Novel practical deprotection of N-Boc compounds using fluorinated alcohols

Article abstract of DOI:10.1080/00397910802238718

The thermolytic deprotection of N-Boc compounds was accomplished using TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) as solvents. Even though the cleavage of the t-butylcarbamate (Boc) group can be achieved at solvent reflux temperature, the deprotection process was significantly accelerated under microwave-assisted conditions. The practicality of this methodology was demonstrated on alkyl, aryl, and heteroaromatic N-Boc-amines. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802238718

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Novel Practical Deprotection
of N-Boc Compounds Using
Fluorinated Alcohols
Jason Choy a , Saul Jaime-Figueroa a , Laurence
Jiang a & Paul Wagner a
a Roche Palo Alto, Palo Alto, California, USA
Published online: 14 Oct 2008.
To cite this article: Jason Choy , Saul Jaime-Figueroa , Laurence Jiang & Paul Wagner
(2008): Novel Practical Deprotection of N-Boc Compounds Using Fluorinated Alcohols,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 38:21, 3840-3853
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Synthetic Communications1, 38: 3840–3853, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802238718
Novel Practical Deprotection of N-Boc
Compounds Using Fluorinated Alcohols
Jason Choy, Saul Jaime-Figueroa, Laurence Jiang, and Paul Wagner
Roche Palo Alto, Palo Alto, California, USA
Abstract: The thermolytic deprotection of N-Boc compounds was accomplished
using TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) as solvents.
Even though the cleavage of the t-butylcarbamate (Boc) group can be achieved at
solvent reflux temperature, the deprotection process was significantly accelerated
under microwave-assisted conditions. The practicality of this methodology was
demonstrated on alkyl, aryl, and heteroaromatic N-Boc-amines.
Keywords: Boc-deprotection, hexafluoroisopropanol, microwave, trifluoroethanol
Among various nitrogen protecting groups in organic chemistry, the t-
butoxycarbonyl (Boc) group is perhaps one of the most widely used
because of its exceptional stability toward a variety of reagents and reac-
tion conditions.[1a] As a result, removal of the Boc group remains of
prime importance in organic synthesis. Cleavage of Boc on nitrogen is
generally achieved under acidic conditions;[1a,1b] however, basic,[2] ther-
molytic,[3] and microwave-assisted conditions[1b,4] are also described in
the literature. In one of the Roche chemistry projects, a new, practical
method was discovered to cleanly deprotect Boc-nitrogens using 2,2,2-tri-
fluoroethanol (TFE) or hexafluoroisopropanol (HFIP) as a solvent in
quantitative yields. The reaction conditions are neutral and do not
require additional reagents (apart from solvents). Thus, the product is
recovered by a simple solvent evaporation without any workup, and in
some cases, no further purification is needed.
Received February 6, 2008.
Address correspondence to Saul Jaime-Figueroa, Roche Palo Alto, 3431
Hillview Ave., Palo Alto, CA 94304. E-mail: saul.jaime@roche.com
3840

Deprotection of N-Boc Compounds
3841
Compared to other solvents, TFE and HFIP are unique because of
their high ionizing power, strong hydrogen bond donor power, and mild
acidic character (pKa ¼ 12.4 and pKa ¼ 9.3 respectively).[5] These out-
standing features encouraged us to explore their use in the deprotection
of N-Boc compounds.
Initially, the cleavage of the Boc group was conducted at the solvent
reflux temperature. Although the deprotection process was successful
under these conditions, long reaction times were often required to achieve
this transformation (see Table 1). To expedite reaction times, the cleavage
was examined under microwave-assisted conditions,[6] and the results are
shown in Table 1. These results suggest that although microwave heating
Table 1. Deprotection of different N-Boc-compounds
Entry
Reflux
Yielda%
Microwave
Yielda (%)
ꢀ
A
B
C
D
E
1 h
6 h
12 h
36 h
ND
83
65
99
81
—
5 min=100 C
97
91
98
80
81
0.5 h=100 ꢀC
1 h=100 ꢀC
1 h=150 ꢀC
2 h=150 ꢀC

