Chemoselective Synthesis of Aryl Ketones from Amides and Grignard Reagents via C(O)-N Bond Cleavage under Catalyst-Free Conditions

Article abstract of DOI:10.1021/acs.joc.9b01699

Conversion of a wide range of N-Boc amides to aryl ketones was achieved with Grignard reagents via chemoselective C(O)-N bond cleavage. The reactions proceeded under catalyst-free conditions with different aryl, alkyl, and alkynyl Grignard reagents. α-Ketoamide was successfully converted to aryl diketones, while α,β-unsaturated amide underwent 1,4-addition followed by C(O)-N bond cleavage to provide diaryl propiophenones. N-Boc amides displayed higher reactivity than Weinreb amides with Grignard reagents. A broad substrate scope, excellent yields, and quick conversion are important features of this methodology.

Full text of DOI:10.1021/acs.joc.9b01699

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Article
Chemo-Selective Synthesis of Aryl Ketones from Amides and Grignard
Reagents via C(O)-N Bond Cleavage Under Catalyst-free Condition
Popuri Sureshbabu, sadaf azeez, Nalluchamy Muniyappan,
Shahulhameed Sabiah, and Jeyakumar Kandasamy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01699 • Publication Date (Web): 22 Aug 2019
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Chemo-Selective Synthesis of Aryl Ketones from Amides and Grignard
Reagents via C(O)-N Bond Cleavage Under Catalyst-free Condition
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9
Popuri Sureshbabu,a# Sadaf Azeez,a# Nalluchamy Muniyappanb Shahulhameed Sabiahb and
Jeyakumar Kandasamya*
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aDepartment of Chemistry, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh-
221005.
bDepartment of Chemistry, Pondicherry University, Pondicherry-605014
TOC
O
O
R2
R3
R3
R1
MgX
R1
N
+
THF, -30 oC
Boc
(1.0 equiv.)
R3= aryl/alkyl
R1 = Aryl/Alkyl
R = Alkyl, aryl or Boc
>40 Products
Yield: 40-94%
2
13 Examples
> 50 examples
Catalyst free
Quick Conversion
Functional group tolerance
Broad Substrate scope




Abstract:
Conversion of a wide range of N-Boc amides into aryl ketones was achieved with Grignard
reagents via chemoselective C(O)-N bond cleavage. The reactions proceeded under catalyst-free
condition with different aryl, alkyl and alkynyl Grignard reagents. α-Ketoamide was successfully
converted into aryl diketones while α,β-unsaturated amide undergoes 1,4-addition followed by
C(O)-N bond cleavage to provide diaryl propiophenones. N-Boc amides displayed higher
reactivity than Weinreb amides with Grignard reagents. Broad substrate scope, excellent yields
and quick conversion are important features of this methodology.
Introduction
Aryl ketones are not only important starting materials but also structural components of various
drugs and bioactive molecules (Figure 1).1 Aryl ketones are typically prepared by Friedel–Crafts
acylation reactions2 or by the oxidation of secondary alcohols.3 Amide is one of the key
functional groups in organic chemistry that present in biomolecules (e.g. proteins), natural
products and pharmaceutics.4 Recently, the activation of amides has emerged as a tool for the
chemo-selective synthesis of various biologically relevant molecules via C(O)-N bond cleavage.5
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In this context, the transformation of amides into ketones catalyzed by transition metals has
received significant interest in organic synthesis.6-9 Garg and co-workers demonstrated the
conversion of twisted amides (i.e. N-Boc and N-tosyl amides) into ketonic compounds with
organozinc and organoboron reagents using nickel catalysts.7 Extensive research work on the
conversion of amides to ketones was carried out by the Szostak research group which focused on
the palladium catalyzed coupling reaction of aryl boronic acids not only with N-Boc but also
various structurally distorted amides.8 Moreover, Szostak et al. also demonstrated the nickel
catalyzed organozinc mediated transformation of N-Boc amides into aryl ketones.9
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O
O
NH2
O
O
OH
Cl
O
Br
O
Bromfenac
Fenofibrate
Anti-inflammatory drug (NSAID)
Anti-hypercholesterolemia
O
H
O
N
I
O
N
O
O
O
C3H7
I
Ethylone
Amiodarone
Psychedelic drug
antiarrhythmic medication
O
O
NH2
N
C4H9O
Cathinone
Dyclocaine
Alkaloid
Anaesthetic
Figure 1. Biologically relevant ketonic compounds
Grignard reagents are powerful aryl donors utilized in many cross-coupling reactions.10 The
reaction of Grignard reagents with Weinreb amides is well known in organic synthesis and
provides ketones in good to excellent yields.11 Synthesis of aryl ketones from structurally
distorted N-acylazetidines and Grignard reagents was demonstrated by Szostak et al.12 However,
unlike organolithium compounds, aryl Grignard reagents showed less reactivity, requiring
elevated reaction temperature i.e. up to 60 °C. Recently, chromium catalyzed Kumada arylation
of unprotected secondary amides to ketone with Grignard reagents was demonstrated by Zeng et
al. in the presence of TMS-Cl.13 This method is attractive; however, it requires four equivalents
of Grignard reagents. In 1989, Giovannini et al. investigated the ring opening reactions of N-acyl
and carbomate (e.g. tBuC(O), Cbz, Boc) protected lactam with Grignard reagents.14 However,
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the scope and limitations of N-protected acyclic amides with Grignard reagent were not
investigated.15 Nevertheless, establishing such methods may allow direct access to aryl-aryl,
aryl-alkyl ketones in a simple manner from amides. Our research group is focused on the
chemistry of N-nitrosamines16 and recently demonstrated the transamidation of secondary amides
using tert-butyl nitrite.16a In continuation of this work, here we report the synthesis of aryl
ketones from N-Boc protected amides and Grignard reagents under catalyst-free condition
(Scheme 1).
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Scheme 1. Conversion of N-Boc amides into ketones.
Catalyst-free
R3 MgBr
(1.0 equiv.)
O
O
R2
R1
N
R1
R3
THF
Boc
R3 = Aryl, Alkyl
R1=Aryl/Alkyl
R2=Boc, Aryl, Alkyl
Results and Discussion
At the outset, the selective C(O)-N bond cleavage of different unprotected as well as
protected/activated amides with Grignard reagents was investigated (Scheme 2). Different
benzamides were subjected to the Grignard reactions with phenylmagnesium bromide (1.0
equiv.) in THF at 0 °C. In fact, no reaction was observed with unprotected primary as well as
secondary amides such as benzamide, N-methyl, N-benzyl and N-phenyl benzamides (Scheme 2,
i-iv). Moreover, tertiary amide such as N,N-diethyl benzamide (v) also failed to provide the
desired ketone. However, N-nitroso N-methyl benzamide (vi) gave the desired diphenyl ketone
(3a) in a trace amount. It is noteworthy that among the different activated amides, N-Boc
protected amides have shown excellent reactivity not only in coupling reactions but also in
transamidation and transesterification reactions under mild conditions.17 Moreover, N-Boc
protected amides can be easily and directly achieved from unprotected primary and secondary
amides in a single step with good yields. Therefore, the Grignard reaction was performed with N-
Boc protected primary and secondary benzamides (1aa and 1ba). To our delight, the coupling
reaction underwent smoothly with both of these amides while N,N-di-Boc benzamide (1aa) gave
the desired product in 77% yield. Further, benzamides with different N-protecting groups such as
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Cbz, Troc, phenyl carbamate, oxazolidine and benzoxazolone was subjected to the C(O)-N bond
cleavage with phenyl magnesium bromide (Scheme 2, vi-xi). Unfortunately, all these amides
gave the desired ketone 3a in low yields.
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Scheme 2. Reaction of different amides with phenylmagnesium bromide.a,b
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O
MgBr
O
THF
R1
N
R2
+
0oC, 15 min
1
2a
3a
O
O
O
O
O
Me
Et
NH2
N
N
H
N
N
H
H
Et
(i)
(ii)
00%
(iii)
00%
O
(iv)
(v)
00%
00%
O
00%
O
O
O
Me
Me
Me
Boc
Me
N
N
N
N
N
Troc
Cbz
Boc
Boc
NO
(vi)
(1aa)
(1ba)
(vii)
11%
(viii)
<10%
~ 10%
77%
71%
O
O
O
O
O
Me
O
N
N
N
O
COOPh
(xi)
(ix)
(x)
20%
24%
10%
aConditions: Substrate (1 mmol) and PhMgBr (2a) (1.0 equiv.) in THF (3 mL) at 0 °C for 15 min. bIsolated yield.
Seeking further optimization, the conversion of N,N-di-Boc benzamide (1aa) into diphenyl
ketone was investigated at different temperatures in THF (Table 1, entries 1-7). It was observed
that the reaction proceeds smoothly at -30 °C, providing the desired product in 93% yield within
30 min (Table 1, entry 5). However, the other solvents including diethyl ether and toluene were
found to be less suitable for the reactions, providing lower yields (Table 1, entries 8 and 9).
Moreover, by increasing the amount of phenylmagnesium bromide from 1.0 equiv. to 1.2, 1.5
and 2.0 equiv. did not show any significant change in the yield (Table 1, entries 10-12) . Overall,
the optimization study indicated that the transformation of N-Boc amides into arylketones can be
efficiently achieved with 1.0 equiv. of Grignard reagent at -30 °C (Table 1, entry 5). The
attractive features of this methodology such as catalyst-free condition, excellent yield and quick
conversion led us to further explore its potential.
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Table 1. Optimized condition.a
5
6
7
8
O
O
MgBr
Temperature
Solvent
Boc
N
+
Boc
30 min
9
3a
1aa
2a
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Entry
Solvent
Temp.
(°C)
25
PhMgBr
(equiv.)
1.0
Yield
(%)b
69
74
80
84
93
65
63
56
71
93
89
86
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
THF
THF
THF
Toluene
Et2O
THF
~5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
-10
-20
-30
-50
-78
-30
-30
-30
-30
-30
10
11
12
1.2
1.5
2.0
THF
THF
aConditions: Substrate (1aa: 321 mg, 1 mmol) and PhMgBr (2a: 1 mL, 1 mmol) in solvent (3 mL) at different
temperature. bIsolated yield.
