Ethyl 2-(tert-Butoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma): An Efficient Reagent for the Racemization Free Synthesis of Ureas, Carbamates and Thiocarbamates via Lossen Rearrangement

Article abstract of DOI:10.1002/adsc.201600661

Boc-Oxyma (Ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate) has been reported previously as an efficient coupling reagent for the synthesis of amides, peptides, esters, thioesters and hydroxamic acids. It is known for its excellent racemization suppression capability, and also as an environment friendly reagent as it generates only Oxyma as solid byproduct that can be recovered easily and recycled for the synthesis of the same reagent. In this update, we report a simple, efficient, environment friendly, chemoselective and racemization free method for the synthesis of ureas, carbamates and thiocarbamates from hydroxamic acids via Lossen rearrangement by using Boc-Oxyma. We have achieved racemization free di- and tri-peptidyl ureas with very good yield by using this protocol. A rigorous mechanistic investigation is also incorporated. (Figure presented.).

Full text of DOI:10.1002/adsc.201600661

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DOI: 10.1002/adsc.201600661
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Ethyl 2-(tert-Butoxycarbonyloxyimino)-2-cyanoacetate
(Boc-Oxyma): An Efficient Reagent for the Racemization Free
Synthesis of Ureas, Carbamates and Thiocarbamates via Lossen
Rearrangement
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Srinivasa Rao Manne,a Kishore Thalluri,a Rajat Subhra Giri,a Jyoti Chandra,a and
Bhubaneswar Mandala,*
a
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, Assam – 781039, India
Fax: (+91)-358-258-2349
Phone: (+91)-361-258-2319; e-mail: bmandal@iitg.ernet.in
Received: June 22, 2016; Accepted: September 24, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600661
high-yielding methods for the preparation of ureas has
Abstract: Boc-Oxyma (Ethyl 2-(tert-butoxycarbo-
nyloxyimino)-2-cyanoacetate) has been reported
received much attention.
The classical methods such as Hofmann,[4] Cur-
previously as an efficient coupling reagent for the
tius,[5] and Lossen rearrangement,[6] have been proven
synthesis of amides, peptides, esters, thioesters and
to be the practical methods for the synthesis of diverse
hydroxamic acids. It is known for its excellent
ureas. However, use of strong hypervalent iodine
racemization suppression capability, and also as an
reagents in Hofmann and potentially explosive azides
environment friendly reagent as it generates only
in Curtius rearrangement limit the practical utility for
Oxyma as solid byproduct that can be recovered
large scale synthesis as well as for the preparation of
easily and recycled for the synthesis of the same
complex natural products. Alternatively, the Lossen
reagent. In this update, we report a simple,
rearrangement provides access to isocyanates under
efficient, environment friendly, chemoselective and
relatively mild conditions. To date, several synthetic
racemization free method for the synthesis of ureas,
methods have been developed for the synthesis of
carbamates and thiocarbamates from hydroxamic
ureas through Lossen rearrangement, for example,
acids via Lossen rearrangement by using Boc-Oxy-
phosgene and its derivatives such as triphosgene[7] are
ma. We have achieved racemization free di- and tri-
widely used reagents for synthesis of ureas; together
peptidyl ureas with very good yield by using this
with chloroformates,[8] cyanuric chloride,[9] 1,1’-carbon-
protocol. A rigorous mechanistic investigation is
also incorporated.
yldiimidazole,[10] 1-propanephosphonic acid cyclic an-
hydride (T3P),[11] N,N’-dicyclohexylcarbodiimide,[12] N-
benzyl-N’-(3-dimethylaminopropyl)carbodiimide,[13]
Keywords: Boc-Oxyma; Hydroxamic acid; Lossen
Zr(IV)-catalyst,[14] Pd-catalyzed[15] and 2-chloro-1-
Rearangement; Ureas; Carbamates, thiocarba-
methylpyridinuim iodide.[16]
mates; Racemization free.
On the other hand, Boc-Oxyma (I, Ethyl 2-(tert-
butoxycarbonyloxyimino)-2-cyanoacetate,
Figure 1)
Introduction
50 Urea is an important structural unit having wide-
51 spread utilities in pharmaceutical, medicinal and
52 material sciences.[1] Due to the presence of hydrogen
53 bonding, it serves as a backbone for the preparation of
54 ureidopeptides that are important in drug discovery.[2]
55 For example, Syringolins is a class of proteasome
56 inhibitors having promising antitumor activity.[3]
57 Therefore, research devoted towards the efficient and
Figure 1. Ethyl 2-cyano-2-(hydroxyimino)acetate (Oxyma)
and Ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate I
(Boc-Oxyma).
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has been described previously as an efficient coupling
Initially, we commenced the optimization studies
reagent. It readily activates the carboxylic acid group with benzhydroxamic acid 1a as a model substrate in
for the formation of amides, peptides, esters, thioest- DCM. Cylohexylamine was used as the amine nucleo-
ers[17] and hydroxamic acids.[18] Notable feature of phile. In a set of base sources screened, DIPEA
Boc-Oxyma is in its excellent racemization suppres- exhibited superior results compared to NMM (N-
sion capability. Also, it is an environment friendly methylmorpholine), Et3N, NMI, DMAP, DBU and
reagent as it generates only Oxyma as solid byproduct DABCO (1,4-diazabicyclo [2.2.2] octane). The reac-
that can be recovered easily and can be recycled for tion worked best in DCM solvent. However, the
the synthesis of the same reagent. Herein, we report a reaction also proceeded well in CHCl3, THF, CH3CN,
10 novel method for the synthesis of ureas from hydroxa- EtOAc, CH3OH, and DMF with very good yield
11 mic acids using Boc-Oxyma as an efficient reagent for (Table 1).
12 urea synthesis via Lossen rearrangement.
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Table 1. Optimization of the reaction conditions.[a]
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Entry
Base
Solvent
Yield (%)[b]
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DBU
NMM
DABCO
NMI
DMAP
NEt3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DCM
DCM
DCM
DCM
DCM
DCM
DCM
CHCl3
THF
CH3CN
EtOAc
CH3OH
DMF
H2O
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Figure 2. HPLC profiles of products (a) L & (b) DL form of
Bz-Phe-Phg-OMe dipeptidyl ureas. (C18 analytical column
27 and a linear gradient of 5% to 30% acetonitrile in water
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during the first 20 min, then linear gradient of acetonitrile in
water from 30% to 70% till 200 min were used for proper
seperation.).
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Results and Discussion
[a] Reaction conditions: benzhydroxamic acid (127 mg,
1 mmol), Boc-Oxyma (242 mg, 1 mmol.), base (2.5 mmol),
cylohexylamine (99 mg, 1 mmol), solvent (2 ml), tempera-
ture: first 15 min at 08C, and then 6 h at room temperature
after addition of amine, total reaction time 6–7 h.
