Direct conversion of N -alkoxyamides to carboxylic esters through tandem nbs-mediated oxidative homocoupling and thermal denitrogenation

Article abstract of DOI:10.1021/jo401435v

Treatment of N-alkoxyamides with NBS in toluene was found to conveniently afford the corresponding carboxylic esters, including those bearing a bulky or long-chain substituent, in satisfactory to excellent yields. This approach not only represents a convenient and economic approach to a direct transformation of an alkoxyamide moiety into the carboxylic ester functional group, via oxidative homocoupling and the subsequent thermal denitrogenation, but also facilitates the synthesis of sterically hindered carboxylic esters.

Full text of DOI:10.1021/jo401435v

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Article
Direct Conversion of N-Alkoxyamides to Carboxylic Esters through Tandem
NBS-Mediated Oxidative Homocoupling and Thermal Denitrogenation
Ningning Zhang, Rui Yang, Daisy Zhang-Negrerie, Yunfei Du, and Kang Zhao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo401435v • Publication Date (Web): 08 Aug 2013
Downloaded from http://pubs.acs.org on August 11, 2013
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Direct Conversion of N-Alkoxyamides to Carboxylic Esters through Tandem
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NBS-Mediated Oxidative Homocoupling and Thermal Denitrogenation
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Ningning Zhang,† Rui Yang,† Daisy ZhangꢀNegrerie † Yunfei Du*,†,‡ and Kang Zhao*,†
,
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†Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and
Technology, Tianjin University, Tianjin 300072, China
‡Synergetic Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn
Abstract: Treatment of Nꢀalkoxyamides with NBS in toluene was found to conveniently afford the
corresponding carboxylic esters, including those bearing a bulky or longꢀchain substituent, in
satisfactory to excellent yields. This approach not only represents a convenient and economic
approach to a direct transformation of an alkoxyamide moiety into the carboxylic ester functional
group, via oxidative homocoupling and the subsequent thermal denitrogenation, but also facilitates
the synthesis of sterically hindered carboxylic esters.
The ester moiety is an important functional group that has found wide occurrences in polymers,
pharmaceutical agents and biologically relevant natural products. Although many methods have been
reported for the synthesis of esters,1 formation of hindered esters continues to remain as a challenge.
In traditional esterification reactions, a bulky group on either the carboxylic acid or the alcohol
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significantly hampers the reaction.2ꢀ4 This effect is also observed in the reactions between acid
chlorides and alcohols.2ꢀ4 Consequently, special reagents and procedures are normally required for
achieving these sterically bulky carboxylic esters.5 Undoubtedly, development of novel methods for
efficient synthesis of hindered esters is in high demand.
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In contrast to the formation of carboxylic esters, it has been reported that bulky substituents do not
hamper the synthesis of hydroxamic esters, either by reactions of acid chlorides with alkoxyamines
or by alkylations of sodium salts of hydroxamic acids.6 In this regard, a direct conversion of
Nꢀalkoxyamides to carboxylic esters as an efficient strategy to the synthesis of hindered esters can be
envisaged. A literature survey7ꢀ10 shows that Nꢀalkoxyamides 1 can be converted to N,Nꢀbisꢀ
heteroatomꢀsubstituted amides A, which are unstable and can thermally decompose to generate the
corresponding esters. However, heavy metal oxidants, such as nickel(IV) peroxide hydrate
.
(NiO2 H2O),7 ceric ammonium nitrate (CAN),7 silver oxide (Ag2O)8 or lead(IV) acetate
(Pb(OAc)4)9ꢀ10 have always been used as oxidants for the dimerization reactions (Figure 1, path a).
In 2002, Glover and coworkers6 reported that Nꢀalkoxyamides, after being converted to
Nꢀchlorohydroxamates, could react with sodium azide to furnish the ester products via Heron
rearrangement (Figure 1, path b). It is worth noting that this attractive twoꢀstep method could be well
applied to the synthesis of some highly hindered esters. In this article, we report a more convenient
oneꢀstep conversion of alkoxyamides to carboxylic esters through reactions of alkoxyamides with
the readily available NBS in toluene (Figure 1, path c). Consistent with Glover’s findings,6 this
alternative approach also provides accesses to sterically hindered esters. The advantages of the
current method, in comparison to the existing methods, are its directness of oneꢀstep and lowꢀcost of
the reagents.
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Figure 1. Methods for conversions of N-alkoxyamides to Hindered Esters.
In fact, our original research objective was focused on forming NꢀbromoꢀNꢀmethoxybenzamide 3
and then to study its role as a nitrenium ion precursor in some intermolecular electrophilic
substitution reactions11 that we were interested in. Knowing the fact that α,βꢀunsaturated
Nꢀacylꢀamino acid ester could be converted to its Nꢀbromo product mediated by NBS,12 we applied
the method to have Nꢀmethoxybenzamide 1a reacting with NBS. However, to our surprise, when 1a
was treated with NBS in DCE at room temperature, ester 2a was formed in 77% yield, with trace of
the desired compound 3 formed. Although unexpected, this new finding led us to establish a novel
method for the synthesis of carboxylic ester compounds from the corresponding alkoxyamides.
