Radical amination of C(sp3)-H bonds using N -hydroxyphthalimide and dialkyl azodicarboxylate

Article abstract of DOI:10.1021/jo301840e

A direct conversion of C(sp³)-H bonds to C(sp³)-N bonds has been achieved by utilizing catalytic N-hydroxyphthalimide (NHPI) and stoichiometric dialkyl azodicarboxylate. NHPI functions as a precursor of the electron-deficient phthalimide N-oxyl radical (PINO) to abstract hydrogens, and dialkyl azodicarboxylate acts as a trapping agent of the resultant carbon radical to generate the hydrazine derivatives. This C-H amination proceeds in a highly chemoselective manner with a wide applicability to functionalize benzylic, propargylic, and aliphatic C-H bonds. Furthermore, the obtained hydrazine compounds were readily converted to the corresponding carbamates or amines. Hence, the present protocol for direct introduction of the nitrogen functionality serves as a powerful tool for efficient construction of nitrogen-substituted natural products and pharmaceuticals.

Full text of DOI:10.1021/jo301840e

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Radical Amination of C(sp3)−H Bonds Using N‑Hydroxyphthalimide
and Dialkyl Azodicarboxylate
Yuuki Amaoka, Shin Kamijo,† Tamaki Hoshikawa, and Masayuki Inoue*
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
S
* Supporting Information
ABSTRACT: A direct conversion of C(sp3)−H bonds to
C(sp3)−N bonds has been achieved by utilizing catalytic N-
hydroxyphthalimide (NHPI) and stoichiometric dialkyl
azodicarboxylate. NHPI functions as a precursor of the
electron-deficient phthalimide N-oxyl radical (PINO) to
abstract hydrogens, and dialkyl azodicarboxylate acts as a
trapping agent of the resultant carbon radical to generate the
hydrazine derivatives. This C−H amination proceeds in a
highly chemoselective manner with a wide applicability to functionalize benzylic, propargylic, and aliphatic C−H bonds.
Furthermore, the obtained hydrazine compounds were readily converted to the corresponding carbamates or amines. Hence, the
present protocol for direct introduction of the nitrogen functionality serves as a powerful tool for efficient construction of
nitrogen-substituted natural products and pharmaceuticals.
Scheme 1. Radical C(sp3)−H Amination Using N-
1. INTRODUCTION
Hydroxyphthalimide (NHPI) and Dialkyl Azodicarboxylate
C−H functionalization represents one of the ideal reactions in
and Potential Reaction Mechanism
organic synthesis.1 Direct C−H transformations eliminate
preactivation steps for preparation of synthetic intermediates
and thus dramatically simplify synthetic routes to multiply
substituted molecules. Among such reactions, transformation of
unreactive C(sp3)−H bonds into C(sp3)−C, C(sp3)−O, and
C(sp3)−N bonds is especially desirable for efficient con-
struction of highly complex natural products because their
nonplanar architectures inevitably consist of a high ratio of sp3-
hybridized atoms and stereogenic centers.2 However, selective
functionalization of a particular C(sp3)−H bond under mild
conditions remains a challenging task given its intrinsic high
bond dissociation energy and the ubiquity of other C(sp3)−H
bonds in organic substrates. Recently, we developed method-
ologies for chemoselective C(sp3)−C and C(sp3)−O for-
mations from C(sp3)−H bonds by employing highly reactive
oxyl radicals as the key species to induce C(sp3)−H cleavages.3
Amines and their derivatives are privileged structures for
drug candidates and are prevalent in many natural products. As
a result, development of C(sp3)−N bond-forming reactions
from C(sp3)−H bonds is an intensively investigated field of the
utmost importance.4,5 We herein report an efficient method for
direct intermolecular conversion of C(sp3)−H bonds to
and versatile tool for efficient synthesis of complex nitrogen-
C(sp3)−N bonds by employing a reagent system composed
substituted natural products and pharmaceutical agents.
of catalytic N-hydroxyphthalimide (NHPI)6 and stoichiometric
2. RESULTS AND DISCUSSION
dialkyl azodicarboxylate (R3O2CNNCO2R3) (Scheme 1).
Our envisioned catalytic cycle for the direct C(sp3)−H
amination is illustrated in Scheme 1. We planned to employ
NHPI as an oxyl radical precursor and dialkyl azodicarboxylate
The present transformation is widely applicable to benzylic,
propargylic and aliphatic C−H bonds (1), and generates the
corresponding hydrazine derivatives 2 under neutral conditions
in a highly chemoselective fashion. The derived adducts 2 were
successfully converted to the corresponding carbamates 3 or
amines 4. Therefore, this methodology will serve as a powerful
Received: August 28, 2012
Published: October 31, 2012
© 2012 American Chemical Society
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both as an oxidant and as a radical acceptor.7,8 First, one-
electron oxidation of NHPI with dialkyl azodicarboxylate would
generate the phthalimide N-oxyl radical (PINO), a key reactive
catalyst for C−H activation.3e,6 Electron-deficient PINO then
abstracts hydrogen from the electron-rich C(sp3)−H bond of 1
to form carbon radical A and NHPI. Electron-rich carbon
radical A would in turn react selectively with electron-deficient
dialkyl azodicarboxylate, furnishing amidyl radical B. Abstrac-
tion of the hydrogen of NHPI by B would regenerate PINO
and provide the hydrazinated product 2. To realize the high-
yielding transformation from 1 to 2, high chemoselectivity of
the C−H abstraction by PINO, facile trapping of B with dialkyl
azodicarboxylate, and prevention of further abstraction of the
Nα-CH bond of 2 by PINO would be the prerequisite factors.
The generated 2 was planned to be converted to carbamate 3
or amine 4 through functional group manipulation.
decelerated the intermolecular reaction between the carbon
radical and the azo compound. Nevertheless, consistent
formation of the adducts under the varied solvents and
reagents demonstrated the high reliability of the present system
for C−H amination. In addition, stability of 2a, 2′a or 2″a
under the reaction conditions confirmed the low reactivity of
the Nα−CH bond toward the abstraction, since it was proximal
to the large and electron-withdrawing hydrazine group
[−N(CO2R3)NHCO2R3].
The kinetic significance of the C−H abstraction step was
probed by the following experiment (Scheme 2). Treatment of
Scheme 2. Kinetic Significance of the C−H Abstraction Step
First, we evaluated the outcome of the NHPI-catalyzed
C(sp3)-H amination of benzylic compound 1a by varying two
elements: the solvent and the alkyl group (R3) of R3O2C−N
N-CO2R3 (Table 1). Treatment of 1a with 20 mol % of NHPI
Table 1. Screening of Reaction Conditions for Direct
Amination
DEAD with ethyl benzene 1b (5 equiv) and its deuterated
analogue 1b-d10 (5 equiv) in the presence of 10 mol % of
NHPI generated 2b as the dominant product (81%) and 2b-d10
as a minor product (5.6%).12 Obviously, the product
distribution of 2b and 2b-d10 was affected by the large rate
difference of the C−H and C−D cleavages mediated by PINO
(1 → A in Scheme 1), indicating that the C−H abstraction is
the product-determining step.13 Therefore, it was expected that
preferential C−H functionalization in the present protocol
would occur at the most easily cleavable C−H bond in a given
starting material, namely the C−H bond with the lowest bond
dissociation energy. In fact, the C−H bond at the benzylic
position generally possesses lower bond dissociation energy
than the alkane C−H bonds, reflecting the high chemoselective
transformation of 1a to 2a, 2′a and 2″a.
a
yield (%)
entry
R3
solvent
2a
recovery of 1a
b
b
1
2
3
4
5
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CH3
CH2CCl3
CH3CN
t-BuOH
EtOAc
benzene
DCE
40
68
54
b
b
22
92
88
93
c
b
b
6
DCE
81
8.2
d
b
b
7
DCE
0
100
8
9
DCE
83 (2′a)
57 (2″a)
C(CH3)3
DCE
35
a
b
Isolated yield. Yield was determined by NMR analysis of the crude
mixture. 1.2 equiv of DEAD was used. Absence of NHPI.
c
d
The secondary C−H bonds of the benzylic compounds 1a−
n having a variety of functional groups on the side chains were
chemoselectively converted to the corresponding DEAD
adducts 2a−n (Table 2). Ethylbenzene 1b, diphenylmethane
1c, and n-butylbenzene 1d were transformed to the aminated
products 2b, 2c, and 2d, respectively. As long as alcohol and
amine functionalities were properly protected to avoid
undesired nucleophilic reactions with highly electrophilic
DEAD, the present reaction gave the expected benzylhydrazine
derivatives in high yields. Namely, similar to benzoyl ester 2a,
TBDPS ether 2e, phthaloyl (Phth) imide 2f, and 2-nitro-
benzenesulfonyl (Ns) amide 2g were obtained. The reaction
occurred without touching electrophilic methyl ester (1h),
methyl ketone (1i), and cyanide (1j) moieties to provide 2h, 2i,
and 2j, respectively. Importantly, the C−H amination
proceeded even in the presence of a free carboxyl group,
resulting in formation of 2k. The C−Br bond of 1l was intact
under these radical reaction conditions, furnishing the product
2l. The benzoyloxy derivatives 2m and 2n were also formed,
but the yield of 2n (54%) was markedly lower than the yields of
and 2 equiv of diethyl azodicarboxylate (DEAD) at 80 °C for
48 h in CH3CN chemoselectively provided the desired product
2a in 40% yield along with the recovered 1a in 54% yield (entry
1).3e,9 Although various solvents such as t-BuOH (entry 2),
EtOAc (entry 3) and benzene (entry 4) were applicable for the
present transformation, the most effective solvent in terms of
the yield was found to be 1,2-dichloroethane (DCE) (93%
yield, entry 5). While the product 2a was formed in 81% yield
in DCE even upon reducing the equivalents of DEAD from 2.0
to 1.2 (entry 6), no reaction occurred without addition of
NHPI (entry 7).10,11 The quantitative recovery of 1a in the
latter confirmed the requirement of NHPI for the present C−H
functionalization. When bis(2,2,2-trichloroethyl) azodicarbox-
ylate (TrocNNTroc, BTCEAD) was used instead of DEAD
(entry 8), the corresponding adduct 2′a was obtained at the
same level of efficiency (83% yield). However, the use of di-tert-
butyl azodicarboxylate (BocNNBoc) lowered the yield
(57%) of 2″a, presumably because the bulky t-Bu group
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retained under the reaction conditions. The m- and o-
substituted aromatic compounds afforded the corresponding
adducts of the m-benzoyloxy 2u, o-benzoyloxy 2v, and o-
cinnamoyloxy 2w ethyl benzene derivatives. In addition,
methylene groups adjacent to naphthalene and thiophene
rings were smoothly functionalized as well to produce 2x, 2y,
and 2z. Clearly, formation of 2a−z showed excellent functional
group compatibility of the present benzylic C−H amination.