With optimized conditions in hand, the substrate scope was investigated with a wide range of
functionalized N,N-di-Boc benzamides in the presence of phenylmagnesium bromide (Scheme
3). To our delight, N,N-di-Boc benzamides bearing electron donating groups (e.g. methyl, OMe,
OEt, tert-butyl) and electron withdrawing groups (e.g. halogens, nitro, trifluoromethane, etc.) at
the para-position underwent C(O)-C bond formation smoothly and provided the corresponding
unsymmetrical diaryl ketones (3b-3j) in good to excellent yields. To identify the general
applicability of the reaction, we have investigated the preparation of 3b-3d at standard cooling
bath temperatures i.e. -20 °C and -78 °C. It was observed that at -20 °C the reactions proceed
smoothly and provides the desired products in comparable yields or slightly lower yields within
30 minutes. On the other hand, at -78 °C the reactions were quite slow and required longer time
(6 h) to obtain the desired products in comparable or slightly better yields. Further we have
investigated the coupling reactions of meta-substituted amides, sterically hindered ortho-
substituted amides, as well as naphthyl amides under optimized conditions (i.e. at -30 °C). These
activated amides were successfully transformed into corresponding ketones (3k-3t) in the
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presence of phenylmagnesium bromide in 67-86% yields. Further to our delight, heterocyclic
amide such as N,N-di-Boc 2-thiophenecarboxamide also participated in the coupling reaction
very efficiently to yield the desired ketone (3u) in 85% yield.
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Scheme 3. Reaction with N,N-di-Boc activated amides with PhMgBr.a,b
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O
O
MgBr
THF
Boc
N
+
-30 oC, 30 min
Boc
R
O
R
1ab-1au
2a
3b-3u
O
O
O
O
F3C
O2N
Me
MeO
EtO
3f:
81%
3e:
79%
O
3b:
94%
(89%)c (94%)d
3c:
83%
3d:
85%
(80%)c (84%)d
(81%)c (87%)d
O
O
O
O
Cl
I
Cl
F
3g:
3h:
3i:
79%
O
80%
O
81%
O
3j:
3k:
81%
O
86%
O
Br
I
F3C
MeO
MeO
3l:
3m:
78%
84%
OMe
3p:
3n:
86%
3o:
79%
76%
F
O
Br
O
O
O
O
S
3t:
3u:
81%
85%
3q:
69%
3r:
3s:
76%
67%
aConditions: Substrate (1 mmol) and PhMgBr (2a) (1 mL, 1.0 equiv.) in THF (3 mL) at -30 °C for 30 min. bIsolated
yield. cReactions were performed at -20 °C for 30 min. dReactions were performed at -78 °C for 6 h.
Further, we have investigated the coupling reactions of different N-Boc protected secondary
benzamides including N-methyl, N-iso-propyl, N-cyclopropyl, N-benzyl and N-phenyl
benzamides (1ba-1fa) with phenylmagnesium bromide under optimized condition (Scheme 4).
All these activated amides were successfully transformed into diphenyl ketone in 81-85% yield.
Scheme 4. Reaction of PhMgBr with different N-substituted benzamides.a,b
O
O
MgBr
THF
R
N
+
-30 oC, 30 min
Boc
3a
1
2a
Ph
Me
Bn
N
N
N
N
N
Boc
1fa
Boc
1ba
Boc
1ea
Boc
1da
Boc
1ca
3a:
85%
83%
81%
81%
82%
aConditions: Substrate (1 mmol) and PhMgBr (2a) (1 mL, 1.0 equiv.) in THF (3 mL) at -30 °C for 30 min. bIsolated
yield.
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Subsequently, to investigate the scope of the methodology, a different N-Boc protected
secondary aryl amides were subjected to the coupling reaction with phenylmagnesium bromide
under optimized conditions (Scheme 5). To our delight, similar to N,N-di-Boc amides, N-Boc N-
methyl benzamides as well as N-Boc N-methyl heterocyclic amides were also participated in the
coupling reaction very efficiently to yield the corresponding unsymmetrical diaryl ketones 3b-3z
in 54-83% yield.
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Scheme 5. Synthesis of aryl ketones: Scope of N-Boc benzamides.a,b
O
O
MgBr
THF
Me
N
+
-30 oC, 30 min
Boc
R
R
1bb-1bz
2a
3b-3z
O
O
O
O
O
F3C
O2N
Cl
Me
MeO
EtO
3e: 75
3f:
%
76%
O
3b:
3c:
3d:
81%
O
83%
79%
O
O
O
F
I
Cl
I
3j:
3k:
83%
74%
O
3i:
80%
O
3g:
3h:
79%
71%
O
O
O
F3C
MeO
MeO
Br
OMe
3p:
71%
3m:
69%
3l: 7
8%
3n:
3o:
81%
75%
O
F
O
Br
O
O
O
S
3u:
77%
3r:
54%
3t:
74%
3q:
3s:
58%
O
67%
O
O
O
O
O2N
O2N
Cl
NC
O
N
3v:
3w:
3x:
3y:
3z:
72%
78%
74%
73%
81%
aConditions: Substrate (1 mmol) and PhMgBr (2a) (1 mL, 1.0 equiv.) in THF (3 mL) at -30 °C for 30 min. bIsolated
yield.
From Scheme 3 and 5, it is clear that the electronic effect of substituents on the aryl ring (i.e.
electron donating and withdrawing groups) is less significant in terms of reaction progress and
the yield. However, sterically hindered ortho-substituted amides gave relatively lesser yields of
the desired ketones (e.g. 3q-3r). It is also interesting to note that nitrile group as well as halo-
substituents (e.g. I, Br, etc.) on the aryl ring were well tolerated during the coupling reactions.
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On the other hand, amides with different N-substituents provided diphenyl ketone in comparable
5
6
yields (Scheme 4) indicating the broad scope of the current methodology.
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Scheme 6. Synthesis of ketones from N,N-diBoc benzamide: Scope of Grignard Reagents.a,b
O
O
THF
Boc
N
R-MgBr
+
R
-30 oC, 30 min
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Boc
2
1aa
3
O
O
O
O
OMe
Cl
3c:
80%
O
3b:
90%
O
3h:
3j:
77%
76%
O
O
OMe
CN
OMe
O
3v:
73%
O
3aa:
3ad:
3ab:
3ac:
O
74%
43%
71%
78%
O
CH3
3ae:c
3af:
57%
71%
3t:
75%
aConditions: Substrate (1aa: 321 mg, 1 mmol) and RMgBr (1.0 equiv.) in THF (3 mL) at -30 °C for 30 min.
bIsolated yield. cBenzyl magnesium chloride was used.
Having explored the scope of different amides, N,N-di-Boc benzamide (1aa) was subjected to
the coupling reaction with a wide range of Grignard reagents including aryl, benzyl, alkyl and
alkynyl magnesium halides (Scheme 6). It was observed that the electron donating and
withdrawing group functionalized aryl magnesium bromides reacted with N,N-di-Boc benzamide
and gave the corresponding diaryl ketones (Scheme 6, 3b, 3c, 3h, 3j, 3v, 3aa-3ac and 3t) in 43-
90% yields. Notably, strongly electron withdrawing group functionalized 4-cyano
phenylmagnesium bromide also participated in the coupling reaction and provided the desired
ketone in 73% yield. Moreover, sterically hindered ortho-substituted Grignard reagents (i.e. 2-
methoxyphenylmagnesium bromide and 2,4,6-tri-methylphenylmagnesium bromide) as well as
2-naphthylmagnesium bromide were successfully coupled with N-Boc N-methyl benzamide in
excellent yields. Further, the amide 1aa was subjected to the coupling reaction with alkyl and
alkynyl Grignard reagents such as methyl, benzyl and phenylethynylmagnesium halides under
optimized conditions. All these reactions gave the desired ketones 3ad-3af in good to moderate
yields.
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After exploring the reactions of N,N-di-Boc benzamide with different Grignard reagents, the
scope of N-Boc protected secondary amide was investigated. N-Methyl N-Boc benzamide (1ba)
was subjected to the coupling reactions with different Grignard reagents under optimized
conditions (Scheme 7). To our delight, diaryl ketones were obtained in 35-84% yields indicating
the broad scope of the developed methodology.
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Scheme 7. Synthesis of ketones from N-methyl N-Boc benzamide: Scope of Grignard
Reagents.a,b
O
O
Me
THF
N
+
R-MgBr
R
Boc
-30 oC, 30 min
2
3
1ba
O
O
O
O
OMe
Cl
3c:
82%
O
3b:
81%
O
3h:
3j:
74%
O
84%
O
OMe
CN
OMe
O
3v:
67%
O
3aa:
3ab:
3ac:
O
71%
68%
71%
O
CH3
3ae:c
3af:
51%
67%
3ad:
35%
3t:
70%
aConditions: Substrate (1ba: 235 mg, 1 mmol) and RMgBr (1.0 equiv.) in THF (3 mL) at -30 °C for 30 min.
bIsolated yield. cBenzyl magnesium chloride was used.
Having studied the scope of aryl amides, transformation of different alkyl amides into aryl
ketones was investigated with phenyl and p-tolylmagnesium bromides (Scheme 8). To our
delight, N-Boc protected N-methylphenylacetamide (1ga), N-benzylhexanamide (1ha) and N-
methyloctanamide (1ia) were efficiently converted into corresponding aryl-alkyl ketones (3ae,
3ag-3ak) in 67-75% yields under optimized condition.
Scheme 8. Synthesis of aryl ketones: Scope of alkyl amides. a,b
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O
O
R2
THF
R1
N
R3-MgBr
R1
R3
+
-30 oC, 30 min
Boc
R =PhCH2; R2 = Me;
1
1ga:
1ha:
1ia:
1
2
R =CH3(CH2)4; R = Bn
R =CH3(CH2)6; R2 = Me
1
O
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O
O
Me
Me
4
3ae:
3ag:
75%
3ah:
71%
68%
70%
O
O
O
Me
Me
4
6
6
3aj:
67%
3ai:
72%
3ak:
aConditions: Substrate (1 mmol) and R3MgBr (1.0 equiv.) in THF (3 mL) at -30 °C for 30 min. bIsolated yield.
The scope of the methodology was further evaluated with sensitive group functionalized
substrates such as 2-ketoamide and α,β-unsaturated amide (Scheme 9 and 10). In the case of 2-
oxo-2-phenylacetamide (1ja), the desired diketone compounds (3al and 3am) were obtained in
45-51% yields with 1.0 equiv. of Grignard reagents. There was only slight increment in yields
observed with 2.0 equiv. of Grignard reagents (Scheme 9).
