Palladium-catalyzed intramolecular diamination of acrylic esters using sulfamates as nitrogen source

Article abstract of DOI:10.1021/jo202507d

An intramolecular diamination of acrylates is reported using sulfamates as nitrogen sources. This reaction proceeds under palladium(II) catalysis with copper bromide as oxidant and gives rise to anti-configured 2,3-diamino carboxylates as bicyclic sulfama

Full text of DOI:10.1021/jo202507d

Article
pubs.acs.org/joc
Palladium-Catalyzed Intramolecular Diamination of Acrylic Esters
Using Sulfamates as Nitrogen Source
Patricia Chavez,† Jonathan Kirsch,† Jan Streuff,‡ and Kilian Muniz*,†,§
́
̃
†Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans, 16, E-43007 Tarragona, Spain
‡Albert-Ludwigs-Universitat Freiburg, Albertstr. 21, 79104 Freiburg, Germany
§Catalan Institution for Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain
̈
S
* Supporting Information
ABSTRACT: An intramolecular diamination of acrylates is reported using sulfamates as nitrogen sources. This reaction
proceeds under palladium(II) catalysis with copper bromide as oxidant and gives rise to anti-configured 2,3-diamino carboxylates
as bicyclic sulfamate derivatives. An aminobrominated intermediate within the diamination reaction was isolated that allowed to
clarify the reaction mechanism and to rationalize the observed preferential product stereochemistry.
Starting materials 2 are available from cross-metathesis
between alkyl acrylate and previously described ω-alkenyl
sulfamides (Scheme 2).6 The reaction employs an excess of the
corresponding acrylate leading to fumarate as an easily
removable byproduct.
INTRODUCTION
■
The 2,3-diamino carboxylic acid motif represents an interesting
nonproteinogenic amino acid1 that has attracted attention for
its presence in biologically active compounds.2 Mannich-type
reactions under transition-metal catalysis or organocatalysis
have been described as particularly suitable approaches to this
class of compounds.3
Oxidative metal catalysis for diamination of alkenes has
recently emerged as a powerful tool for the synthesis of
heterocycles that incorporate the vicinal diamine structural
motif.4 Reactions to this end include palladium,5 nickel,6 gold,7
and copper8 catalysis.9,10 Within this context, some time ago we
reported the diamination of acrylates using ureas as nitrogen
sources (Scheme 1).11
After some experimentation, conditions were found under
which the diamination reaction of 2a to cyclized 3a proceeded
under palladium catalysis with high yield and good diaster-
eoselectivity. Initial attempts to employ high oxidation state
catalysis12 and acetate base did not meet with success (Table 1,
entry 1). Instead, use of copper bromide as oxidant resulted
more convenient (entry 2). Solvent exploration revealed DMF
to be superior than dichloromethane or THF, respectively
(entries 2−4). Further optimization addressed the nature of
base and cesium carbonate was identified as optimum base in
comparison to acetate and hydrogenphosphate (entries 4−6).
Complete conversion was observed for a reaction at slightly
enhanced temperature of 40 °C (entry 7). This optimization
process hence identified cesium carbonate as optimum base and
DMF as best solvent generating product 3a in 83% isolated
yield. No reaction was observed in the absence of a palladium
catalyst (entry 8). As a usual feature in the intramolecular
diamination under palladium catalysis,5a−d,6 the presence of
base is required (entry 9).
This reaction proceeds under palladium catalysis with copper
bromide as terminal oxidant and allows us to selectively
generate syn-configured 2,3-diamino esters. One of these
compounds served as building block in the synthesis of the
natural product absouline.
RESULTS AND DISCUSSION
■
We now became interested in the use of the corresponding
sulfamates as nitrogen sources, which are more conveniently
accessible and usually show a broader potential for structural
diversification. They were already employed in oxidative
diamination reactions of terminal alkenes using nickel catalysis.6
Herein, we describe the application of intramolecular
diamination of acrylates using sulfamate groups as nitrogen
source.
Under the optimized conditions, the diamination reaction of
2a reaches full completion, and an overall yield of 83% (76%
for 3a and 7% for 4a) is obtained. The high yield of 3a is
Received: December 12, 2011
Published: January 18, 2012
© 2012 American Chemical Society
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Scheme 1
Scheme 2. Metathesis Approach to Starting Materials 2
as a single diastereomer displaying syn-configuration (Scheme
1).
We had observed in an earlier case of a different palladium
catalysis that the carbamate nitrogen of the sulfamate group
displays rather low nucleophilic character for a direct C−N
bond formation.6 Assuming a related behavior for the present
reaction, we set to investigate potential intermediates by
conducting the diamination reaction of 2a at lower reaction
temperature (Figure 1). Indeed, when 2a was oxidized at room
temperature (Scheme 3), the corresponding aminobrominated
product 5 was the major product (65% isolated yield) together
with 3a (23%). Compound 4a was not observed. If formed, its
amount was below detection level. Treatment of the isolated
aminobrominated intermediate 5 with base in DMF gave the
expected product 3a as single isomer in 92% isolated yield. This
reaction outcome suggests that the present diamination
reaction proceeds through a catalytic cycle of syn-amino-
palladation5b,d,e,14,15 to A followed by copper-mediated
transient palladium oxidation with concomitant C−Br bond
formation.16 This latter step proceeds with clean SN2 chemistry
leading to inversion of configuration at carbon. Subsequent C−
N bond formation from B under a second inversion of
configuration leads to anti-3a. The minor isomer 4a is either
generated from B within a minor pathway of direct C−N bond
formation or from C within an epimerization of the brominated
center.
particularly remarkable in view of the lower yielding trans-
formation of parent terminal alkenes 1 under similar
conditions.11 The observed coupling constant of J = 4 Hz
3
between the two hydrogen atoms at the newly formed
tetrahedral carbon atoms suggested that the reaction leads to
preferential formation of a trans-configured diamination
product 3a. The corresponding cis-isomer 4a is the minor
product and is generated in less than 10% yield. Both relative
configurations were unambiguously assured from X-ray analyses
(Scheme 3).13 This reaction outcome constitutes a noteworthy
difference to the one from the previous reactions using ureas as
nitrogen source, where the corresponding product was obtained
The reaction is general for a range of different substrates.
Table 2 shows representative examples of several sulfamates
with variation of backbone substitution, the ester groups and
the carbamate group of the sulfamate. All these reactions
proceed with good to high isolated yields. An anti-configuration
was obtained for all major products as judged from the
respective 3J coupling constants and confirmed by an additional
X-ray analysis of product 3l. Diastereomeric ratios range from
Table 1. Optimization of Reaction Conditions
a
b
entry
conditions
conversion (%)
yield (%)
1
2
3
4
5
6
7
8
9
10 mol % Pd(OAc)2, PhI(OAc)2 (1.2 equiv), NaOAc (2 equiv), CH2Cl2, 30 °C
10 mol % Pd(OAc)2, CuBr2 (2 equiv), NaOAc (2 equiv), CH2Cl2, 30 °C
10 mol % Pd(OAc)2, CuBr2 (2 equiv), NaOAc (2 equiv), THF, 30 °C
10 mol % Pd(OAc)2, CuBr2 (2 equiv), NaOAc (2 equiv), DMF, 30 °C
10 mol % Pd(OAc)2, CuBr2 (2 equiv),Na2HPO4 (2 equiv), DMF, 30 °C
10 mol % Pd(OAc)2, CuBr2 (2 equiv), Cs2CO3 (2 equiv), DMF, 30 °C
10 mol % Pd(OAc)2, CuBr2 (2 equiv), Cs2CO3 (2 equiv), DMF, 40 °C
CuBr2 (2 equiv), Cs2CO3 (2 equiv), DMF, 30 °C
<10
40
nd
34
38
54
56
68
83
nd
nd
45
60
70
75
>95
0
10 mol % Pd(OAc)2, CuBr2 (2 equiv), DMF, 40 °C
<10
a
b
1
Estimated conversion from crude H NMR data. Isolated yield of combined diastereoisomers after purification (around 10:1 ratio for all cases,
major diastereomer 3a shown).