[b] Isolated yield.
34 I was synthesized easily by the reaction of Oxyma
35 (ethyl 2-hydroxyimino 2-cyanoacetate) with Boc2O in
36 the presence of DIPEA at 0–58C for 1 h. After that
37 the solvent (chloroform) was evaporated completely
38 and then used in the reaction directly without
39 purification. We hypothesized, hydroxamic acids,
40 which was prepared by using I[18] from carboxylic
41 acids, could further be O-activated by I (1 equiv.) in
Interestingly, the reaction worked well with ali-
42 the presence of DIPEA, and then could be converted phatic as well as aromatic amines, such as aniline and
43 into the corresponding isocyanate via Lossen rear- its derivatives (Table 2, products 3c–3f). Substituted
44 rangement which subsequently be trapped in situ with aromatic carboxylic acids also generated good yield
45 nucleophiles, such as amines or alcohols in an one-pot (products 3g & 3h). Systematic investigation on the
46 manner (Scheme 1) to generate ureas or carbamates, electronic effect of the substituents revealed that the
47 respectively.
electron withdrawing substituents hindered the reac-
tion to a certain extent. Reaction proceeded well for
amino acid derivatives with common amine protecting
groups, such as Boc, Fmoc, CBz, and Bz (benzoyl), as
well as various side-chain alcohol protecting groups of
amino acids, such as tBu and Bzl. The yields were
found to be good to excellent in all the cases including
the sterically hindered amino acids, e.g., leucine,
isoleucine, phenylalanine, and phenylglycine. The
reaction worked well with aliphatic, b-amino alcohols
and methyl ester of amino acids as nucleophile.
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Scheme 1. Synthesis of ureas from hydroxamic acids by I.
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Table 2. Wide scope of the synthesis of ureas by using I.[a].
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[a] Reaction conditions: hydroxamic acid (1 mmol), Boc-
Oxyma (242 mg, 1 mmol.), DIPEA (317 mg, 2.5 mmol),
amine (1 mmol), DCM (2 ml), temperature: first 15 min at
08C and then 6 h at room temperature after addition of
amine, total reaction time 6–7 h.
[b] Isolated yield
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Usually, carbamates are formed in presence of
hydroxyl group in Lossen rearrangement. Interest-
ingly, although tertiary butanol was present as a
byproduct in the reaction mixture, no trace of
hydroxyl addition was observed. Also, when we used
b-amino alcohols, chemoselective addition of amine
occurred resulting in peptidyl ureas with free hydroxyl
group (entries 11, 12, 16 and 19) as sole products.
These ureas are very important intermediates for
preparing anticancer agents.[19]
Design of peptidomimetics often helps to obtain
better active pharmaceutical ingredients, and replace-
ment of peptide bond by peptidyl urea is a common
technique for peptidomimetic design as it allows
generation of H-bond donor and acceptors at desired
sites. Moreover, some naturally occurring small pep-
tidyl ureas have been isolated that have been demon-
strated to inhibit HIV proteases[20] and microbial
alkaline proteases.[21] Here, to extend the scope of our
methodology, we synthesized tripeptidyl ureas from
hydroxamic acid of dipeptides using methyl ester of
amino acids in good yield (Scheme 2).
Finally, we could extend this protocol for the
synthesis of carbamates and thiocarbamates (Table 3)
also, but addition of DMAP and refluxing condition
was required. The requirement of such harsher
condition may be accounted for the relatively lower
nucleophilicity of the alcohol group than the amine
functional group. To a chilled solution of hydroxamic
in DCM, Boc-Oxyma, DIPEA and 0.2 equiv. of
DMAP were added, and the mixture was stirred for 15
minutes. Then, the nucleophile (alcohol or thiol) was
added, and the reaction mixture was refluxed for more
five hours to obtain the desired product.
Further we examined the stereochemical aspects of
this protocol. For that, we synthesized two peptidyl
ureas BzÀL-Phe-L-Phg-OMe and Bz-DL-Phe-L-Phg-
OMe by using I from L and DL form of Bz-phenyl-
alanine hydroxamic acid, respectively, with methyl
ester of phenylglycine. We compared HPLC profiles
of the products. Single peak appeared in the HPLC
profile of the L-isomer indicating the presence of
single stereoisomeric product. On the other hand,
distinct twin peaks appeared in HPLC profile of the
DL analogue in the same gradient indicating the
presence of two diastereomers (Supporting Informa-
tion, Figures S64, S65, S70, and S71). These results
imply that no detectable racemization occurred during
the conversion executed by the current protocol.
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mode, Figure S120) and 1HNMR spectra (Figure
Table 3. Synthesis of carbamates and thiocabamates.[a].
S126) recorded till 5 min before addition of amine.
Finally, two new peaks appeared slowly at 155.5 ppm
(A’’) and 140.3 ppm (B’’), after the addition of the
tertiarybutyl amine, which corresponds to the carbonyl
carbon of urea and the aromatic carbon, respectively.
Now, if the reaction progress via a classical Lossen
rearrangement mechanism, then the intermediate II
should rearrange directly to the isocyanate IV and
nucleophilic amine addition may take place then. But,
unlike our previous work on Lossen rearrangement,[22]
all our efforts to isolate the isocyanate went in vain,
rather intermediate II could be isolated. Possibility of
the formation of the cyclic intermediate III from II
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´
and its conversion to IV as reported by Pascal Dube
and co-workers[10a] was also considered (Figure 3), but
no characteristic peak of III was observed either in
1HNMR or in 13CNMR spectra (Figure S121, S122
and S128).
[a] Reaction conditions: Hydroxamic acid (1 mmol), Boc-
Oxyma (242 mg, 1 mmol.), DIPEA (2.5 mmol), DMAP
(0.2 mmol) amine (1 mmol), DCM (2 ml), temperature:
first 15 min at 08C and then 5 h at reflux after addition of
the nuleophile, total reaction time 5–6 h.
[b] Isolated yield
Scheme 2. Synthesis of tripeptidyl ureas from hydroxamic
acid derivatives of dipeptides by I.
Figure 3. Plausible reaction mechanism for the synthesis
ureas via the current protocol.
