6.3 Hz, CH3); 125 MHz 13C NMR
(CDCl3) d 171.5 (C), 154.7 (C), 130.6 (CH), 128.2 (C),
125.9 (C), 115.4 (CH), 79.8 (C), 69.1 (CH), 54.7 (CH), 37.6
(CH2), 28.3 (CH3), 21.8 (CH3).
One pot synthesis of 13: To a solution of 0.28 g (1.0 mmol)
of 10, 1.2 mg (0.01 mmol) of DMAP and 0.14 mL
(1.0 mmol) of TEA in 1 mL CH2Cl2, 0.28 g (1.3 mmol) of
(Boc)2O was added at room temperature. After stirring for
3 h, to the reaction mixture was added 1 mL (13 mmol) of
isopropanol, 24 mg (0.2 mmol) of DMAP, and 0.25 g
(1.3 mmol) of EDCÆHCl. Then, after stirring for 3 h, the
reaction mixture was added 7.5 mL (75 mmol) of piperi-
dine. After stirring for 2 h, to the reaction mixture was
added 50 mL of ethylacetate and 50 mL of 4% KHSO4 aq
solution. The organic layer was washed with 4% KHSO4
aq solution (50 mL), water (50 mL), and saturated NaCl
aq solution (50 mL), dried over Na2SO4, then evaporated
under reduced pressure. The residue was purified through
a silica gel column (hexane/ethyl acetate ¼ 3/1). The
product was obtained as a white solid; 0.26 g (0.81 mmol),
81% yield.
BocTyr(OBoc)OiPr (12): To
a
solution of 0.38 g
(1.0 mmol) of 11 and 12 mg (0.1 mmol) of DMAP in
1 mL CH2Cl2, 0.1 mL (1.3 mmol) of isopropanol and
0.25 g (1.3 mmol) of 1-ethyl-3-(3-dimethyl aminopropyl)-
carbodiimide hydrochloride (EDCÆHCl) were added at
room temperature. After stirring for 3 h, to the reaction
mixture was added 50 mL of ethylacetate and 50 mL of 4%
KHSO4 aq solution. The organic layer was washed with
4% KHSO4 aq solution (50 mL), water (50 mL), and
saturated NaCl aq solution (50 mL), dried over Na2SO4,
then evaporated under reduced pressure. The residue was
purified through a silica gel column (hexane/ethyl ace-
14. Acids (50 equiv) were used for Boc cleavage and reactions
completed in 6 h at room temperature.
15. By-product content was estimated from 1H NMR spec-
trum ratio of tert-butyl group in crude product.