Scheme 9. Reaction of Grignard reagent with 2-oxo-2-Phenylacetamide.
O
R
MgBr
O
(X. equiv.)
THF
Me
O
N
R
-30 oC, 30 min
O
Boc
3al
3am
X = 1.0: R= H; 45% (
R= Me; 51% (
)
)
)
1ja
X = 2.0:
3al
3am
R= H; 54% (
R= Me; 59% (
)
Interestingly, the N-Boc N-methyl cinnamamide (1ka) undergoes 1,4-addition followed by C(O)-
N cleavage to provide diarylpropiophenones (3an and 3ao) in >40% yields under optimized
conditions. However, the yields of the reactions were increased subsequently (i.e. up to 61%)
with the increased amount of Grignard reagents (Scheme 10).
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Scheme 10. Reaction of Grignard reagent with cinnamamide.
R
6
7
8
9
R
MgBr
O
O
Me
(X. equiv.)
THF
N
Boc
10
11
12
13
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60
-30 oC, 30 min
R
1ka
3an
3ao
X = 1.0: R= H; 41% (
R= Me; 40% (
)
)
3an
3ao
R= H; 59% (
R= Me; 61% (
)
)
X = 2.0:
Finally, the coupling reaction was attempted in a gram scale, where 1.21 gram of benzamide was
successfully converted into diphenyl ketone (3a) in 1.31 g over two steps (72% overall yield)
which clearly demonstrates the practical applicability of the developed methodology (Scheme
11).
Scheme 11. Coupling Reaction in gram scale.
O
O
1. (Boc)2O, DMAP, DCM
NH2
2. PhMgBr, THF
3a
1.21 g (10 mmol )
Isolated: 1.31 g (7.2 mmol)
To understand the reactivity of Boc-protected amides over Weinreb amides, few competitive
experiments were conducted with a controlled amount of Grignard reagents (Scheme 12). For
instance, 1:1 mixture of N,N-di-Boc benzamide (1.0 mmol) and N-methoxy-N-methylbenzamide
(1.0 mmol) was reacted with 1.0 mmol of phenyl magnesium bromide at -30 °C in THF (Scheme
12, A). Interestingly, N,N-di-Boc benzamide is completely consumed providing the desired
diphenyl ketone in 90% yield while the Weinreb amide i.e. N-methoxy-N-methylbenzamide was
remained unreacted (92% was recovered after the reaction).
Scheme 12. Controlled experiments
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O
O
O
O
O
Ph-MgBr (1 mmol)
Boc
Boc
Me
Me
THF
N
N
N
N
+
A
+
(
)
+
Boc
Boc
OMe
OMe
-30 oC, 30 min
3a
1aa
1 mmol
1aa
1la
1 mmol
1la
< 5% Recovered
92% Recovered
90%
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O
O
O
Ph-MgBr (1 mmol)
THF
O
O
10
11
12
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Me
N
Me
Me
Me
N
N
+
N
B
(
)
+
+
Boc
OMe
Boc
-30 oC, 30 min
OMe
3a
1 mmol
1 mmol
1ba
1la
1ba
1la
87%
< 5% Recovered
90% Recovered
O
Ph-MgBr (1 mmol)
THF
O
O
O
O
Boc
Me
N
Me
Boc
N
N
N
+
+
C
(
)
+
Boc
-30 oC, 30 min
Boc
Boc
Boc
1 mmol
1 mmol
3a
1aa
1aa
1ba
1ba
44% Recovered
50% Recovered
85%
Similarly, Boc protected secondary amide i.e. N-methyl N-Boc benzamide also found to be more
reactive than the Weinreb amide (Scheme 12, B). On the other hand, it was observed that the
Boc-protected primary amide (1aa) and secondary amide (1ab) showed equal reactivity with
Grignard reagent (Scheme 12, C). For instance, almost an equal amount of Boc protected
primary and secondary amides was recovered when 1.0 mmol of phenyl magnesium bromide
was treated with 1:1 mixture of N,N-di-Boc benzamide (1.0 mmol) and N-methyl N-Boc
benzamide (1.0 mmol). Overall, the controlled experiments suggest that Weinreb amides are less
reactive when compared with Boc-protected amides in Grignard reactions while Boc-protected
primary and secondary amides have equal reactivities.
A plausible mechanism for the transformation of amide to ketone is shown in Scheme 13. The
nucleophile R3 preferably attacks at the more electrophilic amide carbon and forms magnesium-
chelate intermediate (Scheme 13, A). As seen in the Table 1 (entries 10-12), with excess amount
of Grignard reagent, the coupling reaction gave the desired product approximately in same yield
suggesting that the reaction might proceed through metal-chelate intermediate. This intermediate
undergoes C(O)-N bond cleavage to yield the desired ketone and carbomate by-product. In the
case of N-phenyl N-Boc benzamide (1fa), the carbomate byproduct was isolated and
characterized (Scheme 13, B).
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Scheme 13. (A) A plausible mechanism for the transformation of amide to ketone; (B) Evidence
for the formation of the by-product.
6
7
8
9
O
Mg
A
( )
O
O
O
O
R1 R3
R3MgX
R1
+
R1
N
O
N
R2
O
O
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R3
R2
R2
N
O
"Mg-chelate"
intermediate
H
MgX
R3
tert-butyl phenylcarbamate
B
( )
O
H
O
O
O
PhMgBr (1 equiv.)
THF, -30 oC
N
O
+
Ph
82%
0.82 mmol (142 mg)
Ph
Ph
N
O
Ph
Ph
~ 80%
0.8 mmol (154 mg)
1 mmol (297 mg)
Isolated as by-prodcut
In conclusion, a mild and practical method for the transformation of amides into ketones via
chemoselective C(O)-N bond cleavage was demonstrated with Grignard reagents. A wide range
of aryl and alkyl N-Boc protected amides underwent coupling with different aryl and alkyl
Grignard reagents under catalyst-free conditions. α-Ketoamide was successfully converted into
aryl diketones in the presence of Grignard reagents while unsaturated amide undergoes 1,4-
addition followed by C(O)-N bond cleavage to provide diarylpropiophenones. Broad substrate
scope, excellent functional group tolerance and quick conversion make this a very attractive
methodology in organic synthesis.
Experimental Section
General information: All the solvents and chemicals were purchased from commercial sources
and used without further purifications. The reactions were carried out in round bottom flask
under argon atmosphere. Thin layer chromatography was performed using pre-coated plates
purchased from E. Merck (TLC silica gel 60 F254). TLC plates were visualized by exposure to
ultraviolet light (UV) with 254 nm of wavelength and then further analyzed by using iodine
chamber. The column chromatography was performed on silica gel (100-200 mesh) using a
1
13
mixture of ethyl acetate/hexane as an eluent. The H and C NMR spectra were recorded on
Bruker Avance 500 MHz NMR spectrometer using CDCl3. HRMS-Mass spectra were recorded
1
on UHD Q-Tof (ESI-TOF) using water’s Quattro Micro V 4.1 mass analyzer. In H NMR,
13
1
CDCl3 peak is graduated to 7.26 ppm and it is 77.00 ppm for C NMR spectra. The H NMR
13
and C NMR of the known products were compared with literature reports. All the coupling
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reactions were performed in low temperature reaction bath using Eyela PSL-1810 (Made in
Japan) instrument.
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8
Experimental procedures:
9
Synthesis of amides:18 Amides (i)-(v) were obtained from commercial sources. Preparation of
other amides was accomplished in two alternative methods namely, i) coupling of acid chlorides
with amine in the presence of base (Method A) and ii) coupling of acids with amine in the
presence of CDI (Method B). All these amides are well known in the literature.
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Method A: Benzoyl chloride derivative (10 mmol, 1.0 equiv.) and Et3N (3.5 mL, 25 mmol) was
stirred in DCM (10 mL) to which aqueous solution of ammonia (7 mL) or aqueous solution of
methylamine (40% w/w solution, 3 mL) or benzylamine (1.09 mL, 10 mmol) (or) aniline (0.93
mL, 10 mmol) was added dropwise at 0 °C. The resulting mixture was stirred for 1 h at room
temperature. The crude reaction mixture was washed with water and extracted with DCM. The
organic layer dried over Na2SO4 and the solvent was removed in vacuo to obtain the desired
amides in good yields (>75% yield). Using the above procedure, Benzamide, 4-
Methoxybenzamide, N-Nitrobenzamide, 2-Fluorobenzamide, N-Methylbenzamide, N-
Benzylbenzamide,
N-Phenylbenzamide,
4-Methoxy-N-methylbenzamide,
4-Nitro-N-
methylbenzamide, 2-Fluoro-N-methylbenzamide, N-methyloctanamide and N,N-diethyl
benzamide were synthesized.
Method B: Benzoic acid/heterocyclic acid derivative (10 mmol, 1.0 equiv) and 1,1’-carbonyl
diimidazole (CDI) (1.62 g, 10 mmol) was stirred in DCM (20 mL) for 20 min at room
temperature. After that, aqueous solution of ammonia (7 mL) or aqueous solution of
methylamine (40% w/w solution, 3 mL) (or) benzylamine (1.09 mL, 10 mmol) was added to the
reaction mixture and allowed to stir for 3 hours at room temperature. After completion, the
reaction mixture was quenched by 1N HCl (20 mL), and extracted by DCM (40 mL). The
organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The residue was purified by silica gel flash column chromatography to
afford the desired products in >70% yields. Using the above procedure, 4-Me-Benzamide, 4-
OEt-Benzamide, 4-CN-Benzamide, 4-CF3-Benzamide, 4-I-Benzamide, 4-F-Benzamide, 4-Cl-
Benzamide, 4-t-Bu-Benzamide, 3-Cl-Benzamide, 3-Br-Benzamide, 3-I-Benzamide, 3-NO2-
Benzamide, 3-CF3-Benzamide, 3,5 di-Me-Benzamide, 3-Cl,5-NO2-Benzamide, 3,4,5 tri-OMe-
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Benzamide, 2-Br-benzamide, 2-Furanamide, 3-Thiophenamide, 3-pyridinamide, 4-Me-N-
5
6
methylbenzamide,
4-OEt-N-methylbenzamide,
4-CN-N-methylbenzamide,4-CF3-N-
methylbenzamide, 4-I-N-methylbenzamide, 4-F-N-methylbenzamide, 4-Cl-N-methylbenzamide,
4-t-Bu-N-methylbenzamide, 3-Cl-N-methylbenzamide, 3-Br-N-methylbenzamide, 3-I-N-
methylbenzamide, 3-NO2-N-methylbenzamide, 3-CF3-N-methylbenzamide, 3,5 di-Me-N-
methylbenzamide, 3-Cl,5-NO2-N-methylbenzamide, 3,4,5 tri-OMe-N-methylbenzamide, 2-Br-N-
methylbenzamide, 2-Furan-N-methylamide, 3-Thiophene-N-methylamide, 3-pyridine-N-
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methylamide,
N-benzylhexanamide,
N-methyl-2-phenylacetamide,
N-methyl-2-oxo-2-
phenylacetamide and N-methylcinnamamide were prepared.