To understand the mechanism, we performed the
42 reaction between hydroxamic acid and Boc-Oxyma in
Furthermore, the characteristic quartret of the
43 the presence of DIPEA in an NMR tube using CDCl3 Oxyma that appeared within 5 min remained un-
44 as a solvent, and 13C and 1HNMR spectra were changed during the whole course of the reaction
45 recorded at the specified time intervals. Initially, the eliminating any possibility of further reaction of Oxy-
46 hydroxamic acid reacted with Boc-Oxyma and formed ma with II. Also, the time resolved conversion of
47 a stable intermediate II quickly within 15 minutes 13CNMR peaks (Figure S121 and S122) as well as
48 (Figure 3 and Supporting Information, Figures S114À 1HNMR peaks (Figure S128) indicated absence of any
49 128), evident by the appearance of the peaks at 164.2 further intermediate(s). Therefore, it was inferred that
50 (A’), 136.4 (B’) from 166.8 ppm (A) and 131.9 (B) either direct attack of amine on the intermediate II
51 corresponding to the carbonyl carbon and the adjas- resulted in urea, CO2 and tert-butanol formation via a
52 cent aromatic carbon of the hydroxamic acid, respec- rearrangement that occurred in a concerted manner or
53 tively. The carbonyl carbons of Boc-Oxyma 157.1 (C), the conversion of II to III or IV and subsequent attack
54 148.7 (D) was converted into 163.7 (C’), 153.2 (D’) by amine was so fast that it was impossible to get a
55 corresponding to the intermediate II, respectively. trace of the interemediates III and IV.
56 Presence of the intermediate II and Oxyma could be
All the products were purified by column chroma-
57 verified by ESI (-Ve mode, Figure S119 and +Ve tography and chartacterized using various spectro-
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15 min followed by the addition of alcohols or thiols
(1 mmol) and then stirred at reflux for more 6 h. The
progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was diluted
with 15 mL of DCM and washed with 5% HCl (23 10 mL),
5% NaHCO3 (23 10 mL), saturated NaCl solution (23
10 mL) and dried over anhydrous CaCl2 and the evaporation
of the solvent gave a residue that was purified on silica gel
column chromatography using hexane and ethyl acetate.
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scopic tools. The chemical structure of the product 3b
(Table 2) was further confirmed by X-ray crystallo-
graphic analysis (Figure 4).
Cyclohexyl-3-phenylurea 3a. White solid; (98 mg, 90%), mp
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125–1278C; HNMR (600 MHz, CDCl3) d 7.27-7.26 (m, 4H),
7.05-7.03 (m, 1H), 6.77 (s, 1H), 4.99 (s, 1H), 3.65–3.63 (m,
1H), 1.94–1.91 (m, 2H), 1.68–1.64 (m, 3H), 1.35–1.31 (s, 2H),
1.12–1.06 (m, 3H); 13CNMR (100 MHz, CDCl3,) d 155.7,
139.5, 129.1, 122.8, 120.0, 48.8, 33.7, 25.6, 25.0; FT-IR (KBr)
3328, 2932, 2853, 1680, 1629, 1558, 1317 cmÀ1; HRMS (ESI)
m/z: [M+H]+ calcd for C13H19N2O 219.1497, found 219.1486.
Figure 4. X-ray crystallographic structure of 3b in table 2
(ORTEP diagram with ellipsoid of 50% probability, CCDC
No. 1484427.).
1-(tert-Butyl)-3-phenylurea 3b. White solid; (170 mg, 89%),
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mp 166–1688C; HNMR (400 MHz, CDCl3) d 7.28–7.26 (m,
4H), 7.05–7.02 (m, 1H), 6.63 (s, 1H), 4.96 (s, 1H), 1.35 (s,
9H); 13CNMR (100 MHz, CDCl3,) d 155.4, 139.2, 129.3,
123.4, 120.7, 120.6, 50.8, 29.5; FT-IR (KBr) 3361, 2924, 2853,
1647, 1539, 1211 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C11H17N2O 193.1341, found 193.1347.
Conclusion
22 In summary, we have demonstrated a simple, efficient,
23 environment friendly, chemoselective and racemiza-
24 tion free method for the synthesis of ureas, carbamates
25 and thiocarbamates directly from hydroxamic acid via
26 Lossen rearrangement by using Boc-Oxyma. Impor-
27 tantly, all the hydroxamic acid substrates used in this
28 article were obtained from the corresponding carbox-
29 ylic acids using the same reagent, Boc-Oxyma. Also it
30 is worth mention that Boc-Oxyma produces only
31 Oxyma as a solid byproduct in the reaction that can
32 be easily recovered and reused for the synthesis of the
33 same reagent. This is one of the advantages over the
34 use of the other reagents for the purpose. Therefore,
35 the use of the current method can reduce chemical
36 waste generation in industries.
1-Phenyl-3-(p-tolyl)urea 3c White solid; (101 mg, 90%), mp
1
196–1988C; H NMR (400 MHz, DMSO-d6) d 8.61 (s, 1H),
8.55 (s, 1H) 7.44–7.42 (d, J=7.6 Hz, 2H), 7.34–7.32 (d, J=8.4
Hz, 2H) 7.28–7.24 (t, J=7.6 Hz, 2H), 7.08–7.06 (d, J=8.4 Hz,
2H) 6.96–6.93 (t, J=7.2 Hz, 1H), 2.23 (s, 3H); 13C NMR (100
MHz, DMSO-d6,) d 152.6, 139.8, 137.1, 130.6, 129.2, 128.8,
121.7, 118.3, 118.1, 20.3; FT-IR (KBr) 3301, 2922, 2852, 1789,
1635, 1535 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for C14
H15N2O 227.1184, found 227.1185.
1,3-Diphenylurea 3d White solid; (86 mg, 82%), mp 225–
1
2278C; H NMR (400 MHz, DMSO-d6) d 8.65 (s, 2H), 7.45–
7.43 (d, J=8 Hz, 4H), 7.28–7.24 (t, J=7.6 Hz, 4H) 6.97–6.93
(t, J=7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6,) d 152.6,
139.7, 128.8, 121.8, 118.2; FT-IR (KBr) 3328, 2924, 2845,
1790, 1662, 1552 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C13H13N2O 213.1028, found 213.1024.
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Experimental Section
General procedure for the synthesis of urea: Boc-Oxyma
(1 mmol) was added to a stirred solution of hydroxamic acid
(1 mmol) and DIPEA (1.5 mmol) in 2 mL of DCM at 08C.
Then the reaction mixture was stirred at the same temper-
ature for 15 min followed by the addition of amine (1 mmol)
and stirring at room temperature for more 6 h. The progress
of the reaction was monitored by TLC. After completion of
the reaction, the reaction mixture was diluted with 15 mL of
DCM and washed with 5% HCl (23 10 mL), 5% NaHCO3
(23 10 mL), saturated NaCl solution (23 10 mL) and dried
over anhydrous CaCl2 and the evaporation of the solvent
gave a residue that was purified on silica gel column
chromatography using hexane and ethyl acetate.