The broad scope of the present benzylic C−H amination was
further demonstrated using a different set of substrates (Table
3). The primary C−H bond of 1aa and the tertiary C−H bond
of 1bb were aminated using DEAD in the presence of catalytic
Table 2. Direct Amination of Secondary C−H Bonds at
Benzylic Positions
Table 3. Direct Benzylic C−H Amination Using Various
Aromatic Compoundsa
a
b
Compound 1n was recovered in 42% yield. The reaction was
c
complete within 24 h. Compound 1r was recovered in 12% yield.
d
e
Compound 1s was recovered in 18% yield. Compound 1v was
recovered in 12% yield.
2a (93%) and 2m (92%). These results followed the general
reactivity order of C−H transformations promoted by electro-
philic reactants; electron-rich C−H bonds are more prone to be
functionalized than electron-deficient ones.3,14,15 Specifically,
the lower yield of 2n should originate from the more electron-
poor nature of its benzylic C−H bond due to the shorter tether
length between the benzyl methylene and the electron-
withdrawing benzoyloxy group.
To further clarify the reactivity of the benzylic methylenes,
the substrates 2o−z having various aromatic rings were reacted
using DEAD (Table 2). The p-methoxybutylbenzene derivative
2o was formed in appreciably shorter time compared to
formation of p-(benzoyloxy)butylbenzene derivative 2p, again
supporting the importance of the electron-richness of the
benzylic C−H bonds for the reaction rates. While reaction
acceleration was also observed for the Boc-protected aniline
derivative 2q, deceleration was noticed for derivatives with the
electron-withdrawing acetyl (2r) and cyano (2s) functionalities.
The C−Br bond on the aromatic ring (1t) was completely
a
Reaction conditions: 1 (1 equiv), NHPI (20 mol %), DEAD (2
equiv), DCE (0.3 M), 80 °C, 48 h unless otherwise noted.
b
c
Compound 1aa was recovered in 22% yield. Compound 1cc was
d
recovered in 42% yield (93% ee). DEAD (1.2 equiv) was employed.
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NHPI to produce 2aa and 2bb, respectively (entries 1 and 2).
The yields of the aminated alkyl benzene derivatives 2aa (48%),
2b (Table 2, 77%), and 2bb (92%) correlated to the number of
the alkyl substituents at the reacting carbon, corroborating that
the more electron-rich C−H bond was more easily function-
alized.3,14,15 The tertiary C−H bond of 1cc (entry 3, Table 3)
was functionalized similar to the secondary C−H bond of 2n
(Table 2) despite the increased steric interaction; however, its
stereochemical information was lost during the radical reaction
(95% ee → 11% ee).16 Remarkably, a tetrasubstituted carbon
center was introduced at the most hindered C−H bond on the
cyclohexane ring of 1dd, leading to 2dd (entry 4). Moreover,
the direct benzylic C−H amination occurred on fused
carbocycles (entries 5 and 6). Thus, dihydroindene 1ee was
efficiently converted to the mono-DEAD adduct 2ee using a
reducing amount of DEAD (1.2 equiv). Finally, the C−H
amination of more complex podocarpate derivative 1ff17
exhibited high chemoselectivity, delivering 2ff as the sole
stereoisomer. It is worthy of note that the C−H trans-
formations in Tables 2 and 3 all took place at the benzylic
position regardless of the steric environments and of the
presence of other potentially reactive C−H bonds and polar
functional groups.
1gg (2 equiv) with DEAD (1 equiv) and a catalytic amount of
NHPI chemoselectively afforded propargylic amine derivative
2gg (entry 1). The reactions of both (trimethylsilyl)acetylene
1hh and phenylacetylene 1ii resulted in functionalization at
their secondary C−H bonds, leading to the corresponding
adducts 2hh and 2ii (entries 2 and 3). The tertiary C−H bond
of cyclohexane structure 1jj was also functionalized with similar
efficiency to provide 2jj with a tetrasubstituted carbon. Thus,
the chemoselective propargylic C−H amination was achieved
without affecting the C−C triple bond.
The protocol was then utilized for the direct amination of the
C−H bonds of alkanes, which are known to be less reactive
than those of benzylic and propargylic C−H bonds (Table 5).
The secondary aliphatic C−H bonds of cyclooctane 1kk and
cyclododecane 1ll underwent functionalization, providing the
Table 5. Direct Amination of Aliphatic C−H Bondsa
We next investigated the direct C−H amination of
propargylic compounds (Table 4).18 Treatment of 4-octyne
Table 4. Direct Amination of Propargylic C−H Bondsa
a
Reaction conditions: 1 (5 equiv), NHPI (10 mol %), DEAD (1
a
b
Reaction conditions: 1 (2 equiv), NHPI (10 mol %), DEAD (1
equiv), DCE (0.3 M), 80 °C, 48 h unless otherwise noted. Yields
were calculated with respect to DEAD. The reaction was complete
within 24 h. The reaction was complete within 36 h. Compound
1mm (2 equiv) was employed. Compound 1 (10 equiv) was
b
c
equiv), DCE (0.3 M), 80 °C, 48 h unless otherwise noted. Yields
were calculated with respect to DEAD. The reaction was complete
within 24 h. NHPI (20 mol %) was employed. NHPI (30 mol %)
c
d
e
d
e
f
was employed.
employed.
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expected monoadducts 2kk and 2ll in high yields, respectively
(entries 1 and 2). The reaction of adamantane 1mm proceeded
chemoselectively at the weaker tertiary C−H bond in the
presence of the secondary counterparts to give aminated
adamantane 2mm as a single product (entry 3). High
chemoselectivity toward the more substituted carbons was
observed for the substituted cyclohexane derivatives (entries 4−
6). While methyl cyclohexane 1nn was aminated to generate
the tetrasubstituted carbon of 2nn (entry 4), the reaction of cis-
decalin 1oo chemo- and stereoselectively gave rise to the cis-
fused compound 2oo with the nitrogen functionality at the
angular position (entry 5). When trans-decalin 1pp was used as
the starting material (entry 6), a configurational change of the
bicyclic system occurred to produce the same 2oo as the major
isomer.19 The origin of the cis-selectivity in entries 5 and 6 can
be explained by the smaller steric interactions of the cis-decalyl
radical Aoo during the addition in comparison with the
equilibrating trans-counterpart App, whose axial-oriented Ha
and Hb are proximal to the reacting DEAD (Scheme 3).20
Table 6. Direct C−H Amination under NHPI/BTCEAD
Reagent System and One-Step Conversion of BTCEAD
Adducts to Amine Derivatives
Scheme 3. Potential Mechanism of Stereoselective
Formation of 2oo
Overall, the results in Tables 2−5 demonstrate the generality of
the present methodology for construction of hydrazinated
products from a variety of starting structures, and its efficiency
for installation of tetrasubstituted carbons.
By taking advantage of the hydrazine structures, the DEAD
adducts 2 thus obtained were transformed to carbamate
derivatives 3 using the Magnus protocol21 (Scheme 4).
Scheme 4. Two-step Conversion of the Adducts to Amine
Derivatives
a
Reaction conditions: 1 (1 equiv), NHPI (20 mol %), BTCEAD (2
b
equiv), DCE (0.3 M), 80 °C, 48 h unless otherwise noted. Reaction
conditions: 2′ (1 equiv), Zn (40 equiv), AcOH (0.07 M), room
temperature, 1 h, then acetone (10 equiv), room temperature, 1 h.
c
d
The reaction was complete within 8 h. 1hh (2 equiv), BTCEAD (1
e
equiv) were employed. 1ll (5 equiv), NHPI (10 mol %), BTCEAD (1
equiv) were employed. The reaction was complete within 5 h.
compound 1ll (entry 4) were all converted chemoselectively to
the BTCEAD adducts 2′a, 2′ff, 2′hh, and 2′ll, respectively, in
high yields. Treatment of 2′a, 2′ff, 2′hh, or 2′ll with Zn
induced the reductive removal of the Troc group and cleavage
of the N−N bond,22 leading to the corresponding amines 4a,
4ff, 4hh, or 4ll. Remarkably, the Bz group (entry 1), the acetyl
group and methyl ester (entry 2), and the acetylene group
(entry 3) were left intact, showing the mildness of the present
deprotection procedure.
Alkylation of the nitrogen atom with methyl bromoacetate
and subsequent cleavage of the N−N bond under basic
conditions gave rise to variously functionalized carbamates 3d,
3e, 3f, and 3j in a range of 58−91% yields. Thus, ethyl
carbamates 3 were prepared from the corresponding starting
materials 1 in three steps.
Furthermore, we established a two-step procedure for
construction of free amine derivatives from the starting
materials 1 by applying BTCEAD (TrocNNTroc) instead
of DEAD (Table 6). The high generality of the process was
demonstrated by four representative substrates, one each from
Tables 2, 3, 4 or 5. Benzylic compounds 1a and 1ff (entries 1
and 2), propargylic compound 1hh (entry 3), and aliphatic
3. CONCLUSION
In conclusion, we have developed a chemoselective C(sp3)−H
amination employing catalytic NHPI and stoichiometric DEAD
or BTCEAD. This radical-based reaction is initiated by
hydrogen abstraction by PINO generated from the oxidation
of NHPI, and the carbon radical intermolecularly adds to
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zinedicarboxylate 2′a (57.7 mg, 0.0908 mmol) in glacial acetic acid
(1.3 mL) was added zinc dust (238 mg, 3.63 mmol) at room
temperature. The reaction mixture was stirred at room temperature for
30 min, and then acetone (66.9 μL) was added. The mixture was
stirred at room temperature for additional 30 min. Then CH2Cl2 was
added and the resulting mixture filtered through a pad of Celite. The
solvent was neutralized with saturated aqueous NaHCO3 and extracted
with EtOAc (×3). The extracts were combined and washed with brine,
dried over Na2SO4, and concentrated. The residue was purified with
flash column chromatography (silica gel, CHCl3−MeOH 15:1) to
provide 4-(benzoyloxy)-1-phenylbutylamine 4a in 77% yield (18.8
mg).
DEAD or BTCEAD, resulting in installation of a nitrogen unit.
The salient features of the present protocols are: (1)
predictable chemoselectivity toward benzylic and propargylic
C−H bonds and tertiary C−H bonds of aliphatic compounds;
(2) wide applicability to various carboskeletons; (3) high
compatibility with various functionalities including benzoyl-
and silyl-protected alcohols, nosyl-, phth-, and Boc-protected
amines, as well as carboxylic acids, cyanides, and bromides; and
(4) expeditious transformation of the generated hydrazine
derivatives to the corresponding carbamates and amines.
