Identifying Amidyl Radicals for Intermolecular C-H Functionalizations

Article abstract of DOI:10.1021/acs.joc.9b01774

Recent studies have demonstrated the capabilities of amidyl radicals to facilitate a range of intermolecular functionalizations of unactivated, aliphatic C-H bonds. Relatively little information is known regarding the important structural and electronic features of amidyl and related radicals that impart efficient reactivity. Herein, we evaluate a diverse range of nitrogen-centered radicals in unactivated, aliphatic C-H chlorinations. These studies establish the salient features of nitrogen-centered radicals critical to these reactions in order to expedite the future development of new site-selective, intermolecular C-H functionalizations.

Full text of DOI:10.1021/acs.joc.9b01774

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Article
Identifying Amidyl Radicals for Intermolecular C–H Functionalizations
Matthew M. Tierney, Stefano Crespi, Davide Ravelli, and Erik J. Alexanian
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01774 • Publication Date (Web): 23 Aug 2019
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The Journal of Organic Chemistry
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Identifying Amidyl Radicals for Intermolecular C–H Function-
alizations
Matthew M. Tierney,‡ Stefano Crespi,§ Davide Ravelli,† and Erik J. Alexanian‡*
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‡ Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, United States
§ Present address: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Nether-
lands
† PhotoGreen Lab, Department of Chemistry, University of Pavia, viale Taramelli 12, 27100 - Pavia, Italy
Supporting Information Placeholder
ABSTRACT: Recent studies have demonstrated the capabilities of amidyl radicals to facilitate a range of intermolecular functionaliza-
tions of unactivated, aliphatic C–H bonds. Relatively little information is known regarding the important structural and electronic
features of amidyl and related radicals that impart efficient reactivity. Herein, we evaluate a diverse range of nitrogen-centered radicals
in unactivated, aliphatic C–H chlorinations. These studies establish the salient features of nitrogen-centered radicals critical to these
reactions in order to expedite the future development of new site-selective, intermolecular C–H functionalizations.
INTRODUCTION
We have recently demonstrated the ability of N-
functionalized amides to achieve site-selective, intermolecular
radical-mediated C–H functionalizations27–30. Both N-halo and
N-xanthylamides are useful precursors of amidyl radicals, which
using either photochemical or radical initiation undergo HAT
with a diverse array of organic substrates (Figure 1). These ali-
phatic C–H functionalizations facilitate the introduction of a
range of molecular functionality in concise fashion. Our initial
efforts have used reagents derived from bulky N-t-Bu amides,
which combined with the electrophilicity of the amidyl radical
favor functionalization at sterically accessible, electron-rich C–
H sites.
The functionalization of aliphatic C–H bonds using a variety
of strategies has become a valuable tool in chemical synthesis.1–3
For example, C–H functionalization provides facile access to
molecular analogs of drugs with modified physicochemical and
biological properties.4 A classical approach to C–H functionali-
zation involves the use of heteroatom-centered radicals in in-
tramolecular hydrogen-atom transfer (HAT) processes5–8 (Figure
1). Recent efforts by Suarez9, Du Bois10,11, Nagib12, and others13–
23
have utilized this intramolecular HAT strategy to unlock
practical C–H functionalizations of diverse substrates.
Pioneering work by Minisci24, Greene25, and Deno26 demon-
strated the potential for intermolecular aliphatic C–H func-
tionalizations using nitrogen-centered radicals. The develop-
ment of practical synthetic reactions of this type, however, in-
volves several difficult challenges that must be addressed. For
example, these processes do not benefit from the kinetic ad-
vantages of intramolecular HAT. Furthermore, the highly reac-
tive nature of heteroatom-centered radicals could lead to poor
The modularity of the amide scaffold is amenable to the de-
velopment of alternative reagents in this class. Indeed, we have
begun work in this area via the modification of the aromatic
substituent to increase the sterically-dictated selectivity of our
system30. There is little known concerning the requirements
and limitations of the N-functionalized amide (or related) rea-
gents in promoting efficient intermolecular C–H functionaliza-
tion, however (Figure 2). Herein, we report a detailed analysis
of amidyl radical reactivity for intermolecular HAT, focusing on
aliphatic C–H chlorination. These experimental and computa-
tional studies outline several key components of the amide
scaffold important in developing intermolecular HAT process-
es, and identify several possible side reactions that are problem-
atic with unsuccessful reactions of nitrogen-centered radicals.
reaction site- and chemoselectivity.
Intramolecular C–H functionalization via 1,5-HAT: a remarkably useful manifold
1,5-HAT and
radical trap
activation and
radical initiation
R
R
R
N
H
N
N
H
H
H
X
diverse range of
viable substrates
nitrogen-centered radical
Intermolecular C–H functionalization via hydrogen atom transfer from functionalized amides:
emerging general approach
O
F3C
tBu
N
S
One Step Access to:
OEt
C–H allyation
C–H vinylation
C–H azidation
S
OEt
CF3
1 equiv
S
S
C–H deuteration
C–H hydroxylation
C–H thiolation
C–H trifluoromethylthiolation
blue LEDs
(+)-longifolene
1 equiv
54% isolated yield
Figure 2. Elements of nitrogen-centered radicals addressed in these
studies.
Figure 1. Intra- and intermolecular aliphatic C–H functionaliza-
tion using nitrogen–centered radicals.

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RESULTS AND DISCUSSION
moderate yield (39% yield, entry 8). We note that PhCF3 is the
1
2
3
4
5
6
7
8
solvent of choice, as non–aromatic solvents with abstractable
C–H bonds are not tolerated (See Table S1). For example, the
use of common organic solvents such as 1,2-dichloroethane
revealed significant amounts of 1,1,2-trichloroethane, confirm-
ing C–H chlorination of the solvent.
We commenced our studies by evaluating the C–H chlorina-
tion of (+)–sclareolide as a test substrate with a range of N-
chloroamides containing varied N-alkyl substitution (Table 1).
Our previously reported chlorination of this substrate using N-
tBu amide 2a proceeded in good yield (entry 1, 75%) with ex-
cellent site selectivity and served as our baseline result. Surpris-
ingly, only a slight variation in the chloroamide structure—using
N-iPr amide 2b—led to a far inferior reaction providing only 8%
of the chlorination product 3 (entry 2). Similar primary,
branched, and non-branched N-alkyl chloroamides also dis-
played poor reactivity (entries 3-6). The N-trifluoroethyl amide
2g—which we previously reported was capable of functionalizing
cyclohexane27—also provided very little product (entry 7). At-
tempts using an ester derivative containing a fully substituted -
carbon similar to reagent 2a provided 3 in good yield (entry 8).
However, once again removing full alkyl substitution from the
-substituent completely shut down reactivity (entry 9). We
note that N-aryl amides were not investigated owing to the low
N–H bond strength, preventing an energetically favorable C–H
abstraction.31
Table 2. C–H chlorination of (+)–sclareolide varying N-tBu
chloroamide electronics.