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Scheme 3. Exploration of the Stereochemical Pathways in Diamination of 2a
Figure 1. Catalytic cycle for Pd-catalyzed diamination of 2a. X = OAc, Br.
3:1 to 10:1 for reactions that were typically conducted on a 0.2
mmol scale. For the case of 2d (entry 3), the reaction was
performed on a 3 mmol scale, which demonstrated that up-
scaling does not constitute any problem. It also allowed for
isolation and full characterization of the minor diastereomer
syn-4d in this case. Unlike the related case of ureas,11
cyclization of 2h without backbone substituents did not suffer
any rate decrease or loss of diastereoselectivity, respectively,
and the corresponding product 3h was isolated in 70% yield
(entry 7).
Representative Deprotection and Peptide Coupling.
Since 2,3-diamino carboxylic acids serve as interesting amino
acid derivatives, we briefly investigated the general application
of products 3 in peptide chemistry. To this end, we found that
simple treatment with pyridine in aqueous conditions leads to
selective removal of the carbamate groups in compounds 3.17
More conveniently, use of KOH in THF−methanol solution
cleaves both the carbamate and the ester groups of 3a,f to arrive
at the free carboxylate 6 with intact sulfamate. This aspect
should be of interest as it retains the structural rigidity of the
anti-configured bicyclic system. Coupling of the free acid
terminus to the free amine group of an aminoester such as
glycine methyl ester under standard conditions18 furnished the
coupling product 7 in 52% yield (Scheme 4).
arrangements are now available from diamination of easily
accessible (E)-configured acrylates depending on the nitrogen
sources (trans-diamines from sulfamates and syn-diamines from
ureas, respectively).
EXPERIMENTAL SECTION
■
General Procedure for the Formation of the Acrylate
Starting Materials. The terminal alkenes 1 were first synthesized
according to a literature protocol.6 The subsequent formation of the
acrylates was done by metathesis reaction under conditions described
previously (general procedure A):11 The respective sulfamate 1 was
dissolved in freshly distilled absolute dichloromethane. The respective
acrylic ester (8 equiv) was added in one portion via syringe and the
resulting solution stirred under nitrogen at room temperature.
Grubbs−Hoveyda II catalyst (3 mol %) was added, and the resulting
green solution was heated to reflux for a period of 3 h. It was cooled to
room temperature and the solvent removed under reduced pressure.
Column chromatography (silica gel, EtOAc/hexenes 4:1) gave the
corresponding acrylates as white to brown solids.
(E)-Methyl 6-((N-(Methoxycarbonyl)sulfamoyl)amino)-5,5-diphe-
nylhex-2-enoate (2a). This compound was obtained according to the
general procedure A. The subsequent chromatographic purification
(hexanes/EtOAc, 3:1) gave 407 mg (0.94 mmol, 94%) of 2a as a white
1
solid: mp 164−168 °C; H NMR (400 MHz, CDCl3) δ = 7.69 (s,
1H), 7.14−7.38 (m, 10H), 6.57 (dt, J = 15.8, 7.4 Hz, 1H), 5.89 (d, J =
15.8 Hz, 1H), 4.65 (t, J = 6.4 Hz, 1H), 3.74 (d, J = 6.4 Hz, 2H), 3.71
(s, 3H), 3.68 (s, 3H), 3.15 (d, J = 7.4 Hz, 2H); 13C NMR (101 MHz,
CDCl3) δ = 166.5, 151.5, 143.8, 143.6, 128.7, 127.5, 127.2, 124.8, 53.6,
51.5, 50.4, 49.6, 39.4; IR (cm−1) 595, 699, 753, 779, 849, 1158, 1272,
1342, 1366, 1471, 1705, 3164, 3262; MS (ESI-TOF) m/z 455.1 [M +
Na]+ (100); HRMS-ESI-TOF m/z calcd for C21H24N2NaO6S [M +
Na]+ 455.1253, found 455.1264.
To summarize, we reported an additional intramolecular
diamination reaction that gives rise to 2,3-diamino carboxylic
acid building blocks. The use of sulfamates as nitrogen groups
allows to generate products with relative trans-stereochemistry,
which nicely complements an earlier syn-stereochemistry using
ureas as nitrogen source. Hence, both relative stereochemical
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a
Table 2. Palladium-Catalyzed Intramolecular Diamination of Acrylates to 1,2-Diamines
a
General conditions: starting material (0.2 mmol), DMF (2.0 mL), Pd(OAc)2 (0.02 mmol), Cs2CO3 (0.6 mmol), CuBr2 (0.4 mmol), 40 °C, 12−24
b
c
1
h. Determined by H NMR spectroscopy of the crude reaction mixture after reductive workup. Yield of the isolated major product 3 after
purification. 3 mmol scale up. Isolated yield of major diastereoisomer. The minor diastereoisomer was isolated in 22%. 5 mmol scale up. Isolated
yield of major diastereoisomer. The minor diastereoisomer was isolated in 29%.
d
e
Scheme 4. Conversion of Diamination Products 3a,f into Dipeptide 6
(E)-tert-Butyl 6-((N-((Benzyloxy)carbonyl)sulfamoyl)amino)-5,5-
diphenylhex-2-enoate (2b). This compound was obtained according
to the general procedure A. The subsequent chromatographic
purification (hexanes/EtOAc, 4:1) gave 479 mg (0.87 mmol, 87%)
of 2b as a white solid: mp 104−107 °C; 1H NMR (400 MHz, CDCl3)
δ = 8.48 (brs, 1H), 7.44−7.02 (m, 15H), 6.61−6.38 (m, 1H), 5.78 (d,
J = 15.5 Hz, 1H), 5.10 (s, 2H), 4.72−4.74 (m, 1H), 3.70 (d, J = 6.1
Hz, 2H), 3.06 (d, J = 7.3 Hz, 2H), 1.44 (s, 9H); 13C NMR (101 MHz,
CDCl3) δ = 165.5, 151.1, 143.5, 142.5, 134.6, 128.4, 128.3, 128.2,
128.0, 127.4, 126.8, 126.4, 80.1, 68.1, 50.3, 49.4, 39.1, 27.8; IR (cm−1)
573, 655, 670, 740, 757, 876, 1071, 1147, 1169, 1238, 1319, 1335,
1429, 1467, 1650, 1705, 2980, 3301; MS (ESI-TOF) m/z 573.2 [M +
Na]+ (100); HRMS-ESI-TOF m/z calculated for C30H34N2NaO6S [M
+ Na]+: 573.2051; found: 573.2035.
(E)-ethyl-6-((N-((benzyloxy)carbonyl)sulfamoyl)amino)-5,5-di-
phenylhex-2-enoate (2c). This compound was obtained according to
the general procedure A. The subsequent chromatographic purification
(hexanes/EtOAc, 4:1) gave 444 mg (0.85 mmol, 85%) of 2c as a white
1
solid. mp: 150−155 °C. H NMR (400 MHz, CDCl3) δ = 8.31 (s,
1H), 7.41−6.99 (m, 15H), 6.60 (dt, J = 15.6, 7.4 Hz, 1H), 5.85 (d, J =
15.6 Hz, 1H), 5.11 (s, 2H), 4.72−4.76 (m, 1H), 4.10 (q, J = 7.1 Hz,
2H), 3.71 (d, J = 6.5 Hz, 2H), 3.09 (d, J = 7.4 Hz, 2H), 1.22 (t, J = 7.1
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Hz, 3H). 13C NMR (101 MHz, CDCl3) δ = 166.1, 151.0, 143.6, 143.5,
134.5, 128.4, 128.4, 128.4, 128.0, 127.4, 126.9, 124.8, 68.1, 60.1, 50.2,
49.4, 39.2, 13.9; IR (cm−1) 550, 696, 741, 841, 873, 1068, 1094, 1165,
1195, 1238, 1269, 1332, 1353, 1366, 1426, 1448, 1460, 1654, 1706,
3189, 3294; MS (ESI-TOF) m/z 545.2 [M + Na]+ (100); HRMS-ESI-
TOF m/z calcd for C28H30N2NaO6S [M + Na]+ 545.1717, found
545.1722.
