The first simple method of protection of hydroxy compounds as their O-Boc derivatives under Lewis acid catalysis

Article abstract of DOI:10.1055/s-2006-949609

The first Lewis acid catalyzed protection of alcohols as Boc derivatives is described. Zinc acetate is a very efficient catalyst for this transformation and the reaction can be applied to primary, secondary and aromatic alcohols, providing the first example of a generally applicable method. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949609

2104
LETTER
The First Simple Method of Protection of Hydroxy Compounds as their
O-Boc Derivatives under Lewis Acid Catalysis
Synthesis of Boc
A
i
lcohol
u
s
seppe Bartoli,*a Marcella Bosco,a Armando Carlone,a Renato Dalpozzo,b Manuela Locatelli,a Paolo Melchiorre,a
Paolo Palazzi,a Letizia Sambria
a
Dipartimento di Chimica Organica ‘A. Mangini’, Università di Bologna, viale Risorgimento 4, 40136 Bologna, Italy
Fax +39(051)2093654; E-mail: giuseppe.bartoli@unibo.it
b
Dipartimento di Chimica, Università della Calabria, Ponte Bucci, cubo 12C, 87036 Arcavacata di Rende (Cs), Italy
Received 12 April 2006
All these methodologies work in basic media6,8,9 or in the
Abstract: The first Lewis acid catalyzed protection of alcohols as
Boc derivatives is described. Zinc acetate is a very efficient catalyst
for this transformation and the reaction can be applied to primary,
secondary and aromatic alcohols, providing the first example of a
generally applicable method.
presence of a Lewis base.7,10 Only recently oxometallic
species, such as oxovanadium11 and oxomolybdenum,12
were introduced as amphoteric catalysts for nucleophilic
acyl substitutions of anhydrides and dicarbonates.
Key words: alcohols, esterification, protecting groups, Lewis ac-
ids, zinc acetate
In brief, an efficient and simple protocol for the synthesis
of tert-butyl carbonates under Lewis acid conditions is
still lacking.
In recent years, we were involved in the study of the abil-
ity of metal perchlorates to act as powerful Lewis acids,
exploiting their attitude to activate bidentate compounds.
In particular, metal perchlorates can promote various acy-
lation and esterification reactions13 and the synthesis of b-
enamino esters.14
The importance of organic carbonates has been increasing
in the past few years both in industry and in laboratories.1
Organic carbonates, in fact, find employment as fuel addi-
tives, lubricating oils, herbicides, pesticides, plastics, sol-
vents and for medicinal and biological applications. In
addition, they can act as useful protecting groups of alco-
hols and phenols since more stable than the corresponding
esters under basic conditions.1a
On the other hand, we found a peculiar reactivity of di-
tert-butyldicarbonate in the presence of metal perchlora-
tes. In fact, if protection of amines as Boc derivatives can
be achieved in very good yields with zinc perchlorate as
the catalyst,15 aryl and alkyl tert-butyl ethers instead of the
corresponding Boc derivative are obtained, when alcohols
are allowed to react with magnesium perchlorate as the
catalyst.16
Traditional methods for the preparation of organic car-
bonates required the use of very toxic reagents,1,2 such as
phosgene, pyridine and carbon monoxide, thus many ef-
forts have been recently devoted to develop more environ-
mentally friendly procedures for their synthesis.3
Moreover, for the synthesis of mixed (unsymmetrical)
carbonates, these methods all suffer from many draw-
backs, such as low selectivity, limited scope and difficult
availability of the substrate.
We screened many common Lewis acids in order to find
one able to catalyze O-Boc alcohol formation, by using
the reaction of octanol with Boc2O as sample reaction.17
Perchlorates or triflates gave the exclusive formation of
tert-butyl ether or a mixture of ether and carbonates, with
the prevalence of the former. Other Lewis acids, such as
magnesium, zinc or lanthanide halides, led to complex
mixture of both compounds or were completely ineffi-
cient. We found that only zinc acetate hydrate is a very ef-
ficient catalyst for the synthesis of O-Boc alcohols.
Among carbonic acid derivatives used as protecting
groups, tert-butyl carbonates (O-Boc alcohols) and car-
bamates (N-Boc amines) are of great importance in organ-
ic chemistry. However, whereas N-Boc derivatives are
extensively used for protecting amino groups,4 O-Boc
protection is restricted to aryl alcohols.5 Introduction of
Boc group is generally achieved by using di-tert-butyldi-
carbonate (Boc2O) in a phase transfer protocol,6 or by di-
rect acylation with Boc2O and dimethylaminopyridine
(DMAP) as the catalyst,7 or, finally, by alcoholate nucleo-
philic cleavage of Boc2O.8 Alternatively, reactive Boc
species were employed, such as Boc-imidazole9 or 1-tert-
butoxy-2-tert-butoxycarbonyl-1,2-dihydroisoquinoline
(BBDI).10
The methodology here reported represents the first exam-
ple of protection of alcohols as Boc derivatives under
Lewis acid conditions.
Alcohols (1a–m), di-tert-butyldicarbonate and zinc ace-
tate hydrate (10% mol) were dissolved in the minimum
amount of dichloromethane and refluxed.18 Results are re-
ported in Table 1.