3842
J. Choy et al.
is not essential in this process, the reactions are significantly accelerated
with this protocol.
In an effort to explore the role of the solvent in this deprotection
process, N-Boc-4-chloroaniline (7) was subjected to experiments in dif-
ferent solvents. Thus, TFE and HFIP were replaced with solvents such
as acetone, acetonitrile, tetrahydrofuran, chloroform, and toluene under
the same conditions as those indicated in Table 1, entry D (microwave,
150 ꢀC, 1 h). Using these solvents, unreacted Boc-aniline (7) was cleanly
recovered in most cases with a minor amount of the product (8)
detected by NMR (<10%). When nonfluorinated alcohols such as
MeOH or EtOH were used as solvents, the unreacted N-Boc-aniline
(7) was again the main component in the resulting crude mixture with
some of the deprotected product (<25% by NMR). However, in this
case, the corresponding methyl or ethyl-carbamates were also observed
as side products.
To study the generality and scope of this methodology, the deprotec-
tion of a series of alkyl, aryl, and heteroaromatic N-Boc-amines was
initiated. First, the deprotection of a series of N-Boc indoles was per-
formed, varying the electronic nature of the substituents on the indole
ring. In all cases, the product was obtained in essentially quantitative
yields, and the results are summarized in Table 2.
Encouraged by these findings, the deprotection of a series of anilines
was then explored using the same protocol. The results are summarized in
Table 3. Anilines with electron-withdrawing substituents (7a and 7b,
Table 3) were found to react faster than those with electron-donating
groups (7c, 7d, and 7f, Table 3). The reaction conditions employed were
found to be compatible with other protecting groups such as –NCbz,
–NAlloc, and –OTIPS (entries 15–20, Table 3).
To extend the synthetic potential of this deprotection method, this
protocol was further expanded to a wide range of N-Boc amines, and
the results are shown in Table 4. In all cases, the deprotection product
was obtained in good to excellent yields.
It was again confirmed that these reaction conditions were compati-
ble with other protecting groups including –OAc and –OTBDMS (entries
4 and 5, Table 4). More important, compounds that are sensitive to
typical acidic conditions (TFA and HCl) such as 5d and 23 gave the
corresponding deprotected product in excellent yields.
In general, hexafluoroisopropanol is a more reactive solvent than tri-
fluoroethanol for these deprotection reactions. Thus, the use of HFIP
over TFE on the same substrate under similar conditions consistently
reduced reaction times (see odd vs. even entries, Tables 2 and 3). On the
basis of the reactivity differences between TFE and HFIP, the selective,
sequential Boc deprotection of compound 25 was explored. As outlined

Deprotection of N-Boc Compounds
3843
Table 2. Deprotection of indoles under microwave assisted conditions using TFE
and HFIP as solvents
Entry N-Boc
R
–CONH2
–H
R0
–Cl
Solvent
Time
Product Yielda%
1
2
5
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
5 min
5 min
15 min
5 min
5 min
5 min
1 h
5 min
1 h
15 min
1 h
5 min
15 min
5 min
15 min
15 min
6
98
97
99
97
91
96
98
94
95
98
98
98
91
99
81
70
6
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5a
5b
5c
5d
5e
5f
5g
–H
6a
6a
6b
6b
6c
6c
6d
6d
6e
6e
6f
6f
6g
6g
–CHO
–H
–H
–Cl
–H
–OMe
–CN
–NO2
–NH2
–H
–H
–H
aIsolated yields after chromatography.
in Scheme 1, TFE was used to selectively remove the indole Boc moiety
on 25 in good yields. Further treatment of 26 with HFIP efficiently com-
pleted the cleavage of the remaining N-Boc group on the piperazine ring.
On the other hand, if selectivity is not required, both Boc groups can be
removed simultaneously from 25 using HFIP as a solvent.
In summary, a practical and high-yielding method to deprotect
N-Boc compounds using TFE or HFIP has been discovered. Under
this protocol, the product is isolated by a simple solvent evaporation
and minimal workup conditions. HFIP was found to be more reactive
than TFE under similar conditions, and this difference in reactivity

3844
J. Choy et al.
Table 3. Deprotection of anilines under microwave-assisted conditions using
TFE and HFIP as solvents
Entry
N-Boc
7
G
Solvent
Time
Product
Yielda%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
4-Cl
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
HFIP
TFE
1.5 h
1 h
1 h
15 min
1 h
5 min
2 h
0.5 h
1 h
0.5 h
1 h
1 h
3 h
0.5 h
2 h
0.5 h
2 h
8
8
98
80
97
77
95
76
98
85
95
89
98
—
93
97
81
81
99
86
98
98
7a
7b
7c
4-Br,3-Cl
4-NO2
8a
8a
8b
8b
8c
8c
8d
8d
8e
Dec.
8f
4-OMe
3-OMe
2-I
7d
7e
7f
4-NH2
3-OTIPS
4-NHCbz
4-NHAlloc
8f
7g
7h
7i
8g
8g
8h
8h
8i
HFIP
TFE
HFIP
2 h
1 h
0.5 h
8i
aIsolated yield after chromatography.
may allow the selective removal of different Boc groups in the same
molecule. The mild reaction conditions are compatible with many pro-
tecting groups such as –OTIPS, –OTBDMS, –OAc, –OBn, –NCbz, and
–NAlloc. This methodology can be applied when substrates are sensitive
to deprotection under typical acidic conditions (TFA or HCl).
The extension of this methodology to the saponification of t-butyl-
esters has proven successful, and this work is currently under further
investigation.