Considering that the yield obtained for 2a was somewhat low, 1a was used as a model substrate to
further optimize the reaction conditions. Solventꢀscreening experiments revealed that the reaction
could occur in polar as well as nonpolar solvents (Table 1, entries 1ꢀ8), and the reaction in toluene
gave the best yield within a relatively short period of time (Table 1, entry 8). When the reaction
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temperature was raised to 60 C, the reaction was completed in 0.3 h with negligible decrease in
yield (Table 1, entry 9). A parallel experiment (Table 1, entry 10) of using 0.5 equiv of NBS was
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Scheme 1. Discovery of the Conversion of N-Methoxybenzamide 1a to Ester 2a
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carried out to determine the molar ratio of each reactant, and the result showed that close to 50 mol%
of 1a was recovered. This finding clearly indicated that at least 1.0 equiv of NBS was necessary for
the total conversion of 1a to 2a. Other Nꢀhalosuccinimides (NCS and NIS) were also tested, and the
results showed that they gave inferior yields when compared with NBS (Table 1, entries 11 and 12).
With the optimal reaction conditions (Table 1, entry 9) in hand, the scope of this newly established
NBSꢀmediated direct conversion of alkoxyamide to carboxylic esters was explored. The
Nꢀmethoxybenzamide derivatives 1b-1g, bearing either aromatic electronꢀdonating or
electronꢀwithdrawing groups, could all be converted to the corresponding esters by the method. With
the increasing of the electronꢀwithdrawing ability of the aromatic substituent, the yield of the
reaction decreased (Table 2, entries 1ꢀ7). When the substrate bears a nitro group, other than the
relatively lower yield, the reaction needed longer reaction time for a complete conversion (Table 2,
entry 7). The analogous N-benzyloxybenzamides 1hꢀ1j could also be converted the corresponding
benzyl benzoates 2h-2j under the described conditions which indicates that the R2 group is not
restricted to only the methyl group, but can be extended to other alkyl groups as well (Table 2,
entries 8ꢀ10). Replacing the phenyl ring with a heterocyclic thienyl ring in the substrate does not
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Table 1. Optimization of Reaction Conditions a
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temp
(oC)
time
(h)
yield
(%)b
entry
oxidant
solvent
1
2
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NIS
DCE
rt
rt
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79
88
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94
91
45
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MeCN
EtOAc
MeOH
dioxane
DMF
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3
rt
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4
rt
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5
rt
6
6
rt
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7
THF
rt
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8
toluene
toluene
toluene
toluene
toluene
rt
3
9
60
60
60
0.3
0.3
0.3
2
10c
11
12
NCS
reflux
a Reaction conditions: 1a (1.0 mmol), oxidant (1.0 mmol) in solvent (10 mL)
unless otherwise stated. b Isolated yields. c 0.5 equiv of NBS was used.
hamper the reaction and the desired product 2k could be obtained in moderate yield (Table 2, entry
11). Furthermore, Nꢀmethoxycinnamamides could also be converted the corresponding carboxylic
esters by the same method, with the alkenyl moiety being well tolerated during the process (Table 2,
entries 12 and 13). Finally, the method was also applicable to the substrate bearing aliphatic
carboxylic amides, with the products being achieved in acceptable to moderate yields (Table 2,
entries 14ꢀ17). For this class of substrates, the electronꢀwithdrawing groups in the aromatic ring on
either the acid or the alcohol side do not have an obvious impact on the yield. Furthermore, a
chlorine atom in the substrate could also be well tolerated, albeit the desired product was obtained in
a slightly lower yield (Table 2, entry 18).
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Table 2. Conversion of N-Alkoxyamides to Carboxylic Esters Mediated by NBS a
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yield
(%)b
time
(h)
time yield
(h)
product
entry
1
product
entry
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substrate
substrate
(%)b
O
O
O
O
MeO
MeO
OBn
MeO
MeO
OMe
OMe
N
H
N
H
OMe
OMe
OBn
0.3 91
2
72
O2N
O2N
1j
2j
1a
2a
2b
O
O
O
H
N
OMe
2
63
N
H
11
S
S
OMe
2
0.3 88
O
2k
O
1k
MeO
MeO
1b
O
O
O
O
OMe
OMe
12c
13c
N
H
OMe
N
H
OMe
1
1
3
4
1
1
85
76
85
61
Br
Br
1l
2l
1c
2c
O
O
O
OMe
OPMB
N
H
OMe
N
H
OPMB
I
I
1m
1n
1o
2m
1d
1e
1f
2d
2e
2f
O
O
O
O
MeO
MeO
O2N
OMe
OMe
OMe
O
14c
15c
O
N
H
OMe
OMe
OMe
5
6
7
1
1
2
60
50
61
1
2
53
72
OMe
N
OMe
Cl
F
Cl
F
H
2n
2o
O2N
O
O
N
H
OMe
OBn
N
H
OMe
O
O
F
F
O
O
16c
N
5
72
H
N
OBn
NO2
NO2
O
H
1p
1q
2p
1g
1h
2g
2h
O
O
O
OBn
OBn
NO2
N
OBn
O
8
9
1
1
75
62
O
17
18
1
5
76
43
H
6
N
H
NO2
6
2q
O
O
O
O
N
OBn
Cl
OBn
Cl
H
N
OBn
H
O2N
O2N
1r
2r
1i
2i
a Reaction conditions: 1 (1.0 mmol) and NBS (1.0 mmol) in toluene (10 mL) at 60 oC unless otherwise stated. b Isolated yields.
c The reaction was stirred at 80 oC.
