The direct conversion of carbamates to ureas using aluminum amides

Article abstract of DOI:10.1016/j.tet.2004.02.034

The conversion of carbamates into ureas using aluminum amide complexes is reported. This reaction is a convenient method to prepare bi-, tri- and tetra-substituted ureas from carbamate-protected primary or secondary amines by reaction with primary or secondary amines in the presence of stoichometric quantities of trimethylaluminum. A reactivity trend of the various carbamates was observed and methyl and benzyl carbamates were reacted selectively in the presence of t-butyl carbamates.

Full text of DOI:10.1016/j.tet.2004.02.034

Tetrahedron 60 (2004) 3439–3443
The direct conversion of carbamates to ureas using
aluminum amides
*
Sang-Hyuep Lee, Hana Matsushita, Bruce Clapham and Kim D. Janda
*
Department of Chemistry, The Scripps Research Institute and The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road,
La Jolla, CA 92037, USA
Received 15 January 2004; revised 9 February 2004; accepted 17 February 2004
Abstract—The conversion of carbamates into ureas using aluminum amide complexes is reported. This reaction is a convenient method to
prepare bi-, tri- and tetra-substituted ureas from carbamate-protected primary or secondary amines by reaction with primary or secondary
amines in the presence of stoichometric quantities of trimethylaluminum. A reactivity trend of the various carbamates was observed and
methyl and benzyl carbamates were reacted selectively in the presence of t-butyl carbamates.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Alloc or methyl carbamate, and thus, prior removal of
such a protecting group adds yet another step to the
aforementioned two step reaction sequence. Although the
direct conversion of carbamate-protected primary amines
into ureas has been reported,6 in both cases, carbamate-
protected secondary amines could not be used since these
reactions proceed via the in situ conversion of the carbamate
to the isocyanate by reaction with a halosilane. Accordingly,
a simple and efficient method that enables the conversion of
both carbamate-protected primary and secondary amines
into the corresponding di-, tri- and tetra- substituted ureas is
of great interest and importance to synthetic chemists.
The urea functional group plays an important role in organic
and medicinal chemistry; many biologically active com-
pounds either contain the urea functionality1 or are
synthesized from urea-containing starting materials.2 In
addition, ureas have been utilized for the synthesis of
peptidomimetic compounds whereby the amide bond of the
peptide is replaced by a urea bond so that the peptide mimic
possesses many of the key structural features of the parent
peptide, but has increased bioavailability since the urea
bond is not susceptible to proteolytic cleavage.3 Accord-
ingly, simple and efficient methods for the synthesis of ureas
are of interest. Since ureas are derived from amine
constituents, a common method for their preparation
involves conversion of the first amine component to an
isocyanate or an activated carbamate4 (e.g., p-nitrophenyl)
followed by reaction with the second amine component.
However, the shortcomings of this methodology become
apparent when the first amine component bears more than
one substituent. Specifically, secondary amines cannot be
converted to the corresponding isocyanates and secondary
p-nitrophenyl carbamates suffer from low reactivity toward
a second amine nucleophile; in the latter case, more drastic
conditions such as the preparation of the corresponding
carbamoyl chloride5 are required. Furthermore, quite often
in any given synthetic sequence, the first amino component
may have been previously protected by a common
carbamate protecting group such as Boc, Cbz, Fmoc,
Our own interest in the synthesis of ureas stems from our
recent studies in the solid-phase synthesis of heterocycle
libraries.7 Here, we have utilized an ester moiety to link the
target library scaffold to the polymer-support; a Lewis acid-
mediated amidation reaction8 was employed to afford an
array of amide cleavage products.9 Lewis acid-mediated
amide bond forming reactions have been used extensively in
synthetic chemistry and a plethora of reagents including
AlMe3 and AlCl3 have been used. In addition, the use of
aluminum amides has also been applied toward the
synthesis of guanidines10 and the ring opening of oxa-
zolidinones to form hydroxyl ureas.11 More recently, we
have also expanded the scope of amide forming reactions
using 1,2-phenylenediamines or 1,2-aminothiophenols as
substrates to produce the corresponding benzimidazole or
benzothiazole cleavage products from polymer-bound ester
substrates.12 Unexpectedly, during our investigations of
Lewis acid mediated C–N bond forming reactions, we also
discovered that under mild conditions, carbamates are
converted into the corresponding ureas by reaction with
aluminum amides. Reported herein are these findings.