Deprotection of N-Boc Compounds
3845
Table 4. Deprotection of various N-Boc compounds using HFIP as a solvent and
under microwave-assisted conditions
Entry
1
N-Boc substrate Conditions
Product
Yielda (%)
81
9 150 ꢀC=2 h
10
12
14
2
3
11150 ꢀC=2 h
13150 ꢀC=5 h
85
91
4
5
15150 ꢀC=1 h
16
18
98
85
17100 ꢀC=4 hb
6
7
19150 ꢀC=0.5 h
20
22
89
88
21150 ꢀC=1 h
(Continued )

3846
J. Choy et al.
Table 4. Continued
Entry
8
N-Boc substrate Conditions
Product
Yielda (%)
24
>95c
23150 ꢀC=1 h
aIsolated yields after chromatography.
bAt 150 ꢀC side products are formed and yield is low.
cCrude yield (pure by NMR).
Scheme 1. Regioselective deprotection of compound 25.
EXPERIMENTAL
The experiments under microwave-assisted conditions were performed in
1
a Biotage-InitiatorTM Sixty microwave instrument. H NMR and 13C
NMR were measured on Bruker Avance DPX-300 NMR or Bruker
Avance AMX-300 NMR spectrometers, operating at a proton (1H) fre-
quency of 300.13 MHz and carbon (13C) frequency of 75.43 MHz.
Because starting materials 1,[7a] 3,[8] 7g,[9] 7h,[10] 17[11] and 25[12] are
known compounds in the literature, their experimental data are not
presented here. The N-Boc substrates 5a–g, 7a–f, 11, 13, 19, and 21 were
procured commercially.

Deprotection of N-Boc Compounds
3847
Typical Experimental Procedure for Deprotection of N-Boc Compounds
A solution of the N-Boc protected amine (1 mmol) in TFE or HFIP
(5 mL) was placed in a sealed microwave vial. The reaction mixture
was heated (100 or 150 ꢀC) in a Biotage–InitiatorTM Sixty microwave
instrument with stirring until the disappearance of the starting material
was observed. After cooling to room temperature, the mixture was eva-
porated to dryness under reduced pressure. The crude product was pur-
ified by flash-column chromatography.
1
Compound 2[7a,7b,7c]: Mp 207–208 ꢀC; H NMR (DMSO-d6) d 11.00
(broad s, 1H), 7.35 (s, 1H), 7.22–7.34 (m, 5H), 4.97 (s, 2H), 1.80 (s, 3H);
13C NMR (DMSO-d6) d 164.15, 151.74, 137.81, 136.97, 128.65, 127.94,
127.41, 107.62, 43.20, 12.85; MS ESI: m=z (%) 217 (M þ Hþ, 100). Anal.
calc. for C12H12N2O2: C, 66.64; H, 5.59; N, 12.95. Found: C, 66.66; H,
5.46; N, 13.01.
Compound 4[13]: Mp ¼ 44–45 ꢀC; 1H NMR (CDCl3) d 9.56–9.86
(broad s, 1H), 9.54 (s, 1H), 7.15 (s, 1H), 6.92–7.05 (m, 1H), 6.27–6.43
(m, 1H); 13C NMR (CDCl3) d 180.49, 132.92, 126.44, 121.40, 111.36.
MS ESI: m=z (%) 96 (M þ Hþ, 100). HRMS ESI m=z 96.04388 (M þ Hþ).
Calcd. 96.04439.
1-Boc-3-carboxamido-5-chloroindole (5)
To a solution of 3-carboxamido-5-chloroindole (0.5 g, 2.56 mmol) in acet-
onitrile (30 mL), 0.59 g (2.69 mmol) of (t-Boc)2O and a catalytic amount
of 4-DMAP (3 mg, 0.02 mmol) were added at room temperature. The
reaction mixture was stirred for 4 h at the same temperature. The solid
was collected by filtration and washed with cold MeCN (10 mL) to give
0.63 g (83%) of product (5) as a pale solid. Mp ¼ 174–174.5 ꢀC; 1H NMR
(DMSO-d6) d 8.52 (s, 1H), 8.24 (d, J ¼ 2.26 Hz, 1H), 8.05 (d, J ¼ 8.67 Hz,
1H), 7.93 (br. s., 1H), 7.39 (dd, J ¼ 9.04, 2.26 Hz, 1H), 7.25 (br. s., 1H),
1.64 (s, 9H);13C NMR (DMSO-d6) d 164.62, 148.45, 133.26, 129.71,
129.66, 127.95, 124.63, 121.13, 116.15, 114.13, 85.15, 27.56; MS ESI:
m=z (%) 295 (M þ Hþ, 90). HRMS ESI m=z 295.08440 (M þ Hþ). Calcd.
295.08466.
Compound 6: Mp 248–249 ꢀC; 1H NMR (DMSO-d6) d 11.72 (broad
s, 1 H), 8.15 (d, J ¼ 2.26 Hz, 1 H), 8.09 (d, J ¼ 3.01 Hz, 1 H), 7.60–7.40
(broad s, 1H), 7.45 (d, J ¼ 8.67 Hz, 1 H), 7.15 (dd, J ¼ 8.48, 2.07 Hz,
1 H), 7.00–6.75 (broad s, 1 H);13 C NMR (DMSO-d6) d 166.42, 134.99,
130.17, 127.83, 125.43, 122.15, 120.55, 113.74, 110.54; MS ESI: m=z
(%) 195 (M þ Hþ, 100). HRMS ESI m=z (M þ Hþ) 195.03188. Calcd.
195.03197.