Because of these advantages, the present methodology serves
as a unique tool for the efficient synthesis of complex amine-
substituted natural products and pharmaceuticals.
Compound 2a: 93% yield (145 mg); colorless foam; IR (neat)
1
3296, 1753, 1715, 1602, 1584, 1496, 1276, 759, 714 cm−1; H NMR
(400 MHz, CDCl3, at 50 °C) δ 1.20−1.30 (6H, m), 1.84 (1H, m),
2.00−2.10 (2H, m), 2.19 (1H, m), 4.10−4.24 (4H, m), 4.37 (2H, t, J =
6.0 Hz), 5.35 (1H, m), 6.02 (1H, br), 7.26−7.35 (5H, m), 7.41 (2H, t,
J = 7.5 Hz), 7.53 (1H, t, J = 7.5 Hz), 8.03 (2H, d, J = 7.5 Hz); 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 25.9, 27.3, 60.8, 61.9,
62.6, 64.7, 128.0, 128.2 (×2), 128.6, 129.5, 130.5, 132.7, 138.8, 156.1,
156.6, 166.5; HRMS (ESI-TOF) calcd for C23H28N2NaO6 (M + Na)+
451.1840, found 451.1826.
Compound 2′a: 83% yield (96.4 mg); colorless foam; IR (neat)
3282, 1773, 1717, 1602, 1584, 1495, 1276, 1112, 811, 751, 712 cm−1;
1H NMR (400 MHz, CDCl3, at 50 °C) δ 1.87 (1H, m), 2.05−2.15
(2H, m), 2.25 (1H, m), 4.38 (2H, m), 4.72 (2H, m), 4.81 (2H, m),
5.44 (1H, m), 6.40 (1H, br), 7.35−7.40 (5H, m), 7.43 (2H, t, J = 6.5
Hz), 7.55 (1H, t, J = 6.5 Hz), 8.03 (2H, d, J = 6.5 Hz); 13C NMR (100
MHz, CDCl3, at 50 °C) δ 26.0, 27.3, 61.9, 64.5, 75.1, 75.8, 94.8, 94.9,
128.1, 128.3, 128.5, 128.8, 129.5, 130.4, 132.8, 137.7, 154.1, 154.5,
166.5; HRMS (ESI-TOF) calcd for C23H22Cl6N2NaO6 (M + Na)+
656.9477, found 656.9477.
4. EXPERIMENTAL SECTION
General Information. All reactions sensitive to air or moisture
were carried out under argon atmosphere and anhydrous conditions.
Chemical shifts are reported in δ (ppm) with reference to residual
solvent signals [1H NMR: CHCl3 (7.26); 13C NMR: CDCl3 (77.0)].
Signal patterns are indicated as s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet; br, broad.
General Procedure for Amination of Benzylic C−H Bonds.
To a solution of 4-phenylbutyl benzoate 1a (92.6 mg, 0.364 mmol)
and N-hydroxyphthalimide (11.9 mg, 0.0728 mmol) in 1,2-dichloro-
ethane (1.2 mL) was added diethyl azodicarboxylate (127 mg, 0.728
mmol) at room temperature. The reaction mixture was stirred at 80 °C
for 48 h, and concentrated. The residue was purified with flash column
chromatography (silica gel, hexane−EtOAc 3:1) to provide diethyl 1-
[4-(benzoyloxy)-1-phenylbutyl]-1,2-hydrazinedicarboxylate 2a in 93%
yield (145 mg).
General Procedure for Amination of Propargylic C−H
Bonds. To a solution of N-hydroxyphthalimide (4.9 mg, 0.030
mmol) in 1,2-dichloroethane (1.0 mL) were added 4-octyne 1gg (66.1
mg, 0.600 mmol) and diethyl azodicarboxylate (52.2 mg, 0.300 mmol)
at room temperature. The reaction mixture was stirred at 80 °C for 24
h and concentrated. The residue was purified with flash column
chromatography (silica gel, hexane−EtOAc 5:1) to provide diethyl 1-
(4-octyn-3-yl)-1,2-hydrazinedicarboxylate 2gg in 69% yield (58.7 mg).
General Procedure for Amination of Aliphatic C−H Bonds.
To a solution of N-hydroxyphthalimide (4.9 mg, 0.030 mmol) in 1,2-
dichloroethane (1.0 mL) were added cyclooctane 1kk (168 mg, 1.50
mmol) and diethyl azodicarboxylate (52.2 mg, 0.300 mmol) at room
temperature. The reaction mixture was stirred at 80 °C for 24 h and
concentrated. The residue was purified with flash column chromatog-
raphy (silica gel, hexane−EtOAc 4:1) to provide diethyl 1-cyclooctyl-
1,2-hydrazinedicarboxylate 2kk in 87% yield (74.9 mg).
General Procedure for Synthesis of 3. To a solution of diethyl
1-(1-phenylbutyl)-1,2-hydrazinedicarboxylate 2d (49.3 mg, 0.160
mmol) and Cs2CO3 (130 mg, 0.400 mmol) in CH3CN (0.64 mL)
was added methyl bromoacetate (29.5 μL, 0.320 mmol) at room
temperature. The reaction mixture was stirred at 50 °C for 1 h. The
reaction was quenched with saturated aqueous NH4Cl and extracted
with EtOAc (×3). The extracts were combined, washed with brine,
dried over Na2SO4, and concentrated. The residue was purified with
flash column chromatography (silica gel, hexane−EtOAc 5:1) to
provide the diethyl 1-[(methoxycarbonyl)methyl]-2-(1-phenylbutyl)-
1,2-hydrazinedicarboxylate.
Compound 2″a: 57% yield (73.7 mg); colorless foam; mixture of
rotamers; IR (neat) 3315, 1716, 1603, 1585, 1495, 1392, 1367, 1275,
1
1156, 757, 714, 701 cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ
1.35−1.55 (18H, m), 1.82 (1H, m), 1.97−2.08 (2H, m), 2.15 (1H, m),
4.37 (2H, m), 5.31 (1H, m), 5.79 (1H, br), 7.27−7.33 (5H, m), 7.42
(2H, t, J = 7.2 Hz), 7.54 (1H, t, J = 7.2 Hz), 8.03 (2H, d, J = 7.2 Hz);
detectable signals of 13C NMR (100 MHz, CDCl3, at 50 °C) δ 26.0,
27.5, 27.90, 27.94, 28.21, 28.25, 60.1, 64.8, 80.9, 81.4, 127.7, 128.0,
128.2, 128.4, 129.5, 130.5, 132.7, 139.5, 155.0, 155.6, 166.5; HRMS
(ESI-TOF) calcd for C27H36N2NaO6 (M + Na)+ 507.2466, found
507.2444.
Compound 2b (CAS: 94203-19-7):21 77% yield (97.2 mg);
1
colorless foam; H NMR (500 MHz, CDCl3, at 50 °C) δ 1.24−1.29
(6H, m), 1.57 (3H, d, J = 6.0 Hz), 4.15−4.27 (4H, m), 5.50 (1H, m),
6.02 (1H, br), 7.26−7.34 (5H, m); 13C NMR (125 MHz, CDCl3, at 50
°C) δ 14.2, 14.4, 16.6, 56.4, 61.8, 62.3, 127.1, 127.5, 128.3, 140.6,
155.8, 156.6.
Compound 2c: 64% yield (87.5 mg); colorless foam; IR (neat)
1
3287, 1707, 1497, 760, 743, 725, 698 cm−1; H NMR (400 MHz,
CDCl3, at 50 °C) δ 1.10 (3H, m), 1.25 (3H, t, J = 6.9 Hz), 4.00 (2H,
m), 4.23 (2H, q, J = 6.9 Hz), 6.16 (1H, s), 6.58 (1H, s), 7.26−7.35
(10H, m); 13C NMR (125 MHz, CDCl3, at 50 °C) δ 14.1, 14.3, 61.7,
62.7, 66.0, 127.5, 128.2, 128.7, 138.7, 155.8, 156.2; HRMS (ESI-TOF)
calcd for C19H22N2NaO4 (M + Na)+ 365.1472, found 365.1459.
Compound 2d: 88% yield (122 mg); colorless foam; IR (neat)
3290, 1705, 1312, 1228, 760, 699 cm−1; 1H NMR (400 MHz, CDCl3,
at 50 °C) δ 0.95 (3H, t, J = 7.3 Hz), 1.23−1.40 (8H, m), 1.85 (1H, m),
2.04 (1H, m), 4.08−4.26 (4H, m), 5.28 (1H, m), 5.92 (1H, br), 7.26−
7.34 (5H, m); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 13.7, 14.2,
14.3, 19.5, 32.6, 60.7, 61.7, 62.2, 127.6, 128.0, 128.3, 139.2, 156.0,
156.5; HRMS (ESI-TOF) calcd for C16H24N2NaO4 (M + Na)+
331.1628, found 331.1641.
Compound 2e: 73% yield (105 mg); colorless foam; IR (neat)
3280, 1757, 1709, 1588, 1110, 824, 760, 738, 702 cm−1; 1H NMR (400
MHz, CDCl3, at 50 °C) δ 1.05 (9H, s), 1.20−1.29 (6H, m), 1.61 (1H,
m), 1.72 (1H, m), 2.06 (2H, m), 3.66−3.75 (2H, m), 4.10−4.24 (4H,
m), 5.27 (1H, m), 5.93 (1H, br), 7.27−7.42 (11H, m), 7.63−7.67 (4H,
m); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 19.2, 26.9,
To a solution of the diethyl 1-[(methoxycarbonyl)methyl]-2-(1-
phenylbutyl)-1,2-hydrazinedicarboxylate in CH3CN (0.64 mL) was
added Cs2CO3 (156 mg, 0.480 mmol) at room temperature. The
reaction mixture was stirred at 80 °C for 24 h. The reaction was
quenched with saturated aqueous NH4Cl and extracted with EtOAc
(×3). The extracts were combined and washed with brine, dried over
Na2SO4, and concentrated. The residue was purified with flash column
chromatography (silica gel, hexane−EtOAc 10:1) to provide ethyl 1-
phenylbutylcarbamate 3d in 91% yield (two steps, 32.1 mg).
General Procedure for Synthesis of 4. To a solution of
bis(2,2,2-trichloroethyl) 1-[4-(benzoyloxy)-1-phenylbutyl]-1,2-hydra-
9964
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Featured Article
27.0, 29.4, 60.8, 61.8, 62.4, 63.6, 127.5, 127.7, 128.0, 128.4, 129.5,
134.0, 135.5, 139.2, 156.0, 156.5; HRMS (ESI-TOF) calcd for
C32H42N2NaO5Si (M + Na)+ 585.2755, found 585.2751.