6.9 Hz, 2H), 2.27−2.19 (m, 2H), 1.73−1.64 (m, 2H); 13C NMR (101
MHz, CDCl3) δ = 166.9, 151.4, 147.3, 134.5, 128.9, 128.7, 128.5,
122.0, 68.6, 51.5, 43.1, 28.9, 27.5; IR (cm−1) 696, 736, 776, 849, 977,
1153, 1243, 1343, 1433, 1657, 1720, 2954, 3262; MS (ESI-TOF) m/z
379.1 [M + Na]+ (100); HRMS-ESI-TOF m/z calcd for
C15H20N2NaO6S [M + Na]+ 379.0940, found 379.0945.
(E)-tert-Butyl 4-(1-(((N-(Methoxycarbonyl)sulfamoyl)amino)-
methyl)cyclohexyl)but-2-enoate (2i). This compound was obtained
according to the general procedure A. The subsequent chromato-
graphic purification (hexanes/EtOAc, 4:1) gave 340 mg (0.87 mmol,
(E)-tert-Butyl 6-((N-(tert-Butoxycarbonyl)sulfamoyl)amino)-5,5-
diphenylhex-2-enoate (2d). This compound was obtained according
to the general procedure A. The subsequent chromatographic
purification (hexanes/EtOAc, 4:1) gave 450 mg (0.87 mmol, 87%)
of 2d as a white solid: mp 125−130 °C; 1H NMR (400 MHz, CDCl3)
δ = 7.61 (s, 1H), 7.17−7.38 (m, 10H), 6.47 (dt, J = 15.6, 7.4 Hz, 1H),
5.82 (d, J = 15.6 Hz, 1H), 4.61 (t, J = 6.8 Hz, 1H), 3.71 (d, J = 6.8 Hz,
2H), 3.12 (d, J = 7.4 Hz, 2H), 1.46 (s, 9H), 1.42 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ = 165.5, 149.9, 143.8, 142.4, 128.7, 127.7, 127.2,
126.8, 83.9, 80.2, 50.6, 49.7, 39.5, 28.1, 27.8; IR (cm−1) 551, 587, 698,
726, 818, 842, 914, 936, 970, 1077, 1140, 1175, 1250, 1317, 1350,
1368, 1393, 1443, 1461, 1650, 1656, 1702, 2932, 2980, 3233, 3272;
MS (ESI-TOF) m/z 539.2 [M + Na]+ (100); HRMS-ESI-TOF m/z
calcd for C27H36N2NaO6S [M + Na]+ 539.2182, found 539.2192.
(E)-Methyl 6-((N-(tert-Butoxycarbonyl)sulfamoyl)amino)-5,5-di-
phenylhex-2-enoate (2e). This compound was obtained according
to the general procedure A. The subsequent chromatographic
purification (hexanes/EtOAc, 3:1) gave 422 mg (0.89 mmol, 89%)
of 2e as a white solid: mp 144−146 °C; 1H NMR (400 MHz, CDCl3)
δ = 7.63 (s, 1H), 7.57−7.06 (m, 10H), 6.56 (dt, J = 15.6, 7.5 Hz, 1H),
5.88 (d, J = 15.6 Hz, 1H), 4.56 (t, J = 6.8 Hz, 1H), 3.69 (d, J = 6.8 Hz,
2H), 3.67 (s, 3H), 3.14 (d, J = 7.5 Hz, 2H), 1.40 (s, 9H); 13C NMR
(101 MHz, CDCl3) δ = 166.2, 149.5, 143.5, 143.5, 128.5, 127.3, 127.0,
124.7, 83.7, 51.2, 50.2, 49.3, 39.3, 27.5; IR (cm−1) 540, 578, 647, 698,
727, 822, 910, 1029, 1076, 1141, 1202, 1246, 1366, 1396, 1434, 1495,
1656, 1719, 2950, 2981, 3248; MS (ESI-TOF) m/z 497.2 [M + Na]+
(100); HRMS-ESI-TOF m/z calcd for C24H30N2NaO6S [M + Na]+
497.1719, found 497.1722.
(E)-Methyl 6-((N-((Benzyloxy)carbonyl)sulfamoyl)amino)-5,5-di-
phenylhex-2-enoate (2f). This compound was obtained according
to the general procedure A. The subsequent chromatographic
purification (hexanes/EtOAc, 4:1) gave 468 mg (0.92 mmol, 92%)
of 2f as a white solid: mp 147−153 °C; 1H NMR (400 MHz, CDCl3)
δ = 7.72 (s, 1H), 7.33−7.09 (m, 15H), 6.55 (dt, J = 15.6, 7.4 Hz, 1H),
5.85 (d, J = 15.6 Hz, 1H), 5.12 (s, 2H), 4.63 (t, J = 6.7 Hz, 1H), 3.68
(d, J = 6.7 Hz, 2H), 3.65 (s, 3H), 3.09 (d, J = 7.4 Hz, 2H); 13C NMR
(101 MHz, CDCl3) δ = 166.5, 150.9, 143.8, 143.6, 134.6, 128.8, 128.7,
128.7, 128.3, 127.5, 127.2, 124.8, 68.5, 51.4, 50.4, 49.6, 39.4; IR (cm−1)
470, 550, 696, 745, 842, 1067, 1166, 1200, 1269, 1367, 1448, 1656,
1705, 3182, 3294; MS (ESI-TOF) m/z 531.2 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C27H28N2NaO6S [M + Na]+ 531.1581,
found 531.1566.
(E)-tert-Butyl 6-((N-(Methoxycarbonyl)sulfamoyl)amino)-5,5-di-
phenylhex-2-enoate (2g). This compound was obtained according
to the general procedure A. The subsequent chromatographic
purification (hexanes/EtOAc, 3:1) gave 418 mg (0.88 mmol, 88%)
of 2g as a white solid: mp 75−79 °C; 1H NMR (400 MHz, CDCl3) δ
= 7.34−7.10 (m, 11H), 6.43 (dt, J = 15.6, 7.4 Hz, 1H), 5.76 (d, J =
15.6 Hz, 1H), 4.64 (t, J = 6.6 Hz, 1H), 3.70 (d, J = 6.6 Hz, 2H), 3.65
(s, 3H), 3.07 (dd, J = 7.4, 1.0 Hz, 2H), 1.41 (s, 9H); 13C NMR (101
MHz, CDCl3) δ = 165.6, 151.6, 143.7, 142.4, 128.6, 127.6, 127.1,
126.7, 80.3, 53.5, 50.4, 49.6, 39.4, 28.0; IR (cm−1) 539, 583, 698, 730,
757, 772, 848, 961, 986, 1030, 1075, 1149, 1246, 1316, 1365, 1393,
1446, 1649, 1709, 1737, 2870, 2961, 3057, 3236; MS (ESI-TOF) m/z
497.2 [M + Na]+ (100); HRMS-ESI-TOF m/z calcd for
C24H30N2NaO6S [M + Na]+ 497.1719, found 497.1722.
(E)-Methyl 6-((N-((Benzyloxy)carbonyl)sulfamoyl)amino)hex-2-
enoate (2h). This compound was obtained according to the general
procedure A. The subsequent chromatographic purification (hexanes/
EtOAc, 2:1) gave 418 mg (0.72 mmol, 72%) of 2h as a white solid: mp
92−97 °C; 1H NMR (400 MHz, CDCl3) δ = 7.74 (s, 1H), 7.38−7.33
(m, 5H), 6.89 (dt, J = 15.6, 6.9 Hz, 1H), 5.84 (d, J = 15.6 Hz, 1H),
5.33 (t, J = 6.2 Hz, 1H), 5.17 (s, 2H), 3.72 (s, 3H), 3.05 (dd, J = 13.4,
1
87%) of 2i as a white solid: mp 86−96 °C; H NMR (400 MHz,
CDCl3) δ = 8.20 (s, 1H), 6.81 (dt, J = 15.6, 7.6 Hz, 1H), 5.80 (d, J =
15.6 Hz, 1H), 5.38 (t, J = 7.0 Hz, 1H), 3.78 (s, 3H), 2.91 (d, J = 7.0
Hz, 2H), 2.20 (d, J = 7.6 Hz, 2H), 1.46 (s, 9H), 1.45−1.31 (m, 10H);
13C NMR (101 MHz, CDCl3) δ = 165.8, 152.1, 143.2, 126.0, 80.4,
53.5, 49.7, 37.9, 36.9, 33.0, 28.1, 25.7, 21.2; IR (cm−1) 587, 851, 1064,
1147, 1229, 1289, 1343, 1364, 1410, 1451, 1651, 1691, 1714, 1731,
1755, 2855, 2926, 3271; MS (ESI-TOF) m/z 413.2 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C17H30N2NaO6S [M + Na]+ 413.1741,
found 413.1722.