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1-(4-chlorophenyl)-3-phenylurea 3e White solid; (93 mg,
76%), mp 238–2408C; 1H NMR (400 MHz, DMSO-d6) d 8.81
(s, 1H), 8.70 (s, 1H), 7.49–7.43 (m, 4H), 7.33–7.25 (m, 4H),
6.99–6.95 (m, 1H); 13C NMR (100 MHz, DMSO-d6,) d 152.5,
139.5, 138.7, 128.8, 128.6, 127.3, 125.3, 122.0, 119.7, 118.3; FT-
IR (KBr) 3440, 2922, 2852, 1636, 1594, 1563 cmÀ1; HRMS
(ESI) m/z: [M+H]+ calcd for C13H12ClN2O 247.0638, found
247.0640.
1-(4-acetylphenyl)-3-phenylurea 3f White solid; (92 mg,
73%), mp 190–1928C; 1H NMR (400 MHz, CDCl3, few drops
of CD3OD for solubility) d 8.36 (br s, 1H), 8.03 (br s, 1H),
7.86–7.84 (d, J=8.4 Hz, 2H), 7.49–7.47 (d, J=8.8 Hz, 2H),
7.40–7.38 (d, J=8 Hz, 2H), 7.30–7.27 (m, 2H), 7.06–7.03 (t,
J=7.2 Hz, 1H), 2.54 (s, 3H); 13C NMR (100 MHz, CDCl3) d
198.1, 153.3, 144.1, 138.4, 131.1, 130.0, 129.1, 123.4, 119.6,
117.8, 26.4; FT-IR (KBr) 3440, 2921, 2848, 16631, 1638,
1598 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for C15H15N2O2
255.1134, found 255.1129.
General procedure for the synthesis carbamates and thio-
carbamates: Boc-oxyma (1 mmol) was added to a stirred
solution of hydroxamic acid (1 mmol), DIPEA (1.5 mmol)
and DMAP (0.2 mmol) in 2 mL of DCM at 08C. Then the
reaction mixture was stirred at the same temperature for
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1-(4-methoxyphenyl)-3-phenylurea 3g White solid; (105 mg,
87%), mp 191–1938C; 1H NMR (400 MHz, DMSO-d6) d 8.57
(s, 1H), 8.46 (s, 1H), 7.44–7.42 (d, J=7.6 Hz, 2H), 7.36–7.34
(d, J=9.2 Hz, 2H), 7.28–7.24 (t, J=7.6 Hz, 2H), 6.96–6.92 (t,
127.7, 125.7, 66.7, 65.6, 60.9, 50.0, 40.4, 24.6, 22.8, 21.8; FT-IR
(KBr) 3311, 2954, 2924, 2853, 1679, 1618, 1438, 1259 cmÀ1;
HRMS (ESI) m/z: [M+H]+ calcd for C22H30N3O4 400.2236,
found 400.2230.
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J=7.6 Hz, 1H), 6.87–6.85 (d, J=9.2 Hz, 1H), 3.70 (s, 3H); 13
C
(S)-Methyl 5-(tert–butoxymethyl)-1-(9H-fluoren-9-yl)-3,7-di-
oxo-2-oxa-4,6,8-triazadecan-10-oate 3m. White solid;
NMR (100 MHz, DMSO-d6) d 154.5, 152.8, 139.9, 132.7,
128.8, 121.6, 120.0, 118.1, 114.0, 55.1; FT-IR (KBr) 3298,
2923, 2853, 1720, 1560, 1246 cmÀ1; HRMS (ESI) m/z: [M+
H]+ calcd for C14H15N2O2 243.1134, found 243.1131.
1
(192 mg, 82%), mp 135–1378C; HNMR (400 MHz, CDCl3)
d 7.77–7.75 (d, J=7.6 Hz, 2H), 7.60–7.58 (d, J=7.2 Hz, 2H),
7.42–7.38 (t, J=7.2 Hz, 2H), 7.33–7.29 (t, J=7.2 Hz, 2H),
5.87–5.85 (d, J=8 Hz, 1H), 5.52–5.50 (d, J=7.6 Hz, 1H), 5.33
(br, 1H), 4.43–4.39 (m, 2H), 4.25–4.22 (t, J=7.2 Hz, 1H),
3.98–3.97 (d, J=5.2 Hz, 2H), 3.68 (s, 3H), 3.59–3.51 (m, 2H),
1.21 (s, 9H); 13CNMR (100 MHz, CDCl3) d 171.4, 157.5,
156.8, 143.9, 141.4, 127.9, 127.2, 125.2, 120.1, 67.4, 63.9, 58.9,
52.2, 47.2, 42.2, 27.5; FT-IR (KBr) 3328, 2974, 2924, 1698,
1644, 1539, 1245 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C25H32N3O6 470.2291, found 470.2286.
Ethyl 4-(3-phenylureido)benzoate 3h White solid; (99 mg,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
1
70%), mp 170–1728C; H NMR (400 MHz, CDCl3) d 8.15 (s,
1H), 7.95 (s, 1H) 7.81–7.78 (d, J=8.4 Hz, 2H), 7.23–7.21 (d,
J=8.8 Hz, 2H), 7.18–7.13 (m, 4H), 6.99–6.98 (m, 1H), 4.33–
4.28 (q, J=7.2 Hz, 2H) 1.36–1.32 (t, J=6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) d 166.9, 154.0, 143.1, 137.7, 130.8,
129.2, 124.6, 124.3, 121.2, 118.9, 61.1, 14.4; FT-IR (KBr) 3441,
2922, 2842, 1708, 1600, 1542 cmÀ1; HRMS (ESI) m/z: [M+
H]+ calcd for C16H17N2O3 285.1239, found 285.1241.
(5S,9S)-Methyl 5-(tert–butoxymethyl)-1-(9H-fluoren-9-yl)-
(S)-Methyl 5-methyl-3,7-dioxo-1-phenyl-2-oxa-4,6,8-triazade-
can-10-oate 3i. White solid; (131 mg, 85%), mp 160–1628C;
1HNMR (400 MHz, CDCl3, few drops of CD3OD for
solubility) d 7.37–7.30 (m, 5H), 5.18 (br, 1H), 5.08 (s, 2H),
3.93 (s, 2H), 3.72 (s, 3H), 1.47–1.45 (d, J=6.4 Hz, 3H);
13CNMR (150 MHz, CDCl3, few drops of CD3OD for
solubility) d 171.8, 157.9, 156.5, 136.2, 128.6, 128.2, 128.0,
66.9, 56.0, 52.3, 41.8, 21.3; FT-IR (KBr) 3367, 2964, 2926,
1723, 1697, 1626, 1276 cmÀ1; HRMS (ESI) m/z: [M+H]+
calcd for C14H20N3O5 310.1404, found 310.1403.
3,7-dioxo-9-phenyl-2-oxa-4,6,8-triazadecan-10-oate
3n.