3848
J. Choy et al.
1
Compound 6a: Mp 50–51 ꢀC; H NMR (CDCl3) d s 8.08 (broad s,
1H), 7.65 (dd, 1H), 7.38 (m, 2H), 7.23–7.09 (m, 2H), 6.56–6.54 (m,
1H); 13C NMR (CHCl3-d) d 135.74, 127.82, 124.10, 121.97, 120.72,
119.80, 111.00, 102.61; MS EI: m=z (%) 117 (M þ, 100).
Compound 6b: Mp 196–197 ꢀC; 1H NMR (DMSO-d6) d 12.14 (broad
s, 1H), 9.95 (s, 1H), 8.30–8.09 (m, 2H), 7.56–7.20 (m, 3H); 13C NMR
(DMSO-d6) d 185.34, 138.85, 137.43, 124.49, 123.84, 122.50 m 121.20,
118.54, 112.80; MS ESI: m=z (%) 146 (M þ Hþ; 100). HRMS ESI m=z
(M þ Hþ) 146.05963. Calcd. 146.06004.
Compound 6c: Mp 74–75 ꢀC; 1H NMR (CDCl3), d 8.13 (broad s, 1H,
D2O exch.), 7.61 (s, 1H), 7.31–7.12 (m, 3H), 6.50–6.48 (m, 1H); 13C NMR
(CDCl3) d 134.11, 128.94, 125.51, 125.46, 122.31, 120.11, 111.97, 102.41;
MS EI: m=z (%) 151 (Mþ, 100%). HRMS ESI m=z (M þ Hþ) 152.02585.
Calcd. 152.02615.
Compound 6d: Mp 55–56 ꢀC; 1H NMR (CDCl3), d 8.03 (broad s, 1H,
D2O exch.), 7.28–6.84 (m, 4H), 6.49–6.47 (m, 1H), 3.85 (s, 3H); 13C NMR
(CDCl3) d 154.19, 130.94, 128.27, 124.85, 112.35, 111.70, 102.38, 102.30,
55.85; MS ESI: m=z (%) 148 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ)
148.07531. Calcd. 148.07569.
1
Compound 6e: Mp 102–104 ꢀC; H NMR (CDCl3), d 8.68 (broad s,
1H, D2O exch.), 8.00–7.99 (m, 1H), 7.49–7.40 (m, 2H), 7.36–7.34
(m, 1H), 6.64–6.62 (m, 1H); 13C NMR (CDCl3) d 137.50, 127.66,
126.48, 126.41, 124.87, 120.87, 112.02, 103.43, 102.79; MS EI: m=z
(%) 142 (Mþ, 100%). HRMS ESI m=z (M þ Hþ) 143.06006. Calcd.
143.06037.
1
Compound 6f: Mp 141–142 ꢀC; H NMR (CDCl3), d 8.62 (d, 1H),
8.60–8.45 (broad s, 1H, D2O exch.), 8.15–8.10 (m, 1H), 7.46–7.37 (m,
2H), 6.76–6.74 (m, 1H); 13C NMR (CDCl3) d 141.20, 139.03, 127.75,
126.95, 117.57, 116.83, 111.10, 104.05; MS EI: m=z (%) 162 (Mþ,
100%). HRMS ESI m=z (M þ Hþ) 152.02585. Calcd. 152.02615. Anal.
calc. for C8H6N2O2: C, 59.26; H, 3.73; N, 17.28. Found: C, 59.11;
H, 3.46; N, 17.14.
1
Compound 6g: Mp 129–130 ꢀC; H NMR (CDCl3), d 7.98 (d, 1H),
7.21 (d, 1H), 7.14 (t, 1H), 6.96 (d, 1H), 6.68 (dd, 1H), 6.39 (s, 1H),
3.51 (broad s, 2H); 13C NMR (CDCl3) d 139.54, 130.63, 128.77,
124.69, 112.95, 111.49, 105.52, 101.56; MS ESI m=z (%) 133 (M þ Hþ,
100%). HRMS ESI m=z (M þ Hþ) 133.07560. Calcd. 133.07602. Anal.
calc. for C8H6N2O2: C, 59.26; H, 3.73; N, 17.28. Found: C, 59.11; H,
3.46; N, 17.14.
Compound 8: Mp 71–72 ꢀC; 1H NMR (CDCl3), d 7.04–7.16 (m, 2H),
6.54–6.67 (m, 2H), 3.65 (broad s., 2H); 13C NMR (CDCl3) d 144.92,
129.10, 123.14, 116.21; MS ESI m=z (%) 128 (M þ Hþ, 100%). HRMS
ESI m=z (M þ Hþ) 128.02576. Calcd. 128.02615.