The reaction is general and can be applied to primary and
secondary alcohols, various substituted phenols and naph-
thol. The nature of the substituent on the aromatic ring
seems to influence the reaction rate, in fact an electron-do-
nating group fastened the reaction with respect to an elec-
SYNLETT 2006, No. 13, pp 2104–2108
Advanced online publication: 09.08.2006
DOI: 10.1055/s-2006-949609; Art ID: G10906ST
© Georg Thieme Verlag Stuttgart · New York
1
7
.0
8
.2
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0
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LETTER
Synthesis of Boc Alcohols
2105
tron-withdrawing one (Table 1, entries 6–8). However, an groups, a mixture of monoprotected alcohol on the prima-
almost complete conversion was observed in all cases.
ry function (2l,m), diprotected diol (3l,m) and starting
material (1l,m) was recovered (Table 1, entry 12, 13).19,20
No monoprotected alcohol on the secondary or aromatic
framework was detected.
Neither isomerization of carbon–carbon double bonds
(Table 1, entry 2), nor racemization (Table 1, entries 4,
10) were observed. Various functionalities present in the
substrates, such as an ester and a ketone (Table 1, entries In order to increase the environmental friendliness of the
4, 5) as well as a methoxy and a nitro group, (Table 1, en- reaction, we tested solvent-free conditions in the case of
tries 6, 8) are tolerated under the adopted reaction condi- liquid substrates or those that melt below 60 °C. Higher
tions. The reaction does not work with tertiary alcohols.
temperatures cause decomposition of Boc2O.21
Then we carried out some reaction on diols, in order to test Alcohols (1a–d,f,g,n–z,aa) a slight excess of Boc2O and
chemoselectivity of the reaction. A selective protection of zinc acetate hydrate (10 mol%) were melted together and
the primary hydroxy group of diol 1k, bearing a tertiary stirred at the appropriate temperature (Table 2).22,23
and primary function, can be achieved (Table 1, entry 11).
In diols bearing primary and secondary or arylic hydroxy
The reaction maintained its chemoselectivity. In fact both
the functionalities previously tested and others, such as Z-
double bonds, amino and fluoride groups, were unaffect-
ed.
Table 1 Synthesis of Boc Alcohols with 10% Zn(OAc)2 in CH2Cl2
at Reflux
Conversely from simple alcohols, which are usually unre-
Zn(OAc)2, (10%)
active in the absence of the catalyst,7,24 amino alcohol 1r
CH2Cl2, reflux
ROH + Boc2O
can be protected in the absence of any catalyst. Actually,
ROBoc
although it is reported that Et3N is unable to act as catalyst
1
Entry
1
2
in Boc protection of hydroxy compounds,7 the very simi-
lar dimethylamino group can act as an intramolecular ba-
sic catalyst. The conversion was complete in about 6
hours. However, accordingly with literature,7 a 83:17
mixture of O-Boc derivative 2r and bis[3-(N,N-dimethyl-
amino)propyl]carbonate (4r) was obtained.25
Alcohol
Time (h) Yield (%)
n-C8H17OH (1a)
6
6
98
98
2
OH
1b
3
4
5
PhCH2OH (1c)
8.25
7
98
98
90
It is noteworthy that the ratio of 2r and 4r increases to
94:6 when zinc acetate catalysis works, according to the
assertion that more acidic media give higher amounts O-
Boc products and suppress the symmetrical carbonate for-
mation.7 Reaction with diol 1l was also attempted, but a
messy reaction mixture was obtained.
(S)-MeCH(OH)COOEt (1d)
19
O
Ph
Ph
OH
In order to show the merit of the present work, orthogo-
nality of Boc protection with other classical protective
groups was also checked. Acid-cleavable protective
groups, such as acetonide, THP and silyl, N-Boc functions
survive under these reaction conditions (Table 2, entries
17–20), demonstrating that the current catalytic condi-
tions are not harsh.
1e
6
7
4-MeO-C6H4OH (1f)
7
98
95
98
98
98
98
PhOH (1g)
13
8
4-NO2-C6H4OH (1h)
b-Naphthol (1i)
Cholesterol (1j)
OH
17
9
18.5
15.25
12.33
10
11
In conclusion, the first general and efficient protection of
hydroxy compounds into their Boc derivatives is de-
scribed. The reaction can be carried out in solvent-free
conditions, and by-products are carbon dioxide and tert-
butanol, therefore this method is environmentally benign.
This is the first example of Boc protection obtained under
Lewis acid catalyzed conditions, conversely from all the
other methods, which worked under basic conditions. The
current conditions are not too harsh and allow acid-sensi-
tive functional groups to survive. Only tertiary hydroxy
groups of diols are unaffected. However, some protective
groups are demonstrated to be orthogonal with Boc pro-
tection, so this drawback can be easily overcome in diol
reaction.
OH
1k
12
13
5
96a
74b
OH
OH
1l
12.33
HO
OH
1m
a As sum of 80% of primary monoprotected (2l) and 16% diprotected
diol (3l); trace (<3%) of starting material (1l) was also recovered.19,
b As sum of 39% of primary monoprotected (2m) and 35% diprotect-
ed diol (3m); 24% of starting material (1m) was also recovered.20
Since the intervention of the alcoholate is reported to be
essential for the occurrence of the reaction in base-cata-
lyzed reactions, studies are in progress to understand the
Synlett 2006, No. 13, 2104–2108 © Thieme Stuttgart · New York

2106
G. Bartoli et al.
LETTER
Table 2 Synthesis of Boc Alcohols with 10% Zn(OAc)2 under Sol- Acknowledgment
vent-Free Conditions
Work carried out in the framework of the National Project ‘Stereo-
selezione in Sintesi Organica. Metodologie e Applicazioni’ suppor-
ted by MIUR, Rome, by the University of Bologna, in the
framework of ‘Progetto di Finanziamento Pluriennale, Ateneo di
Bologna’, and by National Project FIRB ‘Progettazione, prepara-
zione e valutazione biologica e farmacologica di nuove molecole
organiche quali potenziali farmaci’.