Table 3. Conversions of N-Alkoxyamides to Hindered Esters Mediated by NBS a
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An important application of this methodology is in the synthesis of hindered esters, which is
known to be difficult to obtain by the classic methods.2ꢀ4,6 Our experiments show that when R2 is a
bulky tꢀbutyl group, substrates 1aaꢀ1ac, bearing an aromatic or benzyl R1 group, rendered the
corresponding esters 2aaꢀ2ac in moderate to good yields (Table 3, entries 1ꢀ3). When the R2
substituent is a longꢀchain alkyl group containing 12 carbons, the reaction afforded the desired
products in excellent yield (Table 3, entries 4 and 5). Besides, for substrates bearing a bulky R1
group, the reaction also delivered the desired products in high yields (Table 3, entries 6ꢀ7). Most
delightedly, we found this method could be applicable to the synthesis of the esters bearing both
bulky R1 and R2 groups (Table 3, entries 8ꢀ10).
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It is worth noting that Nꢀmethoxybenzamide 1c, bearing a bromoꢀsubstituted phenyl group, was
converted to its homodimer 3c if the reaction was run at room temperature. The isolated homodimer
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3c, upon being heated in toluene at 80 C for 1 h, afforded the benzoate 2c in 90% yield. The
observation of 3c demonstrates that the reaction adopts a cascade sequence involving the oxidative
homocoupling step, and followed by the subsequent thermal denitrogenation.
Scheme 2. Formation of the Homodimer 3c and Its Thermal Decomposition
Based on the previous reports in literature7,11g as well as our own studies, we propose here a
possible mechanism for this oxidative homocoupling and thermal denitrogenation process. Since at
least 1 equiv of NBS was needed, we postulate that alkoxyamide 1 firstly reacted with NBS to afford
Nꢀbromohydroxamate B. Then the NꢀBr bond in intermediate B underwent the homolytic cleavage
to give the Nꢀcentered radical species,11g which dimerized to form N,N'ꢀdiacylꢀN,N'ꢀ
dialkoxyhydrazine C, with the concurrent release of a molecular Br2 (formed from the released
bromine radicals). As intermediate C is thermally unstable, it decomposed to generate ester 2 and
nitrene D by a 1,1ꢀelimination pathway.7 Finally, nitrene D decomposed to afford nitrogen and
another molecule of ester 2.7 For all the above reactions studied, it was observed that the reaction
solution displayed a dark red color (likely due to the generated Br2) at the early stage, while
gradually diminished along the progress of the reaction. At the same time, benzyl bromide 4 was
detected being formed in all the reactions as a side product, which obviously resulted from the
reaction between the solvent toluene and the generated Br2.
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Scheme 3. Proposed Reaction Pathway
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In summary, we have demonstrated a novel methodology for the direct conversion of
alkoxyamides to carboxylic esters via NBSꢀmediated oxidative homocoupling and thermal
denitrogenation reactions. The features of the present method include the readily availability of the
starting materials, the mild reaction conditions, and most significantly, its economic application to
the synthesis of a wide range of sterically hindered esters.
Experimental Section
1
I. General Information. H and 13C NMR spectra were recorded on a 600 MHz spectrometer
o
(150 MHz for 13C NMR) at 25 C. Chemical shifts values were given in ppm and referred to the
internal standard TMS set as 0.00 ppm. The peak patterns were indicated as follows: s, singlet; d,
doublet; t, triplet; q, quartet; qui, quintet; m, multiplet; td, triplet of doublets and dd, doublet of
doublets. The coupling constants, J, are reported in Hertz (Hz). High resolution mass spectrometry
(HRMS) was obtained on a QꢀTOF micro spectrometer. Melting points were determined with a
micromelting point apparatus without corrections. TLC plates were visualized by UV fluorescence
quenching and KMnO4 staining. Reagents and solvents were purchased as reagent grade and were
used without further purification. All reactions were performed in standard glassware, heated at 70
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oC for 3 h before use. Flash column chromatography was performed over silica gel 200ꢀ300 mesh
and the eluent was a mixture of ethyl acetate (EA) and petroleum ether (PE).
II. Preparation of Alkoxyamides 1. All the known amides 1a13, 1bꢀ1d14, 1eꢀ1f15, 1h13, 1j16, 1k15,
1l17, 1n11, 1o18, 1r19, 1af20, 1ag7 and 1aj7 were prepared in accordance with the indicated literature
procedures.
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Amides 1g, 1i, 1m, 1p, 1q, 1aa-1ae, 1ah and 1ai were prepared by the following known or
modified procedures.
General Procedure A:14 To the carboxylic acid (10 mmol) was added thionyl chloride (20 mmol)
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followed by a catalytic amount of DMF (1 drop). The mixture was stirred at 60 C until completion
(ca. 3 h). The solvent was then removed under reduced pressure to afford the crude acid chloride.