Deprotection of N-Boc Compounds
3849
Compound 8a: Mp 63–64 ꢀC; 1H NMR (CDCl3), d 7.33 (d,
J ¼ 8.67 Hz, 1H), 6.79 (d, J ¼ 2.64 Hz, 1H), 6.45 (dd, J ¼ 8.67, 2.64 Hz,
1H), 3.74 (broad s, 2H); 13C NMR (CDCl3) d 146.64, 134.62, 133.88,
116.38, 114.92, 109.75; MS ESI m=z (%) 205 (M þ Hþ, 53%). HRMS
ESI m=z (M þ Hþ) 205.93645. Calcd. 205.93667.
Compound 8b: Mp 147–148 ꢀC; 1H NMR (CDCl3), d 8.08 (d,
J ¼ 9.04 Hz, 2H), 6.63 (d, J ¼ 9.04 Hz, 2H), 4.41 (broad s, 2H); 13C
NMR (CDCl3) d 153.41, 138.37, 126.34, 113.16; MS EI m=z (%) 138
(Mþ, 47%). Anal. calc. for C6H6N2O2: C, 52.17; H, 4.38; N, 20.28.
Found: C, 52.50; H, 4.40; N, 19.99.
Compound 8c: Mp 59–60 ꢀC; 1H NMR (CDCl3), d 6.72–6.79 (m, 2H),
6.63–6.70 (m, 2H), 3.76 (s, 3H), 3.43 (broad s, 2H); 13C NMR (CDCl3) d
152.78, 139.90, 116.40, 114.78, 55.72; MS ESI m=z (%) 124 (M þ Hþ,
100%). HRMS ESI m=z (M þ Hþ) 124.07530. Calcd. 124.07569.
1
Compound 8d: Oil; H NMR (CDCl3), d 7.08 (t, J ¼ 8.10 Hz, 1H),
6.21–6.39 (m, 3H), 3.78 (s, 3H), 3.68 (broad s, 2H); 13C NMR (CDCl3)
d 160.72, 147.78, 130.10, 107.90, 103.92, 101.04, 55.07; MS ESI m=z
(%) 124 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 124.07526. Calcd.
124.07569.
Compound 8e: Mp 56–57 ꢀC; 1H NMR (CDCl3), d 7.63 (dd, J ¼ 7.91,
1.32 Hz, 1H), 7.04–7.19 (m, 1H), 6.75 (dd, J ¼ 8.10, 1.51 Hz, 1H), 6.38–
6.54 (m, 1H), 4.07 (broad s, 2H); 13C NMR (CDCl3) d 146.71, 138.96,
129.31, 119.95, 114.70, 84.15; MS ESI m=z (%) 220 (M þ Hþ, 100%).
HRMS ESI m=z (M þ Hþ) 219.96147. Calcd. 219.96177.
1
Compound 8f: Mp 135–136 ꢀC; H NMR (CDCl3), d 6.58 (s, 4H),
3.35 (broad s, 4H); 13C NMR (CDCl3) d 138.57, 116.70; MS ESI m=z
(%) 109 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 109.07565. Calcd.
109.07602.
1
Compound 8g: Oil; H NMR (CDCl3), d 7.00 (t, J ¼ 8.01 Hz, 1H),
6.30–6.20 (m, 3H), 3.60 (broad s, 2H), 1.19–1.33 (m, 3H), 1.09–1.14 (d,
J ¼ 6.78 Hz, 18H); 13C NMR (CDCl3) d 157.48, 148.03, 130.26, 110.76,
108.64, 107.40, 18.36, 13.48; MS ESI m=z (%) 266 (M þ Hþ, 100%).
HRMS ESI m=z (M þ Hþ) 266.19327. Calcd. 266.19347.
1
Compound 8h: Mp 86–87 ꢀC; H NMR (CDCl3), d, 7.30–7.46 (m,
5H), 7.16 (d, J ¼ 7.54 Hz, 2H), 6.61–6.69 (m, 2H), 6.51 (broad s, 1H),
5.19 (s, 2H), 3.57 (broad s, 2H); 13C NMR (DMSO-d6) d 153.97,
144.70, 137.35, 128.76, 128.56, 128.32, 128.26, 120.59, 114.34, 65.66;
MESI m=z (%) 243 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ)
243.11249. Calcd. 243.11280.
Compound 8i: Mp ¼ 52–53 ꢀC; 1H NMR (CDCl3), d 7.16 (d,
J ¼ 7.91 Hz, 2H), 6.69–6.59 (m, 2H), 6.50 (broad s, 1 H), 6.08–5.87 (m,
1H), 5.41–5.30 (m, 1H), 5.29–5.20 (m, 1H), 4.57–4.73 (m, 2H), 3.58
(broad s, 2H); 13C NMR (DMSO-d6) d 153.82, 144.70, 134.00, 128.33,