O
O
O
Me
9
Me
Me
Me
R
N
2 x 10 mol % BPO
Me
Me
+
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60
O
O
Cl
Cl
yield (%)a
75
0.5 eq Cs2CO3
PhCF3, 65oC
Me
Me
1 equiv
1
3
N-tBu chloroamide
entry
1
O
F3C
N
Cl
CF3
2a
F
O
F
F
N
2
75
Cl
F
F
Table 1. C–H chlorination of (+)–sclareolide varying chloro-
amide N–alkyl substitution.
2j
O
O
N
O
O
Me
Me
Me
F3C
R
Me
Cl
N
2 x 10 mol % BPO
Me
Me
X
+
O
O
Cl
Cl
0.5 eq Cs2CO3
PhCF3, 65oC
X = NO2 (2k)
F (2l)
3
4
5
6
7
66
67
68
21b
58
Me
Me
1 equiv
1
3
CF3
H (2m)
N-alkyl chloroamide
yield (%)a
entry
OMe (2n)
tBu (2o)
R = tBu (2a)
iPr (2b)
Et (2c)
Me (2d)
nPr (2e)
iBu (2f)
O
1
2
3
4
5
6
75
8
O
F3C
N
<2
8
<2b
8
39
F
F
Cl
2p
a
<2b
Reactions were performed with [1]0 = 0.5 M. Isolated yields.
bChlorination on the methoxy substituent observed by 1H NMR.
Ar
N
CF3
7
5
Lastly, we investigated the efficiency of C–H chlorination us-
ing several other classes of N-chloro reagents (Figure 3). In addi-
tion to N-chloroamide 2a, N-chlorosulfonamide 2q provided
product 3 in moderate yield (53%). Reactions involving the N-
chlorophosphoramide 2r and N-chlorocarbamate 2s also deliv-
ered product, although both reactions proceeded with incom-
plete conversion. The use of common chlorinating agent N-
chlorophthalimide provided no product. These results are con-
sistent with the requirement of strong parent N–H bonds (i.e.,
>100 kcal/mol) for the C–H chlorination reagents. Our calcu-
lated N–H BDE for the parent amide of 2a is 110.7 kcal/mol,
and those for reagents 2r and 2s are estimated to be within a 3
kcal/mol range of this value.32 According to our calculations,
the N–H BDE of the parent sulfonamide for 2q is 7.2 kcal/mol
weaker than that of 2a but still relatively strong (103.5
kcal/mol). The N–H BDE of phthalimide is only 89 kcal/mol
making C–H abstraction significantly endergonic.33
Cl
2g
O
O
Me
Me
Ar
N
CO2Me
8
9
65
<2
Cl
2h
Me
Ar
N
CO2Me
Cl
2i
Reactions were performed with [1]0 = 0.5 M. aYields determined
by 1H NMR spectroscopy of crude reaction mixture using an inter-
b
nal standard. Minor chlorination of the N-alkyl group was ob-
served by 1H NMR.
We next studied the effect of electronic modification of the
aryl substituent of N-tBu chloroamide 2a on the C–H chlorina-
tion (Table 2). A range of aryl substituents were permitted, with
the exception of p-OMe amide (2n) likely owing to the ab-
stractable C–H bonds of the methoxy group. There is no clear
electronic preference for the aryl substituent, as the electron
poor aryl substituted 2k and 2l (66% and 67% yield, respective-
ly) performed similarly to unsubstituted reagent 2m (68% yield,
entry 5). Furthermore, the aryl group is not required, as a rea-
gent containing a perfluoroalkyl groups (2p) also provided 3 in
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O
O
Me
Me
Me
Me
2 x 10 mol % BPO
Me
Me
1 equiv reagent
+
O
O
0.5 eq Cs2CO3
PhCF3, 65oC
Cl
Me
Me
2
1
3
3
4
5
6
7
8
9
O
O
O
O
P
F3C
S
F3C
N
N
PhO
PhO
N
Cl
Cl
Cl
CF3
CF3
75% yield
2q
2a
2r
34% yielda
x
53% yield
parent N–H BDE =
110.7 kcal/mol
parent N–H BDE =
103.5 kcal/mol
O
Figure 4. Spin density plots for: a) N-t-Bu and b)  and  conform-
ers of N-i-Pr amidyl radicals, along with some relevant geometric
parameters. Spin densities for O, C7 and N have been reported in
red. These data have been obtained from calculations at the
UwB97XD/def2svp level in the gas phase.
O
N
Cl
Cl3C
O
N
10
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Cl
O
2s
2t
<2% yield
32% yielda
parent N–H BDE =
89.1 kcal/mol
In order to study the electronics of the two amidyl radicals in
further detail, we performed a dedicated NBO (natural bond
order) analysis.35 This approach determines the contribution of
the second-order perturbation stabilization terms (E(2)) and the
orbitals involved in them, shedding light on specific stereo-
chemical interactions. It has recently been demonstrated to
provide reliable estimates in predicting the reactivity of species
with diradical transition state character.36 As depicted in Figure
5, the N-i-Pr amidyl radical achieves more stabilization via both
n→* and →n interactions with the C=O group than the N-t-
Bu amidyl radical. This behavior can also be appreciated com-
paring the percentage of  character of the orbital of the N
radical.
Figure 3. Intermolecular C–H chlorination using alternative elec-
tron-poor nitrogen–centered radicals. Incomplete conversion of
the reagent observed, see the Supporting Information for more
details.
a
We next examined the structures of the N-tBu and N-iPr
amidyl radicals computationally to glean any insights into the
remarkable difference in reaction efficiency–85% yield versus
8% yield, respectively–involving these species (Figure 4). While
the C–O and C–N bond lengths of the amidyl radicals are al-
most identical (<0.001 Å difference), the bulkier t-Bu group
induces a more pronounced ―twisting‖ effect of the N-tBu
amidyl. The nitrogen substituent is markedly displaced out of
the plane of the carbonyl group, with a –49° OC7NC10 dihedral
in the case of the N-t-Bu amidyl radical. On the other hand, two
different conformers ( and ; see Figure S4 for the complete
potential energy surface scan) with an almost identical energy
content. Nevertheless, both conformers of the N-iPr analogue
show a less pronounced twisting (–32° and –49° OC7NC10 di-
hedral angle, for  and , respectively). This disparity affects
the distribution of spin density of the radicals, with a larger
share of radical character localized on the nitrogen atom in the
N-tBu amidyl radical, with more spin density located on oxygen
in the N-iPr analogue.34
Figure 5. Stabilization energies and orbital analysis obtained from
the interactions of the N-iPr (the analysis of both conformers has
been reported) and N-tBu amidyl radicals with  and * orbitals of
the neighbouring C=O calculated with the NBO6 software at the
B97X-D/def2-SVP level of theory.
O
2
Given the overall structural and electronic similarities of the
N-tBu and N-iPr amidyl radicals, combined with the similar
parent amide N–H bond strengths,31 we considered other pos-
sibilities to explain the much greater efficiency of the N-tBu
reagents in C–H functionalization. It is clear from Table 1 that
the presence of -C–H bonds on the N-alkyl group leads to a
dramatic decrease in reaction yield. A hypothesis that is con-
sistent with this trend is undesired C–H abstraction on the N-
alkyl group occurring in preference to reaction with the sub-
strate (Scheme 1). This side product pathway would consume
N-chloroamide while providing no C–H chlorination product.