Entry Alcohol
Temp (°C) Time (h) Yield (%)
1
2
3
1a
1b
50
50
50
12.5
6.5
9
98
98
98
OH
1n
1c
References and Notes
4
5
6
50
50
50
6
98
98
98
(1) (a) Parrish, J. P.; Salvatore, R. N.; Jung, K. W. Tetrahedron
2000, 56, 8207. (b) Shaikh, A. A. G.; Sivaram, S. Chem.
Rev. 1996, 96, 951.
PhCH2CH2OH (1o)
16
11.75
O
(2) Hegarty, A. F. In Comprehensive Organic Chemistry, Vol.
2; Sutherland, I. O., Ed.; Pergamon: London, 1979, 1067.
(3) Some selected references follow: (a) Veldurthy, B.;
Clacens, J. M.; Figueras, F. Eur. J. Org. Chem. 2005, 1972.
(b) Tundo, P.; Rossi, L.; Loris, A. J. Org. Chem. 2005, 70,
2219. (c) Srivastava, R.; Srinivas, D.; Ratnasamy, P. Appl.
Catal., A 2005, 289, 128. (d) Veldurthy, B.; Figueras, F.
Chem. Commun. 2004, 734. (e) Bratt, M. O.; Taylor, P. C. J.
Org. Chem. 2003, 68, 5439. (f) Carloni, S.; De Vos, D. E.;
Jacobs, P. A.; Maggi, R.; Sartori, G.; Sartorio, R. J. Catal.
2002, 205, 199. (g) Verdecchia, M.; Feroci, M.; Palombi, L.;
Rossi, L. J. Org. Chem. 2002, 67, 8287. (h) Tundo, P.;
Selva, M. Acc. Chem. Res. 2002, 35, 706. (i) Salvatore, R.
N.; Chu, F.; Nagle, A. S.; Kapxhiu, E. A.; Cross, R. M.;
Jung, K. W. Tetrahedron 2002, 58, 3329.
(4) Greene, T. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999, 518–
525.
(5) Ref. 4, page 281.
(6) Houlihan, F.; Bouchard, F.; Frechet, J. M.; Willson, C. G.
Can. J. Chem. 1985, 65, 153.
(7) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
(8) Haight, A. R.; Stoner, E. J.; Peterson, M. J.; Grover, V. K. J.
Org. Chem. 2003, 8092.
(9) Peri, F.; Binassi, E.; Manetto, A.; Marotta, E.; Mazzanti, A.;
Righi, P.; Scardovi, N.; Rosini, G. J. Org. Chem. 2004, 69,
1353.
OH
1p
7
8
50
50
6
98
Ph
OH
1q
8.25
98a
N
OH
1r
1d
9
10
11
12
13
14
15
16
60
50
50
60
50
50
50
50
4.5
30
98
98
92
96
98
95
97
98
(–)-Menthol (1s)
2-C8H17OH (1t)
19
1f
7
3-MeO-C6H4OH (1u)
6.25
6
1g
4-F-C6H4OH (1v)
29.5
17.33
HO
N
(10) Ouchi, H.; Saito, Y.; Yamamoto, Y.; Takahata, H. Org. Lett.
2002, 4, 585.
H
1w
(11) Chen, C. T.; Kuo, J. H.; Li, C. H.; Barhate, N. B.; Hon, S.
W.; Li, T. W.; Chao, S. D.; Liu, C. C.; Li, Y. C.; Chang, I.
H.; Lin, J. S.; Liu, C. J.; Chou, Y. C. Org. Lett. 2001, 3, 3729.
(12) Chen, C. T.; Kuo, J. H.; Pawar, V. D.; Munot, Y. S.; Weng,
S. S.; Ku, C. H.; Liu, C. Y. J. Org. Chem. 2005, 70, 1188.
(13) (a) Bartoli, G.; Boeglin, J.; Bosco, M.; Locatelli, M.;
Massaccesi, M.; Melchiorre, P.; Sambri, L. Adv. Synth.
Catal. 2005, 347, 33. (b) Gooßen, L.; Döhring, A. Adv.
Synth. Catal. 2003, 345, 943.
17
50
50
16.33
98
OH
O
O
1x
18
19
20
THPO(CH2)4OH (1y)
20.5
21
7
96
97
87
i-Pr3SiO(CH2)6OH (1z) 50
50
COOt-Bu
NHBoc
HO
(14) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Melchiorre, P.; Sambri, L. Synlett 2004, 239.
(15) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Massaccesi, M.; Melchiorre, P.; Sambri, L. Synlett 2004,
1794.
(16) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.;
Melchiorre, P.; Sambri, L. Org. Lett. 2004, 7, 427.
(17) Unpublished results.