CDCl3, at 50 °C) δ 14.28, 14.34, 30.0, 58.1, 62.0, 62.1, 62.6, 128.0,
128.1, 128.2, 128.6, 129.5, 130.4, 132.7, 138.3, 155.9, 156.7, 166.4;
HRMS (ESI-TOF) calcd for C22H26N2NaO6 (M + Na)+ 437.1683,
found 437.1672.
Compound 2f: 87% yield (127 mg); colorless foam; IR (neat)
1
3301, 1753, 1709, 772, 720 cm−1; H NMR (400 MHz, CDCl3, at 50
Compound 2n: 54% yield (86.2 mg); colorless foam; IR (neat)
1
°C) δ 1.10−1.32 (6H, m), 1.77 (1H, m), 1.83−2.02 (2H, m), 2.10
(1H, m), 3.75 (2H, t, J = 5.8 Hz), 3.95−4.25 (4H, m), 5.31 (1H, m),
5.91 (1H, br), 7.26−7.32 (5H, m), 7.68 (2H, dd, J = 4.8, 2.5 Hz), 7.82
(2H, dd, J = 4.8, 2.5 Hz); 13C NMR (100 MHz, CDCl3, at 50 °C) δ
14.2, 14.3, 25.6, 28.0, 37.6, 60.7, 61.7, 62.4, 123.0, 127.8, 127.9, 128.3,
132.2, 133.6, 138.8, 155.9, 156.5, 168.1; HRMS (ESI-TOF) calcd for
C24H27N3NaO6 (M + Na)+ 476.1792, found 476.1787.
3300, 1757, 1715, 1603, 1584, 1497, 1275, 760, 714 cm−1; H NMR
(400 MHz, CDCl3, at 50 °C) δ 1.05−1.25 (6H, m), 4.00−4.20 (4H,
m), 4.62 (1H, m), 5.01 (1H, m), 5.75 (1H, m), 6.34 (1H, br), 7.32−
7.47 (7H, m), 7.55 (1H, t, J = 7.5 Hz), 8.02 (2H, d, J = 7.5 Hz); 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 14.2, 14.3, 59.7 (×2), 61.9, 62.7,
128.3 (×2), 128.4, 128.6, 129.7, 130.0, 133.1, 135.6, 156.0, 156.2,
166.5; HRMS (ESI-TOF) calcd for C21H24N2NaO6 (M + Na)+
423.1527, found 423.1515.
Compound 2g: 79% yield (109 mg); colorless foam; IR (neat)
1
3284, 1702, 1593, 1541, 1414, 1339, 1166, 853, 757, 702 cm−1; H
Compound 2o: 92% yield (142 mg); colorless foam; mixture of
NMR (400 MHz, CDCl3, at 50 °C) δ 1.24−1.31 (6H, m), 1.65 (1H,
m), 1.81 (1H, m), 1.98 (1H, m), 2.14 (1H, m), 3.18 (2H, m), 4.17−
4.26 (4H, m), 5.26 (1H, m), 5.54 (1H, br), 5.89 (1H, br), 7.24−7.35
(5H, m), 7.68−7.71 (2H, m), 7.81 (1H, m), 8.11 (1H, m); 13C NMR
(100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 26.1, 27.4, 43.4, 60.4, 62.2,
62.6, 125.0, 127.8, 128.0, 128.5, 130.9, 132.4, 133.3, 133.7, 138.7,
148.1, 156.1, 156.9; HRMS (ESI-TOF) calcd for C22H28N4NaO8S (M
+ Na)+ 531.1520, found 531.1512.
Compound 2h: 93% yield (104 mg); colorless foam; mixture of
rotamers; IR (neat) 3293, 1735, 1710, 1225, 760, 701 cm−1; 1H NMR
(400 MHz, CDCl3, at 50 °C) δ 1.22−1.33 (6H, m), 1.47 (1H, m),
1.70 (1H, m), 1.92 (1H, m), 2.05 (1H, m), 2.37 (2H, t, J = 7.0 Hz),
3.66 (3H, s), 4.05−4.28 (4H, m), 5.28 (1H, m), 5.99 (1H, br), 7.26−
7.33 (5H, m); Detectable signals of 13C NMR (100 MHz, CDCl3, at
50 °C) δ 14.2, 14.3, 21.7, 29.9, 33.5, 51.2, 51.3, 60.6, 61.7, 62.4, 127.9
(×2), 128.4, 138.8, 156.0, 156.5, 173.6; HRMS (ESI-TOF) calcd for
C18H26N2NaO6 (M + Na)+ 389.1683, found 389.1665.
rotamers; IR (neat) 3287, 1756, 1707, 1612, 1586, 1514, 1249, 835
1
cm−1; H NMR (500 MHz, CDCl3, at 50 °C) δ 0.94 (3H, t, J = 7.2
Hz), 1.18−1.55 (8H, m), 1.81 (1H, m), 2.01 (1H, m), 3.80 (3H, s),
4.10−4.25 (4H, m), 5.24 (1H, m), 5.91 (1H, br), 6.85 (2H, d, J = 8.8
Hz), 7.25 (2H, d, J = 8.8 Hz); Detectable signals of 13C NMR (100
MHz, CDCl3, at 50 °C) δ 13.6, 14.1, 14.3, 19.4, 32.8, 55.0, 55.1, 60.1,
61.6, 62.1, 113.6, 129.1, 131.3, 155.9, 156.5, 159.1; HRMS (ESI-TOF)
calcd for C17H26N2NaO5 (M + Na)+ 361.1734, found 361.1747.
Compound 2p: 88% yield (113 mg); colorless foam; IR (neat)
3288, 1736, 1707, 1601, 1585, 1508, 1265, 1205, 1063, 878, 760, 709
1
cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 0.97 (3H, t, J = 7.2
Hz), 1.23−1.45 (8H, m), 1.86 (1H, m), 2.03 (1H, m), 4.08−4.26 (4H,
m), 5.32 (1H, m), 5.95 (1H, br), 7.19 (2H, d, J = 8.5 Hz), 7.41 (2H, d,
J = 8.5 Hz), 7.51 (2H, t, J = 7.5 Hz), 7.64 (1H, t, J = 7.5 Hz), 8.20
(2H, d, J = 7.5 Hz); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 13.7,
14.2, 14.3, 19.5, 32.8, 60.1, 61.8, 62.3, 121.5, 128.4, 129.1, 129.5, 130.0,
133.4, 136.9, 150.5, 155.9, 156.6, 164.9; HRMS (ESI-TOF) calcd for
C23H28N2NaO6 (M + Na)+ 451.1840, found 451.1850.
Compound 2i: 79% yield (67.1 mg); colorless foam; IR (neat)
1
3287, 1753, 1710, 1496, 1412, 1381, 1226, 760, 700 cm−1; H NMR
Compound 2q: 89% yield (73.5 mg); colorless foam; IR (neat)
(400 MHz, CDCl3, at 50 °C) δ 1.23−1.30 (6H, m), 1.49 (1H, m),
1.63 (1H, m), 1.76 (1H, m), 2.01 (1H, m), 2.12 (3H, s), 2.48 (2H, t, J
= 7.0 Hz), 4.05−4.28 (4H, m), 5.27 (1H, m), 6.01 (1H, br), 7.26−7.33
(5H, m); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 14.2, 14.4, 20.6,
29.6, 29.9, 43.1, 60.7, 61.7, 62.4, 127.9 (×2), 128.4, 138.8, 156.0, 156.4,
208.3; HRMS (ESI-TOF) calcd for C18H26N2NaO5 (M + Na)+
373.1734, found 373.1725.
3304, 1705, 1614, 1598, 1529, 1415, 1315, 1236, 1161, 1055, 840
1
cm−1; H NMR (500 MHz, CDCl3, at 50 °C) δ 0.94 (3H, t, J = 7.5
Hz), 1.23−1.50 (8H, m), 1.52 (9H, s), 1.83 (1H, m), 1.98 (1H, m),
4.10−4.25 (4H, m), 5.23 (1H, m), 5.89 (1H, br), 6.41 (1H, br), 7.25
(2H, d, J = 8.0 Hz), 7.31 (2H, d, J = 8.0 Hz); 13C NMR (125 MHz,
CDCl3, at 50 °C) δ 13.7, 14.3, 14.4, 19.5, 28.3, 32.8, 60.3, 61.8, 62.3,
80.4, 118.6, 128.6, 133.7, 138.1, 152.8, 156.0, 156.6; HRMS (ESI-
TOF) calcd for C21H33N3NaO6 (M + Na)+ 446.2262, found 446.2249.
Compound 2r: 80% yield (126 mg); colorless foam; mixture of
rotamers; IR (neat) 3287, 1754, 1709, 1685, 1608, 1574, 1517, 1268,
Compound 2j: 83% yield (89.4 mg); colorless foam; IR (neat)
1
3289, 2246, 1749, 1705, 1412, 1382, 1231, 759, 701 cm−1; H NMR
(400 MHz, CDCl3, at 50 °C) δ 1.25−1.29 (6H, m), 1.78 (1H, m),
1.98−2.10 (2H, m), 2.20 (1H, m), 2.35−2.49 (2H, m), 4.10−4.30
(4H, m), 5.31 (1H, m), 5.89 (1H, br), 7.27−7.37 (5H, m); 13C NMR
(100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 16.9, 22.5, 29.7, 60.2, 62.1,
62.7, 119.3, 127.9, 128.2, 128.7, 138.4, 156.0, 156.6; HRMS (ESI-
TOF) calcd for C17H23N3NaO4 (M + Na)+ 356.1581, found 356.1564.
Compound 2k: 90% yield (119 mg); colorless foam; IR (neat)
1
842 cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 0.96 (3H, t, J =
7.3 Hz), 1.20−1.50 (8H, m), 1.87 (1H, m), 2.06 (1H, m), 2.58 (3H,
s), 4.10−4.25 (4H, m), 5.31 (1H, m), 5.97 (1H, br), 7.45 (2H, d, J =
8.1 Hz), 7.91 (2H, d, J = 8.1 Hz); detectable signals of 13C NMR (100
MHz, CDCl3, at 50 °C) δ 13.6, 14.1, 14.3, 19.4, 26.2, 26.3, 32.6, 60.4,
61.7, 62.4, 128.3 (×2), 136.5, 144.6, 155.8, 156.5, 197.4; HRMS (ESI-
TOF) calcd for C18H26N2NaO5 (M + Na)+ 373.1734, found 373.1746.