3850
J. Choy et al.
120.66, 117.57, 114.32, 64.61; MS ESI m=z (%) 193 (M þ Hþ, 100%).
HRMS ESI m=z (M þ Hþ) 193.09683. Calcd. 193.09715.
Compound 10: Oil; 1H NMR (CDCl3), d 7.06–6.86 (m, 3H);
3.59–3.51 (m, 1H), 3.70–3.62 (m, 1H), 3.46–3.29 (m, 1H), 2.30 (s, 6H),
1.72 (broad s, 2H), 1.18 (d, J ¼ 6.78 Hz, 3H); 13C NMR (CDCl3) d
155.49, 130.81, 128.88, 123.83, 78.23, 47.29, 19.78, 16.32; MS ESI m=z
(%) 180 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 180.13782. Calcd.
180.13829.
1
Compound 12: Oil; H NMR (CDCl3), d 7.14 (d, J ¼ 6.78 Hz, 1H),
7.04 (t, J ¼ 7.72 Hz, 1H), 6.77–6.70 (m, 1H), 6.67 (d, J ¼ 7.91 Hz, 1H),
3.57 (t, J ¼ 8.48 Hz, 2H), 3.05 (t, J ¼ 8.29 Hz, 2H); 13C NMR (CDCl3)
d 151.57, 123.31, 127.19, 124.62, 118.64, 109.43, 47.32, 29.82; MS ESI
m=z (%) 120 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 120.08030.
Calcd. 120.08078.
Compound 14: Mp ¼ 104–105 ꢀC; 1H NMR (CDCl3), d 7.92 (d,
J ¼ 9.04 Hz, 2H), 6.87 (d, J ¼ 9.04 Hz, 2H), 3.87 (s, 3H), 3.34–3.23 (m,
4H), 3.08–2.94 (m, 4H), 1.74 (s, 1H); 13C NMR (CDCl3) d 167.15,
154.56, 131.18, 119.67, 113.60, 51.65, 54.16, 48.65, 47.50, 45.89; MS
ESI m=z (%) 221 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ)
221.12805. Calcd. 221.12845.
(4-t-Butyldimethylsilyloxycyclopent-2-enyl)carbamic Acid tert-Butyl
Ester 15
To a solution of (4-hydroxycyclopent-2-enyl)-carbamic acid tertbutyl
ester11 (0.75 g, 3.76 mmol) in DMF (10 mL), imidazole (282 mg,
4.14 mmol) and t-butyldimethylsilyl chloride (624 mg, 4.14 mmol) were
added at room temperature. After stirring for 12 h at the same tempera-
ture, the reaction mixture was diluted with EtOAc (100 mL) and washed
with water (3 ꢁ 100 mL). The organic layer was dried (Na2SO4), concen-
trated, and purified by flash column chromatography (silica gel, hexane-
EtOAc, 8:2). 1.15 g (97%) of product 15 as an oil; 1H NMR (DMSO-d6),
d 7.02 (broad d, J ¼ 8.29 Hz, 1H), 5.64–5.79 (m, 2H), 4.71–4.65 (m, 1H),
4.29 (m, 1H), 2.52–2.66 (m, 1H), 1.37 (s, 9H), 1.26–1.36 (m, 1H), 0.85 (s,
9H), 0.05 (s, 6H). 13C NMR (DMSO-d6) d 155.33, 136.07, 134.43, 77.94,
75.51, 54.13, 42.28, 28.61, 26.15, 18.14, ꢂ4.30; MS ESI m=z (%) 314
(M þ Hþ, 65%). HRMS ESI m=z (M þ Naþ) 336.19675. Calcd.
336.19654.
Compound 16: Oil; 1H NMR (CDCl3), d 5.86–5.81 (m, 1H),
5.80–5.74 (m, 1H), 4.75–4.66 (m, 1H), 3.78–3.69 (m, 1H), 2.72–2.60 (m,
1H), 1.96 (broad s, 2H), 1.38–1.22 (m, 1H), 0.90 (s, 9H), 0.09 (s, 6H);
13C NMR (CDCl3) d 137.92, 135.57, 76.37, 56.50, 45.88, 26.32, 18.19,