Keywords: Ureas; Carbamate; Lewis acid.
*
Corresponding authors. Tel.: þ1-858-784-2519; fax: þ1-858-784-2595
(B.C.); tel.: þ1-858-784-2515; fax: þ1-858-784-2595 (K.D.);
e-mail addresses: bclapham@scripps.edu; kdjanda@scripps.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.02.034

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S.-H. Lee et al. / Tetrahedron 60 (2004) 3439–3443
2. Results and discussion
reactivity of mono- and di-substituted carbamates 4 and the
ease of preparation of the corresponding tri- and tetra-
substituted ureas 5, Scheme 2, Table 2.
To begin with, we investigated the conversion of a series of
carbamate protected anilines 1, into the corresponding ureas
3, Scheme 1, Table 1. In this study, we tested the most
widely used carbamate protecting groups, such as methyl
carbamate, Boc, Cbz, Alloc, Troc, Fmoc and Teoc.13 In
most instances, when the carbamates 1a–g were treated
with an excess of piperidine 2 and AlMe3 (amine/metal/
carbamate ratio 3:2.5:1) the corresponding urea 3 was
formed in good to excellent yields after only 2–5 h. at room
temperature. When the t-butyl carbamate 1b was used
(Boc), the rate of conversion proved to be very slow as
estimated by TLC; however, when heated to 50 8C this
reaction was complete within 1.5 h. The only example that
gave a poor yield in these experiments was the Fmoc-
protected aniline 1f where the desired product 3 was only
isolated in 34% yield. This low yield was attributed to the
high lability of the Fmoc group to piperidine 2.
Once again, the reaction showed broad scope and excellent
reliability. There was a discernable difference between the
rate of conversion of primary and secondary carbamates 4
into the respective ureas 5. For example, when ethyl
carbamate 4b was reacted with the piperidine/AlMe3 adduct
(amine/metal/substrate ratio 3:2.5:1), the reaction had to be
heated to 110 8C to give the desired product 5b in 96% yield
after 3 h. However, our previous experiments had shown
that the primary amine 1a (aniline methyl carbamate) was
readily converted into the desired urea 3 at room
temperature over a similar reaction time (Table 1, entry 1
vs Table 2, entry 2). A similar trend was observed when
carbamates derived from secondary amines, N-Cbz piper-
idine and diphenylamine N-ethyl carbamate were converted
into the corresponding urea products 5d and 5e (Table 2,
entries 4 and 5); in both cases, the reactions had to be heated
to 110 8C to enable good conversion to the desired product
in an acceptable period of time.
We also investigated what effect the nature of the amine
component 6 of the reaction would have on the rate of
formation of the urea product 7, Scheme 3, Table 3. It
appears that both the nucleophilicity of the amine coupling
partner and the steric bulk of the amine substituents have a
dramatic effect on the rate of conversion into the desired
ureas. For example, when butylamine 6 (R1¼Bu, R2¼H)
was reacted with N-Alloc aniline 1d, the corresponding urea
7a was formed in 99% yield after heating at 50 8C for
30 min; however, when the bulky diisopropylamine 6
(R1¼R2¼i-Pr) was used, the corresponding urea 7c was
formed in 94% yield after heating to 50 8C for 1 h (Table 3,
entries 1 and 3). In addition, when benzylamine 6 was used
in the reaction, the desired urea 7b was formed within
30 min. but when the similar sized but when less
nucleophilic aniline 6 (R1¼Ph, R2¼H) was used, the
reaction time had to be extended to 4 h to give the
corresponding urea 7d in 83% yield (Table 3, entries 2 vs
4). Finally, when diphenylamine 6 (R1¼R2¼Ph) was used,
the reaction required heating to 110 8C to achieve and
acceptable rate of conversion to product 7f.
Scheme 1. Reagents and conditions: (a) 2 (3 equiv.), AlMe3 (2.5 equiv.),
toluene.
Table 1.
Entry
Substrate (R¼)
1a CH3
1b t-Butyl
1c Bn
1d Allyl
1e Cl3CCH2
1f Fluorenylmethyl
1g Me3Si(CH2)2
Temperature (8C) Time (h) Yield (%)
1
2
3
4
5
6
7
Room temperature
50
2.5
1.5
3.5
2
78
92
93
89
96
34a
90
Room temperature
Room temperature
Room temperature
80
2
2
Room temperature
5
a
5 equiv. of AlMe3 used.