1aa
a As a 94:6 mixture of Boc alcohol (2r) and bis[3-(N,N-dimethylami-
no)propyl]carbonate (4r).25
(18) In a two-necked flask equipped with a magnetic stirring bar,
alcohols 1a–m (1 mmol), di-tert-butyl dicarbonate (1.1
mmol), and Zn(OAc)2·2H2O (0.1 mmol) were dissolved in
CH2Cl2 (1 mL). The mixture was stirred and refluxed until
the GC-MS analysis revealed the presence of 1 or Boc2O for
diols (Table 1). The crude reaction mixture was diluted with
mechanism of this reaction. Moreover, it is still under in-
vestigation how the change of the catalyst counter ion
from perchlorate to acetate shifts the reaction product
from tert-butyl ether to the O-Boc derivative.
Synlett 2006, No. 13, 2104–2108 © Thieme Stuttgart · New York

LETTER
H2O and extracted twice with CH2Cl2. The organic layer was
Synthesis of Boc Alcohols
2107
CH), 128.7 (2 CH), 128.8 (2 CH), 129.1 (2 CH), 129.3
(CH),133.2 (C), 133.4 (CH), 134.6 (C), 152.9 (C=O), 193.9
(C=O) ppm. MS (EI): m/z (%) = 256 (1), 195 (3), 167 (2),
165 (3), 105 (100), 79 (17), 77 (44), 57 (14), 51 (13).
(2-Naphthyl) tert-butyl carbonate (2i): mp 77–78 °C. 1H
NMR: d = 1.58 (s, 9 H, t-Bu), 7.31 (dd, 1 H, J = 8.9, 2.5 Hz,
H-3), 7.40–7.55 (m, 2 H, H-6, H-7), 7.64 (d, 1 H, J = 2.4 Hz,
H-1), 7.75–7.85 (m, 3 H, H-4, H-5, H-8) ppm. 13C NMR:
d = 27.7 (3 Me), 83.6 (C), 118.1 (CH), 120.8 (CH), 125.6
(CH), 126.5 (CH), 127.6 (CH), 127.7 (CH), 129.3 (CH),
131.3 (C), 133.7 (C), 148.7 (C), 152.0 (C=O) ppm. MS (EI):
m/z (%) = 244 (1) [M+], 185 (4), 144 (100), 127 (7), 115 (45),
89 (6), 63 (5), 57 (24).
separated, dried over MgSO4, filtered and the solvent was
removed by rotary evaporation. The Boc alcohols 2a–m
were purified, when necessary, by flash chromatography on
silica gel with a mixture of PE–Et2O = 8:2.
(19) Product ratio was calculated by integration of the triplet at
d = 3.64 ppm (2 H, J = 6.6 Hz, CH2O of 1l) and doublets at
d = 1.26 ppm (d, 3 H, MeCH, 3l) and d = 1.19 ppm (d, 3 H,
MeCH, 2l) in the 1H NMR spectrum of the crude reaction
mixture. Products were then separated by flash
chromatography and recovered amounts confirmed the
calculated ratio.
(20) Product ratio was calculated by integration of the triplet at
d = 3.68 ppm (2 H, J = 6.6 Hz, CH2O of 1m) and singlets at
d = 1.49 ppm (9 H, aromatic Boc) and d = 1.55 ppm (9 H +
9 H, aliphatic Boc) in the 1H NMR spectrum of the crude
reaction mixture. Products were then separated by flash-
chromatography and recovered amounts confirmed the
calculated ratio.
20
Cholesteryl tert-butyl carbonate (2j): mp 141–142 °C; [a]D
(solv) –30.6 (c 0.99, CHCl3). 1H NMR: d = 0.68 (s, 3 H, H-
18), 0.86 (d, 6 H, J = 6.2 Hz, H-26, H-27), 0.91 (d, 3 H, J =
6.4 Hz, H-21), 1.00 (s, 3 H, H-19), 1.49 (s, 9 H, t-Bu), 0.80–
2.06 (m, 27 H), 2.33–2.42 (m, 2 H), 4.34–4.49 (m, 1 H, H-
3), 5.39 (d, 1 H, J = 4.7 Hz, H-6) ppm. 13C NMR: d = 12.1
(C-18), 18.9 (C-21), 19.4 (C-19), 21.1 (C-11), 22.8 (C-26),
23.0 (C-27), 24.0 (C-23), 24.5 (C-15), 28.0 (C-2, C-25), 28.1
(3 Me), 28.2 (C-16), 32.1 (C-7, C-8), 36.0 (C-20), 36.4 (C-
22), 36.8 (C-10), 37.2 (C-4), 38.3 (C-1), 39.7 (C-24), 39.9
(C-12), 42.5 (C-13), 50.2 (C-9), 56.4 (C-17), 56.9 (C-14),
77.6 (C-3), 81.9 (C), 122.9 (C-6), 139.8 (C-5), 153.1 (C=O)
ppm. MS (EI): m/z (%) = 429 (1), 405 (4), 386 (57), 301 (55),
275 (60), 255 (51), 213 (63), 207 (47), 159 (59), 145 (75),
107 (87), 105 (77), 57 (70), 55 (88), 44 (100).
(21) (a) Molina, P.; Alajarin, M.; Sanchez-Andrada, P.