Compound 2s: 72% yield (57.9 mg); colorless foam; mixture of
rotamers; IR (neat) 3290, 2229, 1754, 1709, 1609, 1505, 1412, 1382,
1312, 1220, 842 cm−1; 1H NMR (400 MHz, CDCl3, at 50 °C) δ 0.96
(3H, t, J = 6.5 Hz), 1.18−1.50 (8H, m), 1.83 (1H, m), 2.04 (1H, m),
4.07−4.24 (4H, m), 5.28 (1H, m), 6.00 (1H, br), 7.47 (2H, d, J = 7.0
Hz), 7.62 (2H, d, J = 7.0 Hz); Detectable signals of 13C NMR (100
MHz, CDCl3, at 50 °C) δ 13.6, 14.2, 14.3, 14.4, 19.4, 32.6, 60.4, 62.0,
62.6, 111.7, 118.5, 128.9, 132.1, 144.8, 155.8, 156.5; HRMS (ESI-
TOF) calcd for C17H23N3NaO4 (M + Na)+ 356.1581, found 356.1575.
Compound 2t: 88% yield (144 mg); colorless foam; IR (neat)
1
3273, 1711, 1414, 1382, 1229, 759, 700 cm−1; H NMR (400 MHz,
CDCl3, at 50 °C) δ 1.24−1.31 (6H, m), 1.71 (1H, m), 1.80−2.00 (2H,
m), 2.09 (1H, m), 2.43 (2H, t, J = 7.1 Hz), 4.08−4.30 (4H, m), 5.29
(1H, m), 5.99 (1H, br), 7.22−7.33 (5H, m), CO2-H missing; 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 21.6, 30.0, 33.5, 60.8,
62.0, 62.6, 128.0 (×2), 128.5, 138.8, 156.2, 156.8, 178.2; HRMS (ESI-
TOF) calcd for C17H24N2NaO6 (M + Na)+ 375.1527, found 375.1523.
Compound 2l: 89% yield (139 mg); colorless foam; IR (neat)
1
3283, 1753, 1706, 1411, 1382, 1060, 758, 700 cm−1; H NMR (400
MHz, CDCl3, at 50 °C) δ 1.24−1.31 (6H, m), 1.95 (1H, m), 2.04−
2.18 (3H, m) 3.45 (2H, m), 4.10−4.27 (4H, m), 5.31 (1H, m), 5.92
(1H, br), 7.27−7.37 (5H, m); 13C NMR (100 MHz, CDCl3, at 50 °C)
δ 14.3, 14.5, 29.3, 29.6, 33.6, 60.3, 62.0, 62.6, 128.0, 128.1, 128.6,
138.7, 156.1, 156.6; HRMS (ESI-TOF) calcd for C16H23BrN2NaO4
(M + Na)+ 409.0739, found 409.0720.
1
3283, 1755, 1707, 1591, 1488, 1062, 835 cm−1; H NMR (400 MHz,
CDCl3, at 50 °C) δ 0.95 (3H, t, J = 7.3 Hz), 1.15−1.47 (8H, m), 1.81
(1H, m), 2.01 (1H, m), 4.07−4.25 (4H, m), 5.23 (1H, m), 5.93 (1H,
br), 7.22 (2H, d, J = 8.2 Hz), 7.45 (2H, d, J = 8.2 Hz); 13C NMR (100
MHz, CDCl3, at 50 °C) δ 13.6, 14.2, 14.3, 19.4, 32.6, 60.2, 61.8, 62.4,
121.6, 129.8, 131.3, 138.3, 155.8, 156.5; HRMS (ESI-TOF) calcd for
C16H23BrN2NaO4 (M + Na)+ 409.0739, found 409.0728.
Compound 2m: 92% yield (143 mg); colorless foam; IR (neat)
1
3294, 1752, 1716, 1602, 1584, 1494, 760, 714 cm−1; H NMR (400
MHz, CDCl3, at 50 °C) δ 1.20−1.30 (6H, m), 2.37 (1H, m), 2.53
(1H, m), 4.13−4.25 (4H, m), 4.46 (1H, m), 4.53 (1H, m), 5.58 (1H,
m), 6.03 (1H, br), 7.27−7.38 (5H, m), 7.43 (2H, t, J = 7.5 Hz), 7.55
(1H, t, J = 7.5 Hz), 8.03 (2H, d, J = 7.5 Hz); 13C NMR (100 MHz,
Compound 2u: 71% yield (69.5 mg); colorless foam; mixture of
rotamers; IR (neat) 3288, 1736, 1715, 1588, 1263, 1227, 1062, 785,
1
762, 709 cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 1.20−1.30
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(6H, m), 1.59 (3H, d, J = 7.2 Hz), 4.12−4.27 (4H, m), 5.52 (1H, m),
6.08 (1H, br), 7.15−7.30 (3H, m), 7.39 (1H, t, J = 7.8 Hz), 7.52 (2H,
t, J = 7.8 Hz), 7.64 (1H, t, J = 7.8 Hz), 8.20 (2H, d, J = 7.8 Hz);
Detectable signals of 13C NMR (100 MHz, CDCl3, at 50 °C) δ 14.3,
14.4, 16.6, 56.1, 61.9, 62.5, 120.5, 120.6, 120.9, 124.7, 128.5, 129.4,
129.6, 130.1, 133.5, 142.5, 151.2, 155.7, 156.7, 165.0; HRMS (ESI-
TOF) calcd for C21H24N2NaO6 (M + Na)+ 423.1527, found 423.1511.
Compound 2v: 83% yield (79.5 mg); colorless foam; IR (neat)
3299, 1731, 1601, 1584, 1489, 1265, 1215, 1175, 1063, 757, 710 cm−1;
1H NMR (400 MHz, CDCl3, at 50 °C) δ 0.96 (3H, t, J = 6.1 Hz), 1.21
(3H, t, J = 5.9 Hz), 1.59 (3H, d, J = 5.7 Hz), 3.67 (2H, m), 4.12 (2H,
m), 5.69 (1H, m), 6.10 (1H, br), 7.13 (1H, d, J = 6.8 Hz), 7.30 (1H, t,
J = 6.8 Hz), 7.39 (1H, t, J = 6.8 Hz), 7.46−7.52 (3H, m), 7.63 (1H, t, J
= 7.0 Hz), 8.19 (2H, d, J = 7.0 Hz); 13C NMR (125 MHz, CDCl3, at
50 °C) δ 14.0, 14.3, 16.4, 51.5, 61.7, 62.0, 122.9, 126.2, 128.4, 128.6,
129.0, 129.1, 130.3, 131.9, 133.6, 149.4, 154.9, 156.6, 166.0; HRMS
(ESI-TOF) calcd for C21H24N2NaO6 (M + Na)+ 423.1527, found
423.1536.
64.2, 124.5, 126.1, 127.9, 148.0, 155.5, 157.3; HRMS (ESI-TOF) calcd
for C15H22N2NaO4 (M + Na)+ 317.1472, found 317.1467.
Compound 2cc: 46% yield (62.7 mg); colorless foam; mixture of
rotamers; IR (neat) 3304, 1720, 1602, 1584, 1497, 1272, 763, 713, 702
1
cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 0.88−1.04 (3H, m),
1.25 (3H, m), 1.85 (3H, s), 3.98 (2H, m), 4.22 (2H, m), 4.75 (1H, d, J
= 11.0 Hz), 4.86 (1H, d, J = 11.0 Hz), 6.64 (1H, br), 7.24 (1H, m),
7.34 (2H, t, J = 7.5 Hz), 7.38−7.48 (2H, m), 7.51−7.68 (3H, m),
7.97−8.03 (2H, m); detectable signals of 13C NMR (100 MHz,
CDCl3, at 50 °C) δ 13.9, 14.0, 14.35, 14.38, 22.2, 24.5, 62.2, 65.9, 66.6,
68.9, 69.5, 125.0, 125.7, 126.9, 127.1, 128.3, 128.5, 129.6, 129.7, 130.0,
130.1, 132.9, 133.2, 143.3, 144.3, 155.3, 155.4, 156.9, 157.2, 166.0,
166.2; HRMS (ESI-TOF) calcd for C22H26N2NaO6 (M + Na)+
437.1683, found 437.1672. The enantiomeric excess of 2cc was
determined to be 11% ee by HPLC analysis. HPLC conditions:
column: CHIRALCEL OD 10 × 250 mm; eluent: 90% hexane/10% i-
PrOH; flow rate: 1.0 mL/min; detection: UV 254 nm; retention time:
9.9 min (major isomer) and 12.9 min (minor isomer).
Compound 2dd: 66% yield (133 mg); colorless foam; mixture of
Compound 2w: 79% yield (69.1 mg); colorless foam; IR (neat)
1
3300, 1722, 1635, 1578, 1142, 761, 709 cm−1; H NMR (400 MHz,
rotamers; IR (neat) 3290, 1713, 1498, 1376, 1331, 1241, 761, 701
1
cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 1.07 (3H, t, J = 7.0
CDCl3, at 50 °C) δ 1.12 (3H, t, J = 7.0 Hz), 1.21 (3H, m), 1.59 (3H,
m), 3.95−4.20 (4H, m), 5.70 (1H, m), 6.09 (1H, br), 6.63 (1H, d, J =
15.9 Hz), 7.11 (1H, d, J = 7.8 Hz), 7.28 (1H, d, J = 7.8 Hz), 7.37 (1H,
t, J = 7.8 Hz), 7.40−7.44 (3H, m), 7.46 (1H, d, J = 7.8 Hz), 7.57−7.61
(2H, m), 7.86 (1H, d, J = 15.9 Hz); 13C NMR (125 MHz, CDCl3, at
50 °C) δ 14.3 (×2), 16.4, 51.5, 61.7, 62.2, 116.9, 122.9, 126.0, 128.2,
128.5, 128.89, 128.93, 130.7, 131.8, 134.2, 146.9, 149.2, 155.1, 156.6,
166.1; HRMS (ESI-TOF) calcd for C23H26N2NaO6 (M + Na)+
449.1683, found 449.1676.
Compound 2x: 90% yield (59.2 mg); colorless foam; IR (neat)
3285, 1700, 1600, 803, 781, 761 cm−1; 1H NMR (400 MHz, CDCl3, at
50 °C) δ 1.15−1.35 (6H, m), 1.72 (3H, d, J = 6.8 Hz), 4.05−4.32 (4H,
m), 5.84 (1H, br), 6.29 (1H, m), 7.43−7.56 (4H, m), 7.80 (1H, d, J =
8.0 Hz), 7.86 (1H, d, J = 8.0 Hz), 8.20 (1H, m); 13C NMR (100 MHz,
CDCl3, at 50 °C) δ 14.3, 14.4, 17.0, 52.3, 61.7, 62.5, 123.4, 124.9,
125.0, 125.6, 126.5, 128.5, 128.7, 131.6, 133.9, 135.5, 155.4, 156.5;
HRMS (ESI-TOF) calcd for C18H22N2NaO4 (M + Na)+ 353.1472,
found 353.1487.