Alkoxyamine hydrochloride (11 mmol) was added to a mixture of K2CO3 (20 mmol) in a 2:1
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mixture of EA:H2O (0.2 M). The resulting solution was cooled to 0 C followed by dropwise
addition of the crude acid chloride dissolved in EA (5 mL). The reaction was allowed to stir for 4 h
while reaching room temperature. The two layers were separated and the aqueous phase was
extracted with EA (20 mL × 2). The combined organic phase was dried over anhydrous Na2SO4,
filtered, and evaporated under reduced pressure. The residue was purified by flash column
chromatography on silica gel to give the desired products.
General Procedure B: To the carboxylic acid (10 mmol) was added thionyl chloride (20 mmol)
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followed by a catalytic amount of DMF (1 drop). The reaction was then stirred at 60 C until
completion (ca. 3 h). The solvent was then removed under reduced pressure to afford the crude acid
chloride. TEA (22 mmol) was added to a mixture of alkoxyamine hydrochloride (11 mmol) in DCE
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(0.2 M). The resulting mixture was cooled to 0 C followed by dropwise addition of the crude acid
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chloride dissolved in DCE (5 mL). The reaction was allowed to stir at room temperature overnight.
The reaction mixture was then diluted with DCM (40 mL) and washed with water (40 mL) and brine
(40 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and evaporated under
reduced pressure. The residue was purified by flash column chromatography on silica gel to give the
desired products.
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The novel amides thus obtained were characterized as follows:
N-Methoxy-2-nitrobenzamide (1g). Following the general procedure A, amide 1g was isolated
as a light yellow solid. Yield: 1.72 g, 88%, mp. 88ꢀ89 oC. 1H NMR (600 MHz, CDCl3) δ (mixture of
two rotamers) 8.57 (s, 1H), 8.14 (d, J = 6.6 Hz, 1H), 7.72 (s, 1H), 7.64 (t, J = 7.5 Hz, 1H), 7.55 (d, J
= 6.6 Hz, 1H), 3.94 (s, 2H), 3.44 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 164.4, 146.3, 133.8, 131.0,
+
129.4, 129.1, 124.5, 63.6. HRMS (ESI) m/z calcd for C8H8N2NaO4 [M + Na+] 219.0376; found
219.0357.
N-(Benzyloxy)-3-methylbenzamide (1i). Following the general procedure A, amide 1i was
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isolated as a white solid. Yield: 2.17 g, 90%, mp. 89ꢀ90 C. H NMR (600 MHz, CDCl3) δ 8.88 (s,
1H), 7.51 (s, 1H), 7.46ꢀ7.40 (m, 3H), 7.38ꢀ7.33 (m, 3H), 7.29 (d, J = 7.5 Hz, 1H), 7.25 (m, 1H), 5.01
(s, 2H), 2.34 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 166.4, 138.5, 135.4, 132.7, 131.8, 129.3, 128.7,
+
128.6, 128.5, 127.9, 124.1, 78.3, 21.3. HRMS (ESI) m/z calcd for C15H15NNaO2 [M + Na+]
264.0995; found 264.0971.
N-(4-Methoxybenzyloxy)cinnamamide (1m). Following the general procedure B, amide 1m was
isolated as a white solid. Yield: 1.56 g, 55%, mp. 117ꢀ118 oC. 1H NMR (600 MHz, CDCl3) δ 7.68 (d,
J = 15.7 Hz, 1H), 7.46 (s, 2H), 7.33 (d, J = 8.2 Hz, 5H), 6.87 (d, J = 8.3 Hz, 2H), 6.34 (br s, 1H),
13
4.90 (s, 2H), 3.76 (s, 3H). C NMR (150 MHz, CDCl3) δ 164.7, 159.9, 141.5, 134.8, 131.0, 129.8,
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128.8, 128.0, 127.5, 117.5, 113.9, 78.0, 55.2. HRMS (ESI) m/z calcd for C17H17NNaO3 [M + Na+]
306.1101; found 306.1088.
+
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N-(Benzyloxy)-2-(4-fluorophenyl)acetamide (1p). Following the general procedure A, amide 1p
o
was isolated as a white solid. Yield: 2.43 g, 94%, mp. 103ꢀ104 C. 1H NMR (600 MHz, CDCl3) δ
(mixture of two rotamers) 8.52 (s, 0.77H), 8.09 (s, 0.23H), 7.31 (m, 5H), 7.14 (br s, 2H), 6.96 (m,
13
2H), 4.85 (s, 1.55H), 4.74 (s, 0.45H), 3.62 (s, 0.45H), 3.36 (s, 1.55H). C NMR (150 MHz, CDCl3)
δ 168.7, 162.0 (d, JCꢀF = 245.6 Hz), 135.2, 130.7(d, JCꢀF = 6.6 Hz), 130.1, 129.2, 128.7, 128.5, 115.5
+
(d, JCꢀF = 21.3 Hz), 78.0, 39.3. HRMS (ESI) m/z calcd for C15H14FNNaO2 [M + Na+] 282.0901;
found 282.0867.