1
White solid; (218 mg, 80%), mp 162–1648C; HNMR (600
MHz, CDCl3) d 7.77–7.75 (d, J=7.8 Hz, 2H), 7.53–7.48 (m,
2H), 7.41–7.39 (t, J=7.2 Hz, 2H), 7.34–7.28 (m, 4H), 7.19 (br,
3H), 5.79–5.77 (d, J=8.4 Hz, 2H), 5.50–5.47 (m, 2H), 5.40
(br, 1H), 4.30–4.24 (m, 2H), 4.08 (br, 1H), 3.69 (s, 3H), 3.60–
3.54 (m, 2H), 1.19 (s, 9H); 13CNMR (150 MHz, CDCl3) d
172.2, 156.6, 156.3, 144.0, 143.8, 141.4, 137.1, 128.8, 128.4,
127.9, 127.5, 127.2, 125.2, 120.1, 67.5, 63.9, 58.9, 57.5, 52.7,
47.1, 27.5; FT-IR (KBr) 3321, 2974, 2934, 1698, 1644, 1536,
1243 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for C31H36N3O6
546.2604, found 546.2600.
(5S,9S)-Methyl 9-benzyl-5-methyl-3,7-dioxo-1-phenyl-2-oxa-
4,6,8-triazadecan-10-oate 3j. White solid; (161 mg, 81%), mp
141–1438C; 1HNMR (400 MHz, CDCl3) d 7.35–7.29 (m, 5H),
7.23–7.18 (m, 3H), 7.12–7.10 (d, J=7.2 Hz, 2H), 5.64 (br,
2H), 5.17 (br, 1H), 5.03 (s, 2H), 4.73–4.68 (m, 1H), 3.65 (s,
3H), 3.11–3.06 (m, 1H), 3.02–2.96 (m, 1H), 1.42–1.41 (d, J=
5.6 Hz, 3H); 13CNMR (100 MHz, CDCl3) d 173.3, 156.8,
156.1, 136.6, 136.3, 129.4, 128.6, 128.5, 128.2, 128.1, 126.9,
66.9, 56.1, 54.3, 52.2, 38.5, 21.5; FT-IR (KBr) 3298, 2924,
2849, 1737, 1697, 1640, 1502, 1267 cmÀ1; HRMS (ESI) m/z:
[M+H]+ calcd for C21H26N3O5 400.1872, found 400.1869.
(S)-Methyl
5-benzyl-1-(9H-fluoren-9-yl)-3,7-dioxo-2-oxa-
4,6,8-triazadecan-10-oate 3o. White solid; (182 mg, 77%), mp
1
160–1628C; HNMR (600 MHz, CDCl3, few drops of CD3
OD for solubility) d 7.76–7.75 (d, J=7.2 Hz, 2H), 7.53–7.52
(d, J=6 Hz, 2H), 7.40–7.38 (t, J=7.2 Hz, 2H), 7.28 (br, 4H),
7.23–7.21 (m, 3H), 5.16 (br, 1H), 4.32 (br, 2H), 4.17 (br, 1H),
3.94 (s, 2H), 3.70 (s, 3H), 3.15 (br, 2H); 13CNMR (150 MHz,
CDCl3, few drops of CD3OD for solubility) d 171.6, 157.9,
156.4, 143.8, 141.2, 136.8, 129.2, 128.4, 127.6, 127.0, 126.7,
125.0, 119.8, 66.7, 60.4, 52.0, 47.0, 41.6, 40.2; FT-IR (KBr)
3299, 2922, 2852, 1692, 1649, 1536, 1259 cmÀ1; HRMS (ESI)
m/z: [M+H]+ calcd for C27H28N3O5 474.2029, found
474.2028.
Benzyl ((S)-1-(3-((S)-1-hydroxy-4-methylpentan-2-yl)ureido)
ethyl)carbamate 3k. White solid; (140 mg, 83%), mp 151–
1538C; 1HNMR (600 MHz, CDCl3) d 7.34–7.26 (m, 5H), 5.91
(br, 1H), 5.73 (br, 1H), 5.58 (br, 1H), 5.20 (br, 1H), 5.08 (s,
2H), 3.84 (s, 1H), 3.64–3.61 (m, 1H), 3.46–3.43 (m, 1H), 1.64–
1.51 (m, 1H), 1.43–1.42 (d, J=5.4 Hz, 3H), 1.39–1.23 (m,
2H), 0.90–0.88 (t, J=6.6 Hz, 6H); 13CNMR (100 MHz,
CDCl3) d 158.4, 156.3, 136.0, 128.4, 128.1, 127.8, 66.8, 66.6,
55.8, 50.6, 40.3, 24.7, 23.0, 22.1, 21.3; FT-IR (KBr) 3447, 2953,
2921, 2849, 1697, 1645, 1539, 1263 cmÀ1; HRMS (ESI) m/z:
[M+H]+ calcd for C17H28N3O4 338.2080, found 338.2077.
(S)-(9H-fluoren-9-yl)Methyl ((3-(1-hydroxy-3-methylbutan-
2-yl)ureido)methyl)carbamate 3p. White solid; (165 mg,
83%), mp 174–1768C; 1HNMR (400 MHz, CDCl3, few drops
of CD3OD for solubility) d 7.77–7.75 (d, J=7.6 Hz, 2H),
7.58–7.57 (d, J=7.2 Hz, 2H), 7.41–7.38 (t, J=7.6 Hz, 2H),
7.32–7.28 (m, 2H), 4.46 (s, 2H), 4.34–4.33 (d, J=6 Hz, 2H),
4.22–4.20 (t, J=8 Hz, 1H), 3.66–3.64 (m, 1H), 3.52–3.50 (d,
J=7.6 Hz, 2H), 1.79–1.82 (m, 1H), 0.94–0.89 (m, 6H);
13CNMR (150 MHz, DMSO-D6) d 157.6, 156.6, 143.8, 140.7,
127.7, 127.1, 125.3, 120.1, 65.7, 61.8, 61.3, 55.7, 46.6, 28.1,
19.7; FT-IR (KBr) 3315, 2955, 2923, 2852, 1692, 1647, 1532,
1260 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for C22H27N3O4
398.2080, found 398.2085.
Benzyl ((S)-(3-((S)-1-hydroxy-4-methylpentan-2-yl)ureido)(-
phenyl)methyl)carbamate 3l. White solid; (155 mg, 78%),
mp 192–1948C; 1HNMR (600 MHz, CDCl3, few drops of
CD3OD for solubility) d 7.35–7.24 (m, 10H), 6.16 (br, 1H),
5.03 (s, 2H), 3.77 (s, 1H), 3.56–3.54 (m, 1H), 3.34 (br, 1H),
1.60–1.58 (m, 1H), 1.24 (br, 2H), 0.87–0.85 (t, J=6 Hz, 6H);
13CNMR (150 MHz, CDCl3, few drops of CD3OD for
solubility) d 158.2, 156.2, 136.1, 128.4, 128.3, 127.9, 127.8,
(9H-fluoren-9-yl)Methyl ((S)-1-(3-((S)-1-hydroxypropan-2-
yl)ureido)-3-methylbutyl)carbamate
3q.