Hz), 1.27 (3H, t, J = 7.0 Hz), 1.38−1.55 (4H, m), 1.66 (1H, m), 1.78
(1H, m), 2.23 (2H, m), 2.48 (2H, m), 3.99 (2H, m), 4.17 (2H, m),
6.19 (1H, br), 7.22 (1H, t, J = 7.5 Hz), 7.31 (2H, t, J = 7.5 Hz), 7.50
(2H, d, J = 7.5 Hz); detectable signals of 13C NMR (100 MHz, CDCl3,
at 50 °C) δ 14.0, 14.3, 22.7, 23.0, 25.6, 35.3, 61.67, 61.72, 66.6, 126.6
(×2), 127.9, 144.3, 155.7, 157.1; HRMS (ESI-TOF) calcd for
C18H26N2NaO4 (M + Na)+ 357.1785, found 357.1800.
Compound 2ee: 72% yield (94.5 mg); colorless foam; mixture of
rotamers; IR (neat) 3288, 1708, 1414, 1230, 760 cm−1; 1H NMR (400
MHz, CDCl3, at 50 °C) δ 1.22 (3H, t, J = 7.1 Hz), 1.31 (3H, t, J = 7.1
Hz), 2.20 (1H, m), 2.42 (1H, m), 2.83 (1H, ddd, J = 16.0, 8.5, 7.5 Hz),
2.99 (1H, ddd, J = 16.0, 9.0, 4.7 Hz), 4.15 (2H, m), 4.27 (2H, m), 5.82
(1H, m), 6.05 (1H, br), 7.16−7.26 (4H, m); detectable signals of 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 14.3, 14.39, 14.42, 28.9, 30.4,
61.8, 62.5, 63.5, 124.2, 124.8, 126.5, 128.0, 140.5, 144.0, 156.1, 156.5;
HRMS (ESI-TOF) calcd for C15H20N2NaO4 (M + Na)+ 315.1315,
found 315.1323.
Compound 2ff: 62% yield (64.3 mg); colorless foam; mixture of
rotamers; IR (neat) 3297, 1753, 1714, 1610, 1205, 758 cm−1; 1H
NMR (400 MHz, CDCl3, at 50 °C) δ 0.96 (3H, s), 1.05 (1H, m), 1.23
(3H, m), 1.26 (3H, s), 1.31 (3H, t, J = 7.1 Hz), 1.40 (1H, m), 1.63
(1H, m), 1.87 (1H, m), 1.98 (1H, m), 2.20−2.31 (5H, m), 2.43 (1H,
m), 2.58 (1H, m), 3.66 (3H, s), 4.11 (2H, m), 4.27 (2H, m), 5.47 (1H,
m), 5.99 (1H, br), 6.91 (1H, dd, J = 8.2, 2.2 Hz), 7.03 (1H, d, J = 2.2
Hz), 7.20 (1H, d, J = 8.2 Hz); detectable signals of 13C NMR (100
MHz, CDCl3, at 50 °C) δ 14.4 (×2), 19.8, 20.98, 21.00, 22.0, 26.5,
27.9, 37.8, 38.1, 39.0, 43.9, 46.4, 51.1, 51.2, 54.5, 61.8, 62.6, 118.0,
118.1, 119.4, 129.3, 130.2, 150.4, 151.4, 155.9, 156.1, 169.1, 177.6;
HRMS (ESI-TOF) calcd for C26H36N2NaO8 (M + Na)+ 527.2364,
found 527.2342. The stereochemistry of 2ff was determined by the
NOE experiment.
Compound 2y: 90% yield (127 mg); colorless foam; mixture of
rotamers; IR (neat) 3286, 1756, 1708, 1518, 1411, 1381, 1302, 1217,
760, 700 cm−1; 1H NMR (400 MHz, CDCl3, at 50 °C) δ 0.96 (3H, t, J
= 6.1 Hz), 1.19−1.30 (6H, m), 1.35−1.55 (2H, m), 1.85 (1H, m), 2.04
(1H, m), 4.10−4.38 (4H, m), 5.52 (1H, m), 6.02 (1H, br), 6.96 (1H,
dd, J = 4.2, 3.0 Hz), 7.00 (1H, dd, J = 3.0, 1.0 Hz), 7.22 (1H, dd, J =
4.2, 1.0 Hz); Detectable signals of 13C NMR (100 MHz, CDCl3, at 50
°C) δ 13.5, 14.1, 14.3, 19.4, 34.6, 56.5, 61.7, 62.4, 124.57, 124.64,
125.5, 126.4, 142.4, 155.7, 156.4; HRMS (ESI-TOF) calcd for
C14H22N2NaO4S (M + Na)+ 337.1192, found 337.1190.
Compound 2z: 81% yield (114 mg); colorless foam; IR (neat)
1
3285, 1755, 1706, 1412, 1381, 1302, 1218, 761 cm−1; H NMR (400
MHz, CDCl3, at 50 °C) δ 0.96 (3H, t, J = 7.5 Hz), 1.15−1.55 (8H, m),
1.83 (1H, m), 1.99 (1H, m), 4.10−4.26 (4H, m), 5.36 (1H, m), 5.93
(1H, br), 7.06 (1H, d, J = 4.9 Hz), 7.19 (1H, s), 7.27 (1H, d, J = 4.9
Hz); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 13.6, 14.2, 14.3, 19.4,
33.5, 56.5, 61.7, 62.3, 122.6, 125.4, 127.2, 140.5, 155.9, 156.4; HRMS
(ESI-TOF) calcd for C14H22N2NaO4S (M + Na)+ 337.1192, found
337.1202.
Compound 2aa (CAS: 16396-49-9)23
: 48% yield (115 mg);
colorless foam; 1H NMR (400 MHz, CDCl3, at 50 °C) δ 1.25 (3H, t, J
= 7.0 Hz), 1.29 (3H, t, J = 7.0 Hz), 4.18 (2H, q, J = 7.0 Hz), 4.24 (2H,
q, J = 7.0 Hz), 4.69 (2H, s), 6.31 (1H, br), 7.26−7.36 (5H, m); 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 53.7, 61.9, 62.5,
127.6, 128.5 (×2), 136.4, 155.8, 156.2.
Compound 2gg: 69% yield (58.7 mg); colorless foam; IR (neat)
3297, 2248, 1756, 1712, 1413, 1382, 1297, 1223, 1061 cm−1; 1H NMR
(400 MHz, CDCl3, at 50 °C) δ 0.98 (3H, t, J = 6.1 Hz), 1.01 (3H, t, J
= 6.1 Hz), 1.27 (3H, t, J = 6.0 Hz), 1.28 (3H, t, J = 6.0 Hz), 1.47−1.55
(2H, m), 1.68 (1H, m), 1.77 (1H, m), 2.16 (2H, t, J = 6.0 Hz), 4.15−
4.26 (4H, m), 4.83 (1H, m), 6.31 (1H, br); 13C NMR (100 MHz,
CDCl3, at 50 °C) δ 10.6, 13.3, 14.33, 14.34, 20.6, 22.1, 27.1, 53.1, 61.8,
62.6, 76.9, 85.1, 155.7, 156.2; HRMS (ESI-TOF) calcd for
C14H24N2NaO4 (M + Na)+ 307.1628, found 307.1626.
Compound 2bb: 92% yield (243 mg); colorless foam; 1:1 mixture
of rotamers; IR (neat) 3295, 1716, 1603, 1497, 1261, 1240, 1095,
1
1057, 765, 701 cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 0.97
(3H, t, J = 7.1 Hz), 1.32 (3H, t, J = 7.1 Hz), 1.61 (6/2H, s), 1.76 (6/
2H, s), 3.95 (2H, m), 4.26 (2H, m), 6.45 (1H, br), 7.19 (1H, t, J = 7.2
Hz), 7.30 (2H, t, J = 7.7 Hz), 7.46 (2H, m); detectable signals of 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 13.8, 14.3, 27.7, 28.2, 61.7, 61.8,
9966
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Featured Article
Compound 2hh: 66% yield (65.5 mg); colorless foam; IR (neat)
3oo, which was derivatized from 2oo (70% yield, two steps, 44.4 mg)
and from the known cis-fused carboxylic acid through Curtius
rearrangement (55% yield, 89.5 mg).24
1
3298, 2177, 1758, 1713, 1414, 1382, 1303, 1251, 1064, 843 cm−1; H
NMR (400 MHz, CDCl3, at 50 °C) δ 0.15 (9H, s), 0.93 (3H, t, J = 7.2
Hz), 1.27 (3H, t, J = 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz), 1.40−1.51 (2H,
m), 1.63 (1H, m), 1.74 (1H, m), 4.12−4.27 (4H, m), 4.94 (1H, m),
6.32 (1H, br); 13C NMR (100 MHz, CDCl3, at 50 °C) δ −0.16, 13.4,
14.4 (×2), 19.2, 35.4, 51.5, 61.9, 62.7, 89.3, 102.5, 155.5, 156.2; HRMS
(ESI-TOF) calcd for C15H28N2NaO4Si (M + Na)+ 351.1711, found
351.1719.
Compound 2ii: 67% yield (66.4 mg); colorless foam; IR (neat)
3293, 2234, 1755, 1711, 1598, 1572, 1517, 1413, 1482, 1228, 758, 692
1
cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 0.99 (3H, t, J = 6.3
Hz), 1.28 (3H, t, J = 6.0 Hz), 1.30 (3H, t, J = 6.5 Hz), 1.50−1.60 (2H,
m), 1.78 (1H, m), 1.86 (1H, m), 4.15−4.27 (4H, m), 5.18 (1H, m),
6.38 (1H, br), 7.27−7.31 (3H, m), 7.42 (2H, m); 13C NMR (100
MHz, CDCl3, at 50 °C) δ 13.5, 14.4 (×2), 19.3, 35.5, 51.5, 62.0, 62.7,
84.6, 86.3, 122.7, 128.2, 128.3, 131.7, 155.6, 156.3; HRMS (ESI-TOF)
calcd for C18H24N2NaO4 (M + Na)+ 355.1628, found 355.1641.