The -C–H abstraction of amines is well-documented,37 while
that of amides is much less known. The reported -C–H BDE
of N-iPr acetamide is 93 kcal/mol, making the HAT from the
radicals studied herein exergonic.28
1
F3C
N
7
10
3
4
6
5
CF3
O
7
2
1
6
F3C
N
10
3
4
5
CF3
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documented entropic component of HAT processes.38 The C–
1
2
3
4
5
6
7
8
H chlorination of (+)-sclareolide requires HAT at a single meth-
ylene site, in direct contrast to cyclohexane. This difference in
the kinetic profile enables side reactions to become much more
problematic in the functionalization of complex substrates,
requiring judicious reagent selection.
Scheme 1. Proposed undesired -C–H abstraction pathways of
N-alkyl chloroamides.
O
a)
O
Cl
F3C
R
10 mol % BPO
R
N
Ar
N
H
+
Cl
0.5 eq Cs2CO3
PhCF3, 65oC
CF3
9
1 equiv
1 equiv
R = t-Bu
R = i-Pr
10
11
12
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60
100
50
In order to observe potential products of N-alkyl group func-
tionalization, we performed reactions in the absence of sub-
strate (Figure 6). The reaction of N-chloroamide 2b with benzo-
yl peroxide yielded products with a strong high-resolution mass
spectrometry signal at m/z = 258.03461 (exact mass calculated
for C9H6F6N1O1 [M+H]+ = 258.034789) indicating the for-
mation of primary amide 4, which could result from chlorina-
tion of the iPr group followed by cleavage. We also subjected N-
methyl chloroamide 2d to standard photochemical reaction
conditions, to remove the possibility of HAT involving the
radical initiator. In this case, we observed the production of
presumed -chloro N-methyl amide 5, albeit in low yield (10%).
While the chemical yields of products 4 and 5 are modest, they
could still play a significant role by decreasing the effective
length of the radical chain process involved in the C–H func-
tionalization.
0
0
1
2
3
4
5
6
7
Time (hr)
O
b)
F3C
R
Cl
2 x 10 mol % BPO
N
+
Cl
0.5 eq Cs2CO3
PhCF3, 65oC
16 hr
CF3
R = t-Bu: 63% NMR yield
R = i-Pr: 48% NMR yield
1 equiv
1 equiv
Figure 7. a) Conversion of the C–H chlorination of cyclohex-
ane and N-chloroamide using reagents 2a and 2b at different
time points. b) C–H chlorination of cyclohexane with N-
chloroamide 2a and 2b at 16 hours with sequential additions of
peroxide initiator
O
O
Finally, we investigated the effect of either the N-t-Bu or the
N-i-Pr parent amide on the efficiency of the (+)-sclareolide chlo-
rination using 2a (Figure 8). As the C–H chlorination is stoi-
chiometric in N-chloroamide, these amides are present in sig-
nificant amounts throughout the course of the reaction. When
the successful reaction using 2a (75%, Table 1, entry 1) is per-
formed in the presence of 0.5 equiv of the parent N-t-Bu amide,
only a slight decrease in yield is observed (70%). On the other
hand, the addition of 0.5 equiv of the N-i-Pr amide significantly
lowers the reactions efficiency (16%). We also observed a 35%
yield of N-chloroamide 2b in this reaction from chlorine atom
transfer from 2a. Additionally, the rate of C–H functionaliza-
tion decreased when 0.5 equivalents of the N-i-Pr amide were
added to reaction of cyclohexane with 2b. These results are
consistent with the N-i-Pr amide participating in the same non-
productive pathways previously described, significantly lowering
the yield of 3.
F3C
F3C
50 mol % BPO
N
NH2
0.5 eq Cs2CO3
PhCF3, 65oC
Cl
CF3
CF3
4
2b
observed by ESI(+) HRMS
O
O
F3C
F3C
2 x 23 W CFL
N
Cl
N
H
0.5 eq Cs2CO3
C6D6, 65oC
Cl
CF3
10% 1H NMR yield
CF3
5
2d
Figure 6. Evidence of -C–H abstraction of the N-alkyl substit-
uent.
We next studied the kinetics of the C–H chlorination of cy-
clohexane using N-tBu chloroamide 2a and N-iPr chloroamide
2b (Figure 7a). In these experiments, cyclohexane was chosen as
substrate owing to the significantly higher yield with 2b. These
studies revealed significant differences in reaction rates, with N-
tBu reagent 2a reacting faster at each time point. For example,
at 7 h the conversion of 2a is 93%, whereas that of 2b is only
23%. This is consistent with a much more efficient chain pro-
cess using reagent 2a versus 2b. At longer reaction times and
additional peroxide initiator, conversion of N-iPr chloroamide
2b is significant, while the yield of chlorocyclohexane is moder-
ately lower than N-tBu reagent 2a (Figure 7b). We note that the
large difference in reaction yields between (+)-sclareolide (8%)
and cyclohexane (48%) using 2b is consistent with the well-
O
O
Me
F3C
Me
N
Me
+
O
Cl
O
Me
Me
Me
2a
1 equiv
standard
conditions
CF3
Me
O
O
Cl
F3C
R
N
H
Me
+
3
R = t-Bu: 70% NMR yield
R = i-Pr: 16% NMR yield
0.5 equiv
CF3
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Figure 8. C–H chlorination of (+)-sclareolide in the presence of plates provided by Silicycle. Visualization was accomplished
1
2
3
4
5
6
7
8
with short wave UV light (254 nm), iodine, aqueous basic po-
tassium permanganate solution, or aqueous acidic ceric ammo-
nium molybdate solution followed by heating. Flash chroma-
tography was performed using SiliaFlash P60 silica gel (40-63
μm) purchased from Silicycle. Tetrahydrofuran, diethyl ether,
and dichloromethane were dried by passage through a column
of neutral alumina under nitrogen prior to use.
N-t-Bu and N-i-Pr amides.
The requirement for fully substituted -positions on the N-
alkyl sidechain of functionalized amides reduces the possibili-
ties to diversify these reagents for C–H functionalization. In
order to address this issue, we examined the use of a more hin-
dered aromatic scaffold. We have recently reported the en-
hanced steric selectivity of C–H functionalizations using 2,6-bis-
trifluoromethyl N-t-Bu amides.30 We hypothesized that the sig-
nificantly increased steric profile of this derivative could miti-
gate undesired side reactions (i.e., -C–H abstraction). The
reaction of 2,6-bis-trifluoromethyl N-i-Pr chloroamide 2u with
(+)-sclareolide did provide product 3 in 36% yield (Figure 9),
with up to a 75% yield using excess substrate (3 equiv). For
comparison, the reaction with N-i-Pr reagent 2b under the same
conditions produced only 8% of product. These results suggest
that tuning the steric profile of the amidyl radical can permit
the use of N-substituents which otherwise would have little
chance of success.