(E)-tert-Butyl 4-(1-(((N-(Isopropoxycarbonyl)sulfamoyl)amino)-
methyl)cyclohexyl)but-2-enoate (2j). This compound was obtained
according to the general procedure A. The subsequent chromato-
graphic purification (hexanes/EtOAc, 4:1) gave 343 mg (0.82 mmol,
1
82%) of 2j as a white solid: mp 94−101 °C; H NMR (400 MHz,
CDCl3) δ = 8.11 (s, 1H), 6.81 (dt, J = 15.6, 7.6 Hz, 1H), 5.78 (d, J =
15.6 Hz, 1H), 5.41 (t, J = 6.9 Hz, 1H), 4.98 (hept, J = 6.2 Hz, 1H),
2.90 (d, J = 6.9 Hz, 2H), 2.19 (d, J = 7.6 Hz, 2H), 1.45 (s, 9H), 1.44−
1.30 (m, 10H), 1.26 (d, J = 6.2 Hz, 6H); 13C NMR (101 MHz,
CDCl3) δ = 165.7, 151.3, 143.2, 125.9, 80.20, 71.1, 49.7, 38.0, 36.9,
32.9, 28.1, 25.7, 21.7, 21.2; IR (cm−1) 581, 748, 885, 1105, 1150, 1238,
1365, 1451, 1709, 2927, 3245; MS (ESI-TOF) m/z 441.2 [M + Na]+
(100); HRMS-ESI-TOF m/z calcd for C19H34N2NaO6S [M + Na]+
441.2046, found 441.2035.
(E)-tert-Butyl 4-(1-(((N-(tert-Butoxycarbonyl)sulfamoyl)amino)-
methyl)cyclohexyl)but-2-enoate (2k). This compound was obtained
according to the general procedure A. The subsequent chromato-
graphic purification (hexanes/EtOAc, 4:1) gave 377 mg (0.87 mmol,
1
87%) of 2k as a white solid: mp 121−126 °C; H NMR (400 MHz,
CDCl3) δ = 7.74 (s, 1H), 6.81 (dt, J = 15.6, 7.8 Hz, 1H), 5.78 (d, J =
15.6 Hz, 1H), 5.27 (t, J = 7.0 Hz, 1H), 2.88 (d, J = 7.0 Hz, 2H), 2.19
(d, J = 7.8 Hz, 2H), 1.47 (s, 9H), 1.45 (s, 9H), 1.44−1.30 (m, 10H);
13C NMR (101 MHz, CDCl3) δ = 165.6, 150.4, 143.1, 126.0, 83.6,
80.2, 49.7, 38.1, 36.9, 33.0, 28.1, 28.1, 25.7, 21.2; IR (cm−1) 594, 724,
821, 950, 1136, 1254, 1368, 1442, 1691, 1712, 2927, 3232, 3302; MS
(ESI-TOF) m/z 455.2 [M + Na]+ (100); HRMS-ESI-TOF m/z calcd
for C20H36N2NaO6S [M + Na]+ 455.2196, found 455.2192.
(E)-Methyl 4-(1-(((N-(tert-Butoxycarbonyl)sulfamoyl)amino)-
methyl)cyclohexyl)but-2-enoate (2l). This compound was obtained
according to the general procedure A. The subsequent chromato-
graphic purification (hexanes/EtOAc, 3:1) gave 316 mg (0.81 mmol,
1
81%) of 2l as a white solid: mp 127−131 °C; H NMR (400 MHz,
CDCl3) δ = 7.75 (s, 1H), 6.91 (dt, J = 15.6, 7.9 Hz, 1H), 5.88 (d, J =
15.6 Hz, 1H), 5.33 (t, J = 6.9 Hz, 1H), 3.69 (s, 3H), 2.88 (d, J = 6.9
Hz, 2H), 2.23 (d, J = 7.9 Hz, 2H), 1.46 (s, 9H), 1.45−1.30 (m, 10H);
13C NMR (101 MHz, CDCl3) δ = 166.6, 150.4, 144.7, 124.0, 83.7,
51.4, 49.6, 38.2, 36.9, 33.0, 27.9, 25.7, 21.2; IR (cm−1) 570, 719, 818,
946, 1057, 1136, 1202, 1249, 1343, 1430, 1652, 1694, 1714, 2936,
3243, 3302; MS (ESI-TOF) m/z 413.2 [M + Na]+ (100); HRMS-ESI-
TOF m/z calcd for C17H30N2NaO6S [M + Na]+ 413.1741, found
413.1722.
(E)-Methyl 6-((N-(tert-Butoxycarbonyl)sulfamoyl)amino)-5,5-di-
methylhex-2-enoate (2m). This compound was obtained according
to the general procedure A. The subsequent chromatographic
purification (hexanes/EtOAc, 3:1) gave 330 mg (0.94 mmol, 94%)
of 2m as a white solid: mp 126−129 °C; 1H NMR (400 MHz, CDCl3)
δ = 7.64 (s, 1H), 6.96 (dt, J = 15.6, 7,6 Hz,1H), 5.87 (d, J = 15.6 Hz,
1H), 5.42−5.38 (m, 1H), 3.72 (s, 3H), 2.83 (d, J = 6.8 Hz, 2H), 2.17
(d, J = 7.6 Hz, 2H), 1.48 (s, 9H), 0.95 (s, 3H), 0.94 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ = 166.6, 150.3, 144.9, 124.0, 83.8, 53.5, 51.4,
1926
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Article
42.0, 34.6, 27.9, 24.7; IR (cm−1) 569, 582, 665, 670, 728, 820, 941,
1052, 1179, 1211, 1270, 1366, 1435, 1455, 1656, 1701, 1714, 1967,
3225, 3266; MS (ESI-TOF) m/z 373.1 [M + Na]+ (100); HRMS-ESI-
TOF m/z calcd for C14H26N2NaO6S [M + Na]+ 373.1396, found
373.1409.
126.2, 126.2, 60.0, 59.1, 56.7, 55.2, 54.6, 52.7, 40.1; IR (cm−1) 520,
560, 595, 631, 676, 698, 723, 758, 822, 900, 961, 982, 1017, 1087,
1116, 1174, 1308, 1363, 1437, 1493, 1737, 2951; MS (ESI-TOF) m/z
453.1 [M + Na]+ (100); HRMS-ESI-TOF m/z calcd for
C21H22N2NaO6S [M + Na]+ 453.1096, found 453.1088.
(E)-Ethyl 6-((N-(tert-Butoxycarbonyl)sulfamoyl)amino)-5,5-dime-
thylhex-2-enoate (2n). This compound was obtained according to the
general procedure A. The subsequent chromatographic purification
(hexanes/EtOAc, 3:1) gave 299 mg (0.82 mmol, 82%) of 2n as a white
Methyl 2-Bromo-2-(1-(N-(methoxycarbonyl)sulfamoyl)-4,4-di-
phenylpyrrolidin-2-yl)acetate (5). This compound was obtained
according to the general procedure B, but the temperature was
changed to rt. The subsequent chromatographic purification (hexanes/
EtOAc, 3:1) gave 82 mg (0.16 mmol, 32%) of 5 as a white solid: mp
166−176 °C; 1H NMR (400 MHz, CDCl3) δ = 7.44−7.17 (m, 11H),
5.27 (d, J = 3.4 Hz, 1H), 4.64 (m, 2H), 4.09 (d, J = 11.1 Hz, 1H), 3.79
(s, 3H), 3.54 (s, 3H), 3.33 (dd, J = 13.3, 7.8 Hz, 1H), 2.83 (dd, J =
13.3, 9.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ = 168.3, 151.3,
144.6, 143.30, 128.8, 128.7, 126.8, 126.7, 126.6, 126.4, 60.5, 59.8, 53.3,
53.2, 52.8, 50.8, 40.0; IR (cm−1) 570, 608, 697, 705, 772, 841, 998,
1057, 1079, 1144, 1156, 1164, 1209, 1231, 1279, 1307, 1356, 1367,
1429, 1469, 1729, 3232, 3303; MS (ESI-TOF) m/z 533.0 [M + Na]+
(100); HRMS-ESI-TOF m/z calcd for C21H23BrN2NaO6S [M + Na]+
533.0358, found 533.0361.