Compound 2jj: 69% yield (110 mg); colorless foam; mixture of
rotamers; IR (neat) 3302, 2172, 1722, 1713, 1249, 867, 843 cm−1; 1H
NMR (400 MHz, CDCl3, at 50 °C) δ 0.14 (9H, s), 1.07−1.27 (7H,
m), 1.54−1.70 (5H, m), 1.79 (1H, m), 1.86−2.05 (2H, m), 2.31 (1H,
m), 4.10−4.22 (4H, m), 6.45 (1H, br); detectable signals of 13C NMR
(100 MHz, CDCl3, at 50 °C) δ −0.04, 14.37, 14.41, 23.4, 23.5, 25.2,
35.9, 61.8, 62.0, 62.7, 90.1, 106.2, 155.4, 156.7; HRMS (ESI-TOF)
calcd for C17H30N2NaO4Si (M + Na)+ 377.1867, found 377.1854.
Compound 2kk: 87% yield (74.9 mg); colorless foam; IR (neat)
3288, 1735, 1710, 1692, 1310, 1214, 1062 cm−1; 1H NMR (400 MHz,
CDCl3, at 50 °C) δ 1.26 (3H, t, J = 7.0 Hz), 1.28 (3H, t, J = 7.0 Hz),
1.50−1.62 (8H, m), 1.65−1.87 (6H, m), 4.14−4.28 (5H, m), 6.18
(1H, br); 13C NMR (125 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 24.5,
26.1, 26.6, 30.9, 58.3, 61.7, 62.0, 155.6, 157.0; HRMS (ESI-TOF) calcd
for C14H26N2NaO4 (M + Na)+ 309.1785, found 309.1781.
Compound 3d: 91% yield (two steps, 32.1 mg); colorless oil; IR
1
(neat) 3321, 1692, 1605, 1586, 1537, 1252, 761, 700 cm−1; H NMR
(400 MHz, CDCl3, at 50 °C) δ 0.93 (3H, t, J = 7.2 Hz), 1.21 (3H, t, J
= 7.0 Hz), 1.24−1.43 (2H, m), 1.67−1.80 (2H, m), 4.09 (2H, q, J =
7.0 Hz), 4.66 (1H, m), 4.91 (1H, br), 7.20−7.35 (5H, m); 13C NMR
(100 MHz, CDCl3, at 50 °C) δ 13.7, 14.5, 19.4, 39.0, 55.2, 60.7, 126.3,
127.2, 128.5, 143.1, 156.0; HRMS (ESI-TOF) calcd for C13H19NNaO2
(M + Na)+ 244.1308, found 244.1308.
Compound 3e: 83% yield (two steps, 45.6 mg); colorless oil; IR
(neat) 3327, 1693, 1604, 1589, 1531, 1252, 1110, 823, 742, 701 cm−1;
1H NMR (500 MHz, CDCl3, at 50 °C) δ 1.05 (9H, s), 1.21 (3H, t, J =
7.0 Hz), 1.57 (1H, m), 1.88 (1H, m), 1.83−1.91 (2H, m), 3.67 (2H, t,
J = 6.3 Hz), 4.04−4.12 (2H, m), 4.65 (1H, m), 4.90 (1H, br), 7.22−
7.43 (11H, m), 7.60−7.66 (4H, m); 13C NMR (125 MHz, CDCl3, at
50 °C) δ 14.5, 19.2, 26.9, 29.2, 33.1, 55.3, 60.8, 63.5, 126.3, 127.2,
127.6, 128.6, 129.6, 134.0, 135.6, 142.9, 156.0; HRMS (ESI-TOF)
calcd for C29H37NNaO3Si (M + Na)+ 498.2435, found 498.2430.
Compound 3f: 58% yield (two steps, 40.8 mg); colorless solid; mp
146−147 °C; IR (neat) 3331, 1770, 1709, 1529, 1397, 1245, 1046,
1
757, 720, 701 cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 1.20
(3H, t, J = 7.2 Hz), 1.63−1.87 (4H, m), 3.71 (2H, t, J = 6.5 Hz), 4.08
(2H, q, J = 7.2 Hz), 4.70 (1H, m), 4.91 (1H, br), 7.21−7.33 (5H, m),
7.70 (2H, dd, J = 5.2, 3.0 Hz), 7.83 (2H, dd, J = 5.2, 3.0 Hz); 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 14.5, 25.5, 33.9, 37.6, 55.1, 60.8,
123.1, 126.3, 127.4, 128.6, 132.2, 133.8, 142.4, 155.9, 168.3; HRMS
(ESI-TOF) calcd for C21H22N2NaO4 (M + Na)+ 389.1472, found
389.1469.
Compound 2ll: 84% yield (86.8 mg); colorless foam; IR (neat)
1
3286, 1739, 1710, 1225, 1062 cm−1; H NMR (400 MHz, CDCl3, at
50 °C) δ 1.24−1.65 (28H, m), 4.19 (4H, q, J = 7.5 Hz), 4.35 (1H, m),
6.11 (1H, br); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4,
22.4, 22.5, 23.0, 24.1, 24.3, 28.1, 53.4, 61.8, 62.1, 156.3, 157.0; HRMS
(ESI-TOF) calcd for C18H34N2NaO4 (M + Na)+ 365.2411, found
365.2397.
Compound 3j: 89% yield (two steps, 24.1 mg); colorless oil; IR
Compound 2mm: 74% yield (68.5 mg); colorless foam; IR (neat)
3301, 1712, 1692, 1376, 1336, 1277, 1228, 1047 cm−1; 1H NMR (400
MHz, CDCl3, at 50 °C) δ 1.25 (3H, t, J = 7.0 Hz), 1.28 (3H, t, J = 7.0
Hz), 1.60−1.75 (6H, m), 2.03−2.20 (9H, m), 4.06−4.26 (4H, m),
6.26 (1H, br); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 14.4, 14.5,
30.1, 36.3, 40.1, 60.6, 61.5, 61.7, 155.3, 157.2; HRMS (ESI-TOF) calcd
for C16H26N2NaO4 (M + Na)+ 333.1785, found 333.1799.
Compound 2nn: 72% yield (87.7 mg); colorless foam; mixture of
(neat) 3324, 2246, 1692, 1604, 1585, 1530, 1246, 1055, 764, 702
1
cm−1; H NMR (400 MHz, CDCl3, at 50 °C) δ 1.23 (3H, t, J = 7.0
Hz), 1.65 (1H, m), 1.75 (1H, m), 1.88−2.02 (2H, m), 2.36 (2H, t, J =
7.0 Hz), 4.10 (2H, q, J = 7.0 Hz), 4.69 (1H, m), 4.84 (1H, br), 7.25−
7.38 (5H, m); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 14.5, 16.8,
22.3, 35.5, 54.6, 61.0, 119.1, 126.3, 127.7, 128.8, 141.7, 156.0; HRMS
(ESI-TOF) calcd for C14H18N2NaO2 (M + Na)+ 269.1260, found
269.1268.
1
rotamers; IR (neat) 3302, 1713, 1694, 1250, 1096 cm−1; H NMR
Compound 2′ff: 76% yield (47.6 mg); colorless foam; IR (neat)
1
3281, 1769, 1724, 1610, 1496, 1204, 813, 752 cm−1; H NMR (500
(400 MHz, CDCl3, at 50 °C) δ 1.24 (3H, t, J = 7.0 Hz), 1.28 (3H, t, J
= 7.0 Hz), 1.38−1.53 (9H, m), 1.58−1.68 (2H, m), 1.98 (1H, m), 2.19
(1H, m), 4.08−4.26 (4H, m), 6.30 (1H, br); Detectable signals of 13C
NMR (100 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 22.6, 23.1, 23.5, 25.6,
35.9, 36.4, 61.5, 61.7, 62.6, 155.7, 157.1; HRMS (ESI-TOF) calcd for
C13H24N2NaO4 (M + Na)+ 295.1628, found 295.1615.
MHz, CDCl3, at 50 °C) δ 0.95−1.08 (4H, m), 1.27 (3H, s), 1.39 (1H,
m), 1.64 (1H, m), 1.85 (1H, m), 1.99 (1H, m), 2.20−2.33 (5H, m),
2.50 (1H, m), 2.64 (1H, m), 3.66 (3H, s), 4.63−4.95 (4H, m), 5.56
(1H, m), 6.47 (1H, br), 6.95 (1H, d, J = 8.0 Hz), 7.06 (1H, s), 7.25
(1H, d, J = 8.0 Hz); 13C NMR (100 MHz, CDCl3, at 50 °C) δ 19.8,
21.1, 22.1, 26.7, 28.0, 37.8, 38.2, 39.0, 43.9, 46.5, 51.3, 55.9, 75.2, 75.9,
94.7, 95.1, 118.4, 119.8, 127.9, 130.4, 150.9, 151.7, 154.0, 154.1, 169.2,
177.4; HRMS (ESI-TOF) calcd for C26H30Cl6N2NaO8 (M + Na)+
731.0026, found 730.9992.
Compound 2oo: 74% yield (105 mg); colorless foam; IR (neat)
3302, 1752, 1736, 1712, 1373, 1322, 1230, 1097 cm−1; 1H NMR (500
MHz, CDCl3, at 50 °C) δ 1.17−1.58 (18H, m), 1.70−1.82 (2H, m),
1.99 (1H, m), 2.18 (1H, m), 2.45 (1H, m), 4.00−4.21 (4H, m), 6.40
(1H, br); 13C NMR (125 MHz, CDCl3, at 50 °C) δ 14.3, 14.4, 22.8,
22.9, 28.0, 28.8, 36.5, 61.5, 61.7, 66.6, 155.7, 157.2; HRMS (ESI-TOF)
calcd for C16H28N2NaO4 (M + Na)+ 335.1941, found 335.1926.
Compound 3oo: colorless oil; IR (neat) 3343, 1724, 1713, 1704,
1235, 1218, 1103 cm−1; 1H NMR (400 MHz, CDCl3, at 50 °C) δ 1.19
(3H, t, J = 6.0 Hz), 1.28−1.60 (12H, m), 1.65−1.72 (2H, m), 1.83−
1.91 (3H, m), 4.02 (2H, q, J = 6.0 Hz), 4.53 (1H, br); 13C NMR (100
MHz, CDCl3, at 50 °C) δ 14.6, 22.3, 23.0, 27.5, 32.1, 38.9, 55.3, 59.8,
154.8; HRMS (ESI-TOF) calcd for C13H23NNaO2 (M + Na)+
248.1621, found 248.1627. The stereochemistry of 2oo was
unambiguously established by the data comparison of carbamate
Compound 2′hh: 71% yield (113 mg); colorless foam; IR (neat)
1
3302, 2177, 1780, 1732, 1407, 1251, 1203, 1107, 844, 717 cm−1; H
NMR (500 MHz, CDCl3, at 50 °C) δ 0.18 (9H, s), 0.96 (3H, t, J = 7.2
Hz), 1.45−1.55 (2H, m), 1.73 (1H, m), 1.82 (1H, m), 4.70−4.87 (4H,
m), 5.02 (1H, m), 6.80 (1H, br); 13C NMR (100 MHz, CDCl3, at 50
°C) δ −0.16, 13.4, 19.2, 35.5, 52.6, 75.3, 75.9, 90.7, 94.8, 94.9, 101.3,
153.6, 154.1; HRMS (ESI-TOF) calcd for C15H22Cl6N2NaO4Si (M +
Na)+ 554.9372, found 554.9356.