With these results in hand, the next variable to be
investigated was the effect of the type, and number of
substituents on the nitrogen atom of the carbamate. Thus,
this study would enable us to assess the scope of the Lewis
acid mediated reaction with regards to establishing the
Scheme 2. Reagents and conditions: (a) 2 (3 equiv.), AlMe3 (2.5 equiv.),
toluene.
Scheme 3. Reagents and conditions: (a) 6 (3 equiv.), AlMe3 (2.5 equiv.),
toluene.
Table 2.
Table 3.
Entry Sub.
R1
R2 R3 Temperature Time Prod. Yield
(8C)
(h)
(%)
Entry
R1
R2
Temperature (8C) Time Product Yield (%)
1
2
3
4
5
4a Bn
4b Ph
4c Ph(CH2)2
H
Bn
Me Et
50
110
50
110
110
4.5 5a
95
96
1
2
3
4
5
6
Bu
Bn
i-Pr i-Pr
Ph
Me
Ph
H
H
50
50
50
50
50
110
0.5
0.5
1
4
5
7a
7b
7c
7d
7e
7f
99
94
94
83
95
97
3
4
3
5
5b
5c
5d
5e
H
Et
Bn
98
4d
4e Ph
–(CH2)4–
91a
99
H
Ph
Ph
Ph Et
2
a
Phenylethylamine used in place of piperidine.

S.-H. Lee et al. / Tetrahedron 60 (2004) 3439–3443
3441
We note that when inexpensive and readily available amine
starting materials were used, a slight excess of the amine
over the carbamate was employed to drive the reaction to
completion in shorter period of time, although further
experiments have shown that with more valuable amines or
for chemoselective reactions, the stoichiometry can be
reduced (amine/metal/substrate ratio 1.1:1:1). The use of a
slight excess of amine is also not critical to the work up and
purification of the desired urea products. After completion
of the reaction, (estimated by TLC), the reaction was
quenched using water and then passed through a strong-acid
ion exchange resin to remove unreacted starting materials
and aluminum salt byproducts to furnish an essentially pure
product.
formed exclusively in 92% yield. Moreover, we also
investigated the reaction of Cbz glycine benzyl ester 12b
to unequivocally prove that the ester can be selectively
reacted in the presence of a similarly functionalized
carbamate, the corresponding amide 13 was similarly
formed in 92% yield. Our observations consolidate previous
findings by Martin and co-workers for the synthesis of
carbamate protected peptide fragments via aluminum amide
intermediates.14
Our final investigation of these competition experiments
was to see if we could tune the reactivity of both the
carbamate and ester groups to achieve selective reaction of
the urea in the presence of an ester. Accordingly, methoxy
carbamate glycine t-butyl ester 14 was prepared and reacted
with 1 equiv. of the piperidine trimethylaluminum adduct.
Unfortunately, this experiment failed since both groups
reacted at similar rates; this reaction afforded a mixture of
the piperidine amide urea 15 in 46% yield and the remainder
was unreacted starting material 14 (Scheme 4).
The final part of our study was to investigate if we could
selectively react one carbamate over another and also,
selectively react a carbamate over an ester or vice versa. The
first of these experiments involved the preparation of the
bis-carbamate 8 that was synthesized from 4-nitro aniline by
protecting the aniline with a Boc group, followed by
reduction of the nitro group to the amine, which was then
converted to the benzyl carbamate (Cbz). When 8 was
reacted with 1 equiv. of the piperidine trimethylaluminum
adduct at room temperature for 24 h, the expected reaction
occurred exclusively at the Cbz group, and the Boc
protected product 9 was isolated in 95% yield. A Boc and
Cbz-protected alkyl diamine 10 was also prepared and
subjected to similar urea formation conditions. Once again,
the Cbz group was selectively reacted in the presence of a
Boc group to give the desired product 11 in 92% isolated
yield.
3. Conclusion
In summary, we have developed a highly efficient method
for the direct conversion of carbamates into the correspond-
ing ureas. Our method enabled the synthesis of di-, tri- and
tetra- substituted ureas and we have also been able to show
complete chemoselectivity in the reaction of one carbamate
over another. Further investigations into the reaction of
carbonyls with aluminum amides are ongoing in our
laboratory and will be reported in due course.