1
solid: mp 108−112 °C; H NMR (400 MHz, CDCl3) δ = 7.78 (s,
1H), 6.90 (dt, J = 15.6, 7.8 Hz, 1H), 5.84 (d, J = 15.6 Hz, 1H), 5.44 (t,
J = 6.9 Hz, 1H), 4.16 (q, J = 7.1 Hz, 2H), 2.81 (d, J = 6.9 Hz, 2H),
2.15 (d, J = 7.8 Hz, 2H), 1.46 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H), 0.94 (s,
6H); 13C NMR (101 MHz, CDCl3) δ = 166.2, 150.4, 144.6, 124.3,
83.7, 60.2, 53.5, 42.0, 34.6, 27.9, 24.6, 14.2; IR (cm−1) 581, 726, 818,
940, 979, 1049, 1136, 1254, 1346, 1365, 1444, 1656, 1698, 1720, 2969,
3231, 3289; MS (ESI-TOF) m/z 387.2 [M + Na]+ (100); HRMS-ESI-
TOF m/z calcd for C15H28N2NaO6S [M + Na]+ 387.1572, found
387.1566.
(E)-Methyl 6-((N-(Isopropoxycarbonyl)sulfamoyl)amino)-5,5-di-
methylhex-2-enoate (2o). This compound was obtained according
to the general procedure A. The subsequent chromatographic
purification (hexanes/EtOAc, 3:1) gave 290 mg (0.86 mmol, 86%)
of 2o as a white solid: mp 113−116 °C; 1H NMR (400 MHz, CDCl3)
δ = 7.96 (s, 1H), 6.97 (dt, J = 15.6, 7.8 Hz, 1H), 5.90 (d, J = 15.6 Hz,
1H), 5.55 (t, J = 6.9 Hz, 1H), 5.09−4.98 (m, 1H), 3.76 (s, 3H), 2.88
(d, J = 6.9 Hz, 2H), 2.21 (d, J = 7.8 Hz, 2H), 1.32 (d, J = 6.3 Hz, 6H),
0.99 (s, 6H); 13C NMR (101 MHz, CDCl3) δ = 166.7, 151.2, 144.9,
123.9, 71.3, 53.4, 51.5, 41.9, 34.7, 24.7, 21.7; IR (cm−1) 583, 750, 790,
886, 950, 993, 1053, 1103, 1160, 1255, 1342, 1470, 1653, 1704, 1722,
2968, 3191, 3280; MS (ESI-TOF) m/z 359.1 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C13H24N2NaO6S [M + Na]+ 359.1272,
found 359.1253.
anti-2-Benzyl 3-tert-Butyl 5,5-Diphenyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3b). This
compound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
1
214 mg (0.39 mmol, 78%) of 3b as a white solid: mp 84−89 °C; H
NMR (500 MHz, CDCl3) δ = 7.46−7.21 (m, 15H), 5.32 (d, J = 12.3
Hz, 1H), 5.28 (d, J = 12.3 Hz, 1H), 4.32 (d, J = 4.0 Hz, 1H), 4.21 (d, J
= 10.4 Hz, 1H), 4.15−4.10 (m, 1H), 4.09 (d, J = 10.4 Hz, 1H), 3.16
(dd, J = 12.7, 6.7 Hz, 1H), 2.71 (dd, J = 12.7, 7.2 Hz, 1H), 1.41 (s,
9H); 13C NMR (126 MHz, CDCl3) δ = 166.9, 150.4, 144.2, 143.9,
134.8, 128.8, 128.7, 128.6, 128.5, 128.2, 127.2, 127.0, 126.5, 126.5,
83.9, 68.9, 62.6, 60.1, 59.2, 55.0, 44.9, 27.7; IR (cm−1) 537, 582, 626,
696, 749, 801, 844, 1026, 1093, 1150, 1293, 1369, 1448, 1495, 1729,
2930, 2976; MS (ESI-TOF) m/z 571.2 [M + Na]+ (100); HRMS-ESI-
TOF m/z calcd for C30H32N2NaO6S [M + Na]+ 571.1879, found
571.1865.
General Procedure for the Intramolecular Diamination of
Acrylates (General Procedure B). A Pyrex tube equipped with a
stirrer bar was charged with Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.1
equiv), CuBr2 (223.4 mg, 1.0 mmol, 2 equiv), Cs2CO3 (488.7 mg, 1.5
mmol, 3 equiv), and sulfamide (0.5 mmol, 1.0 equiv). DMF (4 mL)
was added, and the mixture was stirred for 12 h at 40 °C. The reaction
was quenched by addition of 2 mL of satd aqueous Na2S2O3 solution.
The aqueous phase was extracted with ethyl acetate (3×), the
combined organic layers were dried (MgSO4), and the solvent was
evaporated under reduced pressure. The crude reaction mixture was
then analyzed by NMR and the conversion of alkene was 90−100%.
All products were purified by flash chromatography (hexanes/EtOAc).
anti-Dimethyl 5,5-Diphenyltetrahydropyrrolo[1,2-b][1,2,5]-
thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3a). This compound
was obtained according to the general procedure B. The subsequent
chromatographic purification (hexanes/EtOAc, 3:1) gave 140 mg
anti-2-Benzyl 3-Ethyl 5,5-Diphenyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3c). This
compound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
177 mg (0.34 mmol, 68%) of 3c as a white solid: 1H NMR (400 MHz,
CDCl3) δ = 7.44−7.18 (m, 15H), 5.32 (d, J = 12.7 Hz, 1H), 5.25 (d, J
= 12.7 Hz, 1H), 4.41 (d, J = 4.6 Hz, 1H), 4.22−4.18 (m, 2H), 4.16−
4.10 (m, 2H), 4.10−4.06 (m, 1H), 3.15 (dd, J = 12.8, 6.7 Hz, 1H),
2.71 (dd, J = 12.8, 7.2 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ = 167.7, 150.3, 144.0, 143.7, 134.7, 128.8, 128.7,
128.5, 128.4, 128.0, 127.2, 126.9, 126.5, 126.4, 69.0, 62.5, 62.0, 59.9,
59.0, 55.0, 44.8, 13.9; IR (cm−1) 539, 584, 626, 695, 750, 857, 968,
1020, 1093, 1178, 1296, 1371, 1448, 1496, 1598, 1732, 2925, 2961;
MS (ESI-TOF) m/z 543.1[M + Na]+ (100); HRMS-ESI-TOF m/z
calcd for C28H28N2NaO6S [M + Na]+ 543.1566, found 543.1597.
anti-Di-tert-butyl 5,5-Diphenyltetrahydropyrrolo[1,2-b][1,2,5]-
thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3d). This compound
was obtained according to the general procedure B. The subsequent
chromatographic purification on HPLC (hexanes/isopropanol 98:2)
gave 147 mg (0.29 mmol, 57%) of 3d as a white solid: mp 175−178
°C; 1H NMR (400 MHz, CDCl3) δ = 7.34−7.18 (m, 10H), 4.23 (brs,
1H), 4.17 (d, J = 10.4 Hz, 1H), 4.07 (d, J = 10.4 Hz, 1H), 4.05−4.00
(m, 1H), 3.13 (dd, J = 12.7, 6.7 Hz, 1H), 2.69 (dd, J = 12.7, 7.1 Hz,
1H), 1.52 (s, 9H), 1.47 (s, 9H); 13C NMR (101 MHz, CDCl3) δ =
167.1, 148.8, 144.0, 143.9, 128.5, 128.5, 126.9, 126.7, 126.3, 126.3,
84.3, 83.3, 62.3, 59.8, 58.6, 54.7, 44.6, 27.7, 27.6; IR (cm−1) 627, 699,
752, 841, 1028, 1070, 1093, 1147, 1180, 1218, 1258, 1304, 1333, 1368,
1449, 1477, 1726, 2935, 2980; MS (ESI-TOF) m/z 537.2 [M + Na]+
(100); HRMS-ESI-TOF m/z calcd for C27H34N2NaO6S [M + Na]+
537.2035, found 537.2014.