General Procedure for C–H chlorination of (+)–sclareolide
using N-chloro reagents 2a – 2u: A flame-dried 1 dram vial was
charged with a stir bar and brought into the glove where sub-
strate (0.15 mmol, 1 equiv), BPO (0.015 mmol, 10 mol %),
cesium carbonate (0.075 mmol, 0.5 equiv), PhCF3 (0.3mL, 0.5
M), and N-chloro reagent (0.15 mmol, 1.0 equiv) were added.
The reaction was capped with a PTFE lined screw cap, sealed
with Teflon tape, taken out of the glovebox, and stirred at 65
°C on a heating mantle with a pie block for 7 hours. After cool-
ing to room temperature, the reaction was brought back into
the glovebox where BPO (0.015 mmol, 10 mol %) was added.
The reaction was capped and resealed with Teflon tape, taken
out of the glovebox, heated to 65 °C on the pie block, and
stirred for an additional 17 hours. Upon completion, the reac-
tion mixture was then filtered through a silica plug, concentrat-
ed down in vacuo, and analyzed by NMR using 10.0 μL hexa-
methyldisiloxane as an internal standard.
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22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CF3
O
Me
Me
O
Me
O
Me
Me
Me
Me
Me
2 x 10 mol % BPO
N
+
O
O
Cl
0.5 eq Cs2CO3
PhCF3, 65oC
Cl
Me
Me
CF3
1
2u
3
34% 1H NMR yield
3 equiv 1: 75% 1H NMR yield
3 equiv 2b: 8% 1H NMR yield
1 equiv
General Procedure A for amide synthesis: Prepared similarly to
previous reports from our lab.24 To a solution of benzoic acid (10
mmol, 1 equiv) in CH2Cl2 and a few drops of at C was
added oxalyl chloride (20 mmol, 2 equiv) dropwise, and the result-
ing solution was allowed to warm to rt overnight. The mixture was
concentrated in vacuo, resuspended in THF, and chi ed to C.
Amine (20 mmol, 2 equiv) was added, and the mixture was
warmed to room temperature and stirred overnight. The mixture
was concentrated in vacuo and the residue suspended in Et2O and
washed with 3M NaOH, 1M HCl, brine, dried with MgSO4 and
concentrated to afford the corresponding amide which was used
without purification.
Figure 9. C–H chlorination of (+)-sclareolide with an N-i-Pr
chloroamide containing sterically demanding aryl substitution.
In conclusion, these studies provide a set of guidelines for
the design of reagents for intermolecular C–H functionalization
using N-functionalized amides and derivatives. High effective
N–H BDEs (>100 kcal/mol) are necessary to promote HAT of
unactivated C–H bonds, and amides are desirable in this re-
gard. Most importantly, reagents containing -C–H bonds in
the N-substituent can lead to sharply decreased efficiencies of
intermolecular C–H functionalization. Increasing the steric
profile of the aryl substituents can overcome this issue and
permit further reagent diversification. We expect this work will
support further reagent development in intermolecular radical-
mediated aliphatic C–H functionalization in the future.
N-(tert-butyl)-3,5-bis(trifluoromethyl)benzamide. Obtained as
a white powder according to General Procedure A. Spectral
data matched literature values.24
N-isopropyl-3,5-bis(trifluoromethyl)benzamide. Obtained as a
white powder according to General Procedure A. Spectral data
matched literature values39
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all reagents
were obtained from commercial sources and used without fur-
ther purification unless otherwise noted. Proton and carbon
magnetic resonance spectra (1H NMR and 13C NMR) were rec-
orded on a Bruker model DRX 400, or a Bruker AVANCE III
600 CryoProbe (1H NMR at 400 or 600 MHz and 13C NMR at
100 or 151 MHz) spectrometer with solvent resonance as the
internal standard (1H NMR: CDCl3 at 7.26 ppm; 13C NMR:
N-ethyl-3,5-bis(trifluoromethyl)benzamide. Obtained as
a
1
white powder according to General Procedure A. H NMR
(600 MHz, Chloroform-d): δ 8.24 (d, J = 1.5 Hz, 2H), 8.01 (s,
1H), 6.45 (s, 1H), 3.61 – 3.51 (m, 2H), 1.32 (td, J = 7.3, 1.3 Hz,
3H). 13C{1H} NMR (151 MHz, Chloroform-d): δ 164.5, 132.2
(q, J = 33.3, 32.9 Hz), 127.3, 125.4 – 123.8 (m), 122.0, 35.4,
14.8. HRMS (ESI+): Exact mass calcd for C11H10N1O1F6
[M+H]+, 286.0661. Found 286.0658.
1
CDCl3 at 77.16 ppm). H NMR data are reported as follows:
N-methyl-3,5-bis(trifluoromethyl)benzamide. Obtained as a
white powder according to General Procedure A. H NMR
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q
= quartet, dd = doublet of doublets, ddd = doublet of doublet
of doublets, td = triplet of doublets, tdd = triplet of doublet of
doublets, qd = quartet of doublets, m = multiplet, br. s. = broad
singlet, app = apparent), coupling constants (Hz), and integra-
tion. Mass spectra were obtained using a ThermoScientific Q
Exactive HF-X Hybrid Quadrapole-Orbitrap with electrospray
introduction and external calibration. Thin layer chromatog-
raphy (TLC) was performed on SiliaPlate 250μm thick silica gel
1
(600 MHz, Chloroform-d): δ 8.07 (s, 2H), 8.01 (s, 1H), 3.51 (s,
3H). 13C{1H} NMR (151 MHz, Chloroform-d): δ 169.5, 135.5,
131.9 (q, J = 34.1 Hz), 128.4 (d, J = 4.1 Hz), 124.6, 122.8 (d, J =
272.9 Hz), 42.5. HRMS (ESI+): Exact mass calcd for
C10H8N1O1F6 [M+H]+, 272.0504. Found 272.0507.
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N-propyl-3,5-bis(trifluoromethyl)benzamide Obtained as