White
solid;
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UPDATES
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1
(159 mg, 75%), mp 157–1598C; HNMR (400 MHz, CDCl3,
few drops of CD3OD for solubility) d 7.77–7.75 (d, J=
6.8 Hz, 2H), 7.59–7.57 (d, J=6.4 Hz, 2H), 7.42–7.38 (t, J=
7.6 Hz, 2H), 7.33–7.30 (t, J=7.2 Hz, 2H), 4.97 (br, 1H), 4.37–
4.35 (d, J=7.6 Hz, 2H), 4.20 (br, 1H), 3.80 (br, 1H), 3.53–
3.39 (m, 2H), 1.62 (br, 1H), 1.25 (br, 3H), 1.14–1.06 (m, 1H),
0.92 (br, 6H); 13CNMR (150 MHz, CDCl3, few drops of CD3
OD for solubility) d 158.4, 156.8, 143.6, 141.2, 127.6, 127.0,
124.9, 119.8, 66.7, 57.8, 57.7, 47.8, 47.0, 43.2, 24.7, 22.1, 21.9,
17.1; FT-IR (KBr) 3328, 2959, 2923, 2851, 1694, 1634, 1534,
1235 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for C24H32N3O4
426.2393, found 426.2393.
Methyl (((S)-((tert–butoxycarbonyl)amino)(phenyl)methyl)
carbamoyl)phenylalaninate 3v. White solid; (181 mg, 85%),
mp 171–1738C; HNMR (400 MHz, CDCl3) d 7.33–7.22 (m,
1
2
3
4
5
6
7
8
9
1
8H), 7.12–7.10 (d, J=6.8 Hz, 2H), 6.15–6.11 (m, 1H), 5.82–
5.74 (m, 2H), 4.74–4.72 (m, 1H), 3.62 (s, 3H), 3.12–2.98 (m,
2H), 1.40 (s, 9H); 13CNMR (100 MHz, CDCl3, few drops of
CD3OD for solubility) d 173.3, 157.0, 155.6, 139.9, 136.4,
129.3, 128.5, 128.4, 127.8, 126.9, 125.8, 80.3, 60.8, 54.1, 52.1,
38.4, 28.3; FT-IR (KBr) 3368, 3328, 2926, 1744, 1677, 1620,
1211 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for C23H30N3O5
428.2185, found 428.2193.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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(2S,6S)-Methyl 2-benzyl-6-((S)-1-(benzyloxy)ethyl)-10,10-di-
methyl-4,8-dioxo-9-oxa-3,5,7-triazaundecan-1-oate 3w. White
solid; (179 mg, 74%), mp 161–1638C; 1HNMR (400 MHz,
CDCl3) d 7.37–7.16 (m, 10H), 5.35, (br, 1H), 5.18, (br, 1H),
5.03, (br, 1H), 4.71–4.67 (m, 1H), 4.64–4.62 (d, J=6 Hz, 2H),
4.37–4.35 (d, J=11.4 Hz, 1H), 3.63 (s, 3H), 3.11–3.00 (m,
2H), 1.42 (s, 9H), 1.23–1.22 (d, J=6 Hz, 3H); 13CNMR (150
MHz, CDCl3) d 173.1, 156.7, 156.6, 137.6, 136.8, 127.5, 127.4,
128.8, 128.5, 128.3, 128.1, 126.9, 80.7, 76.4, 71.2, 62.2, 54.8,
52.2, 38.6, 28.5, 16.1; FT-IR (KBr) 3328, 2925, 2845, 1732,
1689, 1641, 1250 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C26H35N3O6 486.2604, found 486.2608.
Methyl 2-(3-((R)-1-benzamido-2-phenylethyl)ureido)-2-phe-
nylacetate 3r. White solid; (179 mg, 83%), mp 137–1398C;
1HNMR (400 MHz, CDCl3, few drops of CD3OD for
solubility) d 7.74–7.09 (m, 15H), 5.37 (br, 1H), 5.32 (s, 1H),
3.55 (s, 3H), 3.21–3.16 (m, 2H); 13CNMR (150 MHz, CDCl3,
few drops of CD3OD for solubility) d 172.3, 168.5, 157.2,
136.7, 134.6, 131.8, 129.4, 129.3, 128.9, 128.8, 128.58, 128.53,
128.46, 128.40, 127.3, 127.2, 127.1, 126.8, 59.9, 57.3, 52.6, 39.9;
FT-IR (KBr) 3372, 2923, 2852, 1738, 1641, 1559, 1166 cmÀ1;
HRMS (ESI) m/z: [M+H]+ calcd for C25H26N3O4 432.1923,
found 432.1913.
*Methyl ((1-benzamido-2-phenylethyl)carbamoyl)glycinate
tert-Butyl
((1S,2R)-1-(3-(1-hydroxy-3-phenylpropan-2-yl)
1
3s. White solid; (174 mg, 81%), 137–1398C; HNMR (400
ureido)-2-methylbutyl)carbamate 3x. White solid; (150 mg,
79%), mp 155–1578C; 1HNMR (400 MHz, DMSO-D6) d
7.22–7.12 (m, 5H), 6.85 (br, 1H), 6.01 (br, 1H), 4.88 (br, 1H),
4.75 (br, 1H), 3.7 (br, 1H), 3.31–3.24 (m, 2H), 2.77–2.58 (m,
2H), 1.56 (br, 1H), 3.81 (br, 1H), 1.35 (s, 9H), 1.03–1.00 (m,
2H), 0.81–0.791 (tr, J=4.8 Hz, 1H), 0.75–0.744 (d, J=4.4 Hz,
3H); 13CNMR (100 MHz, CDCl3, few drops of CD3OD for
solubility) d 158.7, 156.4, 138.4, 129.3, 128.4, 126.4, 80.2, 64.5,
62.8, 53.7, 38.7, 37.6, 28.4, 25.3, 14.7, 11.1; FT-IR (KBr) 3344,
2964, 2920, 2872, 1686, 1638, 1571, 1248 cmÀ1; HRMS (ESI)
m/z: [M+H]+ calcd for C20H34N3O4 380.2549, found
380.2552.