We also discovered that esters are significantly more
reactive than the corresponding carbamate under Lewis
acid promoted C–N bond forming conditions. When Cbz
protected glycine methyl ester 12a was reacted with 1 equiv.
of the piperidine trimethylaluminum adduct at room
temperature for 24 h the corresponding amides 13 was
4. Experimental
4.1. Representative procedure
Trimethylaluminum (2.0 M in toluene, 1.25 mL,
Scheme 4. Reagents and conditions: (a) 2 (1.1 equiv.), AlMe3 (1.0 equiv.), toluene.

3442
S.-H. Lee et al. / Tetrahedron 60 (2004) 3439–3443
2.50 mmol) was slowly added to a solution of piperidine 2
(0.30 mL, 3.00 mmol) in toluene (5 mL) at 0 8C under
argon. After being stirred for 10 min at 0 8C, the resulting
solution was allowed to warm up to room temperature and
then stirred for 1 h. The mixture was added dropwise to a
stirred solution of the N-Boc-aniline 1b (152.6 mg,
1.00 mmol) and toluene (3 mL) in a 40 mL vial at 0 8C
under argon and the resulting solution was heated to 50 8C
for 1.5 h. The reaction was quenched by the addition of a
mixture of THF (10 mL) and H2O (3 mL) and stirring was
continued for a further 20 min before the solution was
passed through a work-up cartridge that contained a strong
acid ion exchange resin (DOWEX 500WX2-200) that was
further eluted with THF. The combined filtrates were
concentrated under reduced pressure to yield the crude
product was then purified by column chromatography over
silica (3% CH3CN in CHCl3) to give N-phenyl-N0,N0-
pentamethylene urea as a colorless solid (159.5 mg,
0.78 mmol, 78%).
4.2.6. Compound 5e. Colorless solid; mp 117.5–118 8C; IR
1
2940, 1641, 1588, 1490, 1421 cm21; H NMR (500 MHz,
CDCl3) d 1.38–1.55 (6H, m), 3.32–3.34 (4H, m), 7.03–
7.12 (6H, m), 7.28–7.31 (4H, m); 13C NMR (125 MHz,
CDCl3) d 24.4 (t), 25.4 (t), 46.5 (t), 124.4 (d), 124.8 (d),
129.1 (d), 145.1 (s), 159.8 (s); HRMS m/z¼281.1650
[MþH], calcd for C18H20N2O¼281.1648.
4.2.7. Compound 7a. Colorless solid; mp 129 8C; IR 3378,
2960, 2932, 2870, 1652, 1597, 1552, 1498 cm21; 1H NMR
(500 MHz, CD3OD) d 0.94 (3H, t, J¼7 Hz), 1.34–1.43 (2H,
m), 1.47–1.53 (2H, m), 3.18 (2H, t, J¼7.0 Hz), 6.93–6.96
(1H, m), 7.20–7.24 (2H, m), 7.31–7.33 (2H, m); 13C NMR
(125 MHz, CD3OD) d 14.1 (q), 21.0 (t), 33.4 (t), 40.5 (t),
120.1 (d), 123.3 (d), 129.8 (d), 141.0 (s), 158.4 (s); HRMS
m/z¼193.1336 [MþH], calcd for C11H16N2O¼193.1335.
4.2.8. Compound 7b. Colorless solid; colorless solid; mp
169.5–170 8C; IR 3301, 1599, 1545, 1498, 1469, 1441,
1
1310, 1222 cm21; H NMR (500 MHz, DMSO-d6) d 4.34
4.2. Spectroscopic data
(2H, d, J¼5.9 Hz), 6.65 (1H, t, J¼5.9 Hz), 6.92–6.95 (1H,
m), 7.24–7.30 (3H, m), 7.34–7.39 (4H, m), 7.44–7.46 (2H,
m), 8.59 (1H, s); 13C NMR (125 MHz, DMSO-d6) d 43.7 (t),
118.6 (d), 122.0 (d), 127.7 (d), 128.1 (d), 129.3 (d), 129.6
(d), 141.3 (s), 141.4 (s), 156.2 (s); HRMS m/z¼227.1178
[MþH], calcd for C14H15N2O¼227.1179.