N-(3-Nitrobenzyloxy)octanamide (1q). Following the general procedure B, amide 1q was
isolated as a white solid. Yield: 1.47 g, 50%, mp. 110ꢀ111 oC. 1H NMR (600 MHz, CDCl3) δ 8.26 (s,
1H), 8.21 (d, J = 7.5 Hz, 1H), 7.77 (d, J = 5.8 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 5.01 (s, 2H), 2.09 (s,
2H), 1.66ꢀ1.58 (m, 2H), 1.26 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 171.8,
148.2, 137.7, 134.9, 129.5, 123.5, 123.4, 76.7, 33.1, 31.6, 29.1, 28.9, 25.4, 22.6, 14.0. HRMS (ESI)
+
m/z calcd for C15H22N2NaO4 [M + Na+] 317.1472; found 317.1432.
N-tert-Butoxy-3,4-dimethoxybenzamide (1aa). Following the general procedure A, amide 1aa
o
1
was isolated as a white solid. Yield: 1.99 g, 79%, mp. 114ꢀ115 C. H NMR (600 MHz, CDCl3) δ
7.38 (d, J = 1.7 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 3.91 (d, J = 1.7 Hz, 6H),
1.33 (s, 9H). 13C NMR (150 MHz, CDCl3) δ 167.4, 151.4, 148.9, 124.9, 120.1, 110.7, 110.3, 82.1,
+
77.4, 77.2, 77.0, 55.9, 55.9, 55.9, 55.9, 26.4. HRMS (ESI) m/z calcd for C13H19NNaO4 [M + Na+]
276.1206; found 276.1177.
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4-Bromo-N-tert-butoxybenzamide (1ab). Following the general procedure A, amide 1ab was
isolated as a white solid. Yield: 2.25 g, 83%, mp. 133ꢀ134 oC. 1H NMR (600 MHz, CDCl3) δ 8.60 (s,
1H), 7.62 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 1.32 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
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167.0, 131.7, 131.3, 128.9, 126.4, 82.5, 26.5. HRMS (ESI) m/z calcd for C11H1479BrNNaO2 [M +
Na+] 294.0100; found 294.0088.
N-tert-Butoxy-2-(4-nitrophenyl)acetamide (1ac). Following the general procedure A, amide 1ac
was isolated as a light yellow solid. Yield: 1.58 g, 63%, mp. 131ꢀ132 oC. 1H NMR (600 MHz, CDCl3)
δ (mixture of two rotamers) 8.19 (d, J = 7.9 Hz, 2H), 7.69 (br s, 1H), 7.48 (br s, 2H), 3.86 (s, 0.9H),
3.59 (s, 1.1H), 1.31 (s, 4H), 1.25 (s, 5H). 13C NMR (150 MHz, CDCl3) δ (* denotes minor rotamer
peaks) 168.5, 147.0, 142.5, 142.08*, 130.6*, 130.0, 123.6, 82.5, 82.12*, 40.0, 38.4*, 26.3. HRMS
+
(ESI) m/z calcd for C12H16N2NaO4 [M + Na+] 275.1002; found 275.0980.
N-(Dodecyloxy)benzamide (1ad). Following the general procedure A, amide 1ad was isolated as
a white solid. Yield: 2.68 g, 88%, mp. 49ꢀ50 C. 1H NMR (600 MHz, CDCl3) δ 7.74 (d, J = 7.2 Hz,
o
2H), 7.50 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 4.01 (t, J = 6.7 Hz, 2H), 1.73ꢀ1.67 (m, 2H),
1.35ꢀ1.23 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 166.1, 132.0, 131.9,
128.7, 127.0, 31.9, 29.7, 29.6, 29.6, 29.6, 29.4, 29.4, 28.1, 25.9, 22.7, 14.1. HRMS (ESI) m/z calcd
+
for C19H31NNaO2 [M + Na+] 328.2247; found 328.2216.
N-(Dodecyloxy)-2-(4-nitrophenyl)acetamide (1ae). Following the general procedure A, amide
1ae was isolated as a yellow solid. Yield: 1.63 g, 45%, mp. 91ꢀ92 oC. 1H NMR (600 MHz, CDCl3) δ
(mixture of two rotamers) 8.20 (d, J = 8.5 Hz, 2H), 8.05 (br s, 1H), 7.47 (d, J = 8.5 Hz, 2H), 3.90 (s,
13
1H), 3.86 (s, 2H), 3.56 (s, 1H),1.63 (s, 2H), 1.45ꢀ1.16 (m, 18H), 0.88 (t, J = 7.0 Hz, 3H). C NMR
(150 MHz, CDCl3) δ (* denotes minor rotamer peaks) 167.2, 147.1, 141.9, 130.5*, 130.1, 123.7,
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78.0, 39.8, 38.3*, 31.9, 29.6, 29.6, 29.6, 29.5, 29.4, 29.3, 28.0, 25.8, 22.7, 14.1. HRMS (ESI) m/z
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calcd for C20H32N2NaO4 [M + Na+] 387.2254; found 387.2229.
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N-tert-Butoxy-2,4,6-trimethylbenzamide (1ah). Following the general procedure B, amide 1ah
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was isolated as a white solid. Yield: 1.28 g, 55%, mp. 140ꢀ141 C. H NMR (600 MHz, CDCl3) δ
7.77 (s, 1H), 6.84 (s, 2H), 2.32 (s, 6H), 2.27 (s, 3H), 1.36 (s, 9H). 13C NMR (150 MHz, CDCl3) δ
+
169.4, 139.1, 135.2, 131.7, 128.2, 82.2, 26.6, 21.1, 19.3. HRMS (ESI) m/z calcd for C14H20NNaO2
[M + Na+] 258.1465; found 258.1425.