a
(q, J = 32.0 Hz), 123.1 (q, J = 274.6 Hz), 42.4, 22.2. HRMS
(ESI+): Exact mass calcd for C12H12N1O1F6 [M+H]+,
300.0817. Found 300.0815.
Procedure for synthesis tert-
1
1
2
3
4
5
6
7
8
white powder according to General Procedure A. H NMR
(600 MHz, Chloroform-d): δ 8.23 (s, 2H), 8.02 (s, 1H), 6.37 (s,
1H), 3.49 (dt, J = 7.4, 5.9 Hz, 2H), 1.71 (m, J = 7.3 Hz, 2H),
1.03 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz, Chloroform-
d): δ 164.7, 136.8, 132.1 (q, J = 34.0 Hz), 127.3 (q, J = 3.7 Hz),
125.4 – 124.3 (m), 126.3 – 115.5 (m), 42.2, 22.8, 11.4. HRMS
(ESI+): Exact mass calcd for C12H12N1O1F6 [M+H]+,
300.0817. Found 300.0819.
of
diphenyl
butylphosphoramidate: Prepared similarly to previous reports
in the literature. A solution of diphenyl chlorophosphate (10
mmol, 1 equiv) in CH2Cl2 (25 mL) was cooled in an ice bath. t-
Butylamine (25 mmol, 2.5 equiv) was added dropwise, and the
mixture was warmed to rt and stirred overnight. The mixture
was washed with sat. NaHCO3, 1M HCl, brine, dried with
MgSO4 and concentrated to afford the corresponding phospho-
ramidate as a white solid (3.0 g, 98% yield), which was used
N-isobutyl-3,5-bis(trifluoromethyl)benzamide Obtained as a
9
1
white powder according to General Procedure A. H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(500 MHz, Chloroform-d): δ 8.01 (s, 2H), 8.00 – 7.99 (s, 1H),
3.63 (d, J = 7.3 Hz, 2H), 2.30 (dp, J = 13.7, 6.9 Hz, 1H), 1.00
(d, J = 6.7 Hz, 5H). 13C{1H} NMR (101 MHz, Chloroform-d): δ
164.7, 136.9, 132.4 (t, J = 33.9 Hz), 127.2, 125.4 – 123.0 (m),
121.6, 47.8, 28.6, 20.2. HRMS (ESI+): Exact mass calcd for
C13H14N1O1F6 [M+H]+, 314.0974. Found 314.0976.
1
without purification. H NMR (600 MHz, Chloroform-d): δ
7.35 (t, J = 7.4 Hz, 4H), 7.30 – 7.24 (m, 6H), 7.17 (t, J = 7.3 Hz,
4H), 3.01 (s, 1H), 1.38 (d, J = 1.9 Hz, 9H). 13C{1H} NMR (151
MHz, Chloroform-d): δ 151.1 (d, J = 7.1 Hz), 129.6, 124.7,
120.2 (d, J = 5.1 Hz), 51.8, 31.3 (d, J = 4.9 Hz). HRMS (ESI+):
Exact mass calcd for C16H21N1O3P1 [M+H]+, 306.1254.
Found 306.1247.
N-(2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzamide.
Obtained as a white powder according to General Procedure A.
Spectral data matched the reported literature values27
Procedure
bis(trifluoromethyl)benzenesulfonamide: Prepared similarly to
previous reports in the literature. solution of 3,5-
bis(trifluoromethyl)benzenesulfonyl chloride (15 mmol,
for
synthesis
of
N-(tert-butyl)-3,5-
Methyl
2-(3,5-bis(trifluoromethyl)benzamido)-2-
A
methylpropanoate. Obtained as a white powder according to
1
1
General Procedure A. H NMR (500 MHz, Chloroform-d): δ
equiv) in CH2Cl2 was cooled in an ice bath. t-Butylamine (38
mmol, 2.5 equiv) was added dropwise, and the mixture was
warmed to rt and stirred overnight. The mixture was washed
with sat. NaHCO3, 1M HCl, brine, dried with MgSO4 and
concentrated to afford the corresponding sulfonamide as a
white solid (5.0 g, 95% yield) which was used without purifica-
tion. 1H NMR (600 MHz, Chloroform-d): δ 8.36 (s, 2H), 8.07
(s, 1H), 4.81 (s, 1H), 1.30 (s, 9H). 13C{1H} NMR (151 MHz,
Chloroform-d): δ 146.1, 132.8 (q, J = 34.3 Hz), 127.2 (d, J =
3.9 Hz), 122.5 (q, J = 273.3 Hz), 55.8, 30.2. HRMS (ESI-): Ex-
act mass calcd for C12H12F6N1O2S [M–H]-, 348.0487. Found
348.0487.
8.25 (s, 1H), 8.04 (s, 1H), 6.95 (s, 1H), 3.84 (s, 3H), 1.75 (s,
6H). HRMS (ESI+): Exact mass calcd for C14H14F6N1O3,
358.0872. Found 358.0865.
Methyl (3,5-bis(trifluoromethyl)benzoyl)alaninate. Obtained
as a white powder according to General Procedure A. Spectral
data matched the reported literature values40
N-(tert-butyl)-2,3,4,5,6-pentafluorobenzamide. Obtained as a
1
white powder according to General Procedure A. H NMR
(600 MHz, Chloroform-d): δ 5.70 (s, 1H), 1.49 (s, 9H). 13C{1H}
NMR (151 MHz, Chloroform-d): δ 156.3, 145.9 – 140.6 (m),
139.3 – 134.4 (m), 112.7 (t, J = 20.4 Hz), 53.2, 28.9. 19F NMR
(564 MHz, Chloroform-d): δ -139.1 – -143.2 (m), -151.8 (d, J =
20.4 Hz), -158.0 – -161.5 (m). HRMS (ESI+): Exact mass calcd
for C11H11N1O1F5 [M+H]+, 268.0755. Found 268.0755.
Procedure for synthesis of 2,2,2-trichloroethyl tert-
butylcarbamate: Prepared similarly to previous reports in the
literature. A solution of 2,2,2-trichloroethyl chloroformate (10
mmol, 1 equiv) in CH2Cl2 was cooled in an ice bath. t-
Butylamine (25 mmol, 2.5 equiv) was added dropwise, and the
mixture was warmed to rt and stirred overnight. The mixture
was washed with sat. NaHCO3, 1M HCl, brine, dried with
MgSO4 and concentrated to afford the corresponding carba-
mate as a colorless amorphous solid (2.2 g, 89% yield), which
N-(tert-butyl)-4-nitrobenzamide. Obtained as a white powder
according to General Procedure A. Spectral data matched the
reported literature values41
N-(tert-butyl)-4-fluorobenzamide. Obtained as a white powder
according to General Procedure A. Spectral data matched the
reported literature values41
1
was used without purification. H NMR (600 MHz, Chloro-
N-(tert-butyl)-benzamide. Obtained as a white powder accord-
ing to General Procedure A. Spectral data matched the report-
ed literature values42
form-d): δ 4.94 (s, 1H), 4.69 (s, 2H), 1.38 (s, 9H). 13C{1H}
NMR (151 MHz, Chloroform-d): δ 152.6, 95.9, 73.9, 50.9,
28.7. HRMS (ESI+): Exact mass calcd for C7H12Cl3N1O1
[M+H]+, 248.0006. Found 248.0007.