Tetrahedron Lett. 1993, 34, 5155. (b) Dean, C. S.; Tarbell,
D. S.; Friedergang, A. W. J. Org. Chem. 1970, 35, 3393.
(22) All the reactions were carried out without solvent. A mixture
of alcohols 1a–d,f,g,n–z,aa (1 mmol), di-tert-butyl
dicarbonate (1.1 mmol), and Zn(OAc)2·2H2O (0.1 mmol)
were melted (50–60 °C) in a two-necked flask equipped with
a magnetic stirring bar. The mixture was stirred until the GC-
MS analysis revealed the presence of 1 (Table 2). The crude
reaction mixture was diluted with H2O and extracted twice
with CH2Cl2. The organic layer was separated, dried over
MgSO4, filtered and the solvent was removed by rotary
evaporation. The Boc alcohols 2a–d,f,g,n–z,aa were
purified, when necessary, by flash chromatography on silica
gel with a mixture of PE–Et2O = 8:2.
(3-Hydroxy-3-methylbutyl) tert-butyl carbonate (2k): oil.
1H NMR: d = 1.27 (s, 6 H, 2 e), 1.49 (s, 9 H, t-Bu), 1.87 (t, 2
H, J = 6.8 Hz, CH2), 4.25 (t, 2 H, J = 6.8 Hz, CH2O) ppm.
13C NMR: d = 27.7 (3 Me), 29.5 (2 Me), 41.5 (CH2), 63.9
(CH2), 69.8 (C), 82.0 (C) ppm. MS (EI): m/z (%) = 148 (5),
133 (15), 89 (16), 84 (16), 71 (52), 59 (100), 57 (78).
(23) Benzyl tert-butyl carbonate (2c),6 (4-methoxyphenyl) tert-
butyl carbonate (2f),10 phenyl tert-butyl carbonate (2g),25 (4-
nitrophenyl) tert-butyl carbonate (2h)10 and (2-phenylethyl)
tert-butyl carbonate (2o)12 are known compounds. Physical
data for new compounds follow.
(5-Hydroxyhexyl) tert-butyl carbonate (2l): oil. H NMR:
1
d = 1.19 (d, 3 H, J = 6.1 Hz, MeCH), 1.61–1.74 (m, 4 H,
CH2CH2), 1.49 (s, 9 H, t-Bu), 1.61–1.74 (m, 2 H, CH2), 1.79
(br s, 1 H, disappears with D2O, OH), 3.85–3.74 (m, 1 H,
CHO), 4.07 (t, 2 H, J = 6.5 Hz, CH2O) ppm. 13C NMR: d =
21.9 (Me), 23.4 (CH2), 27.7 (3 Me), 28.6 (CH2), 38.7 (CH2),
66.9 (CH2), 67.8 (CH), 81.8 (C), 153.6 (C=O) ppm. MS (EI):
m/z (%) = 162 (2) [M+ – 56], 145 (3), 119 (8), 100 (7), 85
(20), 83 (28), 57 (100), 56 (61).
Octyl tert-butyl carbonate (2a): oil. 1H NMR: d = 0.88 (t, 3
H, J = 7.1 Hz, Me), 1.20–1.40 [m, 10 H, (CH2)5], 1.49 (s, 9
H, t-Bu), 1.60–1.70 (m, 2 H, CH2), 4.05 (t, 2 H, J = 6.8 Hz,
CH2O) ppm. 13C NMR: d = 14.0 (Me), 22.6 (CH2), 25.7
(CH2), 27.6 (3 Me), 28.7 (CH2), 29.1 (CH2), 29.2 (CH2), 31.7
(CH2), 67.2 (CH2), 81.7 (C), 153.7 (C=O). MS (EI): m/z
(%) = 113 (5), 112 (8), 84 (19), 83 (19), 71 (16), 70 (24), 69
(24) 57 (100).
1
Bis(1,5-tert-butoxycarbonyloxy)hexane (3l): oil. H NMR:
d = 1.26 (d, 3 H, J = 6.7 Hz, MeCH), 1.49 (s, 18 H, 2 t-Bu),
1.50–1.76 (m, 6 H, 3 CH2), 4.06 (t, 2 H, J = 6.4 Hz, CH2O),
4.64–4.76 (m, 1 H, CHO) ppm. 13C NMR: d = 19.9 (Me),
21.7 (CH2), 27.72 (3 Me), 27.74 (3 Me), 28.5 (CH2), 35.5
(CH2), 66.7 (CH2), 73.7 (CH), 81.6 (C), 81.8 (C), 153.2
(C=O), 153.6 (C=O) ppm. MS (EI): m/z (%) = 206 (3) [M+ –
(56 × 2)], 145 (11), 119 (9), 101 (7), 83 (35), 57 (100), 56
(38).
3-(4-Hydroxyphenyl)propyl tert-butyl carbonate (2m): oil.
1H NMR: d = 1.49 (s, 9 H, t-Bu), 1.93 (quint, 2 H, J = 7.0 Hz,
CH2), 2.63 (t, 2 H, J = 7.1 Hz, CH2), 4.07 (t, 2 H, J = 7.0 Hz,
CH2O), 5.17 (br s, 1 H, disappears with D2O, OH), 6.70 and
7.04 (A2B2 system, 2 H + 2 H, ArH) ppm. 13C NMR: d = 27.8
(3 Me), 30.4 (CH2), 31.0 (CH2), 66.4 (CH2), 82.1 (C), 115.3
(2 CH), 129.5 (2 CH, C), 133.4 (C), 153.9 (C=O) ppm. MS
(EI): m/z (%) = 252 (1) [M+] 196 (7), 152 (25), 133 (50), 107
(100), 77 (18), 57 (14), 56 (14).