N-(Dodecyloxy)-2,4,6-trimethylbenzamide (1ai). Following the general procedure B, amide 1ai
was isolated as a white solid. Yield: 2.01 g, 58%, mp. 51ꢀ52 oC. 1H NMR (600 MHz, CDCl3) δ 8.35
(s, 1H), 6.81 (s, 2H), 4.03 (t, J = 6.8 Hz, 2H), 2.27 (d, J = 7.5 Hz, 9H), 1.75ꢀ1.67 (m, 2H), 1.43ꢀ1.21
(m, 18H), 0.88 (t, J = 6.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 167.6, 139.2, 135.3, 130.9, 128.2,
31.9, 29.7, 29.6, 29.6, 29.5, 29.5, 29.4, 28.1, 25.8, 22.7, 21.1, 18.9, 14.1. HRMS (ESI) m/z calcd for
+
C22H37NNaO2 [M + Na+] 370.2717; found 370.2710.
III. Conversion of Alkoxyamides 1 to Esters 2.
General Procedure C: A solution of 1 (1.0 mmol) and NBS (1.0 mmol) in toluene (10 mL) was
stirred at the designated temperature. The reaction was monitored by TLC. After the reaction was
completed, the reaction mixture was allowed to cool to room temperature and EA (20 mL) was
added. The resulting mixture was washed with saturated aqueous Na2S2O3 (10 mL). The organic
layer was dried over anhydrous Na2SO4, filtered and removed under reduced pressure. The residue
was purified by flash column chromatography on silica gel.
Methyl 3,4-dimethoxybenzoate (2a).21 Following the general procedure C, 2a was isolated as a
white solid. Yield: 178 mg, 91%, mp. 57ꢀ58 oC (lit.21 57ꢀ59 oC). 1H NMR (600 MHz, CDCl3) δ 7.68
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(dd, J = 8.4, 1.7 Hz, 1H), 7.55 (d, J = 1.5 Hz, 1H), 6.89 (d, J = 8.4 Hz, 1H), 3.93 (d, J = 2.0 Hz, 6H),
3.90 (s, 3H).
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Methyl 4-methoxybenzoate (2b).22 Following the general procedure C, 2b was isolated as a
white solid. Yield: 146 mg, 88%, mp. 47ꢀ48 oC. (lit.22 47ꢀ49 oC). 1H NMR (600 MHz, CDCl3) δ 7.99
(d, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H).
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Methyl 4-bromobenzoate (2c).21 Following the general procedure C, 2c was isolated as a white
solid. Yield: 182 mg, 85%, mp. 73ꢀ74 oC (lit.21 74ꢀ76 oC). 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J =
8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H).
Methyl 2-iodobenzoate (2d).23 Following the general procedure C, 2d was isolated as a light
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yellow oil. Yield: 199 mg, 76%. H NMR (600 MHz, CDCl3) δ 7.99 (dd, J = 7.9, 0.9 Hz, 1H), 7.80
(dd, J = 7.8, 1.6 Hz, 1H), 7.40 (td, J = 7.7, 1.0 Hz, 1H), 7.15 (td, J = 7.7, 1.7 Hz, 1H), 3.93 (s, 3H).
Methyl 4-chlorobenzoate (2e).24 Following the general procedure C, 2e was was isolated as a
light yellow oil. Yield: 102 mg, 60%. 1H NMR (600 MHz, CDCl3) δ 7.97 (d, J = 8.5 Hz, 2H), 7.41 (d,
J = 8.5 Hz, 2H), 3.92 (s, 3H).
Methyl 4-fluorobenzoate (2f).22 Following the general procedure C, 2f was isolated as a light
yellow oil. Yield: 77 mg, 50%. 1H NMR (600 MHz, CDCl3) δ 8.09ꢀ8.03 (m, 2H), 7.11 (t, J = 8.6 Hz,
2H), 3.91 (s, 3H).
Methyl 2-nitrobenzoate (2g).25 Following the general procedure C, 2g was isolated as a light
yellow oil. Yield: 110 mg, 61%, light yellow oil. 1H NMR (600 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz,
1H), 7.75 (dd, J = 7.6, 1.3 Hz, 1H), 7.68 (td, J = 7.5, 1.0 Hz, 1H), 7.64 (td, J = 7.8, 1.4 Hz, 1H), 3.93
(s, 3H).
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Benzyl benzoate (2h).26 Following the general procedure C, 2h was isolated as a colorless oil.
Yield: 159 mg, 75%. 1H NMR (600 MHz, CDCl3) δ 8.08 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H),
7.43 (dd, J = 15.4, 7.6 Hz, 4H), 7.38 (t, J = 7.4 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 5.36 (s, 2H).
Benzyl 3-methylbenzoate (2i).27 Following the general procedure C, 2i was isolated as a colorless
oil. Yield: 140 mg, 62%. 1H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 9.0 Hz, 2H), 7.45 (d, J = 7.6 Hz,
2H), 7.41ꢀ7.28 (m, 5H), 5.36 (s, 2H), 2.39 (s, 3H).