1
(0.33 mmol, 65%) of 3a as a white solid: mp 200−205 °C; H NMR
(400 MHz, CDCl3) δ = 7.40−7.25 (m, 10H), 4.51 (d, J = 3.6 Hz, 1H),
4.24 (d, J = 10.4 Hz, 1H), 4.14 (ddd, J = 7.3, 6.6, 3.6 Hz, 1H), 4.08 (d,
J = 10.4 Hz, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 3.19 (dd, J = 12.9, 6.6 Hz,
1H), 2.74 (dd, J = 12.9, 7.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ
= 168.1, 150.9, 143.9, 143.7, 128.8, 128.7, 127.0, 126.5, 125.4, 61.9,
60.0, 59.0, 55.0, 53.5, 46.3; IR (cm−1) 583, 708, 801, 906, 983, 1023,
1085, 1112, 1140, 1166, 1178, 1207, 1249, 1271, 1307, 1371, 1432,
1736, 1753, 2897, 2957; MS (ESI-TOF) m/z 453.1 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C21H22N2NaO6S [M + Na]+ 453.1096,
found 453.1088.
syn-Dimethyl 5,5-Diphenyltetrahydropyrrolo[1,2-b][1,2,5]-
thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (4a). This compound
was obtained according to the general procedure B. The subsequent
chromatographic purification (hexanes/EtOAc, 3:1) gave 63 mg (0.15
1
mmol, 29%) of 4a as a white solid: mp 197−200 °C; H NMR (400
MHz, CDCl3) δ = 7.36−7.09 (m, 10H), 4.76 (d, J = 8.7 Hz, 1H), 4.36
(ddd, J = 8.7, 8.7, 6.7 Hz, 1H), 4.25 (dd, J = 9.6, 1.3 Hz, 1H), 3.93 (d, J
= 9.6 Hz, 1H), 3.91 (s, 3H), 3.73 (s, 3H), 2.78 (ddd, J = 12.9, 6.7, 1.3
Hz, 1H), 2.43 (dd, J = 12.9, 8.7 Hz, 1H); 13C NMR (101 MHz,
CDCl3) δ = 167.5, 151.4, 143.8, 143.7, 128.5, 128.5, 127.0, 126.8,
syn-Di-tert-butyl 5,5-Diphenyltetrahydropyrrolo[1,2-b][1,2,5]-
thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (4d). This compound
was obtained according to the general procedure. The subsequent
chromatographic purification on HPLC (hexanes/isopropanol 98:2)
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Article
gave 57 mg (0.11 mmol, 22%) of 3d as a white solid: mp 99−103 °C;
1H NMR (500 MHz, CDCl3) δ = 7.36−7.13 (m, 10H), 4.56 (d, J = 8.5
anti-3′-tert-Butyl 2′-Methyl Dihydro-2′H-spiro[cyclohexane-1,5′-
pyrrolo[1,2-b][1,2,5]thiadiazole]-2′,3′(3′H,6′H)-dicarboxylate 1′,1′-
Dioxide (3i). This compound was obtained according to the general
procedure B. The subsequent chromatographic purification (hexanes/
EtOAc 3:1) gave 156 mg (0.40 mmol, 80%) of 3i as a white solid: mp
Hz, 1H), 4.35 (m, 1H), 4.22 (dd, J = 9.4, 1.0 Hz, 1H), 3.95 (d, J = 9.4
Hz, 1H), 2.84 (ddd, J = 12.7, 7.0, 1.0 Hz, 1H), 2.55 (dd, J = 12.7, 9.0
Hz, 1H), 1.57 (s, 9H), 1.42 (s, 9H); 13C NMR (126 MHz, CDCl3) δ =
166.8, 149.7, 144.5, 144.2, 128.7, 128.7, 127.1, 127.0, 126.6, 126.5,
85.1, 83.8, 61.1, 59.0, 56.7, 55.6, 39.9, 27.9, 27.8; IR (cm−1) 591, 633,
700, 759, 841, 866, 1028, 1043, 1075, 1146, 1229, 1258, 1333, 1368,
1730, 2935, 2981; MS (ESI-TOF) m/z 537.2 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C27H34N2NaO6S [M + Na]+ 537.2035,
found 537.2014.
1
176−178 °C; H NMR (500 MHz, CDCl3) δ = 4.32 (d, J = 6.4 Hz,
1H), 4.01 (ddd, J = 7.7, 6.4, 5.0 Hz, 1H), 3.88 (s, 3H), 3.34 (d, J =
10.1 Hz, 1H), 3.14 (d, J = 10.1 Hz, 1H), 2.28 (dd, J = 13.4, 7.7 Hz,
1H), 1.78 (dd, J = 13.4, 5.0 Hz, 1H), 1.55−1.39 (m, 19H). 13C NMR
(126 MHz, CDCl3) δ = 166.9, 151.2, 83.6, 64.3, 59.5, 54.2, 43.9, 36.9,
35.9, 27.8, 25.6, 23.8, 22.9; IR (cm−1) 578, 611, 969, 1080, 1150, 1185,
1220, 1250, 1267, 1330, 1350, 1367, 1436, 1726, 1755, 2859, 2926;
MS (ESI-TOF) m/z 411.2 [M + Na]+ (100); HRMS-ESI-TOF m/z
calcd for C17H28N2NaO6S [M + Na]+ 411.1566, found 411.1559.
anti-3′-tert-Butyl 2′-Isopropyl Dihydro-2′H-spiro[cyclohexane-
1,5′-pyrrolo[1,2-b][1,2,5]thiadiazole]-2′,3′(3′H,6′H)-dicarboxylate
1′,1′-Dioxide (3j). This compound was obtained according to the
general procedure B. The subsequent chromatographic purification
(hexanes/EtOAc 3:1) gave 156 mg (0.37 mmol, 75%) of 3j as a white
solid: mp 128−131 °C; 1H NMR (500 MHz, CDCl3) δ = 5.08 (dq, J =
6.3, 6.3 Hz, 1H), 4.33 (d, J = 6.4 Hz, 1H), 4.01 (m, 1H), 3.37 (d, J =
10.0 Hz, 1H), 3.16 (d, J = 10.0 Hz, 1H), 2.30 (dd, J = 13.3, 7.7 Hz,
1H), 1.81 (dd, J = 13.3, 5.1 Hz, 1H), 1.58−1.42 (m, 10H), 1.51 (s,
9H), 1.38 (d, J = 6.3 Hz, 3H), 1.36 (d, J = 6.3 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ = 167.1, 150.4, 83.4, 72.2, 64.1, 59.5, 43.9, 37.0,
36.0, 27.9, 25.6, 23.9, 22.9, 21.9, 21.6; IR (cm−1) 549, 579, 613, 654,
681, 819, 877, 909, 950, 977, 1001, 1073, 1146, 1248, 1319, 1378,
1448, 1719, 1755, 2853, 2937, 2982; MS (ESI-TOF) m/z 439.2 [M +
Na]+ (100); HRMS-ESI-TOF m/z calcd for C19H32N2NaO6S [M +
Na]+ 439.1879, found 439.1889.