[(E)-3-Hexenyl] tert-butyl carbonate (2b): oil. 1H NMR: d =
0.97 (t, 3 H, J = 7.5 Hz, Me), 1.49 (s, 9 H, t-Bu), 1.95–2.10
(m, 2 H, CH2), 2.30–2.40 (m, 2 H, CH2), 4.06 (t, 2 H, J = 6.8
Hz, CH2O), 5.30–5.45 [dtt, 1 H, J = 15.2 (d), 6.8 (t), 1.6
(t)Hz, CH=], 5.50–5.65 [dtt, 1 H, J = 15.2 (d), 6.3 (t), 1.4
(t)Hz, CH=] ppm. 13C NMR: d = 13.7 (Me), 25.7 (CH2), 27.9
(3 Me), 32.1 (CH2), 66.7 (CH2), 81.8 (C), 123.8 (CH=),
135.3 (CH=), 153.7 (C=O) ppm. MS (EI): m/z (%) = 144 (1),
82 (100), 67 (74), 57 (64), 55 (44).
Ethyl (S)-2-(tert-butoxycarbonyloxy)propanoate (2d): oil;
[a]D20 (solv) –34.3 (c 1.02, CHCl3). 1H NMR: d = 1.28 (t, 3
H, J = 7.2 Hz, Me), 1.51 (d, 3 H, J = 7.1 Hz, Me) ppm. 13
C
NMR: d = 14.0 (Me), 16.9 (Me), 27.6 (3 Me), 61.3 (CH2),
70.8 (CH), 82.8 (C), 152.7 (C=O), 170.7 (C=O) ppm. MS
(EI): m/z (%) = 163 (3), 145 (10), 101 (16), 87 (3), 75 (5), 73
(13), 57 (100).
2-(tert-Butoxycarbonyloxy)-1,2-diphenylethanone (2e): mp
147–148 °C. 1H NMR: d = 1.49 (s, 9 H, t-Bu), 6.70 (s, 1 H,
CHO), 7.30–7.50 and 7.92–7.96 (m, 8 H + 2 H, ArH) ppm.
13C NMR: d = 27.7 (3 Me), 79.7 (CH), 83.2 (CH), 128.6 (2
3-(4-tert-Butoxycarbonyloxyphenyl)propyl tert-butyl
carbonate (3m): oil. 1H NMR: d = 1.49 (s, 9 H, t-Bu), 1.55
(s, 9 H, t-Bu), 1.90–2.02 (m, 2 H, CH2), 2.63–2.73 (m, 2 H,
CH2), 4.08 (t, 2 H, J = 6.4 Hz, CH2O), 7.08 and 7.18 (A2B2
system, 2 H + 2 H, ArH) ppm. 13C NMR: d = 27.6 (3 Me),
27.7 (3 Me), 30.3 (CH2), 31.4 (CH2), 66.3 (CH2), 81.9 (C),
Synlett 2006, No. 13, 2104–2108 © Thieme Stuttgart · New York

2108
G. Bartoli et al.
LETTER
83.4 (C), 121.2 (2 CH), 129.2 (2 CH,), 138.6 (C), 149.3 (C),
152.2 (C=O), 153.6 (C=O) ppm. MS (EI): m/z = (%) 280 (1)
[M+ – 72], 262 (10), 150 (48), 133 (10), 104 (100), 91 (58),
71 (20), 57 (25).
d = 1.55 (s, 9 H, t-Bu), 7.00–7.15 (m, 4 H, ArH) ppm. 13
C
NMR: d = 27.7 (3 Me), 83.7 (C), 116.0 (d, JC–F 23.6 Hz, 2
CH), 122.7 (d, JC–F = 9.0 Hz, 2 CH), 147.0 (d, JC–F = 3.3 Hz,
C), 151.9 (C=O), 160.1 (d, JC–F = 246.0 Hz, C) ppm. MS
(EI): m/z (%) = 197 (6), 139 (15), 119 (95), 95 (29), 83 (26),
57 (100).
[(Z)-3-Hexenyl] tert-butyl carbonate (2n): oil. 1H NMR: d =
0.97 (t, 3 H, J = 7.5 Hz, Me), 1.48 (s, 9 H, t-Bu), 2.06 (quint,
2 H, J = 7.5 Hz, CH2), 2.41 (q, 2 H, J = 7.1 Hz, CH2), 4.05
(t, 2 H, J = 7.1 Hz, CH2O), 5.27–5.38 (m, 1 H, CH=), 5.46–
5.57 (m, 1 H, CH=) ppm. 13C NMR: d = 14.2 (Me), 20.6
(CH2), 26.8 (CH2), 27.4 (3 Me), 66.4 (CH2), 81.8 (C), 123.3
(CH=), 134.8 (CH=), 153.6 (C=O) ppm. MS (EI): m/z (%) =
144 (1), 82 (100), 67 (86), 57 (88), 55 (54).