N-(tert-butyl)-4-methoxybenzamide. Obtained as a white pow-
der according to General Procedure A. Spectral data matched
the reported literature values41
Procedure
pentafluoropropanamide:
for
synthesis
of
solution
N-(tert-butyl)-2,2,3,3,3-
of 2,2,3,3,3-
A
N,4-di-tert-butylbenzamide. Obtained as a white powder ac-
cording to General Procedure A. Spectral data matched the
reported literature values41
pentafluoropropionic anhydride (11 mmol, 1.1 equiv) in
CH2Cl2 (75 mL) was cooled in an ice bath. t-Butylamine (10
mmol, 1 equiv) and triethylamine (12 mmol, 1.2 equiv) were
carefully added dropwise [caution: reaction is very exothermic]. The
mixture was then warmed to rt and stirred overnight. The mix-
ture was washed with water, sat. NH4Cl, brine, dried with
MgSO4 and concentrated to afford the corresponding amide as
a yellow liquid (1.9 g, 89% yield), which was used without puri-
N-isopropyl-2,6-bis(trifluoromethyl)benzamide. Obtained as
1
colorless crystals according to General Procedure A. H NMR
(600 MHz, Chloroform-d): δ 7.93 (d, J = 8.0 Hz, 2H), 7.68 (t, J
= 8.0 Hz, 1H), 5.58 (s, 1H), 4.37 (m, J = 6.6 Hz, 1H), 1.28 (d, J
= 6.6, 1.7 Hz, 6H). 13C{1H} NMR (151 MHz, Chloroform-d): δ
163.1, 134.5 (d, J = 1.8 Hz), 129.9 (q, J = 4.9 Hz), 129.6, 129.2
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1
fication. H NMR (600 MHz, Chloroform-d): δ 6.18 (s, 1H),
1.44 (s, 9H). 13C{1H} NMR (151 MHz, Chloroform-d): δ 156.6
(t, J = 24.6 Hz), 121.4 – 115.2 (m), 105.6 (dd, J = 266.7, 38.5
Hz), 53.0, 28.2. 19F NMR (564 MHz, Chloroform-d) δ -82.9, -
122.7. HRMS (ESI-): Exact mass calcd for C7H9F5N1O1 [M],
218.0610. Found 218.0603.
3H). 13C{1H} NMR (151 MHz, Chloroform-d): δ 168.8, 136.0,
132.0 (q, J = 34.2 Hz), 128.2, 125.51, 124.1 (d, J = 118.1 Hz),
121.9, 49.5, 12.5. HRMS (ES–): Exact mass calcd for
C11H9Cl1F6N1O1 [M+H]+, 320.0282. Found 320.0270.
1
2
3
4
N-chloro-N-methyl-3,5-bis(trifluoromethyl)benzamide (2d) was
obtained as an off-white solid (0.78 g, 51% yield) according to
5
6
7
8
9
General Procedure B for synthesis of N-chloro reagents. Syn-
thesized according to the literature procedure28. To a foil
wrapped flask under N2, amide (5 mmol, 1 equiv) was added
and dissolved in a mixture of ethyl acetate (10 mL) and tert-
butanol (5 mmol, 1 equiv). 10 equivalents of a sodium hypo-
chlorite solution was then added (~1.5M in H2O Sigma-
Aldrich), followed by acetic acid (50 mmol, 10 equiv). The reac-
tion was stirred at room temperature for 3-4 hours. When the
reaction was complete as judged by TLC analysis (3 hours usu-
ally sufficient) the reaction was diluted with Et2O, washed three
times with saturated sodium bicarbonate solution, once with
water, and once with brine. The organic layer was dried with
magnesium sulfate and concentrated under reduced pressure.
The crude material usually contains traces of chlorinated ethyl
acetate. The crude product was purified via column chromatog-
raphy (EtOAc/Hexane) to give the desired product. General
storage: N-Chloro reagents were stored in foil-wrapped vials in the
freezer when not in use. The reagents can be weighed out on the bench
top without risk of decomposition.
General Procedure B (5.0 mmol). Purified using 1:10
1
EtOAc/hexanes. H NMR (600 MHz, Chloroform-d): δ 8.07
(s, 2H), 8.01 (s, 1H), 3.51 (s, 3H). 13C{1H} NMR (151 MHz,
Chloroform-d): δ 169.5, 135.5, 131.9 (q, J = 34.1 Hz), 128.4 (d,
J = 4.1 Hz), 124.6, 122.8 (q, J = 272.9), 42.5. HRMS (ES–):
Exact mass calcd for C10H7Cl1F6N1O1 [M+H]+, 306.0126.
Found 306.0116.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-chloro-N-propyl-3,5-bis(trifluoromethyl)benzamide (2e) was
obtained as a pale yellow oil (1.68 g, 98% yield) according to
General Procedure
B (5.0 mmol). Purified using 1:20
1
EtOAc/hexanes. H NMR (500 MHz, Chloroform-d): δ 8.02
(s, 2H), 8.00 (s, 1H), 3.81 – 3.72 (m, 2H), 1.85 (h, J = 7.4 Hz,
2H), 0.99 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (151 MHz, Chloro-
form-d): δ 169.0, 136.3, 131.9 (q, J = 33.9 Hz), 128.1 (t, J = 3.8
Hz), 126.1 – 117.0 (m), 60.6, 26.7, 19.4. HRMS (ES–): Exact
mass calcd for C12H11Cl1F6N1O1 [M+H]+, 334.0439. Found
334.0429.
N-chloro-N-isobutyl-3,5-bis(trifluoromethyl)benzamide (2f) was
obtained as a pale yellow oil (0.70 g, 40% yield) according to
General Procedure C for synthesis of N-chloro reagents. To a
foil wrapped flask under N2, amide (5 mmol, 1 equiv) was add-
ed and dissolved in a mixture of ethyl acetate (10 mL) and tert-
butanol (5 mmol, 1 equiv). 1 equivalent of a sodium hypo-
chlorite solution was then added (~1.5M in H2O Sigma-
Aldrich), followed by acetic acid (10 mmol, 2 equiv). The reac-
tion was monitored by TLC until all starting material was con-
sumed. When the reaction was complete the solution was di-
luted with Et2O, washed three times with saturated sodium
bicarbonate solution, once with water, and once with brine.
The organic layer was dried with magnesium sulfate and con-
centrated under reduced pressure. The crude material usually
contains traces of chlorinated ethyl acetate. The crude product
was purified via column chromatography (EtOAc/Hexane) to
give the desired product.
General Procedure
B (5.0 mmol). Purified using 1:20
1
EtOAc/hexanes. H NMR (500 MHz, Chloroform-d): δ 8.01
(s, 2H), 8.00 – 7.99 (s, 1H), 3.63 (d, J = 7.3 Hz, 2H), 2.30 (m,
1H), 1.00 (d, J = 6.7 Hz, 6H). 13C{1H} NMR (151 MHz, Chlo-
roform-d): δ 169.0, 136.3, 131.9 (q, J = 33.9 Hz), 128.1 (t, J =
3.8 Hz), 126.1 – 117.0 (m), 60.6, 26.7, 19.4. HRMS (ES–):
Exact mass calcd for C13H13Cl1N1O1F6 [M+H]+, 348.0584.
Found 348.0588.