anti-2-tert-Butyl 3-Methyl 5,5-Diphenyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3e). This
compound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
1
170 mg (0.36 mmol, 72%) of 3e as a white solid: mp 85−96 °C; H
NMR (500 MHz, CDCl3) δ = 7.35−7.19 (m, 10H), 4.38 (m, 1H),
4.18 (dd, J = 10.4, 0.9 Hz, 1H), 4.11−4.01 (m, 2H), 3.78 (s, 3H), 3.13
(ddd, J = 12.7, 6.6, 0.9 Hz, 1H), 2.71 (dd, J = 12.7, 7.4 Hz, 1H), 1.52
(s, 9H); 13C NMR (126 MHz, CDCl3) δ = 168.6, 149.1, 144.1, 144.0,
128.8, 128.7, 127.2, 127.0, 126.6, 126.5, 85.0, 61.9, 59.9, 58.7, 55.0,
53.1, 44.8, 27.9; IR (cm−1) 632, 701, 751, 832, 976, 1057, 1091, 1134,
1148, 1175, 1193, 1212, 1255, 1312, 1337, 1349, 1368, 1448, 1712,
1737, 1750, 2948, 2987; MS (ESI-TOF) m/z 495.2 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C24H28N2NaO6S [M + Na]+ 495.1566,
found 495.1569.
anti-2-Benzyl 3-Methyl 5,5-Diphenyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3f). This com-
pound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
212 mg (0.42 mmol, 84%) of 3f as a white solid: mp 115−117 °C; 1H
NMR (400 MHz, CDCl3) δ = 7.43−7.20 (m, 15H), 5.40−5.23 (m,
2H), 4.42 (d, J = 4.6 Hz, 1H), 4.18 (d, J = 10.4 Hz, 1H), 4.13−4.05
(m, 2H), 3.69 (s, 3H), 3.14 (dd, J = 12.7, 6.7 Hz, 1H), 2.70 (dd, J =
12.7, 7.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ = 168.2, 150.3,
144.0, 143.7, 134.7, 128.8, 128.7, 128.6, 128.5, 128.0, 127.3, 127.0,
126.5, 126.4, 69.1, 61.9, 59.9, 59.0, 55.0, 53.2, 44.8; IR (cm−1) 542,
591, 626, 748, 968, 990, 1026, 1044, 1072, 1093, 1175, 1211, 1299,
1370, 1447, 1495, 1733, 2925, 2954, 3030; MS (ESI-TOF) m/z 529.1
anti-Di-tert-butyl Dihydro-2′H-Spiro[cyclohexane-1,5′-pyrrolo-
[1,2-b][1,2,5]thiadiazole]-2′,3′(3′H,6′H)-dicarboxylate 1′,1′-Dioxide
(3k). This compound was obtained according to the general procedure
B. The subsequent chromatographic purification (hexanes/EtOAc 3:1)
gave 151 mg (0.35 mmol, 70%) of 3k as a white solid: mp 139−141
1
°C; H NMR (500 MHz, CDCl3) δ = 4.25 (d, J = 6.3 Hz, 1H), 3.96
(m, 1H), 3.32 (d, J = 10.0 Hz, 1H), 3.14 (d, J = 10.0 Hz, 1H), 2.26
(dd, J = 13.3, 7.8 Hz, 1H), 1.77 (dd, J = 13.3, 5.1 Hz, 1H), 1.54 (s,
9H), 1.62−1.39 (m, 10H), 1.48 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ = 167.3, 149.4, 84.5, 83.3, 64.1, 59.3, 43.9, 37.0, 36.0, 28.0,
27.9, 25.6, 23.9, 22.9; IR (cm−1) 539, 594, 627, 769, 816, 924, 983,
1010, 1073, 1153, 1187, 1220, 1267, 1315, 1365, 1451, 1716, 1756,
2852, 2928, 2978; MS (ESI-TOF) m/z 453.2 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C20H34N2NaO6S [M + Na]+ 453.2035,
found 453.2038.
anti-2′-tert-Butyl 3′-Methyl Dihydro-2′H-spiro[cyclohexane-1,5′-
pyrrolo[1,2-b][1,2,5]thiadiazole]-2′,3′(3′H,6′H)-dicarboxylate 1′,1′-
Dioxide (3l). This compound was obtained according to the general
procedure B. The subsequent chromatographic purification (hexanes/
EtOAc 3:1) gave 136 mg (0.35 mmol, 70%) of 3l as a white solid: mp
92−95 °C; 1H NMR (500 MHz, CDCl3) δ = 4.39 (d, J = 6.5 Hz, 1H),
4.02 (ddd, J = 7.7, 6.5, 5.0 Hz, 1H), 3.80 (s, 3H), 3.34 (d, J = 10.0 Hz,
1H), 3.15 (d, J = 10.0 Hz, 1H), 2.27 (dd, J = 13.4, 7.7 Hz, 1H), 1.78
(dd, J = 13.4, 5.0 Hz, 1H), 1.58−1.38 (m, 19H); 13C NMR (101 MHz,
CDCl3) δ = 168.6, 149.2, 84.8, 63.5, 59.1, 52.9, 43.9, 43.1, 36.9, 35.9,
27.9, 27.8, 25.5, 23.8, 22.9; IR (cm−1) 584, 596, 609, 624, 724, 853,
912, 976, 1072, 1099, 1143, 1165, 1183, 1207, 1258, 1331, 1358, 1450,
1721, 1753, 2853, 2931; MS (ESI-TOF) m/z 411.2 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C17H28N2NaO6S [M + Na]+ 411.1566,
found 411.1566.
[M
+
Na]+ (100); HRMS-ESI-TOF m/z calculated for
C27H26N2NaO6S [M + Na]+ 529.1409, found 529.1410.
anti-3-tert-Butyl 2-Methyl 5,5-Diphenyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3g). This
compound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
180 mg (0.38 mmol, 76%) of 3g as a white solid: mp 128−131 °C; 1H
NMR (400 MHz, CDCl3) δ = 7.36−7.22 (m, 10H), 4.36 (d, J = 4.4
Hz, 1H), 4.23 (dd, J = 10.3, 1.1 Hz, 1H), 4.12 (m, 1H), 4.03 (d, J =
10.3 Hz, 1H), 3.89 (s, 3H), 3.15 (ddd, J = 12.8, 6.7, 1.1 Hz, 1H), 2.69
(dd, J = 12.8, 7.4 Hz, 1H), 1.48 (s, 9H); 13C NMR (101 MHz, CDCl3)
δ = 166.8, 151.1, 144.1, 144.0, 128.8, 128.7, 127.2, 127.0, 126.5, 126.5,
83.9, 62.7, 60.1, 59.2, 55.0, 54.3, 44.8, 27.8; IR (cm−1) 632, 700, 760,
812, 909, 1092, 1111, 1131, 1151, 1183, 1226, 1260, 1305, 1360, 1370,
1443, 1739, 1754, 2975; MS (ESI-TOF) m/z 495.2 [M + Na]+ (100);
HRMS-ESI-TOF m/z calcd for C24H28N2NaO6S [M + Na]+ 495.1566,
found 495.1583.
anti-2-Benzyl 3-Methyl Tetrahydropyrrolo[1,2-b][1,2,5]-
thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3h). This compound
was obtained according to the general procedure B. The subsequent
chromatographic purification (hexanes/EtOAc 3:1) gave 124 mg (0.35
mmol, 70%) of 3h as a colorless wax: 1H NMR (500 MHz, CDCl3) δ
= 7.43−7.30 (m, 5H), 5.35 (d, J = 12.4 Hz, 1H), 5.25 (d, J = 12.4 Hz,
1H), 4.30 (d, J = 7.1 Hz, 1H), 4.05 (dt, J = 7.1, 2.2 Hz, 1H), 3.77−3.66
(m, 4H), 3.42 (dt, J = 11.2, 7.6 Hz, 1H), 2.37−2.29 (m, 1H), 2.17−
2.10 (m, 1H), 2.05−1.99 (m, 2H); 13C NMR (126 MHz, CDCl3) δ =
168.2, 150.4, 134.7, 128.6, 128.5, 127.9, 69.1, 62.9, 60.2, 53.1, 51.0,
31.2, 23.2; IR (cm−1) 652, 697, 735, 788, 909, 976, 1074, 1171, 1300,
1368, 1438, 1454, 1498, 1502, 1729, 2956, 3034; MS (ESI-TOF) m/z
377.1 [M + Na]+ (100); HRMS-ESI-TOF m/z calcd for
C15H18N2NaO6S [M + Na]+ 377.0783, found 377.0791.