Deprotection of N-Boc Compounds
3851
ꢂ4.21; MS ESI m=z (%) 214 (M þ Hþ, 25%). HRMS ESI m=z (M þ Hþ)
214.16183. Calcd. 214.16217.
Compound 18: Oil; 1H NMR (CDCl3), d 6.04–5.97 (m, 1H),
5.88–5.79 (m, 1H), 5.58–5.47 (m, 1H), 3.93–3.78 (m, 1H), 2.86–2.69 (m,
1H), 2.05 (s, 3H), 1.62 (broad s, 2H), 1.48–1.32 (m, 1H); 13C NMR
(CDCl3) d 170.79, 141.32, 130.67, 78.46, 56.49, 41.80, 21.65; MS ESI
m=z (%) 142 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 142.08592.
Calcd. 142.08626.
Compound 20: Oil; 1H NMR (CDCl3), d 7.10–7.34 (m, 5H), 3.75–3.71
(dd, J ¼ 7.93, 5.20 Hz, 1H), 3.71 (s, 3H), 3.08 (dd, J¼ 13.38, 5.09 Hz, 1H),
2.84 (dd, J ¼ 13.56, 7.91Hz, 1H), 1.52 (broad s, 2H); 13C NMR (CDCl3),
d 175.34, 137.12, 129.16, 128.47, 126.73, 55.73, 51.87, 41.00; MS ESI m=z
(%) 180 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 180.10156. Calcd.
180.10191.
1
Compound 22: Mp ¼ 111–112 ꢀC; H NMR (CDCl3), d 8.35 (broad
s, 1H), 7.64 (d, J ¼ 7.91 Hz, 1H), 7.44–7.32 (m, 1H), 7.26–7.18 (m, 1H),
7.18–7.09 (m, 1H), 7.04 (d, J ¼ 2.26 Hz, 1H), 1.36 (broad s, 2H), 3.11–
3.01 (m,2H), 2.99–2.86 (m, 2H); 13C NMR (CDCl3) d 136.44, 127.49,
122.06, 121.96, 119.21, 118.87, 113.69, 111.16, 42.34, 29.49; MS ESI
m=z (%) 161 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 161.10693.
Calcd. 161.10732.
N-Boc-trans-4-(1,1-dioxido-2-isothiazolidinyl)cyclohexylamine 23
3-Chloro-propanesulfonyl chloride (5.4 mL, 44 mmol) was added drop-
wise to a solution of N-Boc-trans-1,4-cyclohexanediamine (7.6 g,
35 mmol) and triethylamine (18.25 mL, 131 mmol) in dichloromethane
(250 mL) at 5 ꢀC. The reaction mixture was stirred at room temperature
for 12 h. Then the organic solution was washed with an aqueous solution
of sodium bicarbonate (10%, 250 mL) and water (200 mL). The organic
phase was dried (Na2 SO4), filtered, and concentrated to give 11.52 g
(91%) of N-Boc-trans-4-[(30-chloropropanesulfonyl)amino]cyclohexyl-
1
amine: H NMR (CDCl3), d 4.35 (broad d, 1H), 4.18 (broad d, 1H),
3.68 (t, 2H), 3.40–3.16 (m, 2H), 3.18 (t, 2H), 2.32–2.23 (m, 2H), 2.06
(broad t, 2H), 1.43 (s, 9H), 1.44–1.15 (m, 2H); MS EI m=z (%) 354
(M þ, 10%). To 250 mL of degassed absolute ethanol, 0.344 g (15 mmol)
of sodium and after dissolution, 5.3 g (15 mmol) of the product from pre-
vious step were added. The mixture was refluxed for 5.5 h and cooled to
25 ꢀC, and the solvent was removed under vacuum. Flash chromato-
graphy (SiO2, hexane–EtOAc, 8:2) gave the title compound 23 (3.4 g,
71%): mp ¼ 155–156 ꢀC; 1H NMR (CDCl3), d 4.38 (broad s, 1 H),
3.51–3.30 (m, 2 H), 3.26 (t, J ¼ 6.59 Hz, 2 H), 3.16–3.07 (m, 2 H),