Synthesis of N-methyl-N-nitrosobenzamide (vi)16a: N-Methylbenzamide (135 mg, 1 mmol)
was stirred in dichloromethane (3 mL) approximately for 2 min at room temperature to which
tert-butyl nitrite (0.179 mL, 1.5 mmol) was added via syringe and allowed to stir for 1 h at room
temperature. After completion, dichloromethane was evaporated and then, subjected to silica gel
(60-120 mesh) column chromatography purification (SiO2: ethyl acetate/hexane) to obtain the
corresponding N-methyl N-nitrosobenzamide (vi). The product was obtained as a yellow liquid.
The residue was purified by column chromatography in silica gel eluting with hexane: EtOAc
(90:10), Rf = 0.72; Yield 82% (134 mg).2 1H NMR (500 MHz, CDCl3) δ= 7.78 (dd, J = 8.4, 1.3
13
Hz, 2H), 7.61–7.57 (m, 1H), 7.48 (dd, J = 10.9, 4.6 Hz, 2H), 3.31 (s, 3H). C{1H} NMR (125
MHz, CDCl3) δ= 172.9, 132.7, 132.5, 130.7, 128.1, 26.8.
Synthesis of benzyl benzoyl(methyl)carbamate (vii): N-Methylbenzamide (135 mg, 1 mmol)
was dissolved in THF (5 mL) to which lithium bis(trimethylsilyl)amide (LiHMDS) (1.5 mL, 1.5
mmol) was added via syringe at 0 °C and allowed to stir for 15 min. After that, benzyl
chloroformate (Cbz-Cl) (0.285 mL, 2 mmol) was added slowly to the reaction mixture and
allowed to stir at room temperature for 3 h. After completion, the reaction mixture was quenched
by 1 M HCl solution (5 mL). The resulting mixture was diluted with EtOAc (60 mL) and washed
with H2O (1 × 20 mL), brine (1 × 20 mL). The organic layers were combined, dried over
anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel (60-
120 mesh) column chromatography (SiO2: ethyl acetate/hexane) to obtain the corresponding N-
methyl N-Cbz-benzamide (vii). The product was obtained as a colourless liquid. The residue was
purified by column chromatography in silica gel eluting with hexane: EtOAc (90:10), Rf = 0.67;
1
Yield 90% (242 mg). H NMR (500 MHz, CDCl3) δ = 7.56–7.51 (m, 2H), 7.49–7.45 (m, 1H),
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7.40–7.34 (m, 2H), 7.32–7.25 (m, 3H), 7.02 (dd, J = 7.7, 1.2 Hz, 2H), 5.05 (s, 2H), 3.40 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ = 173.0, 154.8, 136.6, 134.4, 131.2, 128.3, 128.1, 128.0,
127.5, 68.5, 32.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C16H16NO3: 270.1130, Found
270.1116.
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Synthesis of 2,2,2-trichloroethyl benzoyl(methyl)carbamate (viii): N-Methylbenzamide (135
mg, 1 mmol) was dissolved in THF (5 mL) to which lithium bis(trimethylsilyl)amide (LiHMDS)
(1.5 mL, 1.5 mmol) was added via syringe at 0 °C and allowed to stir for 15 min. After that,
2,2,2-trichloroethoxycarbonyl chloride (Troc-Cl) (0.280 mL, 2 mmol) was added slowly to the
reaction mixture and allowed to stir at room temperature for 3 h. After completion, the reaction
mixture was quenched by 1 M HCl solution (5 mL). The resulting mixture was diluted with
EtOAc (60 mL) and washed with H2O (1 × 20 mL), brine (1 × 20 mL). The organic layers were
combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was
purified by silica gel (60-120 mesh) column chromatography (SiO2: ethyl acetate/hexane) to
obtain the corresponding N-methyl N-Troc-benzamide (viii). The product was obtained as a
yellow liquid. The residue was purified by column chromatography in silica gel eluting with
1
hexane: EtOAc (90:10), Rf = 0.65; Yield 80% (248 mg). H NMR (500 MHz, CDCl3) δ = 7.59
(dd, J = 8.1, 1.0 Hz, 2H), 7.46 (dd, J = 11.7, 4.3 Hz, 1H), 7.39 (t, J = 7.6 Hz, 2H), 4.66 (s, 2H),
13
3.41 (s, 3H). C{1H} NMR(125 MHz, CDCl3) δ = 172.5, 153.1, 135.7, 131.5, 127.9, 127.6,
93.8, 75.3, 32.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C11H11Cl3NO3: 309.9805, Found
309.9797.
Synthesis of phenyl benzoyl(methyl)carbamate (ix): N-Methylbenzamide (135 mg, 1 mmol)
was dissolved in THF (5 mL) to which lithium bis(trimethylsilyl)amide (LiHMDS) (1.5 mL, 1.5
mmol) was added via syringe at 0 °C and allowed to stir for 15 min. After that, phenyl
chloroformate (PhOCOCl) (0.251 mL, 2 mmol) was added slowly to the reaction mixture and
allowed to stir at room temperature for 3 h. After completion, the reaction mixture was quenched
by 1 M HCl solution (5 mL). The resulting mixture was diluted with EtOAc (60 mL) and washed
with H2O (1 × 20 mL) and brine (1 × 20 mL). The organic layers were combined, dried over
anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel (60-
120 mesh) column chromatography (SiO2: ethyl acetate/hexane) to obtain the corresponding
phenyl benzoyl(methyl)carbamate (ix). The product was obtained as a white solid. M.p. 79-81
°C. The residue was purified by column chromatography in silica gel eluting with hexane:
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EtOAc (90:10), Rf = 0.64; Yield 81% (206 mg). 1H NMR (500 MHz, CDCl3) δ = 7.71–7.64 (m,
2H), 7.49 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.28 (dd, J = 10.8, 5.1 Hz, 2H), 7.17 (t, J
13
= 7.4 Hz, 1H), 6.86 (d, J = 7.7 Hz, 2H), 3.50 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ =
7
8
9
173.0, 153.3, 150.1, 136.5, 131.6, 129.3, 128.2, 127.7, 126.0, 120.7, 33.3. HRMS (ESI-TOF)
m/z: [M+H]+: Calcd for C15H14NO3: 256.0974, Found 256.0963.
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Synthesis of 3-benzoyloxazolidin-2-one (x)19: Oxazolidinone (0.87 g, 10 mmol) and Et3N (2.78
mL, 20 mmol) was stirred in DCM (20 mL) to which benzoyl chloride (1.16 mL, 10 mmol) was
added dropwise at 0 °C. The resulting mixture was stirred for 4 h at room temperature. The
crude reaction mixture was diluted with water and extracted with DCM. The organic layer dried
over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by silica gel
(60-120 mesh) column chromatography (SiO2: ethyl acetate/hexane) to obtain the corresponding
3-benzoyloxazolidin-2-one (x). The product was obtained as a white solid. M.p. 141-143 °C. The
residue was purified by column chromatography in silica gel eluting with hexane: EtOAc
(90:10), Rf = 0.55; Yield 75% (1.44 g).19 1H NMR (500 MHz, CDCl3) δ = 7.65 (d, J = 8.3 Hz,
2H), 7.57–7.50 (m, 1H), 7.43 (t, J = 7.7 Hz, 2H), 4.46 (t, J = 7.8 Hz, 2H), 4.15 (t, J = 7.8 Hz,
2H). 13C{1H} NMR (125 MHz, CDCl3) δ = 169.7, 153.1, 132.5, 132.3, 129.0, 127.8, 62.2, 43.6.
Synthesis of 3-benzoylbenzo[d]oxazol-2(3H)-one (xi)20: Benzo[d]oxazol-2(3H)-one (0.540 g, 4
mmol) and Et3N (1.114 mL, 8 mmol) was stirred in DCM (10 mL) to which benzoyl chloride
(0.556 mL, 4.8 mmol) was added dropwise at 0 °C. The resulting mixture was refluxed for 2 h.
The crude reaction mixture was diluted with water and extracted with EtOAc. The organic layer
dried over Na2SO4 and the solvent was removed in vacuo. The crude product was purified by
silica gel (60-120 mesh) column chromatography (SiO2: ethyl acetate/hexane) to obtain the
corresponding 3-Benzoylbenzo[d]oxazol-2(3H)-one (xi). The product was obtained as a white
solid. M.p. 182-185 °C. The residue was purified by column chromatography in silica gel eluting
with hexane: EtOAc (90:10), Rf = 0.59; Yield 72% (0.688 g).20 1H NMR (500 MHz, CDCl3) δ =
7.88–7.84 (m, 1H), 7.83–7.79 (m, 2H), 7.67–7.62 (m, 1H), 7.52 (dd, J = 11.1, 4.6 Hz, 2H), 7.31–
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7.26 (m, 3H). C{1H} NMR (125 MHz, CDCl3) δ = 167.7, 150.9, 142.6, 133.5, 132.0, 129.5,
128.3, 125.2, 124.6, 114.9, 110.1.
General procedure for the synthesis of N,N-di-Boc benzamides: The N,N-di-Boc benzamides
were prepared using the general literature prodcure.9a Primary amide (1 mmol, 1.0 equiv.),
DMAP (13 mg, 0.1 mmol.) was dissolved in dichloromethane (5 mL) and placed under a positive
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pressure of argon. Di-tert-butyl dicarbonate (Boc2O) (0.45 mL, ~2.1 mmol) was added to the
reaction mixture with vigorous stirring at 0 °C. The resulting reaction mixture was continued to
stir for 12-15 h at room temperature. After completion, the reaction mixture was quenched with
saturated solution of NaHCO3 (10 mL) followed by extracted with EtOAc (3 × 20 mL). The
organic layer was washed with H2O (1 × 20 mL), brine (1 × 20 mL), dried and concentrated. The
crude product was purified by silica gel (60-120 mesh) column chromatography (SiO2: ethyl
acetate/hexane) to obtain the corresponding N,N-di-Boc benzamide (1aa-1au).