4.2.1. Compound 3. Colorless solid; mp 169.5–171 8C; IR
3284, 2925, 2855, 1629, 1591, 1533, 1434 cm21; 1H NMR
(500 MHz, CDCl3) d 1.56–1.65 (6H, m), 3.42–3.44 (4H,
m), 6.49 (1H, br s), 6.99–7.02 (1H, m), 7.24–7.27 (2H, m),
7.34–7.36 (2H, m); 13C NMR (125 MHz, CDCl3) d 24.3 (t),
25.6 (t), 45.2 (t), 119.8 (d), 122.7 (d), 128.7 (d), 139.3 (s),
155.0 (s); HRMS m/z¼205.1334 [MþH], calcd for
C12H17N2O¼205.1335.
4.2.9. Compound 7c. Colorless solid; mp 113–115 8C; IR
3271, 2961, 2930, 1630, 1594, 1525, 1501, 1444 cm21; 1H
NMR (500 MHz, CDCl3) d 1.32 (12H, d, J¼7.0 Hz), 3.98
(2H, quartet, J¼7.0 Hz), 6.21 (1H, br s), 6.98–7.16 (1H, m),
7.25–7.28 (2H, m), 7.35–7.32 (2H, m); 13C NMR
(125 MHz, CDCl3) d 21.5 (q), 45.4 (d), 119.6 (d), 122.6
(d), 128.8 (d), 139.3 (s), 154.6 (s); HRMS m/z¼221.1650
[MþH], calcd for C13H21N2O¼221.1648.
4.2.2. Compound 5a. Colorless solid; mp 102 8C; IR 3339,
;
1H NMR (500 MHz,
2927, 2850, 1622, 1533 cm21
CDCl3) d 1.52–1.62 (6H, m), 3.32–3.34 (4H, m),
4.42 (2H, d, J¼5.5 Hz), 4.75 (1H, br s), 7.24–7.34
(5H, m); 13C NMR (125 MHz, CDCl3) d 14.4 (t), 25.6 (t),
44.9 (t), 45.0 (t), 127.2 (d), 127.7 (d), 128.5 (d), 139.6 (s),
157.5 (s); HRMS m/z¼219.1491 [MþH], calcd for
C13H19N2O¼219.1492.
4.2.10. Compound 7d. Colorless solid; mp 243 8C; IR
3271, 3034, 1645, 1592, 1545, 1496, 1439 cm21; 1H NMR
(500 MHz, DMSO-d6) d 6.99–7.02 (2H, m), 7.30–7.34
(4H, m), 7.49–7.51 (4H, m), 8.70 (2H, s); 13C NMR
(125 MHz, DMSO-d6) d 119.1 (d), 122.8 (d), 129.7 (d),
140.7 (s), 153.5 (s); HRMS m/z¼213.1023 [MþH], calcd
for C13H13N2O¼213.1022.
4.2.3. Compound 5b. Colorless oil; IR 2934, 1635, 1594,
1
1495, 1429, 1399 cm21; H NMR (500 MHz, CDCl3) d
1.24–1.29 (4H, m), 1.36–1.41 (2H, m), 3.07–3.10 (4H, m),
3.13 (3H, s), 6.99–7.01 (3H, m), 7.22–7.25 (2H, m);
13C NMR (125 MHz, CDCl3) d 24.2 (t), 25.1 (t), 39.1
(q), 46.4 (t), 123.2 (d), 123.8 (d), 129.0 (d), 146.9 (s),
160.9 (s); HRMS m/z¼219.1490 [MþH], calcd for
C13H19N2O¼219.1492.
4.2.11. Compound 7e. Colorless solid; mp 97–99 8C; IR
3270, 3059, 2927, 1652, 1592, 1523, 1493, 1437 cm21; 1H
NMR (500 MHz, CDCl3) d 3.35 (3H, s), 6.23 (1H, br s),
6.97–7.01 (1H, m), 7.22–7.29 (4H, m), 7.33–7.39 (3H, m),
7.47–7.50 (2H, m); 13C NMR (125 MHz, CDCl3) d 37.2
(q), 130.3 (d), 138.8 (s), 142.9 (s), 154.4 (s); HRMS
m/z¼227.1182 [MþH], calcd for C14H15N2O¼227.1179.
4.2.4. Compound 5c. Colorless solid; mp 78–78.5 8C; IR
1
3320, 2916, 2851, 1615, 1541 cm21; H NMR (500 MHz,
CDCl3) d 1.48–1.59 (6H, m), 2.81 (2H, t, J¼7.0 Hz), 3.24–
3.26 (4H, m), 3.47 (2H, dd, J¼7.0, 12.8 Hz), 7.18–7.31
(5H, m); 13C NMR (125 MHz, CDCl3) d 24.4 (t), 25.5 (t),
36.4 (t), 42.0 (t), 44.8 (t), 126.3 (d), 128.5 (d), 128.8 (d),
139.5 (s), 157.5 (s); HRMS m/z¼233.1648 [MþH], calcd
for C14H21N2O¼233.1648.