MHz, CDCl3, few drops of CD3OD for solubility) d 7.63–7.13
(m, 15H), 5.38 (br, 1H), 5.30 (s, 1H), 3.62 (s, 3H), 3.57 (s,
3H), 3.28–3.27. (m, 2H), 3.19–3.16 (m, 2H); 13CNMR (100
MHz, CDCl3, few drops of CD3OD for solubility) d 172.2,
168.6, 168.5, 157.4, 157.2, 137.1, 136.8, 136.7, 133.9, 133.8,
131.8, 129.4, 129.3, 128.9, 128.8, 128.57, 128.55, 128.4, 128.3,
127.3, 127.26, 127.24, 126.7, 59.9, 57.4, 57.3, 52.66, 52.62, 39.8;
FT-IR (KBr) 3372, 2923, 2852, 1738, 1641, 1559, 1166 cmÀ1;
HRMS (ESI) m/z: [M+H]+ calcd for C25H26N3O4 432.1923,
found 432.1913.
Methyl (R)-((1-benzamido-2-phenylethyl)carbamoyl)glyci-
nate 3t. White solid; (142 mg, 80%), mp 166–1688C;
1HNMR (600 MHz, CDCl3) d 7.66–7.65 (d, J=7.2 Hz, 2H),
7.42–7.39 (t, J=7.2 Hz, 1H), 7.27–7.25 (m, 2H), 7.21–7.16 (m,
4H), 7.13–7.10 (t, J=7.2 Hz, 1H), 5.91 (br, 1H), 3.98–3.94 (m,
2H), 3.61 (s, 3H), 3.18–3.16 (d, J=7.2 Hz, 2H); 13CNMR (150
MHz, CDCl3, few drops of CD3OD for solubility) d 171.5,
168.6, 158.2, 137.0, 133.8, 131.8, 129.3, 128.5, 128.4, 127.1,
126.7, 59.7, 52.0, 41.7, 39.9; (KBr) 3340, 2925, 2853, 1751,
1640, 1578, 1207 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C19H21N3O4 356.1610, found 356.1617.
(5S,8R,12S)-Methyl 12-Benzyl-5-methyl-3,6,10-trioxo-1,8-di-
phenyl-2-oxa-4,7,9,11-tetraazatridecan-13-oate 5a. White sol-
id; (100 mg, 75%), mp 193–1958C; 1HNMR (400 MHz,
CDCl3, few drops of CD3OD for solubility) d 8.33–8.31 (d,
J=7.6 Hz, 1H), 7.38–7.13 (m, 15H), 6.36–6.35 (d, J=6.8 Hz,
1H), 5.08–5.07 (d, J=5.2 Hz, 2H), 4.68–4.65 (t, J=6.4 Hz,
1H), 4.20–4.18 (m, 1H), 3.68 (s, 3H), 3.13–2.98 (m, 2H), 1.34–
1.32 (d, J=7.2 Hz, 3H); 13CNMR (150 MHz, DMSO-D6) d
173.3, 172.5, 156.6, 156.2, 141.3, 137.2, 129.6, 128.8, 128.79,
128.7, 128.3, 128.1, 127.9, 127.1, 126.3, 65.9, 58.4, 54.3, 52.3,
50.5, 49.0, 38.1, 18.3; FT-IR (KBr) 3302, 3020, 2925, 1735,
1682, 1558, 1260 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C29H33N4O6 533.2400, found 533.2407.
(R)-N-(1-(3-(2-Hydroxyethyl)ureido)-2-phenylethyl)benza-
mide 3u. White solid; (137 mg, 84%), mp 190–1928C;
1HNMR (400 MHz, CDCl3, few drops of CD3OD for
solubility) d 7.71–7.69 (d, J=7.2 Hz, 2H), 7.52–7.48 (t, J=
7.2 Hz, 1H), 7.43–7.37 (m, 2H), 7.31–7.22 (m, 5H), 5.51–5.47
(t, J=6.8 Hz, 1H), 3.61–3.58 (t, J=5.2 Hz, 2H), 3.27–3.21 (m,
4H); 13CNMR (100 MHz, CDCl3, few drops of CD3OD and
DMSO- D6 for solubility) d 169.5, 159.8, 138.6, 135.6, 132.7,
(6R,9S)-Methyl 9-isopropyl-13,13-dimethyl-4,8,11-trioxo-6-
phenyl-12-oxa-3,5,7,10-tetraazatetradecan-1-oate 5b. White
solid; (156 mg, 72%), mp 180–1838C; 1HNMR (400 MHz,
CDCl3, few drops of CD3OD for solubility) d 7.31–7.18 (m,
5H), 6.53–6.49 (m, 2H), 5.65 (br, 1H), 3.96–3.77 (m, 3H),
dt3.65 (s, 3H), 1.99–1.97 (m, 1H), 1.38 (s, 9H); 0.85–0.84 (d,
J=6.8 Hz, 6H); 13CNMR (100 MHz, CDCl3) d 172.4, 171.7,
157.8, 156.1, 139.4, 128.5, 128.4, 127.5, 126.19, 126.13, 79.8,
60.8, 58.6, 52.3, 42.1, 29.8, 28.5, 19.2, 18.3 cmÀ1; FT-IR (KBr)
3340, 3271, 2964, 2917, 2870, 1703, 1657, 1558, 1206 cmÀ1;
53 130.5, 129.57, 129.5, 128.4, 127.7, 62.4, 60.7, 43.4, 41.7, 40.0;
54
55
56
(KBr) 3361, 3251, 2926, 2852, 1647, 1622, 1573, 1276 cmÀ1;
HRMS (ESI) m/z: [M+H]+ calcd for C18H21N3O4 328.1661,
found 328.1670.
57
Adv. Synth. Catal. 2016, 358, 1–10
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HRMS (ESI) m/z: [M+H]+ calcd for C21H33N4O6 437.2400,
found 437.2404.
1
2
References
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Lett. 1998, 39, 3631–3634; b) J. S. Carey, D. Laffan, C.
Thomson, M. T. Williams, Org. Biomol. Chem. 2006, 4,
2337–2347; c) W. Harrison, J. Biomol. Screen. 1999,
4(2), 61-65; d) A. P. Kozikowski, J. Zhang, F. Nan, P. A.
Petukhov, E. Grajkowska, J. T. Wroblewski, T. Yama-
moto, T. Bzdega, B. Wroblewska, J. H. Neale, J. Med.
Chem. 2004, 47, 1729–1738; e) T. Kanbara, A. Honma,
K. Hasegawa, Chem. Lett. 1996, 1135–1136; f) A.
Honma, T. Kanbara, K. Hasegawa, Mol. Cryst. Liq.
Cryst. 2000, 345, 449–454.
[2] a) L. Fischer, G. Guichard, Org. Biomol. Chem. 2010, 8,
3101-3117; b) D. L. Holmes, E. M. Smith, J. S. Nowick,
J. Am. Chem. Soc. 1997, 119, 7665–7669; c) L. Fischer, P.
Claudon, N. Pendem, E. Miclet, C. Didierjean, E.