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N,N-Boc2-benzamide (1aa)9a: The title compound was obtained as a white solid. M.p. 58-60 °C.
The residue was purified by column chromatography in silica gel eluting with hexane: EtOAc
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(90:10), Rf = 0.57; Yield 85% (272 mg). H NMR (500 MHz, CDCl3) δ = 7.80 (t, J = 8.8 Hz,
2H), 7.56 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 1.34 (d, J = 10.9 Hz, 18H). 13C{1H} NMR
(125 MHz, CDCl3) δ = 169.1, 149.6, 134.0, 133.3, 128.9, 128.5, 84.1, 27.4.
N,N-Boc2-4-methylbenzamide (1ab)9a: The title compound was obtained as a white solid. M.p.
65-67 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.59; Yield 79% (265 mg). 1H NMR (500 MHz, CDCl3) δ = 7.71 (d, J = 8.2
Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 2.40 (s, 3H), 1.35 (s, 18H). 13C{1H} NMR (125 MHz, CDCl3)
δ = 169.0, 149.8, 144.5, 131.3, 129.3, 129.3, 84.0, 27.6, 21.7.
N,N-Boc2-4-methoxybenzamide (1ac)9a: The title compound was obtained as a white solid.
M.p. 71-73 °C. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (90:10), Rf = 0.35; Yield 62% (217 mg). H NMR (500 MHz, CDCl3) δ = 7.81
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(d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 1.36 (s, 18H). C{1H} NMR (125
MHz, CDCl3) δ = 168.1, 163.9, 149.7, 131.6, 126.3, 113.9, 83.8, 55.4, 27.5.
N,N-Boc2-4-ethoxybenzamide (1ad): The title compound was obtained as a white solid. M.p.
114-116 °C. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (90:10), Rf = 0.32; Yield 65% (237 mg). H NMR (500 MHz, CDCl3) δ = 7.78
(d, J = 8.9 Hz, 2H), 6.90 (d, J = 8.9 Hz, 2H), 4.08 (q, J = 7.0 Hz, 2H), 1.41 (t, J = 7.0 Hz, 3H),
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1.35 (s, 18H). C{1H} NMR (125 MHz, CDCl3) δ = 168.1, 163.4, 149.7, 131.6, 126.0, 114.3,
83.7, 63.8, 27.5, 14.5. HRMS (ESI-TOF) m/z: [M+H]+: Calcd for C19H28NO6: 366.1917, Found
366.1900.
N,N-Boc2-4-(trifluoromethyl)benzamide (1ae)9a: The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (90:10), Rf = 0.43; Yield 72% (281 mg). 1H NMR (500 MHz, CDCl3) δ= 7.90 (d,
J = 8.1 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 1.40 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ=
168.3, 149.5, 137.5, 134.56 (q, J= 33.75 Hz), 129.1, 125.65 (q, J= 3.75 Hz), 125.58 (q, J=
271.25 Hz), 84.9, 27.5.
N,N-Boc2-4-nitrobenzamide (1af)8c: The title compound was obtained as a yellow solid. M.p.
63-65 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.41; Yield 84% (307 mg). 1H NMR (500 MHz, CDCl3) δ = 8.30 (d, J = 8.9
Hz, 2H), 7.92 (d, J = 8.9 Hz, 2H), 1.42 (s, 18H). 13C{1H} NMR (125 MHz, CDCl3) δ = 167.8,
150.1, 149.3, 139.6, 129.5, 123.7, 85.2, 27.5.
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N,N-Boc2-4-iodobenzamide (1ag)8f: The title compound was obtained as a white solid. M.p.
114-117 °C. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (90:10), Rf = 0.52; Yield 88% (393 mg). 1H NMR (500 MHz, CDCl3) δ= 7.83 (d,
J = 8.6 Hz, 2H), 7.52 (d, J = 8.6 Hz, 2H), 1.39 (s, 18H). 13C{1H} NMR (125 MHz, CDCl3) δ =
168.78, 149.5, 137.9, 133.5, 130.3, 101.1, 84.5, 27.5.
N,N-Boc2-4-chlorobenzamide (1ah)9a: The title compound was obtained as a white solid. M.p.
58-61 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.51; Yield 70% (249 mg). 1H NMR (500 MHz, CDCl3) δ = 7.76 (d, J = 8.7
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Hz, 2H), 7.45 (d, J = 8.7 Hz, 2H), 1.39 (s, 18H). C{1H} NMR (125 MHz, CDCl3) δ = 168.3,
149.5, 139.8, 132.5, 130.4, 129.0, 84.5, 27.5.
N,N-Boc2-4-fluorobenzamide (1ai)9a: The title compound was obtained as a white solid. M.p.
67-68 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.50; Yield 73% (247 mg). 1H NMR (500 MHz, CDCl3) δ = 7.88–7.80 (m,
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2H), 7.13 (td, J = 8.4, 3.4 Hz, 2H), 1.37 (s, 18H). C{1H} NMR (125 MHz, CDCl3) δ = 168.0,
165.84 (d, J = 255 Hz), 149.6, 131.71 (d, J = 8.75 Hz), 130.38 (d, J = 2.5 Hz), 115.91 (d, J =
22.5 Hz), 84.3, 27.5.
N,N-Boc2-4-tert-butylbenzamide (1aj): The title compound was obtained as a white solid. M.p.
68-70 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.60; Yield 72% (271 mg). 1H NMR (500 MHz, CDCl3) δ = 7.75 (d, J = 8.4
Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 1.36 (s, 18H), 1.33 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3)
δ = 169.0, 157.4, 149.9, 131.4, 129.1, 125.6, 84.0, 35.1, 31.0, 27.5. HRMS (ESI-TOF) m/z:
[M+Na]+: Calcd for C21H31NNaO5: 400.2100, Found 400.2090
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N,N-Boc2-3-chlorobenzamide (1ak)9a: The title compound was obtained as a colourless liquid.
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The residue was purified by column chromatography in silica gel eluting with hexane: EtOAc
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(90:10), Rf = 0.51; Yield 71% (252 mg). H NMR (500 MHz, CDCl3) δ = 7.77 (t, J = 1.8 Hz,
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18H). C{1H} NMR (125 MHz, CDCl3) δ = 168.1, 149.5, 135.9, 134.8, 133.1, 129.9, 128.8,
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126.9, 84.6, 27.5.
N,N-Boc2-3-bromobenzamide (1al): The title compound was obtained as a colourless liquid.
The residue was purified by column chromatography in silica gel eluting with hexane: EtOAc
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(90:10), Rf = 0.53; Yield 69% (276 mg). H NMR (500 MHz, CDCl3) δ = 7.92 (t, J = 1.8 Hz,
1H), 7.77–7.66 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 1.39 (s, 18H). C{1H} NMR (125 MHz,
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CDCl3) δ = 167.9, 149.5, 136.10, 131.7, 130.1, 127.4, 122.6, 84.7, 27.5. HRMS (ESI-TOF) m/z:
[M+ Na ]+: Calcd for C17H22BrNNaO5: 422.0579, Found 422.0562.
N,N-Boc2-3-iodobenzamide (1am)8f: The title compound was obtained as a yellow solid. M.p.
68-70 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.56; Yield 80% (358 mg). 1H NMR (500 MHz, CDCl3) δ = 8.11 (t, J = 1.6
Hz, 1H), 7.90 (ddd, J = 7.9, 1.6, 1.1 Hz, 1H), 7.76 (ddd, J = 7.8, 1.6, 1.1 Hz, 1H), 7.20 (t, J = 7.8
Hz, 1H), 1.39 (s, 18H). 13C{1H} NMR (125 MHz, CDCl3) δ = 167.8, 149.6, 142.0, 137.6, 136.1,
130.3, 128.0, 93.8, 84.7, 27.6.
N,N-Boc2-3-(trifluoromethyl)benzamide (1an)9a: The title compound was obtained as a waxy
liquid. The residue was purified by column chromatography in silica gel eluting with hexane:
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EtOAc (90:10), Rf = 0.65; Yield 77% (300 mg). H NMR (500 MHz, CDCl3) δ = 8.03 (s, 1H),
7.99 (d, J = 7.5 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.8 Hz, 1H), 1.40 (s, 18H).
13C{1H} NMR (125 MHz, CDCl3) δ = 168.2, 149.5, 135.1, 132.0, 131.35 (q, J = 32.5 Hz),
129.57 (q, J = 3.75 Hz), 129.3, 125.69 (q, J = 3.75 Hz), 125.59 (q, J = 271.25 Hz), 84.9, 27.5.
N,N-Boc2-3,5-(dimethyl)benzamide (1ao): The title compound was obtained as a colourless
liquid. The residue was purified by column chromatography in silica gel eluting with hexane:
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EtOAc (90:10), Rf = 0.60; Yield 67% (234 mg). H NMR (500 MHz, CDCl3) δ= 7.43 (s, 2H),
7.21 (s, 1H), 2.34 (s, 6H), 1.37 (s, 18H). C{1H} NMR (125 MHz, CDCl3) δ= 169.4, 149.9,
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138.3, 135.0, 134.0, 126.7, 84.0, 27.4, 20.9. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for
C19H27NNaO5: 372.1787, Found 372.1771.
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N,N-Boc2-(trimethoxy)benzamide (1ap): The title compound was obtained as a colourless
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EtOAc (80:20), Rf = 0.30; Yield 52% (214 mg). H NMR (500 MHz, CDCl3) δ = 7.06 (s, 2H),
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3.90 (s, 3H), 3.86 (s, 6H), 1.38 (s, 18H). 13C{1H} NMR (125 MHz, CDCl3) δ = 168.5, 153.0,
149.8, 142.8, 128.9, 106.4, 84.2, 60.9, 56.2, 27.5. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for
C20H29NNaO8: 434.1791, Found 434.1777.
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N,N-Boc2-2-fluorobenzamide (1aq)8c: The title compound was obtained as a colourless liquid.