N-chloro-N-(2,2,2-trifluoroethyl)-3,5-
bis(trifluoromethyl)benzamide (2g) was obtained as an off-
white solid (1.7 g, 91% yield) according to General Procedure B
(5.0 mmol). Purified using 1:20 EtOAc/hexanes. 1H NMR
(600 MHz, Chloroform-d) δ 8.11 (s, 2H), 8.09 (s, 1H), 4.49 (q,
J = 8.1 Hz, 2H). 13C NMR{1H} (151 MHz, Chloroform-d) δ
169.3, 133.9, 132.1 (q, J = 34.3 Hz), 128.5 (q, J = 3.8 Hz), 126.1
– 118.9 (m), 52.8 (q, J = 35.6 Hz). 19F NMR (564 MHz, Chlo-
roform-d): δ -63.1, -69.7. HRMS (ES–): Exact mass calcd for
C11H6Cl1F9N1O1 [M+H]+, 373.9999. Found 373.9989.
N-(tert-butyl)-N-chloro-3,5-bis(trifluoromethyl)benzamide (2a)
was obtained as a pale yellow oil (0.75 g, 86% yield) according
to General Procedure B (2.5 mmol). Purified using 1:20
EtOAc/hexanes. Spectral data are in accordance with the litera-
ture28
Methyl
2-(N-chloro-3,5-bis(trifluoromethyl)benzamido)-2-
methylpropanoate (2h) was obtained as an off-white solid (0.31
g, 63% yield) according to General Procedure B (1.25 mmol).
Purified using 1:20 EtOAc/hexanes. 1H NMR (600 MHz,
Chloroform-d): δ 8.13 (s, 2H), 8.05 – 7.98 (s, 1H), 3.79 (s, 3H),
1.69 (s, 6H). 13C{1H} NMR (151 MHz, Chloroform-d): δ 172.0,
170.9, 135.9, 131.8 (d, J = 34.2 Hz), 127.1 – 119.2 (m), 66.5,
53.0, 23.4. Exact mass calcd for C14H13Cl1F6N1O3 [M+H]+,
392.0493. Found 392.0482.
N-chloro-N-isopropyl-3,5-bis(trifluoromethyl)benzamide (2b)
was obtained as a pale yellow oil (1.5 g, 90% yield) according to
General Procedure
B (5.0 mmol). Purified using 1:20
EtOAc/hexanes. 1H NMR (600 MHz, Chloroform-d): δ 8.07 –
7.96 (m, 3H), 4.77 (m, 1H), 1.36 (d, J = 8.7, 6H). 13C{1H} NMR
(151 MHz, Chloroform-d): δ 168.8, 136.8, 132.8 – 131.0 (m),
128.0, 124.3, 122.8 (q, J = 273.1 Hz), 52.7, 19.7. HRMS (ES–):
Exact mass calcd for C12H11Cl1F6N1O1 [M+H]+, 334.0439.
Found 334.0430.
Methyl N-(3,5-bis(trifluoromethyl)benzoyl)-N-chloroalaninate
(2i) was obtained as an off-white solid (0.95 g, 50% yield) ac-
cording to General Procedure B (5.0 mmol). Purified using
N-chloro-N-ethyl-3,5-bis(trifluoromethyl)benzamide (2c) was
obtained as a pale yellow oil (0.60 g, 75% yield) according to
1
1:20 EtOAc/hexanes. H NMR (500 MHz, Chloroform-d): δ
General Procedure
B (2.5 mmol). Purified using 1:10
8.09 (d, J = 1.7 Hz, 2H), 8.03 (s, 1H), 5.27 (br s, 1H), 3.85 (s,
3H), 1.68 (d, J = 7.0 Hz, 3H). 13C{1H} NMR (151 MHz, Chlo-
roform-d): δ 169.9, 169.5, 135.5, 132.0 (q, J = 34.1 Hz), 128.3
EtOAc/hexanes. 1H NMR (600 MHz, Chloroform-d): δ 8.05
(s, 2H), 8.01 (s, 1H), 3.86 (q, J = 1.4 Hz, 2H), 1.39 (t J = 1.4 Hz,
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(q, J = 3.5 Hz), 125.3 – 124.6 (m), 122.8 (d, J = 273.0 Hz), 57.9,
53.0, 14.7. HRMS (ES–): Exact mass calcd for
C13H11Cl1F6N1O3 [M+H]+, 378.0337. Found 378.0326.
34.1 Hz), 107.7 (tq, J = 274.4, 36.4 Hz), 67.2, 27.7. 19F NMR
(564 MHz, Chloroform-d): δ -81.5, -112.1 – -118.0 (m). HRMS
(ES-): Exact mass calcd for C7H10Cl1F5N1O1 [M+H]+,
254.0365. Found 254.0370.
1
2
3
4
5
6
7
8
N-(tert-butyl)-N-chloro-2,3,4,5,6-pentafluorobenzamide
was obtained as a white solid (1.0 g, 66% yield) according to
General Procedure (5.0 mmol). Purified using 1:20
(2j)
N-(tert-butyl)-N-chloro-3,5-
B
bis(trifluoromethyl)benzenesulfonamide (2q) was obtained as
a colorless solid (0.82 g, 85% yield) without purification accord-
1
EtOAc/hexanes. H NMR (600 MHz, Chloroform-d): δ 1.64
(s, 9H). 13C{1H} NMR (151 MHz, Chloroform-d): δ 156.3,
145.9 – 140.6 (m), 139.3 – 134.4 (m), 112.7 (t, J = 20.4 Hz),
53.2, 28.9. 19F NMR (564 MHz, Chloroform-d) δ -141.7 (d, J =
21.8 Hz), -152.5 (t, J = 20.9 Hz), -158.8 – -161.8 (m). HRMS
(ES–): Exact mass calcd for C11H10Cl1F5N1O1 [M+H]+,
302.0376. Found 302.0365.
1
ing to General Procedure B (2.5 mmol). H NMR (600 MHz,
Chloroform-d) δ 8.46 (s, 2H), 8.14 (s, 1H), 1.60 (s, 9H).
13C{1H} NMR (151 MHz, Chloroform-d): δ 141.1, 132.8 (q, J =
34.8 Hz), 129.1 (q, J = 3.8 Hz), 127.1 (p, J = 3.6 Hz), 122.4 (q, J
= 273.5 Hz), 69.5, 29.3. HRMS (ES+): Exact mass calcd for
C12H13Cl1N1O2S1F6 [M+H]+, 384.0247. Found 384.0254.
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N-(tert-butyl)-N-chloro-4-nitrobenzamide (2k) was obtained as a
Diphenyl tert-butylchlorophosphoramidate (2r) was obtained
white solid (0.31 g, 61% yield) according to General Procedure
as a pale yellow oil (1.7 g, 98% yield) without purification ac-
1
1
B. Purified using 1:20 EtOAc/hexanes (2.0 mmol). H NMR
cording to General Procedure C (5.0 mmol). H NMR (600
(600 MHz, Chloroform-d): δ 8.28 (d, J = 8.8 Hz, 2H), 7.78 (d, J
= 8.8 Hz, 2H), 1.62 (s, 9H). 13C{1H} NMR (151 MHz, Chloro-
form-d): δ 129.1, 123.4, 64.6, 28.0. HRMS (ES+): Exact mass
calcd for C11H14Cl1N2O3 [M+H]+, 257.0698. Found
257.0694.