4.2.12. Compound 7f. Yellow solid; mp 106–107 8C; IR
3409, 1669, 1593, 1515, 1486, 1435 cm21 1H NMR
;
(500 MHz, CDCl3) d 6.45 (1H, br s), 7.02–7.04 (1H, m),
7.25–7.42 (14H, m); 13C NMR (125 MHz, CDCl3) d 119.3
(d), 123.3 (d), 126.7 (d), 127.5 (d), 128.9 (d), 129.6 (d),
138.4 (s), 142.3 (s); HRMS m/z¼289.1328 [MþH], calcd
for C19H17N2O¼289.1335.
4.2.5. Compound 5d. Colorless oil; IR 2928, 2849, 1639,
1413 cm21; 1H NMR (500 MHz, CDCl3) d 1.52–1.60 (12H,
m), 3.15–3.17 (8H, m); 13C NMR (125 MHz, CDCl3) d 24.8
(t), 25.8 (t), 47.9 (t), 164.8 (s); HRMS m/z¼197.1651
[MþH], calcd for C11H21N2O¼197.1648.
4.2.13. Compound 9. Colorless solid; mp .300 8C; IR
3305, 2934, 1693, 1641, 1543, 1514, 1416 cm21; 1H NMR
(600 MHz, DMSO-d6) d 1.46 (9H, s), 1.43–1.49 (4H, m),

S.-H. Lee et al. / Tetrahedron 60 (2004) 3439–3443
3443
1.54–1.58 (2H, m), 3.38 (4H, t, J¼5.7 Hz), 7.27–7.30
(4H, m), 8.28 (1H, s), 9.13 (1H, br s); 13C NMR
(150 MHz, DMSO-d6) d 24.1 (t), 25.5 (t), 28.2 (q), 44.6
(t), 78.6 (s), 118.2 (d), 120.3 (d), 133.6 (s), 135.2 (s), 152.9
(s), 155.0 (s); HRMS m/z¼320.1969 [MþH], calcd for
C17H26N3O3¼320.1969.
Scripps Research Institute, The Skaggs Institute for
Chemical Biology and Novartis Pharma AG Switzerland.
References and notes
1. Dressman, B. A.; Singh, U.; Kaldor, S. W. Tetrahedron Lett.
1998, 39, 3631.
4.2.14. Compound 11. Colorless solid; mp 94–96 8C;
1
IR cm21; H NMR (500 MHz, CDCl3) d 1.19–1.23 (4H,
2. Gilchrist, T. L. Heterocylic chemistry; Longman: Great
Britain, 1991.
m), 1.36 (9H, s), 1.32–1.40 (8H, m), 1.48–1.53 (2H, m),
2.88 (2H, q, J¼6.6 Hz), 2.97 (2H, q, J¼6.6 Hz), 3.22 (4H, t,
J¼5.3 Hz), 6.32 (1H, t, J¼5.3 Hz), 6.76 (1H, t, J¼5.3 Hz);
13C NMR (150 MHz, CDCl3) d 24.2 (t), 25.4 (t), 26.1 (t),
26.1 (t), 28.3 (q), 29.5 (t), 29.9 (t), 44.3 (t), 77.3 (s), 155.6
(s), 157.3 (s); HRMS m/z¼350.2412 [MþNa], calcd for
C17H33N3O3Na¼350.2414.
3. (a) Patil, S. P.; Vananthakumar, G.-R.; Suresh Babu, V. V.
J. Org. Chem. 2003, 68, 7274. (b) Boeijen, A.; van Ameijde,
J.; Liskamp, R. M. J. J. Org. Chem. 2001, 66, 8454.
(c) Kruijister, J. A. W.; Lefeber, D. J.; Liskamp, R. M. J.
Tetrahedron Lett. 1997, 38, 5335. (d) Burgess, K.; Ibrazo, J.;
Linthicum, D. S.; Shin, H.; Shitangkoon, A.; Totani, R.;
Zhang, A. J. J. Am. Chem. Soc. 1997, 119, 1556.
4. Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1994, 35,
4055.