Compound 2′ll: 87% yield (143 mg); colorless foam; IR (neat)
1
3288, 1777, 1728, 1410, 1262, 1213, 1134, 1106, 1051, 720 cm−1; H
NMR (500 MHz, CDCl3, at 50 °C) δ 1.25−1.75 (22H, m), 4.45 (1H,
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Featured Article
m), 4.70−4.85 (4H, m), 6.80 (1H, br); 13C NMR (125 MHz, CDCl3,
at 50 °C) δ 22.5 (×2), 23.0, 24.1, 24.2, 28.1, 55.0, 75.2, 75.9, 94.9,
95.0, 154.7, 155.1; HRMS (ESI-TOF) calcd for C18H28Cl6N2NaO4 (M
+ Na)+ 569.0072, found 569.0045.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of newly synthesized compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Compound 4a: 77% yield (18.8 mg); colorless oil; IR (neat) 3371,
1
1715, 1602, 1584, 1493, 1451, 1275, 1116, 764, 712, 702 cm−1; H
NMR (400 MHz, CDCl3) δ 1.65−1.89 (6H, m), 3.95 (1H, t, J = 6.9
Hz), 4.30 (2H, t, J = 6.1 Hz), 7.22−7.36 (5H, m), 7.43 (2H, t, J = 7.8
Hz), 7.55 (1H, t, J = 7.8 Hz), 8.02 (2H, d, J = 7.8 Hz); 13C NMR (100
MHz, CDCl3) δ 25.8, 35.8, 56.0, 64.8, 126.3, 127.1, 128.3, 128.6,
129.5, 130.3, 132.8, 146.0, 166.6; HRMS (ESI-TOF) calcd for
C17H19NNaO2 (M + Na)+ 292.1308, found 292.1309.
AUTHOR INFORMATION
Corresponding Author
*E-mail: inoue@mol.f.u-tokyo.ac.jp.
■
Present Address
†Graduate School of Science and Engineering, Yamaguchi
University, Yoshida, Yamaguchi 753−8511, Japan.
Compound 4ff: 60% yield (9.2 mg); colorless foam; IR (neat)
1
3369, 1759, 1723, 1607, 1582, 1493, 1370, 1204, 823, 755 cm−1; H
Notes
NMR (500 MHz, CDCl3) δ 0.97 (3H, s), 1.15 (1H, m), 1.27 (3H, s),
1.43 (1H, m), 1.64 (1H, m), 1.91 (1H, m), 1.96 (1H, m), 2.10 (1H,
m), 2.17 (1H, m), 2.22−2.60 (7H, m), 3.66 (3H, s), 4.14 (1H, d, J =
3.5 Hz), 6.89 (1H, dd, J = 6.9, 2.0 Hz), 6.95 (1H, d, J = 2.0 Hz), 7.26
(1H, d, J = 6.9 Hz); 13C NMR (100 MHz, CDCl3) δ 19.8, 21.1, 22.1,
28.3, 29.6, 37.4, 38.8, 38.9, 43.6, 45.3, 49.0, 51.3, 118.4, 119.5, 130.8,
135.3, 149.5, 149.9, 169.6, 177.7; HRMS (ESI-TOF) calcd for
C20H27NNaO4 (M + Na)+ 368.1832, found 368.1831.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was financially supported by the Funding
Program for Next Generation World-Leading Researchers
(JSPS) to M.I. Fellowship from JSPS to Y.A. is gratefully
acknowledged.
Compound 4hh: 55% yield (13.8 mg); colorless oil; IR (neat)
REFERENCES
1
■
3366, 2164, 1458, 1251, 842 cm−1; H NMR (400 MHz, CDCl3) δ
(1) Recent reviews on direct C−H transformations, see: (a) Hand-
book of C−H Transformations; Dyker, G., Ed.; Wiley-VCH: Weinheim,
2005; Vols. 1 and 2. (b) Handbook of Reagents for Organic Synthesis:
Reagents for Direct Functionalization of C−H Bonds; Paquette, L. A.,
Fuchs, P. L., Eds.; Wiley: Chichester, 2007. (c) Special issue on “C−H
Functionalizations in Organic Synthesis”: Chem. Soc. Rev. 2011, 40 (4).
(2) (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52,
6752. (b) Dandapani, S.; Marcaurelle, L. A. Nature Chem. Biol. 2010, 6,
861.
0.14 (9H, s), 0.93 (3H, t, J = 6.0 Hz), 1.40−1.59 (4H, m), 1.90 (2H,
br), 3.54 (1H, t, J = 5.9 Hz); 13C NMR (100 MHz, CDCl3) δ 0.02,
13.8, 19.2, 40.0, 43.9, 86.3, 110.0; HRMS (ESI-TOF) calcd for
C9H19NNaSi (M + Na)+ 192.1179, found 192.1181.
Compound 4ll [CAS: 1502-03-0].25 89% yield (12.2 mg);
1
colorless solid; H NMR (500 MHz, CDCl3) δ 1.20−1.45 (22H, m),
1.50−1.60 (2H, m), 2.89 (1H, m); 13C NMR (100 MHz, CDCl3) δ
21.4, 23.38, 23.44, 23.8, 24.3, 33.2, 47.7.
(3) For our recent publications on direct C(sp3)−H functionaliza-
tions using in situ generated oxyl radicals, see: (a) Kamijo, S.;
Matsumura, S.; Inoue, M. Org. Lett. 2010, 12, 4195. (b) Kamijo, S.;
Hoshikawa, T.; Inoue, M. Tetrahedron Lett. 2010, 51, 872. (c) Kamijo,
S.; Hoshikawa, T.; Inoue, M. Tetrahedron Lett. 2011, 52, 2885.
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4654.
Compound 1e: colorless oil; IR (neat) 1603, 1588, 1494, 1108,
823, 740, 699 cm−1; 1H NMR (400 MHz, CDCl3) δ 1.11 (9H, s), 1.66
(2H, m), 1.78 (2H, m), 2.66 (2H, t, J = 6.0 Hz), 3.74 (2H, t, J = 6.5
Hz), 7.20−7.26 (3H, m), 7.30−7.35 (2H, m), 7.39−7.50 (6H, m),
7.70−7.75 (4H, m); 13C NMR (100 MHz, CDCl3) δ 19.2, 26.9, 27.5,
32.1, 35.6, 63.7, 125.6, 127.6, 128.2, 128.4, 129.5, 134.1, 135.6, 142.6;
HRMS (ESI-TOF) calcd for C26H32NaOSi (M + Na)+ 411.2115,
found 411.2125.
(4) For recent reviews on direct C(sp3)−H amination, see: (a) Díaz-
Compound 1g: colorless solid; mp 73−75 °C; IR (neat) 3342,
́
Requejo, M. M.; Perez, P. J. Chem. Rev. 2008, 108, 3379. (b) Collet, F.;
1
1593, 1538, 1495, 1339, 1163, 781, 740, 699 cm−1; H NMR (400
Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061. (c) Du Bois, J.
Org. Process Res. Dev. 2011, 15, 758. (d) Roizen, J. L; Harvey, M. E.;
Du Bois, J. Acc. Chem. Res. 2012, 45, 911.
MHz, CDCl3) δ 1.50−1.68 (4H, m), 2.58 (2H, t, J = 7.5 Hz), 3.11
(2H, q, J = 6.5 Hz), 5.24 (1H, br), 7.10 (2H, d, J = 7.5 Hz), 7.18 (1H,
t, J = 7.5 Hz), 7.26 (2H, t, J = 7.5 Hz), 7.72 (2H, dd, J = 6.0, 3.5 Hz),
7.84 (1H, dd, J = 6.0, 3.5 Hz), 8.11 (1H, dd, J = 6.0, 3.5 Hz); 13C
NMR (100 MHz, CDCl3) δ 28.1, 29.0, 35.1, 43.6, 125.3, 125.8, 128.26,
128.29, 130.9, 132.7, 133.5, 133.6, 141.6, 147.9; HRMS (ESI-TOF)
calcd for C16H18N2NaO4S (M + Na)+ 357.0879, found 357.0878.
Compound 1q: pale yellow solid; mp 57−59 °C; IR (neat) 3332,
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(a) Zhdankin, V. V.; Krasutsky, A. P.; Kuehl, C. J.; Simonsen, A. J.;
Woodward, J. K.; Mismash, B.; Bolz, J. T. J. Am. Chem. Soc. 1996, 118,
5192. (b) Viuf, C.; Bols, M. Angew. Chem., Int. Ed. 2001, 40, 623.
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̈
1
1702, 1595, 1524, 1162, 832 cm−1; H NMR (500 MHz, CDCl3) δ
0.92 (3H, t, J = 7.1 Hz), 1.34 (2H, m), 1.52 (9H, s), 1.57 (2H, m),
2.56 (2H, t, J = 7.5 Hz), 6.50 (1H, br), 7.26 (2H, d, J = 8.3 Hz), 7.09
(2H, d, J = 8.3 Hz); 13C NMR (125 MHz, CDCl3) δ 13.9, 22.2, 28.3,
33.7, 34.9, 80.2, 118.7, 128.8, 135.9, 137.6, 152.9; HRMS (ESI-TOF)
calcd for C15H23NNaO2 (M + Na)+ 272.1621, found 272.1613.
Compound 1w: colorless solid; mp 60−62 °C; IR (neat) 1727,
1633, 1578, 1488, 1449, 1139, 976, 764, 747, 705 cm−1; 1H NMR (400
MHz, CDCl3) δ 1.22 (3H, t, J = 7.6 Hz), 2.60 (2H, q, J = 7.6 Hz), 6.67
(1H, d, J = 16.0 Hz), 7.09 (1H, m), 7.19−7.31 (3H, m), 7.40−7.46
(3H, m), 7.58−7.63 (2H, m), 7.89 (1H, d, J = 16.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 14.2, 23.2, 117.1, 122.2, 126.1, 126.8, 128.2,
128.9, 129.4, 130.6, 134.1, 135.9, 146.5, 148.8, 165.3; HRMS (ESI-
TOF) calcd for C17H16NaO2 (M + Na)+ 275.1043, found 275.1043.
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9969
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