MHz, Chloroform-d): δ 7.42 – 7.32 (m, 8H), 7.22 (t, J = 8.2
Hz, 2H), 1.45 (s, J = 1.0 Hz, 9H). 13C{1H} NMR (151 MHz,
Chloroform-d): δ 150.6, 129.7, 125.3, 120.4, 63.4, 29.3. 31P
NMR (243 MHz, Chloroform-d): δ -4.97. HRMS (ES+): Exact
mass calcd for C16H20Cl1P1N1O3 [M+H]+, 340.0864. Found
340.0862.
N-(tert-butyl)-N-chloro-4-fluorobenzamide (2l) was obtained as
a white solid (0.50 g, 48% yield) without purification according
2,2,2-trichloroethyl tert-butylchlorocarbamate (2s) was ob-
tained as a colorless oil (0.46 g, 65% yield) according to Gen-
1
to General Procedure B (5.0 mmol). H NMR (600 MHz,
Chloroform-d): δ 7.73 – 7.65 (m, 2H), 7.13 – 7.06 (m, 2H),
eral Procedure
B
(2.5 mmol). Purified using 1:20
1
1.58 (s, 9H). 13C{1H} NMR (151 MHz, Chloroform-d):
δ
EtOAc/hexanes. H NMR (600 MHz, Chloroform-d): δ 4.79
(s, 2H), 1.55 (s, 9H). 13C{1H} NMR (151 MHz, Chloroform-d):
δ 154.5, 94.9, 76.0, 64.5, 28.7. HRMS (ES–): Exact mass calcd
for C7H12Cl4N1O2 [M+H]+, 281.9628. Found 281.9611.
174.6, 165.1, 147.8 (d, J = 4721.3 Hz), 131.0 (d, J = 8.8 Hz),
115.0 (d, J = 21.8 Hz), 78.7 – 74.5 (m), 63.8, 27.9.19F NMR
(564 MHz, Chloroform-d): δ -108.4 (d, J = 10.0 Hz). HRMS
(ES+): Exact mass calcd for C11H14F1Cl1N1O1 [M+H]+,
230.0742. Found 230.0740.
N-chloro-N-isopropyl-2,6-bis(trifluoromethyl)benzamide (2u)
was obtained as a white solid (0.30 g, 45% yield) according to
General Procedure
B (2.5 mmol). Purified using 1:10
N-(tert-butyl)-N-chlorobenzamide (2m) was obtained as a white
solid (0.55 g, 52% yield) according to General Procedure C.
Purified using 1:10 EtOAc/hexanes. 1H NMR (600 MHz,
Chloroform-d): δ 7.68 – 7.64 (m, 2H), 7.50 – 7.46 (m, 1H),
7.42 (dd, J = 8.2, 6.7 Hz, 2H), 1.60 (s, 9H). 13C{1H} NMR (151
MHz, Chloroform-d): δ 175.6, 136.3, 130.9, 128.42, 128.0,
78.3 – 75.4 (m), 63.7, 28.0. HRMS (ES+): Exact mass calcd for
C11H15Cl1N1O1 [M+H]+, 212.0837. Found 212.0834.
1
EtOAc/hexanes. H NMR (600 MHz, Chloroform-d): δ 7.94
(d, J = 8.0 Hz, 2H), 7.74 – 7.67 (m, 1H), 5.21 (p, J = 6.5 Hz,
1H), 1.30 (d, J = 6.5 Hz, 6H). 13C{1H} NMR (151 MHz, Chlo-
roform-d): δ 166.2, 132.8 – 132.1 (m), 130.5 – 129.5 (m),
128.3 (q, J = 32.5 Hz), 123.0 (q, J = 274.7 Hz), 49.9, 19.0.
HRMS (ES–): Exact mass calcd for C12H11Cl1F6N1O1
[M+H]+, 334.0439. Found 334.0426.
N-(tert-butyl)-N-chloro-4-methoxybenzamide (2n) was obtained
ASSOCIATED CONTENT
Supporting Information
as a white solid (0.40 g, 34% yield) according to General Proce-
1
dure C. Purified using 1:10 EtOAc/hexanes. H NMR (500
MHz, Chloroform-d): δ 7.69 (d, J = 8.8 Hz, 2H), 6.91 (d, J =
8.8 Hz, 2H), 3.87 (s, 3H), 1.57 (s, 9H). HRMS (ES+): Exact
mass calcd for C12H17Cl1N1O2 [M+H]+, 244.0904. Found
244.0921.
Computational data and spectral data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
N,4-di-tert-butyl-N-chlorobenzamide (2o) was obtained as a
AUTHOR INFORMATION
Corresponding Author
white solid (0.39 g, 24% yield) according to General Procedure
1
C. Purified using 1:10 EtOAc/hexanes. H NMR (600 MHz,
* eja@email.unc.edu
Notes
The authors declare no competing financial interest.
Chloroform-d): δ 7.62 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.6 Hz,
2H), 1.58 (s, 9H), 1.35 (s, 9H). 13C{1H} NMR (151 MHz,
Chloroform-d): δ 175.7, 154.5, 133.2, 128.5, 124.9, 63.5, 34.9,
31.2, 28.0. HRMS (ES+): Exact mass calcd for
C15H23Cl1N1O1 [M+H]+, 268.1474. Found 268.1459.
ACKNOWLEDGMENT
This work was supported by Award R01 GM 120163 from the
National Institute of General Medical Sciences. M.M.T. thanks the
NSF for a Graduate Research Fellowship. We would also like to
thank Christina Na for performing N–H BDE calculations. Amide
radical and structure calculations were carried out at the CINECA
N-(tert-butyl)-N-chloro-2,2,3,3,3-pentafluoropropanamide (2p)
obtained as a yellow oil (70 mg, 15%) according to General
Procedure B (2.5 mmol). Purified using 1:10 EtOAc/hexanes.
1H NMR (600 MHz, Chloroform-d): δ 1.56 (s, 9H). 13C{1H}
NMR (151 MHz, Chloroform-d): δ 159.9, 118.1 (qt, J = 286.6,
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23. Tang, N.; Wu, X.; Zhu, C.; Practical, Metal-free Remote Het-
Supercomputer Center (Italy), with computer time granted by
eroarylation of Amides via Unactivated C(sp3)–H Bond Functionaliza-
tion. Chem. Sci. 2019, 10, 6915-6919.
24. Minisci, F.; Vismara, E.; Fontana, F.; Platone, E.; Faraci, G. J.
Selective Aromatic Chlorination and Bromination with N-
Halogenoamines in Acidic Solution. Chem. Soc. Perkin Trans. 2 1989, 2,
123–126.
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ISCRA projects (code: HP10C30YAJ).
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O
O
Me
Me
Me
Me
F3C
R
2 x 10 mol % BPO
N
Me
Me
+
O
O
Cl
Cl
0.5 eq Cs2CO3
PhCF3, 65 oC
Me
Me
CF3
1 equiv
R = tBu, 75% yield
R = iPr, 8% yield
1 equiv
identifying key elements of nitrogen-centered radicals for intermolecular HAT
10
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