5-Indolyl tert-butyl carbonate (2w): mp 111–112 °C. 1H
NMR: d = 1.57 (s, 9 H, t-Bu), 6.53 (br s, 1 H, H-3), 6.99 (dd,
1 H, J = 8.7, 2.2 Hz, H-6), 7.22 (t, 1 H, J = 2.9 Hz, H-2), 7.33
(d, 1 H, J = 8.7 Hz, H-7), 7.41, (d, J = 2.1 Hz, H-4), 8.17 (br
s, 1 H, NH) ppm. 13C NMR: d = 27.7 (3 Me), 83.1 (C), 102.8
(C-3), 111.3 (C-4), 112.4 (C-7), 115.8 (C-6), 125.6 (C-2),
128.0 (C-3¢), 133.6 (C-7¢), 144.8 (C), 153.0 (C) ppm. MS
(EI): m/z (%) = 233 (2) [M+], 174 (4), 133 (100), 116 (5), 104
(16), 77 (6), 57 (20).
4-(tert-Butoxycarbonyloxy)-3-methyl-2-butanone (2p): oil.
1H NMR: d = 1.15 (d, 3 H, J = 7.3 Hz, Me), 1.48 (s, 9 H,
t-Bu), 2.21 (s, 3 H, MeCO), 2.85–2.95 (m, 1 H, CH), 4.07
(dd, 1 H, J = 11.0, 5.8 Hz, CHO), 4.27 (dd, 1 H, J = 11.0, 7.4
Hz, CHO) ppm. 13C NMR: d = 13.6 (Me), 27.9 (3 Me), 29.0
(Me), 46.2 (CH), 67.9, (CH2), 82.5 (C), 153.5 (C=O), 209.5
(C=O) ppm. MS (EI): m/z (%) = 146 (2), 105 (11), 85 (30),
69 (11), 57 (100).
3-(tert-Butoxycarbonyloxy)-2-methyl-1-phenylpropene
(2q): oil. 1H NMR: d = 1.51 (s, 9 H, t-Bu), 1.91 (s, 3 H, Me),
4.62 (s, 2 H, CH2O), 6.55 (s, 1 H, CH=), 7.20–7.35 (m, 5 H,
ArH) ppm. 13C NMR: d = 15.5 (Me), 27.8 (3 Me), 72.7
(CH2), 82.1 (C), 126.7 (CH), 128.1 (2 CH), 128.6 (CH),
128.9 (2 CH), 132.5 (C), 137.0 (C), 153.5 (C=O) ppm. MS
(EI). m/z (%) = 192 (47), 148 (26), 131 (61), 130 (100), 129
(67), 115 (60), 91 (58), 57 (23).
[3-(N,N-Dimethylamino)propyl] tert-butyl carbonate (2r):
oil. 1H NMR: d = 1.47 (s, 9 H, t-Bu), 1.75–1.90 (m, 2 H,
CH2), 2.21 (s, 6 H, NMe2), 2.34 (t, 2 H, J = 7.4 Hz, CH2N),
4.10 (t, 2 H, J = 6.7 Hz, CH2O) ppm. 13C NMR: d = 27.1
(CH2), 27.8 (3 Me), 45.5 (2 Me), 56.2 (CH2), 65.5 (CH2),
81.9 (C), 153.6 (C=O). MS (EI): m/z (%) = 203(5) [M+], 130
(5), 86 (12), 58 (100).
2,2-Dimethyl-4-(tert-butoxycarbonyloxymethyl)-1,3-
dioxolane (2x): oil. 1H NMR: d = 1.36 (s, 3 H, Me), 1.43 (s,
3 H, Me), 1.49 (s, 9 H, t-Bu), 3.78 (dd, 1 H, J = 8.5, 5.9 Hz,
H-5a), 4.04–4.16 (m, 3 H, CH2 and H-5b), 4.33 (quint, 1 H,
J = 5.7 Hz, H-4) ppm. 13C NMR: d = 25.2 (Me), 26.6 (Me),
27.6 (3 Me), 66.3 (CH2), 66.9 (CH2), 73.3 (CH), 82.3 (C),
109.7 (O–C–O), 153.2 (C=O). MS (EI): m/z (%) = 217 (5)
[M+ – 15], 161 (67), 117 (100), 101 (64), 57 (64).
4-(Tetrahydropyranyloxy)butyl tert-butyl carbonate (2y):
oil. 1H NMR: d = 1.49 (s, 9 H, t-Bu), 1.45–1.88 (m, 10 H, 5
CH2), 3.36–3.55 (m, 2 H, CH2), 3.70–3.90 (m, 2 H, CH2),
4.10 (t, 2 H, J = 6.80 Hz, CH2-OBoc), 4.58 (t, 1 H, J = 3.50
Hz, CH) ppm. 13C NMR: d = 19.5 (CH2), 25.4 (CH2), 25.7
(CH2), 26.0 (CH2), 27.7 (3 Me), 30.6 (CH2), 62.2 (CH2), 66.8
(CH2), 66.9 (CH2), 81.7 (C), 98.7 (O–C–O), 153.6 (C=O)
ppm. MS (EI): m/z (%) = 217 (1) [M+ – 57], 160 (1), 117
(18), 101 (31), 85 (100), 73 (35), 57 (57), 55 (67).