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Benzyl 4-nitrobenzoate (2j).28 Following the general procedure C, 2j was isolated as a light
yellow solid. Yield: 185 mg, 72%, mp. 81ꢀ82 oC (lit.28 82ꢀ83 oC). 1H NMR (600 MHz, CDCl3) δ 8.28
(d, J = 8.8 Hz, 2H), 8.24 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 7.2 Hz, 2H), 7.43ꢀ7.37 (m, 3H), 5.41 (s,
2H).
Methyl thiophene-2-carboxylate (2k).24 Following the general procedure C, 2k was isolated as a
1
light yellow oil. Yield: 89 mg, 63%. H NMR (600 MHz, CDCl3) δ 7.81 (dd, J = 3.7, 1.0 Hz, 1H),
7.55 (dd, J = 5.0, 0.9 Hz, 1H), 7.10 (dd, J = 4.7, 3.9 Hz, 1H), 3.89 (s, 3H).
Methyl cinnamate (2l).29 Following the general procedure C, 2l was isolated as a light yellow oil.
Yield: 137 mg, 85%. 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 16.0 Hz, 1H), 7.52 (dd, J = 6.4, 2.7
Hz, 2H), 7.42ꢀ7.35 (m, 3H), 6.44 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H).
4-Methoxybenzyl cinnamate (2m).30 Following the general procedure C, 2m was isolated as a
white solid. Yield: 163 mg, 61%, mp. 57ꢀ58 oC. 1H NMR (600 MHz, CDCl3) δ 7.71 (d, J = 16.0 Hz,
1H), 7.53ꢀ7.49 (m, 2H), 7.41ꢀ7.34 (m, 5H), 6.94ꢀ6.88 (m, 2H), 6.46 (d, J = 16.0 Hz, 1H), 5.19 (s,
2H), 3.82 (s, 3H).
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Methyl 2-(4-methoxyphenyl)acetate (2n).31 Following the general procedure C, 2n was isolated
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as a light yellow oil. Yield: 95 mg, 53%. H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 8.6 Hz, 2H),
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6.88ꢀ6.84 (m, 2H), 3.79 (s, 3H), 3.68 (s, 3H), 3.57 (s, 2H).
Methyl 2-(4-nitrophenyl)acetate (2o).32 Following the general procedure C, 2o was isolated as a
o
o
light yellow solid. Yield: 140 mg, 72%, mp. 48ꢀ49 C (lit.32 46ꢀ48 C). 1H NMR (600 MHz, CDCl3)
δ 8.20 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 3.74 (s, 2H), 3.73 (s, 3H).
Benzyl 2-(4-fluorophenyl)acetate (2p).33 Following the general procedure C, 2p was isolated as a
light yellow oil. Yield: 175 mg, 72%. 1H NMR (600 MHz, CDCl3) δ 7.37ꢀ7.29 (m, 5H), 7.24 (dd, J =
8.3, 5.2 Hz, 2H), 7.00 (t, J = 8.7 Hz, 2H), 5.13 (s, 2H), 3.64 (s, 2H).
3-Nitrobenzyl octanoate (2q). Following the general procedure C, 2q was isolated as a light
yellow oil.Yield: 212 mg, 76%. 1H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 8.19 (d, J = 8.2 Hz, 1H),
7.68 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H), 5.20 (s, 2H), 2.39 (t, J = 7.5 Hz, 2H), 1.69ꢀ1.64 (m,
2H), 1.32ꢀ1.25 (m, 8H), 0.87 (t, J = 6.8 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 173.4, 148.4, 138.3,
133.8, 129.5, 123.1, 122.8, 64.6, 34.2, 31.6, 29.1, 28.9, 24.9, 22.6, 14.0. HRMS (ESI) m/z calcd for
+
C15H21NNaO4 [M + Na+] 302.1363; found 302.1333.
Benzyl 2-chloroacetate (2r).34 Following the general procedure C, 2r was isolated as a colorless
oil. Yield: 79 mg, 43%. 1H NMR (600 MHz, CDCl3) δ 7.39ꢀ7.33 (m, 5H), 5.22 (s, 2H), 4.10 (s, 2H).
tert-Butyl 3,4-dimethoxybenzoate (2aa).35 Following the general procedure C, 2aa was isolated
as a colorless oil. Yield: 200 mg, 84%. 1H NMR (600 MHz, CDCl3) δ 7.62 (dd, J = 8.4, 1.8 Hz, 1H),
7.52 (d, J = 1.8 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 3.93 (d, J = 1.9 Hz, 6H), 1.59 (s, 9H).
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tert-Butyl 4-bromobenzoate (2ab).36 Following the general procedure C, 2ab was isolated as a
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light yellow oil. Yield: 128 mg, 50%. H NMR (600 MHz, CDCl3) δ 7.84 (d, J = 8.4 Hz, 2H), 7.55
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(d, J = 8.4 Hz, 2H), 1.59 (s, 9H).
tert-Butyl 2-(4-nitrophenyl)acetate (2ac).37 Following the general procedure C, 2ac was isolated
1
as a light yellow oil. Yield: 166 mg, 70%. H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 8.6 Hz, 2H),
7.45 (d, J = 8.5 Hz, 2H), 3.64 (s, 2H), 1.45 (s, 9H).
Dodecyl benzoate (2ad).38 Following the general procedure C, 2ad was isolated as a colorless oil.