Ennifar, G. Guichard, Angew. Chem. 2010, 122, 1085–
1088; d) J. M. Lozano, L. P. Lesmes, L. F. Carreno, G. M
Gallego, M. E. Patarroyo, Molecules. 2010, 15(12), 8856-
8889.
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4-Nitrobenzyl phenylcarbamate 6a. Light yellow solid;
(105 mg, 77%), mp 121–1238C; HNMR (400 MHz, CDCl3)
1
d 8.24–8.22 (d, J=8 Hz, 2H), 7.56–7.54 (d, J=8 Hz, 2H),
7.40–7.38 (d, J=7.6 Hz, 2H), 7.34–7.30 (t, J=7.6 Hz, 2H),
7.11–7.07 (t, J=7.2 Hz, 1H), 6.81 (br, 1H), 5.29 (s, 2H);
13CNMR (150 MHz, CDCl3) d 153.0, 147.8, 143.6, 137.5,
129.3, 128.4, 124.0, 123.9, 119.2, 65.5 cmÀ1; FT-IR (KBr) 3343,
2932, 1705, 1535, 1511, 1235 cmÀ1; HRMS (ESI) m/z: [M+
H]+ calcd for C14H13N2O4 273.0875, found 273.0888.
4-Methoxybenzyl phenylcarbamate 6b. White solid; (102 mg,
1
80%), mp 87–898C; HNMR (400 MHz, CDCl3) d 7.38–7.25
14 (m, 6H), 7.07–7.03 (t, J=7.6 Hz, 1H), 6.91–6.89 (d, J=
15
7.2 Hz, 2H), 6.67 (br, 1H) 5.13 (s, 2H), 3.81 (s, 3H); 13CNMR
(100 MHz, CDCl3) 159.8, 153.6, 137.9, 130.3, 129.1, 128.2,
123.5, 118.8, 114.1, 66.9, 55.4 cmÀ1; FT-IR (KBr) 3315, 2945,
2828, 1701, 1533, 1236 cmÀ1; HRMS (ESI) m/z: [M+Na]+
calcd for C15H15NO3Na 280.0950, found 280.0964.
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4-Nitrophenyl undecylcarbamate 6c. Pale yellow solid;
1
[3] W. A. V. Linden, L. I. Willems, T. B. Shabeneh, N. Li,
M. Ruben, B. I. Florea, G. A. V. Marel, M. Kaiser, A. F.
Kisselev, H. S. Overkleeft, Org. Biomol. Chem. 2012,
10, 181-194.
(128 mg, 76%), mp 83–858C; HNMR (400 MHz, CDCl3) d
8.25–8.23 (d, J=9.2 Hz, 2H), 7.32–7.30 (d, J=8.8 Hz, 2H),
3.30–3.25 (m, 2H), 1.60–1.55 (m, 4H), 1.26–1.25 (m, 14H),
0.89–0.86 (t, J=6.4 Hz, 3H), ; 13CNMR (100 MHz, CDCl3)
156.1, 153.3, 144.8, 125.3, 122.1, 41.6, 32.0, 29.8, 29.79, 29.77,
29.72, 29.5, 29.4, 26.9, 22.8, 14.3 cmÀ1; FT-IR (KBr) 3342,
2922, 2852, 1703, 1542, 1352, 1217 cmÀ1; HRMS (ESI) m/z:
[M+H]+ calcd for C18H29N2O4 337.2127, found 337.2148.
[4] M. E. Wolff, Chem. Rev. 1963, 63, 55-64.
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b) E. F. V. Scriven, K. Turnbull, Chem. Rev. 1988, 88,
297-368
[6] R. G. Wallace, J. M. Barker, M. L. Wood, Synthesis
1990, 12, 1143-1144.
[7] U. Petersen, in Methoden der Organischen Chemie;
Houben-Weyl, E4; Georg Thieme Verlag: New York,
1983; p 334.
S-Benzyl phenylcarbamothioate 6d. White solid; (87 mg,
1
71%), mp 84–868C; HNMR (400 MHz, CDCl3) d 7.40–7.39
(d, J=5.6 Hz, 2H), 7.36–7.35 (d, J=4.8 Hz, 2H), 7.31–7.29
(m, 4H), 7.25–7.24 (t, J=2.4 Hz, 1H), 7.12–7.09 (t, J=4.8 Hz,
1H), 4.22 (s, 2H); 13CNMR (100 MHz, CDCl3) 165.6, 138.0,
137.7, 129.2, 129.0, 128.7, 127.4, 124.7, 120.0, 34.6 cmÀ1; FT-
IR (KBr) 3243, 3038, 2925, 1653, 1535, 1242, 1165, 751,
701 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for C14H14NOS
244.0796, found 244.0796.
[8] J. Kittenringham, M. R. Shipton, M. Voyle, Synth.
Commun. 2000, 30, 1937À1943.
[9] F. Hamon, G. Prie, F. Lecornue, S. Papot, Tetrahedron
Lett. 2009, 50, 6800À6802.
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C. L. Aboussafy, S. Pichette, M. L. Jorgensen, M.
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J. Rodrigues, L. Evans, B. Hinkle, L. Ballantyne, M.
Pena, J. Org. Chem. 1997, 62, 6420À6423.
S-p-Tolyl phenylcarbamothioate 6e. White solid; (90 mg,
1
74%), mp 129–1318C; HNMR (400 MHz, CDCl3) d 7.51–
7.49 (d, J=8 Hz, 2H), 7.37–7.35 (d, J=8 Hz, 2H), 7.30–7.25
(m, 4H), 7.15 (br, 1H), 7.11–7.09 (t, J=2.4 Hz, 1H), 7.12–7.09
(d, J=7.2 Hz, 1H), 2.40 (s, 3H); 13CNMR (100 MHz, CDCl3)
165.0, 140.6, 137.7, 135.8, 130.6, 129.2, 124.7, 124.6, 119.6,
21.5 cmÀ1; FT-IR (KBr) 3258, 3012, 2976, 1662, 1541, 1233,
1196, 784, 695 cmÀ1; HRMS (ESI) m/z: [M+H]+ calcd for
C14H14NOS 244.0796, found 244.0818.
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Acknowledgements
Authors are grateful to Central Instruments Facility (CIF) and
Department of Chemistry of Indian Institute of Technology
Guwahati for NMR and HRMS facilities and to the Depart-
ment of Biotechnology, Govt. of India (twinning programme
for the North Eastern Region, sanction no. BT/347/NE/TBP/
2012) for financial support. We are also thankful to SAIF,
North Eastern Hill University for NMR facility.
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Chem. Res. 2013, 22, 3170–3176.
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243-250. b) S. Stella, G. S. Saddler, E. Sarubb, S.
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H. Nisshida, R. Okamoto, H. Akagawa, S. Mitsuno, J.
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S. R. Manne, K. Thalluri, R. S. Giri, J. Chandra, B.
Mandal*