6-(Triisopropyloxy)hexyl tert-butyl carbonate (2z): oil. 1H
NMR: d = 0.97–1.08 (m, 21 H), 1.30–1.41 (m, 4 H, 2 CH2),
1.48 (s, 9 H, t-Bu), 1.43–1.58 (m, 2 H, CH2), 1.59–1.70 (m,
2 H, CH2), 3.66 (t, 2 H, J = 6.9, CH2OSi), 4.05 (t, 2 H, J =
7.3 Hz, CH2OBoc) ppm. 13C NMR: d = 12.0 (3 CH), 18.0 (6
Me), 25.5 (CH2), 25.6 (CH2), 27.8 (3 Me), 28.7 (CH2), 32.8
(CH2), 63.3 (CH2), 67.1 (CH2), 81.7 (C), 153.7 (C=O) ppm.
MS (EI): m/z (%) = 275 (3) [M+ – 99], 231 (13), 171 (12),
149 (16) 131 (83), 119 (51), 103 (44), 83 (93), 75 (50), 55
(100).
Menthyl tert-butyl carbonate (2s): oil; [a]D20 (solv) –42.5 (c
0.97, CHCl3). 1H NMR: d = 0.79 (d, 3 H, J = 6.9 Hz, Me),
0.89 (d, 3 H, J = 7.1 Hz, Me), 0.91 (d, 3 H, J 6.4 Hz, Me),
0.95–1.10 (m, 2 H), 1.35–1.45 (m, 2 H), 1.48 (s, 9 H, t-Bu),
1.60–1.70 (m, 2 H), 1.90–2.10 (m, 2 H), 4.47 [dt, 1 H, J =
11.2 (t), 4.4 (d)Hz, CHO] ppm. 13C NMR: d = 16.1 (Me),
20.7 (Me), 21.9 (Me), 23.2 (CH2), 26.0 (CH), 27.8 (3 Me),
31.4 (CH), 34.1 (CH2), 40.9 (CH2), 46.9 (CH), 77.0 (CH),
81.4 (C), 153.3 (C=O) ppm. MS (EI): m/z (%) = 138 (64),
123 (28), 95 (56), 81 (54), 71 (24), 57 (100).
tert-Butyl 3-(tert-butoxycarbonyloxy)-2-(tert-butoxy-
carbonylamino)propanoate (2aa): mp 85–87 °C. 1H NMR:
d = 1.45 (s, 9 H, t-Bu), 1.47 (s, 18 H, 2 t-Bu), 4.23 (dd, 1 H,
J = 11.0, 3.0 Hz, CHH), 4.43 [dt, 1 H, J = 8.0 (d), 3.0 (t) Hz,
CH], 4.51 (dd, 1 H, J = 11.0, 3.0 Hz, CHH), 5.34 (br d, 1 H,
J = 8.0 Hz, NH) ppm. 13C NMR: d = 27.6 (3 Me), 27.8 (3
Me), 28.2 (3 Me), 53.5 (CH), 66.7 (CH2), 79.9 (C), 82.4 (C),
82.6 (C), 153.0 (C=O), 155.1 (C=O), 168.5 (C=O) ppm. MS
(EI): m/z (%) = 234 (2) [M+ – 127], 232 (2), 204 (11), 176
(9), 148 (8), 104 (36), 59 (23), 57 (100).
2-Octyl tert-butyl carbonate (2t): oil. 1H NMR: d = 0.88 (t, 3
H, J = 7.1 Hz, Me), 1.25 (d, 3 H, J = 6.2 Hz, Me) 1.25–1.35
[m, 8 H, (CH2)4], 1.48 (s, 9 H, t-Bu), 1.44–1.70 (m, 2 H,
CH2), 4.66–4.74 (m, 1 H, CHO) ppm. 13C NMR: d = 14.0
(Me), 20.0 (Me), 22.5 (CH2), 25.4 (CH2), 27.8 (3 Me), 29.1
(CH2), 31.7 (CH2), 36.0 (CH2), 74.2 (CH), 81.5 (C) 153.3
(C=O). MS (EI): m/z (%) = 129 (4), 113 (7), 112 (10), 97 (6),
84 (6), 83 (6), 71(14), 57 (100).
(24) In a blank run, octanol and Boc2O were stirred together for
144 h and only 13% conversion to carbonate was detected by
NMR.
(25) Product ratio was calculated by integration of the triplets at
d = 4.10 (J = 6.7 Hz) and 4.18 (J = 6.4 Hz) ppm (typical of
2r and 4r, respectively) in the 1H NMR spectrum of the
crude reaction mixture.
(3-Methoxyphenyl) tert-butyl carbonate (2u): oil. 1H NMR:
d = 1.56 (s, 9 H, t-Bu), 3.79 (s, 3 H, OMe), 6.70–6.80 (m, 3
H, H-2, H-4, H-6), 7.26 (t, 1 H, J = 8.4 Hz, H-5) ppm. 13
C
NMR: d = 27.7 (3 Me), 55.4 (OMe), 83.5 (C), 107.3 (CH),
111.6 (CH), 113.5 (CH), 129.7 (CH), 151.7 (C), 152.0
(C=O), 160.4 (C) ppm. MS (EI): m/z (%) = 165 (10), 124
(100), 95 (17), 94 (25), 81 (13), 57 (34).
(26) Nakamura, K.; Nakajima, T.; Kayahara, H.; Nomura, E.;
Taniguchi, H. Tetrahedron Lett. 2004, 45, 495.
1
(4-Fluorophenyl) tert-butyl carbonate (2v): oil. H NMR:
Synlett 2006, No. 13, 2104–2108 © Thieme Stuttgart · New York