The residue was purified by column chromatography in silica gel eluting with hexane: EtOAc
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(90:10), Rf = 0.62; Yield 70% (238 mg). H NMR (500 MHz, CDCl3) δ = 7.68 (td, J = 7.5, 1.8
Hz, 1H), 7.54–7.49 (m, 1H), 7.23 (td, J = 7.6, 1.0 Hz, 1H), 7.12–7.08 (m, 1H), 1.43 (s, 18H).
13C{1H} NMR (125 MHz, CDCl3) δ = 165.4, 159.97 (d, J = 252.5 Hz), 149.4, 134.09 (d, J =
8.75 Hz), 130.76 (d, J = 1.25 Hz), 124.36 (d, J = 3.75 Hz), 123.08 (d, J = 12.5 Hz), 115.97 (d, J
= 22.5 Hz), 84.6, 27.4. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C17H22FNNaO5: 362.1380,
Found 362.1374.
N,N-Boc2-2-bromobenzamide (1ar): The title compound was obtained as a white solid. M.p.
94-96 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
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EtOAc (90:10), Rf = 0.56; Yield 67% (268 mg). H NMR (500 MHz, CDCl3) δ = 7.57 (dd, J =
7.9, 0.9 Hz, 1H), 7.44 (dd, J = 7.6, 1.6 Hz, 1H), 7.35 (td, J = 7.5, 1.0 Hz, 1H), 7.29 (td, J = 7.7,
1.6 Hz, 1H), 1.41 (s, 18H).13C NMR (125 MHz, CDCl3) δ = 167.6, 149.1, 136.9, 133.0, 131.6,
128.8, 127.1, 119.7, 84.9, 27.3. HRMS (ESI-TOF) m/z: [M+H]+: Calcd for C17H23BrNO5:
400.0760, Found 400.0769.
N,N-Boc2-1-naphthamide (1as)21: The title compound was obtained as a white solid. M.p. 67-
69 °C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.58; Yield 77% (285 mg). 1H NMR (500 MHz, CDCl3) δ= 8.37 (d, J = 8.3
Hz, 1H), 7.99 (d, J = 8.2 Hz, 1H), 7.88 (d, J = 7.6 Hz, 1H), 7.78 (dd, J = 7.1, 0.9 Hz, 1H), 7.59
(ddd, J= 8.4, 6.9, 1.3 Hz, 1H), 7.56–7.52 (m, 1H), 7.50–7.45 (m, 1H), 1.26 (s, 18H). 13C{1H}
NMR (125 MHz, CDCl3) δ = 169.3, 149.9, 133.4, 132.7, 132.4, 130.5, 128.3, 127.85, 126.9,
126.6, 124.8, 124.4, 84.4, 27.3.
N,N-Boc2-2-naphthamide (1at)9a: The title compound was obtained as a white solid. M.p. 69-71
°C. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (90:10), Rf = 0.57; Yield 90% (334 mg). 1H NMR (500 MHz, CDCl3) δ = 8.37 (d, J = 0.8
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Hz, 1H), 7.97–7.86 (m, 4H), 7.62 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.59–7.54 (m, 1H), 1.36 (s,
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18H). C{1H} NMR (125 MHz, CDCl3) δ = 169.2, 149.8, 135.6, 132.3, 131.3, 130.6, 129.3,
128.72, 128.6, 127.8, 127.0, 124.6, 84.2, 27.5.
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N,N-Boc2-thiophene-3-carboxamide (1au)9a: The title compound was obtained as a white solid.
M.p. 71-73 °C. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (90:10), Rf = 0.49; Yield 72% (235 mg). 1H NMR (500 MHz, CDCl3) δ = 8.01–
7.93 (m, 1H), 7.38 (ddd, J = 10.0, 3.8, 2.4 Hz, 1H), 7.31 (dd, J = 4.2, 2.4 Hz, 1H), 1.34 (s, 18H).
13C{1H} NMR (125 MHz, CDCl3) δ = 163.0, 149.4, 137.3, 133.2, 127.3, 126.6, 83.9, 27.4.
General procedure for the synthesis of N-Boc amides: The N-Boc benzamides were prepared
using the literature prodcure.17d An oven-dried round-bottomed flask (100 mL) was charged with
a secondary amide (5.0 mmol, 1.0 equiv.), DMAP (61 mg, 0.5 mmol) was dissolved in
dichloromethane (10 mL). Di-tert-butyl dicarbonate (Boc2O) (1.5 mL, 6.5 mmol.) was added in
one portion and the reaction mixture was allowed to stir for 10-12 h at room temperature. After
completion, the reaction mixture was quenched with saturated solution of NaHCO3 (10 mL)
followed by extracted with EtOAc (3 × 20 mL). The organic layer was washed with H2O (1 × 20
mL), brine (1 × 20 mL), dried and concentrated. The crude product was purified by silica gel
(60-120 mesh) column chromatography (SiO2: ethyl acetate/hexane) to obtain the corresponding
N-Boc benzamide (1ba-1bz).
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tert-Butyl benzoyl(methyl)carbamate (1ba)17d: The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (95:05), Rf = 0.55; Yield 80% (188 mg). H NMR (500 MHz, CDCl3) δ = 7.47
(dd, J = 8.0, 1.0 Hz, 2H), 7.44–7.40 (m, 1H), 7.35 (dd, J = 10.6, 4.3 Hz, 2H), 3.27 (s, 3H), 1.12
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(s, 9H). C{1H} NMR (125 MHz, CDCl3) δ = 173.4, 153.3, 137.8, 130.7, 127.8, 127.2, 82.8,
32.3, 27.2.
tert-Butyl benzoyl(isopropyl)carbamate (1ca)22: The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (90:10), Rf = 0.55; Yield 74% (194 mg).1H NMR (500 MHz, CDCl3) δ= 7.54
(dd, J = 8.0, 1.0 Hz, 2H), 7.45 (t, J = 7.4 Hz, 1H), 7.37 (t, J = 7.5 Hz, 2H), 4.72–4.63 (m, 1H),
1.42 (d, J = 6.9 Hz, 6H), 1.10 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ = 173.4, 153.3, 138.6,
131.0, 128.1, 127.4, 82.4, 48.8, 27.3, 20.3.
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tert-Butyl benzoyl(cyclopropyl)carbamate (1da): The title compound was obtained as a white
solid. M.p. 78-81 °C. The residue was purified by column chromatography in silica gel eluting
with hexane: EtOAc (90:10), Rf = 0.54; Yield 76% (200 mg). 1H NMR (500 MHz, CDCl3) δ = δ
= 7.56–7.51 (m, 2H), 7.50–7.44 (m, 1H), 7.38 (t, J = 7.6 Hz, 2H), 2.88–2.82 (m, 1H), 1.17 (s,
9H), 1.0–0.97 (m, 2H), 0.76–0.71 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ = 174.7, 153.6,
137.6, 131.6, 128.0, 127.8, 82.6, 28.1, 27.4, 8.6. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for
C15H19NaNO3: 284.1263, Found 284.1247.
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tert-Butyl benzoyl(benzyl)carbamate (1ea)17d: The title compound was obtained as a colourless
liquid. The residue was purified by column chromatography in silica gel eluting with hexane:
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EtOAc (90:10), Rf = 0.58; Yield 71% (220 mg). H NMR (500 MHz, CDCl3) δ = 7.51 (dd, J =
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7.9, 0.8 Hz, 2H), 7.47–7.42 (m, 3H), 7.40–7.29 (m, 5H), 4.99 (s, 2H), 1.12 (s, 9H). C{1H}
NMR (125 MHz, CDCl3) δ = 173.1, 153.4, 137.78, 137.6, 131.0, 128.4, 128.1, 128.0, 127.4,
127.3, 83.1, 48.8, 27.3.
tert-Butyl benzoyl(phenyl)carbamate (1fa)17d: The title compound was obtained as a white
solid. M.p. 99-102 °C. The residue was purified by column chromatography in silica gel eluting
1
with hexane: EtOAc (90:10), Rf = 0.57; Yield 73% (217 mg). H NMR (500 MHz, CDCl3) δ =
7.78–7.73 (m, 2H), 7.57–7.52 (m, 1H), 7.49–7.42 (m, 4H), 7.39–7.33 (m, 1H), 7.31–7.28 (m,
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2H), 1.25 (s, 9H). C{1H} NMR (125 MHz, CDCl3) δ = 172.7, 153.2, 139.0, 136.9, 131.6,
129.1, 128.2, 128.0, 127.9, 127.7, 83.4, 27.4.
tert-Butyl methyl(4-methylbenzoyl)carbamate (1bb)23: The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (95:05), Rf = 0.56; Yield 82% (204 mg). H NMR (500 MHz, CDCl3) δ = 7.36
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(d, J = 8.2 Hz, 2H), 7.12 (d, J = 7.9 Hz, 2H), 3.23 (s, 3H), 2.32 (s, 3H), 1.12 (s, 9H). C{1H}
NMR (126 MHz, CDCl3) δ = 173.3, 153.3, 141.1, 134.5, 128.3, 127.4, 82.4, 32.3, 27.1, 21.2.
tert-Butyl (4-methoxybenzoyl)(methyl)carbamate (1bc)17d: The title compound was obtained
as a white solid. M.p. 68-71°C. The residue was purified by column chromatography in silica gel
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eluting with hexane: EtOAc (95:05), Rf = 0.35; Yield 78% (206 mg). H NMR (500 MHz,
CDCl3) δ = 7.52 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 3.84 (s, 3H), 3.27 (s, 3H), 1.22 (s,
9H). 13C{1H} NMR (125 MHz, CDCl3) δ = 173.2, 162.0, 153.8, 129.9, 129.7, 113.1, 82.6, 55.4,
32.8, 27.5.
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tert-Butyl (4-ethoxybenzoyl)(methyl)carbamate (1bd): The title compound was obtained as a
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white solid. M.p. 94-96 °C. The residue was purified by column chromatography in silica gel
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eluting with hexane: EtOAc (95:05), Rf = 0.38; Yield 75% (209 mg). H NMR (500 MHz,
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CDCl3) δ = 7.54–7.49 (m, 2H), 6.90–6.86 (m, 2H), 4.08 (q, J = 7.0 Hz, 2H), 3.29 (s, 3H), 1.23 (s,
9H). 13C{1H} NMR (125 MHz, CDCl3) δ = 173.2, 161.4, 153.8, 129.9, 129.5, 113.6, 82.5, 63.6,
32.7, 27.4, 14.6. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C15H21NNaO4: 302.1368, Found
302.1370.