4.2.15. Compound 13. Colorless solid; mp 106–107 8C; IR
3309, 2940, 2923, 1713, 1631, 1442 cm21 1H NMR
;
(500 MHz, CDCl3) d 1.51–1.57 (4H, m), 1.61–1.66 (2H,
m), 3.29 (2H, br dd, J¼5.1, 5.1 Hz), 3.54 (2H, br dd, J¼5.1,
5.1 Hz), 3.99 (2H, d, J¼4.0 Hz), 5.11 (2H, s), 5.89 (1H, br s),
7.28–7.36 (5H, m); 13C NMR (125 MHz, CDCl3) d 24.2 (t),
25.3 (t), 26.0 (t), 42.5 (t), 43.0 (t), 45.3 (t), 66.7 (t), 127.9 (d),
127.9 (d), 128.4 (d), 136.4 (s), 156.1 (s), 165.8 (s); HRMS
m/z¼277.1546 [MþH], calcd for C15H21N2O3¼277.1547.
5. Wang, G. T.; Chen, Y.; Wang, S.; Sciotti, R.; Sowin, T.
Tetrahedron Lett. 1997, 38, 1895.
6. (a) Gastaldi, S.; Weinreb, S. M.; Stien, D. J. Org. Chem. 2000,
65, 3239. (b) Chong, P. Y.; Janicki, S. Z.; Petillo, P. A. J. Org.
Chem. 1998, 63, 8515.
7. (a) Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3,
2173. (b) Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.;
Janda, K. D. J. Comb. Chem. 2003, 5, 188. (c) Clapham, B.;
Lee, S.-H.; Koch, G.; Zimmermann, J.; Janda, K. D.
Tetrahedron Lett. 2002, 43, 5407. (d) Lee, S.-H.; Clapham,
B.; Koch, G.; Zimmermann, J.; Janda, K. D. Org. Lett. 2003, 5,
511.
4.2.16. Compound 14. Colorless oil; IR 3348, 2980, 1707,
1523, 1367 cm21; 1H NMR (500 MHz, CDCl3) d 1.41 (3H,
s), 1.41 (3H, s), 1.42 (3H, s), 3.63 (3H, s), 3.79–3.81 (2H,
m), 5.31 (1H, br s); 13C NMR (125 MHz, CDCl3) d 27.9 (q),
43.2 (t), 52.2 (q), 81.9 (s), 156.9 (s), 169.2 (s); HRMS
m/z¼212.0894 [MþNa], calcd for C8H15NO4Na¼212.0863.
8. Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977,
18, 4171.
9. (a) Barn, D. R.; Morphy, J. R.; Rees, D. C. Tetrahedron Lett.
1996, 37, 3213. (b) Ley, S. V.; Mynett, D. M.; Koot, W.-J.
Synlett 1995, 1017.
4.2.17. Compound 15. Colorless oil; IR 3385, 2929, 2853,
1
1618, 1509, 1440, 1251, 1222 cm21; H NMR (500 MHz,
CDCl3) d 1.47–1.64 (12H, m), 3.29–3.34 (6H, m), 3.50–
3.54 (2H, m), 3.99 (2H, d, J¼3.3 Hz), 5.62 (1H, br s); 13C
NMR (125 MHz, CDCl3) d 24.3 (t), 24.3 (t), 25.3 (t), 25.5
(t), 26.0 (t), 42.5 (t), 43.0 (t), 44.7 (t), 45.2 (t), 157.1 (s),
167.2 (s); HRMS m/z¼254.1859 [MþH], calcd for
C13H24N3O2¼254.1863.
10. Atwal, K. S.; Ferrara, F. N.; Ahmed, S. Z. Tetrahedron Lett.
1994, 35, 8085.
´
11. Bon, E.; Reau, R.; Bertrand, G.; Bigg, D. C. H. Tetrahedron
Lett. 1996, 37, 1217.
12. Matsushita, H.; Lee, S.-H.; Joung, M.; Clapham, B.; Janda,
K. D. Tetrahedron Lett. 2004, 45, 313.
13. For a comprehensive discussion of carbamate amine protect-
ing groups see: Greene, T. W.; Wuts, P. G. M. Protective
groups in organic synthesis; Wiley: New York, 1999.
14. Martin, S. F.; Dwyer, M. P.; Lynch, C. L. Tetrahedron Lett.
1998, 39, 1517.
Acknowledgements
We gratefully acknowledge financial support from The