3852
J. Choy et al.
2.40–2.24 (m, 2 H), 2.13–1.86 (m, 4 H), 1.66–1.47 (m, 2 H), 1.43 (s, 9 H),
1.32–1.15 (m, 2 H); 13C NMR (CDCl3) d 155.14, 79.29, 51.89, 48.73,
46.94, 41.19, 32.21, 29.38, 28.36, 18.68; MS ESI m=z (%) 319 (M þ Hþ,
100%). HRMS ESI m=z (M þ Hþ) 319.16846. Calcd. 319.16860.
1
Compound 24: Oil; H NMR (CDCl3), d 3.34–3.48 (m, 1H), 3.27
(t, J ¼ 6.78 Hz, 2H), 3.12 (t, 2H), 2.55–2.69 (m, 1H), 2.25–2.40 (m, 2H),
1.85–2.02 (m, 4H), 1.45–1.62 (m, 2H), 1.36 (broad s, 2H), 1.14–1.30
(m, 2H); 13C NMR (CDCl3) d 52.56, 49.75, 47.07, 41.54, 35.50, 29.41,
18.70; MS ESI m=z (%) 219 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ)
219.11609. Calcd. 219.11618.
1
Compound 26: Mp ¼ 139–140 ꢀC; H NMR (CDCl3), d 8.27 (broad
s, 1H), 7.25–7.07 (m, 3H), 6.60–6.54 (m, 2H), 3.67 (t, 4H), 3.19 (t, 4H),
1.50 (s, 9H);
13
C NMR (CDCl3), d 154.94, 145.53, 136.97, 122.87,
122.66, 121.36, 106.87, 106.18, 100.94, 76.60, 51.31, 43.69, 28.47; MS
ESI m=z (%) 302 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ)
302.18616. Calcd. 302.18630.
Compound 27: Mp ¼ 198–199 ꢀC (dec.); 1H NMR (DMSO-d6), d
10.99 (broad s, 1H), 7.21 (t, J ¼ 2.73 Hz, 1H), 7.04–6.90 (m, 2H), 6.41
(dd, J ¼ 7.16, 1.13 Hz, 1H), 6.35 (t, J ¼ 2.17 Hz, 1 H), 3.06–2.97 (m,
4H), 2.95–2.86 (m, 4H); 13C NMR (DMSO-d6), d 145.99, 136.96,
123.25, 121.57, 120.78, 105.75, 105.30, 99.93, 52.28, 45.98; MS ESI m=z
(%) 202 (M þ Hþ, 100%). HRMS ESI m=z (M þ Hþ) 202.13351. Calcd.
202.13387.
ACKNOWLEDGMENT
The authors thank Joseph Muchowski, who suggested the use of HFIP as
an alternative fluorinated solvent in this study. We also thank Yanzhou
Liu and Kate Comstock for assistance in the analysis of all the com-
pounds by NMR and HRMS.
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