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tert-Butyl methyl(4-(trifluoromethyl)benzoyl)carbamate (1be)17d: The title compound was
obtained as a white solid. M.p. 61-64. The residue was purified by column chromatography in
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silica gel eluting with hexane: EtOAc (95:05), Rf = 0.65; Yield 77% (233 mg). H NMR (500
MHz, CDCl3) δ = 7.66 (d, J = 8.5 Hz, 2H), 7.62–7.55 (m, 2H), 3.32 (d, J = 0.9 Hz, 3H), 1.17 (d,
J = 0.9 Hz, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ = 172.0, 152.9, 141.3, 132.34 (q, J = 32.5
Hz), 127.4, 125.03 (q, J = 3.75 Hz), 123.66 (q, J = 270 Hz), 83.6, 32.4, 27.3.
tert-Butyl methyl(4-nitrobenzoyl)carbamate (1bf): The title compound was obtained as a pale
yellow solid. M.p. 148-149 °C. The residue was purified by column chromatography in silica gel
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eluting with hexane: EtOAc (95:05), Rf = 0.41; Yield 72% (202 mg). H NMR (500 MHz,
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CDCl3) δ = 8.31–8.25 (m, 2H), 7.67–7.61 (m, 2H), 3.35 (s, 3H), 1.24 (s, 9H). C{1H} NMR
(125 MHz, CDCl3) δ = 171.2, 152.6, 148.6, 143.7, 127.8, 123.3, 84.1, 32.3, 27.4. HRMS (ESI-
TOF) m/z: [M+Na]+: Calcd for C13H16N2NaO5: 303.0957, Found 303.0946.
tert-Butyl (4-iodobenzoyl)(methyl)carbamate (1bg): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.59; Yield 67% (242 mg). 1H NMR (500 MHz, CDCl3) δ = 7.74–
7.69 (m, 2H), 7.23–7.18 (m, 2H), 3.26 (s, 3H), 1.18 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ
= 172.5, 153.1, 137.1, 137.0, 128.9, 97.2, 83.2, 32.4, 27.3. HRMS (ESI-TOF) m/z: [M+Na]+:
Calcd for C13H16INNaO3: 384.0073, Found 384.0065.
tert-Butyl (4-chlorobenzoyl)(methyl)carbamate (1bh): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.57; Yield 74% (199 mg). 1H NMR (500 MHz, CDCl3) δ = 7.43 (s,
2H), 7.37 (s, 2H), 3.28 (s, 3H), 1.20 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ = 172.4, 153.2,
136.9, 136.0, 128.8, 128.1, 83.2, 32.5, 27.4. HRMS (ESI-TOF) m/z: [M+H]+: Calcd for
C13H17ClNO3: 270.0897, Found 270.0894.
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tert-Butyl (4-fluorobenzoyl)(methyl)carbamate (1bi)23: The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.56; Yield 77% (195 mg). 1H NMR (500 MHz, CDCl3) δ = 7.56–
7.48 (m, 2H), 7.10–7.03 (m, 2H), 3.28 (s, 3H), 1.19 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ
= 172.4, 164.25 (d, J = 250 Hz), 153.3, 133.77 (d, J = 3.75 Hz), 129.82 (d, J = 8.75 Hz), 115.01
(d, J = 21.25 Hz), 83.1, 32.6, 27.4.
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tert-Butyl (4-(tert-butyl)benzoyl)(methyl)carbamate (1bj): The title compound was obtained
as a colourless liquid. The residue was purified by column chromatography in silica gel eluting
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with hexane: EtOAc (95:05), Rf = 0.61; Yield 74% (215 mg). H NMR (500 MHz, CDCl3) δ=
7.44 (d, J = 8.5 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 3.28 (s, 3H), 1.31 (s, 9H), 1.13 (s, 9H).
13C{1H} NMR (125 MHz, CDCl3) δ = 173.5, 154.4, 153.6, 134.9, 127.3, 124.8, 82.6, 34.8, 32.5,
31.1, 27.2. HRMS (ESI-TOF) m/z: [M+H]+: Calcd for C17H26NO3: 292.1913, Found 292.1907.
tert-Butyl (3-chlorobenzoyl)(methyl)carbamate (1bk): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (95:05), Rf = 0.56; Yield 71% (191 mg). H NMR (500 MHz, CDCl3) δ = 7.41
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(d, J = 1.6 Hz, 1H), 7.39–7.32 (m, 2H), 7.31–7.24 (m, 1H), 3.24 (s, 3H), 1.13 (s, 9H). C{1H}
NMR (125 MHz, CDCl3) δ = 171.5, 152.8, 139.2, 133.6, 130.4, 129.2, 127.2, 125.2, 83.1, 32.2,
27.1. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C13H16ClNNaO3: 292.0716, Found 292.0723.
tert-Butyl (3-bromobenzoyl)(methyl)carbamate (1bl): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.57; Yield 70% (219 mg). 1H NMR (500 MHz, CDCl3) δ = 7.60–
7.47 (m, 2H), 7.44 – 7.34 (m, 1H), 7.26–7.16 (m, 1H), 3.24 (s, 3H), 1.13 (s, 9H). 13C{1H} NMR
(125 MHz, CDCl3) δ = 171.5, 152.9, 139.5, 133.4, 130.1, 129.5, 125.7, 121.7, 83.2, 32.3, 27.2.
HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C13H16NaBrNO3: 336.0211, Found 336.0199.
tert-Butyl (3-iodobenzoyl)(methyl)carbamate (1am): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.58; Yield 72% (260 mg). 1H NMR (500 MHz, CDCl3) δ = 7.79–
7.73 (m, 2H), 7.47–7.43 (m, 1H), 7.11 (dd, J = 11.8, 4.1 Hz, 1H), 3.26 (s, 3H), 1.16 (s, 9H).
13C{1H} NMR (125 MHz, CDCl3) δ = 171.4, 152.9, 139.6, 139.3, 135.8, 129.7, 126.3, 93.0,
83.3, 32.3, 27.3. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C15H21NNaO4: 302.1368, Found
302.1370.
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tert-Butyl methyl(3-(trifluoromethyl)benzoyl)carbamate (1bn): The title compound was
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obtained as a colourless liquid. The residue was purified by column chromatography in silica gel
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eluting with hexane: EtOAc (95:05), Rf = 0.63; Yield 76% (230 mg). H NMR (500 MHz,
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CDCl3) δ = 7.77–7.63 (m, 3H), 7.50 (t, J = 7.8 Hz, 1H), 3.28 (s, 3H), 1.12 (s, 9H). 13C{1H} NMR
(125 MHz, CDCl3) δ = 171.8, 152.8, 138.6, 130.4, 130.38 (d, J = 32.5 Hz), 128.6, 127.06 (q, J =
3.75 Hz), 124.09 (q, J = 3.75 Hz), 123.58 (q, J = 270 Hz), 83.4, 32.3, 27.1. HRMS (ESI-TOF)
m/z: [M+Na]+: Calcd for C14H16NaF3NO3: 326.0980, Found 326.0972.
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tert-butyl (3,5-dimethylbenzoyl)(methyl)carbamate (1bo)23: The title compound was obtained
as a white solid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.60; Yield 84% (220 mg). 1H NMR (500 MHz, CDCl3) δ = 7.12–
7.09 (m, 2H), 7.08 (s, 1H), 3.28 (s, 3H), 2.31 (s, 6H), 1.15 (s, 9H). 13C{1H} NMR (125 MHz,
CDCl3) δ = 173.8, 153.7, 137.6, 137.5, 132.3, 125.1, 82.6, 32.4, 27.3, 21.0. HRMS (ESI-TOF)
m/z: [M+Na]+: Calcd for C15H21NNaO3: 286.1419, Found 286.1415.
tert-Butyl methyl(3,4,5-trimethoxybenzoyl)carbamate (1bp): The title compound was
obtained as a colourless liquid. The residue was purified by column chromatography in silica gel
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eluting with hexane: EtOAc (85:15), Rf = 0.35; Yield 60% (195 mg). H NMR (500 MHz,
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CDCl3) δ = 6.75 (s, 2H), 3.86 (s, 3H), 3.85 (s, 6H), 3.28 (s, 3H), 1.21 (s, 9H). C{1H} NMR
(125 MHz, CDCl3) δ = 173.1, 153.6, 152.8, 140.6, 132.9, 105.0, 82.8, 60.9, 56.1, 32.7, 27.4.
HRMS (ESI-TOF) m/z: [M+H]+: Calcd for C16H24NO6 : 326.1604, Found 326.1622.
tert-Butyl (2-fluorobenzoyl)(methyl)carbamate (1bq): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
1
hexane: EtOAc (95:05), Rf = 0.58; Yield 76% (192 mg). H NMR (500 MHz, CDCl3) δ = 7.48
(td, J = 7.4, 1.8 Hz, 1H), 7.43–7.39 (m, 1H), 7.19 (td, J = 7.6, 1.0 Hz, 1H), 7.07–7.01 (m, 1H),
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3.33 (s, 3H), 1.21 (s, 9H). C{1H} NMR (125 MHz, CDCl3) δ = 168.1, 158.47 (d, J = 248.75
Hz), 152.7, 131.78 (d, J = 8.75 Hz), 129.24 (d, J = 2.5 Hz), 126.60 (d, J = 15.0 Hz), 124.19 (d, J
= 3.75 Hz), 115.21 (d, J = 21.25 Hz), 83.3, 31.9, 27.3. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd
for C13H16FNNaO3: 276.1012, Found 276.1020.
tert-Butyl (2-bromobenzoyl)(methyl)carbamate (1br): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
1
hexane: EtOAc (95:05), Rf = 0.55; Yield 72% (226 mg). H NMR (500 MHz, CDCl3) δ = 7.54
(dd, J = 8.0, 0.9 Hz, 1H), 7.36 (td, J = 7.5, 1.1 Hz, 1H), 7.31–7.23 (m, 2H), 3.36 (s, 3H), 1.18 (s,
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9H). C NMR (125 MHz, CDCl3) δ = 170.4, 152.1, 140.6, 132.3, 130.1, 127.5, 127.2, 118.2,
83.4, 31.3, 27.3. HRMS (ESI-TOF) m/z: [M+H]+: Calcd for C13H17BrNO3: 314.0392, Found
314.0391.