Yield: 261 mg, 90%. 1H NMR (600 MHz, CDCl3) δ 8.05 (d, J = 7.9 Hz, 2H), 7.55 (t, J = 7.4 Hz, 1H),
7.44 (t, J = 7.7 Hz, 2H), 4.31 (t, J = 6.7 Hz, 2H), 1.81ꢀ1.72 (m, 2H), 1.48ꢀ1.23 (m, 18H), 0.88 (t, J =
7.0 Hz, 3H).
Dodecyl 2-(4-nitrophenyl)acetate (2ae). Following the general procedure C, 2ae was isolated as
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a yellow solid. Yield: 261 mg, 75%, mp. 46ꢀ47 C. H NMR (600 MHz, CDCl3) δ 8.19 (d, J = 8.4
Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 4.11 (t, J = 6.7 Hz, 2H), 3.73 (s, 2H), 1.61 (dd, J = 13.5, 6.7 Hz,
2H), 1.27 (d, J = 16.1 Hz, 18H), 0.88 (t, J = 6.9 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 170.2,
147.2, 141.5, 130.3, 123.7, 65.6, 41.1, 31.9, 29.6, 29.6, 29.5, 29.3, 29.2, 28.5, 25.8, 22.7, 14.1.
HRMS (ESI) m/z calcd for C20H31NNaO4 [M + Na+] 372.2145; found 372.2118.
+
Methyl 2,4,6-trimethylbenzoate (2af).39 Following the general procedure C, 2a
f was isolated as a
colorless oil. Yield: 151 mg, 85%. 1H NMR (600 MHz, CDCl3) δ 6.84 (s, 2H), 3.89 (s, 3H), 2.28 (d,
J = 3.5 Hz, 9H).
Methyl adamantan-1-carboxylate (2ag).40 Following the general procedure C, 2ag was isolated
as a colorless oil. Yield: 165 mg, 85%. 1H NMR (600 MHz, CDCl3) δ 3.65 (s, 3H), 2.01 (s, 3H), 1.89
(d, J = 2.1 Hz, 6H), 1.71 (q, J = 12.2 Hz, 6H).
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tert-Butyl 2,4,6-trimethylbenzoate (2ah).41 Following the general procedure C, 2ah was isolated
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as a colorless oil. Yield: 154 mg, 70%. H NMR (600 MHz, CDCl3) δ 6.83 (s, 2H), 2.30 (d, J = 2.5
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Hz, 6H), 2.26 (s, 3H), 1.59 (dd, J = 1.9, 1.3 Hz, 9H).
Dodecyl 2,4,6-trimethylbenzoate (2ai). Following the general procedure C, 2ai was isolated as a
1
colorless oil. Yield: 278 mg, 84%. H NMR (600 MHz, CDCl3) δ 6.85 (s, 2H), 4.30 (t, J = 6.7 Hz,
2H), 2.28 (d, J = 8.1 Hz, 9H), 1.77ꢀ1.69 (m, 2H), 1.32ꢀ1.26 (m, 18H), 0.88 (t, J = 6.9 Hz, 3H). 13C
NMR (150 MHz, CDCl3) δ 170.3, 139.1, 135.0, 131.3, 128.4, 65.0, 31.9, 29.7, 29.6, 29.5, 29.4, 29.3,
28.7, 26.1, 22.7, 21.1, 19.7, 14.1. HRMS (ESI) m/z calcd for C22H36NaO2 [M + Na+] 355.2608;
+
found 355.2575.
tert-Butyl adamantane-1-carboxylate (2aj).6 Following the general procedure C, 2aj was
1
isolated as a colorless oil. Yield: 99 mg, 42%. H NMR (600 MHz, CDCl3) δ 1.99 (s, 3H), 1.83 (s,
6H), 1.69 (q, J = 12.4 Hz, 6H), 1.42 (d, J = 3.5 Hz, 9H).
IV. Formation of Dimer 3c and Its Thermal Decomposition.
A solution of 1c (1.0 mmol) and NBS (1.0 mmol) in toluene (10 mL) was stirred at room
temperature for 1 h. Then EA (20 mL) was added and the mixture was washed with saturated
aqueous Na2S2O3 (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and
1
removed under reduced pressure to give a white solid 3c in quantitative yield. H NMR (600 MHz,
CDCl3) δ 7.55 (s, 8H), 3.87 (s, 6H). 13C NMR (150 MHz, CDCl3) δ 168.8, 131.6, 130.8, 130.2,
127.2, 63.6. HRMS (ESI) m/z calcd for C16H1479Br2N2NaO4 [M + Na+] 478.9213; found 478.9200.
+
A solution of 3c (1.0 mmol) in toluene (5 mL) was stirred at 80 oC for 1 h. Then the solvent was
removed under reduced pressure. The residue was purified by flash column chromatography on
silica gel to afford 2c in 90% yield.
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Acknowledgements
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Y. Du acknowledges the National Natural Science Foundation of China (#21072148), Foundation
(B) for Peiyang ScholarꢀYoung Core Faculty of Tianjin University (2013XRꢀ0144), and the
Innovation Foundation of Tianjin University (2013XJꢀ0005) for financial support.
Supporting Information
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1H and 13C NMR spectra data for all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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