anti-2-tert-Butyl 3-Methyl 5,5-Dimethyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3m). This
compound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
1
127 mg (0.36 mmol, 73%) of 3m as a colorless wax: H NMR (500
MHz, CDCl3) δ = 4.41 (d, J = 6.3 Hz, 1H), 4.06 (m, 1H), 3.79 (s,
3H), 3.21 (d, J = 9.7 Hz, 1H), 3.15 (d, J = 9.7 Hz, 1H), 2.20 (dd, J =
13.1, 7.6 Hz, 1H), 1.81 (dd, J = 13.1, 5.9 Hz, 1H), 1.52 (s, 9H), 1.20
(s, 3H), 1.16 (s, 3H); 13C NMR (126 MHz, CDCl3) δ = 168.6, 149.2,
84.8, 63.4, 62.5, 59.4, 52.9, 45.9, 40.0, 27.8, 27.4, 26.5; IR (cm−1) 462,
515, 568, 625, 696, 752, 815, 880, 962, 988, 1035, 1080, 1143, 1172,
1928
dx.doi.org/10.1021/jo202507d | J. Org. Chem. 2012, 77, 1922−1930

The Journal of Organic Chemistry
Article
1257, 1307, 1366, 1458, 1726, 2875, 2961; MS (ESI-TOF) m/z 371.1
[M + Na]+ (100); HRMS-ESI-TOF m/z calcd for C14H24N2NaO6S
[M + Na]+ 371.1253, found 371.1237.
126.8, 126.8, 126.5, 64.2, 59.1, 56.6, 56.1, 52.5, 41.0, 39.3; IR (cm−1)
514, 589, 700, 752, 786, 863, 908, 1026, 1163, 1225, 1337, 1352, 1406,
1437, 1447, 1489, 1550, 1653, 1745, 2909, 2957, 3029, 3133, 3354;
MS (ESI-TOF) m/z 452.1 [M + Na]+ (100); HRMS-ESI-TOF m/z
calcd for C21H23N3NaO5S [M + Na]+ 452.1256, found 452.1240.
anti-2-tert-Butyl 3-Ethyl 5,5-Dimethyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-dioxide (3n). This
compound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
118 mg (0.32 mmol, 65%) of 3n as a white solid: 1H NMR (400 MHz,
CDCl3) δ = 4.41 (d, J = 6.1 Hz, 1H), 4.31−4.22 (m, 2H), 4.07 (m,
1H), 3.22 (d, J = 9.7 Hz, 1H), 3.16 (dd, J = 9.7, 0.6 Hz, 1H), 2.22
(ddd, J = 13.1, 7.5, 0.6 Hz, 1H), 1.83 (dd, J = 13.1, 5.9 Hz, 1H), 1.54
(s, 9H), 1.30 (t, J = 7.1 Hz, 3H), 1.21 (s, 3H), 1.17 (s, 3H); 13C NMR
(101 MHz, CDCl3) δ = 168.1, 149.3, 84.7, 63.4, 62.6, 62.2, 59.5, 46.0,
40.0, 27.9, 27.4, 26.5, 14.0; IR (cm−1) 569, 624, 1034, 1080, 1143,
1176, 1257, 1308, 1368, 1727, 2937, 2968; MS (ESI-TOF) m/z 385.1
[M + Na]+ (100); HRMS-ESI-TOF m/z calcd for C15H26N2NaO6S
[M + Na]+ 385.1409, found 385.1409.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C spectra for the new compounds; graphics of the
crystal structures showing thermal ellipsoids with 50%
probability. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: kmuniz@iciq.es.
■
anti-2-Isopropyl 3-Methyl 5,5-Dimethyltetrahydropyrrolo[1,2-b]-
[1,2,5]thiadiazole-2,3(3H)-dicarboxylate 1,1-Dioxide (3o). This
compound was obtained according to the general procedure B. The
subsequent chromatographic purification (hexanes/EtOAc 3:1) gave
125 mg (0.37 mmol, 75%) of 3o as a white solid: 1H NMR (400 MHz,
CDCl3) δ = 5.04 (dq, J = 6.4, 6.4 Hz, 1H), 4.46 (d, J = 6.2 Hz, 1H),
4.09 (m, 1H), 3.80 (s, 3H), 3.21(d, J = 9.7 Hz, 1H), 3.17(d, J = 9.7 Hz,
1H), 2.23 (dd, J = 13.0, 7.5 Hz, 1H), 1.82 (dd, J = 13.0, 5.8 Hz, 1H),
1.35 (d, J = 6.4 Hz, 3H), 133 (d, J = 6.4 Hz, 3H), 1.20 (s, 3H), 1.17 (s,
3H); 13C NMR (101 MHz, CDCl3) δ = 168.5, 150.2, 72.5, 63.5, 62.6,
59.6, 53.1, 46.1, 40.1, 27.4, 26.5, 21.7, 21.6; IR (cm−1) 567, 625, 766,
906, 963, 987, 1038, 1080, 1098, 1171, 1292, 1362, 1438, 1465, 1729,
2875, 2961; MS (ESI-TOF) m/z 357.1 [M + Na]+ (100); HRMS-ESI-
TOF m/z calcd for C13H22N2O6SNa [M + Na]+ 357.1096, found
357.1093.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by ICREA, ICIQ
Foundation, the Consolider INTECAT 2010 (Project
■
́
CSD2006-0003), the Spanish Ministerio de Economia y
Competitividad (CTQ2011-25027), and the Fonds der
Chemischen Industrie. J.K. is a predoctoral student from
Strasbourg University on leave at ICIQ. We thank Drs. J. Benet,
E. C. Escudero and M. Martinez from the X-ray Diffraction
Unit at ICIQ for the X-ray structure determination and Dr. C.
́
H. Hovelmann for several discussions.
̈
anti-5,5-Diphenylhexahydropyrrolo[1,2-b][1,2,5]thiadiazole-3-
carboxylic Acid 1,1-Dioxide (6). An aqueous solution of KOH (5N,
20 mL) was added to a solution of sulfamide (1.00 mmol) in 10 mL of
THF/MeOH (5:1) at rt. After 2 h at 40 °C, the resulting solution was
cooled to 0 °C and adjusted to pH ∼2 by dropwise addition of
aqueous HCl solution (12 N). The reaction mixture was extracted
with CHCl3 (3×), and the combined organic layers were dried
(MgSO4). The solvent was removed under reduced pressure, and the
crude product was purified by crystallization from CH2Cl2/MeOH/
hexanes to give 301 mg (0.84 mmol, 84%) of the deprotected product
6 as a white solid: mp 74−75 °C; 1H NMR (500 MHz, acetone-d6) δ
= 7.53−7.45 (m, 2H), 7.38−7.31 (m, 6H), 7.27−7.20 (m, 2H), 6.69
(d, J = 5.9 Hz, 1H), 4.45−4.38 (m, 1H), 4.35−4.29 (m, 2H), 3.71 (d, J
= 9.6 Hz, 1H), 3.18 (dd, J = 12.5, 6.2 Hz, 1H), 2.62 (dd, J = 12.5, 9.9
Hz, 1H); 13C NMR (126 MHz, acetone-d6) δ = 171.1, 147.1, 146.2,
130.1, 130.0, 128.3, 128.2, 128.1, 128.1, 67.9, 62.2, 59.2, 58.9, 44.5; IR
(cm−1) 509, 588, 621, 696, 752, 774, 809, 869, 907, 966, 1026, 1103,
1164, 1268, 1323, 1447, 1494, 1598, 1732, 2598, 2873, 2926, 2957,
3026, 3058; MS (ESI-TOF) m/z 357.1 [M − H]− (100); HRMS-ESI-
TOF m/z calcd for C18H17N2O4S [M − H]− 357.0909, found
357.0909.
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