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tert-Butyl (1-naphthoyl)(methyl)carbamate (1bs): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (95:05), Rf = 0.61; Yield 65% (185 mg). H NMR (500 MHz, CDCl3) δ = 7.86
(dt, J = 9.4, 4.7 Hz, 3H), 7.53–7.42 (m, 4H), 3.46 (s, 3H), 0.75 (s, 9H). C{1H} NMR (125
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MHz, CDCl3) δ = 172.4, 152.9, 136.7, 133.2, 129.8, 129.5, 128.2, 126.9, 126.2, 124.7, 124.4,
123.7, 82.9, 31.7, 26.8. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C17H19NNaO3: 308.1263,
Found 308.1261.
tert-Butyl (2-naphthoyl)(methyl)carbamate (1bt): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.60; Yield 68% (194 mg). 1H NMR (500 MHz, CDCl3) δ = 8.03 (s,
1H), 7.85 (t, J = 8.4 Hz, 3H), 7.59 (d, J = 8.5 Hz, 1H), 7.55–7.48 (m, 2H), 3.37 (s, 3H), 1.06 (s,
9H). C{1H} NMR (125 MHz, CDCl3) δ = 173.5, 153.5, 134.8, 134.2, 132.2, 128.5, 127.6,
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127.5, 127.4, 126.6, 124.3, 82.8, 32.5, 27.2. HRMS (ESI-TOF) m/z: [M+Na]+: Calc. for
C17H19NNaO3: 308.1263, Found 308.1262.
tert-Butyl methyl(thiophene-3-carbonyl)carbamate (1bu): The title compound was obtained
as a colourless liquid. The residue was purified by column chromatography in silica gel eluting
1
with hexane: EtOAc (95:05), Rf = 0.51; Yield 68% (164 mg). H NMR (500 MHz, CDCl3) δ =
7.70–7.66 (m, 1H), 7.25–7.22 (m, 1H), 7.18 (dd, J = 5.0, 1.1 Hz, 1H), 3.23 (s, 3H), 1.24 (s, 9H).
13C{1H} NMR (125 MHz, CDCl3) δ = 168.0, 153.4, 138.8, 128.8, 127.1, 124.9, 82.7, 32.5, 27.4.
HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C11H15NNaO3S: 264.0670, Found 264.0676.
tert-Butyl (4-cyanobenzoyl)(methyl)carbamate (1bv): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
hexane: EtOAc (95:05), Rf = 0.45; Yield 73% (190 mg). 1H NMR (500 MHz, CDCl3) δ = 7.71–
7.67 (m, 2H), 7.57–7.53 (m, 2H), 3.30 (s, 3H), 1.19 (s, 9H). 13C{1H} NMR (125 MHz, CDCl3) δ
= 171.4, 152.6, 141.9, 131.8, 127.5, 118.0, 113.9, 83.9, 32.3, 27.3. HRMS (ESI-TOF) m/z:
[M+Na]+: Calcd for C14H16NaN2O3: 283.1059, Found 283.1049.
tert-Butyl methyl(3-nitrobenzoyl)carbamate (1bw): The title compound was obtained as a
white solid. M.p. 91-93 °C. The residue was purified by column chromatography in silica gel
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eluting with hexane: EtOAc (95:05), Rf = 0.36; Yield 68% (190 mg). H NMR (500 MHz,
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CDCl3) δ = 8.32 (d, J = 7.9 Hz, 2H), 7.83 (dd, J = 7.4, 0.5 Hz, 1H), 7.60 (t, J = 7.7 Hz, 1H), 3.33
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(s, 3H), 1.22 (s, 9H). C{1H} NMR (125 MHz, CDCl3) δ = 170.8, 152.7, 147.6, 139.2, 133.0,
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129.1, 125.1, 122.4, 83.9, 32.5, 27.4. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for
C13H16N2NaO5: 303.0957, Found 303.0962.
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tert-Butyl (3-chloro-5-nitrobenzyl)(methyl)carbamate (1bx): The title compound was
obtained as a colourless liquid. The residue was purified by column chromatography in silica gel
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eluting with hexane: EtOAc (95:05), Rf = 0.30; Yield 65% (204 mg). H NMR (500 MHz,
CDCl3) δ = 7.98 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.3, 2.0 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 3.30
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(s, 3H), 1.28 (s, 9H). C{1H} NMR (125 MHz, CDCl3) δ = 169.9, 152.6, 147.2, 137.2, 131.6,
131.5, 129.1, 124.5, 84.2, 32.5, 27.5. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for
C13H15ClN2NaO5: 337.0567, Found 337.0561.
tert-Butyl (furan-2-carbonyl)(methyl)carbamate (1by)17d: The title compound was obtained as
a colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (95:05), Rf = 0.52; Yield 69% (155 mg). H NMR (500 MHz, CDCl3) δ = 7.47
(dd, J = 1.7, 0.8 Hz, 1H), 7.04 (dd, J = 3.5, 0.8 Hz, 1H), 6.51–6.47 (m, 1H), 3.22 (s, 3H), 1.31 (s,
9H). 13C{1H} NMR (125 MHz, CDCl3) δ = 162.62, 153.2, 148.7, 143.9, 116.3, 111.9, 82.7, 32.3,
27.5.
tert-Butyl methyl(nicotinoyl)carbamate (1bz): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (95:05), Rf = 0.37; Yield 57% (135 mg). H NMR (500 MHz, CDCl3) δ = 8.64
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(dd, J = 3.6, 2.2 Hz, 2H), 7.31–7.23 (m, 2H), 3.26 (s, 3H), 1.14 (s, 9H). C{1H} NMR (125
MHz, CDCl3) δ = 170.9, 152.3, 149.6, 145.4, 136.8, 130.0, 120.5, 84.0, 31.9, 27.1. HRMS (ESI-
TOF) m/z: [M+H]+: Calcd for C12H17N2O3: 237.1239, Found 237.1235.
tert-Butyl methyl(2-phenylacetyl)carbamate (1ga): The title compound was obtained as a
colourless liquid. The residue was purified by column chromatography in silica gel eluting with
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hexane: EtOAc (95:05), Rf = 0.52; Yield 54% (134 mg). H NMR (500 MHz, CDCl3) δ = 7.33
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(dd, J = 9.4, 5.5 Hz, 2H), 7.28–7.24 (m, 3H), 4.26 (s, 2H), 3.18 (s, 3H), 1.53 (s, 9H). C{1H}
NMR (125 MHz, CDCl3) δ = 174.2, 153.2, 135.1, 129.5, 128.2, 126.6, 83.0, 44.3, 31.7, 27.9.
HRMS (ESI-TOF) m/z: [M+H]+: Calcd for C14H20NO3: 250.1443, Found 250.1444.
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tert-Butyl benzyl(hexanoyl)carbamate (1ha): The title compound was obtained as a colourless
liquid. The residue was purified by column chromatography in silica gel eluting with hexane:
EtOAc (95:05), Rf = 0.51; Yield 67% (204 mg). 1H NMR (500 MHz, CDCl3) δ = 7.32–7.25 (m,
5H), 4.91 (s, 2H), 2.95–2.89 (m, 2H), 1.70 (dd, J = 14.9, 7.5 Hz, 2H), 1.43 (s, 9H), 1.35 (dq, J =
13
5.9, 3.9 Hz, 4H), 0.92 (t, J = 6.9 Hz, 3H). C{1H} NMR (125 MHz, CDCl3) δ = 176.2, 153.1,
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138.3, 128.2, 127.4, 126.9, 82.9, 47.2, 38.2, 31.3, 27.8, 24.8, 22.4, 13.9. HRMS (ESI-TOF) m/z:
[M+H]+: Calcd for C18H28NO3: 306.2069, Found 306.2074.
tert-Butyl methyl(octanoyl)carbamate (1ia): The title compound was obtained as a colourless
liquid. The residue was purified by column chromatography in silica gel eluting with hexane:
1
EtOAc (95:05), Rf = 0.50; Yield 66% (170 mg). H NMR (500 MHz, CDCl3) δ = 3.12 (s, 3H),
2.83 (dd, J = 9.6, 5.6 Hz, 2H), 1.65–1.60 (m, 2H), 1.52 (s, 9H), 1.34–1.21 (m, 8H), 0.87 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ = 176.3, 153.3, 82.7, 38.3, 31.7, 31.4, 29.2, 29.1, 28.0, 25.1,
22.6, 14.0. HRMS (ESI-TOF) m/z: [M+H]+: Calc. for C14H28NO3: 258.2069, Found 258.2070.
tert-Butyl methyl(2-oxo-2-phenylacetyl)carbamate (1ja): The title compound was obtained as
a white solid. M.p. 72-74 °C. The residue was purified by column chromatography in silica gel
1
eluting with hexane: EtOAc (95:05), Rf = 0.62; Yield 64% (168 mg). H NMR (500 MHz,
CDCl3) δ = 7.87–7.79 (m, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 3.29 (s, 3H),
1.26 (s, 9H). C{1H} NMR (125 MHz, CDCl3) δ = 187.8, 169.8, 151.7, 134.1, 132.8, 129.4,
13
128.7, 86.0, 29.8, 27.5. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C14H17NNaO4: 286.1055,
Found 286.1062.
tert-Butyl cinnamoyl(methyl)carbamate (1ka): The title compound was obtained as a white
solid. M.p. 82-83 °C. The residue was purified by column chromatography in silica gel eluting
1
with hexane: EtOAc (95:05), Rf = 0.46; Yield 63% (164 mg). H NMR (500 MHz, CDCl3) δ =
7.67 (d, J = 15.6 Hz, 1H), 7.58–7.49 (m, 3H), 7.40–7.33 (m, 3H), 3.23 (s, 3H), 1.55 (s, 9H).
13C{1H} NMR (125 MHz, CDCl3) δ = 168.9, 153.4, 142.9, 135.1, 129.8, 128.7, 128.0, 121.4,
83.0, 31.8, 28.0. HRMS (ESI-TOF) m/z: [M+Na]+: Calcd for C15H19NNaO3: 284.1263, Found
284.1272.
Experimental procedure for the transformation of amides into ketones:
Procedure for the Scheme 2: Reaction of different amides with phenylmagnesium bromide:
Protected and unprotected benzamide (1 mmol) was stirred in dry THF (3 mL) under argon at -0
°C to which a solution of phenylmagnesium bromide (1.0 mL, 1M Sol. in THF, 1 equiv.) was
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